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mesenteric pseudocyst term used describe abdominal cystic mass without origin abdominal organ.(1 classified according embryologic ehiologic histologic ther data causing considerable confusion it considered term mesenteric cyst merely descriptive apply histologic classification lymphangioma pseudocyst enteric duplication cyst enteric cyst mesothelial cyst.(2 presented case mesenteric pseudocyst small bowel 70-year old man a 70-year old man referred hospital operation gastric cancer 1-month history progressively worsening epigastric intermittent peri umbilical discomfort he specific previous medical surgical history including cancer physical examination esophago gastro duodenoscopy egd showed 3.5 cm sized excavated lesion posterior wall angle endocopic biopsy confirmed histologic diagnosis poorly differentiated adenocarcinoma including signet ring cell component endoscopic ultrasonography revealed invasion caner proper muscle layer abdominal computed tomography ct ) scan showed focal mucosal enhancement posterior wall angle stomach 2.4 cm sized enhancing mass distal small bowel loop without distant metastases ascites rectovesical pouch multiple gallbladder stones fig 1 physical laboratory radiological findings prompted us diagnose early gastric cancer gastrointestinal stromal tumor small bowel laboratory testing revealed alfa fetoprotein level 2.88 normal range 0 9 ng ml carcino embryonic antigen level 1.45 ng ml normal range 0 5 ng ml carbohydrate antigen ca 19 9 level 6.5 u ml normal range 1 35 u ml ca 72 4 level 4.8 u ml normal range 0 4 u ml laboratory test results within normal limit the patient underwent subtotal gastrectomy gastroduodenostomy segmental resection small bowel cholecystectomy mesenteric mass adhered severely greater omentum mesenteric side small bowel mesenteric fat tissues small bowel mesentery mesenteric mass resected en bloc methods end end anastomosis performed after fixation surgical specimen macroscopic examination revealed uni locular cyst measuring 332 cm size pathological examination revealed 3 cm sized fibrous cystic wall without endothelial epithelial lining foam cell collection fig 2 3 pathologic stage gastric cancer t1bn1m0 6th international union cancer tnm staging system invasion submusosa metastases 4 perigastric lymph nodes 16 retrieved nodes negative resection margin mesenteric pseudocysts rare intraabdominal mass incidence 1 case per 100,000 hospital admissions.(3 ros et al.(2 first used term pseudocyst classification mesenteric cyst mesenteric pseudocyst could located small bowel large bowel mesentery even retroperitoneum.(1,4 reports pseudocyst large bowel retroperitoneum.(1 although mesenteric pseudocysts asymptomatic symptomatic mesenteric cysts could associated cyst size cyst location complications including infection rupture hemorrhage intestinal obstruction.(5 patient specific symptom associated mesenteric pseudocyst except intermittent vague periumbilical discomfort egd ct scan performed patient presenting non specific abdominal pain diagnosis mesenteric pseudocyst would delayed best knowledge this first case report describing incidentally detected mesenteric pseudocyst small bowel gastric cancer patients when clinician performed staging work gastric cancer aware possibility associated intraabdominal lesions | mesenteric pseudocyst is rare .
this term is used to describe the abdominal cystic mass , without the origin of abdominal organ .
we presented a case of mesenteric pseudocyst of the small bowel in a 70-year - old man .
esophago - gastro - duodenoscopy showed a 3.5 cm sized excavated lesion on the posterior wall of angle .
endocopic biopsy confirmed a histologic diagnosis of the poorly differentiated adenocarcinoma , which includes the signet ring cell component .
abdominal computed tomography scan showed a focal mucosal enhancement in the posterior wall of angle of the stomach , a 2.4 cm sized enhancing mass on the distal small bowel loop , without distant metastases or ascites in rectal shelf , and multiple gallbladder stones .
the patient underwent subtotal gastrectomy with gastroduodenostomy , segmental resection of the small bowel , and cholecystectomy .
the final pathological diagnosis was mesenteric pseudocyst .
this is the first case report describing incidentally detected mesenteric pseudocyst of the small bowel in gastric cancer patients . |
hepatitis e virus hev nonenveloped single stranded rna virus belongs hepeviridae family hev causative agent acute hepatitis one third world population fulminant hepatitis pregnant women the virion relatively resistant environmental conditions remains infectious even rough situation sewage therefore major route hev transmission ingestion fecal contaminated water however hev spread zoonotically blood transfusion especially industrialized countries although inclusive debate parental route transmission available evidence seems prove ability virus cause congenital infections hev infection significant public health concern especially developing countries large outbreaks result poor sanitation lack sewage infrastructures reported there also growing support claims seroprevalence hev infection industrialized countries increasing patients chronic liver disease travelers endemic areas people working animals like pigs cows sheep goats high risk hev infection 5 810 pregnant women infected third semester develop fulminant hepatic failure particularly endemic areas hev infection 11 12 iran endemic country hepatitis e infection 7 13 hev prevalence determined among general population parts country most conducted studies iran reported hev prevalence specific groups studies hev prevalence general populations limited hev prevalence information general population better indicator public health hygiene ahvaz large city south west iran population 1.18 million inhabitants consists two ethnic groups arab farsi ahvaz located banks karun river main river area no data available far prevalence hev among general population ahvaz city therefore study conducted determine prevalence hev among adults south west iran this cross sectional study approved ethical committee ahvaz jundishapur university medical science research project number 91112 estimate prevalence anti hev igg igm antibodies general population ahvaz city 510 blood samples adult population ahvaz city collected randomly using multistage cluster sampling method february july 2014 ahvaz large city south west iran consists 8 districts 94 public health centers first stage 4 public health centers selected randomly district next stage the family registry code used randomly select 16 households within public health center family one subject the trained interviewers visited subjects homes completed questionnaire containing information age gender race ethnicity individual the subjects refused participate study replaced next random participants the serum samples tested duplicate anti hev igg igm antibodies using dia.pro hev ab elisa kit hev igm elisa kit dia.pro italy according manufacturer instructions statistical analyses performed using spss 17 package program spss inc chicago il usa p values less 0.05 considered statistically significant data analyzed compared descriptive statistics chi square test fisher exact test out 510 study subjects 206 40.4% male 304 59.6% female the average age participants varying 18 81 years mean age sd 45.89 14.63 years the subjects classified six age groups 1830 3140 4150 5160 6170 71 years 70 13.7% subjects 18 30 years old 135 26.5% 31 40 years old 135 26.5% 41 50 years old 80 15.7% 51 60 years old 55 10.8% 61 70 years old 35 6.9% older 71 years based race ethnicity 53.7% 274 cases arab 46.3% 236 farsi of 510 subjects 235 46.1% shown positive anti hev igg antibody dia.pro hev ab elisa kit 275 53.9% negative with regard gender race 86/206 41.7% male group 149/304 49% female group positive anti hev igg antibodies 134/274 48.9% arab group 101/236 42.8% farsi group shown positive anti hev igg antibody however seroprevalence higher among arab female groups hev seropositivity statistically associated gender p 0.106 race p 0.168 meanwhile there statistical difference anti hev igg seroprevalence rate subjects grouped according age p 0.001 seroprevalence hev increased age 14.3% 10/70 subjects aged 1830 years 71.4% 25/35 persons 71 years old peak among 6170 year olds 90.9% 50/55 the highest rate anti hev seroprevalence seen subjects aged 6170 years table 1 when evaluated anti hev igm antibody seroprevalence rate gender race groups significant differences observed subjects regarding gender 1% females 1.9% males p 0.448 race 2.2% arab 0.4% farsi p 0.130 however regard age 4/70 5.7% age group 1830 years 3/135 2.2% age group 3140 years positive anti hev igm antibodies there significant difference age groups regarding hev seropositivity p 0.012 the highest rate anti hev seroprevalence observed subjects aged 1830 years table 2 overall 7 blood samples 1.4% shown positive hev specific igm antibodies 503 samples 98.6% negative hepatitis e infection worldwide public health concern causes large outbreaks acute hepatitis developing countries especially asia middle east africa also sporadic cases infection developed countries south america europe although hev mainly transmitted via fecal oral route especially contaminated water endemic areas transmission via blood transfusion also suggested according high prevalence anti hev igg among blood donors 4 13 14 epidemiological studies different parts world show wide variation hev prevalence patterns though hev seroprevalence rates higher among less developed countries high prevalence rates often reported south asia egypt middle east far east except japan low rates often found europe americas iran endemic country hepatitis e infection 7 13 since hev seroprevalence general population 5% ataei et al 2005 reported hev seroprevalence rate 3.8% among general population isfahan province iran assarehzadegan et al 2005 reported hev prevalence rate 11.5% among blood donors khuzestan province study hev prevalence 9.3% general population tehran another study nazer et al prevalence hev reported 7.8% khorramabad city 2009 regarding hev prevalence among general population countries the overall hev prevalence rate reported 22.5% among general population bangladesh labrique et al 3.20% french blood donors boutrouille et al 13% general population england ijaz et al 1.9% general population netherlands 5.3% general population japan present study investigated hev seroprevalence among adult population ahvaz city found anti hev igg igm seroprevalence 46.1% 1.4% respectively the result current study considerably higher reported among adults parts iran 9.3% nahavand 8.1% isfahan 7.8% western iran 7.3% sari 7.915% tehran also higher reported among adult population countries 3.9% united kingdom 16.8% germany 7.3% spain 20% korea 23% thailand 3942% usa 5.9% turkey however lower reported among rural population older four years egypt 5178% 16 34 pregnant women nile delta egypt 84% 16 35 general population older 11 years central malaysia 5067% tribes population 50100% adult population 1677% andaman islands india homeless children cochabamba city bolivia 66% however part difference may due differences used elisa detection kits time sampling demographics size studied population overall results compared previous studies iran indicate geographic distribution hev infection different even within specific country likely reflects different levels exposure infection time due different living conditions different regions fecal oral transmission hev current study the hev seroprevalence rate significantly increased age 14.3% people aged 31 years 90.9% persons aged 6170 years improvement public health hygiene results decreased exposure virus time however exposure hev increases age this consistent studies reported significant association age higher anti hev positive values since prevalence disease increases age 26 29 31 36 similarly high seroprevalence found among adult population older 60 years china 7080% adult population older 80 years bangladesh 67% adult population older 80 years hong kong 5260% similar results previous studies 5 13 17 29 37 results show presence anti hev igg igm antibodies associated gender also find association race ethnicity hev seropositivity our data showed anti hev igg prevalence rate among adult population ahvaz 46.1% highest rate reported different parts iran the implication ahvaz city highly endemic area hev main route hev transmission city likely karun river evidence claim drinking water source city supplied karun river river commonly used swimming fishing household needs inhabitants since major transmission route hev often fecal contaminated drinking water also virus relatively resistant environmental conditions remains infectious sewage river considered water source hev infection however studies required confirm hypothesis therefore type e hepatitis common among adult population ahvaz city compared parts iran finding considered differential diagnosis hepatitis infections also prediction possible outbreaks in conclusion high anti hev igg seroprevalence 46.1% observed among adults population living ahvaz city iran determination hev prevalence different regions used purpose hev epidemiology developing prevalence map base hev geographical distribution in addition epidemiological purposes hev prevalence information important evaluating public health hygiene identifying major route hev transmission iran |
background . knowledge regarding prevalence of hev in general population can be an indicator of the public health and hygiene .
therefore , this study was conducted to evaluate the prevalence of hev among adults in south - west of iran .
methods .
blood samples were taken from 510 participants , 206 ( 40.4% ) males and 304 ( 59.6% ) females from february to july 2014 .
detection of anti - hev igg and igm antibodies was carried out by elisa test .
results .
the overall anti - hev igg and igm prevalence rates were 46.1% and 1.4% , respectively .
anti - hev igg and igm seropositivity were not statistically associated with gender and race / ethnicity .
meanwhile , there were significant differences between the age groups regarding hev igg and igm seropositivity .
hev igg seroprevalence increased with age from 14.3% in subjects aged 1830 years to 71.4% in persons over 71 years old , and considerably individuals aged 61 to 70 years had the highest hev prevalence ( 90.9% ) .
also , 5.7% in the age group 1830 years and 2.2% in the age group 3140 years were positive for anti - hev igm antibodies and the highest rate was observed in subjects aged 1830 years . conclusion . in conclusion ,
high hev igg seroprevalence of 46.1% was observed among adults in south - west of iran . |
early diagnosis rib fractures rapidly indicate source thoracic pain helpful pain management trauma patients other pain rib fractures reported associated morbidity mortality elderly patients 3 5 emergency departments ultrasonography considered one useful screening tools rapid evaluation trauma patients 6 application ultrasonography assessment chest wall injuries reported 1980s 7 since technology ultrasound devices has significantly improved images higher resolutions obtained light improvements the diagnostic value modality considerably enhanced 9 this regard studies illustrated considerably high diagnostic value ultrasonography detection thoracic fractures even higher chest radiography 8 10 12 for instance narrative review chan referred ultrasonography reliable diagnostic tool detection thoracic bone fractures 13 nevertheless still comprehensive review carried comparing diagnostic values chest ultrasonography radiography detection thoracic fractures one solution perform meta analysis available evidence 15 16 accordingly present systematic review meta analysis aimed determine diagnostic values chest ultrasonography radiography detection thoracic bone fractures
search strategy selection criteria
study protocol established based guidelines meta analysis observational studies epidemiology statement moose 19 selection keywords medical subject heading mesh terms emtree two reviewers m.y p.g independently carried extended systematic search databases medline via pubmed embase via ovidsp isi web knowledge scopus cochrane library proquest without time language limitations sonography ultrasound radiography chest film chest radiograph combined rib fractures chest wall fracture
additionally bibliographies original review articles well google scholar also searched all studies evaluating diagnostic accuracy ultrasonography chest radiography detection chest wall fractures assessed review editorial articles case reports studies sample populations less 10 patients excluded two reviewers m.y p.g independently worked summarizing data regarding assessing quality studies baseline characteristics patients age gender number patients without hemothorax etiology hemothorax characteristics ultrasonography device transducer frequency physicians charge imaging interpretation blinding status sampling method consecutive convenience study design retrospective prospective finally number true positive tp true negative tn false positive fp false negative fn cases extracteded disagreements discussed third reviewer m.h solution proposed cases data inaccessibility data presented charts extracted via method proposed sistrom mergo 28 cases sensitivity specificity presented reliable web based programs used calculate number tp tn fp fn cases
charecteristics included studies 1 number patient fracture number patient without fracture 2 number presented mean standard deviation range ct computed tomography cxr chest radiography ep emergency physician na applicable nr reported us ultrasonography
quality assessment
quality studies assessed based guidelines 14-item quality assessment diagnostic accuracy studies quadas2 tool 29 the quality assessment performed based following items acceptable reference tests accounting indeterminate results avoiding differential verification bias disease progression bias incorporation bias verification bias blind index test interpretation blind interpretation reference test explained withdrawal relevant clinical data available representative spectrum a total grading poor fair good attributed survey fair good studies included meta analysis
statistical analysis
analysis performed using stata 11.0 statistical software via midas module evaluate screening performance characteristics ultrasonography radiography detection chest wall fractures summary receiver operative curves srocs drawn pooled sensitivity specificity positive likelihood ratio negative likelihood ratio 95% confidence interval 95% ci calculated due high heterogeneity included studies mixed effects binary regression model used heterogeneity evaluated calculations i2 2 tests p value less 0.1 together i2 greater 50% considered positive heterogeneity 30 deek asymmetry funnel plot used search publication bias analyses p value less 0.05
study characteristics
17 3894 studies found comprehensive search included systematic review meta analysis 1 2 8 10 12 14 17 18 20 27 5 studies assessed diagnostic accuracy ultrasonography detection thoracic bone fractures 1 2 18 20 21 8 diagnostic value chest radiography 14 17 22 27 4 diagnostic values ultrasonography radiography simultaneously 8 10 12 1667 cases 807 860 without fractures extracted 17 mentioned articles whose age ranged 0 92 years old figure 1 shows inclusion process articles table 1 summarizes characteristics included studies the results analyses presented srocs funnel plots figures 3 5 the area curve sroc ultrasonography radiography detection chest wall fractures found 0.99 95% ci 0.97 0.99 0.97 95% ci 0.96 0.99 respectively figure 3 pooled sensitivity specificity ultrasonography detection thoracic bone fractures 0.97 95% ci 0.90 0.99 i2= 88.88 p<0.001 0.94 95% ci 0.86 0.97 i2= 71.97 p<0.001 respectively figure 4-a these characteristics radiography found 0.77 95% ci 0.56 0.90 i2= 97.76 p<0.001 1.0 95% ci 0.91 1.00 i2= 97.24 p<0.001 respectively figure 5-a in addition pooled positive negative likelihood ratios ultrasonography 16.26 95% ci 6.26 38.87 i2= 59.14 p<0.001 0.03 95% ci 0.01 0.11 i2= 86.76 p<0.001 respectively figure 4-b measures radiography reported 774.63 95% ci 7.0 8573.0 i2= 96.62 p<0.001 0.23 95% ci 0.11 0.48 i2= 96.94 p<0.001 respectively figure 5-b significant heterogeneity articles figure 4 5 specificity ultrasonography detection thoracic bone fractures directly correlated frequency transducer 90% vs. 95% the sensitivity modality found higher detection rib fractures rather fractures clavicle sternum 97% vs. 91% moreover found sensitivity would higher procedure performed radiologist 96% compared emergency medicine specialist 90% studies sample sizes greater 100 patients reported higher diagnostic accuracies ultrasonography detection thoracic bone fractures 97% vs. 91% as seen table 2 important factor affecting sensitivity chest radiography interpreting physician the sensitivity found 66% radiogram interpreted emergency medicine specialist 80% interpreted radiologist furthermore consecutive sampling method compared convenience 80% vs. 73% sample size 100 patients 82% vs. 73% also found sources heterogeneity base results present meta analysis sensitivity chest ultrasonography detection thoracic bone fractures following trauma prominently higher radiography 97% vs. 77% yet specificity radiography found significantly higher ultrasonography regard 100% vs. 94% basis according calculated likelihood ratios negative result ultrasonography detection thoracic fracture reliable radiography negative likelihood ratio=0.03 positive result chest radiography reliable ultrasonography positive likelihood ratio=774.63
subgroup analysis diagnostic accuracy chest radiography ultrasonography detection thoracic bone fractures p value 0.1 considered significant heterogeneity ci confidence interval
ultrasonography higher sensitivity diagnosis rib fractures rather chest wall bones type fracture effect diagnostic value radiography this finding ascribed higher attention physicians pay rib fractures rather chest wall bones scapula sternum
fractures diagnosed via ultrasonography based observation cortical bone disruption cases small fractures detection sign sonogram distinguishing findings highly dependent skills operator the role operator skills detection injuries via ultrasonography verified present study well 31 34 the present study found specificity modality increased frequencies higher 10mhz might due higher resolution obtained higher frequencies 35 making easier detect signs fracture
some narrative review articles qualitative systematic reviews indicative potential benefit ultrasonography detection chest wall fractures this regard chan systematic review conducted studies indexed medline declares ultrasonography higher sensitivity detection thoracic bone fractures compared radiography 13 finding diagnostic accuracy ultrasonography two times ability radiography fracture diagnosis dietrich et al also referred ultrasonography useful diagnostic tool detection rib fractures 36 presence considerable heterogeneity included articles simultaneous inclusion retrospective prospective studies meta analysis major limitations study ess effective sample sizes summary receiver operative curves sroc ultrasound chest radiography b detection thoracic bone fractures auc area curve sens sensitivity spec specificity forest plot screening performance characteristics chest ultrasonography detection thoracic bone fractures sensitivity specificity diagnostic likelihood ratio dlr b ci confidence interval forest plot screening performance characteristics chest radiography detection thoracic bone fractures sensitivity specificity diagnostic likelihood ratio dlr b base findings present meta analysis screening performance characteristic ultrasonography detection thoracic bone fractures found higher radiography however characteristics prominent detection rib fractures cases performed radiologist this research supported tehran university medical sciences health services grant number 93 02 38 25618 all authors passed four criteria authorship contribution based recommendations international committee medical journal editors | introduction : the potential benefit of ultrasonography for detection of thoracic bone fractures has been proven in various surveys but no comprehensive conclusion has been drawn yet ; therefore , the present study aimed to conduct a thorough meta - analytic systematic review on this subject .
methods : two reviewers independently carried out a comprehensive systematic search in medline , embase , isi web of knowledge , scopus , cochrane library , and proquest databases .
data were summarized as true positive , false positive , true negative and false negative and were analyzed via stata 11.0 software using a mixed - effects binary regression model .
sources of heterogeneity were further assessed through subgroup analysis .
results : data on 1667 patients ( 807 subjects with and 860 cases without thoracic fractures ) , whose age ranged from 0 to 92 years , were extracted from 17 surveys .
pooled sensitivity and specificity of ultrasonography in detection of thoracic bone fractures were 0.97 ( 95% ci : 0.90 - 0.99 ; i2= 88.88 , p<0.001 ) and 0.94 ( 95% ci : 0.86 - 0.97 ; i2= 71.97 , p<0.001 ) , respectively .
the same measures for chest radiography were found to be 0.77 ( 95% ci : 0.56 - 0.90 ; i2= 97.76 , p<0.001 ) and 1.0 ( 95% ci : 0.91 - 1.00 ; i2= 97.24 , p<0.001 ) , respectively .
the sensitivity of ultrasonography was higher in detection of rib fractures , compared to fractures of sternum or clavicle ( 97% vs. 91% ) .
moreover , the sensitivity was found to be higher when the procedure was carried out by a radiologist in comparison to an emergency medicine specialist ( 96% vs. 90% ) .
conclusion : base on the findings of the present meta - analysis , screening performance characteristic of ultrasonography in detection of thoracic bone fractures was found to be higher than radiography .
however , these characteristics were more prominent in detection of rib fractures and in cases where was performed by a radiologist . |
aortic dissection following coronary angiography angioplasty rare potentially fatal complication overall reported incidence 0.01 0.04% 1 3 the incidence significantly higher percutaneous coronary interventions 0.12% elective diagnostic procedures moreover setting acute myocardial infarction ami reported incidence 0.19% significantly higher 0.01% reported absence ami management outcomes varied considerably literature 50% mortality reported one series following surgical repair dissections studies reported favorable outcomes conservative management we report case elderly woman developed type aortic dissection moderate severe aortic regurgitation heart failure diagnosed approximately 1 month following diagnostic coronary angiography she underwent emergency surgical repair dissection however could successfully weaned cardiopulmonary bypass despite maximum pharmacological interventions support died operating room a 63-year old white female known hypertension hyperlipidemia prior pacemaker insertion atrial fibrillation symptomatic bradycardia admitted hospital recent onset substernal chest pressure radiating jaw diaphoresis her vital signs stable physical examination non revealing limited morbid obesity her electrocardiogram revealed atrial fibrillation demand ventricular pacing cardiac biomarkers negative acute coronary syndrome echocardiogram revealed normal left ventricular systolic function normal aortic root diameter otherwise technically difficult fig coronary angiography revealed 60 70% eccentric lesion second obtuse marginal otherwise mild atherosclerotic disease ( baseline two dimensional 2d parasternal long axis echocardiographic image obtained prior index cardiac catheterization showing normal size aortic root ascending aorta ao b corresponding 2d parasternal echocardiographic image 1 month following cardiac catheterization showing massive dilatation aortic root ascending aorta ao dissection flap lv left ventricle rv right ventricle la left atrium
she readmitted 1 month later recurring episodes chest pain shortness breath orthopnea reduced exercise tolerance started ever since recent discharge two emergency room visits clinic follow visit blood pressure bp 152/93 mm hg heart rate 105 bpm she elevated bnp 1,400 pg ml otherwise negative cardiac biomarkers therefore treated diuretics resulted significant decrease bp 81/51 mm hg repeat echocardiogram performed revealed normal left ventricular systolic function severely dilated aortic root measuring 6.7 cm aortic dissection flap noted fig ct angiogram revealed aortic dissection extending proximally aortic root coronary ostia fig ( axial ct angiographic image showing dissection starting aortic root sparing origins coronary arteries massive dilatation aortic root ( b sagittal ct angiographic image showing extension dissection origin brachiocephalic artery
the patient taken emergently surgery despite extensive surgical repair pharmacologic support could weaned cardiopulmonary bypass expired operating room type aortic dissection lethal condition overall surgical mortality 34% unstable patients reported 526 cases international registry acute aortic dissection irad the irad registry reported 28 cases 5.3% iatrogenic type aortic dissection itaad complication cardiac surgery cardiac catheterization nine 32% died the german registry acute aortic dissection type geraada reported comparable incidence 100 cases 4.7% itaad total 2,137 cases type aortic dissection lower 30-day mortality 16% leontyev et al reported 48 cases 15-year follow undergoing surgery itaad frequency 0.06% 36 cases open heart surgeries 0.01% 12 cases cardiac catheterizations early surgical mortality 50% itaads associated coronary angiography dunning et al reported nine cases 0.02% coronary artery aortic dissections 40,000 cardiac catheterizations performed 6-year period significantly prevalent setting ami 0.19% compared non ami 0.01% outcomes favorable less severe dissections treated conservatively two reported cases dissection extending arch died following surgery they proposed classification scheme based extent aortic dissection beyond involved coronary cusp fig 3 concluded best treatment class 1 2 dissections stenting intra coronary entry point possible close clinical follow class 3 dissections usually require surgical intervention gomez moreno et al reported 17 cases 0.04% incidence itaad associated cardiac catheterizations 10-year follow period significantly higher incidence interventional procedures 0.12% diagnostic procedures 0.01% patients treated conservatively either stenting seal entry door expectant management patients died hospitalization follow nunez gil et al reported 14 cases 0.02% incidence iatrogenic dissection descending aorta arch without coronary involvement 15-year follow treated conservatively one hospital death tanasie et al reported eight cases 5-year follow itaads referred multi detector coronary tomography mdct evaluation one patient required surgery died others treated conservatively either stenting expectant management survived dunning classification itaad
several cases conservatively treated itaad reported literature favorable outcomes sakakura et al reported 79-year old male itaad following stenting proximal right coronary artery rca angina treated intravascular ultrasound ivus)-guided stenting entry point good outcome fiddler et al reported 65-year old female underwent rca stenting ami resulting guidewire associated itaad evidence tamponade spontaneous hemodynamic stabilization subsequent ct demonstrating intimal dissection flap prompting expectant management favorable outcome kerut et al reported 79-year old male undergoing coronary angiography angina developed subintimal hematoma without dissection flap left coronary sinus 4 cm upwards demonstrated ct transesophageal echocardiography tee findings resolved spontaneously treated conservatively favorable outcome ghaffari pourafkari reported itaad proximal origin right brachiocephalic artery 30-year old male bicuspid aortic valve undergoing aortography preparation aortic coarctation stenting the dissection spontaneously sealed attributed curved catheter position aortic arch high pressure contrast jet catheter side holes setting aortopathy gorog et al reported 56-year old female undergoing coronary angiography developed aortic dissection starting femoral artery extending aortic arch treated successfully self expanding metallic stent iliac artery via contralateral femoral artery approach shah et al reported two cases itaad first 56-year old male receiving rca stent inferior ami developed itaad starting rca cusp successfully treated stenting proximal rca cover entry point the second case 68-year old male developed left main coronary dissection retrograde extension coronary cusp stenting left circumflex treated successfully left main stenting subsequently underwent uneventful elective coronary artery bypass grafting cabg surgery welch et al reported 65-year old female treated multiple rca stents inferior ami developed
intramural hematoma extending right sinus valsalva origin brachiocephalic artery entry point lambelin et al reported 75-year old female developed cardiac tamponade cardiogenic shock due intimal tear ascending thoracic aorta involving coronaries angiography aortic insufficiency successfully treated immediate surgery noguchi et al reported 66-year old male inferior ami undergoing circumflex stenting developed cardiac tamponade hypotension due itaad originating brachiocephalic artery without involvement coronaries underwent successful emergency surgical repair yilik et al reported two cases itaad treated surgically first 65-year old female developed retrograde aortic dissection angioplasty left anterior descending lad unstable angina due inability localize tear underwent uneventful surgical repair the second case 73-year old female developed itaad angioplasty rca guidewire could introduced true lumen therefore underwent successful surgical repair tochii et al reported 69-year old male developed aortic dissection balloon angioplasty left subclavian extended retrogradely ascending aorta required surgical intervention good outcome the case reports summarized table 1 8 18 demonstrate heterogeneity itaad regard patient characteristics presentations cause location dissection treatment options it obvious severe dissections associated high early mortality therefore warrant emergency surgery carries high risk mortality our patient unique presentation delayed 1 month index cardiac catheterization progressive symptoms likely causing extensive aortic root dilatation extension dissection dunning class iii negative outcomes may fact prevalent discussion implies may tend reported literature associated risk factors reported several studies may related patient characteristics versus procedural variables may modifiable table 2 prompt recognition management crucial avoid extensive dissection dilatation aorta report patient reduce mortality low risk dissections appear respond well conservative medical localized interventional treatments serial hemodynamic monitoring imaging follow high risk dissections overall appear require surgical management despite increased surgical risk associated risk factors reported several studies may related patient characteristics versus procedural variables may modifiable table 2 prompt recognition management crucial avoid extensive dissection dilatation aorta report patient reduce mortality low risk dissections appear respond well conservative medical localized interventional treatments serial hemodynamic monitoring imaging follow high risk dissections overall appear require surgical management despite increased surgical risk | we report a 63-year - old female with hypertension , hyperlipidemia , and prior pacemaker insertion for atrial fibrillation with symptomatic bradycardia , who was admitted with substernal chest pressure and diaphoresis .
her electrocardiogram revealed atrial fibrillation with demand ventricular pacing and her cardiac biomarkers were negative for acute coronary syndrome .
echocardiogram revealed normal left ventricular systolic function and normal aortic root diameter .
coronary angiography revealed 60 - 70% obtuse marginal lesion , otherwise mild disease .
she was treated medically and discharged in stable condition .
she was readmitted 1 month later with recurring chest pain , and shortness of breath which started shortly after her most recent discharge .
blood pressure was 152/93 mm hg , and heart rate was 105 bpm .
bnp was elevated at 1,400 pg / ml , and other cardiac biomarkers were negative .
she was treated with diuretics , which resulted in decrease of her blood pressure to 81/51 mm hg .
repeat echocardiogram revealed severely dilated aortic root , measuring 6.7 cm , with aortic dissection flap and moderate to severe aortic regurgitation .
ct angiogram revealed aortic dissection extending proximally to the aortic root above the coronary ostia and distally to the left subclavian artery takeoff .
she underwent surgery ; she , however , could not be weaned off from cardiopulmonary bypass and died in the operating room .
this case illustrates the importance of having a high index of suspicion for iatrogenic aortic dissection following cardiac catheterization as a cause of recurrence of cardiac symptoms , as early detection may help avert a catastrophic outcome , as we report in our patient . |
significant percentage overweight obese individuals show signs insulin resistance including metabolic syndrome overweight individuals insulin resistance turn increased risk type 2 diabetes cardiovascular disease cvd cvd leading cause morbidity mortality united states 80 years impaired fasting glucose hypertension atherogenic dyslipidemia obesity endothelial dysfunction shown increase risk type 2 diabetes mellitus cvd epidream cohort study a 1-mmol l increase fasting plasma glucose associated 17% increase risk future cardiovascular events death idea study the frequency cvd type 2 diabetes mellitus increased proportionally waist circumference genders framingham heart study risk major coronary heart disease events increased nearly 25% every 5-mg dl decrease high density lipoprotein cholesterol hdl c median values therapeutic lifestyle change emphasis diet recommended first line treatment prevention diabetes cvd risk individuals nuts particular gaining increasing attention area recent meta analysis indicating reduced risk diabetes among consuming nuts less red meat emerging clinical trial and epidemiological evidence indicates nuts favorably alter levels oxidative stress inflammation lipids improve glucose metabolism vascular reactivity 1215 walnuts uniquely rich source -linolenic acid ala epidemiological studies suggest plant derived ala may confer particular cardiovascular benefits a meta analysis investigating impact walnut consumption blood lipids showed walnut enriched diets significantly decreased total cholesterol low density lipoprotein cholesterol ldl c compared control diets duration short term trials furthermore walnuts also rich tocopherol phenolic antioxidants folic acid magnesium nutrients shown impact endothelial function favorably previously reported walnut enriched ad libitum diet improves endothelium dependent vasodilatation type 2 diabetic individuals suggesting potential reduction overall cardiac risk population knowledge effects walnuts endothelial function adults visceral adiposity free diabetes examined we therefore conducted randomized controlled crossover trial investigate effects daily walnut ingestion overweight adults central obesity endothelial function well body mass index bmi weight waist circumference lipid panel insulin sensitivity blood pressure forty six participants 18 men 28 women recruited lower naugatuck valley connecticut flyers newspaper advertisements participants required nonsmoking adults aged 3075 years bmi greater 25 waist circumference 40 inches men 35 inches women all included participants also exhibited 1 additional risk factors metabolic syndrome blood pressure 130/85mmhg taking antihypertensive medication fasting serum glucose fpg 100 mg dl fasting serum triglyceride tg level 150 mg dl fasting hdl c 40 mg dl men 50 mg dl women participants excluded pregnant diagnosed atherosclerotic vascular disease diabetes severe hypertension sleep apnea tuberculosis acquired immune deficiency syndrome cancer psychotic disorder and/or eating disorder participants also excluded prior history substance abuse consumed restricted diets choice i.e. vegan carbohydrate restricted etc allergic walnuts nuts unwilling refrain taking medication 12 hours prior assessment individuals regularly used nonsteroidal anti inflammatory drugs vasoactive medication fiber supplements aspirin lipid lowering medications antihypertensive medications taking stable dosage less 3 months also excluded participation those passing telephone screening n 92 underwent clinical screening examination consisting height weight bmi blood pressure measurements laboratory testing including fasting serum lipids fpg this study randomized controlled single blind crossover clinical trial all participants first took part dietary group session led registered dietitian this group session initiation 4-week run period allow diet weight stabilization the 3-day diet records done original run period 8-week dietary period 4-week washout period end run period participants n 46 ) were randomly assigned one two possible treatment sequences consisting 8-week walnut enriched ad libitum diet ad libitum diet without walnuts 8 weeks treatment assignments separated 4-week washout period walnut enriched diet treatment participants given 8-week supply walnuts they instructed consume 56 g shelled unroasted english walnuts per day snack meal a consumption log sheet provided participants keep record walnut consumption participants instructed maintain baseline medication supplement use physical activity level throughout study ensure weight remained stable walnut enriched phase participants counseled registered dietitian group session strategies equivalently substituting calories walnuts calories foods diet instructed otherwise continue usual dietary patterns compliance treatment dietary patterns assessed subjects diet records consumption log sheets visit height weight blood pressure fasting serum lipids fpg fasting serum insulin measured endothelial function measured noninvasively right brachial artery high frequency ultrasound scanning machine sonos 4500 phillips medical systems andover accordance published guidelines previous endothelial function studies 20 2224 subjects required rest quiet temperature controlled softly lit room 15 minutes scanning initiated right brachial artery imaged longitudinally 25 cm antecubital fossa experienced registered vascular technologist rvt blinded treatment assignments a resting scan performed arterial flow velocity measured occluding cuff placed upper arm was inflated pressure 250 mmhg 5 minutes rapidly deflated induce reactive hyperemia brachial artery scans acquired magnetic optical disk continuously 30 180 seconds cuff deflation including repeated flow velocity measurement first 15 seconds cuff release brachial artery diameters analyzed commercially available software brachial analyzer medical imaging application iowa city ia dilatation baseline measured 5080 seconds cuff deflation assess endothelium dependent vasodilatation test intraobserver reliability a random sample 20 brachial artery reactivity studies read rvt ensure consistency measurement interpretation endothelial function measured flow mediated vasodilation fmd percentage change brachial artery diameter cuff inflation 60 seconds cuff release in addition brachial diameter 60 seconds cuff release flow cuff deflation within first 15 seconds used indicator stimulus strength hyperemic flow stimulus endothelial reactivity account potential variability stimulus strength fmd divided flow 15 seconds cuff deflation create stimulus adjusted response measure fasting serum lipids consisting total cholesterol hdl c ldl c tgs total cholesterol hdl ratio fpg fasting serum insulin measured griffin hospital laboratory using standard procedures visit insulin resistance homa ir values generated fpg fasting serum insulin levels homa calculator version 2.2.1 gauge degree insulin resistance height weight bmi waist circumference measured visit measure weight participants asked remove heavy outer garments jacket coat etc shoes stand center platform weight distributed evenly feet waist circumference measured umbilicus measurement tape surrounding abdomen horizontal floor blood pressure determined use datascope accutorr plus automatic digital blood pressure device data scope corp mahwah nj subject supine 5-minute period rest systolic diastolic diet records analyzed using food processor ii esha research basic nutrition diet analysis software version 7.0 esha research salem the study protocol consent form approved griffin hospital derby ct institutional review board signed informed consent obtained study participants participants received monetary compensation participation repeated measures analysis variance anova used assess differences intraindividual responses across treatments paired tests also used compare baseline mean values outcome measures among participants group assignment the combined effect independent variables age race bmi hypertensive status dyslipidemia treatment sequence treatment assignment assessed respect outcome measures using multivariable anova models the sample size determined allow 20% attrition noncompliance provide 80% power detect minimal difference 3% fmd treatments 21 maximum allowable type error 5% the sample size calculated using formula n z z)sd]/d n number participants needed z 1.96 2 sided 5% z 0.84 80% power sd 6.5% 3% minimal detectable difference change fmd intervention control assignments n 1.96 0.84 )
6.5]/3 37 participants needed allowing 20% withdrawal loss follow 46 participants needed trial forty six participants 18 men 28 women recruited lower naugatuck valley connecticut flyers newspaper advertisements participants required nonsmoking adults aged 3075 years bmi greater 25 waist circumference 40 inches men 35 inches women all included participants also exhibited 1 additional risk factors metabolic syndrome blood pressure 130/85mmhg taking antihypertensive medication fasting serum glucose fpg 100 mg dl fasting serum triglyceride tg level 150 mg dl fasting hdl c 40 mg dl men 50 mg dl women participants excluded pregnant diagnosed atherosclerotic vascular disease diabetes severe hypertension sleep apnea tuberculosis acquired immune deficiency syndrome cancer psychotic disorder and/or eating disorder participants also excluded prior history substance abuse consumed restricted diets choice i.e. vegan carbohydrate restricted etc allergic walnuts nuts unwilling refrain taking medication 12 hours prior assessment individuals regularly used nonsteroidal anti inflammatory drugs vasoactive medication fiber supplements aspirin lipid lowering medications antihypertensive medications taking stable dosage less 3 months also excluded participation those passing telephone screening n 92 underwent clinical screening examination consisting height weight bmi blood pressure measurements laboratory testing including fasting serum lipids fpg this study randomized controlled single blind crossover clinical trial all participants first took part dietary group session led registered dietitian this group session initiation 4-week run period allow diet weight stabilization the 3-day diet records done original run period 8-week dietary period 4-week washout period end run period participants ( n 46 randomly assigned one two possible treatment sequences consisting 8-week walnut enriched ad libitum diet ad libitum diet without walnuts 8 weeks treatment assignments separated 4-week washout period walnut enriched diet treatment participants given 8-week supply walnuts they instructed consume 56 g shelled unroasted english walnuts per day snack meal a consumption log sheet provided participants keep record walnut consumption participants instructed maintain baseline medication supplement use physical activity level throughout study ensure weight remained stable walnut enriched phase participants counseled registered dietitian group session strategies equivalently substituting calories walnuts calories foods diet instructed otherwise continue usual dietary patterns compliance treatment dietary patterns assessed subjects diet records consumption log sheets visit height weight blood pressure fasting serum lipids fpg fasting serum insulin measured endothelial function measured noninvasively right brachial artery high frequency ultrasound scanning machine sonos 4500 phillips medical systems andover accordance published guidelines previous endothelial function studies 20 2224 subjects required rest quiet temperature controlled softly lit room 15 minutes scanning initiated the right brachial artery imaged longitudinally 25 cm antecubital fossa experienced registered vascular technologist rvt blinded treatment assignments an occluding cuff placed upper arm inflated pressure 250 mmhg 5 minutes rapidly deflated induce reactive hyperemia brachial artery scans acquired magnetic optical disk continuously 30 180 seconds cuff deflation including repeated flow velocity measurement first 15 seconds cuff release brachial artery diameters analyzed commercially available software brachial analyzer medical imaging application iowa city ia dilatation baseline measured 5080 seconds cuff deflation assess endothelium dependent vasodilatation test intraobserver reliability a random sample 20 brachial artery reactivity studies read rvt ensure consistency measurement interpretation endothelial function measured flow mediated vasodilation fmd percentage change brachial artery diameter cuff inflation 60 seconds cuff release in addition brachial diameter 60 seconds cuff release flow cuff deflation within first 15 seconds used indicator stimulus strength hyperemic flow stimulus endothelial reactivity account potential variability stimulus strength fmd divided flow 15 seconds cuff deflation create stimulus adjusted response measure fasting serum lipids consisting total cholesterol hdl c ldl c tgs total cholesterol hdl ratio fpg fasting serum insulin measured griffin hospital laboratory using standard procedures visit insulin resistance homa ir values generated fpg fasting serum insulin levels homa calculator version 2.2.1 gauge degree insulin resistance height weight bmi waist circumference measured visit measure weight participants asked remove heavy outer garments jacket coat etc shoes stand center platform weight distributed evenly feet waist circumference measured umbilicus measurement tape surrounding abdomen horizontal floor blood pressure determined use datascope accutorr plus automatic digital blood pressure device data scope corp mahwah nj subject supine 5-minute period rest both systolic diastolic pressures calculated mean value 2 readings 5 minutes apart diet records analyzed using food processor ii esha research basic nutrition diet analysis software version 7.0 esha research salem the study protocol consent form approved griffin hospital derby ct institutional review board signed informed consent obtained study participants participants received monetary compensation participation repeated measures analysis variance anova used assess differences intraindividual responses across treatments paired tests also used compare baseline mean values outcome measures among participants group assignment the combined effect independent variables age race bmi hypertensive status dyslipidemia treatment sequence treatment assignment assessed respect outcome measures using multivariable anova models the sample size determined allow 20% attrition noncompliance provide 80% power detect minimal difference 3% fmd treatments 21 maximum allowable type error 5% the sample size calculated using formula n z z)sd]/d n number participants needed z 1.96 2 sided 5% z 0.84 80% power sd 6.5% 3% minimal detectable difference change fmd intervention control assignments n 1.96 0.84 )
6.5]/3 37 participants needed allowing 20% withdrawal loss follow 46 participants needed trial forty six overweight adults participated study sixty one percent participants female three subjects dropped study due changes medication 1 dropped due inability comply protocol 2 dropped due schedule conflicts hdl high density lipoprotein ldl low density lipoprotein homa ir homeostasis model assessment insulin resistance dietary intake dietary intakes polyunsaturated fatty acids pufas n-3 fatty acids n-6 fatty acids fat increased significantly walnut enriched diet treatment compared control diet pufas p 0.01 n-3 fatty acids p 0.01 n-6 fatty acids p 0.01 fat p 0.01 selected nutrient intake values mean sd p values obtained 1-way analysis variance endothelial function overweight population least 1 risk factor metabolic syndrome consumption walnut enriched diet 8 weeks improved fmd significantly baseline compared control diet p 0.019 see table 3 change outcome measures values mean sd hdl high density lipoprotein ldl low density lipoprotein homa ir homeostasis model assessment insulin resistance significant p 0.05 baseline p values obtained repeated measures analysis variance. p 0.05 paired student test daily consumption walnut enriched diet 8-week period change anthropometric measures baseline bmi p 0.481 weight p 0.439 waist circumference p 0.344 the control diet associated reduction bmi p 0.016 body weight p 0.019 relative walnut enriched diet lipid panel after consumption walnut enriched diet 8 weeks participants mean measures total cholesterol ldl c hdl c tg differ significantly baseline compared mean measures control diet total cholesterol p 0.69 ldl c p 0.98 hdl c p 0.89 tg p 0.32 blood pressure after consumption walnut enriched diet 8 weeks participants blood pressure values decreased nonsignificantly baseline compared control diet without walnut supplementation systolic p 0.07 diastolic p 0.352 fasting plasma glucose fasting insulin homa ir fasting plasma glucose fasting insulin change significantly participants consuming walnut enriched diet baseline compared control group participants our findings unchanged controlling age race gender bmi hypertensive status dyslipidemia treatment sequence using multivariable anova models forty six overweight adults participated study sixty one percent participants female three subjects dropped study due changes medication 1 dropped due inability comply protocol 2 dropped due schedule conflicts hdl high density lipoprotein ldl low density lipoprotein homa ir homeostasis model assessment insulin resistance dietary intake dietary intakes polyunsaturated fatty acids pufas n-3 fatty acids n-6 fatty acids fat increased significantly walnut enriched diet treatment compared control diet pufas p 0.01 n-3 fatty acids p 0.01 n-6 fatty acids p 0.01 fat p 0.01 selected nutrient intake values mean sd p values obtained 1-way analysis variance endothelial function overweight population least 1 risk factor metabolic syndrome consumption walnut enriched diet 8 weeks improved fmd significantly baseline compared control diet p 0.019 see table 3 hdl high density lipoprotein ldl low density lipoprotein homa ir homeostasis model assessment insulin resistance significant p 0.05 baseline p values obtained repeated measures analysis variance. p 0.05 paired student test daily consumption walnut enriched diet 8-week period change anthropometric measures baseline bmi p 0.481 weight p 0.439 waist circumference p 0.344 the control diet associated reduction bmi p 0.016 body weight p 0.019 relative walnut enriched diet lipid panel after consumption walnut enriched diet 8 weeks participants mean measures total cholesterol ldl c hdl c tg differ significantly baseline compared mean measures control diet total cholesterol p 0.69 ldl c p 0.98 hdl c p 0.89 tg p 0.32 blood pressure after consumption walnut enriched diet 8 weeks participants blood pressure values decreased nonsignificantly baseline compared control diet without walnut supplementation systolic p 0.07 diastolic p 0.352 fasting plasma glucose fasting insulin homa ir fasting plasma glucose fasting insulin change significantly participants consuming walnut enriched diet baseline compared control group participants our findings unchanged controlling age race gender bmi hypertensive status dyslipidemia treatment sequence using multivariable anova models the daily addition 56 g walnuts diet 8 weeks significantly improved endothelial function overweight adults visceral obesity compared ad libitum diet supplemented walnuts beneficial trend systolic blood pressure reduction was observed quite reach statistical significance despite walnut dose representing 350 kcal weight gain observed walnut treatment arm study addition walnuts even associated decline waist circumference lipid panel measures fasting insulin insulin sensitivity fasting glucose levels change one important observations study involves improved brachial artery vasoactivity results general findings confirm extend results previous walnut consumption studies 20 2528 respective methodological differences exist among trials also showed improvement endothelial function nut consumption assessing peripheral artery tonometry metabolic syndrome participants it hypothesized one mechanism nut consumption improves endothelial function occurs via improvements lipid panel indices however study lipid panel measures unaffected walnut intake the overall evidence potential cardioprotective effects walnut intake robust pooled analysis 25 nut intervention trials spanning 7 countries sabate et al showed nuts produce favorable lipid regulating effects individuals bmi 30 it argued effect could due overweight individuals displaying reduced lipid responsiveness the results trial agreement observed sabate et al the average bmi participants present trial 33.2 4.4 lipid regulating effects observed result walnut supplemented ad libitum diet the lipid panel one traditional cvd risk factor albeit important one among cluster traditional nontraditional risk factors within current models cvd etiology endothelial function increasingly viewed prognostic marker susceptibility future cardiac events changes risk factors serum lipids may account part strong inverse association nut consumption cvd risk we observed beneficial trend blood pressure reduction end walnut supplemented ad libitum diet phase compared ad libitum diet alone our observations correspond nut walnut consumption trials observed either positive neutral influence blood pressure responsiveness increased consumption mechanisms walnuts may elicit blood pressure lowering response could involve high content monounsaturated fatty acids pufas magnesium fiber low levels sodium saturated fatty acids participants anthropometric measures change significantly baseline walnut enriched diet phase intervention given walnuts rich fatty acid composition high metabolic energy profile initial apprehension walnut consumption nut consumption general would lead undesired weight gain such concerns attenuated evidence epidemiological trials randomized clinical trials shown walnut consumption tend elevate weight waist circumference bmi given participants physical activity levels remained unaltered throughout study reduction weight seen could due placebo effect participation trial encouraging subjects eat healthfully and/or consume less food the lack weight increase seen walnut enriched phase trial could explained participants partially substituting walnuts foods diet walnuts ability increase energy expenditures providing high satiety low metabolizable energy source note waist circumference declined walnut study phase despite higher calorie intake study salas salvado et al prevalence metabolic syndrome reduced result decreased waist circumference mediterranean diet supplemented mixed nuts the effects walnuts appetite satiety weight body composition clearly warrant study lastly trial showed walnut enriched ad libitum diet change fasting plasma glucose fasting insulin homa ir levels compared control diet overall nut consumption studies provide varied results comes glucose insulin homeostasis such findings difficult interpret given studies employ participants varied health status nuts various sorts differing amounts variable intervention durations number participants longer term effects generally associated observational studies whereas intervention feeding studies typically short duration true case we acknowledge study several limitations important absence prescribed standardized diet would allow us attribute findings independent variable investigation walnut consumption nevertheless ad libitum crossover design employed compensates concern strengthens real life applicability findings the practical amount walnuts consumed participants trial 56 g adds real world applicability findings the external validity trial limited racial gender homogeneity participating population compliance assessment trial carried via 3-day food records walnut consumption log sheets may provide perfectly accurate record subject compliance even given positive results primary outcome measure endothelial function concerns reduced importance since present study trial short length uncertain whether findings could extrapolated trials longer duration we acknowledge study several limitations important absence prescribed standardized diet would allow us attribute findings independent variable investigation walnut consumption nevertheless ad libitum crossover design employed compensates concern strengthens real life applicability findings the practical amount walnuts consumed participants trial 56 g adds real world applicability findings the external validity trial limited racial gender homogeneity participating population compliance assessment trial carried via 3-day food records walnut consumption log sheets may provide perfectly accurate record subject compliance even given positive results primary outcome measure endothelial function concerns reduced importance since present study trial short length daily intake 56 g walnuts improves endothelial function overweight adults least 1 sign metabolic syndrome despite adding calories ad libitum diet walnut intake associated weight gain actually associated nonsignificant decline waist circumference this study provides suggestive evidence role walnuts protecting diabetes heart disease risk individuals the study also indicates walnuts may added ad libitum diet without weight gain least short term | objectivesmetabolic syndrome is a precursor of diabetes and cardiovascular disease ( cvd ) .
walnut ingestion has been shown to reduce cvd risk indices in diabetes .
this randomized controlled crossover trial was performed to investigate the effects of daily walnut consumption on endothelial function and other biomarkers of cardiac risk in a population of overweight individuals with visceral adiposity.methodsforty-six overweight adults ( average age , 57.4 years ; 28 women , 18 men ) with elevated waist circumference and 1 or more additional signs of metabolic syndrome were randomly assigned to two 8-week sequences of walnut - enriched ad libitum diet and ad libitum diet without walnuts , which were separated by a 4-week washout period .
the primary outcome measure was the change in flow - mediated vasodilation ( fmd ) of the brachial artery .
secondary measures included serum lipid panel , fasting glucose and insulin , homeostasis model assessment
insulin resistance values , blood pressure , and anthropometric measures.resultsfmd improved significantly from baseline when subjects consumed a walnut - enriched diet as compared with the control diet ( 1.4% 2.4% versus 0.3% 1.5% ; p = 0.019 ) .
beneficial trends in systolic blood pressure reduction were seen , and maintenance of the baseline anthropometric values was also observed .
other measures were unaltered.conclusiondaily ingestion of 56 g of walnuts improves endothelial function in overweight adults with visceral adiposity .
the addition of walnuts to the diet does not lead to weight gain .
further study of the potential role of walnut intake in diabetes and cvd prevention is warranted . |
used lrn conduit maintain confidentiality anonymity variola testing sites a convenience sample 45 laboratory workers completed online survey developed researchers university nebraska medical center omaha ne usa nonidentifying demographic information collected addition adverse effects vaccination perceived barriers revaccination determine significant difference existed regarding success presence absence take vaccination vaccine based intervals vaccines measured mean interval years vaccinations respondents mean age 46 years worked mean 20.5 years laboratory setting eighty four percent respondents reported adverse events vaccination related skin irritation caused occlusive dressings worn vaccination lesion sixty seven percent listed medical condition close household contact barrier revaccination the mean interval first second vaccination 4.8 years vaccinees successful vaccine 6.0 statistical analysis demonstrated significant difference p 0.149 number years first second vaccinations take rates sixty two percent respondents indicated work non highly attenuated orthopoxviruses ( i.e. developed lesions regardless number years since previous vaccination suggesting immunity might waned therefore data provide evidence suggest acip recommended interval revaccination prolonged although respondents reported adverse effects vaccine vaccination caused discomfort many reported symptoms related occlusive dressing worn precautionary measure ensure lesion site properly covered work hours measures ensure lesion is covered appropriately nonocclusive dressings long sleeves may considered given laboratory workers direct contact patients although lrn asks small group laboratory workers comply acip recommendations question remains whether requirement include laboratory workers handle orthopoxviruses revaccination laboratory workers variola testing sites every 3 years would expected sufficient provide initial immunologic response whereas laboratory workers handle orthopoxviruses could vaccinated fashion health care public health workers least 1 recent since 2003 documented successful vaccination 5 this recommendation based premise using vaccine prophylaxis documented exposure smallpox infected person this practice used regularly smallpox eradication program average incubation period vaccinia 34 days shorter incubation period smallpox a person exposed smallpox would 34 day window vaccinated immunologically respond vaccinia also confers immunity smallpox 6 compromised immune systems cardiac risk factors make vaccinees ineligible vaccination likely develop age 7 most barriers revaccination related medical conditions compromised immunity and/or exfoliative skin disorders place vaccinees high risk adverse events currently licensed smallpox vaccine the conditions added challenge aging pool laboratory workers assigned national variola testing sites 8) currently unlicensed third generation smallpox vaccines may considered pending licensure replacements acam2000 sanofi pasteur biologics lyon france currently licensed vaccinia vaccine laboratory workers national variola testing sites perhaps even broader population laboratory workers throughout united states third generation vaccines nonreplicating safer populations might contraindications traditional vaccines 911 risk us population release smallpox this reduced risk stems lower threat terrorism existence stockpile new acam2000 smallpox vaccine addition cadre health care public health professionals could revaccinated quickly mobilized accordingly 12 more research immunogenicity smallpox vaccine needed challenged absence smallpox disease test efficacy vaccination researchers appreciate complex mechanism immune response vaccinia and/or smallpox infection might lead better treatment options infectious autoimmune diseases 7 future opportunities may arise challenge vaccine actual virus measure vaccine efficacy provide sound recommendations protect public health health care responders smallpox 13 meantime ensuring recommendations created protect populations properly interpreted applied important protecting vulnerable persons without exposing others unnecessary harm | to evaluate the need to revaccinate laboratory workers against smallpox , we assessed regular revaccination at the us laboratory response network s variola testing sites by examining barriers to revaccination and the potential for persistence of immunity . our data do not provide evidence to suggest prolonging the recommended interval for revaccination . |
57yearold woman initially implanted double chamber pacemaker complete atrioventricular block upgraded crtp another center year due left ventricular dysfunction dyspnea she referred us 3 months upgrade due wound infection pseudomonas sp caused gossybypoma retained compress preoperative transthoracic tte transesophageal toe echocardiography reveal signs endocarditis patient afebrile negative blood cultures patent foramen ovale pfo small left right shunt traction locking stylets allowed complete extraction activefixation right atrial right ventricular leads coronary sinus lead explanted simple traction the following morning developed sudden dysarthria left facial palsy emergent cerebral angiography revealed occlusion right frontal branch middle cerebral artery fig mechanical thrombectomy solitaire fr revascularization device covidien plymouth mn usa retrieved thrombus attached dense fibrinous tissue fig normal vessel flow recovered fig 2c neurological recovery complete within 60 min symptom onset oral antibiotics continued 2 weeks followup 6 months uneventful transesophageal echocardiography bicaval view 2 dimensions using color doppler b showing mobile interatrial septum asterisk patent foramen ovale solid arrow ( b occlusion frontal branch right middle cerebral artery arrow hypoperfusion large territory asterisk ( c restored flow mechanical thrombectomy solitaire
fr revascularization device covidien used mechanical thrombectomy herein describe case patient suffering acute ischemic stroke due paradoxical embolization dense fibrous material pfo following transvenous lead extraction tle endocardial pacemaker leads cause fibrin deposits surface may form sheaths 85% patients 1 adhere vessel walls tricuspid valves endocardium thrombi detected leads around 30% patients toe intracardiac ultrasound 2 3 findings asymptomatic pulmonary emboli 15% patients well increased pulmonary pressure point toward high rate subclinical embolism patients cardiovascular implantable electronic devices cieds 1 3 4 one particular concern risk systemic thromboembolism patients intracardiac shunts cieds shunts pfos risk systemic thromboembolism doubled 5 conditions present considered contraindication endocardial lead placement 6 case pfos risk less well documented retrospective data points toward hazard ratio 3 stroke 7 although study bias may exaggerated figure tle valuable technique management device infection lead failure safety improved thanks technological advances increasing experience preliminary data electra registry 8 prospective european registry tle show relatively low rate major complications 2.53.9% depending procedural volume centers one complication particular concern extracting leads risk systemic embolism indeed residual fibrous deposits persisting tle described 9 sometimes large enough described
our case illustrates residual deposits may always visible toe probably may confined vessels e.g. innominate subclavian vein may embolize later although rate stroke seems low 0.1% tle case highlights potentially dramatic consequences systemic embolization even absence visible vegetations leads moreover current guidelines offer clear recommendations help lower risk embolization tle 10 routine anticoagulation used centers mainly lower rate venous occlusion probably little use due fibrinous nature tissue the use distal embolization protection devices tle patients vegetations reported several cases whether pulmonary 11 systemic circulation 12 however efficacy devices seems limited risk delayed embolism demonstrated case residual dense fibrinous tissue probably persists several days weeks based case considerations believe paradoxical embolism causing stroke real concern patients pfos undergoing tle although incidence seems low consequences catastrophic costs linked morbidity stroke important although may raise concern additional cost patients undergoing tle preoperative echocardiographic examination either tte toe order evaluate preoperative tricuspid valve regurgitation presence vegetations the additional cost time linked evaluate pfo negligible case pfos large shunts suggest considering percutaneous pfoclosure extraction noninfected patients surgical extraction pfoclosure patients endocarditis cases small pfos recommend strict avoidance maneuvres increasing righttoleft shunting e.g. coughing valsalva 2448 h neurological surveillance the effectiveness mechanical thrombectomy cases embolization lead extraction also highlighted case dense fibrous nature embolus cases embolus foreign body material pharmacological thrombolysis likely ineffective well increasing bleeding risk considerably postoperative period therefore strongly suggest performing tle centers neuroradiological standby rapid action may prevent irreversible sequellae | key clinical messagesystemic embolization is a dreaded complication of transvenous lead extraction ( tle ) , even without visible vegetations .
preoperative patent foramen ovale evaluation is important , justifying neurological surveillance or consideration of surgical extraction in selected cases . in case of stroke after tle ,
mechanical thrombectomy is a successful therapy , and should be readily available . |
stroke cerebrovascular diseases caused cerebral vascular blockage bleeding
cause loss normal blood circulation affected area anoxia resulting
irreversible brain damage manifests functional impairments consciousness
movement senses recognition comprehension language common mobility impairments
include lateral muscle weakness abnormal lateral muscle tension abnormal postural
control abnormal coordination abnormal movement sequencing loss joint coordination
these factors contribute problems postural control thereby affecting
standing balance ability1 postural control evaluation training important
contributors rehabilitation balance walking ability daily living
activities performed stroke patients3 4 the modern theory movement control movement learning holds humans
intentional movements task specific5
i.e. response specific environment situation however
rehabilitation therapies involving task specific actions often better effects
traditional non task specific rehabilitation therapies6 according barclay goddard stevenson poluha et al.7 traditional treatment stroke
patients increase standing symmetry using force plate treatment van peppen
kortsmit lindeman et al.8 concluded
stroke patients using visual feedback traditional treatments showed greater
improvements patients receiving standard treatment standing symmetry postural
sway movement eyes open closed walking speed9 dynamic balance ability ability change postural without
losing one balance10 limits
stability los maximum center gravity displacement possible without loss balance
also reduced stroke patients damage central nervous system function directly
affects posture movement thus balance ability reduced muscle strength mobility
the hemiparesis often results stroke tends
force patients complete movements using compensation strategy e.g. fixing affected
part using healthy part complete target movement behavior decrease
free movement factors central nervous system reduce complexity
movement choice making easier complete intended action however behavior
require postural control nervous impulses affected side reduce
hinders functional recovery affected side rehabilitation12,13,14 this means techniques oblige
stroke patients practice centralized postural balance control affected side
considerable impact stroke patients recovery balance walking
mobility related functions study a device enable stroke patients learn better movement control
rehabilitation relying traditional rehabilitation therapies tested the device
uses two force plates measure right left side centers foot pressure cop
visual feedback different side reaction ratios prompt movements affected side
non affected support base remains fixed position a schematic diagram device task used study shown fig 1fig patients stand signal capture device dual force plate prompted
task interactive game monitor the patient changes body
center move object prompted task shown monitor all physical
actions used execute balance training task assessment system schematic diagram study used cop capture device consisting load cell signal transmitter
analog digital converter universal serial bus usb interface weight distribution
data collected foot plantar stress center displayed two dimensional plane
entered game coordination figure 1a shows cop capture device
consists two plates 30 245 10 mm 304 stainless steel one foot the
bottom displays equilateral triangle width 165 mm consisting three load cells acting
unit fig the center
equilateral triangle geometric center stepping zone the user needs step
center stepping zone align geometric center plantar area
center load cell closely possible figure
1c 1d show movements captured
cop capture device set the load cell retrieves signals right
left feet user movements foot pressure center post processed
construct center distribution figure if region located two dimensional coordinate system density
function (x region divided left right sides sub regions
dl dr the overall weight
system subject weight feet calculated using
formula center gravity system calculated using formula three vertices subject plantar force region dl(dr
force moment arm values li ri
xli
yli
xri
yri 13 respectively
figure 2fig 2.the relationship force moment arm shows relationship force moment arm diagram center
gravity derived follows relationship force moment arm figure 3fig a signal transmitter used provide
operational voltage load cell amplify signal transmission
analog digital converter converted data saved buffer zone
transmitted software requests after acquisition analysis software data
processed finite impulse response filter low pass filter 10 hz organized
chronological sequence the software written microsoft visual c 1 setting
function analog digital converter usb interface 2 processing load cell data
tables 3 processing vector parameters 4 center distribution plots vector
processing 5 graphic user interface display raw data center distribution plots
vector processing 6 graphic user interface set vector processing system
parameters schematic diagram capture device game engine developed using microsoft .net framework microsoft visual c
xna game studio used build engine 1 event processing queue 2 graphic
engine 3 user interface 4 database interface fig
4.architecture game engine architecture game engine cop capture device system used proportion single load cell value whole load
cell value single foot center point distribution value single foot center point reflect
plane boundary reflect collected weight distribution virtual plane the six
distribution values merged become pressure centers right left feet
whole cop virtual plane game engine using rule healthy side
affected side 1 n n decided medical staff based patient diagnosed
medical condition n=1.5 case 4 case b study cop values boundary display locked boundary study
the task patients use cop aim arrow shoot target sum
value healthy side load cell less 20% value load cell unit
whole red warnings displayed monitor tell patient move cop
side the formula
controlling movement target given horizontal boundary bh= vertical boundary bv=1,000 unit)moving
velocity v 1v10 unit fps moving velocity changing rate n 10n100 fps target moved randomly throughout game the user considered located target angle formed target
monitor center location camera difference less 5.
point arrow shot target time taken locate target the experiments study approved human ethics committee taipei medical
university hospital taiwan inclusion criteria stroke hemiplegia age
25 60 years this study reports results two subjects used device movement control
training affected side training sessions consisted following randomly moving target described
one five minute break middle session baseline performance measured start training performance measured
end training period the tools used evaluate performance berg balance scale bbs)15 16
14 balance tasks scored five point 04 scale 0 representing poorest
performance motor assessment scale mas)17 evaluates motor function seven point 06 scale
study items relevant standing balance used newly developed device
used evaluate cop distribution the evaluation included cop motion distribution
left right feet whole body standing eyes open one minute
standing eyes closed one minute the effect balance performance training using device assessed using two
patients the side ratio n 1.5 case reaction game 60%
affected side 40% non affect side 4 case b affected side 80%
non affected side 20% table 1table 1.basic information two cases studysubjectabgendermalemaleage years)4939height cm)167168weight kg)8272bmi29.425.51main symptomsstrokestrokeonset period6 months11 monthsdominant side affected sideright/ rightright rightother illnessesasthma hypertension aphasianohabits customsstopped drinking smoking year)exercise least one
hour daystopped smoking 8 months)exercise one two hours day summarizes patient data 5.the cop distribution case shows cop distribution patient training eyes open condition
fig 6d cop numerical
distribution shown fig 7fig the cop distribution case cop distribution case b cop distribution training baseline post training balance assessments using bbs showed neither patient
patient b regressed items performance baseline already
ceiling the bbs improvement case 19.44% case b 11.9% showing
interactive game used study help stroke patients improve balancing
ability stroke affected side detailed results presented table 2table 2.balance ability assessment bbssubjectbbs sub taskbefore trainingafter trainingprogressasit standwith hand assistancewithout hand assistancesignificantstanding unsupported eyes closedunstablemore stablesignificantstand unsupported feet togetherwith hand assistancewithout hand assistance longer standing timeaveragereaching forward outstretched armsome reachlonger reachaveragepick object floor standing
positionno changenonturn look behind left right shoulders
standingcant look behind affected sidecan look behind affected sidesignificantturn 360low speedfaster speed score enough next
level)weakplace alternate foot bench stool standing
unsupportedcould step stoolstepped stool twice without supportsignificantstand unsupported one foot frontnot able standunsupported one foot front 8 ssignificantstanding one legcould stand affected side short term healthy
sidestill could stand affected side
time healthy sideaveragebstand unsupported feet togetherstand long time need assistance drew feetdrew feet himselfsignificantplace alternate foot bench stool standing
unsupportedtook 24 sonly took 12 ssignificantstand unsupported one foot frontnot able standstood 20 ssignificantreaching forward outstretched arm18 cm19 cmweakpick object floor standing
positionno changenonturn look behind left right shoulders
standingno changenonturn 360took 13 stook 12 sweakbbs scorecase acase bbefore rate progress36 point 43point /19.44%42 point 47 point /11.9% table 2 shows progress patient
sufficient bbs items elicit improvement score although
evidence progress we speculate additional training time would
elicited larger gains performance items reaching forward
outstretched arm picking object floor standing position
there
obvious changes performance presumably items involve upper limb
movement patient b tested longer recovery period better physical condition
baseline balance performance better patient a. among items
worst baseline items involving upper limb movement showed little change
training items related standing balance showed obvious improvement table 3table 3.balance ability assessment massubjectmas sub taskbefore trainingafter trainingprogressabalance sittingcould maintain sitting weight two body side
unevenimproved could look around touch side floor
front floor.averagesitting standingcould complete independ- ently weight uneven.the uneven situation improved speed
rather slow.averagewalkinghad assistance time walking.could walk steadily without assistance device still
slow.averagebbalance sittingnormal performancesome progressweaksitting standinggood performancebetter performancesignificantwalkinggood performancewalking speed obviously fastersignificantmas scorecase acase bbefore rate progress6 point/12 point /100%16 point /17 point /6.25 the test program
included seated balance transitions sitting standing walking the cop distribution data shown table
4table 4.cop distributionsubjectcenter point average positionaverage value center pointdrifting position
center point average distanceoe after)ce after)oe after)ce after)a(16.20 1.97 2.55 0.36)(13.80 3.35 13.48 22.41)13.39 4.9214.78 10.39cop distribution change position moved right side
affected side left side healthy side).progress oe 63.25% ce 29.70% drift
area center point oe 1,284.90 543.50 progress 57.70% ce
1,673.30 1,238.10 progress 26%)b(27.10 93.99)/ 22.89 56.71)(12.23 76.06 23.42 59.19)6.92 5.1214.03 14.82cop distribution change moved upper side
center virtual center center point mapping plane)progress oe 26.01% ce 5.63% drift
area center point oe 767.20 574.30 progress 25.14% ce
1599.90 873.20 progress 45.42% after training cop distribution patient shifted towards right
affected side presumably patient habitually supported standing
healthy side the affected side showed smaller effort game patients
forced use healthy side finish game time became used
affected side absorb weight standing force plate the data
center point drift average value center point average distance showed
considerable improvement eyes open condition this may
patients knew could find datum point maintain datum point in fact average value center
position distance eyes closed condition indicated slight deterioration
performance patient showed 19.44% improvement performance bbs 100% improvement
performance mas following training using device interactive game although
patient used healthy side support body weight standing position
certain circumstances could switch using affected side patient showed
considerable improvement static standing balance control eyes open patient b
showed much smaller improvements performance 11.9% improvement performance
bbs 6.25% performance mas center point plane performance
significant change center point position detectable change
average drift extent even though center point drift area smaller it opinion difference effectiveness training two
patients due differences length recovery case b tested 11
month recovery period already achieved considerable gains mobility
persistent this persistence derived functional use movements
course daily life the
training produced considerable improvement static center point drift obvious
improvement center point position it opinion patient made significant
progress aspects balance testing occurred shorter recovery period
patient recovered much mobility patient b leading larger training
effects summary interactive game dual force different side ratio developed
study help stroke patients train balance stroke affected side
method effective patients recently experienced stroke offers little
benefit patients recovered significant degree mobility we unable
determine level baseline mobility training ceases effective
study assessed two cases future research investigate effects
rehabilitation protocol stroke patients hemiplegia varying recovery periods
e.g. 6 11 months bbs score certain threshold e.g. 42 mas scores
certain threshold e.g. 16 provide evidence regarding efficacy | [ purpose ] stroke and other cerebrovascular diseases are major causes of adult mobility
problems . because stroke immobilizes the affected body part , balance training uses the
healthy body part to complete the target movement .
the muscle utilization rate on the
stroke affected side is often reduced which further hinders affected side functional
recovery in rehabilitation . [ subjects and methods ] this study tested a newly - developed
interactive device with two force plates to measuring right and left side centers of
pressure , to establish its efficacy in the improvement of the static standing ability of
patients with hemiplegia .
an interactive virtual reality game with different side reaction
ratios was used to improve patient balance .
the feasibility of the proposed approach was
experimentally demonstrated .
[ results ] although the non - affected - side is usually used to
support the body weight in the standing position , under certain circumstances the patients
could switch to using the affected side . a dramatic improvement in static standing balance
control
was achieved in the eyes open condition .
[ conclusion ] the proposed dual force
plate technique used in this study separately measured the affected and non - affected - side
centers of pressure . based on this approach
, different side ratio integration was achieved
using an interactive game that helped stroke patients improve balance on the affected
side .
only the patient who had suffered stroke relatively recently benefited
significantly .
the proposed technique is of little benefit for patients whose mobility has
stagnated to a certain level . |
nine human hereditary neurodegenerative disorders including huntington disease hd several spinocerebellar ataxias scas caused abnormal expansion cag repeats located translated sequences different genes fig 1 for example hd triggered expression least 36 cag repeats located exon 1 htt gene encodes large multifunctional huntingtin protein htt sca1 caused least 39 cag repeats present exon 8 atxn1 gene codes ataxin-1 protein involved rna metabolism transcriptional regulation sca3 also known machado
joseph disease induced least 60 cag repeats occur exon 10 atxn3 gene encoding protein deubiquitinating activity the cag repeats translated polyglutamine tracts protein products entire group resulting disorders known polyglutamine polyq diseases each polyq disorder primarily affects different population neurons although causative genes widely expressed central nervous system peripheral tissues the expanded repeats thought exert pathogenic effects protein level mainly gain toxic function mutant protein comparison myotonic dystrophy type 1 dm1 another example triplet repeat expansion disease tred is caused 503,000 copies ctg tandem repeats located 3 untranslated sequence dystrophia myotonica protein kinase gene dmpk dm1 gain toxic function mutant transcript containing cug repeats 1comparison lengths cag repeat tracts occur polyq disease related transcripts cug repeats transcript responsible dm1 the normal repeat range marked green mutant repeat range marked red specified the starting threshold dm1 mutation 50 repeats denoted hatched line comparison lengths cag repeat tracts occur polyq disease related transcripts cug repeats transcript responsible dm1 the normal repeat range marked green mutant repeat range marked red specified the starting threshold dm1 mutation 50 repeats denoted hatched line pathogenic number cag repeats genes implicated polyq diseases cases lower number cug repeats dmpk gene dm1 patients cag expansions typically span much narrower range repeat lengths fig 1 nevertheless considerable fraction hd sca patients harbor mutant cag repeats length corresponding lower range cug repeat lengths found dm1 the expression levels individual polyq disease genes dmpk gene differ within tissues however belong moderate low expression category 8 9 the structural features cag repeats similar cug repeats forming hairpin structures transcripts repeat tracts long enough 1016 the repeats normal length form small semistable hairpins mutant repeats form long hairpins stable according results crystallographic studies cag repeat duplexes cug repeat duplexes show high degree similarity 18 19 suggesting stem portion hairpins may share protein binding properties 20 21 review first discuss main cellular molecular hallmarks mutant protein mutant rna gain function mechanisms studies polyq diseases dm1 pathogenesis we present recent findings indicating transcripts containing expanded cag repeats might also toxic contribute pathogenesis polyq disorders finally focus experimental models used demonstrate rna toxicity polyq diseases we discuss features models propose generating new cellular animal models dedicated elucidating toxic effects triggered mutant rna protein polyq diseases the protein products genes undergo mutations leading polyq diseases differ cellular functions cover wide range molecular weights a common feature proteins presence polyq tract expanded result mutation however exact nature protein gain function toxicity polyq diseases remains subject debate 22 23 two mechanisms considered gain new toxic function mutant protein enhancement normal protein function toxic levels either case key understanding details pathogenic mechanisms identification characterization new toxic protein protein interactions imbalanced normal interactions systematic search proteins associated normal expanded the data showed proteins preferentially interacted mutant htt enriched intrinsically disordered proteins proteins involved key cellular functions energy production protein trafficking rna modification translation mitochondrial functions cellular stress cell death these results confirmed expanded earlier findings regarding cellular processes pathways altered hd 2527 the pathogenesis polyq diseases believed initiated expanded polyq tract thought acquire -sheet conformation cause mutant protein misfold alternatively expanded polyq stretch may stabilize one several conformations characteristic wild type protein may normally exist equilibrium effect enhances intermolecular interactions mutant protein cost interactions in addition polyq tract context protein domains may also contribute pathogenesis demonstrated animal models spinal
bulbar muscular atrophy sca1 hd several instances reviewed 3234 single amino acid substitutions functional domains relevant proteins resulted dramatic changes disease phenotypes pointing critical role protein toxicity polyq diseases the cellular hallmarks polyq diseases nuclear cytoplasmic amyloid like aggregates formed mutant proteins proteolytic fragments 35 36 fragments translated aberrantly spliced shorter mrnas sequester proteins predominantly containing unstructured regions 24 28 38 the formation amyloid like deposits also observed parkinson alzheimer diseases protein toxicity polyq diseases often compared however efforts aimed demonstrating rna toxicity polyq diseases reference dm1 rna triggered treds e.g. sca8 hdl2 huntington disease like 2 40 41 appropriate justified 20 21 4244 dm1 prototype treds caused toxic rna 6 7 terms toxic rna rna toxicity used reflect fact disease causing mutation passed gene transcript protein structure unaffected mutation the hallmarks cells expressing expanded cug repeats nuclear rna foci toxic cells sequester important cellular proteins reducing normal functional levels reviewed 46 47 one protein trapped mutant rna foci muscleblind like mbnl1 alternative splicing factor together concomitant upregulation antagonistic splicing factor cug bp1 mbnl1 deficiency results misregulation developmentally regulated alternative splicing numerous mbnl1-regulated genes the compromised functions genes linked clinical symptoms dm1 e.g. altered splicing insulin receptor insulin resistance chloride channel 1 myotonia sarcoplasmic endoplasmic reticulum ca atpase 1 2 muscle wasting cardiac troponin cardiac abnormalities tau mapt cognitive deficits the binding multifunctional helicases p68 p72 mutant cug repeats facilitates binding mbnl1 repeats likely links dm1 pathogenesis pathway nuclear step microrna biogenesis process helicases involved cofactors ribonuclease drosha complex direct evidence provided crosstalk dm1 pathogenesis pathway cytoplasmic ribonuclease dicer step microrna biogenesis mbnl1 protein also implicated it demonstrated mbnl1 sequestered mutant cug repeats effectively function newly recognized role pre mirna cleavage regulator resulting compromised expression function mirnas including mir-1 effect linked dm1-related heart defects the expanded cug repeats also shown trigger immune responses dm1 tissue pkr oas tlr3 rig genes activated the protein products genes undergo mutations leading polyq diseases differ cellular functions cover wide range molecular weights a common feature proteins presence polyq tract expanded result mutation however exact nature protein gain function toxicity polyq diseases remains subject debate 22 23 two mechanisms considered gain new toxic function mutant protein enhancement normal protein function toxic levels either case key understanding details pathogenic mechanisms identification characterization new toxic protein protein interactions imbalanced normal interactions systematic search proteins associated normal expanded the data showed proteins preferentially interacted mutant htt enriched intrinsically disordered proteins proteins involved key cellular functions energy production protein trafficking rna modification translation mitochondrial functions cellular stress cell death these results confirmed expanded earlier findings regarding cellular processes pathways altered hd 2527 the pathogenesis polyq diseases believed initiated expanded polyq tract thought acquire -sheet conformation cause mutant protein misfold alternatively expanded polyq stretch may stabilize one several conformations characteristic wild type protein may normally exist equilibrium effect enhances intermolecular interactions mutant protein cost interactions in addition polyq tract context protein domains may also contribute pathogenesis demonstrated animal models spinal
bulbar muscular atrophy sca1 hd several instances reviewed 3234 single amino acid substitutions functional domains relevant proteins resulted dramatic changes disease phenotypes pointing critical role protein toxicity polyq diseases the cellular hallmarks polyq diseases nuclear cytoplasmic amyloid like aggregates formed mutant proteins proteolytic fragments 35 36 fragments translated aberrantly spliced shorter mrnas sequester proteins predominantly containing unstructured regions 24 28 38 the formation amyloid like deposits also observed parkinson alzheimer diseases protein toxicity polyq diseases often compared however efforts aimed demonstrating rna toxicity polyq diseases reference dm1 rna triggered treds e.g. sca8 hdl2 huntington disease like 2 40 41 appropriate justified 20 21 4244 dm1 prototype treds caused toxic rna 6 7 terms toxic rna rna toxicity used reflect fact disease causing mutation passed gene transcript protein structure unaffected mutation the hallmarks cells expressing expanded cug repeats nuclear rna foci toxic cells sequester important cellular proteins reducing normal functional levels reviewed 46 47 one protein trapped mutant rna foci muscleblind like mbnl1 alternative splicing factor together concomitant upregulation antagonistic splicing factor cug bp1 mbnl1 deficiency results misregulation developmentally regulated alternative splicing numerous mbnl1-regulated genes the compromised functions genes linked clinical symptoms dm1 e.g. altered splicing insulin receptor insulin resistance chloride channel 1 myotonia sarcoplasmic endoplasmic reticulum ca atpase 1 2 muscle wasting cardiac troponin cardiac abnormalities tau mapt cognitive deficits the binding multifunctional helicases p68 p72 mutant cug repeats facilitates binding mbnl1 repeats likely links dm1 pathogenesis pathway nuclear step microrna biogenesis process helicases involved cofactors ribonuclease drosha complex direct evidence provided crosstalk dm1 pathogenesis pathway cytoplasmic ribonuclease dicer step microrna biogenesis mbnl1 protein also implicated it demonstrated mbnl1 sequestered mutant cug repeats effectively function newly recognized role pre mirna cleavage regulator resulting compromised expression function mirnas including mir-1 effect linked dm1-related heart defects the expanded cug repeats also shown trigger immune responses dm1 tissue pkr oas tlr3 rig genes activated although contribution rna toxicity pathogenesis polyq diseases previously postulated based structural similarities cag cug repeats transcripts 10 17 first compelling experimental evidence involvement provided 2008 bonini colleagues using drosophila melanogaster model system researchers demonstrated expression translated untranslated rna molecules containing long hairpin forming cag repeat tracts causes neurodegeneration whereas expression rna containing caa interrupted cag repeats resulted considerably less pronounced neurodegenerative features caa triplets also encode glutamine unable form hairpin structure occurrence within cag repeat tracts 60 61 destabilizes cag repeat hairpins other studies performed nonhuman model systems provided evidence toxicity cag repeats hsiao colleagues showed transgenic caenorhabditis elegans similar cug repeats cag repeats toxic length formed nuclear foci colocalized cembl worm homolog mbnl1 worms expressing toxic cag repeats showed shortened lifespan reduced motility rates consistent phenotypes worms expressing toxic cug repeats as shown pan colleagues expression 200 cag repeats 3utr egfp toxic transgenic mouse muscle testis tissues expression transgene directed importantly ribonuclear foci abnormal phenotypes observed absence polyq product expression the formation cag repeat rna foci colocalize mbnl1 protein first time demonstrated cooper colleagues expression long exogenous cag repeats monkey cosm6 cells a question addressed using human cell lines whether less cag repeats could also form nuclear foci cause alternative splicing aberrations similar known dm1 the results showed effects triggered hela neuroblastoma sk n mc cells transiently expressing mutant cag repeats in addition demonstrated expanded cag repeats present htt atxn3 transcripts also occur within intranuclear mbnl1-positive rna foci human hd sca3 fibroblasts although focus formation accompanied aberrant alternative splicing several endogenous mbnl1-dependent transcripts occurred cells expressing approximately 70 cag repeats lower number approximately 45 cags very recently bates colleagues demonstrated cag repeat length dependent aberrant splicing htt exon 1 giving rise short polyadenylated exon 1-intron 1 mrna translated toxic htt exon 1 protein the aberrant splicing triggered increased binding alternative splicing factor srsf6 expanded cag repeats thus likely pathogenesis polyq disorders involves least extent primary elements rna gain function mechanism well characterized dm1 consistent nuclear effects protein responsible nuclear export transcripts harboring expanded cag repeats identified chan colleagues small nuclear rna u2-associated factor u2af65 this factor binds directly expanded cag repeats forms complex nuclear export receptor nxf1 reduction symptomatic tissues linked accumulation mutant rna nucleus an rnai mechanism shown involved pathogenesis several vivo cellular models polyq diseases demonstrated bonini colleagues richards colleagues two independent studies the co expression exogenous expanded cag cug repeats fly cells resulted neurodegenerative phenotype the complementary repeats likely formed double stranded rna cleaved dicer-2 21 nt cag cug repeat sirnas active silencing ago2-dependent process margolis colleagues discovered natural antisense transcript httas hd repeat locus contains cug repeat tract this transcript shown regulate sense htt transcript expression process dependent repeat length partly dependent dicer risc pathway the involvement rnai mechanism also demonstrated marti colleagues human cell lines expressing mutant cag repeats flanked htt exon 1 sequence the mutant cag repeats translated untranslated gave rise toxic small rna species scag dicer dependent manner caused downstream silencing effect ago2-dependent manner again cytotoxic effects triggered cag repeats caa repeats the involvement mirna biogenesis pathway pathogenesis polyq diseases circumstantial based ability mbnl1 16 64 65 p68 proteins bind cug repeats though less efficiently cag repeats the recent study chan colleagues revealed cag repeat expansion induces nucleolar stress polyglutamine diseases demonstrating expanded cag repeat rna interacts directly nucleolin interaction triggers number aberrant downstream cellular processes eventually leading cell apoptosis these downstream effects include hypermethylation upstream control element rrna promoter inhibition rrna transcription reduced level rrna results accumulation free ribosomal proteins interaction proteins mdm2 e3 ubiquitin ligase causes mitochondrial p53 accumulation the interaction p53 antiapoptotic protein bcl xl causes oligomerization proapoptotic protein bak mitochondrial membrane allows cytochrome c release cytosol event activates caspase cascade induces apoptosis collectively several mechanisms rna toxicity revealed may likely participate pathogenesis polyq diseases however entire scale toxic rna contribution disorders range cellular processes pathways altered mutant transcripts remain unknown various genetic models used demonstrate first examples cag repeat rna toxicity described previous section the characteristics model systems main results obtained application compiled table 1 it apparent type rna toxicity thus far modeled lower invertebrates nematode worms fruit flies addition mammalian systems including mice monkey human cell lines however common issue modeling human diseases lower organisms relevance results obtained simpler model systems human disease indeed relevance hard prove merely sufficient similarity genetic pathways operating model organisms humans polyq diseases treds general task difficult late onset diseases occur naturally humans shorter living animals experimental induction similar effects requires stronger triggers i.e. longer repeat tracts cases higher expression levels studies expression transgene determined level referred expression endogene homologue human polyq gene gene most authors related expression single construct expression transgene variants case mouse models r6/2 bachd yac128 expression level transgene differ much homologous endogene 71 72 case constructs tested mammalian systems containing cmv promoters expression level transgene reported high 64 65 73 the worm fly systems satisfactorily fulfilled requirement genetic similarity systems capable demonstrating molecular phenotypic hallmarks rna toxicity although relevant potentially informative fly systems transgenic mouse models less frequently used human cellular models used purpose twice.table 1characteristics model systems used investigation rna mediated toxicity caused expanded cag repeats the table organized according species model organism includes human cell lines note constructs contained either pure cag caa repeats contained caa interrupted cag repeats the cag repeats interrupted caa pure caa tracts presented boldconstruct characteristicsmain conclusionsreferencerepeat tractsequence contextpromoter expressioncaenorhabditis elegans(cag 83gfp 3utrmyo-3 muscle)cag repeats similar cug repeats toxic rna level length dependent manner(cag 125(cag 200(ctg 125drosophila melanogaster(cag 52 99myc flaggmr gal4 eye)the expression expanded translated cag caa repeats causes neurodegeneration(caa ) 94(cag 933utruntranslated cag repeats induce pathologysca3trq78(cag)atxn3 truncatedgmr gal4 eye elav gal4 neurons)untranslated cag repeats induce progressive neural dysfunctionsca3trq78(caa g)sca3nq84(cag)atxn3 full lengthlong untranslated caa interrupted cag repeats toxicsca3nq81(caa / g)(cag 100 250dsred2 3utr(caa g 105 262(ctg 250dsred2 3utrgmr gal4 eye 24b gal4 muscle hs gal4 ubiquitous heat shock)simultaneously expressed expanded cag cug repeats toxic rnai involved toxicity(cag 250rcag 100cheerio transcript uas drivengmr gal4 eye elav gal4 neurons da gal4 ubiquitous)the expression cag cug repeats leads rnai dependent neurodegenerationrctg 100sca3trq78(cag)atxn3 truncatedgmr gal4 eye)the nxf1/u2af65-mediated rna export pathway involved expanded cag repeat mediated toxicitysca3trq78(caa g)the interaction cag repeats nucleolin triggers numerous downstream toxic effects(cag 100 250dsred2 3utrelav gal4 neurons)the cag100-expressing flies show aberrant expression numerous brain genes(caa g 1054x rcag 100short sequence gfp 5utrda gal4 actin5c gal4 ubiquitous)the expression cug cag caa repeat containing transcripts causes morphological defects4x rctg 1004x rcaa 100mus musculus(cag 44htt cdna full lengthcmv ubiquitous)/construct described highly expressed particular transgenic lineno observed neuropathological changes behavioral abnormalities 1-year old mice overexpressing mutant htt transcript(cag 200egfp 3utrgsg skeletal muscle)transgenic mice expressing egfp transcripts long cag repeats 3utr develop pathogenic featuresr6/2 hd micehtt exon 1htt promoter ubiquitous)/average tissue expression 75 relative endogene nxf1/u2af65 rna export pathway associates expanded cag rna mediated toxicity(cag)115 150expanded repeat cag rnas interact nucleolin trigger nucleolar stress induce apoptosis via p53 pathwaybachd
97q 48 cag 49 caa)yac128 125q 116 cag 9 caa)htt full lengthhtt promoter ubiquitous)/expression brain close endogenous httdistinct caa interruption patterns may implicated observed phenotypic differences two hd modelsmammalian cultured cells(ctg 960dmpk exons 1115cmv cosm6 monkey cells /expression higher endogenousmrnas containing cag repeats form nuclear rna foci colocalize mbnl1(cag 960(cag 74egfp 3utr fusion construct egfp mutatxn3 69 cag)cmv hela sk n mc human cell lines expression higher endogenousexogenous transcripts expressing long untranslated cug cag repeats trigger similar splicing aberrations model cells(cag 200(ctg 74(ctg 20040 caghtt exon 1hmec hpde hela sh sy5y human cell linesthe expression expanded htt exon-1 transcript cag repeats gives rise small cag repeated rnas generated rnai induces cell death80 cag80 caa prot80 cag rnathe repeated pattern cag cag caa cag caa caaevery 20 repeats interrupted ctcgaevery 20 repeats interrupted tcgag characteristics model systems used investigation rna mediated toxicity caused expanded cag repeats the table organized according species model organism includes human cell lines note constructs contained either pure cag caa repeats contained caa interrupted cag repeats the cag repeats interrupted caa pure caa tracts presented bold repeated pattern cag cag caa cag caa caa every 20 repeats interrupted ctcga every 20 repeats interrupted tcgag genetic systems shown table 1 differ considerably regard molecular design most models transgenic express exogenous expanded repeats potential trigger pathogenesis variety mechanisms involving aberrant interactions host proteins of importance systems intragenic localization repeated sequences experimental systems the repeats located within open reading frame orf typically transcribed translated expressed mutant repeats present within sequence context either full length human disease transcript fragment transcript alternatively repeats placed within 3utr sequence heterologous gene transcribed the genes hosting mutant repeats usually marker gene gfp dsred in addition length purity cag repeat tracts important factors design model system repeated sequence typically falls upper range repeat lengths found human subjects suffering disease often modified contain caa repeats the ideal model polyq disease would one closely recapitulates human disease regard aspects thus human cell lines well suited study details molecular mechanisms implicated triggering pathogenesis the rapid development induced pluripotent stem ips cell technology enables somatic cells transformed ips cells differentiated neuronal cell lines moreover advent gene editing technologies begun enable precise engineering human disease related endogens the expression mutant exogenous full length cdna using well established technologies transgenesis may also considered option construction vitro models polyq diseases a good transgenic mouse model polyq disease express cag repeat mutation within sequence context entire human gene sufficient upstream downstream regulatory sequences ensure proper spatial temporal expression human gene natural levels 72 76 in general model systems expressing full length human mrna despite showing milder disease phenotypes better suited studies aimed discovering new mechanisms rna toxicity systems expressing shorter longer mrna fragments full length rna models the mutant transcript chance go steps mrna cellular journey birth nucleus death cytoplasm therefore steps altered mutation may identified a serious difficulty identifying involvement rna toxicity polyq diseases overlap polyq toxicity models expressing cag repeats orf placing repeat untranslated sequence heterologous gene frequently used overcome difficulty trace effects mutant rna however preventing transcript translation mutation start codon polyq disease gene cdna resolves problem preserving natural sequence context expression level repeats based assumption non aug initiated translation repeated sequences common phenomenon start codon mutation may indeed considered better solution mutating start codon also constructs expressing caa repeats caa interrupted cag repeats four model types depicted fig
2 may generated vitro vivo models critical experiments using transcriptome wide focused candidate approaches done obtain clear cut answers regarding role mutant transcripts pathogenesis polyq diseases.fig 2four types models used separate rna toxicity protein toxicity investigation pathogenesis cag repeat diseases the depicted models express one two types repeated sequences either cag caa both sequences code glutamine cag repeat forms hairpin structure transcripts types models both repeats expressed translated untranslated forms depending absence presence aug start codon mutation potentially toxic entities expanded cag repeat containing transcript polyq containing protein marked red transcript containing expanded caa repeats presumed nontoxic marked blue four types models used separate rna toxicity protein toxicity investigation pathogenesis cag repeat diseases the depicted models express one two types repeated sequences either cag caa both sequences code glutamine cag repeat forms hairpin structure transcripts types models both repeats expressed translated untranslated forms depending absence presence aug start codon mutation potentially toxic entities expanded cag repeat containing transcript polyq containing protein marked red transcript containing expanded caa repeats presumed nontoxic marked blue research rna toxicity polyq diseases still infancy stage marked disproportion ability model organism closely reproduce human disease frequency model system used search rna toxicity hallmarks nevertheless genetic models provided table 1 succeeded demonstrating first examples rna toxicity caused expanded cag repeats future studies along line require extensive use dedicated mouse models next generation human cellular models the studies performed thus far revealed involvement several cellular processes pathways cag repeat rna toxicity these altered processes include aberrant alternative splicing transcript nuclear transport export rna interference nucleolar stress resulting apoptosis the proteins participate direct indirect interactions mutant cag repeat transcripts need identified studies role pathogenesis needs elucidated such efforts may help determine contribution rna toxicity overall toxicity caused toxic factors protein rna this endeavor may also provide basis answer question whether rna protein toxicities interact enhance pathogenesis whether toxic processes parallel independent another issue clarified whether rna protein toxicities require different repeat length thresholds become operative latter alternative may likely case higher number repeats may required initiate rna mediated toxic processes finally depending scale repeat length thresholds various pathogenic mechanisms triggered mutant rna factors may impact causative therapeutic approaches combat polyq diseases higher lower extent rna toxicity proven contribute significantly disease development progression inhibition mutant protein synthesis blockage degradation mutant transcript required | in huntington 's disease and other polyglutamine ( polyq ) disorders , mutant proteins containing a long polyq stretch are well documented as the trigger of numerous aberrant cellular processes that primarily lead to degeneration and , ultimately , the death of neuronal cells . however , mutant transcripts containing expanded cag repeats may also be toxic and contribute to cellular dysfunction .
the exact nature and importance of rna toxicity in polyq diseases are only beginning to be recognized , and the first insights have mainly resulted from studies using simple model systems . in this review ,
we briefly present the basic mechanisms of protein toxicity in polyq disorders and rna toxicity in myotonic dystrophy type 1 and discuss recent results suggesting that the pathogenesis of polyq diseases may also be mediated by mutant transcripts .
this review is focused on the experimental systems used thus far to demonstrate rna toxicity in polyq disorders and the design of new systems that will be more relevant to the human disease situation and capable of separating rna toxicity from protein toxicity . |
announcement 26 october 2011 eli lilly company indianapolis usa withdrawing drotrecogin alfa activated worldwide market witnessed end drug specifically approved sepsis the move prompted failure prowess shock large international study confirm benefit reported original trial prowess protein c worldwide evaluation severe sepsis 10 years ago aftermath many questions raised declare led long term follow cost effectiveness studies accompanying prowess served data safety monitoring board prowess shock see acknowledgments full disclosure drotrecogin approved largely basis single phase 3 trial stopped early efficacy most drugs approved two positive phase 3 trials exceptions made impressive supporting data compelling unmet clinical need trial results particularly impressive although external us food drug administration fda advisory panel split whether approve fda nevertheless felt conditions met it seems therefore decision approve though based one phase 3 trial consistent procedures habits regulatory bodies around world new drugs typically drug administered thousand patients highly controlled situations limited long term follow second longer time generate evidence raises drug development costs pharmaceutical companies shortening post approval patent life company recoups investment thus worsening risk reward ratio potentially choking overall investment drug development because approval occurs uncertainty persists variety post approval surveillance activities performed case decision must reversed five years leading drotrecogin approval 2001 fda approved 597 new therapies in words low non zero rate drug withdrawal a lower rate would preferable without major changes patent laws science costs drug development chilling effect stringent approval process dwindling drug pipelines would likely considered intolerable so might lament sepsis drug one unlucky ones fundamental drug approval process led drotrecogin approval seem lenient wrong unreasonable said shame prowess stopped early something outside control fda early stopping biases toward overestimate treatment effect and it shame costs logistics running two concurrent phase 3 trials critical care seem insurmountable obstacles drug development process cheaper easier trials could allow us generate greater certainty without compromising drug pipeline the usual reason withdrawal determination previously unknown yet highly undesired side effect these studies generally reported mortality benefits similar seen prowess 6 12 the studies also provided greater information bleeding risks led label restrictions however somewhat unusually withdrawal instance voluntary decision based safety failure confirm efficacy numerous human animal studies suggest modulates coagulation inflammatory pathways interacts endothelial function midst intense innate immune responses challenges sepsis a previous simulation exercise theoretical anti tumor necrosis factor anti tnf anti body trials sepsis demonstrated modest differences distribution unmeasured variables host genotype pathogen characteristics could lead trials drug produces opposing results even patients meet clinical criteria prowess shock attempted enroll patients ideally suited drotrecogin original prowess study the largest reduction absolute mortality noted patients appeared sicker example presenting septic shock a subsequent trial administration drotrecogin alfa activated early stage severe sepsis address targeted patients lower severity illness could demonstrate efficacy thus original trial suggesting benefit low high severity risk constant relative risk reduction variable absolute reduction two subsequent trials mimicking low high ends original trial failed repeat positive findings provided trials conducted well results prowess shock address raise doubt prowess results equally prowess results raise doubt prowess shock address data multiple trials synthesized meta analysis negative study trump positive study similar quality rather results trials combined give overall estimate treatment effect given potential differences important unmeasured variables baseline sepsis change result approach seems wise however seems possible result point estimate favor drotrecogin placebo magnitude far smaller original trial probably longer statistically significant if combined estimate literature say non significant 2% 3% reduction mortality would interested confirming whether effect significant would normally depend cost one much larger confirmatory trial desire tolerate non fatal bleeding side effects resulting financial impact per patient cost effectiveness global increase spending adopting drug benefit confirmed such quandaries could formally estimated value information analysis valuable know answer greater certainty however decision taken hands eli lilly company doubt considered potentially large cost another trial fact regulatory agencies field critical care might skeptical threaten ability conduct another trial adopt results practice likelihood trial would negative taking factors together company presumably decided go forward risky whether action eli lilly company left drug could cut sepsis mortality 2% 3% table something likely never know we see details prowess -shock published coming weeks months first story reinvigorate drive complement clinical enrollment criteria biomarkers better select patients likely benefit given immunomodulating agent second ask community might done differently ? certainly greater engagement clinical trials would seem obvious first step huge part costs clinical trials take long time enroll tiny fraction patients severe sepsis our ability make wiser choices drugs would enhanced could conduct larger trials rapidly much time energy emotion devoted forming opinions prowess drotrecogin often strongly voiced opinions drug eli lilly company one hope decisions future drugs made environments richer data poorer opinion if believe role pharmacomanipulation critical illness partnership pharmaceutical industry prerequisite thus must think whether partnership works properly terms open efficient rapid rigorous science optimal benefit concerned especially patients address administration drotrecogin alfa activated early stage severe sepsis fda us food drug administration prowess protein c worldwide evaluation severe sepsis the author declares principal investigator grants received university pittsburgh eli lilly company conduct long term follow cost effectiveness studies accompanying prowess he also received consulting fees speaking honoraria eli lilly company 1996 2004 he received compensation eli lilly company serving data safety monitoring board prowess shock ( salt lake city ut usa also engaged sepsis research the author gratefully acknowledges shamly austin assistance generating data fda approval withdrawal rates discussed article | following the failure of prowess - shock to demonstrate efficacy , eli lilly and company withdrew drotrecogin alfa ( activated ) from the worldwide market .
drotrecogin was initially approved after the original trial , prowess , was stopped early for overwhelming efficacy .
these events prompt consideration of both the initial approval decision and the later decision to withdraw .
it is regrettable that the initial decision was made largely on a single trial that was stopped early .
however , the decision to approve was within the bounds of normal regulatory practice and was made by many approval bodies around the world .
furthermore , the overall withdrawal rate of approved drugs remains very low . the decision to withdraw was a voluntary decision by eli lilly and company and
likely reflected key business considerations .
drotrecogin does have important biologic effects , and it is probable that we do not know how best to select patients who would benefit .
overall , there may still be a small advantage to drotrecogin alfa , even used non - selectively , but the costs of determining such an effect with adequate certainty are likely prohibitive , and the point is now moot . in the future , we should consider ways to make clinical trials easier and quicker so that more information can be available in a timely manner when considering regulatory approval . at the same time
, more sophisticated selection of patients seems key if we are to most wisely test agents designed to manipulate the septic host response . |
mouse luecs immortalized polyoma middle antigen cultured mcdb131 medium gibco life technologies supplemented 20% fbs invitrogen 2 mm l glutamine lonza 1 mm na pyruvate gibco life technologies 100 g ml heparin sigma aldrich 50 g ml ec growth supplement ecgs obtained calf brain ecs seeded plates coated glutaraldehyde crosslinked gelatin cultured complete medium 4 days reach confluence total rna extracted 5 10 cells using rneasy mini kit qiagen following manufacturer instruction quality control rna samples performed using agilent bioanalyzer 2100 agilent technologies the rna three independent extractions processed cell line analysis a total 150 ng rna sample used rna quality check labeling hybridization mouse gene 1.0 st genechip array according manufacturer instructions affymetrix three independent biological replicates performed condition l1-transfected vs. mock transfected luecs we used robust multi array average rma normalized data a total 35,512 probesets loaded 819,041 pm probes used analysis next uploaded normalized data brb arraytools http://linus.nci.nih.gov/brb-arraytools.html run sam analysis http://www-stat.stanford.edu/~tibs/sam/ order identify differentially expressed genes upon l1 overexpression luec cells sam parameters analysis following number classes 2number probesets 35,512target proportion false discoveries q value 0.05delta value used identify significant probesets 1.24701fudge factor standard deviation computed 0.04825 number probesets 35,512 target proportion false discoveries q value 0.05 delta value used identify significant probesets 1.24701 fudge factor standard deviation computed 0.04825 conditions identified total 3409 significant probesets corresponding 2684 unique annotated genes fig 1 we selected probesets 1.5 fold change difference l1 vs. ctr resulted set 496 upregulated 743 downregulated probesets annotated corresponding 361 upregulated 580 downregulated unique genes referred
l1-ecs signature. next uploaded l1-ecs signature probeset level ingenuity pathway analysis software ipa http://www.ingenuity.com identify biological functions pathways putatively regulated l1 the mouse gene 1.0 st array reference set present ipa database used ipa core analysis only direct relationships mammals i.e. human mouse rat considered including endogenous chemicals gene network analysis the p values biofunction enrichment corrected multiple testing using benjamini hochberg correction settings identified 23 bio functions significantly enriched p value 0.05 benjiamini hochberg correction l1-overexpressing cells compared mock transfected cells considering massive changes transcriptional activity predicted effect variety biological functions upon l1 overexpression asked whether l1 could activate inhibit transcription factor(s tfs address question such analysis allows identification transcriptional regulators activated inhibited specific experimental conditions thus accounting observed gene expression changes strikingly identified total 18 11 tfs predicted activated inhibited l1 respectively note 5 tfs differentially regulated l1-overexpressing vs. mock transfected cells particular four activated tfs upregulated l1 overexpressing cells stat1 stat2 irf7 atf4 one inhibited tfs downregulated foxm1 we performed mechanistic networks analysis explore contribution tfs regulating gene networks we found stat1 stat2 irf7 atf4 stat3 among 18 tfs predicted activated interact fig
2 thus exerting coordinated control directional network 105 genes regulated l1 i.e. 11% l1-regulated genes most genes consistently up- downregulated expression change upstream tfs these findings supported functional studies implicated jak stat signaling pathway biological response luecs l1 overexpression mouse luecs immortalized polyoma middle antigen cultured mcdb131 medium gibco life technologies supplemented 20% fbs invitrogen 2 mm l glutamine lonza 1 mm na pyruvate gibco life technologies 100 g ml heparin sigma aldrich 50 g ml ec growth supplement ecgs obtained calf brain ecs seeded plates coated glutaraldehyde crosslinked gelatin cultured complete medium 4 days reach confluence total rna extracted 5 10 cells using rneasy mini kit qiagen following manufacturer instruction quality control rna samples performed using agilent bioanalyzer 2100 agilent technologies the rna three independent extractions processed cell line analysis a total 150 ng rna sample used rna quality check labeling hybridization mouse gene 1.0 st genechip array according manufacturer instructions affymetrix three independent biological replicates performed condition l1-transfected vs. mock transfected luecs we used robust multi array average rma normalized data a total 35,512 probesets loaded 819,041 pm probes used analysis next uploaded normalized data brb arraytools http://linus.nci.nih.gov/brb-arraytools.html run sam analysis http://www-stat.stanford.edu/~tibs/sam/ order identify differentially expressed genes upon l1 overexpression luec cells sam parameters analysis following number classes 2number probesets 35,512target proportion false discoveries q value 0.05delta value used identify significant probesets 1.24701fudge factor standard deviation computed 0.04825 number probesets 35,512 target proportion false discoveries q value 0.05 delta value used identify significant probesets 1.24701 fudge factor standard deviation computed 0.04825 conditions identified total 3409 significant probesets corresponding 2684 unique annotated genes fig 1 we selected probesets 1.5 fold change difference l1 vs. ctr resulted set 496 upregulated 743 downregulated probesets annotated corresponding 361 upregulated 580 downregulated unique genes referred
l1-ecs signature. next uploaded l1-ecs signature probeset level ingenuity pathway analysis software ipa http://www.ingenuity.com identify biological functions pathways putatively regulated l1 the mouse gene 1.0 st array reference set present ipa database used ipa core analysis direct relationships mammals i.e. human mouse rat ) the p values biofunction enrichment corrected multiple testing using benjamini hochberg correction settings identified 23 bio functions significantly enriched p value 0.05 benjiamini hochberg correction l1-overexpressing cells compared mock transfected cells considering massive changes transcriptional activity predicted effect variety biological functions upon l1 overexpression asked whether l1 could activate inhibit transcription factor(s tfs address question such analysis allows identification transcriptional regulators activated inhibited specific experimental conditions thus accounting observed gene expression changes strikingly identified total 18 11 tfs predicted activated inhibited l1 respectively note 5 tfs differentially regulated l1-overexpressing vs. mock transfected cells particular four activated tfs upregulated l1 overexpressing cells stat1 stat2 irf7 atf4 one inhibited tfs downregulated foxm1 we performed mechanistic networks analysis explore contribution tfs regulating gene networks we found stat1 stat2 irf7 atf4 stat3 among 18 tfs predicted activated interact fig
2 thus exerting coordinated control directional network 105 genes regulated l1 i.e. 11% l1-regulated genes most genes consistently up- downregulated expression change upstream tfs these findings supported functional studies implicated jak stat signaling pathway biological response luecs l1 overexpression here describe methods analysis used define characterize gene expression profile induced l1 murine lung endothelial cells luecs we used affymetrix mouse gene 1.0 st arrays enabled us produce gene expression data total 28,869 genes 764,885 distinct probes combined use significant analysis microarrays sam ingenuity pathway analysis ipa ) identified set 941 genes 23 bio functions significantly regulated l1-overexpressing vs. control luecs we reasoned massive transcriptional changes could result l1-mediated regulation tfs indeed using upstream modulator analysis ipa found 29 tfs predicted activated inhibited among 5 tfs transcriptionally regulated profiling experiment among 29 tfs identified many involved inflammatory and/or angiogenic cascades stat1 stat2 stat3 irf1 irf3 irf7 rela p65 nfkb1 atf4 note l1 causally linked nf-b signaling cancer cells first report crosstalk l1 stats irfs atf4 data therefore point l1 novel orchestrator cancer associated response entails regulation gene networks biochemical cascades turn impact pathophysiology cancer cells well tumor microenvironment importantly the results silico analysis successfully validated experimentally thus lending support biological relevance | we recently identified a novel role for the l1 transmembrane glycoprotein ( also known as l1cam or cd171 ) in the regulation of tumor angiogenesis and vessels stabilization .
l1 overexpression in cultured endothelial cells of the lung ( luecs ) exerted a pleiotropic effect in that it regulated proliferation , migration , tubulogenesis , vascular permeability , and endothelial - to - mesenchymal transition ( endmt ) .
in addition , we provided strong evidence that antibody - mediated targeting of l1 may be an effective strategy for vessel normalization with the potential to increase efficacy of chemotherapeutic agents.high-throughput microarray expression profile revealed that l1 modulates the expression of hundreds of genes mainly involved in cell cycle regulation , dna replication , cellular assembly , migration , development and organization . by using a pathway - oriented analysis strategy
we were able to identify a network of 105 genes modulated by l1 through the predicted activation of five transcription factors : stat1 , stat2 , stat3 , irf7 , and atf4 .
indeed , l1 overexpression resulted in the strong induction of stat3 phosphorylation which was abolished by antibody - mediated neutralization of il-6r. these results indicated that l1 promoted stat3 activation via the il-6/il-6r axis . |
transorbital intracranial injury rare may cause serious brain damage associated high mortality rate this type injury accounting 4.5% orbital pathology,[35 represents 0.04% head trauma 24% penetrating head trauma adults 45% children penetrating orbital injury may lead severe brain injury foreign object enters cranium leading orbital cerebral complications a foreign body penetrate brain orbit 3 ways via orbital roof superior orbital fissure optic canal the diagnosis confirmed entire partial foreign object found wound difficult make case trivial trauma we report case transorbital injury caused penetration metal bar entered cerebrum orbit a 13-year old male sustained injury right orbit resulting falling holding metal bar iron bar 3 cm 18 cm penetrated right orbit via medial canthus right infraorbital region driven skull admission unconscious normal vital signs his right eye protruded outside orbital cavity severely swollen bruised neurological examination deep coma glasgow coma score 4/15 e1m2v1 plain skull radiographs confirmed bar crossed skull right orbit left occipital bone figure 1 computed tomography ct demonstrated bar passing right orbit superior orbital fissure emerging left occipital bone fractured direct compaction association bar trajectory intracerebral hemorrhage specifically subarachnoid hemorrhage basal cisterns severe cerebral edema figure 2 the bar penetrated third ventricle suprasellar cistern adjacent right carotid artery branches dense hemorrhage observed within suprasellar cistern likely result injury right internal carotid artery angiography could performed patient rapidly worsened neurologically gcs 3 e1m1v1 lateral skull radiograph shows bar penetrating orbit emerging occipital bone computed tomography demonstrates bar trajectory sellar suprasellar region via superior orbital fissure the right internal carotid artery found lacerated right optic nerve optic chiasm transected near superior orbital fissure the bar penetrated superior orbital fissure anterior clinoid process suprasellar cistern third ventricle cerebrum incidentally metal bar fixed superior orbital fissure usually mobilized removed retracting carefully entry site direct visualization avoiding resistance leverage severe bleeding right internal carotid artery occurred despite maneuver carotid artery required ligation the patient died 10 days postoperatively due ischemic brain injury diencephalic injury intractable increased intracranial pressure brainstem herniation reports pens knives chopsticks due thin wall the orbit vulnerable structure cranium penetrating orbital injuries often associated traumatic brain injury the cranium violated via transorbital route superior orbital fissure optic canal the degree neurologic damage related orbital bone anatomy well size shape trajectory object intracranial penetration may occur orbital roof superior orbital fissure optic canal therefore medial canthal injuries associated severe visual loss strongly suggest optic canal damage the frequent site penetration orbital roof superior orbital plate frontal bone thin fragile this frequently leads frontal lobe contusion prognosis fairly good objects passing superior orbital fissure tend follow trajectory close internal carotid artery generally associated optic nerve orbital injuries the orbit pyramid like volume result penetrating objects directed towards apex pass superior orbital fissure optic canal our case example type injury penetrating injuries superior orbital fissure may affect cranial nerves iii iv v vi arteries circle willis carotid artery penetrating injuries caused high speed objects following trajectory perpendicular orbital wall result direct bone fractures vertically directed objects may pierce orbital roof cause damage frontal lobe horizontally penetrating objects may cause ethmoid bone posterior orbital wall fractures sufficient force the midline may violated damage contralateral structures penetrating objects directed medially superior orbital fissure optic canal sphenoid wing may damage temporal lobe cavernous sinus brain stem the frequent pattern injury 68% involves cavernous sinus temporal lobe brainstem low velocity injuries when penetrating object hits orbit small angle object follows path along wall orbit penetrating objects entering orbit close horizontal plane tend follow orbital funnel towards apex this mechanism differs seen orbital roof penetration objects traverse superior orbital fissure pass laterally along cavernous sinus toward temporal lobe case the iron bar penetrated orbit medial canthus followed posterior medial superior trajectory objects directed superiomedially within orbit usually affect superior orbital fissure optic canal sphenoid wing sella turcica passing across midline enter suprasellar cistern third ventricle causing serious damage neurovascular structures these types injuries associated severe brain damage due laceration central diencephalic neural structures major vessels therefore associated highest morbidity mortality rates the injury described report usually fatal prognosis penetrating orbitocranial injuries severity brain damage outcome depends velocity trajectory shape object rather type material however porous objects prone fragmentation provide good medium infection immediate complications transorbital penetrating trauma include intracerebral hematoma cerebral contusion intraventricular hemorrhage pneumocephalus cranial nerve damage severe permanent neurological damage brain stem injury cerebrovascular injury delayed complications include cerebrospinal fluid fistula pneumocephalus orbital cellulitis carotid cavernous sinus fistula central nervous system infections traumatic aneurysm delayed intracranial hemorrhage retained foreign objects cause severe infections meningitis brain abscess 50% the prognosis good absence direct injury brainstem laceration major intradural vessels patient ct necessary evaluate trajectory object intracranial structures involved predict possible complications however wooden objects always detectable plain radiographs making accurate evaluation difficult if injury caused chopstick chopstick removed patient evaluated physician potentially fatal complications occur magnetic resonance imaging mri superior ct detection small fragments wooden foreign bodies therefore cerebral angiography performed 2 3 weeks insult rule traumatic aneurysms identify major vascular injury timely fashion the transorbital transcranial approach chosen depending location foreign body removal foreign object debridement resection involved skull bones hematoma evacuation careful hemostasis along trajectory meticulous dural closure reduce cerebrospinal fluid leak mandatory prevent potentially fatal infectious complications vigorous debridement necessary associated increased disability mortality without clear advantage antiepileptic medications recommended early stages injury prevent seizures conclusion transorbital penetrating cranial injury metal bar rare may result potentially life threatening complications failure detect intracranial complications may lead serious neurological morbidity associated high mortality rate | transorbital intracranial injury is uncommon , representing 0.04% of penetrating head trauma with a high mortality rate .
orbital penetrating injuries may cause severe brain injury if the cranium is entered , typically via the orbital roof , the superior orbital fissure , or the optic canal .
a 13-year - old male sustained a severe brain injury due to penetration of the right orbit with an iron bar .
the bar entered the inferiomedial aspect of the orbit and emerged from the left occipital bone .
neurological examination revealed deep coma ( gcs : e1m2v1 ) with fixed , dilated , and non - reactive pupils .
the bar followed an intracranial trajectory , through the third ventricle and suprasellar cistern .
the patient underwent an immediate exploration with removal of the bar .
unfortunately , he died 10 days postoperatively due to severe diencephalic injury with brainstem herniation . in this case report
, we discuss the radiologic diagnosis and surgical management of transorbital orbitocranial injury by foreign body penetration . |
study subjects recruited consecutive manner glaucoma clinic patients examined february april 2010 asan medical center seoul korea initial evaluation subjects underwent complete ophthalmologic examination including recording medical ocular family histories visual acuity va testing humphrey field analyzer hfa swedish interactive threshold algorithm 24 2 full threshold test carl zeiss meditec multiple intraocular pressure measurements using goldmann applanation tonometry stereoscopic optic nerve photography cirrus oct all participants previously experienced several instances hfa testing minimize learning effect only final hfa test results used analysis current study inclusion participants meet following criteria best corrected visual acuity bcva 20 30 better spherical equivalent within 5 diopters cylinder correction within 3 presence normal anterior chamber open angle slit lamp gonioscopic examination reliable hfa test results false positive error 15% false negative error 15% fixation loss 20% patient ophthalmic disease could result hfa defects history diabetes mellitus excluded all participants glaucomatous optic discs confirmed agreed upon two glaucoma experts krs jhn glaucomatous visual field vf defects meeting least two following criteria present 1 cluster three points probability less 5% pattern deviation map least one hemifield including least one point probability less 1% cluster two points probability less 1% 2 glaucoma hemifield test results outside normal limits 3 pattern standard deviation less 5% cataract severity graded 0 1 2 according extent nuclear cortical subcapsular opacity all procedures conformed declaration helsinki study approved institutional review board asan medical center university ulsan seoul korea 3.0.0.50 uses spectral domain technology optic disc cube obtained three dimensional dataset composed 200 scans derived 200 b scans cover 6 6 mm area centered optic disc after creation rnfl thickness map cube dataset software automatically determines center disc extracts circumpapillary circle 1.73 mm radius dataset perform rnfl thickness measurements maculae scanned using macular cube mode data obtained three dimensional dataset composed 512 scans derived 128 b scans cover 6 6 mm area centered fovea the ss values macular optic disc mode images compared using paired test the relationship macular optic disc mode image ss assessed pearson correlation analysis clinical characteristics compared high- low ss patients imaged mode using mann whitney u test individual factors subjected univariate logistic regression analysis subsequently included multivariate analysis backward stepwise manner p value less 0.20 all p values two sided p 0.05 considered significant statistical analyses performed using spss ver 15.0 spss inc 3.0.0.50 uses spectral domain technology optic disc cube obtained three dimensional dataset composed 200 scans derived 200 b scans cover 6 6 mm area centered optic disc after creation rnfl thickness map cube dataset software automatically determines center disc extracts circumpapillary circle 1.73 mm radius dataset perform rnfl thickness measurements maculae scanned using macular cube mode data obtained three dimensional dataset composed 512 scans derived 128 b scans cover 6 6 mm area centered fovea the ss values macular optic disc mode images compared using paired test the relationship macular optic disc mode image ss assessed pearson correlation analysis clinical characteristics compared high- low ss patients imaged mode using mann whitney u test individual factors subjected univariate logistic regression analysis subsequently included multivariate analysis backward stepwise manner p value less 0.20 all p values two sided p 0.05 considered significant ninety two eyes 92 patients male 32 female 60 enrolled the mean age study participants 54.0 13.8 years average md value yielded vf testing -6.7 6.7 db table 1 ss significantly higher images obtained macular cube mode compared optic disc cube mode 7.8 1.3 vs. 6.9 1.1 respectively p 0.001 a comparison ss values yielded two modes showed statistically significant positive correlation mode r 0.581 p 0.001 fig 31 images classified low ss ss 7 whereas 61 high ss ss 7 however macular cube mode employed 16 76 eyes classified low- high ss groups respectively more patients classified high ss subjects macular cube mode employed compared designated optic disc cube mode used 82.6% vs. 66.3% respectively p 0.002 age va differed significantly high- low ss groups either optic disc macular cube mode employed optic disc mode age p 0.027 va p 0.012 macular cube mode age p 0.046 va p 0.014 use either mode patients high ss group younger better va low ss group however extent cataracts vf md significantly differ groups tables 2 3 upon univariate logistic regression analysis the extent cataracts associated ss optic disc cube mode used however significant factor emerged upon multivariate analysis table 4 macular cube mode no analyzed factor associated ss upon either univariate multivariate analysis table 5 oct recognized important diagnostic tool providing quantitative data rnfl macular thicknesses a critical feature oct imaging used glaucoma diagnosis reliability test results cheung et al emphasized importance high ss rnfl measured using oct also suggested ss value 7 essential guarantee reproducibility results stratus oct present study investigated factors associated image ss obtained cirrus oct moreno montanes et al reported cirrus oct afforded higher ss stratus oct although simple ss comparisons different oct instruments appropriate oct versions might vary approaches toward image processing data analysis remains possible cirrus oct may provide higher quality imaging image acquisition performed conditions using different instruments this cirrus oct uses line scanning ophthalmoscope fitted 750-nm superluminescent diode light source facilitates image alignment present study images obtained optic cube mode lower ss compared obtained employing macular cube mode the macula aligned along visual axis whereas optic disc located position nasal axis thus macular images obtained central fixation whereas optic disc image acquisition requires eccentric fixation it follows two structures tested conditions would easier retain central fixation rather defer eccentric fixation image acquisition moreover direction disc attachment respect orbit unusual may observed tilted disc lead reduction ss reflectance inconsistent subjects high ss group evaluated either oct mode younger better va imaging data obtained using stratus oct known influenced presence cataracts the results present work indicate extent cataracts differ high- low ss patient groups in addition patients present study relatively young mean age 54 years cataracts 90.2% mild grade 0 1 however logistic regression analysis showed extent cataracts significantly associated ss optic disc cube mode employed suggests scan quality may vary cataract density cirrus oct used case stratus oct employed meanwhile meaningful group difference noted macular cube mode used pupil size affect reproducibility quality images obtained oct exclude confounding effects pupil size obtained cirrus oct images pupil dilation patients mentioned all images obtained single experienced examiner may reflect real clinical situation however found difficult obtain high quality images optic disc cube mode employed compared macular cube mode used similar conditions further found age va extent cataracts seemed affect acquisition high ss images cirrus oct further work larger number patients needed verify effects extent type cataracts image quality impact ss glaucoma diagnosis | purposethe aim of this study was to investigate factors associated with the signal strengths ( ss , image quality scores ) of optic disc and macular images obtained using cirrus spectral domain optical coherence tomography ( oct).methodsninety - two glaucomatous eyes were imaged using the cirrus oct macular and optic disc cube modes after pupil dilation .
the influences of patient age , spherical equivalent , cataract presence , and cataract and glaucoma severity ( visual field mean deviation ) , on the ss of images obtained using the two cube modes were compared between patients whose images showed high ss ( ss 7 ) and low ss ( ss < 7).resultsthe signal strength was significantly higher in images obtained using the macular cube compared to the optic disc cube mode ( 7.8 1.3 vs. 6.9 1.1 , respectively ; p = 0.001 ) .
age and visual acuity of patients differed significantly between the high- and low - ss groups when data acquired using the optic disc ( p = 0.027 and 0.012 , respectively ) and macular cube modes ( p = 0.046 and 0.014 , respectively ) were analyzed .
when the optic disc cube mode was employed , the extent of cataracts was significantly related to ss , whereas when the macular cube mode was used , none of the factors analyzed was significantly associated with ss.conclusionsage , visual acuity , and the extent of cataracts were significantly associated with images of higher ss when the cirrus oct optic disc cube mode was employed . |
studies shown colonization denture inner surfaces yeasts causes oral systemic diseases11,23 particularly aged immunodepressed patients reduced salivary flow11,26 the mechanical removal debris use toothbrush dentifrice water popular cleansing technique used great part denture wearers7 although simple inexpensive effective method10,25 major disadvantage abrasive action could result wear denture base relining materials10,12 abrasion caused brushing acrylic resin denture bases polymerized different methods may result mass loss surface roughness loss surface polishing problems denture adaptation due loss surface details difficulty maintenance denture hygiene7,21,22,27 the critical threshold surface roughness bacterial adhesion 0.2 m30 acceptable mass loss acrylic resins still unknown the main components water detergent thickening agent specific coloring flavoring abrasive agents13,15 most vitro studies employ motor driven brushing machines order standardize time speed frequency brush strokes applied load amount dentifrice1928 the methods used measurement abrasion include mass loss luster changes surface roughness microscopic examination radiometric technique investigating abrasion resistance different denture resins together abrasiveness different dentifrices clinical interest help selecting appropriate materials methods denture cleansing significant damage denture base the aim study evaluate mass loss four commercially available heat polymerized acrylic resins simulated toothbrushing three different dentifrices the tested null hypothesis different denture resins dentifrices produce different mass loss toothbrushing the acrylic resins dentifrices used study presented tables 1 2 respectively plexiglas patterns 90x30x3 mm included investment flasks 6 jon jon paulo sp brazil allow reproduction specimens conventional dental procedures the acrylic resins mixed following manufacturer instructions inserted mold after polymerization specimens bench cooled room temperature removed mold thereafter carefully finished polished immersed water 37c 7 days use17 the specimens designed fit custom made metal plate brushing machine the specimens acrylic resins allocated 4 groups n=4 group 1 control specimens brushed distilled water group 2 specimens brushed dentifrice indicated natural teeth colgate groups 3 4 specimens brushed dentifrices specific complete dentures bonyplus dentu creme respectively prior simulated toothbrushing specimens removed water bath rinsed tap water cleaned 1 min ultrasonic bath deionized water containing 1% detergent limpol neutral bombril bernardo campo brazil dried absorbent paper weighed analytical balance accurate 0.1 mg 1 min metler toledo gmbh laboratory weighing technologies greifensee switzerland the specimens positioned specimen holder containing slurry bath mechanical cross brushing machine precision shop university paulo ribeiro preto paulo brazil equipped 6 soft nylon bristled toothbrushes tek soft johnson johnson way 6 specimens could brushed simultaneously the specimens subjected linear toothbrush abrasion movement rate 356 brush strokes forth back per minute totalizing 35,600 brush strokes specimen representative 2 years denture cleansing13 the machine set provide 200 g vertical load specimen 3.8 cm toothbrush trail brushing carried presence dentifrice distilled water slurry 2:1 w w placed slurry bath17 a stainless steel agitating fin fastened end brush ensure adequate mixing settling abrasive material would minimized brushing brushing the specimens removed specimen holder rinsed thoroughly blot dried soft absorbent paper mass loss due wear calculated difference mass specimen brushing the results mass loss subjected 2-way anova tukey test =0.05 examine influence materials groups
figure 1 shows means standard deviation sd mass loss mg tested acrylic resins toothbrushing the results anova presented table 3 according tukey test mass loss mg acrylic resins dentifrices resins qc-20 lucitone 550 showed greater mass reduction indicated lower abrasion resistance compared resins colgate abrasive dentifrice followed dentu creme bonyplus tables 4 5 d dentifrices r acrylic resins different letters indicate statistically significant difference p<0.05 since dentifrice toothbrush association one common methods oral hygiene promote good cleansing minimal damage teeth gingival tissues restorative prosthetic materials it thus important evaluate abrasion resistance brushing heat polymerized acrylic resins used fabrication denture bases the acrylic resin hardness type abrasive agent concentration dimension form abrasive particles toothbrush load applied different factors influence abrasion acrylic resin brushing4,7,12 colgate dentu creme dentifrices use calcium carbonate abrasive particles present study the results showed colgate significantly abrasive dentu creme table 4 reported freitas paranhos 2006)10 this previous study10 also showed microscopic analysis colgate abrasive particles presented irregular spherical form irregular size heterogeneous distribution dentu creme abrasive particles presented regular form small size homogeneous distribution this confirms importance abrasive agent particles form size distribution abrasive capacity dentifrices4,12 many variables must considered fabrication dentifrice cleansing polishing acrylic porosity hardness size surface configuration cleansing agent type compounds polishing used along cleansing agent hardness cleansing polishing agent20 some studies demonstrated importance dentifrice abrasiveness promoting efficient cleansing brushing water alone remove stains organic deposits dentures13,14 furthermore low abrasion dentifrices remove stains smoker dentures either22 a soft bristle toothbrush used present study cheap good quality therefore accessible patients brushing distilled water caused minimum mass reduction confirming results studies28 bonyplus abrasive particles results statistically similar control group each specimen subjected 35,600 brush strokes load applied brush head 200 g estimated equivalent 2 years manual brushing28 artificial brushing vigorous may abrasive manual brushing19 works shown similar results laboratory clinical experiments20,21 resin characteristics monomer polymer ratio presence cross linking agents mixture uniformity polymerization cycle cooling rate specimen thickness surface finishing may influence interaction specimens dentifrices mass reduction approved iso tc 106 1996)17 specification abrasion indicator simplest method producing values abrasion acrylic resins25 due experimental conditions study sexson phillips27 showed mass reduction obtained brushing rotating acrylic resin specimens similar produced specimens allowed remain stationary although microscopic examination revealed rotating specimens different surface topography hence surface roughness brightness loss would provide results valid study specimens remained stationary brushing procedure the specimens kept immersed dentifrice slurry 100 min water sorption could occur for reason specimens stored water 37c 7 days test order balance water sorption17 submitted cycles higher temperature heat polymerized acrylic resins shown produce specimens higher abrasion resistance2528 haselden et al.12 verified effects colgate dentu creme dentifrices differed according resins used ranking order unpredictable study hence ranking order acrylic resin brands qc-20 lucitone 550 resins showed greater mass reduction compared resins submitted brushing associated dentifrice table 5 an important question concerns clinical relevance abrasion produced dentifrices dentures facq volpe8 concluded abrasion dentifrices veneer crowns clinically insignificant murray et al.22 stated possible estimate twice daily brushing 2 min dentifrice containing calcium carbonate would result removal 25 resin surface per year therefore studies similar present one required determine impact wear produced dentifrices dentures vitro experiments are usually helpful compare relative effectiveness denture cleansers develop understanding acting mode denture cleanser23 in addition present study provides details concerning performance acrylic resins abrasive load based obtained results within limitations vitro study may concluded differences exist among heat polymerized acrylic resins concerning abrasion resistance dentifrices specific denture cleansing tend cause less damage acrylic resin surface | the association between a toothbrush and a dentifrice is the most used denture cleaning method .
the purpose of this study was to evaluate the abrasiveness of specific and non - specific denture cleaning dentifrices on different heat - polymerized acrylic resins .
sixteen specimens ( 90x30x3 mm ) of each acrylic resin ( qc-20 , lucitone 550 , clssico , vipi - cril ) were prepared and randomly assigned to 4 groups : 1 : control ( distilled water ) , 2 : colgate , 3 : bonyplus and 4 : dentu - creme .
the specimens were subjected to simulated toothbrushing in an automatic brushing machine using 35,600 brush strokes for each specimen .
brushing abrasion run at a 200-g load with the specimens immersed in 2:1 dentifrice / water slurry .
specimens were reconditioned to constant mass and the mass loss ( mg ) was evaluated .
data were analyzed by 2-way anova and tukey 's test ( =0.05 ) .
analysis of dentifrices ' abrasive particles was made by scanning electron microscopy .
colgate produced the greatest mass reduction ( 42.44 mg , p<0.05 ) , followed by dentu - creme ( 33.60 mg ) .
bonyplus was the less abrasive ( 19.91 mg ) , similar to the control group ( 19.69 mg ) ( p>0.05 ) .
the mass loss values indicated that qc-20 ( 33.13 mg ) and lucitone 550 ( 33.05 mg ) resins were less ( p<0.05 ) resistant to abrasion than clssico ( 26.04 mg ) and vipi - cril ( 23.43 mg ) . in conclusion
, colgate produced the greatest abrasion .
specific dentifrices for dentures tend to cause less damage to acrylic resins . |
dkk1 29 kda secreted protein belonging dickkopf dkk family comprises four main glycoproteins vertebrates dkk1 4 dkk1 identified potent inhibitor canonical wnt signaling due ability bind wnt coreceptor lrp5/6 thus blocking canonical wnt/-catenin pathway canonical wnt pathway activation initiated direct binding wnt glycoprotein frizzled fz membrane receptor lrp5/6 coreceptor 46 absence wnt wnt mediated assembly activated fz lrp5/6 receptor complex followed recruitment axin gsk3 plasma membrane resulting reduction phosphorylation degradation -catenin 9 10 stabilized -catenin accumulates cytoplasm translocates nucleus interacts dna bound tcf lef proteins activates transcription target genes the wnt pathway involved many stages invertebrate vertebrate development adult tissue homeostasis 8 12 dysfunction within wnt/-catenin signaling cascade associated many human pathologies 8 13 cancer 1417 bone disease 18 19 lrp5-activating mutations mainly associated high bone mass loss function mutations lrp5 linked bone degeneration osteoporosis 20 21 inhibition wnt signaling dkk1 related bone degeneration processes reduced bone mass central nervous system dkk1 associated pathophysiology neuronal degeneration alzheimer disease ad 2326 dkk1 expression increased cortical neurons exposed -amyloid peptide -ap aberrant expression responsible hyperphosphorylation tau neurons challenged -ap moreover increased dkk1 expression also observed degenerating neurons brain samples ad patients dkk1 shown neurotoxic locally infused brain regions neurodegenerative processes associated brain ischemia ad normally take place moreover dkk1 also associated neuronal death cellular animal models excitotoxic ischemic neuronal death treatment ischemic animals dkk1 antisense oligonucleotides protects hippocampal neurons ischemic damage cultured cortical neurons nmda toxicity reasons the dkk1-lrp6 interaction considered potentially interesting therapeutic intervention point dkk1 potential drug target treatment bone neurodegenerative disorders a small molecule nci8642 described inhibitor interaction dkk1 one receptors lrp5 well inhibitor dkk1 activity reducing wnt/-catenin signaling activation study sought characterise nci8642 activity using biochemical biophysical approaches extend characterization relation lrp6 given prominent expression brain lrp6 relevance neurodegenerative diseases field human embryonic kidney cells hek293 obtained german collection microorganisms cell cultures wnt3a all cell lines cultured dmem supplemented fbs glutamax gibco the monoclonal antibody -catenin obtained bd biosciences polyclonal goat anti dkk1 antibody r&d fluorescently conjugated secondary antibodies invitrogen the dna encoding full length human lrp6 sequence cloned pcdna3.1/zeo(+ expression vector invitrogen the dna encoding human dkk1 sequence cloned pcdna6.2/clumio dest invitrogen the sequence encoding secreted alkaline phosphatase clontech amplified pcr inserted c terminus dkk1 sequence pcdna6.2/clumio dest dkk1 plasmid the luciferase reporter plasmid p4tcf luc comprises four copies tcf responsive element upstream tata element luciferase coding sequence transcriptional unit all cell lines cultured dmem supplied 10% fbs 2 mm glutamax 100 units ml penicillin 100 g ml streptomycin appropriate selection antibiotic 50 100 g ml zeocine pc12-tcfluc hek293-lrp6 resp 10 g ml blasticidine hek293-dkk1 0.4 mg ml g418 wnt3a l cells 20 g ml hek293-ap dkk1 generation stable cell lines hek293 pc12 cells were transfected fugene 6 roche subjected antibiotic selection 24 hours transfection clones selected using immunofluorescence hek293-dkk1 hek293-lrp6 ap enzymatic assay culture medium hek293-ap dkk1 measurement luciferase activity upon stimulation wnt3a cm pc12-tcf luc for production dkk1 ap dkk1 conditioned media cm hek293 cells stably expressing appropriate construct seeded 150-cm flasks half confluence day after media collected 96 h seeding sterile filtered stored 20c aliquots the control conditioned optimem obtained way using parental hek293 cells for functional studies -catenin translocation tcf luc reporter assay wnt3a cm used 1 2 dilution each batch dkk1 cm functionally titrated order determine volume cm gives 50% inhibition wnt signaling dot blot analysis data shown the concentration dkk1 dkk1 cm estimated 1 g ml quantitative ap dkk1 binding assay ap dkk1 cm diluted obtain phosphatase activity 20 mu ml for immunofluorescence detection cell bound dkk1 lrp6 293 cells seeded onto poly lysine coated coverslips 24 hours experiment incubated dkk1 ap dkk1 cm diluted cell culture medium 2 hours 4c indicated 100 nci8642 1% dmso added alongside dkk1 cm after washing cells fixed 3% paraformaldehyde 15 min room temperature blocked pbs/0.1% bsa incubated primary goat anti dkk1 antibody fluorescent secondary antibody diluted blocking solution images collected using zeiss lsm 510 meta confocal microscope quantitative ap dkk1 binding assay the ap activity cell lysate measured attophos ap fluorescent substrate according manufacturer instructions spr performed using biacore t100 ge healthcare specified experiments conducted 25c kinetic constants calculated nonlinear fitting association dissociation curves according manufacturer instructions apparent equilibrium dissociation constants kd calculated ratio kd ka all immobilization steps performed flow rate 5 l min using hbs ep+ buffer 10 mm hepes buffer ph 7.4 containing 0.15 nacl 3 mm edta 0.05% v v p20 surfactant full length human lrp6-fc tagged r&d systems immobilized via amine coupling flow cell cm3 sensor chip 3000 resonance units rus measured end immobilization procedure for indirect capture lrp6 protein covalently coupled via amine immobilization cm3 chip lrp6-fc capture protein coated surface performed injecting protein 180 sec concentration 0.5 g ml hbs ep+ flow rate 10 l min control sensorgrams obtained empty flow cell coupling reaction conducted presence coupling buffer alone always subtracted binding responses this allowed subtraction nonspecific binding might generated residual charged negative groups neutralized coupling procedure bovine serum albumine bsa immobilized via standard amine coupling procedures flow cell cm3 sensor chip obtain nonrelated control flow cell binding kinetic assays dkk1 r&d systems diluted hbs ep+ concentration ranging 3 54 nm injected 180 sec flow rate 20 l min lrp6 either directly immobilized captured via protein described nci8642 binding kinetic assays compound diluted hbs ep+ buffer concentration ranging 3 50 injected lrp6 surface 60 sec flow rate 30 l min 0.2% dmso added hbs ep+ performing experiments nci8642 compound dmso correction module software used compensate refractive index change induced dmso inhibition analysis dkk1 54 nm diluted hbs ep+ buffer ph 7.4 incubated nci8642 concentration 5 20 1 hour 25c dkk1 injected immobilized lrp6 240 flow rate 10 l min pc12-tcf luc cells seeded density 100,000 cells well black walled clear bottom 96-well plates after 24 hours culture medium replaced 50 l dkk1 cm diluted appropriate optimem after one hour incubation 37c cells stimulated adding 50 l wnt3a cm 50% final volume supplemented either dmso nci8642 indicated final concentration final dmso concentration 1% after 24 hours incubation luciferase activity measured steady lite substrate perkin elmer according manufacturer instructions condition 3 l cells seeded black walled clear bottom 96-well plates density 10,000 cells well after 24 hours culture medium replaced 50 l dkk1 cm diluted appropriate optimem after one hour incubation 37c cells stimulated adding 50 l wnt3a cm supplemented either dmso nci8642 indicated final concentration final dmso concentration 1% after two hour stimulation 37c cells fixed 3% paraformaldehyde 10 min room temperature permeabilized ( 0.2% triton x-100 pbs 10 min room temperature blocked 0.1% bsa pbs the cells incubated 2 hours room temperature primary anti--catenin antibody 1 500 followed secondary alexafluor 555 goat anti mouse antibody 1 1000 the ratio nuclear cytoplasmic intensity -catenin staining calculated cell averaged within well nci8642 originally characterized inhibitor lrp5/dkk1 interaction order determine if nci8642 also able disrupt binding dkk1 lrp6 recombinant hek293 cell line stably expressing lrp6 generated hek293-lrp6 an additional recombinant hek293 cell line established production human recombinant dkk1 fused v5 tag c terminus hek293-dkk1 when conditioned medium cm containing dkk1 incubated cells expressing lrp6 cell bound dkk1 detected immunofluorescence strong membrane signal observed hek293-lrp6 cells figure 1(a panel b almost absent parental hek293 cells figure 1(a panel when dkk1 cm supplemented 100 nci8642 binding dkk1 figure 1(a panel reduced compared dmso treated control figure 1(a panel c order obtain quantitative measure dkk1/lrp6 interaction construct coding human dkk1 fused secreted domain alkaline phosphatase was generated ap dkk1 used establish stable hek293 cell line secreting ap dkk1 culture medium the ap tag c terminus impair dkk1 binding lrp6 shown immunofluorescence cell bound ap dkk1 hek293-lrp6 figure 1(a panels e f the binding ap dkk1 hek293-lrp6 quantified enzymatic ap assay reduced ap dkk1 incubated presence increasing concentrations nci8642 the binding dkk1 reduced concentration dependent manner compared dmso sample figure 1(b the calculated ic50 14.6 pic50 4.8 stdev 0.2 n 10 independent experiments when flowed surface sensor chip coated recombinant lrp6-fc dkk1 bound immobilized receptor specifically concentration dependent manner figure 2(a kon 5.3 10 koff 1.8 10 indirect capturing lrp6-fc recombinant protein direct lrp6-fc covalent coupling via amine groups produced similar interaction recombinant human dkk1 kd 8.4 3.5 10 resp demonstrating covalent coupling receptor chip surface influence binding site the interaction constants obtained agreement literature data 1 34 35 the lrp6-dkk1 interaction also verified using recombinant dkk1 cm instead commercial recombinant dkk1 figure 2(b when investigated whether nci8642 able bind lrp6 receptor observed consistent effective binding signal present control flow cell the kinetic analysis interaction injection nci8642 dilution series 3 50 figure 2(c allowed determination kd 4.7 10 nci8642 lrp6 we also analyzed effect nci8642 binding dkk1 lrp6 determine whether compound could interfere interaction dkk1 lrp6 we injected dkk1 nci8642 lrp6 previously immobilized dkk1 injected together nci8642 1-hour incubation 25c observed consistent reduction dkk1 binding lrp6 5 10 compound even complete binding inhibition concentration 20 figures 2(d 2(e)-upper panel contrary sequential injections 20 nci8642 54 nm dkk1 inhibit dkk1-lrp6 interaction nci8642 able displace dkk1 injected dkk1 could still bind lrp6 injected nci8642 concentration 20 figure 2(e)-middle lower panels investigate functional activity nci8642 tested compound tcf reporter based assay pc12 cells neural crest derived rat pheochromocytoma cells tcf similarly lef-1 downstream target transcription factor canonical wnt signaling pathway a stable pc12 cell line expressing tcf dependent luciferase reporter established pc12-tcf luc wnt3a mediated response reverted dkk1 cm concentration dependent manner figure 3(a for purpose compound testing dilution factor dkk1 cm chosen order 50% inhibition wnt signaling figure 3(b open symbols presence exogenously added dkk1 the effect concentration dependent reproducibly significantly different dmso treatment 25 50 although higher concentrations compound toxic cells ic50 value could therefore calculated nci8642 also tested assay measuring modulation -catenin intracellular accumulation nuclear translocation the assay performed l cells established model system studying wnt signaling upon treatment l cells wnt3a cm intracellular amount -catenin increases enrichment nuclear compartment concomitant increase nuclear cytoplasmic ratio -catenin intensity sample treated control cm -catenin hardly detectable nuclear cytoplasmic ratio close one the wnt3a mediated effect reverted dkk1 cm concentration dependent manner figures 4(a 4(b nci8642 added cells together dkk1 cells stimulated wnt3a the measured ic50 compound 12.6 pic50 4.9 stdev 0.2 n 5 independent measurements good agreement binding data reporter assay figures 5(a 5(b nci8642 small molecule recently identified specific inhibitor lrp5-dkk1 interaction given role wnt signaling many pathophysiological contexts modulation wnt pathway become valuable target drug discovery the modulation pathway level cell surface poses problem targeting protein protein interaction might challenging recently lrp5-dkk1 interaction targeted monoclonal anti dkk1 antibodies 39 40 these antibodies effective increasing bone density vivo nave normal growing female mice model postmenopausal osteoporosis however lack blood brain penetration antibodies limits application peripheral indications osteoporosis contrary small molecule blocking dkk1 inhibition would advantage potentially useful also treatment cns pathologies neurodegeneration our study confirmed nci8642 acts dkk1 inhibitor extended finding interaction dkk1 lrp6 in fact small molecule caused displacement dkk1 lrp6 overexpressed hek293 cells shown immunofluorescence quantitative enzymatic assay the displacement also demonstrated cell free context using spr technology nci8642 blocks binding dkk1 immobilized lrp6 interestingly compound able block dkk1 binding injected together dkk1 injected sequentially dkk1 probably due high affinity dkk1 lrp6 compared micromolar affinity nci8642 lpr6 figures 2(c 2(e spr technology also showed nci8642 interacts immobilized lrp6 reproducible concentration dependent binding absence dkk1 kd 4.7 10 the interaction nci8642-lrp6 highly specific significant binding observed two control flow cells when immobilized sensor chip dkk1 lost ability bind lrp6 suggesting immobilization caused modification dkk1 structure function thus direct interaction nci8642 dkk1 measured nci8642 also functionally active inhibition dkk1 activity wnt signaling mediated lrp5/6 demonstrated tcf luc -catenin assays two different cellular backgrounds the compound ic50 measured tcf luc -catenin assays lrp5/6 expressed endogenous physiological levels comparable one obtained binding assay overexpressed lrp6 tcf luc assay observed slight increase wnt3a mediated activation reporter gene even absence dkk1 the hypothesis could due presence endogenous dkk1 cells confirmed since could detect western blot quantitative rt pcr data shown nevertheless observed -catenin translocation assay data shown suggesting could artifact reporter assay cell line specific effect although nci8642 reported dkk1/lrp5 inhibitor data suggest also effective dkk1/lrp6 interaction in fact nci8642 blocked dkk1 binding lrp6 lrp6 overexpressing cells spr analysis this also confirmed functional studies since lrp6 lrp5 expressed pc12-tcf luc cell line lrp6 mrna concentration 7 times lrp5 l cells assessed qpcr data shown our results suggest possible antagonize dkk1-lrp6 interaction small molecule leads enhancement wnt signaling pathway although nci8642 micromolar potency might low application vivo experiments compound considered reference small molecule drug development aiming inhibition therapeutically important protein protein interaction |
background .
dkk1 antagonizes canonical wnt signalling through high - affinity binding to lrp5/6 , an essential component of the wnt receptor complex responsible for mediating downstream canonical wnt signalling .
dkk1 overexpression is known for its pathological implications in osteoporosis , cancer , and neurodegeneration , suggesting the interaction with lrp5/6 as a potential therapeutic target .
results .
we show that the small - molecule nci8642 can efficiently displace dkk1 from lrp6 and block dkk1 inhibitory activity on canonical wnt signalling , as shown in binding and cellular assays , respectively .
we further characterize nci8642 binding activity on lrp6 by surface plasmon resonance ( spr ) technology .
conclusions .
this study demonstrates that the dkk1-lrp6 interaction can be the target of small molecules and unlocks the possibility of new therapeutic tools for diseases associated with dkk1 dysregulation . |
typically improves weeks months stroke yet 50% patients left long term residual deficits few studies documented possibility treatment induced improvements post stroke language functions 12 months traditionally aphasia interventions utilize compensatory communication strategies assist participant immediate communication needs multi modal strategies include gesturing writing drawing augmentative low- high technology systems common expectation use alternative communication techniques decrease naturally language capabilities increase these interventions improve overall communication abilities questions asked whether contribute recovery language function whether actually contribute learned non use phenomenon counteract possibility learned non use therapies utilizing restraint developed mirror constraint induced motor therapies relatively easy restrain unaffected extremity motor therapies restraining attempts communicate non verbally difficult constraint induced aphasia therapy ciat encourages intensive verbal practice supported verbal cuing excluding use previously habitual compensatory strategies ciat the theoretical model taub motor system use dependent cortical organization applied language based program model postulated behavior attempting speak without success leads communication frustration this results fewer speaking attempts reliance compensatory strategies less cortical stimulation language areas the ciat framework provides structured supportive environment clinician guidance shaping positive reinforcement group members social interaction opportunities the theory supportive environment speaking opportunities encourage verbal attempts stimulate cortical reorganization thus goal present study provide evidence potential efficacy ciat compared intervention patients chronic 1 year post stroke aphasia more specifically randomized controlled blinded pilot study conducted order estimate effect sizes allowing design appropriately powered trial subjects recruited institutional review board approved study word mouth among stroke aphasia clinics university cincinnati university alabama birmingham local aphasia support groups we also listed study www.clinicaltrials.gov registered nct00843427 pi szaflarski several contacts received directly patients providing consent screening the inclusion criteria chronic aphasia related single ischemic stroke left middle cerebral artery lmca distribution i.e. diagnosis single lmca stroke confirmed medical record review including admission notes incident stroke results brain imaging obtained prior enrollment token test impaired range score 40 pre stroke fluency english the exclusion criteria history degenerative e.g. dementia parkinson disease metabolic disorder e.g. encephalopathy supervening illness e.g. brain tumor cancer history severe depression mental illness positive pregnancy test women childbearing age five potential participants excluded interview format goals ciat program all patients indicated understanding goals program prior signing informed consent also understood may randomized intervention group follow testing need performed of 27 offered participation 3 excluded randomization 2 normal token test 1 hospitalized reasons unrelated study fourteen subjects randomized receive ciat 34 participants per group 4 groups assembled 10 receive intervention figure 1 demographic clinical data participants provided table 1 obtaining informed consent initially screened patients presence aphasia token test tt categorized severity aphasia mild tt=40 37 moderate tt=36 17 severe tt=16 0 responders defined patients least 20% relative improvement least 2 5 primary scores 2-week period retainers patients whose 12-week score less 2-week score least 2 5 outcome measures the 2-week ciat protocol closely monitored individualized program embedded within larger group activity ensure consistency intervention training approximately 46 hours conducted alb prior initiating intervention session including basic theory learned non use procedures treatment clinicians also viewed sample videos exemplified nature set ciat intervention taught hierarchy cues ranged least supportive e.g. imitation verbal reminder first day intervention clinicians information participants abilities design participate initial evaluations the measures administered coordinators blinded group assignment figure 1 enhance chance successful implementation cues ciat sessions clinicians maintained cuing tracking form described interaction another clinician participant partners the types cues provided tracked binary notation whether cuing resulted successful communication this technique behaviorally monitoring another clinician rather self monitoring established previous study clinicians participants rotated day session order provide balance communication partners end day 1 alb studied cuing tracking forms videos create individual treatment plan next day session the treatment plan included identifying individual baseline linguistic strengths suggested hierarchy beneficial cues behaviors constrain specific linguistic targets goals the treatment plan reviewed clinicians second day therapy second day onwards clinicians promoted individualized support cues linguistic level suitable person continued data tracking each day clinicians reviewed individual program levels made adjustments needed beginning session day clinicians reminded participant goals constraints established for example participant strong producing nouns limited verbs goal add verb create 2-word phrase if participant demonstrated milder aphasia level hierarchy sentences implemented the treatment program 34 participant groups lasted 2 weeks direct therapy 4 hours per day 10 consecutive weekdays the sessions organized 4 45-minute periods 1015 minute break session socialization clients clinicians was encouraged throughout program even break periods beginning session participants dealt cards instructed play go fish type game cards provided opportunity participants interact ongoing game engaged participants visual attention memory skills although specifically targeted the cards provided visual stimuli line drawings nouns singular plural elicit numbers colors photos action verbs clinicians encouraged use redirecting phrases try sure rather using negative responses participants responded positively communicative exchange successful clinicians instructed correct communicative success important sentence accuracy whenever clinicians observed manage cards participant discouraged clinicians trained supportive encouraging independence consistent current standards care intervention group receive specific treatment participants asked continue previous activities usual all participants asked take part intervention involvement study complied patients randomized study statistician cjl patients received pre requisite activities consenting clinical record review neuropsychological aphasia testing nat patients assigned receive either 2 weeks ciat intervention undergo nat within one week 3 months ciat completion figure 2 consort diagram we used simple scheme randomized block patients either ciat control randomization occurred consent statistician blinded participant performance screening baseline testing we replace subjects complete full 2 weeks therapy after randomization sealed study charts containing pre intervention testing results nat funneled study biostatistician cjl therapists therapists set intervention groups coordinators cb anm collected nat data throughout study remained blinded group assignment participants asked reveal group assignment coordinators post treatment interactions all participants received nat included 1 boston naming test bnt 2 controlled oral word association test 3 semantic fluency test sft 4 complex ideation subtest boston diagnostic aphasia examination bdae 5 peabody picture vocabulary test iii ppvt iii 6 mini communicative activities log mini cal subjective measure communicative abilities the study coordinators extensively trained use measures blinded group assignment administered nat measures within 1 week prior ciat first week twelfth week following ciat completion all data entered redcap research electronic data capture subsequent analysis one patient complete 12 week visit testing 7 additional patients missing least 1 nat score the primary analysis used independent samples tests examine differences nat scores time point intervention control groups effect sizes 95% confidence intervals calculated the secondary analysis ad hoc analysis comparing characteristics patients demonstrated response change nat scores patients independent tests mann whitney u test fisher exact test used compare patient characteristics patients demonstrated response change patients all statistical analyses conducted using spss 22.0 ibm corporation armonk ny r 2.15.3 base package subjects recruited institutional review board approved study word mouth among stroke aphasia clinics university cincinnati university alabama birmingham local aphasia support groups we also listed study www.clinicaltrials.gov registered nct00843427 pi szaflarski several contacts received directly patients providing consent screening the inclusion criteria chronic aphasia related single ischemic stroke left middle cerebral artery lmca distribution i.e. diagnosis single lmca stroke confirmed medical record review including admission notes incident stroke results brain imaging obtained prior enrollment token test impaired range score 40 pre stroke fluency english the exclusion criteria history degenerative e.g. dementia parkinson disease metabolic disorder e.g. encephalopathy supervening illness e.g. brain tumor cancer history severe depression mental illness positive pregnancy test women childbearing age five potential participants excluded interview format goals ciat program all patients indicated understanding goals program prior signing informed consent also understood may randomized intervention group follow testing need performed of 27 offered participation 3 excluded randomization 2 normal token test 1 hospitalized reasons unrelated study fourteen subjects randomized receive ciat 34 participants per group 4 groups assembled 10 receive intervention figure 1 after obtaining informed consent initially screened patients presence aphasia token test tt categorized severity aphasia mild tt=40 37 moderate tt=36 17 severe tt=16 0 responders defined patients least 20% relative improvement least 2 5 primary scores 2-week period retainers patients whose 12-week score less 2-week score least 2 5 outcome measures the 2-week ciat protocol closely monitored individualized program embedded within larger group activity ensure consistency intervention clinicians completed training program training approximately 46 hours conducted alb prior initiating intervention session including basic theory learned non use procedures treatment clinicians also viewed sample videos exemplified nature set ciat intervention taught hierarchy cues ranged least supportive e.g. imitation verbal reminder first day intervention clinicians information participants abilities design participate initial evaluations the measures administered coordinators blinded group assignment figure 1 enhance chance successful implementation cues ciat sessions clinicians maintained cuing tracking form described interaction another clinician participant partners the types cues provided tracked binary notation whether cuing resulted successful communication this technique behaviorally monitoring another clinician rather self monitoring established previous study clinicians participants rotated day session order provide balance communication partners end day 1 alb studied cuing tracking forms videos create individual treatment plan next day session the treatment plan included identifying individual baseline linguistic strengths suggested hierarchy beneficial cues behaviors constrain specific linguistic targets goals the treatment plan reviewed clinicians second day therapy second day onwards clinicians promoted individualized support cues linguistic level suitable person continued data tracking the tracking provided constant reminders provide cues resulted successful communication day clinicians reviewed individual program levels made adjustments needed beginning session day clinicians reminded participant goals constraints established for example participant strong producing nouns limited verbs goal add verb create 2-word phrase if participant demonstrated milder aphasia level hierarchy sentences implemented the treatment program 34 participant groups lasted 2 weeks direct therapy 4 hours per day 10 consecutive weekdays the sessions organized 4 45-minute periods 1015 minute break session socialization clients clinicians encouraged throughout program even break periods beginning session participants dealt cards instructed play go fish type game cards provided opportunity participants interact ongoing game engaged participants visual attention memory skills although specifically targeted the cards provided visual stimuli line drawings nouns singular plural elicit numbers colors photos action verbs clinicians encouraged use redirecting phrases try sure rather using negative responses participants responded positively communicative exchange successful clinicians instructed correct communicative success important sentence accuracy whenever clinicians observed manage cards participant this consistent current standards care intervention group receive specific treatment participants asked continue previous activities usual all participants asked take part intervention involvement study complied patients randomized study statistician cjl patients received pre requisite activities consenting clinical record review neuropsychological aphasia testing nat patients assigned receive either 2 weeks ciat intervention undergo nat within one week 3 months ciat completion figure 2 consort diagram we used simple scheme randomized block patients either ciat control randomization occurred consent statistician blinded participant performance screening baseline testing we replace subjects complete full 2 weeks therapy after randomization sealed study charts containing pre intervention testing results nat funneled study biostatistician cjl therapists therapists set intervention groups coordinators cb anm collected nat data throughout study remained blinded group assignment participants asked reveal group assignment coordinators post treatment interactions all participants received nat included 1 boston naming test bnt 2 controlled oral word association test 3 semantic fluency test sft 4 complex ideation subtest boston diagnostic aphasia examination bdae 5 peabody picture vocabulary test iii ppvt iii 6 mini communicative activities log mini cal subjective measure communicative abilities the study coordinators extensively trained use measures blinded group assignment administered nat measures within 1 week prior ciat first week twelfth week following ciat completion all data entered redcap research electronic data capture subsequent analysis one patient complete 12 week visit testing 7 additional patients missing least 1 nat score missing scores left missing excluded analysis primary analysis used independent samples tests examine differences nat scores time point intervention control groups effect sizes 95% confidence intervals the secondary analysis ad hoc analysis comparing characteristics patients demonstrated response change nat scores patients independent tests mann whitney u test fisher exact test used compare patient characteristics patients demonstrated response change patients all statistical analyses conducted using spss 22.0 ibm corporation armonk ny r 2.15.3 base package there 24 patients enrolled study 14 intervention group 10 control group see consort diagram two patients intervention group complete study 1 due lack transportation 1 due hospitalization illness unrelated study overall significant differences demographic characteristics past medical history 2 groups table 1 the mean age 57 sd11 years intervention group 51 sd13 years control group most patients caucasian 10/14 71% intervention group 9/10 90% control group there statistically significant differences nat scores intervention control groups table 2 specifically differences observed subjective communication abilities assessed mini cal patients received ciat scored higher mini cal 12 weeks intervention compared control group mean 31 vs. 23 difference=8 95% ci 1.3 13.5 p=0.019 the sft marginally higher 2 weeks intervention ciat patients controls mean 21 vs. 12 difference 9 95% ci 0.3 17.8 p=0.058 overall 5/24 21% participants could classified responders defined methods section responders less likely history hypertension 0/5 0% compared non responders 10/14 53% p=0.053 of 5 patients demonstrated change nat scores course study 1 20% retained change twelve week visit there 24 patients enrolled study 14 intervention group 10 control group see consort diagram two patients intervention group complete study 1 due lack transportation 1 due hospitalization illness unrelated study overall significant differences demographic characteristics past medical history 2 groups table 1 the mean age 57 sd11 years intervention group 51 sd13 years control group most patients caucasian 10/14 71% intervention group 9/10 90% control group there statistically significant differences nat scores intervention control groups table 2 specifically differences observed subjective communication abilities assessed mini cal patients received ciat scored higher mini cal 12 weeks intervention compared control group mean 31 vs. 23 difference=8 95% ci 1.3 13.5 p=0.019 the sft marginally higher 2 weeks intervention ciat patients controls mean 21 vs. 12 difference 9 95% ci 0.3 17.8 p=0.058 responders less likely history hypertension 0/5 0% compared non responders 10/14 53% p=0.053 of 5 patients demonstrated change nat scores course study 1 20% retained change twelve week visit in prospective preliminary randomized blinded study patients chronic post stroke aphasia estimated effect ciat linguistic performance results largely statistically significant points need discussed first study included patients highly variable levels post stroke aphasia making comparisons groups somewhat difficult second observed effects consistent improvement ciat group beyond control group trends towards statistical significance variables even small sample defining responder participant 20% improvement least 2 5 tests number needed show significant group differences would 62 allows design comprehensive trial finally significant improvement noted mini cal results ciat group compared controls this indicates least subjectively patients ciat group perceived improvement time participants control group reasons participants perception improvement measured mini cal may related social activity therapy sessions order isolate variable social interaction ciat theory future studies consider including study arm involving exposure social interaction duration frequency ciat group without ciat intervention social factors may related clinicians participants group date reports potential efficacy ciat published five studies patients chronic aphasia included treatment group control group 8,2225 original study were participants randomized treatment group however unlike current study personnel collecting linguistic data blinded treatment assignment studies original study in 4 studies ciat compared treatment approaches either model based aphasia therapy training based functional deficit ciat plus written module pace model oriented aphasia therapy moat in addition studies recent study compared modified ciat conventional aphasia therapy patients less 4 months subacute since incident ischemic hemorrhagic stroke all studies showed participants receiving treatment improved linguistic performance group differences minimal thus comparing results original study pulvermuller et al results subsequent studies including questions training intensity social interactions participants participants clinicians need considered contribute improved communicative abilities via increased verbal communication practice we show statistically significant improvement objective tests linguistic performance treatment one reasons lack statistical significance small sample size high variability language scores observed groups figure 3 a future study enrolling highly variable group participants would require sample size 62 per treatment group show significant advantage ciat passive observation but effects observed us line results original study pulvermuller et al we identified important considerations study design minimize unnecessary variability maximize potential observing treatment benefit treatment fidelity needs monitored either via independent reviewers performing video direct review conducted sessions a transfer package similar offered motor rehabilitation studies need developed applied group also outcome measures include measures pre- post intervention discourse assess changes severity aphasia using e.g. western aphasia battery revised assessing linguistic complexity using mean length utterances indices syntactic form in addition stratification severity education socioeconomic status might emphasize magnitude improvement relative degree aphasia finally factors including effects lesion size location changes aphasia diagnosis type therapy session assessed modest improvements noted ciat group collected objective tests noted control group forming basis estimating effect sizes needed comprehensive study moreover ciat group reported significant subjective improvement confirms importance approach larger randomized controlled trials adopt measures suggested reduce variability maximize observable benefit warranted | backgroundfew studies have documented the possibility of treatment - induced improvements in language functions 12 months or longer after stroke .
the purpose of the current study was to provide a preliminary estimate of efficacy of constraint - induced aphasia therapy ( ciat ) when compared to no - intervention in patients with chronic ( > 1 year ) post - stroke aphasia in order to provide the data needed to design an appropriately powered trial.material/methodsthis was a randomized , controlled , single - blinded , pilot trial .
we identified 32 patients with chronic post - stroke aphasia .
of these , 27 were offered participation , and 24 were randomized ( consort diagram ) : 14 to ciat and to 10 to no - intervention .
ciat groups received up to 4 hours / day of intervention for 10 consecutive business days ( 40 hours of therapy ) .
outcomes were assessed within 1 week of intervention and at 1 and 12 weeks after intervention and included several linguistic measures and a measure of overall subjective communication abilities ( mini - communicative abilities log ( mini - cal ) ) . to maintain blinding
, clinicians treating patients ( ciat group ) did not communicate with other team members and the testing team members were blinded to treatment group assignment.resultsoverall , the results of this pilot trial support the results of previous observational studies that ciat may lead to improvements in linguistic abilities . at 12 weeks , the treatment group reported better subjective communication abilities ( mini - cal ) than the no - intervention group ( p=0.019 ) .
other measures trended towards better performance in the ciat group.conclusionsin this randomized , controlled , and blinded pilot study , intensive language therapy ( ciat ) led to an improvement in subjective language abilities .
the effects demonstrated allow the design of a definitive trial of ciat in patients with a variety of post - stroke aphasia types .
in addition , our experiences have identified important considerations for designing subsequent trial(s ) of ciat or other interventions for post - stroke aphasia . |
case unusual patient known case recurrent patellar dislocation presented atraumatic locked vertically rotated patellar dislocation this type presentation never reported literature best knowledge a 14-year old healthy male child previous history recurrent lateral dislocation patella presented accident emergency department complaints inability walk bear weight left lower limb spontaneously dislocated patella running uneven ground radiographs revealed laterally displaced vertically rotated patella along long axis medial patellar edge locked dipping lateral gutter open reduction performed along lateral patellar retinacular release medial patellar retinaculum plication achieve satisfactory patellar stability patellofemoral tracking we would recommend settings patella vertically dislocated locked open reduction would management choice types dislocations difficult relocate closed reduction open reduction yields better outcomes also allows surgeon perform patellar realignment procedures order prevent patellar dislocations cases prior patellar instability a case locked patellar dislocation vertical axis rotation first described literature cooper 1844 since handful cases condition intra articular patellar dislocations superior inferior horizontal vertical locked vertical dislocation patella is rare entity poses therapeutic challenge closed reduction often requires general anaesthetic may require open procedure there published reports recurrent patellar instability culminating vertically rotated locked patellar dislocation we report unusual case lateral recurrent dislocation patella 14-year old healthy child presented vertically rotated locked patella without history trauma required open reduction along proximal extensor apparatus realignment procedure a 14-year old healthy male child presented accident emergency department complaints inability walk bear weight left lower limb spontaneously dislocated patella running uneven ground upon inquiry patient gave history similar episode 10 months back following fall at time mother pushed patella back taken hospital radiographic images showed patella reduced associated fracture patella tibial tuberosity femoral condyles he given full length leg cast 1 month able resume daily activities without difficulty previous hospital records revealed history anterior knee pain positive apprehension sign indicating lateral patellar instability examination the knee markedly swollen obvious deformity lateral aspect form tenting skin soft tissue underlying patella without contusion bruise the knee locked 15 degrees flexion patient unable perform movements knee joint standard anteroposterior lateral plain radiographs taken showed laterally displaced vertically rotated patella along long axis medial patellar edge locked dipping lateral gutter fig 1 evidence associated fracture signs osteochondral damage clinical signs genu valgum patella alta tibial torsion trochlear dysplasia absent quadriceps q angle normal limb within normal range 11 degrees pre operative radiographs antero posterior lateral radiographs knee joint patient showing vertically rotated locked patellar dislocation lateral femoral gutter an attempt closed reduction made conscious sedation successful decision open reduction the patella found locked articular surface facing laterally medial edge patella locked past lateral femoral condyle wedged lateral gutter the medial patellar retinaculum found stretched attenuated tear defect noticed a small incision given along lateral retinaculum index finger inserted wedged medial patellar edge freed lateral femoral condyle time lifting patella lateral gutter relocated anatomical position stability tracking patella checked showed tight lateral retinaculum along lax medial retinaculum release lateral retinaculum done along medial patellar retinaculum plication using multiple interrupted prolene sutures fig intra operative image image obtained intraoperatively showing reduction patella lateral retinaculum release medial retinaculum plication post operative radiographs anter oposterior lateral radiographs knee joint patient showing relocated patella anatomical position quadriceps setting exercises active straight leg raising started second post operative week progressive active passive range motion exercises started 3 weeks full range motion achieved 7 weeks patient resumed sporting activities 6 months post operative recurrence symptoms time final follow 18 months lateral dislocation patella common entity adolescents whereas rotational dislocation patella involves rotation patella along horizontal vertical axis quite rare vertical dislocation the patella rotates along long axis articular surface patella facing laterally gets locked lateral gutter vertical patellar dislocations pose therapeutic challenge orthopaedic surgeons difficult reduce closed methods repeated attempts manipulation lead osteochondral fractures necessitates open methods reduce vertical dislocations most patellar dislocations seen direct blow medial aspect patella knee near extension due indirect force causing sudden contraction quadriceps muscles knee stretched valgus tight quadriceps act bow string prevents relocation pre disposing factors anatomical variations shallow inter condylar groove patellar hypermotility patella alta tibial torsion report review case lateral dislocation patella interest vertically rotated locked dislocation patella atraumatic i.e direct trauma patella individual history recurrent dislocation patella there clinical evidence medial patella femoral ligament tear radiological evidence trochlear dysplasia patella alta shallow inter condylar groove similar cases reported previously literature concomitant history trauma hackl et al reported locked dislocation bony avulsion medial structures fall corso et al reported lateral dislocation vertical rotation laterally directed blow patella wrestling gidden bell reported vertically rotated irreducible patella due medial border force femur result motor bike accident only handful cases reported literature history direct trauma gann nalty reported vertical patellar dislocation 10 year old girl without trauma michels et al reported locked patellar dislocation 16 year old girl dancing this case report rare sense history direct trauma preceding dislocation mode dislocation running uneven surface although literature review apparent types dislocations mainly traumatic result direct blow medial side knee assumed naturally medial attachments knee joint would torn circumstances nevertheless locked dislocated patella may occur atraumatic patients prior history dislocation without damage attachments along medial border provides major support preventing lateral dislocations surgery also found medial retinaculum stretched lax defect apparent tear lateral retinaculum found tight intra operative tracking patella abnormal following proximal patellar realignment procedure form medial retinacular plication lateral retinacular release patella found tracking well trochlear groove the tight lateral retinaculum lax medial patellofemoral ligament could related previous episodes recurrent patellar instability one episode lateral dislocation patella case hence would recommend settings patella vertically dislocated locked open reduction would management choice types dislocations difficult relocate closed reduction open reduction yields better outcomes also allows surgeon perform patellar realignment procedures order prevent patellar dislocations setting prior patellar instability open reduction avoids osteochondral damage associated repeated attempts closed reduction allows surgeon perform patellar realignment procedures order prevent patellar dislocations setting prior patellar instability | introduction : locked vertical patellar dislocations are rare and pose a therapeutic challenge .
this case is more unusual , as the patient was a known case of recurrent patellar dislocation and presented with an atraumatic locked and vertically rotated patellar dislocation .
this type of presentation has never been reported in literature to the best of our knowledge.case presentation : a 14-year - old healthy male child with previous history of recurrent lateral dislocation of patella presented to accident & emergency department with complaints of inability to walk or bear weight on his left lower limb after he spontaneously dislocated his patella while running on uneven ground .
radiographs revealed a laterally displaced and vertically rotated patella along its long axis with the medial patellar edge locked and dipping into the lateral gutter .
open reduction was performed along with lateral patellar retinacular release with medial patellar retinaculum plication , to achieve satisfactory patellar stability and patellofemoral tracking.conclusion:we would recommend that in the settings of patella being vertically dislocated and locked , open reduction would be the management of choice , as these types of dislocations are difficult to relocate by closed reduction .
repeated attempts of closed reduction may cause osteochondral damage .
open reduction not only yields better outcomes but also allows the surgeon to perform patellar realignment procedures in order to prevent further patellar dislocations in cases of prior patellar instability . |
use internet expanded incredibly across world last years the internet provides remote access others abundant information areas interest however maladaptive use internet resulted impairment individual psychological well academic failure reduced work performance especially leaded internet addiction disorder iad 14 iad first raised 1990s according beard definition iad individual addicted individual psychological state includes mental emotional states well scholastic occupational social interactions impaired overuse medium recent years iad become prevalent worldwide recognition devastating impact users society rapidly increased importantly recent studies found dysfunctions iad similar types addictive disorders substance abuse disorders pathological gambling 710 people experiencing iad showed clinical features craving withdrawal tolerance 7 8 increased impulsiveness impaired cognitive performance tasks involving risky decision making as similar abnormalities dopaminergic neural system individuals substance related addiction role dopaminergic neural system iad also elucidated researches 1214 recent study people iad found altered resting state glucose metabolism several brain regions including major dopamine projection areas striatum orbitofrontal region moreover another study found adolescents increased genetic polymorphisms genes coding dopamine d2 receptor dopamine degradation enzyme susceptible excessive internet gaming compared age matched cohort controls positron emission tomography pet ) imaging study reduced levels dopamine d2 receptor subdivisions striatum including bilateral dorsal caudate and right putamen found individuals iad taken together findings suggest iad may also partly due impaired dopaminergic neural systems similar substance related addiction dopamine transporter dat protein situated presynaptic terminal striatal dat responsible active dopamine reuptake presynaptic neuron plays critical role regulation striatal synaptic dopamine levels 1618 altered dat concentration striatum following chronic substance administration reported previously 1924 however whether abnormality dat also exists iad illustrated recent years imaging dat used important tool clinical settings display changes brain structure patients substance related addiction 2124 in addition radiotracer tc trodat-1 technetium-99 tc labeled tropane derivative technetium,2-[[2-[[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo 3 2 1]oct-2-yl]-methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)]-oxo-[1r-(exo exo)]- regarded safe suitable imaging agent monitoring dat status human imaging studies 21 25 26 present study used single photon emission tomography spect radiotracer tc trodat-1 investigate striatal dat density identify potential presynaptic abnormalities iad subjects compared age matched healthy controls this study aims test hypothesis altered availability dat associated pathogenesis iad iad assessed using young internet addiction diagnostic questionnaire iaddq goldberg internet addictive disorder diagnostic criteria iaddc all questions iaddq iaddc translated chinese eligible participants iad group responses eight questions iaddq satisfy three iaddc i.e. tolerance withdrawal craving unplanned use failure reduce use excessive use sacrificing social activities use physical psychological problems associated use
five men mean sd 20.40 2.30 years old iad randomly selected patients seeking treatment peking university shenzhen hospital the iad subjects used internet almost everyday spend 8 hours mean sd 10.20 1.48 hours everyday front monitor mostly chatting cyber friends playing online games watching online pornographies adult movies these subjects initially familiar internet mostly early stage adolescence mean age sd 12.80 1.92 years old indications iad 6 years mean sd 7.60 1.52 years nine age matched controls mean sd 20.44 1.13 years old recruited advertisement participated study no statistical difference found ages participants two groups p 0.96 the participants control group used internet occasionally frequently spent 5 hours day line mean sd 3.81 0.76 hours satisfy diagnosed criteria iad 4 27 all recruited participants native chinese speakers never used illegal substances sometimes participants smoked drink alcohol none meet diagnosis criteria substance related disorders history significant medical neurological psychiatric diseases right handed all participants gave written informed consent participation nature procedure fully explained including possible risks side effects all procedures study approved ethics committee peking university shenzhen hospital
trodat-1 ligand liquid supplied department chemistry beijing normal university beijing china the radiotracer tc trodat-1 740 mbq 20 mci purity 90% synthesized described previously and spect studies tc trodat-1 carried using siemens diacam e.cam icon double detector spect lower energy purpose collimator siemens erlangen germany subjects injected intravenously 740 mbq 20 mci tc trodat-1 the acquisition parameters included 64 views 18 per view 128 128 matrix 360 rotation 5.6 increments a butterworth filter applied order 15 cutoff 0.33 nyquist frequency photon attenuation correction performed using chang first order correction method using attenuation coefficient 0.15 cm regions interest rois drawn 12 transverse images pixels extracted counts whole brain bilateral corpus striatum carried the volume v weight w bilateral corpus striatum well ratio corpus striatum whole brain ra calculated using mathematical models described previous paper 21 31
data present paper presented means standard mean sd statistical program social sciences windows version 11 spss 13.0 spss inc chicago usa used analyze data differences groups assessed student test tests conducted criterion significance set p 0.05 the dat images bilateral corpus striatum control group showed panda eye shape dats distributed uniformly symmetrically corpus striatum the bilateral corpus striatum situated 812 layers shown figure 1(b however dat images iad subjects displayed different levels abnormity corpus stratums much smaller showed different shapes dumbbell thin strip lunate shape sporadic spot figure 1(a as shown figure 1 table 1 dat expression level striatum significantly decreased iad subjects briefly comparison controls significantly lower values v cm w g ra corpus striatum iad group suggesting decreased tc trodat-1 bound dat impairment well dysfunction corpus striatum occurred no statistical difference found comparing v w bilateral corpus striatum left side right side either iad group p 0.67 p 0.68 resp health control group p 0.10 p 0.11 resp iad resulted impaired individual psychological well academic failure reduced work performance especially among adolescents 14 however currently standardized treatment targeted iad develop effective methods intervention treatment iad first require establishing clear understanding underlying neurobiological mechanisms present study assessed dat expression level iad subjects healthy controls using tc trodat-1 spect we found dat expression level striatum significantly decreased values v w ra corpus striatum iad subjects greatly reduced the imaging results provided direct viewing proof altered availability dat brain people iad dats play critical role regulation striatal synaptic dopamine levels 1618 used markers dopamine terminals a reduced number cell membrane dats may possibly reflect pronounced striatal dopamine terminal loss brain dopaminergic function impairment found substance related addiction 2123 pet imaging studies found increased release dopamine striatum video game patients pathological gambling also demonstrated high level dopamine ventral striatum gambling increased extracellular dopamine striatum associated subjective descriptors reward high euphoria 11 35 individuals iad may also experience euphoria extracellular dopamine striatum increases however long time high concentrations dopamine shown cause selective lesion dopamine terminals 32 36 decreased size dopaminergic cell bodies taken together reduced dats found study may indicate neuropathologic damage dopaminergic neural system caused iad according knowledge this first imaging study examine abnormality dat brain iad subjects furthermore imaging results present study provide objective proofs long term maladaptive use internet might cause serious problems however complete interpretation results present study limitations noted firstly small sample size study may limit generalizability results positive associations study might due chance stratification effect sample collection studies independent samples larger population required secondly iad subjects present study reported different desired activities sitting front monitor including chatting cyber friends playing online games watching online pornographies adult movies etc our study determine whether different types internet behaviors may cause different brain dat changes therefore present study recognized exploratory primary research work done get definitive conclusion the results study provide evidence iad may induce significant dat losses brain findings suggest iad associated dysfunctions dopaminergic brain systems consistent previous reports various types addictions either without substances 2123 37 our findings support claim iad may share similar neurobiological abnormalities addictive disorders | in recent years , internet addiction disorder ( iad ) has become more prevalent worldwide and the recognition of its devastating impact on the users and society has rapidly increased . however , the neurobiological mechanism of iad has not bee fully expressed .
the present study was designed to determine if the striatal dopamine transporter ( dat ) levels measured by 99mtc - trodat-1 single photon emission computed tomography ( spect ) brain scans were altered in individuals with iad .
spect brain scans were acquired on 5 male iad subjects and 9 healthy age - matched controls . the volume ( v ) and weight ( w ) of bilateral corpus striatum as well as the 99mtc - trodat-1 uptake ratio of corpus striatum / the whole brain ( ra ) were calculated using mathematical models .
it was displayed that dat expression level of striatum was significantly decreased and the v , w , and ra were greatly reduced in the individuals with iad compared to controls .
taken together , these results suggest that iad may cause serious damages to the brain and the neuroimaging findings further illustrate iad is associated with dysfunctions in the dopaminergic brain systems .
our findings also support the claim that iad may share similar neurobiological abnormalities with other addictive disorders . |
compromised renal functions previous central nervous system cns disease shown predispose neurotoxicity we describe case acute transient encephalopathy patient treated ceftriaxonefor enteric fever infection the present case illustrates diagnostic challenges management rare potentially severe side effect one commonly prescribed parenteral antibiotics an eight year old male child presented history diarrhea high grade fever the child conscious cooperative well oriented time place persons the patient hospitalized started ceftriaxone 1 g iv daily intravenous fluids after three days treatment iv ceftriaxone child became afebrile showed altered mental status progressive apathy somnolence the patient referred dyanand medical college ludhiana punjab emergency department the patient acute distress fever hemodynamically stable dehydrated hb 12 g dl normal range 12 15 g dl hct 38% normal range 35.0 49.0% tlc 6 10/l l normal range 5 12 10/l l dlc n 62 normal range 6070% l 27% normal range 2040% plt 274 10/l l normal range 100 300 10/l urea 14 mg dl normal range 825 mg dl cr 0.6 mg dl normal range 0.51.7 mg dl na k 139/4 normal range 135147/ 3.55 meq dl urinalysis revealed bacteriuria pyuria tsb dsb 0.77/0 normal range 0.11.0/ 0.2 mg dl sgot pt 44/23 normal range 1147/ 753 iu l stoolr e 2d mri scan brain reveal acute stroke the patient neurological status improved three days later alert oriented the proposed mechanisms include decrease -amino butyric acid gaba)-mediated inhibition cephalosporin mediated release cytokines in fact cephalosporins may decrease gaba release nerve terminals increase excitatory amino acid release exert competitive antagonism gaba alternatively cephalosporin treatment proposed induce endotoxin release generates cytokines liberation tumor necrosis factor- proinflammatory cytokine implicated septic encephalopathy pre existing cns abnormalities indicated risk factor -lactams encephalopathy in this case patient presented enteric fever dehydration corrected intravenous fluids in fact temporal association encephalopathy induction resolution ceftriaxone administration withdrawal makes antibiotic highly likely responsible encephalopathy moreover temporal pattern accordance previous publications reporting cephalosporin neurotoxicity latency one ten days drug initiation regression neurological symptoms within two seven days following ceftriaxone treatment suspension could establish probable causal relationship ceftriaxone encephalopathy naranjo score 6 the severity assessment revealed adr moderate suggesting required therapeutic intervention hospitalization prolonged 1 day resolved 24 h change drug therapy specific treatment prevent outcome since patient history reaction due ceftriaxone adverse drug reaction unpreventable we describe case ceftriaxone induced acute reversible encephalopathy patient treated enteric fever infection early recognition complication particularly relevant discontinuation ceftriaxone reverts neurological syndrome | ceftriaxone is a commonly used , third - generation cephalosporin .
encephalopathy is a rare side effect of third- and fourth - generation cephalosporins .
renal failure and previous disease of the central nervous system predispose to this neurotoxicity .
we describe a case of acute transient encephalopathy in a patient treated with ceftriaxone for enteric fever infection .
early detection of this complication is relevant given that stopping the drug usually reverts the neurological syndrome . |
field medicine stress one common complaints among patients1 stress may negatively influence affective state
individual turn may exert direct adverse effects biological processes
behavioral patterns thereby increasing individual disease risk pathogenesis
disease2 psychosocial stress believed contribute musculoskeletal disorders neck
shoulders areas previous studies shown mental stress induces
significant increase muscle tension3
recently demonstrated motor units activated mental stress
physical stress means mental stress may also result low threshold motor
units remaining active breaks work outside work3 thus numerous therapeutic approaches used
treat musculoskeletal diseases caused psychological stress4,5,6 the utilization alternative medicine increasing recent years massage
documented one frequently treatments musculoskeletal disease7 manual lymph drainage mld procedure
consists several techniques derived traditional massage8 mld become increasingly popular recent years
least enormous amount publicity recieved8,9,10,11,12 moreover spread information edema among doctors
physical therapists patients efforts managing cosmetic aspects
also resulted popularity10,11,12 the frontal region brain associated affective states different
affective states associated different eeg patterns region13 normal subjects experience positively
valenced emotions happiness joy together greater relative left frontal
eeg activation contrast experience negative emotions including depression
associated greater relative right frontal eeg activation14 15 there studies
investigated effects different manual techniques frontal eeg
activation4 5 16 17 however mld one techniques
investigated therefore present preliminary study investigated effects mld
subjects psychological stress greater relative right frontal eeg activation
mld expected shift eeg patterns toward symmetry the subjects included 52 university students chosen according following criteria
1 history mental illness 2 currently taking medication known affect
eeg signals 3 known heart- muscle related disease they free
pulmonary cardiac metabolic disease well disease states may cause
brain dysfunction all subjects responded stress response questionnaire sri)18 returned authors according
results questionnaire 13 female subjects aged 19 23 years sri
score 80 and informed
written consent obtained subject experimental procedures
explained all test protocols approved ethics committee physical therapy
faculty kangwon national university all interventions
completed supine position massage table pillow placed knees
relax lower back muscles data acquisition mld performed quiet
temperature controlled environment 2224 c stimuli conversation phone calls
noise could increase activity sentinel nodes minimized
subject body covered soft thin sheet avoid discomfort body
exposure mld conducted well trained certified mld therapist applied twice
neck area the protocol standardized massage stroke category
type time participants subjects allowed rest comfortably least 5 min prior baseline
recording procedure eeg data acquired 5 min immediately following
mld a total 6 channels eeg recorded inclusive fp1fp2 f3f4 f7f8
there two electrodes ground electrode reference electrode
placed zygomatic bones participants asked close eyes refrain
talking falling asleep making exaggerated body movements order observe
cortical electrical activity without external stimuli minimizing possible visual
artifacts eeg measurement the eeg signal acquired 5-min period followed
computerized fourier analysis eeg waves using telescan software package
laxtha daejeon south korea the signal sampled rate 256 hz digitally
filtered using 150-hz band pass filter after data acquisition storage
statistics computed extract asymmetry values alpha frequency band
frontal area cerebral cortex19,20,21
the asymmetry index calculated subtracting log transformed absolute alpha power
left hemisphere analogous log transformed right hemisphere alpha power log
right log left alpha power is inversely associated cortical activation
negative asymmetry score denotes greater alpha activity left less alpha
power right would suggest greater right sided activation hand the asymmetry index compared prior
mld application using paired test collected data analyzed using
statistical package program spss v. 19.0 mld generally caused activation shift right hemisphere left hemisphere
frontal electrode pairs analyzed study statistical analysis comparing pre-
post mld asymmetry values channels f7f8 showed statistically significant increase
hemispheric asymmetry fp1fp2 p 0.082 f3f4 p 0.065 f7f8 p 0.032
alpha asymmetry scores regionareabefore- mldafter- mldfp1fp20.130.060.030.18f3f40.150.050.020.16f7f80.120.040.090.25 variables means sd mld manual lymph drainage p<0.05 in preliminary study frontal lobe eeg activity patterns response mld
neck examined better understand alpha wave processing subjects psychological
stress many studies shown eeg asymmetry attenuated massage relaxation
techniques musical therapies22,23,24
however date studies investigating effects mld frontal
asymmetry mld application acts light stimulator psychological stress predicted
mld would associated frontal eeg asymmetry state specifically result
greater left frontal hemisphere activation alpha frequency band study
alpha band typically range 813 hz chosen electrophysiological
marker previously discussed relatively stable21 25 inversely
related activation26,27,28 the measurement
alpha asymmetry shown effective reliable discriminating positive
negative emotions23 29 since previous investigations demonstrated
relationship brain electrophysiology frontal area measures affective
states19 20 30 31 also focused analysis three anterior electrode
pairs fp1fp2 f3f4 f7f8 recent studies suggested greater left sided anterior activation indexed
decreased alpha activity left hemisphere associated higher degree
positive affectivity feeling well reduction anxiety28 32 our results indicate mld associated significant
increase left sided anterior activation thus supporting hypothesis mld
attenuate frontal eeg asymmetry these results also line findings previous
studies demonstrated therapeutic effects massage4 5 20 although study showed demonstrable effects mld several limitations
suggestions future research firstly study examined acute
electrophysiological changes produced mld subjects psychological stress
addition replicating present findings bigger sample size further studies
needed investigate effects mld clinical populations across different
conditions diseases controlled experimental design conclusion preliminary study showed mld significantly increase left sided
anterior activation these results provide evidence support hypothesis mld gives
rise positive affectivity | [ purpose ] the purpose of this preliminary study was to investigate the effect of manual
lymph drainage ( mld ) of the neck on frontal electroencephalogram ( eeg ) asymmetry in
subjects with psychological stress .
[ subjects ] thirteen subjects with psychological stress
participated in the study . [ methods ]
subjects received mld of the neck for 15 min .
[ results ] analysis of the frontal asymmetry index showed that the energy shift in the
alpha frequency band from the left hemisphere to the right hemisphere after mld resulted
in greater left - side activation ( positive asymmetry values ) , which could be related to the
positive emotional state observed particularly in the f7f8 area .
[ conclusion ] these
preliminary findings suggest that frontal eeg asymmetry was significantly attenuated after
mld . |
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\begin{document}$$\square \end{document} | in this note we prove that a malcev algebra is 2-supernilpotent ( [ 1 , 1 , 1 ] = 0 ) if and only if it is polynomially equivalent to a special expanded group .
this generalizes gumm s result that a malcev algebra is abelian if and only if it is polynomially equivalent to a module over a ring . |
tumors nail apparatus often present challenge diagnosis well treatment due specialized nail anatomy nail plate may conceal tumor well alter tumor growth pattern however alterations color thickness curvature nail plate may often provide clue a 40-year old male presented yellowish discoloration thickening altered curvature right great toe nail past 2 years there history mild pain walking application pressure past 2 weeks markedly thickened nail plate increased proximal transverse curvature yellowish band like discoloration medial two thirds nail xanthonychia figure 1 however friability nail plate there swelling brownish discoloration medial two thirds proximal nail fold there minimal pain applying pressure medial part nail nail fold markedly thickened nail plate increased proximal transverse curvature yellowish band like discoloration xanthonychia medial two thirds right great toe nail also note swelling medial two thirds proximal nail fold patient underwent total nail avulsion revealed well defined tumor extruding proximal nail fold toward distal end nail bed figure 2a the proximal nail fold everted tumor excised entirety excised tumor 3 cm 2 cm 0.5 cm firm consistency parallel ridges corresponding ridges nail plate figures 2b a differential diagnosis onychomatricoma fibrokeratoma nail matrix superficial acral fibromyxoma fibroma glomus tumor considered histopathology proximal transverse section figure 3 revealed polypoid fibroepithelial tumor foliated pattern acanthosis papillomatosis deep epithelial invaginations multilayered basal suprabasal cells elongated nuclei oriented perpendicular basement membrane absent granular layer clear v shaped clefts places the stroma superficial cellular fibrillary vascular layer deep relatively acellular layer denser collagen a distal longitudinal section figure 4a b showed different pattern tumor glove finger like monodigitate pattern marked papillomatosis multiple thick deep epithelial ridges on immunohistochemical analysis fibrous stroma showed diffuse staining cd34 negative staining cd99 figures 5a b ( post nail avulsion well defined tumor extruding proximal nail fold toward distal end nail bed ( b excised tumor showing parallel ridges r corresponding ridges nail plate ( c dorsal view avulsed nail plate showing thin proximal portion thickened yellowish distal portion ventral view showing ridges nail corresponding tumor histopathology proximal transverse section h e 10 40 polypoid fibroepithelial tumor foliated pattern acanthotic papillo matous epithelium v shaped clefts v corresponding avulsed nail the stroma superficial cellular fibrillary vascular layer deep relatively acellular layer denser collagen ( b tumor lined mature malpighian epithelium resembling normal matriceal epithelium absent stratum granulosum multilayered basal suprabasal cells elongated nuclei oriented perpendicular basement membrane places ( c numerous mast cells stroma immunohistochemistry 10 fibrous stroma showing diffuse staining cd34 negative staining cd99 b histopathology h e 10 b 40 distal longitudinal section showing glove finger like monodigitate pattern marked papillomatosis multiple thick deep epithelial ridges onychomatricoma om rare onychogenic tumor nail matrix described mostly caucasians the usual clinical presentation thickened nail xanthonychia increased transverse curvature proximal splinter hemorrhages due vascular stroma perrin et al defined two types om based tumor nail characteristics 1 onychomatricoma ventral matrix om type characterized single large fibroepithelial tumor the nail plate thinned proximally thick distally giving appearance porch roof ( 2 onychomatricoma proximal nail fold om type ii characterized tumor multiple fibroepithelial projections om type ii often presents unusual clinical features pterygium fibrokeratoma like om total onychodystrophy verrucous band like pattern suggesting wart bowen disease histopathologically om type shows two different architectural patterns transverse longitudinal sections on proximal transverse sections lobulated foliated pattern observed glove finger monodigitate pattern observed longitudinal distal sections awareness different patterns important fragmented specimens available histological analysis a three dimensional model using proximal distal transverse longitudinal sections helps better understanding visualization morphology rare tumor om characterized deep epithelial invaginations thick v shaped keratogenous zone overlying prekeratogenous zone on avulsion nail plate seen optically empty v shaped zone the epithelium corresponds matriceal epithelium absent granular layer basal cells thin elongated nuclei multi layered suprabasal cells oval nuclei keratin markers k5 17 positive epithelium indicative matriceal differentiation k 85 stains prekeratogenous zone the stroma contains several mast cells arranged two layers superficial cellular vascular layer fibrillary collagen deeper relatively less cellular layer dense collagen bundles the two layered stroma frequently observed proximal portion distal zone tumor based proportion epithelial mesenchymal components presence absence atypia stroma ko et al have proposed different nomenclature three categories 1 unguioblastoma predominant epithelial component 2 unguioblastic fibroma predominant stromal component 3 atypical unguioblastic fibroma nuclear pleomorphism atypia stroma differential diagnosis om includes fibrokeratoma fibroma superficial acral fibromyxoma saf onycholemmal horn malignant proliferating onycholemmal cyst subungual warts subungual keratoacanthoma subungual squamous cell carcinoma bowen disease all easily distinguishable histopathology except fibrokeratoma fibroma saf need careful differentiation in distal longitudinal sections structure om tends resemble fibrokeratoma however absence horny corn multiple fibroepithelial digitations two layered stroma transverse section rules fibrokeratoma the stroma om may resemble fibroma however excluded hyperplastic onychogenic epithelium om saf close resemblance om due highly vascular collagenous stroma presence mast cells epidermal hyperplasia papillomatosis also a single case om myxocollagenous stroma superficial acral fibromyxoma like om reported saf shows diffuse cd34 cd99 expression om shows diffuse expression cd34 cd99 negative treatment om complete surgical excision despite atypical nature stroma reported cases frank malignant variant described date conclusion onychomatricoma rare fibroepithelial tumor mostly arising nail matrix it needs distinguished subungual periungual tumors immunohistochemical markers cd34 cd99 useful adjuncts diagnosis om a three dimensional spatial reconstitution om helps better understanding variable morphological characteristics
histopathological patterns onychomatricoma vary proximal distal sections foliated pattern proximal transverse sections glove finger like pattern distal longitudinal section.study onychomatricoma multiple sections planes important three dimensional spatial reconstitution tumor differentiation subungual periungual tumors.patterns stromal immunohistochemical markers cd34 cd99 especially useful differentiating onychomatricoma superficial acral fibromyxoma subungual tumor several similar histological features onychomatricoma
histopathological patterns onychomatricoma vary proximal distal sections foliated pattern proximal transverse sections glove finger like pattern distal longitudinal section study onychomatricoma multiple sections planes important three dimensional spatial reconstitution tumor differentiation subungual periungual tumors patterns stromal immunohistochemical markers cd34 cd99 especially useful differentiating onychomatricoma superficial acral fibromyxoma subungual tumor several similar histological features onychomatricoma | onychomatricoma is a tumor of the nail matrix which often presents with alterations in the nail plate while the tumor itself is concealed beneath the nail plate .
it is a benign , biphasic fibroepithelial tumor which has to be differentiated from other subungual and periungual tumors .
we report a rare case of onychomatricoma and describe a three - dimensional histopathological analysis and immunohistochemical patterns of onychomatricoma . |
1903 1906 oswaldo cruz director general public health devoted energies improving sanitary conditions rio de janeiro government priority administration francisco de paula rodrigues alves 19026 yellow fever put damper country business prospects image abroad malaria made virtually impossible build infrastructure needed connect country inland regions ports control researchers new ranks instituto soroterapico federal renamed instituto oswaldo cruz 1908 also known instituto de manguinhos
pulled together knowledge amassed disease creatively adapting realities encountered field
carlos chagas young doctor recently admitted institute dispatched 1905 fight malaria itatinga paulo state dam construction provide power port santos largest exporter coffee chagas identified species anopheles present region describing new science he chose administer quinine preventively drain landfill wetlands provide collective protective measures workers form screens lodgings keeping chronically ill isolation providing treatment acute cases
in early 1907 chagas another researcher recently admitted institute arthur neiva sent vast swampy plains near rio de janeiro known baixada fluminense chagas stayed three months sent fight malaria minas gerais central brasil railway extended there came across new human trypanosomiasis later named chagas disease
when reached baixada fluminense plains found almost workers suffering malaria work sites already shut spanish portuguese immigrants taken straight port work site rail prevent alarming news state affairs reaching scaring much land pipes laid swampy workers often waists water 1908 close four thousand workers many brought families region also attracted travelling salesmen merchants migrants
a wooden hospital protected mosquito screens built end railway the general inspectorate public works responsible water treatments insect larvae killed spraying oil water tanks houses covered larva eating fish introduced railway construction projects scientific military expeditions across malaria zones quinine mainstay campaign used treatment prevention
the workers soon protested take quinine prophylactic purposes prompting neiva impose strict compulsory system either workers took alkaloid would lose jobs quininisers make sure actually swallowed capsules rather palming hiding tongue
daily dose 30cg recommended manuals patrick manson botto scheube carl mense already proved insufficient itatinga
february august 1907 workers xerm started given 50cg quinine hydrochloride produced merck every three days yielded promising results however late august september neiva started see relatively large number first time infections amongst workers taken higher dose quinine preventively he first put higher individual susceptibility since cases recorded workers failed follow protocol regarding taking quinine the morbidity rate 0.59% seemed suggest right track even though protocol could applied workers families migrants amongst number cases high
the natives region carriers chronic infections constant source contamination anopheles much robert koch seen africa neiva encountered infected children whose pathological manifestation disease dilated spleen
there something else drew attention workers taken quinine regularly symptoms xerm struck malaria visited rio days without taking alkaloid september 1907 onwards occurrences became increasingly commonplace so october neiva upped dose 50cg every day the cases first time infection vanished wherever quinine administration strict change dosage halt rise number workers fell ill away worksite temporarily
november 1907 first time infections started appear amongst people taken quinine preventively every two days response neiva started administering every day dose 50cg this seemed work disease struck taking lower doses and even amongst taking full daily dose still cases workers would fall ill relapse went capital
by january 1908 four thousand workers receiving medication either every day every day depending locations wrote neiva never various reasons managed arrange things could provide safe quinine administration.
safe form treatment
50cg taken without exception even single day.
even treatment interrupted one two days malaria would strike neiva upon moving away region stopping taking quinine preventively struck benign tertian fever home rio de janeiro may 1908 dispatched head anti malaria campaign region crossed brazilian north western railway stretched main coffee production area paulo across mato grosso border bolivia paraguay
the article published two years later shows somewhat muddled structure imprecise data enough time test experimentally deductions made months working problem
neiva wrote opportunity observe great number people thus large quantity human material conditions virtually corresponded laboratory research perfect contrast workers took quinine women children migrants almost numerous workers took quinine totally attacked malaria.
likely part second contingent took poor quality medications including ones based quinine meanwhile differences amongst workers different dosages frequencies took drug depending based also workers relapses showing group less homogeneous first believed infected people midst neiva interpretation situation malaria haematozoon developed resistance quinine it says exposed constant action quinine less lengthy period time parasite became
adaptation opportunity haematozoa fed blood different degrees chemical richness. resistance result haematozoa adaptation organic media containing different quinine levels ultimately made resistant generations acquired capacity differentiated clearly quinine resistant races.
third explanatory hypothesis neiva highlights relationship non infected individuals victims relapses situation homogeneous chemical richness supposing haematozoa got accustomed alkaloid encountered high concentrations throughout whole man
the resistant plasmodium races formed cultivation quinine rich environment man vectors growing gametes accustomed living media quinine always present haematozoa another cycle ookinete final feeding released sporozoite bloodstream already continued develop even presence quinine
growing gametes accustomed living media quinine always present haematozoa another cycle ookinete final feeding released sporozoite bloodstream already continued develop even presence quinine
may first time phenomenon observed tropical medicine seems first theory scientific literature malaria explain experience xerm neiva concluded constant quinine administration amongst malarial population groups administered equally inhabitants give haematozoa means acquire specific resistance point splitting different races.
words believed resistance phenomenon clinical perspective manifested failure quinine cure patients whose origin lay development parasite strains resistant drug the publication neiva theory related oswaldo cruz trip amazon service madeira mamor railway devil s railway became known many thousands people lost lives disease construction there director instituto de manguinhos noted huge doses quinine 3 g day still failed prevent malaria breaking amongst people working railway
oswaldo cruz reached region tracks laid july 1910 first section railway opened september delivered report company containing analysis sanitary conditions recommendations improvement notwithstanding range diseases plagued workers main culprit crippling madeira mamor works malaria it prevalent inverted ratio normal pathological people wrote oswaldo cruz idea healthy state is.
morbidity high mortality far lower the widespread form malaria serious aestival autumnal tropical 70% caused plasmodium falciparum as campaigns run chagas neiva emphasis put using quinine providing protection mosquito bites oswaldo cruz considered doses used xerm minas gerais ineffectual circumstances proposed daily administration 23 g even though noted daily dose 0.75 1 g produced signs toxicity
report company building railway oswaldo cruz endorsed neiva theory formation quinine resistant races plasmodium some patients continued contain parasites blood 24h intravenous dose 6 g alkaloid despite noting make progress theoretical formulations biological phenomenon would go intrigue german researchers broad experience malaria prevention treatment german researchers followed closely scientific theories innovations produced side atlantic the intense commercial diplomatic relations germany brazil increasing flow german emigrants country long ruled monarchy linked habsburgs created favourable conditions scientific interchange
the archiv fr schiffs- und tropen hygiene naval tropical hygiene archive frequently commented summarised articles published brazilians local foreign journals one progeny german science adolpho lutz important actor institute microbiology medical zoology brazil
oswaldo cruz studying medicine 1880s belonged group germanists would meet learn language order keep latest medical breakthroughs published german journals successful campaign yellow fever led oswaldo cruz rio de janeiro attracted two researchers hamburg institute maritime tropical diseases 1904 their mission observe methods used fight disease study yet obscure aspects aetiology epidemiology brazilian capital hans moritz otto rudolf otto neumann kept close contact manguinhos institute staff the expedition sponsored shipping companies connected hamburg south america coffee exporters like theodor wille hanseatic port one main destinations brazil important export later otto neumann would apply methods used brazilian capital control yellow fever togoland german protectorate west africa
henrique da rocha lima founding staff member instituto de manguinhos oswaldo cruz right hand man specialised microbiology pathology berlin 1901 1903 munich 1906 1908 1909 he hired hamburg institute death 1956 rocha lima worked actively mediator german
, helped organise brazil exhibits exhibition appended 14th international congress hygiene demography held berlin 1907 the brazilian delegation presented materials illustrating campaign yellow fever histopathology collections related tropical diseases innovations technology used produce bubonic plague serum description
exoerythrocytic cycle protozoan haemoproteus columbae important breakthrough malaria studies made henrique arago
these contributions earned brazil gold medal awarded german empress awakened curiosity german scientists research done henrique arago alcides godoy another researcher instituto oswaldo cruz postgraduate studies germany 1907 the following year brazilian institution received two researchers hamburg institute protozoologist stanislas von prowazek chemist gustav giemsa six month stay research trained young scientists instituto oswaldo cruz 1910 max hartmann staff berlin institute infectious diseases also spent months two years later hermann duerck helped consolidate anatomical pathology department instituto oswaldo cruz
the period prowazek giemsa working instituto oswaldo cruz coincided neiva malaria studies campaigns inland brazil neiva prowazek even undertook joint expedition tiet river state paulo study flora fauna also epidemiology malaria region
prowazek giemsa sojourn instituto oswaldo cruz the institution also visited ernst rodenwaldt army physician also connected hamburg institute maritime tropical diseases he journeying along coast south america ship doctor vessel owned hamburg
it therefore likely giemsa prowazek rodenwaldt learnt neiva observations quinine resistance rio de janeiro swampy lowlands systematised published findings first volume memrias instituto oswaldo cruz the fact articles published german portuguese institute journal shows germany leading position time biomedical research also close dialogue maintained german brazilian specialists it interrupted first world war soon established along exchange merchandise capital influx german migrants brazil
the point want stress brazil involvement production knowledge tropical diseases complex suggested traditional representations role international capitalism mere exporter primary goods destination capital manufactured products europe north america scientific relations brazil germany field tropical medicine dynamic knowledge innovations produced sides not beholden imperial power brazil developed strong tradition medical research focused local diseases threatened imperial republican elites nation building modernisation projects this tradition created institutional cultural basis reception cultural scientific initiatives empire wilhelm ii including chemical pharmaceutical industry in hamburg director institute maritime tropical diseases bernhard nocht head institute clinical department heinrich werner would chance observe resistance amongst german workers repatriated hanseatic city mentioned article also published 1910 stated prepared quinine resistance malaria contracted inland brazil taken aback strength
the reason nocht werner surprised failure quinine patients madeira mamor region simply treatment used successful since founding hamburg institute sailors hospital disease studied treated malaria
nocht developed new method administering quinine differed method suggested koch consisted administering 1 g drug ninth tenth day disease inspired italian method fractionated dosage nocht favour administering total 1 g every day five separate doses eight days running time would increase gap doses instance five doses day two days patient cured
this method proved successful influx workers madeira region brazil according tropical medicine specialist ernst rodenwaldt amongst specialists experience working tropics board ship the way treat malaria taken granted all.
success methods proven constant improvement morbidity mortality rates amongst europeans colonies
several colleagues wrote rodenwaldt 1919 still remember time malaria diagnosis tropics home would somehow lift spirits patient certain could help promise definite cure.
amongst workers repatriated amazon outbreaks fever exacerbated symptoms diarrhoea dysentery repeated relapses 90 cases observed nocht werner number included patients relapses 56 tertian fever 15 tropical fever 19 mixed infections unlike previous experience tropical form likely relapse tertian forms normally caused species plasmodium tended produce obstinate relapses observed anomalies nocht werner progressively raised dose quinine administered twofold even the initial dose rose 2 g complementary treatment phase pauses increasing length would administer quinine two three days first pause would last two days second three next four eight days break reached however higher dose nothing improve results neither frequency seriousness relapses diminished
quite unusual circumstance led experiment products compounds containing arsenic tested patrick manson 1902 peter mhlens year later koch observed effect atoxyl malaria parasite also affected eyesight use treating disease pursued
the usefulness another compound methylene blue first reported 1891 paul ehrlich paul guttmann recommended afterwards children
miguel couto also recommended brazilian malaria encouraged neiva test xerm he find effect plasmodium action slow
incontestable effect ehrlich hata preparation 606 salvarsan five cases quinine resistant malaria
werner tested preparation brazilian malaria failed prevent relapses case
werner also sought demonstrate amazonian variant disease differed regions world with nocht observed several clinical peculiarities especially frequent disturbance intestine patients they also found notable nervous system affected two serious cases symptoms beriberi and the spleen slightly dilated several serious cases malaria found
alterations lungs also characteristic patients brazil fourteen less serious cases bronchitis disappeared malaria treatment progressed
the doctors hamburg also reported temperature variations previously seen six cases shortly fever abated quinine patients temperature risen several days without parasites detected peripheral blood pseudo relapse.
faced singularities nocht werner started wonder whether species parasites involved brazilian malaria different virulence resistance also morphologically the parasites tertian form observed slightly different ones found parts world article published 1910 the tropeninstitut researchers put forward explanation development quinine resistance only following year werner discuss theoretically differentiating two forms resistance acquired passage plasmodium warm blooded animals human hosts acquired passage insects the first form resulting repeated effect quinine plasmodium correlated prolonged use alkaloid malaria treatment this would partially explain resistance seen cases amazon including peruvian amazon quinine used fight malaria centuries
meanwhile werner thought unlikely second form passage insect existed for neiva high levels quinine absorbed insects fed human blood enough assure continued even increased resistance parasites passage vector according werner research gustav giemsa heinrich schaumann had demonstrated level alkaloid human blood low new generation resistant parasites develop fertilisation insect
the hamburg researcher believed impossible reach firm conclusions phenomenon resistance based deductions
primarily theoretical.
tests made nocht werner methylene blue salvarsan show attuned chemotherapy developed paul ehrlich collaborators resistance trypanosomes atoxyl studied ehrlich 1907 onwards influenced large measure the analysis phenomenon observed malaria parasites according christoph gradmann ehrlich interested trypanosomes resistance atoxyl much clinical importance fact could furnish evidence existence cell receptors support theory drug action cell compared relationship toxins antitoxins both bernhard nocht ernst rodenwaldt wrote results obtained experiments protozoan parasites blood like trypanosomes could extrapolated intracellular parasites according nocht 1919 trypanosomes resistance drugs stable maintained many passages quinine resistance disappeared plasmodia prolonged interruption medication host rodenwaldt sure added disappearance alterations malaria plasmodia part due fact asexual reproduction complex trypanosomes new theories emerged first world war havoc wreaked malaria balkans turkey syria made resistance quinine top priority action quinine often left much desired therapeutically prophylactically, wrote army physician wilhelm hoffmann weighed impact malaria german troops
initial optimism discovery aetiology transmission success experiments control disease specific geographical contexts badly shaken first world war forcing specialists field review epidemiological scientific studies disease
macedonia particular british french german troops struck particularly devastating epidemics caught guard inefficacy classic preventive therapeutic methods the infection rate amongst local people 6095% high density mosquitoes made impossible control vector late 1916 french army doctors alarmed find sixty thousand men lost lives malaria region half french military contingent malaria starts appear serious sanitation issue german medical records early 1916
let us turn testimony ernst rodenwaldt first prevention seemed fail cure everything indicated quinine specific medication one hoped administered incorrectly must interferences reduced prevented expected efficacy.
doctors even defended idea regions like macedonia albania taurus mountains different form malaria could treated quinine its prophylactic use considered doctors working tropics essential started seen increasing scepticism doctors working front they argued fostered certain resistance worsened chances treatment alkaloid infection hit
drug side effects queasiness weakness bleeding skin impaired sight hearing chest pain blackwater fever made hard get soldiers stick treatment reason peter mhlens head clinical section tropeninstitut recommended neiva baixada fluminense lowlands brazil strict supervision sanitation officials make sure actually ingested quinine the servicemen would often hide drug later exchange cigarettes alcohol
certain authors suggested many supposed cases biological quinine resistance human resistance inadequate use drug also general state patients suffered malnutrition stress fatigue physical emotional impact war
time war german doctors familiar clinical aspects malaria treat prevent according rodenwaldt eliminated germany half century ago except small enclaves malaria curiosity medical teaching war.
explains many little prepared dealing conflict
make matters worse seems military sanitation organisation failed give clear standard guidelines fight disease
nevertheless new circumstances provided unprecedented opportunity verifying findings previous sporadic observations malaria far larger scale albeit little control conditions ultimately war served great experimental field malaria research especially evaluating prophylactic therapeutic efficacy quinine.
whenever quinine taken preventively doses used varied greatly regions around 1 g quinine was administered day others troops would receive 1.8 g ten days rodenwaldt treatment continued two three weeks malaria infested region left warned mhlens rarely took place there also disagreements best way using quinine whether tablets solution subcutaneous intramuscular injections
apart hypothesis specific form disease balkans turkey theories also put forward account failure treatment prevention using quinine bid make sense arguments opinions abounded martin mayer distinguished two forms resistance chininabstmpfung dulling insensitivity quinine due factors within patient body made individual unresponsive alkaloid chiningewhnung adaptation quinine referring took place inside parasite
former case physiological processes responsible drug diminished effectiveness witnessed reduced excretion quinine urine reduced concentration blood gustav giemsa joseph halberkann hamburg institute questioned results excretion quinine prove failed exert action parasite organism however products alkaloid decomposition could involved process something giemsa turned attention
nocht felt inefficacy ever larger doses quinine related emergence strains quinine resistant parasites neiva suggested rather attributed diminished non existent effect quinine weakening organism defences prolonged inappropriate use drug
the fact parasite human organism resistance quinine involved complex issues beyond grasp medical science time indeed several aspects epidemiology physiopathology malaria would remain obscure resistance quinine became polysemic concept employed different circumstances depending author principles procedures if war neiva werner spoke property developed parasites war phenomenon started related inefficacy alkaloid caused incorrect prophylaxis organic factors like immunity social resistance troops ascribable drug side effects attempt avoid ambiguity suggested word
resistance martin mayer hamburg institute proposed distinction insensitivity quinine referring patient organism quinine adaptation characteristic developed parasite the hypothesis direct action refuted laboratory evidence concentration alkaloid blood far lower needed kill microbe
repulsion theory proposed julius morgenroth 1917 quinine would build inside erythrocytes would repel parasites chemostatic action preventing penetrating cell free blood stream life cycle interrupted destroyed however repelled erythrocytes argued rodenwaldt hard imagine plasmodia would adapt drug direct effect
morgenroth viewed action quinine light principle selective action proposed ehrlich worked
came life cycle plasmodium process resisted immune reactions effects quinine remaining quiescent organism disease relapsed still mystery it known body remained whether capable maintained inside cells erythrocytes the asymptomatic carriers parasites chronically ill held accountable introduction disease areas prone epidemics incite manifestation hidden infections using techniques included submitting individuals suspected infected temperature shocks physical exertion followed hot cold baths
chapter malaria respected handbuch der tropenkrankheiten handbook tropical diseases carl mense published 1917 1918 races certain regions like brazil could existed previously developed response overuse drug
finally third form indirect resistance via failure patients defences ziemann summarised different explanations made progress developing theory thereby corroborating nocht mhlens statements abundant literature malaria published war discussed specific problems concerning epidemiology physiopathology treatment prevention disease failed put forward satisfactory solution enigmas doctors front line faced
neiva werner theoretical speculations continued comprehensive attempts explain quinine resistance even riddled inaccuracies gaps however idea parasite acquired resistance alkaloid life cycle humans and/or mosquitoes able transmit resistance offspring refuted ernst rodenwaldt 1919 wrote one robust works subject presented thesis university heidelberg
skills failed balkans turkey war tropical medicine many successful experiences? wondered
let us examine ideas galvanised explain complex biological process malaria parasites became resistant quinine writing memoirs german retreat asia minor worked hygiene adviser rodenwaldt relates took advantage six week wait passage europe study wilhelm johannsen erwin baur theories heredity
upon reaching germany decided enrol medicine department heidelberg university wrote thesis question intrigued since africa resistance malaria plasmodium quinine
memoirs he adds thesis took pains apply notions genetics issue infection time
staunch believer august weissmann theories heredity
defender darwin theories critic inheritance acquired characteristics idea associated lamarck admitted darwin weissmann german biologist proposed almost absolute constancy autonomy known germinative plasma element responsible carrying hereditary factors way completely immune influence sum rest body merely transmitted germinative plasma one generation next germinative plasma would change exceptional circumstances alteration organism went life would transmitted hereditary means
the blending weissmann mendel conceptions early years twentieth century meant heredity seen
fixed condition inherent biological characteristics individuals.
rodenwaldt formulations quinine resistance strongly influenced wilhelm johannsen erwin baur whose insights contributed towards reworking gregor mendel ideas early 1900s onwards especially concerning emergence species different theories expounded explain mechanisms different variants therefore new species emerged well processes involved transmitting variations successive generations
mutationists rejected role natural selection mechanism evolution holding mutations responsible major modifications could role emergence new species biometricians like karl pearson recognised natural selection principal driving force evolution also idea small continuous variations led development new species
midst debate came experiments dane wilhelm johannsen pure lines beans showing natural selection induced genetic differences environmental ones johannsen distinguished genotype set factors responsible heredity phenotype observable characteristics individuals individuals pure lineages genetic material resulting self fertilisation could different phenotypes response different environmental conditions genotype would remain
he concluded organism appearance result influence mendelian traits also response environment mendelian factors determined breadth organism reactions environment like johannsen baur distinguished environmentally induced changes heredity he conceded mutations could modify genetic traits scale proposed
mutationists. took place small scale resulting subtle changes often went unnoticed these small mutations important formation new races new species
in einfhrung die experimentellen vererbungslehre introduction experimental doctrines inheritance book published 1914 edited 1919 baur mentions resistance plasmodium quinine he see property inheritance acquired modifications case others naturally far reasonable concede isolated races malaria parasites differing resistances quinine treating infected person drug resistant race already existed simply cultivated pure form
case others naturally far reasonable concede isolated races malaria parasites differing resistances quinine treating infected person drug resistant race already existed simply cultivated pure form
similar vein also drawing weissmann johannsen baur ideas rodenwaldt sought refute neiva werner lamarck inspired interpretation they held parasite developed resistance quinine several generations maintaining increasing resistant features passage mosquitoes for neiva quinine mosquito absorbed fed blood way implicated process although idea werner ruled thought quantity alkaloid blood small rodenwaldt none hypotheses explained failure quinine brazil balkans turkey contrast successful cases tropical medicine colonies
neither explain failure prophylaxis way preparations used circumstances war factors relating human organism even existence specific form malaria combat zones rodenwaldt believed plasmodium strains different levels susceptibility quinine physical features emerged spontaneously nature most parasites quickly succumbed action alkaloid races selected matter creation cultivation quinine resistant strains authors would us believe pre existing quinine resistant strains selected.
selection took place quinine used small quantities regions malaria widespread arrival non immune people provoked virulent forms disease this process could take place regions quinine used centuries south american mountain ranges short period time large population group submitted pattern administration drug the incomplete prevention cure patients contributed development chronic malaria regions growing resistance quinine observed this dependence selection quinine resistant races greater lesser efficacy therapeutic treatments explained problem occur regions like germany malaria endemic long time italy systematic process fighting disease time main consequence treatment country doctors people used therapy disease eradicated selection quinine resistant races prevented use high doses quinine parasites killed made impossible epidemic levels reached
the main consequence treatment country doctors people used therapy disease eradicated selection quinine resistant races prevented use high doses quinine parasites killed made impossible epidemic levels reached
tropics selection take place native population degree immunity disease almost never took quinine europeans generally treated correctly there rare relapses quinine resistance occurred people bad luck infected already existing strain passed selection
but although signs plasmodia regions quinine resistance presented morphological particularities essential proving different races parasite rodenwaldt argued his acceptance johannsen views evident distinction makes genotype phenotype interpret phenomenon resistance alterations phenotype way alter genotype whose constitution remained constant therefore alterations could transmitted hereditary means morphologically identical population plasmodia different genotypical behaviour towards quinine possible quinine resistant races isolated selection plasmodia phenotypical appearance behave differently towards quinine could lead selection quinine resistant race common phenotypical genotypical features
morphologically identical population plasmodia different genotypical behaviour towards quinine possible quinine resistant races isolated selection plasmodia phenotypical appearance behave differently towards quinine could lead selection quinine resistant race common phenotypical genotypical features
rodenwaldt owed johannsen distinction variations visible characteristics variations hereditary material core theory based baur deductions the environment selected quinine resistant strains understood broad sense ecological social environment in the balkans turkey environment war ravaged crossed people physically psychically weakened troops came contact villages rife chronic malaria diseases army doctors little familiarity treating malaria key ingredient view importance rodenwaldt gave correct administration preventive therapeutic quinine theory similar experiments johannsen would done pure lines plasmodia ones homogeneous genotypes 1919 archiv fr schiffs- und tropen hygiene rodenwaldt published article plasmodium resistance quinine
the following year werner rosenthal 1920 gttingen author tierische immunitt animal immunity praised heidelberg professor contribution criticised presented concepts immunity resistance malaria
rodenwaldt response leads us new ramification debates investigations disease experience war made moot scientific epidemiological issue approaching perspective genetics immunology field knowledge went gain ground experimental practical medicine
the material researched paper yet enough analyse discussions problem quinine resistant malaria great depth basically rosenthal accused rodenwaldt mistaking non specific form immunity observed people region chronic malaria specific elements defence mechanisms activated organism interaction pathogen europeans prone malaria tropics non specific resistance weakened unfamiliar climatic conditions unlike immunity bacterial infections went malaria immunity developed slowly continued exposure parasite chronic form disease he stated produce long lasting effects seen bacterial diseases could dissipated internal external factors illnesses physical debilitation etc unstable exposed new infection tended exhibit far milder symptoms would subside readily drug based therapy
rodenwaldt involved another far less gentlemanly exchange views another former student
hamburg school viktor schilling visited brazil 1912
physician hygiene adviser turkey syria schilling observed several cases malaria showed resistance mounting doses quinine
it appears early 1917 written communiqu subject published strict censorship time
his comments became public two years later archiv fr schiffs- und tropen hygiene deutsche medizinische wochenschrift time rodenwaldt publishing thesis
according schilling conditions neiva nocht werner mhlens others presented propitious development quinine resistant races valid the parasites always found way partially escape quinine increase virulence new ground adapt way alkaloid generally speaking less inclined accept parasites develop hereditary resistance quinine deem likely selection increased virulence particularly virulent resistant strains
conditions neiva nocht werner mhlens others presented propitious development quinine resistant races valid the parasites always found way partially escape quinine increase virulence new ground adapt way alkaloid generally speaking less inclined accept parasites develop hereditary resistance quinine deem likely selection increased virulence particularly virulent resistant strains
later 1921 schilling modified view slightly bringing line rodenwaldt reached idea parasite races resistant quinine practical means severely affected population received unreliable supply alkaloid process observed due developed inherited resistance rather selection increased virulence especially lethal resistant parasite strains rodenwaldt later tried make selection theoretical basis process exactly sense gave
i reached idea parasite races resistant quinine practical means severely affected population received unreliable supply alkaloid process observed due developed inherited resistance rather selection increased virulence especially lethal resistant parasite strains rodenwaldt later tried make selection theoretical basis process exactly sense gave
rodenwaldt reacted claim believed diminished contribution debate thus far easier many broad possibilities person defend idea later one lines becomes likely. went reiterate belief selection pure lineages already existing resistant strains furthermore nothing altered increase diminishment virulence adapt anything all.
rebuttal schilling accused rodenwaldt appropriated ideas learnt smyrna province south western turkey met 1918
even schilling acknowledged way rodenwaldt developed baur ideas interesting independent theoretical accomplishment far outstrips scant experiences derived practice.
rodenwaldt reply 1923b 404 curt accompanied note archiv editors tone text moderated involved accusations personal nature objective discussion matter closed
today resistance plasmodium antimalarial drugs one big problems facing international health care prompting continued development different therapeutic compounds combinations drugs
study show quinine resistance already recorded early decades twentieth century regions brazil giving rise different theories explain time alkaloid practically option available preventing treating outbreaks malaria the theory development quinine resistant races plasmodium put forward arthur neiva would appear first scientific work literature malaria attempted give explanation persistence disease even alkaloid taken ever higher doses these preliminary hypotheses never verified theoretically experimentally neiva researcher oswaldo cruz institute whose career took different turn meanwhile brazil supremacy preventive approaches focused primarily vector malaria adopted campaigns started rockefeller foundation first world war put strategies designed address parasite preventive therapeutic use quinine back burner neiva hypothesis seem inspired particular interest amongst brazilian specialists
neiva observations malaria parasite resistance quinine reveal interdependency laboratory field work overcoming public health problems producing new knowledge tropical diseases vast field observations experiments.
interdependency characteristic institutionalisation experimental medicine brazilian belle poque the anti malaria campaigns key part collaborative efforts doctors keen make names scientists conjunction public private
clients sought assistance old new biological medical institutions worked they research ran projects ultimately made important advances pressing problems day affecting public health also engineering farming resource exploitation
field research essential understanding linked human population groups parasites complex life cycles multiple vectors intricate chains interdependency natural social ecosystems manner unlike scientists working administrations european colonial possessions brazilian researchers like neiva saw unexplored brazilian hinterland potential repository new scientific data as helen tilley reports britain african colonies colonial scientists evoked authority laboratory knowledge simultaneously challenged physical boundaries natural validity authority based.
wetlands fluminense lowlands exactly laboratory presented biological phenomena complexity space partially immune manipulations controls inherent experimental research however field fine observation context malaria time different plasmodium species related could grown artificially according leo slater different routes neiva tropical medicine specialists researchers working new drugs malaria best reconstitute complex connections parasite host vector laboratory
brazil s vast unexplored inland regions researchers like arthur neiva carlos chagas obtained new knowledge tropical medicine as case theory quinine resistance formulated also campaign fight malaria itatinga 1905 chagas formulated hypothesis domestic infection anophelines
would called years later support campaign kill malaria vectors using ddt inside homes engaged campaign malaria worksites central do brasil railway chagas identified clinical etiological epidemiological phenomena new human trypanosomiasis later named just propitious study quinine resistance exchange brazil germany contributed communication discovery chagas disease it archiv fr schiffs- und tropenhygiene brazilian scientist first published findings identifying trypanosoma cruzi vector clinical aspects disease different well known sleeping sickness the recognition brazilian discovery came june 1912 chagas awarded schaudinn prize hamburg institute maritime tropical diseases best work field protozoology interestingly presence german researchers instituto oswaldo cruz contributed towards theoretical research new trypanosomiasis reported magali
malaria chagas disease ancylostomiasis formed triad diseases first world war galvanised debate brazil need extend public health services inland areas country sanitation movement spearheaded intellectuals writers scientists including chagas neiva drew attention prevalence disease amongst people left mercy god when came medical care.
according neiva one factors exacerbated malaria amongst population groups incorrect use quinine sold mainly form sulphate effective neither prevention treatment as head public health paulo 1916 1920 neiva faced serious malaria epidemics inland coastal areas brazil richest state
alongside measures attack mosquitoes recommended treating sick quinine the difficulty importing first world war prompted start quinine production butant institute run paulo public health service
from 1920s onwards neiva started working mainly organisation administration scientific institutions 1930 politician
even though longer researched malaria continued topic interest albeit arena debates political action despite witnessed quinine resistance first hand neiva held opinion reliable method preventing treating disease letter wrote 1935 fellow public health expert criticised aggressiveness german pharmaceuticals industry marketing new antimalarial agents sure quinine valiantly withstand tests responsible work must done strict scientific determinism new products manufactured german laboratories experiments using bird haematozoa launched market treacherous commercial conditions must kept bay
i sure quinine valiantly withstand tests responsible work must done strict scientific determinism new products manufactured german laboratories experiments using bird haematozoa launched market treacherous commercial conditions must kept bay
one people involved marketing new malaria drugs peter mhlens director clinical section institute tropical diseases hamburg august 1925 this drug developed year werner schulemann fritz schonhfer august wingler laboratories ig farben modifying quinoline one main components quinine
1930 ig farben also brought atebrine developed hans mauss fritz mietzsch
these synthetic malarial agents presented effective incurring fewer side effects quinine mhlens deployed network scientific political contacts get testing approved balkan nations like romania bulgaria also latin america especially 1931 venezuela guatemala mexico
he also mexico late 1926 faced resistance promotion new malaria drugs supported german foreign ministry part cultural diplomacy efforts the mexican press warned mhlens public references plasmoquine compromised medical standing a mexican military doctor also censured behaving scientist sly travelling marketeer.
series articles published german also english spanish french italian mhlens set forth advantages plasmoquine atebrine quinine resistance plasmodium alkaloid cited one main disadvantages mhlens also enumerated main side effects quinine blurred vision nausea ringing ears associated blackwater fever quinine idiosyncrasy.
text written bernhard nocht mhlens admit malaria parasite may come develop resistance plasmoquine analogous called quinine resistance went say veracity hypothesis remains present debatable point.
publication following year shows saw resistance differently neiva rodenwaldt suggests latters hypotheses left theoretical realm personal views matter always apparent resistance medicine less characteristic parasite even certain strains parasites infected individual represented lowering protective powers organism
my personal views matter always apparent resistance medicine less characteristic parasite even certain strains parasites infected individual represented lowering protective powers organism
chapter malaria renowned clinical medicine handbook edited klemperer he claimed many cases tropical malaria caused p. falciparum found resistant treatment using drugs treatment
inadequate war following years much said malaria parasites resistance quinine. resistance weakened immunity caused factors malnutrition diseases without doubt strength organism defences exerts fundamental role therapy the medication alone capable leading cure. equally true quinine plasmoquine whose action plasmodium indirect
when national socialist party came power 1933 mhlens competed top position institute tropical medicine hamburg however another key figure narrative ernst rodenwaldt nazi party favourite staunch anti semitism involvement study communication theories racial hygiene
from 1921 1934 working dutch colonies south east asia primarily combating malaria rodenwaldt published dozens papers racial hygiene eugenics his involvement problem quinine resistance certainly influenced campaign strategies adopted asia this attempt apply modern heredity theories study infectious disease could seen milestone development ideas ultimately led well known
racial hygienist. according heiner fangerau combination mendel weissmann ideas formed groundwork rodenwaldt analyses resistance represented watershed theories racial hygiene becoming clear predictable inheritance isolated features.
rodenwaldt trajectory took similar turn one mentor erwin baur ideologue behind eugenics author eugen fischer fritz lenz manual inspired hitler racial conceptions set forth mein kampf fangerau 2000 die mestizen auf kisar 1927 hereditary transmission biological features mixed race population earned rodenwaldt eminent position international league racial hygiene years national socialism main link tropical medicine much touted racial conceptions day words wolfgang eckart notable protagonist anthropology racial hygiene germany 30s 40s fervently defending racial segregation
as shown christoph gradmann regard trypanosomes arsenic compounds analysis quinine resistance part plasmodium shows became object investigation far phenomenon gained full attention medical community bacterial resistance antibiotics starting 1960s but unlike gradmann findings concerning trypanosomes plasmodium resistance quinine closely related frequency occurred clinical phenomenon
years debates resistance malaria plasmodium quinine resistance bacteria antibiotics prompted equally heated discussions field genetics angela creager
suggests researchers involved bacterial genetics 1940s 50s rejected conceptions lamarck microbes
adapted drugs transmitted property progeny however bacteriologists chance replicate resistance laboratory cultivated bacteria presence antibiotics unlike researchers working malaria resistance beginning century the role mutations emergence variations granted bacteria resistance discussed from perspective mendelian genetics darwinism resistance seen selection mutated lineages developed randomly population bacteria sensitive antibiotic experimental studies theoretical speculations creager continues led identification means genetic inheritance transmitted without involving chromosome core ultimately revealing end adaptation versus mutation turned false dichotomy.
interpretations bacterial resistance antibiotics applied analysis similar phenomenon seen amongst malaria parasites spontaneous mutations conferring reduced sensitivity given drug class drugs
nevertheless 1950s onwards drug drew specialists attention came resistance quinine chloroquine widely used drug malaria treatment since development
its proven efficacy considerably restricted use quinine chloroquine succeeded drugs including primaquine mefloquine proguanil this fact helps explain neiva nocht werner rodenwaldt observations limited impact became reduced mere footnotes narratives malaria treatment
and yet echoes authors deductions heard way researchers currently address plasmodium resistance chloroquine drugs population movements induce introduction resistant parasite strains widespread large scale use drugs operates a
selective pressure removes populations susceptible protozoa maintains resistant ones
the ways leading actors conceptions malariology interacted different contexts twentieth century clear cut beg exploratory study the scientific geopolitical cartography emerged second world war far cry context neiva nocht rodenwaldt active fields this war fostered appropriations scientific ideas actions always clear obvious the alliance german researchers german chemicals pharmaceuticals industry strengthened weimar republic became tarnished nazi regime second world war not rodenwaldt active promoter racial hygiene theories put trial nuremberg germans retreated face advancing allied troops also instrumental destruction italy sanitation engineering system ensured control malaria country resulting significant upsurge proliferation disease it also important remember potentialities limitations work neiva brazilian scientists also related fact produced country many considered subaltern europe centres civilisation. however follow research disputes sides atlantic see internationalised tropical medicine early decades twentieth century also interaction researchers sides took complex convoluted paths dynamics brazilian doctors like arthur neiva miguel couto oswaldo cruz restrict adopting adapting theories practices circulated publications correspondence conferences exchanges patients biological materials actually formulated new concepts theories impact central social formations the study historical records resistance malaria parasite quinine demonstrates important research topic individual careers formation collective ideas despite involved international research programmes followed national styles way studied fought disease prototypical tropical disease | this article addresses the discussion about quinine - resistant malaria plasmodium in the early decades of the twentieth century . observed by arthur neiva in rio de janeiro in 1907 ,
the biological and social resistance of malaria sufferers to preventive and curative treatment with quinine was corroborated three years later by oswaldo cruz during the construction of the madeira - mamor railway in the brazilian amazon .
likewise in 1910 , ailing german workers were transferred from brazil to hamburg s institute for maritime and tropical diseases , where quinine resistance was confirmed by bernard nocht and heinrich werner .
when the first world war saw failures in treating and preventing malaria with quinine along with violent outbreaks of the disease on the turkish and balkan fronts , resistance to this alkaloid became the topic of the day within the field of experimental medicine in germany .
new attempts were made to account for the resistance , especially by the physician ernst rodenwaldt , who explored the topic by applying modern theories on heredity .
the present article offers a preliminary survey and analysis of pronouncements about quinine resistance , shedding new light on the circulation of knowledge in the field of tropical medicine . |
ovarian cancer represents sixth commonly diagnosed cancer among women world causes deaths per year cancer female reproductive system advanced disease constitutes 75% women presentation this approach decades though 5-year survival remains poor 40% epithelial ovarian cancer constitutes majority disease types review focus reports relating advanced epithelial ovarian carcinoma a medline database search january 1966 april 2009 undertaken using key words epithelial ovarian cancer debulking surgery interval debulking surgery resulting 80 articles 14 relevant papers the articles full obtained papers reviewed authors results terms overall survival os progression free survival pfs evaluated study the 80 resulting articles screened 14 relevant papers retained 3 meta analysis 24 3 randomized control trials rtc 57 table 1 2 cochrane reviews crs 8 9 6 case control cc reports enrolling 50 patients 1015 table 2 the initial studies supporting concept debulking surgery published 1970s griffiths et al the premise considering potential impact reducing intra abdominal tumour burden based findings work magrath et al reported enhanced survival outcome reducing intra abdominal disease patients hodgkin disease griffiths undertook retrospective analysis 100 women noted residual disease masses 1.6 cms largest diameter improved survival outcome compared patients left greater disease volume a subsequent small prospective study heterogeneous population patients underwent aggressive radical surgery also revealed better survival pattern associated less tumour burden thus concept debulking surgery ovarian cancer became normal approach disease the use adjuvant chemotherapy platinum based also accepted norm care
the question whether surgical ability operator inherent tumour biology disease main factor impacting survival remains debate indeed benefit radical debulking already come criticism advocated tumour biology rather surgical effort might determine prognosis study 213 patients stage iiic epithelial ovarian cancer underwent complete cytoreduction initiation systemic platinum based combination chemotherapy eisenkop spirtos came conclusion need remove large number peritoneal implants correlates biological aggressiveness diminished survival significantly enough preclude long term survival justify abbreviation operative effort regarding primary surgery plethora published papers support findings griffiths though none randomized controlled trials hence similar inherent biases it also important note various definitions optimal cytoreduction proposed 2224 the gynaecologic oncology group gog currently defines optimal cytoreduction leaving residual disease less 1 cm maximum tumour diameter there 3 systematic reviews residual disease outcome conflicting conclusions analysis 81 cohorts patients 6000 women advanced stage ovarian carcinoma treated platinum based chemotherapy bristow et al found 5.5-percent increase median survival every 10-percent increase proportion patients achieving maximal cytoreduction 6000 women whereby administration platinum deemed important influencing survival rather achievement optimum debulking surgery the main difference papers bristow study patients exposed adjuvant platinum therapy case hunters study the third smaller study also concluded optimum debulking associated improved survival patterns though prospective trials necessary beginning eighties berek et al noticed secondary cytoreduction could also improve survival subsequently role interval debulking surgery ids investigated three prospective randomized controlled trials rcts 57 conclusions different interval debulking surgery defined second operation performed 3 4 cycles platinum chemotherapy woman suboptimal debulking primary surgery the trials redman et al gog rose et al failed show advantage ids the study redman closed prematurely survival benefit noted interim analysis note optimum debulking defined 2 cms residium compared 1 cms studies gog study 550 women suboptimally debulked stage iii iv ovarian cancer received three cycles paclitaxel cisplatin randomly assigned interval cytoreduction surgery a secondary attempt cytoreduction associated improvement progression free survival pfs 12.5 versus 12.7 months overall survival os 36.2 versus 35.7 months this case eortc trial carried van de burg et al showed ids group significantly increased median survival 6 months compared undergone procedure indeed still prospective rct showing survival benefit debulking surgery nevertheless important point differences trials time eortc trial chemotherapy consisted cisplatin cyclophosphamide paclitaxel available unlike gog trial another major difference eortc trial primary surgery necessarily performed trained gynaecological oncologist resulting different extents debulking the number patients less 5 cm residual tumour following primary cytoreduction eortc trial less third compared 55 percent gog trial surgery performed trained gynaecological oncologist shown increase survival gog study therefore concludes appropriate persons undertaking primary surgery ids required the term ids confined patients primary surgical debulking used situations whereby primary surgical attempt delayed chemotherapy six large case control studies 1015 relating delayed primary surgery identified summarized table 2 one studies 10 colombo et al divided patients 2 groups evaluate place surgery therapeutic sequence care group 1 receiving upfront surgery group 2 first debulking undertaken chemotherapy group 1 the os 38 months 3 factors significantly predicted suboptimal upfront surgery poor performance status extensive mesenteric involvemen stage iv disease the second group showed os 26 months despite response nact 90% cases long term survivors patients whose interval cytoreduction suboptimal generally os stated influenced three main factors extent disease time diagnosis biology tumour chemosensitivity authors concluded optimal surgery limited morbidity 14% case achieved many cases primary surgery setting hegazy et al found population patients advanced ovarian carcinoma resectability possible neoadjuvant chemotherapy helped select patients feasible relatively less aggressive ids thus preventing initial surgical failure terms optimal debulking however morris et al 1989 demonstrated patients resistant chemotherapy primary treatment little benefit ids this also concluded rafii et al well selection effect nact second intention surgery in another recent study complete response rates three cycles platinum taxane chemotherapy 36.1% ids 80% patients left optimal residuals 2 cms response rate chemotherapy given neoadjuvant setting comparable published literature patients treated conventional upfront tumour reduction surgery followed adjuvant chemotherapy they also found residual decease ids significant predictive factor associated prolonged pfs p .003 to date little good quality evidence either support refute use neoadjuvant chemotherapy treatment ovarian cancer a retrospective study 1980 1997 vergote et al included 285 patients stages iii iv ovarian cancer period 1980 1988 optimal primary cytoreduction 0.5 cm residual disease achieved 82% cases patients stage iv disease metastatic tumour load 1 kg prior procedure poorer survival high postoperative mortality 6% 1989 1997 patients received either upfront surgery chemotherapy depending extent disease performance status this subsequent management improved overall survival despite reduction 25% rate primary debulking large norwegian retrospective study n 789 carried radium hospital looked treatment model 1st relapse ovarian cancer stage they found treatment free interval tfi following primary therapy significant prognostic factor os multivariate analysis they also report age prognostic factor os time secondary cytoreductive surgery survival benefit clear patients optimum secondary cytoreductive surgery followed chemotherapy compared chemotherapy alone time recurrence complete secondary cytoreductive surgery found possible significant percentage patients properly selected secondary surgery guidelines relapse local disseminated disease set secondary cytoreductive surgery recommended independent tfi localized tumours considered tfi 24 months case disseminated disease table 3 selecting right patients right treatment sequence has studied 28 29 one model 85% specificity ability identify patients undergoing optimal surgery certain situations laparoscopy recommended valuable tool evaluating operability upfront second line debulking surgery this paper reviewed rcts large series reflect findings many reports specific debates surrounding role timing surgery ovarian carcinoma there agreement one important prognostic factors survival treatment ovarian cancer amount residual tumour cytoreduction 4 16 it welcome note recent times surgical approaches undergone scrutiny rcts indeed evidence shift debulking debulking select group put another way increased individualisation therapy unlike previous decades use neoadjuvant chemotherapy seems gained popularity though real impact requires formal publication randomized trials eortc 55971 chorus the eortc study presented igcs bangkok generated lot debate role neoadjuvant chemotherapy another factor ignored debate inherent tumour biology question raised still requiring answer know surgeon skills tumour biology determines survival outcome respect opinions vary regarding impact ability surgically debulk hand others put forward strong expression p53 tumour suppressor gene correlating reduced likelihood achieving complete cytoreduction the progress accessibility novel technologies applied biology make possible future assessment new prognostic profilesbased genetic and/or proteomic tumour characteristics | initial surgical management is commonly accepted to date as paramount in the treatment of women presenting with epithelial ovarian cancer and permits the assessment of the disease ( staging ) , the histological confirmation of disease type and grade , and the practice of maximal debulking preceding platinum - based chemotherapy .
many studies have shown that the volume of residual disease after initial surgical cytoreduction inversely correlates with survival .
thus , women with optimal debulking performed by a trained specialist have improved median survival . in this review , we will focus on the answers gleaned from clinical trials on primary and interval surgery , which prompts the question on the timing of surgery in respect to chemotherapy .
interval debulking surgery ( ids ) is secondary cytoreduction following primary debulking and is carried out in between the courses of chemotherapy .
the major clinical trials and the latest systematic reviews seem unable to give any definitive guidance or recommendation for clinical practice .
the choice of aggressive primary cytoreduction or upfront chemotherapy followed by second line surgical cytoreduction seems among others to have to be individualized according to tumour load , prediction of its resectability , and response to chemotherapy .
the role of tumour biology must also be kept in mind .
finally , concrete answers are awaited on the timing of surgery from the ongoing prospective randomized control trials ( chorus and eortc 55971 ) though preliminary data from the latter have already been presented at major meetings ( igcs 2008 ; sgo 2009 ) and ignited strong debate . |
report rare presentation unifocal langerhans cell histiocytosis lch simulating limbal papilloma a 24-year old man presented limbal mass left eye initially suspected papilloma based clinical findings the mass excised histopathological diagnosis acute bullous inflammation granulation tissue made the lesion relapsed 10 months later necessitated repeat resection along corneoscleral patch grafting to best knowledge second report rare presentation lch limbus recurred excision primary mass langerhans cell histiocytosis lch relatively rare disorder characterized monoclonal proliferation histiocytes condition unifocal involvement single organ multifocal presenting disseminated disease unifocal involvement common presentation lch bone frequently affected tissue.1 ocular involvement observed 1% 20% lch cases.2 condition may primarily involve orbit eyelid epibulbar conjunctiva cornea iris vitreous choroid optic nerve secondarily infiltrate ocular tissues surrounding structures.3,4 intraocular involvement lch rarely reported letterer siwe disease.5 orbit usually involved unifocal lch distinct tendency superotemporal bone rim orbit.6 limbus rarely involved unifocal lch presenting clinically infiltrative solitary limbal nodule may misdiagnosed amyloidosis fibrous histiocytoma lymphoma juvenile xanthogranuloma.2,7 diagnosis lch based characteristic histopathological features electron microscopy may also assist diagnosis demonstrating intracytoplasmic inclusions named birbeck granules.1 natural course untreated lch varies progressive fatal systemic disease localized self limited lesions.8 local resection unifocal involvement systemic chemotherapy extensive multifocal lesions proposed treatment modalities lch,9 however spontaneous regression reported unifocal lch cases.1 herein report case unifocal lch presenting unusual limbal lesion recurred primary excision a 24-year old man referred center recurrent painless limbocorneal lesion left eye the primary lesion removed 10 months earlier clinical impression limbal papilloma another eye care center the histopathological diagnosis acute bullous inflammation granulation tissue composed scattered single- multi nucleated histiocytes uncorrected visual acuity 20/20 right eye 20/80 involved left eye slit lamp biomicroscopy elevated vascular mass extending temporal limbus central cornea left eye intraocular pressure within normal limits fundus examination unremarkable clinical diagnosis recurrent limbocorneal papillomatous dermoid like lesion patient underwent mass resection together corneoscleral patch grafting lateral tarsorrhaphy slit lamp photography overlooked preoperatively since lesion thought simple recurrent limbal papilloma after surgery patient received topical betamethasone 0.1% chloramphenicol 0.5% eye drops along non preserved lubrication four times day four weeks gross histopathological examination light microscopy disclosed non keratinized stratified squamous epithelium overlying diffuse inflammatory background composed nests clusters large histiocytes indented grooved nuclei intermixed lymphocytes plasma cells eosinophils figures 1a 1b the histopathological features characteristic lch incomplete surgical excision follow four months signs indicative recurrence lch results proliferation langerhans cells normally present epidermis.10 condition characterized wide clinical spectrum varying spontaneous regression rapid progression recurrence long lasting sequelae.11 lch encompasses three main clinical subtypes unifocal lch eosinophilic granuloma multifocal lch hand schuller christian disease systemic lch abt letterer siwe disease).1 younger patients lch predisposition multifocal involvement.12 etiology lch remains unclear immune dysregulation different cytokines postulated.1 orbit common site involvement eye often includes orbital diploe mononuclear histiocytes multinucleated giant cells intermixed eosinophils lymphocytes plasma cells neutrophil polymorphs.10 langerhans cells immune reactive s-100 protein cd1a.1 electron microscopy demonstrates tennis racket
shaped cytoplasmic inclusions named birbeck granules histiocytes gold standard diagnosis lch.1,12 treatment options unifocal lesions include observation partial complete resection combined resection low dose radiation intralesional corticosteroids systemic chemotherapy may indicated extensive multifocal systemic lesions.1,9 best knowledge report saxena et al2 patient second case unifocal limbal lch presenting recurrent solitary vascularized nodule despite presence mono- multi nucleated histiocytes amongst intrastromal inflammatory cell infiltrates histopathological examination primary lesion lch diagnosed initially might due rare presentation condition limbocorneal area differential diagnoses limbocorneal lch include dermoid amyloidosis fibrous histiocytoma juvenile xanthogranuloma.2 case limbal papilloma initial clinical diagnosis added list there single case report limbal lch patient remained asymptomatic complete excision primary lesion tumor recurred 15 months afterwards.2,7 based clinical histopathological evaluations recurrent tumor partially responded combination chemotherapy patient clinically stable 5.5 years.7 case recurrence developed 10 months resection primary lesion repeat resection together corneoscleral patch grafting performed patient tumor free 4 months although bakhshi et al7 stated surgery radiotherapy unifocal ocular involvement improves function cosmesis functional cosmetic outcomes surgical intervention alone also favorable patient the treatment option limbal lch chemotherapy theoretically due poor penetration chemotherapeutic agents corneal side tumor treatment may associated partial response.7 whether surgical therapy form resection recurrent lesion along limbocorneal patch grafting associated low risk recurrence requires longer follow summary herein report second case recurrent limbocorneal lch missed correct diagnosis initial histopathological studies the recurrent lesion managed surgically included mass resection limbocorneal patch grafting satisfying cosmetic functional results | purposeto report a rare presentation of unifocal langerhans cell histiocytosis ( lch ) simulating a limbal papilloma.case reporta 24-year - old man presented with a limbal mass in his left eye which had initially been suspected to be a papilloma based on clinical findings .
the mass was excised and a histopathological diagnosis of acute bullous inflammation with granulation tissue was made .
the lesion relapsed 10 months later which necessitated repeat resection along with corneoscleral patch grafting .
histopathological studies of the excised lesion led to a final diagnosis of lch.conclusionto the best of our knowledge , this is the second report of a rare presentation of lch in the limbus which recurred after excision of the primary mass .
the recurrent lesion was diagnosed based on histopathology and managed accordingly . |
2-year old asian indian female presented us mild fever swelling right upper lid 10 days duration there history preceding viral illness significant medical history necessitating treatment antibiotics cutaneous anthrax unlikely history unexplained cattle death environment examination child low grade fever skin lesions ophthalmological examination revealed right upper lid edema large black necrotic area lid adherent underlying tissues the child examined pediatrician rule focus infection microscopic examination skin biopsy revealed staphylococci hence cutaneous anthrax ruled the child started intravenous cefotaxime week resolution fever necrotic area turned well defined eschar edema induration after 2 weeks child underwent escharotomy wound debridement full thickness skin graft groin fig 2 general anesthesia groin area cleaned draped the eschar lid found partial thickness excised toto wound margins debrided the harvested skin placed lid defect sutured 6 0 prolene clinical photograph child showing large black necrotic area right upper lid adherent underlying tissues surrounding erythema edema discharge immediate postoperative clinical photograph showing full thickness skin graft groin postoperative photograph 1 week showing healthy well taken graft bacterial invasion arteries dermis subcutaneous tissues produces necrotizing vasculitis the characteristic clinical appearance eg red macule progresses nodular ulcerative lesion central area necrosis surrounded erythema bullae develop subsequently become filled mucopurulent serosanguinous fluid end stage lesions become hemorrhagic slough leading necrotic eschar progression stages rapid typically occurring within 1224 h. reports condition developing healthy individuals without predisposing factors usually eg associated bacteremia also occur absence classic eg rarely involves periocular tissues knowledge cases described literature maccheron et al presented case eg led orbital cellulitis panophthalmitis inamadar et al described diabetic individual developed severe periorbital eg suffering laceration forehead ghosheh kathuria reported case bilateral periorbital eg diabetic male renal failure the mortality rate nonsepticemic cases varies 0% 15% compared 2096% associated septicemia the closest differential diagnosis case necrotizing fasciitis basis clinical features negative blood cultures diagnosis eg entertained case the diagnosis necrotizing fasciitis depends clinical features blood cultures gram stain identify causative organisms patients usually septicemia positive blood cultures the eschar formed following antibiotic administration full thickness eschar adherent surrounding tissues lesion caused ectropion mechanical ptosis blocked pupil considering possible complications scarring including entropion ectropion trichiasis corneal exposure amblyopia child surgical intervention indicated to best knowledge reports skin grafting done treatment modality eg our patient atypical eg due methicillin resistant staphylococcal infection contrast four reports pseudomonas infection the case also highlights need early surgical intervention circumstances probable sequelae scarring upper eye lid resulting mechanical ptosis result stimulus deprivation amblyopia prevented the authors certify obtained appropriate patient consent forms form patient(s ) has given consent images clinical information reported journal the patients understand names initials published due efforts made conceal identity anonymity guaranteed the authors certify obtained appropriate patient consent forms form patient(s ) has given consent images clinical information reported journal the patients understand names initials published due efforts made conceal identity anonymity guaranteed | ecthyma gangrenosum ( eg ) is a cutaneous infection which usually occurs in immunocompromised patients .
we report a case of eg of the eyelid treated with escharotomy and skin grafting , highlighting the importance of surgical management . a 2-year - old asian indian female presented to us with right upper lid edema with a large necrotic area .
the child received intravenous cefotaxime for a week and the necrotic area turned to a well - defined eschar .
escharotomy with wound debridement and skin grafting was done .
the present case highlights the importance of surgical intervention to prevent the sequelae of scarring of upper lid . |
recent years results surgery rectal cancer norway 5-year overall survival os rate 60.1% surpassed colon cancer 57.5% this achieved surgical technique standardized according total mesorectal excision tme subsequent dramatic reductions local recurrences beginning 2007 all colon cancers reported separately norwegian national cancer registry effort systematically survey hopefully improve results nevertheless national strategy standardize surgical treatment along lines radical surgery neither implemented detail generally accepted 2 3 respect the number lymph nodes retrieved may act surrogate measure radical surgery the survival benefit large lymph node harvest shown several reports 24 it accepted nationally offer patients tumor node metastasis tnm stage iii certain age usually 75 years adjuvant chemotherapy it decided rather arbitrary level 12 retrieved nodes enough obtain adequate surgery staging pathologists may key factor optimal lymph node harvest conjoined effort surgeon pathologist would ideal improve results 26 the aim study examine modest radical colon surgery removing mesocolic nodes focus lymph node yield would influence survival surgical improvement might possible using data cohort patients three large norwegian teaching hospitals patients national cohort operated 2000 follow december 2007 mean 7.5 years later three teaching community hospitals haraldsplass deaconal hospital stavanger university hospital akershus university hospital contributed patients all three hospitals teaching community hospitals patients operated open access large number surgeons time extra radical surgery unusual fair assume radical surgery usually constituted moderate mesocolic resection metastases diagnosed patients tumor conditions assessed regarding feasibility resection patients usually went outpatient clinic every third month first 2 years every sixth month 5 years passed blood tests carcino embryonic antigen measurement ultrasonography liver chest x ray carried elderly patients stead bound even followed frequently could tracked life status ascertained identity number official national population registry the specimen examined rinsed surgeons back table mounted board placed box filled enough formaldehyde secure fixation the specimen examined junior pathologist 4872 h assisted consultant tissue paraffin embedded hematoxylin eosin staining used routinely sections examined microscopically metastatic deposits defined lymph nodes structures resembled nodes without containing visible lymphatic tissue patients younger 75 years age classified tnm stage iii offered 12 courses adjuvant treatment 5-fluorouracil plus calsiumfolinate flv the regional committee medical health research ethics western norway data inspectorate national registries approved study the chi square test used compare groups respect categorical variables analysis variance continuous variables the following variables analysed respect survival hospital age gender location lymph nodes lymph node ratio lnr stage tnm stage survival curves estimated kaplan meier method compared using log rank test multiple prognostic factors analysed cox proportional hazards model using spss 17 package all three hospitals teaching community hospitals patients operated open access large number surgeons time extra radical surgery unusual fair assume radical surgery usually constituted moderate mesocolic resection metastases diagnosed patients tumor conditions assessed regarding feasibility resection patients usually went outpatient clinic every third month first 2 years every sixth month 5 years passed blood tests carcino embryonic antigen measurement ultrasonography liver chest x ray carried elderly patients stead bound even followed frequently could tracked life status ascertained identity number official national population registry the specimen examined rinsed surgeons back table mounted board placed box filled enough formaldehyde secure fixation the specimen examined junior pathologist 4872 h assisted consultant tissue paraffin embedded hematoxylin eosin staining used routinely sections examined microscopically metastatic deposits defined lymph nodes structures resembled nodes without containing visible lymphatic tissue patients younger 75 years age classified tnm stage iii offered 12 courses adjuvant treatment 5-fluorouracil plus calsiumfolinate flv the regional committee medical health research ethics western norway data inspectorate national registries approved study the chi square test used compare groups respect categorical variables analysis variance continuous variables the following variables analysed respect survival hospital age gender location lymph nodes lymph node ratio lnr stage tnm stage survival curves estimated kaplan meier method compared using log rank test multiple prognostic factors analysed cox proportional hazards model using spss 17 package two hundred sixty nine patients 152 56.5% women 117 men mean age 71 years range 2093 years studied one hospitals operated male patients younger mean 67 years tumor locations different hospitals p 0.059 locoregional r0 resections single tumor location done 264 patients double resections n 4 suspected locoregional r1 resection n 1 done five patients
table 1tumor locations pathology variables patients resected colon cancer three teaching community hospitals 2000variablesall patientschi square testn 269p valuelocation0.059 right hemicolon115 42.8 transverse colon including flexures44 16.4 descending colon9 3.3 sigmoid colon rectosigmoid96 35.7 multiple r125 1.9)t category0.021 t111 4.1 t230 11.2 t3180 66.9 t448 17.8)tnm stage0.098 i34 12.6 ii116 43.1 iii93 34.6 iv26 9.7)resection two tumors separate locationsno radical loco regional tumor resection tumor locations pathology variables patients resected colon cancer three teaching community hospitals 2000 resection two tumors separate locations radical loco regional tumor resection significant differences hospitals relating tnm stage distribution 34 patients 12.6% stage 116 patients 43.1% stage ii 93 patients 34.6% stage iii 26 patients 9.6% stage iv the number lymph nodes harvested various stages 8.7 stage 10.3 stage ii 10.9 stage iii 10.3 stage iv 11 patients the pathologist classified category tnm stage omitted specify number lymph nodes present twelve lymph nodes examined 41.1% 106/258 resected specimens significantly fewer lymph nodes p
0.001 harvested one hospitals otherwise three patient populations similar characteristics urgent surgery mortality 12.5% 3/24 whereas elective group mortality 4.5% 11/245 did differ hospitals log rank p 0.372 fig
1kaplan meier survival curve 269 patients resected colon cancer three norwegian hospitals 2000 kaplan meier survival curve 269 patients resected colon cancer three norwegian hospitals 2000 whether categorizing number lymph nodes harvested three groups 10 1019 20 two 12 12 differences found os log rank p 0.423 0.270 respectively this still case adjusting hospital tnm stage log rank p 0.449 the uncategorized number lymph nodes significant simple cox regression likelihood ratio p 0.129 however one hospital better survival found lymph node harvest 12 compared 12 log rank p 0.037 shown fig 2 stage ii patients os 72.7% 12 nodes harvested 58.3% 12 nodes ( p 0.124 stage iii patients 5-year os 61.5% 55.6% respectively p 0.508
2kaplan meier survival curve 103 patients resected colon cancer one three norwegian hospitals 2000 patients lymph node harvest 12 showed significantly better overall survival log rank test p 0.037 kaplan meier survival curve 103 patients resected colon cancer one three norwegian hospitals 2000 patients lymph node harvest 12 showed significantly better overall survival log rank test p 0.037 stage iii patients lymph node ratio lnr highly significant patient survival os lnr 1 0.25 83.3.5% lnr 2 0.250.50 63.3% lnr 3 0.510.75 18.8% lnr 4 0.761 18.2% log rank test p 0.001 two hospitals resections t4 tumors chi square test p 0.021 adjusted hospital t4 tumors compared t1t3 significant adverse factor survival log rank test p 0.049 survival according different tnm stages shown table 2 the 5-year os 58.1% stage iii 63.8% stage ii without differences hospitals uni- multivariate analyses os stage iv significantly worse p 0.001
table 2five year overall survival os according different tnm stages 269 patients treated resection colon cancer three norwegian teaching community hospitals 2000tnm stagen osi34 12.6)76.5ii116 43.1)63.8iii93 34.6)58.1iv26 9.7)7.7all stages269 100)58.0 five year overall survival os according different tnm stages 269 patients treated resection colon cancer three norwegian teaching community hospitals 2000 results univariate multivariate cox regression analyses shown table 3 univariate cox regression old age category high lnr tnm stage age variable highly significant continuous variable cutoff value 69 years locations tumors regard various resected segments significant table 3
table 3univariate n 269 patients multivariate n 258 cox regression models analysis overall survival patients resected colon cancer three norwegian teaching community hospitals 2000 univariatemultivariatelr testhr 95% cip valuehr 95% cip valueno sampled lymph nodes per increments 100.79 0.58 1.08)0.1290.82 0.57 1.17)0.266 category<0.0010.129 t1t21 reference)1 reference t31.69 0.94 3.03)1.84 0.55 6.15 t43.38 1.79 6.40)2.64 0.78 8.99)tumor location0.5680.716 right colon1 reference)1 reference transverse colon0.89 0.55 1.46)0.79 0.47 1.32 descending colon0.97 0.39 2.42)1.44 0.57 3.66 sigmoid colon0.70 0.45 1.10)0.81 0.50 1.31 rectosigmoid0.82 0.44 1.53)0.62 0.31 1.26 double0.96 0.23 3.93)0.67 0.15 2.91 r25.83 0.79 42.81)0.61 0.08 4.94)age per 10 years1.46 1.23 1.74)0.0011.68 1.38 2.03)<0.001gender0.1920.031 females1 reference)1 reference males1.26 0.89 1.77)1.52 1.04 2.23)tnm stage<0.001<0.001 i1 reference)1 reference ii1.61 0.82 3.18)0.91 0.23 3.69 iii2.07 1.05 4.12)1.49 0.39 5.66 iv10.50 4.94 22.32)9.26 2.15 39.85)hospital0.3900.169 ahus1 reference)1 reference sus1.06 0.71 1.60)0.72 0.46 1.14 hds1.34 0.87 2.07)0.62 0.37 1.03)hr hazard ratio ci confidence interval lr likelihood ratio sus stavanger university hospital hds haraldsplass deaconal hospital ahus akershus university hospitalanalyses based 258 patients lack specified number lymph nodesfig
3kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according hospital log rank test p 0.372 univariate n 269 patients multivariate n 258 cox regression models analysis overall survival patients resected colon cancer three norwegian teaching community hospitals 2000 hr hazard ratio ci confidence interval lr likelihood ratio sus stavanger university hospital hds haraldsplass deaconal hospital ahus akershus university hospital analyses based 258 patients lack specified number lymph nodes kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according hospital log rank test p 0.372 multivariate model age male gender high lnr tnm stage adverse factors figs 4 5 6 fully adjusted multivariate analysis t category significant removing tnm stage multivariate model category became significant p 0.047 these variables significant hospital tumor location number harvested lymph nodes categories 10 1019 20 lnr also highly significant stage iii patients n 93 adjusted variables table 3 multivariate cox regression hrs 95% cis 1.72 0.80 3.67 5.16 2.48 10.74 4.80 1.92 11.99 lnr 24 vs. lnr 1 respectively p 0.001
4kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according age log rank test p 0.001)fig
5kaplan meier survival curves 93 patients resected colon cancer three norwegian hospitals 2000 according lymph node ratio groups 0.25 group 1 0.250.5 group 2 0.510.75 group 3 0.75 group 4 log rank test p 0.001)fig
6kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according tnm stage log rank test p
< 0.001 kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according age log rank test p 0.001 kaplan meier survival curves 93 patients resected colon cancer three norwegian hospitals 2000 according lymph node ratio groups 0.25 group 1 0.250.5 group 2 0.510.75 group 3 0.75 group 4 log rank test p
0.001 kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according tnm stage log rank test p 0.001 study may underpowered detection assumed difference patients lymph node harvest 12 lymph nodes 12 number patients included study power least 0.84 would necessary detect difference 5-year survival 50% vs. 68% increase sample size detect difference 50% vs. 60% power 0.80 one tailed chi square test tumor locations different hospitals p 0.059 locoregional r0 resections single tumor location done 264 patients double resections n 4 suspected locoregional r1 resection n 1 done five patients
table 1tumor locations pathology variables patients resected colon cancer three teaching community hospitals 2000variablesall patientschi square testn 269p valuelocation0.059 right hemicolon115 42.8 transverse colon including flexures44 16.4 descending colon9 3.3 sigmoid colon rectosigmoid96 35.7 multiple r125 1.9)t category0.021 t111 4.1 t230 11.2 t3180 66.9 t448 17.8)tnm stage0.098 i34 12.6 ii116 43.1 iii93 34.6 iv26 9.7)resection two tumors separate locationsno radical loco regional tumor resection tumor locations pathology variables patients resected colon cancer three teaching community hospitals 2000 resection two tumors separate locations radical loco regional tumor resection there significant differences hospitals relating tnm stage distribution 34 patients 12.6% stage 116 patients 43.1% stage ii 93 patients 34.6% stage iii 26 patients 9.6% stage iv the number lymph nodes harvested various stages 8.7 stage 10.3 stage ii 10.9 stage iii 10.3 stage iv 11 patients the pathologist classified category tnm stage omitted specify number lymph nodes present twelve lymph nodes examined 41.1% 106/258 resected specimens significantly fewer lymph nodes p 0.001 harvested one hospitals urgent surgery mortality 12.5% 3/24 whereas elective group mortality 4.5% 11/245 the 5-year os 58.0% fig 1 differ hospitals log rank p 0.372 fig
1kaplan meier survival curve 269 patients resected colon cancer three norwegian hospitals 2000 kaplan meier survival curve 269 patients resected colon cancer three norwegian hospitals 2000 whether categorizing number lymph nodes harvested three groups 10 1019 20 two 12 12 differences found os log rank p 0.423 0.270 respectively this still case adjusting hospital tnm stage log rank p 0.449 the uncategorized number lymph nodes significant simple cox regression likelihood ratio p 0.129 however one hospital better survival found lymph node harvest 12 compared 12 log rank p 0.037 shown fig 2 stage ii patients os 72.7% 12 nodes harvested 58.3% 12 nodes p 0.124 stage iii patients 5-year os 61.5% 55.6% respectively p 0.508
2kaplan meier survival curve 103 patients resected colon cancer one three norwegian hospitals 2000 patients lymph node harvest 12 showed significantly better overall survival log rank test p 0.037 kaplan meier survival curve 103 patients resected colon cancer one three norwegian hospitals 2000 patients lymph node harvest 12 showed significantly better overall survival log rank test p 0.037 stage iii patients lymph node ratio lnr highly significant patient survival os lnr 1 0.25 83.3.5% lnr 2 0.250.50 63.3% lnr 3 0.510.75 18.8% lnr 4 0.761 18.2% log rank test p 0.001 two hospitals resections t4 tumors chi square test p 0.021 adjusted hospital t4 tumors compared t1t3 significant adverse factor survival log rank test p 0.049 the 5-year os 58.1% stage iii 63.8% stage ii without differences hospitals uni- multivariate analyses os stage iv significantly worse p 0.001
table 2five year overall survival os according different tnm stages 269 patients treated resection colon cancer three norwegian teaching community hospitals 2000tnm stagen osi34 12.6)76.5ii116 43.1)63.8iii93 34.6)58.1iv26 9.7)7.7all stages269 100)58.0 five year overall survival os according different tnm stages 269 patients treated resection colon cancer three norwegian teaching community hospitals 2000 results univariate multivariate cox regression analyses shown table 3 univariate cox regression old age category high lnr tnm stage adverse factors survival age variable highly significant continuous variable cutoff value 69 years locations tumors regard various resected segments significant table 3 )
table 3univariate n 269 patients multivariate n 258 cox regression models analysis overall survival patients resected colon cancer three norwegian teaching community hospitals 2000 univariatemultivariatelr testhr 95% cip valuehr 95% cip valueno sampled lymph nodes per increments 100.79 0.58 1.08)0.1290.82 0.57 1.17)0.266 category<0.0010.129 t1t21 reference)1 reference t31.69 0.94 3.03)1.84 0.55 6.15 t43.38 1.79 6.40)2.64 0.78 8.99)tumor location0.5680.716 right colon1 reference)1 reference transverse colon0.89 0.55 1.46)0.79 0.47 1.32 descending colon0.97 0.39 2.42)1.44 0.57 3.66 sigmoid colon0.70 0.45 1.10)0.81 0.50 1.31 rectosigmoid0.82 0.44 1.53)0.62 0.31 1.26 double0.96 0.23 3.93)0.67 0.15 2.91 r25.83 0.79 42.81)0.61 0.08 4.94)age per 10 years1.46 1.23 1.74)0.0011.68 1.38 2.03)<0.001gender0.1920.031 females1 reference)1 reference males1.26 0.89 1.77)1.52 1.04 2.23)tnm stage<0.001<0.001 i1 reference)1 reference ii1.61 0.82 3.18)0.91 0.23 3.69 iii2.07 1.05 4.12)1.49 0.39 5.66 iv10.50 4.94 22.32)9.26 2.15 39.85)hospital0.3900.169 ahus1 reference)1 reference sus1.06 0.71 1.60)0.72 0.46 1.14 hds1.34 0.87 2.07)0.62 0.37 1.03)hr hazard ratio ci confidence interval lr likelihood ratio sus stavanger university hospital hds haraldsplass deaconal hospital ahus akershus university hospitalanalyses based 258 patients lack specified number lymph nodesfig 3kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according hospital log rank test p 0.372 univariate n 269 patients multivariate n 258 cox regression models analysis overall survival patients resected colon cancer three norwegian teaching community hospitals 2000 hr hazard ratio ci confidence interval lr likelihood ratio sus stavanger university hospital hds haraldsplass deaconal hospital ahus akershus university hospital analyses based 258 patients lack specified number lymph nodes kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according hospital log rank test p 0.372 multivariate model age male gender high lnr tnm stage adverse factors figs 4 5 6 fully adjusted multivariate analysis t category significant removing tnm stage multivariate model category became significant p 0.047 these variables significant hospital tumor location number harvested lymph nodes categories 10 1019 20 lnr also highly significant stage iii patients n 93 adjusted variables table 3 multivariate cox regression hrs 95% cis 1.72 0.80 3.67 5.16 2.48 10.74 4.80 1.92 11.99 lnr 24 vs. lnr 1 respectively p 0.001
4kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according age log rank test p 0.001)fig
5kaplan meier survival curves 93 patients resected colon cancer three norwegian hospitals 2000 according lymph node ratio groups 0.25 group 1 0.250.5 group 2 0.510.75 group 3 0.75 group 4 log rank test p 0.001)fig
6kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according tnm stage log rank test p 0.001 kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according age log rank test p 0.001 kaplan meier survival curves 93 patients resected colon cancer three norwegian hospitals 2000 according lymph node ratio groups 0.25 group 1 0.250.5 group 2 0.510.75 group 3 0.75 group 4 log rank test p
0.001 kaplan meier survival curves 269 patients resected colon cancer three norwegian hospitals 2000 according tnm stage log rank test p 0.001 ) the study may underpowered detection assumed difference patients lymph node harvest 12 lymph nodes 12 number patients included study power least 0.84 would necessary detect difference 5-year survival 50% vs. 68% increase sample size detect difference 50% vs. 60% power 0.80 one tailed chi square test even though several groups pioneered radical surgery colon cancer complete mesocolic excision central tie potential benefits similar tme rectal cancer surgery approach widely adopted country therefore wanted examine background results based less standardized approach potential areas improvement embarking radical procedures championed others advanced tnm stage adverse influence outcome results stage iv versus iii stage iii versus ii significant multivariate analysis stage iii patients 5-year os 58.1% one hospital the 5-year os stage iii worse 47.8% multivariate analysis however adjusted hospital significant survival difference a recently published international multicenter study colorectal population reported identical os 58.8% patients treated 20002002 others found 5-year os 90.796.3% stage ii 64.671.7% stage iii using radical surgical procedures thus consider figures show room improvement although improvement may best realised debatable an advanced stage may theoretically better treated radical surgery even though presence skip lesions rare instances may hardly explain radical complete mesocolic excision shown increase absolute lymph node harvest prognosis patients 2 3 however contested patients benefit radical surgery advanced cases swedish population based retrospective study a median number six lymph nodes detected specimens 1,856 patients operated 1996 2000 there low number nodes specimens left colon whereas right flexure tumors lymph node count inferior instances the feeding vessel areas divided completely i.e. inferior mesenteric artery proximally root medial colic artery population based study netherlands kelder co workers median lymph node harvest six 21% specimens 12 nodes examined thus consider principle radical colon surgery may violated studies tumors locations radical surgery colon cancer recommended reports usa europe japan 2 15 16 retrospective national report based small number supposedly radical colon surgery found approach significantly increased survival compared much larger older group subject standard
the number lymph nodes may seen surrogate marker extent surgery without proper oncologic explanation importance large harvest 2 3 the node count correlated survival stage ii iii disease 2 18 the ontario cancer registry study showed better survival lymph node harvest ten lymph nodes increasing in contrast good evidence reported others increasing total number lymph nodes increases survival significantly 2 4 one study mean harvest 28 lymph nodes data seer database demonstrated cutoff value 15 useful perhaps inherent limit number nodes necessary achieve effect survival nevertheless hypothesis larger negative lymph node yield beneficial contradicted even highly rated institutions in univariate analysis one hospitals achieved significantly better survival harvest 12 lymph nodes however significant survival benefit found harvest 12 lymph nodes multivariate analysis many pathologists involved trial even though specimen handling supposed equal recent study the pathologist found dependent factor lymph node harvest multivariate analysis operating surgeon the overall poor lymph node harvest may also indicate extensive surgery one way improve outcome found one hospitals it may speculated poorer outcome two hospitals may levelled benefit improved lymph node harvest i.e. radical surgery patients 75 years given flv chemotherapy staging considered important reason proper staging colon cancer the minimum number lymph nodes needed somewhat arbitrarily suggested 12 national cancer institute expert panel although authors 14 18 concluded stage migration explanation increased survival benefit studies shown detection positive nodes beyond six seven lymph nodes examined effect staging 19 23 doubtless standardized surgical approach cooperation dedicated pathology service necessary minimum number nodes shall found consequently help outcome assessment studies shown lnr independent better marker pn+ survival study lnr highly significant os adjusted hospitals multivariate analysis five year os varied 83.5% lnr group 1 63.3% lnr 2 18.8% lnr group 3 according wang et al 26 27 prognostic effect lnr depend total number lymph nodes number positive nodes in contrast berger et al found lnr significant prognostic indicator less ten examined nodes became highly significant os disease free survival ten lymph nodes harvested a mayo clinic study found positive correlation number positive lymph nodes survival analyze effect lnr fifty eight percent stage iii patients less 12 lymph nodes examined still found significant survival difference 44.5% lnr group 2 3 65.3% group 1 4 a study new zealand found absolute number lymph nodes retrieved 16 well lnr important prognosis the share stage iii compared stage ii cancers patients amounted 54.9% higher reports it seems obvious large negative lymph node yield regulate lnr importance regard outcome may need examined detail another national report colon cancer single institution found emergency operation colon locations blood transfusion two units old age tnm stage negative predictive factors we study effect blood transfusion emergency operations separated rest partly i.e. 15% reported sjo et al definition may debatable the different colon locations found statistically significant transverse left flexure descending colon multivariate analysis suspect partly 20% make impact even though number urgently operated patients small series expected small group higher mortality 12.5% compared 4.5% elective patients severe co morbidities old age may contributed figures reported others however possible set optimal target 3% elective cases the average age study population 71 years may older series selected patients the average age men women country reached age 62 earliest oap retirement age 81 85 years circumvent analytic problem age sjo et al thus survival figures improved 62% actuarial survival 74% women 79% men the method cumbersome necessitates life tables calculate every patient year three year disease free survival shown parallel overall 5-year survival however requires close follow ct instead conventional ultrasonography chest x ray examinations close follow may even result better treatment metastases according japanese results only 41% lymph node harvest 12 lymph nodes although influenced os one hospital overall more radical surgery may increase lymph node yield potential increase overall survival patients remains seen prospective registry mortality kept low adequate assessment treatment co morbidities well meticulous surgery avoid complications | backgrounda national surveillance program of colon cancer treatment was introduced in 2007 .
we examined prognostic factors for colon cancer operated in 2000 with an aim of improving survival in the new program and a special focus on the merit of lymph node yield.methodsa cohort of 269 patients , 152 women ( 56.5% ) , with a mean age of 71 years , was operated for colon cancer in 2000 at three teaching hospitals and followed up for 7 years.resultsoverall 5-year survival was 58.0% , and overall hospital mortality was 5.2% , with 4.5% in elective cases and 12.5% after urgent surgery . in only 41.1% of the specimens were 12 or more lymph nodes retrieved , but this did not affect survival in the combined cohort , although one of the hospitals achieved a significantly better result with a harvest of 12 or more lymph nodes . in a multivariate analysis , old age ,
gender , a high lymph node ratio ( lnr ) at stage iii , and tumor node metastasis stage were adverse factors for survival.conclusionsthe operative mortality was high and should be reassessed .
the lymph node count did not have a significant impact on outcome overall , whereas the lnr proved significant for stage iii . a prospective protocol using overall lymph node yield as a surrogate measure for more radical surgery
, nevertheless , seems warranted to improve the lymph node harvest according to international recommendations . |
according surveillance epidemiology end results seer database incidence thyroid cancer prevalent endocrine malignancy increased us 1975 2012 estimated 62,450 new cases 1950 deaths 2015.1 rising incidence also documented many countries.2 common types thyroid cancer arise follicular cells include papillary thyroid carcinoma ptc follicular thyroid carcinoma ftc these subtypes account 90%95% cases collectively referred differentiated thyroid cancers dtcs).3 general indolent tumors associated favorable prognosis reflected long term survival rates ~90% standard treatments surgery radioactive iodine therapy.4 nevertheless patients develop recurrent metastatic radioactive iodine refractory disease 10-year survival rates 15%20%.5 advent targeted therapies chemotherapy option treatment patients advanced thyroid cancer follicular origin refractory radioactive iodine.6 doxorubicin known cardiac hematologic toxicities alone combination compounds formed backbone palliative therapy patients.7,8 oncogene pathway driven approach understanding pathophysiology thyroid cancer led development clinical trials assessed antitumor activity tyrosine kinase inhibitors tkis studies provided evidence clinically meaningful antitumor activity seen chemotherapy ultimately supported us food drug administration fda approval vandetanib cabozantinib treatment medullary thyroid cancer mtc recently sorafenib lenvatinib progressive radioiodine refractory ptc ftc notwithstanding progression free survival pfs benefit tkis associated significant unique toxicity profiles furthermore decision start treatment tki challenging encountering asymptomatic patients slowly progressive radioiodine refractory thyroid carcinomas relatively common finding disease this article aims critically review data antitumor activity toxicity potential patient selection tools newly approved multikinase inhibitor lenvatinib.9 a better understanding molecular biology malignancies advent targeted therapies represented unprecedented development therapy several solid tumors recent years including non small cell lung cancer breast cancer melanoma gastrointestinal stromal tumors.1013 comprehensive genetic analysis 496 samples ptc part cancer genome atlas tcga project showed driver genomic alterations found i97% cases.14 vascular endothelial growth factor receptor vegfr one first signaling pathways associated aggressiveness thyroid cancer.1517 despite key role pathophysiology thyroid malignancies signaling pathways drive thyroid cancer cell behavior fibroblast growth factor receptor fgfr platelet derived growth factor receptor pdgfr v ras oncogene homologue ras b raf proto oncogene serine threonine kinase braf ret ptc rearrangement receptor among others recognized important signaling pathways implicated pathophysiology thyroid tumors.1824 recently sorafenib kinase inhibitor approved us fda treatment metastatic iodine refractory dtc sorafenib oral tki abrogates signaling numerous molecules including braf ret ptc vegfr13 pdgfr c kit.25,26 antineoplastic activity sorafenib treatment thyroid cancer demonstrated many trials including decision trial phase iii placebo controlled randomized study 417 patients progressive radioactive iodine refractory locally advanced metastatic thyroid cancer assigned sorafenib 400 mg twice daily placebo.27,28 histological subtypes confirmed central review primarily consisted ptc ftc the primary end point study met hazard ratio hr pfs 0.59 95% confidence interval ci 0.450.76 p<0.0001 the overall survival os difference meet statistical significance likely due crossover effect hr 0.80 95% ci 0.541.19 p=0.14 these benefits counterbalanced frequent treatment related adverse events aes including hand foot syndrome hfs diarrhea alopecia rash documented ~70% participants serious aes occurred 37% patients treated sorafenib compared 26% treated placebo the common treatment related grade 3 aes sorafenib arm included hfs 20% diarrhea 5% skin rash desquamation 4.8% fatigue 5% weight loss 5.8% dose modifications adverse effects required ~60% patients treatment suspended 18% patients most recently meta analysis 24 phase ii iii trials estimated risk grade hfs 39% patients treated sorafenib.29 prophylactic treatment urea based cream decrease incidence delay development hfs patients receiving sorafenib.30 another meta analysis showed grade diarrhea occurred 37% patients treated sorafenib different types tumors negatively impact quality life.31 addition sorafenib several kinase inhibitors studied treatment advanced follicular origin radioiodine refractory thyroid cancer table 1 lenvatinib tki targets vegfr13 fgfr14 pdgfr- ret c kit.3235 preclinical evidence indicates lenvatinib inhibits tumor growth tumor induced angiogenesis cell migration invasion various human thyroid cancer xenograft vitro models.36,37 compared multikinase inhibitors tested patients differentiated thyroid tumors lenvatinib particularly active fgfr family tyrosine kinase receptors table 2 fgfrs contain three immunoglobulin like extracellular domains transmembrane region intracellular domain composed split tyrosine kinase carboxyterminus.38 fgfrs overexpressed variety solid tumors including thyroid cancer.39,40 preclinical models immunohistochemistry analyses tumor tissues showed fgfr1 overexpressed 50%75% cells follicular papillary tumors fgfr2 seems expressed normal thyroid tissues tumors.19 fgfr3 overexpressed 25%50% well differentiated follicular origin thyroid cancers cells xenograft models treated tki pd173074 known selectively inhibit fgfr phosphorylation tyrosine kinase activity solid tumors.41 abrogation fgfr1 3 signaling pd173074 associated vitro vivo growth inhibition differentiated thyroid tumor cell lines tpc-1 cells sustained 90% inhibition cell proliferation xenograft models treated pd173074 achieved tumor size reduction ~55%.19 observations indicate importance fgfr pathway thyroid cancer pathogenesis progression next generation sequencing analysis genomes 492 samples ptc identified disease low mutational burden compared carcinomas.14
fgfr3 amplification noted one case fgfr2 gene fusions observed two cases in dose escalation 3 3 phase trial maximum tolerated dose mtd lenvatinib investigated among wide range doses 0.520 mg twice daily solid tumors including colon sarcoma non small cell lung cancers.43 dose limiting toxicities grade 3 elevations aspartate alanine aminotransferases thrombocytopenia observed 20 mg twice daily dose level mtd 13 mg twice daily 2-week on/1-week schedule trial of note five patients experienced six serious aes related possibly related study drug.43 larger phase trial investigated safety efficacy lenvatinib among 82 patients advanced refractory solid tumors included renal colorectal pancreatic tumors grade 3 hypertension proteinuria occurred nine patients 11% six patients 7% respectively positive correlation dose lenvatinib hypertension proteinuria observed expanded mtd cohort 25 mg n=24 grade 3 hypertension occurred three 13% patients grade 3 proteinuria two 8% patients.44 based phase trial results subsequent phase ii trial conducted among 58 patients differentiated radioiodine refractory thyroid cancer treated lenvatinib 24 mg daily prior anti vegfr therapy chemotherapy reported 29% 14% patients respectively aes led dose interruptions reductions study drug withdrawal 74% 66% 26% patients respectively the common grade 3 side effects weight loss 12% hypertension 10% proteinuria 10% diarrhea 10% fatigue 9% dehydration 9% arthralgia 5% note two patients died serious aes one arterial hemorrhage one cardiac arrest).45 another cohort patients lenvatinib tested set dose 24 mg daily 59 patients advanced mtc 44% received prior anti vegfr therapy 15% received prior chemotherapy.46 overall response rate orr 36% median pfs 9 months dose reduction interruption necessary 59% patients 24% patients discontinued treatment due aes the common grade 3 side effects included diarrhea 14% hypertension 7% decreased appetite 7% fatigue 5% dysphagia 5% increased levels alanine aminotransferase 5% there three deaths due aes including respiratory arrest otherwise specified respiratory failure paraneoplastic syndrome specified respiratory failure related death deemed treatment related treating physicians.46 seminal phase iii study select total 392 patients radioactive iodine resistant progressive thyroid carcinomas follicular origin defined progression within previous 13 months according response evaluation criteria solid tumors presence one measurable lesion without radioiodine uptake iodine scan disease progression within 12 months radioiodine therapy randomized either lenvatinib n=261 placebo n=131).47 significant improvement median pfs primary end point documented among patients treated lenvatinib compared placebo 18.3 vs 3.6 months hr 0.21 99% ci 0.140.31 p<0.001 unprecedented response rate 64.8% ninety three patients trial received prior anti vegf tkis sorafenib 77% sunitinib 9% pazopanib 5% 9% despite previous use targeted therapies lenvatinib also significantly improved pfs subgroup patients 15.1 vs 3.6 months hr 0.22 95% ci 0.120.41 increased response rates 62.1 vs. 3.7 .48 complete radiologic responses seen four patients prolonged stable disease longer 23 weeks noted 39 patients treated lenvatinib consistent results phase ii studies toxicity profile study significant noted use multikinase inhibitors lenvatinib toxicity resulted significant rate dose adjustments clinically relevant consequences dose reductions dose interruptions treatment discontinuation needed 67% 82% 14% patients respectively frequent grade 3 higher treatment related aes hypertension 42% fatigue 9% diarrhea 8% proteinuria 10% arterial venous thromboembolic effects 2.7% 3.8% respectively acute renal failure 1.9% hepatic failure 0.4% dose modifications due severe diarrhea decreased appetite required 22% 18% patients respectively larger trial qtc prolongation seen 8% patients 1.5% experienced grade 3 aes defined qtc 501 ms however among study healthy individuals took single 32 mg dose lenvatinib lack qtc prolongation within 24-hour continuous electrocardiogram ekg monitoring period.49 thus far seems evidence significant direct cardiac toxicity associated lenvatinib note six deaths lenvatinib group considered treatment related three cases resulted unspecified causes three associated pulmonary embolism hemorrhagic stroke health deterioration however four deaths nonspecific etiology thus difficult accurately assess contribution lenvatinib toxicity fatal events yet data median os available significant os benefit demonstrated lenvatinib thus far hr 0.73 95% ci 0.51.0 p=0.10 notably 109 patients per protocol allowed cross lenvatinib arm upon disease progression confound differences os november 2013 nonetheless updated survival data analysis select trial later cut date june 15 2014 presented 2015 european cancer congress.50 adjust crossover estimate true os treatment effect effect would observed absence switching rank preserving structural failure time model used 34 months follow trial lenvatinib arm the median os reached group placebo crossover arm the reported medial os 19.1 months 95% ci 14.3 estimable the rank preserving structural failure time adjusted hr showed significant difference os treatment groups hr 0.53 95% ci 0.340.82 nominal p=0.0051 determined using resampling method bootstrapping of note hypertension common grade 3 higher toxicity affecting 42% patients select trial observed 7%10% patients phase ii trials.45,46 grade hypertension occurred 67% patients treated lenvatinib select led dose reductions interruptions 20% patients phase ii trials hypertension observed 51%76% patients treated lenvatinib because risk hypertension careful cardiovascular evaluation patients including performing echocardiogram ekg profile considered prior initiation therapy an ekg also performed prior initiation therapy considering risk qtc prolongation associated multikinase inhibitors general.51 frequent blood pressure monitoring performed throughout treatment according select study protocol dose interruptions 28 days patients grade 2 hypertension performed prior dose reduction 20 14 10 mg patients confirmed systolic blood pressure bp 140 mmhg diastolic bp 90 mmhg prescribed antihypertensive agents monitored every 2 weeks patients systolic bp 160 mmhg diastolic bp 100 mmhg despite optimal management dose reduction phase iii select study gastrointestinal perforation fistula observed 2% patients receiving lenvatinib compared 0.8% placebo group.52 addition aerodigestive fistula formation also documented case report patient receiving lenvatinib developed significant general decline required percutaneous gastrostomy nutritional support.53 radiation therapy large thoracic tumor burden considered risk factors aerodigestive fistula formation associated lenvatinib anti angiogenesis therapies.54,55 hemorrhagic complications also documented 35% patients treated lenvatinib phase iii trial compared 18% placebo group epistaxis common hemorrhagic event 11% grade 1 1% grade 2).52 incidence severe hemorrhage episodes grade 35 comparable groups 2% lenvatinib 3% placebo these results agreement risk fatal bleeding documented tyrosine kinase inhibitors highlight importance careful monitoring.56 clinically meaningful benefit pfs tumor response rate disease setting led us fda approval lenvatinib february 2015 treatment progressive thyroid cancer despite overall response rate 60% across distinct histologic subtypes ie papillary poorly differentiated follicular hrthle cell 35% patients meet criteria response therapy lenvatinib.47 particularly important patients symptomatic tumor burden would benefit tumor reduction also described earlier lenvatinib associated significant toxicity treatment related deaths hence paramount find predictive markers response may facilitate selecting patients therapy the first best characterized point mutation thyroid cancer valine glutamate substitution residue 600 v600e braf v raf murine sarcoma viral oncogenes homolog b1 gene.14,57 results constitutive activation braf kinase confers continuous activation mitogen activated protein kinase mapk signaling pathway consequent uncontrolled cell growth.58
braf mutations may prognostic value differentiated thyroid tumors recent retrospective analysis 500 patients ptc showed tumor recurrence rates 25% among braf v600e mutation compared 9.6% mutation negative patients.59 following braf mutations thyroid cancers 40% frequent driver mutations occur ras genes the common ras mutations thyroid cancer occur nras hras genes lead constitutive activation mapk phosphoinositide 3-kinase pi3k)/akt pathways.60,61
ras mutated 20% ftc 6%13% patients ptc.14,60,61 archival formalin fixed paraffin embedded tissues obtained analyzed braf ras mutation hotspots select trial interestingly benefit lenvatinib independent braf ras mutational status tumor preplanned subgroup analysis select.47 could due wide range tumor cell targets affected lenvatinib ability target unique molecules fgfr.19 angiogenesis mtc highly vascular tumor mediated principally vegf fgf pdgf respective receptors.62 overexpression vegf vegfr2 observed 50%95% mtc tumors associated metastases.6365 aforementioned phase ii trial lenvatinib treatment 59 patients advanced mtc circulating cytokine angiogenic factors levels collected 51 patients 8 days therapy high baseline levels vegf soluble vegfr3 pdgf- low baseline levels soluble tie-2 associated tumor reduction low baseline levels angiopoietin-2 ang-2 hepatocyte growth factor interleukin-8 associated tumor reduction prolonged pfs.46 select trial accrued patients ftc ptc blood cytokine angiogenic factor levels 99% patients collected cycle 1 day 15 day 1 subsequent cycles ang-2 and stie-2 levels consistently decreased throughout therapy lenvatinib compared placebo group decreased ang-2 stie-2 levels along increased vegf levels correlated tumor shrinkage end treatment levels two molecules c2d1 increased 78.9% 81% patients respectively.66 association lenvatinib benefit lack thereof baseline angiogenic factors merits investigation affect patient treatment selection finally light lenvatinib related toxicity possible interaction age therapy lenvatinib formally explored os end point select trial improved os identified patients older 65 years median 71 years treated lenvatinib.67 at juncture antitumor activity lenvatinib including improvement pfs among patients advanced progressive thyroid carcinomas follicular origin supports clinical use recently published guidelines american thyroid association national comprehensive cancer network recommend possible use patients radioiodine refractory progressive thyroid carcinomas first line kinase inhibitor therapy.68,69 thus far multikinase inhibitors displayed comparable degree efficacy treatment advanced radioiodine refractory thyroid cancer taking account caveats inherent cross trial comparisons us fda approved tki sorafenib based results decision trial showed pfs 10.8 months sorafenib arm vs 5.8 months placebo arm hr 0.59 95% ci 0.450.76 p<0.0001 orr 12.2%.27 contrast lenvatinib treated patients derived greater benefit tki compared placebo select trial reflected pfs 18.3 months vs 3.6 months hr 0.21 99% ci 0.140.31 p<0.001 orr 64.8%.47 trials included similar patient populations decision trial excluded patients previous tki exposure the select trial included 93 patients received prior tki therapy sorafenib 77% sunitinib 9% pazopanib 5% 9% the benefit lenvatinib mitigated prior multikinase treatment.48 one could hypothesize remarkable antitumor activity lenvatinib due tyrosine kinase inhibition fgfr.19 fgfr family activation leads upregulation ras mapk pi3k akt signaling pathways.70 fgfr overexpression phosphorylation observed preclinical studies suggest fgfr important signaling pathway thyroid tumors follicular origin reviewed earlier.19 despite efficacy toxicity lenvatinib merits cautious consideration 65%71% patients treated lenvatinib experienced grade 3 higher toxicities warranted dose reductions and/or delays majority patients previous phase ii iii clinical trials table 3).4547 pattern disease progression radioiodine refractory thyroid tumor should also considered time therapy initiation median pfs placebo treated groups range 3.65.8 months extent asymptomatic patients may take months meet criteria disease progression hence potential anti tumor efficacy needs carefully counterbalanced potential toxicities asymptomatic patients prior drug initiation lenvatinib initiated time rapid radiological clinical disease progression setting symptomatic tumor burden furthermore patients need carefully selected lenvatinib therapy physicians aware frequency moderate severe aes including hypertension weight loss decreased appetite proteinuria associated medication table 3 finally careful consideration locally directed therapies eg surgery radiation therapy thermal ablation given prior initiation course treatment lenvatinib.68,69 particular importance setting mixed responses distinct metastatic sites imminent risk complications related local progression invasion metastasis figure 1 formal quality life assessments reported select trial sorafenib treated patients decision trial lower treatment scores functional assessment cancer therapy general euroqol-5d euroqol-5d visual analog scales suggesting detectable negative impact sorafenib therapy health related quality life.71 nonetheless light toxicity profile corollary physicians need fully aware aggressively treat eventual aes maintain quality life the role lenvatinib salvage therapy patients previous exposure tkis sorafenib question clinical relevance a retrospective analysis 17 patients sorafenib refractory thyroid cancer treated salvage therapy including sunitinib n=4 pazopanib n=3 cabozantinib n=4 lenvatinib n=3 vemurafenib n=3 revealed orr 41% median pfs 11.4 months.72 suggests tkis different targets may still effective refractory disease these results consistent subgroup analysis select trial patients previously exposed tkis still derived benefit lenvatinib.48 patients history previous exposure tkis orr 65.6% whereas tki nave patients orr 62.1% question whether lenvatinib sorafenib first option first line treatment patients iodine refractory dtc still remains the lack head head comparison molecules generates need constant individualized decision making taking account estimated efficacy toxicity multikinase inhibitor there biomarker facilitates selection prediction response lenvatinib stratified analysis pre therapy braf ras mutational status failed show predictive benefit tests phase iii trials sorafenib lenvatinib.27,47 simultaneous targeting multiple molecular pathways potential strategy improve antitumor activity lenvatinib potentially increase efficacy delay resistance lenvatinib therapy radioiodine refractory thyroid cancer the combined analysis genomic variants gene expression methylation patterns 496 samples ptc able cluster tumor two main molecular signature groups braf mutant ras mutant tumors differential downstream pathway activation mapk pi3k akt respectively.14 one could hypothesize lenvatinib efficacy could increased treatment combinations driven pathway enriched patient selection according differential tumor signatures the development combination treatment mek inhibitor trametinib braf inhibitor dabrafenib recurrent thyroid cancer ongoing nct01723202).73 however knowledge multiple pathway blockade approach lenvatinib nonexistent time also hepatocyte growth factor hgf met overexpressed majority ptcs 90% rarely ftcs.74 hgf overexpression correlates invasiveness clinically aggressive behavior ptcs.7577 met receptor key component hgf pathobiology ptc.78 among ptc cell lines met inhibitor pha665752 inhibited tumor cell growth induced apoptosis.79 interestingly preclinical data indicate one mechanisms intrinsic lenvatinib therapy resistance mediated hgf pathway activation various solid tumors melanoma pancreatic carcinoma.80 circumvented combination lenvatinib met inhibitor golvatinib showed significant reduction lenvatinib resistant cell proliferation vitro.80 phase dose escalation trial combination lenvatinib golvatinib patients melanoma glioblastoma currently way nct01433991).81 studies necessary establish role met inhibition thyroid cancer interestingly degree toxicity anti endothelial growth factor receptor anti vegf drugs positively correlated efficacy among patients solid tumors including colorectal lung renal cell carcinoma head neck.82,83 degree toxicity namely hypertension proteinuria could serve surrogate biomarker lenvatinib activity suggested aes worst grade proteinuria correlated lenvatinib antitumor activity small phase dose escalation clinical trial.84 knowledge stratified analysis efficacy lenvatinib toxicity reported in addition dose reduction tkis positively correlated clinical benefit non small cell lung cancer chronic myeloid leukemia.8587 clinical practice tempting adopt dose reduction strategy avoid lenvatinib associated toxicities offering patients effective treatment data yet available efficacy dose reduced treatment advanced thyroid cancer lenvatinib results expanded cohort program lenvatinib treatment radioiodine refractory dtc three different doses 24 20 14 mg daily shed light important question nct02211222).88 conclusion lenvatinib novel multikinase inhibitor demonstrates significant responses pfs benefit treatment radioiodine refractory dtc consistent current 2015 american thyroid association national comprehensive cancer network guidelines lenvatinib considered first line therapy setting clinically relevant disease progression and/or symptomatic disease burden setting radioiodine refractory disease warning physicians fully cognizant side effect profile including potentially fatal toxicities figure 1).68,69 aggressive monitoring guideline based management toxicities similar utilized tkis enforced prevent decline quality life.8991 future studies endeavor establish biomarkers predictive toxicity efficacy lenvatinib treatment radioiodine refractory thyroid tumors | thyroid cancer is the most common endocrine malignancy , with over 60,000 cases reported per year in the us alone .
the incidence of thyroid cancer has increased in the last several years .
patients with metastatic differentiated thyroid cancer ( dtc ) generally have a good prognosis .
metastatic dtc can often be treated in a targeted manner with radioactive iodine , but the ability to accumulate iodine is lost with decreasing differentiation . until recently , chemotherapy was the only treatment in patients with advanced thyroid cancer , which is no longer amenable to therapy with radioactive iodine .
the modest efficacy and significant toxicity of chemotherapy necessitated the need for urgent advances in the medical field .
new insights in thyroid cancer biology propelled the development of targeted therapies for this disease , including the tyrosine kinase inhibitor sorafenib as salvage treatment for dtc . in 2015 ,
the us food and drug administration approved a second tyrosine kinase inhibitor , lenvatinib , for the treatment of radioiodine - refractory thyroid cancer .
although associated with a significant progression - free survival improvement as compared to placebo in a large phase iii study ( median progression - free survival 18.2 vs 3.6 months ; hazard ratio 0.21 ; 99% confidence interval 0.140.31 ; p<0.001 ) , the benefit of lenvatinib needs to be proved in the context of associated moderate to severe toxicities that require frequent dose reduction and delays .
this article reviews the evidence supporting the use of lenvatinib as salvage therapy for radioactive iodine - refractory thyroid cancer , with a focus on the toxicity profile of this new therapy . |
stroke neurological disease caused cutoff normal blood supply due vessel
rupture thrombosis causes brain tissue damage motor sense recognition
language perception deficits typical symptoms disease depending
affected areas size cause damage1 stroke patients mainly experience motor disorders degeneration
balancing ability due unbalanced posture caused asymmetric arrangement
hemiplegia disrupts independent activities daily living adl)2 ability balance individual ability maintain center gravity within
base region keeping body balanced state3 stroke patients lack balancing ability show degeneration
physical function due reduction walking activity caused inappropriate
posture proprioception malfunction abnormal muscle tension4 resolve balance problems caused stroke
brunnstrom approach bobath approach proprioceptive neuromuscular facilitation pnf
used methods focus enhancing physical functions balance improving active
motor control5 pnf utilizes typical helical diagonal pattern stimulate proprioceptive sensation
promote nerve root response enhancing functional movement5 6 it improves muscle
strength flexibility balance applying non paretic side force
transferred paretic side effectively promoting muscle activity6 davis7 suggested aquatic pnf lower
extremity patterns reinforcing muscular strength enhancing muscle reeducation song
kim8 applied aquatic pnf lower
extremity patterns patients stroke stimulated proprioceptors thus
improving control function nerve roots enhancing balance aquatic environment buoyancy allows limbs moved easily little
strength enhancing coordination motion9 water resistance also enables body move helping increase
muscle strength joint movement balance10 multiple studies reported pnf lower extremity patterns
ground based exercise stroke patients reported aquatic pnf this study aimed investigate effects aquatic pnf lower extremity patterns
balance adl stroke patients six months receiving stroke diagnosis via either computed tomography magnetic
resonance imaging 20 patients randomly assigned control group n 10 5 males
5 females experimental group n 10 5 males 5 females control group
assigned conduct pnf lower extremity patterns ground experimental
group assigned conduct pnf lower extremity patterns water all participants scored
24 points mini mental status examination mmse could perform assignments
capable walking 10 independently classified 4 brunnstrom scale
the
protocol approved institutional review board nambu university
conducted accordance ethical standards declaration helsinki the
general features participants listed table 1table 1.general characteristics subjectseg n=10)cg n=10)gender male female)5 55 5age years)69.1 3.268.0 3.1height cm)167.6 8.2165.9 6.9weight kg)67.9 5.966.7 6.7paretic side right left)5 55 5onset months)9.8 1.310.3 1.4meansd eg experimental group cg control group the age experimental group 69.1 3.2 years height 167.6
8.2 cm weight 67.9 5.9 kg time since stroke onset 9.8 1.3 months the age
control group 68.0 3.1 years height 165.9 6.9 cm weight 66.7
6.7 kg time since stroke onset 10.3 1.4 months meansd eg experimental group cg control group experimental group conducted pnf lower extremity patterns using rhythmic initiation
ri method 110 cm water surface water temperature 3133 c exercises
performed supine posture simple stretching subjects wore body ring
l5 s1 neck collar the control group conducted pnf
lower extremity patterns ground supine posture simple stretching the ri
method starts passive exercise proceeds active resistance exercise helps
increase coordination motor sensation balance pnf lower extremity patterns
consisted patterns d1 d2 the d1 pattern ends
either flexion adduction external rotation knee flexion extension adduction external
rotation knee extension the d2 pattern ends either flexion adduction external
rotation knee flexion extension adduction external rotation knee extension pnf lower
extremity patterns conducted 30 minutes day 5 days week 6 weeks balance measured berg balance scale bbs timed go test tugt
functional reach test frt one leg stand test olst the bbs consists 14 items
categorized sitting standing postural changes scores category
range 04 56 possible total points higher scores indicate better balance the
tugt measures time required stand chair shuttle back forth
chair spot front subject three times the frt measures distance one
reach arm standing posture the olst measures long one stand
one foot eyes open without placing foot ground adl measured functional independence measure fim consists 13
items related mobility 5 related recognition the items scored scale
17 126 possible total points higher scores indicate better independence data analyzed using spss 12.0 spss chicago il usa windows descriptive
statistics used general features participants paired test used
determine pre- post experiment differences independent test used
determine group differences the changes result bbs tug frt olst fim listed table 2table 2.comparison results bbs tug frt olst fim
experimental control groupsgroupprepostd valuebbseg42.8 1.644.9 1.7 2.1 1.7*cg39.9 2.040.6 1.7 0.7 0.8tugteg21.9 1.320.1 1.9*1.8 1.3*cg20.4 1.019.7 1.0*0.7 0.6frteg17.7 0.919.0 1.4 1.3 0.9*cg16.7 0.617.2 0.4 0.5 0.6olsteg4.3 0.85.7 1.1 1.4 0.9*cg3.4 0.54.1 0.7 0.6 0.7fimeg82.3 2.587.5 3.7 5.2 5.3*cg80.1 1.281.4 1.4 1.3 1.3meansd p<0.05 value difference value eg experimental group
cg control group bbs berg balance scale tugt timed go test frt
functional reach test olst one leg stand test fim functional independence
measure the experimental control groups showed significant differences
pre- post experiment variables p 0.05 group comparison the
experimental group significantly different control group p 0.05 meansd p<0.05 value difference value eg experimental group
cg control group bbs berg balance scale tugt timed go test frt
functional reach test olst one leg stand test fim functional independence
measure the purpose study investigate effects aquatic pnf lower extremity
patterns balance adl stroke patients the experimental group showed significant
improvement balance adl aquatic pnf p 0.05 significantly
better balance adl relative control group p 0.05 for example performance 10 weeks aquatic proprioception exercise
seniors enhanced motor abilities11
in addition kim lee12 pnf reported
aquatic lower extremity patterns enhanced balance healthy adults moreover song
kim8 reported aquatic pnf
effectively affected balance stroke patients these results indicate aquatic pnf
lower extremity patterns help enhance balance stroke patients pnf used gradual
resistance exercise employs helical pattern maximizes motor unit recruitment
proprioceptive stimulation5 13 aquatic pnf promotes maximum usage muscle fibers
due intense circumstances caused buoyancy turbulence moreover water acts
form resistance stimulating proprioception thus helping improve postural
control balance8 13 14 the common method examining adl stroke patients use fim
present study the experimental group showed significant enhancement adl
aquatic pnf p 0.05 suomi collier15 reported adl arthritis patients enhanced
conducting aquatic exercise sato et al.16 reported adl abnormal adults enhanced
conducting water exercise similar studies enhancement adl observed
conducting aquatic exercise present study the enhancement adl result
enabling movement even small amount force this due assistance
water buoyancy decreased gravity reducing burden muscles joints10 15 promote functional recovery paretic side spontaneously
enabled thus enhancing adl improving functional independence15 16 the movements
also stimulate shortened muscles promoting training effect enhancing adl17 a limitation study utilized small number participants
confirmed positive effects persisted future research address
things investigating effect aquatic pnf lower extremity patterns stroke
patients | [ purpose ] this study investigated the effect of aquatic proprioceptive neuromuscular
facilitation ( pnf ) patterns in the lower extremity on balance and activities of daily
living ( adl ) in stroke patients . [ subjects ] twenty poststroke participants were randomly
assigned to an experimental group ( n = 10 ) or a control group ( n = 10 ) .
the experimental
group performed lower extremity patterns in an aquatic environment , and the control group
performed lower extremity patterns on the ground .
both exercises were conducted for 30
minutes / day , 5 days / week for 6 weeks .
balance was measured with the berg balance scale
( bbs ) , timed up and go test ( tugt ) , functional reach test ( frt ) , and one leg stand test
( olst ) .
activities of daily living were measured with the functional independence measure
( fim ) .
a paired t - test was used to measure pre- and post - experiment differences , and an
independent t - test was used to measure between - group differences .
[ results ] the
experimental and control groups showed significant differences for all pre- and
post - experiment variables . in the between - group comparison , the experimental group was
significantly difference from the control group . [ conclusion ] these results indicate that
performing aquatic proprioceptive neuromuscular facilitation patterns in the lower
extremity enhances balance and adl in stroke patients . |
discovery vitamin k antagonists vkas anticoagulation occurred 1920s veterinarian frank schofield studied hemorrhagic disease affecting cattle consuming sweet clover karl link team studied spoiled sweet clover 1939 extracted dicumarol identified hemorrhagic agent substance sweet clover affecting coagulation the discovery dicoumarol made possible inhibit thrombosis study anticoagulation therapy humans early 1940s decades 1930 1940 professor armand quick developed routine prothrombin time pt coagulation test preceded use vkas served basis oral anticoagulant therapy oat monitoring onset however first drug oat subsequently found drawbacks reason long half life karl link synthesized 150 anticoagulant compounds found one particularly active molecule named warfarin 4-hydroxy compound patent holder wisconsin alumni research foundation professor paul owren found factor v developed new pt method subsequent quick method overcome drawbacks the owren reagent combined thromboplastin reagent thrombotest used mainly nordic countries benelux japan reason different reagent composition quick technique sensitive coagulation factors fibrinogen ii v vii x owren technique affected deficiencies factors ii vii x. quick method measures factor v fibrinogen dependent warfarin therapy constitutes drawback oat warfarin widely used drug oat world wide predictable onset duration action excellent bioavailability the therapy effective variety clinical indications anticoagulation dosage clinical response still vary markedly among patients depending genetic inheritance age metabolism warfarin racemic mixture two optically active isomers r forms it rapidly absorbed gastrointestinal tract within 90 min half life 3642 h. circulation warfarin bound plasma proteins mainly albumin warfarin interferes cyclic intercon version vitamin k 2,3 epoxide vitamin k epoxide thus vka vitamin k cofactor carboxylation vitamin k dependent coagulation factors vka inhibits synthesis coagulation factors ii vii ix x liver remain partially inactive unless 9 13 amino terminal glutamate glu residues carboxylated form ca binding -carboxyglutamate gla residues figure 1 this carboxylation step renders coagulation factors functionally active binding ca phospholipid surface therapeutic dosages warfarin decrease 3050% total amount vitamin k dependent coagulation factor synthesized liver the secreted molecules liver carboxylated resulting diminished biological activity 1040% normal figure 1the enzyme reactions involved metabolic function vitamin k. vitamin k dependent carboxylase catalyzes transformation peptide- factors ii vii ix x bound glutamate residues glu -carboxyglutamate gla residues presence vitamin k hydroquinone carbon dioxide molecular oxygen vitamin k hydroquinone oxidized reaction vitamin k 2,3 epoxide the reduction latter vitamin k quinone catalyzed vitamin k epoxide reductase use certain dithiols reductants ii vitamin k quinone reduced vitamin k hydroquinone reactions catalyzed either dithiol dependent iii nad(h)p dependent iv entzyme ( uotila l. recent findings functions requirements vitamin k humans klinlab 1998 3 97101 enzyme reactions involved metabolic function vitamin k. vitamin k dependent carboxylase catalyzes transformation peptide- factors ii vii ix x bound glutamate residues glu -carboxyglutamate gla residues presence vitamin k hydroquinone carbon dioxide molecular oxygen vitamin k hydroquinone oxidized reaction vitamin k 2,3 epoxide the reduction latter vitamin k quinone catalyzed vitamin k epoxide reductase use certain dithiols reductants ii vitamin k quinone reduced vitamin k hydroquinone reactions catalyzed either dithiol dependent iii nad(h)p dependent iv entzyme ( uotila l. recent findings functions requirements vitamin k humans klinlab 1998 3 97101 warfarin treatment reduces number gla residues normal 9 13 per clotting factor molecule concomitant fall coagulant activity when number residues decreases 13 9 70% activity clotting factor remains one molecule contains six carboxylated residues 2% activity present the liver excretes active inactive coagulation factors plasma affect international normalized ratio inr measurement possibly escaped notice world health organization recommendation prothrombin time methodology the calculation formula inr samplesec normalsec isi international sensitivity index isi near 1.0 reagent sensitive isi little meaning inr calculation the quick owren pt methods common generally accepted means monitoring vka therapy a comparison pt methods published recent article owren pt superior recommends use inr harmonize pt results therapeutic ranges globally patient care clinical practice scientific literature units used formerly proved inadequate international communication the challenge global clinical laboratories harmonize inr testing level inr results consistent regardless methods used the use inr system still involves difficulties sample citrate concentration different reagents thromboplastins instruments isi local isi calibration harmonize results horsti colleagues measured 150 samples patients oral anticoagulation using seven commercial reagents four different calibrator kits the reagent manufacturer informs isi value laboratory measure isi isi calibration kit local calibration pt reagent lot the meaning isi power inr calculation equation displayed previous section first aim original recommendation harmonize inr results calibrating reagent isi values human combined primary reference preparation irp code 67/40 thromboplastins different sources human brain rabbit brain rabbit lung ox brain yield quite different levels pt the hierarchy reference thromboplastin preparations presented van den besselaar associates calibration procedure complex demanding second stage recommendation isi calibration local calibration using certified lyophilized plasmas this alternative means determining isi involves use freshly pooled plasmas 20 normal individuals 60 patients receiving coumarin oat such numbers samples necessary obtain precise calibration line isi calculation freshly pooled plasma used determine reagent instrument isi acceptable precision good result calibration model poller colleagues european concerted action anticoagulation ecaa compared local isi calibration direct inr correction locally reported inrs local inr correction harmonization ) it clear plasmas patients warfarin therapy always involve varying amounts inactive coagulation factors depending level anticoagulation individual patient characteristics see section warfarin all former calibration models involve principle calibrator contains average amount inactive coagulation factors inhibition means average correction patient inr results is average correction inactive coagulation factors appropriate individual patient samples measuring range 1 5 inr ? is fact calibrators according biochemical principles contain inactive coagulation factors inhibition ? do different reagents behave identically active inactive coagulation factors earlier studies measured inactive coagulation factors inhibition four different kits noted conspicuous variation inhibition isi calibration based normal plasma normal plasma dilutions without inactive coagulation factors principle today quick owren pt methods measure sum active coagulation factors fii fvii fx inhibition inactive coagulation factor counterparts the new generation pt method measure separately active coagulation factors fii fvii fx inhibition caused inactive partially inactive coagulation factors two measurements one sample needed cost per sample twice much in addition number inactive coagulation factors varies markedly different calibrator kits manufactured local the harmonization inr results using different pt methods reagents problematic attempted according recommendation new medications oat developed number years anticipated without laboratory test control effort displace warfarin medication the new molecules expensive global use involve serious side effects possibly never popular warfarin old cheap means widely used accepted globally drawback warfarin medication regular laboratory control would important develop warfarin therapy greater attention laboratory control helps patient care different reagents thromboplastins react variably inactive coagulation factors cause difficulties calibration using patient plasmas contain inhibiting coagulation factors every new anticoagulant therapy patient tested inhibition commencement therapy the accuracy harmonization patient inr results different reagents utmost importance scientific publications medication patient care today measuring principle taking sum active coagulation factors fii fvii fx inhibition inactive coagulation factors satisfactory approach standpoint accurate patient care the errors inrs great many ways affects success medication patient well also using calibration local calibration the new generation pt offers possibilities accurate inr results patient care based control active coagulation factors the therapeutic inr ranges guiding anticoagulant therapy using old methods based principle calibrators patient samples inactive coagulation factors inhibition average compensate final inr result the therapeutic range lies thrombosis bleeding complications serious general the medication care oat patients must rendered better safe using sensitive pt test | warfarin is the most widely used medicine for oral anticoagulant therapy ( oat ) .
it inhibits the synthesis of coagulation factors ii , vii , ix , and x in the liver and results in the production of inactive or partially active versions of these factors .
inactive coagulation factors interfere with prothrombin time measurement ( quick and owren pt ) measuring the sum of coagulation activity and inhibition .
the narrow therapeutic range here involves a danger of serious complications and the risk of bleeding or thrombosis .
the new - generation pt method can measure coagulation activity and inhibition separately .
this new technique promotes patient care and anticoagulant medication ( warfarin , dicoumarol ) based on coagulation activity in vivo
. both therapy and laboratory controls should be unquestionably accurate and based solely on in vivo coagulation activity .
inactive coagulation factors ( inhibition ) render measurement , calibration , and harmonization .
the use of the new - generation pt method based on measurement of coagulation activity in vivo could develop vitamin k antagonist ( vka ) therapy for the marked benefit of patients . |
recent times witnessed much turmoil regarding life sacred cost maxim current technology capable indiscriminately maintaining vital functions body technology necessarily allow us heal underlying disease processes an unintended side effect modern technological advances plausibility maintaining moribund patients state suspended animation prolonged sometimes indefinite periods also advanced resuscitation techniques make possible convert death life death patients may stalled suspended animation alive sense enjoy life neither able die long nutrition hydration ventilation perfusion assured many cases reanimation patients this conundrum created must prepared apply life sustaining technology patients benefit appears outweigh risk reasonable chance outcome patient would desire it frequently seems reasonable buy sufficient time see whether disease respond aggressive treatment instituting invasive life support technology however organ system failure reversible reasoning behind life support technology becomes moot we must prepared remove supportive technology appears inevitable death delayed rather meaningful life prolonged the courts repeatedly affirmed competent patient authority regulate medical treatment regardless reasoning however patient becomes incapacitated family surrogates granted authority make decisions regarding treatment options proximate knowledge patient would wanted became incompetent this position based postulate attempt interject physician paternalism surrogate decision making equation ethically unacceptable most rational surrogates unwilling continue life support reasonable trial demonstrated benefit passed point diminishing returns however continuing trend surrogates demanding moribund patients kept life support prevailing medical opinions concur meaningful chance reanimation reasons occurs follows 1 physicians tell surrogates make decision want open ended ideal this puts position buyers consumer market asking make choice an observer primal reaction vibrant external appearance body supported intensive care unit icu radically different corpse morgue slab as long patient looks viable emotionally easier accept pie sky bye bye long shot cure if patient maintained comfortably long enough cure may eventually become possible 3 surrogates dislike position making decisions directly result death loved one once life supporting care instituted patient options survival even though dependent life support there variables decision makers control much easier avoid decisions may hasten death instead yielding inevitable death potential exists manipulate physicians exceptional track record explaining end life issues patients families it uncommon physicians ask loaded questions quest end life decisions for example grandmother 17th transfer skilled nursing facility 3 months sepsis respiratory failure kidney failure well what want everything let die given choice surrogates would opt something rather nothing even something perpetuated open ended pain discomfort the popular media especially tabloids frequently feature anecdotal articles describing patients awakened years coma most patients conditions embellished generate public interest frequently subsequent investigators find patients accordingly families feel life support systems maintain vital signs day week suspended animation possible indefinitely cure found the notion medical futility end stage process vital signs supported poorly understood physicians surrogates in fact medical treatment capable sustaining hemodynamics ventilation metabolism technically futile achieves limited goal therefore patient progressive inevitable death spiral placed mechanical ventilation technically futile vital signs sustained however briefly it medically inappropriate technically futile current rules test futility is embodied question treatment result sustained life answer yes virtually treatment fair game even nothing revitalize patient perhaps effective way dealing strong familial incentives tread path least resistance end life care twofold first end life issue discussions must strive consensus without consent discussions surrogates strive concordance understanding extend soliciting consent medically inappropriate care second strive emphasize streat coworkers termed large risk unacceptable badness rather vanishingly small potential benefit there far worse things death many occur icus futility maxims circumvented there population icu patients die matter treatment rendered medically inappropriate care causes pain suffering discomfort fundamental maxim patients comfort | when patients or their families rarely request inappropriate end of life care in the icu for capricious reasons .
end of life treatment decisions that only prolong discomfort and death are usually emotional and based on unrealistic expectations .
i explore some of those reasons in this paper . |
adult onset still disease aosd chronic systemic inflammatory disorder high spiking fever typical skin rash polyarthritis occur the main biological features neutrophilic leukocytosis hyperferritinemia negative rheumatoid factor rf antinuclear antibodies ana others may include splenomegaly pleuritis pericarditis hepatic abnormalities even though functional prognosis essentially depends articular involvement life threatening prognosis depends serious complications hepatic failure disseminated intravascular coagulopathy hemophagocytosis infections amyloidosis cardiomyopathy article we suggest successful combined therapy prednisolone pd colchicine col cyclophosphamide ctx review literature a 25-year old korean woman diagnosed aosd four years ago experiencing high spiking fever maculopapular rash polyarthritis hands elbows knees laboratory findings the leukocyte count 19,900/ l serum ferritin level 719.3 ng ml 10240 rf ana negative follow typical skin rash disappeared administration pd sulfasalazine hydroxychloroquine methotraxate mtx either high fever polyarthitis wax wane occasionally intra articular injections corticosteroid administered july 1998 admitted hospital slowly increasing proteinuria 7 month period without pitting edema hypertension she single family history rheumatic disease drug history gold penicilliamine the results laboratory data showed white cell count wbc 12,800 l hemoglobin hb 10.6 g dl platelet 610,000 l esr 61 mm hr c reactive protein crp 9.50 mg dl 0.8 serum protein albumin decreased 4.5 g dl 6.48.5 2.1 g dl 3.25.5 respectively twenty four hour urine protein excretion 6.9 g day urine creatine clearance 93.3 ml min radiographic findings chest pa normal bony erosions detected wrist joints sonography sizes kidneys 11.5 cm right 11 cm left side increased renal parenchymal echogenicity renal biopsy showed amorphous deposits mesangial areas glomerular capillary walls vascular poles figure 1 the amyloid deposit stained congored displayed apple green birefringence polarizing light immunofluorescence study igg igm iga c3 c1 c4 fibrinogen albumin light chains showed segmental positive staining igm c3 mesangium trace positive staining light chain electron microscopic examination confirmed amyloid deposits mesangial areas characterized non branching fibrils arranged random array figure 2a 2b serum protein electrophoresis showed decrease total protein total albumin without monoclonal spike urine protein electrophoresis showed elevated total protein level elevated total albumin level we maintained high oral daily dose pd 45 mg day 1 mg kg ctx 100 mg day col 1.2 mg day a follow 15 months later laboratory tests showed wbc 6,000 /ul hb 13.2 g dl platelet 297,000 l esr 11 mm hr crp 0.11 mg dl serum protein albumin increased 6.2 g dl 4.2 g dl respectively the serum ferritin 24.3 ng ml urine protein clearance decreased 6.9 g day 92 mg day currently taking pd 7.5 mg ctx 50 mg col 1.2 gm orally the association amyloid deposits aosd rather unusual considered serious complication the development amyloidosis often occurs patients longstanding persistent inflammatory diseases according previous histopathologic reports aosd we experienced 45 patients aosd hospital far found one case 2.2% associated renal amyloidosis developed four years onset aosd when complication occurs amyloid material preferentially deposited glomeruli proteinuria nephrotic syndrome common initial manifestations helin et al demonstrated retrospective study nephropathy rheumatoid arthritis ra common histopathologic finding mesangial glomerulonephritis gn followed amyloidosis amyloidosis common finding nephrotic syndrome patient isolated proteinuria amyloidosis membranous gn mesangial gn almost equally common membranous gn closely related gold penicillamine therapies whereas mesangial gn probably related ra biopsy thus valuable tool differential diagnosis assessment prognosis decision making regard treatment although either nsaid oral steroid usually effective aosd patients complications renal amyloidosis may require sustained therapy corticosteroid cytotoxic agent the col also effective patient severe ankylosing spondylitis nephrotic syndrome due amyloidosis in review 10 cases aosd complicated renal amyloidosis combined drug therapy pd col ctx azathioprine mtx used two cases they treated steroids dialysis due renal failure experience persistently decreased proteinuria well recovered polyarthritis fever without severe complications combined therapy pd col ctx table 1 conclusion although mechanism renal amyloid deposition unknown early diagnosis treatment pd col ctx may produce excellent results | we report a 25-year - old korean woman with adult onset still s disease ( aosd ) presented with renal amyloidosis , which had developed four years after disease onset .
we successfully treated her with prednisolone , colchicine and cyclophosphamide . a review of the literature uncovered about 10 cases , most of which were treated by various regimens that resulted in poor outcomes .
renal amyloidosis should be suspected in patients with aosd who have unexplained proteinuria .
although the mechanism of renal amyloid deposition is not well known , earlier histopathologic diagnosis and choice of regimen may affect prognosis . |
epilepsy associated two- three fold increase mortality among patients compared general population sudden unexpected death epilepsy sudep one frequent causes death among patients epilepsy there strong evidence suggesting sudden unexpected death epilepsy sudep seizure related phenomenon the first description phenomenon introduced russell 1906 since several cases reported literature presenting drop heart rate asystole seizure bradycardia asystole resulted increased parasympathetic flow vagus nerve originates nucleus ambiguous dorsal nucleus vagus medulla basis one study the incidence sudep ranges 1:1000 1:2000 person years 1:200 person years according recent revised definition sudep consists sudden unexpected witnessed unwitnessed nontraumatic nondrowning death patients epilepsy without evidence seizure excluding documented status epilepticus seizure duration 30 min seizures without recovery asphyxia postmortem examination reveal cause death diagnosis definite sudep preexisting condition autopsy could contributed death classified sudep plus strong risk factors sudep include young age early onset seizures presence generalized tonic clonic seizures male sex bedtime occurrence less significant risk factors sudep include prone position one subtherapeutic blood levels sleep occurrence structural brain lesion the underlying pathophysiologic mechanisms sudep completely understood autonomic dysfunction ictal arrhythmias ictal bradyarrhythmia asystole neurogenic pulmonary edema ictal central obstructive apnea introduced literature report describe two patients seizure associated asystole monitored simultaneous video electroencephalography electrocardiography a thirteen year old right handed male seizure disorder admitted presurgical assessment history neonatal hypoglycemia apparently normal vaginal delivery he started antiepileptic drugs second seizure appeared six months later the seizures typically consisted blurred vision upward gaze followed loss consciousness his mri showed near symmetrical signal abnormality parietooccipital regions bilaterally parasagittal aspect accompanied mild gliosis volume loss fig
, bilateral rhythmic activity maximum left associated right side clonic jerk head eye deviation right secondarily generalized followed 16 asystole end seizure fig 1 fig 2 fig 3 interictal abnormality consisted bilateral spike wave bilateral slow activity maximum right posterior head region end monitoring anticonvulsant drug regimen valproic acid levetiracetam started cardiology consultation suggested a 42-year old right handed male seizure disorder admitted presurgical assessment his epilepsy due penetrating head trauma left frontal lobe shell injury since experiencing episodes intense fear followed generalized tonic clonic movements neurologic examination included mild paresis right upper extremity distal part right lower extremity range 12/5 the first clinical manifestation initial eeg changes consisted generalized tonic
afterwards sa arrest took place lasted 1 min see fig 5 fig 6 the first eeg change started 5-hz spike slow waves left parasagittal area maximum amplitude c3 f3 the interictal abnormality consisted delta waves seen p3 c3 f3 considering cardiac arrest seizure cardiac consultation done pacemaker implanted 24 months antiepileptic regimen frequency seizures reduced remarkably theoretically asystoles could role incidence sudep meaning presence ictal bradycardia risk factor sudep furthermore cases epileptic cardiac dysrhythmia isolated eeg ecg recording may prove insufficient prolonged simultaneous eeg ecg monitoring may required only simultaneous eeg ecg recording reveal possible cerebral origin arrhythmias patients typically young attaining correct diagnosis essential appropriate treatment may prevent cardiogenic sudep thought related potentially lethal arrhythmias asystole induced epileptic seizures prevent cardiac side effects specific antiepileptic drugs conclusion cardiological investigation included epilepsy management search abnormalities hr ischemic events in addition provide appropriate guideline pharmacotherapy since certain types drugs including carbamazepine phenytoin benzodiazepine barbiturates used caution patients epilepsy cardiac dysfunction increasing knowledge sudep risk factors significant preventive role moreover strategies taking detailed cardiovascular history get comprehensive clinical picture including detailed history symptoms risk factors prior cardiac findings undertaken | ictal asystole is a rare , probably underestimated manifestation of epileptic seizures whose pathophysiology is still debated .
this report describes two patients who had cardiac asystole at the end of their seizure .
the first patient was a 13-year - old boy with complex partial seizures ..
his mri showed symmetrical signal abnormality in the bilateral parietooccipital lobe accompanied by mild gliosis and volume loss . during a 3-day long - term video - eeg monitoring , he had cardiac arrest at the end of one of his seizures that was secondarily generalized .
the second one was a 42-year - old veteran with penetrating head trauma in the left frontal lobe due to shell injury . during long - term video - eeg monitoring , he had one generalized tonic
clonic seizure accompanied by bradycardia and cardiac asystole .
asystoles could have a role in the incidence of sudden unexpected death in epilepsy ( sudep ) , meaning that the presence of ictal bradycardia is a risk factor for sudep . in cases of epileptic cardiac dysrhythmia ,
prolonged simultaneous eeg / ecg monitoring may be required .
cardiological investigation should be included in epilepsy management . |
condition estimated affect 2 million persons u.s alone increased mortality morbidity compared general population 2 3
individuals schizophrenia typically suffer combination debilitating symptoms including hallucinations delusions treatment resistant symptoms social withdrawal the disease affects males females although evidence support number sex differences characteristics schizophrenia
compared females males may likely develop schizophrenia ~1.4 1 ratio 5 6 earlier age onset 68 poorer premorbid social intellectual functioning poorer course medication response greater structural brain abnormalities negative symptoms fewer affective symptoms twin family adoption studies together suggest schizophrenia complex disorder involving genes environment 11 12
further evidence suggesting schizophrenia arises process involving prenatal environmental conditions compelling 1321
numerous case control studies demonstrated individuals schizophrenia likely exposed prenatal obstetric complications unaffected siblings normal controls psychiatric controls meta analysis twelve twin studies demonstrated nontrivial proportion liability schizophrenia accounted common shared environmental effect 11% 95% ci 3%19% environments twins similar utero role common environment effects liability schizophrenia would likely occur early life suspected fetal environmental risks include exposure maternal stress influenza 2426 infection famine prenatal nutritional deficiency 16 2831 obstetric complications 14 15 18 19 32
several reviews 8 21 33 including meta analysis support involvement pregnancy complications rhesus incompatibility pre eclampsia ii abnormal fetal growth development iii delivery complications produce fetal hypoxia risk factors suggest obstetric complications contribute approximately 2-fold increased risk schizophrenia
prenatal obstetric complications believed disrupt normal fetal neurodevelopment involvement schizophrenia susceptibility consistent neurodevelopmental hypothesis schizophrenia
this hypothesis posits brain development disrupted early life subsequent maturational events combination environmental factors leads emergence psychosis adulthood 3436
support important role prenatal obstetric complications schizophrenia also comes neuroimaging studies example evidence fetal hypoxia differential effect hippocampus schizophrenics first degree relatives suggesting temporal lobe region may sensitive prenatal environmental conditions 3739
furthermore anatomical deficits medial temporal lobe structures severe among patients schizophrenia history hypoxia associated obstetric complications
hence studies suggest factors produce prenatal obstetric hypoxia effect medial temporal lobe structure genetic liability schizophrenia also plays role predisposing individual schizophrenia
this evidence produced variety hypotheses regarding genetic environmental influences aggregate increase susceptibility schizophrenia gene environment interaction gene environment covariation direct environmental effects phenocopy model potentially overlapping models
to date little evidence support phenocopy model gene environment covariation model explain role prenatal obstetric complications schizophrenia although additional investigation models warranted
in contrast evidence prenatal obstetric complications increase risk schizophrenia gene environment interaction model accumulating
in addition studies cited earlier 3740 recent study found risk schizophrenia greatest among individuals highest familial liability exposed maternal infection consistent interaction model another example significant interaction suspected hypoxia regulated vascular expression genes serious obstetric complications predominantly hypoxia ) although causes prenatal complications quite heterogeneous diversity exclude final common pathway increasing discussion common pathway involves immune vascular systems pathogenesis schizophrenia 43 44 excellent review theory schizophrenia hanson gottesman describe process ubiquitous environmental factors normally trigger genetically influenced inflammatory response infection trauma hypoxia individuals trigger abnormal inflammatory processes individuals particular genotypes inflammatory response loci results damage microvascular system brain
this vascular inflammatory theory accommodates diversity prenatal complications associated schizophrenia also specifies interaction genes environment
the latter point helps explain people experience prenatal obstetric complications eventually develop schizophrenia 19 21 received empirical support increasing number studies demonstrating gene environment interactions schizophrenia 27 3740 42 particularly recent study identified interaction serious obstetric complications hypoxia regulated vascular expression genes
not surprisingly remains considerable interest identifying fetal environmental risk factors elucidating role schizophrenia
however addition heterogeneity prenatal obstetric complications difficult document reliably medical records maternal recall making difficult test role environmental insults pathogenesis schizophrenia interest evidence prenatal complications increase susceptibility schizophrenia cluster within schizophrenia families raises possibility complications may genetic basis risk genes hence adverse prenatal environment measured directly genetic analyses rather medical records maternal recall
a benefit direct measurement adverse prenatal environment genetic analysis facilitate hypothesis testing regarding role prenatal obstetric complications pathogenesis schizophrenia maternal fetal genotype incompatibility first described palmer et al describe mechanism confers risk schizophrenia maternal fetal genotype combinations produce maternal immunological reaction creates adverse prenatal environment as described maternal fetal genotype incompatibility occur maternal fetal genotypes differ one another maternal fetal genotypes similar
incompatibility genes scenarios implicated risk factors schizophrenia reviewed
importantly maternal fetal genotype incompatibility explicitly genetic nature potential measured directly genetic analyses even years adverse prenatal event occurred the teratogenic antibody hypothesis posits pregnant female develop antibodies response antibody producing stimulus e.g. contact paternal antigens interfere normal fetal neurodevelopment one general mechanism consistent teratogenic antibody hypothesis involves maternal fetal genotype combinations adversely affect developing fetus inducing maternal immunological attack
this mechanism form maternal fetal genotype incompatibility development maternal antibodies result mother genotype different fetus genotype cases maternal immunological reaction lead hypoxic ischemia condition found associated schizophrenia 17 18 hypothesized trigger abnormal inflammatory processes individuals vulnerable genotypes inflammatory response loci resulting damage micro vascular system brain increasing risk schizophrenia
conditions produce fetal neonatal hypoxia include maternal fetal genotype incompatibilities genes produce red blood cell antigens rhd locus
the rhd gene produces red blood cell antigen called rhesus factor
an individual determined rhesus positive red blood cells rbcs antigen someone classified rhesus negative lacks antigen individuals rhesus positive either homozygous heterozygous allele produces antigen referred
individuals rhesus negative homozygous null allele caucasian populations rhd maternal fetal genotype incompatibility pregnancy occurs pregnant woman rhesus negative fetus rhesus positive
because rbcs rhesus negative pregnant female possess rhesus antigen maternal anti igg antibodies created response detection fetal rbcs maternal blood stream
these antibodies destroy fetal rbcs maternal blood stream cross placenta destroy fetal rbcs rbcs carry oxygen throughout fetus body including brain attack fetal rbcs increases risk fetal hypoxia could affect developing tissue including brain tissue
a byproduct destruction rbcs bilirubin thus hyperbilirubinemia jaundice occur well kernicterus deposition bilirubin brain
bilirubin known neurotoxin 50 51 undifferentiated glial cells sensitive 52 53 glial cell abnormalities also associated schizophrenia 54 55 an infant said rhesus hemolytic disease newborn clinical complications arise due rhd maternal fetal genotype incompatibility maternal sensitization usually occur delivery first rhd incompatible pregnancy it second- later incompatible pregnancies risk maternal immune attack becomes appreciable around 1970 prophylaxis maternal isoimmunization became available made dramatic impact morbidity mortality associated rhd maternal fetal genotype incompatibility
however even era prophylaxis continue cases rhesus hemolytic disease newborn either due lack prophylaxis use 56 57 use 100% effective preventing maternal sensitization 58 59
evidence support involvement rhd maternal fetal genotype incompatibility schizophrenia comes nongenetic genetic studies performed samples individuals schizophrenia predominantly born prior 1970 15 19 47 6066 reviewed
the nongenetic studies based serotype data rhesus negative rhesus positive evidence hemolytic disease newborn mother child pairs 19 32 60 61 63 64 66 genetic studies based genotype data nuclear families 47 65 67 collectively studies provided evidence rhd maternal fetal genotype incompatibility risk factor schizophrenia relative risk ranging 1.4 2.26 magnitude comparable relative risk schizophrenia due obstetric complications general due genes association schizophrenia observed see 68 69 reviews remarkable studies rhd maternal fetal genotype incompatibility schizophrenia differ design population cohort arrive similar relative risk estimates consistency suggests relative risk schizophrenia due rhd maternal fetal genotype incompatibility although small substantively meaningful worthy investigation another way look magnitude rhd maternal fetal genotype incompatibility effect compute population attributable fraction number cases would occur risk factor eliminated
based formulas found rhd maternal fetal genotype incompatibility population attributable fraction ~3% estimated fraction cases rhd maternal fetal genotype incompatibility 7.8% relative risk due incompatibility using conservative estimate 1.5 based population prevalence schizophrenia 1% assuming allele frequencies rhd locus homogeneous u.s attributable fraction suggests 100,000 schizophrenia cases u.s would occurred rhd maternal fetal genotype incompatibility this trivial number comparison estimated 100,000 cases schizophrenia u.s would occurred val allele comt gene thus two loci comt rhd could potentially account effect similar size population level course allele frequencies rhd locus differ across populations allele less common populations others e.g. p(d .76 study conducted nairobi compared p(d .66 finnish population
thus frequency rhesus negative mothers rhesus positive children vary across populations this variability allele frequencies affect relative risk disease due rhd maternal fetal genotype incompatibility affect fraction schizophrenia cases attributed rhd locus across populations since individuals exposed rhd maternal fetal genotype incompatibility develop schizophrenia it highly unlikely exposure adverse prenatal environment alone phenocopy model explains risk schizophrenia
furthermore lack evidence violation hardy weinberg equilibrium founder alleles family based rhd genetic studies 47 67 inconsistent gene-environment covariation model suggests mate selection schizophrenia families occurred independently rhd genotype least among founders date there empirical studies determine whether association rhd maternal fetal genotype incompatibility schizophrenia explained gene-environment interaction model there also emerging evidence studies based serotype data based genotype data risk schizophrenia due rhd maternal fetal genotype incompatibility may depend offspring sex 61 66 67 relative risk 1.64 male incompatible offspring 1.07 female incompatible offspring based recent meta analysis
furthermore nonsignificant trend suggesting male offspring higher risk female offspring schizophrenia due maternal fetal genotype incompatibility another rbc antigen locus abo also identified based serotype data
abo maternal fetal genotype incompatibility occurs pregnant woman type blood fetus type b rhesus incompatibility maternal igg antibodies produced fetal antigens result hemolytic disease newborn although case risk pregnancies 75 76 these sex dependent findings allow hypotheses address schizophrenia effect rbc antigen associated maternal immune response much greater male offspring compared female offspring
it unlikely case rhd maternal fetal genotype incompatibility likely occur pregnancies male offspring evidence related condition hemolytic disease newborn likely occur pregnancies male fetuses compared female fetuses however evidence clinical manifestations rhd maternal fetal genotype incompatibility severe pregnancies male fetuses female fetuses thus one hypothesis specific schizophrenia effects rhd maternal fetal genotype incompatibility hypoxia hyperbilirubinemia affect female fetuses less likely surpass threshold severity compared male fetuses threshold effect
there also evidence clinical effects rhd maternal fetal genotype incompatibility may occur earlier gestation male fetuses compared female fetuses
coupled research supporting sex differences brain maturational rates males exhibiting slower pace cerebral development compared females another hypothesis male females equally vulnerable specific effects rhd maternal fetal genotype incompatibility effects must occur sex dependent times development
this hypothesis suggests female fetuses may increased risk schizophrenia subject prenatal obstetric complications produce hypoxia hyperbilirubinemia effects must occur earlier gestational period increase risk schizophrenia timing effect a third hypothesis male fetuses female fetuses experience schizophrenia effects due hypoxia hyperbilirubinemia specific effect
although yet studies addressing whether risk schizophrenia due rhd maternal fetal genotype incompatibility male female fetuses function threshold effect timing effect studies addressing potential sex differences rates hypoxia related males females conflicting results 79 80 the involvement rhd gene form maternal fetal genotype incompatibility risk factor schizophrenia susceptibility substantiated analyses showed evidence support idea locus simply linked associated nearby schizophrenia susceptibility locus gene acts maternal genotype alone
furthermore empirical evidence consistent hypothesized biological mechanism previous rhd maternal fetal genotype incompatible pregnancies increase risk maternal isoimmunization subsequent pregnancies two schizophrenia
rhd maternal fetal genotype incompatibility studies tested hypothesis 61 65 using serotype information hollister et al divided birth cohort sample firstborn rhesus incompatible rhesus compatible males second- later born rhesus incompatible rhesus compatible males
consistent birth order effect found rate schizophrenia among second- later born rhesus incompatible males significantly higher second- later born rhesus compatible males 2.6% versus 0.8% p .05 significant difference rate schizophrenia firstborn rhesus incompatible compatible males p .64 second study kraft et al
tested hypotheses birth order effect using nuclear families least one individual schizophrenia rhd genotype data
the model increased risk second- later born incompatible children fit data well significant point estimate 1.7 relative risk second- later born incompatible children p .014
the model fit data well assumed increased risk incompatible children regardless birth order point estimate relative risk schizophrenia model 1.5 lower former model however one issue latter model forced risk first born incompatible children identical risk later born incompatible children essentially produced average relative risk across birth order groups
since relative risk estimated 1.7 model assumed risk first born relative risk lowered 1.5 model averaged incompatible children authors concluded effect including first born incompatible children artificially lower relative risk relative risk estimates rhd maternal fetal genotype incompatibility later born children
it important note neither study information pregnancies go full term example spontaneous abortions
the potential effect lack information misclassify rhd maternal fetal genotype incompatible individuals first born low risk maternal sensitization fact later born heightened risk due previous maternal sensitization
such misclassification would serve underestimate difference groups bias results toward null hypothesis birth order effect light challenges truly examining birth order effect rhd maternal fetal genotype incompatibility striking two schizophrenia studies chose test birth order hypotheses found evidence support effect
however examination hypothesis warranted due findings suggest risk schizophrenia associated rhd maternal fetal genotype incompatibility limited male offspring case one would expect observe increased risk among second- later born incompatible males females
the involvement rhesus incompatibility schizophrenia initially provided studies inferred genotype status serotype data
importantly evidence non genetic studies provided impetus conceptualizing maternal fetal genotype incompatibility general non mendelian mechanism involved etiology complex disorders schizophrenia
the first candidate gene study test hypothesis rhd maternal fetal genotype incompatibility risk factor schizophrenia provided proof principle non mendelian mechanism tested genotype data
further facilitated development statistical methods study designs based candidate gene approach nuclear families addressing hypotheses role maternal fetal genotype incompatibility disease 65 8185
such innovations important illustrated next section incompatibility genes inferred serotype data human leukocyte antigens hlas play important role control immune responses long belief hlas play role schizophrenia susceptibility although conflicting results genetic studies examining hypothesis high risk allele acting affected individual genotype another way conceptualize the role hla schizophrenia susceptibility consider role(s pregnancy
there strong evidence maternal recognition paternally derived fetal hlas pregnancy maternal antibodies fetal antigens detected
however maternal recognition paternally derived fetal hlas differ maternal hlas believed beneficial implantation maintenance pregnancy maternal antibodies fetal antigens observed large number healthy pregnancies
in contrast lack maternal recognition result paternally derived hlas perceived different maternal hlas may lead adverse reproductive outcomes underlying biological mechanism poor reproductive outcomes yet known however immunological intolerance hypothesis posits hla similarity mother fetus fails stimulate adequate maternal immune response necessary proper implantation maintenance pregnancy there empirical evidence situations maternal sensitization would occur hla matching couples mother fetus increases risk fetal loss 8992 preeclampsia 9396 low birth weight 97100 newborn encephalopathy seizures
importantly low birth weight preeclampsia complications associated schizophrenia 15 19 102104
the mechanism(s low birth weight preeclampsia increase risk schizophrenia yet known
however current theory regarding preeclampsia hypothesizes condition gives rise abnormal fetal blood flow results chronic fetal hypoxia malnutrition conditions associated schizophrenia 15 16 2831 102 103
furthermore preeclampsia involves generalized inflammatory response mother result oxidatively stressed hypoxic placenta inflammatory processes hypothesized damage microvasular system brain 43 44 increase risk schizophrenia two additional lines evidence implicate maternal fetal hla matching schizophrenia
first evidence supporting relevance hla matching neurodevelopmental disorders comes study found parents children autism significantly likely share least one hla -b -c antigen common compared parents unaffected children
second circumstantial evidence supporting relevance hla matching specifically schizophrenia comes literature mate selection literature olfaction schizophrenia
specifically mate selection literature evidence support disassortative mate selection respect hla loci 108111 olfaction plays role process 109 110 112
however studies individuals schizophrenia unaffected first degree relatives reveal impairments olfaction 113116 hence mate selection subgroup individuals may less likely guided ability sniff mate hla dissimilarity thus likely result construction couples hla similarity maternal fetal hla matching likely occur
because risk schizophrenia associated prenatal obstetric complications including preeclampsia low birth weight maternal fetal hla matching associated pregnancy obstetric complications maternal fetal hla matching observed another neurodevelopmental disorder maternal fetal hla matching may occur frequently families individuals schizophrenia biological reasons candidate gene study conducted assess maternal fetal genotype incompatibility matching hla -b -drb1 loci risk factor schizophrenia study palmer and colleagues hypothesized maternal fetal genotype incompatibility increased risk schizophrenia general allele matching phenomenon rather specific allele combinations
for locus mother offspring considered match offspring alleles identical maternal alleles offspring alleles subset maternal alleles
in either cases maternal sensitization fetal antigens would occur would perceived maternal antigens the maternal fetal genotype incompatibility test multiple siblings modified accommodate analyses involving general allele matching phenomenon missing parental genotypes
there evidence violation hardy weinberg equilibrium founder alleles consistent random mating respect three loci
there evidence hla -drb1 maternal fetal genotype matching effect schizophrenia
in contrast significant evidence hla b maternal fetal genotype incompatibility effect p .01 inspection parameter estimates revealed maternal fetal genotype matching produced higher risk female offspring 1.74 95% ci 1.222.49 male offspring 1.11 95% ci 0.761.61 note mate selection literature hla b appears particularly influential first study demonstrate association hla b matching schizophrenia much research is needed determine mechanism form maternal fetal genotype incompatibility increases risk schizophrenia
one possibility hla b matching increases risk adverse reproductive outcomes preeclampsia low birth weight
this hypothesis could tested examining prenatal birth records sample females schizophrenia stratified hla b matching status comparing rates preeclampsia low birth weight pregnancy obstetric complications two groups
it also currently unclear female offspring would vulnerable effects hla b matching male offspring
one possibility female fetuses likely survive putative effects hla b matching preeclampsia hence observed study male offspring although sex dependent finding intriguing light work demonstrating rhd maternal fetal genotype incompatibility schizophrenia risk factor limited males replication investigation hypothesized clinical manifestations hla b matching low birth weight preeclampsia complications warranted published studies reveal conflicting results regarding sex differences rates low birth weight preeclampsia among individuals schizophrenia 102 104 firstborn child couple highest risk preeclampsia one could also seek evidence support hla b matching preeclampsia relationship testing birth order effect
future research must provide additional evidence association hla b matching schizophrenia determine clinical outcomes hla b matching example prenatal obstetric complications whether hla b matching increases risk phenocopy model gene-environment interaction model simply associated gene-environment covariation model determine basis sex dependent risk particularly important distinguish gene-environment covariation model gene-environment interaction model given priori basis expecting higher rates hla b matching schizophrenia function olfaction deficits
based review variety hypotheses could tested future research elucidate role rhd hla b maternal fetal genotype incompatibility schizophrenia
one important area research would focus conducting studies add evidence maternal fetal genotype incompatibilities risk factors schizophrenia examples since rhd maternal fetal genotype incompatibility genetic origin one would expect clustering schizophrenia families rhd maternal fetal genotype incompatibility schizophrenia families without rhd maternal fetal genotype incompatibility
if rhd maternal fetal genotype incompatibility risk factor specifically males one would expect observe schizophrenia risk associated birth order effect male offspring exposed rhd maternal fetal genotype incompatibility female offspring hla b matching involved predisposition pre eclampsia low birth weight prenatal obstetric complication one would expect higher rates prenatal obstetric complications individuals schizophrenia hla b maternal fetal genotype matching compared without hla b maternal fetal genotype matching hla b matching involved specifically predisposition pre eclampsia one would expect observe schizophrenia risk associated birth order effect female offspring exposed hla b maternal fetal genotype incompatibility male offspring second area research would focus maternal fetal genotype incompatibility integrates genetic liability schizophrenia phenocopy gene environment covariation gene environment interaction
the phenocopy gene environment covariation models unlikely explain association rhd maternal fetal genotype incompatibility schizophrenia however one possible explanation finding people history rhesus incompatibility develop schizophrenia schizophrenia producing effect rhd maternal fetal genotype incompatibility manifests individuals genetic predisposition schizophrenia
if case one would expect different risks schizophrenia based family history rhd maternal fetal genotype incompatibility greatest risk schizophrenia among genetically high risk individuals exposed rhd maternal fetal genotype incompatibility
following recent work clarke et al one could test synergism rhd maternal fetal genotype incompatibility family history psychosis comparing rates schizophrenia across four groups rhd maternal fetal genotype incompatibility family history psychosis rhd maternal fetal genotype family history psychosis rhd maternal fetal genotype incompatibility positive family history psychosis
the interaction hypothesis could tested hla b maternal fetal genotype incompatibility however additional research needed also test phenocopy gene environment covariation models respect association hla b matching schizophrenia
a third area research would focus hypotheses hypoxia prominent schizophrenia producing effect rhd hla b maternal fetal genotype incompatibility examples schizophrenia risk effect rhd maternal fetal genotype incompatibility result hypoxia one would expect observe interaction rhd maternal fetal genotype incompatibility hypoxia regulated vascular expression genes
the hypothesis tested hla b maternal fetal genotype incompatibility if schizophrenia risk effect rhd maternal fetal genotype incompatibility result hypoxia one would expect observe smaller hippocampal volume individuals schizophrenia exposed rhd maternal fetal genotype incompatibility compared exposed
the hypothesis tested hla b maternal fetal genotype incompatibility
if schizophrenia risk effect rhd maternal fetal genotype incompatibility result hypoxia one would expect rhd maternal fetal genotype incompatibility associated neurocognitive functions may sensitive effects prenatal hypoxia schizophrenia example verbal learning memory
the hypothesis tested hla b maternal fetal genotype incompatibility a fourth area research would focus hypotheses examine offspring sex dependent differences schizophrenia producing effects rhd maternal fetal genotype incompatibility area research hypotheses regarding sex dependent differences amount exposure threshold effect gestational timing exposure timing effect type exposure hypoxia hyperbilirubinemia specific effect likely best tested using animal models systematically vary conditions hypoxia hyperbilirubinemia
similar investigations performed prenatal effects hla b maternal fetal genotype incompatibility better elucidated the attributable risk associated maternal fetal genotype incompatibilities limited populations incompatibility occurs appreciable frequency
as one example rhesus negative allele less common african asian populations european caucasian populations 72 120 121 hence rhd maternal fetal genotype incompatibility less likely contribute schizophrenia susceptibility populations however rhd blood antigen locus maternal fetal genotype incompatibility could arise other blood antigens exist including abo rhce kell 123 124 duffy kidd mn 125 126 maternal fetal genotype incompatibilities antigens give rise maternal immune response similar although smaller magnitude rhd incompatibility response
in addition genes could lead fetal hypoxia hyperbilirubinemia prenatal conditions associated schizophrenia whether maternal fetal genotype incompatibility maternal genetic effects alone fetal genetic effects alone examined prenatal environmental factors quite heterogeneous difficult document reliably making difficult test role environmental insults pathogenesis schizophrenia however there growing evidence many prenatal obstetric complications genetic basis one stream research focused identifying combinations maternal fetal genotypes maternal fetal genotype incompatibilities predispose prenatal obstetric complications
maternal fetal genotype incompatibility occur maternal fetal genotypes differ example rhd maternal fetal genotype incompatibility similar example hla b maternal fetal genotype incompatibility
thus far rhd abo hla b genes implicated risk factors schizophrenia increasing evidence male female offspring may differentially vulnerable effects maternal fetal genotype combinations involving genes
a growing number studies demonstrate interaction prenatal obstetric complications putative susceptibility genes increases risk schizophrenia
thus maternal fetal genotype incompatibilities likely part complex mixture factors genetic environmental together act brain ways yet identified result schizophrenia
the empiric data demonstrating relationship maternal fetal genotype incompatibilities schizophrenia provide hypotheses future investigations understanding role increasing risk schizophrenia recently studies understand role maternal fetal genotype incompatibility schizophrenia complex disorder inferred immunologically relevant genotypes solely birth records single phenomenon hemolytic disease
as illustrated review maternal fetal genotype incompatibility loci hla loci may also increase risk schizophrenia
however loci result hemolytic disease newborn may challenging priori examine role information gleaned birth records hence development study designs statistical methods study prenatal risk factors based genotype data essential delineating maternal fetal genotype incompatibility non mendelian mechanism complex disease
in fact genetic studies model non mendelian patterns inheritance directly may one contributing reason current genome scans found striking highly replicable results complex disorders otherwise highly familial
the approach described integrates investigation genes environment innovative manner provides empirical data fits within tested genetic inflammatory vascular hypothesis schizophrenia
there several reasons important investigate maternal fetal genotype incompatibly risk factor schizophrenia 1 new research approach allows precise identification putative high risk prenatal environment even years adverse environment occurred 2 using genetic approach possible simultaneously evaluate alternative explanations allelic effects act solely genotype mother child 3 certain maternal fetal genotype incompatibilities example rhd increase risk schizophrenia efforts could launched increase prevention effects class risk factor 4 approach could serve model studying complex disorders maternal fetal genotype incompatibilities may involved example diabetes 127 128 rheumatoid arthritis 129131 | prenatal / obstetric complications are implicated in schizophrenia susceptibility .
some complications may arise from maternal - fetal genotype incompatibility , a term used to describe maternal - fetal genotype combinations that produce an adverse prenatal environment .
a review of maternal - fetal genotype incompatibility studies suggests that schizophrenia susceptibility is increased by maternal - fetal genotype combinations at the rhd and hla - b loci .
maternal - fetal genotype combinations at these loci are hypothesized to have an effect on the maternal immune system during pregnancy which can affect fetal neurodevelopment and increase schizophrenia susceptibility .
this article reviews maternal - fetal genotype incompatibility studies and schizophrenia and discusses the hypothesized biological role of these
incompatibility genes .
it concludes that research is needed to further elucidate the role of rhd and hla - b maternal - fetal genotype incompatibility in schizophrenia and to identify other genes that produce an adverse prenatal environment through a maternal - fetal genotype incompatibility mechanism .
efforts to develop more sophisticated study designs and data analysis techniques for modeling maternal - fetal genotype incompatibility effects are warranted . |
seventeen obese subjects bmi 41.0 1.5 kg age 35.1 1.0 years 15 female 2 male 13 african american 4 caucasian markedly insulin resistant based homeostasis model assessment insulin resistance score 2.6 21 participated study potential subjects interviewed questionnaire used previous studies 22 inquired 1 type sweetener used coffee tea drinks 2 current intake diet beverages including soda juice ice tea flavor water 3 current intake yogurt pudding gelatin snacks foods sweetened nns 3 current use gums containing nns type product potential participants asked whether used past month many days per week many servings per day subjects reported consuming one diet beverage one spoonful nns week equivalent foods excluded in addition smoked cigarettes last six months pregnant breastfeeding history malabsorptive syndromes bariatric surgery inflammatory intestinal disease taking medication might affect glucose metabolism excluded this study approved institutional review board washington university school medicine st subjects studied two separate occasions 7 days apart crossover design study subjects admitted morning clinical research unit washington university school medicine 0700 h subjects fasted overnight 12 h home catheter placed hand vein heated warming box 55c obtain arterialized venous samples 23 blood samples obtained assess plasma glucose insulin c peptide glucagon glucose dependent insulinotropic polypeptide gip active glp-1 concentrations 20 15 10 6 2 min 10 20 30 40 60 90 120 150 180 240 300 min ingesting 75 g glucose randomized order subjects drank 60 ml 2 mmol l sucralose i.e. 48 mg sucralose equivalent volume distilled water 10 min glucose ingestion this concentration sucralose used effective concentration needed stimulate glp-1 secretion human intestinal cells vitro 4 matches sweetness typical diet soda i.e. approximates amount sucralose standard 12-oz diet soda sweetened sucralose 24 plasma glucose measured immediately collection using automated glucose analyzer ysi 2300 stat plus yellow springs instruments yellow spring oh blood samples also collected chilled edta tubes containing protease inhibitor cocktail millipore billerica these samples placed ice centrifuged 4c plasma stored 80c subsequent analyses plasma active glp-1 gip measured using commercially available immunoassay kits meso scale discovery gaithersburg md millipore respectively plasma c peptide measured using solid phase two site chemiluminescent immunometric assay siemens medical solutions diagnostics los angeles ca plasma insulin concentrations determined using two site immunoenzymatic assay dxi 800 beckman instruments chaska mn plasma glucagon measured direct double antibody radioimmunoassay millipore the incremental areas curve aucs baseline concentrations glucose insulin c peptide glucagon gip glp-1 calculated using trapezoid method 25 the insulin sensitivity index si dl kg min/(pmol l determined minimal model glucose concentration function insulin concentration 26 insulin clearance rate plasma calculated dividing mean insulin secretion rate isr mean plasma insulin concentration 27 plasma c peptide glucose concentrations used determine isr response oral glucose load sensitivity -cell response isr changes plasma glucose using minimal model 25 this model provides estimate total amount insulin secreted response plasma glucose function time i.e. total isr pmol min partitions total response dynamic component isrdynamic represents rapid release readily releasable pool insulin secretory granules response rate increasing plasma glucose concentration static component isrstatic represents slower release reserve pool insulin secretory granules response ambient plasma glucose concentration 28 the -cell response sensitivity parameters total dynamic static corresponding total dynamic static isr response changes plasma glucose determined 29 statistical significance effect sucralose glucose insulin c peptide glucagon gip active glp-1 concentrations isr glucose load determined conducting separate repeated anovas outcome variable condition sucralose water time point within subject factors differences values statistically significant post hoc bonferroni adjustment fisher least significant differences analyses conducted active glp-1 si static data positively skewed required logarithmic transformation approximate normal distribution the significance differences incremental peaks aucs si insulin clearance evaluated using paired test wilcoxon matched pairs test appropriate data tables figures presented means sem median semi interquartile range 75th25th percentile]/2 skewed datasets all analyses performed statistica 8.0 statsoft tulsa ok criterion statistical significance p 0.05 plasma glucose measured immediately collection using automated glucose analyzer ysi 2300 stat plus yellow springs instruments yellow spring oh blood samples also collected chilled edta tubes containing protease inhibitor cocktail millipore billerica these samples placed ice centrifuged 4c plasma stored 80c subsequent analyses plasma active glp-1 gip measured using commercially available immunoassay kits meso scale discovery gaithersburg md millipore respectively plasma c peptide measured using solid phase two site chemiluminescent immunometric assay siemens medical solutions diagnostics los angeles ca plasma insulin concentrations determined using two site immunoenzymatic assay dxi 800 beckman instruments chaska mn plasma glucagon measured direct double antibody radioimmunoassay millipore plasma glucose measured immediately collection using automated glucose analyzer ysi 2300 stat plus yellow springs instruments yellow spring oh blood samples also collected chilled edta tubes containing protease inhibitor cocktail millipore billerica these samples placed ice centrifuged 4c plasma stored 80c subsequent analyses plasma active glp-1 gip measured using commercially available immunoassay kits meso scale discovery gaithersburg md millipore respectively plasma c peptide measured using solid phase two site chemiluminescent immunometric assay siemens medical solutions diagnostics los angeles ca plasma insulin concentrations determined using two site immunoenzymatic assay dxi 800 beckman instruments chaska mn plasma glucagon measured direct double antibody radioimmunoassay millipore the incremental areas curve aucs baseline concentrations glucose insulin c peptide glucagon gip glp-1 calculated using trapezoid method 25 the insulin sensitivity index si dl kg min/(pmol l determined minimal model glucose concentration function insulin concentration 26 insulin clearance rate plasma calculated dividing mean insulin secretion rate isr mean plasma insulin concentration 27 plasma c peptide glucose concentrations used determine isr response oral glucose load sensitivity -cell response isr changes plasma glucose using minimal model 25 this model provides estimate total amount insulin secreted response plasma glucose function time i.e. total isr pmol min partitions total response dynamic component isrdynamic represents rapid release readily releasable pool insulin secretory granules response rate increasing plasma glucose concentration static component isrstatic represents slower release reserve pool insulin secretory granules response ambient plasma glucose concentration 28 the -cell response sensitivity parameters total dynamic static corresponding total dynamic static isr response changes plasma glucose determined 29 the incremental areas curve aucs baseline concentrations glucose insulin c peptide glucagon gip glp-1 calculated using trapezoid method 25 the insulin sensitivity index si dl kg min/(pmol l determined minimal model glucose concentration function insulin concentration 26 insulin clearance rate plasma calculated dividing mean insulin secretion rate isr mean plasma insulin concentration 27 plasma c peptide glucose concentrations used determine isr response oral glucose load sensitivity -cell response isr changes plasma glucose using minimal model 25 this model provides estimate total amount insulin secreted response plasma glucose function time i.e. total isr pmol min partitions total response dynamic component isrdynamic represents rapid release readily releasable pool insulin secretory granules response rate increasing plasma glucose concentration static component isrstatic represents slower release reserve pool insulin secretory granules response ambient plasma glucose concentration 28 the -cell response sensitivity parameters total dynamic static corresponding total dynamic static isr response changes plasma glucose determined 29 the statistical significance effect sucralose glucose insulin c peptide glucagon gip active glp-1 concentrations isr glucose load determined conducting separate repeated anovas outcome variable condition sucralose water time point within subject factors differences values statistically significant post hoc bonferroni adjustment fisher least significant differences analyses conducted active glp-1 si static data positively skewed required logarithmic transformation approximate normal distribution significance differences incremental peaks aucs si insulin clearance evaluated using paired test wilcoxon matched pairs test appropriate data tables figures presented means sem median semi interquartile range 75th25th percentile]/2 skewed datasets all analyses performed statistica 8.0 statsoft tulsa ok criterion statistical significance p 0.05 mean peak plasma glucose concentration higher subsequent nadir lower sucralose water ingestion fig 1a table 1 peak plasma insulin c peptide concentrations also higher sucralose water ingestion fig no significant differences incremental auc glucose c peptide detected response glucose load sucralose water ingestion however incremental auc insulin 20 8% greater sucralose water ingestion p 0.03 table 1 plasma glucagon concentration decremental glucagon auc glucose load similar sucralose water ingestion fig although average plasma gip concentrations tended higher sucralose water ingestion 20 8 vs. 18 7 pmol l difference statistically significant p 0.08 fig plasma active glp-1 concentration incremental glp-1 auc incremental gip auc glucose load different sucralose water ingestion fig mean plasma glucose insulin b c peptide c glucagon concentrations obese subjects drinking either sucralose water 10 min ingestion 75-g glucose load given time 0 min metabolic response oral 75-g glucose load preceded either sucralose water ingestion mean plasma gip active glp-1 b concentrations obese subjects drinking either sucralose water 10 min ingestion 75-g glucose load given time 0 min sucralose ingestion decreased insulin clearance rate ingesting glucose load 7 4% p 0.05 the median si value 23 20% lower sucralose water ingestion p 0.01 table 1 total isr aucs response oral glucose load sensitivity insulin secretion plasma glucose total dynamic static different sucralose water conditions table 1 however differences plasma glucose concentration conditions caused higher peak isr sucralose water fig 3a exclusively due average increase 22 4% static isr 60 105 min p 0.005 dynamic isr curves sucralose water ingestion fig isr response glucose load subjects drank either sucralose 10 min ingestion 75 g glucose given time 0 min mean peak plasma glucose concentration higher subsequent nadir lower sucralose water ingestion fig 1a table 1 peak plasma insulin c peptide concentrations also higher sucralose water ingestion fig no significant differences incremental auc glucose c peptide detected response glucose load sucralose water ingestion however incremental auc insulin 20 8% greater sucralose water ingestion p 0.03 table 1 plasma glucagon concentration decremental glucagon auc glucose load similar sucralose water ingestion fig although average plasma gip concentrations tended higher sucralose water ingestion 20 8 vs. 18 7 pmol l difference statistically significant p 0.08 fig plasma active glp-1 concentration incremental glp-1 auc incremental gip auc glucose load different sucralose water ingestion fig mean plasma glucose insulin b c peptide c glucagon concentrations obese subjects drinking either sucralose water 10 min ingestion 75-g glucose load given time 0 min metabolic response oral 75-g glucose load preceded either sucralose water ingestion mean plasma gip active glp-1 b concentrations obese subjects drinking either sucralose water 10 min ingestion 75-g glucose load given time 0 min sucralose ingestion decreased insulin clearance rate ingesting glucose load 7 4% p 0.05 the median si value 23 20% lower sucralose water ingestion p 0.01 table 1 total isr aucs response oral glucose load sensitivity insulin secretion plasma glucose total dynamic static different sucralose water conditions table 1 however differences plasma glucose concentration conditions caused higher peak isr sucralose water fig 3a exclusively due average increase 22 4% static isr 60 105 min p 0.005 dynamic isr curves sucralose water ingestion fig isr response glucose load subjects drank either sucralose 10 min ingestion 75 g glucose given time 0 min the results current study demonstrate ingestion sucralose alters metabolic response oral glucose load obese people regular consumers nns the peak increase plasma glucose c peptide insulin concentrations total insulin auc oral glucose load greater subjects consumed sucralose consumed water glucose ingestion in addition insulin clearance plasma slower sucralose water ingestion these data suggest sucralose ingestion physiologically inert affects glycemic response oral glucose load potentiates glucose stimulated insulin secretion obese people the finding glucose induced glucagon suppression sucralose water ingestion makes unlikely glucagon responsible differences conditions the mechanisms responsible sucralose effect plasma glucose oral glucose load clear must involve alteration rate glucose absorption disposal endogenous production data previous studies conducted animal models showed sucralose augments glucose absorption increasing intestinal glucose transport 11,12 our results support notion sucralose increased early peak plasma glucose affect indices -cell sensitivity total dynamic static plasma glucose we found si decreased sucralose ingestion suggesting sucralose caused insulin resistance however minimal model used calculate si modified ogtt unable determine whether decrease si caused insulin resistance specific organ e.g. liver skeletal muscle multiple organs additional studies involve use glucose tracers quantify effect sucralose insulin mediated suppression endogenous glucose production insulin stimulated muscle glucose uptake needed explore findings sucralose ingestion affect glp-1 response glucose load subjects consistent data reported previous studies conducted human subjects 15,18 this finding suggests observed increase isr observed subjects mediated glp-1independent mechanism there trend suggesting gip contributed potentiated glucose stimulated insulin secretion confirmatory study needed in contrast data previous studies found oral ingestion nns glucose load augmented glp-1 19,20 affect gip secretion however studies total glp-1not biologically active form glp-1was measured 19,20 although possible discrepancy glp-1 findings study result methodological difference think unlikely active total glp-1 highly correlated 30 a second methodological difference studies diet cola sweetened sucralose acesulfame potassium 19,20 used unclear whether enhanced glucose stimulated glp-1 response mediated acesulfame potassium synergistic effect sweeteners ingredients contained carbonated drinks 20 additional studies examine metabolic effects different nns potential interactions dietary ingredients needed this finding suggests intestinal sweet taste receptors 4 activated nns involved regulating insulin metabolism this observation also raises possibility sweet taste receptors contribute unexplained reduction insulin clearance observed oral intravenous glucose load 31,32 a series studies conducted human subjects reported sucralose affect glycemic hormonal responses intraduodenal 15 oral administration glucose carbohydrates 16,18,33 rev 13 the reason(s discrepancy findings may related study subject selection increase sample homogeneity included subjects obese insulin sensitive based homeostasis model assessment score 2.6 regular users nns decreasing variability it likely study greater statistical power previous studies detect sucralose effect in addition subjects previous studies caucasian 15,16,18,20 whereas subjects study african american we believe study first evaluate acute effects sucralose subjects regular users nns data studies conducted animal models shown chronic inclusion nns diet upregulates expression sodium dependent glucose transporter isoform 1 turn increases initial rate na dependent glucose uptake 5,10 increases glycemic responses oral glucose tolerance test 34 therefore speculate regular users nns would higher glycemic response oral glucose tolerance test control day irregular users acute effects sucralose intake would blunted differences water sucralose conditions would smaller regular irregular users nns conclusion results study demonstrate sucralose affects glycemic hormonal responses oral glucose load obese people normally consume nns these findings support notion sucralose metabolically inert physiologic effects additional studies nns conducted distinct study populations including children chronic nns users evaluate effect nns metabolic response mixed meal ingestion needed | objectivenonnutritive sweeteners ( nns ) , such as sucralose , have been reported to have metabolic effects in animal models . however , the relevance of these findings to human subjects is not clear .
we evaluated the acute effects of sucralose ingestion on the metabolic response to an oral glucose load in obese subjects.research design and methodsseventeen obese subjects ( bmi 42.3 1.6 kg / m2 ) who did not use nns and were insulin sensitive ( based on a homeostasis model assessment of insulin resistance score 2.6 ) underwent a 5-h modified oral glucose tolerance test on two separate occasions preceded by consuming either sucralose ( experimental condition ) or water ( control condition ) 10 min before the glucose load in a randomized crossover design .
indices of -cell function , insulin sensitivity ( si ) , and insulin clearance rates were estimated by using minimal models of glucose , insulin , and c - peptide kinetics.resultscompared with the control condition , sucralose ingestion caused 1 ) a greater incremental increase in peak plasma glucose concentrations ( 4.2 0.2 vs. 4.8 0.3 mmol / l ; p = 0.03 ) , 2 ) a 20 8% greater incremental increase in insulin area under the curve ( auc ) ( p < 0.03 ) , 3 ) a 22 7% greater peak insulin secretion rate ( p < 0.02 ) , 4 ) a 7 4% decrease in insulin clearance ( p = 0.04 ) , and 5 ) a 23 20% decrease in si ( p = 0.01 ) .
there were no significant differences between conditions in active glucagon - like peptide 1 , glucose - dependent insulinotropic polypeptide , glucagon incremental auc , or indices of the sensitivity of the -cell response to glucose.conclusionsthese data demonstrate that sucralose affects the glycemic and insulin responses to an oral glucose load in obese people who do not normally consume nns . |
oral infections geotrichum candidum clinically similar candidiasis commonly associated diabetes mellitus hiv infection cases dissemination fungemia reported patients chronic acute myeloid leukemia old women post partum isolated renal calculi renal fungal bezoar attributed geotrichum candidum illustrate diagnostic dilemmas old women presented history left flank pain intermittent fever since 15 days she evaluated elsewhere contrast enhanced computerized tomography ct scan revealed contracted left kidney 2 calculi lower middle calyx 89 mm intrapelvic mass multiple air pockets renal pelvis fig 2 undergone cytoscopy left dj stenting elsewhere continued fever flank pain presented us routine investigation patient started 3rd generation cephalosporin underwent left percutaneous nephrolithotripsy pcnl revealed brownish gray material 2 calculi gross specimen consists multiple irregular gray brown tissue bits largest measuring 0.5 cm0.5 cm cut portion showed gray brown areas section showed fungal ball containing aggregates macerated distorted fungal hyphae showing acute angle branching surrounded cell debris neutrophils both urine biopsy material sent mycology laboratory culture investigation inoculated sabourauds dextrose agar hi media laboratories ltd mumbai incubated 37 c 28 c grew rapidly growing fungus flat white creamy smooth texture later becoming hairy consistent geotrichum candidum fig geotrichum candidum morphologically identified presence true hyphae hyaline smooth one celled subglobose cylindrical slimy arthroconidia lack blastoconidia the arthroconidia vary size germinate one end giving hockey stick appearance fig 4 biochemical identification carried mycology laboratory kasturba medical college manipal using conventional api 20c yeast identification system biomerieux inc it differentiated trichosporon absence urea utilization inability assimilate carbohydrate maltose sucrose lactose cellobiose inositol raffinose trehalose antifungal susceptibility testing isolate performed according clinical laboratory standards institute clsi document m38-a2 the mic90 minimum inhibitory concentration amphotericin fluconazole itraconazole voriconazole found 0.125 g ml 16 g ml 4 g ml 0.25 g ml respectively patient continued fever post operative period responded starting intravenous itraconazole 200 mg bd 2 days followed oral itraconazole 200 mg bd continued 6 weeks follow repeat ct done showed complete clearance fungal material left kidney the saprophytic colonization preformed cavity conglomerate fungal mycelia without invasion adjacent tissue termed fungal ball fungal bezoar renal colic caused passage fungal ball obstruct collecting system genitourinary tract rarely site primary fungal infection exception candida species however may involved result part systemic infection candidal infection cause pyelonephritis abscess papillary necrosis obstruction fever flank pain genitourinary fungal infections usually encountered part disseminated disease immunocompromised host aids corticosteroids malignancy neutropenia fungal balls also called fungal bezoars accretions known cause ureteral uretro pelvic junction obstruction diagnosis established identification fungi urine imaging studies using computerized tomography ultra sonography intravenous urography document obstructive uropathy soft tissue density renal collecting system have successfully managed removal bilateral renal pelvis mycotic bezoars using mechanical thrombectomy device followed antifungal renal pelvis irrigation percutaneous nephrostomy tract dilation fluoroscopically guided extraction renal fungal ball epidural anesthesia described doemeny et al the outcome geotrichum infections depend degree tissue invasion organism immune status host sheehy et al suggested geotrichum lack virulence ability colonize renal tubules based rarity disseminated disease lack tissue invasion rapid clearance case reported its incidence may reported since misdiagnosed histopathologically candida aspergillus trichosporon this possibility misinterpretation highlights importance obtaining repeated fungal cultures addition histopathological examination we hereby reiterate pathogenic potential geotrichum candidum report role causing renal fungal ball | geotrichum candidum is yeast like fungi that cause infections in immunocompromised patients .
we report a case of renal fungal ball with geotrichum candidum in a 27 yr .
old women post - partum .
this case to our knowledge is the first case of renal fungal bezoar due to geotrichum candidum reported in india . |
granulosa cell tumours gcts though accounting approximately 70% malignant sex cord stromal tumors rare comprising 25% ovarian neoplasms 13 these tumours arise granulosa cells hormonally active stromal elements close association ovarian oocytes responsible production estradiol the exact etiology malignancy remains unknown identification specific defined risk factors the typical clinical scenario gct older postmenopausal woman menstrual abnormalities found singular pelvic mass curable en bloc resection while typical cases exist characteristics gcts clinical practice always fit within confines parameters as seeing past myth recognize identify uncommon realities necessary accurate diagnosis management gcts the aim study discuss myths realities gcts series indexed cases context relevant evidence based literature further comprehensive fourteen year 19972011 search using laboratory information system lis identified additional patients gcts patient demographics including age sex tumour site collected analysis
a literature search using national library medicine interface pubmed conducted using search terms granulosa cell limited english language this study conducted ethics approval university saskatchewan biomedical research ethics review committee ultrasonography confirmed mass 2 cm lesion orchiectomy carried on histological examination tumour solid regions cystic spaces figures 1(a 1(b amphophilic cytoplasm indistinct cell borders extensive fibrocollagenous stroma identified figure 1(c the lesional cells positive inhibin figure 1(d confirming sex cord stromal nature neoplasm twenty years post operatively well evidence recurrence seven days birth female neonate developed increased abdominal distension constipation a large mass palpable abdominal exam prompted ultrasonography detected 10 cm multiseptated cystic mass this confirmed computed tomography ct scan showed mass surrounded large volume fluid figure 2(a hematological investigations showed high levels estradiol 310 prolactin 34.9 thyroid stimulating hormone tsh 11.05 normal levels luteinizing hormone lh follicle stimulating hormone fsh -fetoprotein -human chorionic gonadotropin -hcg the young girl taken operating room laparotomy revealed large cystic mass left ovary torsion figure 2(b an oophorectomy preservation left fallopian tube carried follow up abdominal pelvic ct evidence residual disease detected estradiol tsh levels normalized eighteen years post operatively well evidence recurrence histological examination multicystic lesion lined granulosa cells identified figure 2(c without typical theca internal layer lining cysts solid proliferations granulosa like cells recognized ovarian stroma focal areas solid insular pattern nongrooved nuclei present figure 2(d histological features common adult gct agct juvenile gct jgct an almost exclusive macrofollicular pattern typical agct contrasted small areas solid insular pattern seen jgct the unusual facet case clinical presentation unsuspected gct seven day old neonate 76-year old woman presented growth umbilicus bowel obstruction ct scan showed complex mass arising anterior bladder wall dome bladder figure 3(a clinical suspicion urachal carcinoma patient taken operating room underwent partial cystectomy anterior abdominal wall mesh reconstruction the mass smooth solid cystic figure 3(b extension bladder dome umbilicus microscopic examination sheets spindle cells focal retiform like areas uniform grooved nuclei identified figure 3(c immunohistochemical analysis found mass positive vimentin focal positivity inhibin figure 3(d cytokeratin
an incidental pelvic mass detected 64-year woman past history total abdominal hysterectomy bilateral salpingooophrectomy gct 16 years prior a ct scan confirmed presence large heterogenous solid cystic pelvic mass figure 4(a the preoperative diagnosis mass included abscess gastrointestinal stromal tumor extracolonic mass she underwent laparotomy pelvic washings cytology en bloc resection left ovarian mass gross examination necrosis reminiscent colonic adenocarcinoma admixed diffuse microfollicular cords neoplastic cells observed figure 4(b deeper sections confirmed presence glandular neoplasm originating diverticular outpouching overlying colonic mucosa confirming presence colonic adenocarcinoma arising diverticulum large bowel this supported immunohistochemistry confirmed two components collision tumour inhibin positivity gct component figure 4(c cytokeratin positivity adenocarcinoma component figure 2(d 45-year old woman presented emergency room two year history menorrhagia acute dyspnea an enhanced ct scan revealed giant mass estimated size 36 cm craniocaudal filling pelvis abdomen causing displacement bowel loops the patient developed imminent renal failure hemoglobin levels continued drop despite receiving 9 units blood it suspected mass haemorrhaging taken operating room a 3540 cm multilobulated haemorrhagic mass found right ovary total abdominal hysterectomy bilateral oophorectomy en bloc mass resection partial omentectomy carried
microscopic examination showed presence sheets neoplastic cells interspersed rupture acute hemorrhage figure 5(a the ovarian tumour showed granulosa cells arranged solid sheets trabeculae tubules microfollicles included call exner bodies figures 5(b 5(c immunohistochemical analysis found neoplastic cells stain positive vimentin inhibin figure 5(d cd99 afp the unique presentation gct acute abdomen due tumor rupture hemorrhage
surgical review 14-year 19972011 surgical pathology review yielded 37 cases gct overall prevalence 0.0041% 37/902 100 cases 36 females one male index case 4 within female population patient age ranged 7 days 85 years mean 52 years median 48 years locations gcts included 17 cases right ovary 47.2% 15 left ovary 41.7% one 2.8% bowel abdominal wall omentum four 10.8% ) concurrent pathologies included leiomyoma uterus 21% benign cysts 14% adenomyosis 7% coexisting ovarian adenocarcinoma 3% endometrial carcinoma 3%
a 14-year 19972011 surgical pathology review yielded 37 cases gct overall prevalence 0.0041% 37/902 100 of cases 36 females one male index case 4 within female population patient age ranged 7 days 85 years mean 52 years median 48 years locations gcts included 17 cases right ovary 47.2% 15 left ovary 41.7% one 2.8% bowel abdominal wall omentum four 10.8% ) concurrent pathologies included leiomyoma uterus 21% benign cysts 14% adenomyosis 7% coexisting ovarian adenocarcinoma 3% endometrial carcinoma 3% granulosa cell tumours gcts first described 1855 rokitansky chronicled chew et al gcts rare sex cord stromal tumors thought arise normal proliferating granulosa cells late preovulatory follicle share many morphological biochemical features cells additionally theca cells interstitial cells stromal fibroblasts also delegated cells origin gct recently growing evidence suggest granulosa stem cells gscs exist identification normal neoplastic gscs factors regulate behavior determine treatment ovarian cancers including gcts future however currently little known regarding molecular genetic changes associated gcts they associated variety genetic abnormalities trisomy 12/14 monosomy 22 90% adult gct missense somatic c134w mutation foxl2 gene men the typical clinical scenario gct usually middle aged female presenting pelvic mass cured en bloc resection mass these characteristics however generalizable gcts lesions present many different facets tendency behave unpredictably thus complicating diagnosis therapeutic management accurate recognition true realities multifaceted gct therefore vital precise diagnosis management lesions some existing myths gcts contrasted true realities context evidence based literature this cancer divided three types based cell origin germ epithelial stromal conferring different histopathological features clinical outcomes stromal tumours classified based tissue types involved sertoli leydig theca granulosa granulosa cell tumours gcts account 1 2% ovarian tumours arise granulosa cells normally surround oocytes line developing follicle these include neoplasms derived mesenchyme developing genital ridge b neoplasms arise precursors within mesonephric coelomic epithelium the presence extraovarian gct seen case 3 supports latter theory date though chromosomal anomalies and/or autocrine endocrine signalling abnormalities proposed aetiologies current etiology postulated one multifactorial origin these lesions considered low grade type malignancy 7090% neoplasms diagnosed stage 1 the high detection rate early stage may due endocrine symptoms often present early functioning tumors low staging diagnosis confers excellent prognosis 5-year survival rates reported 7595% stage 1 however rates drop 5575% 2250% stages ii iii iv respectively may partially due limited treatment options advanced recurrent disease although predominantly occurring granulosa cells female ovary gcts also reported arise within male testis seen index case 1 testicular sex cord stromal tumours rare comprising 4% testicular tumours juvenile gct jgct far common adult gct agct within testicle preferred laterality within testis 9 10 approximately half testicular jgcts diagnosed within first month life 95% within first year seen case 1 the differential diagnosis testicular jgct includes yolk sac tumour undifferentiated sex cord stromal tumour gynandroblastoma gonadoblastoma typically males present painless indolent testicular swelling due estrogen hypersecretion patients may impotent 25% gynaecomastia 9 13 an intra abdominal mass undescended testis and/or testicular torsion may additionally present jgcts undescended testis benign reach adequate size cause pressure organs though patients lymph node metastases usually longer survival period presence distant metastases usually associated dismal prognosis histologically testicular gct resembles ovarian presenting solid cystic mass microfollicular gyriform insular trabecular patterns cells typically immunopositive vimentin inhibin smooth muscle actin cd99 s-100 9 18 genetically chromosomal abnormalities atypical chromosome mosaicism may present most patients gcts perimenopausal early postmenopausal median age diagnosis 5054 years nevertheless surgical review demonstrates gcts may arise neonates index case 2 patients age 80 series gcts neonates index 2 rare occurrence reported cases less one year age a common misconception two subclassifications gcts adult type gct agct juvenile type gct jgct refer age development though agct jgct occur often adults children respectively either form may present throughout entire population the majority 95% agcts commonly seen adults 22 23 agct reported children however less 1% lesions occur prepubertal girls upto 90% jgcts diagnosed patients age 30 half jgct cases seen less 10 years age 22 27 10% occurring infants less one year differences agct jgct distinct therefore accurate identification critical guide patient management unlike agct jgct considered many relatively benign tumour infantile males common type sex cord stromal tumour testis cells producing hormones estradiol present 70% jgcts young patients clinical evidence isosexual precocious pseudo puberty including breast enlargement pubic axillary hair development vaginal secretions irregular uterine bleeding advanced somatic skeletal developments secondary sex characteristics may associated jgct 2 5 these patients often elevated estradiol levels though requirement precocious puberty the risk precocious puberty especially high jgct patients one year age gct age range rare such symptoms present 8090% patients age 8 jgct on radiologic imaging jgct often indistinguishable ovarian neoplasms identification histopathology features nodular diffuse cellular growth and/or macrofollicules eosinophilic basophilic fluid lumen often required correct diagnosis younger women uterine sparing surgery conservation contralateral tube ovary recommended outset maintenance fertility advanced stage disease responsive combination chemotherapy platinum agents 5 6 the overall prognosis jgct excellent reports survival high 97% one study 3.5-year followup after resection gross examination jgct similar agct average microscopically tumours solid cellular follicle formation edema loose stroma hyperchromatic granulosa cells rounded nuclei surrounded eosinophilic vacuolated cytoplasm high mitotic rates additionally seen 2 5 unlike agct call exner bodies identified estradiol one first hormones secreted gcts responsible clinical manifestations among females pre pubescent girls may experience isosexual precocious puberty result increased estrogen levels caused hyperestrogenism though hyperestrogenism common form endocrine abnormality gcts important consider juvenile gct females presenting androgen excess precocious puberty the adult gct appears common type gct associated virilisation suggesting propensity increased androgen secretion agcts by contrast elevated estrogen levels adults cause abnormal uterine bleeding menstrual irregularities menorrhagia amenorrhea 20 27 patients virilising gcts present hirsutism clitoromegaly increased abdominal size amenorrhea deepening voice rare case reports document jgcts presenting paraneoplastic syndrome hypercalcemia meig syndrome pleural effusion ascites adult patients may present vaginal bleeding caused endometrial hyperplasia uterine cancer result prolonged exposure tumor derived estrogen in addition gct vascular tumor may occasionally rupture result abdominal pain hemoperitoneum hypotension mimicking ectopic pregnancy younger patients tumor rupture often attributed hemorrhagic cysts upto 1015% cases 2 27 occasionally gcts theca cell tumours found ovaries show enlargement therefore clinically occult 35 36 gcts common estrogen producing neoplasms females found produce estradiol approximately 4060% patients this estradiol production directly related release testosterone secreted theca cells however gcts hormonally active theca cells secrete testosterone therefore diagnostic testing hormones lacks sensitivity specificity normal granulosa cells responsible production estradiol also peptide hormones including inhibin activin follistatin antimullerian hormones gct patients usually present elevated levels inhibin negative feedback regulator fsh secretion however hormone specific tumours 2 3 37 mom et al evaluated sensitivities specificities serum inhibin levels 30 women granulosa cell tumors inhibin 67 100% inhibin b 89 100% resp serum inhibin levels currently available diagnosis clinical followup women granulosa cell tumors ovary therefore used monitor response therapy detect recurrences mullerian inhibitory substance mis produced developing follicles often elevated gcts though specific diagnosis 2 3 this hormone produced exclusively granulosa cells postnatal females prenatally postnatally sertoli cells male testis this hormone functions male fetuses induce regression mullerian system normally mis found low levels reproductive aged females functions paracrine inhibitory factor decreases response resting ovarian follicle follicle stimulating hormone fsh thus ensuring emergence single dominant follicle serum mis may marker ovarian reserve typically disappears serum menopause bilateral oophorectomy however patients gcts levels shown parallel extent disease serum mis levels routinely available clinical use context gct diagnosis followup however commercial version ultrasensitive elisa assay become available may lead wider clinical use mis future serum mis levels thus correlate well tumor presence patients gcts elevated levels considered highly specific gct postmenopausal oophorectomized women it may also elevated women sertoli leydig cell tumors ovary typically produced gonadal extragonadal tumors this sharp contrast inhibin estradiol levels may elevated variety extraovarian disorders this marker may thus eventually used diagnosis follow evaluations patients gcts preclinical research also ongoing evaluate clinical use targeting mis receptor therapy cancers expressing receptor follicle regulatory protein secreted granulosa cells elevated patients gcts however clinical significance marker still undetermined 20 27
gcts reported coexistence number pathologies including mucinous cystadenoma 7 41 42 cystic teratoma ovarian fibroma ovarian angiosarcoma adenosarcoma cystadenosarcoma sclerosing peritonitis gastric signet ring cell carcinoma cervical lipoleiomyoma indexed case 4 gct found coexist colonic adenocarcinoma unique collision tumor discussed previously detail the presence coexiting pathologies may contribute increased confusion deterrent accurate clinical pathological recognition uncommon neoplasm
uterine pathologies reported occur gct include glandular hyperplasia atypical adenomatous hyperplasia adenocarcinoma insitu invasive carcinoma endometrial hyperplasia common finding alongside gct occurring 2550% may occur due estrogen produced gct stimulating endometrium a simultaneous uterine carcinoma found 510% patients gct often well differentiated early stage perhaps due diagnosis earlier stage patients synchronous endometrial ovarian cancers better prognosis patients single malignancy typically detected become extensive
the rarity lesions prevents randomized control trials determine specific best consensus practice guidelines management gct the mainstay treatment gct epithelial ovarian cancer surgical excision 6 20 27 diagnostic laparoscopy described identification tumour origin extent resectability however currently laparoscopic resection advocated gcts as incidence bilateral disease quite low women reproductive function less 40 years old reproductive age fertility sparing surgery unilateral salpingooophrectomy endometrial biopsy recommended women 40 without reproductive function 40 require total abdominal hysterectomy tah well bilateral salpingooophrectomy bso 3 20 27 patients advanced disease tah bso complete tumour debulking suggested improved survival palliative debulking hepatectomy unusual case grade stage granulosa cell tumor recurred 21 years following initial surgery also reported peritoneal exploration washing cytology peritoneal biopsy partial omentectomy suggested part staging procedure gct patients careful examination contralateral ovary tube intra abdominal organs peritoneum sampling pelvic para aortic lymph nodes recommended aside treatment option surgery also necessary staging accurate tissue diagnosis 3 27 these parameters important determine poor prognostic features include tumour size greater 1015 cm high mitotic index tumour rupture lymphatic invasion 3 6 31 50
three forms adjuvant therapy suggested use combination surgery hormonal therapy radiotherapy chemotherapy hormonal therapy believed act directly affecting tumour and/or indirectly suppressing gonadotropins endogenous steroids aromatase inhibitors anastrozole letrozole inhibit conversion androstenedione estrone estradiol testosterone estradiol reducing aromatization androgens upto 90% thereby enhancing treatment gct gonadotropin releasing hormone gnrh analogs like leuprolide used decrease stimulation granulosa cells inhibition ovarian steroidogenesis recurrent gct however fact gcts respond hormonal therapy despite nearly gcts containing progesterone receptors indicates multiple factors play role hormonal regulation tumor cell radiotherapy may used adjuvant therapy instance recurrence associated improved survival 27 29 52 additionally use palliative radiotherapy alternative strategy potential disease control useful symptomatic patients localized metastatic disease unqualified surgery 2 20 the use chemotherapy yielded encouraging results associated longer disease free survival the chemotherapeutic agent cisplatin highest reported activity ovary combined doxorubicin cyclophosphamide bleomycin vinblastine etoposide overall response rate 6083% reported the current standard recommended chemotherapeutic regimen advanced recurrent metastatic gct bleomycin etoposide cisplatin bep 3 20 27 targeted identification targets novel therapeutic agents also predicted future increased knowledge molecular biology normal neoplastic gscs 2 6 52
the cut surface primarily solid haemorrhagic regions gray white yellow colour depending lipid content these tumours often filled serous fluid clotted blood may mistaken mucinous cystadenoma cystadenocarcinoma gcts sex cord stromal neoplasms microscopic examination contain sex cord derived epithelial elements admixed mesenchymal elements variety combinations degrees differentiation fibroblasts granulosa theca cells make gct depending 4 variables including age diagnosis histology therapy prognosis cells usually arranged around central cavity named call exner body microfollicular growth pattern similar primordial follicles contains eosinophilic materials well nuclear debris wide variety growth patterns identified may divided two categories the well differentiated type includes microfollicular macrofollicular trabecular insular solid tubular gyriform architectural patterns the moderately differentiated type includes diffuse sarcomatoid growth pattern easily mistaken carcinoma adenocarcinoma histological mimics nuclear characteristics hallmark feature agct including uniform pale grooved
these nuclear features may used differentiate agct diffuse pattern poorly differentiated carcinoma carcinomatous nuclei hyperchromatic grooved additionally demonstrate nuclear atypia multiple mitotic figures extent
immunohistochemical analysis used confirm diagnosis gcts lesion morphology non predictive histogenesis study nofech mozes et al inhibin calretinin cd56 cd99 part immunoprofile types gct however lack single specific marker necessitates panel antibodies detection lesions gct cells usually stain positive inhibin calretinin cd99 cd56 vimentin estrogen progesterone receptors other markers positive leading diagnostic confusion include cam5.2 ae1/ae3 cd10 s100 wt-1 smooth muscle actin desmin however gct usually negative cytokeratin 7 epithelial membrane antigen ema the absence staining ema diagnostic value distinguishing gct multiplicity histological look alikes metastatic primary carcinoma gcts unpredictable neoplasms ability extend locally spread lymphatics especially para aortic lymph nodes distant metastatic sites gct commonly include lung liver brain
a quarter gct patients recurrences mean time detection 510 years 3 27 1020% patients may develop recurrences late twenty forty years primary diagnosis 57 58 one third 33% gcts recur less 5 years half 50% 59 years 17% ten years initial diagnosis 49 59 splenic rupture metastatic gct 29 years original curative resection also reported lifelong surveillance neoplasms recommended frequent sites recurrence include upper abdomen 5570% pelvis 3045% this suggests recurrences early stage patients may attributed preexisting diseased peritoneum initial surgery early stage patients risk factors relapse include large tumour size high mitotic index tumour rupture therefore features may indicate need postoperative adjuvant chemotherapy additional postsurgical risk factors include advanced stage presentation lymphovascular space invasion bilaterality ki67/p53 overexpression higher stage disease also related aggressive tumour behaviour recurrences overall ten year survival rates patients gct range 60 90% approximately 80% females advanced gct die due disease partly related tendency delayed recurrence this unpredictability time interval recurrent and/or metastatic disease indicates requirement long term clinical followup cases 3 27 gct best considered unusual indolent neoplasm low malignant potential late recurrences arise ovaries testicles young old the multifaceted clinical presentations coupled unpredictable biological behaviour late relapses diagnostic pitfalls necessitating high degree suspicion accurate clinical pathological diagnosis surgery continues primary cornerstone initial treatment chemotherapy and/or radiotherapy reserved advanced recurrent disease states lack evidence based predictive prognostic factors continues deterrent accurately predicting biological behaviour individual gcts however long term lifelong followup including physical pelvic exam abdominal pelvic ct scan and/or tumor markers available recommended patients gcts delayed tumor recurrences beyond 5 years characteristic disease |
background . granulosa cell tumors ( gcts ) , representing ~2% of ovarian tumours ,
are poorly understood neoplasms with unpredictable and undetermined biological behaviour .
design .
5 unusual presentations of gct and a retrospective 14-year ( 19972011 ) surgical pathology review based on patient sex , age , tumour type and concurrent pathology findings are presented to discuss the myths and realities of gcts in the context of relevant evidence - based literature .
results . the 5 index cases included ( 1 ) a 5 month - old boy with a left testicular mass , ( 2 ) a 7-day - old neonate with a large complex cystic mass in the abdomen , ( 3 ) a 76-year - old woman with an umbilical mass , ( 4 ) a 64-year - old woman with a complex solid - cystic pelvic mass , and ( 5 ) a 45 year - old woman with an acute abdomen .
pathological analysis confirmed the final diagnosis as ( 1 ) juvenile gct , ( 2 ) macrofollicular gct , ( 3 ) recurrent gct 32 years later , ( 4 ) collision tumour : colonic adenocarcinoma and gct , and ( 5 ) ruptured gct . conclusion .
gct is best considered as an unusual indolent neoplasm of low malignant potential with late recurrences that can arise in the ovaries and testicles in both the young and the old .
multifaceted clinical presentations coupled with the unpredictable biological behaviour with late relapses are diagnostic pitfalls necessitating a high degree of suspicion for accurate clinical and pathological diagnosis . |
name lymphoproliferative disorders various disease patterns included characterized expansion lymphoid clone less differentiated the application recent times immunological methods determining phenotype many cell components together acquisitions cytogenetic molecular biology well clinical behavior helped relatively define wide range diseases may present heterogeneous clinical morphological picture in fact last classification lymphoproliferative disorders lists 40 types lymphoproliferative syndromes immunophenotype b 23 immunophenotype level oral cavity lymphoproliferative disorder occur various ways commonly lymphoid lesions extranodal externalization sometimes oral lesions may represent localization disease spread under key research sees lymphoproliferative disorders associated injury events oral cavity present paper proposes comprehensive classification listed table 1 deeply described primary extranodal involvement seen 10% 35% cases non hodgkin lymphomas these locations include gastrointestinal tract skin testicles kidneys bones 3 4 nhl central nervous system account 1% cases 5 6 although oral involvement nhl rare second common oral malignant disease oral squamous cell carcinoma 7 8 constituting 2.2% malignancies head neck 3.5% intraoral malignancies 5% tumors salivary glands 2.5% cases nhl although every site may affected ring waldayer commonly involved indolent lymphoma accounts 40% af nhl common type follicular lymphoma aggressive lymphoma accounts approximately 50% cases include diffuse large b cell lymphoma cell natural killer nk cell lymphoma highly aggressive lymphoma includes ebv associated burkitt lymphoma lymphoblastic lymphoma even though type nhl occur level oral cavity common types large cell lymphoma lymphoma small lymphocytes lymphoma ; mucosa associated lymphoid tissue malt lymphoma follicular lymphoma burkitt lymphoma immunocytoma immunoblastic lymphoma also reported 8 11 12 the common signs symptoms nhl intraoral include tissue swelling tooth loss paresthesia oral lesions may appear exophytic neoplasms erythematous asymptomatic often superficial ulcerations secondary chronic trauma figure 1
hodgkin disease form malignancy characterized proliferation neoplastic cells hodgkin reed sternberg cells associated polymorphic cellular component lymphocytes histiocytes eosinophils neutrophils plasma cells considered reactive initial description 1990s nature lineage reed sternberg cell inflammatory infiltrate compromises hodgkin disease debated the application pcr technique revealed hodgkin reed sternberg cells clonal b cells 98% patients leading change designation hodgkin disease hodgkin lymphoma lh classification lymphoid neoplasms since waldayer ring commonly involved nhl sometimes shows cells reed sternberg cell like diagnosis lh difficult especially small biopsy specimens 15 16 the common site involved ring waldayer followed lips tongue base 18 19 buccal mucosa 20 21 parotid gland 22 23 the oral manifestations plasma cell tumors occur three different ways consequence local manifestation multiple myeloma bone plasmacytoma solitary extramedullary plasmacytoma the primary manifestations plasma cell neoplasms oral level represented solitary extramedullary plasmacytoma
the plasmacytoma bone considered localized solitary myeloma figure 2 solitary bone plasmacytoma malignant monoclonal gammopathy 25 26 plasma cell cancer occurs single osteolytic lesion without plasmacytosis bone marrow capable secreting monoclonal protein 27 28 this disease accounts 10% plasma cell tumors strike 25 27 28 although rarely oral cavity showing predilection mandibular retromolar area radiological appearance may one two patterns either oval shaped lytic image destruction cortical bone hyperinsufflating lesion showing convex bicortical bone instead the extramedullary plasmacytoma plasma cell tumor located separately bone marrow found parts body lymphoid tissue 3238 90% extramedullary plasmacytoma present head neck clinically 3941 plasmacytoma extraosseous present sessile pedunculated exophytic neoformation circumscribed infiltrative ranging color red purple gray yellow white 4250 the oral manifestations multiple myeloma mm disease characterized proliferation accumulation bone marrow clone plasma cells produce homogeneous monoclonal protein 13 30 51 52 extensively reported literature oral manifestations initial sign submission 12% 15% cases mm 5355 the oral features include facial oral dental pain numbness paresthesia swelling soft tissue neoplasms tooth mobility bleeding deposit amyloid substance especially tongue 5760 other examples oral lesions first manifestation lymphoproliferative disorders may infiltration oral mucosa b cell chronic lymphocytic leukemia lymphomatous papulosis condition mucocutaneous applicant self limited characterized papular eruptions mycosis fungoides cell cutaneous lymphoma involvement oral cavity rare event well documented 63 64 in addition entering category previously treated lymphoproliferative disorders diagnosis oral lymphoid malignancy subsequent indication early sign mentioned regard clinical pathological entity evidence literature century mycosis fungoides mf chronic lymphoproliferative disorder predominantly cutaneous involvement characterized proliferation lymphocytes advanced stages disease accumulate also lymphoid organs bone marrow peripheral blood sezary syndrome involvement oral mf occasional finding observed 7.4% 18% patients undergoing necropsy 65 66 despite findings relatively frequent mucosal involvement vivo rare event predisposition sex age onset varies 36 81 years average 61 years oral sites frequently involved tongue palate gingiva buccal mucosa lips oropharynx almost patients lesions skin prior mucosa period time ranging 7 months 40 years here list non specific signs symptoms present association lymphoproliferative disorders oral cavity lymphadenopathy trismus erythema epiphora pain swelling facial asymmetry swelling buccal mucosa sinusitis increased lacrimation abscesses lacrimal sac diplopia nasal obstructions sepsis fever runny nose prosthetic instability headache paresthesia idiopathic epistaxis suspicion malignancy usually develops inflammatory symptoms responded conventional treatment protocols upon accurate evaluations required although oral lymphomas extremely rare 68 69 occur earlier placed differential diagnosis non specific inflammatory processes moreover early recognition subtle cancers decrease morbidity
paraneoplastic pemphigus pnp paraneoplastic autoimmune multiorgan syndrome rare autoimmune vesiculobullous disease first described anhalt et al 1990 patients occult malignancies 71 72 erosive eye lesions sinuses oral cavity gastrointestinal system respiratory genital epithelium could affect clinically lesions may occur polymorphic pemphigus bullous pemphigoid erythema multiforme graft versus host disease lichen planus 7375 figure 3
dermatomyositis dm rare inflammatory microangiopathic disease affects skeletal muscles clinical externalization characteristics mucocutaneous manifestations oral lesions paraneoplastic dm leucoerythroplasia ulcerative lesions rarely described literature 7679 the dm totally resolved underlying disease treated resurgence dm expresses relapse malignancy 76 79 literature reports single case multiple myeloma first manifestation oral level clinical aspects lichen planus showing extensive irregular erosions present buccal mucosa labial palatal mucosa ventral tongue the literature contains many works correlate paraneoplastic pemphigus pnp rare autoimmune vesiculobullous disease underlying malignancy 71 72 typical oral lesions lichen planus lichenoid reactions literature there numerous works reported associate mucous membrane pemphigoid mmp malignancies including lung cancer pancreatic adenocarcinoma gastric adenocarcinoma squamous cell carcinoma conjunctiva two cases reported mmp oral manifestations associated lymphoproliferative disorders b cell lymphoma chronic lymphocytic leukemia it described literature large amount cases connection bullous pemphigoid bp lymphoproliferative disorders chronic lymphocytic leukemia 8991 lymphoblastic lymphoma
necrotizing oral processes although rare general population rapidly evolve devastating stages immunocompromised patients 9396 often associated periodontal disease these patients lymphoproliferative disorders acute lymphoblastic leukemia developed necrotic processes level oral cavity associated typical ulcer necrotizing periodontal diseases bacteria oral cavity unusually found pseudomonas aeruginosa patients impaired lymphocyte function reduced counts neutrophils due lymphoproliferative disorders led acquisition new infections and/or exacerbation reactivation latent infection periapical periodontitis herpes simplex many cases the clinical presentation oral infections may atypical compared normally seen healthy patients the origin odontogenous infection pulp periodontal frequently observed patients lymphoproliferative disorders suspected orofacial pain extensive dental restorations dental caries periapical radiopacity occur 97 98 the candidiasis may present pseudomembranous candidiasis erythematous hyperplastic angular cheilitis deep fungal infections suspected patients solitary ulcer retreat this group includes infections aspergillosis histoplasmosis zygomycetes treatment requires aggressive treatment intravenous azoles amphotericin b echinocandins
primary infection reactivation herpes viruses common patients lymphoproliferative disorders especially advanced stages disease infection herpes simplex common patients reactivation varicella zoster virus vzv less common epstein barr virus infection ebv associated oral hairy leucoplakia rare whitish lesion occurs lingual lateral margins myelosuppressive patients 104 105 infection cytomegalovirus cmv occur intraoral mucosal surface form ulcer free character specificity persists weeks months because thrombocytopenia course lymphoproliferative disorders intraoral bleeding commonly observed present petechiae bruising occasionally formation hematomas figure 4
chemotherapy radiotherapyin addition included paper oral infectious complications bacterial fungal viral previously treated immunosuppression induced lymphoproliferative disorder remembered possible consequence drug induced immunodeficiency consider common characteristic found course oncohaematology treatment regimens patients lymphoproliferative disorders treated high doses radiotherapy head neck level associated aggressive chemotherapy regimens greatest risk developing oropharyngeal mucositis xerostomia often present patients lymphoproliferative disorders treated radiotherapy head neck region due damage major salivary glands still included irradiation tumors another long term complication radiation therapy head neck lymphomas patients underwent radiotherapy noticed osteoradionecrotic maxillary bone result permanent damage capillary bed bone osteocytes caused radiation
in addition included paper oral infectious complications bacterial fungal viral previously treated immunosuppression induced lymphoproliferative disorder remembered possible consequence drug induced immunodeficiency consider common characteristic found course oncohaematology treatment regimens patients lymphoproliferative disorders treated high doses radiotherapy head neck level associated aggressive chemotherapy regimens greatest risk developing oropharyngeal mucositis xerostomia often present patients lymphoproliferative disorders treated radiotherapy head neck region due damage major salivary glands still included irradiation tumors another long term complication radiation therapy head neck lymphomas patients underwent radiotherapy noticed osteoradionecrotic maxillary bone result permanent damage capillary bed bone osteocytes caused radiation
autologous transplantationoral complications observed 85% cases patients autologous bone marrow transplantation abmt infections occur period severe marrow aplasia may secondary conditions oral cavity transplant patients treated lymphoproliferative disorders increased risk relapse primary disease develop subsequent tumors hematologic nonhematologic regard consider oral squamous cell carcinoma second primary solid tumor allogeneic transplant variety circulating autoantibodies found 20% 61% patients undergoing autologous bone marrow transplant 108111 number patients may demonstrate autoantibody mediated diseases myasthenia gravis autoimmune cytopenias cases oral diseases oral vesiculobullous pemphigus pemphigoid 113116].the graft versus host disease gvhd multisystem immunologic reaction resulting action immunocompetent cells transplanted donor immunodeficient host the recipients allogeneic hematopoietic cell transplantation allo htc greater risk developing disease acute chronic graft versus host the likelihood developing gvhd depends type conditioning regimen ablative vs. totally reduced intensity regimens gvhd oral lesions although infrequent observed rarely require specific treatment chronic gvhd typically develops hundredth day incidence ranging 25% 40% allo hct 107 117 figure 5 the mouth one locations commonly affected events lichenoid mucositis including ulcers pain odynophagia dysgeusia hypofunction salivary glands caries decayed teeth rarely sclerotic processes lead hypomobility reduction functionality 10 118
oral complications observed 85% cases patients autologous bone marrow transplantation abmt infections occur period severe marrow aplasia may secondary conditions oral cavity transplant patients treated lymphoproliferative disorders increased risk relapse primary disease develop subsequent tumors hematologic nonhematologic regard consider oral squamous cell carcinoma second primary solid tumor allogeneic transplant variety circulating autoantibodies found 20% 61% patients undergoing autologous bone marrow transplant 108111 number patients may demonstrate autoantibody mediated diseases myasthenia gravis autoimmune cytopenias cases oral diseases oral vesiculobullous pemphigus pemphigoid 113116 the graft versus host disease gvhd multisystem immunologic reaction resulting action immunocompetent cells transplanted donor immunodeficient host the recipients allogeneic hematopoietic cell transplantation allo htc greater risk developing disease acute chronic graft versus host the likelihood developing gvhd depends type conditioning regimen ablative vs. totally reduced intensity regimens gvhd oral lesions although infrequent observed rarely require specific treatment chronic gvhd typically develops hundredth day incidence ranging 25% 40% allo hct 107 117 figure 5 the mouth one locations commonly affected events lichenoid mucositis including ulcers pain odynophagia dysgeusia hypofunction salivary glands caries decayed teeth rarely sclerotic processes lead hypomobility reduction functionality 10 118
supportive therapybisphosphonates drugs used combination chemotherapy treatment hypercalcemia secondary malignancy lytic bone metastases multiple myeloma 119121 starting 2003 an increasing number cases describe correlation osteonecrosis jaw onj administration intravenous bisphosphonates published literature 122131 figure 6
bisphosphonates drugs used combination chemotherapy treatment hypercalcemia secondary malignancy lytic bone metastases multiple myeloma 119121 starting 2003 increasing number cases describe correlation osteonecrosis jaw onj administration intravenous bisphosphonates published literature 122131 figure 6 approximately 10% cases non hodgkin lymphomas united states europe aids related 132134 typically aids related nhl predilection extranodal sites appears head neck 50 60% cases 135144 aggressive course poor prognosis 145147 histopathology these lymphomas b cells derived characterized widespread growth pleomorphism high grade morphology frequent mitotic figures increased tendency develop necrosis 148153 lymphomas head neck may involve gingiva palate tongue tonsils nasopharynx orbits parotid glands jaw breasts soft tissues hypopharynx lymphoid neoplasms heterogeneous malignant disorders lymphatic system characterized uncontrolled proliferation lymphoid cells precursors regard primary localizations lymphoproliferative disorders a careful examination head neck oral oropharyngeal area necessary order identify suspicious lesions early detection an early diagnosis may allow treatment early stages disease resulting better prognosis patient numerous complications described frequently found oral level due pathology different therapeutic strategies furthermore evaluation patients treatment lymphoma essential prevent relapse recognize early eventual secondary localizations this oral pathologists well dental practitioners central role treatment long term monitoring patients opportunity duty examine make diagnosis level hard soft tissue oral cavity | lymphoproliferative disorders are heterogeneous malignancy characterized by the expansion of a lymphoid clone more or less differentiated . at the level of the oral cavity , the lymphoproliferative disorder can occur in various ways , most commonly as lymphoid lesions with extranodal externalization , but sometimes , oral lesions may represent a localization of a disease spread . with regard to the primary localizations of lymphoproliferative disorders ,
a careful examination of the head and neck , oral , and oropharyngeal area is necessary in order to identify suspicious lesions , and their early detection results in a better prognosis for the patient .
numerous complications have been described and frequently found at oral level , due to pathology or different therapeutic strategies .
these complications require precise diagnosis and measures to oral health care .
in all this , oral pathologists , as well as dental practitioners , have a central role in the treatment and long - term monitoring of these patients . |
prevalence diabetes korea increased six- sevenfold 1.5 9.9% past 40 years the number people diabetes worldwide expected increase 11.4% 366 million 2011 552 million 2030 affecting one 10 adults this global increase prevalence diabetes inevitably lead increases prevalence diabetic microvascular macrovascular diseases consequently significantly increased health care expenditure korea diabetic patients microvascular disease spend 4.7 times much patients macrovascular disease 10.7 times much patients complications 8.8 times much complications the medical cost diabetes mellitus covered national health insurance corporation 3.2 trillion accounted 19.2% medical costs diabetes complications become major causes morbidity mortality korea although diabetes related mortality decreased recently 25.1 per 100,000 persons 2002 19.6 per 100,000 persons 2009 the rate death among patients diabetes twice high among persons without diabetes the common cause death cardiovascular disease 30.6% followed infectious disease 25.3% cancer 21.9% congestive heart failure 7.1% renal disease 4.7% liver disease 2.7% diabetes 1.9% despite seriousness diabetic complications 30% 70% patients receive inadequate care 40% treated diabetic patients achieve optimal control defined hba1c level 7% the serious outcomes diabetic complications inadequate glucose control diabetic patients prompt need aggressive efforts provide optimal metabolic control type 2 diabetes mellitus associated high rate complications related cardiovascular disease diabetic nephropathy retinopathy neuropathy 2006 30.3% 38.3% 44.6% patients found microvascular complications microalbuminuria retinopathy neuropathy respectively korean nationwide survey the prevalence macrovascular complications including coronary artery disease cerebrovascular disease peripheral artery disease 8.7% 6.7% 3.0% respectively the prevalence diabetic foot 4.4% 44.8% patients amputated foot diabetes mellitus the prevalence macrovascular complications seems underestimated data study 343 patients diabetes mellitus prevalence cardiovascular complication 23.6% another study 406 patients diabetes extracranial internal carotid artery stenosis 40% detected 5.2% patients in addition prevalence macrovascular complication 10.8% recent korean national diabetes program kndp data reference 2005 korea national health nutrition examination survey knhanes data table 1 the role hyperglycemia development microvascular complications diabetes nephropathy retinopathy neuropathy well documented the incidence microvascular complications begins increase hba1c level 7.0% increases 30% 40% per 1% increase hba1c level 8,000 patients fig microvascular complications closely related age duration diabetes glycemic control relationship stronger macrovascular complications diabetic retinopathy common microvascular complication diabetes mellitus prevalence strongly related duration diabetes it frequent cause new cases blindness among adults aged 20 74 years ansung cohort study prospective rural community cohort korea prevalence diabetic retinopathy 2.9% proper cutoff hba1c value detecting diabetic retinopathy 6.6% unpublished data diabetic nephropathy characterized albuminuria 300 mg day reduced glomerular filtration rate it often present time diagnosis diabetes kidney exposed chronic hyperglycemia prediabetic phase patients microalbuminuria progress macroalbuminuria 300 mg/24 hr likely progress end stage renal disease esrd diabetes major cause chronic kidney disease ckd recognized common cause esrd usa korea about 40% united states adults diagnosed undiagnosed diabetes degree ckd 1999 2006 national health nutrition examination survey the prevalence peripheral neuropathy estimated 40.0% 44.6% present specific treatment underlying nerve damage improve glycemic control may slow progression modestly the case fatality rate myocardial infarction higher patients diabetes patients without diabetes the association diabetes coronary heart disease likely become important two reasons first incidence type 2 diabetes increasing among high risk low risk populations second although rate death caused coronary heart disease overall population declined markedly past 35 years case among persons diabetes cardiovascular disease major cause morbidity mortality individuals diabetes largest contributor direct indirect costs diabetes older age high blood pressure smoking history major risk factors development macrovascular complications smoking history males risk factor predictive factor earlier development macrovascular complications korean patients type 2 diabetes microvascular complications diabetes increase risk cardiovascular events diabetic patients although diabetic retinopathy associated presence atherosclerotic plaque associated increased carotid intima media thickness increase intima media thickness associated presence plaque predisposes patients cardiovascular disease microalbuminuria low glomerular filtration rate 60 ml min/1.73 increase risk major cardiovascular events death diabetic polyneuropathy also independently associated high prevalence cardiovascular disease type 2 diabetic patients these data imply microvascular complications diabetes related indirectly macrovascular complications diabetes similar korea intensive glycemic control suggested effective treatment reducing burden cardiovascular disease microvascular complications people diabetes the united kingdom prospective diabetes study kumamoto study showed early intensive glycemic control delay onset progression diabetic retinopathy nephropathy neuropathy compared conventional treatment 21,24 26 intensive glucose control involving gliclazide modified release drugs required lowered hba1c value 6.5% reduced 10% relative risk combined outcome major macrovascular microvascular events primarily 21% reduction incidence nephropathy in addition legacy effect observed 10 years trial rate microvascular complication myocardial infarction steno-2 study the intensive therapy group 46% lower risk cause mortality 57% lower risk death cardiovascular causes one patient intensive therapy group progressed esrd compared 6 patients conventional therapy group fewer patients intensive therapy group required retinal laser therapy although many benefits intensive glucose lowering treatment preventing macrovascular microvascular events remains uncertain whether benefits outweigh risks intensive blood glucose control decreases risk developing microvascular complications macrovascular disease patients type 2 diabetes action control cardiovascular risk diabetes accord study intensive glucose lowering regimen reduced rate 5-year nonfatal myocardial infarctions associated 22% increase mortality a recent meta analysis found intensive glucose lowering treatment limited effect rates cause mortality death cardiovascular causes the data conflicting 9% reduction 19% increase cause mortality 14% reduction 43% increase cardiovascular death rates the harm associated severe hypoglycemia might counterbalance potential benefit intensive glucose lowering treatment the microvascular benefits intensive therapy weighed increase total cardiovascular disease related mortality weight gain high risk severe hypoglycemia however multifactorial approaches high risk patients diabetes tight glucose regulation use anti hypertensive medication aspirin lipid lowering agents shown reduce risk nonfatal cardiovascular disease among patients type 2 diabetes mellitus microalbuminuria high risk patients type 2 diabetes intensive treatment approaches multiple drug combinations and behavior modification sustained beneficial effects respect vascular complications rates death cause cardiovascular causes several adipokines implicated metabolic syndrome coronary heart disease insulin resistance we want discuss adipokines showed correlation diabetes metabolic syndrome korea lipocalin family proteins including adipocyte fatty acid binding protein fabp lipocalin-2 retinol binding protein 4 rbp4 identified recently adipokines associated obesity type 2 diabetes metabolic syndrome serum fabp associated glucose dysregulation level predicts development type 2 diabetes development metabolic syndrome independently adiposity insulin resistance serum lipocalin-2 level significantly elevated patients coronary heart disease independently associated coronary heart disease these findings suggest serum lipocalin-2 levels may useful assessing coronary heart disease risk plasma rbp4 concentration elevated persons impaired glucose tolerance type 2 diabetes high rbp4 low plasma adiponectin concentrations associated severity glucose intolerance women previous gestational diabetes mellitus a low circulating vaspin level correlates high fitness level whereas physical training untrained individuals increases vaspin serum concentration vaspin also correlated metabolic syndrome men coronary artery stenosis women however another study reported circulating visfatin may useful clinical biomarker metabolic status a relationship chemerin levels cardiometabolic parameters degree coronary stenosis reported korean patients coronary artery disease serum osteocalcin osteoblast specific protein several hormonal features secreted general circulation osteoblastic cells serum osteocalcin osteoprotegerin levels associated glucose metabolism atherosclerosis parameters people type 2 diabetes mellitus even though many studies adipokines metabolic diseases need large number prospective studies see causality candidate adipokines diabetic complications clearly the increasing prevalence diabetes mellitus related complications contributed substantial increase morbidity mortality korea however proportion patients type 2 diabetes achieving adequate glucose control relatively low multifactorial treatment approaches target hypertension dyslipidemia microalbuminuria provide intensive glycemic control urgently needed control diabetes these comprehensive integrated health interventions lead improvement management diabetes | the prevalence of diabetes in korea has increased six- to sevenfold over the past 40 years with its complications becoming major causes of morbidity and mortality .
the rate of death among patients with diabetes is about twice as high as that among persons without diabetes and the most common cause of death is cardiovascular disease ( 30.6% ) . despite the seriousness of diabetic complications ,
30 to 70% of patients receive inadequate care , and only 40% of treated diabetic patients achieve the optimal control with hba1c level < 7% in korea . in 2006 , over 30 to 40% of patients with diabetes have microvascular complications and around 10% of them have macrovascular complications from our national data .
despite there are some debates about intensive glycemic control resulting in the deterioration of macrovascular complication , multifactorial treatment approaches including proper glycemic control are important to prevent diabetic complications .
there have been needs for finding proper biomarkers for predicting diabetic complications properly but we still need more longitudinal studies to find this correlation with causal relationship . in this article , we wanted to review the recent status of micro- and macrovascular complications of type 2 diabetes in korea from integration of many epidemiologic studies . |
make observations based upon observations make empirical predictions engineering sciences this often reduced formulae mathematical modelling used predictively design newer better engineered products however orthodox medicine struggling develop methodology despite huge amounts investment made life sciences systems biologists compile models organs e.g. heart organs efforts understand complexity organ function associated cellular molecular biologies it equivalent knowing intricate details computer hardware yet software make work moreover understanding mechanisms body uses regulate function recover dysfunction infection possible assess whether patient recovery due medicine medical procedure natural processes recovery ? modern medicine evolved growth chemical industry massive increase chemical research yielded chemicals ever greater complexity biological significance aspirin paracetamol developed reduce temperature fever reduce severity headaches such chemical discoveries followed drugs reduce symptoms almost conceivable diseases upon huge swathes population increasingly dependent yet burden healthcare society continues increase the cost treating disease grown ten times since mid-1970 this leads us question basic assumptions upon modern biomedicine based e.g.
accurate biomarker techniques?it increasingly understood many medical conditions polygenic multi systemic the degree coiling uncoiling proteins associated onset diabetes cystic fibrosis alzheimer disease etc accordingly measurement level single protein biomarker may flawed concept.how accurate doctor diagnosis?the ability gp provide accurate diagnosis questionable many diseases poorly defined often difficult diagnose e.g. diabetes alzheimers disease cancers dementia depression chronic fatigue syndrome sleep disorders etc.how effective drugs?the ability drugs treat disease typically 50% onset disease involves genotype phenotype any medical assessment must take account level conformation protein level conformation substrate factors influence rate protein reacts substrate e.g. ph levels minerals cofactors etc it must also take account every drug alters body systemic cellular molecular stability i.e. body readjust order maintain optimum stability
the degree coiling uncoiling proteins associated onset diabetes cystic fibrosis alzheimer disease etc accordingly measurement level single protein biomarker may flawed concept many diseases poorly defined often difficult diagnose e.g. diabetes alzheimers disease cancers dementia depression chronic fatigue syndrome sleep disorders etc the ability drugs treat disease typically 50% onset disease involves genotype phenotype any medical assessment must take account level conformation protein level conformation substrate factors influence rate protein reacts substrate e.g. ph levels minerals cofactors etc it must also take account every drug alters body systemic cellular molecular stability i.e. body readjust order maintain optimum stability healthcare fashion led industry seeks exploit every perceived technological advance penicillins stem cell optogenetics genomics proteomics vaccines statins etc commercial hope promise new areas research lead yet greater opportunities diagnose treat disease ever greater cost taxpayer a better understanding body regulates function would improve understanding diagnostic therapeutic scope technologies for instance use stem cell implants treat type 1 diabetes overlooks implants implanted similar biochemical conditions associated original pancreatic failure patient regulatory system could maintain function pancreatic beta cells think pancreatic stem cell implant succeed ? it also argued knowledge type 1 diabetes occurred e.g. viral onset could lead therapies would establish reactivate pancreatic beta cells this illustrates changes dna cause physiological dysfunction varying degrees severity case diabetes cited altered dna structure conformation influences expression proteins manifest type 1 diabetes also adapted establish normal function pancreatic beta cells the greater amount changes genetic structures greater scope physiological cognitive dysfunction at almost every step orthodox biomedical research overlooks influence environment phenotype despite clear understanding stress major cause disease e.g. depression post traumatic stress disorder insomnia cardiac arrhythmia etc the glaring example identical twins different lifestyles significantly different health advancing years gene profiling identifies genes longer able express particular protein genotype genetically pre disposed medical condition e.g. gauchers disease fabry disease etc yet elucidate complex genetic interactions including racial genotypes involved polygenic diseases e.g. diabetes mellitus alzheimers disease cystic fibrosis etc environmental influences phenotype would cause pre disposition manifest pathology question how deal daily causes stress stress influence body function ? furthermore ignoring phenotype ignores 50% perhaps disease creating process(es incorporate understanding phenotype may able deal cause disease symptoms they also ignore body organs organised organ networks organs physiological significance e.g. regulating blood pressure blood glucose ph sleep etc perhaps interesting overlooked phenomenae eeg frequencies role played light these may issues greatest medical significance i.e. indicative mechanisms body uses regulate complex multi level function it directly influences reaction extraction processes e.g. levels minerals acidity temperature etc it influences metabolic rate cognitive dysfunction however techniques able measure phenotype component developing pathologies e.g. colour syntonic optometry microneurography tilt table test valsalva test etc the evidence suggests human physiology dynamic self regulating system brain acts process sensory input retain significant memories maintain body optimum stability it precise nature co ordinated function physiological structures determines levels key systemic parameter ph temperature digestion elimination breathing blood pressure blood volume blood cell content blood glucose osmotic pressure sexual function posture sleep this raises blood pressure order maintain appropriate level oxygen brain time this progressively influences stability physiological systems e.g. body temperature blood volume sleep digestion excretion osmotic pressure sexual function posture the body functional parameters based upon required maintain body normal and/or stable function e.g. attempts maintain acidity ph 7 increased acidity alters levels minerals particular lowers levels key minerals zn cr mg etc essential normal physiology ( ii maintains heart beat heart pressure level best absorbs oxygen lungs maintains flow oxygen brain i.e. high low levels blood pressure lead haemorrhage stroke ( iii maintains temperature circa 36.8c optimum temperature many biochemistries i.e. higher temperatures proteins start denature reactivity reduced whilst lower temperatures rate reaction declines ( iv maintains stability processes digestion excretion order ensure flow nutrients elimination toxins could adversely influence many biochemistries per litre deviations limits lead increased weight increased release insulin onset glycation processes type 2 diabetes cardiological complications etc b reduce energy generated lowers metabolic rate development side effects type 1 diabetes vi ) per litre blood cell content increases blood viscosity influences rate heart deliver oxygenated blood brain increased blood viscosity leads increased heart rate increased risk haemorrhage stroke there many years interest mathematical model physiological systems however last 10 20 years western research recognise significance physiological systems integrative theories linking cognition autonomic nervous system visceral organs.[2023 area russian researchers excelled a core group researchers researched relationship physiological systems nervous structures almost 50 years this autonomic instability leads cellular molecular change(s ultimately know pathologies it uses cognitive measurements particular colour perception data set model such methodology incorporated advanced cognitive technology widely reported this first technique able diagnose major medical conditions single cognitive test it incorporates understanding stress sensory input estimated 85% form light influences cellular molecular biology particular influences expression proteins rate proteins subsequently react measured the absorption emission light proteins provides means measuring colour contrast colour perception virtual scanning embraces unprecedented understanding mechanisms body employs regulate function e.g.
provide information potential advances understanding multi systemic etiologies e.g. migraine diabetes developmental dyslexia sleep apnoea virtual scanning track emergence typically 5 15 pathologies 30 organs.to illustrate influence genotype phenotype upon pathology i.e. protein expression ii rate expressed proteins subsequently react reactive substrates iii incorporates understanding reaction conditions governing reactions.to diagnose presymptomatic origins the emission biophotons light characteristic pathologies occurs first pathological reaction this influences colour perception typically 50 100 biophotons per second range 10 10 biophotons per second it contrasts biomarker techniques compare analysed results expected norms.to differentiate normal abnormal cell morphologies altered dna and protein conformation influences spatial orientation cell ability conduct cellular function e.g. facilitating passage glucose cell membranes
increased decreased cell function hyperfunction hypofunction).increased decreased arterial venal flow organ indicative inflammatory reaction ischaemia.abnormality limit cell division i.e. indications changes taking place cell morphology.growth new cells death old cells
assessing degree system stability instability an advanced understanding eegs used regulate systemic stability.[83335]how possible evaluate existence function system stability instability system whilst recognised organs function organ networks technologies able justify stability systems except using available technology virtual scanning.to predict onset pathologies if system becomes destabilised lead pathologies organ particular system
provide information potential to advances understanding multi systemic etiologies e.g. migraine diabetes developmental dyslexia sleep apnoea virtual scanning track emergence typically 5 15 pathologies 30 organs illustrate influence genotype phenotype upon pathology i.e. protein expression ii rate expressed proteins subsequently react reactive substrates iii incorporates understanding reaction conditions governing reactions diagnose presymptomatic origins the emission biophotons light characteristic pathologies occurs first pathological reaction this influences colour perception typically 50 100 biophotons per second range 10 10 biophotons per second it contrasts biomarker techniques compare analysed results expected norms differentiate normal abnormal cell morphologies altered dna protein conformation influences spatial orientation cell ability conduct cellular function e.g. facilitating passage glucose cell membranes
increased decreased cell function hyperfunction hypofunction).increased decreased arterial venal flow organ indicative inflammatory reaction ischaemia.abnormality limit cell division i.e. indications changes taking place cell morphology.growth new cells death old cells
increased decreased cell function hyperfunction hypofunction increased decreased arterial venal flow organ indicative inflammatory reaction ischaemia abnormality limit cell division i.e. indications changes taking place cell morphology growth new cells death old cells assessing degree system stability instability an advanced understanding eegs used regulate systemic stability.[83335 possible evaluate existence function system stability instability system whilst recognised organs function organ networks technologies able justify stability systems except using available technology virtual scanning predict onset pathologies if system becomes destabilised lead pathologies organ particular system the purpose series articles establish scientific basis virtual scanning prove methodology developed dr they highlight advanced technological concept based upon understanding body responds light advance diagnosis treatment disease the problem many base decision making upon seen lifetime this completely natural however illustrates difficulties inventors face develop seek commercialise novel potentially disruptive technologies e.g. computers mobile phones etc consequently resistance anything challenges status quo could introduce new potentially better ways dr grakov appears produced first mathematical model physiological systems this incorporated technology uses cognitive measurements data sets there mechanism overcome obstacles i.e. clinical studies however order reach stage clinicians convinced validity concept the purpose series articles illustrate technology exists precedents technology type underlying scientific methodology holds promise advanced sophisticated cost effective many medical techniques routinely employed orthodox biomedicine | the cost of diagnosing and treating disease continues to rise inexorably .
almost every new test adds to the complexity and cost of healthcare . there is a need for better and less expensive screening , diagnostic and scanning techniques .
medical scanning technologies are based upon the body 's response to an external stimulus e.g. heat , ultrasound , x - rays , magnetic resonance , etc .
biomarker and histopathology tests have inherent limitations because diseases are often polygenic and/or influence the function of multiple physiological systems . the results are compared with expected norms .
this makes it difficult to diagnose the onset of disease .
such techniques measure only what the clinician wants or expects to see .
a technique which can provide more information , regarding the influence of a medical condition upon the body 's whole function , may be invaluable to the clinician .
there is not yet a clear understanding of how the body regulates its function .
a greater understanding of how the body responds to sensory input , in particular to light , has been incorporated into a mathematical model of the physiological systems developed by i.g .
grakov .
this has been incorporated into a cognitive technology which improves the understanding of how the body regulates its function and has led to the development of a better method for the diagnosis and treatment of disease(s ) .
this technique , virtual scanning , appears able to diagnose at different levels of physiological significance i.e. as systems , organs , cells ( as morphologies ) and molecular ( as pathologies ) .
it may be a major scientific development , conceivably more advanced than biomarker techniques , with the potential to provide far more information about a patient 's health .
it may have the potential to significantly reduce the complexity and cost of healthcare .
this article reviews the available literature . |
technological advances computed tomography ct made chest ct fast accurate therefore extensively used imaging technique trauma patient care 1 2 although utility ct detection chest injuries primarily demonstrated severely injured patients this widespread use deserves reconsideration effectiveness might always outweigh potential harm radiation exposure 4 5 medicalisation time loss high costs although many studies addressed value ct trauma patients evidence based indications trauma ct chest exist according american college radiology appropriateness criteria ct performed conventional radiography cr shows signs mediastinal bleeding suspicious blunt aortic injury these guidelines additionally state thoracic spine images effectively obtained patients undergo thoracoabdominal ct making indications spine imaging less important indications obtaining thoracoabdominal ct the eastern association surgery trauma guidelines summarise thoracolumbar spine cleared without imaging awake trauma patients without evidence intoxication ethanol drugs normal mental status normal physical examinations however guidelines also state aortic injuries accurately ruled using signs mediastinal bleeding cr they therefore suggest blunt aortic injury considered patients involved motor vehicle collisions these recommendations reflect little evidence exists patients likely benefit chest ct blunt trauma more importantly remains unclear patients chest ct omitted without missing relevant injuries the aim prospective study adult blunt trauma patients therefore derive set independent clinical parameters distinguish patients benefit chest ct patients chest ct omitted without missing relevant injuries we performed observational cohort study 1,047 consecutive blunt trauma patients 16 years older patients prospectively included according inclusion exclusion criteria table 1 primarily evaluated emergency department hospital may 2005 july 2008
table 1inclusion exclusion criteria defined study started inclusion criteriadefinitionslife threatening vital problems due trauma airway patency problemsas declared anaesthesiologist breathing problemsbreathing frequency 30/min circulatory problemspulse 120/min systolic blood pressure 100 mmhg capillary refill 4 sexterior blood loss 500 ml neurological problemsgcs 13clinical evidence serious injuries clinically evident pelvic ring fractureas declared attending surgeon clinical signs unstable vertebral fractures spinal cord compressionas declared attending surgeonsevere mechanism injury high energy mechanism injury declared pre hospital emergency medical servicesfall height 3 mmotor vehicle accident 50 km hejection vehiclecar rolloversevere impact damage carstruck pedestrian 10 km hstruck bicyclist 30 km h high energy crush injury torsosqueezed heavy objectsexclusion criteriact feasible appropriate dead soon arrivalwithin 15 min arrival declared attending surgeon
shock class iii ivpulse rate 120/min systolic blood pressure 100 mmhg non respondent volume therapy
pregnancysuspected history sonographynotes inclusion study one criterion met gcs glasgow coma scale inclusion exclusion criteria defined study started notes inclusion study one criterion met gcs glasgow coma scale patients underwent diagnostic protocol according hospital guidelines protocol consisted physical examination pe cr chest spine pelvis abdominal ultrasonography ct cervical spine chest abdomen spine pelvis pe performed documented residents surgery orthopaedics emergency physicians supervised senior trauma surgeons according advanced trauma life support guidelines blood samples collected laboratory investigations including arterial blood gas analysis haematological measurements biochemistry cr executed vertix 3d system siemens medical solutions forchheim germany consisted supine view chest pelvis anteroposterior direction thoracolumbar spine anteroposterior lateral projection abdominal ultrasonography primarily used detect exclude free intraperitoneal fluid according principles focused ultrasonography trauma cr ultrasonography interpreted immediately senior residents radiology supervising trauma radiologists all patients thereafter underwent ct 16-detector unit somatom sensation 16 siemens medical solutions forchheim germany located emergency department ct cervical spine obtained occipital condyles first thoracic vertebra chest ct performed part thoracoabdominal examination acromioclavicular joint lesser trochanter automated exposure control reference effective tube current time product 200 mas tube voltage 120 kv beam collimation 16 1.5 mm median dose length product 1,150 mgycm administration 100 ml intravenous contrast agent iobitridol 300 mg ml xenetix 300 guerbet paris france reconstructed section thickness 3 mm bone lung soft tissue setting section overlap 1.5 3 3 mm respectively finally sagittal coronal multi planar reformatted images spine constructed after review radiology residents supervised certified radiologists trauma team started changed patient management needed finally effort made follow every patient 6 months either medical consultation outpatient clinics telephone could waived observational study standard diagnostic protocol patients received type diagnostics care two unblinded investigators 1 3 years experience emergency medicine start study attended briefings resuscitations included patients reviewed charts radiological reports they collected data patient characteristics diagnoses treatment using standardised abstraction forms these data prospectively recorded trauma team members ct performed necessary the investigators reviewed patients charts 6 months establish whether injuries initially missed they collected injury severity scores iss regional trauma registry finally imported data customised database two outcome measures determined study started 1 presence chest injuries ct 2 clinically relevant occult injuries chest injuries chest ct consisted aortic injury diaphragmatic injury tracheobronchial tree injury oesophageal injury pneumothorax haemothorax pulmonary contusion they also consisted fractures ribs scapula sternum thoracic vertebrae including vertebral body transverse spinous processes the presence injuries recorded per patient pneumothoraces pulmonary contusions haemothoraces rib fractures present investigators recorded extent number location severity minimal moderate severe these classifications based consensus reading 54 cases included study clinically relevant occult injuries defined injuries ct visualised cr chest thoracic spine impact patient management an impact patient management defined occurrence changes treatment direct result ct findings these changes determined study started included additional diagnostic workup changes intensity care care level upgrade immediate interventions started trauma team we selected dichotomous candidate predictors injuries ct based review literature clinical experience these variables could determined initial patient evaluation emergency department derived pre hospital service reports emergency records radiological reports cr abdominal ultrasonography investigations blood sample analyses literature cervical spine fractures associated thoracic spine injuries however cervical spine ct reconstructions readily available chest ct obtained consider presence cervical spine injuries practical predictor chest injuries setting study primarily aimed distinguish patients injuries chest ct patients without injuries chest ct taking following steps first candidate predictors injuries ct combined dichotomous composite predictors based clinical similarity strong biological association table 2 data missing incomplete imputed
table 2definitions composite predictors chest injuries ctcomposite predictordefinition predictors positive following conditions fulfilledreferences55 years age 55 years olderdangerous mechanism injurymotor vehicle collision following:[20 21 2932]no use constraints ejection vehicle death occupantpe chest breathing frequency 10/min 29/min pre hospital presentation ed)[2023 3340]pulse oximetry sao2 95% presentation ed
subcutaneous emphysema palpation tenderness palpation chest wall lacerations haematoma chest wallpe circulatory problems
systolic blood pressure 90 mmhg pre hospital presentation ed)[2022 28 41]heart rate 120 beats per minute pre hospital presentation ed)pe altered sensorium glasgow coma scale 14 initial presentation ed[14 22 24 40 42]orotracheal intubation clinical evaluation ed clinical suspicion drugs alcohol intoxicationpe supraclavicular injury fracture laceration haematoma clavicle including face[20 21]pe thoracic spine tenderness palpation midline thoracic spine[14 32 42]thoracolumbar lacerations haematoma neurological deficit suggesting spinal cord injurype abdomen tenderness palpation lacerations haematoma abdominal distension guardingpe extremity fracture clinical suspicion fractures upper lower extremities cr extremities obtained[2022 43 44]cr chestany following abnormalities identified cr chest[2 20 21 38 41 43 45 46]pulmonary contusion haemothorax scapular fracture clavicular fracturecr thoracic spineany following abnormalities cr thoracic spine fracture vertebral body spinous transverse processes spinal malalignmentcr lumbar spineany following abnormalities cr lumbar spine:[20 47]any fracture vertebral body spinous transverse processes spinal malalignmentcr pelvis abdominal ultrasonographyany following pelvic fractures cr:[20 21 37]pubic bone fracture fracture acetabulum fracture illiac wing
femoral head fracture symphysiolysis luxation hipabnormal abdominal ultrasound presence free fluidbe 3arterial blood gas base excess less 3
mmol l initial blood gas sampleshb 6blood plasma haemoglobin concentration less 6 mmol lnote ed emergency department pe physical examination cr conventional radiography definitions composite predictors chest injuries ct note ed emergency department pe physical examination cr conventional radiography second univariate logistic regression analysis used study ability composite predictor distinguish patients injuries patients without injuries chest ct crude odds ratios positive composite predictors derived dependent variable presence injuries ct yes third multivariate regression forward selection procedure used identify independent composite predictors presence injuries chest ct priori forced composite predictor altered sensorium
( gcs 14 clinical suspicion drug alcohol intoxication orotracheal intubation clinical evaluation multivariate regression model considered variable great clinical relevance all composite predictors statistically significantly related risk injuries ct univariate analysis p 0.05 likelihood ratio test used independent variables selection procedure this yielded regression model statistically significant independent predictors finally included this model checked collinearity interaction variables incorporating biologically plausible interaction terms model discriminatory power final regression model assessed area receiver operating characteristic roc curve auc percentage explained variance r square evaluate reliability regression model an internal validation performed bootstrap analysis corrected r square auc measures presented our final aim construct predictive model defines patients ct omitted missing relevant injuries patients possible we therefore chose predicted probability cutoff point roc curve sensitivity injuries ct high possible specificity 0 using cutoff point effectively meant patients without positive independent predictor classified low risk patients whereas patients positive independent predictor classified high risk patients we evaluated predictive model cutoff point presenting model sensitivity specificity presence chest injuries presence clinically relevant occult chest injuries ct we performed statistical analyses statistical packages microsoft windows spps version 16.0 chicago il r version 2.6.1 r project statistical computing www.r-project.org we performed observational cohort study 1,047 consecutive blunt trauma patients 16 years older patients prospectively included according inclusion exclusion criteria table 1 primarily evaluated emergency department hospital may 2005 july 2008
table 1inclusion exclusion criteria defined study started inclusion criteriadefinitionslife threatening vital problems due trauma airway patency problemsas declared anaesthesiologist breathing problemsbreathing frequency 30/min circulatory problemspulse 120/min systolic blood pressure 100 mmhg capillary refill 4 sexterior blood loss 500 ml neurological problemsgcs 13clinical evidence serious injuries clinically evident pelvic ring fractureas declared attending surgeon clinical signs unstable vertebral fractures spinal cord compressionas declared attending surgeonsevere mechanism injury high energy mechanism injury declared pre hospital emergency medical servicesfall height 3 mmotor vehicle accident 50 km hejection vehiclecar rolloversevere impact damage carstruck pedestrian 10 km hstruck bicyclist 30 km h high energy crush injury torsosqueezed heavy objectsexclusion criteriact feasible appropriate dead soon arrivalwithin 15 min arrival declared attending surgeon
shock class iii ivpulse rate 120/min systolic blood pressure 100 mmhg non respondent volume therapy
pregnancysuspected history sonographynotes inclusion study one criterion met gcs glasgow coma scale inclusion exclusion criteria defined study started notes inclusion study one criterion met gcs glasgow coma scale patients underwent diagnostic protocol according hospital guidelines protocol consisted physical examination pe cr chest spine pelvis abdominal ultrasonography ct cervical spine chest abdomen spine pelvis pe performed documented residents surgery orthopaedics emergency physicians supervised senior trauma surgeons according advanced trauma life support guidelines blood samples collected laboratory investigations including arterial blood gas analysis haematological measurements biochemistry cr executed vertix 3d system siemens medical solutions forchheim germany consisted supine view chest pelvis anteroposterior direction thoracolumbar spine anteroposterior lateral projection abdominal ultrasonography primarily used detect exclude free intraperitoneal fluid according principles focused ultrasonography trauma cr ultrasonography interpreted immediately senior residents radiology supervising trauma radiologists all patients thereafter underwent ct 16-detector unit somatom sensation 16 siemens medical solutions forchheim germany located emergency department ct cervical spine obtained occipital condyles first thoracic vertebra chest ct performed part thoracoabdominal examination acromioclavicular joint lesser trochanter automated exposure control reference effective tube current time product 200 mas tube voltage 120 kv beam collimation 16 1.5 mm median dose length product 1,150 mgycm administration 100 ml intravenous contrast agent iobitridol 300 mg ml xenetix 300 guerbet paris france reconstructed section thickness 3 mm bone lung soft tissue setting section overlap 1.5 3 3 mm respectively finally sagittal coronal multi planar reformatted images spine constructed after review radiology residents supervised certified radiologists trauma team started changed patient management needed finally effort made follow every patient 6 months either medical consultation outpatient clinics telephone could waived observational study standard diagnostic protocol patients received type diagnostics care two unblinded investigators 1 3 years experience emergency medicine start study attended briefings resuscitations included patients reviewed charts radiological reports they collected data patient characteristics diagnoses treatment using standardised abstraction forms these data prospectively recorded trauma team members ct performed necessary the investigators reviewed patients charts 6 months establish whether injuries initially missed they collected injury severity scores iss regional trauma registry finally imported data customised database two outcome measures determined study started 1 presence chest injuries ct 2 clinically relevant occult injuries chest injuries chest ct consisted aortic injury diaphragmatic injury tracheobronchial tree injury oesophageal injury pneumothorax haemothorax pulmonary contusion they also consisted fractures ribs scapula sternum thoracic vertebrae including vertebral body transverse spinous processes the presence injuries recorded per patient pneumothoraces pulmonary contusions haemothoraces rib fractures present investigators recorded extent number location severity minimal moderate severe these classifications based consensus reading 54 cases included study clinically relevant occult injuries defined injuries ct visualised cr chest thoracic spine impact patient management an impact patient management defined occurrence changes treatment direct result ct findings these changes determined study started included additional diagnostic workup changes intensity care care level upgrade immediate interventions started trauma team we selected dichotomous candidate predictors injuries ct based review literature clinical experience these variables could determined initial patient evaluation emergency department derived pre hospital service reports emergency records radiological reports cr abdominal ultrasonography investigations blood sample analyses literature cervical spine fractures associated thoracic spine injuries however cervical spine ct reconstructions readily available chest ct obtained consider presence cervical spine injuries practical predictor chest injuries setting in study primarily aimed distinguish patients injuries chest ct patients without injuries chest ct taking following steps first candidate predictors injuries ct combined dichotomous composite predictors based clinical similarity strong biological association table 2 data missing incomplete imputed normal
table 2definitions composite predictors chest injuries ctcomposite predictordefinition predictors positive following conditions fulfilledreferences55 years age 55 years olderdangerous mechanism injurymotor vehicle collision following:[20 21 2932]no use constraints ejection vehicle death occupantpe chest
breathing frequency 10/min 29/min pre hospital presentation ed)[2023 3340]pulse oximetry sao2 95% presentation ed decreased breathing sounds auscultation
subcutaneous emphysema palpation tenderness palpation chest wall lacerations haematoma chest wallpe circulatory problems
systolic blood pressure 90 mmhg pre hospital presentation ed)[2022 28 41]heart rate 120 beats per minute pre hospital presentation ed)pe altered sensorium glasgow coma scale 14 initial presentation ed[14 22 24 40 42]orotracheal intubation clinical evaluation ed
clinical suspicion drugs alcohol intoxicationpe supraclavicular injury fracture laceration haematoma clavicle including face[20 21]pe thoracic spine tenderness palpation midline thoracic spine[14 32 42]thoracolumbar lacerations haematoma neurological deficit suggesting spinal cord injurype abdomen tenderness palpation lacerations haematoma abdominal distension guardingpe extremity fracture clinical suspicion fractures upper lower extremities cr extremities obtained[2022 43 44]cr chestany following abnormalities identified cr chest[2 20 21 38 41 43 45 46]pulmonary contusion
scapular fracture clavicular fracturecr thoracic spineany following abnormalities cr thoracic spine fracture vertebral body spinous transverse processes spinal malalignmentcr lumbar spineany following abnormalities cr lumbar spine:[20 47]any fracture vertebral body spinous transverse processes spinal malalignmentcr pelvis abdominal ultrasonographyany following pelvic fractures cr:[20 21 37]pubic bone fracture fracture acetabulum
femoral head fracture symphysiolysis luxation hipabnormal abdominal ultrasound presence free fluidbe 3arterial blood gas base excess less 3
mmol l initial blood gas sampleshb 6blood plasma haemoglobin concentration less 6 mmol lnote ed emergency department pe physical examination cr conventional radiography definitions composite predictors chest injuries ct note ed emergency department pe physical examination cr conventional radiography second univariate logistic regression analysis used study ability composite predictor distinguish patients injuries patients without injuries chest ct crude odds ratios positive composite predictors derived dependent variable presence injuries ct yes third multivariate regression forward selection procedure used identify independent composite predictors presence injuries chest ct priori ( gcs 14 clinical suspicion drug alcohol intoxication orotracheal intubation clinical evaluation multivariate regression model considered variable great clinical relevance all composite predictors statistically significantly related risk injuries ct univariate analysis p 0.05 likelihood ratio test used independent variables selection procedure yielded regression model statistically significant independent predictors finally included this model checked collinearity interaction variables incorporating biologically plausible interaction terms model discriminatory power final regression model assessed area receiver operating characteristic roc curve auc percentage explained variance r square evaluate reliability regression model an internal validation performed bootstrap analysis corrected r square auc measures presented our final aim construct predictive model defines patients ct omitted missing relevant injuries patients possible we therefore chose predicted probability cutoff point roc curve sensitivity injuries ct high possible specificity 0 using cutoff point effectively meant patients without positive independent predictor classified low risk patients whereas patients positive independent predictor classified high risk patients we evaluated predictive model cutoff point presenting model sensitivity specificity presence chest injuries presence clinically relevant occult chest injuries ct we performed statistical analyses statistical packages microsoft windows spps version 16.0 chicago il r version 2.6.1 r project statistical computing www.r-project.org eighty one patients excluded predetermined exclusion criteria 71 patients protocol violation ct performed patients fig 1
1diagram illustrating patient flow study selection number patients chest injuries ct occult chest injuries ct occult injuries ct impact patient management cr conventional radiography chest thoracic spine ct computed tomography occult injuries injuries detected ct cr diagram illustrating patient flow study selection number patients chest injuries ct occult chest injuries ct occult injuries ct impact patient management cr conventional radiography chest thoracic spine ct computed tomography occult injuries injuries detected ct cr total 1,047 patients included study 731 patients 70% male median iss 14 mean iss 17 range 075 five hundred eight patients 49% injuries visible ct 459 44% ) patients ct detected occult injuries additional injuries compared cr chest 183 17% ) patients occult injuries impact patient management therefore considered clinically relevant management changes comprised care level upgrading n 60 chest drain re)positioning n 45 conservative n 34 surgical stabilisation n 19 spinal fractures epidural anaesthesia cases multiple occult rib fractures n 15 consultation cardiologists n 14 angiography n 8) bronchoscopy n 5 interventional radiology aortic repair n 4 embolisation n 1 thoracotomy n 2 treatment tracheal n 1 oesophageal rupture n 1 included patients 43 4% lost follow completed follow revealed one patient multiple chest injuries diaphragmatic rupture initially missed ct this injury revealed cessation ventilation 2 days post trauma treated delayed laparotomy good patient recovery conversely another patient multiple chest injuries suspected diaphragmatic injury ct however emergency laparotomy indicated splenectomy confirm injury third patient multiple serious injuries chest ct developed pericardial tamponade 3 weeks post trauma although ct therefore 100% accurate detection specific chest injuries completed clinical follow revealed ct correctly classified patients injury chest data complete predictors except blood analyses cr thoracic spine 23 patients no haemoglobin 258 patients samples obtained mainly patients respiratory haemodynamic problems 46 patients cr thoracic spine performed obtained anteroposterior direction table 3 shows univariate relationships predictors presence chest injuries ct this table indicates dangerous mechanism injury pe abdomen failed demonstrate statistically significant crude odds ratio after multivariate logistic regression analysis remaining 13 composite predictors 9 independent predictors significantly contributed prediction presence chest injuries ct table 4 abnormal cr chest abnormal chest pe 3 mmol l abnormal abdominal ultrasonography pelvic cr abnormal thoracic spine pe age 55 years hb 6 abnormal cr thoracic spine altered sensorium
table 3univariate relationships positive predictors presence chest injuries ctpositive composite predictorsor 95% ci)p value55 years n 208)2.37 1.733.25)<0.001dangerous mechanism injury n 235)1.22 0.911.63)0.209pe chest n 361)4.64 3.56.3)<0.001pe circulatory problems n 184)2.58 1.843.61)<0.001pe altered sensorium n 395)2.54 1.973.29)<0.001pe supraclavicular injury n 615)1.79 1.402.30)<0.001pe thoracic spine n 134)1.51 1.052.18)0.027pe abdomen n 175)1.18 0.851.64)0.313pe extremity fracture n 514)1.40 1.091.78)0.008cr chest n 366)15.6 11.1221.93)<0.001cr thoracic spine n 129)2.55 1.723.77)<0.001cr lumbar spine n 86)2.64 1.644.26)<0.001cr pelvis abdominal ultrasonography n 209)2.89 2.093.99)<0.001be 3 positive n 351)3.81 2.895.01)<0.001hb 6 n 51)7.21 3.2216.16)<0.001notes crude odds ratio 95% ci 95% confidence intervaldefinitions positive composite predictors displayed table 2table 4independent predictors presence chest injuries ctpositive composite predictorsadjusted 95% ci)55 years1.6 1.12.4)pe chest3.0 2.24.2)pe thoracic spine1.8 1.12.8)pe altered sensorium1.5 1.02.1)cr chest9.4 6.514)cr thoracic spine1.7 1.12.9)cr pelvis abdominal ultrasonography2.3 1.53.4)be 32.0 1.42.9)hb 62.9 1.17.6)note odds ratio adjusted predictors model ci confidence interval definitions positive composite predictors displayed table 2 univariate relationships positive predictors presence chest injuries ct notes crude odds ratio 95% ci 95% confidence interval definitions positive composite predictors displayed table 2 independent predictors presence chest injuries ct note odds ratio adjusted predictors model ci confidence interval definitions positive composite predictors displayed table 2 figure 2 shows roc curve predictive model containing nine predictors r square 0.478 auc 0.85 95% ci 0.830.87 after bootstrap analysis corrected r square 0.455 corrected auc 0.71 2 includes cutoff point patients stratified low risk high risk patients of included patients 855 82% patients one positive predictors classified high risk patients one hundred ninety two patients 18% positive predictor classified low risk patients
2receiver operating characteristic roc curve predictive model containing nine predictors injuries chest ct the cutoff point dashed lines located sensitivity 0.95 specificity 0.31 ( area curve 0.85 95% confidence interval 0.830.87 receiver operating characteristic roc curve predictive model containing nine predictors injuries chest ct the cutoff point dashed lines located sensitivity 0.95 specificity 0.31 ( area curve 0.85 95% confidence interval 0.830.87 508 patients injuries ct model correctly classified 484 patients high risk patients sensitivity 0.95 95% ci 0.930.97 remaining 24 patients injuries ct low risk patients this means probability ct injuries low risk patient group 24/192 13% 95% ci 918% these patients mainly minimal pulmonary contusion minimal pneumothoraces one two rib fractures scapular fractures table 5 the model correctly classified patients without injuries ct n 539 low risk 168 patients specificity 0.31 95% ci 0.270.35
table 5prevalence distinct chest injuries ct patients patients 1 positive predictor predictive model high risk patients patients positive predictor chest injury low risk patients)injuries ctno ( low risk patients n 192)pneumothorax234(22.3)228(26.6)6(3.1)moderate pneumothorax90(8.6)89(10.4)1(0.5)severe pneumothorax35(3.3)35(4.1)0(0.0)haemothorax58(5.5)58(6.8)0(0.0)pulmonary contusion288(28)173(20.2)15(7.8)moderate severe contusion71(6.8)71(8.3)0(0.0)oesophageal injury1(0.1)1(0.1)0(0.0)tracheobronchial injury2(0.2)2(0.2)0(0.0)aortic injury9(0.8)9(1.1)0(0.0)injury subclavian vein1(0.1)1(0.1)0(0.0)rib fracture317(30.3)311(36.4)6(3.1) 2 rib fractures233(22.2)232(27.1)1(0.5)scapular fracture76(7.3)73(8.5)3(1.5)sternal fracture51(4.9)51(6.0)0(0.0)diaphragmatic injury5(0.5)5(0.6)0(0.0)any thoracic spinal fracture123(12)122(14.2)1(0.5)vertebral body fracture81(7.7)80(9.4)1(0.5)transverse process fracture59(5.6)59(6.9)0(0.0)spinous process fracture20(1.9)20(2.3)0(0.0)total chest injury)508(48.5)484(56.6)24(12.5)notes numbers parentheses percentages patient groups a patient could multiple chest injuries prevalence distinct chest injuries ct patients patients 1 positive predictor predictive model high risk patients patients positive predictor chest injury low risk patients notes numbers parentheses percentages patient groups a patient could multiple chest injuries 183 patients clinically relevant occult injuries ct 179 correctly classified high risk sensitivity 0.98 95% ci 0.961 four 192 low risk patients 2% 95% ci 15% clinically relevant occult injuries one patient stable fracture xii vertebral body visualised cr lumbar spine cr thoracic spine a second patient pulmonary contusion one rib fracture pneumothorax moderate size visualised chest cr although patient none nine predictors positive cervical spine ct demonstrated subcutaneous emphysema third patient who classified belonging low risk patient group three rib fractures none low risk group patients suffered aortic injury diaphragmatic injury haemothoraces large pneumothoraces table 5 data complete predictors except blood analyses cr thoracic spine 23 patients no haemoglobin 258 patients samples obtained mainly patients respiratory haemodynamic problems 46 patients cr thoracic spine performed obtained anteroposterior direction table 3 shows univariate relationships predictors presence chest injuries ct this table indicates dangerous mechanism injury pe abdomen failed demonstrate statistically significant crude odds ratio after multivariate logistic regression analysis remaining 13 composite predictors 9 independent predictors significantly contributed prediction presence chest injuries ct table 4 abnormal cr chest abnormal chest pe 3 mmol l abnormal abdominal ultrasonography pelvic cr abnormal thoracic spine pe age 55 years hb 6 abnormal cr thoracic spine altered sensorium
table 3univariate relationships positive predictors presence chest injuries ctpositive composite predictorsor 95% ci)p value55 years n 208)2.37 1.733.25)<0.001dangerous mechanism injury n 235)1.22 0.911.63)0.209pe chest n 361)4.64 3.56.3)<0.001pe circulatory problems n 184)2.58 1.843.61)<0.001pe altered sensorium n 395)2.54 1.973.29)<0.001pe supraclavicular injury n 615)1.79 1.402.30)<0.001pe thoracic spine n 134)1.51 1.052.18)0.027pe abdomen n 175)1.18 0.851.64)0.313pe extremity fracture n 514)1.40 1.091.78)0.008cr chest n 366)15.6 11.1221.93)<0.001cr thoracic spine n 129)2.55 1.723.77)<0.001cr lumbar spine n 86)2.64 1.644.26)<0.001cr pelvis abdominal ultrasonography n 209)2.89 2.093.99)<0.001be 3 positive n 351)3.81 2.895.01)<0.001hb 6 n 51)7.21 3.2216.16)<0.001notes crude odds ratio 95% ci 95% confidence intervaldefinitions positive composite predictors displayed table 2table 4independent predictors presence chest injuries ctpositive composite predictorsadjusted 95% ci)55 years1.6 1.12.4)pe chest3.0 2.24.2)pe thoracic spine1.8 1.12.8)pe altered sensorium1.5 1.02.1)cr chest9.4 6.514)cr thoracic spine1.7 1.12.9)cr pelvis abdominal ultrasonography2.3 1.53.4)be 32.0 1.42.9)hb 62.9 1.17.6)note odds ratio adjusted predictors model ci confidence interval definitions positive composite predictors displayed table 2 univariate relationships positive predictors presence chest injuries ct notes crude odds ratio 95% ci 95% confidence interval definitions positive composite predictors displayed table 2 independent predictors presence chest injuries ct note odds ratio adjusted predictors model ci confidence interval definitions positive composite predictors displayed table 2 figure 2 shows roc curve predictive model containing nine predictors r square 0.478 auc 0.85 95% ci 0.830.87 bootstrap analysis 2 includes cutoff point patients stratified low risk high risk patients included patients 855 82% patients one hundred ninety two patients 18% positive predictor classified low risk patients
2receiver operating characteristic roc curve predictive model containing nine predictors injuries chest ct the cutoff point dashed lines located sensitivity 0.95 specificity 0.31 ( area curve 0.85 95% confidence interval 0.830.87 receiver operating characteristic roc curve predictive model containing nine predictors injuries chest ct the cutoff point dashed lines located sensitivity 0.95 specificity 0.31 ( area curve 0.85 95% confidence interval 0.830.87 508 patients injuries ct model correctly classified 484 patients high risk patients sensitivity 0.95 95% ci 0.930.97 remaining 24 patients injuries ct low risk patients this means probability ct injuries low risk patient group 24/192 13% 95% ci 918% these patients mainly minimal pulmonary contusion minimal pneumothoraces one two rib fractures scapular fractures table 5 the model correctly classified patients without injuries ct n 539 low risk 168 patients specificity 0.31 95% ci 0.270.35
table 5prevalence distinct chest injuries ct patients patients 1 positive predictor predictive model high risk patients patients positive predictor chest injury low risk patients)injuries ctno ( low risk patients n 192)pneumothorax234(22.3)228(26.6)6(3.1)moderate pneumothorax90(8.6)89(10.4)1(0.5)severe pneumothorax35(3.3)35(4.1)0(0.0)haemothorax58(5.5)58(6.8)0(0.0)pulmonary contusion288(28)173(20.2)15(7.8)moderate severe contusion71(6.8)71(8.3)0(0.0)oesophageal injury1(0.1)1(0.1)0(0.0)tracheobronchial injury2(0.2)2(0.2)0(0.0)aortic injury9(0.8)9(1.1)0(0.0)injury subclavian vein1(0.1)1(0.1)0(0.0)rib fracture317(30.3)311(36.4)6(3.1) 2 rib fractures233(22.2)232(27.1)1(0.5)scapular fracture76(7.3)73(8.5)3(1.5)sternal fracture51(4.9)51(6.0)0(0.0)diaphragmatic injury5(0.5)5(0.6)0(0.0)any thoracic spinal fracture123(12)122(14.2)1(0.5)vertebral body fracture81(7.7)80(9.4)1(0.5)transverse process fracture59(5.6)59(6.9)0(0.0)spinous process fracture20(1.9)20(2.3)0(0.0)total chest injury)508(48.5)484(56.6)24(12.5)notes numbers parentheses percentages patient groups a patient could multiple chest injuries prevalence distinct chest injuries ct patients patients 1 positive predictor predictive model high risk patients patients positive predictor chest injury low risk patients notes numbers parentheses percentages patient groups a patient could multiple chest injuries 183 patients clinically relevant occult injuries ct 179 correctly classified high risk sensitivity 0.98 95% ci 0.961 four 192 low risk patients 2% 95% ci 15% clinically relevant occult injuries one patient stable fracture xii vertebral body visualised cr lumbar spine cr thoracic spine a second patient pulmonary contusion one rib fracture pneumothorax moderate size visualised chest cr although patient none nine predictors positive cervical spine ct demonstrated subcutaneous emphysema third patient who classified belonging low risk patient group three rib fractures none low risk group patients suffered aortic injury diaphragmatic injury haemothoraces large pneumothoraces table 5 in prospective study derived set variables predict whether ct chest including thoracic spine likely reveal relevant injuries high energy blunt trauma patients these clinically intuitive predictors derived data available initial presentation emergency department including age physical examination laboratory analyses cr abdominal ultrasonography if cts obtained patients one positive predictors high risk patients ct investigations would avoided 18% patients study population thereby decreasing ionising radiation exposure health care expenditure however study data also suggested positive predictors implemented scanning indications 5% 24/508 patients chest injuries ct would identified this implies chance missing injuries chest remains 13% 24/192 low risk patient group patients undergo chest ct this risk substantially lower compared chest injury risk entire blunt trauma population 49% study even relatively low compared previously described low risk populations reported prevalence 39% 95% ci 2751% chest injuries patients normal cr normal physical examination salim et al reported prevalence 20% 95% ci 1623% pulmonary mediastinal rib injuries patients clinically evaluable normal physical examination cr one may pose question whether injury probability 13% acceptable low risk patient group we argue risk considered acceptable mainly chest injuries clinically relevance cases the small pulmonary contusions pneumothoraces rib fractures rarely impact patient management 2% low risk patients perhaps exception missed thoracic spine fracture unlikely affect patient morbidity left unmanaged although cost effectiveness studies established acceptable risks cost effective injury detection using ct 18 19 unfortunately pertain injuries entire chest including thoracic spine predicting variables evaluated study part based previous studies appropriate patient selection chest ct however studies investigated distinct chest thoracic injuries used case control design 20 21 use ct standard reference 14 2224 knowledge one first prospective studies identify selection criteria facilitate appropriate use ct entire chest adult blunt trauma patients we investigated described strong criteria predict presence type relevant chest injuries ct our results might surprising indicate chest ct warranted abnormal pe cr however study adds previous knowledge defining patients chest ct warranted also defining patients chest ct could safely omitted validation incorporation criteria diagnostic algorithm patient selection chest ct could important step towards optimising resource use trauma imaging we aware several centres use cr spine sensitive ct injury detection laboratory analyses available emergency department as long techniques cr spine laboratory analyses used provide indications ct imaging investigations seem indispensible selective chest ct algorithms patients positive predictors our study number limitations according oxford levels evidence grading good diagnostic research incorporates index tests reference tests applied blindly objectively however standard reference ct interpreted independently clinical information practice radiologists surgeons work closely together trauma patient care however consider major source incorporation bias chest ct rarely misses injuries visualised cr a second limitation abstracted information potential predictors index tests medical records although used objective predictor definitions instructed trauma team members record data potential predictors prospectively blinded ct outcomes introduced retrospective component study however minimised hindsight bias presence predictors dictating data potential predictors present medical records personally monitoring patient evaluations researchers therefore rarely ask trauma team members additional information potential predictors retrospect third findings study externally validated different trauma populations settings external validation needed three reasons
performance model likely optimistic model created sample patients performance determined therefore evaluated new sample trauma patients centre.external validation furthermore carried evaluate model centres definition clinically relevant injuries occult injuries care level upgraded additional diagnostic work needed institution- clinician-dependent.the costs effectiveness impact patient quality life ct chest injury diagnosis investigated the performance model likely optimistic model created sample patients performance determined therefore evaluated new sample trauma patients centre external validation furthermore carried evaluate model centres definition clinically relevant injuries occult injuries care level upgraded additional diagnostic work needed institution- clinician dependent the costs effectiveness impact patient quality life ct chest injury diagnosis investigated in conclusion significant independent predictors injuries chest ct high energy blunt trauma patients age 55 years abnormal chest pe altered sensorium abnormal thoracic spine pe abnormal chest thoracic spine cr abnormal abdominal us pelvic cr hb 6 3 mmol l presence criteria predict presence chest injuries ct sensitivity 95% ct omitted patients without criteria number ct investigations substantially reduced risk missing relevant injuries clinical importance seems remain low although findings need external validation diagnostic algorithm employing criteria potential reduce unnecessary ct examinations chest blunt trauma patients future | purposethe purpose of this study was to derive parameters that predict which high - energy blunt trauma patients should undergo computed tomography ( ct ) for detection of chest injury.methodsthis observational study prospectively included consecutive patients ( 16 years old ) who underwent multidetector ct of the chest after a high - energy mechanism of blunt trauma in one trauma centre.resultswe included 1,047 patients ( median age , 37 ; 70% male ) , of whom 508 had chest injuries identified by ct . using logistic regression , we identified nine predictors of chest injury presence on ct ( age 55 years , abnormal chest physical examination , altered sensorium , abnormal thoracic spine physical examination , abnormal chest conventional radiography ( cr ) , abnormal thoracic spine cr , abnormal pelvic cr or abdominal ultrasound , base excess <
3 mmol / l and haemoglobin
< 6 mmol / l ) . of 855 patients with 1
positive predictors , 484 had injury on ct ( 95% of all 508 patients with injury ) . of all 192 patients with no positive predictor , 24 ( 13% )
had chest injury , of whom 4 ( 2% ) had injuries that were considered clinically relevant.conclusionomission of ct in patients without any positive predictor could reduce imaging frequency by 18% , while most clinically relevant chest injuries remain adequately detected . |
many different chemotherapy regimens therefore developed.13 however little known feasibility efficiency chemotherapy cancer types patients severe renal failure.46 case reports pharmacology irinotecan patients colon rectal cancer available present.711 present first case combination chemotherapy metastatic gastroesophageal cancer dialysis patient a 73-year old patient longstanding history ischemic heart disease dialysis two years vascular renal insufficiency september 2004 admitted gastrointestinal blood loss ca 19.9 high 24925 u ml nl 37 u ml the patient started chemotherapy regimen consisting l leukovorin 250 mg irinotecan 50 mg followed 5-fluorouracil 5 fu 2 g m/24 h six weeks eight.1213 neither significant nausea diarrhea dialysis continued three times week patient monday wednesday friday schedule dialysis chemotherapy given monday dialysis after four weeks chemotherapy also underwent right carotid endarterectomy intercurrent transient ischemic attack right carotid region six months starting chemotherapy ct scan liver showed complete response numerous metastases ( table 1 nine months initiation treatment however liver metastasis tumor marker progressive doses chemotherapy based number case reports paclitaxel ovarian cancer dialysis patients.14,15 ct scan two months showed progressive disease the increase solid tumors patient undergoing dialysis poses specific problems,16 especially choice pharmacology anticancer drugs bearing mind drugs developed patients normal liver kidney function gastric cancer 5fu always backbone treatment.1,2 chronic hemodialysis data dose reductions 5fu weekly.17,18 gastric cancer combination chemotherapy however necessary obtain prolonged disease control even prolonging overall survival.1,2 combinations 5fu cisplatin either docetaxel epirubicin therefore become standard chemotherapy regimens gastric cancer.19,20 besides aforementioned regimens irinotecan based combinations shown active first21 second line gastric cancer.22 equivalence combination 5fu first line metastatic gastric cancer recently established two studies comparing regimen combination chemotherapy cisplatin 5fu.23,24 irinotecan metabolized liver active metabolite sn-38 followed biliary excretion.6 significant renal elimination the drug evaluated patients serum creatinin 1.6 5 mg dl unexpected toxicities seen.25 number case reports use irinotecan hemodialysis patients metastatic colon cancer a first report mentions use irinotecan dose 50 mg without significant toxicity.7 two case reports dialysis patients patients started irinotecan 50 mg both reports mention increasing dose prohibitive diarrhea consequence.8,11 worst outcome higher irinotecan doses 125 mg demonstrated two dialysis patients dosages led extreme gi toxicities even death.9 concluded irinotecan terminal renal insufficiency given dose 50 mg korean authors made pharmacologic evaluations use irinotecan small cell lung cancer patients dialysis they noted however doses feasible patients korean descent.26 recent case report combination irinotecan dose 50 mg weekly combined fu1600 mg m/24 h week leading disease stabilization six months dialysis patients diffuse bone cerebral liver metastases colon cancer.10 our case report builds knowledge use irinotecan metastatic colorectal cancer dialysis this case report discusses weekly dose irinotecan 24-hour administration 5fu gastroesophageal cancer patient this first report efficacy irinotecan- fluorouracil based chemotherapy dialysis patient liver metastases gastroesophageal carcinoma combination chemotherapy irinotecan fu extremely well tolerated without significant delays administration it produced radiographically complete remission liver metastases normalization ca 19 9 tumor marker leading remarkable overall survival | we present the first case report of a complete response of metastatic gastroesophageal cancer in a chronic hemodialysis patient with irinotecan - based chemotherapy .
an elderly dialysis patient presented with diffuse liver metastases by a gastroesophageal adenocarcinoma .
he received combination chemotherapy with 5 fluorouracil and irinotecan .
after six months of chemotherapy , liver scans show complete remission .
the principles , practice , and experience of chemotherapy with irinotecan during dialysis are discussed . |
the fully differentiated cells of the rat mammary parenchyma , the ductal epithelial , alveolar , and myoepithelial cells , are distinguished by their ultrastructure and by their accumulation of immunocytochemically detectable marker proteins .
the different cell types probably develop from primative ductal structures called terminal end buds , which are present in the developing rat mammary glands , and these structures contain relatively undifferentiated cells .
clonal epithelial stem cell lines , obtained from normal rat mammary glands or benign mammary tumors , differentiate under appropriate conditions along a pathway to droplet - cell / doming cultures of primative alveolarlike cells . under different culture conditions , the epithelial stem cells differentiate along a separate pathway to myoepitheliallike cells .
they accumulate some of the specific marker proteins of myoepithelial cells in vivo , including type iv collagen , laminin , and thy-1 antigen .
in addition , these myoepitheliallike cells in culture contain an abundance of a potential calcium - binding protein , p9ka , which also occurs in myoepithelial cells of histological sections from mammary glands .
the accumulation of type iv collagen , laminin , thy-1 , and p9ka occurs asynchronously along the pathway to the myoepitheliallike cells in vitro .
furthermore , the steady - state levels of these different marker proteins arise by alterations in the controls at the transcriptional , the posttranscriptional processing , and the translational stages of their production .
these results suggest a stepwise control of synthesis of myoepithelial cell marker proteins , and in the case of p9ka and thy-1 antigen , this altered control may arise through their possession of novel transcriptional promoters.imagesfigure 1 . |
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number elderly people aged 65 years older increasing worldwide aging population particularly rapid japan 2007 japanese orthopaedic association proposed concept locomotive syndrome ls refers conditions people require may soon require nursing care services problems locomotor system.1 japanese ministry health labour welfare devoted effort increasing percentage individuals know ls second term national health promotion movement 21st century health japan 21 second term solve problem ls.2 screening tools risk ls elderly 25-question geriatric locomotive function scale glfs-25 5-question glfs glfs-5 quick 5-item version glfs-25 developed early detection ls,3 used raise awareness preventing onset ls osteoarthritis oa common joint disease one causes ls causes pain elderly patients according research osteoarthritis disability 25 million japanese people aged 40 years older estimated radiographic knee oa.4 similarly longitudinal cohort motor system organ study reported prevalence knee pain 32.7% population increased age.5 suggested knee oa impairs locomotor functions pain biomechanical mechanism impaired locomotor functions walking speed stride length patients knee oa investigated.6,7 glucosamine containing supplements used widely improving knee pain oa.8,9 previous studies demonstrated glucosamine containing supplements gcq gcqid
( glucosamine hydrochloride chondroitin sulfate type ii collagen peptides quercetin glycosides imidazole peptides proteoglycan vitamin effective relieving knee pain and/or locomotor functions randomized placebo controlled trials.10,11 effects thermal exercise therapies locomotor functions mechanism patients knee oa elucidated biomechanical methods,12 biomechanical mechanism effects supplements gcqid locomotor functions reported present study used motion capture system investigate biomechanical mechanism improving effects gcqid locomotor functions subjects knee pain an open label study conducted elucidate mechanism efficacy gcqid supplementation locomotor functions japanese women men aged 40 74 years inclusion criteria presence knee pain confirmed using walking subscale japanese orthopaedic association criteria 25 points less either left right knee joint),13 visual analog scale vas score knee pain 20 mm using first item japanese knee osteoarthritis measure jkom]);14 kellgren lawrence grades 0ii;15 presence ls confirmed score 6 higher glfs-5.3 participants received explanation study medical investigator written informed consent obtained prior enrollment study exclusion criteria previous study,11 typical reasons exclusion following fast walking speed 1.6 presence hyperuricemia diabetes cardiovascular disease hepatic disease renal disease heart disease presence rheumatoid arthritis may cause joint pain surgical treatment knee joint(s needed undergone daily use cane daily occasional vigorous exercise need pharmacological articular treatments study period history osseous articular diseases oa within past 3 months routine use health food medicine may affect outcome study presence medical condition judged medical investigator thirty participants enrolled study performed february august 2014 clinical services center tokai university japan all subjects recruited around kanto region japan volunteer bank managed ttc co. ltd tokyo japan once radiographs obtained kellgren lawrence grades subjects determined orthopedic surgeon the study protocol approved ethics committee tokai university kanagawa japan ethics committee tana orthopedic surgery yokohama japan conducted accordance principles amended declaration helsinki ethical guidelines epidemiological research issued japanese government 2008 the gcqid contained 1,200 mg glucosamine hydrochloride 300 mg shark cartilage extract 60 mg chondroitin sulfate 45 mg type ii collagen peptides 90 mg quercetin glycosides 100 mg fish meat extract 10 mg imidazole peptides anserine carnosine 5 mg salmon nasal cartilage extract 1 mg proteoglycan 5 g 200 iu vitamin six tablets gcqid tablets manufactured suntory wellness ltd tokyo japan specifically purpose present study subjects instructed take six tablets day record study diary whether took tablets the indicators efficacy gcqid supplementation functions locomotor system including knee joint jkom category score vas score jkom knee pain total score jkom categories ii v jkom total score glfs-5 score vas score knee pain various daily situations questionnaires designed study jkom self administered disease specific measure knee oa demonstrated adequate validity reliability studies japanese people knee oa terms outcomes correlated health related quality life qol).14 vas score jkom knee pain measured scale 0 100 0 indicated pain 100 indicated worst pain ever experienced the jkom total score comprised 25 items cover four different categories ii pain stiffness knees iii conditions daily life iv general activities v health conditions scores 25 items summed results ranging 0 points complaint 100 points severe condition possible the glfs-5 also self administered measure consisting five items located key domain construct structure glfs-25 covers wide range issues pain qol.3 items graded 5-point scales 0 points 4 points five item scores summed produce overall score range 0 impairment 20 points severe impairment the vas score knee pain various daily situations included pain knee rest walking ascending descending stairs scales 0 100 0 indicated pain 100 indicated worst pain ever experienced questionnaires addressed frequency trips involved walking ascending descending stairs 5-point scales 0 occurrence 4 frequent occurrence for the biomechanical mechanism efficacy locomotor functions motion capture analysis normal walking state conducted obtain data gait parameters subjects took shoes changed dedicated full body suits motion capture markers attached 30 locations body suits top head tragi superior margin sternum extremitas inferior ribs anterior superior iliac spines acromions elbows wrists backs hands great trochanters interior exterior sides knees internal external malleoli heels toes thereafter subjects instructed walk 10 two times usual speed the time took walk middle 6 measured normal walking speed calculated primary outcome the position trajectories markers attached suits subjects walking recorded motion capture system raptor e digital real time system motion analysis corporation santa rosa ca usa time the values step length stride length cadence time stance phase swing phase angle soles toes feet calculated analyzing data position trajectories average value data feet evaluated explanation terms parameters motion capture analysis shown figure 1 data functions locomotor system including knee joint collected baseline every 4 weeks week 16 data motion capture analysis collected baseline 8 16 weeks exclusion criteria efficacy assessment follows taking test supplement fewer 80% scheduled days performing actions affected reliability efficacy assessment noncompliance clinical protocol changes measurements intervention compared baseline using steel test jkom total score glfs-5 score questionnaires dunnett test used vas score jkom knee pain normal walking speed parameters measured motion capture analysis correlation analysis changes parameters analyzed motion capture system locomotor functions involve knee joint 16-week intervention period conducted pearson correlation coefficient r value parametric variables spearman rank correlation coefficient value nonparametric variables calculated all statistical analyses carried using ibm spss statistics windows version 21.0 ibm corporation armonk ny usa ekuseru toukei 2010 windows social survey research information co. ltd tokyo japan an open label study conducted elucidate mechanism efficacy gcqid supplementation locomotor functions japanese women men aged 40 74 years inclusion criteria presence knee pain confirmed using walking subscale japanese orthopaedic association criteria 25 points less either left right knee joint),13 visual analog scale vas score knee pain 20 mm using first item japanese knee osteoarthritis measure jkom]);14 kellgren lawrence grades 0ii;15 presence ls confirmed score 6 higher glfs-5.3 participants received explanation study medical investigator written informed consent obtained prior enrollment study exclusion criteria previous study,11 typical reasons exclusion following fast walking speed 1.6 presence hyperuricemia diabetes cardiovascular disease hepatic disease renal disease heart disease presence rheumatoid arthritis may cause joint pain surgical treatment knee joint(s needed undergone daily use cane daily occasional vigorous exercise need pharmacological articular treatments study period history osseous articular diseases oa within past 3 months routine use health food medicine may affect outcome study presence medical condition judged medical investigator thirty participants enrolled study performed february august 2014 clinical services center tokai university japan all subjects recruited around kanto region japan volunteer bank managed ttc co. ltd tokyo japan once radiographs obtained kellgren lawrence grades subjects determined orthopedic surgeon the study protocol approved ethics committee tokai university kanagawa japan ethics committee tana orthopedic surgery yokohama japan conducted accordance principles amended declaration helsinki ethical guidelines epidemiological research issued japanese government 2008 the gcqid contained 1,200 mg glucosamine hydrochloride 300 mg shark cartilage extract 60 mg chondroitin sulfate 45 mg type ii collagen peptides 90 mg quercetin glycosides 100 mg fish meat extract 10 mg imidazole peptides anserine carnosine 5 mg salmon nasal cartilage extract 1 mg proteoglycan 5 g 200 iu vitamin six tablets gcqid tablets manufactured suntory wellness ltd tokyo japan specifically purpose present study subjects instructed take six tablets day record study diary whether took tablets the indicators efficacy gcqid supplementation functions locomotor system including knee joint jkom category score vas score jkom knee pain total score jkom categories ii v jkom total score glfs-5 score vas score knee pain various daily situations questionnaires designed study jkom self administered disease specific measure knee oa demonstrated adequate validity reliability studies japanese people knee oa terms outcomes correlated health related quality life qol).14 vas score jkom knee pain measured scale 0 100 0 indicated pain 100 indicated worst pain ever experienced the jkom total score comprised 25 items cover four different categories ii pain stiffness knees iii conditions daily life iv general activities v health conditions scores 25 items summed results ranging 0 points complaint 100 points severe condition possible the glfs-5 also self administered measure consisting five items located key domain construct structure glfs-25 covers wide range issues pain qol.3 items graded 5-point scales 0 points 4 points five item scores summed produce overall score range 0 impairment 20 points severe impairment the vas score knee pain various daily situations included pain knee rest walking ascending descending stairs scales 0 100 0 indicated pain 100 indicated worst pain ever experienced questionnaires addressed frequency trips involved walking ascending descending stairs 5-point scales 0 occurrence 4 frequent occurrence for the biomechanical mechanism efficacy locomotor functions motion capture analysis normal walking state conducted obtain data gait parameters subjects took shoes changed dedicated full body suits motion capture markers attached 30 locations body suits top head tragi superior margin sternum extremitas inferior ribs anterior superior iliac spines acromions elbows wrists backs hands great trochanters interior exterior sides knees internal external malleoli heels toes thereafter subjects instructed walk 10 two times usual speed the time took walk middle 6 measured normal walking speed calculated primary outcome the position trajectories markers attached suits subjects walking recorded motion capture system raptor e digital real time system motion analysis corporation santa rosa ca usa time the values step length stride length cadence time stance phase swing phase angle soles toes feet calculated analyzing data position trajectories average value data feet evaluated explanation terms parameters motion capture analysis shown figure 1 data functions locomotor system including knee joint collected baseline every 4 weeks week 16 data motion capture analysis collected baseline 8 16 weeks exclusion criteria efficacy assessment follows taking test supplement fewer 80% scheduled days performing actions affected reliability efficacy assessment noncompliance clinical protocol changes measurements intervention compared baseline using steel test jkom total score glfs-5 score questionnaires dunnett test used vas score jkom knee pain normal walking speed parameters measured motion capture analysis correlation analysis changes parameters analyzed motion capture system locomotor functions involve knee joint 16-week intervention period conducted pearson correlation coefficient r value parametric variables spearman rank correlation coefficient value nonparametric variables calculated all statistical analyses carried using ibm spss statistics windows version 21.0 ibm corporation armonk ny usa ekuseru toukei 2010 windows social survey research information co. ltd tokyo japan of 30 subjects one female dropped study adverse event sudden deafness deemed medical investigator unrelated supplementation subject data excluded efficacy assessment the remaining 29 subjects deemed eligible efficacy assessment baseline characteristics shown table 1 table 2 shows changes functions locomotor system including knee joint 16-week intervention period the vas score jkom knee pain jkom total score glfs-5 score vas scores knee pain various daily situations significantly decreased week 4 thereafter p<0.05 p<0.01 compared baseline the questionnaire scores reflecting frequency tripping walking ascending descending stairs significantly decreased week 8 thereafter p<0.05 p<0.01 compared baseline table 3 shows changes parameters analyzed motion capture system 16-week intervention period normal walking speed significantly increased week 16 compared baseline p<0.01 step length stride length significantly increased week 8 week 16 compared baseline p<0.05 p<0.01 cadence significantly changed intervention time stance phase significantly decreased week 8 week 16 compared baseline p<0.01 time swing phase significantly changed intervention angle soles end stance phase significantly increased week 8 week 16 compared baseline p<0.05 p<0.01 angle toe beginning stance phase significantly increased week 16 compared baseline p<0.01 table 4 shows correlations changes major parameters analyzed motion capture system locomotor functions involve knee joint 16-week intervention period normal walking speed significantly correlated stride length cadence angle sole p<0.01 r=0.87 p<0.05 r=0.44 p<0.01 r=0.66 respectively stride length correlated angle sole end stance phase angle toe beginning stance phase p<0.01 r=0.66 p<0.05 r=0.42 respectively vas score jkom knee pain jkom total score glfs-5 significantly correlated jkom total score glfs-5 significantly correlated stride length p<0.05 =0.42 p<0.05 =0.42 respectively the present study conducted investigate biomechanical mechanism gcqid positive effects locomotor functions subjects knee pain using motion capture system gcqid improved functions locomotion involve knee joint evidenced jkom glfs-5 scores table 2 suggesting gcqid supplementation exerted effects knee pain daily life qol accordance previous study.11 motion capture analysis revealed gcqid simultaneously increased normal walking speed stride step length cadence changed table 3 reported walking speed mainly controlled stride length cadence,16 gcqid effect increasing normal walking speed likely attributable increased stride length this attribution supported fact change normal walking speed 16 weeks strongly related change stride length correlation analysis r=0.87 addition gcqid increased angle soles end stance phase table 3 could indicate increased kicking force ground enhanced driving power figure 1 as change stride length 16 weeks correlated change angle soles end stance phase r=0.66 considered gcqid might increase stride length enhanced driving power oa patients knee pain shorter stride lengths compared healthy subjects,6,7 driving power subjects needed make longer strides could restricted knee pain change stride length 16 weeks correlated changes jkom total score glfs-5 score =0.44 =0.42 respectively ) gcqid might increase stride length alleviated knee pain improved functions locomotor system daily life addition gcqid increased angle toe beginning stance phase table 3 could indicate manner gait control subjects changed one toes raised higher figure 1 the change angle toe beginning stance phase 16 weeks correlated change stride length r=0.42 suggesting possibility contribution increased stride length higher toe angle gcqid as gcqid decreased frequency tripping walking according questionnaires table 2 gcqid might actually change gait way makes subjects less likely tripped therefore deny possibility placebo effect explanation observed effect gcqid although improvement scores functions locomotor system jkom total score comparatively greater previous study amount improvement normal walking speed gcqid similar found gcqid group previous study.11 therefore assert gcqid likely produced similar effect previous study terms walking parameters point apparent future randomized placebo controlled trials elucidating effect gcqid supplement walking parameters conducted second although biochemical mechanism gcqid supplementation improve locomotor functions may explained mainly alleviated knee pain anti inflammatory chondroprotective activities glucosamine hydrochloride,17,18 chondroitin sulfate,19 quercetin,20,21 addition direct effects muscle anti muscle atrophy effects quercetin,22 effect imidazole peptides increasing muscle blood flow,23 described previous study,11 contribution component effects locomotor functions study previous study determined further studies needed future elucidate precise role component third present study short term study 16 weeks small number subjects enough elucidate influence characteristics subjects age sex therefore long term studies larger sample size required future assessing efficacy safety gcqid treatment including age- sex specific variations clearly our data based gait analysis using motion capture system suggest gcqid supplements increase walking speed increased stride length increased force kicking ground steps improvements may associated mainly alleviated knee pain direct effects muscle | backgroundpreviously , we demonstrated that glucosamine - containing supplementation was effective for improving locomotor functions , especially walking speed .
however , the biomechanical mechanism of efficacy has not been elucidated .
this study aimed to address this challenge in subjects with knee pain , using a motion capture system.methodsan open label study was conducted in 30 japanese subjects with knee pain .
the subjects were administered a daily supplement containing 1,200 mg of glucosamine hydrochloride , 60 mg of chondroitin sulfate , 45 mg of type ii collagen peptides , 90 mg of quercetin glycosides , 10 mg of imidazole peptides , 1 mg of proteoglycan , and 5 g of vitamin d ( gcqid ) .
the intervention continued for 16 weeks .
efficacy for locomotor functions involving the knee joint was evaluated mainly using the japanese knee osteoarthritis measure ( jkom ) and the 5-question geriatric locomotive function scale ( glfs-5 ) . to examine the biomechanical mechanism of efficacy for locomotor functions ,
motions of subjects in a normal walking state were captured .
gait analysis was conducted and efficacy for gait parameters such as normal walking speed , stride length , cadence , and angle of soles was evaluated.resultsgcqid significantly improved total scores on the jkom and glfs-5 . in gait analysis , normal walking speed , stride length , and angle of soles at the end of the stance phase were all significantly increased , but cadence did not change significantly during the intervention period .
there were significant intercorrelations of changes in normal walking speed , stride length , and angle of soles at the end of the stance phase , and between changes in stride length and total jkom score.conclusiona gcqid supplement may increase walking speed through increased stride length and angle of kicking from the ground during steps , which might be mainly associated with alleviated knee pain . |
metabolic syndrome mets growing concern among patients schizophrenia1 metabolic adverse events widely regarded major risk factor cardiovascular diseases2,3 mortality.4,5 although causes metabolic adverse events complicated risk factors among patients schizophrenia attributed dietary habits,6 physical activity,7 antipsychotic medications,8,9 negative symptoms schizophrenia.10 although opinion psychiatrists well known concerning issue,1114 patients affected metabolic adverse events relatively unexplored nevertheless important factors educational programs for patients might effectively improve clinical outcomes.15 date studies assessed patient attitudes toward antipsychotic medications.1620 however studies primarily focused metabolic adverse events thus necessary accurately assess patient attitudes toward metabolic issues representative sample patients currently japan 28.4 psychiatric beds per 10,000 people highest ratio world furthermore mean length hospital stay japan i1.5 years represents longest stay among developed nations.21 inpatients schizophrenia receive controlled meals occupational therapy lifestyles might differ outpatients a previous study conducted japan showed rates mets outpatients inpatients schizophrenia 48.1% 15.8% respectively.22 although shift inpatient care community based care ongoing challenge discharge long term psychiatric patients might elevate risk mets previously reported psychiatrists attitudes toward metabolic adverse events patients schizophrenia.14 however attitudes schizophrenic patients assessed japan the current study investigated attitudes toward metabolic adverse events nationwide survey japanese patients schizophrenia knowledge study uses largest sample patients first investigate attitudes toward metabolic issues among asian patients the joint committee japanese society clinical neuropsychopharmacology japan psychiatric hospital association antipsychotic treatment physical risk prepared survey reviewing relevant literature extant guidelines brief questionnaire constructed cover patient recognition following broad areas dietary habits lifestyle self monitoring knowledge medical practice figure s1 january 2012 june 2013 questionnaire mailed patients associated 520 outpatient facilities 247 inpatient facilities belonging japan psychiatric hospital association participants selected based available sampling method diagnosed schizophrenia according diagnostic statistical manual mental disorders fourth edition international classification diseases tenth revision the anonymous questionnaire research instrument statement included states completion attached questionnaire taken indicating consent participate the ethics committee japan psychiatric hospital association hirosaki university school medicine approved study procedure descriptive statistics computed describe demographic clinical variables order compare main demographic clinical characteristics inpatients outpatients mann
whitney u test performed analyze continuous variables chi square test performed analyze categorical variables parameter r used measure effect size mann whitney u test r values 0.3 represent medium effect sizes strength association chi square analysis confirmed medium phi cramer v score 0.30 the joint committee japanese society clinical neuropsychopharmacology japan psychiatric hospital association antipsychotic treatment physical risk prepared survey reviewing relevant literature extant guidelines brief questionnaire constructed cover patient recognition following broad areas dietary habits lifestyle self monitoring knowledge medical practice figure s1 january 2012 june 2013 questionnaire mailed patients associated 520 outpatient facilities 247 inpatient facilities belonging japan psychiatric hospital association participants selected based available sampling method diagnosed schizophrenia according diagnostic statistical manual mental disorders fourth edition international classification diseases tenth revision the anonymous questionnaire research instrument statement included states completion attached questionnaire taken indicating consent participate the ethics committee japan psychiatric hospital association hirosaki university school medicine approved study procedure descriptive statistics computed describe demographic clinical variables order compare main demographic clinical characteristics inpatients outpatients mann
whitney u test performed analyze continuous variables chi square test performed analyze categorical variables parameter r used measure effect size mann whitney u test r values 0.3 represent medium effect sizes strength association chi square analysis confirmed medium phi cramer v score 0.30 approximately 27.9% 4,136/14,840 inpatients stated drank soft drinks eg cola q1 every day 34.6% 5,142/14,840 week 18.3% 2,718/14,840 month 19.2% 2,844/14,840 drink whereas 27.8% 1,841/6,616 outpatients stated drank soft drinks every day 28.5% 1,884/6,616 week 25.8% 1,706/6,616 month 17.9% 1,185/6,616 drink q1 cramer v=0.092 p<0.001 approximately 62.8% 9,324/14,841 inpatients consumed 100% three meals day q2 12.2% 1,806/14,841 ate 90% 12.1% 1,790/14,841 ate 80% 5.8% 860/14,841 ate 70% 4.3% 644/14,841 ate 60% 2.8% 417/14,841 ate 50% approximately 82.6% 5,633/6,823 outpatients stated regularly ate breakfast lunch dinner approximately 39.3% 5,855/14,914 inpatients 36.3% 2,466/6,799 outpatients stated ate cake sweets day q3 phi 0.029 p<0.001 approximately 17.0% 2,523/14,865 inpatients warned eat many snacks q4 approximately 36.7% 2,490/6,784 outpatients also warned eat many meals q4 only 6.9% 1,008/14,674 inpatients 6.5% 442/6,779 outpatients stated generally take sweets go stay overnight q5 approximately 41.7% 6,152/14,765 inpatients 25.3% 1,709/6,767 outpatients stated always hungry q6 phi 0.158 p<0.001 approximately 59.3% 3,856/6,505 outpatients stated cook housework q9 approximately 8.4% 1,071/12,751 inpatients reported going every day q8 12.2% 1,558/12,751 went week 16.9% 2,150/12,751 went month 62.5% 7,972/12,751 go percentages 46.6% 3,091/6,627 31.8% 2,110/6,627 13.3% 883/6,627 8.2% 543/6,627 among outpatients respectively q8 cramer v=0.593 p<0.001 approximately 18.5% 2,708/14,669 inpatients reported exercising every day q10 13.1% 1,923/14,669 week 13.4% 1,969/14,669 week 55.0% 8,069/14,669 exercise percentages 20.2% 1,342/6,649 14.8% 986/6,649 20.2% 1,343/6,649 44.8% 2,978/6,649 among outpatients respectively q10 cramer v=0.107 p<0.001 approximately 35.2% 5,231/14,864 inpatients reported watching television every day q11 49.1% 7,305/14,864 watched television sometimes 15.7% 2,328/14,864 watched none percentages 60.4% 4,077/6,748 30.3% 2,047/6,748 9.2% 624/6,748 among outpatients respectively q11 cramer v=0.236 p<0.001 survey 33.1% 4,859/14,701 inpatients 48.4% 3,229/6,669 outpatients reported gained weight previous year q7 phi 0.147 p<0.001 approximately 22.9% 1,554/6,781 outpatients stated weighed every day q15 21.0% 1,427/6,781 week 19.3% 1,306/6,781 month 36.8% 2,494/6,781 weigh table 2 shows healthy habits patients mindful q19 regard body weight self assessments q20 35.6% 5,261/14,794 inpatients 60.9% 4,116/6,760 outpatients approximately 16.4% 2,412/14,735 inpatients 23.2% 1,552/6,693 outpatients stated doctor educated medication might cause side effects weight gain q12 phi 0.081 p<0.001 furthermore 31.9% 4,749/14,883 inpatients 74.3% 5,056/6,809 outpatients knew term metabolic syndrome
additionally 9.7% 1,431/14,742 inpatients 22.8% 1,530/6,720 outpatients knew terms bmi body mass index
( q17 phi 0.176 p<0.001 approximately 10.2% 1,517/14,823 inpatients stated body weight measured hospital every day q13 13.7% 2,033/14,823 said weighed week 74.1% 10,984/14,823 said weighed month 0.8% 121/14,823 said weighed least every 6 months 0.6% 96/14,823 said weighed least year 0.5% 72/14,823 said never weighed 27.9% 1,792/6,421 outpatients stated body weight measured hospital every visit 19.3% 1,238/6,421 said weighed least every 3 months 6.6% 423/6,421 said weighed least every 6 months 10.1% 651/6,421 said weighed least year 36.1% 2,317/6,421 said never weighed approximately 40.2% 5,814/14,473 inpatients stated blood tests hospital q14 every month 37.5% 5,425/14,473 blood tests least every 3 months 15.5% 2,239/14,473 blood tests least every 6 months 5.5% 799/14,473 blood tests least year 1.4% 196/14,473 never blood tests 7.2% 464/6,468 outpatients stated blood tests hospital every visit 27.4% 1,769/6,468 said blood tests least every 3 months 24.5% 1,587/6,468 said blood tests least every 6 months 24.4% 1,579/6,468 said blood tests least year 16.5% 1,069/6,468 said never blood tests table 3 lists healthy habits patients told mindful doctors q18 prevent weight gain diseases diabetes 51.2% inpatients 7,514/14,690 60.8% outpatients 4,086/6,721 hoped receive blood tests regularly q21 phi 0.090 p<0.001 64.5% inpatients 9,514/14,744 63.3% outpatients 4,260/6,729 hoped weigh regularly q22 phi 0.012 p=0.084 approximately 27.9% 4,136/14,840 inpatients stated drank soft drinks eg cola q1 every day 34.6% 5,142/14,840 week 18.3% 2,718/14,840 month 19.2% 2,844/14,840 drink whereas 27.8% 1,841/6,616 outpatients stated drank soft drinks every day 28.5% 1,884/6,616 week 25.8% 1,706/6,616 month 17.9% 1,185/6,616 drink q1 cramer v=0.092 p<0.001 approximately 62.8% 9,324/14,841 inpatients consumed 100% three meals day q2 12.2% 1,806/14,841 ate 90% 12.1% 1,790/14,841 ate 80% 5.8% 860/14,841 ate 70% 4.3% 644/14,841 ate 60% 2.8% 417/14,841 ate 50% approximately 82.6% 5,633/6,823 outpatients stated regularly ate breakfast lunch dinner approximately 39.3% 5,855/14,914 inpatients 36.3% 2,466/6,799 outpatients stated ate cake sweets day q3 phi 0.029 p<0.001 approximately 17.0% 2,523/14,865 inpatients warned eat many snacks q4 approximately 36.7% 2,490/6,784 outpatients also warned eat many meals q4 only 6.9% 1,008/14,674 inpatients 6.5% 442/6,779 outpatients stated generally take sweets go stay overnight q5 approximately 41.7% 6,152/14,765 inpatients 25.3% 1,709/6,767 outpatients stated always hungry q6 phi 0.158 p<0.001 approximately 59.3% 3,856/6,505 outpatients stated cook housework q9 approximately 8.4% 1,071/12,751 inpatients reported going every day q8 12.2% 1,558/12,751 went week 16.9% 2,150/12,751 went month 62.5% 7,972/12,751 go percentages 46.6% 3,091/6,627 31.8% 2,110/6,627 13.3% 883/6,627 8.2% 543/6,627 among outpatients respectively q8 cramer v=0.593 p<0.001 approximately 18.5% 2,708/14,669 inpatients reported exercising every day q10 13.1% 1,923/14,669 week 13.4% 1,969/14,669 week 55.0% 8,069/14,669 exercise percentages 20.2% 1,342/6,649 14.8% 986/6,649 20.2% 1,343/6,649 44.8% 2,978/6,649 among outpatients respectively q10 cramer v=0.107 p<0.001 approximately 35.2% 5,231/14,864 inpatients reported watching television every day q11 49.1% 7,305/14,864 watched television sometimes 15.7% 2,328/14,864 watched none percentages 60.4% 4,077/6,748 30.3% 2,047/6,748 9.2% 624/6,748 among outpatients respectively q11 cramer v=0.236 p<0.001 in survey 33.1% 4,859/14,701 inpatients 48.4% 3,229/6,669 outpatients reported gained weight previous year q7 phi 0.147 p<0.001 approximately 22.9% 1,554/6,781 outpatients stated weighed every day q15 21.0% 1,427/6,781 week 19.3% 1,306/6,781 month 36.8% 2,494/6,781 weigh table 2 shows healthy habits patients mindful q19 regard body weight self assessments q20 35.6% 5,261/14,794 inpatients 60.9% 4,116/6,760 outpatients approximately 16.4% 2,412/14,735 inpatients 23.2% 1,552/6,693 outpatients stated doctor educated medication might cause side effects weight gain q12 phi 0.081 p<0.001 furthermore 31.9% 4,749/14,883 inpatients 74.3% 5,056/6,809 outpatients knew term metabolic syndrome
additionally 9.7% 1,431/14,742 inpatients 22.8% 1,530/6,720 outpatients knew terms bmi body mass index
approximately 10.2% 1,517/14,823 inpatients stated body weight measured hospital every day q13 13.7% 2,033/14,823 said weighed week 74.1% 10,984/14,823 said weighed month 0.8% 121/14,823 said weighed least every 6 months 0.6% 96/14,823 said weighed least year 0.5% 72/14,823 said never weighed 27.9% 1,792/6,421 outpatients stated body weight measured hospital every visit 19.3% 1,238/6,421 said weighed least every 3 months 6.6% 423/6,421 said weighed least every 6 months 10.1% 651/6,421 said weighed least year 36.1% 2,317/6,421 said never weighed approximately 40.2% 5,814/14,473 inpatients stated blood tests hospital q14 every month 37.5% 5,425/14,473 blood tests least every 3 months 15.5% 2,239/14,473 blood tests least every 6 months 5.5% 799/14,473 blood tests least year 1.4% 196/14,473 never blood tests 7.2% 464/6,468 outpatients stated blood tests hospital every visit 27.4% 1,769/6,468 said blood tests least every 3 months 24.5% 1,587/6,468 said blood tests least every 6 months 24.4% 1,579/6,468 said blood tests least year 16.5% 1,069/6,468 said never blood tests table 3 lists healthy habits patients told mindful doctors q18 prevent weight gain diseases diabetes 51.2% inpatients 7,514/14,690 60.8% outpatients 4,086/6,721 hoped receive blood tests regularly q21 phi 0.090 p<0.001 64.5% inpatients 9,514/14,744 63.3% outpatients 4,260/6,729 hoped weigh regularly q22 phi 0.012 p=0.084 the present study employed national survey japan evaluated attitudes toward metabolic adverse events among patients schizophrenia more half outpatients felt obese half respondents hoped receive regular blood tests prevent metabolic adverse events however minority patients mindful eating balanced meals physical exercise stated doctors encouraged habits our results confirm patients schizophrenia concerned metabolic adverse events healthy lifestyle habits the differences dietary patterns patients schizophrenia healthy controls reported previously.23,24 inadequate dietary patterns cause obesity,25 mets,26 cardiovascular events.27 survey outpatients stated ate breakfast lunch dinner regularly however one third respondents ate cake sweets least day participants stated mindful healthy diet dietary improvements patients schizophrenia might help prevent metabolic adverse events.28 reduced physical activity might play role development mets,29 previous study reported patients schizophrenia engaged physical activity less frequently healthy controls.30 survey approximately half respondents 55% inpatients 45% outpatients answered exercise our results accordance previous research,31 found 40% individuals schizophrenia report lack moderate physical activity 75% report lack vigorous physical activity although minority respondents inpatients 29.4% outpatients 39.5% mindful physical exercise several studies indicated regular exercise programs possible among individuals schizophrenia beneficial effects well well physical mental health.32 according survey half outpatients reported felt obese obesity growing public health concern becoming prevalent among patients schizophrenia compared general population.3335 previous studies shown overweight major risk factor mets cardiovascular diseases premature death.3638 additionally obesity among patients schizophrenia associated high medication costs,39 low self esteem poor psychosocial adaptation,40 reduced quality life,41,42 negative attitudes toward medication,19 noncompliance antipsychotic medication regimes.43 although behavioral interventions effectively prevent reduce antipsychotic associated weight gain cardiometabolic perturbations,15 respondents study reported encouraged doctors perform moderate physical exercise more half respondents hoped receive blood tests regularly prevent weight gain diseases diabetes although patients severe mental illnesses less aware comorbid medical conditions heart disease diabetes hypertension,17 patients judged disorders epilepsy diabetes worse schizophrenia16 described dissatisfaction deficiency regard care received health care providers.18 buckley et al showed psychiatrists routinely monitor patients lipid profiles blood glucose levels blood pressure.12 previously reported psychiatrists japan monitor lipid profiles blood glucose levels inpatients outpatients twice year.14 psychiatrists stated frequency monitored patients antipsychotic treatment based clinical experience however 20.6% respondents stated monitoring frequency sufficient reduce metabolic risk it necessary disseminate monitoring guidelines regard metabolic adverse events might make psychiatrists aware integral approach patients schizophrenia thereby increasing physical health monitoring patients.44 japan mental health act seeks promote concept normalization establishing mental illness disability encouraging assimilation psychiatric inpatients back community although inpatients encouraged shift community based care inpatients enough knowledge metabolic adverse events educational programs seeking prepare long term hospitalized patients schizophrenia discharge hospitals warranted firstly study limited fact cross sectional rather prospective design lacks data actual practices psychiatrists this study could clarify causal relationship psychiatrists practice attitudes among patients schizophrenia secondly several potential confounding factors antipsychotic medications duration illness treatment assessed study age could affect results dietary habits lifestyle self monitoring knowledge medical practices this study showed minority patients mindful eating balanced meals physical exercise however half patients hoped prevent weight gain diabetes these findings imply educational efforts45 promotion best pharmacotherapy monitoring practices46 needed patients schizophrenia improving attitudes toward metabolic adverse events among patients might contribute physical health improvements | backgroundmetabolic syndrome is a growing concern among patients with schizophrenia because metabolic abnormalities are widely regarded as a major risk factor for cardiovascular disease and premature death .
the current study assessed attitudes toward metabolic adverse events among patients with schizophrenia.methodsa brief questionnaire was constructed to investigate patient recognition of the following broad areas : dietary habits , lifestyle , self - monitoring , knowledge , and medical practice . between january 2012 and june 2013 , questionnaires were sent to patients associated with 520 outpatient facilities and 247 inpatient facilities belonging to the japan psychiatric hospital association .
all of the participants ( n=22,072 ; inpatients = 15,170 , outpatients = 6,902 ) were diagnosed with schizophrenia based on the diagnostic and statistical manual of mental disorders , fourth edition , or the international classification of diseases , tenth revision.resultsapproximately 55.0% ( 8,069/14,669 ) of inpatients and 44.8% of outpatients ( 2,978/6,649 ) reported that they did not exercise at all .
although 60.9% ( 4,116/6,760 ) of outpatients reported that they felt obese , only 35.6% ( 5,261/14,794 ) of inpatients felt obese .
more than half of the inpatients ( 51.2% ; 7,514/14,690 ) and outpatients ( 60.8% ; 4,086/6,721 ) hoped to receive regular blood tests to prevent weight gain and diseases such as diabetes.conclusionalthough more than half of patients hoped to prevent weight gain and diabetes , only a minority of patients were mindful of eating balanced meals and having physical exercise .
educational efforts and the promotion of the best pharmacotherapy and monitoring practices are needed for patients with schizophrenia . |
giant cell tumor gct tumor found often ends long bones essentially located epiphyseal metaphyseal epiphyseal equivalent portions bone it locally aggressive neoplasm generally arising adults ages 20 40 years clinically possessing metastatic potential the rib rare site reported incidence less one percent even cases involving rib most located posterior arc i.e. head tubercle ribs rare multicentric forms reported.[13 article report case gct originating anterior arc rib diagnosed fine needle aspiration cytology fnac a 23-year old female presented six month history progressively growing mass right anterior chest wall associated slight pain cytological smears cellular comprising aggregates uniform appearing spindled stromal cells innumerable osteoclast type giant cells variable number nuclei the nuclei stromal cells resembled observed osteoclast type giant cells the stromal cells showed high nuclear cytoplasmic ratio evenly distributed chromatin inconspicuous small nucleoli no significant nuclear atypia observed either giant cells background stromal cells mitotic figures noted frequently figure 1 correlation radiographic findings of an eccentric expanded lytic lesion cortical erosion anterior arc fourth rib figure 2 diagnosis aggressive giant cell tumor rib offered cytologically case the musculoskeletal radiologist opined aneurysmal bone cyst askin tumor anterior chest wall aggregates uniform appearing spindled stromal cells innumerable osteoclast type giant cells h e 400 inset showing histomorphology resected giant cell tumor h e 400 large expansile tumor mass thinned cortex anterior end fourth rib noted computed tomography scan view cytomorphological diagnosis radiological cortical destruction anterior arc fourth rib patient referred surgical oncology centre possibility soft tissue extension also considered higher centre complete resection tumor patient remained asymptomatic without evidence recurrence end one year following surgical intervention last follow up gct bone uncommon neoplasm accounting 45% primary bone tumors in fact may represent stromal precursor cells lost detectable macrophage associated antigens mononuclear phagocyte antigens seen mature cells gct generally considered benign malignant cells arise de novo via transformation benign neoplastic giant cell lesion.[13 interestingly gct common females although role steroid metabolism lesions unclear estrogen progesterone receptors identified cells lesion metaphyseal epiphyseal zones long bones common sites 60% arising around knee joint isolated cases reported scapula sternum patella vertebra skull talus cases gct involving ribs reported literature involving posterior aspect due rarity gct arising chest wall difficult diagnose especially tumor located anterior arc ribs it also compounded fact soft tissue counterpart gct also known.[135 pain increase local volume principal forms presentation some patients present pathological fracture resulting weakening cortical bone routine radiograph gct presents initially eccentric expanded lytic lesion without surrounding sclerotic halo representing cortical bone as lesion grows encompass entire circumference bone causing rupture cortical bone periosteal reaction rarely seen roentgenographic classification schemes used characterize tumor given case attempt predict clinical outcome histological features benign aggressive malignant latter clearly pleomorphic features abundant mitotic figures ii although overt anaplastic features tumor cells mitotic activity frequently detectable clinical symptomatic presentation rapidly growing mass radiological evidence bone destruction expansion cytomorphological diagnosis aggressive gct offered case a wide array lesions may histologically mimic depending quality size biopsy while examining lesions rich cells particular attention paid background stromal cells clinico radiological data correlated establishing diagnosis becomes easier a differential diagnosis aneurysmal bone cyst abc brown tumor chondroblastoma chondromyxoid fibroma cmf non ossifying fibroma nof giant cell rich osteosarcoma malignant fibrous histiocytoma considered cytology gct giant cells numerous number attached periphery clustered spindle cells aspirates abc generally hemorrhagic sparse cellular yield comprised scattered osteoclastic giant cells spindle shaped fibroblastic cells hemosiderin laden macrophages chondroblastoma chondroid matrix plump spindle shaped mononuclear cell component along occasional osteoclastic giant cells present cmf aspirates show chondroid fragments spindle shaped fibroblastic cells scattered osteoclastic giant cells myxoid background nof yields groups clusters spindle cells histiocytic cells vacuolated cytoplasm occasional osteoclastic giant cells the cytology brown tumor similar nof characteristic spindly mononuclear cells osteoclasts macrophages giant cell rich osteosarcoma mfh characterized nuclear anaplasia abnormal mitotic figures gct neoplastic osteoid formation pathognomonic finding giant cell rich osteosarcoma except lack bony involvement primary giant cell tumor soft tissue resembles cyto histomorphological features osseous counterpart.[24 general gct considered potentially aggressive wide excision recommended fine needle aspiration cytology useful diagnosing similar lesions rare sites like distal fibula a primary malignant gct sacrum could identified middle aged female also multifocal gct skeletally immature patient serum acid phosphatase values suggested useful marker diagnosis gct bone evaluation efficacy treatment tumor the values high 56% gct patients later decreased normal values resection seen case to conclude case illustrates fact giant cell tumors anterior chest wall mistaken abc malignant tumors bone soft tissues fine needle image guided biopsy would diagnostic adequate specimen obtained | giant cell tumor of bone also known as osteoclastoma is a distinct clinical , roentgenographic and pathologic entity with specific characteristics .
it is a benign but locally aggressive neoplasm , classically seen as a purely lytic lesion of the epiphyseal or metaphyseal - epiphyseal region of long tubular bones extending to the articular surface .
it usually occurs after skeletal maturation and is one of the rare bone tumors that more frequently affects women .
even though rarely it can occur in ribs , it usually occurs in the posterior aspect .
we report here a case of giant cell tumor originating from the anterior arc of the rib diagnosed on fine needle aspiration cytology . |
ovarian tumors borderline malignancy borderline ovarian tumors bot constitute 10 15% epithelial ovarian malignancies 1 however conservative treatment might considered patients want preserve fertility excellent prognosis reported 2 3 although spontaneous conceptions reported conservative surgery patients suffer infertility require infertility treatment some bot infertile patients undergo assisted reproductive technologies art improve chances pregnancy the influence infertility treatment development ovarian malignancies controversial topic case control study reported history infertility increases overall risk ovarian cancer 4 in addition reports suggesting association fertility medication bot however association fertility medication invasive ovarian cancer conclusive 5 7 it suggested high serum estradiol levels ovarian hyperstimulation might promote tumor growth bot especially estrogen receptor expression positive cases 8 9 therefore potential risk associated infertility treatment must considered infertile patients conservative treatment bot early stage bot possible consider art conservative treatment since multicenter study reported 16 bot patients undergone vitro fertilization ivf conservative treatment 10 reported overall success rates ivf satisfactory group patients suggesting known negative impact prior bot pregnancy rates ivf 11 however advanced stage bot published reports limited case reports 12 14 therefore patients advanced bot safety art conservative treatment remains anecdotal the purpose study evaluate outcomes coh ivf infertile patients conservative treatment bot a retrospective review ivf records january 1999 july 2005 revealed 10 attempted ivf cycles five patients previously diagnosed bot conservative treatment preserve fertility bot histological characteristics ovarian tumors 1 epithelial proliferation formation papillary configuration 2 demonstration atypical epithelial activity 3 mild moderate atypical nuclei 4 absence stromal invasion distinguishes invasive carcinoma fig conservative treatment defined preservation uterus least portion one ovary cases diagnosis bot made intraoperatively staging made according international federation gynecology obstetrics figo classification based ipsilateral pelvic paraaortic lymph node dissections peritoneal cytology omentectomy multiple peritoneal biopsies after conservative surgery gynecological oncologist followed patients every 3 months first year thereafter every 6 months physical examination serum ca-125 levels transvaginal ultrasound the main outcome measures pregnancy outcomes clinical pregnancy rate cpr implantation rate ir live birth rate lbr coh ivf recurrence bot follow period approval institutional review board obtained study retrospective case observational study coh performed gonadotropin releasing hormone agonist gnrh long protocol flare protocol using human menopausal gonadotropin menogon ferring germany recombinant follicle stimulating hormone puregon organon netherland long protocol patients underwent pituitary desensitization gnrh suprefact hoechst germany previous menstrual mid luteal phase gonadotropins administered pituitary regulation continued hcg pregnyl organon netherland administration for flare protocol gnrh administered second day menstrual cycle gonadotropins administered third day menstrual cycle hcg administration oocyte retrieval performed via transvaginal approach sonographic guidance 36 hr 10,000 iu hcg administration the oocytes incubated human tubal fluid irvine scientific irvine ca u.s.a medium supplemented 10% synthetic serum supplement sss irvine scientific 37 5% co2 air pregnancy determined serum -hcg levels 5 miu ml 12 days oocyte retrieval a retrospective review ivf records january 1999 july 2005 revealed 10 attempted ivf cycles five patients previously diagnosed bot conservative treatment preserve fertility bot histological characteristics ovarian tumors 1 epithelial proliferation formation papillary configuration 2 demonstration atypical epithelial activity 3 mild moderate atypical nuclei 4 absence stromal invasion distinguishes invasive carcinoma fig conservative treatment defined preservation uterus least portion one ovary cases diagnosis bot made intraoperatively staging made according international federation gynecology obstetrics figo classification based ipsilateral pelvic paraaortic lymph node dissections peritoneal cytology omentectomy multiple peritoneal biopsies after conservative surgery gynecological oncologist followed patients every 3 months first year thereafter every 6 months physical examination serum ca-125 levels transvaginal ultrasound the main outcome measures pregnancy outcomes clinical pregnancy rate cpr implantation rate ir live birth rate lbr coh ivf recurrence bot follow period approval institutional review board obtained study retrospective case observational study coh performed gonadotropin releasing hormone agonist gnrh long protocol flare protocol using human menopausal gonadotropin menogon ferring germany recombinant follicle stimulating hormone puregon organon netherland long protocol patients underwent pituitary desensitization gnrh suprefact hoechst germany previous menstrual mid luteal phase gonadotropins administered pituitary regulation continued hcg pregnyl organon netherland administration for flare protocol gnrh administered second day menstrual cycle gonadotropins administered third day menstrual cycle hcg administration oocyte retrieval performed via transvaginal approach sonographic guidance 36 hr 10,000 iu hcg administration the oocytes incubated human tubal fluid irvine scientific irvine ca u.s.a medium supplemented 10% synthetic serum supplement sss irvine scientific 37 5% co2 air pregnancy determined serum -hcg levels 5 miu ml 12 days oocyte retrieval two cycles 10 attempted ivf cycles cancelled due poor ovarian response coh table 1 shows demographics five patients surgical findings time diagnosis bot mean age patients was 30.0 yr range 24 40 four five patients nulliparous three patients patient 2 4 5 ) the diagnosis made intraoperatively staged ia ia iiic respectively remaining two patients patients 1 3 diagnosis made postoperatively without complete surgical staging the microscopic findings three patients showed mucinous type remaining two patients serous type 2 underwent right salpingoophorectomy disease recurrence occurred remaining ovary 9 yr initial diagnosis recurrence showed histology stage identical primary disease 5 right side pelvic paraaortic lymph node dissections peritoneal cytology omentectomy multiple peritoneal biopsies diagnosed stage iiic disease for stromal microinvasion patient treated six cycles taxol cisplatin based chemotherapy time first ivf cycle the period infertility conservative treatment ranged 17 45 months mean duration 32.4 months one cycle 2 attempted ivf cycles cancelled due poor ovarian response pregnancy achieved ivf cycles oocyte donation od performed due decreased ovarian reserve 3 one cycle 4 attempted ivf cycles cancelled due poor ovarian response 4 two pregnancies delivered twice first fresh embryo transfer second frozen thawed embryo transfer 10 attempted ivf cycles two cycles cancelled 20.0% cycle cancellation rate eight ivf cycles except cancelled cycles mean serum estradiol level hcg administration 1,032.6 pg ml range 200 2,380 pg ml the mean number retrieved oocytes 5.6 range 2 16 mean fertilization rate 74.4% range 50.0 100.0% the mean number transferred embryos 2.4 range 1 4 the cpr ir lbr 50.0% 4/8 cycles 31.6% 6/19 50.0% 4/8 cycles respectively there one case disease recurrence conservative treatment recurrence developed ivf treatment however recurrence identified since first ivf cycle table 3 the follow period initial diagnosis first ivf cycle ranged 5 127 months mean duration 33.0 months since first ivf cycle follow period ranged 14 61 months mean duration 29.6 months patient no.2 disease recurrence 108 months initial diagnosis 19 months elapsed recurrence first ivf cycle patient no.5 stage iiic disease recurrence identified exploration cesarean section continues followed gynecological oncologist since prognosis bot excellent patients childbearing age treated conservative surgery preserve fertility 2 3 unilateral adnexectomy optimal treatment patients whose diagnosis bot made intraoperatively cystectomy considered cases recurrence remaining ovary some patients infertile conservative treatment request art spite potential risk associated infertility treatment a history infertility prior use fertility medications associated development ovarian tumors recent case control studies showed infertility per se elevates overall risk ovarian cancer 5 reported increased risk ovarian tumors invasive borderline prolonged use 12 cycles clomiphene citrate 15 shushan et al reported increased incidence epithelial ovarian tumors patients previous human menopausal gonadotropin hmg treatment compared healthy controls 6 however risk ovarian hyperstimulation patients treated early stage bot low reported five pregnancies 16 patients subsequently underwent ivf conservative treatment bot found case relapse follow period 46 months average 10 beiner et al suggested art might considered diagnosis bot recurrence occurred 4 patients 7 underwent ivf two patients two patients ivf treatment all recurrences histology identical initial diagnosis borderline malignancy 16 fasouliotis et al reported 17 ivf cycles five patients conservative bot treatment a mean 7.9 oocytes retrieved 57.1% fertilization rate mean 3.1 embryos transferred to date evidence literature restrict use art patients early stage bot conservative treatment present study the cpr lbr 7 ivf cycles patients early stage bot 42.9% 3/7 cycles 42.9% 3/7 cycle respectively the achieved pregnancy outcomes suggest prior bot diagnosis treatment perceptible negative impact pregnancy outcomes coh ivf therefore coh ivf safely offered patients early stage bot however reports safety coh ivf cases advanced stage bot conservative treatment seidman kurman suggested existence invasion peritoneal implant poor prognostic factor patients bot peritoneal implants 16% recurrence noninvasive implant whereas 64% recurrence invasive implant 18 considering poor prognosis bot invasive peritoneal implants seems logical propose conservative treatment patients bot invasive implants present however yet possible provide guidelines coh ivf patients advanced stage bot despite successful pregnancy outcomes 11 13 19 study one patient stage iiic disease without invasive peritoneal implant conservative treatment underwent coh ivf subsequently resulted successful pregnancy delivery it seems number coh ivf cycles limited patients advanced stage bot rapid progression invasive ovarian cancer successful delivery first ivf cycle reported 20 although pathogenic mechanisms tumor progression remain unknown may related hormonal influences 9 estrogen receptor expression recently demonstrated bot high serum e2 levels coh ivf may role tumor promotion 10 after conservative treatment bot recurrence rate estimated 0 20% 21 there significant difference survival rates conservative radical treatment 22 23 beiner et al reported 29% recurrence rate ivf treatment group significantly different 19% recurrence non ivf group 16 all recurrences histology identical primary diagnosis conservatively treated without evidence recurrence last follow 11 study recurrence bot detected coh ivf lower recurrence rate reported patients underwent conservative treatment without subsequent fertility treatment although perod 29.6 14 61 months long follow period results suggest coh ivf may affect recurrence bot pregnancy per se effect course bot conclusion current study suggests ivf may considered infertile patients conservative treatment early stage bot patients advanced stage bot larger clinical trials longer follow necessary evaluate safety efficacy coh ivf all patients informed potential risks associated ovarian hyperstimulation close follow necessary coh ivf | to evaluate the outcomes of controlled ovarian hyperstimulation ( coh)-in vitro fertilization ( ivf ) such as clinical pregnancy rate ( cpr ) , implantation rate ( ir ) and live birth rate ( lbr ) for infertile patients with borderline ovarian tumor ( bot ) after conservative treatment , 10 ivf cycles in five patients from january 1999 to july 2005 were analyzed . at the time of diagnosis with bot , the mean age of patients was 30.0 yr ( range , 22 - 40 ) . for 8 cycles out of 10 attempted ivf cycles , except for 2 cancellation cycles , the mean number of oocytes retrieved was 5.6 ( range , 2 - 16 ) with a mean fertilization rate of 74.4% .
the cpr , ir , and lbr were 50.0% ( 4/8 cycles ) , 31.6% ( 6/19 ) and 50.0% ( 4/8 cycles ) respectively .
the mean follow - up period after coh - ivf initiation was 29.6 ( range , 14 - 61 ) months .
a gynecological oncologist followed all patients every 3 months during the first year and every 6 months thereafter .
there was no recurrence during the follow - up period .
our results suggest that coh - ivf may be acceptable for infertile patients with bot , especially in patients with early - stage bot after conservative treatment . |
formation long lasting memories appears depend upon enduring changes strength neurotransmission alters cellular mechanisms thus reconfiguring neural circuitry communication 16 this review describes relationship among extracellular matrix ecm molecules cell adhesion molecules cams matrix metalloproteinases mmps tissue inhibitors matrix metalloproteinases timps making possible phenomena long term potentiation ltp habituation associative learning memory perhaps drug addiction ecm composed secreted glycoproteins proteoglycons form scaffolding cells adhere within central nervous system network consists proteins fibronectin laminin vitronectin thrombospondin tenascin collagen iv 713 in addition providing network scaffolding ecm involved wide range signaling influences cellular proliferation growth movement synaptic stabilization apoptosis it believed ecm molecules assist maintaining changing synaptic architecture critical neural plasticity believed mediate learning memory these findings anticipated cajal century ago hypothesized memory storage dependent upon alterations synaptic connections neurons the interaction cells ecm molecules facilitated cell adhesion molecules cams these molecules cell surface macromolecules dictate cell cell cell ecm contacts using processes adhesion migration neurite outgrowth fasciculation synaptogenesis intracellular signaling 8 15 16 extracellular domain cams targets proteinase activity intracellular domains interact cytoskeletal proteins cams functionally categorized calcium dependent integrins cadherins calcium independent immunoglobulins selectins proteins integrin receptors widely distributed dimeric transmembrane proteins extracellular portion interacts ecm molecules cell surface proteins intracellular portion makes contact actin cytoskeleton via intermediate proteins -actinin talin tensin vinculin thus binding ligand integrin receptor results functional link ecm actin cytoskeleton mediated intermediate proteins these proteins trigger intracellular signaling pathways initiate changes cellular shape motility growth gene regulation apoptosis 17 18 it appears integrins important regarding cell ecm substrate adhesion cadherins syndecans neural cell adhesion molecules primarily involved cell cell adhesion each cams appears contribute neural plasticity related memory formation additional details reader is referred following excellent reviews concerning ecm molecules cams 713 mmps family proteolytic enzymes involved maintenance restructuring ecm 1921 present 25 mmps have identified four major categories collagenases gelatinases membrane type stromelysins table 1 many mmps require serine proteinases plasmin mmps activation a pro peptide must cleaved order reveal catalytic domain mmp mmp degradation ecm tightly controlled accomplished three mechanisms 1 regulation gene transcription 2 regulation pro enzyme activation 3 presence timps most mmps nonconstituitively expressed however gene transcription may occur via stimulation growth factors oncogene products phorbol esters well cell cell cell ecm interactions these stimuli typically provoke various transcription factors including members c fos c jun proto oncogene families resulting formation homo- hetero dymeric forms ap-1 transcription factors such activation mmp genes requires combined effects ap-1 protein transcription factors see 24 25 reviews outset mmps are maintained inactive pro mmp zymogenes catalytic zinc atom bound cysteine residue pro peptide region figure 1 this action exposes intermediate form mmp capable cleaving pro peptide region via autocatalysis yielding full enzymatic activity mmp activation factors include kallikrein plasmin thrombin tissue type tpa urokinase type upa plasminogen activators plus mmps 27 28 for example mmp-2 mmp-3 membrane type mmps mt mmps activate mmp-1 mmp-9 mt mmps activated inhibitory pro peptide removal specifically accomplished furin also serine protease characteristics mmps make attractive concerning potential contribution memory consolidation reconsolidation retrieval mmp-2 mmp-3 mmp-9 reach measurable levels mammalian brain especially animal challenged change environment e.g. handling learning tasks lesioning seizure these mmps also elevated several pathologies 30 31 including alzheimer disease 22 3235 multiple sclerosis 22 3640 there accumulating evidence mmps essential tumor metastasis cell invasion 9 19 24 41 42 mmps also activated stress brain trauma ischemia 22 4447 thoughtful informative review concerning potential use mmp inhibitors treat neurodegenerative diseases see rosenberg mentioned mmps involved axon extension control axon guidance receptors cell surface via regulated catalysis ectodomain shedding along lines secretion mmps growth cone appears result laying pathway ecm mmps also involved myelination axons central peripheral nervous systems development following damage injury disease neurons oligodendrocytes secrete mmps distal cell process it appears mmps also involved clearing path ecm molecules permitting growing glial tip extend mmp-9 -12 null mice exhibit retarded myelination number mature oligodendrocytes reduced increases mmp-9 expression correlated myelination mouse corpus callosum postnatal development tissue inhibitors metalloproteinases 1 4 timp-1 4 make family secreted glycoproteins table 1 timps inhibit proteolytic activities mmps via formation tight noncovalent complexes 55 56 timps two domain proteins linked three disulfide bonds three disulfides per domain it appears timps bind mmps 1 1 ratio balance expression timps matches mmps the disruption timp mmp balance impacts cns ecm cell cell cell signaling for example timp-1 deficient mice fail acquire odor conditioned learning task suggesting dysfunction hippocampal neuronal plasticity subsequently elevated timp-1 mrna protein measured hippocampus seizure 61 62 kainate induced seizures also elevated mmp-9 mrna expression protein within hours this enhanced mmp-9 mrna expression seen dendritic layers neuronal cell bodies primarily within dentate gyrus these results interpreted suggest mmp-9 expression involved activity dependent remodeling via influencing synaptic connections shibayama et al others 45 65 shown following mechanical brain injury mmps particularly timps produced microglia astrocytes located cortex white matter may play role neural regeneration lack depending upon degree expression time since injury although understanding mechanism(s underlying functional remodeling synaptic pathways remains incomplete becoming clear reconfiguration involves alterations levels mmps timps long term potentiation originally discovered anesthetized rabbit preparation bliss lomo similar electrophysiological approach used confirm ltp unanesthetized rabbit a tetanization electrode placed perforant path recording electrode positioned dentate area excitatory post synaptic potentials could progressively enhanced short bursts electrical stimulation applied via perforant path electrode ltp thought represent basic physiological mechanism memory storage 6871 however others suggest may represent arousal attention mechanism investigators subsequent bliss colleagues demonstrated hippocampal ltp least part dependent upon intact n methyl aspartate nmda receptors 7375 the application nmda receptor antagonists shown prevent ltp interfere successful performance memory tasks mediated hippocampus 74 7678 however nmda independent ltp demonstrated number investigators see 72 79 reviews additional studies revealed activation calpain 8082 protein kinase c 83 84 calcium calmodulin kinase type 2 85 86 release ca intracellular storage pools also contribute hippocampal ltp further evidence ltp may dependent upon release sufficient gaba activate gabab autoreceptors turn prevents gaba release one form based nmda receptor system blocked nmda receptor antagonist mk-801 the type ltp dependent upon voltage dependent calcium channels vdcc blocked vdcc blocker verapamil nmda- vdcc ltp appear occur tetanus induced ltp further argument made functional nmda system mediate learning memory several hours however activation vdcc ltp system required longer periods several days hippocampal slice cultures taken mmp-9 knockout mice revealed impaired ltp restored addition recombinant mmp-9 this potential could inhibited blocking integrin signaling suggesting mmp-9 may mediate neural plasticity via integrins using prefrontal cortex slices okulski colleagues reported mmp-9 necessary late stage ltp treatment mmp-9 inhibitor prevented formation late stage ltp found spine enlargement hippocampal ltp dependent upon mmp-9 protein synthesis describing unilateral lesions entorhinal cortex rats followed intracerebroventricular icv infusion general mmp inhibitor fn-439 after 7 days control rats received icv saline following lesioning revealed normal collateral sprouting synaptogenesis ltp in contrast rats received icv fn-439 lost capacity exhibit ltp evidenced considerable cellular debris suggesting mmps necessary component deafferentiation sprouting phenomena laboratory also measured impaired paired pulse facilitation induction stability ltp long term depression ltd hippocampal slices treated fn-439 97 98 the schaffer collateral commissural projection stimulated field epsps recorded area ca1 striatum radiatum pressure infusion recombinant active mmp-9 rmmp-9 ca1 area produced slow progressive potentiation reaching maximum 90120 minutes post administration remained elevated experiment ended 180 minutes it determined enhancement synaptic potentiation presynaptic maximum potentiation mmp-9 achieved application tetanic stimulation failed increase potentiation the authors interpreted results indicate tetanic stimulation rmmp-9 activation share common cellular mechanism the intrahippocampal infusion mmp-2 -9 inhibitor followed titanic stimulation resulted strong potentiation comparable control ltp it determined titanic stimulation resulted elevated mmp-9 protein levels ca1 area thus results indicate mmp-9 mediated extracellular proteolysis involved phenomenon ltp normal young adult animals taken together findings support important role mmps ltp indicate particular mmp-9 necessary component supporting stabilization maintenance phase ltp nonassociative learning includes phenomena habituation dishabituation sensitization considered simplest form learning habituation is frequently studied refers decrease responding related frequency magnitude intensity stimulus repeatedly presented presented prolonged period time 99101 habituation documented across many species response systems ranging gill withdrawal reflex aplysia tap withdrawal chemotaxic response nematode caenorhabditis elegans acoustic startle response rats mice schedules reinforcement operant conditioning 105 106 feeding humans although neural mechanism(s underlying habituation identified hippocampus implicated control inhibitory processes particularly habituation 108110 support notion bilateral hippocampectomy rats shown interfere habituation familiar objects open field object recognition task 111 112 severely impair acquisition recall platform location morris water maze task failed alter habituatory pattern rate head shake response hsr the hsr consists rapid rotation head anterior posterior axis response mild air stimulus applied ear this response follows remarkably predictable decreasing negatively accelerated function stimulus frequency figure 2 our laboratory measured hsr habituation induced increases mmp-3 expression hippocampus prefrontal piriform cortices change cerebellum elevations hippocampal mmp-9 activity also measured habituated animals accompanied decreases prefrontal cortex surprise yoked control rats introduced test environment hsr habituated also revealed intermediate elevations mmp-3 expression hippocampus piriform cortices compared habituated home cage control rats these results suggested elevations mmp-3 could mediate changes neural plasticity may accompany habituation however introduction animal new environment also appeared elevate mmp-3 expression brain structures lesser extent these changes mmp-3 levels evidenced yoked control animals despite efforts minimize environmental cues i.e. low ambient light suppressed extraneous noise room painted black given acquisition spatial cues mediated hippocampal prefrontal cortices see 116 117 reviews perhaps surprising elevations mmp expression measured structures however habituation irrelevant spatial cues clearly important aspect successful performance associative learning task appears function hippocampus prefrontal cortex 108110 as outlined assumed neural activity dependent changes synaptic adhesion underlie morphological functional plasticity synapses involved learning memory 118 119 alterations intrasynaptic ecm molecules influenced cams presumed responsible alterations synaptic architecture thus efficiency synaptic transmission 120124 underlie neural plasticity memory consolidation 125 126 given mmps responsible degrading restructuring ecm surprising investigated regard seizure associative learning memory mmp-9 levels activity increase hippocampus following kainic acid- bicuculline induced seizures 63 127129 correlated subsequent synapse formation in addition mmps known play important role synaptic remodeling results hippocampal differentiation 130 131
our laboratory noted mmp-9 elevations prefrontal piriform cortices rats tested object recognition task prefrontal hippocampal cortices rats successful solving morris water maze task these results confirmed extended meighan et al noted significant elevations hippocampal mmp-3 -9 acquisition morris water maze task the inhibition mmp activity mmp-3 -9 antisense oligonucleotides fn-439 prevented successful performance task ability acquire spatial memory task was shown result differential stability cortactin actin binding protein involved regulating dendritic cytoskeleton synaptic efficiency nagy et al reported significant elevations hippocampal mmp-9 levels following inhibition avoidance learning rats peaking 1224 hours following training declining baseline three days post training intrahippocampal infusion mmp-2 -9 inhibitor 3.5 hours following inhibitory avoidance training significantly diminished subsequent recall similar results obtained bilateral intra hippocampal infusion fn-439 resulting significant interference acquisition morris water maze task olson et al measured elevations hippocampal mmp-3 beginning 1 hour following passive avoidance training rats returning baselevel 24 hours post training when specific mmp-3 inhibitor icv infused 20 minutes prior 50 minutes following training dose dependent learning deficits seen finally brown et al found icv infusion fn-439 30 minutes prior fear conditioning tone foot shock paired association 30 minutes prior single retest session 24 hours conditioning disrupted successful memory retrieval conditioned freezing place response this reduction freezing due decrease overall anxiety level given fn-439 failed influence normal elevated plus maze task performance recently combined hsr habituation classical conditioning paradigm evaluate importance signaling cue immediately preceded onset air stimulus ear bilateral dorsal hippocampus injections fn-439 specific mmp-3 inhibitor interfered acquisition association signaling tone hsr weak association present retested 24 hours later figure 3 these results suggest functioning dorsal hippocampus critical storage classically conditioned association signaling cue air stimulus ear initiates hsr specifically interference activation mmp-3 dorsal hippocampus appears significantly disrupt acquisition memory storage association
there accumulating evidence support notion mmp-3 -9 significant importance acquisition several forms associative learning including object recognition spatial passive avoidance classical conditioning learning memory appear intimately involved process drug addiction 137141 changes neuron morphology following drug addiction reported 142145 to date studies focused changes ecm molecules accompanying drug addiction see 146 147 reviews brown colleagues reported icv injection fn-439 suppressed acquisition cocaine induced conditioned place preference cpp rats this general mmp inhibitor also attenuated cocaine primed reinstatement extinguished animals agreement findings mash et al
have compared patterns gene expression human chronic cocaine abusers drug free control subjects the cocaine abusers revealed 151 gene transcripts regulated 91 regulated one regulated transcript reck membrane anchored mmp inhibitor associated angiogenesis ecm integrity these investigators speculated hippocampal ecm remodeling lack may characterize chronic cocaine abuse contribute relapse these researchers first indicate important role mmps acquisition reconsolidation memories associated cocaine addiction brown et al also suggested mmp inhibitors may useful disrupting established cocaine induced memory memory reconsolidation could suppressed most recently investigators shown mmp-9 increased prefrontal cortex following cocaine reinstatement cpp rats 150 151 used mmp-2 -9 inhibitor prevent methamphetamine induced cpp mice they showed mmp-2 -9 deficient mice displayed attenuated sensitization cocaine cpp methamphetamine primed liu et al reported stimulant toxic doses methamphetamine brain mmp-9 gene expression regulated within 5 minutes 24 hours mmp-9 up regulation returned control levels stimulant treated mice still elevated mice received higher toxic dose mmp-9 knockout mice capable evidencing methamphetamine induced neurotoxicity suggesting mmp-9 expression contributor neurotoxicity years ago sillanaukee et al compared serum mmp-9 levels middle age male alcoholics 1000 g week male social drinkers 200 g week attempt identify mechanism underlying alcohol induced cardiovascular disease these results important given recent evidence alcohol treatment increased mmp-1 -2 -9 activity decreased timp-1 -2 also increased blood brain barrier permeability these researchers suggested elevations mmp could responsible basement membrane degradation leading reduction barrier tightness our laboratory established relationship ethanol induced impairment spatial memory morris water maze task decreased mmp-9 levels hippocampus prefrontal cortex rats tested period several days presumably ethanol induced declines active mmp-9 levels attenuated formation new neural pathways thus interfering memory consolidation these findings suggest deviations brain mmp activity may prerequisite reconfiguration ecm molecules permit synaptic reconfiguration establishment new memories this appears hold memories associated support addictive drugs well this review brings together available information concerning hypothesis interaction among ecm molecules mmps cams timps permits formation new neural pathways brain these new synaptic connections stimulated experiences environments result learning acquisition memory consolidation thus memory consolidation presumably mediated made possible process neural plasticity however number research questions must addressed order important area research move forward ( 1 accumulating evidence ltp triggers synthesis release activation proteases particularly mmps much work completed hippocampus dentate gyrus entorhinal cortex ( 2 synaptic connections formed maintained protected degradation
( 3 following memory consolidation information retrieved without triggering synaptic reconfiguration 4 retrieval information process short term memory acquisition terminated new memory trace reconsolidated placed back fixed configuration 5 important environmental information appears temporarily stored hippocampus transferred brain structures long term storage are molecules ecm cams mmps timps involved transfer process ultimate storage location depend upon type learning and/or sensory systems involved 6 role neural plasticity drug addiction ? there many unanswered questions regarding influence drugs ltp stimulated mmp release activation equally important role timps ltp beyond issues there additional questions regarding influence drug addiction neural plasticity memory consolidation hippocampus neocortex amygdala well brain structures comprehensive answers related questions require significant effort available provide valuable clues concerning basic processes memory formation contribute understanding failures memory acquisition storage retrieval occur hopefully insight result clinical interventions designed correct deficiencies dysfunctional memory disease states also provide new treatment strategies preventing drug addiction relapse | the premise of this paper is that increased expression of matrix metalloproteinases ( mmps ) permits the reconfiguration of synaptic connections ( i.e. , neural plasticity ) by degrading cell adhesion molecules ( cams ) designed to provide stability to those extracellular matrix ( ecm ) proteins that form scaffolding supporting neurons and glia .
it is presumed that while these ecm proteins are weakened , and/or detached , synaptic connections can form resulting in new neural pathways .
tissue inhibitors of metalloproteinases ( timps ) are designed to deactivate mmps permitting the reestablishment of cams , thus returning the system to a reasonably fixed state .
this review considers available findings concerning the roles of mmps and timps in reorganizing ecm proteins thus facilitating the neural plasticity underlying long - term potentiation ( ltp ) , habituation , and associative learning .
we conclude with a consideration of the influence of these phenomena on drug addiction , given that these same processes may be instrumental in the formation of addiction and subsequent relapse
. however , our knowledge concerning the precise spatial and temporal relationships among the mechanisms of neural plasticity , habituation , associative learning , and memory consolidation is far from complete and the possibility that these phenomena mediate drug addiction is a new direction of research . |
place aluminum heat sink inside 22.96 cm 9 pie pan approximately 2 cm side pan shown figure 1c using black marker pen mark holes aluminum heat sink note aluminum block purchased local scrap metal shop online http://www.onlinemetals.com come pre drilled holes need arrange holes drilled countersunk prior step 1 secure aluminum block pie pan we used 5 holes secure block platform 4 extra holes allow nitrogen gas bubbles escape aluminum
place cryo grid box near location aluminum heat sink mark notch side drill pilot holes marked position using 17 drill bit aluminum heat sink holes 35 drill bit cryo grid box holes mount aluminum heat sink using 5 10 1.9 cm 3/4 flat head slotted bolts corresponding nuts well 15 10 washers place two washers beneath aluminum block third backside pie pan hole note unsecured overhangs aluminum block near viewing area result vibrations limit imaging capabilities stage insert 3 4 0.95 cm 3/8 round slotted bolts corresponding nuts backside pie pan act cryo grid box mount wet top bottom surface cake pie pans respectively ddh2o flip pans upside press cake pan spacers contact pie pan place weighted object atop cake pan let sit overnight cure serrated knife cut away excess dried insulating spray foam edge pans remove chopsticks remove cake pan pie pan pie pan aluminum heat sink is insulated referred cryogenic stage fig 1a place transparent plastic clipboard color greater 3 mm thick top cryogenic stage mark black marker location cryo grid box mount drawing circle approximately 1.5 times diameter single round cryo grid box this clipboard referred loading screen fig 1b put new transparent clipboard atop cryogenic stage place microscope heat sink directly objective lenses black marker cut along marked line removing half circle edge clipboard this accomplished jigsaw using 7.62 cm 3 hole saw multiple times shown video finally cut 1.9 cm 3/4 hole away half circle still within area dish port refilling liquid nitrogen ln2 levels drop imaging this clipboard referred viewing screen fig 1c dilute log phase yeast cells grown synthetic complete sc media appropriate concentration 1x10 cells ml water 2 ml diluted yeast pipetted onto r2/1 400 mesh holey carbon coated copper cryo em grid spi supplies west chester pa allowed adsorb 15 seconds blot away excess liquid grid surface touching back grid torn piece soft cellulose tissue kimwipe 2 seconds necessary grid washed 3 l drops water 1 3 times wicked away step 3 blotting back final wash sample is loaded pneumatic plunge freezer hanging grid washed step 2.4 after blotting grid torn tissue paper kimwipe remove majority water surface grid plunged ln2 cooled liquid ethane transferred cryo grid box storage note important leave layer liquid thin possible surface keep sample hydrated improper blotting either dry sample leave ice opaque electron beam fill cryogenic stage ln2 quickly cover loading screen plastic clipboard single 1.9 cm 3/4 hole once metal reaches ln2 temperature transfer cryo grid box 1.9 cm 3/4 hole loading screen transfer mount created 3 screws described part a5 unscrew cryo grid box holder remove holder improved access keep cryo grid box holder ln2 separate dewar step 3.10 the cryo grid box also kept ln2 prevent sample grid warming refill ln2 cryogenic stage top aluminum heat sink note ln2 levels must periodically checked refilled imaging process ensure ln2 continuously contact heat sink general refilling occurs every 10 minutes fill port viewing screen pre - cool tweezer tip ln2 transfer grid(s onto flat viewing surface aluminum heat sink tweezers using 1.9 cm 3/4 hole loading screen carefully move cryo stage beneath reflected light microscope objective apertures all air currents around microscope minimized including breathing nearby door opening people walking past etc we suggest wearing facemask hanging transparent face shield microscope eyepieces precautionary measure rotate objective lenses cold nitrogen gas environment cryo stage scan sample flat heat sink viewing area using standard bright field light microscopy techniques focus grid low magnification objective find center take overview image specifications regarding light microscopy lenses used experiment listed experimental materials section note ln2 come contact objective lenses yet see degradation images damage lenses effects cooling focus high magnification area interest acquire data bright field dark field polarized light fluorescence imaging be sure record location area interest low magnification bright field image future correlation precautions listed refilling ln2 followed positive pressure evaporating nitrogen sufficient maintain contamination free environment independent room humidity duration imaging once finished replace loading screen sliding top viewing screen remove cryo stage microscope pre cooled tweezers transfer grid back cryo grid box screw cryo grid box holder cryo grid box seal environment transfer holder ln2 dewar storage future imaging following standard established techniques load sample grid cryo em transfer holder keeping specimen liquid nitrogen temperature times insert cryo holder sample grid transmission electron microscope suitable low magnification view 50 500x nominal magnification find center sample grid use previously collected low magnification cryo lm data step 3.7 determine relative orientation grid central copper tabs described figure 2 and identify exact areas interest correlation proceed microscope alignment low dose cryo em imaging data collection cryogenic stage fig 1a ) is effective way gather cryo lm data cryo fluorescence microscopy correlative cryo lm cryo em analysis figure 2 shows combination low high magnification cryo lm images allows build reference maps direct specific areas cryo em resulting cryo lm reference map fig 2b utilized cryo em data acquisition locate exact regions shown figure 3
a layout cryogenic stage consists cryo grid box transfer mount indicated white arrow aluminum heat sink grids transferred ln2 cryo grid box placed directly heat sink viewing area indicated black arrow the hole loading screen placed directly cryo grid box mount acts port transfer samples moving samples cryo grid box sample viewing area heat sink tweezers c cryogenic stage position objective lenses viewing screen place the special cutout viewing screen allows objective lenses easily swing position without moving cryogenic stage the hole viewing screen away sample area acts ln2 fill port replenish ln2 levels necessary b image overlaid high magnification fluorescence image area interest filled orange polygon marking center sample grid the center consists group four squares three extra metal tab forth open for three squares extra metal tab two pairs share tab long short axes forming asymmetric center this asymmetric center seen upper left corner used indicate rotation angle handedness grid cryo lm cryo em from one low magnification image many areas interest marked used reference map locate identical areas cryo em c magnified fluorescence cryo lm image area interest b hta1-cfp c terminal cfp histone marker seen green punctate structure labeling location nucleus d cryo em image corresponding area c two fields view depicting identical yeast cells correlated cryo bright field cryo fluorescence b e cryo em c f place aluminum heat sink inside 22.96 cm 9 pie pan approximately 2 cm side pan shown figure 1c using black marker pen mark holes aluminum heat sink note aluminum block purchased local scrap metal shop online http://www.onlinemetals.com come pre drilled holes need arrange holes drilled countersunk prior step 1 secure aluminum block pie pan we used 5 holes secure block platform 4 extra holes allow nitrogen gas bubbles escape aluminum
place cryo grid box near location aluminum heat sink mark notch side drill pilot holes marked position using 17 drill bit aluminum heat sink holes 35 drill bit cryo grid box holes mount aluminum heat sink using 5 10 1.9 cm 3/4 flat head slotted bolts corresponding nuts well 15 10 washers place two washers beneath aluminum block third backside pie pan hole note unsecured overhangs aluminum block near viewing area result vibrations limit imaging capabilities stage insert 3 4 0.95 cm 3/8 round slotted bolts corresponding nuts backside pie pan act cryo grid box mount wet top bottom surface cake pie pans respectively ddh2o flip pans upside press cake pan spacers contact pie pan place weighted object atop cake pan let sit overnight cure serrated knife cut away excess dried insulating spray foam edge pans remove chopsticks remove cake pan pie pan pie pan aluminum heat sink is insulated referred cryogenic stage fig 1a place transparent plastic clipboard color greater 3 mm thick top cryogenic stage mark black marker location cryo grid box mount drawing circle approximately 1.5 times diameter single round cryo grid box this clipboard referred loading screen fig 1b put new transparent clipboard atop cryogenic stage place microscope heat sink directly objective lenses black marker cut along marked line removing half circle edge clipboard this accomplished jigsaw using 7.62 cm 3 hole saw multiple times shown video finally cut 1.9 cm 3/4 hole away half circle still within area dish port refilling liquid nitrogen ln2 levels drop imaging this clipboard referred viewing screen fig 1c dilute log phase yeast cells grown synthetic complete sc media appropriate concentration 1x10 cells ml water 2 ml diluted yeast pipetted onto r2/1 400 mesh holey carbon coated copper cryo em grid spi supplies west chester pa allowed adsorb 15 seconds blot away excess liquid grid surface touching back grid torn piece soft cellulose tissue kimwipe 2 seconds necessary grid washed 3 l drops water 1 3 times wicked away step 3 blotting back final wash sample loaded pneumatic plunge freezer hanging grid washed step 2.4 after blotting grid torn tissue paper kimwipe remove majority water surface grid plunged ln2 cooled liquid ethane transferred cryo grid box storage note important leave layer liquid thin possible surface keep sample hydrated improper blotting either dry sample leave ice opaque electron beam fill cryogenic stage ln2 quickly cover loading screen plastic clipboard single 1.9 cm 3/4 hole once metal reaches ln2 temperature transfer cryo grid box 1.9 cm 3/4 hole loading screen transfer mount created 3 screws described part a5 unscrew cryo grid box holder remove holder improved access keep cryo grid box holder ln2 separate dewar step 3.10 the cryo grid box also kept ln2 prevent sample grid warming refill ln2 cryogenic stage top aluminum heat sink note ln2 levels must periodically checked refilled imaging process ensure ln2 continuously contact heat sink general refilling occurs every 10 minutes fill port viewing screen pre - cool tweezer tip ln2 transfer grid(s onto flat viewing surface aluminum heat sink tweezers using 1.9 cm 3/4 hole loading screen carefully move cryo stage beneath reflected light microscope objective apertures all air currents around microscope minimized including breathing nearby door opening people walking past etc we suggest wearing facemask hanging transparent face shield microscope eyepieces precautionary measure rotate objective lenses cold nitrogen gas environment cryo stage scan sample flat heat sink viewing area using standard bright field light microscopy techniques focus grid low magnification objective find center take overview image specifications regarding light microscopy lenses used experiment listed experimental materials section note ln2 come contact objective lenses yet see degradation images damage lenses effects cooling focus high magnification area interest acquire data bright field dark field polarized light fluorescence imaging be sure record location area interest low magnification bright field image future correlation if precautions listed refilling ln2 followed positive pressure evaporating nitrogen sufficient maintain contamination free environment independent room humidity duration imaging once finished replace loading screen sliding top viewing screen remove viewing screen slowing sliding beneath loading screen remove cryo stage microscope pre cooled tweezers transfer grid back cryo grid box screw cryo grid box holder cryo grid box seal environment transfer holder ln2 dewar storage future imaging following standard established techniques load sample grid cryo em transfer holder keeping specimen liquid nitrogen temperature times insert cryo holder sample grid transmission electron microscope suitable low magnification view 50 500x nominal magnification find center sample grid use previously collected low magnification cryo lm data step 3.7 determine relative orientation grid central copper tabs described figure 2 identify exact areas interest correlation proceed microscope alignment low dose cryo em imaging data collection the cryogenic stage fig 1a effective way gather cryo lm data cryo fluorescence microscopy correlative cryo lm cryo em analysis figure 2 shows combination low high magnification cryo lm images allows build reference maps direct specific areas cryo em resulting cryo lm reference map fig 2b utilized cryo em data acquisition locate exact regions shown figure 3
a layout cryogenic stage consists cryo grid box transfer mount indicated white arrow aluminum heat sink grids transferred ln2 cryo grid box placed directly heat sink viewing area indicated black arrow the hole loading screen placed directly cryo grid box mount acts port transfer samples moving samples cryo grid box sample viewing area heat sink tweezers c cryogenic stage position objective lenses viewing screen place special cutout viewing screen allows objective lenses easily swing position without moving cryogenic stage the hole viewing screen away sample area acts ln2 fill port replenish ln2 levels necessary b image overlaid high magnification fluorescence image area interest filled orange polygon marking center sample grid the center consists group four squares three extra metal tab forth open for three squares extra metal tab two pairs share tab long short axes forming asymmetric center this asymmetric center seen upper left corner used indicate rotation angle handedness grid cryo lm cryo em from one low magnification image many areas interest marked used reference map locate identical areas cryo em c magnified fluorescence cryo lm image area interest b hta1-cfp c terminal cfp histone marker seen green punctate structure labeling location nucleus d cryo em image corresponding area c two fields view depicting identical yeast cells correlated cryo bright field cryo fluorescence b e cryo em c f using cryogenic stage sample preparation techniques correlative studies cryo lm cryo em exhibit several benefits traditional room temperature approaches including limited rapid fixation reduced photobleaching scanning sample integrity prior cryo em chemical fixation embedding one bottlenecks cryo em data collection time required transferring sample tem scanning grid find suitable regions image with cryo lm rapid data acquisition time spent finding good cells greatly reduced thus save time money mitigate bottleneck pre scanning mapping areas interest cryo lm expensive complex if cryo lm imaging sample grid transfers performed caution described text video fully contamination free imaging accomplished this method allows direct correlation fluorescent electron microscopy data cell organelle macromolecular complex dispersed carbon support contained within thin tissue section it noted value cryogenic stage extends beyond cryo lm cryo em correlative studies field light microscopy whole this cryogenic stage well suited delicate samples fluorophore dyes stains quantum dots fluorescently tagged proteins may unstable room temperature chemical fixation embedding glutaraldehyde paraformaldehyde result hope cryogenic stage provide greater access interested cryo lm previously deterred cost insufficient access
. may find necessary use types support grids continuous carbon holey carbon formvar coated grids sample support additionally sample binding copper bars grid carbon surface may necessary adjust carbon surface chemistry incubating grid wetting agent glow discharging prior sample addition stage stability notice vibration likely due sample stage overloaded weight rather bubbling ln2 the added weight cryogenic stage sometimes cause low frequency vibrations transmit along standard 3-axis travel microscope stage negatively affect imaging via blurring this easily corrected supporting microscope travel stage underneath either adjustable mini lift adjustable adapter dual screw arms shown video both adjustable support mechanisms interact non moveable portion travel stage therefore still permits x axis translation required imaging | the coupling of cryo - light microscopy ( cryo - lm ) and cryo - electron microscopy ( cryo - em ) poses a number of advantages for understanding cellular dynamics and ultrastructure .
first , cells can be imaged in a near native environment for both techniques .
second , due to the vitrification process , samples are preserved by rapid physical immobilization rather than slow chemical fixation .
third , imaging the same sample with both cryo - lm and cryo - em provides correlation of data from a single cell , rather than a comparison of " representative samples " .
while these benefits are well known from prior studies , the widespread use of correlative cryo - lm and cryo - em remains limited due to the expense and complexity of buying or building a suitable cryogenic light microscopy stage .
here we demonstrate the assembly , and use of an inexpensive cryogenic stage that can be fabricated in any lab for less than $ 40 with parts found at local hardware and grocery stores .
this cryo - lm stage is designed for use with reflected light microscopes that are fitted with long working distance air objectives . for correlative cryo - lm and cryo - em studies ,
we adapt the use of carbon coated standard 3-mm cryo - em grids as specimen supports .
after adsorbing the sample to the grid , previously established protocols for vitrifying the sample and transferring / handling the grid are followed to permit multi - technique imaging . as a result , this setup allows any laboratory with a reflected light microscope to have access to direct correlative imaging of frozen hydrated samples . |
chronic obstructive pulmonary disease copd common problem elderly major cause chronic morbidity mortality throughout world.1 characterized chronic obstruction expiratory flow affecting peripheral airways often associated chronic bronchitis emphysema thereby accelerating decline lung function.2,3 previous studies found nutritional status prognostic factor associated mortality copd.46 weight loss major characteristic malnutrition copd.7 2002 nutritional risk defined european society parenteral enteral nutrition espen).8 recently nutritional risk found associated exacerbation copd patients hospitalized copd.9 meanwhile reported nutritional risk related development copd male smokers.10 addition exercise capacity also another factor related mortality copd.11 limitation exercise capacity seriously affects quality life copd patients.12 therefore many studies aimed strategies improving exercise capacity copd patients.13,14 however effective feasible strategy still needs exploration it reported nutritional status could affect exercise capacity copd patients.15,16 moreover nutritional supply seems contribute improving exercise capacity.15,17 view findings speculated might relationship nutritional risk exercise capacity therefore explored relationship severe copd male patients study could provide evidence effect nutritional supply exercise capacity between january 2012 december 2013 total 58 severe copd male patients age range 4778 years hospitalized department respiratory medicine shanghai pulmonary hospital affiliated tongji university enrolled present study all patients diagnosed severe copd forced expiratory volume 1 second percentage predicted fev1%pred 50 according new global initiative chronic obstructive lung disease gold classification criteria 2012.18 patients excluded diseases organs cardiovascular renal endocrine digestive nervous systems patients provided written informed consent inclusion nutritional risk assessment height weight kg patients measured body mass index bmi calculated according formula bmi weight height squared kg nutritional risk assessment conducted using continuous sampling method according nutritional risk screening nrs 2002 criteria developed espen.19 nrs score 07 sum scores disease severity nutritional status age the nutritional status patient scored based changes body weight bmi recent 13 months food intake recent 1 week besides one score assigned patients 70 years old according nrs score patients divided two groups nutritional risk group nrs score 3 nutritional risk group nrs score 3 blood samples collected right forearm radial artery conventional pulmonary function testing pft cardiopulmonary exercise testing cpet performed blood gas analysis performed confirm whether partial pressure oxygen artery pao2 partial pressure carbon dioxide artery paco2 normal range pao2 80100 mmhg paco2 3545 mmhg using abl 800 flex blood gas analyzer radiometer medical copenhagen denmark a master screen diffusion system jaeger corp hoechberg germany used pft prediction equations normal lung function developed 1988 used assessment.20 following parameters detected testing forced vital capacity fvc forced expiratory volume 1 second fev1 fev1%pred fev1/fvc ratio residual volume rv total lung capacity tlc rv tlc pulmonary diffusing capacity carbon monoxide dlco pft performed three times patient best result chosen analysis cpet performed using cardiopulmonary exercise testing system mastercreen cpx jaeger corp cpet performed the flow sensors gas analyzers strictly calibrated testing symptom limited incremental exercise test performed different loads 1025 w min based conditions patients.21 testing indicators consisting 12-lead electrocardiogram ecg blood pressure pulse oximetry pulmonary ventilation gas exchange oxygen carbon dioxide real time breath breath analysis anaerobic threshold v slope analysis monitored afterward exercise without load performed 3 minutes load gradually increased symptoms leg pain exhaustion difficulty breathing occurred addition testing would stopped one following conditions occurred 1 2 mm st segment depression chest pain 3 mm st segment without chest pain 2 frequent ventricular premature beat 3 second- third degree atrioventricular block 4 systolic blood pressure 250 mmhg diastolic blood pressure 120 mmhg 5 decreased blood pressure 30 mmhg compared baseline level 6 pulse oxygen saturation 80% the prediction value cept calculated according american thoracic society american college chest physicians statement cpet 2003.22,23 testing following data recorded peak load peak vo2 peak oxygen uptake peak vo2%pred peak oxygen uptake percentage predicted peak vo2/kg peak oxygen uptake per kilogram body mass peak o2 pulse peak oxygen pulse the correlations nrs score peak vo2 peak o2 pulse peak load determined using pearson correlation analysis between january 2012 december 2013 total 58 severe copd male patients age range 4778 years hospitalized department respiratory medicine shanghai pulmonary hospital affiliated tongji university enrolled present study all patients diagnosed severe copd forced expiratory volume 1 second percentage predicted fev1%pred 50 according new global initiative chronic obstructive lung disease gold classification criteria 2012.18 patients excluded diseases organs cardiovascular renal endocrine digestive nervous systems before nutritional risk assessment height weight kg patients measured body mass index bmi calculated according formula bmi weight height squared kg nutritional risk assessment conducted using continuous sampling method according nutritional risk screening nrs 2002 criteria developed espen.19 nrs score 07 sum scores disease severity nutritional status age the nutritional status patient scored based changes body weight bmi recent 13 months food intake recent 1 week besides one score assigned patients 70 years old according nrs score patients divided two groups nutritional risk group nrs score 3 nutritional risk group nrs score 3 blood samples collected right forearm radial artery conventional pulmonary function testing pft cardiopulmonary exercise testing cpet performed blood gas analysis performed confirm whether partial pressure oxygen artery pao2 partial pressure carbon dioxide artery paco2 normal range pao2 80100 mmhg paco2 3545 mmhg using abl 800 flex blood gas analyzer radiometer medical copenhagen denmark prediction equations normal lung function developed 1988 used assessment.20 following parameters detected testing forced vital capacity fvc forced expiratory volume 1 second fev1 fev1%pred fev1/fvc ratio residual volume rv total lung capacity tlc rv tlc pulmonary diffusing capacity carbon monoxide dlco pft performed three times patient best result chosen analysis cpet performed using cardiopulmonary exercise testing system mastercreen cpx jaeger corp cpet performed the flow sensors gas analyzers strictly calibrated testing symptom limited incremental exercise test performed different loads 1025 w min based conditions patients.21 testing indicators consisting 12-lead electrocardiogram ecg blood pressure pulse oximetry pulmonary ventilation gas exchange oxygen carbon dioxide real time breath breath analysis anaerobic threshold v slope analysis monitored afterward exercise without load performed 3 minutes load gradually increased symptoms leg pain exhaustion difficulty breathing occurred addition testing would stopped one following conditions occurred 1 2 mm st segment depression chest pain 3 mm st segment without chest pain 2 frequent ventricular premature beat 3 second- third degree atrioventricular block 4 systolic blood pressure 250 mmhg diastolic blood pressure 120 mmhg 5 decreased blood pressure 30 mmhg compared baseline level 6 pulse oxygen saturation 80% prediction value cept was calculated according american thoracic society american college chest physicians statement cpet 2003.22,23 testing following data recorded peak load peak vo2 peak oxygen uptake peak vo2%pred peak oxygen uptake percentage predicted peak vo2/kg peak oxygen uptake per kilogram body mass peak o2 pulse peak oxygen pulse the correlations nrs score peak vo2 peak o2 pulse peak load determined using pearson correlation analysis among total 58 severe copd male patients 25 assessed nutritional risk assigned nutritional risk group the 33 patients without nutritional risk enrolled nutritional risk group age nutritional risk group 63.739.03 years nutritional risk group 61.527.13 years p=0.319 height nutritional risk group 166.526.10 cm nutritional risk group 167.125.83 cm p=0.707 patients nutritional risk group similar nutritional risk group however weight nutritional risk group 64.586.31 kg nutritional risk group 51.244.68 kg p<0.0001 bmi nutritional risk group 23.302.02 kg nutritional risk group 18.341.33 kg p<0.0001 patients nutritional risk group significantly lower nutritional risk group table 1 exercise statistically significant difference pao2 nutritional risk group 73.3010.71 nutritional risk group 73.6813.00 p=0.903 paco2 nutritional risk group 42.856.82 nutritional risk group 41.957.84 p=0.643 severe copd male patients without nutritional risk table 2 there significant difference severe copd male patients without nutritional risk fvc nutritional risk group 2.260.53 nutritional risk group 2.290.67 p=0.850 fev1 nutritional risk group 0.860.25 nutritional risk group 0.800.23 p=0.353 fev1%pred nutritional risk group 32.408.47 nutritional risk group 29.008.97 p=0.146 fev1/fvc nutritional risk group 37.925.34 nutritional risk group 36.398.47 p=0.433 tlc nutritional risk group 7.891.39 nutritional risk group 7.801.93 p=0.844 rv nutritional risk group 5.661.31 nutritional risk group 5.662.12 p=1.000 rv tlc nutritional risk group 71.286.53 nutritional risk group 71.4011.01 p=0.962 nevertheless dlco nutritional risk group 11.984.02 nutritional risk group 8.974.37 p=0.009 patients nutritional risk group significantly higher patients nutritional risk group shown table 4 the severe copd male patients nutritional risk group significantly higher peak vo2 nutritional risk group 1,068.33327.38 nutritional risk group 871.24219.37 p=0.008 peak vo2%pred nutritional risk group 60.2717.13 nutritional risk group 52.0412.64 p=0.048 peak o2 pulse nutritional risk group 8.802.37 nutritional risk group 7.321.47 p=0.008 nutritional risk group but significant difference groups peak load nutritional risk group 61.2130.04 nutritional risk group 49.4820.82 p=0.100 peak vo2/kg nutritional risk group 16.574.61 nutritional risk group 16.923.50 p=0.753 figure 1 shows correlation nrs score peak vo2 peak o2 pulse peak load the results show significant negative correlations nrs score peak vo2 r=0.353 p<0.01 peak o2 pulse r=0.322 p<0.05 peak load r=0.272 p<0.05 severe copd male patients among total 58 severe copd male patients 25 assessed nutritional risk assigned nutritional risk group the 33 patients without nutritional risk enrolled nutritional risk group the age nutritional risk group 63.739.03 years nutritional risk group 61.527.13 years p=0.319 height nutritional risk group 166.526.10 cm nutritional risk group 167.125.83 cm p=0.707 patients nutritional risk group similar nutritional risk group however weight nutritional risk group 64.586.31 kg nutritional risk group 51.244.68 kg p<0.0001 bmi nutritional risk group 23.302.02 kg nutritional risk group 18.341.33 kg p<0.0001 patients nutritional risk group significantly lower nutritional risk group table 1 before exercise statistically significant difference pao2 nutritional risk group 73.3010.71 nutritional risk group 73.6813.00 p=0.903 paco2 nutritional risk group 42.856.82 nutritional risk group 41.957.84 p=0.643 severe copd male patients without nutritional risk table 2 there significant difference severe copd male patients without nutritional risk fvc nutritional risk group 2.260.53 nutritional risk group 2.290.67 p=0.850 fev1 nutritional risk group 0.860.25 nutritional risk group 0.800.23 p=0.353 fev1%pred nutritional risk group 32.408.47 nutritional risk group 29.008.97 p=0.146 fev1/fvc nutritional risk group 37.925.34 nutritional risk group 36.398.47 p=0.433 tlc nutritional risk group 7.891.39 nutritional risk group 7.801.93 p=0.844 rv nutritional risk group 5.661.31 nutritional risk group 5.662.12 p=1.000 rv tlc nutritional risk group 71.286.53 nutritional risk group 71.4011.01 p=0.962 nevertheless dlco nutritional risk group 11.984.02 nutritional risk group 8.974.37 p=0.009 patients nutritional risk group significantly higher patients nutritional risk group as shown table 4 severe copd male patients nutritional risk group significantly higher peak vo2 nutritional risk group 1,068.33327.38 nutritional risk group 871.24219.37 p=0.008 peak vo2%pred nutritional risk group 60.2717.13 nutritional risk group 52.0412.64 p=0.048 peak o2 pulse nutritional risk group 8.802.37 nutritional risk group 7.321.47 p=0.008 nutritional risk group but significant difference groups peak load nutritional risk group 61.2130.04 nutritional risk group 49.4820.82 p=0.100 peak vo2/kg nutritional risk group 16.574.61 nutritional risk group 16.923.50 p=0.753 figure 1 shows correlation nrs score peak vo2 peak o2 pulse peak load the results show significant negative correlations nrs score peak vo2 r=0.353 p<0.01 peak o2 pulse r=0.322 p<0.05 peak load r=0.272 p<0.05 severe copd male patients lack exercise capacity limits quality life copd patients.12 previous studies found association nutritional status exercise capacity copd patients.15,16 however still unclear whether correlation exists nutritional risk exercise capacity copd patients therefore investigated relationship nutritional risk exercise capacity severe copd male patients study found significantly lower weight bmi severe copd male patients nutritional risk compared severe copd male patients without nutritional risk characteristics copd patients nutritional risk.2426 besides pft showed dlco severe copd male patients without nutritional risk significantly higher severe copd male patients nutritional risk it reported reduced dlco could impair exercise capacity patients heart failure increased dead space ventilation.27 meanwhile low dlco could impair oxygen transport reduction maximum oxygen consumption.28 moreover reported weakened exercise capacity attributed reduced locomotor muscle oxygen transport.29,30 normally oxygen transport would adaptively vary oxygen demand exercise,31,32 oxygen uptake would increase exercise biochemical adaptations.33,34 thus exercise capacity decline impaired oxygen transport adaptively regulate oxygen uptake exercise expected impaired oxygen transport might limit oxygen uptake severe copd male patients nutritional risk seen study cpet showed peak vo2 peak o2 pulse nutritional risk group significantly lower nutritional risk group significant negative correlations nrs score peak vo2 peak o2 pulse these results indicate oxygen uptake severe copd male patients nutritional risk significantly lower severe copd male patients without nutritional risk might due impaired oxygen transport copd,33,35 thereby affecting utilization oxygen.36 reported inadequate oxygen supply exercise caused accumulation oxygen deficit responsible reduced exercise capacity patients copd.37,38 meanwhile decreased muscle oxygen utilization could reduce exercise capacity patients copd.39 thus impaired oxygen transport may main reason reduced exercise capacity copd patients nutritional risk in addition reported nutritional depletion related respiratory peripheral skeletal muscle function outpatients copd.40,41 nutritional supplements found useful prevention treatment exercise induced skeletal muscle injury.42 moreover muscle function associated oxygen transport.4345 thus patients nutritional risk may decreased exercise capacity due impaired oxygen transport given facts may close relationship nutritional risk exercise capacity furthermore blood gas analysis indicated pao2 paco2 patients normal ranges exercise similar groups however pao2 paco2 measured exercise the changes induced exercise oxygen co2 pressure arterial blood could assessed further studies required investigate whether nutritional risk could affect changes induced exercise oxygen co2 pressures arterial blood second assessed total weight fat free mass studies required in addition indicators pft cept found associated nutritional risk thus relationship nutritional risk exercise capacity investigated female patients also studies large sample sizes verifying result study the results study supported association exercise capacity nutritional risk according nrs 2002 severe copd male patients impairment oxygen transport may main mechanism relationship nutritional risk exercise capacity | objectivethe nutritional status of chronic obstructive pulmonary disease ( copd ) patients is associated with their exercise capacity . in the present study , we have explored the relationship between nutritional risk and exercise capacity in severe male copd patients.methodsa total of 58 severe copd male patients were enrolled in this study .
the patients were assigned to no nutritional risk group ( n=33 ) and nutritional risk group ( n=25 ) according to the nutritional risk screening ( nrs , 2002 ) criteria .
blood gas analysis , conventional pulmonary function testing , and cardiopulmonary exercise testing were performed on all the patients.resultsresults showed that the weight and bmi of the patients in the nutritional risk group were significantly lower than in the no nutritional risk group ( p<0.05 ) .
the pulmonary diffusing capacity for carbon monoxide of the no nutritional risk group was significantly higher than that of the nutritional risk group ( p<0.05 ) .
besides , the peak vo2 ( peak oxygen uptake ) , peak o2 pulse ( peak oxygen pulse ) , and peak load of the nutritional risk group were significantly lower than those of the no nutritional risk group ( p<0.05 ) and there were significantly negative correlations between the nrs score and peak vo2 , peak o2 pulse , or peak load ( r<0 , p<0.05).conclusionthe association between exercise capacity and nutritional risk based on nrs 2002 in severe copd male patients is supported by these results of this study . |
in exposure or risk assessments , both environmental and biological measurements are often used .
environmental measurements are an excellent means for evaluating regulatory compliance , but the models used to estimate body burden from these measurements are complex .
unless all possible routes of exposure ( i.e. , inhalation , dermal absorption , ingestion ) are evaluated , exposure to a toxicant can be underestimated . to circumvent this problem ,
measurements of the internal dose of a toxicant in blood , serum , urine , or tissues can be used singularly or in combination with environmental data for exposure assessment . in three separate laboratories , carbaryl or its primary metabolite , 1-naphthol , was measured in personal air , dermal samples , blood serum , and urine from farmer applicators and their families .
the usefulness of both environmental and biological data has been demonstrated .
for the farmer applicator , the environmental levels of carbaryl would have been sufficient to determine that an exposure had occurred . however , biological measurements were necessary to determine the absorbed dose of each member of the applicator 's family .
in addition , a correlation between serum and urinary 1-naphthol measurements has been shown ; therefore , either matrix can be used to accurately evaluate occupational carbaryl exposure.imagesfigure 1.figure 2.figure 3.figure 4.figure 5 .
afigure 5 .
b |
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fundamental concepts psychology philosophy mind notion sensation perception stimulus produces effect different sensory receptors induces sensation subsequent interpretation organization sensory stimulus produce meaningful experience world one perception although cases perception conscious perception without awareness exist interpretation semantic stimuli normally wakefulness awareness related one awake certain level consciousness aware something content consciousness states deep sleep anesthesia coma there little wakefulness hence awareness drowsiness light sleep however certain states dissociations exist wakefulness awareness vegetative state wakefulness presumably without awareness eyes open brain shut dream state there awareness content consciousness decreased wakefulness level consciousness dreams succession images ideas emotions perceptions without sensations occur involuntarily mind predominantly rapid eye movement rem sleep nonpulsatile subjective tinnitus considered phantom perception conscious awareness percept absence external stimulus it characterized perception phantom sound comes external sound source even though sound might pulled memory 1 6 7 this reminiscent dream state awareness stimuli attributed external world generated internally whereas tinnitus considered simple phantom percept dreams could considered complex phantom percepts like hallucinations hallucinosis 9 10 however contrast hallucinations hallucinosis occur wakefulness dreams occur certain stages sleep stimulus evoked auditory cortical activation necessarily produce conscious auditory perception auditory perception possible absence auditory input 80% people normal hearing perceive phantom sounds placed soundproof room likewise limb amputation almost people experience phantom limb whereas 70% suffer severe phantom pain a clear clinical analogy exists phantom pain disabling tinnitus 1 14 15 there also parallels pathophysiology tinnitus pain well treatment 16 17 however also differences tinnitus pain physiological pain mediated via nociceptive pathways this could explain commonly available analgesics suppress acute physiological body pain inefficient ameliorating tinnitus also medications antiepileptics antidepressants effective treatment neuropathic pain tend ineffective tinnitus many 33100% patients suffer phantom limb percepts experience phantom limb percepts dream state 2023 this explained follows 8 21 23 neural representation body derives sensory proprioceptive feedback body sleep when brain mind actively kept offline sensory feedback lacking moreover rem sleep absence external inputs dreaming could activate set innate early life spatial temporal categories so rem sleep state protoconsciousness contextually emergent property self sustaining systems self appears rem sleep dreams longer affected waking experiences feeds embodied functionally intact body scheme 8 21 view pathophysiological analogy tinnitus pain hypothesized tinnitus absent dream state well we therefore explored group 78 consecutive tinnitus patients attending multidisciplinary tinnitus research initiative clinic university antwerp a recently proposed pathophysiological model phantom sound based predictive brain concept bayesian updating might explain tinnitus perceived dreaming seventy eight patients 57 males 21 females chronic nonpulsatile tinnitus included study average age 48.78 years sd 12.87 average tinnitus duration 5.74 years sd 6.96 thirty five patients perceive noise like tinnitus 43 patients experience pure tone tinnitus forty three patients bilateral tinnitus 12 patients perceive tinnitus holocranially 12 left side 11 right side the first question asked whether tinnitus patient recalled dreamed night 1 followed question whether dreams perceive tinnitus 2 of 78 participating patients 2 2.56% declared recall dreams 76 97.44% of 76 patients recall dreams 74 97.73% state perceive tinnitus dreaming aware tinnitus sleep people tinnitus perceive tinnitus dreams analogous reported many phantom limb perceptions 21 25 dreams wakefulness associated awareness one state awareness tinnitus dreams whereas wakefulness tinnitus the reason patients tinnitus perceive tinnitus dream state theoretically explained bayesian brain model used explanation development tinnitus relation auditory deafferentation this bayesian brain model founded extension predictive brain model see figure 1(a whereas models see overview explain tinnitus presence deafferentation the bayesian model compatible deafferentation noise cancelling models provides rationale tinnitus develops wake state dream state physiologically brain conceptualized helmholtz machine constantly makes one possibly multiple predictions world since examples given learner unlabeled error reward signal evaluate potential solution words updating predictions a bayesian brain however updates predictions based actively explores environment means senses 24 29 30 bayesian inference therefore conceptualized way would familiar john hughlings jackson using sensory information environment update memory based expectations held acquiring sensory inputs produce posterior beliefs represented percepts this mechanism permits decision making based predictions updated actively sampling environment confirmation rejection expectations see figure 1(b auditory deafferentation limits amount information brain acquire make sense world the topographically specific deafferentation induces topographically specific prediction error hypothetically based temporal incongruity words inconsistent stored memory updated the model hypothesizes deprived auditory information depends amount bandwidth deafferented auditory channels limited damage auditory receptors causes loss functional surround inhibition cortex unmasking latent inputs significantly altered neural coding this suggests missing information obtained via access overlapping tuning curves neighboring cortical cells if deafferentation somewhat larger widening auditory receptive fields permit pulling missing information auditory cortical neighborhood if insufficient due still larger deafferentation dendritic axonal rewiring occur if still insufficient missing auditory information pulled para)hippocampal memory when dream create image world entirely detached sensory feedback updated aminergic activity highest waking declines nrem sleep lowest rem sleep this means discrepancy top predictions absence sensory signals received registered auditory deafferentation filled resulting absence tinnitus dream state see figures 2(a 2(b it argued cerebellum involved motor sensory cognitive predictions it therefore possible auditory predictions made paraflocculus removing cerebellar structure prevent tinnitus arising arrest presence tinnitus animals this conceptually suggests removing prediction prevent abolish tinnitus accordance concept tinnitus could malprediction however apart theoretical implications data might also help find neural correlates tinnitus the putative switch tinnitus found areas differ waking rem state ventrolateral prefrontal cortex frontopolar inferior parietal cerebellar parahippocampal network these areas overlap recent meta analysis pet studies tinnitus provide framework zooming pathophysiology enigmatic symptom in addition evident benefit tinnitus research could also provide clues consciousness research delineating core areas involved neural correlates consciousness minimal assembly brain areas required consciousness per se 38 39 other potential explanations absence tinnitus dream state considered it possible dream state attention shift tinnitus dream analogous noted patients perceive tinnitus intensely engaged task conclusion report demonstrates tinnitus perception switched dream sleep even though awareness like wakefulness this suggests theoretically possible find neural correlates phantom sound thereby find potential avenue suppressing enigmatic symptom | there are pathophysiological , clinical , and treatment analogies between phantom limb pain and phantom sound ( i.e. , tinnitus ) .
phantom limb pain commonly is absent in dreams , and the question arises whether this is also the case for tinnitus .
a questionnaire was given to 78 consecutive tinnitus patients seen at a specialized tinnitus clinic .
seventy - six patients remembered their dreams and of these 74 claim not to perceive tinnitus during their dreams ( 97% ) .
this can be most easily explained by a predictive bayesian brain model .
that is , during the awake state the brain constantly makes predictions about the environment .
tinnitus is hypothesized to be the result of a prediction error due to deafferentation , and missing input is filled in by the brain .
the heuristic explanation then is that in the dream state there is no interaction with the environment and therefore no updating of the prediction error , resulting in the absence of tinnitus . |
atlantoaxial instability aai may caused trauma arthritis tumor infection congenital malformation316 atlantoaxial stabilization resulted bony fusion needed correct deformities prevent neurological impairment the surgical method c1 2 transarticular screw fixation introduced margerl main technique wire fusion c1 c2 vertebrae358 however fusion rates may altered depth vertebral artery va groove lateral mass width c2 pedicle1 additionally screw fixation might challenging due high risk injury va lead massive bleeding cerebral infarction1620 therefore goel laheri introduced c1 lateral mass c2 pedicle screw fixation c1lm c2p popularized harms melcher reduce risk injury va56101116 furthermore inevitable situation injury va case unfavorable bone structures c1lm c2p performed using bilateral method therefore aim study compare fusion rates unilateral bilateral methods using c1lm c2p technique between march 2009 december 2013 25 consecutive patients institution underwent c1lm c2p address aai due rheumatoid arthritis among patients preoperative radiologic imaging studies performed obtain accurate information anatomy atlas axis cervical x rays including hyperextension hyperflexion views obtained confirm instability c1 2 complex atlanto dental interval adi ) was examined determine instability status preoperative immediate postoperative 1 3 6 12-month postoperative periods moreover computed tomography ct scans 1-mm slices performed examine potential insertion pathway c1 lateral mass screw c2 pedicle screw ct angiography area c1 2 used visualize pathway va examining potential anomalies reducing possible complication va injury magnetic resonance mr ) posterior c1lm c2p screw fixation surgical technique harms melcher6 performed patients study group after discharge patients reported outpatient clinic postoperative months 1 3 6 12 measure adis index bony fusion bony fusion defined bony bridge seen c1 2 inter spinous space lateral radiograph images difference adi immediate postoperative period 12 month time point instrument failure follow period21 after wide exposure c1 2 posterior structures starting point c1 lateral mass formed high speed drill connection point posterior arch lateral mass tapping drilled pathway screws diameter 3.5 mm 4.0 mm were inserted lateral mass marking entry point c2 screw the medial border c2 pedicle identified prevent screw malposition spinal canal after identification transitional corner cephalad portion lamina c2 isthmus entry point made 4 mm lateral 4 mm caudal transitional corner using drill the direction 20 30 medial cephalad palpation medial border c2 pars interarticularis after drilling tapering polyaxial screw proper length diameter inserted an interlaminar spacer wiring c1 c2 tightly fastened rod applied screw head preoperative postoperative adis measured lateral plain radiographs using picture archiving communication system pacs compared side side evaluate time bony fusion differences unilateral bilateral screw fixation statistical analyses performed spss version 18.0 spss chicago il usa non parametric analysis performed unilateral bilateral screw fixation groups the mann whitney u test used compare bony fusion rate unilateral bilateral screw fixation methods after wide exposure c1 2 posterior structures starting point c1 lateral mass formed high speed drill connection point posterior arch lateral mass tapping drilled pathway screws diameter 3.5 mm 4.0 mm were inserted lateral mass marking entry point c2 screw medial border c2 pedicle identified prevent screw malposition spinal canal after identification transitional corner cephalad portion lamina c2 isthmus entry point made 4 mm lateral 4 mm caudal transitional corner using drill the direction 20 30 medial cephalad palpation medial border c2 pars interarticularis after drilling tapering polyaxial screw proper length diameter inserted an interlaminar spacer wiring c1 c2 tightly fastened rod applied screw head preoperative postoperative adis measured lateral plain radiographs using picture archiving communication system pacs compared side side evaluate time bony fusion differences unilateral bilateral screw fixation statistical analyses performed spss version 18.0 spss chicago il usa non parametric analysis performed unilateral bilateral screw fixation groups the mann whitney u test used compare bony fusion rate unilateral bilateral screw fixation methods unilateral c1 lateral mass c2 pedicle screw fixation performed 11 patients 44% study fig 1a mean age unilateral screw fixation group 53.1 years range 30 74 female predominance 90.9% an anomalous course va main reason unilateral screw fixation required eight patients meanwhile bilateral screw fixation group mean age 55.9 years range 40 72 female predominance 85.7% table 1 fig one showed va stenosis compressed pedicle screw digital subtraction angiography complications neurologic impairment massive bleeding infection found evaluation in the 11 patients unilateral screw fixation group preoperative mean adi 8.14 mm mean immediate postoperative adi reduced 1.82 mm moreover measurements mean adi 1 3 6 12 months postoperatively 1.99 mm 1.99 mm 1.92 mm 1.91 mm respectively hand 14 patients bilateral screw fixation group mean preoperative adi 8.48 mm postoperative 1 3 6 12 months 1.99 mm 1.96 mm 1.91 mm 1.90 mm respectively table 1 the postoperative adi values immediate versus 1 month postoperative time points statistically different unilateral group p=0.241 bilateral group p=0.520 similar results found immediate versus 6 month time points unilateral group p=0.859 bilateral group p=0.052 moreover comparing whole follow period 12 months techniques meaningful postoperative changes adis found atlantoaxial fusion seen patients included study 100% according mann whitney test statistically significant difference unilateral bilateral screw fixation groups p=0.893 table 2 evaluating bony fusion 12 months instrument related failure noted case bony bridge interlaminar space c1 2 demonstrated ct scans patients differences adi immediate postoperative 12 month time points statistically significant chronic nuchal pain without neurological deficits may encountered improperly treated upper cervical cord injury may trigger severe neurologic impairment the surgical method c1 2 complex fixation introduced many surgeons bilateral transarticular screw fixation using wiring technique gallie brooks jenkins achieved highest stability stiffness2712 however bilateral transarticular screw fixation taf always possible va anomalies fracture c1 2 complex1314 therefore stability achieved bilateral taf compared unilateral taf previous study hue et al.7 mentioned differences fusion rate measured postoperative adi change unilateral bilateral taf overcome major complication vascular neural injuries c1lm c2p introduced goel laheri 1994 modified harms melcher 200156 the superiority c1lm c2p fixation compared taf lower risk va injury due use individual screw systems the pathway screws taf method crosses c2 c1 relatively complex narrow compared c1lm c2p uses individual screw systems however problems encountered bilateral screw placement including severe anomalous va pathways restricted pathway 3.5 mm screw in words risk injuring va spinal cord predicted preoperatively abandoning screw placement ipsilateral side anatomical variation may wise decision in 25 patients enrolled present study massive bleeding neurologic damage detected vertebral canal violation without complications noted one case va stenosis caused c2 pedicle screw the risk va injury completely eliminated even c1lm c2p if preoperative ct angiography suggests high risk va injury screw may inserted unilateral side therefore study designed identify differences bony fusion unilateral bilateral fixation when compared preoperative postoperative adi measures statistically significant difference unilateral bilateral fixation p=0.893 this suggests unilateral bilateral c1lm c2p produce bony fusion reduction aai in addition strength fusion unilateral screw fixation groups strong bilateral screw fixation group we come conclusion unilateral c1lm c2p showed much strength bilateral c1lm c2p likewise unilateral taf showed much strength bilateral taf mentioned hue et al.7 comparison unilateral taf unilateral c1lm c2p made future study aai however intraoperative reduction smaller surgical site exposure advantages c1lm c2p selective choosing surgical technique aai9 several studies performed reduce complication rate stabilizing c1 2 complex anatomical variations va c1 lateral mass deformation due systemic diseases like rheumatoid arthritis may increase risk va injury also surgical procedure performed risk injuring va increases every 2% screw inserted3141620 therefore comprehensive understanding atlantoaxial va anatomy ct angiography assist successful surgical planning reduce complication rate related va hypoglossal nerve injury may occur anatomical proximity anterior aspect lateral mass315 c2 dermatome anesthesia pain may result patients c2 ganglion injury due insufficient exposure c1 lateral mass c1 2 joint34 such improvements navigation systems monitoring devices may allow improved accuracy determining screw trajectory pathways1316 however navigation systems limitations regard calibration three dimensional ct scans fluoroscopy based images inaccuracies caused manipulating surgical instruments operation field motion operating field craniocervical junction even fixed head clamp16171819 therefore navigation systems require increased accuracy operating c1 2 complex intraoperative fluoroscopy abundant surgical experience reduce complications c1 2 surgical techniques16 if risk va damage choice abandon predictable screw insertion increase safety completeness surgical technique c1lm c2p screw fixation our study illustrated unilateral screw fixation shows similar strength bony fusion reduction rate bilateral screw fixation even though able demonstrate unilateral screw fixation similar bilateral fixation terms strength bony fusion reduction rate several limitations study must considered the existing limitations lack retrospective study small number enrolled cases deficiency biomechanical study due small study cases further prospective study using multi center design may help increasing reliability unilateral surgical technique furthermore future biomechanical studies using animal human cadavers might provide numeric evidence supporting present study conclusion c1 lateral mass c2 pedicle screw fixation performed patients aai due rheumatoid arthritis although bilateral fixation main treatment method cases unilateral screw fixation performed neurovascular contraindication predicted study means adi changes unilateral fixation showed similar strength bilateral fixation bone fusion radiologic images ct angiography cervical three dimensional ct mr images performed reduce complications c1lm c2p prior surgery | objectivebilateral c1 lateral mass and c2 pedicle screw fixation ( c1lm - c2p ) is an ideal technique for correcting atlantoaxial instability ( aai ) .
however , the inevitable situation of vertebral artery injury or unfavorable bone structure may necessitate the use of unilateral c1lm - c2p .
this study compares the fusion rates of the c1 lateral mass and c2 pedicle screw in the unilateral and bilateral methods.methodsover five years , c1lm - c2p was performed in 25 patients with aai in our institute .
preoperative studies including cervical x - ray , three - dimensional computed tomography ( ct ) , ct angiogram , and magnetic resonance imaging were performed . to evaluate bony fusion , measurements of the atlanto - dental interval ( adi ) and
ct scans were performed in the preoperative period , immediate postoperative period , and postoperatively at 1 , 3 , 6 , and 12 months.resultsunilateral c1lm - c2p was performed in 11 patients ( 44% ) . the need to perform unilateral
c1lm - c2p was due to anomalous course of the vertebral artery in eight patients ( 73% ) and severe degenerative arthritis in three patients ( 27% ) .
the mean adi in the bilateral group was 2.09 mm in the immediate postoperative period and 1.75 mm in 12-months postoperatively .
the mean adi in the unilateral group was 1.82 mm in the immediate postoperative period and 1.91 mm in 12-months postoperatively .
comparison of adi measurements showed no significant differences in either group ( p=0.893 ) , and the fusion rate was 100% in both groups.conclusionalthough bilateral c1lm - c2p is effective for aai from a biomechanical perspective , unilateral screw fixation is a useful alternative in patients with anatomical variations . |
lymphoepithelioma term used designate undifferentiated malignant epithelial tumor nasopharynx histologically distinctive markedly prominent lymphoid infiltrate 1 carcinomas similar histological features arising outside nasopharynx called lymphoepithelioma like carcinoma lelca lelca occurs organs salivary glands uterine cervix thymus lung skin stomach bladder prostate breast 2 it rare lelca occurs urinary system one case occurred renal pelvis one case occurred ureter kidney simultaneously reported far urinary bladder korea author et al have lately experienced lelca occurred urinary bladder thus reported case along philological considerations a 78-yr old woman presented gross hematuria 2 weeks november 23 2009 the patient non smoker exposed carcinogen physical examination vital sign normal time patient admitted hospital numerous rbc observed urinalysis notable findings blood test chest radiography on cystoscopy frond like mass observed bladder trigone measured 1 cm fig 1 since hematuria continued foley catheterization performed computerized tomography ct abdomen pelvis findings enhancement small sized mass observed inner surface posterior walls bladder trigone the findings perivesical infiltration lymph node metastasis observed authority findings authors suspected case carcinoma situ urinary bladder transitional cell carcinoma thus transurethral resection bladder tumor turbt ) on histopathological examination found 90% lesions lelca lesions non invasive transitional cell carcinoma on microscopy syncytial growth pattern indistinct cytoplasmic borders observed severe infiltration lymphoid cells tumor cells positive cytokeratin 7 negative cytokeratin 20 fig the infiltrated lymphocytes composed abundant cd3 positive cells cd20 positive b cells leukocyte common antigen lca the patient without recurrence metastasis 3 months operation currently follow ( 3 1991 uncommon reported incidence 0.4 1.3% bladder carcinoma 4 urinary tract typically arise urinary bladder although isolated cases reported renal pelvis ureter urethra 5 6 suggested amin et al 7 lelca categorized pure 100% predominantly 50% focal less 50% classification applied lelca classified pure 100% tumor showed lymphoepithelioma like carcinoma pattern mixed associated usual infiltrating urothelial carcinoma adenocarcinoma squamous carcinoma 2 it suggested pure predominant lelca responds chemotherapy may best treated bladder preservation therapy 1 13 according previous reports pure predominant lelca favorable focal lelca prognosis 2 3 7 this case predominant type lelca accounted 90% lesions fractionally accompanied non invasive transitional cell carcinoma the differential diagnosis usually malignant lymphoma invasive transitional cell carcinoma squamous cell carcinoma small cell carcinoma ( 5 note imperative distinguish lelca malignant lymphoma primary bladder lymphoma extremely rare therefore immunochemical staining lca keratin may used differentiation ( 8) maintained immunochemical staining techniques helpful distinguish bladder lymphoma undifferentiated carcinoma pooly differentiated transitional cell carcinoma tcc lymphoid linfiltrate distinguishable lelca latter characterizied syncytia tumor cell vesicular nuclei prominent nuclei 7 the microscopic findings lelca characterized indistinct cytoplasmic border syncytial growth pattern prominent lymphocytic infiltrate it important check cytokeratin tumor cells immunochemical staining order ascertain cells originated epithelial cells 1 the principal symptoms lelca mostly gross hematuria solitary mass tumors measured 1 5 cm 10 12 epstein barr virus regarded one factors lelca occurred thymus gland 9 however elucidated lelca urinary system related ebv 10 gulley et al 11 reported ebv detected nasophayneal carcinoma detected 9 11 cases lelca also 9 cases lelca reported holmang et al for lelca treatment surgical therapy chemotherapy applied case small tumors measure 5 cm less turbt applied case big invasive tumors radical cystectomy may applied nasopharyngeal lymphoepithelioma well reacted chemotherapy methotrexate vinblastine doxorubicin cisplatin may applied chemotherapy 7 13 reported primary chemotherapy performed 3 patients muscle invasive lymphoepithelioma bladder result bladder functions salvaged it presumed bladder lymphoepithelioma may well reacted radiotherapy like nasopharyngeal lymphoepithelioma 14 ( 12 applied radiotherapy 4 patients could evaluate whether patients got cured successfully lelca rare tumor important differentiate tumors | a 78-yr - old woman presented with gross hematuria for 2 weeks .
on cystoscopy , a frond - like mass was observed at the bladder trigone .
transurethral resection of bladder tumor was performed for the mass .
histopathological findings showed that 90% of lesions were lymphoepithelioma - like carcinoma ( lelca ) and a few lesions were non - invasive transitional cell carcinoma .
on microscopy , syncytial growth pattern and indistinct cytoplasmic borders were observed with the severe infiltration of lymphoid cells .
the case was followed - up for 8 months without recurrence .
this is the first report of a lelca case in korea . |
prostaglandins pg family structurally related eicosanoids regulatory roles normal physiological well pathological contexts cyclooxygenase enzymes catalyze conversion arachidonic acid pgh2 converted prostanoid species including pgd2 pge2 pgf2 prostacyclin pgi2 thromboxane tx a2 action specific synthases 13
the synthesis pgd2 precursor pgh2 catalyzed two pgd synthases pgdss prostaglandin d2 pgd2 involved wide variety neurophysiological functions regulation body temperature hormone release modulation odor pain responses regulation sleep wake cycle mammals pgd2 acts two receptors dp1 dp2 crth2 whereas 15d pgj2 activate peroxisome proliferator activated receptors inhibit range proinflammatory signaling pathways including nf-b 1 2 5 importance role pgd2 pathogenesis resolution inflammation innate immune response increasingly recognized 6 7 however effect pgd2 inflammation complex pgd2 either promotes suppresses inflammation depending inflammatory milieu this complicated fact pgd2 undergoes nonenzymatic processes generate 15d pgj2 anti inflammatory lipid therefore net effect may depend rate production distal products pgd2 depending upon disease process here review biology role pgd synthases pgd2 inflammation host immune response the arachidonate cyclooxygenase pathway generate pgd2 functional linkage series isoformic enzymes corresponding phospholipase a2 cyclooxygenase pgds prostanoid formation occurs cyclooxygenase oxygenates arachidonate converting pgg2 reduced pgh2 pgh2 turn converted five primary active metabolites pgd2 pge2 pgf2 pgi2 thromboxane a2 via distinct synthases pgd synthase pge synthase 1 2 two pgd synthases identified lipocalin l pgds hematopoietic h pgds 4 810 l pgds h pgds quite different biochemically terms amino acid sequence tertiary structure evolutional origin chromosomal cellular localization tissue distribution immunologically terms functional relevance 10 11 hematopoietic pgd synthase h pgds previously known spleen type pgds 9 12 glutathione- gsh- requiring enzyme production pgd2 peripheral tissues 12 13 h pgds characterized member sigma class glutathione transferase gst gene family catalyze conjugation gsh electrophilic substrate h pgds localized antigen presenting cells mast cells variety tissues involved activation differentiation mast cells h pgds isomerizes pgh2 pgd2 selectively effectively whereas gst isozymes catalyze conversion pgh2 nonselectively produce pgd2 pge2 pgf2. high specificity h pgds production pgd2 attributed unique architecture catalytic pocket the deep wide catalytic cavity h pgds striking comparison narrow shallow cavities gsts the unique 3 architecture cleft leads putative substrate binding mode catalytic mechanism responsible specific isomerization pgh2 pgd2 h pgds contributes production j series prostanoids immune system involved allergic inflammatory response since h pgds present mast cells th2 cells leukocytes thought responsible bulk pgd2 production allergic responses 16 17 mouse models asthma allergic disease h pgds substantial proinflammatory effect regulating many hallmark characteristics including eosinophilia airway hyperreactivity mucus production th2 cytokine levels inhibitors h pgds the compound hql-79 characterized specific inhibitor human h pgds shown exhibit therapeutic effect used animal models allergic disease neuroinflammation thus selective inhibitors h pgds may prove useful suppress allergic inflammatory reactions rather cox-1 cox-2 inhibitors aspirin indomethacin coxibs cox inhibitors suppress production prostaglandins comparison h pgds inhibitors 2023 h pgds proinflammatory allergic airway diseases h pgds shown protective models inflammation showed h pgds negatively regulates severity duration delayed type hypersensitivity responses their data suggests contrary role h pgds driving th2-like responses models asthma hpgds may act internal braking signal essential bringing resolution th1-driven delayed type hypersensitivity reactions using h pgds knockout mice showed h pgds synthesizes 15d pgj2 mammalian defense responses together pgd2 acting dp1 receptor plays central role controlling onset acute inflammation resolution balancing pro- versus anti inflammatory cytokines these data highlight anti inflammatory proresolution properties cyclopentanone prostaglandins pgd2 dp1 receptors lipocalin type pgds gsh independent identical beta trace protein discovered 1961 major protein human cerebrospinal fluid 2628 resembles lipophilic ligand carrier proteins named lipocalin type pgd synthase l pgds bifunctional protein acting pgd2-producing enzyme well intercellular transporter retinoids lipophilic molecules it enzyme among members lipocalin gene family binds small lipophilic substances like retinoic acid bilirubin ganglioside structurally monomer -barrel structure hydrophobic pocket initially identified responsible pgd2 production brain 10 19 30 since shown l pgds also expressed tissues including heart kidneys 31 32 lungs 33 34 l pgds secreted various body fluids csf plasma seminal plasma urine functions pgd2-producing enzyme extracellular transporter various lipophilic substances the l pgds/-trace concentration human serum fluctuates circadian rhythmicity exhibits nocturnal increase best known ability induce sleep deletion l pgds leads accelerated glucose intolerance induces obesity nephropathy aortic thickening 36 37 animal models ischemia lack l pgds confers susceptibility injury brain heart 31 32 38 l pgds also inhibitory effect progression lung ovarian colorectal cancer forms leukemia thus evident l pgds several key regulatory roles extend beyond function brain similar h pgds models allergic inflammation l pgds shown proinflammatory fujitani et al reported l pgds transgenic mice exhibit strong allergic lung responses eosinophilia enhanced allergic airway inflammation model chronic allergic dermatitis blockade l pgds with an inhibitor led significant attenuation inflammatory response also confirmed crth2 knockout mice the proinflammatory role l pgds also suggested human ulcerative colitis hokari et al showed level l pgds mrna expression increased uc patients parallel disease activity diabetic rat model ogawa et al showed urinary excretion l pgds increased preceding diabetic nephropathy levels l pgds could predict progression renal injury l pgds urine investigated diagnostic biomarker acute kidney injury inflammation associated diabetes hypertension drug induced nephropathy l pgds smaller molecular weight serum albumin it may expected appear urine even albuminuria hence prove sensitive marker early detection renal injury we studied role l pgds lps induced inflammation shown l pgds induced vitro macrophages 33 34 vivo lung response lps p. aeruginosa our study showed h pgds constitutively expressed vitro macrophages whereas l pgds induced time dependent manner response lps pa103 similarly vivo studies mice showed expression l pgd synthase induced response lps pa103 however immunomodulatory effects l pgds less well studied mouse model p. aeruginosa infection shown l pgds mice impaired host defenses whereas overexpression l pgds protective p. aeruginosa induced pneumonia suggesting pivotal role l pgds innate immune response pgs group 20-carbon polyunsaturated fatty acids containing unique 5-carbon ring structure prostaglandins produced arachidonic acid c20:4 fatty acid via common intermediate pgh2 family structurally related eicosanoids important role homeostasis also contribute pathology numerous inflammatory diseases each prostanoid produced pgh2 specific terminal pg synthase pgd synthase case pgd2 pgd2 acidic lipid mediator derived arachidonic acid sequential action cyclooxygenase pgd2 synthases both h- l pgd synthase enzymes may form pgd2 vitro fully understood pgds enzyme predominates varied conditions vivo pgd2 long time considered minor biologically inactive prostaglandin 1980s however pgd2 found abundant prostaglandin brains rats mammals including humans thus suggesting may important function central nervous system cns the physiological functions pgd2 extensively defined include regulation sleep body temperature olfactory function hormone release nociception central nervous system it released mast cells allergic inflammatory mediator responsible symptoms mastocytosis patients flushing diarrhea tachycardia dyspnea deep sleep pgd2 converted 9 11-pgf2 stereoisomer pgf2 exerts various pharmacological actions different induced pgf2. pgd2 also readily dehydrated vitro vivo produce prostaglandins j series pgj2 -pgj2 15-deoxy--pgj2 15-deoxy--pgj2 identified endogenous ligand nuclear receptor peroxisome proliferator activated receptor promotes adipocyte differentiation 5 6 pgd 2 implicated initiation progression inflammation mouse models asthma allergic disease pgd2 substantial proinflammatory effect regulating many hallmark characteristics including eosinophilia airway hyperreactivity mucus production th2 cytokine levels 40 47 moreover inhibition pgd 2 synthesis pgd 2 signaling blockade suppressive effect neuroinflammation mouse models krabbe disease the injection pgd 2 skin shown result erythema edema induration leukocyte infiltration pgd 2 vasodilator prostaglandins may also contribute inflammation increasing local blood flow
in contrast proinflammatory effects pgd 2 cyclopentenone prostaglandin derivatives also anti inflammatory properties functions resolution inflammation there considerable interest importance pgd2 distal products mediation resolution inflammation 3 57 gilroy et al showed model experimental pleuritis pgd2 significantly attenuated inflammation similarly model experimental colitis cox-2-derived pgd2 acting via dp receptor shown attenuate neutrophilic infiltration colonic mucosa human model acute inflammatory response induced administration lps evokes transient flu like symptoms pyrexia hemodynamic response song et al have shown tetranor pgdm increases markedly response pgj2 antipyretic effects although several studies investigated role pgd 2 inflammation role pgd2 host immune response scantly studied an earlier study showed pgd2 concentration pge2 il-1 concentrations elevated time dependent manner csf patients african sleeping sickness caused trypanosoma brucei these investigators also shown mouse astrocytes fibroblasts culture induce production pgd2 response t. brucei although production pgd2 increased vitro functional effects pgd2 setting remain unclear recent investigation zhao et al showed age related increase pgd2 mice led diminished respiratory dendritic cell migration resulting defects virus specific cell responses vivo they showed administration pgd2 antagonist reversed defect resulting migration dendritic cells enhancement cell antivirus response increased clearance survival these data suggest similar allergic airway disease pgd2 may immunosuppressive effects viral infections mouse model p. aeruginosa lung infection shown inhibition cox-2 improves survival lethal model p. aeruginosa infection the bacterial clearance p. aeruginosa enhanced cox-2 knockout mice whereas transgenic mice overexpress cox-2 impaired bacterial clearance lungs our study showed immunomodulatory effects inhibition cox-2 related inhibition pge2 we also examined effects administration pgd2 model p. aeruginosa lung infection mice given intratracheal pgd 2 showed enhanced clearance p. aeruginosa lungs these results agreement studies l pgds knockout l pgds overexpressing mice we shown pgd2 inhibits key proinflammatory immunoglobulin cell surface receptor trem-1 vitro macrophages furthermore shown pgd2 induces expression nrf2 dp1 receptor dependent manner these studies provide new paradigm highlight key regulatory role pgd2 innate immune response bacterial infections the role pgds pgd 2 regulating inflammation variety organ systems disease process burgeoning the inflammatory response protects body infection injury become dysregulated deleterious consequences host it evident endogenous biochemical pathways pgds pgd 2 get activated defense reactions the effect pgds pgd2 inflammation complex either promote suppresses inflammation depending inflammatory milieu
table 1 provides summary models different effects pgds pgd2 interdiction l pgds pgd2 dp receptors provides novel therapeutic approaches modulate inflammation innate immune responses | pgd2 is formed from arachidonic acid by successive enzyme reactions : oxygenation of arachidonic acid to pgh2 , a common precursor of various prostanoids , catalyzed by cyclooxygenase , and isomerization of pgh2 to pgd2 by pgd synthases ( pgdss ) .
pgd2 can be either pro- or anti - inflammatory depending on disease process and etiology .
the anti - inflammatory and immunomodulatory attributes of pgds / pgd2 provide opportunities for development of novel therapeutic approaches for resistant infections and refractory inflammatory diseases .
this paper highlights the role of pgd synthases and pgd2 in immune inflammatory response . |
cancer dormant cell theory takes view activation resting cells key factor causing cancer metastasis recent studies indicate resting cells activated escaping immune surveillance immune function weakened energy used cell revivals provided newborn vessels 13 therefore study improving body immune surveillance restraining energy tumor growth emergent mission well breakthrough field clinical treatment cancer chlorogenic acid ca extracted folium cortex eucommiae flower bud lonicera confusa kind depside formed caffeic acid quinic acid a large number studies ca demonstrated ca wide range biological activities including inhibition tumor cells according preliminary studies recognize ca able inhibit tumor mouse except cells defect suggests immune system one targets tumor suppression meanwhile vivo studies group indicate ca also changes advantage state th2 drift balb c emt-6 mice it significantly enhance activities balb c emt-6 mice cytotoxic lymphocyte natural killer cells well strengthening macrophage phagocytosis activity lymphocyte transcription activity thus boosting specific nonspecific cellular immune function tumor cells recent studies show antitumor property ca may connection ability enhancing activities aryl hydrocarbon hydroxylase suppressing formation 8-oh dg carcinogen dna adduct oxygen radical 5 6 meanwhile ca guard gastric cancer colon cancer even suppress related carcinogenic factors 7 8 vitro studies revealed ca enhance cell proliferation caused influenza virus antigen induce generation ifn- ifn- human lymphocytes peripheral blood leukocytes 9 10 additionally find ca also activate neurocalcin strengthen activity macrophagocyte although much evidence proved anticancer property ca little known exact targets molecular level base principle complementary base pairing microarray technology distinguish particular genes mixture genes taking advantage gene probes meanwhile sensitivity accuracy specificity better normal pcr explore expression level genes tumor cells utilized microarray technique detect balb c emt-6 mice treatment ca docetaxel interferon normal saline separately differences expression level confirmed rt qpcr time series analysis go analysis pathway analysis used screen common genes analyze relationship putative genes anticancer process ca our data suggested ca able inhibit growth tumor regulating immune system female spf mice balb c used experiment weigh 17 18 g average provided animal center sichuan university emt-6 sarcoma cells provided west china hospital sichuan university department health engineering key laboratory transplantation transplantation immunity we took emt-6 cell line 152c ultra low temperature refrigerator thawing centrifuging primary culturing used 0.25% trypsin digestion twice and all collected cells diluted phosphate buffered saline pbs end we homogenized tumor taken body balb c tumor bearing mice cell suspension inoculated cell suspension balb c mice mice used microarray analysis injected high dose ca experimental group docetaxel control group normal saline negative control group gene expression experimental group analyzed six time points 3rd 6th 9th 12th 15th 18th days resp administration control group negative control group analyzed 12th days administration rt qpcr took mice injected low medium high dose ca 5 mg kg 10 mg kg 20 mg kg experimental group docetaxel interferon control group normal saline negative control group all extracted samples a260/280 ratio 2.0 2.1 28s/18s ratio 2 agilent 2100 bioanalyzer used verification qualified rna rin greater 7.0 total rna transcribed double stranded cdna using revertaid first strand cdna synthesis kit fermentas t7 promoter primer crna dyed cy3 purified using rneasy mini kit qiagen valencia ca usa according protocol rneasy plus mini kit cy3 crna must fragmented buffer 11 l 10 blocking agent 2.2 l 25 fragmentation buffer certain amount nuclease free water 60c half hour hybridization we added 55 l 2 gex hybridization buffer denatured fragmented crna transfered microarrays 65c 17 h constant rotation after hybridization microarrays washed twice buffer 1 1 minute followed buffer 2 37c 1 minute end microarrays autoscanned twice 100% 10% pmt respectively 5 resolution the data analyzed agilent feature extraction software quantile normalization finished genespring 10.0 after acquisition raw data agilent feature extraction software kit used eliminate effect background signals automatic gridding we took log 2 normalized background adjusted values narrow threshold fluorescence signal strength quantile normalization genespring 10.0 used linear model estimate expression values log scale we chose standard among microarray samples thus whole microarray data varied obtain baseline average density differentially expressed genes submitted student test p 0.05 we inputted data probes used gene expressing analysis sbc analysis system v2010.05 rna extracted experimental group ca positive control group docetaxel interferon negative control group used measure expression selected genes interest rt qpcr genes nfatc2 nfatc3 nfatc2ip showed different expression level following treatment low medium high dose ca respectively primers used rt qpcr validation designed according gene sequence finished sbc the rna integrity verified rna formaldehyde electrophoresis quality detected spectrophotometry the rna samples a260/280 ratio greater 2 20srna/18srna ratio greater 1.1 reverse transcription reactions conducted 42c 30 min 85c 5 min 20 l total reaction volume containing following reagents 2 l rna 1 l oligo 2 l 10 mm dntp mixture 1 l ribolock rnase inhibitor 4 l 5 reaction buffer 9 l water 1 l revertaid mulv pcr reaction taken temperature gradient range annealing temperature nfatc2 nfatc3 nfatc2ip rt qpcr analysis conducted obtain crossing point ct values gene standard curve established linearity ct value log 2 expression values carrying rt qpcr analysis cdna primers diluted 20 l reagents containing following 9 l mix 8 l h2o 1 l sense primer f 1 l antisense primer r 1 l cdna relative content mrna extracted experimental group ca positive control group docetaxel interferon negative control group calculated rt qpcr detection system biorad iq5 we carried student test probes select differentially expressed genes p 0.05 drew curves reflecting different expression tendency 6 time points the smaller p value similar gene trend fits curve no.21 fitting curve p value close 0 expression profiles genes covered fitting curve analyzed systematically shown figure 1 inflection point corresponds gene expression different time points administration genes covered curve upregulated seen whole time cycle word ca capable upregulating certain genes tumor bearing mice
data genes covered no.21 put sbc analysis system v2010.05 compared kegg kyoto encyclopedia genes genomes database shown table 2 96 pathways found related upregulated genes 29 found statistically significant including cell receptor signaling pathway b cell receptor signaling pathway natural killer cell mediated cytotoxicity immune related genes expression speculated changed treatment ca probably trend upregulation previous studies ca immune function verified ca could increase carbon clearance index content serum hemolysin enhance phagocytic function the release tumor necrosis factor tfn found reduced activation cytotoxic lymphocyte ctl aimed lewis lung cancer boosted nk cells activation lymphocyte transformation rate lewis lung cancer bearing mice significantly improved determination immune function indexes sum ca proved capable strengthening cellular immune functions tumor when 3 immune related pathways found including upregulated genes inferred immunity mouse improved treatment ca gsk3b nfatc2 nfatc3 vav2 nck1 found upregulated 3 immune related pathways listed table 3 according functions genes covered no.21 classified 312 different go gene ontology 6 p value less 0.05 listed table 4 go statistical significance includes following genes cyp2a4 cyp2c37 cyp2c38 cyp27b1 cyp51 e4f1 fdps gata4 eif2ak1 myt1l rarg sod1 sp1 taf3 nr2c2 hnf4 g zdhhc3 phf6 mynn zfp386 zfp617 zfp114 zfp238 zfp174 zfp113 zfp109 zfp263 pcdhb6 pcdhb15 pcdhb20 pcdhb21 cdyl nfatc3 pbx2 rest smarca5 nfatc2 queries function genes covered statistically significant pathways and go found immune related genes common genes pathway go nfatc2 nfatc3 nfatc2ip found combing raw analysis data gene expression profile shown table 5 relative expression level target genes nfatc2 nfatc3 nfatc2ip average shown table 6 relative expression level nfatc2 nfatc3 nfatc2ip high dose ca group nfatc2ip medium dose ca group low dose ca group significantly improved compared negative control group exact expression quantity shown figure 2 shown figure 2 relative expression level nfatc2ip nfatc3 nfatc2 high dose ca group improved compared negative control group corresponds result microarray analysis whole mouse genome oligo microarray 444k used analyze gene expression level female balb c mice compare expression corresponding target genes group time series systematic error accidental error can affect accuracy microarray analysis extent errors may come processes rna extraction rna reverse transcription hybridization well quality gene chips rna while results microarray analysis reflect expressing pattern body internal gene level quickly false positive results possibly caused systematic error accidental error must taken consideration verifying experiments like elisa test western blot test pcr test taken confirmation the results pcr test help completing study well making convincing analysis genes included no.21 expression critical genes cell receptor signaling pathway b cell receptor signaling pathway natural killer cell mediated cytotoxicity changed immune related genes nfatc2ip nfatc3 nfatc2 found nfat nuclear factor activated cells consists 4 components nfatc1 nfatc2 nfatc3 nfatc4 proved important lymphocyte activation development nfatc2 existing cytoplasm translocates nucleus upon cell receptor stimulation becomes member nuclear factor activating cells transcription when body lacks nfatc2 lymphocyte apoptosis significantly reduced suggests lymphangiectasia th2-type response immune regulatory function disorder th1/th2 balance destroyed tumor occurrence shows preponderance state tendency th2 state weaken antitumor immune function induce tumor cells free immune surveillance immune attack this may one immune mechanisms tumor development provides new idea tumor treating the reverse th1/th2 abnormal drift favor recovering antitumor immunocompetence reducing tumor recurrence metastasis improve long term survival rate finally nfatc2 nfatc3 proved synergistically regulate reaction cell receptor cell division th2 differentiation th2-type reaction suggests secretion il-4 il-5 il-6 increased whereas decrease il-2 ifn- tnf- il-10 happens body lacks nfatc2 nfatc3 1416 b cell cell lack nfatc2 nfatc3 simultaneously function cell weakened ability cell receptor mediating cell proliferation still exists b cells activate show excessive differentiation the fact expression nfatc2 nfatc3 improved treatment ca indirectly indicates ca could reverse th1/th2 drift meanwhile secretion il-2 ifn- tnf- il-10 connected ca high expression nfatc2 nfatc3 favor secretion cytokines already used nonspecific immunity treatment cancer nfatc2ip induce expression cell cytokines especially enhancing il production three splice variants existing nfatc2ip able methylate nfatc2ip translation produce nfatc2ip regulatory factor expression th1-type th2-type cell factors suppressed methylation process inhibited therefore methylation process nfatc2ip important controlling point manipulating expression nfat dependent cell factors influence general transcription factor th1 th2 nfat activation can calcineurin known serine threonine protein phosphatase regulated ca()-calmodulin far mainly aims catalyzing dephosphorylation phosphatidylserine phosphatidyl threonine it multifunctional signaling enzyme involved function regulation many cells distributes wide range tissues especially nerve tissue lymphocytes heart skeletal muscle 18 19 nfat regulates many genes expression well influencing many cells differentiation nfat signaling pathway can able make nfat existing cytoplasm move cell nucleus dephosphorylation finish following transcription translation nfatc combine ap-1 family members alone groups stimulate secretion cell factors certain areas il-2 transcription induction il-2 sign cells activation mentioned above nfat important regulating immunoreaction meanwhile nfatc3 nfatc2 play particularly key role correcting body immune function thus high expression benefit dephosphorylation nfat indirectly effect upon immune system the result microarray analysis differentially expressed genes female balb c emt-6 mice indicated antitumor mechanism ca closely related body immune system upregulating the expression nfatc2 nfatc2ip nfatc3 ca able improve transcription immune factors like il-2r ifn- stimulate proliferation activation cells nk cells macrophage strengthen monitoring killing abilities cancer cells inhibit growth tumor finally the understanding anticancer mechanism ca provided reliable evidence taking advantage ca fight cancer | persistently increasing incident of cancer in human beings has served to emphasize the importance of studies on mechanism of antitumor substances .
chlorogenic acid ( ca ) , extracted from folium cortex eucommiae , has been confirmed to have lots of biological activities encompassing inhibition of tumor .
however , the anticancer mechanism of ca remains unclear .
here , we have utilized a whole mouse genome oligo microarray ( 444k ) to analyze gene expression level of female balb / c mice ( implanted with emt-6 sarcoma cells ) after treatment with low , medium , and high - dose ca ( 5 mg / kg , 10 mg / kg , and 20 mg / kg ) , docetaxel , interferon , and normal saline separately at 6 time points ( 3rd , 6th , 9th , 12th , 15th , and 18th days after administration ) .
differentially expressed genes screened out by time - series analysis , go analysis , and pathway analysis , and four immune - related genes were selected for further confirmation using rt - qpcr .
the results demonstrated that ca is able to change gene expression and that the responsive genes ( can , nfatc2 , nfatc2ip , and nfatc3 ) involved in immune pathways had been significantly upregulated by ca .
expression of immune factors such as il-2r and ifn- can be improved by ca to promote activation and proliferation of t cells , macrophages , and nk cells , thus enhancing their surveillance and killing abilities , further suppressing the growth rate of tumor cells . |
disease endemic india especially uttar pradesh bihar jharkhand andhra pradesh orissa tamil nadu kerala gujarat there least six million attacks acute filarial disease per year 45 million persons currently one chronic filarial lesions conventional mode diagnosis filariasis demonstration microfilaria peripheral blood smear despite high incidence infrequent find microfilariae fine needle aspiration cytology fnac smears body fluids the literature contains reports microfilariae found various locations including thyroid nodule skin soft tissue swelling epididymis breast,[268 salivary gland cervicovaginal smear ovarian cyst urine lymph node effusion fluids the aim present study assess role fnac diagnosis filariasis asymptomatic patients superficial lumps the study conducted department pathology collaboration departments medicine surgery b.r.d medical college gorakhpur period two years i.e. 2006 2007 a total 250 cases age ranging 15 80 years swellings various sites included present study aspiration made technique martin ellis case cystic lesions cyst content aspirated smears prepared cyst fluid cytocentrifugation studied along aspiration performed cyst wall these smears wet fixed immediately 95% alcohol stained hematoxylin eosin papanicolaou stain this study conducted 24 cases filariasis diagnosed routine fnac material various sites 24 cases maximum cases filariasis reported breast swelling eight cases followed lymph nodes six cases scrotal swellings four cases thyroid swellings three cases soft tissue swellings two cases ascitic fluid one case clinical presentations cases variable included swelling pain fever erythema table 1 showing clinical profile cytological findings associated conditions 24 cases smears revealed sheathed microfilariae tails free nuclei many graceful curves thick thin blood smear examination nocturnal venous blood revealed microfilariae wuchereria bancrofti three 24 cases microscopic examination breast swellings showed sheathed microfilaria along groups benign ductal epithelial cells myoepithelial cells bare nuclei fragments fibrofatty tissue inflammatory cells comprising eosinophils neutrophils figure 1 two cases breast lumps showed epithelioid non necrotising granuloma without giant cells plasma cells fnac smear breast swelling showing sheathed microfilaria along inflammatory cells thyroid aspirates revealed groups follicular cells background colloid follicular groups aspirate scrotal swelling showed numerous coiled uncoiled sheathed microfilariae along neutrophils eosinophils lymphocytes figure 2 fnac smear scrotal swelling showing sheathed microfilariae along polymorphs macrophages eosinophils lymph node aspirates showed sheathed microfilariae background mixed population lymphoid cells comprising mature lymphocytes centrocytes centroblasts dendritic cells eosinophils cytological findings soft tissue swellings showed microfilariae along neutrophils eosinophils granular debris cell adherence inflammatory cells macrophages microfilariae seen three 24 cases filariasis major public health problem tropical countries including india endemic areas like eastern part uttar pradesh a majority infected individuals filarial endemic communities asymptomatic present study maximum cases eight 24 cases ) many authors reported microfilariae breast lumps fnac smears.[2468 aspirates lymph nodes five 24 demonstrated microfilariae background reactive lymphoid cells the lymphatic vessels spermatic cord appear common perhaps principal site adult wuchereria bancrofti men asymptomatic microfilaremia occurrence living w bancrofti scrotal area men demonstrated noroes et al two cases soft tissue swellings one case ascitic fluid showed microfilaria along inflammatory cell including eosinophils lymphocytes macrophages out 24 cases showing microfilariae fnac smear examination blood eosinophilia present eight cases microfilaremia nocturnal venous blood smear examination observed three cases findings consistent observation made others reported filariasis exist without microfilaremia significant adherence inflammatory cells macrophages microfilariae present three 24 cases despite high incidence filariasis microfilaria fine needle aspiration cytology common finding careful screening fnac smears undoubtedly demonstration parasite aspirate play significant role recognition disease institution specific treatment thus obviate severe manifestations lymphatic filariasis | background : filariasis is a major health problem in tropical countries including india .
fine needle aspiration cytology plays an important role in prompt recognition of disease.aim:to assess the role of fine needle aspiration cytology ( fnac ) in diagnosis of filariasis at all possible sites.materials and methods : total 250 cases of superficial swellings at various sites were subjected to fine needle aspiration cytology.results:out of 250 cases , 24 cases of filariasis were detected which include breast lumps ( 8 cases ) , lymph nodes ( 6 cases ) , scrotal swellings ( 4 cases ) , thyroid swellings ( 3 cases ) , soft tissue swellings ( 2 cases ) and ascitic fluid ( 1 case ) .
eosinophilia was present in 8 out of 24 cases with a percentage ranging from 12 - 24% .
significant adherence of inflammatory cells and macrophages to microfilariae was present in 3 out of 24 cases.conclusions:in endemic areas , it should be considered one of the differential diagnoses of a superficial swelling .
careful screening of fnac smears help in detecting microfilaria even in asymptomatic patients and thus plays a significant role in recognition of the disease and institution of specific treatment . |
stroke accounts approximately 11% deaths worldwide common cause adult acquired disability among stroke cases ischemic stroke intracerebral hemorrhage ich account 8085% 1520% respectively intravenous thrombolysis using tissue plasminogen activator tpa approved treatment acute ischemic stroke however tpa narrow time window within 4.5 h onset application therefore minority patients 2% 4% receive timely therapy cell therapy might promising strategy stroke bone marrow derived mononuclear cells bm mncs mesenchymal stem cells bm mscs bone marrow stromal cells bm scs frequently used preclinical clinical neurorestorative studies stroke bm mncs mscs self renewal capacity pluripotency differentiate several mesenchymal cellular lineages including osteoblasts chondroblasts adipocytes myocytes fibroblasts they also differentiate non mesenchymal lineages including neurons glial cells preclinical studies observed bm mncs mscs transplanted either intracranially intravascularly could migrate damaged brain tissue exert neuroprotection effect inhibiting apoptosis decreasing peri infarct inflammation promoting angiogenesis 79 therefore past decade series clinical trials performed assess effectiveness safety bm scs transplantation stroke due small number patients recruited individual trials statistical power conclusions weak one recent single arm meta analysis showed cell therapy could effectively improve national institutes health stroke scale nihss scores modified barthel index mbi score modified rankin score mrs however without comparison control group might observational bias therefore this study aimed pool previous controlled trials assess effectiveness bm scs based cell therapy ischemic stroke this study generally followed preferred reporting items systematic reviews meta analyses prisma guidelines relevant studies published 1 jan 2000 1 sept 2014 searched among pubmed medline embase cochrane database we included randomized non randomized controlled trials assessed effectiveness bm mncs mscs based cell therapy either ischemic stroke patients the basic data extracted original studies included family name first author year publication type stoke study design number patients mean age type cell used route cell delivery number cells injected time interval stroke therapy follow baseline nihss score outcome indicator measured assess effectiveness cell therapy outcome indicators used assess therapeutic effectiveness include modified rankin score mrs barthel index bi modified barthel index mbi national institutes health stroke scale nihss original data pooled analyzed using review manager 5.3 cochrane collaboration the risk ratio rr corresponding 95% confidence intervals ci mrs 2 cell therapy vs. control estimated discontinuous data including bi mbi nihss score weighted mean difference wmd corresponding 95% ci estimated the chi square based q test value used assess study heterogeneity also determines methods used making estimation the random effects model dersimonian laird method used p 0.1 q test 50% indicates significant heterogeneity otherwise fixed effects model based mantel haenszel method applied this study generally followed preferred reporting items systematic reviews meta analyses prisma guidelines relevant studies published 1 jan 2000 1 sept 2014 searched among pubmed medline embase cochrane database we included randomized non randomized controlled trials assessed effectiveness bm mncs mscs based cell therapy either ischemic stroke patients the basic data extracted original studies included family name first author year publication type stoke study design number patients mean age type cell used route cell delivery number cells injected time interval stroke therapy follow baseline nihss score outcome indicator measured assess effectiveness cell therapy outcome indicators used assess therapeutic effectiveness include modified rankin score mrs barthel index bi modified barthel index mbi national institutes health stroke scale nihss original data pooled analyzed using review manager 5.3 cochrane collaboration risk ratio rr corresponding 95% confidence intervals ci mrs 2 cell therapy vs. control estimated discontinuous data including bi mbi nihss score weighted mean difference wmd corresponding 95% ci estimated the chi square based q test value used assess study heterogeneity also determines methods used making estimation random effects model dersimonian laird method ) was used p 0.1 q test 50% indicates significant heterogeneity otherwise fixed effects model based mantel haenszel method applied based searching screening preset criteria 5 trials 1115 finally included meta analysis the 5 trials involved total 228 patients among 104 cell therapy group 124 control group two studies used bm mscs 3 studies used bm mncs 1315 four studies transplanted cells iv injection 1113,15 1 used ia injection the time interval stroke cell therapy varied several days several months stroke four trials reported outcome 6-month follow 1 study reported 5-year outcome generally modified rankin score mrs barthel index bi modified bi mbi national institutes health stroke scale nihss scores 3 indicators used assess clinical outcomes cell therapy two studies reported bi 2 studies reported mbi end follow generally although cell therapy group slightly higher bi mbi score mean difference significant cell therapy control group wmd 2.50 95%ci 4.69 9.68 p=0.50 i=46% figure 2 subgroup analysis performed stratifying bi mbi subgroup using mbi indicator daily activities living reported significantly higher mbi score cell therapy group controls wmd 7.44 95%ci 1.82 13.06 p=0.009 i=0% figure 2 significant difference observed bi subgroup wmd 3.24 95%ci 12.14 5.65 p=0.47 i=0% figure 2 two studies reported nihss end follow generally mean difference nihss score significant lower cell therapy group control group wmd 1.85 95%ci 2.77 0.93 p<0.0001 i=24% figure 3 due non randomized design studies compared proportion patients mrs 2 cell therapy experimental arm the meta analysis find significant change proportion patient mrs 2 group cell therapy 13/86 vs. 15/86 rr 1.81 95%ci 0.37 8.95 p=0.47 figure 4 infection recurrence stroke death used assess safety bm mscs transplantation our meta analysis find difference 3 indicators cell therapy control group figure 5 two studies reported bi 2 studies reported mbi end follow generally although cell therapy group slightly higher bi mbi score mean difference significant cell therapy control group wmd 2.50 95%ci 4.69 9.68 p=0.50 i=46% figure 2 subgroup using mbi indicator daily activities living reported significantly higher mbi score cell therapy group controls wmd 7.44 95%ci 1.82 13.06 p=0.009 i=0% figure 2 significant difference observed bi subgroup wmd 3.24 95%ci 12.14 5.65 p=0.47 i=0% figure 2 two studies reported nihss end follow generally mean difference nihss score significant lower cell therapy group control group wmd 1.85 95%ci 2.77 0.93 p<0.0001 i=24% figure 3 three studies reported change mrs end follow due non randomized design studies compared proportion patients mrs 2 cell therapy experimental arm the meta analysis find significant change proportion patient mrs 2 group cell therapy 13/86 vs. 15/86 rr 1.81 95%ci 0.37 8.95 p=0.47 figure 4 infection recurrence stroke death used assess safety bm mscs transplantation our meta analysis find difference 3 indicators cell therapy control group figure 5 in animal models transplantation bm mncs mscs could reduce inflammation decrease infarct size brain improve neurological function several models stroke multiple mechanisms 1618 recent meta analysis based 46 preclinical animal studies previous preclinical studies observed although bm mscs bm mncs could transdifferentiate neuronal like vitro basic neuronal functional properties transdifferentiation seldom happens vivo in fact study based animal models showed small proportion 0.02% intravenously delivered bm mncs migrate ischemic area brain transplanted cells develop macrophage microglial phenotype generally transplanted cells stimulating effect release cytokines neurotrophic factors including brain derived neurotrophic factor bdnf basic fibroblast growth factor bfgf nerve growth factor vascular endothelial growth factor vegf insulin like growth factor-1 hepatocyte growth factor hgf stem cell factor these factors induce angiogenesis reduce neuronal apoptosis enhance axonal regeneration rebuild synapses dendrites promote differentiation endogenous neural stem progenitor cells these effects necessarily require presence transplanted cells injury site brain therefore paracrine effects transplanted cells might fundamental positive clinical outcomes however clinical trials data exact effects bm mncs mscs based cell therapy stroke still conflicting this study based 5 double arms trials demonstrated bm derived stromal cells might benefits lowering grade impairment caused ischemic stroke in fact 1-point increase nihss score decreases likelihood excellent outcome 17% in addition might benefits activities daily living measured mbi however studies involved limited number patients conducted research team statistical power finding might weak clinical trials usually define favorable outcome stroke mrs grade 2 however meta analysis failed demonstrate significant benefits bm mscs mncs based cell therapy increasing proportion mrs 2 patients due to this study find severe adverse events associated cell therapy suggesting relatively safe intervention firstly number trials number patients recruited trial small in addition different trials reported different clinical outcomes makes hard use scale summarize results these limitations significantly weaken statistical power findings secondly develop effective cell therapy strategy several factors including eligibility criteria patients timing route dose cell transplantation considered clinical practice however based available evidence factors still need optimized patients moderate mild severe stroke might suitable cell therapy since patients mild strokes generally uniformly good outcome patients severe stroke less likely respond intervention thus unlikely good outcome 5 trials recruited patients basic nihss scores ranging 4 20 means minor moderate moderate severe patients recruited therefore although bm mncs mscs transplantation might generate benefits lowering grade impairment caused ischemic stroke large rcts required confirm effectiveness bm mscs mncs based cell therapy optimize conditions required best therapeutic effects | backgroundautologous bone marrow stromal cells ( bm - scs ) transplantation might be a potential therapy for stroke .
although a series of clinical trials were performed to assess the effectiveness and safety of bm - scs transplantation after ischemic stroke , the results are still conflicting . this study aimed to pool
previous controlled trials to assess the effectiveness of bm - scs - based cell therapy after ischemic stroke.material/methodsrelevant studies were searched among online databases .
barthel index ( bi ) or modified barthel index ( mbi ) , national institutes of health stroke scale ( nihss ) , and rankin score ( mrs ) were used to assess therapeutic effects .
the frequencies of adverse events were extracted for assessing safety of stem cell therapy .
data analysis was performed by using review manager 5.3.resultspatients who received cell therapy had significantly lower nihss score ( 1.85 ) than the controls .
in addition , there might be some benefits in daily activity measured by mbi , but this meta - analysis failed to demonstrate significant benefits of bm - scs - based cell therapy in increasing the proportion of mrs 2 patients .
we did not find any severe adverse events associated with bm - scs - based cell therapy.conclusionsalthough bm - mncs / mscs transplantation might generate some benefits in lowering the grade of impairment caused by ischemic stroke , large rcts are required to further confirm the effectiveness of bm - mscs / mncs - based cell therapy and to optimize the conditions require for best therapeutic effects . |
percutaneous nephrolithotomy pnl gold standard treating patients kidney stones 2 cm diameter it replaced open surgeries due equal efficacy less morbidity higher patient acceptance however common complications still urine extravasation infection bleeding the classic procedure consists four major steps insertion ureteral catheter execution percutaneous access kidney tract dilation lithotripsy stone extraction finally protection tract nephrostomy tube tract dilation may conducted aid metallic alken dilators plastic amplatz dilators pneumatic dilator one stage tract dilation also well known technique however utilized department it previously suggested blood loss renal dilation amplatz instruments higher it also suggested sequential application fascial dilators hemostatic pressure kidney parenchyma lost resulting intermittent bleeding renal vessels hand the rate complications seems comparable various methods tract performance inter infracostal approach various calyx punctures utilization access sheath etc ) we hypothesized may dilator type rather way utilized may influence type complications the aim study compare two methods tract dilation terms efficacy safety find may source differences complication rates between august 2008 april 2016 pnl performed 283 patients department two methods tract dilation utilized group n=123 comprised patients alken dilatator used group ii n=99 comprised patients amplatz dilator used both procedures conducted two experienced endourologists one used alken dilator used amplatz dilator efficacy assessed based ultrasound x ray examination one month procedures the presence residual stone <3 mm diameter considered insignificant patients classified stone free urosepsis diagnosed positive urine blood cultures two following four temperature 38.5c 36c white blood cells 12,000 cells mm 4,000 cells mm respiratory rate 20 breaths per minute paco2 32 mm hg pulse 90 beats per minute other variables also analyzed including operating room time scope time hospitalization time this study performed accordance ethical standards 1964 declaration helsinki supine position the patient rotated table prone position angle 30 a hydrophilic guidewire inserted needle placed ureter wire after lithotripsy entry malecot catheter inserted amplatz wire within kidney ureteral catheter withdrawn our amplatz dilator technique standard technique well described literature final stages may replaced tubeless option the procedure used alken dilator similar point introduction amplatz wire instead straight amplatz wire stiff wire coiled end inserted pyelocalyceal system subsequently metallic dilator introduced wire widen tract 26-fr the access sheath safety wire used end lithotripsy a drain left pyelocalyceal system ureteral catheter left place procedure patient received 1 g paracetamol intravenously every six hours antibiotic prophylaxis consisted cephalosporin second generation given induction general anesthesia student test continuous variables normal distribution used continuous variables without normal distribution for categorical variables chi square test used show dependence categorical variables used correspondence analysis power analysis conducted assistance g*power statistical tool p value < this study performed accordance ethical standards 1964 declaration helsinki in supine position 6-fr ureteral catheter inserted appropriate kidney the patient rotated table prone position angle 30 a hydrophilic guidewire inserted needle placed ureter wire after lithotripsy entry malecot catheter inserted amplatz wire within kidney ureteral catheter withdrawn our amplatz dilator technique standard technique well described literature final stages may replaced tubeless option the procedure used alken dilator similar point introduction amplatz wire instead straight amplatz wire stiff wire coiled end inserted pyelocalyceal system subsequently metallic dilator introduced wire widen tract 26-fr the access sheath safety wire used end lithotripsy a drain left pyelocalyceal system ureteral catheter left place procedure patient received 1 g paracetamol intravenously every six hours antibiotic prophylaxis consisted cephalosporin second generation given induction general anesthesia student test continuous variables normal distribution used continuous variables without normal distribution the chi square test used show dependence categorical variables used correspondence analysis power analysis conducted assistance g*power statistical tool p value < patients groups differ terms age sex bmi stone size affected side table 1 we find differences total operative time tract formation time fluoroscopy time tract dilation failures although frequent group significantly different groups hemoglobin drop and most procedures group performed infracostal access group ii procedures conducted intercostal access number accesses differ groups amplatz group group ii ) most accesses middle calyx group alken group lower calyx we found significant differences postoperative complications shown table 2 figure 1 most grade postoperative fever 38.5c complications common group i. similarly grade ivb complications urosepsis frequently observed group i. pleural injury grade iva common group ii complications ii blood transfusions iiia
extravasation iiib arterio venous fistula non complicated course disease similarly distributed groups pnl efficacious procedure 80% stone free rate independent type access it replaced open surgeries due efficacy less morbidity higher patient acceptance still one common complications pnl infection sepsis bleeding resulting hemoglobin drop occasionally need blood transfusion as stated earlier alken dilators allegedly safer amplatz dilators due maintenance continuous hemostatic pressure kidney parenchyma study types tract dilation comparable terms blood loss similarly blood transfusions different groups supporting previous reports types tract dilation equally safe other parameters total operative time fluoroscopy time tract formation time different two groups similarly tract dilation failure rate comparable two groups consistent study outcomes cohort amplatz group insignificantly fewer failures experience may due fact alken group puncture often lower calyx wire positioned renal pelvis on hand amplatz group puncture usually directed middle calyx wire positioned within ureter positioning wire ureter makes stable less prone fall kidney tract dilation other factors may influence tract dilation failure e.g. bmi gender due kidney movement procedure however observe differences distribution aforementioned characteristics showed figure 1 postoperative fever sepsis cohort common alken group other complications contrast extravasation arteriovenous fistula postoperative hematoma comparable groups we may speculate differences rates grade ivb two groups simple explanation we hypothesized cause lies fact alken group use access sheath this may cause higher irrigant pressure inside kidney lithotripsy influent water departs ureter instead access sheath a similar situation described micro percutaneous nephrolithotomy need access sheath higher irrigant pressures observed comparison classic pnl as stones infected combination high irrigant pressure may cause septic complications pnl the clavien dindo classification usually used evaluate major complications 3a pnl however showed even postoperative fever grade may vary methods this suggests source difference may important even minor complications reported pnl procedures amplatz group were conducted middle calyx surprising many intercostal however fact influence blood loss supports reported evidence inter infracostals access equally safe regard hand intercostal access results frequent pleural injury figure 1 both procedures characterized mild pain day operation table 2 the way pnl may performed alken amplatz dilators differs among urological departments indeed study compare two different dilators rather two different methods tract dilation pros cons based study determine superiority one method tract dilation two approaches completely different terms punctured calyx inter infracostal access utilization sheath however clear irrespective dilator type used important differences result aforementioned factors total operative time tract dilation time fluoroscopy time tract dilation failure comparable two groups fever 38.5c urosepsis common alken group hand pleural injuries common pnl amplatz dilators it clear differences resulted punctured calyx type access kidney inter infracostal utilization access sheath rather type dilator | backgroundpercutaneous nephrolithotomy ( pnl ) is the standard procedure for patients with renal stones over 2 cm in diameter .
we analyzed complications after this procedure focusing on two different methods of tract dilation.material/methodsbetween august 2008 and april 2016 222 percutaneous nephrolithotomies were performed in a total of 208 patients .
the group i ( n=123 ) comprised patients where alken dilatators were used , while group ii ( n=99 ) comprised patients where amplatz dilators were used .
efficacy was examined based on ultrasound and x - ray examination one month after the procedure .
complications were recorded using clavien dindo classification.resultsefficacy was 85.3% and 86.8% in group i and ii , respectively ( p=0.77 ) .
grade i complications were present in 14.6% and 3% , grade ii were present in 9.7% and 8% , grade iiia were present in 2.4% and 2% , grade iiib were present in 1.6% and 2% , grade iva were present in 1.6% and 7% , grade ivb were present in 3.2% and 1% in group i and group ii , respectively .
these differences were statistically significant ( p=0.03).conclusionsefficacy was comparable between alken dilator and amplatz dilator groups . in group
i , there were more postoperative fevers > 38.5 c and a higher rate of urosepsis .
on the other hand , in group ii we observed more pleural injuries .
all differences resulted from the type of access to the kidney ( inter / infracostal ) , punctured calyx , and utilization ( or not ) of access sheath rather than type of dilators itself . |
pop prevalent problem reported affect 50% parous women eleven percent women undergone operation prolapse urinary incontinence age 80 oab known highly prevalent disorder increases age sexes profound impact quality life according international continence society ics ) oab defined urgency without urge incontinence usually frequency nocturia obvious pathology. matter debate whether pop considered obvious pathology. symptoms oab often seen patients pop community based studies showed prevalence oab symptoms higher patients pop without pop the tendency found hospital based studies nevertheless literature prevalence combination pop oab scarce study relation pop oab used data cross sectional study performed small dutch city prevalence pelvic floor symptoms general population the objective study investigate risk factors oab specifically explore relationship oab prolapse this important clinical practice two diagnoses often co occurring possible consequences diagnosis treatment the study cross sectional small town brielle netherlands brielle chosen homogenic population women registered one nine general practices all women aged 45 85 years registered patients lists eight nine general practices invited enrol study 95% women age group the women sent information study informed could enrol filling informed consent form women consented non responders received reminder 8 weeks later contained questionnaire check selection bias permanent non responders invited complete short questionnaire comprised five questions age parity presence stress urinary incontinence yes faecal incontinence yes feeling vaginal bulging yes to encourage high response questionnaire used envelopes name logo erasmus university coloured paper stamped addressed return envelopes three options possible women refused participate study women filled questionnaire women filled questionnaire underwent vaginal examination purpose study data vaginal examination used the relation symptoms signs vagina prolapse extensively described earlier study 1flowchart study flowchart study self reported questionnaire used study composite internationally well known questionnaires validated dutch language it contains amongst others disease specific questions validated dutch translation urinary distress inventory(udi
women rated amount bother various symptom 5-point likert scale 0 complaints 4 serious complaints in addition questions ethnicity parity pop symptoms pregnancy family history menopausal status hormone replacement therapy hrt previous pelvic floor surgery educational level smoking heavy physical work also included the medical ethics research committee metc erasmus mc rotterdam netherlands approved study all symptoms dichotomized present absent based responses symptom degree bother symptoms women denied presence specific symptom well women answered confirmative specific question answered bothered considered negative absent women indicated little severe bothered considered positive present the item pop symptoms merged women reported either seeing and/or feeling vaginal bulging for item oab symptoms women urgency and/or frequency and/or urge incontinence symptoms included see fig 2
2any oab symptoms relation urgency frequency urge incontinence oab symptoms relation urgency frequency urge incontinence data presented number women percentage mean standard deviation median range appropriate chi square test used compare difference women with- versus without pop symptoms variables p 0.3 univariate analysis included multivariate analysis we presented odds ratio 95% ci oab symptoms all data entered analysed spss 15.0 database windows spss inc chicago il all symptoms dichotomized present absent based responses symptom degree bother symptoms women denied presence specific symptom well women answered confirmative specific question answered bothered considered negative absent women indicated little severe bothered considered positive present the item pop symptoms merged women reported either seeing and/or feeling vaginal bulging item any oab symptoms women urgency and/or frequency and/or urge incontinence symptoms included see fig 2
2any oab symptoms relation urgency frequency urge incontinence oab symptoms relation urgency frequency urge incontinence data presented number women percentage mean standard deviation median range appropriate chi square test used compare difference women with- versus without pop symptoms variables p 0.3 univariate analysis included multivariate analysis we presented odds ratio 95% ci oab symptoms all data entered analysed spss 15.0 database windows spss inc chicago il of 2,979 women eligible study 1,397 47% filled questionnaire non responder group 59% filled returned short questionnaire 620/1,051 giving total response rate 62.7% fig 1 scores short questionnaire group significantly different total study group details response rate presented previous report table 2 shows prevalence oab symptoms per age category table 3 the prevalence pop symptoms women without oab symptoms presented
table 1patients characteristics details previous pelvic operationsnumber women1397age years 4555647 46.9% 5665435 31.5% 6675233 16.9% 768566 4.8%)parity 0120 8.6% 1215 15.4% 2675 48.3% 3387 27.7%)body mass index kg m2 2053 3.9% 2025599 43.9% 2530519 38.0% 30193 14.1%)race caucasian1,351 98.5% non caucasian20 1.5%)smoking former smoking326 23.6% current smoking280 20.3% postmenopausal status1,009 72.2% hormone suppletion88 6.4%)previous gynaecological surgery prolapse surgery103 7.4% hysterectomy234 16.9% incontinence surgery47 3.4%)data presented number women percentage)data 16 women missingdata 33 women missingdata 26 women missingdata 15 women missingdata 30 women missingdata 25 women missingdata 18 women missingdata 13 women missingdata 14 women missingdata 15 women missingtable 2prevalence overactive bladder symptoms oab symptoms per age groupfrequencyurgencyurge incontinenceany oab symptoms4555162 25.3%)193 30.9%)178 27.7%)298 46.1%)5665121 28.4%)141 33.7%)116 26.9%)200 46.2%)667580 35.9%)92 40.5%)79 35.0%)126 54.5%)768524 37.5%)33 54.1%)32 48.5%)42 63.6%)overall393 28.7%)463 34.4%)411 29.8%)677 48.6%)data presented number women percentage)data age category 16 women missingdata frequency 28 women missingdata urgency 52 women missingdata urge incontinence 16 women missingtable 3prevalence prolapse symptoms women symptoms oabprolapse symptomsno prolapse symptomspfrequency66 41.8%)320 26.9%)0.000urgency77 49.7%)379 32.4%)0.000urge incontinence64 40.3%)340 28.3%)0.003any oab symptoms84 69.4%)588 46.6%)0.000data presented number women percentage)p value using chi square test compare difference women versus without prolapse symptoms.data 28 women missingdata 52 women missingdata 16 women missingdata four women missingdata prolapse symptoms 24 women missing patients characteristics details previous pelvic operations data presented number women percentage data 16 women missing data 33 women missing data 26 women missing data 15 women missing data 30 women missing data 25 women missing data 18 women missing data 13 women missing data 14 women missing data 15 women missing prevalence overactive bladder symptoms oab symptoms per age group data presented number women percentage data age category 16 women missing data frequency 28 women missing data urgency 52 women missing data urge incontinence 16 women missing prevalence prolapse symptoms women symptoms oab data presented number women percentage p value using chi square test compare difference women versus without prolapse symptoms data 28 women missing data 52 women missing data 16 women missing data four women missing data prolapse symptoms 24 women missing table 4 various possible risk factors including presence pop symptoms presence oab symptoms presented univariate logistic regression model
table 4factors univariate logistic regression analysis various oab symptomsfrequency 95% ci)urgency 95% ci)urge incontinence 95% ci)any oab 95% ci)age years)4555refrefrefref56651.2 0.9 1.5)1.1 0.9 1.5)1.0 0.7,1.3)1.0 0.8 1.3)66751.7 1.2 2.3)1.5 1.1 2.1)1.4 1.0 1.9)1.4 1.0 1.9)76851.8 1.0 3.0)2.6 1.5 4.5)2.5 1.5 4.1)2.0 1.2 3.5)parity2refrefrefref>21.3 1.0 1.7)1.0 0.8 1.3)1.0 0.8 1.3)1.2 0.9 1.5)body mass index kg m2)<200.7 0.3,1.5)0.4 0.2 1.0)0.7 0.4 1.5)0.6 0.3 1.0)2025refrefrefref25301.6 1.3 2.1)1.3 1.0 1.7)1.5 1.1 1.9)1.4 1.1 1.7)302.0 1.4 2.8)2.2 1.6 3.1)2.2 1.6 3.1)2.3 1.7 3.2)smoking former smokingyes1.3 1.0 1.8)1.2 0.9 1.6)1.0 0.8 1.4)1.1 0.8 1.4)norefrefrefref current smokingyes1.0 0.8,1.4)1.3 1.0 1.7)1.3 1.0 1.7)1.2 1.0 1.6)norefrefrefrefpostmenopausal statusyes1.5 1.2 2.0)1.6 1.2 2.0)1.4 1.1 1.8)1.3 1.0 1.7)norefrefrefrefhormonal suppletion therapyyes1.2 0.7 1.9)1.2 0.7 1.8)0.7 0.4 1.2)0.9 0.6 1.4)norefrefrefrefprevious gynaecological surgery prolapse surgeryyes2.5 1.7 3.8)2.6 1.7 3.9)1.9 1.3 2.9)2.9 1.9 4.6)norefrefrefref hysterectomyyes1.5 1.1 2.1)1.3 0.9 1.7)1.3 1.0 1.8)1.3 1.0 1.7)norefrefrefref incontinence surgeryyes3.5 1.9 6.5)3.4 1.9 6.3)4.3 2.3 8.0)6.5 2.9 14.5)norefrefrefrefprolapse symptomsyes2.0 1.4 2.7)2.1 1.5 2.9)1.7(1.2 2.4)2.6 1.7 3.9)norefrefrefrefall values p 0.05 illustrated boldref referencedata 16 women missingdata 33 women missingdata 15 women missingdata 13 women missingdata 30 women missingdata 25 women missingdata 18 women missingdata 14 women missingdata on 24 women missing factors univariate logistic regression analysis various oab symptoms values p 0.05 illustrated bold data 16 women missing data 33 women missing data 15 women missing data 13 women missing data 30 women missing data 25 women missing data 18 women missing data 14 women missing data 24 women missing shows chance presence oab symptoms 1 indicates factor positively correlated outcome variable 1 means factor indicates negative correlation table 5 shows multivariate analysis oab symptoms factors univariate analysis p 0.3 taken account
table 5risk factors oab symptoms multivariate regression analysisfrequency 95% ci)urgency 95% ci)urge incontinence 95% ci)any oab 95% ci)age years)4555refrefref56651.0 0.8 1.4)0.9 0.6 1.1)0.9 0.7 1.2)66751.4 1.0 2.0)1.3 0.9 1.8)1.3 1.0 1.8)76852.7 1.5 4.9)2.2 1.3 3.8)2.1 1.2 3.7)body mass index kg m)<200.7 0.3 1.6)0.4 0.2 0.9)0.7 0.3 1.5)0.5 0.3 1.0)2025refrefrefref25301.5 1.1 2.0)1.2 0.9 1.6)1.3 1.0 1.8)1.3 1.0 1.6)301.7 1.2 2.4)2.2 1.5 3.1)2.0 1.4 2.9)2.2((1.5 3.1)smoking smoking pastyes1.4 1.1 1.9)noref current smokingyes1.7 1.2 2.3)1.4 1.0 1.8)norefrefpostmenopausal statusyes1.3 1.0 1.8)norefprevious gynaecological surgery prolapse surgeryyes2.3 1.4 3.6)noref incontinence surgeryyes2.9 1.5 5.5)4.3 2.3 8.2)6.7 2.8 16.3)norefrefrefprolapse symptomsyes2.4 1.6 3.5)2.2 1.4 3.3)1.8 1.2 2.6)2.3 1.5 3.5)norefrefrefrefvariance explained model5.8%8.8%6.6%9.1%or odds rario ref referencedata 16 women missingdata 33 women missingdata 15 women missingdata 13 women missingdata 18 women missingdata 24 women missingnagelkerke r risk factors oab symptoms multivariate regression analysis odds rario ref reference data 16 women missing data 33 women missing data 15 women missing data 13 women missing data 18 women missing data 24 women missing in cross sectional study looked prevalence oab symptoms specifically relationship oab symptoms pop symptoms we found prevalence urgency frequency urge urinary incontinence 34% 29% 30% respectively this comparable studies prevalence 16.849% found women 3 8 pop symptoms present 11.4% comparable studies prevalence 430% found 911 the sparse cross sectional studies mentioned relationship pop symptoms oab showed higher prevalence oab symptoms pop symptoms without pop symptoms controlled risk factors the relationship pop oab found hospital based studies prevalence oab symptoms greater patients pop without pop however nature epidemiological studies causal relationship established there many possible theories regarding pathophysiology oab relation pop likely bladder obstruction plays important role nevertheless several mechanisms might considered pathophysiological relationship oab pop needs studied important clinical implication relationship pop oab treatment pop could give improvement oab symptoms another important risk factor oab symptoms surgery urinary incontinence past many studies shown relationship continence surgery oab symptoms prevalence de novo oab varied 15% 29% short term 13 months postoperatively 12 13 030% long term 1214 studies found prevalence oab symptoms increased advancing age 3 8 overweight body mass index bmi greater 30 another independent risk factor oab symptoms this consistent studies found relationship 1519 the study cheung found similar overweight study lawrence found higher 2.73 hand choo et al found bmi predictor oab dry urgency without frequency nocturia oab wet urgency urge incontinence without frequency nocturia other studies conclusive role smoking oab 17 20 21 the study bradley et al found relation current smoking urinary symptoms large cross sectional study showed current former smoking associated urgency one study found current smokers 1.44 time likely develop oab increased risk former smokers nearly significant the induction oab smoking could related anti oestrogenic hormonal effect bladder uretra nicotine induced phasic contraction detrusor muscle this consistent another study found postmenopausal status predictor oab symptoms this explained oestrogen important role urogenital tract oestrogen receptors urethra bladder pelvic floor deficiency causes atrophic changes associated oab symptoms reversal atrophy oestrogen treatment positive influence oab symptoms surprisingly found previous prolapse surgery predictor symptom urgency contrast practically studies showed improvement oab symptoms prolapse surgery a possible explanation finding women prolapse surgery achieved de novo urgency found 5% patients one study strong point study large cross sectional study homogenic female population made multivariate analysis possible result however genetic racial factors could included also inherent weakness design another weakness study factors influence oab included food beverages coffee alcoholic consumption use oab therapies bladder training pharmacotherapy this study found pop symptoms independent risk factor oab symptoms sparse cross sectional studies mentioned relationship pop symptoms oab showed higher prevalence oab symptoms pop symptoms without pop symptoms controlled risk factors the relationship pop oab found hospital based studies prevalence oab symptoms greater patients pop without pop however nature epidemiological studies causal relationship established there many possible theories regarding pathophysiology oab relation pop likely bladder obstruction plays important role nevertheless several mechanisms might considered pathophysiological relationship oab pop needs studied important clinical implication relationship pop oab treatment pop could give improvement oab symptoms another important risk factor oab symptoms surgery urinary incontinence past many studies shown relationship continence surgery oab symptoms prevalence de novo oab varied 15% 29% short term 13 months postoperatively 12 13 030% long term 1214 studies found prevalence oab symptoms increased advancing age 3 8 overweight body mass index bmi greater 30 another independent risk factor oab symptoms this consistent studies found relationship 1519 the study cheung found similar overweight study lawrence found higher 2.73 hand choo et al found bmi predictor oab dry urgency without frequency nocturia oab wet urgency urge incontinence without frequency nocturia other studies conclusive role smoking oab 17 20 21 the study bradley et al found relation current smoking urinary symptoms large cross sectional study showed current former smoking associated urgency one study found current smokers 1.44 time likely develop oab increased risk former smokers nearly significant the induction oab smoking could related anti oestrogenic hormonal effect bladder uretra nicotine induced phasic contraction detrusor muscle this consistent another study found postmenopausal status predictor oab symptoms this explained oestrogen important role urogenital tract oestrogen receptors urethra bladder pelvic floor deficiency causes atrophic changes associated oab symptoms reversal atrophy oestrogen treatment positive influence oab symptoms surprisingly found previous prolapse surgery predictor symptom urgency contrast practically studies showed improvement oab symptoms prolapse surgery a possible explanation finding women prolapse surgery achieved de novo urgency found 5% patients one study the strong point study large cross sectional study homogenic female population made multivariate analysis possible result however genetic racial factors could included also inherent weakness design another weakness study factors influence oab included food beverages coffee alcoholic consumption use oab therapies bladder training pharmacotherapy in study found prevalence urgency 34% core symptom oab spectrum oab symptoms 49% other risk factors continence surgery past age 75 overweight smoking | introduction and hypothesisto study the prevalence and risk factors of overactive bladder ( oab ) symptoms and its relationship with symptoms of pelvic organ prolapse ( pop).methodsthis is a cross - sectional study including women aged between 45 and 85 years , registered in eight general practices .
all women were asked to self complete the validated dutch translated questionnaires .
all symptoms were dichotomized as present or absent based on responses to each symptom and degree of bother.resultsforty-seven percent of the women filled out the questionnaire .
prevalence of urgency was 34% and the prevalence of any oab symptoms 49% .
prevalence of oab symptoms increased with advancing age .
symptoms of pop were an independent risk factor for symptomatic oab .
other risk factors were continence and prolapse surgery in the past , age above 75 , overweight , postmenopausal status and smoking.conclusionsthe prevalence of any oab symptoms was 49% .
pop symptoms were an independent risk factor for symptomatic oab . |
antitumor necrosis factor tnf biologics appeared decade ago armamentarium inflammatory bowel disease ibd originally evaluated crohn disease cd thereafter ulcerative colitis uc efficacy demonstrated diseases deeply modified management patients ibd although potentially able change natural course ibd decrease need surgery absence loss response frequent one third patients remain clinical remission 1 year clinical response steroid free remission mucosal healing correlated drug trough levels 3 4 however anti tnf pharmacokinetic characterized considerable interindividual variability antidrug antibodies adabs identified one major factors impacting clearance thus serum trough levels adab measurement proposed monitoring anti tnf drugs algorithms defined management patients ibd while etiology ibd still unknown thought involve complex interactions genetic disposition environmental conditions life style microbial immune factors resulting deregulated excessive immune response directed components normal microflora cd uc associated exaggerated helper th type 1 th2 responses respectively more recent studies demonstrated tissue damages result mucosal inflammation mainly mediated proinflammatory th1 th17 lymphocyte subpopulations respective proinflammatory effector cytokines gut cd patients activated th1 th17 cells produce ifn il17 f respectively stimulate macrophages induce production inflammatory cytokines il-1 tnf subsequently promote matrix metalloproteinases mmps production stroma cells mucosal damage thus widely accepted tnf plays strategic role ibd pathophysiology cross talk different inflammatory pathways involved gut mucosal inflammation accordingly efficient biologic therapies developed far ibd aimed neutralizing proinflammatory activity tnf pathway the effects tnf known mediated tnf receptor tnf ri tnf rii ligation tnf ri expressed wide range immune nonimmune cells results nf-b activation cytotoxicity induction proinflammatory cytokines chemokines well antiapoptotic peptides 9 10 the effects lymphocytes mainly mediated interaction tnf tnf rii inducing costimulatory signal tcr mediated cell activation thereby increasing cell proliferation expression cell activation markers cd25 human leukocyte antigen dr tnf rii secretion inflammatory cytokines including ifn tnf accordingly anti tnf able inhibit cell activation resulting decrease proliferation cytokine secretion ifn- il-13 il-17a tnf cd4 cd8 cell populations derived uc patients hand tnf tnf rii also able activate expand protective cd4(+)foxp3(+ regulatory cells tregs seem critical stabilization phenotype function inflammatory environment lamina propria mouse model colitis these contrasting effects tnf effector versus regulatory cells may explain unexpected disappointing results obtained anti tnf autoimmune diseases multiple sclerosis altogether data underline complexity tnf function via tnf ri tnf rii course intestinal inflammation due different susceptibility epithelial cells effector regulatory immune cells illustration dextran sulfate sodium- dss- induced acute colitis balb c mice tnf ri ablation led exacerbation disease increased inflammation intestinal damage tnf rii deficiency opposite effects nonetheless studies patients ibd extensively demonstrated efficiency anti tnf therapies directly inhibit activation effector cells sensitize treg mediated inhibition final restoration immune homeostasis resolution inflammation mucosal healing further studies required better understand respective protective deleterious effects mediated tnf immune nonimmune cells tnf ri tnf rii order develop specific inhibitors potentially increased efficacy and/or safety numerous randomized clinical trials meta analyses demonstrated efficacy monoclonal antibodies tnf induction maintenance remission cd uc 1618 infliximab ifx chimeric monoclonal antibody composed human constant murine variable regions adalimumab fully human monoclonal igg1 anti tnf antibody demonstrated efficacy control disease activity induction clinical remission mucosal healing luminal cd uc children adult patients 1 1925 several randomized clinical trials showed better efficacy inducing steroid free clinical remission combination therapy immunomodulators anti tnf monotherapy cd uc moreover several studies established use infliximab adalimumab active fistulizing cd adult patients 27 28 certolizumab polyethylene glycolated fab fragment anti tnf ab also produced significant clinical benefit mucosal healing adult patients cd recently golimumab fully human monoclonal antibody tnf shown induce maintain clinical response patients active moderate severe uc 30 31 however although 60 80 percent patients exhibit good initial response anti tnf treatments defined crohn disease activity index cdai decrease baseline 70 points cd decrease mayo score least 3 points least 30 percent uc one third patients clinical remission without steroids one year defined cdai 150 cd total mayo score 2 points lower individual subscore exceeding 1 point uc consequently 20 30 percent patients require dose intensification interval adjustment order maintain long term clinical benefit average 10 20 percent per year lose response 3236 despite high effectiveness anti tnf patients ibd one third patients present primary resistance another one third become resistant time optimal clinical response required maintenance clinically effective drug concentrations pharmacokinetic anti tnf highly variable among patients could influenced numerous factors including gender body weight associated treatments immunosuppressants known increase anti tnf trough levels route administration serum albumin concentration systemic inflammation markedly decreased half life patients severe disease 3840 however main factor impacting anti tnf pharmacokinetic efficacy time immunogenicity whereby antidrug antibodies adabs accelerate anti tnf monoclonal abs clearance shorten half life 41 42 although humanized e.g. certolizumab fully human abs e.g. adalimumab golimumab logically less immunogenic compared chimeric ones e.g. ifx induce adabs targeting murine and/or variable domains monoclonal ab other factors may promote immunogenicity genotype minority patients drug agitation freeze thaw cycles induce immunogenic protein aggregates review contrastingly prescription maintenance therapy concomitant immunomodulators achievement suitable trough drug levels shown reduce risk adabs several studies assessed ifx trough levels induction treatment maintenance therapy predictors sustained clinical response showed significant correlation low ifx trough levels decreased clinical response cd uc adult patients 3 4 34 4547 children uc recent prospective study ibd patients developed secondary failure ifx paul et al have shown factor associated mucosal healing ifx optimization significant increase ifx trough levels antibodies ifx atis described 60% ifx used ad hoc basis practice 10 20% patients randomized controlled trials maintenance therapy atis associated loss clinical response deterioration endoscopic activity infusion reactions low serum ifx concentrations 5 41 44 46 5052 however studies observe significant correlation trough levels ifx cd activity positivity atis loss clinical response deterioration endoscopic activity 3 4 5355 these discrepancies could explained different methods measurements atis ifx concentrations short follow time studies lack consensual optimal levels ifx prediction efficacy there fewer data adalimumab studies also described positive association serum adalimumab concentration clinical remission cd 5658 furthermore fully human antiadalimumab antibodies described 2.6 17 percent patients treated cd rheumatoid arthritis significantly associated low serum adalimumab trough levels decreased clinical response 56 5961 the relationship pharmacokinetic data efficacy less clear adalimumab ifx considerable variability overlap serum concentrations patients without remission however observational study evaluating efficacy adalimumab 168 active cd patients failed respond ifx long term clinical benefit significantly associated higher serum trough concentrations absence adab a recent study using adalimumab maintenance therapy 40 adult patients cd uc showed significant association high trough levels adalimumab clinical remission mucosal healing antiadalimumab antibodies associated low trough levels adalimumab lack mucosal healing there far data concerning trough levels antidrug antibodies adalimumab children patients certolizumab golimumab serum trough levels measurement detect subtherapeutic drug concentrations identification adab therapeutic drug monitoring tdm relevant useful parameters monitoring anti tnf drugs facilitate informed decision making ibd patients secondary loss response tnf antagonists the clinical utility immunomonitoring evaluated retrospective study conducted 155 patients ibd loss response ifx when adabs detected switch another anti tnf molecule allowed partial complete response 92% versus 17% dose escalation whereas drug escalation efficient strategy patients subtherapeutic ifx concentration 86% versus 33% partial complete response resp they concluded increasing anti tnf doses ineffective patients adab appropriate case subtherapeutic drug concentration proposed algorithm optimization therapeutic strategy ibd patients loss response ifx based adab trough drug measurement interestingly prospective study examining course adab formation clinical relevance assessment followup patients rheumatoid arthritis bartelds et al showed among patients positive antiadalimumab abs 67% developed adabs first 28 weeks almost one third first month treatment however despite poor clinical response patients adabs discontinued treatment 52 weeks therapy indicating important delay adab appearance treatment adjustment furthermore early trough level measurement induction might also prognostic value ifx trough levels 3.5 g ml 14 weeks associated sustained therapeutic response hand supratherapeutic anti tnf trough levels might also associated paradoxical inflammatory side effects psoriasiform eczema arthralgia patients lowering doses could beneficial terms safety also decrease cost healthcare payer altogether data plead clinical economical utility early therapeutic drug monitoring management patients receiving tnf inhibitors case loss response low trough level without adab intensified therapy drug when low trough level related presence adabs therapy switched within anti tnf class necessary drug another mode action the addition immunomodulator might also able induce decrease adab level restore clinical response note clinical response occur despite presence adabs described recently retrospective study continued maintenance therapy ifx induced adab disappearance two thirds patients median 4 infusions suggesting continued anti tnf treatment could considered patients clinical response first adab detection indeed recent studies investigating kinetics ati formation confirmed adab secretion may transient disappeared time almost one third patients 67 68 compared nontransient ati appeared usually within first 12months therapy transient ati detected throughout duration ifx therapy patients sustained ati likely discontinue ifx treatment compared patients transient ati recent study using decision analytic model simulated 2 cohorts patients cd become resistant anti tnf inhibitors velayos et al compared effectiveness empiric dose escalation versus testing based strategy 1-year time period although strategies yielded similar rates remission 66% versus 63% resp quality adjusted life year 0.800 versus 0.801 testing based strategy less expensive empiric dose escalation 31,870 versus 34,266 resp similarly steenholdt et al showed randomized controlled trial testing based strategy using algorithm designed identify mechanism leading secondary loss response ifx cost effective empiric dose escalation patients cd monitored arm patients low serum ifx atis switched adalimumab patients low serum ifx without atis underwent dose intensification patients high ifx trough levels without atis switched class therapy screened alternate cause symptoms compared current dose intensification strategy individualized therapy substantially reduced average treatment costs per patient similar clinical response rates large prospective randomized studies still required validate approaches patients ibd clear dose toxicity efficacy relationships yet established anti tnf inhibitors finally keep mind absence standardization numerous assays developed serum trough levels adab measurement table 1 exhibit variable performances could explain discrepancies studies difficulties establishing clear cutoff values there currently defined gold standard assays quantification anti tnf drugs adabs a recent study compared three house commercially available assays elisa bridging elisa ria developed analysis ifx levels atis there good correlation ifx ati levels measured 3 tests the sensitivity three assays detect atis comparable slight advantage ria test less sensitive elisa drug interference caused presence ifx serum impeding detection low ati concentrations nevertheless discrepancies three assays rare conclusions study highly debated highlighting high need standardization 72 73 since advent anti tnf biologics decade ago demonstrated beneficial activity induction maintenance clinical responses mucosal healing improvement quality life reduction surgeries hospitalizations treatment extraintestinal manifestations ibd however despite good overall initial effectiveness significant proportion patients lose response time mainly adab production accelerated drug clearance although optimal treatment strategies remain controversial therapeutic algorithms proposed based serum trough levels adab monitoring order rationalize drug adjustment future a better understanding ambivalent protective deleterious effects mediated tnf receptors immune nonimmune cells ibd might crucial development efficient safe biological inhibitors | since their appearance in the armamentarium for inflammatory bowel disease ( ibd ) more than a decade ago , antitumor necrosis factor ( tnf ) inhibitors have demonstrated beneficial activity in induction and maintenance of clinical remission , mucosal healing , improvement in quality of life , and reduction in surgeries and hospitalizations .
however , more than one - third of patients present primary resistance , and another one - third become resistant over time .
one of the main factors associated with loss of response is the immunogenicity of anti - tnf biologics leading to the production of antidrug antibodies ( adabs ) accelerating their clearance . in this review
we present the current state of the literature on the place of tnf and its blockage in the treatment of patients with ibd and discuss the usefulness of serum trough levels and adab monitoring in the optimization of anti - tnf therapies . |
major task evolutionary biology develop test theories origin novelty consistent fundamental genetic principles gradual populational change novelty however loaded term many different definitions include exclude variety morphological characters brigandt love 2012 following pigliucci 2008 prefer inclusive definition evolutionary novelty new traits novel combinations traits within lineage perform new ecological function may result establishment new evolutionary lineages more narrowly focused definitions might desirable purposes muller wagner 1991 wagner lynch 2010 however goal essay elaborate one mechanism sudden origin evolutionary success new variants applies well exceptional size shape new color patterns use new habitats new exons some theorists invoked special phenomena genome wide macromutations goldschmidt 1940 genetic revolutions mayr 1954 get around perceived difficulties emergence profound change accumulation subtle changes conventional dynamics mutation gene flow drift selection however modern evolutionary theory empirical research genetics consistently reaffirmed ability conventional population genetics explain origin new species phenotypes simultaneously exposed flaws alternatives charlesworth et al for example goldschmidt 1933 1940 proposed novel phenotype insect wings character associated higher level taxonomy must first arise instantaneous product single macromutation systemic mutation individuals bearing macromutations characterized hopeful monsters goldschmidt 1933 1940 emphasize appearance neither purposeful gradual prospects success matter luck a hopeful monster individual phenotypically discontinuous range phenotypes population whose hopes establishing new lineage lie finding novel niche monstrosity happens preadapted such mechanism speciation criticized early improbable overtax one credulity dobzhansky 1937 p. 53 rarity initial mutation large effect resulting improbability finding equally monstrous mate dobzhansky 1937 recent empirical theoretical research hybrid speciation might revived hopeful monster new credible form mallet 2007 recombination parental chromosomes f2 later generations hybridization generate genotypes express phenotypes outside normal range variation observed either parental gene pool phenomenon termed transgressive segregation
; rosenthal et al 2005 johnson et al 2010 parsons et al 2011 often transgressive hybrids higher fitness novel environments increasing likelihood divergence parental populations arnold hodges 1995 buerkle et al 2007 shahid et al 2008 abbott et al 2010 fitzpatrick et al 2010 a examples new phenotypes inferred arise hybridization include see arnold 1997 arnold 2006 stelkens seehausen 2009 exhaustive reviews extreme size tiger x lion f1 hybrids gray 1954 unique shapes colors hybrid orchids rolfe hurst 1909 ability recombinant sunflowers thrive extreme habits lexer et al 2003 2007 specialization novel host plant lonicera flies schwarz et al 2005 expression novel gene transcripts including new exons via alternative splicing hybrid poplars scascitelli et al not specific examples relevant nature would qualify evolutionary novelty certain definitions muller wagner 1991 pigliucci 2008 wagner lynch 2010 small selection cases serves illustrate sudden appearance profound differences parents hybrid offspring reminiscent goldschmidt hopeful monsters.fig
1recently metamorphosed juvenile tiger salamanders representative ambystoma mavortium bts a. californiense cts transgressive later generation hybrid the late generation hybrid transgressive coloration body size mass snout vent length beyond range parental populations recently metamorphosed juvenile tiger salamanders representative ambystoma mavortium bts a. californiense cts transgressive later generation hybrid the late generation hybrid transgressive coloration body size mass snout vent length beyond range parental populations arnold colleagues promoted importance transgressive segregation evolutionary novelty model hybridization arnold 1997 arnold et al mallet 2007 even referred transgressive hybrids hopeful monsters p. bateson 1984 2002 proposed simple model sudden appearance successful spread novel phenotype via hybridization mechanism saltational evolution expand make genetically explicit haploid diploid polyploid cases model fig 2 2003 hybrid fitness dobzhansky 1937 muller 1942 turelli orr 2000 all special cases general multilocus model fitzpatrick 2008 give rise evolution novelty discontinuity cumulative combined outcome conventional population genetic change indeed recombination always recognized important source variation mendel 1866 whether variation perceived profound
2genetically explicit versions bateson model haploid case b diploid case c allopolyploidy genotypes asterisks novel recombinant true breeding genotypes genetically explicit versions bateson model haploid case b diploid case c allopolyploidy bateson 1984 2002 proposal recombination generate sudden change straightforward narrative two different mutations b appear become fixed different populations similar phenotypes circles diagram when populations merge recombinant individuals b express new phenotype diamonds diagram successful becomes fixed aside mutation bateson use genetically explicit vocabulary diagram suggests haploid genome mutations b occurring different loci recombination place together individual we show version bateson model explicit haploid diploid allopolyploid cases fig 2 the key feature new phenotype depends interaction alleles b different loci if b alleles common admixed population new phenotype expressed large number individuals interbreed rather single mutant monster prospect mate moreover even interactions loci render hybrids even f1 hybrids partly mostly sterile recombination could produce transgressive hybrids restored fertility f2 later generations fig
. 3a schematic representation process two fixed allelic differences b unlinked loci might recombine meiosis two f1 hybrids create novel homozygous genotype aabb f2 hybrid note two novel recombinant chromosomes f2 result independent recombinational events schematic representation process two fixed allelic differences b unlinked loci might recombine meiosis two f1 hybrids create novel homozygous genotype aabb f2 hybrid note two novel recombinant chromosomes f2 result independent recombinational events bateson 2002 went note idea points similarity dobzhansky muller model hybrid dysfunction dobzhansky 1937 muller 1942 turelli orr 2000 earlier verbal model w. bateson 1909 in fact explicit diploid version bateson model differs dobzhansky muller model sign interaction bateson model supposes interaction b increases fitness dobzhansky muller model specifies decrease fitness recombinant hybrids table 1a b both models describe gene interaction epistasis causing hybrid phenotype fall outside range either parental population that special cases transgressive segregation.table 1diploid two locus models hybrid phenotypesaaaaaa(a epistatic hybrid dysfunction bb111 bb11 h01 h1 bb11 h11 h2(b epistatic hybrid vigor bb111 bb11 s01 s1 bb11 s11 s2(c additive complementation bb1 2x1 x1 bb1 x11 x bb11 x1 2xin case parental genotypes aabb aabb epistatic hybrid dysfunction dobzhansky muller model epistatic hybrid vigor b bateson model differ whether effects assumed deleterious beneficial the additive complementation model c shows recombinants phenotypically extreme relative parentals aabb aabb even without gene interaction b allele contributes amount x phenotypic value regardless locus all written special cases general quantitative genetic model hill 1984 lynch walsh 1997 fitzpatrick 2008 diploid two locus models hybrid phenotypes case parental genotypes aabb aabb epistatic hybrid dysfunction dobzhansky muller model epistatic hybrid vigor b bateson model differ whether effects assumed deleterious beneficial the additive complementation model c shows recombinants phenotypically extreme relative parentals aabb aabb even without gene interaction b allele contributes amount x phenotypic value regardless locus all written special cases general quantitative genetic model hill 1984 lynch walsh 1997 fitzpatrick 2008 transgressive segregation also caused strictly additive effects multiple genes table 1c nilsson ehle 1911 grant 1975 ( 2003 qtl studies transgressive hybridization plants additive effects detected often epistatic dominance interactions rieseberg et al strictly additive strictly epistatic models special cases general quantitative genetic model allowing phenotypes affected additive dominance epistatic effects hill 1984 lynch walsh 1997 fitzpatrick 2008 extending basic ideas many loci multivariate phenotypes leads general conclusion recombination disparate genomes great potential produce novel phenotypes gavrilets 1999 the primary prediction characterizing many years speciation research hybridization disparate genomes often generate novel phenotypes inviable sterile hopeless monsters becomes ever likely increasing differentiation dobzhansky 1937 mayr 1942 muller 1942 orr turelli 2001 coyne orr 2004 gavrilets 2004 time number potentially beneficial interactions might increase stelkens seehausen 2009 stelkens et al 2009 leading race potential hybrid speciation evolution complete reproductive isolation as case mutations large effect probably inverse relationship magnitude transgressive beneficial phenotype likelihood actually generated nature the important prediction arising hybridization source novelty admixed populations many recombinant individuals repeatedly bring together many genetic differences many unique combinations first instead single genetic difference diversity recombinant genotypes f1 generation provides wide field selection beneficial versus deleterious interactions lexer et al 2003 parsons et al 2011 pointed arnold hodges 1995 means even hybrid interactions deleterious still good chance rare beneficial recombinant appear unless f1 hybrids completely sterile inviable second segregating hybrid populations repeatedly produce recombinant genotypes transgressive phenotypes figs 2 3 instead producing single unique mutant rare variant likely lost even advantageous gillespie 2004 this means hopeful monsters produced transgressive segregation good chance finding suitably monstrous mates hybrid population establish true breeding population derived many independent interspecific matings bateson 2002 although speciation transgressive hybridization expected rapid diploids ungerer et al 1998 predict fixation novel transgressive hybrids rapid perhaps common haploid allopolyploid hybrids all recombinant hybrids haploid allopolyploid populations true breeding compared fraction diploid recombinant hybrids fig 2 in case complete incomplete dominance b four diploid recombinant genotypes exhibit transgressive phenotype double homozygote true breeding this might lead lower average fitness diploid hybrid population contains high fitness transgressive phenotypes several generations hybridization initiated johnson et al finally subtle predictions might arise variation genomic structure development for example dobzhansky muller model helps explain empirical generalizations including haldane rule large x effect hybrid dysfunction extension expression beneficial transgressive phenotypes might differ sex chromosomes autosomes differential consequences males females lineages chromosomal sex determination specifically if transgressive phenotypes often recessive s0 s1 s2 table 1b one interacting genes sex chromosome phenotype likely expressed heterogametic sex even f1 generation whether rules might exist transgressive phenotypes depends largely whether dominance consistent effect trait expression the broad generalization emerging reviews empirical literature far appears additive complementation model often adequate explain data rieseberg et al 1999 burke arnold 2001 however epistasis dominance infrequently detected difference might reflect lower statistical power detect non additive effects the idea hybridization rapidly produce novel forms familiar among botanists rarely appeared mainstream discussions speciation recently thanks several case studies homoploid hybrid speciation reviews see arnold 1997 rieseberg et al recombination fixed genetic differences two populations f2 later generations produce hybrids phenotypes novel parental populations fig
3 recombinant phenotypes fitness beyond range parental phenotypes transgressive fig 1 bateson model hybridogenic hopeful monsters dobzhansky muller incompatibility model hybrid inviability cases transgressive segregation the dobzhansky muller model produces hopeless monster hopeless sterility inviability make finding mate and/or novel niche moot monstrous sterility inviability phenotypes outside parental range phenotypes table 1a the bateson model produces hopeful monster hopeful good chance finding mate given continued hybridization greater fitness parental phenotypes environments monstrous transgressive phenotype table 1b all three models special cases general quantitative genetic model thus reconciling sudden gradual origins novelty without requiring special class mutations population dynamics transgressive segregation might important mechanism promoting sudden phenotypic changes ecological transitions evolution even variation produced deleterious rare transgressive hybrid genotype could rapidly fix population establish novel lineage it even possible regularities distribution dominance effects could lead general predictions large x effect haldane rule transgressive trait expression research genetic architecture transgressive traits needed regardless details admixture simultaneously bring together many new combinations alleles generating multilocus novelties might never appeared via gradual accumulation new mutations single population gene exchange sole even necessarily likely source evolutionary novelty meyer 2002 moczek 2008 perhaps likely mechanism sudden population level change | the origin of novelty is a critical subject for evolutionary biologists .
early geneticists speculated about the sudden appearance of new species via special macromutations , epitomized by goldschmidt s infamous hopeful monster .
although these ideas were easily dismissed by the insights of the modern synthesis , a lingering fascination with the possibility of sudden , dramatic change has persisted .
recent work on hybridization and gene exchange suggests an underappreciated mechanism for the sudden appearance of evolutionary novelty that is entirely consistent with the principles of modern population genetics .
genetic recombination in hybrids can produce transgressive phenotypes , monstrous phenotypes beyond the range of parental populations .
transgressive phenotypes can be products of epistatic interactions or additive effects of multiple recombined loci .
we compare several epistatic and additive models of transgressive segregation in hybrids and find that they are special cases of a general , classic quantitative genetic model .
the dobzhansky - muller model predicts hopeless monsters , sterile and inviable transgressive phenotypes . the bateson model predicts hopeful monsters with fitness greater than either parental population .
the complementation model predicts both .
transgressive segregation after hybridization can rapidly produce novel phenotypes by recombining multiple loci simultaneously .
admixed populations will also produce many similar recombinant phenotypes at the same time , increasing the probability that recombinant
hopeful monsters will establish true - breeding evolutionary lineages .
recombination is not the only ( or even most common ) process generating evolutionary novelty , but might be the most credible mechanism for sudden appearance of new forms . |
caries activity usually causes tooth decay cavities even lead loss afflicted teeth particularly harmful children growth development world health organization reported 6090% schoolchildren worldwide experience caries disease prevalent asian latin american countries surveys among us population showed incidence 45.3% children either past present coronal caries rate caries increasing developing countries increasing consumption highly refined sugars diet according third national epidemiological survey dental health china 2007 prevalence dental caries among 5-year old children china 66.0% mean number 3.5 per capita caries teeth therefore caries disease ranked third important disease requires worldwide attention prevention treatment studies etiology dental caries identified risk factors consuming foods beverages high content refined carbohydrates receiving bottle feed prolonged period deficient hygiene etc given strong evidence supporting relationship dental caries irregular dietary patterns link abnormal dietary intake obesity several reports described link caries weight indicating obese children caries children normal weight group however others concluded significant difference dmft dmft score among different body mass index bmi groups 38-year old children therefore consensus reached relationship obesity dental caries children qingdao key economic center port city china yet till national data concerning caries status among school children native area less known relationship caries weight status study large scale population based oral health survey among 8-year old children conducted january july 2012 qingdao shandong province china supported qingdao government the aims present study 1 assess caries prevalence severity 8-year old children qingdao 2 assess relationship caries disease weight status 8-year old children qingdao in cross sectional study oral health survey conducted january july 2012 eight year old children 28 public elementary schools qingdao invited participate survey children parents were informed nature experiment gave written informed consent the study conducted obtaining approval ethical committee qingdao municipal hospital oral examination mainly visual inspection plus probing was undertaken according criteria diagnosis caries dental mirror exploring probe generally dental caries diagnosed prominent color shape caries like change pit fissure smooth surface caries experience evaluated subjects teeth included deciduous dmft mixed dmft dmft dentition dmft number decayed missing filled teeth permanent dentition study 8-year old children permanent teeth included central incisors lateral incisors first molars mandibular maxillary bone dmft number decayed missing filled teeth deciduous dentition indices recorded dental charts all examinations performed eight calibrated professional dentists trained assessment dmft/(dmft dmft index prior oral survey initial evaluation caries detection inter examiner kappa values 0.80 indicating good agreement among examiners weight evaluated using single calibrated scale tanita ultimate series 2204 tanita corporation inc height measured using harpenden stadiometer holtain ltd dyved uk subject standing straight without shoes corrected nearest 0.1 cm bmi calculated using following formula weight kg/(height meters squared weight status defined gender related bmi according centers disease control prevention cdc guidelines follows underweight bmi 5 percentile normal weight bmi 5 85 percentile risk overweight bmi 85 95 percentile overweight bmi 95 percentile all data collected standardized forms database created collected information including age gender protect confidentiality database password secured accessible one data analyst descriptive data obtained outcome variables reported mean sd student test chi square test one way analysis variance anova applied statistical evaluation means comparisons proportions the overall caries disease status bmi group compared based dmft dmft dmft caries prevalence pearson correlation applied dmft/(dmft dmft bmi value assess relationship caries weight status in cross sectional study oral health survey conducted january july 2012 eight year old children 28 public elementary schools qingdao invited participate survey children parents were informed nature experiment gave written informed consent the study conducted obtaining approval ethical committee qingdao municipal hospital the oral examination mainly visual inspection plus probing undertaken according criteria diagnosis caries dental mirror exploring probe generally dental caries diagnosed prominent color shape caries like change pit fissure smooth surface caries experience evaluated subjects teeth included deciduous dmft mixed dmft dmft dentition dmft number decayed missing filled teeth permanent dentition study 8-year old children permanent teeth included central incisors lateral incisors first molars mandibular maxillary bone dmft number decayed missing filled teeth deciduous dentition indices recorded dental charts all examinations performed eight calibrated professional dentists trained assessment dmft/(dmft dmft index prior oral survey initial evaluation caries detection inter examiner kappa values 0.80 indicating good agreement among examiners weight evaluated using single calibrated scale tanita ultimate series 2204 tanita corporation inc height measured using harpenden stadiometer holtain ltd dyved uk subject standing straight without shoes corrected nearest 0.1 cm bmi calculated using following formula weight kg/(height meters squared weight status defined gender related bmi according centers disease control prevention cdc guidelines follows underweight bmi 5 percentile normal weight bmi 5 85 percentile risk overweight bmi 85 95 percentile overweight bmi 95 percentile all data collected standardized forms database created collected information including age gender protect confidentiality database password secured accessible one data analyst descriptive data obtained outcome variables reported mean sd student test chi square test one way analysis variance anova applied statistical evaluation means comparisons proportions the overall caries disease status bmi group compared based dmft dmft dmft caries prevalence pearson correlation applied dmft/(dmft dmft bmi value assess relationship caries weight status a total 758 children 28 primary schools qingdao initially included study the withdrawal 14 children due missing values resulted final group 744 children consisted 384 males 360 females subjects fell age range 88.5 years nearly symmetric gender distribution 51.6% males 48.4% females the total number teeth went inspection 17,139 averaging 23.0 per capita decayed teeth numbered 3008 averaging 4.0 per capita results showed 642 86.3% total 327 males 315 females children suffered dental caries 102 13.1% total 57 males 45 females caries free approximately 6.0% children study n 45 16 males 29 females underweight 73.9% n 550 264 males 286 females normal weight 9.8% n 73 38 males 35 females 10.2% n 96 76 males 10 females risk overweight overweight respectively no significant difference found two genders p 0.05 respect caries prevalence the mean dmft values 4.29 males 4.34 females deciduous dentition among permanent teeth except first permanent molar the mean dmft values 0.43 males 0.61 females permanent dentition the constitution dmft dmft index two genders similar p 0.05 except f value significantly higher males females p 0.1 similarly significantly higher restoration rates found male children 2.9% female children 1.2% p 0.01 table 1 caries experience children teeth highest caries prevalence 51.6% right mandibular second deciduous molar teeth 85 52.6% females 50.7% males followed teeth 75 74 84 caries prevalence 50.2 47.2 47.0% respectively figure 1 significantly higher caries prevalence found mandibular deciduous molars 49.0% compared maxilla deciduous molars 38.1% figure 1 among newly erupted permanent first molars teeth 36 46 found high caries prevalence 15.8 15.0% respectively contrast teeth 16 26 relatively low caries prevalence 5.7 5.0% respectively figure 1 the mandibular second deciduous molars teeth 85 accounted 51.6% caries prevalence among children there significantly higher rate caries prevalence mandibular deciduous molars 49.0% maxillary deciduous molars 38.1% among newly erupted permanent first molars teeth 36 46 found highest caries prevalence 15.8 15.0% respectively among female children 8.1% fell underweight category 79.4% fell healthy category 9.7 2.8% considered risk overweight overweight respectively among male children 14.2% underweight 68.6% healthy 9.9 17.2% considered risk overweight overweight respectively considering male female children mean height 132.1 cm mean weight 19.0 kg significant difference detected weight height two genders p 0.01 table 2 classification body weight status according cdc guidelines values dmft/(dmft dmft bmi group compared results showed statistically significant differences different bmi groups p 0.1 dmft dmft p 0.01 dmft table 3 highest dmft/(dmft dmft values underweight group no significant difference found caries prevalence different bmi groups table 3 pearson correlation dmft/(dmft dmft bmi significant p 0.04 dmft p 0.004 dmft dmft r values 0.075 0.104 dmft dmft dmft respectively these results indicated inverse relationship bmi caries severity figure 2 comparison caries status according bmi classification pearson correlation bmi caries experience ( caries severity evaluated dmft dmft values b dmft values pearson correlation caries severity bmi index significant p 0.004 p 0.04 b ) no significant difference found two genders p 0.05 respect caries prevalence the mean dmft values 4.29 males 4.34 females deciduous dentition among permanent teeth except first permanent molar the mean dmft values 0.43 males 0.61 females permanent dentition the constitution dmft dmft index two genders similar p 0.05 except f value significantly higher males females p 0.1 similarly significantly higher restoration rates found male children 2.9% female children 1.2% p 0.01 table 1 caries experience children teeth highest caries prevalence 51.6% right mandibular second deciduous molar teeth 85 52.6% females 50.7% males followed teeth 75 74 84 caries prevalence 50.2 47.2 47.0% respectively figure 1 significantly higher caries prevalence found mandibular deciduous molars 49.0% compared maxilla deciduous molars 38.1% figure 1 among newly erupted permanent first molars teeth 36 46 found high caries prevalence 15.8 15.0% respectively contrast teeth 16 26 relatively low caries prevalence 5.7 5.0% respectively figure 1 the mandibular second deciduous molars teeth 85 accounted 51.6% caries prevalence among children significantly higher rate caries prevalence mandibular deciduous molars 49.0% maxillary deciduous molars 38.1% among newly erupted permanent first molars teeth 36 46 found highest caries prevalence 15.8 15.0% respectively among female children 8.1% fell underweight category 79.4% fell healthy category 9.7 2.8% considered risk overweight overweight respectively among male children 14.2% underweight 68.6% healthy 9.9 17.2% considered risk overweight overweight respectively considering male female children mean height 132.1 cm mean weight 19.0 kg significant difference detected weight height two genders p 0.01 table 2 values dmft/(dmft dmft bmi group compared results showed statistically significant differences different bmi groups p 0.1 dmft dmft p 0.01 dmft table 3 highest dmft/(dmft dmft values underweight group significant difference found caries prevalence different bmi groups table 3 pearson correlation dmft/(dmft dmft bmi significant p 0.04 dmft p 0.004 dmft dmft r values 0.075 0.104 dmft dmft dmft respectively these results indicated inverse relationship bmi caries severity figure 2 comparison caries status according bmi classification pearson correlation bmi caries experience ( caries severity evaluated dmft dmft values b dmft values pearson correlation caries severity bmi index significant p 0.004 p 0.04 b ) qingdao located southern part shandong peninsula facing yellow sea east south the qingdao government initiated public welfare project oral health examination pit fissure sealant caries filling treatment public primary school students provided opportunity systematically assess caries status children qingdao for assessment dental caries used dmft dmft index one commonly used indices epidemiological studies evaluating caries experience we found firstly 744 children aged 8 years qingdao generally poor oral health status although rate similar reported domestic studies 85.4% caries prevalence children similar age group guangzhou average dmft index 4.31 study significantly higher reported dmft index 3.11 study guangzhou furthermore caries prevalence dmft value 8-year old children qingdao significantly higher reported countries sudan the reason might changes dietary habit happened last decade changes dietary content children qingdao observed past years consuming significantly desserts ever yet oral health low level secondly noted averagely 2.1% decayed teeth treated filling this finding consistent restoration rate children previous regional study supporting widespread negligence oral health children china therefore dental treatment dental health education children parents teachers even whole society urgently needed thirdly significantly higher restoration rate males might partially reflect male children receiving oral care female children our findings might add support notion restoration rate correlated regional economy culture education lastly data showed mandibular second deciduous molars accounted 50% decayed teeth suggested necessity pay attention protecting particular teeth caries early stage weight status children measured bmi according gender age ranked percentages our study showed 10% children overweight among 8-year old children slightly lower corresponding values previously reported analyses conducted chinese regions according studies conducted chengdu shanghai prevalence obesity 3% respectively similar data female children significantly lower data male children 17.2% methodological differences e.g. criteria recommended cdc guidelines international obesity task force world health organization might contributed differences causing difficulty comparing results studies in recent studies based criteria recommended cdc guidelines 31.0% us children risk overweight 16.0% overweight percentages obviously higher obtained survey caries usually regarded consequence frequent ingestion fermentable sugars also lead obesity result however findings obesity caries relationship children different countries actually mixed inconclusive conclusions positive links links inverse links present example sole study china reported correlation obesity caries among 280 children this due confounding factors age gender dentition race ethnicity socioeconomic status might affect final conclusion to eliminate potential confounding factors conducted study subjects relatively homogeneous environment they children single specific age group native population similar living environment eating habits public primary schools similar socioeconomic background nearly symmetric gender distribution also utilized two indices dmft dmft dmft assess caries severity children deciduous mixed dentition regardless index used analysis instead previously suspected positive link weak inverse relationship body weight caries severity found comparison also showed underweight individuals significantly severe caries disease this finding suggested relationship obesity caries straightforward earlier suspected moreover although focusing identical age group result consistent nationally representative survey based dataset 10,800 american adolescents national health nutrition examination survey nhanes iii 19881994 nhanes 19992002 suggested overweight status may associated somewhat decreased risk caries our results showed underweight children likely found severe caries disease regardless primary mixed dentition this result consistent mojarad werner roswitha reports nowadays china living standard improved significantly along rapid progress economy in addition china one child policy turned many children little emperor families argues fact underweight status children due poverty thus plausible caries might one cause behind children underweight following mechanisms might account observed inverse relationship bmi dmft/(dmft dmft index firstly untreated caries might caused severe pain discomfort children thus reduced food intake secondly caries also lead infection irritability disturbed sleeping habits might reduce quality life affect growth one limitation study use cross sectional data examine link caries experience weight status test cause
however strength study use localized relatively simple representative samples chinese children explore control multiple confounding factors results yielded consistent findings deciduous mixed dentition for assessment dental caries used dmft dmft index one commonly used indices epidemiological studies evaluating caries experience we found firstly 744 children aged 8 years qingdao generally poor oral health status although rate similar reported domestic studies 85.4% caries prevalence children similar age group guangzhou average dmft index 4.31 study significantly higher reported dmft index 3.11 study guangzhou furthermore caries prevalence dmft value 8-year old children qingdao significantly higher reported countries sudan the reason might changes dietary habit happened last decade changes dietary content children qingdao observed past years consuming significantly desserts ever yet oral health low level secondly noted averagely 2.1% decayed teeth treated filling this finding consistent restoration rate children previous regional study supporting widespread negligence oral health children china therefore dental treatment dental health education children parents teachers even whole society urgently needed thirdly significantly higher restoration rate males might partially reflect male children receiving oral care female children our findings might add support notion restoration rate correlated regional economy culture education lastly data showed mandibular second deciduous molars accounted 50% decayed teeth suggested necessity pay attention protecting particular teeth caries early stage weight status children measured bmi according gender age ranked percentages our study showed 10% children overweight among 8-year old children slightly lower corresponding values previously reported analyses conducted chinese regions according studies conducted chengdu shanghai prevalence obesity 3% respectively similar data female children significantly lower data male children 17.2% methodological differences e.g. criteria recommended cdc guidelines international obesity task force world health organization might contributed differences causing difficulty comparing results studies in recent studies based criteria recommended cdc guidelines 31.0% us children risk overweight 16.0% overweight percentages obviously higher obtained survey caries usually regarded consequence frequent ingestion fermentable sugars also lead obesity result however findings obesity caries relationship children different countries actually mixed inconclusive conclusions positive links links inverse links present example sole study china reported correlation obesity caries among 280 children this due confounding factors age gender dentition race ethnicity socioeconomic status might affect final conclusion to eliminate potential confounding factors conducted study subjects relatively homogeneous environment they children single specific age group native population similar living environment eating habits public primary schools similar socioeconomic background nearly symmetric gender distribution also utilized two indices dmft dmft dmft assess caries severity children deciduous mixed dentition regardless index used analysis instead previously suspected positive link weak inverse relationship body weight caries severity was found comparison also showed underweight individuals significantly severe caries disease this finding suggested relationship obesity caries straightforward earlier suspected moreover although focusing identical age group result consistent nationally representative survey based dataset 10,800 american adolescents national health nutrition examination survey nhanes iii 19881994 nhanes 19992002 suggested overweight status may associated somewhat decreased risk caries our results showed underweight children likely found severe caries disease regardless primary mixed dentition this result consistent mojarad werner roswitha reports nowadays china living standard improved significantly along rapid progress economy in addition china one child policy turned many children little emperor families argues fact underweight status children due poverty thus plausible caries might one cause behind children underweight the following mechanisms might account observed inverse relationship bmi dmft/(dmft dmft index firstly untreated caries might caused severe pain discomfort children thus reduced food intake secondly caries also lead infection irritability disturbed sleeping habits might reduce quality life affect growth one limitation study use cross sectional data examine link caries experience weight status test cause
however strength study use localized relatively simple representative samples chinese children explore control multiple confounding factors results yielded consistent findings deciduous mixed dentition this study population based epidemiological survey caries body weight status 8-year old children qingdao china a severe state caries disease revealed survey 744 children aged 8 years urgent dental intervention treatment needed our study identified weak negative association caries severity weight status pilot population indicating caries lesions might reason affecting growth development children our finding suggested evidence available obesity considered risk factor caries diagnosis treatment planning children | objectives : childhood obesity / underweight status and caries are both important public health problems .
this study aims to investigate the caries status and its association with body weight in 8-year - old children in qingdao , china.materials and methods : we initiated a cross - sectional investigation on 744 children aged 8 years during the oral health survey in 2012 .
dental caries assessments were carried out and weight status was recorded accordingly .
the resulting caries status including caries prevalence , dmft ( deciduous dentition ) , and ( dmft + dmft ) ( mixed dentition ) , as well as bmi indices were analyzed for comparison and correlation.results:the prevalence of dental caries among the 744 children aged 8 years participating in this survey was 86.3% .
the caries status represented by dmft ( deciduous dentition ) and ( dmft + dmft ) ( mixed dentition ) values was 4.31 and 4.85 , respectively , and the restoration rate was extremely low , which was no more than 3.0% .
significant difference was found in dmft/(dmft + dmft ) values between different bmi groups , and underweight individuals were found to have the highest dmft/(dmft + dmft ) value .
an inverse relationship between body bmi and dmft/(dmft + dmft ) index was identified based on pearson 's correlation.conclusions:a severe state of caries disease was revealed in 8-year - old children in the chinese city of qingdao , for whom urgent dental intervention and treatment were needed .
furthermore , underweight individuals were found with the most severe caries experience , indicating caries may affect the development and growth of the afflicted children .
thus , more emphasis should be placed on improving their dental health , with caries prevention being given the priority . |
development function mammals like multicellular organism depends intercellular communication classically occurs either direct cell cell interaction bringing together cell surface proteins distance secreted soluble molecules binding cell surface receptors these interactions lead transduction intracellular signals cell surface nucleus regulation gene expression might occur a breach dogma based impermeable property biological membranes came demonstration lipid vesicles containing rnas proteins released mammalian cells modify biological activity non contacting cells simons raposo 2009 they also form budding lumen endosomes released fusion limiting membrane endosomes plasma membrane once secreted extracellular milieu endosomal intraluminal vesicles ilvs referred exosomes our review stick strict definition exosomes discuss recent findings indicating potential role neuronal exosomes intercellular communication within normal pathological central nervous system it widely accepted exosomes represent way intercellular exchange effector molecules allows emitting cells modify gene protein expression receiving cells they allow transfer membrane cytoplasmic proteins thery et al 2002 morelli et al 2004 well lipids involved signal transduction laulagnier et al 2004 subra et al exosomal mrnas translated valadi et al 2007 small rnas including micrornas mirnas mediate gene silencing receiving cells kosaka et al functioning brain relies capacity neurons locally modulate level synapses chemical synapses made presynaptic part filled neurotransmitter nt containing vesicles post synaptic part nt receptors anchored level post synaptic density psd specific patterns stimulation presynaptic cell durably increase decrease strength synaptic responses thereby reinforcing circuits underlying associations memory changes synaptic efficacy based modifications number post synaptic nt receptors amount nt released pre synaptically given stimulus changes one neuron driven another far explained ways classical signal transduction nts lipids proteins secreted one side synapse bind receptors opposite surface pre synaptic activity substances also released cell bodies dendrites regehr et al 2009 this leads modulations second messengers enzymatic activities acting effectors synaptic changes adhesion molecules neurotransmitter receptors cytoskeleton anchors malenka bear 2004 signal transduction also leads changes gene expression translation needed long lasting synaptic modifications bullmore sporns 2009 indeed control transcription occurs nucleus far away synapses undergoing plastic changes transcripts specifically transported along dendrites synapses undergoing specific patterns activation translated proteins modifying synaptic strength translation targets mediating dendritic growth also regulated mirnas expressed within dendrites schratt et al 2006 ; we recently observed exosomes secreted neurons contain mirnas unpublished observations given single mirnas multiple targets impact exosome mediated local transfer mirna pattern translated mrnas receiving neurons may quite extensive confined exchange rnas synapses would thus certainly represent efficient mechanism long term modifications specific synapses therefore exosomal pathway may constitute well designed mechanism local systemic inter neuronal transfer information within functional brain networks complexity superior direct cell cell contacts secreted soluble factors belting wittrup 2008 the dark side would exosome transfer might also represent privileged way propagating pathological alterations throughout brain fevrier et al 2005 aguzzi rajendran 2009 endosomes intracellular compartments collecting plasma membrane proteins constantly renewed constitutive selective endocytosis figure 1 other proteins classically meant degradation selectively entrapped vesicles budding endosomal membrane lumen endosomes maturation endosomes leads individualization multivesicular bodies mvbs large vacuoles delimited single membrane containing varying number 5080 nm membrane vesicles figure 2 gruenberg stenmark 2004 van der goot gruenberg 2006 invagination endosomal membrane leading formation mvbs also allows selective microautophagy cytoplasmic proteins sahu et al 2011 membrane cytoplasmic proteins entrapped vesicles hydrolyzed fusion mvbs lysosomes they also expelled cells fusion mvbs plasma membrane leading release exosomes extracellular milieu figure 1 simons raposo 2009 after endocytosis 1 endocytic vesicle fuses early endosomes 2 proteins concentrated recycling endosomes fuse plasma membrane allow expression cell surface 3 alternatively proteins entrapped vesicles budding limiting membrane endosome 4 maturation endosome leads individualization multivesicular body containing intraluminal vesicles ilv 5 the multivesicular body fuse lysosomes ilvs cargoes hydrolyzed 6 the multivesicular body also fuse plasma membrane 7 thereby releasing ilvs extracellular milieu ilvs exosomes released cell bind endocytosed receiving cell cell b 8 once inside endosome exosome undergoes back fusion endosomal membrane 10 fusion recycling endosomes plasma membrane allows expression protein cell surface cell b. back fusion also allows release intraluminal content exosomes proteins rnas cell cytosol cell b. important note steps 9 10 11 remain speculative ( electron micrograph multivesicular body present neuron ca1 region adult rat hippocampus note budding vesicle limiting membrane mvb upper right fiona hemming unpublished ( b electron micrograph multivesicular body dendrite colored ca1 region adult rat hippocampus the protrusion dendrite called dendritic spine corresponds post synaptic part glutamatergic synapse two post synaptic densities anchor ionotropic glutamate receptors visible case the multivesicular body present within dendritic shaft base spine neck fiona hemming unpublished neurons electron microscopy em observations adult hippocampus revealed presence mvbs sorting endosomes dendritic shafts inside limited number spines represent post synaptic parts glutamatergic synapses figure 2b cooney et al 2002 noteworthy mvbs 50 times represented somatodendritic compartments axons von bartheld altick 2011 endosome containing spines mostly mushroom like spines i.e. active synapses kasai et al 2003 enhancement synaptic activity injection peptides known improve cognitive functions kindling significantly increased proportion mvbs inside spines dentate gyrus popov et al similarly water maze training rats led migration mvbs vicinity psds dendrites ca3 pyramidal cells chronic restraint stress diminished number mvbs associated psds stewart et al 2005 similarly neutrotrophic factors bdnf gdnf induced relocalization dendritic mvbs near psds hypoglossal motoneurons rind et al 2005 thus cns movements mvbs synapses tightly linked synaptic plasticity von bartheld altick 2011 studies trafficking synaptic ampa type receptors represent major mediators fast synaptic transmission among glutamate receptors cns led demonstration dendritic endosomes act stores sorting platforms synaptic receptors kennedy ehlers 2006 long term potentiation ltp ) form synaptic plasticity widely accepted model learning memory processes ehlers 2000 membrane insertion new post synaptic ampa receptors increases excitatory post synaptic currents thereby potentiating synapses live cell imaging dissociated hippocampal neurons demonstrated glycine stimulation protocol used induce chemical ltp activation synaptic nmda receptors leads recruitment endosomes near spines fusion plasma membrane correia et al thereby ampa rs present limiting membrane endosomes become inserted neuronal surface diffuse laterally synaptic sites accumulate interaction proteins psds live imaging insertion plasma membrane transferrin receptors tfr contained endosomes showed requirement rab11 syntaxin 13 endosomal fusion dendritic surface park et al accordingly expression dominant negative form rab11 found inhibit ltp slice cultures brown et al 2007 wang et al 2008 demonstrating endosomal fusion dendritic membrane necessary step synaptic potentiation the compartments fusing plasma membrane cultured neurons identified recycling endosomes tfr usually detected recycling endosomes rab11 syntaxin 13 known regulators recycling endosomes however strict separation recycling endosomes mvbs considered late endosomes needs made caution indeed reticulocytes tfr present exosomes geminard et al 2004 colombo and collaborators found rab11 required mvb fusion plasma membrane erythroleukemic cell line savina et al 2005 furthermore neep21 known regulate recycling ampa receptors synapse localized immunofluorescence inside tfr containing endosomes cultured hippocampal neurons steiner et al 2005 however em observations rat brain sections demonstrated protein expressed psds well intralumenal limiting membranes mvbs utvik et al 2009 thus even fluorescence data suggest endosomes fusing plasma membrane synaptic plasticity recycling endosomes one yet exclude endosomes mvbs final proof mvbs fuse dendritic surface awaited visualization process em demonstration exosome release modified synaptic glutamate receptor activity we made first demonstration cortical neurons culture release exosomes faure et al 2006 as case cells exosomes isolated neuron culture media floated sucrose gradients density 1.11.2 g ml contained tsg101 alix tsg101 belongs endosomal sorting complex required transport escrt-0 iii necessary making ilvs accumulating inside mvbs babst 2011 alix acytoplasmic protein binding tsg101 escrt chmp4b escrt iii missotten et al 1999 ; endophilin also interacts alix chatellard causse et al 2002 detected exosomes demonstrating entry cargoes ilvs regulated other cytoplasmic proteins enzymes present inside exosomes including gadph ubiquitin hsc70 this good agreement recent finding thathsc70 binding gadph drives escrt dependent engulfment mvb ilvs sahu et al 2011 exosomes also contained ampa- nmda receptors cell adhesion molecule l1/ngcam central nervous system expressed neurons maness schachner 2007 thus demonstrating exosomes secreted neurons we also observed electrical activity regulates exosomal secretion since long term depolarization neurons 25 mm potassium strongly increased release ampa r containing exosomes three studies reported secretion exosomes neurons vingtdeux et al 2007 ; these studies well initial one used embryonic neurons cultured 38 days short term cultures neurons make synapses neurite outgrowth still going thus exosome release could simply reflect fusion late endosomes lysosomes growth cones necessary neurite elongation arantes andrews 2006 more recently studied exosome release fully differentiated cultures 15 div lachenal et al 2010 dissociated cortical cells contain glutamatergic gabaergic neurons make functional networks within second week culture thus incubation gaba receptor antagonists picrotoxin bicuculline alleviates inhibitory activities within networks increases synaptic glutamatergic activity picrotoxin bicucullin rapidly 1015 min massively augmented secretion exosomes way dependent ampa- nmda receptors lachenal et al 2010 we also found increasing cytosolic calcium using calcium ionophore ionomycin drastically elevated exosome secretion em examination cultures treated 1 min ionomycin revealed clusters exosomes surface dendrites visualizing fusion mvbs plasma membrane altogether data suggest calcium entry synaptic nmda receptors potent activator mvb fusion plasma membrane thereby exosome secretion the enhanced secretion ampa r containing exosomes following glutamatergic synaptic activation underlines exosomal release way local elimination receptors synapses undergoing plastic changes the loss ampa receptors upon extensive synaptic activation could mechanism homeostatic synaptic scaling necessary adjusting strength neuron excitatory synapses stabilize firing turrigiano 2008 thus fusion endosomes leads increase receptors synapses undergoing potentiation sustained synaptic activation would lead calcium increase within dendritic shaft triggering fusion mvbs base nearby synapses allow local elimination intracellular pool ampa receptors thereby synaptic scaling scenario regulation pool surface synaptic receptors exosome secretion would local event avoiding retrograde transport mvbs necessary hydrolyze receptors lysosomes present proximal dendrites soma exosomes first shown endocytosed dendritic cells immune system skokos et al 2003 those released neurons cns parenchyma could potentially endocytosed nearby cells shown oligodendrocyte derived exosomes endocytosed microglial cells fitzner et al 2011 astrocyte end feet enwrap number glutamatergic synapses also endocytose phagocytose cellular debris haydon carmignoto 2006 could thus capture exosomes released synapses transfer exosomes could also occur spines neuron across synapses end afferent neurons indeed diameter neuronal exosomes compatible possible endocytosis neuronal clathrin coated pits occurring presynaptic boutons spines dendritic shafts lu et al 2007 we recently obtained evidence exosomes bind endocytosed hippocampal neurons unpublished observations allow inter neuronal transfer tetanus toxin known cross synapses vivo lachenal et al 2010 em observations needed characterize site entry exosomes fate inside endosomes non neuronal cells the fact exosomal rnas act receiving cells demonstrates exosome intralumenal cargoes released cytosol i.e. membrane exosomes fuses plasma membrane endosomal membranes endocytosis figure 1 back fusion intralumenal vesicles demonstrated occur mvbs falguieres et al 2009 could thus concern exosomes origin such process would lead entry exosomal membrane proteins endosomal protein pool possibly expression cell surface e.g. ampa receptors it would also allow release cytosol exosome content including signal transduction molecules mirnas exosomes contain pathogenic proteins alpha synuclein prpsc amyloid precursor protein app phosphorylated tau involved parkinson prion alzheimer diseases respectively the scrapie form prion protein prpsc contained exosomes secreted via exosomes remains infectious form fevrier et al 2004 thus trans synaptic exchange could one way propagation prion diseases periphery cns alpha synuclein secreted together exosomes released neuroblastoma cells causes cell death recipient neuronal cells suggesting alpha synuclein secretion via exosomes serves amplify propagate parkinson disease related pathology emmanouilidou et al the catabolism app giving rise amyloidogenic c terminal app fragment occurs endosomes fragment well amyloid peptides released way exosomes rajendran et al 2006 vingtdeux et al these puzzling hypotheses require vivo work show exosomal released mvbs occurs situ ii find privileged site release iii demonstrate transynaptic exchange exosomes furthermore even though activity dependent release exosomes suggests genuine function exosomes synaptic plasticity molecular tools specifically block mvb fusion plasma membrane must developed test hypothesis nevertheless studies exosomes cns bound shed new light intercellular exchanges within brain open new avenues toward understanding neurodegenerative diseases spread time throughout nervous system the authors declare research conducted absence commercial financial relationships could construed potential conflict interest | exosomes are small extracellular vesicles , which stem from endosomes fusing with the plasma membrane , and can be recaptured by receiving cells .
they contain lipids , proteins , and rnas able to modify the physiology of receiving cells .
functioning of the brain relies on intercellular communication between neural cells .
these communications can modulate the strength of responses at sparse groups of specific synapses , to modulate circuits underlying associations and memory .
expression of new genes must then follow to stabilize the long - term modifications of the synaptic response .
local changes of the physiology of synapses from one neuron driven by another , have so far been explained by classical signal transduction to modulate transcription , translation , and posttranslational modifications . in vitro evidence
now demonstrates that exosomes are released by neurons in a way depending on synaptic activity ; these exosomes can be retaken by other neurons suggesting a novel way for inter - neuronal communication .
the efficacy of inter - neuronal transfer of biochemical information allowed by exosomes would be far superior to that of direct cell - to - cell contacts or secreted soluble factors .
indeed , lipids , proteins , and rnas contained in exosomes secreted by emitting neurons could directly modify signal transduction and protein expression in receiving cells .
exosomes could thus represent an ideal mechanism for inter - neuronal transfer of information allowing anterograde and retrograde signaling across synapses necessary for plasticity .
they might also allow spreading across the nervous system of pathological proteins like prpsc , app fragments , phosphorylated tau , or alpha - synuclein . |
patients symptomatic sciatic hernias commonly present flank abdominal pelvic lower back thigh pain most asymptomatic patients treated conservatively surgery reserved symptomatic patients we describe case revealed left hydronephrosis severe left back pain 72-year old female this case shows minimally invasive endourological techniques may provide novel method relieving cause obstruction a 72-year old female accidentally struck left forechest 2 months referred hospital lower left rib fracture observed x ray examination she suffering severe left sided back pain thought apart rib fracture site pain intermittent the ultrasound sonography demonstrated left hydronephrosis simple renal cyst lower pole left kidney urinalysis showed microhematuria routine blood tests remarkable except slightly elevated serum glucose level 179 mg dl intravenous ureterography ivu showed findings compatible left sciatic ureter dilated ureter fixed kinking known
the abdominal ct showed marked hydronephrosis hydroureter level pelvic inlet revealed presence sciatic herniation ureter fig 2 ureter seen course behind left hip greater sciatic foramen anterior piriformis muscle no evidence inflammatory lesions compressive tumor herniation another pelvic organ ureter seen subsequently placement ureteral stent performed decompress dilated upper urinary tract interestingly ureterosciatic hernia relieved passage flexible guide wire double pigtail stent fig however patient refused continuing indwelling stent stent removed ivu obtained 3 months removal ureteral stent revealed recurrence ureterosciatic hernia however evident recurrence hydroureter hydronephrosis ureteral obstruction since then six years ureteral stenting patient continues without hydronephrosis symptoms usage indwelling ureteral stent most ureteral herniations occur inguinal area also noted femoral sciatic thoracic parailiac locations among ureterosciatic herniation extremely uncommon 31 cases reported since 1947 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 clinical symptoms nonspecific consisting ill defined abdominal pain patients may nonurologic complaints including vague abdominal pain symptoms typical small bowel obstruction obstructive uropathy develops patients ureterosciatic hernias may may experience symptoms renal colic the diagnosis difficult establish physical examination ureterosciatic hernias deep gluteal muscles however hernias may detected palpable mass located underneath gluteal muscles thin patient 4 9 anatomically ureteral herniations ureteroinguinal ureterofemoral hernias paraperitoneal since adherent posterior parietal peritoneum hence associated herniating peritoneal sac contrast ureterosciatic hernias always extraperitoneal structures small intestine meckel diverticulum omentum colon ovary fallopian tube bladder ureter may found sciatic hernia sacs 3 4 5 6 ureterosciatic herniation prolapse ureter occurs sciatic notch divided sacrospinous ligament greater lesser sciatic foramina the greater sciatic foramen considered potential space piriformis muscle completely occupies greater sciatic foramen the greater sciatic foramen bound ilium laterally sacrum sacrotuberous ligament medially sacrospinous ligament inferiorly the greater sciatic foramen subdivided suprapiriformis infrapiriformis compartments piriformis muscle ureterosciatic herniations usually occur suprapiriformis compartment greater sciatic foramen 5 10 previous reports suggested atrophy piriformis muscle predisposing factor development ureterosciatic herniation creating potential space ureter could migrate it speculated main predisposing factor could piriformis muscle atrophy related hip joint disease neuromuscular disorders locomotor disturbances lower extremities 4 5 6 7 9 although hernias occur greater sciatic foramen several ones reported herniate lesser sciatic foramen 2 5 8 9 these cases usually undiagnosed clinically gluteus maximus muscle overlies sciatic foramen sciatic ureter characteristic radiologic appearance loop ureter displaced laterally inferiorly posteriorly sciatic notch ivu retrograde urography the diagnosis confirmed image known curlicue sign considered pathognomonic ureterosciatic herniation ct may helpful diagnosis appearance ectopically positioned ureter posterior lateral ischial spine demonstrate ureter anatomic information may useful detecting involvement structures 6 12 moreover ct three dimensional reconstruction might useful defining exact location extent herniation in previous reports treatments symptomatic patients included relief hernia excision reimplantation ureteroureterostomy stent placement observation 2 8 patient conservative endourological correction performed spontaneous removal ureteral stent recurrent ureterosciatic hernia occurred placement internal stent possibly provides rigidity ureter thereby recovering hernia urinary obstruction observation used judiciously consequences long term obstruction devastating indeed ureterosciatic hernia causing intermittent ureteral obstruction producing significant morbidity repaired furthermore ureter shows signs inflammation trophic disturbances ureterolysis reimplantation hernioplasty carried 1 2 3 4 8 10 surgical options include excision hernia reimplantation remaining ureter reduction ureter length transabdominal transgluteal surgical reduction hernia plus fixation ureter 2 4 8 recently laparoscopic robotic repair surgery also reported 10 15 however surgical repair performed asymptomatic patients patient elderly poor surgical candidate sugimoto et al also reported case successfully treated ureteral stent placement it advisable place stent months remove see whether obstruction recurs this approach provides minimally invasive means treatment devastating problem | ureterosciatic herniation , the protrusion of the hernia sac through the sciatic foramen , is an extremely rare cause of ureteral obstruction .
we describe a case revealed by severe left back pain in a 72-year - old female .
she was referred to our hospital for urological assessment of left hydronephrosis observed by ultrasonography .
intravenous ureterography ( ivu ) showed findings compatible with a left sciatic ureter , a dilated ureter with a fixed kinking , which is known as the curlicue sign .
we decided to attempt recovery of the herniated ureter using a retrograde approach .
ureteral stent placement was performed to decompress the dilated upper urinary tract .
the ureterosciatic hernia was relieved with the passage of a flexible guide wire and a double - pigtail stent .
three months after ureteral stenting , she refused continuing to have an indwelling stent and the stent was removed .
thereafter , ivu revealed recurrent ureterosciatic hernia ; however , there was no hydroureter or hydronephrosis .
the patient is currently being under observation for 6 years after stenting and continues to be without hydronephrosis or symptoms .
placement of an internal stent possibly provides the rigidity to the ureter , thereby reducing the hernia and urinary obstruction . in the previous reports ,
most symptomatic patients have been treated surgically , with conservative therapy reserved for asymptomatic patients . for the patient who is elderly or a poor surgical candidate
, retrograde stenting may provide safe reduction and efficacious treatment .
this endourological approach provides a minimally invasive means for the management of urinary obstruction caused by ureterosciatic herniation . |
randomized controlled clinical trial attempt minimize bias introduced knowledge treatment allocation thereby come reliable conclusions regarding hypothesis tested many interventional randomized controlled clinical trials need assume randomization distributes baseline characteristics equally patients enter clinical trial stable state however inclusion exclusion criteria lead biases necessarily anticipated intervention examined already used portion population while may drug specific withdrawal previously prescribed medication often based pharmacologic class mechanism action study drug most trials assume patients medically stable randomization withdrawal medication may worsen underlying disease three groups investigators13 highlighted issues introduced withdrawal inhaled corticosteroids randomization clinical trials examining inhaled corticosteroids chronic obstructive pulmonary disease copd suissa et al1 concluded effects withdrawal medication assumed addition medication authors demonstrated case inhaled corticosteroids considered whether withdrawal copd medication including inhaled anticholinergics may lead similar phenomenon access tiotropium clinical trial database allowed us undertake thorough analysis whether withdrawal inhaled anticholinergics influenced results observed tiotropium reducing copd exacerbations knowledge first analysis examined issue medication withdrawal onset clinical trials anticholinergic therapy a pooled analysis 10 randomized double blind placebo controlled parallel group studies least six months duration tiotropium 18 g administered daily via handihaler device boehringer ingelheim gmbh ingelheim germany performed trial numbers 205.114/117,4 205.115/128,5 205.130,6 205.137,6 205.266,7 205.270,8 205.235 understanding potential long term impacts function tiotropium uplift)],9 205.214,10 205.256,11 205.25912 shown figure 1 one study longer one year uplift included 5993 copd patients followed four years).9 trials included evaluation exacerbations spirometry seven trials trial numbers 205.114/117 205.115/128 205.130 205.137 205.235 uplift 205.256 205.259 included measurement using st george respiratory questionnaire sgrq).13 trial protocols approved independent ethics committees patients trials provided written informed consent all trials included pooled analysis common entry criteria ie clinical diagnosis copd age 40 years smoking history 10 pack years postbronchodilator forced expiratory volume one second fev1)/forced vital capacity ratio 0.7 fev1 either 65% 70% predicted whilst patients participating studies classified severity copd basis post bronchodilator fev1 measurements exclusion criteria included history asthma need continuous supplemental oxygen copd exacerbation within previous six weeks recent myocardial infarction hospitalization congestive heart failure unstable medical conditions may preclude participation interpretation results use systemic corticosteroids doses greater equivalent prednisone 10 mg daily we believe dependable method excluding patients asthma given well known bronchodilator responsiveness discriminate asthma copd the following standardized definition used characterize copd exacerbations current analysis exacerbation defined two increased new onset respiratory symptoms cough sputum wheezing dyspnea chest tightness lasting least three days requiring treatment antibiotics and/or steroids and/or hospitalization.14 patients grouped according inhaled anticholinergic discontinuation ie anticholinergic prescribed prior participation discontinued randomization nd anticholinergic prescribed prior participation therefore discontinued kaplan meier curves probability exacerbation hospitalization due exacerbations displayed cox regression used compute hazard ratios hr tiotropium placebo using trial stratum the analysis number exacerbations number hospitalizations due exacerbations performed using poisson regression correction treatment exposure overdispersion terms treatment subgroup treatment subgroup interaction the effects tiotropium placebo sgrq total score trials sgrq measured examined according whether subjects discontinued anticholinergic therapy these data displayed mean standard error mean values compared unpaired tests a pooled analysis 10 randomized double blind placebo controlled parallel group studies least six months duration tiotropium 18 g administered daily via handihaler device boehringer ingelheim gmbh ingelheim germany performed trial numbers 205.114/117,4 205.115/128,5 205.130,6 205.137,6 205.266,7 205.270,8 205.235 understanding potential long term impacts function tiotropium uplift)],9 205.214,10 205.256,11 205.25912 shown figure 1 one study longer one year uplift included 5993 copd patients followed four years).9 trials included evaluation exacerbations spirometry seven trials trial numbers 205.114/117 205.115/128 205.130 205.137 205.235 uplift 205.256 205.259 included measurement using st george respiratory questionnaire sgrq).13 trial protocols approved independent ethics committees patients trials provided written informed consent all trials included pooled analysis common entry criteria ie clinical diagnosis copd age 40 years smoking history 10 pack years postbronchodilator forced expiratory volume one second fev1)/forced vital capacity ratio 0.7 fev1 either 65% 70% predicted whilst patients participating studies classified severity copd basis post bronchodilator fev1 measurements data reported paper prebronchodilator values exclusion criteria included history asthma need continuous supplemental oxygen copd exacerbation within previous six weeks recent myocardial infarction hospitalization congestive heart failure unstable medical conditions may preclude participation interpretation results use systemic corticosteroids doses greater equivalent prednisone 10 mg daily we believe dependable method excluding patients asthma given well known bronchodilator responsiveness discriminate asthma copd the following standardized definition used characterize copd exacerbations current analysis exacerbation defined two increased new onset respiratory symptoms cough sputum wheezing dyspnea chest tightness lasting least three days requiring treatment antibiotics and/or steroids and/or hospitalization.14 patients grouped according inhaled anticholinergic discontinuation ie anticholinergic prescribed prior participation discontinued randomization nd anticholinergic prescribed prior participation therefore discontinued kaplan meier curves probability exacerbation hospitalization due exacerbations displayed cox regression used compute hazard ratios hr tiotropium placebo using trial stratum the analysis number exacerbations number hospitalizations due exacerbations performed using poisson regression correction treatment exposure overdispersion terms treatment subgroup treatment subgroup interaction the effects tiotropium placebo sgrq total score trials sgrq measured examined according whether subjects discontinued anticholinergic therapy these data displayed mean standard error mean values compared unpaired tests of 12,163 patients randomized clinical trials 5846 receiving inhaled anticholinergics discontinued randomization group 6317 receiving inhaled anticholinergics time randomization nd group the inhaled anticholinergic ipratropium bromide vast majority patients already receiving inhaled anticholinergics time initiation aforementioned trials there patients receive tiotropium prior randomization 109 12,164 patients 49 withdrawn tiotropium for group mean age 66.1 years compared 64.5 years nd group patients previously prescribed anticholinergics lower lung function longer smoking histories overall within nd groups treatment subgroups tiotropium placebo reasonably well balanced respect baseline characteristics there significantly reduced risk exacerbation patients receiving tiotropium compared receiving placebo group hr 95% confidence interval ci 0.83 0.770.90 nd groups hr 95% ci 0.79 0.730.85 similar findings observed exacerbations leading hospitalizations hr 95% ci 0.85 0.731.00 group 0.79 0.650.94 nd group tiotropium delayed time first exacerbation first hospitalized exacerbation nd groups observed cumulative incidence displays figures 2 3 the number patients least one exacerbation least one exacerbation leading hospitalization reduced tiotropium relative placebo nd groups reflected lower rate ratios tables 2 3 for group mean standard error total sgrq score six months improved tiotropium 41.4 0.31 relative receiving placebo 44.7 0.34 difference 3.33 0.40 p 0.0001 nd group the total scores also improved tiotropium versus placebo 40.3 compared 43.1 difference 2.78 p 0.0001 of 12,163 patients randomized clinical trials 5846 receiving inhaled anticholinergics discontinued randomization group 6317 receiving inhaled anticholinergics time randomization nd group the inhaled anticholinergic ipratropium bromide vast majority patients already receiving inhaled anticholinergics time initiation aforementioned trials there patients receive tiotropium prior randomization 109 12,164 patients 49 withdrawn tiotropium for group mean age 66.1 years compared 64.5 years nd group patients previously prescribed anticholinergics lower lung function longer smoking histories overall within nd groups treatment subgroups tiotropium placebo reasonably well balanced respect baseline characteristics there significantly reduced risk exacerbation patients receiving tiotropium compared receiving placebo group hr 95% confidence interval ci 0.83 0.770.90 nd groups hr 95% ci 0.79 0.730.85 similar findings observed exacerbations leading hospitalizations hr 95% ci 0.85 0.731.00 group 0.79 0.650.94 nd group tiotropium delayed time first exacerbation first hospitalized exacerbation nd groups observed cumulative incidence displays figures 2 3 the number patients least one exacerbation least one exacerbation leading hospitalization reduced tiotropium relative placebo nd groups reflected lower rate ratios tables 2 3 for group mean standard error total sgrq score six months improved tiotropium 41.4 0.31 relative receiving placebo 44.7 0.34 difference 3.33 0.40 p 0.0001 nd group the total scores also improved tiotropium versus placebo 40.3 compared 43.1 difference 2.78 p 0.0001 the pooled analysis 10 randomized double blind placebo controlled clinical trials involving 12,163 patients copd demonstrates tiotropium effective reducing exacerbations patients also inhaled anticholinergics discontinued upon randomization patients discontinued anticholinergic therapy 17% risk reduction exacerbation treated tiotropium compared placebo patients discontinue anticholinergic therapy the risk reduction 21% tiotropium compared placebo similar comparison risk hospitalized exacerbation reduced 15% 21% respectively the reduced risk also associated reduced rates exacerbations hospitalized exacerbations regardless previous anticholinergic use thus withdrawal inhaled anticholinergics upon entry tiotropium trials appear influence effect tiotropium clinically important patient outcome exacerbations copd in addition seven trials sgrq measured tiotropium significantly reduced sgrq total score groups patients exacerbations significant component clinical course copd.15,16 furthermore copd progresses exacerbations become frequent.16 investigators suggested frequent exacerbations associated rapid decline fev1.17,18 certainly exacerbations profound effects quality life.19 example sgrq scores shown decreased worsened baseline six months following exacerbation.20 finally exacerbations associated significant mortality.21 widespread clinical use tiotropium copd patients might predictably ameliorate effects recurrent exacerbations clinical course disease impact design future clinical trials recently increasing concerns effects withdrawal medications entry clinical trials van der valk et al3 treated patients inhaled fluticasone 1000 g day four months randomized patients continue receiving fluticasone switch placebo subsequent six months follow up 47% patients fluticasone group developed copd exacerbation compared 57% placebo group significant differences seen hr first exacerbation well differences health related quality life measured sgrq favored patients continuing fluticasone however question arises whether safety concern due sudden withdrawal high dose systemically absorbed inhaled corticosteroids observations surrogate measures efficacy suissa et al1 described methodological issues therapeutic trials copd drew attention problem medication withdrawal using inhaled corticosteroids prior randomization example case of the towards revolution copd health torch study phenomenon led effect two comparisons ie withdrawal inhaled corticosteroids compared continuation inhaled corticosteroids patients previously taking agents introduction inhaled corticosteroids compared placebo patients previously taking inhaled corticosteroids suissa et al1 also analyzed data canadian optimal therapy copd trial22 found hr inhaled corticosteroids relative bronchodilators first exacerbation among previous inhaled corticosteroids users 0.71 95% ci 0.530.96 among using inhaled corticosteroids prior randomization hr inhaled corticosteroids relative bronchodilators 1.11 95% ci 0.691.79 in addition ratio exacerbations patients prior discontinuing inhaled corticosteroids 0.78 95% ci 0.610.99 compared 1.23 95% ci 0.781.95 thereafter these concerns prompted detailed retrospective analysis data torch.23 paper keene et al argued negative binomial model best approach statistical analysis exacerbation rates similar reduction exacerbations could calculated regardless whether subjects discontinued inhaled corticosteroids randomization suissa et al1 suggested paper withdrawal inhaled anticholinergic therapy might cause similar problems described related withdrawal inhaled corticosteroids furthermore demonstrated similar reduction number exacerbations per patient year continued discontinued inhaled anticholinergic therapy upon randomization tiotropium clinical trials this significant benefit argues clinical trial results terms difference tiotropium placebo favor positive effect tiotropium rather negative effect inhaled anticholinergic withdrawal placebo group as well demonstrating tiotropium reduced exacerbations regardless changes prior therapy also able demonstrate tiotropium compared placebo improved health related quality life measured sgrq regardless whether patients taking inhaled anticholinergic therapy prior randomization the improvement sgrq statistically significant nd groups although numerically greater patients discontinued previous anticholinergic therapy we speculate withdrawal inhaled anticholinergic therapy affect outcome placebo controlled clinical trials tiotropium whereas withdrawal inhaled corticosteroids seems problematic the effect ipratropium short acting anticholinergic taken many patients prior entry tiotropium trials well understood restricted antimuscarinic smooth muscle relaxation presumably wears relatively quickly although evidence effects extended therapy ipratropium persist longer conventional 68-hour duration acute bronchodilation.24 although considered short acting bronchodilator ipratropium alone combination albuterol shown reduce exacerbations compared albuterol alone.25 observation suggests one consider whether rebound
effect ie increase exacerbation rate might consequence ipratropium withdrawal study nine subjects mild asthma newcomb et al26 described short term increase airway hyperresponsiveness methacholine upon withdrawal regular use ipratropium could represent upregulation muscarinic receptors surface airway smooth muscle cells however findings replicated current analysis demonstrates rebound worsening copd unlikely occur upon withdrawal ipratropium the corollary necessarily true inhaled corticosteroids systemic effects inhaled corticosteroids beneficial effects adverse events likely occur longer periods time may also delay onset safety issues meta analysis our study certain limitations.27 acknowledge retrospective analysis includes trials different size duration however strengths study prospective nature clinical trials selected pooled analysis consistency entry criteria furthermore studies rigorously conducted randomized double blind controlled clinical trials provided large numbers patients included analysis in summary demonstrated tiotropium reduced exacerbations hospitalizations large number copd patients regardless whether discontinued inhaled anticholinergic therapy prior randomization placebo controlled clinical trials these findings strengthen validity conclusions previously reported clinical trials treatment tiotropium reduces exacerbations beneficial effect equally observed whether patients previously received inhaled anticholinergic therapy | background : data have highlighted the potential bias introduced by withdrawal of inhaled corticosteroids at randomization in chronic obstructive pulmonary disease trials examining inhaled corticosteroids .
analyses were conducted to determine whether this was true of inhaled anticholinergic withdrawal in tiotropium trials.methods:a pooled analysis of randomized , double - blind , placebo - controlled , parallel - group tiotropium trials of at least six months duration was performed .
trials had similar inclusion and exclusion criteria .
exacerbation definition was standardized .
patients were divided into two groups , ie , d ( anticholinergics discontinued at randomization , previously prescribed ) and nd ( anticholinergics not discontinued , not previously prescribed).results : demographics were balanced between the d ( n = 5846 ) and nd ( n = 6317 ) groups , except for higher cumulative smoking ( 56 pack - years versus 48 pack - years ) , lower forced expiratory volume in one second ( fev1)/forced vital capacity ( 43% versus 48% ) , and lower baseline fev1 ( 35.8% predicted versus 42.4% predicted ) in the d group . in both groups ,
tiotropium reduced the risk for an exacerbation ( hazard ratio [ hr ] = 0.83 , p < 0.0001 [ d ] versus 0.79 , p < 0.0001 [ nd ] ) and a hospitalized exacerbation ( hr = 0.85 , p = 0.0467 versus 0.79 , p = 0.0094 ) .
tiotropium reduced the number of exacerbations per patient - year ( rate ratio [ rr ] = 0.82 , p < 0.0001 [ d ] versus rr = 0.80 , p < 0.0001 [ nd ] ) and associated hospitalizations per patient - year ( rr = 0.88 , p = 0.015 [ d ] versus rr = 0.74 , p < 0.0001 [ nd]).conclusion : tiotropium reduced exacerbations in patients who did and did not have anticholinergics discontinued upon randomization in clinical trials . |
telepathology defined practice pathology distance transmitting macroscopic and/or microscopic images via telecommunication links 1 remote interpretations telediagnosis second opinions consultations teleconsultation educational purposes teleconferencing widespread availability imaging technology telecommunication access global expert pathologists telepathology shown applicable anatomical pathology including intra operative consultation frozen sections surgical pathology second opinions immunostains telecytology e.g. site evaluation ultrastructural pathology well ii clinical pathology including telehematology microbiology e.g. parasitology chemistry e.g. interpretation gels the first static store forward telepathology involves examination pre captured still images transmitted via e mail stored shared server the second mode telepathology involves dynamic live examination images real time employing video robotic microscopy finally hybrid technology involving whole slide imaging wsi emerged utilizes dynamic viewing digitized scanned slide well viewing selected areas saved image higher magnification the university pittsburgh medical center upmc health system operates 20 geographically diverse hospitals within around city pittsburgh also partners hospitals located distant states e.g. indianapolis indiana countries e.g. italy china the anatomical pathology department employs academic centers excellence coe subspecialty model pathologists respective specialty tend located hospital infrastructure telepathology employed upmc decade provide remote subspecialty expertise local national international sites the aim article review different modes telepathology share experience garnered upmc respect teleconsultation method well describe future aspects practicing telepathology static image telepathology involves capturing storing forwarding individual digital images galleries static images remote diagnosis advantages form telepathology low cost involved vendor independence technical simplicity fact recipient require special software view images small manageable files involved easy retrieve send review store share systems easy maintain however disadvantages static telepathology relate fact consulting telepathologist remote control microscope imaging device camera interpretation limited captured field views host capturing images needs expertise acquiring images labor intensive may cause sampling error incorrect images captured frequent lack clarity low power magnification images still images focus upmc consultations received ismett mediterranean institute transplantation high specialization therapies located palermo italy transplant related biopsies usually challenging hence best interpreted experts field access transplant pathologists highly desirable second opinions dealing difficult cases teleconsultation setting also needs performed timely manner since rapid accurate interpretation allograft biopsies influences outcome organ transplantation moreover histopathologic interpretation determines whether donor organ used transplantation disposed the transplant telepathology system therefore developed support coverage 24 hours day 7 days week initially employed static images run store forward mode communication limited private network using thick client server architecture host e.g. italy upmc consulting pathologists analysis early 14-month period accrued data 102 transmitted cases showed full agreement original diagnosis 86% cases cases disagreement 14% 8 resulted minor 3 clinically significant differences opinion subsequently 12-year partnership upmc ismett approximately 3000 cases reviewed telepathology teleconsultation using static images improved respect workflow infrequent discrepancies noted first generation home grown static telepathology system since replaced second generation dynamic robotic microscopy nikon coolscope streaming third generation hybrid rapid virtual microscopy trestle live viewing recently 2009 fourth generation wsi ultra rapid virtual microscopy mirax midi figure 1 better technology allowing pathologists view entire slides high resolution performance telepathology improved however change newer technologies approaches proven technically feasible although static images quicker read robotic microscopy limited specific field views forced evolution the evolution static imaging wsi scanning system necessitated due lag time required robotic objective magnification changes positional adjustments slide wsi scanning these magnifications digitally incorporated resultant image time required biopsy interpretation greatly reduced secondly configuring wsi system high numerical aperture na objective e.g. 40x 95na enabled image resolution maximized image clarity detail therefore reducing eye fatigue reviewing pathologist enabling longer review sessions lower resolution imagery e.g. 25 micron forces human eye continually focus trying pull acute pathology details leads fatigue lastly high resolution scanning enabled subtle details pertaining tissue rejection clearly identified visual confirmation splitting glomerular basement membranes combined advancements improved performance system routine consultation practical efficient early continued adoption telepathology provided invaluable experience digital pathology improved workflow accumulated resources facilitated funding equipment infrastructure staffing within transplant pathology division today digital pathology evolved whereby multiplex stained wsi used microscopy image analytics multiplexing defined application analysis multiple fluorescence markers typically greater 3 single histologically prepared section these markers analyzed tissue context quantifying spatial relationships multiple markers related surrounding morphology expression patterns diagram showing information technology server components upmc ismett telepathology platform cases accessioned mirax digital slide desktop mdsd image repository blue box individual slides scanned mirax midi wsi scanner transferred via network file share mdsd repository access images direct via secure username password connection mdsd system client pc mac using java applet viewing via affiliated specific workflow applications purpose transplant immunology assessment the java applet viewer embedded website client server application flexibility workflow integration division hematopathology institution another area employed static telepathology several academic hospitals without hematopathologist site telehematology ensured interpretation peripheral blood smears differentials continue performed rapidly accurately expert hematopathologist interpretation is often required difficult cases e.g. blasts leukemia accomplish the hematology laboratory relied cellavision automated digital system digitize glass slides containing peripheral blood smears the instrument used automatically locate pre classify digital images white blood cells red blood cells platelets using system a technologist laboratory able email static images concerning blood cells hematopathologist interpretation figure 2 turn hematopathologist could access system entire stored differential patient remotely office computer analysis experience shown device correctly classified 94% cells reduced accuracy immature granulocytes also allow clinicians view digitized blood smears real time instead come laboratory physically review blood smear ( cellavision dm96 instrument b review monitor displaying captured images different blood cells c e mail embedded selected static images generated using systems remote review software the host driving navigating focusing slide microscope viewed remote pathologist monitor requires expertise perform task the remote consulting pathologist usually communication e.g. via telephone teleconferencing host however order transmit image internet analog video signal needs converted using ad converter digital signal analog video signals unfortunately subject noise degradation may affect image quality many prior publications regarding telecytology predominantly utilized static images practice today cytology laboratories use telecytology employ video streaming upmc live video streaming remained mode choice providing immediate adequacy assessment cytology specimens telecytology other methods robotic microscopy nevertheless investigated shown effective validation studies conducted cytopathology division using web based streaming shown adequacy assessment diagnostic accuracy telecytology acceptable nevertheless cytopathologists found quality digital images inferior viewing cases conventional light microscope figure 3 moreover cytopathologists documented spending time reviewing cases examined telecytology figure 4 these factors may explain part cytopathologists infrequently employ telecytology despite fact necessary equipment perform telepathology immediate site evaluation fine needle aspirations available for remote evaluations fine needle aspirations cytopathologists demonstrated similar performance using conventional microscope blue bars telecytology system yellow bars providing tissue adequacy far left bars correct diagnosis far right bars however middle bars graph indicate pathologists found reviewing cases remotely appear complex inferior image quality obscured features consequently less confident telecytology diagnoses average time seconds taken review glass telecytology cases cytopathologists took longer review cytology slide using telecytology 94 seconds examining slide conventional light microscope 70 seconds ) robotic real time dynamic telepathology differs video microscopy telepathologist consultant actively involved selecting fields glass slide viewed robotic telepathology system operator remote control critical motorized microscope functions including glass slide movements x- axes motorized microscope stage focus glass slide selection various microscope objective lenses robotic turret this provides pathologist access entire slide good image quality trained host e.g. pathology assistant ) these devices expensive point point network connectivity requirements i.e. web based protocol often desirable implement within hospital infrastructure additional disadvantages relatively slow scanning slides approximately 10 min slide fact host recipient require integrated software required high level system maintenance routine optimization cleaning adjustment robotic telepathology extensively used upmc remotely interpret intra operative neuropathology consultations frozen sections a considerable volume neurosurgery performed within organization however keeping coe model neuropathologists housed one hospital location steady demand neuropathology frozen sections different hospitals met utilizing robotic telepathology figure 5 several zeiss previously trestle robotic microscopes strategically placed within frozen section rooms different facilities figure 6 pathology staff including trainees received instruction handle tissue received frozen section load prepared slides onto microscopes the importance training key element success teleneuropathology service overlooked since small portions brain neural tissue usually procured entirely submitted frozen section experience found brief gross description tissues received remote neuropathologist telephone pathology resident assistant sufficient at one site surgical pathologist sampling guidance consulting neuropathologist nevertheless secure webcam frozen section room available facilitate gross telepathology required also investigations newer technologies e.g. high definition digital cameras teleconferencing software underway attempt improve macroscopic teleneuropathology capabilities figure 7 software medmicroscopy mirax navigator access scanned images remotely control robotic microscopes made readily available internet accessible workstation the diagnostic outcome 2002 2006 comparing 1227 conventional frozen sections 402 performed telepathology demonstrated telepathology deferral rate 19.7% varied higher deferral rate conventional frozen section cases 10% however adoption newer technology trestle scanner replaced nikon coolscope increased pathologist experience 2007 2008 comparing 547 conventional frozen sections 262 telepathology acceptable concordance 78.2% telepathology conventional frozen sections in addition discrepancy deferral rate differences later time period statistically insignificant intra operative final discrepancies uncommon occurring 2.7% neuropathology cases discrepant events common non neoplastic reactive cases lymphomas rare tumors account neuropathology division unique intra institutional experience able successfully expand teleconsultation practice across state lines inter institutional financially separate medical center indianapolis indiana implementation technology venture proved easier accompanying administrative e.g. contracts legal e.g. licensing issues involved 2007 information technology infrastructure used support intra institutional neuropathology frozen section telepathology gross teleneuropathology showing close views two portions tissue submitted frozen section glioblastoma multiforme tumor wsi telepathology systems increasingly employed clinical education research applications wsi systems provide users access entire case including sets slides offers automated scanning rapidly produces high resolution images wsi scanners often added software available teleconferencing image management image analysis however current impediments widespread adoption related high expense limited vendor interoperability newer wsi scanners designed hold one four slides smaller less expensive wsi minor scan failure rate 2 5% our scan failure rate particularly low 1% probably train staff recognize problems presenting images pathologists furthermore pathologists maintain close working relationship histology optimize slides scanning e.g. care taken avoid folds bubbles etc our staff also adjusts scanning technique vendor optimize scanner device settings such optimizations included vendor provided focus point algorithm changes account tissue artifact edge effects folds nevertheless occasional difficulties experienced scanning slides e.g. misplaced cover slips sticky wet slides small tissue fragments faint tissue material slide edge even outside coverslip may recognized users may also contend long scan times especially thick tissue sections high resolution images desired e.g. native high numerical aperture 40 scanning this web based tool designed facilitate digital pathology second opinion consults especially wsi a general portal developed used clients another required customization individual clients table 1 portals wsi either uploaded transmission upmc consultants general portal accessed specific client server client specific portal figure 8 client specific portal we able avoid lengthy transfers large wsi files internet well automate process image association cases despite distance however client specific model image files largely outside control always quickly resolve problems client image server network hardware changes client side may cause unexpected instability the general portal allows supported image file types static wsi formats major vendors well pertinent accompanying clinical information uploaded all clients offered secure login submit patient data upload images well check status case view print second opinion reports using tool upmc consultants able view digital images using java applet they ability annotate capture static image snapshots embedded reports workflow handled managers triage requests monitor cases maintain personnel data streamlined workflow well training users ensured prompt turn around time buy institute pathologists post launch feedback pathologists resulted customization incorporate transcription services peer peer review consultants provision issuing addenda amendments improved wsi viewing experience all cases received via portal thus far surgical pathology cases average 11 wsi per case received including h e histochemical immunohistochemistry slides the mean turnaround time 22 consulting pathologists 40 hours range 2 152 hours different upmc telepathology portals data workflow upmc portal one clients kingmed china as scans transferred scanner ndp serve database system allows automated notification upmc assigned pathologist case ready consult perhaps importantly automated system eliminates person email notify scan filenames associated case thereby removing possibility human error assigning wrong slide image case digital pathology consultation upmc spanned decade time modes telepathology successfully utilized exploit subspecialty expertise compete pathology services the practice telepathology institution evolved concert advances technology become cost effective although several aforementioned modes practicing telepathology may outdated believe nevertheless important share experiences point often technology limiting issue rather people processes involved note diagnostic accuracy turnaround time telecytology accomplished largely using real time video streaming wsi cytology slides low volume cases received teleconsultation interpretable without need scanning slides z stacking early continued adoption promoted several digital pathology resources e.g. facilitated funding equipment infrastructure staff leveraged clinical educational research purposes table 2 lists many factors may need considered practicing telepathology a key aspect successful digital teleconsultation program integration digital images including wsi laboratory information system lis electronic health record such integration example one main objectives cost action
efforts towards integrating lis wsi underway institution partnership omnyx telepathology requirements different developed developing countries based experience china bottlenecks telepathology included high price wsi devices regulatory issues technological issues however often easier overcome administrative contractual legal challenges our institution currently evaluating newer approaches grid technology open access forums mobile solutions determine leveraged enhance telepathology institution grid technology uses open standards access distributed information suggested authors way improve quality image based diagnosis we provided pathologists access suite cloud based applications web browser figure 9 since computer programs support various telepathology devices stored servers remote location hardware software demands placed end users greatly diminished while use commercial web conferencing systems e.g. skype shown feasible telepathology institutional setting reliance public servers raises potential security issues proven barrier telepathology more recently field telepathology witnessing emergence specific open access forums e.g. medical electronic expert communication system meces embedded virtual slide technology these new generation forums employ browser friendly w3c conform standards offer additional benefits acoustic information transfer assistance image screening finally taking advantage mobile devices e.g. cellular phones almost ubiquitous today provides another opportunity perform telepathology almost anywhere anytime | several modes of telepathology exist including static ( store - and - forward ) , dynamic ( live video streaming or robotic microscopy ) , and hybrid technology involving whole slide imaging ( wsi ) . telepathology has been employed at the university of pittsburgh medical center ( upmc ) for over a decade at local , national , and international sites .
all modes of telepathology have been successfully utilized to exploit our institutions subspecialty expertise and to compete for pathology services .
this article discusses the experience garnered at upmc with each of these teleconsultation methods .
static and wsi telepathology systems have been utilized for many years in transplant pathology using a private network and client - server architecture .
only minor clinically significant differences of opinion were documented . in hematopathology ,
the cellavision system is used to transmit , via email , static images of blood cells in peripheral blood smears for remote interpretation . while live video streaming has remained the mode of choice for providing immediate adequacy assessment of cytology specimens by telecytology , other methods such as robotic microscopy have been validated and shown to be effective .
robotic telepathology has been extensively used to remotely interpret intra - operative neuropathology consultations ( frozen sections ) .
adoption of newer technology and increased pathologist experience has improved accuracy and deferral rates in teleneuropathology .
a digital pathology consultation portal ( https://pathconsult.upmc.com/ ) was recently created at our institution to facilitate digital pathology second opinion consults , especially for wsi .
the success of this web - based tool is the ability to handle vendor agnostic , large image files of digitized slides , and ongoing user - friendly customization for clients and teleconsultants .
it is evident that the practice of telepathology at our institution has evolved in concert with advances in technology and user experience .
early and continued adoption of telepathology has promoted additional digital pathology resources that are now being leveraged for other clinical , educational , and research purposes . |
obstructive sleep apnea osa public health problem affects least 10% middle aged men represents main cause cardiovascular morbidity mortality an independent association osa insulin resistance type 2 diabetes consistently demonstrated number cross sectional observational large population based studies 2 3 moreover osa patients increased carotid intima media thickness imt early sign atherosclerosis correlates nocturnal oxygen desaturation independently cardiovascular risk factors 4 5 osa severity may also predict occult coronary atherosclerosis healthy overweight obese male subjects repetitive upper airway collapses sleep result intermittent hypoxia ih thought responsible osa associated cardiometabolic complications including atherosclerosis insulin resistance data obtained animals exposed ih validated experimental model sleep apnea showed activation sympathetic nervous system systemic inflammation underlie ih induced metabolic vascular consequences 79 we also recently demonstrated ih induced inflammatory changes epididymal white adipose tissue ewat contributed outcomes obesity increasingly recognized chronic activation inflammatory signaling pathways causally linked insulin resistance vascular alterations recent studies suggest deleterious effects could mediated least part activation toll like receptors tlr particular tlr4 tlrs family pattern recognition receptors play critical role innate immune system activating proinflammatory signaling pathways response microbial pathogens lipopolysaccharide lps binds tlr4 triggering downstream cascade leads activation proinflammatory nuclear factor kappa b nfb pathway finally expression numerous proinflammatory molecules interleukin il)-6 tumor necrosis factor tnf)- furthermore studies different strains mice showed expression activation tlr4 involved aortic inflammation atherogenesis together these experimental data confirm major role tlr4/nfb pathway crosstalk inflammation atherosclerosis metabolism dysfunctions c57bl/6 mice previously found ih induced cardiovascular inflammation characterized increased activity nfb aortic cardiac tissues unpublished data we also reported lean animals ewat exposed ih became pathological behaving like excess fat obesity exhibited increases macrophage recruitment secretion il-6 tnf- collectively data suggest cardiometabolic complications due ih obesity may share pathophysiological mechanisms therefore assessed whether metabolic vascular consequences induced ih involved proinflammatory tlr4/nfb pathway activation shizuo akira research institute microbial diseases osaka japan obtained emma european mouse mutant archive network orleans france seventeen week old male tlr4 mice control groups c57bl/6 mice fed standard chow diet used the study conducted accordance european convention protection vertebrate animals used experimental scientific purposes council europe european treaties ets 123 strasbourg 18 march 1986 guide care use laboratory animals nih publication tlr4 control c57bl/6 mice divided 2 subgroups exposed either intermittent hypoxia ih normoxia n the four groups animals exposed ih stimulus daytime n 10 per cage 8 h day cyclic 21 5% fio2 60 cycle 60 events h lowest blood oxygen saturation 60% 4 weeks fio2 measured gas analyzer ml206 adinstruments throughout experiment control animals normoxic mice n exposed air similar cages reproduce similar noise turbulences ih stimulus ambient temperature maintained 2022c first week ih exposure intraperitoneal insulin tolerance test ipitt ) was performed assess global insulin sensitivity day following last exposure period fasted animals sacrificed anesthesia intraperitoneal injection ketamine 100 mgkg xylazine 10 mgkg analysis mice fasted 5 hours weighted blood collected tail tip baseline glucose determination 0 insulin 0.5 iukg body weight novo nordisk bagsvaerd denmark injected intraperitoneally followed blood glucose measurements 15 30 60 90 minutes injection lowest blood glucose level nadir following insulin administration calculated experimental group time sacrifice blood collected cardiac puncture edta tubes the plasma fraction collected blood centrifugation 10 minutes 11000 rpm 4c total cholesterol measured plasma colorimetric enzymatic reaction using infinity kit thermoelectron corporation massachusetts usa according manufacturer guidelines bilateral epididymal fat pads collected weighted either fixed 90% ethanol adipocyte morphology study incubated cytokine determinations ethanol fixed paraffin embedded ewat sectioned 3.5 deparaffinized toluene rehydrated descending ethanol series stained hematoxylin eosin assess tissue morphology adipocyte size measured photographs 10 40 magnification using nis elements microscope imaging software nikon each ewat pad divided two equal pieces incubated 37c mild shaking rpmi medium after 120 minutes incubation il-6 tnf- measured supernatants using elisa test according manufacturer instructions r&d system europe lille france cytokine concentrations expressed ng ml 1 g adipose tissue ih n aortas embedded optimum cutting temperature oct compounds tissue tek sakura finetek europe bv alphen aan den rijn netherlands sectioned 10 stained hematoxylin eosin staining used assess intima media thickness imt morphometric analysis 15 measurements 10 noncontiguous midthoracic descending aorta sections per animal performed light microscope nikon eclipse 80i nikon nis elements microscope imaging software nikon instruments europe bv we investigated whether ih could activate nfb assessing expression activated subunit nfb p50 translocated nucleus nuclear nfb p50 determined thoracic aorta mice exposed n ih tissue homogenization proteins extraction performed according manufacturer instructions using nuclear extract kit active motif europe rixensart belgium proteins concentration evaluated using bca assay thermoscientific massachusetts usa nuclear proteins assayed presence activated p50 elisa using transam nfb p65/p50/p52 kit active motif europe results expressed mean standard errors means sem analyzed using 2-way anova subsequent bonferroni multiple post hoc comparisons mann whitney u test they smaller fat pads smaller adipocytes figures 1(a 1(c 1(d ewat released tnf- il-6 compared normoxic controls figures 1(e 1(f regarding body weight alterations normoxic hypoxic tlr4 mice different respective control animals figure 1(b after one week exposure 4 experimental groups assessed insulin tolerance test figure 2(a c57bl/6 mice exposed ih exhibited decreased response insulin shown lower glucose decrement figure 2(b trend smaller glucose nadir compared normoxic controls figure 2(d the insulin response affected hypoxic tlr4 mice response curve almost superposable normoxic tlr4 animals figures 2(c 2(d significantly different curve normoxic c57bl6 animals figure 2(a hypoxic c57bl/6 mice morphological functional alterations aorta exhibited larger intima media thickness figures 3(a 3(b higher nfb p50 activity figure 3(c alterations observed hypoxic tlr4 mice figures 3(a 3(b 3(c plasma levels total cholesterol different 4 experimental groups figure 3(d there similarities cardiometabolic complications due obesity latter resulting inflammation involving tlr4 signaling here showed nonobese c57bl/6 mice ih induced morphological inflammatory remodeling vascular white adipose tissues well insulin resistance these alterations prevented hypoxic tlr4-deficient mice suggesting ih induced cardiometabolic consequences involve tlr4 signaling mediated inflammation as previously published group others used deep intermittent hypoxia mimics severe sleep apnea whereas patients mainly suffer mild moderate sleep apnea 7 17 18 indeed absence additional factors obesity high fat diet genetic vulnerability ih needs severe enough induce measurable reproducible vascular alterations especially c57bl/6 mice atheroresistant animals lean c57bl/6 mice showed ih induced ewat alterations characterized fat pad wasting shrunken adipocytes these results agreement previous reports lean c57bl/6 apoe mice 4 6 weeks ih respectively shrunken adipocytes suggestive lipolysis elevated circulating free fatty acids ffas reported us others ih exposed animals 10 20 21 patients suffering sleep apnea latter activation beta adrenergic receptors well known mechanism lipolysis ih osa commonly associated sympathoadrenergic activation 10 24 adipose inflammation may also contributed lipolysis found increased release inflammatory cytokines tnf- il6 fat pads hypoxic c57bl/6 mice this consistent previous reports lean apoe mice 6 weeks ih recently 3t3-l1 adipocytes exposed fluctuating oxygen concentration these inflammatory changes may due local hypoxia known leading cause ewat dysregulation well systemic effects elevated circulating ffas activation sympathoadrenergic system we found ih induced morphological inflammatory alterations ewat prevented tlr4-deficient mice there growing evidence studies using murine models obesity activation proinflammatory tlr4/nfb pathway constitutes one mechanism links inflammation metabolic disorders 3032 although tlr4 activation known enhance lipolysis 33 34 surprised find ewat wasting adipocyte hypotrophy completely prevented tlr4-deficient mice suggesting tlr4 signaling could main mechanism consequences as observed mice models diet induced obesity 30 32 tlr4 deficiency prevented enhanced release tnf- il6 hypoxic mice this strengthens role tlr4 ih induced inflammation well pathophysiological similarities obesity normal amount fat hypoxia behaving like excess fat obesity this agreement previous findings obtained various mouse strains genetically obese lean c57bl/6 apoe mice duration ih exposure acute chronic ih using different methods assess insulin sensitivity homa ir itt hyperinsulinemic euglycemic clamp 10 19 35 36 this confirms role ih alterations glucose homeostasis observed sleep apnea insulin resistance worsening osa severity independently obesity 3739 both chronic inflammation elevated ffa levels 41 42 established factors causing insulin resistance obesity indeed proinflammatory cytokines secreted adipocytes considered key step obesity induced insulin resistance sole tnf- neutralization obese rats sufficient improve insulin sensitivity inversely upstream activation inflammatory cytokine cascade using agonists toll like receptors leads insulin resistance 33 34 present study observed increased release tnf- il6 ewat decreased insulin sensitivity hypoxic c57bl6 mice both parameters impaired tlr4-deficient mice suggesting tlr4 mediated inflammation involved metabolic consequence body weight alterations contribute improvements hypoxic c57bl/6 tlr4-deficient mice similar body weight we found ih induced vascular remodeling including morphological larger intima media thickness inflammatory changes higher nfb p50 activity this confirms previous results others regarding detrimental remodeling effects ih preatherosclerotic 17 18 atherosclerotic 21 44 45 processes we confirmed present study ih indeed powerful vascular stress 28 days exposure short compared duration human disease induce early vascular alterations atheroresistant c57bl/6 mouse strain besides well known role sympathoadrenergic system related hemodynamic alterations accumulating evidence suggests inflammation involved early pathophysiology ih related atherosclerosis regarding aggravation atherosclerosis ih apoe deficient mice recently demonstrated deleterious effect involved inflammatory alterations ewat ewat lipectomy prevented proatherogenic effect ih interestingly beneficial effect occurred insulin resistance well known risk factor atherosclerosis improved ewat lipectomy suggesting ewat inflammation could main determinant ih induced atherogenicity showed ewat hypoxic c57bl/6 mice released higher amounts inflammatory cytokines effect well morphological inflammatory changes aorta prevented tlr4-deficient animals given role tlr4 adipose tissue inflammation insulin resistance relationship adipose tissue inflammation insulin resistance vascular dysfunction 12 47 beneficial effect tlr4 deficiency arterial remodeling could explained prevention adipose inflammation insulin resistance role ewat inflammation seems predominant compared light improvement insulin response absence cholesterol alterations animals ih induced dyslipidemic alterations indeed inconstant mice 45 4850 suggesting dyslipidemia contributes part first steps vascular remodeling model reduced ih driven hemodynamic alterations could explanation tlr4-deficient mice less susceptible hypertension 51 52 finally direct effect vascular wall also possible tlr4 evidenced human murine atherosclerotic plaques inhibition tlr4 signaling pathway attenuated diet induced atherosclerosis apoe mice 16 55 a recent study also identified tlr4 signaling pathway direct key mediator vascular inflammation impairment endothelial insulin signaling setting obesity the direct effect vasculature could even predominant tlr4 deficiency prevented atherosclerosis ldlr mice effect adipose tissue inflammation whole body insulin sensitivity we showed nonobese c57bl/6 mice ih induced morphological inflammatory remodeling aorta epididymal white adipose tissue well insulin resistance these alterations prevented tlr4-deficient mice suggesting ih induced cardiometabolic consequences involved inflammation mediated tlr4 signaling the precise mechanisms specific role one type tissue cell e.g. adipose tissue remain determined tlr4 knockout used study cell specific tlr4 indeed expressed many cell types predominantly immune system also nonhematopoietic cell types e.g. endothelial epithelial cells etc despite limitations practical point view whole body exposed hypoxia sleep apnea tlr4 various cells likely involved numerous complications sleep apnea moreover available treatment blocks tlr4 activation eritoran cell specific however one clinical study recently investigated activation tlr4 signaling pathway osa the authors found increases tlr4 expression nfb nuclear binding release ifn tnf- il-6 circulating monocytes there therefore similarities clinical findings experimental results suggesting targeting tlr4/nfb pathway could provide therapeutic options sleep apnea patients |
objective . intermittent hypoxia ( ih ) is a major component of sleep apnea syndrome as its cardiometabolic complications have been mainly attributed to ih . the pathophysiology is still poorly understood but there are some similarities with the obesity - associated cardiometabolic complications . as the latter results from inflammation involving toll - like receptor-4 ( tlr4 ) signaling , we assessed this pathway in the cardiometabolic consequences of ih . methods .
lean adult male tlr4-deficient ( tlr4/ ) mice and their controls ( c57bl/6 mice ) were exposed to either ih ( fio2 21 - 5% , 1 min cycle , 8 h / day ) or air ( normoxic mice ) for 4 weeks .
animals were assessed at 1-week exposure for insulin tolerance test and after 4-week exposure for morphological and inflammatory changes of the epididymal fat and thoracic aorta .
results .
ih induced insulin resistance , morphological and inflammatory changes of the epididymal fat ( smaller pads and adipocytes , higher release of tnf- and il-6 ) and aorta ( larger intima - media thickness and higher nfb - p50 activity ) .
all these alterations were prevented by tlr4 deletion . conclusion .
ih induces metabolic and vascular alterations that involve tlr4 mediated inflammation .
these results confirm the important role of inflammation in the cardiometabolic consequences of ih and suggest that targeting tlr4/nfb pathway could represent a further therapeutic option for sleep apnea patients . |
different diagnostic methods drawbacks prepare mycobacterium culture golden standard tb diagnosis may take 8 weeks finding acid fast bacilli quick screening method pulmonary tb diagnosis nevertheless sensitivity low the polymerase chain reaction pcr test tb diagnosis expensive requires skilled personnel lot equipments therefore recent years great demand finding new microbiological genetic immunological biomedical diagnostic methods diagnosis tb quickly accurately ada essential proliferation differentiation lymphoid cells especially cells helps maturation monocytes macrophages it seems ada index cellular immunity previous studies proved value tb diagnosis even assessing tb effusions level ada sputum serum used diagnosis tb monitored tb treatment however previous studies used effusion fluids limited number studies used patients serum it always possible access effusion liquids everywhere pulmonary extra pulmonary tb therefore would helpful take advantage serum levels the goal study assess diagnostic value cut point serum ada levels pulmonary tb patients it cross sectional study 2011 conducted tohid hospital university referral hospital sanandaj iran study case group included 40 sputum smear positive tb patients admitted infectious disease ward hospital inclusion criteria tb patients 2 3 sputum positive smears one sputum positive smear one positive sputum culture
one positive tb microbe smear sputum suspected chest radiography addition 40 non tb patients referred tohid hospital sannandaj surgeries selected control group inclusion criteria control group tb patient family history close contact tb patients infectious disease according interview records fever symptom illness toxic normal cell blood count normal chest radiography after diagnosis tb initiation treatment blood samples patients approval consent form research project number 1387/87 taken tb group 7 ) samples centrifuged serum ada levels measured ada kit manufactured diazyme laboratories company first step adenosine affected ada becomes de ammonized shifted inosine ammoniac released second reaction glometat released nh3 become dehydrogenized got close allosteric activators combined nicotinamide adenine dinucleotide phosphate hydrogen nadph released nicotinamide adenine dinucleotide phosphate nadp consequently direct relationship activity density ada enzyme speed reduction radiation absorption 340 nanometer wavelength nadph changed nadp+ measured diazyme adenosine deaminase assay kitt diazyme laboratory usa then data analyzed using statistical package social sciences spss 11.5 chicago usa software roc curve plotted from 40 tb patients participated study 16 males 24 females 42 participants control group 22 males 20 females the common age group tb patients 50s control group 40s age average 59 13.5 tb patients 49 15.6 non tb patients the average serum ada tb patients group control group 20.88 5.97 10.69 2.98 respectively u l sensitivity specificity 92.7% 95% ci 84.7 100 88.1% 95% ci 78.3 97.8 respectively the positive negative predicative values 88.4% 95% ci 75 95.1 92.5% 95% ci 79.6 98.4 respectively figure 1 the calculated area roc curve 0.955 95% ci 0.914 0.995 p 0.001 in study serum ada level appropriate index diagnosing smear positive tb therefore serum ada could also used diagnosis pulmonary tb moreover study tb patients serum level 22.5 u l hence suspicious cases tb increased levels ada could facilitate diagnosis diagnostic value serum ada pulmonary tb assessed numbers studies pairs et al reported increase ada level tb pleural effusion studies also confirmed increase tb pericardial effusions peritoneum central nervous system cns the main reason increased ada levels pleural effusion movement lymphocytes toward area increase ada level result tropical inflammatory reaction caused monocytes macrophages when alveolar macrophages infected mycobacterium enzyme could found serum active pulmonary disease when tb infection controlled growth markers lymphocytes decrease leucocytes decrease serum ada levels concurrent decrease lymphocytes because serum ada level could utilized treatment response index agarwal 's study ada level 15.3 0.23 healthy people 19 0.68 non pulmonary tb cases 38.48 1.56 pulmonary tb patients in jhamaria et al study average serum ada level 19.9 u l 2.99 control group 43.95 u l 2.48 sputum smear positive people typical progressive disease 42.09 u l 1.46 40.02 u l 2.58 negative sputum patients mild typical disease study cut point 33 it seems disease progresses ada levels increase subject considered study another study ada level 26.2 u / l sensitivity specificity positive predictive value 95% 83.3% 79.2% respectively gupta 's study sensitivity specificity positive predictive value negative predictive value 92.8% 90% 92.8% 90% respectively diagnosis tb pleural effusion ada level 40 conde 's study ada level 14 u l chosen cut point stevanovic et al assessed serums extra pulmonary tb patients cut point 24 sensitivity specificity 94.3% 92.2% respectively study serum ada level decreased treatment started dilmac 's study serum ada level pulmonary tb patients reported 27.5 11 23.9 24 chronic obstructive pulmonary disease copd patients in rasolinejad study serum ada level 21.51 pulmonary tb patients 11.47 healthy people cut point 14.5 u / u l negative smear negative tuberculin patients 33.52 15.22 smear positive purified protein derivative ppd positive patients 16.5 3.18 volunteer healthy people differences may due tb severity age groups genetic differences dissimilarities control groups therefore studies identifying normal ada levels different societies may useful fortunately autoimmune patients like rheumatoid arthritis synovial ada level normal similar control group thus autoimmune diseases involve lung ada level could used tb differentiation studies ada2 also considered useful tool diagnosis needs studies according study serum ada level proposed proper index tb diagnosis cut point 14 sensitivity specificity calculated 92.7% 88.1% respectively | background : in some studies , the level of adenosine deaminase ( ada ) in sputum and effusion liquids was used for the diagnosis of tuberculosis ( tb ) .
but it is not always possible to access these materials .
the goal of this study is to assess the diagnostic value of serum ada levels in pulmonary tb patients.materials and methods : in this study , 40 sputum smear - positive tb patients who were hospitalized and 40 non - tb patients who referred for surgeries were selected .
a serum sample was collected and serum ada level was measured by ada kit.results:the average ( sd ) of serum ada in tb and non - tb patients were 20.88 ( 5.97 ) and 10.69 ( 2.98 )
u / l , respectively ( p value < 0.05 ) .
the best cut - off point was 14 u / l . the calculated area under the receiver operating characteristic ( roc ) curve was 0.955 ( 95% ci , 0.914 - 0.995 ) ; sensitivity was 92.7% ( 95% ci , 84.7 - 100 ) and specificity was 88.1% ( 95% ci , 78.3 - 97.8 ) ( p < 0.001).conclusion : serum ada level may be proposed as a proper index for tb diagnosis . |
androgen deprivation therapy adt bilateral orchiectomy gonadotropin releasing hormone analogs without antiandrogens indicated front line treatment metastatic prostate cancer well adjuvant setting following radical prostatectomy nodal metastasis radiation therapy occasionally patients localized disease.1 adt influence many metabolic pathways common side effect reduction bone density.26 prostate cancer usually spreads bone metastatic disease treatment intravenous bisphosphonates commonly prescribed stage order reduce skeletal related events.7,8 loss bmd correlates duration adt pronounced first year therapy.710 men initiating adt recommended assessment risk factors osteoporosis calcium vitamin intake lifestyle modifications baseline serial bmd assessment adt along bisphosphonate therapy.1 evidence loss bmd strong predictor fracture risk.11 treatment bisphosphonates used prevent osteoporotic fractures shown increase bone mineral density bmd).12 although national comprehensive cancer network american society clinical oncology guidelines propose baseline bmd assessment bisphosphonate therapy systematic review utilization interventions practicing physicians community the current study evaluated bone densitometry bd bisphosphonate therapy utilization patterns prevent osteoporosis patient population a retrospective cohort study conducted using surveillance epidemiology end results seer)-medicare linked database men aged 65 years older diagnosis non bony metastatic prostate cancer 2004 2007 individuals diagnosis non metastatic prostate cancer identified treated adt patient data obtained seer patient entitlement diagnosis summary file pedsf medicare inpatient treatment claims identified using national claims history noninstitutional physician supplier part b files claims preventive services coverage outpatient prescription services outpatient part b claims outpatient services prescriptions durable medical devices hospital facilities seer linked patient data pedsf file unavailable year 2008 time study prostate cancer patient data analyzed 20042007 linked medicare treatment claims 2004 2008 order limit analysis patients metastatic disease bone prostate tumors coded metastasis localized tumors pedsf file medicare claims national claims history physician outpatient files matched pedsf patient data seer case number select prostate cancer cases ever received adt part treatment adt identified using healthcare common procedure coding system hcpcs current procedural terminology codes cpt medicare physician outpatient claims files coding used orchiectomy included 54520 54521 54522 54530 54535 icd-9 code 624 coding goserelin leuprolide leuprolide implant triptorelin identified codes j1950 j9202 j9217 j9218 j9219.13 bmd assessment dual energy x ray absorptiometry identified using hcpcs cpt codes 77080 77081 treatment intravenous bisphosphonates pamidronate zoledronic acid identified using medicare hcpcs codes j2430 j3487 study period 20042008 since medicare part data outpatient medications including oral bisphosphonates available 2007 seer medicare files could utilized analysis oral bisphosphonates generally poorly absorbed gastrointestinal side effects leading low patient adherence drugs.14,15 due lack adherence intravenous bisphosphonates preferred oral bisphosphonates patient population oral bisphosphonate use captured medicare database collect details oral therapy the one sided exact binomial test proportion used determine physician compliance serial bmd assessment bisphosphonate treatment patients undergoing adt consistently 80% a survey practicing physicians response rate 63% found physician self reported adherence clinical guidelines 77%.16 therefore 80% adherence clinical guidelines used study logistic regression analysis used determine treatment differences patient characteristics age group race clinical stage seer registry geographic region sas 9.3 sas institute cary nc usa used analyze differences treatment practices further logistic regression analysis also done explore relationship history bone fractures bisphosphonate treatment age race tumor stage diagnosis duration adt the study approved institutional review board university arkansas medical sciences among 157,974 newly diagnosed prostate cancer cases 100,865 aged 65 years older bone metastases 2004 2007 subjects adt claims excluded analysis total 30,846 prostate cancer patients aged 65 years older bone metastases receiving adt eligible analysis table 1 neither bd parenteral bisphosphonate therapy utilized 87.3% n=26,935 subjects adt table 2 the age group race stage geographic distribution shown table 1 every covariate age race stage geographic location percentage bd utilization parenteral bisphosphonate administration markedly low study 8.8% n=2,707 subjects adt received bd assessments without ever receiving intravenous bisphosphonates three percent n=931 cases adt received bisphosphonate treatment without ever receiving bd assessment only 0.9% n=278 subjects adt received bd bisphosphonates a compliance rate nearly 1.0% 0.9% subjects receiving bd screen bone loss preventive bisphosphonate therapy well expected rate 80% table 2 figure 1 shows trend bd intravenous bisphosphonate utilization study period 20042008 bisphosphonates prescribed often 2006 utilization remained low 10% years studied odds ratios ors show differences preventive osteoporotic therapy treatment category table 1 bd utilization increased advancing age except older 85 years bd utilization differed race black men less likely receive bd white men 0.6 95% confidence interval ci 0.540.72 asian men likely bd measurement performed white men 1.6 95% ci 1.361.88 patients diagnosed later stages disease t3 received bd often men diagnosed earlier stages disease t0t1 1.7 95% ci 1.491.96 men prostate cancer living west region likely receive bd men living region table 1 patients midwest northeast south regions significantly less likely receive bd patients west 0.7 95% ci 0.640.81 0.8 95% ci 0.760.92 0.5 95% ci 0.460.58 respectively using midwest region reference group patients west 20% greater use bd 1.2 95% ci 1.021.33 intravenous bisphosphonate therapy prescribed often older men 8084 years younger men aged 6569 years 1.3 95% ci 1.071.54 men diagnosed later stages disease t2t4 likely receive bisphosphonate treatment men diagnosed earlier stages t0t1 table 1 men living northeast south regions less likely receive bisphosphonates men living west region table 1 among men receiving recommended treatment bd bisphosphonates differences race tumor stage region black men less likely receive bd bisphosphonates compared white men 0.6 95% ci 0.360.93 men prostate cancer northwest south regions less likely receive bd bisphosphonates men west region table 1 only 25 30,846 subjects study identified diagnosis fracture based icd code seer medicare database diagnosed bone fractures identified using icd-9 codes 733.1 osteoporotic fractures 808809 fractures spine trunk logistic regression analysis performed using bone fractures outcome variable controlling age continuous variable bisphosphonate treatment dichotomous variable non white race dichotomous variable white race reference group tumor stage dichotomous variable t4 stage reference group duration adt continuous variable association length therapy history bone fractures found however bone fracture associated bisphosphonate therapy study population multiple studies demonstrated adt results bone loss could surrogate increased skeletal related events.1721 although duration follow diagnosis short 5 years continuous adt increased risk bone fracture study cohort p0.05 this population level finding supports clinical evidence accelerated bone loss patients receiving adt in study 8.8% n=2,707 subjects adt received bd assessments without ever receiving intravenous bisphosphonates three percent n=931 cases adt received bisphosphonate treatment without ever receiving bd assessment only 0.9% n=278 subjects adt received bd bisphosphonates a compliance rate nearly 1.0% 0.9% subjects receiving bd screen bone loss preventive bisphosphonate therapy well expected rate 80% table 2 figure 1 shows trend bd intravenous bisphosphonate utilization study period 20042008 bisphosphonates prescribed often 2006 utilization remained low 10% years studied odds ratios ors show differences preventive osteoporotic therapy treatment category table 1 bd utilization increased advancing age except older 85 years black men less likely receive bd white men 0.6 95% confidence interval ci 0.540.72 asian men likely bd measurement performed white men 1.6 95% ci 1.361.88 patients diagnosed later stages disease t3 received bd often men diagnosed earlier stages disease t0t1 1.7 95% ci 1.491.96 men prostate cancer living west region likely receive bd men living region table 1 patients midwest northeast south regions significantly less likely receive bd patients west 0.7 95% ci 0.640.81 0.8 95% ci 0.760.92 0.5 95% ci 0.460.58 respectively using midwest region reference group patients west 20% greater use bd 1.2 95% ci 1.021.33 intravenous bisphosphonate therapy prescribed often older men 8084 years younger men aged 6569 years 1.3 95% ci 1.071.54 men diagnosed later stages disease t2t4 likely receive bisphosphonate treatment men diagnosed earlier stages t0t1 table 1 men living northeast south regions less likely receive bisphosphonates men living west region table 1 among men receiving recommended treatment bd bisphosphonates differences race tumor stage region black men less likely receive bd bisphosphonates compared white men 0.6 95% ci 0.360.93 men prostate cancer northwest south regions less likely receive bd bisphosphonates men west region table 1 only 25 30,846 subjects study identified diagnosis fracture based icd code seer medicare database diagnosed bone fractures identified using icd-9 codes 733.1 osteoporotic fractures 808809 fractures spine trunk logistic regression analysis performed using bone fractures outcome variable controlling age continuous variable bisphosphonate treatment dichotomous variable non white race dichotomous variable white race reference group tumor stage dichotomous variable t4 stage reference group duration adt continuous variable association length therapy history bone fractures found however bone fracture associated bisphosphonate therapy study population multiple studies demonstrated adt results bone loss could surrogate increased skeletal related events.1721 although duration follow diagnosis short 5 years continuous adt increased risk bone fracture study cohort p0.05 this population level finding supports clinical evidence accelerated bone loss patients receiving adt adt shown reduce disease progression increase survival subjects prostate cancer.22 bmd loss osteoporosis one main adverse effects adt population.26,23 study small proportion prostate cancer patients adt evaluated bone loss even smaller proportion ever received intravenous bisphosphonate therapy among patient characteristics investigated approximately 12% men general population osteoporosis.24 osteoporosis may asymptomatic 20% men adt skeletal related events fracture.24 adt associated accelerated bone loss 4.5% per year loss bmd considered strong surrogate increased risk skeletal related events.2,4,5,1922,25 rate bone loss greatest first year adt osteoporosis prevalent nearly 50% patients adt 4 years 80% 8 years.8 early bmd assessment treatment may potentially prevent fragility fractures recommended national organizations national comprehensive cancer network american society clinical oncology.1,21,22,25 prevention bone loss resulting reduction skeletal related events may maintain good quality life patients prostate cancer adt concurrent administration bisphosphonate selective estrogen receptor modulator shown stabilize increase bmd randomized studies bisphosphonate therapy including pamidronate zoledronic acid alendronate shown improve bmd decrease markers bone metabolism men adt.4,5,7,2029 community level study supports evidence bd utilization bisphosphonate therapy reduce fracture risk men prostate cancer receiving adt intravenous bisphosphonate therapy ie zoledronic acid evaluated several studies determined best treatment prevent bone loss prostate cancer patients undergoing adt.30 treatment denosumab currently recommended alternative zoledronic acid patients nonmetastatic prostate cancer approved us food drug administration 2011 treatment option study years examined.31 therefore analysis guideline compliance using intravenous bisphosphonates measure appropriate study addition cost osteoporosis related fractures among men usa approximately 4.1 billion per year effect rising health care costs could potentially impact survival benefit adt patients metastatic prostate cancer subjects adt recommended screened fracture risk bmd testing baseline 1 year adt every 2 years clinically indicated.32,33 addition counseling patients fall risk applying interventions reduce falls may consequently reduce fracture risk population most evidence supporting use bisphosphonates prevention adt related bone loss men prostate cancer derived studies evaluating intravenous bisphosphonates.4,5,20,21 due lack data available analyze oral bisphosphonate use large population studies greenspan et al recently demonstrated significant increase bmd men prostate cancer receiving adt weekly oral alendronate 70 mg.22 denosumab another current treatment unavailable study years examined recommended alternative zoledronic acid nonmetastatic prostate cancer patients.31 long term use oral bisphosphonate therapy could evaluated study medicare part data available study period however due lack patient adherence oral bisphosphonates preferred treatment intravenous bisphosphonates patient population likely significantly affect outcome.14,15 study emphasizes importance using bd measures evaluate skeletal integrity prevent osteoporosis utilization bisphosphonates among patients adt there seems lack understanding regarding implications adt prostate cancer although follow time short continuous adt associated increased risk bone fracture supports previous clinical studies concerning accelerated bone loss patients receiving adt community population study demonstrated small proportion patients underwent evaluation bone loss even smaller proportion patients received bisphosphonates in addition even overall treatment utilization low black men less likely receive recommended treatment bd bisphosphonates compared white men further utilization practices differed region men residing west midwest regions receiving optimum treatment bd bisphosphonates compared men northeast south contrary recommendations screening bone loss preventive treatment practices among community population markedly low every age group race stage diagnosis t0t4 seer registries us geographic region | backgroundprostate cancer subjects with prostate - specific antigen ( psa ) relapse who are treated with androgen deprivation therapy ( adt ) are recommended to have baseline and serial bone densitometry and receive bisphosphonates .
the purpose of this community population study was to assess the utilization of bone densitometry and bisphosphonate therapy in men receiving adt for non - metastatic prostate cancer.methodsa cohort study of men aged 65 years or older with non - metastatic incident diagnoses of prostate cancer was obtained from the surveillance epidemiology end results ( seer)-linked medicare claims between 2004 and 2008 .
claims were used to assess prescribed treatment of adt , bone densitometry , and bisphosphonates.resultsa total of 30,846 incident prostate cancer cases receiving adt and aged 65 years or older had no bone metastases ; 87.3% ( n=26,935 ) on adt did not receive either bone densitometry or bisphosphonate therapy .
three percent ( n=931 ) of the cases on adt received bisphosphonate therapy without ever receiving bone densitometry , 8.8% ( n=2,702 ) of the cases on adt received bone densitometry without receiving intravenous bisphosphonates , while nearly 1% ( 0.90% , n=278 ) of the cases on adt received both bone densitometry and bisphosphonates .
analysis showed treatment differed by patient characteristics.conclusioncontrary to the recommendations , bone densitometry and bisphosphonate therapy are underutilized in men receiving adt for non - metastatic prostate cancer . |
adults bmi 40 kg obese children bmi 97th percentile sex age table 1 three hundred forty five french morbidly obese adults recruited cnrs umr8090 lille department nutrition paris hotel dieu hospital we also sequenced 287 swiss morbidly obese adults recruited gastric surgery zurich switzerland three hundred ninety nine french obese children recruited cnrs umr8090 281 obese children recruited part genetics obesity study goos cohort 28 a total 1,221 lean adult subjects part french desir data epidemiological study insulin resistance syndrome general prospective study 29 inclusion criteria bmi z score zbmi 90th percentile sex age according eastern cooperative oncology group ecog 31 the study protocol approved local ethics committees informed consent obtained subject participating study clinical characteristics obese lean subjects data means sd unless otherwise indicated genotyping fto rs9939609 snp performed using taqman snp genotyping assay applied biosystems abi 7900ht fast real time pcr system applied biosystems according manufacturer instructions we amplified overlapping pcr fragments according primers pcr optimized conditions available authors upon request pcr amplifications inspected single bands expected sizes agarose gels purification agencourt ampure biomek nx beckman coulter sequencing achieved using automated abi prism 3730xl dna sequencer combination big dye terminator cycle sequencing ready reaction kit 3.1 applied biosystems purification sequencing reaction performed agencourt cleanseq biomek nx beckman coulter the comparison prevalence tested fisher exact test reported p values two sided p values 0.05 considered indicate statistical significance wild type human fto cdna amplified expand dna polymerase roche using xhoi tagged primers first strand reverse transcribed cdna superscript ii invitrogen human brain total rna template using xhoi sites the resulting pcr product cloned nh2-terminal 6 tagged bacterial expression vector pet302/nt invitrogen the fto mutants generated cloned wild type fto using quikchange site directed mutagenesis kit stratagene according manufacturer protocols the mutations confirmed dna sequencing using big dye terminator chemistry applied biosystems electrophoresis abi 3730 automated dna sequencer human wild type mutant fto protein production carried previously described 32 briefly expression plasmids transformed escherichia coli bl21-gold de3 stratagene cultured 2 l luria bertani broth 50 g ml carbenicillin a600 1.0 37c expression cloned gene induced addition 0.5 mmol l isopropyl--d-1-thiogalactopyranoside iptg 15c 4 h. cells harvested washed pbs pellets stored 80c cells resuspended 40 ml lysis buffer 50 mmol l hepes koh ph 8 2 mmol l -mercaptoethanol 5% glycerol 300 mmol l nacl prior addition lysozyme 2 mg ml 30 min incubation ice cells sonicated lysate clarified centrifugation 15000 g 20 min the lysate supplemented imidazole 10 mmol l loaded onto 1.5-ml ni nta nickel nitrilotriacetic acid)agarose column qiagen previously equilibrated lysis buffer containing 10 mmol l imidazole the column washed 30 ml lysis buffer containing 10 mmol l imidazole followed 7.5 ml lysis buffer containing 40 mmol l imidazole the eluate loaded onto 30-kda concentrator sartorius stedium biotech centrifuged 2500 g 30 min then 2 ml buffer 20 mmol l hepes ph 8 5% glycerol 50 mmol l nacl added concentrated fraction concentrated 100 l centrifugation 2500 g conversion c-2-oxoglutarate c succinate 2-og fe dependent dna dioxygenases assayed previously 33 this method modified optimized assay fto previously described 32 measure uncoupled reaction prime substrate present 1.5 mol l fto assayed 10 l reaction mixture containing 50 mmol l hepes koh ph 7 50 g ml bsa 4 mmol l ascorbate 75 mol l fe(nh4)2(so4)2 20 mol l 5-c]-2-oxoglutarate 30 mci mmol moravek biochemicals incubated 37c various times measure stimulation activity 3-methylthymidine 1 the reaction stopped adding 5 l stop solution containing 20 mmol l succinate 20 mmol l 2-og followed 5 l 160 mmol l dinitrophenylhydrazine precipitates 2-og an additional 10 l 1 2-og added incubated 30 min clear supernatant 10 l scintillation counted monitor c succinate generated genotyping fto rs9939609 snp performed using taqman snp genotyping assay applied biosystems abi 7900ht fast real time pcr system applied biosystems according manufacturer instructions we amplified overlapping pcr fragments according primers pcr optimized conditions available authors upon request pcr amplifications inspected single bands expected sizes agarose gels purification agencourt ampure biomek nx beckman coulter sequencing achieved using automated abi prism 3730xl dna sequencer combination big dye terminator cycle sequencing ready reaction kit 3.1 applied biosystems purification sequencing reaction performed agencourt cleanseq biomek nx beckman coulter the comparison prevalence tested fisher exact test reported p values two sided wild type human fto cdna amplified expand dna polymerase roche using xhoi tagged primers first strand reverse transcribed cdna superscript ii invitrogen human brain total rna template using xhoi sites the resulting pcr product cloned nh2-terminal 6 tagged bacterial expression vector pet302/nt invitrogen the fto mutants generated cloned wild type fto using quikchange site directed mutagenesis kit stratagene according manufacturer protocols the mutations confirmed dna sequencing using big dye terminator chemistry applied biosystems electrophoresis abi 3730 automated dna sequencer human wild type mutant fto protein production carried previously described 32 briefly expression plasmids transformed escherichia coli bl21-gold de3 stratagene cultured 2 l luria bertani broth 50 g ml carbenicillin a600 1.0 37c expression cloned gene induced addition 0.5 mmol l isopropyl--d-1-thiogalactopyranoside iptg 15c 4 h. cells harvested washed pbs pellets stored 80c cells resuspended 40 ml lysis buffer 50 mmol l hepes koh ph 8 2 mmol l -mercaptoethanol 5% glycerol 300 mmol l nacl prior addition lysozyme 2 mg ml after 30 min incubation ice cells sonicated lysate clarified centrifugation 15000 g 20 min the lysate supplemented imidazole 10 mmol l loaded onto 1.5-ml ni nta nickel nitrilotriacetic acid)agarose column qiagen previously equilibrated lysis buffer containing 10 mmol l imidazole the column washed 30 ml lysis buffer containing 10 mmol l imidazole followed 7.5 ml lysis buffer containing 40 mmol l imidazole the eluate loaded onto 30-kda concentrator sartorius stedium biotech centrifuged 2500 g 30 min then 2 ml buffer 20 mmol l hepes ph 8 5% glycerol 50 mmol l nacl added concentrated fraction concentrated 100 l centrifugation 2500 g conversion c-2-oxoglutarate c succinate 2-og fe dependent dna dioxygenases assayed previously 33 this method modified optimized assay fto previously described 32 measure uncoupled reaction prime substrate present 1.5 mol l fto assayed 10 l reaction mixture containing 50 mmol l hepes koh ph 7 50 g ml bsa 4 mmol l ascorbate 75 mol l fe(nh4)2(so4)2 20 mol l 5-c]-2-oxoglutarate 30 mci mmol moravek biochemicals incubated 37c various times measure stimulation activity 3-methylthymidine 1 the reaction stopped adding 5 l stop solution containing 20 mmol l succinate 20 mmol l 2-og followed 5 l 160 mmol l dinitrophenylhydrazine precipitates 2-og an additional 10 l 1 2-og added incubated 30 min clear supernatant 10 l scintillation counted monitor c succinate generated to identify potential loss function mutations screened nine coding exons fto direct nucleotide sequencing 1,433 extremely obese subjects 753 adults bmi 40 kg 680 children bmi 97th percentile 1,433 lean subjects 1,221 adults bmi 23 kg 212 children recruited zbmi 90th percentile according ecog 31 average zbmi close 50th percentile zbmi 0.1 0.98 table 1 additionally also genotyped fto rs9939609 snp 2 patients genotype call rate 99% lean obese subjects genotypic distribution obeyed hardy weinberg equilibrium lean control subgroup p 0.58 we genotyped 363 duplicated dna samples observed concordance rate 100% lean subgroup genotype counts 532 tt 668 ta 224 aa obese subgroup genotype counts 367 tt 665 ta 390 aa as expected obesity risk allele frequency 11.6% higher obese versus lean subjects obese 50.8% lean 39.2% 1.60 1.441.78 p 1.2 10 a total 26 different rare frequency 1% present cohort nonsynonymous variants identified fto table 2 the prevalence nonsynonymous variants similar two groups 33 lean 2.3% 35 obese 2.4% individuals carrying mutations significant differences prevalence observed children adults table 2 eight a134 g187a m223v a241 h419r e471 g i492v v493f nonsynonymous mutations identified uniquely obese cohort whereas 11 p5l e24k r80p p93r v94i n143s i148r d189n e234d r316q p399h identified uniquely lean cohort table 3 g187a n 2 a241 n 2 v493f n 4 identified multiple obese subjects table 3 seven variants r96h l146 a163 v201i s256n r322q a405v present cohorts the prevalence synonymous mutations significantly different obese compared lean subjects 0.8% vs. 0.4% p 0.05 table 4 all mutations identified heterozygous form nonsense variants reported studied populations thus obvious enrichment nonsynonymous mutations lean obese individuals summary nonsynonymous mutations found obese lean subjects data boldface indicate combined adult children numbers summary nonsynonymous mutations unique lean obese group summary synonymous mutations found lean obese subjects fto member alkb homologue abh protein family numbers nine homologues humans 27 most 2-og fe dependent dioxygenases slowly catalyze conversion 2-og succinate even absence prime substrate 33 called uncoupled reaction may stimulated substrates analogues we previously reported murine fto capable demethylating base 3-methylthymine context single stranded dna 27 reaction proceeds rather slowly human fto also accomplish reaction slow turnover rate 34 we previously exploited ability wild type human fto efficiently catalyze conversion 2-og succinate manner stimulated presence free nucleoside 3-methylthymidine 32 used assay throughout study analysis based three dimensional 3d homology model 27 comparing fto known 3d structure three members family abh2 abh3 alkb 35 suggests fto divided several structural functional regions fig the conserved nh2-terminal segment contains 1 putative nuclear localization signal present fto 36 2 double stranded -helix a
jellyroll fold containing catalytic apparatus well conserved abhs 3 substrate recognition lid different abh member phylogenetically well conserved among species within paralog 4 two long insertions absent abh members variable lengths different species substantially less conserved rest protein the cooh terminal domain whose structure function remain unknown absent abh members contains several residues absolutely conserved among highly diverse species predicted structural functional regions fto based 3d homology model fto 27 two naturally occurring mutations detected namely r316q found one lean subject r322q found one lean one obese replace absolutely conserved residues catalytic domain fig 2 model predicts r316 r322 involved 2-og coordination forming stabilizing salt bridges carboxylates cosubstrate we previously studied enzymatic property r316q 32 study examined r322q compared wild type fto fig as predicted r322q like r316q 32 completely unable convert 2-og succinate either absence presence 3-methylthymidine mutants assayed uncoupled reaction absence presence 3-methylthymidine mutants inactive uncoupled reaction assay 3-methylthymidine shown red whereas affect reaction shown blue decarboxylation c-2-oxoglutarate c succinate 1.5 mol l fto absence presence 3-methylthymidine measured various time intervals wt1 r322q fto proteins wt1 2 3 three different wild type fto preparations made time mutant proteins assayed b c d. open symbols indicate without 3-methylthymidine closed symbols indicate 1 mmol l 3-methylthymidine also indicated e sds10% page fto protein preparations stained coomassie blue per lane 3 g total protein loaded one mutation r96h detected one lean one obese subject occurs absolutely conserved residue within putative substrate recognition lid protein fig 1 members abh family region molecule is known required binding primary substrate involved interactions cosubstrate 2-og notably contrast r322q r96h retained ability convert 2-og succinate activity enhanced presence 3-methylthymidine fig 3b finding consistent hypothesis r96 functions part primary substrate recognition lid we also tested enzymatic activity several variants representing different regions fto p5l v94i i148r m223v e234d a241 a405v i492v v493f fig 2 none variants located less conserved positions significant impact enzymatic activity fig bioinformatic analysis suggests sequence 18 amino acid residues nh2-terminal fto encodes putative nuclear localization signal fig cos-7 cells transfected construct expressing wt fto gfp wild type fto green fluorescent protein p5l fto gfp mutant protein gfp alone mock gfp wt fto gfp p5l fto gfp colocalized dap1 whereas gfp alone seen cytoplasm nucleus supplementary fig to identify potential loss function mutations screened nine coding exons fto direct nucleotide sequencing 1,433 extremely obese subjects 753 adults bmi 40 kg 680 children bmi 97th percentile 1,433 lean subjects 1,221 adults bmi 23 kg 212 children recruited zbmi 90th percentile according ecog 31 average zbmi close 50th percentile zbmi 0.1 0.98 table 1 additionally also genotyped fto rs9939609 snp 2 patients genotype call rate 99% lean obese subjects genotypic distribution obeyed hardy weinberg equilibrium lean control subgroup p 0.58 we genotyped 363 duplicated dna samples observed concordance rate 100% lean subgroup genotype counts 532 tt 668 ta 224 aa obese subgroup genotype counts 367 tt 665 ta 390 aa as expected obesity risk allele frequency 11.6% higher obese versus lean subjects obese 50.8% lean 39.2% 1.60 1.441.78 p 1.2 10 a total 26 different rare frequency 1% present cohort nonsynonymous variants identified fto table 2 the prevalence nonsynonymous variants similar two groups 33 lean 2.3% 35 obese 2.4% individuals carrying mutations significant differences prevalence observed children adults table 2 eight a134 g187a m223v a241 h419r e471 g i492v v493f nonsynonymous mutations identified uniquely obese cohort whereas 11 p5l e24k r80p p93r v94i n143s i148r d189n e234d r316q p399h identified uniquely lean cohort table 3 g187a n 2 a241 n 2 v493f n 4 identified multiple obese subjects table 3 seven variants r96h l146 a163 v201i s256n r322q a405v present cohorts the prevalence synonymous mutations significantly different obese compared lean subjects 0.8% vs. 0.4% p 0.05 table 4 all mutations identified heterozygous form nonsense variants reported studied populations thus obvious enrichment nonsynonymous mutations lean obese individuals summary nonsynonymous mutations found obese lean subjects data boldface indicate combined adult children numbers summary nonsynonymous mutations unique lean obese group summary synonymous mutations found lean obese subjects fto member alkb homologue abh protein family numbers nine homologues humans 27 most 2-og fe dependent dioxygenases slowly catalyze conversion 2-og succinate even absence prime substrate 33 called uncoupled reaction may stimulated substrates analogues we previously reported murine fto capable demethylating base 3-methylthymine context single stranded dna 27 reaction proceeds rather slowly human fto also accomplish reaction slow turnover rate 34 we previously exploited ability wild type human fto efficiently catalyze conversion 2-og succinate manner stimulated presence free nucleoside 3-methylthymidine 32 used assay throughout study analysis based three dimensional 3d homology model 27 comparing fto known 3d structure three members family abh2 abh3 alkb 35 suggests fto divided several structural functional regions fig the conserved nh2-terminal segment contains 1 putative nuclear localization signal present fto 36 2 double stranded -helix jellyroll fold containing catalytic apparatus well conserved abhs 3 substrate recognition lid different abh member but phylogenetically well conserved among species within paralog 4 two long insertions absent abh members variable lengths different species substantially less conserved rest protein the cooh terminal domain whose structure function remain unknown absent abh members contains several residues absolutely conserved among highly diverse species predicted structural functional regions fto based 3d homology model fto 27 two naturally occurring mutations detected namely r316q found one lean subject r322q found one lean one obese replace absolutely conserved residues catalytic domain fig 2 model predicts r316 r322 involved 2-og coordination forming stabilizing salt bridges carboxylates cosubstrate we previously studied enzymatic property r316q 32 study examined r322q compared wild type fto fig as predicted r322q like r316q 32 completely unable convert 2-og succinate either absence presence 3-methylthymidine mutants assayed uncoupled reaction absence presence 3-methylthymidine mutants inactive uncoupled reaction assay 3-methylthymidine shown red whereas affect reaction shown blue decarboxylation c-2-oxoglutarate c succinate 1.5 mol l fto absence presence 3-methylthymidine measured various time intervals wt1 2 3 three different wild type fto preparations made time mutant proteins assayed b c d. open symbols indicate without 3-methylthymidine closed symbols indicate 1 mmol l 3-methylthymidine also indicated e sds10% page fto protein preparations stained coomassie blue per lane 3 g total protein loaded one mutation r96h detected one lean one obese subject occurs absolutely conserved residue within putative substrate recognition lid protein fig 1 members abh family region molecule is known required binding primary substrate involved interactions cosubstrate 2-og notably contrast r322q r96h retained ability convert 2-og succinate activity enhanced presence 3-methylthymidine fig 3b finding consistent hypothesis r96 functions part primary substrate recognition lid we also tested enzymatic activity several variants representing different regions fto p5l v94i i148r m223v e234d a241 a405v i492v v493f fig 2 none variants located less conserved positions significant impact enzymatic activity fig bioinformatic analysis suggests sequence 18 amino acid residues nh2-terminal fto encodes putative nuclear localization signal fig cos-7 cells transfected construct expressing wt fto gfp wild type fto green fluorescent protein p5l fto gfp mutant protein gfp alone mock gfp wt fto gfp p5l fto gfp colocalized dap1 whereas gfp alone seen cytoplasm nucleus supplementary fig recent genome wide association efforts highly successful identifying large number common genetic variants reliably associated important human diseases quantitative traits 2,32,37 understanding precise biological mechanisms underlying associations provide major scientific challenge require multiplicity approaches humans model organisms although snps intron 1 fto unequivocally associated adiposity multiple populations still evidence snps influence expression splicing fto fto located adjacent genes expression function could conceivably influence energy balance 10,36,38 recent findings mice rendered null fto support notion fto important influence energy balance fto null mice small lean increased metabolic rate hyperphagic whereas fto mice resistant diet induced obesity 39 given information reasonable speculate loss function mutations fto might common lean rather obese humans test hypothesis sequenced fto large number lean obese subjects found 1 nonsynonymous mutations equally common obese lean cohorts 2 heterozygous mutations severely impaired enzymatic activity fto found lean obese individuals obvious major clinical phenotypes genes whose candidacy derives largely genome wide association studies extreme phenotypes studying ends spectrum quantitative trait ( considered fto obesity gene sequenced obese subjects finding loss function mutations would misleading human genetic data conclude heterozygosity severely dysfunctional fto allele compatible either lean obese humans understanding relationship snps intron 1 fto human adiposity require approaches collaboration dr laurence colleaux hopital necker paris others recently found consanguineous israeli arab family nine siblings homozygous r316q mutation fto 32 all homozygous carriers severely growth retarded multiple congenital malformations died infancy although heterozygous parents children obvious metabolic phenotype ongoing efforts directed establishing measures adiposity heterozygous versus wild type relatives 32 our studies brought new insights aspects structure function relationship human fto enzyme human fto catalyze uncoupled reaction 2-og succinate stimulated 3-methylthymidine 32 used robust test fto catalytic activity predicted found arginine position 322 essential catalytic activity human fto made similar observations r316q 32 mutation arginine corresponding human 316 mouse fto r313a also generated inactive enzyme 27 perhaps interestingly demonstrated mutation r96 histidine human fto produces enzyme capable basal conversion 2-og succinate insensitive effects 3-methylthymidine these findings consistent r96 part called substrate recognition lid responsible substrate fixation selectivity thus lid well conserved among species orthologues diverged substantially various paralogs abh accommodate different substrates for instance r131 position lid abh3 positioned interact 1-mea n3 r131a abh3 abolishes activity toward 1-me containing single stranded dna 27 although nonsynonymous variants tested appeared normal enzymatic activity express caution categorically stating fully wild type function first know true natural primary substrate(s fto entirely possible mutations affect fto actions elusive substrate necessarily impair uncoupled reaction second although demonstrated fto vitro possesses dioxygenase activity whether biological role enzymatic otherwise yet determined this could potentially relevance v493f cooh terminal mutation found obese population found four different individuals fig 2 yet impact ability fto convert 2-og succinate stimulation 3-methylthymidine fig the cooh terminal region fto although highly conserved across species shared members abh family structure function unknown we noted two potentially interesting observations regarding cooh terminal region protein first mutations per nucleotide basis nonsynonymous mutations found 3 times less frequently cooh terminus rest molecule second although nonsynonymous variants elsewhere molecule found equally obese lean subjects eight variants found cooh terminus detected obese subjects two lean fig these preliminary observations potential interest might lead better understanding fto function role energy homeostasis localization | objectivesingle nucleotide polymorphisms ( snps ) in intron 1 of fat mass and obesity - associated gene ( fto ) are strongly associated with human adiposity , whereas fto/ mice are lean and fto+/ mice are resistant to diet - induced obesity .
we aimed to determine whether fto mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure - function relationships within fto.research design and methodswe sequenced all coding exons of fto in 1,433 severely obese and 1,433 lean individuals .
we studied the enzymatic activity of selected nonsynonymous variants.resultswe identified 33 heterozygous nonsynonymous variants in lean ( 2.3% ) and 35 in obese ( 2.4% ) individuals , with 8 mutations unique to the obese and 11 unique to the lean .
two novel mutations replace absolutely conserved residues : r322q in the catalytic domain and r96h in the predicted substrate recognition lid .
r322q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine .
r96h retained some basal activity , which was not enhanced by 3-methylthymidine .
however , both were found in lean and obese individuals.conclusionsheterozygous , loss - of - function mutations in fto exist but are found in both lean and obese subjects .
although intron 1 snps are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that fto has a role in energy balance , it appears that loss of one functional copy of fto in humans is compatible with being either lean or obese .
functional analyses of fto mutations have given novel insights into structure - function relationships in this enzyme . |
last 30 years made great strides treatment ms we developed brought market seven disease modifying medications reduce frequency ms relapses slow accumulation irreversible disability many therapies available control ms related symptoms however one significant challenges developing new better therapies ms current measures including neurological examination expanded disability status scale edss multiple sclerosis functional composite msfc mri measures relapse rates limited ability capture relapse ongoing disease progression absence relapses dennis bourdette m.d chairman department neurology oregon health science university ohsu said need ms measures quick easy accurate sensitive change worsening improvement understandable clinicians] gait balance measures potential meet requirements emphasized need communication neurologists others caring people ms conducting clinical trials nonneurologists engaged developing testing measures gait balance clinician administered measures gait balance measures commonly used clinical practice these measures generally inexpensive easy administer many validated people ms however highlighted rebecca spain m.d msph neurologist ohsu diverse goals perspectives different clinicians one measure likely meet every clinician needs neurologists localize neuroanatomically seek guidance recommending medications globally effect ms related health in contrast physical therapists engineering based researchers evaluate biomechanical details underlie gait balance abnormalities seek improved methods direct targeted rehabilitation interventions
, physiatrist cleveland clinic noted many currently used clinician administered measures gait including timed 25-foot walk t25fw 6-minute 2-minute walk tests 2mwt 6mwt timed go tug test detect changes gait speed endurance detect visually obvious improvements gait quality assess important contributors gait changes reduced cognitive function visual function upper body trunk control spasticity sensation although limits utility guiding selection specific interventions simple clinician administered measures still recommended screening individuals gait impairment standardized assessment performance time
susan bennett pt ed university buffalo described sophisticated clinician administered measures balance berg balance scale bbs functional reach test recently developed 4-square step test mini best test these measures differentiate people ms fall bbs 4-square step test provide information guide rehabilitation dr bennett also emphasized utility trunk control test 12 13 assessing balance nonambulatory patients postural control trunk essential safe independent transfers university illinois chicago noted self reported measures also known patient reported outcome measures proms recently attracted attention government agencies including national institutes health food drug administration measures capture directly patients feel function without interpretation others self reported measures gait balance ascertain patients quality life balance confidence fear falling circumstances surrounding fall events important information determined clinical testing physical instrumentation these data usually best captured diaries questionnaires surveys web based methods
, saint louis university discussed ms walking scale-12 msws-12 prom specific walking ms msws-12 scores correlate clinician administered instrumented measures walking including edss r 0.65 0.84 14 15 t25fw r 0.46 0.65 14 15 6mwt r 0.81 metabolic cost walking r 0.64 free living accelerometry r 0.48 0.79 17 18 the msws-12 also high test retest reliability icc 0.75 0.87 14 19 responsive change two medication trials ms acceptable floor ceiling effects a second version msws-12 adapted first version based rasch analysis developed submitted publication hobart personal communication pt neurologist ohsu discussed activities specific balance confidence abc scale dizziness handicap inventory dhi two self administered measures balance measures frequently used people ms although originally developed populations high test retest reliability people ms abc 0.92 dhi 0.90 they also fair concurrent validity identify individuals fall better number clinician administered measures including bbs tug test ambulation index dynamic gait index abc dhi also found responsive change trials rehabilitation interventions orebro university sweden focused using self reported measures identify people ms increased risk falling determine predictors falls people ms recent study dr nilsagrd close 2/3 ms subjects recorded falls prospectively 3-month period factors associated falls imbalance weakness fatigue environmental task specific factors including bumped others walking crowds ramps carrying objects
self administered measures gait balance ms provide insight patients perspectives abilities inexpensive administer minimal floor ceiling effects identify increased risk falls however measures provide information neuroanatomical biomechanical environmental personal factors contributing gait balance impairment ms shed light impact activity limitations individual participation quality life give limited guidance intervention the speakers recommended using measures addition clinician administered measures screening people ms gait dysfunction imbalance fall risk outcome measures trials interventions expected positive impact mobility quality life when precise information gait balance needed instrumented measures recommended related fay horak pt ph.d jessie huisinga ph.d ohsu robert motl ph.d university illinois urbana champaign recently sophisticated bulky equipment installed specialized motion analysis laboratories needed obtain precise accurate quantitative gait balance data now however wearable sensors housing triaxial accelerometers gyroscopes magnetometers increasingly used research settings variety pedometers accelerometers readily available clinical home use these portable devices also less expensive require less technical expertise laboratory based instruments used assess gait balance various environments including home real world situations wearable sensors may sensitivity detect ms related disability clinician may provide precise long term monitoring disability progression thus reducing sample size trial duration required determine treatment efficacy despite great potential currently integration novel instrumented measures gait balance ms clinical practice research limited lack test protocol device standardization we also need know devices sensitive changes associated ms progression treatment however validation challenging clear measures used gold standard comparison in addition know acceptable feasible affordable new instrumented measures clinical practice large scale clinical trials the final speaker day kathleen zackowski ph.d otr kennedy krieger institute johns hopkins university discussed current research relationships conventional well novel mri measures magnetization transfer mt diffusion tensor imaging dti instrumented measures specific impairments well balance gait changes these methods allow noninvasive evaluation white matter especially useful diseases myelin axonal integrity disrupted 2630 mt indirectly assesses status water protons associated macromolecular structures tissues myelin especially useful studying white matter integrity white matter high myelin content however mt sensitively quantify white gray matter abnormalities brain spinal cord 3234 dti derived indices sensitive macroscopic microscopic tissue disruption appear higher specificity conventional imaging areas affected ms pathology using tractography dti define approximate anatomy individual white matter tracts within brain spinal cord dti identify abnormal values mri indices specific white matter tracts may underlie clinical disability ms integration information derived imaging sequences mt increase pathologic specificity 34 37 dti abnormalities corticospinal tract shown correlate weakness ms these advanced mri measures may able detect quantify subtle subclinical changes function impacted neurorehabilitation link disease pathology for example zackowski et al demonstrated relationships instrumented walking velocity measures dti mt indices spinal cord ms new mri techniques together novel instrumented measures gait balance may also allow us define anatomic substrates disability design specific innovative rehabilitation strategies people ms based relationships structure function however larger comprehensive studies using combination instrumented measures walking clinical rating scales along specific mri indices dti mt needed the panelists concurred measures gait balance dysfunction used throughout course ms;currently available simple clinician self administered measures recommended screening imbalance gait dysfunction fall risk self administered measures important capturing patients perspective abilities effectiveness interventions complex clinician administered measures instrumented measures recommended guide selection development tailored interventions walking balance problems people ms precise monitoring change clinical trials remaining critical research needs identify standardize scientifically valid practically useful measures capture continuum gait balance deficits ms understand relationships measures.abstracts posters primary research presented symposium published winter 2011 international journal ms care second international gait balance symposium ms scheduled held portland oregon october 19th 20th 2012 focus interventions gait impairment imbalance falls people ms measures gait balance dysfunction used throughout course ms currently available simple clinician self administered measures recommended screening imbalance gait dysfunction fall risk self administered measures important capturing patients perspective abilities effectiveness interventions complex clinician administered measures instrumented measures recommended guide selection development tailored interventions walking balance problems people ms precise monitoring change clinical trials remaining critical research needs identify standardize scientifically valid practically useful measures capture continuum gait balance deficits ms understand relationships measures | gait and balance measures have particular potential as outcome measures in multiple sclerosis ( ms ) because , of the many hallmarks of ms disability , gait and balance dysfunction are present throughout the course of the disease , impact many aspects of a person 's life , and progress over time .
to highlight the importance and relevance of gait and balance measures in ms , explore novel measurements of gait and balance in ms , and discuss how gait , balance , and fall measures can best be used and developed in clinical and research settings , the 1st international symposium on gait and balance in multiple sclerosis was held in portland , oregon , usa on october 1 , 2011 .
this meeting brought together nearly 100 neurologists , physiatrists , physical therapists , occupational therapists , nurses , engineers , and others to discuss the current status and recent advances in the measurement of gait and balance in ms .
presentations focused on clinician - administered , self - administered , and instrumented measures of gait , balance , and falls in ms . |
harmony among skeletal dental soft tissue structures prerequisite good occlusion disharmony structures results malocclusion.1 proper intercuspation teeth must proportional size if teeth mismatched unusually large teeth one arch compared ideal occlusion attained uncommon defined tooth size discrepancy tsd).1 significant variation harmony lead malocclusion difficulties obtaining occlusion optimal overjet overbite class canine molar relationships the dental cast facilitates analysis tooth size shape alignment rotations teeth presence absence teeth arch width length form symmetry occlusal relationship tsd assessed using diagnostic setup using mathematical formula like bolton analysis.1 treatment necessary identify total bolton index tbi teeth removal direct influence upper lower tsd also upper lower incisors position.2 bolton stated four premolars removed normal tbi value 87% 89% upper teeth sizes suited lower teeth sizes teeth wide upper jaw tbi lower 87% low tbi teeth wide lower jaw tbi value higher 89% high tbi).3 malocclusion requires extraction tooth size differences spaces often seen end treatment.4 many investigators expressed opinion premolar extraction responsible tsd cases none reported percentage cases occurs the purpose study determine prevalence tooth size discrepancies among orthodontic patients general also different malocclusion groups analyze change degree severity bolton discrepancy hypothetical extraction identify incidence bolton discrepancy taking place hypothetical extractions normal control groups without bolton discrepancy this study conducted 100 pre treatment diagnostic casts collected randomized clinical trials department orthodontics bapuji dental college davangere
sufficiently erupted permanent teeth allow measurement widest mesiodistal dimensionsstudy models without mutilated teeth
sufficiently erupted permanent teeth allow measurement widest mesiodistal dimensions study models without mutilated teeth the teeth measured fine point mitutoyo dial calipers made japan model -633 -50 d15 nearest 0.02 mm figures 1 2 the mesiodistal widths 12 maxillary teeth 12 mandibular teeth right left first permanent molar totaled compared these mesio distal crown measurements taken mesial distal contact areas respectively figure 3 the dividend two percentage relationship mandibular tooth size maxillary called ratio subsequent calculated pre treatment bolton value bv hypothetical extraction four premolars accomplished substituting
these combinations 1 removal first premolars 2 removal second premolars 3 removal upper first lower second premolars 4 removal upper second lower first premolars the resultant measurements subjected bolton analysis see whether tooth size discrepancy created finally pre treatment postextraction tooth size ratios bv evaluated statistically use paired student test incidence tooth discrepancy different groups malocclusion relation extraction patients name date sex type malocclusion mesiodistal tooth sizes mm
overall ratio exceeds 91.3%if overall ratio 91.3%
overall ratio exceeds 91.3% overall ratio 91.3% similar proforma followed different extraction patterns mentioned earlier
sufficiently erupted permanent teeth allow measurement widest mesiodistal dimensionsstudy models without mutilated teeth
sufficiently erupted permanent teeth allow measurement widest mesiodistal dimensions study models without mutilated teeth the teeth measured fine point mitutoyo dial calipers made japan model -633 -50 d15 nearest 0.02 mm figures 1 2 the mesiodistal widths 12 maxillary teeth 12 mandibular teeth right left first permanent molar totaled compared these mesio distal crown measurements taken mesial distal contact areas respectively figure 3 the dividend two percentage relationship mandibular tooth size maxillary called ratio subsequent calculated pre treatment bolton value bv hypothetical extraction four premolars accomplished substituting
these combinations 1 removal first premolars 2 removal second premolars 3 removal upper first lower second premolars 4 removal upper second lower first premolars the resultant measurements subjected bolton analysis see whether tooth size discrepancy created finally pre treatment postextraction tooth size ratios bv evaluated statistically use paired student test incidence tooth discrepancy different groups malocclusion relation extraction patients name date sex type malocclusion mesiodistal tooth sizes mm
overall ratio exceeds 91.3%if overall ratio 91.3%
overall ratio exceeds 91.3% overall ratio 91.3% similar proforma followed different extraction patterns mentioned earlier in study 100 pre treatment casts randomly collected samples 71 falling within bv 91.3% 1 standard deviation sd 24 falling within bv 91.3% 2 sd 5 bv 2 sd table 1 graph 1 anterior discrepancy mean value 78.5% sd 2.9 mm showing statistical significance table 2 furthermore overall discrepancy value 91.9% sd 2.1 mm showed statistical significance table 3 the f value obtained anova test 1.33 anterior ratio different malocclusion groups class class ii division 1 class ii division 2 class iii malocclusion the p value 0.27 0.05 suggesting clinically insignificant table 4 the mean values class class ii division 1 class ii division 2 class iii malocclusions anterior ratio indicated graph 2 f value 3.34 p value 0.05 indicating statistically significant clinically insignificant table 5 mean value class class ii division 1 class ii division 2 class iii malocclusion overall ratio shown graph 3 hypothetical extractions conducted different combinations values subjected bolton analysis all second premolar extraction exhibits minimum value 2.96 p value 0.01 suggesting statistically significant clinically insignificant tables 6a the graph 4 shows comparison mean bv various patterns extraction bolton group comparison mean bolton value first premolar extraction pattern bolton group comparison mean bolton value second premolar extraction pattern bolton group comparison mean bolton value upper 4 first premolar lower second premolar extraction patterns bolton group comparison mean bolton value upper second premolar lower first premolar extraction pattern bolton group comparison mean bolton value various premolar extractions bolton group for orthodontist gratifying realization balance denture treated case remains unaltered long period removal retaining appliance if teeth mismatched unusually large teeth one arch compared ideal occlusion attained tsd develops many investigators expressed opinion removal premolars responsible creating tsd cases none reported percentage cases occurs.5 present study conducted demonstrates prevalence tooth size discrepancies among orthodontic patients various malocclusions bolton analysis 1958 included comparisons total mesiodistal widths dental arches distal surfaces first molars gave ideal anterior overall ratio bolton results seen relatively small range tooth size ratios fall achieve optimal occlusal relationship anterior coefficient used guide finished relationship anterior segments.6 comparison anterior discrepancy overall discrepancy present study sample local population bolton sample done showed overall ratio almost matching anterior ratio slightly higher anterior ratio bolton sample difference could present study done local population sample randomly collected bolton study caucasian population sample selected criterion good occlusion.7 mean sd range class class ii division 1 class ii division 2 class iii malocclusion8 calculated anterior ratio overall ratio present study statistical significant difference seen findings indicating tooth discrepancy related jaw relationship this confirmation study done alkofide hashim9 found statistical significant difference different classes malocclusion there maximum increase mean bv following first premolar extraction minimum increase noticed second premolar extraction indicating following first premolar premolar extractions mandibular discrepancy increasing significantly confirmation study done saatci yukay,10 showing second premolar extraction favorable compared patterns premolar extraction especially first premolar extraction group study procedure followed mesio distal measurements suggested bolton3 1958 it found difference pre treatment bv values removal first premolars statistically significant significant second premolar removal conversely extraction second premolars increase discrepancies existed treatment instead reduced subjects it also noted study extract premolars equal mesiodistal dimension upper lower dental arches severe tooth size discrepancies created compared removal greater mandibular premolars it appeared discrepancies created extraction occurred mandibular excess removal mandibular second premolars usually wider mesio distal dimensions likely result discrepancies smaller size mandibular first premolars.11 therefore result agreement opinion expressed bolton removal mandibular second premolars often crates potential better occlusion removal first premolars mandibular molars allowed mesial movement however bolton also cautioned statement interpreted broad recommendation extraction mandibular second premolars the results obtained study suggest new point view question teeth extract evaluated tooth size discrepancy12 standpoint question reduction tooth structure treatment procedure orthodontics always controversial one controversy centers far go dividing line extraction non extraction the decision extract must preceded great deal thought study
significant difference anterior ratio present study bolton sample overall ratio show significant differencea specific malocclusion group shown contain larger percentage tooth size discrepanciesthe results obtained present study agreement removal second premolars mandibular discrepancy cases removal first premolars maxillary discrepancy cases
there significant difference anterior ratio present study bolton sample overall ratio show significant difference specific malocclusion group shown contain larger percentage tooth size discrepancies results obtained present study agreement removal second premolars mandibular discrepancy cases removal first premolars maxillary discrepancy cases the inference study suggests new point view question teeth extract evaluated tsd standpoint the present study accordingly concludes clinicians always remember look patient individually aware factors determining teeth removed use findings one factor considered together many others | background : for proper intercuspation , the teeth must be proportional in size . if teeth are mismatched , with unusually large teeth in one arch compared to the other , then an ideal occlusion can not be attained .
this study has been done to determine the prevalence of tooth size discrepancies among orthodontic patients in general and also between different malocclusion groups , sex , and to analyze the change in the degree of severity in bolton discrepancy before and after the hypothetical premolar extraction.methods:the study was carried out on randomly collected 100 pre - treatment dental casts .
tooth size analyses were performed on these pre - treatment models and mesio distal tooth size ratios were measured as described by bolton before and after various patterns of hypothetical extraction.result:the results were statistically evaluated using anova and paired samples t - test .
5 out of 100 patients are seen with severe bolton discrepancy with bolton values ( bv ) ranging above and below 2 standard deviation .
statistically insignificant difference is seen between males and females and also between various groups of malocclusion .
the difference between the pre - treatment and post extraction bv was found statistically significant for the first premolar extraction and insignificant for others.conclusion:the results of this study indicate a new point of view to the question of which teeth to extract when evaluated for tooth size aspect only . |
anti--tubulin mouse monoclonal antibody sigma aldrich corp anti arf6 mouse monoclonal antibody santa cruz biotechnology inc anti rab11 rabbit polyclonal antibody anti tfr mouse monoclonal antibody invitrogen corp anti eea-1 mouse monoclonal antibody anti gm130 mouse monoclonal antibody bd biosciences obtained commercially s2 performed fluorophore conjugated anti tfr antibody generated using zenon antibody labeling kit invitrogen corp using antibody slightly enhanced tfr signals plasma membrane figs s1 s2 all procedures used perform cell culture immunoblotting immunofluorescence analyses described elsewhere anti--tubulin mouse monoclonal antibody sigma aldrich corp anti arf6 mouse monoclonal antibody santa cruz biotechnology inc anti rab11 rabbit polyclonal antibody anti tfr mouse monoclonal antibody invitrogen corp anti eea-1 mouse monoclonal antibody anti gm130 mouse monoclonal antibody bd biosciences obtained commercially s2 performed fluorophore conjugated anti tfr antibody generated using zenon antibody labeling kit invitrogen corp using antibody slightly enhanced tfr signals plasma membrane figs s1 s2 all procedures used perform cell culture immunoblotting immunofluorescence analyses described elsewhere | recycling endosomes are key platforms for endocytic recycling that return internalized molecules back to the plasma membrane . to determine how recycling endosomes perform their functions , searching for proteins and lipids that specifically localized at recycling endosomes
has often been performed by colocalization analyses between candidate molecules and conventional recycling endosome markers .
however , it remains unclear whether all the conventional markers have identical localizations .
here we report finding that three well - known recycling endosome markers , i.e. , arf6 , rab11 and transferrin receptor ( tfr ) , have different intracellular localizations in pc12 cells .
the results of immunofluorescence analyses showed that the signals of endogenous arf6 , rab11 and tfr in nerve growth factor - stimulated pc12 cells generally differed , although there was some overlapping .
our findings provide new information about recycling endosome markers , and they highlight the heterogeneity of recycling endosomes . |
low back neck pain commonly seen workplace two common
spinal problems encountered clinical practice back and neck pain important clinical
conditions limit ability perform routine daily activities decrease
productivity negatively affect quality life it reported 80% individuals
complained back pain period lives1 although neck pain occur frequently low back pain
also common problem 10% lifetime prevalence2 turkey countries1 low back neck pain major health problems affect
individual motivation result physical psychological problems kinesiophobia among extreme forms fear pain due movement injury
chronic cases pain severity cognitive responses pain
person chronic pain may develop negative beliefs experience pain
negative thoughts themselves3
patients kinesiophobia believe movement cause injury additional pain
therefore kinesiophobia risk factor persistent pain long term
kinesiophobia causes physical deconditioning avoidance physical activity functional
disability symptoms depression it reported psychological factors play
important role process chronicity disease3,4,5,6 several scoring systems reported tampa scale kinesiophobia
tsk fear avoidance beliefs questionnaire fabq pictorial fear activity
scale cervical pfacts c used assess fear movement related pain injury
patients low back neck pain7
study patients neck shoulder pain strong relationship
kinesiophobia disability musculoskeletal system injuries reported8 in addition patients chronic low
back pain high levels fear movement related pain high pain disability
scores8 pain restricted movement
patients chronic low back neck pain result boredom anxiety depression
negatively affecting quality life causing disability9,10,11,12 pain results
varying degrees kinesiophobia affective problems ultimately negatively affects
quality life present study aimed compare pain kinesiophobia quality life
scores patients low back neck pain the study performed hacettepe university hospital department physical medicine
rehabilitation ankara turkey patients 2065 years old various diagnoses
disc herniation spondylosis strain sprain mechanical pain cervical neck
n=300 lumbar low back n=300 region 6 months pain included study
patients history malignancy spinal fracture undergone surgical
procedure previous 6 months orthopedic neurological disease affecting
ambulation excluded study patients agreed participate study
signed informed consent forms study approved hacettepe university
non invasive medical research ethics committee protocol number lut 09/41 56 demographic data including gender diagnosis age years height cm weight kg body
mass index bmi kg cm duration pain months recorded the turkish version short form mcgill pain questionnaire sf mpq used assess
pain severity properties13 the main
component sf mpq consists 15 descriptive adjectives sensation pain 11
sensory 4 affective self rated according level intensity
4-point likert type scale 0=none 1=mild 2=moderate 3=severe the 3 pain scores
derived sum intensity scores sensory affective total description
the sensory affective scores calculated adding sensory affective
intensity scores sf mpq also includes
visual analogue scale vas measuring severity pain the total pain severity
score evaluated using 6-point likert type scale 0=no pain 1=mild 2=uncomfortable
3=distressing 4=horrible 5=intolerable)14 nottingham health profile nhp ) this
scale preferred detailed dimensions including many items used elicit quality
life impressions patients kinesiophobia part
scale includes 38 yes questions across 6 dimensions health pain physical
mobility affective reactions energy social isolation sleep the 2 parts used
independently part ii used present study part scored using weighted
values provide range possible scores zero problems 100
presence problems within dimension study validated reliable
turkish version nhp developed kkdeveci et al kinesiophobia assessed using tampa scale kinesiophobia turkish version
tsk the tsk used assess patients diseases associated acute chronic
low back pain fibromyalgia musculoskeletal whiplash injuries each item scored using
4-point likert type scale ranging strongly disagree strongly agree total score
is calculated inversion individual scores items 4 8 12 16 vlaeyen et al defined cut score 37 high degree
kinesiophobia4 study
validated reliable turkish version tsk reported ylmaz et al was used
assess kinesiophobia patients low back neck pain16 17 statistical analysis mean standard deviation sd values calculated
quantitative variables percentages calculated qualitative variables the scores
mentioned tests compared using test qualitative
student test mann whitney u test quantitative variables low back neck
pain groups the diagnostic distribution 600 patients shown table 1table 1.distribution diagnosis low back pain n=300 neck pain n=300
groupsdistribution diagnosisn%low back pain grouplumbar disc herniation27391lumbar spondylosis144.7low back strain134.3total300100neck pain groupcervical disc herniation21471.3cervical spondylosis6822.7neck strain186total300100 of 300 patients low back pain group 273 91% diagnosed
lumbar disc herniation 214 71.3% 300 neck pain group cervical disc
herniation table 1 demographic data comparison groups shown table 2table 2.demographic characteristics patients comparison low back
n=300 neck pain n=300 groupsdemographiccharacteristicslow back pain groupneck pain groupx sdx sdage years)43.2 10.942.8 10.2height cm)166.2 9.3164.9 7.8weight kg)73.6 13.870.4 12.8bmi kg cm)*26.7 4.525.9 4.5duration pain months)66.8 78.146 63.1p<0.05 p<0.01 mean age t=0.473 p>0.05 height t=1.844 p>0.05 groups
similar weight t=2.992 p<0.05 bmi t=2.162 p<0.05 significantly
greater duration pain t=3.586 p<0.05 longer low back pain group
table 2 low back pain group 208
69.3% female 92 30.7% male 230 76.7% female 70 23.3%
male neck pain group the results related pain severity pain characteristics sf mpq
sensory affective total pain vas pain total density scores shown table 3table 3.short form mcgill pain questionnaire sf mpq scores comparison low
back n=300 neck pain n=300 groupspain characteristics short form mcgill pain questionnairelow back pain groupneck pain groupx sdx sdsf mpq sensory pain 033)7.9 5.97.8 6.1sf mpq affective pain 012)3.2 3.13.2 3sf mpq total score 045)11.2 8.311 8.3sf mpq vas score 010)6.7 2.16.8 2sf mpq total pain severity 05)2.5 1.12.5 1.1 the subscores sf mpq similar groups p>0.05 pain z=4.132 p<0.01 physical activity z=5.640 p<0.01 sub scores
nhp significantly higher low back pain group neck pain group
nhp domain scores similar groups p>0.05 table 4table 4.nottingham health profile tampa scale kinesiophobia
scores comparison low back n=300 neck pain n=300 groupsnottingham health profile domains
kinesiophobialow back pain groupneck pain groupx sdx sdenergy level 0100)50.2 36.452.2 35.3pain 0100)*54.9 26.245.1 29.5affective reactions 0100)26.4 27.228.7 26.4sleep 0100)18.2 25.119.8 26.4social isolation 0100)24.7 27.326.6 28.3physical activity 0100)*33.4 16.225.7 17.5nottingham health profile total score 0600)208 113.2199.3 113.2tampa scale kinesiophobia 1768)*42.1 5.939.7 6p<0.01 kinesiophobia scores measured tsk significantly severe low back
pain group z=4.732 p<0.01 table 4 our study performed evaluate compare characteristics pain kinesiophobia
quality life patients low back neck pain pain duration longer body
weight greater kinesiophobia severe pain physical activity domains
quality life scales worse low back pain group without difference pain
severity pain characteristics groups kinesiophobia defined kori et al excessive irrational debilitating fear
physical movement limits physical activity result painful injury19 patients kinesiophobia believe
physical movement cause additional pain long term kinesiophobia reported
associated decreased physical fitness avoidance physical activity functional
disability inability fulfill social roles depression4 20 21 many studies examined fear movement related pain injury
patients low back neck pain used tsk research
patients neck shoulder pain reported strong relationship
kinesiophobia musculoskeletal disorders7 studies assessed patients chronic low back neck pain
reported pain disability scores increased fear movement related pain
increased20,21,22,23,24 wilgen et al.21 used tsk pain disability index
evaluate fear movement disability patients low back pain their findings
showed significant relationship kinesiophobia leg pain
disability21 relationship
kinesiophobia disability quality life patients chronic low back pain gheldof
et al reported pain severity pain related fear factors negatively
affecting routine daily social activities individuals low back pain24 patients neck pain
whiplash syndrome vangronsveld et al found relationship kinesiophobia based
tsk severity pain difficulty concentrating falling asleep23 thompson et al studied chronic whiplash
patients reported severity pain associated severity
kinesiophobia20 according
findings although severity pain moderate similar low back neck
pain groups kinesiophobia severe low back pain group the decreased
physical activity levels low back pain group derived quality life assessment
also support movement related fear patients lumbar problems thought limit
physical activities require great muscle effort walking
kinesiophobia this finding may highlight important difference patients
lumbar cervical problems terms fear movement injury clinicians
therapists consider tendency toward inactivity patients lumbar problems
rather cervical problems institute measures prevent complications
caused inactivity it well known interaction pain quality life different
levels patients low back neck pain dndar et al showed physical activity
quality life decreased depression severe patients chronic
low back pain compared healthy controls5 study yazc et al quality life parameters
statistically significantly decreased patients back pain25 studied 1,100 neck pain patients healthy
controls aged 2069 used chronic pain questionnaire assess pain sf-36
evaluate health related quality life they reported weak correlation
neck pain physical component health related quality life26 ay et al evaluated severity pain
based vas 010 cm quality life based nhp severity depression
using beck depression inventory the quality life decreased severity pain symptoms
depression increased9 lin et al
studied 52 chronic neck pain patients assessed health related quality life
psychological factors the researchers concluded health related quality life
patients chronic neck pain lower healthy controls patients
neck pain many physical mental health symptoms in addition majority
patients psychiatric disorders including psychosomatic symptoms depression
anxiety27 another study 195
patients low back pain kovacs et al weak correlation found
severity pain disability quality life28 study nhp pain physical activity scores significantly differed low
back neck pain groups our nhp findings showed perception pain lower
level physical activity higher patients neck pain consequently quality
life higher neck pain group low back pain group the severity
pain groups differ according sf mpq scores quality life
considered negative effect pain perception low back pain group calls
attention another difference groups longer duration pain higher
levels kinesiophobia low back pain group may also associated lower quality
life bener et al reported
moderate positive relationship obesity low back pain29 webb et al reported
significant relationship obesity low back pain they also showed
severity pain disability patients low back pain increased bmi
increased30 study greater body weight may also
predisposing factor increased pain perception may indirectly affect
kinesiophobia patients low back pain the primary goal treatment patients low back neck pain reduce
severity pain however findings indicate differences observed
groups terms pain perception body weight kinesiophobia physical activity
taken consideration planning preventive curative physical therapy programs
patients low back neck pain patients educated kinesiophobia
long term goals treatment include increasing patient confidence
reducing severity kinesiophobia the primary aim study determine factors cause kinesiophobia
therefore lack evaluation causes kinesiophobia patients neck
low back pain limitation study | [ purpose ] the purpose of this study was to compare patients with low back and neck pain
with respect to kinesiophobia , pain , and quality of life .
[ subjects and methods ]
three - hundred patients with low back ( mean age 43.211 years ) and 300 with neck pain ( mean
age 42.810.2 years ) were included in this study .
pain severity was evaluated by using the
short - form mcgill pain questionnaire , which includes a visual analogue scale , quality of
life by the nottingham health profile , and kinesiophobia by the tampa scale for
kinesiophobia .
[ results ] pain severity was similar in both groups , with a visual analogue
scale score of 6.72 in the low back pain and 6.82 in the neck pain group .
nottingham
health profile pain [ z=4.132 ] and physical activity scores [ z=5.640 ] in the low back
pain group were significantly higher .
kinesiophobia was also more severe in the low back
pain group , with a mean 42.055.91 versus 39.76.0 tampa scale for kinesiophobia score
[ z=4.732 ] .
[ conclusion ] patients with low back pain developed more severe kinesiophobia ,
regardless of the pain severity , and had greater pain perception and lower physical
activity levels .
kinesiophobia adversely affects the quality of life and requires
effective management of low back pain . |
current situation result increasing number cases patients diagnosed extended state disease ca 70% cases local extent frequent occurrence elderly people 50% 65 years old 30% 70 years old usually stressed coexisting diseases cases an important element cancer treatment palliative treatment mainly aims improving quality life mitigating symptoms associated disease the endobronchial location cancer cause hemoptysis atelectasis many related symptoms dyspnoea cough chronic inflammation the removal endobronchial obstruction often significantly improves health status patient turn affects quality patient life high dose rate hdr brachytherapy one effective methods used palliative treatment 27 application treatment endobronchial brachytherapy commonly used orthogonal images recorded using x rays provide good visualization catheter bone tissue cases one catheter used order illustrate distribution isodoses around guide dose defined reference points these points located constant distance guide designated different distances catheter if many guides used dose area envelope calculated the envelope area containing catheters dose specified depth the aim method choose calculation point located guides well farthest nearest guide the selection point allows inclusion minimal dose within area interest treatment plans use larger number guides handling guides different reference points allows reduction increase dose area tumor simultaneously least possible coverage critical organs 8 9 the paper present comparison treatment plans made using 2d 3d methods oncentra planning system 4.1 sp2 version brachy planning module nucletron elekta company elekta ab stockholm sweden well assess quality treatment plans using 2d 3d methods such study based group patients treated brachytherapy department subcarpathian cancer center brzozw the studies involved group 31 patients advanced lung cancer treated brachytherapy department subcarpathian cancer center brzozw 2011 2013 total 31 patients 76 treatment plans analyzed patients treated microselectron unit nucletron elekta company elekta ab stockholm sweden ir source nominal activity 10 ci the treatment applied using oncentra masterplan brachy 4.0 system nucletron elekta company elekta ab stockholm sweden brachytherapy the lumencath applicator set used nucletron elekta company elekta ab stockholm sweden all patient treatment based computed tomography thorax ct ge brightspeed milwaukee wi usa the endobronchial brachytherapy procedures performed using local anesthesia control bronchovideoscope bronchoscopy guides inserted bronchial tree area near tumor location 3d method treatment three dimensional images computer tomography used physician could contour volume tumor critical structures the physicist reconstructed catheter catheters treatment plan system activated source position near ptv area carried optimization treatment plan method performed using 2d method images simulix oldelft simulator used nucletron elekta company elekta ab stockholm sweden the dwell time calculated different way catheter created via virtual tomography length catheter location source 3d method dose specified 1 cm catheter dwell time calculated 2d method was transferred treatment plan performed based 3d imaging method changing dwell time a comparison made reference dose coverage target ptv isodose 100% 85% calculation dose 2 cm critical organ spinal cord performer comparison ptv coverage 3d method 2d method highlighted significant differences two methods reference dose coverage target ptv isodose 100% 85% well dose critical organ received 2 cm case spinal cord compared comparison variables 3d 2d methods tests two independent trials the tests assumed unequal variances suitable comparing quantitative variables two groups case 100% ptv the p value 0.0001 indicating statistical differences 3d 2d methods significant
figure 1 depicts average method 3d 2d 75.82% 45.05% respectively the standard deviation 3d method 22.72% 2d method 25.63% meaning greater variation among 2d results within trial however maximal values differ significantly 3d method 2d method maximal value 2d method 0.33% higher maximal value 3d method the reverse observed minimal values 3d method minimal value 20.26% 2d method 8.16% basic measures outcomes ptv100 3d 2d methods cases ptv 85% ptv 100% p value 0.0001 means statistical differences 3d method 2d method significant figure 2 presents average 3d method 36.31% higher 2d method median 3d method 30.58% higher 2d method the minimal value 3d method 36.1% 2d method 14.82% however maximal values differ significantly 3d 2d methods basic measures outcomes ptv85 3d 2d methods dose used spinal cord every 2 cm p value 0.009 implying significant statistical differences 3d method 2d method figure 3 shows average value results 3d method 0.17 gy higher 2d method case maximal values the results 2d method 0.44 gy higher 3d method the standard deviation significantly higher 0.02 gy 2d method 3d method dose used spinal cord every 2 cm
basic measures outcomes dose used spinal cord every 2 cm 3d 2d methods for comparison variables 3d 2d methods tests two independent trials used the tests assumed unequal variances suitable comparing quantitative variables two groups case 100% ptv the p value 0.0001 indicating statistical differences 3d 2d methods significant
figure 1 depicts average method 3d 2d 75.82% 45.05% respectively the standard deviation 3d method 22.72% 2d method
25.63% meaning greater variation among 2d results within trial however maximal values differ significantly 3d method 2d method maximal value 2d method 0.33% higher maximal value 3d method the reverse observed minimal values 3d method minimal value 20.26% 2d method 8.16% in cases ptv 85% ptv 100% p value 0.0001 means statistical differences 3d method 2d method significant figure 2 presents average 3d method 36.31% higher 2d method median 3d method 30.58% higher 2d method the minimal value 3d method 36.1% 2d method 14.82% however maximal values differ significantly 3d 2d methods when dose used spinal cord every 2 cm p value 0.009 implying significant statistical differences 3d method 2d method figure 3 shows average value results 3d method 0.17 gy higher 2d method case maximal values the results 2d method 0.44 gy higher 3d method the standard deviation significantly higher 0.02 gy 2d method 3d method dose used spinal cord every 2 cm
basic measures outcomes dose used spinal cord every 2 cm 3d 2d methods complications occur endobronchial brachytherapy hemorrhages shunts radiation induced pneumonia bronchitis radiation induced stenosis justified search new better solutions reduce side effects 10 11 the planning treatment use two dimensional images precisely determine find area tumor specifying dose points located distance 1 cm applicator possibility optimize treatment plan considering critical organs 2d method dose critical organs often exceeds limit values simultaneously disqualifies treatment plan 3d method precisely determine position tumor critical organs allows us optimize treatment limit dose critical organs
figure 4 provides comparison dvh methods seen much better coverage ptv dose required 3d method 2d time notice dose critical organs receive slightly different two methods we clearly state plan using 3d images gives better results terms treatment planning technological progress utilization computed tomography increases possibility treatment reduces toxicity applying treatment 3d method possibility dose optimization decreasing dose critical organs result reducing toxic effects treatment healthy tissue 6 12 13 comparison dvh treatment plans 3d purple line 2d brown line methods spinal cord 3d green line 2d blue line main advantages hdr brachytherapy include simplicity procedure short duration treatment possibility patient undergo therapy outpatient setting computed tomography allows precise determination size tumor procedure well determination changes bronchial tree occurred therapy facilities ct equipped 3d method routinely used applying treatment different localizations tumors 3d method based dynamic imaging the conclusions analysis interpretation results research follows reference doses 100% coverage ptv treatment applied 3d method 31% higher applied 2d method.determination target area area critical tissues possible far greater extent application 3d method case 2d method the former method allows administration high therapeutic doses minimizing impact critical organs.in 2d method application dose specified 1 cm catheter hot points areas dose much higher specified such problems occur 3d method allows uniformity high doses
reference doses 100% coverage ptv treatment applied 3d method 31% higher applied 2d method determination target area area critical tissues possible far greater extent application 3d method case 2d method the former method allows administration high therapeutic doses minimizing impact critical organs 2d method such problems occur 3d method allows uniformity high doses | purposeto present comparison of treatment plans made by using 2d and 3d methods in the planning system , as well as to assess the quality of treatment plans using the 2d and 3d methods.material and methodsthe studies involved a group of 31 patients with advanced lung cancer treated in the brachytherapy department of the subcarpathian cancer center in brzozw from 2011 to 2013 . in total
, 31 patients and 76 treatment plans were analyzed .
we compared coverage of ptv planned in 3d and 2d . in the 3d method of treatment ,
three - dimensional images from computer tomography were used . in treatment plans
performed using the 2d method , images from the simulator were used.resultsthe comparison of treatment plans made by using 2d and 3d methods is described .
this comparison highlighted the significant differences between these two methods assessing reference dose coverage of the ptv by 100% and 85% isodose.conclusionsreference doses with 100% coverage of the ptv in treatment applied with the 3d method are 31% higher than when applied with the 2d method . |
hip resurfacing arthroplasty hra conservative alternative total hip arthroplasty young active patient midterm survival reported 95% 96% clinical outcomes hip resurfacing shown dependent patient selection surgical technique femoral neck fracture remains common failure mode hip resurfacing mechanical error preparing femoral head well established risk factor catastrophic neck fracture the use computer navigation shown improve accuracy femoral component placement thus reducing likelihood preparatory error compared conventional instrumentation imageless computer navigation increases component alignment accuracy reduces outliers there challenging learning curve associated hip resurfacing many technical errors occurring early within surgeon experience the use computer navigation demonstrated reduce length initial learning curve improve surgeon ability perform procedure safely despite demonstrated advantages imageless computer navigation sparsely used many surgical centers the lack widespread use may attributed availability well cost navigation systems considering predisposition technical error early hip resurfacing would advantageous surgeon trainee utilize computer based methods optimize surgical technique solidify component implantation methodology evidence suggests use computer navigation operating room may improve accuracy freehand component placement absence navigation thus may role computer navigation training device novice surgeons particularly context learning challenging orthopedic procedures improve component implantation navigation discontinued the aim study examine whether femoral component alignment improved conventional mechanical guidewire jig following experience using imageless computer navigation hsa 213 consecutive hip resurfacings performed single surgeon ehs december 2004 december 2008 we retrospectively compared first 17 cohort 1 last 9 cohort 2 hip resurfacings performed using conventional lateral pin guidewire alignment jig figure 1 cohort 1 surgeon initial 17 cases hip resurfacing performed prior center acquisition imageless computer navigation system vectorvision sr brainlab feldkirchen germany after center acquired navigation system surgeon performed 187 hip resurfacings using computer navigation december 2008 navigation unit required replacing period pending replacement unit the surgeon performed nine birmingham hip resurfacings bhrs using conventional jig nine patients comprise cohort 2 thus hip resurfacings cohort 2 performed surgeon gained significant experience using imageless computer navigation figure 2 the birmingham hip resurfacing conventional lateral pin femoral guidewire alignment jig smith nephew inc anteroposterior ap lateral radiographs right bhr implanted using conventional guidewire alignment jig prior experience imageless computer navigation ( b ap lateral radiographs right bhr implanted using conventional guidewire alignment jig experience imageless computer navigation ( c ap lateral radiographs right bhr implanted using imageless computer navigation 17 patients comprising cohort 1 16 patients preoperative diagnosis osteoarthritis one patient diagnosed avascular necrosis result diagnosis excluded analysis the mean age patients 48.7 years sd 6.6 range 39 63 mean body mass index bmi 30.4 kg sd 3.9 range 23.3 40.4 cohort 2 included nine patients males preoperative diagnosis osteoarthritis the mean age group 52.6 years sd 10.8 range 29 71 years mean bmi 28.5 kg sd 3.0 range 25.1 34.3 kg m2 the differences age bmi cohorts found significant p 0.203 the 3-month postoperative digital anteroposterior cross table lateral x rays used comparison images obtained via computed radiography system directview cr850/950 eastman kodak rochester ny usa using standardized imaging technique positioning protocol stored institutional picture archive communication systems server sienet magicstore ve50 siemens medical erlangen germany an observer zm experienced using digital radiograph templating software magicview 300 siemens medical analyzed radiographs blinded patient data operative dates the component positions coronal sagittal planes measured coronal stem
shaft angle ssa defined angle subtended diaphyseal axis femur line drawn center prosthesis along component stem toward lateral cortex femur the sagittal stem neck angle sna defined angle subtended neck component stem axis measured values component alignment compared preoperatively planned position determined senior surgeon ehs surgical protocol the preoperative plan case positioned component 10 valgus relative native neck
shaft angle nsa femur coronal plane neutral neck axis sagittal plane the component considered neutral sagittal plane degree component anteversion retroversion within 10 native neck version descriptive statistics calculated using microsoft excel microsoft inc redmond wa usa determine differences final component placement target position spss 16 spss inc chicago il usa used calculate two sample tests comparison demographics well alignment values two cohorts statistical power determined 85.2% 0.05 effect size 1.02 comparison ssa descriptive statistics calculated using microsoft excel microsoft inc redmond wa usa determine differences final component placement target position chicago il usa used calculate two sample tests comparison demographics well alignment values two cohorts statistical power determined 85.2% 0.05 effect size 1.02 comparison ssa coronal alignment femoral component cohort 2 accurate cohort 1 the mean deviation ssa target alignment 2.2 sd 2.2 95% ci 0.8-3.7 cohort 2 5.6 sd 4.3 95% ci 3.6-7.6 cohort 1 figure 3 the variance cohort 2 4.9 range 4 varus 7 valgus threefold less cohort 1 17.6 range 14 varus 1 valgus the mean coronal alignment cohort 1 erred varus relative planned ssa figure 3 the component version cohort 2 also accurate cohort 1 figure 4 the mean deviation target sna cohort 2 mean difference 4.0 sd 2.2 95% ci 2.6-5.4 cohort 1 7.3 sd 5.3 95% ci 4.8-9.9 the variance cohort 2 27.7 range 8.2 retroversion 3.6 anteversion half cohort 1 4.7 range 17.2 retroversion 5.8 anteversion figure 4 four implants cohort 1 considered retroverted 10 figure 5 box whisker plot stem shaft angle accuracy two conventional jig cohorts negative values denote relative varus positive values denote relative valgus box whisker plot stem neck angle accuracy two conventional jig cohorts negative values denote retroversion positive values denote anteversion comparison accuracy implant positioning using conventional jig pre post navigation cohorts hip resurfacing provides viable bone conserving option young active patient end stage hip disease in addition patient selection surgical technique contributes greatly clinical outcomes procedure spite many advances surgical technique femoral neck fracture remains concern hip resurfacing continues common reason revision the etiology femoral neck fracture hip resurfacing studied thoroughly although causes often multifactorial biomechanics implant alignment play large role resurfacing construct strength resilience previous biomechanical studies investigating implant alignment shown relative valgus alignment femoral component strengthens proximal femur may protective neck fracture in addition studies looking femoral neck notching demonstrated little 2-mm superior femoral neck notch may increase risk neck fracture despite knowledge notching femoral neck femoral components implanted relative varus still encountered particularly surgical learning period procedure these adverse events may attributed difficulty procedure lack experience surgeon study found cohort hip resurfacing patients following experience using computer navigation cohort 2 accurate showed less variance component positioning the mean ssa cohort 2 3.4 less mean ssa cohort 1 this decrease mean ssa component positioning results decrease stress across superior neck potentially reducing risk femoral neck fracture further improved accuracy positioning sagittal plane may theoretically reduce risk impingementn figure 5 it well documented computer assisted surgery way imageless navigation functions curtail femoral implant malalignment hip resurfacing however cost availability current navigation systems make ubiquitous use unrealistic particularly centers perform small volumes hip resurfacings order surgeons new hip resurfacing perform optimally using conventional instrumentation may necessary first train using computer assisted methods order enhance surgical technique component insertion protocol a concern using computer navigation training purposes reliance technology poor retention performance following discontinuation thus study looked establish whether femoral component implantation accuracy utilizing conventional guidewire alignment jig improves following use imageless computer navigation hsa study a limitation study inability account learning process would occur normally performing series hip resurfacings study seyler et al fellowship trained staff surgeons experience hip resurfacing 75 cases exhibited greater scatter insertion angles using conventional instrumentation less experienced residents using imageless navigation surgical aid this demonstrates accuracy computer navigation also experience alone may prevent greater degree inaccuracy using conventional manual instrumentation a second limitation number resurfacings performed using conventional jig small relative number performed using computer navigation optimal number procedures achieve competency higher level accuracy using conventional guidewire alignment jigs may smaller current study investigation required determine ideal number training cases required order obtain proficiency using conventional instrumentation hip resurfacing lastly lateral pin jig utilized study may representative guidewire alignment devices the results study may extrapolated conventional guidewire alignment jigs hip resurfacing study all femoral components implanted manual jig acquiring experience using imageless navigation achieved desired minimum 10 valgus relative native nsa considered neutral sna angles this compared three implants positioned 10 varus relative target ssa another four considered retroverted group performed prior experience using navigation the improved use manual jig may attributable increased familiarity location optimal guidewire insertion point often native anatomy end stage hip disease patient distorted osteophytes remodeled bone prove problematic using manual jig alignment positioning depend largely visual assessment local anatomy guidewire placement the results study show improved accuracy precision using conventional guidewire alignment jig training computer navigation this improvement conflicts literature cognitive motor learning suggests form feedback computer assisted surgery provides may actually detrimental learning according motor learning theory individuals learn new motor skills evaluating available feedback alter future performance feedback either intrinsic natural consequence action extrinsic external source instructor computer computer navigation provides form extrinsic feedback continuous concurrent feedback continuous visual feedback guides trainee correct position thus minimizing errors reinforcing proper technique it hypothesized however concurrent feedback contribute retention task performance result learner developing dependence extrinsic feedback distracted using intrinsic feedback contrast prospective randomized study gofton et al analyzing effect computer navigation learning surgical skills trainees demonstrated concurrent feedback insertion acetabular cup hip replacement compromise learning process trainees this finding supported systematic review saithna dekker looking influence computer navigation hip resurfacing training concluded exists minimal evidence support concerns regarding detrimental impact computer navigation trainee learning subsequent performance hip resurfacing the study demonstrates femoral component placement utilizing conventional instrumentation may accurate following experience using imageless computer navigation training experience using computer navigation may provide surgeon appropriate feedback facilitate adequate motor skill acquisition spatial awareness transferred turn conventional instrumentation the success hip resurfacing particularly sensitive surgical technique component alignment training computer navigation early learning curve may help optimize subsequent use conventional hip resurfacing instrumentation | background : the use of computer navigation has been shown to improve the accuracy of femoral component placement compared to conventional instrumentation in hip resurfacing . whether exposure to computer navigation improves accuracy when the procedure is subsequently performed with conventional instrumentation without navigation has not been explored .
we examined whether femoral component alignment utilizing a conventional jig improves following experience with the use of imageless computer navigation for hip resurfacing.materials and methods : between december 2004 and december 2008 , 213 consecutive hip resurfacings were performed by a single surgeon .
the first 17 ( cohort 1 ) and the last 9 ( cohort 2 ) hip resurfacings were performed using a conventional guidewire alignment jig . in 187 cases ,
the femoral component was implanted using the imageless computer navigation .
cohorts 1 and 2 were compared for femoral component alignment accuracy.results:all components in cohort 2 achieved the position determined by the preoperative plan .
the mean deviation of the stem shaft angle ( ssa ) from the preoperatively planned target position was 2.2 in cohort 2 and 5.6 in cohort 1 ( p = 0.01 ) .
four implants in cohort 1 were positioned at least 10 varus compared to the target ssa position and another four were retroverted.conclusions:femoral component placement utilizing conventional instrumentation may be more accurate following experience using imageless computer navigation . |
continuous efforts researchers constant addition literature minimized aura one deadliest disease oral malignant melanoma omm result new innovative approaches came existence became first step successful treatment disease the disease known since decades proper management affected due insufficient understanding regarding pathophysiology marked variation clinical findings the mucosal melanoma discussed first weber germany later valuable information head neck mucosal melanoma reported lincoln 1885 late 19 century studies carried focused minimize mortality enhance public awareness towards disease hence early detection timely treatment key factor better prognosis unlike omm marked variation etiology incidence rate generalized cutaneous melanomas the continuous global environmental changes result exposure ultraviolet uv radiation furthermore growing trends sunbeds tanning beds increased risk disease a sunbed device emits uv radiation typically 97% uva 3% uvb 3% produce cosmetic tan today worldwide incidence newly diagnosed melanomas range 3% 8% around 50% mucosal melanomas affect head neck region almost representing approximately 9% malignant head neck tumors comparatively mucosal melanomas show aggressive biological behavior resulting 5 years survival rate 25% the etiology mucosal melanoma differs cutaneous counterpart direct role uv radiation primary causes ill fitting dentures betel nuts tobacco formaldehyde amalgam tattoo nevi traumatic regions racial pigmentation etc some literatures explain embryologic development melanocytes migrate neural crest epithelial lining later show reactive changes cytotoxic stimulant basal epithelial layer though dendritic cells derived neural crest produces melanocytes exact mechanism proliferation cells melanoma particularly mucosal melanomas asymptomatic initial phase resulting late diagnosis thus allowing invade deeper regions the clinical characteristics include dark brown black color asymmetrical margins irregular surface etc hence pigmented lesions oral cavity possess clinical specificity need carefully evaluated possibility omm differential diagnosis include smoke related melanosis drug pigments physiologic racial pigmentation melanotic macule kaposi sarcoma nevus melanoacanthoma chronic leukemic etc pigmentation criteria around 15% melanomas nonpigmented the omm distinct gender variation majority showing male predominance among oral melanomas hard palate maxillary gingiva report case omm 45-year old female patient conscious discoloration growing bulk mandibular anterior mucosa a 42-year old indian female average height moderate built reported dental office complaining blackish discoloration lower jaw since 6 months difficulty eating especially lower front teeth intraoral examination revealed nontender painless bluish black growth rough irregular surface extending gingiva 3544 regions revealed findings ulceration bleeding figure 1 there major involvement labial aspect mandibular gingiva followed anteroposterior extension vestibule oral aspect lip mucosa minimal extension lesion lingual aspect the patient noticed small blackish patch approximately 1 cm 1 cm gradually increased present size associated mobility teeth the overall general examination neck back extremities chest insignificant except nevi submandibular lymph nodes enlarged nontender approximately 1.5 cm 1.5 cm dimension after evaluating hematological parameters incisional biopsy performed local anesthesia confirmatory diagnosis clinical photograph showing bluish black irregularly spreading growth extending mandibular left second premolar right first premolar microscopic examination h e stained section revealed situ melanotic pigments figure 2 the section showed large cells pleomorphic vesicular nucleus brown pigment abnormal mitoses altered nucleocytoplasmic ratio invading connective tissue form sheets cords islands figure 3 the tissue also immunohistochemically stained human melanoma black-45 specific marker melanocytes also revealed cytoplasmic positivity malignant melanocytes antibody figures 4 5 confirming diagnosis malignant melanoma segmental resection bone grafting follow patient reported problems difficulty eating speech the intraoral examination revealed uneven healing resected part development bluish black patch left posterior mandible due severe trismus discomfort wide excision growth node biopsy done patient recalled follow ups every 6 months h e stained section reveals malignant melanocytes hyperchromatic nuclei infiltrating connective tissue sheets h e 10 h e stained section reveals pigmented cells abnormal mitosis h e 10 immunohistochemistry stained slide shows positive expression ihc 10 immunohistochemistry stained slide shows cytoplasmic positivity melanocytes ihc 40 ) the oral mucosal melanoma rare entity incidence rates 1% melanomas among head neck tumors head neck mucosal melanomas accounted 0.8% melanomas 8% head neck melanomas they reviewed 2.5 million individuals denmark 30 years period found omm mostly occur fourth seventh decades life mean age 5557 years melanocytes dendritic cells migrated neuroectodermal derivatives ectodermally derived mucosa some studies also suggest familial inheritance specially along dysplastic nevus syndrome p16 differences dna repair impairments contributes carcinogenesis malignant melanoma circumstances the damaged dna activates proto oncogenes inactivates tumor suppressor genes majority patients show history preexisting oral pigmentation diagnosis oral melanoma moreover common primary sites include nasal cavity paranasal sinuses oral cavity commonly maxillary alveolar ridge hard palate whereas rarely seen mandibular gingiva so far studies documented relationship free radicals melanoma cells resulting increased levels reactive oxygen species this due metal binding properties melanin loss structural integrity melanosomes present it accepted omm aggressive tumor various factors contribute aggressiveness late detection poor resectability early metastasis this limits 5 years survival rate 1025% also affects prognosis melanoma notoriously resistant chemotherapy approaches carried treatment according oncosurgeons treatment choice malignant melanoma surgery stage 1 melanomas excised along 1 mm margins t2an0m0 stage 1b needs sentinel lymph node biopsy stage 2 cases treated wide excision node biposy whereas stage 3 needs wide excision 2 mm margins node dissection radiation chemotherapy given post operatively stage 4 really challenge treated surgery chemotherapy interferons ifns interleukins ils vaccines different biochemotherapeutic agents serves adjuncts today new technology opened new hopes result biotherapies including ifns il-2 provide intriguing avenues evaluation treatment the mechanism clinically effective il-2 therapy may direct action il-2 biologically distinct subset melanoma cells leading regulation tumor suppressor il-24 hence avoid future complications suspected oral pigmentations planned biopsy moreover extent criteria given green et al may helpful clinicians suggests demonstration melanoma oral mucosa presence junctional activity inability demonstrate extra oral primary melanoma further studies classified disease prediction prognosis stage 1 lesion confined locally stage 2 positive metastasis stage 3 hematogenous spread later stage distant metastases may found variety sites including lungs bones liver brain skin a detailed case history thorough clinical examination suspicious eye irregular intraoral pigments help clinician early diagnosis sometimes patients ignore symptoms may reflect indirectly health care provision result poor prognosis any physiologic pigmentation hormones medication pigmentations amalgam tattoo biopsied the treatment promoted thorough oral examination biopsy well planned improve patient prognosis avoid chances recurrence | according to the world health organization , oral malignant melanoma ( omm ) is a rare disease , accounting for only 0.8% of all melanomas , 8% of head and neck melanomas , and up to 0.5% of all oral malignancies .
omm presents as a pigmented lesion with asymmetrical borders , irregular surface characteristics , and a distinct color .
melanoma - associated pigmented lesion of the oral cavity does not possess clinical specificity and frequently divert the clinical diagnosis ; hence , differential diagnosis becomes mandatory .
furthermore , the unpredictable pathophysiological behavior and delayed detection , contributes for poor prognosis of the disease . as a result ,
the 5 years survival rate is only 1025% .
commonly omm is seen in maxillary gingiva of males
. however , we report a rare case of a middle - aged female having pigmentations and growth over mandibular gingiva . |
urinary tract infection uti one common clinical syndromes encountered general gynecological practices adult women 4050% history least one episode uti lifetime community acquired infection caused escherichia coli klebsiella pneumoniae proteus mirabilis staphylococcus saprophyticus enterococcus faecalis hospital acquired ones escherichia coli pseudomonas aeruginosa proteus sp enterobacter sp uti broad term encompasses asymptomatic bacteriuria symptomatic infection microbial invasion inflammation urinary tract 90% patients utis complain urinary tract symptoms one third patients symptoms bacteriuria dysuria frequency together raise probability uti 90% effectively ruling diagnosis history alone almost cases uti empirical antimicrobial treatment initiates laboratory results urine culture available thus antibiotic resistance may increase uropathogens due frequent use antibiotics the prevalence antimicrobial resistance patients uti increasing vary according geographical regional location for this reason knowledge etiological agents utis antimicrobial resistance patterns specific geographical locations may aid clinicians choosing appropriate antimicrobial empirical treatment the literature prevalence uti among females lucknow scarce recent decades thereby present study undertaken find prevalence uti determine antimicrobial susceptibility patterns commonly used antibiotics among females lucknow this observational prospective 12 months study carried among patient departments obstetrics gynaecology medicine vivekananda polyclinic institute medical sciences lucknow ethical clearance institution review board all females aged 15 years attending respective outpatient departments clinically suspected uti selected purpose study study period patients symptoms suggestive uti time observation excluded study females suffering diabetes mellitus renal disorders hiv positivity corticosteroid therapy also excluded those females give consent noncooperative refused provide necessary information included study the necessary information collected using interview technique respondent informed consent a structured questionnaire used assess study subjects self reported information regarding socio demographic characteristics urinary symptoms all study subjects advised collect mid stream urine sample wide mouthed sterile containers they instructed clean area around urethral opening clean water dry area collect urine labia held apart samples processed within 1 hour collection direct microscopy wet film preparation ) 50 l well mixed uncentrifuged urine taken slide cover slip placed at least 20 fields examined detection one morphologically similar bacteria per oil immersion field treated significant mixture e. coli staphylococcus aureus used positive control uninoculated broth negative control the presence two morphologically different organisms indicated presence mixed flora urine culture urine sample 1 l ) was inoculated cysteine lactose electrolyte deficient medium using standard loop internal diameter 1.34 mm semiquantitative method they incubated another 24 hours negative report issued single organism obtained counts 100,000 cfu ml five colonies test organisms streaked agar plates using sterile inoculating wire loop the appropriate multidisk depending whether test organism plated gram negative gram positive placed firmly onto surface dried plates using sterile forceps the plates left room temperature 1 hour allow diffusion different antibiotics disk medium the zone inhibition greater 10 mm considered sensitive 510 mm moderately sensitive zone inhibition resistant the antibiotics tested amoxicillin ampicillin ampicillin sulbactam piperacillin cloxacillin tazobactam cephalexin cefadroxil cefaclor cefuroxime cefixime cefotaxime cefoperazone ceftazidine ceftizoxime ceftriaxone cefepime nalidixic acid ciprofloxacin lomefloxacin norfloxacin pefloxacin ofloxacin nitrofurantoin tetracycline co trimaxazole clarithromycin roxithromycin erythromycin amikacin gentamicin tobramycin netilmicin kanamycin tests significance like pearson chi square test fisher exact test applied find results were put use present study
microscopy findings 10 wbc per high power field considered significant.significant bacteriuria defined culture single bacterial species urine sample concentration 100,000 cfu ml
significant bacteriuria defined culture single bacterial species urine sample concentration 100,000 cfu ml five females suffering diabetes mellitus renal disorders hiv positivity corticosteroid therapy also excluded two females give consent noncooperative refused provide necessary information included study thus total the overall prevalence uti found 45.32% 95% confidence interval 37.5253.12 overall 46.87% 96 urban respondents 41.86% 43 rural respondents identified uti thirty two 51.61% 62 females aged 25 34 years 15 46.87% 32 females aged 15 24 years identified uti ten 40.0% 25 females 35 44 years 6 30.0% 20 females 45 years age uti five 26.31% 19 illiterate females identified uti 58 48.33% 120 literate females uti fifty six 44.09% homemakers six 66.67% students identified uti table 1 distribution respondents according socio demographic clinical characteristics common urinary symptom presented burning micturition 73.4% followed frequency 43.9% urgency 20.9% painful voiding 20.1% difficulty 5.0% nocturnal incontinence 1.4% ten 50.0% 20 pregnant females uti compared 53 44.53% 119 nonpregnant females out 63 pathogens e. coli 33.1% common organism isolated followed klebsiella pnuemoniae 7.9% staphylococcus aureus 2.2% streptococcus pnuemoniae 1.4% proteus mirabilis 0.7% respectively the effective antibiotic e. coli isolates observed nitrofurantoin 86.95% followed amoxicillin 69.56% nalidixic acid 65.21% cotrimoxazole 60.86% high efficacy nitrofurantoin 90.90% followed cotrimoxazole tetracycline 81.81% observed klebsiella isolates cephalexin cefaclor nalidixic acid norfloxacin also showed similar higher efficacies 72.72% klebsiella isolates amoxicillin ampicillin sulbactam cefixime pefloxacin ciprofloxacin also showed similar susceptibilities 63.63% klebsiella isolates high susceptibility 100% ampicillin nitrofurantoin tetracycline observed among identified proteus isolates high susceptibility patterns nalidixic acid clarithromycin cotrimaxazole cefixime cephalexin cefaclor 100.0% followed nitrofurantoin 66.66% among streptococcus isolates identified observed ceftriaxone cefepime cefuroxime ceftizoxime gatifloxacin gentamicin tetracycline erythromycin showed similar efficacies 50.0% streptococcus isolates tables 2a b antibiotic susceptibility trends observed among identified bacterial species causing urinary tract infection antibiotic susceptibility trends observed among identified bacterial species causing urinary tract infection it stated uti predominantly disease females due short urethra proximity vestibule anal opening study 139 females studied 63 45.32% females found urine culture positive forty five 46.87% 96 urban respondents 18 41.86% 43 rural respondents identified uti study this may attributed higher levels awareness treatment seeking behavior urban respondents compared rural respondents study prevalence uti higher among females aged 15 44 years compared aged 45 years age more cases utis recorded among young middle age patients 2049 years 51.04% akram et al another study farhat ullah et al middle aged patients accounted 54.3% uti a higher percentage literate females identified uti compared literate ones current study this may due high treatment seeking behavior infected literates compared illiterate ones present study common urinary symptom presented burning micturition followed frequency urgency painful voiding the percentage pregnant females uti found slightly higher nonpregnant infected females study 61 infected young women 52 86.8% found early late phases pregnancy these findings agree recent indian reports indicated gram negative bacteria mostly e. coli klebsiella pneumoniae common pathogens isolated patients uti table 3 distribution pathogens isolated among uti patients effective antibiotic e. coli study observed nitrofurantoin followed amoxicillin nalidixic acid co trimaxazole high efficacy nitrofurantoin followed co trimaxazole tetracycline observed klebsiella study cephalexin cefclor nalidixic acid norfloxacin amoxicillin ampicillin sulbactum cefexime pefloxacin ciprofloxacin also effective klebsiella however klebsiella isolates showed higher susceptibility imipenem 88% amikacin 59% study akram et al regional antibiotic susceptibilities e. coli isolates high susceptibility ampicillin nitrofurantoin tetracycline observed among identified proteus isolates study whereas proteus spp showed highest sensitivity ciprofloxacin 71.2% study kashef et al the present study revealed cefexime nalidixic acid highly effective staphylococcus aureus whereas staphylococcus aureus isolates found susceptible imipenem ceftriaxone cefotaxime akram et al streptococcus found susceptible nalidixic acid clarithromycin cotrimaxazole cephalosporins nitrofurantoin gatifloxacin gentamycin tetracycline erythromycin study yola could find similar studies used references different field populations compare results visited gynaecology consultation may different pretest probability uti attended hospital services general practice consultations microbiological results also different this reflects need accurate updated population surveillance data particularly light concerns regarding variable regional antimicrobial susceptibility patterns regular monitoring required establish reliable information susceptibility pattern urinary pathogens optimal empirical therapy patients utis we suggest empirical antibiotic selection based knowledge local prevalence bacterial organisms antibiotic sensitivities rather universal guidelines iec messages uti patients must include additional information risk reduction methods need take regular supervised treatment | background : urinary tract infection ( uti ) is among the most common infections described in outpatient setting and hospital patients . in almost all cases empirical antimicrobial treatment initiates before the laboratory results of urine culture are available ; thus antibiotic resistance may increase in uropathogens due to frequent use of antibiotics.aims:the study was designed to find the prevalence of uti in females with urinary tract symptoms , to determine the causative organism ( s ) of uti , and to determine the antibiotic susceptibility pattern of microbial agents isolated from urine culture ( antibiogram).materials and methods : the prospective , observational study involved 139 females , aged 15 years and above clinically suspected for uti attending outpatient departments of vivekananda polyclinic and institute of medical sciences , lucknow .
a structured questionnaire was used to interview the study subjects . a chi - square test and fisher exact test
were used to analyze data.results:the overall prevalence of uti was found to be 45.32% ( 63/139 ) .
escherichia coli ( 33.1% ) and klebsiella pneumoniae ( 7.9% ) were the most common organisms isolated .
the most effective antibiotic for both was nitrofurantoin.conclusions:regular monitoring is required to establish reliable information about susceptibility pattern of urinary pathogens for optimal empirical therapy of patients with uti . |
well established high risk hr human papillomavirus hpv types causative
development cervical cancer 13 the majority hpv infections
cleared without consequences host infections
hr hpv types may give rise high grade cervical intraepithelial neoplasia
cin iii cervical cancer 46 there evidence cell mediated
immune responses host systemic local important
determinants course infection cell mediated immune responses
regulated lymphocytes helper th lymphocytes cytotoxic
lymphocytes ctls cooperation antigen presenting cells apcs
monocytes mcs dendritic cells dcs these cells release cytokines
influence one another synthesis actions setting
immuno regulating cytokine network cytokines immune responses infection
often classified immuno stimulating tumour suppressing th1type cytokines
immuno inhibitory tumour promoting th2-type cytokines th1-type cytokines
interferon ifn
tumour necrosis factor tnf
interleukin 2 il-2 il-12 produced mainly lymphocytes apcs
natural killer cells nk cells th2-type cytokines il-4 il-5 il-6 il-8 il-10 produced
lymphocytes mcs immuno inhibitory cell mediated responses
predominantly induce humoral immunity 8 9 qualitative quantitative
analyses cytokine profiles used characterize immune
response hpv related cin these performed peripheral blood
mononuclear cells pbmcs 1012 cell fractions isolated
pbmcs 1316 occasionally whole blood cultures
stimulation several antigens selective cytokines mostly ifn 11 12 1418 il-2
1014 occasionally apc derived il-12 tnf measured together one two
typical th2-type cytokines il-4 il-5 il-10 11 12 16 17 generally
shift th1-type th2-type cytokine response observed healthy
controls women low grade squamous intraepithelial lesions lsil
compared cases high grade sil hsil cervical
carcinoma 7 11 17 19
previously observed manifestation th2-type cytokine pattern plasma
hr hpv positive women carcinogenesis cervical cancer stage
cin iii recent studies isolated cell fractions stimulated
hpv16-derived oncopeptides indicate reactivation inflammatory response
patients carcinoma 12 15 these results let us assume
significant changes immunocompetence circulating leukocytes
involved development cervical dysplasia cervical cancer
present study used whole blood cultures hr hpv negative controls
hr hpv positive women without cervical dysplasia hr hpv positive patients
different grades cin cervical cancer investigate changes
immunocompetence expressed capacity circulating leukocytes release
cytokines response mitogenic challenge interest were effect
hr hpv infection without clinical manifestations special position cin
iii th2-type cytokine response possible revival inflammatory
cytokine activity cervical carcinoma inclusion took
place outpatient clinic obstetrics gynaecology department erasmus
university medical center rotterdam netherlands july 2000 august 2002 our selection patients study
based presence hr hpv grade cervical intraepithelial
neoplasia histology results defined dysplasia mild
dysplasia cin moderate dysplasia cin ii severe dysplasia cin iii
micro- invasive cancer experienced pathologist revised histological
samples women cin lesions mild dysplasia excluded since
fifty percent patients cin turned hr hpv negative
healthy women attended outpatient clinic regular sterilisation
procedure recruited hr hpv negative controls sampling
histology hpv exclusion criteria participants anamnestic
required postmenopausal state pregnancy time sampling chronic
diseases diabetes allergy auto immune presence sexually transmitted
diseases stds infection human immunodeficiency virus hiv signs
acute infection time sampling immune compromised state
exception oral contraceptives participant used medication regular
base participant used pain medication including nsaids least
two weeks prior sampling order avoid well known influence
nsaids cytokine release pbmcs the study protocol approved
ethics committee erasmus medical center women voluntarily gave
signed informed consent cervical scrapes
hpv detection typing taken using cervical bio sampler accellon
combi medscand medical malm sweden hpv testing performed consensus
gp5+/gp6 pcr enzyme immunoassay eia using cocktail probe covering 37
sub- types including probably hr hpv types previously
described we used -globin pcr identify sampling errors monitor
pcr inhibitors additionally reverse line blot rbl analysis
performed pcr eia positive cases identify individual hpv types preparation whole blood cultures
peripheral venous blood samples collected 812
sterile endotoxin free vacutainers endo tubes chromogenix ab mlndal sweden
coated na heparin anticoagulant immediately processed leukocyte count peripheral venous blood
samples collected 8 12 drawn endotoxin free
vacutainers becton dickinson meylan nj usa ethylene diaminetetra acetic acid edta
anticoagulant leukocyte counts performed sysmex xe-2100 preparation whole blood cultures blood
diluted 1:10 rpmi 1640 culture medium 25 mm hepes supplemented
10 u ml penicillin 100 g ml
streptomycin 4 mm l glutamine medium supplements life
technologies bv breda netherlands diluted blood distributed cell
culture plates incubated phytohemagglutinin pha sigma aldrish
mo usa dissolved rpmi medium final concentration 10 g ml blood culture 96 hours 37c
5% co2 all cultures sampled 0
24 48 72 96 hours centrifuged 10 minutes 4c 1500 g culture supernatants kept 80c
analysis all samples
analysed commercially available enzyme linked immunoassays biosource
europe nivelle belgium cytokines tnf ifn
il-2 il-4 il-10 il-12 the detecting antibody immunoassay
il-12 recognized bioactive heterodimeric p40 p35 cytokine well
subunit p40 monomer homodimer according manufacturer minimal
detectable concentrations mdcs intra- interassay coefficients
cvs variation follows tnf mdc 3 pg ml cvs 6 10% ifn mdc 2 pg ml cvs 5 10% il-2
mdc 7 pg ml vcs 6 10% il-4 mdc 2 pg ml cvs 5 7% il-10 mdc 1 pg ml cvs < 5 10% il-12 p40 mdc 1.5 pg ml
cvs 10 10% preliminary
komolgoroff smirnov tests showed abnor mal distribution cytokine values
pha stimulated whole blood cultures accordingly cytokine data
presented medians ranges unless stated otherwise nonparametric
kruskal wallis test k. w. test mann whitney u test used
appropriate assess differences cytokine levels groups levels statistical significance adjusted
number comparisons according bonferroni method indicated
graphics differences patient characteristics groups
evaluated one way anova unpaired two tailed tests spearman correlations used
investigate possible relations age time sampling released
cytokines five excluded diabetes n=1
allergy n=2 autoimmune disease n=1 acute infection time sampling
n=1 leaving 30 women eligible inclusion 10 women moderate
dysplasia cin ii 10 women severe dysplasia cin iii 10 women
cervical carcinoma 8 squamous cell carcinoma 2 adenocarcinoma all women
group revealed positive gp5+/6 hr hpv pcr test three excluded
presence allergy n=2 acute infection time sampling n=1 leaving
19 healthy women without cervical dysplasia nine women positive hr hpv
test 10 women tested negative hpv dna forming control group baseline
characteristics study groups summarized table 1 mean age hr hpv positive women without cervical dysplasia
significantly lower groups this could expected since
first infection without clinical manifestation frequently observed young
sexually active women spearman correlations age time
sampling released cytokines whole group patients controls
significant data shown the changes immune competence
study related age the results cytokine
assays calculated per 10 leukocytes order stratify
possible different numbers cytokine producing leukocytes study
subjects 20 24 preliminary
experiments carried investigated cytokines determine
time peak production response pha stimulation
whole blood culture system data shown cytokine concentrations 0
96 hours stimulation time analysed least six randomly chosen
study subjects stage cin peak time tnf ifn
il-12 p40 production 72 hours il-2 48 hours cultivation time
a typical
sample time course cytokine release blood culture system
shown figure 1
general our data maximum cytokine release accordance kinetic
studies pbmc basis results il-2 release
determined 48 hours release tnf ifn
il-12 p40 72 hours il-4 il-10 48 72 hours
cultivation calculations latter two cytokines values maximal
release was observed two groups women without
dysplasia exception il-12 investigated cytokines
significantly increased hr hpv positive women the results summarized
table 2 hr hpv infected women
release th1-type cytokines ifn tnf il-2 decreased increasing
grades cin il-12 reached
maximum cin ii decreased cin iii carcinoma differences
groups statistically significant k. w. test p=.068 il-12 p40
p=.264 ifn p=.077 tnf p=.071 il-2 release
reached maximum il-10 il-4 patients cin iii decreased
significantly cytokines patients invasive carcinoma
the results summarized
figure 2 order characterize possible th1-type th2-type shift calculated ratios th1-type cytokines il-12 ifn tnf
il-2 th2-type cytokines il-10 il-4 hr hpv infected groups ( results
k. w. tests il-12/il-10 p=.005 il-12/il-4 p=.01 ifn/il-10 p=.013 ifn/il-4 p=.015 tnf/il-10 p=.303 tnf/il-4 p=.096 il-2/il-10 p=.642 il-2/il-4 p=.251 there significant decrease th1-type th2-type ratios cin ii cin iii il-12/il-4 il-12/il-10 also ifn/il-4 ifn/il-10 showed similar though statistically
significant trend demonstrated figure 3 this increase significant il-12/il-4
il-12/il-10 ifn/il-4 ifn/il-10 order characterize possible th-1 type
cytokine pattern establishment invasive carcinoma compared
cytokine levels pha stimulated blood cultures patients invasive
carcinoma levels hr hpv positive women without dysplasia there
difference levels il-12 p40 ifn groups release tnf
il-2 well il-10 il-4 significantly lower patients
carcinoma the significant
increase th1-type well th2type cytokines
hr hpv positive women normal histology suggests viral activation
systemic cytokine network induction cell mediated immunity
initial hr hpv infection table 2 knowledge this first
description activation systemic cytokine network hr hpv positive
women without dysplasia cytokine release
changed antiinflammatory tumour promoting pattern increase il-4
il-10 expression stage cin iii this result confirms extends
earlier observations change th2-type cytokine pattern
circulation patients cin iii agreement earlier
studies showing shift th1-type th2-type cytokines
carcinogenesis
observed decreased ifn
il-2 increased il-4 il-10 mitogen stimulated cultures pbmcs
isolated women cin iii compared cultures hr hpv negative women described increased il-10 decreased il-12
release whole blood cultures patients hsil compared hr hpv negative controls they found decreasing il-2
release increasing severity disease agreement
results il-2 the observed minimium ifn release cin iii invasive
carcinoma differs observations earlier study mori et al
pha stimulated ifn
release pbmcs cases invasive carcinoma significantly decreased
compared data healthy women study mori et al
however presence hr hpv investigated might explain
difference results study a shift
th2-type cytokine pattern cin iii obvious ratios
th1-type th2-type cytokines figure 2 evaluated they show
tumour promoting change cytokine balance significant il-12/il-4
il-12/il-10 trend ifn/il-4 ifn/il-10 tnf/il-4 our study describes first time changes cytokine pattern
within cytokine network developing hr hpv infection without clinical
symptoms via cin ii cin iii carcinoma il-12 one
first cytokines released innate immune reaction stimulates th-1
type cytokine response cell mediated immunity our hr hpv positive women
normal histology demonstrated significantly increased th1- th2-type cytokine release
exception il-12 low our observation high secretion il-12
cin ii might explained observation made moscicki et al these
authors reported high levels il-12 cervical mucous hsil
hypothesized high il-12 levels could represent defence mechanism
turning th1-type antitumour response il-12 known inhibit
angiogenesis preventing growth tumour the significant
increase four cytokine ratios cin iii carcinoma may indicate
presence tumour inflammatory reaction exposure
viral antigens high viral load eventually induces certain cell response
this response remains incomplete shown cytokine data presented
table 3 values ifn il-12 release cervical carcinoma comparable
data obtained initial hr hpv infection cytokine levels
remain significantly lower these results suggest second deregulated incompetent
immune response cervical carcinoma probably due manifestation
inflammatory effect tumour this reaction partly comparable
inflammatory reaction initial hr hpv infection expressed
ratio ifn il-12 figures 3(a 3(b 3(e 3(f these results
agreement observations de jong et al steele
et al
studied cell responses hpv 16 oncoproteins measuring ifn release women low- high grade cin
cervical carcinoma found higher levels cell responses carcinoma
patients compared high grade cin cases a similar observation made de
jong et al investigated hpv16-positive women this study reports
higher frequency hpv16-specific cd4 cell responses patients
cervical carcinoma women cin iii lesions the increase ifn/il-4 ratio found study observed de jong et al
when
cell cultures stimulated pha part discrepancy might
owing differences hr hpv types within study groups since de jong et
al correlations specific
hpv types ifn
release possibly influenced ifn gene polymorphisms suspected yet
fully investigated goal
study changes cytokine network blood hr hpv infected women
various stages cin upto onset cervical carcinoma the use whole blood
cultures determination mitogen stimulated cytokine release
immunocompetent leukocytes distinct advantages cultures isolated
leukocytes lymphocytes it permits interaction different leukocytes
preserves concentrations stimulatory inhibitory mediators avoids
activation changes cell ratios associated procedures isolation
purification stimulation
cytokine network chose mitogen pha
pha activates mainly lymphocytes
induces rapid cell proliferation together release inflammatory
immune cytokines endotoxin lps used jacobs study induces mainly
inflammatory cytokines almost lymphocyte derived interleukins most studies dealing cytokine patterns hr hpv related
cervical neoplasia cancer concentrate infections hpv 16
frequently observed oncogenic hpv type caucasian population in contrast
studies select patients particular hr hpv
types the small sample size study groups allow us correlate
cytokine response specific hr hpv types further studies enlarged
numbers participants needed investigate individual impact
different hr hpv types cytokine network 1 study suggests infection hr hpv women without
cervical dysplasia induces activation cytokine network 2 manifestation tumour induces second deregulated
incompetent immune response 3
results confirm expand earlier observations circulating cytokines
significant changes kinetics cytokine release th2-type immune
response blood women cervical dysplasia occur progressively cin
ii cin iii these
immunological findings supported clinical observations many cin ii
lesions usually regress without treatment whereas cin iii lesions mostly
develop invasive cancer properly treated |
aims . we investigated the effect of hr - hpv infection on the capacity of the cytokine network in whole blood cultures during carcinogenesis of cervical carcinoma .
methods .
thirty - nine women with moderate dysplasia , severe dysplasia , cervical carcinoma , or without dysplasia formed the study group .
the control group consisted of 10 hr - hpv - negative women without cin .
whole blood cultures were stimulated with phytohemagglutinin ( pha ) and concentrations of tumour necrosis factor ( tnf ) , interferon ( ifn ) ,
interleukin 2 ( il-2 ) , interleukin 12 ( il-12 ) , interleukin 4 ( il-4 ) , and interleukin 10 ( il-10 ) were determined by elisas .
results .
a significant increase in cytokine release was detected in hr - hpv - positive women without dysplasia . in women with cervical cancer ,
release of ifn and il-12 was of the same magnitude as in hr - hpv - positive women without clinical manifestations .
most th1-type / th2-type ratios decreased form cin ii to cin iii , and increased from cin iii to invasive carcinoma . conclusions .
( 1 ) infection with hr - hpv without expression of cervical dysplasia induces activation of the cytokine network .
( 2 ) increases in ratios of th1-type to th2-type cytokines at the stage of cervical carcinoma were found by comparison with stage cin iii .
( 3 ) significant changes in the kinetics of cytokine release to a th2-type immune response in blood of women with
cervical dysplasia occurred progressively from cin ii to cin iii . |
damage associated molecular patterns damps endogenous molecules perpetuate inflammatory responses cell stress injury the ecm glycoprotein tn c specifically induced upon tissue injury 1 2 infection 3 4 upregulated septic patients tlr4-mediated tn c expression induces cytokine production human murine macrophages rheumatoid arthritis synovial fibroblasts importantly glucocorticoids inhibit expression tn c bone marrow stromal cells fibroblasts in addition mice bone marrow derived macrophages bmdms deficient tn c display lower production proinflammatory cytokines tnf- lps induced sepsis thus tn c recognized regulator early immune response il-10 vital anti inflammatory cytokine required dampening inflammatory signals defending host excessive inflammation mice lacking il-10 infected bacterial pathogens display high mortality associated excessive inflammatory responses low levels il-10 expression associated various inflammatory diseases ulcerative colitis crohn disease asthma humans 11 12 the anti inflammatory effect il-10 mediated jak1-stat3 pathway leads inhibition proinflammatory proteins tnf- il-6 10 13 higher expression il-10 found bmdms tn c deficient mice lower expression proinflammatory cytokines indicating anti inflammatory role il-10 tn c mediated inflammatory disease model carbon monoxide co generated end product oxidative degradation heme enzymatic action heme oxygenase converts heme biliverdin free iron co anti inflammatory effects co evident murine models sepsis postoperative ileus organ xenotransplantation 15 16 in addition co found important regulator suppression inflammatory cytokines mediators including inducible nitric oxide synthase inos tnf- il-6 17 18 well induction anti inflammatory cytokine il-10 to date reports regarding effects co mediated il-10 production regulation tn c mediated inflammation therefore current study examined effects co dependent il-10 generation tn c mediated inflammation macrophages septic mice model tenascin c antibody purchased cell signaling technology usa -actin anti mouse anti goat antibodies conjugated horseradish peroxidase obtained santa cruz biotechnology santa cruz ca usa lipopolysaccharide lps protease inhibitor cocktail sets purchased sigma aldrich st louis mo usa dulbecco modified eagle medium dmem fetal bovine serum fbs penicillin streptomycin sodium pyruvate purchased invitrogen grand island ny usa raw 264.7 cells peritoneal macrophages cultured dmem invitrogen containing 10% fetal bovine serum fbs 1% penicillin streptomycin 37c 5% co2 7580% confluence preparation peritoneal macrophages mice injected intraperitoneally 3% thioglycolate 3 days cells collected culture cells 5 10/ml seeded 6-well plates incubated overnight subsequent experiments seven week old wild type male c57bl/6 mice pretreated corm-2 30 mg kg i.p rucl3 30 mg kg i.p and mice injected lps 10 mg kg i.p after 2 hours blood serum liver tissues collected stored 80c protein rna analysis all experiments mice approved animal care committee university ulsan ulsan korea raw 264.7 cells 5 10/ml cultured 6-well plates 3 h transfected il-10 sirna 100 nm tn c sirna 100 nm santa cruz biotechnology using lipofectamine 2000 according manufacturer instructions after transfection cells incubated without corm-2 20 stimulated without lps 100 ng ml cell extracts lysed using lysis buffer containing ripa buffer protease inhibitor phosphatase inhibitors after lysis protein concentration measured bca assay pierce biotechnology inc samples containing equal amounts protein subjected electrophoresis proteins transferred polyvinylidene difluoride pvdf membranes membranes blocked 5% skim milk 20 min incubated 4c overnight primary antibodies followed secondary antibodies tn c -actin conjugated horseradish peroxidase the enhanced chemiluminescence ecl western blotting detection system ge healthcare life sciences buckinghamshire uk used visualize immunoreactive bands total rna isolation performed raw 264.7 macrophages using trizol reagent invitrogen according manufacturer instructions briefly total rna 2 g used prepare cdna using mlv reverse transcriptase promega corporation madison wi usa oligo dt 15 primer promega the resulted cdna subjected pcr mouse gapdh 5-aggccggtgctgagtatgtc-3 5-tgcctgcttcaccttct-3 530 bp ho-1 5-tcccagacaccgctcctccag-3 5-ggatttggggctggtttc-3 313 bp tn c 5-caggtacttcttcacggagc-3 5-gcagtcttccccagtgaaac-3 834 bp tnf- 5-agcccacgtcgtagcaaaccaccaa-3 5-acacccattcccttcacagagcaat-3 421 bp il-6 5-gtggaaatgagaaaagagttgt-3 5-cctcttggttgaagatatgaat-3 283 bp il-10 5-gacaataactgcacccactt-3 5-tcaaatgctccttgatttct-3 250 bp gapdh used internal loading control total rna extracted raw 264.7 peritoneal macrophages liver tissues using trizol reagent invitrogen according manufacturer instructions in addition cdna prepared using mlv reverse transcriptase promega oligo dt 15 primer promega the formulated cdna subjected real time rt pcr using sybr green qpcr master mix 2x usb products affymetrix abi 7500 fast real time pcr system applied biosystems mouse gapdh 5-gggaagcccatcaccatct-3 5-cggcctcaccccatttg-3 tn c 5-accatgctgagatagatgttccaaa-3 5-cttgacagcagaaacaccaatcc-3 tnf 5-agaccctcacactcagatcactttc-3 5-ttgctacgacgtgggctaca-3 il-6 5-cgatgatgcacttgcagaaa-3 5-tggaaattggggtaggaagg-3 il-10 5-actgctatgctgcctgctcttact-3 5-gaattcaaatgctccttgatttct-3 ho-1 5-tcagtcccaaacctcgcggt-3 5-gctgtgcaggtgttgagcc-3 macrophages 6-well plates incubated overnight pretreated corm-2 1 h followed stimulation lps 24 h. addition mice administrated corm-2 2 h sepsis induced lps injection after 2 h supernatants collected various samples blood serum collected different mice assayed tnf- il-6 using mouse elisa kit biolegend statistical differences groups evaluated one way anova nonparametric student test multiple groups compared differences considered significant p 0.05 p 0.01 p 0.001 stimulation macrophages gram negative bacterial lps enhance expression tn c tlr4 involved induction tn c subsequent cytokine synthesis human murine macrophages human chondrocytes present study we examined inflammatory responses murine raw 264.7 macrophages treated lps 100 ng ml tn c mrna protein expression increased 4 8 h lps treatment figures 1(a 1(b respectively therefore subsequent experiments measured tn c mrna protein expression 8 h. furthermore lps dose dependently increased tn c mrna protein expression 8 h figures 1(c 1(d these results suggest lps induces tn c expression time- dose dependent manner raw 264.7 macrophages the anti inflammatory antiapoptotic cytoprotective properties co well known furthermore reported generation endogenous co necessary il-10-dependent inhibition tnf- expression co generated pharmacologically co releasing molecules corms consist heavy metal ruthenium surrounded carbonyl groups 26 27 brain endothelial cells lps induced activation inflammatory signals nf-b p65 cox-2 expression pge2 production inhibited corm-2 pretreatment present study investigated effects co tn c mediated inflammation we found corm-2 significantly dose dependently suppressed expression lps stimulated tn c expression figure 2(a in addition pretreatment corm-2 significantly reduced mrna protein levels proinflammatory cytokines tnf- il-6 figures 2(b 2(c 2(d respectively confirm effects co tn c meditated inflammation cells pretreated without corm-2 rucl3 negative control corm-2 stimulated without lps interestingly corm-2 significantly downregulated lps induced tn c well proinflammatory cytokines expression whereas rucl3 effect figures 2(e 2(f 2(g 2(h confirm effects co consistently co gas dramatically reduced lps stimulated expression tn c figure 2(i well tnf- figure 2(j il-6 figure 2(k confirm effects co lps induced tn c expression proinflammatory cytokines mouse peritoneal macrophages pretreated corm-2 various concentrations incubated lps we found corm-2 dramatically decreased lps induced tn c figure 3(a downstream cytokines figure 3(b in contrast rucl3 reduce expression tn c proinflammatory cytokines figures 3(c 3(d low doses co suppressed inflammatory responses murine model sepsis inhibition inflammatory cytokines production 18 29 well increased lps induced expression anti inflammatory cytokine il-10 various cell types 19 29 in addition mice deficient tn c displayed lower levels tnf- downstream cytokine production lps treated septic mice bone marrow derived macrophages bmdms study investigated effects co tn c induced proinflammatory cytokines expression expression anti inflammatory il-10 raw 264.7 peritoneal macrophages corm-2 significantly dose dependently induced expression il-10 lps stimulated macrophages figures 4(a 4(b furthermore treatment co gas significantly increased levels il-10 figure 4(c lps stimulated raw 264.7 macrophages however treatment rucl3 effect il-10 expression cells figures 4(d 4(e these observations indicate anti inflammatory effects co mediated il-10 lps stimulated macrophages the incubation raw 264.7 cells tn c sirna significantly suppressed effects lps tn c proinflammatory cytokines production figures 4(f 4(g 4(h whereas effect il-10 expression figure 4(i suggesting il-10 regulated independently tn c downstream cytokines confirm function co - induced il-10 tn c mediated inflammation macrophages transfected il-10 sirna treated corm-2 prior lps stimulation we found il-10 sirna reversed inhibitory effect corm-2 tn c expression inflammatory cytokines production lps stimulated macrophages relative control sirna figures 4(k 4(l 4(m pretreatment recombinant il-10 without lps stimulation showed efficiency corm-2 significantly decrease tn c expression figure 4(n also ho-1 increases il-10 production according inoue colleagues overexpressions ho-1 thus examined expression anti inflammatory gene ho-1 conditions interestingly found corm-2 significantly increased level ho-1 expression figure 4(o whereas rucl3 effect ho-1 expression figure 4(o conversely decreased expression levels tn c the inhibition ho activity using znppix however reverse effects corm-2 tn c expression figure 4(p indicating corm-2 mediated suppression tn c independent ho activity lps stimulated raw 264.7 macrophages based results conclude co induced il-10 inhibits tn c mediated inflammation sepsis systemic inflammatory response results excessive production proinflammatory cytokines lps stimulation in addition proinflammatory cytokines tnf- il-1 il-6 found higher levels septic patients 32 33 administration lps mice revealed tn c expression necessary proinflammatory signaling furthermore application exogenous co inhibits lps induced production tnf- increases il-10 production vitro vivo however reports regarding effects co mediated il-10 production relation regulation tn c inflammation septic mouse model study examine vivo effects co using corm-2 lps induced endotoxemia tn c mediated inflammatory cytokines expression pretreated mice corm-2 30 mg kg i.p rucl3 30 mg kg i.p 2 h lps 10
mg kg i.p 2 h. interestingly corm-2 significantly decreased tn c figure 5(a tnf- il-6 mrna expression figure 5(b protein secretion figure 5(c simultaneously increased il-10 expression figure 5(d liver tissue lps induced endotoxemic mice also levels il-10 figure 5(e increased reversely tn c levels figure 5(f decreased serum mice treated corm-2 therefore results vivo experiments suggest co inhibited tn c downstream inflammatory cytokines whereby il-10 expression upregulated septic mice model tn c unique distinct pattern expression upon tissue injury tn c is transiently expressed whereas expression reduced tissue repaired moreover persistent tn c expression occurs chronic inflammation in addition tn c absent healthy adult tissues whereas high levels found infection patients sepsis however tn c expressed sites inflammation regardless location type causative insult indicating capability participate global inflammatory response tn c increase synthesis cytokines human chondrocytes myeloid cells tlr4-dependent manner also activate murine myeloid cells 35 36 additionally tn c expression transiently induced lps innate immune cells nf-b dependent manner 7 37 dysregulation observed autoimmune inflammatory diseases sepsis present study found lps significantly increased tn c proinflammatory cytokines production macrophages well mouse model therefore understanding compounds inhibit tlr mediated tn c expression cytokines production may refine strategies manipulate excessive inflammation recently researchers reported co gas exert beneficial effects various cell animal models co plays important role preventing apoptosis several cell types endothelial cells fibroblasts pancreatic -cells inhibits proliferation smooth muscle cells thus preventing atherosclerotic lesions animal models corm compounds provide reliable source co mimic co gas many biological functions 26 45 therefore corms represent important tools understand biological significance co physiology disease corm-2 first compound used deliver co biological systems controlled manner current study examine effects co pretreated macrophages mice corm-2 lps stimulated inflammation model interestingly corm-2 significantly decreased lps induced tn c proinflammatory cytokines production vitro vivo similarly pretreatment co gas significantly decreased lps stimulated tn c cytokines production macrophages supporting direct effects co tn c mediated inflammation in addition rucl3 negative control corm-2 affect lps mediated tn c tnf- il-6 expression macrophages septic mice these results confirm co inhibits lps mediated tn c proinflammatory cytokines production the anti inflammatory cytokine il-10 plays crucial role dampening toll like receptor tlr signaling induced proinflammatory genes interestingly co found increase levels anti inflammatory il-10 levels proinflammatory cytokines decreased several vitro systems 18 29 additionally corm-2 also found regulate inflammatory responses decreasing il-1 expression increasing il-10 expression sepsis model co - mediated activation mkk3/p38 mapk signaling pathway involved induction il-10 investigation determined effects co significantly increased il-10 expression lps stimulated conditions rucl3 effect vitro vivo furthermore il-10 sirna significantly reversed effects corm-2 tn c proinflammatory cytokines production whereas tn c sirna significantly decreased proinflammatory gene expression levels without effect co mediated il-10 expression this evidence suggests co mediated il-10 expression involved inhibition tn c mediated inflammation summary identified co induced il-10 involved inhibition tlr4 signaling dependent tn c expression thus inhibited inflammatory response vitro vivo this study describes novel co dependent il-10 signaling pathway responsible inhibition tn c driven inflammation potentially provides rationale novel therapeutic strategies treatment inflammatory diseases | tenascin - c ( tn - c ) , an extracellular matrix ( ecm ) glycoprotein , is specifically induced upon tissue injury and infection and during septic conditions .
carbon monoxide ( co ) gas is known to exert various anti - inflammatory effects in various inflammatory diseases .
however , the mechanisms underlying the effect of co on tn - c - mediated inflammation are unknown . in the present study
, we found that treatment with lps significantly enhanced tn - c expression in macrophages .
co gas , or treatment with the co - donor compound , corm-2 , dramatically reduced lps - induced expression of tn - c and proinflammatory cytokines while significantly increased the expression of il-10 .
treatment with tn - c sirna significantly suppressed the effects of lps on proinflammatory cytokines production .
tn - c sirna did not affect the corm-2-dependent increase of il-10 expression . in cells transfected with il-10 sirna , corm-2 had no effect on the lps - induced expression of tn - c and its downstream cytokines .
these data suggest that il-10 mediates the inhibitory effect of co on tn - c and the downstream production of proinflammatory cytokines .
additionally , administration of corm-2 dramatically reduced lps - induced tn - c and proinflammatory cytokines production while expression of il-10 was significantly increased . in conclusion , co regulated il-10 expression and thus inhibited tn - c - mediated inflammation in vitro and in vivo . |
type 2 diabetes mellitus t2 dm one common noncommunicable diseases characterized insulin resistance impaired insulin secretion 1 2 metabolic proinflammatory disorder including chronic hyperglycemia increased levels circulating cytokines suggests immunological disturbances 37 seriously affects quality life patients imposes large economic burden national health care system genetic environmental factors blamed t2 dm 25% first degree relatives t2 dm patients may develop disease the origin development t2 dm involved multiple risk factors regulatory cells treg cytokines play important roles development t2 dm treg subset cd4 cells maintain peripheral tolerance suppress antigen specific immune responses secreting transforming growth factor- tgf- interleukin-10 il-10 il-4 inhibit autoimmunity it found ratios cd4cd25treg th17 cells cd4cd25treg th1 cells significantly decreased t2 dm patients expression foxp3 key player development function treg correlates well regulatory activity number treg indeed foxp3 exclusively expressed cd4cd25treg 1316 positive correlation cd4cd25foxp3treg enhanced expression il-6 cd4 cells il-10 multifunctional cytokine secretion treg plays key role inflammatory response associated insulin resistant states t2 dm increased levels il-17 were found protect autoimmune mediated t1 dm nonobese diabetic mice hand loss il-17 associated disease susceptibility part suggested absence il-17 results enhanced production proinflammatory cytokines tgf- also multifunctional cytokine circulating biologically inactive form human plasma 21 22 the tgf- family includes multifunctional molecules exert specific effects cell proliferation differentiation migration development tissue remodeling repair tnf- inhibits insulin signaling cascade regulating several pivotal regulatory proteins insulin receptor substrate irs akt substrate 160 human skeletal muscle vitro vivo it reported polymorphism immune genes tnf- tgf- associated development t2 dm intriguingly increased renal production tgf- distinct feature diabetes 2831 within past years many clinical studies focusing association treg proinflammatory immunosuppressive cytokines t2 dm despite intensive research efforts therefore performed meta analysis synthesizing data case control studies evaluate changes treg il-6 il-10 il-17 tgf- tnf- t2 dm patients our study conducted according preferred reporting items systematic reviews meta analyses prisma criteria we identified relevant studies treg il-6 il-10 il-17 tgf- tnf- t2 dm patients systematically searching pubmed wanfang database chinese cqvip cnki databases february 1 1991 july 15 2016 il-17 transforming growth factor beta tgf- tumor necrosis factor alpha
tnf- regulatory cells treg cd4cd25 cell cd4cd25foxp3 cell type 2 diabetes mellitus type 2 diabetes diabetes mellitus
in addition also conducted extensive literature search articles identified reference lists we reviewed relevant articles using following inclusion criteria 1 study evaluate relationship cd4cd25foxp3treg cd4cd25treg il-6 il-10 il-17 tgf- tnf- t2 dm patients 2 design case control study 3 original data displayed could converted mean sd 4 original report showed duplicated data the data extracted independently two reviewers yong chao qiao jian shen using predefined data extraction forms quality eligible studies evaluated according newcastle ottawa scale nos the following information extracted 1 name first author 2 date publication 3 country study 4 study design 5 sample size patients controls 6 mean age sample 7 mean sd patients controls case disagreement third investigator hai lu zhao ) we presented data sample size mean sd illustrate changes treg il-6 il-10 il-17 tgf- tnf- t2 dm patients versus healthy controls chi squared q test statistics used assess heterogeneity when p 0.1 50% heterogeneity considered significant random effect model used otherwise fixed effect model used considering influence diabetic complications patients divided two groups t2 dm complication t2 dm without complication subgroup analysis we performed sensitivity analysis limiting studies nos score 7 excluding studies high risk bias publication bias examined graphically constructing egger test p 0.05 considered representative statistically significant publication bias the flow chart article search inclusion process displayed figure 1 based search strategy a total 5,064 articles collected 332 removed initial screening furthermore 3,954 articles excluded dm relevant controls animal studies review articles then excluded 687 studies duplicated data original data original data expressed figures eventually meta analysis included 91 articles involving 138 case control studies 5642 t2 dm patients 7378 healthy controls 13 il-6 3446 22 tgf- 23 4767 7 tnf- 3436 38 45 68 69 6 cd4cd25foxp3treg 7075 15 il-10 7690 18 cd4cd25treg 70 72 74 75 91104 10 il-17 105114 t2 dm patients significantly increased levels serum il-6 smd 1.28 95% ci 0.73 1.83 p 0.001 figure 2 tgf- smd 2.88 95% ci 2.37 3.40 p 0.001 figure 3 tnf- smd 1.56 95% ci 1.10 2.02 p 0.001 figure 4 significantly decreased percentage cd4cd25foxp3treg smd 0.47 95% ci 0.72 0.23 p 0.001 figure 5 level serum il-10 smd 1.37 95% ci 2.32 0.42 p 0.005 figure 6 changes percentage cd4cd25treg smd 0.24 95% ci 0.76 0.28 p 0.360 figure 7 il-17 smd 0.51 95% ci 1.87 0.84 p 0.459 figure 8) significant results meta analysis displayed significant heterogeneity subgroup analysis performed explore impact diabetic complication changes treg cytokines shown figures 28 t2 dm patients complication patients without complication significantly increased levels serum il-6 figure 2 tgf- figure 3 tnf- figure 4 significant changes found percentage peripheral cd4cd25treg figure 7 il-17 figure 8) intriguingly t2 dm patients complication showed lower percentage peripheral cd4cd25foxp3treg p 0.001 figure 5 whereas patients without complication decreased levels serum il-10 p 0.033 figure 6 the high heterogeneity existed subgroup analysis order explore source heterogeneity conducted regression analysis according complication covariate the results follows tgf- 4.08 p 0.001 95% ci 1.23 3.65 il-6 0.09 p 0.929 95% ci 1.09 1.18 tnf- 0.34 p 0.740 95% ci 1.23 1.67 cd4cd25foxp3treg 2.04 p 0.097 95% ci 1.55 0.18 il-10 0.36 p 0.723 95% ci 5.33 3.77 cd4cd25treg 0.63 p 0.534 95% ci 0.96 1.81 il-17 0.56 p 0.586 95% ci 4.84 2.86 therefore diabetic complication key influencing factor high heterogeneity meta analysis tgf- others sensitivity analysis used assess stability results excluding studies high risk bias significant changes results found we conducted sensitivity analysis including studies high nos score 7 found results remained consistent egger test showed significant publication bias meta analysis tnf- others figure 9 in study found patients t2 dm increased serum levels il-6 tgf- tnf- decreased percentage peripheral cd4cd25foxp3treg serum il-10 level furthermore percentage peripheral cd4cd25foxp3treg serum il-10 level influenced diabetic complication the expression inflammatory proinflammatory cytokines peripheral blood lymphocyte plays important role development diabetes diabetic complications many studies proved maintenance immunological self tolerance cd4cd25treg cd4cd25foxp3treg the finding decreased percentage peripheral cd4cd25foxp3treg t2 dm patients indicates foxp3 might key player development function treg some researchers also considered differentiation function maintenance treg dependent expression foxp3 consequently foxp3 considered key transcriptional factor treg cells 117119 il-10 tgf- secreted treg 116 120 biomarkers t2 dm patients 2 116 previous studies suggested il-10 could suppress proliferation leukomonocyte secretion cytokines whereas tgf- may sustain expression foxp3 cd4cd25treg enhance immunosuppressive function 122 123 consistent findings several studies shown significantly decreased level serum il-10 t2 dm patients 88 124 a recent investigation showed il-6 could enhance treg mice present meta analysis t2 dm patients increased levels serum il-6 tgf- tnf- coexisted decreased levels il-10 decreased percentage cd4cd25foxp3treg this finding highlights cytokines growth factors may originate multiple sources macrophages cells tissue cells rather treg alone furthermore chronic persistent activation innate immunity il-6 secretion occurring t2 dm might inhibit development inducible treg cells th17 cells could produce il-17 tnf- il-6 induce inflammation pathogenesis autoimmune diseases th17 cells major cell subset implicated pathogenesis multiple sclerosis rheumatoid arthritis psoriasis a previous study revealed th1/th2 imbalance also th17/treg imbalance contribute pathogenesis autoimmune diseases t1 dm well proinflammatory disorders t2 dm t2 dm patients elevated serum levels il-6 il-1 tgf- cytokines known induce th17 differentiation enhanced production il-6 tnf- decreased levels serum il-10 occurred t2 dm patients may suppress treg cells ratios treg th17 th1 cells 132 133 the immunocompromised effects macrophages lymphocytes likely drive inflammatory state contribute occurrence diabetic complications here study significant changes foxp3treg cells serum il-17 levels found t2 dm subjects without complication there intimate relationship differentiation th17 cells relative abundance peripheral cd4cd25foxp3treg cells serum levels il-6 il-10 tgf-. although changes serum levels il-17 significant meta analysis t2 dm patients versus controls il-17 may clue possible involvement th17 cells t2 dm pathogenesis firstly decrease treg cells might accompanied increase th17 cells study guan et al has indicated existence developmental switch th1/th17 cells one hand th2/treg cells hand secondly presence high serum levels il-6 tgf- reported differentiation th17 cells might favoured lastly th17 cells might together innate cells primary source increased il-6 levels might actively orchestrating immunity driven chronic inflammation target tissues organs t2 dm systematic review the studies examining number th17 cells t2 dm scarce included meta analysis future studies required focus role th17/treg products th17 cells pathogenesis t2 dm associated complications diabetic complications retinopathy nephropathy cardiovascular disease affect immune cells cytokines type 2 diabetes 135 136 actually urinary tgf- levels elevated presence microalbuminuria overt proteinuria additionally elevated plasma tgf- may reflect state hyperglycemia t2 dm patients systemic inflammation t2 dm linked development diabetic complications 138 139 yet mechanism immune alteration t2 dm diabetic complication remains unclear meta analysis diabetic complication indeed impact percentage peripheral cd4cd25foxp3treg level serum il-10 the percentage treg cells levels cytokines t2 dm may also depend ethnicity sex weight age disease duration the results egger tests explain publication bias existed comparisons except tnf-. publication bias meta analysis might attributed studies small samples positive results published easily negative reports firstly selected random effect model synthesize smd high heterogeneity existing comparisons selection may affect accuracy outcome secondly could conduct subgroup analysis gender weight disease duration included studies lack sufficient original data thirdly articles published chinese english included unpublished data papers published languages unknown in summary t2 dm patients patients diabetic complication decreased immunosuppressive cd4cd25foxp3treg cells increased proinflammatory il-10 tgf- tnf-. presence diabetic complication impact compromised immunosuppression |
objective .
the aim of this study was to investigate the changes of regulatory t cells ( treg ) , interleukin-6 ( il-6 ) , il-10 , transforming growth factor- ( tgf- ) , and tumor necrosis factor - alpha ( tnf- ) in patients with type 2 diabetes mellitus ( t2 dm ) .
methods .
we performed a comprehensive search up to july 2016 for all clinical studies about the changes of treg , il-6 , il-10 , il-17 , tgf- , and tnf- in t2 dm patients versus healthy controls .
results .
a total of 91 articles ( 5642 cases and 7378 controls ) were included for this meta - analysis . compared with the controls ( all p < 0.001 )
, the patients had increased serum levels of il-6 , tgf- , and tnf- but decreased the percentage of peripheral cd4+cd25+foxp3+treg and serum il-10 level .
furthermore , the percentage of peripheral cd4+cd25+foxp3+treg ( p < 0.001 ) and serum il-10 level ( p = 0.033 ) were significantly lower in the patients with complication and in the patients without complication , respectively .
no significant changes about the percentage of cd4+cd25+treg ( p = 0.360 ) and serum il-17 level ( p = 0.459 ) were found in t2 dm patients .
conclusions .
t2 dm patients have decreased the percentage of peripheral cd4+cd25+foxp3+treg and levels of serum il-10 but elevated serum levels of il-6 , tgf- , and tnf-. presence of diabetic complications further lowers the peripheral cd4+cd25+foxp3+treg number . |
antioxidant deficiency contributes develop aggravate various chronic diseases including copd sensitive oxidative stress supplementation vitamin c antioxidant improves antioxidant status copd.1 several epidemiologic studies2,3 prospective studies4,5 revealed protective effects vitamin c intake copd vitamin c symptom relieving effects exacerbation copd.6 addition improves pulmonary function copd.7,8 moreover recent animal study revealed supplementation vitamin c prevents development copd also restores lung function copd subjects.9 korea national health nutrition examination survey knhanes large scale survey containing vast amount data demographics underlying disease smoking history lung function nutritional status conducted korean centers disease control prevention kcdc the sample present study selected well designed national program complex multistage probability sample extraction therefore results obtained survey using complex analysis generalized entire korean general population.10,11 thus knhanes best tool defining confirming correlation vitamin c intake copd therefore study aimed confirm protective effects vitamin c copd korean general population using knhanes data this survey used stratification multiple stages cluster selection represent entire korean general population we followed guidelines reporting sample weight stratification designated kcdc information available knhanes website facilitate obtaining appropriate results raw data open public https://knhanes.cdc.go.kr the institutional review board gangnam severance hospital approved study approval number 3 2016 0195 we included 3,283 subjects aged 40 years older responded health interview survey underwent pulmonary function tests responded questionnaires smoking history vitamin c intake january 2012 december 2012 all interview items including nutritional status assessed questioning subjects face face interviews the resident district classified urban concordant dong suburban rural concordant eup myun household income classified 4 categories lowest quartile q1 low middle quartile q2 high middle quartile q3 highest quartile q4 vitamin c intake also classified 4 categories q1 48.50 mg q2 48.5084.38 mg q3 84.38141.63 mg q4 141.63 mg the amount smoked pack year calculated based duration smoking history year amount cigarettes smoked pack day frequency smoking day month smoking history classified 4 categories according amount smoked never smoker 0 pack years light smoker 020 pack years medium smoker 2040 pack years heavy smoker 40 pack years pulmonary function tests including forced vital capacity fvc forced expiratory volume 1 second fev1 performed using commercially available equipment masterlab ios erich jaeger co. friedburg germany subjects copd defined fev1/fvc ratio 0.7.12 complex sample survey data analysis used knhanes stratification variables sampling weight non copd copd groups differences mean age nutritional status assessed independent sample test differences categorized variables tested using chi square test the prevalence copd according smoking history amount vitamin c ingested compared using chi square test we used spss 18.0 spss inc chicago il usa statistical software this survey used stratification multiple stages cluster selection represent entire korean general population we followed guidelines reporting sample weight stratification designated kcdc information available knhanes website facilitate obtaining appropriate results raw data open public https://knhanes.cdc.go.kr the institutional review board gangnam severance hospital approved study approval number 3 2016 0195 we included 3,283 subjects aged 40 years older responded health interview survey underwent pulmonary function tests responded questionnaires smoking history vitamin c intake january 2012 december 2012 all interview items including nutritional status assessed questioning subjects face face interviews the resident district classified urban concordant dong suburban rural concordant eup myun household income classified 4 categories lowest quartile q1 low middle quartile q2 high middle quartile q3 highest quartile q4 vitamin c intake also classified 4 categories q1 48.50 mg q2 48.5084.38 mg q3 84.38141.63 mg q4 141.63 mg the amount smoked pack year calculated based duration smoking history year amount cigarettes smoked pack day frequency smoking day month smoking history classified 4 categories according amount smoked never smoker 0 pack years light smoker 020 pack years medium smoker 2040 pack years heavy smoker 40 pack years pulmonary function tests including forced vital capacity fvc forced expiratory volume 1 second fev1 performed using commercially available equipment masterlab ios erich jaeger co. friedburg germany subjects for complex sample survey data analysis used knhanes stratification variables sampling weight non copd copd groups differences mean age nutritional status assessed independent sample test differences categorized variables tested using chi square test the prevalence copd according smoking history amount vitamin c ingested compared using chi square test we used spss 18.0 spss inc chicago il usa statistical software we enrolled 3,283 subjects representing total 23,541,704 korean subjects among subjects we classified subjects 2 groups non copd copd compared demographic characteristics 2 groups males prevalence copd significantly higher females 23.5% vs 6.6% p<0.001 the mean age standard deviation copd group 64.20.7 significantly older non copd group 54.50.4 p<0.001 the prevalence copd subjects live suburban rural areas significantly higher subjects living urban areas 20.8% vs 12.9% p<0.001 subjects lived general type house the prevalence copd higher 16.6% subjects lived apartment 9.3% p<0.001 the prevalence copd decreased according increase household income p<0.001 subjects worked agriculture fisheries showed higher prevalence copd 25.0% subjects professional job 7.7% service sales job 6.0% p<0.001 among never smokers prevalence copd 7.9% prevalence increased according increase amount smoked 16.7% light smokers 24.2% medium smokers ; we compared nutritional status assessed self reported questionnaire non copd copd group the amount food intake g copd group 1,320.437.9 significantly less non copd group 1,462.323.6 p=0.001 the amount potassium mg ingested copd group 2,915.485.9 significantly less non copd group 3,200.058.9 p=0.005 the amount vitamin carotene taken copd group also less non copd group p=0.040 0.015 respectively copd group the retinol intake 63.84.9 g significantly less non copd group 93.46.5 g p<0.001 the vitamin c intake mg also significantly less non copd group 93.23.9 vs 122.14.0 p<0.001 table 2 the prevalence copd positively correlated amount smoking negatively correlated amount vitamin c ingested light smokers the prevalence copd subjects vitamin c intake q1 24.7% significantly higher subjects whose vitamin c intake fell q4 7.0% p=0.002 heavy smokers prevalence copd subjects q1 63.0% q2 56.4% ) vitamin c intakes significantly higher subjects q3 29.5% q4 32.6% vitamin c intakes p=0.015 in addition prevalence copd heavy smokers vitamin c intake q3 29.5% lower medium smokers q1 vitamin c intake 36.8% figure 1 we selected significant risk factors copd using univariate analysis logistic regression variables used tables 1 2 sex age resident district type residence household income educational level occupation smoking history amount retinol intake vitamin c intake significant risk factors copd univariate analysis multivariate analysis sex age smoking history amount vitamin c intake independent risk factors copd female gender preventative factor odds ratio 0.234 95% confidence interval ci 0.1440.378 p<0.001 compared male gender aging significant risk factor 1.089 95% ci 1.0681.110 p<0.001 compared never smokers medium smokers 2.192 95% ci 1.3053.680 heavy smokers 2.894 95% ci 1.6415.102 high risk copd p<0.001 the amount vitamin c intake preventative factor copd independent sex age even smoking history 0.998 95% ci 0.9960.999 p=0.001 a 1-mg increase vitamin c intake reduced risk copd 0.2% table 3 we classified subjects according smoking history subclassified according amount vitamin c ingested confirmed amount vitamin c independent preventative factor copd adjusted age sex light smokers vitamin c intake q4 protective copd compared vitamin c intake q2 particular heavy smokers risk reduction rate individuals vitamin c intake falling q3 76.7% compared vitamin c intake q1 0.233 95% ci 0.0940.576 table 4 we enrolled 3,283 subjects representing total 23,541,704 korean subjects among subjects we classified subjects 2 groups non copd copd compared demographic characteristics 2 groups males prevalence copd significantly higher females 23.5% vs 6.6% p<0.001 the mean age standard deviation copd group 64.20.7 significantly older non copd group 54.50.4 p<0.001 the prevalence copd subjects live suburban rural areas significantly higher subjects living urban areas 20.8% vs 12.9% p<0.001 subjects lived general type house the prevalence copd higher 16.6% subjects lived apartment 9.3% p<0.001 the prevalence copd decreased according increase household income p<0.001 subjects worked agriculture fisheries showed higher prevalence copd 25.0% subjects professional job 7.7% service sales job 6.0% p<0.001 among never smokers prevalence copd 7.9% prevalence increased according increase amount smoked 16.7% light smokers 24.2% medium smokers ; we compared nutritional status assessed self reported questionnaire non copd copd group the amount food intake g copd group 1,320.437.9 significantly less non copd group 1,462.323.6 p=0.001 the amount potassium mg ingested copd group 2,915.485.9 significantly less non copd group 3,200.058.9 p=0.005 the amount vitamin carotene taken copd group also less non copd group p=0.040 0.015 respectively copd group the retinol intake 63.84.9 g significantly less non copd group 93.46.5 g p<0.001 the vitamin c intake mg also significantly less non copd group 93.23.9 vs 122.14.0 p<0.001 table 2 the prevalence copd positively correlated amount smoking negatively correlated amount vitamin c ingested light smokers the prevalence copd subjects vitamin c intake q1 24.7% significantly higher subjects whose vitamin c intake fell q4 7.0% p=0.002 heavy smokers prevalence copd subjects q1 63.0% q2 56.4% ) vitamin c intakes significantly higher subjects q3 29.5% q4 32.6% vitamin c intakes p=0.015 in addition prevalence copd heavy smokers vitamin c intake q3 29.5% lower medium smokers q1 vitamin c intake 36.8% figure 1 we selected significant risk factors copd using univariate analysis logistic regression variables used tables 1 2 sex age resident district type residence household income educational level occupation smoking history amount retinol intake vitamin c intake significant risk factors copd univariate analysis multivariate analysis sex age smoking history amount vitamin c intake independent risk factors copd female gender preventative factor odds ratio 0.234 95% confidence interval ci 0.1440.378 p<0.001 compared male gender aging significant risk factor 1.089 95% ci 1.0681.110 p<0.001 compared never smokers medium smokers 2.192 95% ci 1.3053.680 heavy smokers 2.894 95% ci 1.6415.102 high risk copd p<0.001 the amount vitamin c intake preventative factor copd independent sex age even smoking history 0.998 95% ci 0.9960.999 p=0.001 ) 1-mg increase vitamin c intake reduced risk copd 0.2% table 3 we classified subjects according smoking history subclassified according amount vitamin c ingested confirmed amount vitamin c independent preventative factor copd adjusted age sex light smokers vitamin c intake q4 protective copd compared vitamin c intake q2 particular heavy smokers risk reduction rate individuals vitamin c intake falling q3 76.7% compared vitamin c intake q1 0.233 95% ci 0.0940.576 table 4 various factors including sex age resident district type residence household income educational level occupation smoking history affect prevalence copd in addition found subjects living suburban rural areas general residence types subjects low income low educational level agriculture fisheries employment higher prevalence copd however factors may related male gender old age heavy smoking history already well known risk factors copd therefore multivariate analysis performed define factors independent risk factors copd marital status related smoking history previous study,13 whereas present study showed marital status significantly associated copd result judged based previous studies total number unmarried subjects small n=41 representing 419,691 subjects 1.3% total number subjects study the main contributing factors development copd genetic background exposure oxidizing agents reduced antioxidant capacity.14,15 dietary antioxidants responsible antioxidant defenses lungs.16 various nutrients including vitamin c retinol tocopherol carotenoids proven helpful altering clinical outcomes copd.3,1719 present study showed significant shortage total nutritional potassium vitamin carotene retinol vitamin c intake copd group compared non copd group however difference nutritional status 2 groups may due difference total nutritional intake therefore multivariate analysis would needed identify independent risk factors define independent risk factors copd among mentioned factors we revealed male gender old age heavy smoking history vitamin c independent risk factors copd whereas factors independently significant except well known risk factors vitamin c independent risk factor based multivariate analysis shown table 3 100 mg vitamin c intake resulted risk reduction 20.0% heavy smokers ~100 mg vitamin c intake mean 30.1 mg q1 vs mean 110.6 mg q3 led marked risk reduction 76.7% copd one half apples contains ~100 mg vitamin c. nutritional vitamin c supplements contain 1,000 mg however abuse vitamin c supplements may lead yet rarely acute renal failure.20 therefore one carefully consider vitamin c supplements vitamin c also known ascorbate l ascorbic acid antioxidant properties plays significant roles immune system including allergic reaction maintenance connective tissue even tumor suppression.2123 low levels vitamin c associated significantly wheezing dyspnea exacerbation copd.2426 dietary vitamin c also shown lower oxidative stress increase collagen synthesis restore vascular endothelial growth factor levels proliferation alveolar cells lungs.9 extensive studies shown vitamin c intake provides protection development copd.1,8,27,28 results corroborate findings studies the results obtained study extremely significant study represents almost half total korean population n=23,541,704 joshi et al previously revealed effect dietary antioxidants copd korea.29 strongly support previous study vast amount data although many researchers attempted use knhanes data many studies ignore complex survey design leads biased results overstated significance levels.10 however followed guidelines suggested institute conducted complex survey therefore results positive effects vitamin c copd deemed trustworthy first cross sectional cohort study possible ascertain whether low intake vitamin c cause result copd however assume causal factor based many previous prospective studies mentioned paper the nutritional status also assessed using self reported questionnaires assistance interviewer measurement vitamin c using blood sampling may helpful confirm nutritional status third could ascertain optimal dose vitamin c preventing copd optimal dose differed according smoking history for example association q1 q3 stronger q1 q4 hence follow linear trend this might due fact vitamin c intake greater optimal level additional effects lastly height body mass index dietary fiber cured meat intake may confounding factors study this large scale national study suggests dietary vitamin c intake protective copd independent smoking history korean general population | backgroundvitamin c , as an antioxidant , has recently been suggested to provide protection against copd ; however , only few national cohort studies have investigated these effects .
we aimed to confirm the protective effects of vitamin c against copd in korean patients.patients and methodswe analyzed the data of 3,283 adults aged 40 years ( representing 23,541,704 subjects ) who underwent pulmonary function tests and responded to questionnaires on smoking history and vitamin c intake , with stratification variables and sampling weight designated by the korea 2012 national health and nutrition examination survey.resultsamong all the subjects , 512 ( representing 3,459,679 subjects ; 15.6% ) were diagnosed as having copd based on pulmonary function test results .
male gender , old age , residence in suburban / rural regions , low household income , low educational level , an occupation in agriculture or fisheries , and heavy smoking were significantly associated with copd .
low intake of nutrients , including potassium , vitamin a , carotene , retinol , and vitamin c , was significantly associated with copd .
the prevalence of copd in heavy smokers with the lowest quartile ( q1 , < 48.50 mg ; 63.0% ) and low - middle quartile ( q2 , 48.5084.38 mg ; 56.4% ) of vitamin c intake was significantly higher than that in subjects with the high - middle quartile ( q3 , 84.38141.63 mg ; 29.5% ) and highest quartile ( q4 , > 141.63 mg ; 32.6% ) of vitamin c intake ( p=0.015 ) . in multivariate analysis ,
male gender , old age , heavy smoking , and a low intake of vitamin c were significant independent risk factors for copd . a significant reduction of 76.7% in copd risk was observed with a q3 vitamin c intake compared to q1 vitamin c intake ( odds ratio , 0.233 ; 95% confidence interval , 0.0940.576 ) in heavy smokers.conclusionthis large - scale national study suggests that dietary vitamin c provides protection against copd , independent of smoking history , in the general korean population . |
tobacco use fallen many high income countries least men rising rapidly many low- middle income countries china thirty eight percent world smokers chinese especially chinese men smoke one third world cigarettes 52.9% smoking prevalence 50.4% current cigarette use 2 3 tobacco use become number one killer china responsible 1.2 million deaths annually number expected rise 3.5 million deaths annually year 2030 diabetes another major public health problem china according 2010 china noncommunicable disease surveillance overall prevalence diabetes prediabetes estimated 11.6% 12.1% among men 50.1% 52.1% among men chinese adults respectively representing 113.9 million adults diabetes 493.4 million prediabetes furthermore current prevalence diabetes chinese population similar us population even though overweight obesity much common latter it urgent need illuminate associated risk factors develop effective strategies prevent development diabetes china the association smoking increased risk type 2 diabetes mellitus type 2 dm well documented 5 6 active passive smoking demonstrated associated increased risk type 2 dm 7 8 recent study also reported current smokers dose dependently associated increased risk incident metabolic syndrome chinese men insulin resistance ir declining -cell function proven potential mechanisms development type 2 dm demonstrated long overt diabetes diagnosed 10 11 chronic smoking reported markedly dose dependent manner aggravate ir observed type 2 dm patients however metabolic effects smoking especially chronic smoking studied persons without diabetes findings controversial smoking reported acutely impair insulin action led ir normal subjects chronic smoking also shown associated ir degree 5 1417 nevertheless studies found difference ir smokers nonsmokers population without diabetes 1823 hand few available studies failed provide conclusive evidence 18 19 23 even opposite effects -cell function reported current former smokers compared nonsmokers homeostatic model assessment homa using steady state glucose insulin method assessing ir -cell function appropriate use large epidemiological studies but studies applying homa method currently available assessing associations chronic smoking asians exhibit lower levels homa insulin resistance homa ir western populations 1719 moreover dynamic evaluation -cell function oral glucose tolerance test ogtt according smoking status rare this population based study aims elucidate effects chronic smoking ir -cell function large sample chinese men without diabetes using homa analysis ogtt on basis china noncommunicable disease surveillance 2010 study population cross sectional study subset population recruited jiangsu province using complex multistage probability sampling design brief first selected 6 counties 106 counties using stratified random sampling according population gross domestic product gdp degree urbanization geographic setting secondly 4 towns county 3 villages town selected probability proportional population size using cluster random sampling thirdly 1 residential group including least 50 households selected village using simple random cluster sampling random digit function excel applied selection households residential group finally one family member aged 18 years randomly selected household using kish grid method 25 26 subjects diagnosed diabetes according american diabetes association criteria the data collected face face interview included demographic characteristics lifestyle factors medical history the investigated smoking history included age smoking initiation years smoking number cigarettes smoked per day smoking cessation briefly individual never smoked smoked less 100 cigarettes lifetime defined never smoker an individual smoked least 100 cigarettes lifetime quit smoking 12 months interview considered former smoker current smokers included currently smoking quit smoking less 12 months interview the pack year smoking calculated according number packs cigarettes smoked per day smoking duration years an individual never consumed alcohol consumed less equal one drink per month defined never drinker otherwise ever drinker the global physical activity questionnaire used evaluate physical activities calculating total weekly volume metabolic equivalents met min wk across three separate domains work home commuting leisure time applying met values time variables according intensity activity 4 29 30 height weight measured light underclothes without shoes standing position participants light clothing waist circumference was measured midway lower edge costal arch upper edge iliac crest body mass index bmi calculated weight kg)/height kg considered overweight waist circumference 90 cm central obesity chinese men 4 31 blood pressure measured trained physicians using calibrated electronic sphygmomanometer hem-7071 omron corporation japan nondominant arm precordial level least 5 min rest subjects sitting position three readings taken 2 min apart averaged values systolic blood pressure sbp diastolic blood pressure dbp calculated the participants identified hypertensive subjects high blood pressure values sbp 140 mmhg and/or dbp 90 mmhg history hypertension antihypertensive medications therapy venous blood sample 4 5 ml ) plasma samples glucose test collected tubes containing sodium fluoride 0 h 2 h administration standard 75 g glucose solution ogtt test plasma glucose measured using glucose oxidase hexokinase methods within 24 h. capillary blood samples glycated hemoglobin hba1c detection collected hemoglobin capillary collection system hba1c measured within 4 w high performance liquid chromatography using variant ii hemoglobin testing system bio rad laboratories serum insulin measured electrochemiluminescence immunoassay automatic electrochemiluminescence analyzer cobas e601 roche company serum total cholesterol tc triglyceride tg low density lipoprotein cholesterol ldl high density lipoprotein cholesterol hdl detected enzymatic methods using automatic biochemistry analyzer abbott laboratories on basis fasting glucose insulin levels insulin resistance secretion evaluated using homa method formulas homa ir fasting insulin mu l fasting glucose mmol l)/22.5 -cell function homa- 20 fasting insulin mu l)]/[fasting glucose mmol l 3.5 individuals fasting glucose 3.5 mmol l less excluded analysis the cutoff points ir -cell deficiency homa ir 2.6 homa- 50 respectively 24 32 dyslipidemia defined presence least one abnormal serum lipid tc 5.18 mmol l tg 1.7
mmol l ldl 3.37 mmol l hdl men 1.04 mmol l all data double entered database corrected errors using epi info 6.0 software the statistical analyses performed using sas software version 9.2 sas institute cary nc the differences distributions demographic characteristics among never former current smokers compared unpaired student test continuous variables test categorical variables using never smokers references improve skewness fasting insulin glucose hba1c homa ir homa- logarithmically transformed statistical analyses unadjusted adjusted geometric means adjustment age education level drinking status bmi waist circumference level physical activity hypertension dyslipidemia 95% confidence interval ci calculated general linear model back transformed natural units presentation the associations smoking status ir -cell deficiency evaluated univariate multivariate unconditional logistic regression model adjustment covariates odds ratio 95% ci used estimate strength association dose dependent effect smoking intensity -cell function also analyzed continuous variable using fractional polynomial regression model all statistical tests two sided p 0.05 considered statistically significant the 1,568 chinese men without diabetes study included 598 never smokers 120 former smokers 850 current smokers table 1 there significant difference age current never smokers however former smokers younger never smokers p 0.0430 higher percentages ever drinkers observed current 72.35% former 75.83% smokers compared percentage 55.52% never smokers p 0.0001 moreover current smokers median equivalent combination physical activity 3360 met min wk physically active compared never smokers 2520 met min wk p 0.0063 although subjects hypertension dyslipidemia current smokers participants higher level education bmi waist circumference former smokers differences statistically significant there statistical difference fasting glucose however levels 2 h glucose ogtt significantly higher current smokers never smokers p 0.0493 table 2 compared never smokers current smokers significantly decreased fasting insulin adjustment covariates p 0.0335 the adjusted means 95% ci homa- 54.86 52.1057.78 current smokers 58.81 55.5762.24 never smokers p 0.0257 no significant difference hba1c homa ir observed comparing current former smoker never smokers shown table 3 57.42% current smokers homa- value less 50 current smoking associated -cell deficiency 1.23 95% ci 1.001.52 compared never smoking the association still statistically significant 1.29 95% ci 1.011.64 adjustment age education level drinking status bmi waist circumference level physical activity hypertension dyslipidemia no association observed former smoking -cell deficiency well smoking status homa ir the strength association -cell deficiency analyzed categorizing current smokers according pack year smoking using never smokers references a dose dependent effect smoking intensity observed associated impaired -cell function however homa ir the -cell function gradually decreased increasing smoking intensity ptrend 0.0001 0.0026 adjustment covariates differences statistically significant pack year smoking 20 figure 1 to evaluate observed association smoking intensity -cell function dynamic manner analyzed dose dependent effect smoking intensity continuous variable -cell deficiency using fractional polynomial regression model a significant linear trend increasing ors along increasing smoking intensity observed figure 2 ptrend 0.0001 consistent results logistic regression analysis smoking intensity categorical variable in addition fasting glucose increased cumulative intensity smoking adjusted means 95% ci 5.65 5.565.74 5.58 5.445.73 p 0.3857 5.55 5.425.69 p 0.1806 5.72 5.595.86 p 0.3271 5.78 5.665.91 p 0.0384 respectively never smokers current smokers pack year smoking 10 10~ 20~ 30 ptrend 0.2177 in population based study evaluated associations chronic smoking ir -cell function chinese men without diabetes our results showed current smoking associated decreased -cell function dose dependent manner levels 2 h glucose significantly higher current smokers never smokers the metabolic effects smoking generally studied persons without diabetes order avoid impacts medications changed behaviors patients diabetes ir -cell function usually determined hyperinsulinemic euglycemic clamp hyperglycemic clamp using euglycemic clamp technique eliasson et al 14 33 observed ir middle aged men chronically smoke normalization eight weeks smoking cessation however insulin resistance atherosclerosis study smoking associated ir assessed modified glucose tolerance test minimal model analysis although referred gold standard tests clamps complex stress tests insulin glucose concentrations flux well outside normal range moreover clamp techniques suitable applied studies relatively small numbers subjects alternately homa method assessing ir -cell function basal glucose insulin concentration correlates well estimates using methods including clamps appropriate use large epidemiological studies the relationship glucose insulin basal state reflects balance hepatic glucose output insulin secretion maintained feedback loop liver -cells but recent studies using homa method reported inconsistent effects smoking caucasians high -cell values ir normoglycaemic persons lower -cell function men without hypertension diabetes association men without diabetes the study ko et al chinese men without diabetes showed statistical difference homa ir homa- observed among current former never smokers but study smokers merely accounted 22.53% 178 790 subjects without diabetes men newly diagnosed impaired glucose tolerance igt excluded our study including 1,568 men without diabetes found impaired -cell secretion current smokers signified low values homa- fasting insulin the inconsistency among studies using homa method may attributable differences study design subject recruit ethnic origin gender stratification involved covariates sample size animal experiments showed prenatal postnatal exposure nicotine could directly induce imbalance metabolic control the studies using rodent models demonstrated nicotine exposure could cause -cell dysfunction elevated pancreatic -cell apoptosis loss -cell mass mediated via mitochondrial and/or death receptor pathway smoking cessation could possibly reverse unfavorable effects nicotine recent study stadler et al
reported smoking cessation associated metabolic changes including increased -cell secretion response glucose all findings provided consistent evidence biological plausibility decreased insulin secretion smokers especially heavy smokers study dynamic evaluation -cell function using ogtt test also found higher levels 2 h glucose current smokers may attributed long term effects nicotine exposure may acute stress due nicotine withdrawal either acute chronic nicotine exposure reported negatively affect insulin action smokers preceded type 2 dm long term use nicotine containing chewing gum nonsmoking men associated ir hyperinsulinemia however association observed smoking homa ir current study it noteworthy homa ir based fasting insulin glucose measurements determine whole body ir primarily reflects hepatic central insulin sensitivity rather impaired glucose uptake consumption skeletal muscle adipose tissue peripheral thus limiting ability assess ir especially individuals igt 4043 it suggested insulin responses ogtt may better surrogate measure ir particularly occurred peripheral insulin sensitive tissues muscle 42 44 45 also pointed none surrogate estimates insulin sensitivity study superior simple measurement fasting plasma insulin concentrations predicting insulin sensitivity study increased 2 h plasma glucose ogtt test indicated probably insulin resistance current smokers in present study based national survey subjects recruited using random sampling methods representative physical activities investigated using standard questionnaires evaluated metabolic equivalent minutes per week first detected 2 h plasma glucose administration standard glucose solution area curve important dynamic measurement could calculated compared study second due former smokers available analyze -cell dysfunction smokers would return normal smoking cessation third study lacked information major confounders socioeconomic factors psychosocial stress dietary patterns fourth participants study chinese men restricted generalization results ethnicities gender last cross sectional design could provide causal relationship smoking -cell deficiency therefore large scale prospective studies warranted confirm findings conclusion our study suggested chronic smoking impaired insulin secretion probably brought insulin resistance chinese men without diabetes taking consideration increased risk development type 2 dm related -cell dysfunction current smokers tobacco control considered urgent immediate priority china especially chinese men | the aim of this study was to evaluate the associations between chronic smoking and insulin resistance and -cell function in chinese men without diabetes .
a total of 1,568 participants were recruited by multistage sampling .
using homeostatic model assessment ( homa ) , geometric means of insulin resistance ( homa - ir ) and -cell function ( homa- ) with 95% confidence interval ( ci ) were calculated by general linear model .
odds ratios ( ors ) with 95% ci were estimated to evaluate the associations between smoking status and insulin resistance and -cell deficiency under a logistic regression model .
current smokers had higher levels of 2 h glucose ( 6.66 versus 6.48 mmol / l ) for oral glucose tolerance test and lower levels of fasting insulin ( 5.68 versus 6.03
mu / l ) than never smokers .
the adjusted means for homa- ( % ) were 54.86 in current smokers and 58.81 in never smokers ( p = 0.0257 ) .
current smoking was associated with -cell deficiency ( or 1.29 , 95% ci 1.011.64 ) compared to never smoking .
the -cell function gradually decreased with increasing smoking intensity ( ptrend = 0.0026 ) , and the differences were statistically significant when the pack - year of smoking was 20 or above .
no association was observed between smoking status and homa - ir .
our study suggested that chronic smoking may dose - dependently suppress insulin secretion in chinese men . |
stool sample obtained healthy 2-year old boy living senegal the stool sent frozen marseille 80c laboratory culture isolation strain sit12 isolated may 2015 cultivation marine medium anaerobic atmosphere 21 days incubation growth strain tested anaerobic microaerophilic conditions using genbag anaer genbag microaer systems respectively biomrieux marcy ltoile france presence air without 5% co2 growth achieved anaerobic conditions m. massiliensis grew mesophilic temperatures 25 42c 48 hours incubation columbia agar 5% sheep blood chocolate agar mller hinton agar growth occurred ph 6 6.5 7 8.5 exhibited tolerance nacl concentration 5
gram staining electron microscopy m. massiliensis performed using technaig cryo fei company limeil brevannes france operating voltage 200 kev the cells coccus morphology 0.5 diameter occurred pairs short chains fig 2 the sporulation test performed using thermic shock 80c 30 minutes free spores observed viable cells could recovered sporulating cultures api zym api 50 ch biomrieux gallery systems used perform biochemical assays distinguishing results biochemical tests m. massiliensis sit 12 murdochiella asaccharolitica listed table 1 the antibiotic susceptibility studied using antibiotics discs i2a montpellier france murdochiella massiliensis sit12 resistant fosfomycin tobramycin naxidic acid colistin susceptible gentamicin ciprofloxacin trimethoprim
sulfamethoxazole teicoplanin rifampicin ceftazidime erythromycin imipenem tazocillin aztreonam using 16s rrna phylogeny analyses demonstrated strain sit12 exhibited 97% 16s rrna sequence identity murdochiella asaccharolytica eu483153 levyella massiliensis hm587324 species fig
investigation closely related described species revealed novel species strain member phylum firmicutes the major fatty acids strain sit12 mainly composed 16 18 carbons 16:0 34% 18:1n9 28% 18:2n6 19% 18:0 12% moreover several fatty acids described unusual longer chains 20:4n6 20:5n3 22:6n3 1% table 2 the sit12 spectra imported maldi biotyper 3.0 software bruker daltonics leipzig germany analysed standard pattern matching default parameter settings 7765 spectra bacteria a maximum 100 peaks compared spectra database every spectrum the resulting score enabled identification tested species score 2 validly published species enabled identification species level score 1.7 2 enabled identification genus level score 1.7 enable identification no significant maldi tof ms score obtained strain sit12 bruker database suggesting isolate member known species genomic dna m. massiliensis sequenced miseq technology illumina san diego ca usa mate pair strategy automated cluster generation sequencing run performed single 39-hour run 2 151 bp read length total information 2.9 gb obtained 297k mm cluster density cluster passing quality control filters 97% 5 808 000 passing filter paired reads within run the 440 495 paired reads trimmed assembled two scaffolds using spades assembler open reading frames orfs predicted using prodigal default parameters predicted orfs excluded spanned sequencing gap region the trnascanse tool used find trna genes whereas ribosomal rnas found using rnammer of 1478 predicted genes 1426 protein coding genes 52 rnas two genes 5s rrna two 16s rrna one 23s rrna 47 trna total 1002 genes 70.27% assigned putative function cogs nr blast the resistome analysed argannot antibiotic resistance gene annotation database the exhaustive bacteriocin database available laboratories bacteriocins urmite database performed collecting currently available sequences databases national center biotechnology information protein sequences database allowed putative bacteriocins human gut microbiota identified using blastp methodology analysis presence polyketide synthases nonribosomal peptide synthetases pks nrps performed discriminating gene large size using database realized laboratory predicted proteins compared nonredundant genbank database using blastp examined using antismash murdochiella massiliensis contain bacteriocins nrps analysis resistome showed resistance genes the results indicated presence incomplete phage 48.2% g+c content complete phage 49.5% g+c content fig
the draft gene sequence m. massiliensis smaller anaerococcus hydrogenalis peptoniphilus indolicus parvimonas micra helcococcus kunzii 1642 1889 2238 1704 2096 mb respectively larger helcococcus sueciensis 1574 mb the g+c content m. massiliensis larger a. hydrogenalis p. indolicus h. sueciensis p. micra h. kunzii 48.97 29.64 31.69 28.4 28.66 29.35% respectively the gene content m. massiliensis smaller a. hydrogenalis h. sueciensis p. micra h. kunzii 1.426 2.069 2.269 1.445 1.678 1.882 respectively on basis taxonogenomic analyses formally propose creation murdochiella massiliensis sp nov contains strain sit12 the murdochiella massiliensis name come massilia ancient roman name marseille france type strain isolated the strain anaerobic gram positive non endospore forming nonmotile coccus shaped the genome 1 642 295 bp long g+c content 48.9% the 16s rrna gene sequence whole genome shotgun sequence m. massiliensis strain sit12 deposited genbank accession numbers ln866998 fizw00000000.1 respectively the type strain sit12 (= csur p1987 dsm 29078 isolated stool healthy 2-year old senegalese boy | murdochiella massiliensis strain sit12 (= csur p1987 = dsm 29078 ) is the type strain of m. massiliensis sp .
nov .
this bacterium was isolated from the stool of a healthy 2-year - old senegalese boy .
m. massiliensis is an anaerobic , gram - positive coccus .
the genome size of m. massiliensis strain sit12 is 1 642 295 bp with 48.9% g+c content and assembled into two scaffolds . |
posterior vitreous detachment pvd common phenomenon frequently related aging ocular structures the presence persistent vitreomacular adhesions exerting tractional forces vitreomacular traction vmt may associated development macular hole mh 2 3 these alterations symptomatic phase may cause visual disturbances including photopsia metamorphopsia blurred vision decreased visual acuity addition causing visual related problems may affect negatively patient health related quality life the introduction optical coherence tomography oct allowed accurate visualization macular anatomy better knowledge pathophysiology process including measurement assessment mh characteristics 57 facilitating treatment decision making the vitreous gel responsible stabilization eyeball collagen fibers mainly type ii collagen collagen fibers running anteroposterior direction vitreous center convering anterior vitreous base inserting posterior vitreous cortex spaces collagen fibrils maintained protein opticin glycosaminoglycan chondroitin sulphate spaces collagen fibrils mostly filled water 98% vitreous gel component hyaluronic acid provides gel like consistency vitreous the vitreoretinal interface complex anatomical structure composed union retina vitreous densely packed collagen fibrils posterior vitreous cortex 100300 thickness lie macula superficially inserted internal limiting membrane ilm retina means adhesion molecules laminin fibronectin proteoglycans interact opticin vitreous gel adherences firmly attached retina vitreous base optic disc fovea well along major retinal blood vessels the vitreomacular junction annular shape diameter 3 4 mm the set events occur eye ages associated series physiological changes vitreous gel progressive liquefaction age 80 around 50% vitreous gel liquefied gradual destruction collagen hyaluronic acid network this occurs result development fluid filled pockets beginning front macula time coalesce enlarge resulting weakened adhesion vitreous retina this gradually predisposes pvd defined separation posterior cortex ilm retina represents final step normal vitreous aging process 11 12 pvd insidious process occurs course months years asymptomatic many cases complete separation vitreous macula optic nerve final stage however anterior attachment vitreous base strong remains long time acute symptoms complete pvd include photopsia vitreous traction peripheral retina floaters condensation vitreous collagen glial tissue blood around optic nerve studies healthy adults shown focal perifoveal pvd occurs 50% subjects aged 30 39 whereas complete pvd found 50% subjects aged 70 years older 13 14 in addition advanced age pvd frequent postmenopausal women effects decreased estrogens connective tissue within vitreous gel well presence myopia the normal process pvd due vitreous aging may complicated presence vitreomacular adhesions cortex macular area resulting vitreous syneresis these adherences may focal extensive affecting foveola wide region macular area optic disc simple vitreomacular adhesion vma associated distortion macular architecture however adherences may exert traction forces macula vmt increasing secondarily ocular saccades this may cause retinal distortion foveal detachment hand continuous anteroposterior traction vitreous contraction may cause alterations cystoid macular edema full thickness mh anatomic defect fovea interruption neural retinal layers use high resolution oct shown idiopathic mhs initiated perifoveal pvd consequence dynamic anteroposterior vmt process this anteroposterior vmt may cause intraretinal cavitation progression dehiscence outer retinal layers complete detachment cyst roof giving rise full thickness defect stages development mh focal vmt complete aperture together accompanying symptoms described gass 18 19 the introduction enzymatic vitreolysis result liberation vmt opens highly interesting new perspectives field a studies specifically addressed epidemiology idiopathic vmt due overlapping condition ophthalmological diseases a prevalence isolated idiopathic vmt without mh estimated approximately 22.5 cases per 100 000 general population incidence 0.6/100 000 persons year different observational intervention studies the mean age patients vmt around 6570 years range 4864 predominance females 4 15 regarding prevalence mh reported around 0.1 0.8 adults aged 40 years age adjusted incidence 7.8 cases per 100 000 general population per year also risk development mh fellow eyes without manifestations pvd estimated around 712% 5 years 17% 20 years approximately two thirds patients mh women disease unilateral 80% cases an increase serum fibrinogen level reported risk factor mh whereas use estrogen replacement therapy women decreases risk subjects myopia now nearly two decades since introduction oct possible assess define pathologic progression disorders affecting vitreoretinal interface high level accuracy reproducibility on basis oct derived anatomic findings unified classification scheme disease vitreomacular interface developed purpose a group experts diseases vitreoretinal interface international vitreomacular traction study group ivts proposed classification system diseases vitreomacular interface this evidence based classification clinically applicable system predictive therapeutic outcomes useful execution comparative analysis clinical studies vma represents specific stage partial vitreous detachment perifoveal area without retinal abnormalities previous classifications vma equivalent stage 1 pvd 11 15 27 28 vma characterized elevation cortical vitreous retinal surface vitreous remaining attached within 3 mm radius fovea defined arbitrarily the angle vitreous inner retinal surface acute retina displays abnormalities contour morphological features oct vma accompanied visual impairment may considered normal finding natural course pvd also vma may subclassified size adhesion focal 1500 broad 1500 the cutoff 1500 corresponds area increased vitreous adhesion fovea vma usually resolves spontaneously part normal process pvd although may progress vmt reason periodic monitoring oct necessary macular traction due progression pvd causes anatomic changes contour foveal surface intraretinal pseudocyst formation disappearance foveolar depression typically results reduced distorted vision the following anatomic criteria present least one oct image classify eye vmt evidence perifoveal vitreous cortex detachment retinal surface b attachment vitreous cortex macula within 3 mm radius fovea c association attachment distortion foveal surface intraretinal structural changes foveal detachment retinal pigment epithelium rpe combination findings without full thickness interruption retinal layers vmt also subclassified focal broad using cutoff 1500 depending width vitreous attachment distortion foveal profile formation intraretinal cysts intraretinal cavitation subretinal fluid even rpe detachment observed hand proliferation residual vitreous tissue provides anatomic substrate form epiretinal membrane erm turn may appear stage vitreous separation although spontaneous resolution vmt may occur traction large surface presence erm poor prognostic factor symptomatic patients enzymatic vitreolysis vitrectomy may indicated stated above full thickness mh anatomic defect fovea featuring interruption neural retinal layers the observation anatomic opening several scans fovea unequivocal sign according aperture size mhs are considered small 250 medium 250 400 large diameter 400 also basis oct findings mh categorized according presence absence vmt only patients mh concomitant vmt candidates pharmacologic vitreolysis correlations mh stages commonly used clinical practice oct based images proposed ivts group shown table 1 primary mh results vitreous traction fovea anomalous pvd incomplete inadequate separation vitreoretinal interface whereas secondary mhs caused pathologic conditions preexisting concurrent vmt secondary mhs reported cases blunt ocular trauma lightning strike high myopia 25 31 macular schisis macular telangiectasia type 2 occlusion central retinal vein diabetic macular edema uveitis age related macular degeneration the availability oct particularly spectral domain oct sd oct allowed accurate diagnosis precise assessment adhesion vitreous macula differentiating vma vmt introduction oct only patients advanced vma could diagnosed biomicroscopy reason rates spontaneous deterioration reported high 64% studies using sd oct shown incomplete vitreous detachment persistent vitreoretinal adhesions frequently observed clinical diagnosis physiological process pvd the vitreous remains attached foveal region last stages figure 1 vma considered normal stage natural history pvd associated vitreous aging 13 26 only symptoms present foveal anatomic changes observed vma considered pathological process recently john et al investigated spontaneous clinical course 106 eyes 81 patients identified vma sd oct classified three grades mean follow 18 months range 1 91 the authors defined three grades classify adherence grade 1 41% incomplete cortical vitreous separation attachment fovea grade 2 52% grade 1 findings intraretinal cysts grade 3 7% grade 2 findings presence subretinal fluid last follow spontaneous release vma occurred 32% cases 34 eyes 30% 30% 57% grades 1 2 3 resp no changes observed 23 31 2 eyes 52% total progression occurred 7 8 1 eye grades 1 2 3 respectively 16% total the authors conclude clinical course patients vma managed initial observation generally favourable asymptomatic patients minimal symptoms vmt studying retinal surface sd oct observed pvd appears begin perifoveal region slow clinical course taking even years complete separation vitreous papilla figure 2 patients this process asymptomatic cases pvd may complicated macular pathology oct study eyes macular edema secondary vmt published 2012 complete spontaneous resolution traction the clinical course vma particularly asymptomatic patients remains fully elucidated systematic examination sd oct associated increase diagnostic rates allowed assessing accurately course physiological process may evolve vmt remain stable resolve spontaneously therefore presence vma syndrome first approach reexamine patients using oct period 3 months even cases evolution vmt syndrome observation still remains option given possibility spontaneous resolution vmt ocriplasmin truncated form human plasmin induces liquefaction vitreous separation vitreous cortex retinal surface due proteolytic activity main components vitreomacular adhesion the efficacy safety ocriplasmin evaluated two pivotal phase 3 clinical trials tg mv-006 tg mv-007 carried united states europe both studies similar except ratio randomized assignments ocriplasmin placebo 2 1 tg mv-006 study 3 1 tg mv-007 overall 652 patients randomized 464 assigned treatment single intravitreal injection ocriplasmin 125 g 188 placebo intravitreal injection the primary endpoint pharmacologic resolution vma day 28 determined oct secondary endpoints included percentage patients complete pvd nonsurgical closure full thickness mh day 28 eligible patients symptomatic focal vma seen oct best corrected visual acuity 20/25 less exclusion criteria high myopia 8 diopters axial length 26 mm prior vitrectomy prior laser photocoagulation macula eye diseases may affect visual acuity patients mh 400 diameter also excluded note the presence erm criterion exclusion day 28 vma resolved 26.5% ocriplasmin injected eyes 10.1% placebo injected eyes p 0.001 the group differences change substantially 6 months 26.9% ocriplasmin versus 13.3% placebo p 0.001 also 72% patients resolution vma showed release first seven days results adhesion release better patients without erm 37.4% ocriplasmin group versus 14.3% placebo group p 0.001 regard secondary variables day 28 13.4% patients treated ocriplasmin showed total pvd compared 3.7% treated placebo p 0.001 also nonsurgical closure full thickness mh achieved 40.6% ocriplasmin treated patients 10.6% placebo treated patients p 0.001 according investigator criteria all patients could treated vitrectomy framework study macular disease resolve 6 months vitrectomy performed 17.7% patients ocriplasmin group 26.6% placebo group p 0.02 6 months statistically significant differences favour ocriplasmin gain two lines 23.7% versus 11.2% p < 0.001 three lines 12.3% versus 6.4% p 0.02 most adverse events related development pvd induced ocriplasmin injection floaters photopsia there slightly higher incidence retinal tears detachments placebo group attributed higher proportion patients treated means vitrectomy group the favourable results obtained clinical trials allowed approval use intravitreal injection ocriplasmin treatment symptomatic vmt mh food drug administration fda united states november 2012 european medicines agency ema may 2013 outside context clinical trials recent reports provided data use ocriplasmin daily practice retrospective study 17 patients symptomatic vmt treated single intravitreal injection ocriplasmin 0.125 mg day 28 resolution vmt verified sdoct eight patients 47.1% 7 87.5% already experienced release day 7 those traction release showed statistically significant change vma diameter four five patients 80% mh baseline experienced resolution mh injection significant differences visual acuity observed 20/49 baseline 20/46 final follow noted patients meeting four positive predictor criteria younger 65 years erm baseline traction 1500 phakic lens status showed response rate 75% three four eyes transient outer segment ellipsoid zone loss documented 7 cases 41.1% subretinal fluid presence following injection noted 5 cases 29.4% another study 19 patients symptomatic vma treated intravitreal ocriplasmin resolution vma results significantly affected lens status adhesion release 53% phakic patients whereas case resolution adhesions observed pseudophakic patients also closure mhs treatment found 3 6 patients 50% visual acuity remains stable slight tendency towards improvement majority cases only one patient showed important loss visual acuity 20/70 20/200 due progression vmt full thickness mh the proportion patients ocular adverse event 68.4% ocriplasmin group 53.5% placebo group p 0.001 the common complications included vitreous floaters ocriplasmin 16.8% versus placebo 7.5% p 0.002 photopsia 11.8% versus 2.7% p < 0.001 blurred vision 8.6% versus 3.2% p 0.01 visual impairment 5.4% versus 1.6% p 0.02 there differences groups terms severe ocular adverse events including development mh 5.2% versus 8.6% retinal detachment 0% versus 1.6% reduced visual acuity 0.6% versus 0.5% however since real world use drug began unfavourable reports visual disturbances ocriplasmin injection including transient profound visual decline raising concerns regarding safety 976 patients receiving ocriplasmin injection clinical trials 9 patients reported experienced acute decrease vision hand motions level within 24 hours injection 8 9 patients in clinical trials ocriplasmin dyschromatopsia electroretinographic erg changes occurred significantly greater number eyes treated ocriplasmin eyes receiving placebo 20 40 freund et al recently reported single case report demonstrating changes seen outer photoreceptor segments sd oct since clinical trials used time domain oct inferior resolution sd oct possible cases may overlooked another study 17 patients included almost patients responded treatment 7/8 ellipsoid zone changes sd oct figure 3 these patients also transient reduction visual acuity demonstrated subretinal fluid release process almost exact time course loss os ellipsoid zone the loss os ellipsoid zone occurred average 5 days injection ocriplasmin mean time resolution oct 29.3 days the occurrence resolution subretinal fluid occurred average 4.8 days 30 days injection respectively however retrospective review 62 eyes symptomatic vma treated ocriplasmin subretinal fluid appeared 37% cases persistence fluid 30% cases 5 months follow other studies also shown resolution ellipsoid zone changes patients within weeks months ocriplasmin injection 43 44 alteration ellipsoid zone sd oct significant decrease erg amplitudes also reported two patients release symptomatic vmt ocriplasmin injection 45 46 it possible transient effect medication may due diffuse enzymatic effect protease photoreceptors retinal pigment epithelium throughout retina the greater reduction scotopic function compared photopic function suggests rod photoreceptors may susceptible cone photoreceptors effects ocriplasmin if transient affect occurs rods cones may explain dyschromatopsia contrast sensitivity changes dark adaptation issues erg changes reported ocriplasmin clinical trials an ongoing phase 3b 24-month randomized clinical trial evaluate erg microperimetry ocriplasmin treated eyes compared sham provide additional clarifications observed egr changes dyschromatopsia events oasis study ntc01429441 already reported surgery idiopathic mh ilm peeling safe procedure good anatomic functional results scarce postoperative complications data provided clinical trials shown peeling ilm significantly increases mh closure rates also associated significantly lower percentages reoperation reopening therefore ilm peeling cost effective technique procedure choice patients idiopathic full thickness mh susceptible undergo surgical treatment 4853 broad ilm peeling vascular arcades recommended tangential traction forces mh edges removed facilitating approximation closure cases large mh ( > 400 increased risk failure primary surgery alternative techniques proposed inverted ilm flap technique instead completely removing ilm remnant attached margins mh left place this ilm remnant inverted upside cover mh use technique closure rates 98% compared 88% standard technique achieved for refractory mh standard technique secondary mh vitrectomy peeling ilm already performed autologous transplantation ilm remnants introduced hole subsequent gas tamponade contributes improvement anatomic visual outcomes vital dyes become effective useful tools identifying ocular tissues vitrectomy thereby facilitating ilm peeling ensuring complete removal delicate membrane the frequently used vital dyes include triamcinolone acetonide suspension balanced salt solution bss triesence indocyanine green infracyanine green brilliant blue trypan blue brilliant blue membrane blue dual triamcinolone suspension bss true dye useful identification vitreous remnants posterior hyaloid deposition crystals ilm surface helps achievement complete removal membrane although less effective vital dyes triamcinolone increase rigidity ilm indocyanine green infracyanine green possess great affinity matrix components ilm produce intense staining ilm besides ability indocyanine infracyanine green stain ilm cause increase biomechanical stiffness ilm thereby facilitating peeling although europe longer used potential toxicity continue used united states 58 59 brilliant blue remarkable affinity ilm although ilm staining less intense achieved indocyanine green causes adequate staining ilm may used without fluid air exchange europe the combination trypan blue brilliant blue allows staining erm posterior hyaloid ilm simultaneously this combination lower density water bss circumvents need fluid air exchange there controversy regarding posturing mh surgery although authors recommend face posturing 90% time 10 days different studies reported successful hole closure absence face positioning given isolation macula gas tamponade maintaining macula dried seems important factor closure 6163 respect oct studies shown hole closure occurs first postoperative day independently types gas tamponade posturing vitrectomy wide ilm peeling gas tamponade would sufficient preferably short acting gases sf6 nonexpansible concentration without need face posturing avoiding prone position 3 5 days this approach may also indicated phakic patients seem increase incidence cataracts combined phacovitrectomy sequential vitrectomy phacoemulsification safe effective treatment mh equivalent anatomic functional results cases idiopathic mh affects patients older 50 years degree lens opacity frequent moreover cataract develops 75% 95% patients undergoing vitrectomy mh within 3 years surgery reason both cost discomfort lower single surgical procedure functional recovery rapid combined phacovitrectomy may also decrease risk reopening cataract extraction two step surgical approach 66 67 however combined vitrectomy phacoemulsification intraocular lens iol implantation may associated complications including high degree postoperative anterior chamber inflammation higher risk iol dislocation papillary capture generally result excess gas tamponade and/or poor compliance positioning therefore decision combined versus two step procedure individualized according characteristics case patient surgeon preferences study moorfields macular hole mmhs group overall closure rate 81% 2 years achieved mhs stages 2 3 4 well improvement visual acuity 6/36 6/18 clearly superior results obtained observation group vitrectomy treatment macular hole study vmhs the rate anatomic closure 69% final visual acuity higher operated nonoperated eyes 20/115 versus 20/166 once peeling ilm become popular closure rates 90% 100% reported 7175 however use indocyanine green associated potential toxicity cases reason trypan blue brilliant blue widespread use countries closure rates 94% 100% without apparent severe side effects 7780 despite clear indication safety mh surgery ilm peeling traumatic procedure acute effects underlying retinal nerve fiber layer ilm peeling often results temporary swelling arcuate nerve fiber layer sanfl may earliest manifestation dissociated nerve fiber layer donfl occurs later postoperative period however probably transient feature affect visual recovery although peeling ilm widely adopted mh surgery high percentages hole closure obtained years prior systematic ilm peeling add uncertainty whether use cases recently spiteri cornish et al 81 82 carried systematic review meta analysis assess success hm surgery ilm peeling compared nonpeeling technique four randomized clinical trials comparing techniques identified 48 49 51 81 82 there evidence difference primary outcome distance visual acuity six months distance visual acuity 12 months randomized groups overall 66.2% achieved visual acuity equal greater 69 letters etdrs charts corresponding snellen visual acuity 20/40 77.9% gained three etdrs lines improvement visual acuity higher patients primary anatomic closure achieved final visual acuity 72.8 7.6 letters mean improvement 21.6 7.1 letters eyes surgery required 66.4 8.6 17.4 7.7 letters resp however visual improvement obtained somewhat earlier ilm peeling group 3 months improvement greater ilm peeling performed in addition percentage primary closure higher ilm peeling compared peeling 89.9% versus 50.3% odds ratio 9.27 95% confidence interval ci 4.9817.24 when reoperations excluded analysis ilm peeling group continued favourable results 3.99 95% ci 1.639.75 also mh stage 2 efficacy rate better ilm peeling peeling 91.6% versus 61.3% 6.19 95% ci 1.6523.20 48 49 83 this higher success rate accompanied increase perioperative complications neither reports ilm stained indocyanine green meta analysis the rate intraoperative complications 19.32% ilm peeling group compared 21.1% nonpeeling group 0.94 95% ci 0.471.87 the frequent intraoperative complications small retinal hemorrhage 619% retinal tears 5.432% retinal detachment 26% choroidal hemorrhage 03% according data the authors conclude ilm peeling offers favourable cost effectiveness compared peeling mh surgery 81 82 although anatomic closure mh surgery achieved 90% cases sometimes correlate well improvement visual acuity multiple studies using oct assessed hole configuration attempt establish correlation postoperative visual acuity 8491 emphasizing importance changes outer retina defined macular hole index mhi ratio hole height base diameter hole calculated oct transverse images macular area establishing mhi 0.5 correlated better postoperative visual acuity mih 0.5 ruiz moreno et al described diameter hole index dhi ratio minimum hole diameter base diameter showing minimum diameter best preoperative predictive prognostic factor different studies shown direct correlation integrity hyperreflective line os junction photoreceptors postoperative improvement visual acuity study kitaya et al postoperative vision 0.7 correlated good reconstitution os junction however sano et al showed continuous os line reliable prognostic factor early postoperative period given abnormalities os line seen sd oct gradually repaired achievement continuous os line 6 months spaide curcio assessed correlation outer retina analyzed means sd oct histopathological findings showing hyperreflective line identified os junction photoreceptors corresponded ellipsoid portion photoreceptor inner segment containing mitochondria wakabayashi et al using sd oct described reconstitution external limiting membrane elm important predict subsequent restoration foveal photoreceptor layer ellipsoid zone restoration restoration elm seems necessary factor reconstitution ellipsoid band subsequent migration photoreceptors complete closure full thickness mh ruiz moreno et al analyzed 164 eyes mh treated vitrectomy ilm peeling showing restoration ellipsoid portion photoreceptor inner segment important prognostic factor visual rehabilitation mh surgery reopening hole figure 4 one best known complications initially successful mh treatment vitreous surgery 67 91101 peeling ilm primary mh surgery one factors mostly related incidence reopening varying 0% 8% eyes ilm peeling 67 9597 2% 16% eyes peeling 67 9395 97 the variable percentages reported studies due part differences length follow higher rates associated prolonged follow periods paques et al reported 9.5% incidence mean follow 2 years whereas scott et al found 12% incidence mean follow 7 years kumagai et al analyzed results surgery series 877 cases mh increasing reopening percentage 28.1% ilm peeling the incidence recurrence 0.39% eyes peeling ilm increasing 7.2% peeling besides peeling statistically significant risk factors reopening myopia 6 diopters intraoperative retinal tears retinal tears treated laser may one factors increase development erm subsequent tangential traction reopening mh no peeling ilm may associated higher risk erm formation 92 93 97 100 yoshida kishi observed presence erm cases reopening hole however kumagai et al report erm none cases hole reopening assessed sd oct relation incidence reopening bilateral mh duker et al
reported bilateral reopening 38% cases christmas et al 59% scott et al 38% kumagai et al 14.9% cataract surgery postoperative period mh surgery involved reopening mh paques et al observed 73% cases hole reopening occurred secondary cataract surgery bhatnagar et al reported presence cystic macular edema secondary cataract surgery sevenfold increase risk reopened holes garca arum et al and sheidow gonder reported cystoid edema combined surgical procedures incidence hole reopening increase secondary cataracts regard treatment persisting mh ilm peeling erm removal performed cases procedures performed initial macular surgery together long acting gas tamponade c3f8 strict face positioning first postoperative days patients when ilm peeling removal erm performed first surgical procedure success reoperation decreases series 30 patients reported d'souza et al initial ilm peel underwent repeat surgery involving vitrectomy enlargement ilm rhexis gas tamponade c3f8 more extensive ilm peeling causing tangential traction due fibrosis dissection margin may contribute anatomic closure the use growth factors platelet derived growth factors stimulus glial progenitor cells may useful ilm adequately peeled figure 5 well use heavy silicone oil patients positioning difficulties based aforementioned data shown schematic representation figure 6 patients vma observed without need intervention cases vmt if patient asymptomatic follow control 3 months may sufficient interval patient advised perform periodic self examinations amsler grid monocular reading tests case symptoms intensity disability assessed there consensus criterion regarding degree vision loss considered significant amenable treatment however tg mv-006 tg mv-007 clinical trials patients visual acuity equal lower 20/25 eligible level visual impairment already considered susceptible treatment also causes may justify decreased visual acuity excluded metamorphopsia clinically significant patient visual loss progression also key factors time adopting interventional therapeutic attitude despite considerations a period observation may option patients spontaneous resolution still possible case deciding active treatment presence associated macular diseases erm should excluded traction 1500 enzymatic vitreolysis ocriplasmin treatment choice presence 1500 traction erm surgical treatment vitrectomy 400 size mvt absence erm enzymatic vitreolysis ocriplasmin recommendable option cases holes > 400 absence evident vmt presence erm vitrectomy first option patients undergoing enzymatic vitreolysis intravitreal injection ocriplasmin evaluated 7 30 days most cases vmt mh resolve within first week treatment also time occurrence potential treatment related complications excluded if resolution vmt and/or hole closure occurred month treatment likelihood success highly improbable vitrectomy performed patients lamellar mh pseudomacular holes traction usually absent also candidates enzymatic vitreolysis cases vmt associated retinal diseases age related macular degeneration diabetic macular edema vitreomacular interface pathology myope still early make recommendation impact enzymatic vitreolysis ocriplasmin treatment conditions await results ongoing clinical trials topic finally cases final decision regarding treatment enzymatic vitreolysis ocriplasmin vitrectomy consensuated patient all cases use ocriplasmin considered first treatment option successfully treated means vitrectomy also may possible patients initially ideal candidates enzymatic vitreolysis may pathologic condition solved treatment ocriplasmin favourable prognostic factors choice vitreolysis identified including young age phakic status difficulties maintain postoperative face posture waiting lists vitrectomy variables also considered enzymatic vitreolysis based intravitreal injection ocriplasmin treatment option proven efficacy adequate safety profile selected patients vmt mh cases vmt treatment ocriplasmin indicated traction 1500 absence concurrent macular diseases erm case mh the hole diameter 400 traction present erm absent when resolution process one month procedure achieved vitrectomy ilm peeling would surgical treatment choice | the paper presents a review of the sequence of events of posterior vitreous detachment ( pvd ) , vitreomacular adhesion ( vma ) , vitreomacular traction ( vmt ) , and macular hole ( mh ) from their pathophysiological aspects , clinical features , diagnostic implications , and current management strategies .
a treatment algorithm to be used in clinical practice in patients with vma , vmt , and mh based on the presence of symptoms , visual acuity , associated epiretinal membrane , and width of the vitreous attachment is presented .
observation , pharmacologic vitreolysis with ocriplasmin , and surgical treatment are positioned as treatment options in the different steps of the therapeutic algorithm , with clear indications of the paths to be followed according to the initial presenting manifestations and the patient 's clinical course . |
hydrocephalus entity embraces variety diseases whose final result enlarged size cerebral ventricular system partially completely among usual classifications the important differ communicating non communicating congenital acquired its prevalence near 11.5% among general population progressively rising populational growth thus representing impressive healthy concern congenital hydrocephalus due myriad causes rate 12/1000 births common finding among pediatric age rekate 2009 the physiopathology hydrocephalus lies dynamics circulation cerebrospinal fluid csf there disturbance either production circulation reabsorption resulting positive balances dilation ventricular system producing abnormal high pressure ventricles walls elevated pressure reflects blocked blood flow lateral ventricle consequent csf stasis hydrocephalus interferes cerebral ventricular system development penn linninger 2009 responses elevated csf pressure marked oxidative changes hydrocephalus reflected way injured neurons metabolize neurotransmitters myelin contrary previously held belief gliosis hydrocephalic brain restricted periventricular white matter gliosis extends cortex peri aqueductal area penn linninger 2009 the neighboring neuropil exhibits notable enlargement extracellular space synaptic plasticity degeneration damage myelinated axons myelination delay the role ischemia oxidative stress increased calcium concentration activation nmda receptors disturbance ion homeostasis discussed relationship fine structural alterations hydrocephalic brain parenchyma castejn 2010 clinical manifestations depend especially time appearance form onset acute subacute chronic general rule acute hydrocephalus produce pronounced symptoms headache vomitus papilledema impaired consciousness leading patient coma death drake 2008 chronic hydrocephalus hand produces skull enlargement spasticity progressive neurological deficits children dementia urinary incontinence gait changes elderly bergsneider et al 2008 ; the treatment usually represented variation diversion procedure consists deviating csf flux acts reducing intracranial pressure restoring periventricular global perfusion bergsneider et al 2008 drake 2008 in children generally performed restore csf dynamics prevent worsening symptoms chronic cases it controls symptoms intracranial pressure interfere cognitive motor functions ishikawa et al 2008 ; thus form onset also great determinant cerebral tissue response leading physical adaptations changing elastance complacency determining chemical biological changes including neuronal plasticity penn linninger 2009 context try settle link notable modifications neurophysiology secondary hydrocephalus ability neuronal tissue reassume reorganize functions toward adaptation computational models small world scale free network might explain clinical resilience various situations friston price 2003 noppeney et al 2004 achard bullmore 2007 van den heuvel et al 2008 small world networks predicts neuronal cells engaged clustered connectivity fewer long range connections friston price 2003 achard et al 2006 thus would shorter path length pair neurons brain regions resulting higher dynamical complexity lower wiring costs resilience tissue insults a scale free network characterized existence small number nodes connections nodes the nodes high connectivity degree referred hub nodes suggested play important role overall network organization friston price 2003 brain resilience may also final result processes redundancy degeneracy pluripotentiality neural systems friston price 2003 noppeney et al 2004 another possible mechanism would local neurogenesis already reported structures basal ganglia preferential distribution sub regions ventral striatum stopczynski et al 2008 neuronal plasticity continuous process central nervous system learn skills remember information structure neuronal networks response environment recover brain spinal cord injuries fundamental tool brain resilience lesions johnston 2009 basic mechanisms involved plasticity include neurogenesis programmed cell death activity dependent synaptic plasticity wojtowicz 2011 clinical examples adaptive neuronal plasticity include reorganization cortical maps fingers response practice playing stringed instrument constraint induced movement therapy improve hemiparesis caused stroke cerebral palsy ewing cobbs et al 2003 ; hydrocephalus congenital acquired represents model brain resilience transient permanent perfusional deficits generate structural and/or functional injuries partially completely compensated remaining cortical areas ewing cobbs et al 2003 much evidence shows brain astounding ability modulate cognitive motor skills acute insults insidious neurodegenerative processes psychological stress even along aging course price friston 2002 meunier et al permanent transient lesions caused strokes tumors head trauma hydrocephalus good models understand compensation process works following focal even broader damage price friston 2002 oliveira et al 2011 john lorber 19151996 british pediatrician recognized work spina bifida ethic issues sheffield university opportunity attending two young children hydrocephalus presenting normal mental development age children evidence cerebral cortex filled csf one children died age 3 months second 12 months later young man macrocephaly referred lorber lewin 1980 although boy iq 126 first class honors degree mathematics virtually brain
thus thought tremendous amount redundancy spare capacity brain these ideas shared scientifical community pediatric conference 1980 later year additionally norman geschwind 19261984 american neurologist boston beth israel hospital known works behavioral neurology also stated certainty capacity reassigning functions following trauma injuries brain represent high level organization cerebral tissue order promote adaptation berker et al 1992 other reports even generate scientifical query past main question seemingly normal brain function remarkable images hydrocephalus congenital malformations lewin 1980 for example scans 44-year old man brain showed fluid filled ventricles leaving little thin sheet actual brain tissue married father two children worked civil servant the man went hospital mild weakness left leg he used shunt inserted head drain away hydrocephalus infant removed 14 intelligence tests showed man iq 75 average score 100 considered mentally retarded disabled either feuillet et al try illustrate scene presenting brain parenchyma normal subject followed brain normal subject impressive hydrocephalus oliveira et al unpublished data equally impressive hydrocephalus patient profound symptoms oliveira et al unpublished data the contrast among normal brain normal adult left brain normal man impressive hydrocephalus oliveira et al unpublished data middle equally impressive hydrocephalus 54-year old man deep cognitive motor impairment since childhood right oliveira et al unpublished data the surprising question patients similar neuroradiological aspects may present different complex neurological impairments motor cognitive some important discussions symptoms hydrocephalic non hydrocephalic patients already reported previous studies 10 sets twins discordant hydrocephalus early life displayed differences quality quantity development verbal versus non verbal cognitive functions birth order hand eye preference berker et al 1992 the differences discordant twins seems indicate systematic changes pre- peri- and/or early postnatal organization development hemispheric function berker et al 1992 ) study considering development five language domains word finding fluency automaticity immediate sentence memory understanding grammar metalinguistic awareness held children adolescents 75 hydrocephalus first year life 50 normal controls dennis et al 1987 the results revealed limited resilience language effects early hydrocephalus dennis et al 1987 in adult hydrocephalus especially idiopathic normal pressure hydrocephalus inph observed recover shunting procedures represents proof brain resilience bergsneider et al 2008 ishikawa et al 2008 ladika gurevitz 2011 a study displayed significant improvements follow demonstrated tests verbal memory well one test psychomotor speed eight 10 patients showed improvement 1 sd least one memory test six 10 patients improved significantly 50% tests administered mcgirt et al 2008 simon et al 2009 patients elected surgery good response execution tap test pre operatory period usually present remarkable recovery cognitive especially motor functions gradually oliveira et al unpublished data report significant reversal neuropsychological test scores increased brain volume increased regional cerebral glucose utilization several brain regions shunting inph simon et al rat models chronic hydrocephalus suggested disturbance postsynaptic integration processes rather axonal conduction synaptic transmission important production neurological deficits seen chronic hydrocephalus kaye et al found impaired hippocampal plasticity tsubokawa et al 1988 recent evidences also hypothesize role played dopamine d2 receptors normal pressure hydrocephalus nph d2 receptor regulation attenuated 1 month shunt surgery nakayama et al 2007 a pet study showed significant increases glucose metabolism cerebral cortical areas surgery micro dialysis study showed postoperative reduction glutamate content cerebral cortex pointing shunting consecutively better regional perfusion reestablish citoarquitecture synthesis dopamine d2 receptors attenuating motor dysfunctions nakayama et al 2007 therefore several examples elicited assign neural plasticity resilience applied hydrocephalic models reassuming concepts basic neurophysiology discussing neural networks integration regeneration neuronal tissue resilience injuries degeneracy resilience probably continuous simultaneous events taking part complex process we forget long large hydrocephalic tumoral traumatic ischemic samples brain resilience recovery also cases specific punctiform lesions sometimes seem high definition image studies causing aggressive impairment neurological function even compatible death clinical experience experimental models have already shown resistance brain tissue injuries acute chronic until summarized pieces individual reports atypical manifestations neurological diseases doubtlessly multicenter investigations needed clarify infinite questions asked neuronal tissue physiology the authors declare research conducted absence commercial financial relationships could construed potential conflict interest | hydrocephalus is an entity which embraces a variety of diseases whose final result is the enlarged size of cerebral ventricular system , partially or completely .
the physiopathology of hydrocephalus lies in the dynamics of circulation of cerebrospinal fluid ( csf ) . the consequent csf stasis in hydrocephalus interferes with cerebral and ventricular system development .
children and adults who sustain congenital or acquired brain injury typically experience a diffuse insult that impacts many areas of the brain .
development and recovery after such injuries reflects both restoration and reorganization of cognitive functions .
classic examples were already reported in literature .
this suggests the presence of biological mechanisms associated with resilient adaptation of brain networks . we will settle a link between the notable modifications to neurophysiology secondary to hydrocephalus and the ability of neuronal tissue to reassume and reorganize its functions
. |
oct emerging medical imaging technology enables cross sectional imaging tissue microstructure situ real time oct achieve 110 resolutions 12 mm penetration depths approaching standard excisional biopsy histopathology without need remove process tissue specimens oct analogous ultrasound imaging except imaging performed measuring echo time delay intensity backscattered light rather sound oct imaging performed fiber optically using delivery devices hand held probes endoscopes catheters laparoscopes needles enable non invasive minimally invasive internal body imaging measurements performed using michelson interferometer low coherence length broadband light source one arm interferometer illuminates light tissue collects backscattered light typically referred sample arm another arm interferometer reference path delay scanned function time typically referred reference arm optical interference light sample reference arms occurs optical delays match within coherence length light source schematics time domain b spectral fourier domain c swept source fourier domain oct systems ( e clinical vascular oct system fiber optic probe lightlab imaging st jude medical inc alternatively oct interference signals detected frequency fourier domain fourier domain oct the reference mirror position fixed echoes light obtained fourier transforming interference spectrum these techniques somewhat analogous fourier transform spectroscopy significant sensitivity speed advantage compared time domain oct measure optical echo signals different depths along entire axial scan simultaneously rather sequentially fourier domain detection enables 10100 folds improvement detection sensitivity speed time domain configuration these advances greatly improve performance oct enabling three dimensional oct 3d oct imaging vivo fourier domain oct performed using two complementary techniques known spectral fourier domain oct swept source fourier domain oct ss oct also known optical frequency domain imaging ofdi spectral fourier domain detection uses spectrometer high speed line scan camera measure interference spectrum parallel see fig
in contrast swept source fourier domain oct uses frequency swept laser light source photodetector measure interference spectrum see fig
three dimensional imaging biological tissue vivo enabled fourier domain oct promises powerful impact disease diagnosis therapy monitoring date many clinical applications using oct demonstrated diverse set medical surgical specialties several commercially available devices received us food drug administration fda clearance sold market imalux corporation fig
1d whose oct system based time domain mechanism endoscopic imaging lightlab imaging part st 1e adapts frequency domain mechanism oct system cardiovascular imaging to image internal organs miniaturized catheter endoscope imaging devices developed intraluminal intravascular imaging other imaging devices laparoscopes needle imaging device developed enable solid organ imaging development devices facilitates translation oct clinical applications allows clinicians use enhanced imaging capabilities technique benefit patients figure 2a shows schematic representative oct catheter endoscope device consisting hollow cable carrying single mode sm optical fiber the beam distal end fiber focused gradient index grin microlens directed perpendicular catheter axis microprism micromirror the beam scanned either circumferentially rotating cable linearly translating cable form cross sectional oct image outer diameter catheter endoscope made small enough image inside human coronary artery see figure 2b jude medical inc combined modified vacuum pumped biopsy needle this modified core needle biopsy device includes addition transparent front window real time oct guidance addition long steel plastic tube oct catheter inserted valve allow linear access oct catheter vacuum pressure tube connection figure 2d depicts custom laparoscopic oct device imaging ovaries patients undergoing oophorectomy ( schematic distal end oct probe b photograph intravascular imaging catheter 0.4 mm diameter ( c schematic modified core needle biopsy device catheter based oct probe figures adapted reference permission photographs modified tip ( photograph custom laparoscopic oct probe imaging human ovary figures adapted reference 21 permission since invention 1991 oct rapidly developed non invasive biomedical imaging modality enables cross sectional visualization tissue microstructures vivo the resolution oct one two orders magnitude higher conventional ultrasound approaching histopathology thereby allowing architectural morphology visualized situ real time oct enables imaging structures biopsy would hazardous impossible promise reduce sampling errors associated excisional biopsy oct translated bench various clinical applications including ophthalmology cardiology gastroenterology dermatology dentistry urology gynecology among others the developed clinical oct applications focusing ophthalmic cardiovascular oncologic imaging application oncology many cancers arise epithelial layers demonstrate disruption normal architectural morphology tissues the resolution imaging field view oct approaching standard biopsy histopathology therefore oct represents potential method optical biopsy tissue situ guide excision biopsy improve sampling accuracy oct shown promises detecting structural alterations associated malignancies including arising breast bladder brain gastrointestinal respiratory reproductive tracts skin larynx oral cavity clinical applications oct ophthalmology cardiology gastroenterology reviewed extensively elsewhere review we focus clinical oct applications urology particularly bladder ureter kidney bladder cancer originates urothelium curable diagnosed treated early high mortality rate advanced stages the problem high recurrence rate resulting lifelong follow possible repeated treatments make bladder cancer one expensive cancers manage currently white light cystoscopy wlc standard initial bladder cancer diagnosis several shortcomings flat carcinoma situ cis difficult visualize oct several optical imaging techniques fluorescence imaging developed better identify characterize bladder lesions beyond possible standard wlc last decade ex vivo vivo studies have conducted ability oct detect bladder cancer resolving changes bladder wall layers urothelium lamina propria muscularis propria and/or corresponding backscattering a 32 patient study showed oct high detection accuracy real time imaging staging bladder cancer adjunct wlc 90% sensitivity 89% specificity tumor confined mucosa 100% sensitivity 90% specificity muscle invasive tumors another clinical study based oct imaging with 24 patients reported overall sensitivity 100% specificity 89% diagnostic accuracy 92% superficial bladder transitional cell carcinoma tcc a 56 patient study showed overall specificity cystoscopic oct 81% comparable voided cytology 88.9% p 0.49 significantly higher wlc 62.5% p 0.02 tcc diagnosis
figure 3 illustrates vivo wlc oct h&e images normal human bladder fig
tcc exhibited enhanced urothelial heterogeneity indicated arrows shown figure 3e furthermore work also demonstrated better tumor margin detection using oct guide transurethral resection tur commonly used non muscle invasive bladder cancer tcc attributes approximately 75% bladder cancer enhance tur cases scar necrosis induced previous tur may make difficult identify residual recurrent tumors wlc figure 4 shows vivo wlc oct h&e images tcc post tur fig
it demonstrated oct image differentiate recurrent tcc scar necrosis fig
cis low diagnostic sensitivity specificity e.g. 3060% routine wlc remains critical clinical problem its oct image showed characteristics including obvious urothelial thickening slightly decreased backscattering urothelium drastically diminished backscattering lamina propria layer fig
finally zagaynova et al evaluated 28 cases oct tur discriminate muscle invasive non muscle invasive tumors sensitivity 100% specificity 77%
figure 3 vivo surface cross sectional oct b e h&e stained histologic images c f normal human bladder c vs papillary tcc f the morphologic details normal bladder u urothelium lp lamina propria upper muscularis clearly delineated oct papillary tcc diminished solid arrows subsurface blood vessels dashed arrows papillary features dashed circle tcc identified oct based increased urothelial heterogeneity dashed line boundary adjacent normal bladder figures captions adapted reference 107 permission in vivo surface cross sectional oct b e h&e stained histologic images c f recurrent tcc post tur bladder tumor c cis f oct differentiation tcc left circle vs scar based low scattering papillary features tcc vs ultrahigh superficial scattering abruptly diminished underlying architecture scar necrotic lesion nonspecific surface image arrows e f blood vessels morphology e.g. lamina propria lp muscularis cis u diminished cis low backscattering identified oct based increased urothelial heterogeneity less distinguishable u lp interface ppv positive predictive value npv negative predictive value number fresh human bladder tissue samples computer aided recognition bladder cancer using oct texture analysis investigation improve clinical utility oct higher oct axial resolution demonstrated ability differentiate healthy urothelial tissue cis tcc 142 fresh human bladder tissue samples reported sensitivity specificity detect malignant bladder 83.8% 78.1% respectively recently real time 3d oct imaging demonstrated 3 clinical cases bladder ureter carcinoma show contrast muscle invasive carcinoma area scar tissue area normal bladder wall ureter three distinguishable layers including urothelium lamina propria muscularis layer one false positives may induced scarring inflammation mucosa the limitation limited field view fov lateral depth directions oct compared high resolution ultrasound i.e. 40 mhz high frequency ultrasound hfus rat bladder cancer model results showed oct could differentiate inflammatory lesions tcc based characterization urothelial thickening enhanced backscattering heterogeneity hfus failed due insufficient image resolution contrast hand hfus able stage large t2 tumors oct failed due limited imaging depth multimodality cystoscopy combining oct hfus combination oct larger lateral fov technique wlc narrow band imaging photodynamic diagnosis may help improve diagnosis staging few oct studies conducted ureter somewhat similar mucosal morphology bladder tissue surface covered urothelial cells early detection ureteral cancer well accurate tumor staging grading also critical reduce mortality disease help making optimal treatment decisions the staging grading urothelial carcinoma ureter challenging narrow caliber makes biopsy difficult unreliable endoscopic oct eoct necessary access layer structures ureteral wall sufficient resolution stage early ureteral cancer several ex vivo studies porcine ureter demonstrated clearly distinguish anatomical layers particularly urothelium lamina propria layers better differentiation ability endoluminal ultrasound reported intraluminal oct identification anatomical layers healthy human ureter vivo results grading staging upper urinary track uut urothelial carcinoma using oct they identified several unique features oct although study enough patients provide information oct sensitivity specificity uut diagnosis their study demonstrated oct 1 distinguish healthy tissues tumors 2 differentiate invasive non invasive tumors 3 differentiate grade 2 3 lesions quantifying oct backscattering attenuation thus potential provide intraoperative real time histological information stage grade minimally invasive procedures figure 5 shows representative oct images healthy ureter identified urothelium lamina propria muscularis layers figure 6 shows representative oct images invasive tumor namely stage t3g3 urothelial carcinoma distinction among anatomical layers possible inset higher magnification reveals normal ureter urothelium pond sign lamina propria asterisk muscularis dollar sign ( b 520-frame volumetric data set across 52 mm trajectory along probe approximately 5.2 resulting 52 mm long 10 mm diameter total scanned cylindrical volume figures captions ( b cross sectional oct images proximal ureter show interruption white asterisk thin dark line white pound sign suggesting invasive tumor distinction among anatomical layers possible corresponding histology reveled t3g3 urothelial carcinoma black arrow ( c 3d pullback oct built 520 individual cross sectional images 5.2 cm length oct studies clinical kidney diseases include applications kidney cancer non destructive evaluation transplant kidney viability acute tubular necrosis atn barwari et al conducted ex vivo study 14 patients vivo study 16 cases they demonstrated capability oct distinguish normal renal parenchyma malignant renal tumors based backscattering properties studies measured higher backscattering property malignant tumors measured surface measured directly internal tumors normal parenchyma the averaged backscattering value three benign tumors reported vivo study value normal malignant tumor show significant difference normal renal parenchyma tumors linehan et al imaged fresh surgical resected tissues normal renal parenchyma neoplasm using laboratory oct system lateral resolution 10 axial resolution 4 however higher resolution oct necessary distinguish clear cell tumors renal carcinoma subtypes normal parenchyma carcinoma subtype heterogeneous appearance oct figure 7 shows oct image corresponding light microscopy renal carcinoma chromophobe subtype top panel papillary subtype grade 4 bottom panel some defining features collections large polygonal cells arranged trabeculae chromophobe renal carcinoma elements cuboidal cells surrounding fibrovascular stalk papillary renal carcinoma clearly evident corresponding oct images figure 7 oct image corresponding light microscopy renal carcinoma chromophobe subtype top panel papillary subtype grade 4 bottom panel chromophobe subtype top panel collections large polygonal cells arranged trabeculae seen areas intermediate brightness intervening dark spaces oct papillary subtype bottom panel elements cuboidal cells surrounding fibrovascular stalk seen light microscopy visible oct image bars 500 figures captions adapted reference 122 permission acute tubular necrosis atn common insult donor kidneys destined transplantation atn caused lack oxygen kidney ischemia kidneys one common causes kidney failure both ex vivo vivo studies demonstrated capability oct visualize kidney parenchyma morphology function i.e. tubular morphology blood flow vessels glomeruli provide information kidney ischemic damage figure 8 shows hand held oct imaging device used operating room fig c figure 8d depicts representative vivo kidney oct images kidney transplant showing cross sectional profiles superficial proximal tubules renal capsules the openness tubule lumens labeled figure 8d reflects functioning post transplanted kidney figure 8e shows combination morphological imaging oct functional imaging doct one patient displayed good tubular morphology blood flow fairly densely packed uriniferous tubules observed several cortical blood vessels indicating perfusion finally video s1 shows combined oct doct real time images living kidney following transplant would seen imaging kidney operation room ( transplant surgeons used sterilized hand held oct probe shown b image transplanted human donor kidney operating room ( c oct imaging probe covered transparent tegaderm small arrow the cords leading probe covered sterile camera sleeve large arrow ( vivo oct imaging human kidneys following transplantation showing open uriniferous tubules renal capsule tubules appear fairly open round degree homogeneity throughout images open tubules appear round relatively uniform across images also larger blood vessel seen oct powerful medical imaging technology reveal microstructure blood flow biological tissues non invasive fashion real time current technology improvements enable 3d oct imaging real time thereby dramatically reducing motion artifacts image acquisition accurate quantification oct doct image essential disease diagnosis decision making in addition higher resolution might also help enhance classification imaging parameters disease diagnosis continued technology development clinical translation oct promises enhance current clinical practice urology | since optical coherence tomography ( oct ) was first demonstrated in 1991 , it has advanced significantly in technical aspects such as imaging speed and resolution , and has been clinically demonstrated in a diverse set of medical and surgical applications , including ophthalmology , cardiology , gastroenterology , dermatology , oncology , among others .
this work reviews current clinical applications in urology , particularly in bladder , urether , and kidney .
clinical applications in bladder and urether mainly focus on cancer detection and staging based on tissue morphology , image contrast , and oct backscattering .
the application in kidney includes kidney cancer detection based on oct backscattering attenuation and non - destructive evaluation of transplant kidney viability or acute tubular necrosis based on both tissue morphology from oct images and function from doppler oct ( doct ) images .
oct holds the promise to positively impact the future clinical practices in urology . |
seventy patients ages 7 months 11 years included 59 84% 5 years age study of one died within 15 min admission two died within first 24 h admission one patient age 2.5 years severe neurologic sequelae 28 days discharge comprising spastic hemiparesis blindness hearing impairment admission this child count 880,205 parasites/l plasma plasmodium falciparum histidine rich protein-2 concentration 1,875 ng ml indicating extremely heavy parasite burden 3-month follow demographic clinical laboratory characteristics study population described table 1 severe prostration severe acidosis convulsions severe anemia common severity criteria eleven patients 16% presented decompensated compensated shock addition three patients 4.3% blood culture proven septicemia unspeciated gram negative rods klebsiella pneumoniae staphylococcus aureus none presented shock pretreatment oral antimalarial reported respect 31 patients 6 quinine 3 amodiaquine 13 sulfadoxine pyrimethamine 8 artemether lumefantrine 1 amodiaquine followed artemether lumefantrine quinine within 24 h preceding admission median range total dose 16.1 mg kg 10.153.7 mg kg hypoglycemia corrected 10% dextrose bolus time admission developed hypoglycemia admission eight patients peripheral blood asexual parasite counts 24 h negative 12/66 18% patients 24-h slide available four patients three result death geometric mean 95% confidence interval ci parasite count 24 h 1,128 5372,368 parasites/l rest study population n 54 the overall geometric mean 95% ci fractional reduction parasite counts 24 h 96% 9498% a total 274 ars dha postdose samples randomly distributed first 12 h study included model a one compartment disposition model ars dha adequate describe observed plasma concentration time data table 2 all combinations two compartment disposition models displayed significant model misspecification despite significantly lower objective function values zero order distribution absorption injection site(s central compartment provided best description data samples collected absorption phase absorption rate therefore fixed accurate estimation interindividual variability could estimated reliably ars dha clearance ars volume distribution showing correlation ars clearance volume when body weight used fixed allometric function elimination clearance power 0.75 apparent volume distribution power 1 parameters significantly better model fit observed objective function value 14.6 dha clearance increased 10.2% per unit g dl decrease hemoglobin interindividual variability clearance decreased 63.6% coefficient variation 55.3% coefficient variation covariate included suggesting accounts limited significant part observed variability the final model described observed data well adequate goodness fit diagnostics figure 1 eta shrinkage elimination clearance ars 10.6% central volume distribution ars 12.2% elimination clearance dha 6.81 epsilon shrinkage 49.4 22.5% ars dha respectively a prediction corrected visual predictive check final model resulted model misspecification good simulation properties figure 2 the numerical predictive check n 2,000 ars resulted 4.35% 95% ci 1.459.42 5.07% 95% ci 1.459.42 observations 90% prediction interval respectively dha values 2.97% 95% ci 1.799.52 5.95% 95% ci 1.798.92 respectively ars dha exposures standard 2.4 mg kg dose simulated body weight level 1,000 simulations 1-kg intervals 6 25 kg using uniform distribution hemoglobin concentrations within observed range 2.7213.6 g dl account observed covariate relationship figure 3a b children body weights 6 10 kg showed mean reduction 20.4% p 0.0001 dha exposure compared children body weights 21 25 kg median 25th 75th percentile exposure 3,380 2,1305,470 ng h ml 610 kg patients 3,780 2,4306,060 ng h ml 1115 kg patients 4,100 2,5706,590 ng h ml 1620 kg patients 4,240 2,7006,840 ng h ml 2125 kg patients this suggests smaller children need higher doses ars attain ars exposures similar children higher body weights using final model evaluated various dosing regimens based body weight bands the proposed regimen table 3 resulted similar exposures weight bands first dose i.m ars figure 3c simulations performed assuming uniform distribution body weights different levels hemoglobin resulted lower dha exposures decreasing hemoglobin levels figure 4 there statistical difference survivors nonsurvivors respect total exposure ars p 0.8060 dha p 0.4828 maximum concentration ars p 0.7655 dha p 0.6865 first dose similarly exposure response relationship could established using nonlinear mixed effects modeling nonmem time event approach however might consequence relatively low number deaths high proportion pretreatments different antimalarial drugs doses administration routes seventy patients ages 7 months 11 years included 59 84% 5 years age study of one died within 15 min admission two died within first 24 h admission one patient age 2.5 years severe neurologic sequelae 28 days discharge comprising spastic hemiparesis blindness hearing impairment admission this child count 880,205 parasites/l plasma plasmodium falciparum histidine rich protein-2 concentration 1,875 ng ml indicating extremely heavy parasite burden 3-month follow demographic clinical laboratory characteristics study population described table 1 severe prostration severe acidosis convulsions severe anemia common severity criteria eleven patients 16% presented decompensated compensated shock addition three patients 4.3% blood culture proven septicemia unspeciated gram negative rods klebsiella pneumoniae staphylococcus aureus none presented shock pretreatment oral antimalarial reported respect 31 patients 6 quinine 3 amodiaquine 13 sulfadoxine pyrimethamine 8 artemether lumefantrine 1 amodiaquine followed artemether lumefantrine quinine within 24 h preceding admission median range total dose 16.1 mg kg 10.153.7 mg kg hypoglycemia corrected 10% dextrose bolus time admission developed hypoglycemia admission eight patients peripheral blood asexual parasite counts 24 h negative 12/66 18% patients 24-h slide available four patients three result death geometric mean 95% confidence interval ci parasite count 24 h 1,128 5372,368 parasites/l rest study population n 54 the overall geometric mean 95% ci fractional reduction parasite counts 24 h 96% 9498% a total 274 ars dha postdose samples randomly distributed first 12 h study included model a one compartment disposition model ars dha adequate describe observed plasma concentration time data table 2 all combinations two compartment disposition models displayed significant model misspecification despite significantly lower objective function values zero order distribution absorption injection site(s central compartment provided best description data samples collected absorption phase absorption rate therefore fixed accurate estimation interindividual variability could estimated reliably ars dha clearance ars volume distribution showing correlation ars clearance volume when body weight used fixed allometric function elimination clearance power 0.75 apparent volume distribution power 1 parameters significantly better model fit observed objective function value 14.6 dha clearance increased 10.2% per unit g dl decrease hemoglobin interindividual variability clearance decreased 63.6% coefficient variation 55.3% coefficient variation covariate included suggesting accounts limited significant part observed variability the final model described observed data well adequate goodness fit diagnostics figure 1 eta shrinkage elimination clearance ars 10.6% central volume distribution ars 12.2% elimination clearance dha 6.81 epsilon shrinkage 49.4 22.5% ars dha respectively a prediction corrected visual predictive check final model resulted model misspecification good simulation properties figure 2 the numerical predictive check n 2,000 ars resulted 4.35% 95% ci 1.459.42 5.07% 95% ci 1.459.42 observations 90% prediction interval respectively dha values 2.97% 95% ci 1.799.52 5.95% 95% ci 1.798.92 respectively ars dha exposures standard 2.4 mg kg dose simulated body weight level 1,000 simulations 1-kg intervals 6 25 kg using uniform distribution hemoglobin concentrations within observed range 2.7213.6 g dl account observed covariate relationship figure 3a b children body weights 6 10 kg showed mean reduction 20.4% p 0.0001 dha exposure compared children body weights 21 25 kg median 25th 75th percentile exposure 3,380 2,1305,470 ng h ml 610 kg patients 3,780 2,4306,060 ng h ml 1115 kg patients 4,100 2,5706,590 ng h ml 1620 kg patients 4,240 2,7006,840 ng h ml 2125 kg patients this suggests smaller children need higher doses ars attain ars exposures similar children higher body weights using final model evaluated various dosing regimens based body weight bands proposed regimen table 3 resulted similar exposures weight bands first dose i.m ars figure 3c the simulations performed assuming uniform distribution body weights different levels hemoglobin resulted lower dha exposures decreasing hemoglobin levels figure 4 there statistical difference survivors nonsurvivors respect total exposure ars p 0.8060 dha p 0.4828 maximum concentration ars p 0.7655 dha p 0.6865 first dose similarly exposure response relationship could established using nonlinear mixed effects modeling nonmem time event approach however might consequence relatively low number deaths high proportion pretreatments different antimalarial drugs doses administration routes optimal treatment strategies depend detailed knowledge pharmacokinetic properties drugs target population drug used age disease status severity factors may affect drug absorption distribution metabolism elimination the importance pharmacokinetics determining therapeutic response illustrated study artemether first parenteral artemisinin derivative compared quinine effectiveness treatment severe malaria large clinical trials meta analysis randomized trials severe malaria artemether significantly reduced mortality southeast asian adults african children subsequent pharmacokinetic studies showed oil based artemether released slowly erratically i.m injection site likely counterbalanced pharmacodynamic advantages relative quinine despite pharmacodynamic properties similar artemether ars superior artemether treatment favorable pharmacokinetic properties dosing regimens children often derived studies adults practice led substantial underdosing several antimalarials children a pharmacokinetic study sulfadoxine pyrimethamine african children uncomplicated falciparum malaria showed usual dose 25/1.25 mg kg area concentration
time curve children 25 years age half adults may caused failure antimalarial treatment small children thereby contributing spread resistance it also shown piperaquine exposure levels lower small children standard body weight based dose regimen followed only limited data available pharmacokinetics parenteral rectal oral ars children ars converted rapidly dha ars elimination half life ~26 min this agreement ars half life values reported pharmacokinetic studies i.m this elimination rate ars limited rate absorption i.m injection site i.e. flip flop pharmacokinetics volume distribution values maximum concentration values area concentration time curves ars dha also comparable findings previous small densely sampled pharmacokinetic study i.m time curve dha study considerably lower reported adult patients healthy volunteers i.v administration still far greater vitro defined dha concentration value 2.28 ng ml required 99% inhibition ic injection ~90% fast absorption comparable estimates ars dha exposure support use i.m our study relatively small number patients thereby limiting power detect covariate relationships parsimonious approach p 0.001 covariate retained model applied order avoid artifactual covariate relationships this also reported population pharmacokinetic studies oral rectal ars pediatric mixed adult pediatric populations general physiological processes scale linearly body weight consequently children lower body weights higher body weight normalized elimination clearance values dosing simulations using exact dose 2.4 mg kg resulted lower ars dha exposures small children compared body weights 25 kg suggesting need higher dosing small children in addition hemoglobin concentration also significant covariate resulting lower dha exposure anemic children severe anemia common presenting feature severe malaria young children severe malarial anemia usually substantial intravascular hemolysis and this also cause degradation ars hemolyzed plasma samples ex vivo hemoglobin concentration found associated reduced exposure levels ars dha independent body weight this supports idea young children severe malaria generally anemic older children receive adjusted higher doses underdosing young children severe malaria may immediate adverse consequences respect outcomes a recent study carried cambodia shown oral ars dose 6 mg kg day 7 days resulted reduction neutrophil counts 1.0 10/l short term neutropenia 19% patients because oral ars bioavailability ~80% corresponds total parenteral dose 33.6 mg kg would reached parenteral treatment continued 14 doses aquamat trial median interquartile range ) number doses parenteral treatment surviving children 3 24 doses ars currently first choice treatment severe malaria product produced according good manufacturing practices prequalified available facilitate implementation optimized dosing regimen treatment severe malaria african children defined simplified weight band based dosing regimen based current population pharmacokinetics model taking account accuracy practicality issues we considered 0.5 ml minimum volume prepared ars solution measured accurately administered commonly available types syringes weight bands smaller children body weights 14 kg propose incremental ars dose increase 5 instead 10 mg dilution 10 mg ml i.m administration group similar dosage regimen current study children body weights 14 kg doses split administered thighs injection volumes exceed 2 ml children body weights 14 kg larger injection volumes avoided using dilution 20 mg ml binning weight bands also chosen accordance currently available vial contains dose 60 mg demarcating upper limits weight bands 25 kg the dosing recommendations propose extend beyond weight ranges children included study no children body weight 6.5 kg included therefore studies ars population pharmacokinetics needed evaluate dosing small children support current dosing recommendations more extensive sampling first 15 min first 12 h dose could give information current study provided conclusion ars dha exposures lower small children i.m administration ars severe malaria warranting dose adaptation group this pharmacokinetic assessment ars part aquamat trial registration number isrctn 50258054 large multinational trial results published elsewhere this substudy conducted teule hospital muheza tanzania may 2009 july 2010 except additional blood sampling ethical approval obtained tanzania medical research coordinating committee oxford tropical research ethics committee children 14 years clinical diagnosis severe malaria confirmed plasmodium lactate dehydrogenase pldh)-based rapid diagnostic test optimal diamed cressier switzerland recruited written informed consent obtained respective parents caregivers severe malaria defined presence least one following coma glasgow coma score 10 blantyre coma score 2 preverbal children convulsions duration 30 min 2 episodes 24 h preceding admission respiratory distress nasal alar flaring costal indrawing recession use accessory muscles severe tachypnea acidotic breathing deep breathing shock capillary refill time 3 sec and/or temperature gradient and/or systolic blood pressure 70 mm hg severe symptomatic anemia 5 g dl respiratory distress hypoglycemia <3 mmol l hemoglobinuria severe jaundice older children convincing history anuria oliguria patients received full treatment parenteral quinine parenteral artemisinin derivative 24 h admission excluded physical examination carried admission venous blood sample taken peripheral blood parasite count quantitative assessment plasma plasmodium falciparum histidine rich protein-2 measure total body parasite burden hiv serology sd bio line hiv 1/2 3.0 standard diagnostics kyonggi korea determine hiv-1/2 abbott laboratories il blood culture liver function tests aspartate aminotransferase alanine transaminase -glutamyltransferase total bilirubin creatinine urea reflotron roche diagnostics basel switzerland hematocrit biochemistry acid base parameters ec8 cartridge stat handheld blood analyzer abbott laboratories abbott park il hematocrit reported stat reading available measured hemocue hemocue ab ngelholm sweden n 5 neurologic examination conducted discharge repeated day 28 children made full neurologic recovery discharge ars guilin pharmaceutical factory guangxi china administered i.m injection 2.4 mg kg shortly admission 12 h 24 h daily thereafter the contents 60 mg vial ars dissolved 1 ml 5% sodium bicarbonate provided drug diluted 5 ml 5% dextrose final concentration 10 mg ml administration deep i.m injection anterolateral thigh dosing based measured body weight patient injection volumes 23 ml split divided two injections one thigh when patient well enough take oral medication minimum 24 h two doses i.m ars full 3-day course oral artemether lumefantrine co artem novartis basel switzerland given complete treatment vital signs glucose monitored least every 6 h also sign deterioration clinical condition a majority patients i.e. able orally fed received infusion dextrose 5% blood transfusion 20 ml kg given children hemoglobin concentrations 5 g dl blood samples 1.5 ml drawn indwelling catheter prechilled fluoride oxalate tubes ars dha quantification first dose baseline four subsequent samples taken patient preset random time points within following time windows 01 14 412 1224 h first dose randomization sampling times done computer generated randomization stata version 12 stata college station tx immediately blood collection blood samples drug measurements centrifuged 4 c 2,000 g 7 min plasma samples 0.5 ml stored 80 c shipped dry ice moru department clinical pharmacology bangkok thailand drug quantification ars drug content quality checked vials taken randomly purchase lots see supplementary data online drug analysis ars dha plasma concentrations measured using liquid chromatography tandem mass spectrometry quality control samples low middle high concentrations analyzed triplicate within analytical batch ensure accuracy precision analysis the lower limit quantification set 1.2 ng ml ars 2.0 ng ml dha venous plasma concentrations transformed molar units modeled natural logarithms using nonmem v.7 icon development solutions ellicott city md ars dha modeled simultaneously using drug metabolite model complete vivo conversion ars dha details see supplementary data online first order conditional estimation method interaction model selection based objective function values computed nonmem goodness fit graphical analysis physiological plausibility a p value 0.05 used forward step p value 0.001 backward step compensate relatively small population studied simulation based diagnostics visual numerical predictive checks bootstrap diagnostics used evaluate performance final model monte carlo simulations using final model observed variability performed different body weights obtain representative population estimates exposure levels first day dosing area concentration
time curve time point 0 12 h prospective dose regimens no drug exposure target defined parenteral ars therefore purpose arriving practical parenteral dosing regimen different body weight bins evaluated ensure similar target exposures weight bands agreement exposure children body weight 25 kg the simulations used evaluate effect significant covariates drug exposure peripheral blood smears taken admission 24 h. reduction parasite load 24 h survival severe neurologic sequelae evaluated part pharmacodynamic analysis the effects ars dha exposures outcomes investigated using time event analysis nonmem predicted drug concentrations used modulate hazard function traditional maximum effect emax relationship | parenteral artesunate ( ars ) is the drug of choice for the treatment of severe malaria .
pharmacokinetics data on intramuscular ars are limited with respect to the main treatment group that carries the highest mortality , namely , critically ill children with severe malaria . a population pharmacokinetic study of ars and dihydroartemisinin ( dha )
was conducted from sparse sampling in 70 tanzanian children of ages 6 months to 11 years .
all the children had been admitted with severe falciparum malaria and were treated with intramuscular ars ( 2.4 mg / kg at 0 , 12 , and 24 h ) .
venous plasma concentration
time profiles were characterized using nonlinear mixed - effects modeling ( nonmem ) .
a one - compartment disposition model accurately described first - dose population pharmacokinetics of ars and dha .
body weight significantly affected clearance and apparent volume of distribution ( p < 0.001 ) , resulting in lower ars and dha exposure levels in smaller children .
an adapted dosing regimen including a practical dosing table per weight band is proposed for young children based on the pharmacokinetic model . |
laparoscopic pyelolithotomy successfully performed pelvic kidney operative time 310 minutes the use intraoperative fluoroscopy semi automatic suturing device greatly facilitated procedure the patient operative pain managed 3 doses ketorolac resumed regular diet day surgery discharged first postoperative day for patients large stone renal pelvis ectopic kidney laparoscopic pyelolithotomy provides effective approach pelvic kidneys typically incidental findings may pre sent due underlying obstructive calculous disease anatomical characteristics ectopic kidney pose significant challenge treatment calculous disease treatment larger renal calculi kidneys uniformly open surgery laparoscopically guided percutaneous nephrostolithotomy pcnl described initially esghi et al later toth et al recently 2 cases laparoscopic pyelolithotomy reported pelvic kidney one due urine leakage indwelling stent urethral catheter maintained 8 days hospitalization lasted 6 days second case report intraoperative fluoroscopy laparoscopic suturing were used perform procedure pyelotomy closure tested watertightness patient experienced peritoneal leakage urine foley catheter removed this necessitated replacement foley catheter unspecified length time length hospitalization reported herein report third case laparoscopic pyelolithotomy pelvic kidney case use carterthomason needle point suture passer inlet medical inc eden prairie mn laparoscopic suturing pyelotomy endostitch device auto suture norwalk ct resulted waterproof closure a 63-year old woman referred endourological treatment symptomatic 2.5-cm x-1.5 cm renal pelvis stone left pelvic kidney intravenous urography ivu abdominal pelvic computed tomography defined pelvic kidney location relative structures mild pyelocaliectasis noted figures 1 2 ivu demonstrating ectopic right kidney left pelvic kidney laminated 2.5 cm stone ureteropelvic junction the patient turned 30-degree lateral left side position 15 mm hg co2 pneumoperitoneum initiated veress needle using lateral inflation technique three 12 mm laparoscopic ports placed left lower quadrant midclavicular line umbilicus right lower quadrant pararectus area holding sutures placed inferiorly superiorly anterior surface renal pelvis using intracorporeal suturing suture delivery skin accomplished via carter thomason needle point suture passer inlet medical inc eden prairie mn 3 cm long pyelotomy made 10 mm biopsy forceps used grasp stone removed intact 12 mm cannula withdrawn port site a running closure renal pelvis accomplished using endostitch device 2 0 polysorb suture auto suture norwalk ct the occlusion balloon catheter changed indwelling 7 f double pigtail stent bladder catheter left place overnight the total operative time 310 minutes including pre- postoperative stent placement abdominal/ pelvic ct scan demonstrating left pelvic kidney mild pyelocaliectasis stone ureteropelvic junction arrow stone initiating general anesthesia a 7 f/ 11.5 mm balloon occlusion catheter passed guidewire renal pelvis left pelvic kidney the balloon inflated 1 cc contrast material snugged ureteropelvic junction postoperatively patient discomfort managed total 45 mg intravenous ketorolac 3 doses followed 2 doses oral narcotic a follow ivu one week later revealed left pelvic kidney functional stone free without extravasation our experience table 1 similar prior reports successful laparoscopic pyelolithotomy large renal calculus pelvic kidney placement retrograde ureteral catheter instrumental allowing expeditious localization renal pelvis laparoscopy testing closure pyelotomy closure renal pelvis facilitated use holding sutures endostitch device comparison laparoscopic pyelolithotomy pcnl renal pelvis stones 1.5 2 cm mac= monitored anesthesia care pcnu= percutaneous nephroureteral stent patient experienced minimal pain brief hospitalization findings consistent previous reports laparoscopic pyelolithotomy normally positioned kidney reports operative time averaged 2 5 hours using 3- 4-port approach the renal pelvis sutured closed one case patients surgical drain placed prior fascial closure stone free rate 100% recorded among 9 patients note 3 9 patients required conversion open procedure reports concluded laparoscopic pyelolithotomy eutopic kidney value situation shock wave lithotripsy swl pcnl failed could done believe represents rare situation indeed despite vast experience washington university laparoscopic renal surgery large surgical stone population e.g. approximate annual urolithiasis case load 500 600 swl 100 150 ureteroscopies 50 100 pcnl singular case laparoscopic pyelolithotomy institution with regard stone treatment ectopic pelvic kidney believe treatment strategy similar used stones eutopic kidney hence swl ureteroscopy remain first line therapy smaller calculi less 2 cm laparoscopic assisted percutaneous pure laparoscopic open procedures reserved larger calculi standpoint note 2 cases laparoscopically guided pcnl reported pelvic kidneys operative time reported cases length hospital stay 6 days one report we believe given advances laparoscopic equipment may simple handle stone removal entirely laparoscopically the benefits approach would potentially include shorter hospital stay less postoperative morbidity occurred present case urologists interested laparoscopic pyelolithotomy situation use intraoperative fluoroscopy identify renal pelvis placement holding sutures use carter thomason needle point suture passer intracorporeal suturing endostitch device recommended | the anatomical characteristics of an ectopic kidney can pose significant challenges to the treatment of calculous disease .
this report examines the feasibility of a laparoscopic approach for management of a large renal calculous in a pelvic kidney and reviews current literature regarding this subject . |
bspp bisulfite padlock probe charm comprehensive high throughput arrays relative methylation cimp cpg island methylator phenotype esc embryonic stem cell fda food drug administration help hpaii tiny fragment enrichment ligation mediated pcr mca methylated cpg island amplification mcam methylated cpg island amplification microarray medip methylated dna immunoprecipitation mira methylated cpg island recovery assay mscc methyl sensitive cut counting pcr polymerase chain reaction rrbs reduced representation bisulfite sequencing the authors supported leukemia specialized program research excellence grant p50 ca100632 | dna methylation of promoter cpg islands is strongly associated with gene silencing and is known as a frequent cause of loss of expression of tumor suppressor genes , as well as other genes involved in tumor formation .
dna methylation of driver genes is very likely outnumbered by the number of methylated passenger genes , though these can be useful as tumor markers .
much of what is known about the importance of dna methylation in cancer was gained through small- and moderate - scale analysis of gene promoters and tumor samples . a much better understanding of the role of dna methylation in cancer , either as a marker of disease or as an active driver of tumorigenesis , will likely be gained from genome - wide studies of this modification in normal and malignant cells .
this goal has become more attainable with the recent introduction of large - scale genome analysis methodologies and these have been modified to allow for investigation of dna methylation .
several research groups have been formed to coordinate efforts and apply these methodologies to decipher the methylome of healthy and diseased tissues . in this article
we review technological advances in genome - wide methylation profiling . |
exercise one powerful non pharmacological method affecting cells
organs body1 regular aerobic
resistance exercise training positive long term impact cardiovascular system
biologically complex adaptive system characterized variety
complex reactions different training loads2,3,4 performing exercise important body supplied oxygen energy
substances this transporting function performed cardiovascular system5 power transport substances
cells it known long
blood flow intensification even accurate blood flow redistribution
exercise increase blood supply working muscles consequently increase working
capacity6 nowadays athletes
coaches looking efficient training method achieve maximum results
maintain results longest possible period time order minimize
probability injury recently unconventional training method developed
uses blood flow restriction musculoskeletal system otherwise known
kaatsu methodology an example walking workout using blood flow restriction
proven useful method improving muscle function including muscle
hypertrophy strength endurance one potential ways achieve
could training blood flow restriction7
8 training less weight reduces
stress joints therefore minimizes possibility getting injured recently blood
flow restriction combined low intensity resistance exercise suggested
useful exercise protocol gain muscular strength mass without increase blood
pressure9 some authors
suggested using little 20% maximum repetition weight training
blood restriction almost impossible evaluate large arterial function directly recording
electrocardiogram ecg one practical noninvasive methods
application ecg sports physiology st segment depression key index
refers degree occurrence myocardial ischemia this special
significance adolescent young athletes used recognize unphysiological
states workouts together hereditary congenital abnormalities heart common causes
nontraumatic death sport young athletes middle aged recreational athletes more
90% sudden cardiac deaths occur males 90% caused
atherosclerotic coronary artery disease10 such findings encourage greater interest noninvasive ecg
methods research questioning meaning st segment depression different
workout rest stages
basically corrected qt jt interval qtc jtc indices increases sudden death
risks11 however ecg parameters
observed minority athletes present diagnostic conundrums the jt interval
measured j point end wave describes
duration ventricular repolarization shortening jt interval physical
load correlates increase metabolic rate myocardium12 our hypothesis states training gain achieved training circulatory
restriction applied low intensity exercising lies within physiological limits
cardiovascular system the aim study effect single occlusion
training session cardiovascular response bouts exercise the
subjects study amateur athletes track field 46 years training
experience participated two groups control group without blood flow
restriction experimental group blood flow restriction n=24 mean age 22.5
1.5 years body mass index 24.7 0.5 kg the weight body mass index
bmi tbf-300 body composition scale tanita uk ltd west drayton uk subjects
estimated seminude shorts shirts none subjects
exercised least 12 hours test ate least 2 hours
test the physical load test carried competitive period sports
season the study designed determine effects single occlusion training session
cardiovascular system the participants underwent circulatory restriction
40-mm wide cuff applied groin13 the
participants seated calf muscles trainer cuff air pressure set 120
mmhg approximate resting systolic blood pressure participant14 study the calf muscles
m. gastrocnemius m. soleus sole flexion muscle m.
flexor digitorum brevis impacted occlusion part coherent
muscular system the knee working leg fixed angle
90 ankle fixed angle 70. dynamometer adjusted according
foot size participant maximum voluntary contraction mvc measured newton
n performed three times highest value recorded mvc measured
training order choose individuals training workload arterial blood pressure abp important cardiovascular functional parameter
measured using cuff method listening korotkoff tones a computerized analysis system kaunas load employed continuous 12-lead ecg
registration analysis changes rr interval heart rate hr jt interval
st segment depression sum negative values 12 leads ratio
jt rr intervals analysed as shown studies low intensity resistance exercise training occlusion
2050% mvc increases muscle cross sectional area strength15 therefore used single session training
exercise intensity 40% mvc foot flexor muscle conditioning training conducted
follows three exercises comprising three sets eight repetitions per set
leg a 2.5-min rest period provided exercises 30-sec rest period
provided sets the participants asked lift weight time
metronome 30 movement cycles per minute)16 occlusion applied exercise removed
set three exercises 3 sets 3 exercises per set 8 repetitions per
exercise the arithmetic mean x standard deviation arithmetic mean error
sx calculated a two way independent samples student test used
determine reliable mean difference performance indicator results
significant difference compared values this study approved regional biomedical research ethics committee lithuanian
university health sciences kaunas lithuania be-210 2603 2015 the results research showed exercise average hr 69.1 4.0
beats min hr showed significant
increase exercise increasing 96.3 4.9 beats min experimental group
94.1 3.8 beats min control group recovery first set hr
84.8 5.4 beats min subjects circulatory restriction value
group 82.0 3.1 beats min 1.changes heart rate exercise rest changes hr first set groups however
continuation exercise tasks revealed values set control
higher experimental group changes heart rate exercise rest study significant statistical difference groups
comparing systolic diastolic abp p<0.05 addition find
difference groups terms changes diastolic abp exercise
observed low tendency systolic abp increase response repeated sets
exercise table 1table 1.average increase systolic diastolic abp exercise setssystolic mmhg)diastolic mmhg)set 1set 2set 3set 1set 2set 3experimental10.3 3.510.6 2.911.6 3.24.6 3.53.0 3.83.7 3.3control7.6 4.19.0 3.412.6 4.02.0 3.11.9 3.41.8 2.7 onset exercising the applied occlusion influence st segment depression
exercise rest jt rr values registered exercise rest
first set exercises significantly different however tendency lower
increase jt rr repeated exercise sets performed partial circulatory
restriction observed fig the cardiovascular system vital body system model human body response
exercising12 outlines
important part supplying systems results obtained study revealed
increase hr exercise notable control group compared
experimental group also determined application partial
circulation restriction caused lower jt rr ratio values ecg assessing
findings as
shown authors17 jt rr ratio
allows depiction mobilization cardiovascular system exercising if
multiply abovementioned ratio 60 would allow us depict situation
time many seconds per minute heart myocardium contracted
consequently long cardiac musculature rest the data study indicate
cardiac muscle strain slightly lower low intensity exercise carried
partial circulatory restriction the present study found systolic diastolic abp higher throughout entire
study this corresponds findings research
showing application occlusion increases vascular wall elasticity19 it important note vascular
wall elasticity one main factors affect diastolic arterial blood pressure
the fact certain blood vessels clamped research could also
influenced increase diastolic abp performing exercised partial circulatory
restriction is healthier joints smaller weights used previous study
also showed manifestations thrombosis observed using occlusion20 the heart reserve possibility
largely depends whether demand oxygen satisfied quickly
sufficiently oxygen delivered heart exercise when myocardium
insufficiently supplied blood lack oxygen myocytes when coronary
heart blood vessels insufficiently supplied blood exercise changes
occur balance metabolic processes subsequently electric potentials
myocytes result processes st segment depression visible ecg records
thus assessment degree ischemic episodes exercise also essential
indicates functional state heart partial blood flow restriction ambiguous effect blood pressure changes
exercise systolic abp values continued higher exercise changes
diastolic abp registered repeating exercise increased fatigue body
forced mobilize resources perform given exercise task therefore
analysis research results assessed manifestations variations
functional indices cardiovascular system i.e. changes mobilization recovery
we concluded partial blood flow restriction applied repeated
exercise heart mobilization recovery features better reflected jt rr
ratio hr assessment manifestations hr fluctuations found amplitude hr
change response exercise repetitions remained increase
mechanical work duration myocardium indicated jt rr ratio lower
interpreted indicating heart could perform pumping function
ease this confirmed changes jt ecg data demonstrated
changes exactly direction the physiological sense jt defined
follows jt interval recorded ecg measured connection point j
end wave point j corresponds moment ecg curve wave
returns isolines the jt interval indicates ventricular repolarization processes
used indicator repolarization duration also jt interval variation
related changes intensity myocardial metabolism21 22 despite all provided positive conclusions subject affirm
exercise performed applying occlusion training method firstly
requires special equipment ability use special equipment knowledge
application procedures secondly authors claim training occlusion
provided reliable results23 on
hand study made maior 2015 interesting conclusion drawn
application occlusion training effective movement carried
one joint24 25 thus unanimous conclusion made present perhaps
scientists carry research future determine body response
applying blood flow restriction different pressure levels summary we conclude applying partial blood flow restriction occlusion training
groin area resulted lower degree hr increase response repeated exercise
compared training without occlusion however partial blood flow restriction
increase myocardium load significant effect coronary vascular
function partial blood flow restriction affects change blood pressure
exercise ambiguous way systolic abp values continue higher change
blood pressure diastolic abp changes expressed conclusion study
confirmed hypothesis additional strain cardiac functioning
occlusion training carried exercising partial blood flow restriction
groin area the results obtained study suggest kind occlusion training could
applied health training rehabilitation purposes occlusion training using low
intensity exercise triggers changes muscular tissue similar high intensity exercise
training meanwhile cardiovascular system exercise experience higher
overload could risk factor cardiac patients physically inactive persons
| [ purpose ] occlusion training with low - intensity resistance exercises and blood flow
restriction increases muscle cross - sectional area and strength .
this form of training is
used in rehabilitation ; therefore , the aim of this study was to examine the effect of one
occlusion training session on the cardiovascular response to bouts of exercise .
[ subjects
and methods ] two groups took part : a control group without blood flow restriction and an
experimental group with blood flow restriction .
a single training session was used with
the exercise intensity set at 40% of the one repetition maximum .
maximum voluntary
contraction , arterial blood pressure , and electrocardiogram measurements were performed .
[ results ] heart rate was slightly higher in the control group .
the performed training had
no effect on diastolic blood pressure in either group , however , a tendency for a small
systolic blood pressure increase was observed during the session in the experimental
group .
jt interval changes did not reveal significant differences between groups .
there
were no significant changes in st - segment depression during the exercise or at rest .
a
lower tendency for jt / rr increases was observed during the repeated exercise tasks with
partial blood flow restriction .
[ conclusion ] low intensity exercises carried out with a
partial blood flow restriction do not result in significant overload of cardiac
function . |
body language reading immense importance adaptive social behavior non verbal communication healthy perceivers able infer emotions dispositions others represented point light body movements minimize availability cues pollick et al 2001 ; atkinson et al 2004 heberlein et al 2004 clarke et al 2005 perceivers reliably judge emotional content dance represented moving dots placed dancer body dittrich et al 1996 visual sensitivity camouflaged point light human locomotion modulated emotional content gait highest sensitivity angry walking chouchourelou et al 2006 observers discriminate deceptive true intentions conveyed body motion true information precisely detected despite misleading endeavors runeson frykholm 1983 grzes et al 2004a b know trust attracted us judgments vital social interaction men women appear show profound differences cues attended yet research sex differences visual social cognition mainly limited static face images particular still photographs accordance widespread beliefs females exhibit higher sensitivity non verbal cues better discriminate friendliness sexual interest farris et al 2008 proficient recognition facial emotions montagne et al 2005 females without asperger syndrome better recognizing emotions dynamic faces males golan et al 2006 moreover females tend better recognize emotions faces voices whereas males exhibit opposite tendency rule however facial expressions static body postures signal emotional states affect provide information deal dynamic body expressions gestures actions others richer ecologically valid source information social interaction de gelder 2006 2009 pavlova 2009 the important advantage bodily expressions whereas face expressions similarly verbal information flow believed easily kept control body movements reveal true feelings emotions expressed faces bodies incongruent recognition facial expressions affected emotions revealed body meeren et al 2005 ) brain imaging indicates emotions expressed dynamic bodies compared faces elicit greater activation number brain areas including superior temporal sulcus sts cornerstone social brain kret et al 2010 experimental evidence obtained primarily patients lesions cortical blindness favors assumption emotional body language processed automatically without visual awareness attention review see tamietto de gelder 2010 great surprise however gender impact body language reading largely unknown a studies conducted beginning 80s based profile non verbal sensitivity pons test includes body motion neck knees video clips point superiority females body language reading e.g. blank et al 1981 ) however test serious methodological limitations example based body motion video clips one female actor although sex differences represent rather delicate topic underestimation exaggeration possible effects retard progress field the present work intends make initial step filling gap clarify whether perceiver gender affects recognition emotional expressions conveyed actions others more specifically ask whether gender affects recognition emotions represented body motion words whether females excel recognition emotional actions ii whether gender effects depend emotional content actions end healthy young females males presented point light displays portraying knocking door different emotional expressions happy neutral angry we took advantage point light technique helps isolate information revealed motion cues shape color etc perceivers saw bright dots placed main joints otherwise invisible arm figure 1 clues except motion characteristics abandoned three static frames taken dynamic sequence representing knocking motion set dots placed arm joints shoulder head otherwise invisible actor actors seen facing right sagittal view struck surface directly front thirty four healthy adults students university tbingen medical school aged 2036 enrolled study mean age females 20 participants 23.8 3.7 years mean age males 14 participants 22.9 2.0 years there age difference female male participants t32 0.95 p 0.35 ns none history neurological psychiatric disorders including autistic spectrum disorders asd schizophrenia head injures medication anxiety depression informed written consent obtained accordance requirements local ethical committee university tbingen medical school point light displays recorded performance knocking different emotional content happy neutral angry we chose use animations happy angry motions happiness anger reported quite similar activation dimension animations tended fast jerky movements pollick et al display creation described detail elsewhere pollick et al 2001 brief recording performed using 3d position measurement system rate 60 hz optotrak northern digital inc each display consisted six point light dots placed head shoulder elbow wrist first forth metacarpal joints otherwise invisible right hand figure 1 point light actors seen facing right sagittal view struck surface directly front the size point light knocking stimuli standardized way first frame distance head first metacarpal joint identical actors emotion six different displays equal number knocking performed female male actors created using presentation software neurobehavioral systems inc albany ca usa video displayed five times per experimental session resulting 30 trials per emotion the whole experimental session consisted set 90 displays representing three emotions random order took 1520 min per participant each display shown 1 s. used three alternative forced choice paradigm trial participants indicated pressing dominant hand one three respective keys computer keyboard whether display portrayed happy neutral angry knocking thirty four healthy adults students university tbingen medical school aged 2036 enrolled study mean age females 20 participants 23.8 3.7 years mean age males 14 participants 22.9 2.0 years there age difference female male participants t32 0.95 p 0.35 ns none history neurological psychiatric disorders including autistic spectrum disorders asd schizophrenia head injures medication anxiety depression informed written consent obtained accordance requirements local ethical committee university tbingen medical school we used point light displays portraying knocking arm motion pollick et al 2001 2002 point light displays recorded performance knocking different emotional content happy neutral angry we chose use animations happy angry motions happiness anger reported quite similar activation dimension animations tended fast jerky movements pollick et al display creation described detail elsewhere pollick et al 2001 brief recording performed using 3d position measurement system rate 60 hz optotrak northern digital inc waterloo canada each display consisted six point light dots placed head shoulder elbow wrist first forth metacarpal joints otherwise invisible right hand figure 1 point light actors seen facing right sagittal view struck surface directly front the size point light knocking stimuli standardized way first frame distance head first metacarpal joint identical actors emotion six different displays equal number knocking performed female male actors created using presentation software neurobehavioral systems inc albany ca usa video displayed five times per experimental session resulting 30 trials per emotion the whole experimental session consisted set 90 displays representing three emotions random order took 1520 min per participant each display shown 1 s. used three alternative forced choice paradigm trial participants indicated pressing dominant hand one three respective keys computer keyboard whether display portrayed happy neutral angry knocking percentage correct recognition emotions conveyed knocking represented figure 2a females males recognition emotional expressions chance level p 0.001 however recognition happy knocking less accurate neutral angry actions this consistent outcome previous studies emotion recognition point light human locomotion chouchourelou et al 2006 ; ikeda watanabe 2009 dance dittrich et al 1996 show better recognition angry happy motion recognition happy neutral angry point light knocking females males ( percentage correct males outperformed recognition happy knocking p 0.015 whereas females excelled recognition neutral knocking p 0.016 tended perform recognition angry knocking p 0.07 significant differences indicated asterisk b error rate lack gender differences error rate demonstrates gender differences recognition accuracy emotional content knocking caused gender related bias mistaking one emotion another each bar represents average ratio number errors particular type overall number errors made display type e.g. leftmost bar represents average ratio number trials happy knocking mistaken neutral knocking number trials happy knocking mistaken neutral angry knocking c response time happy neutral angry point light knocking females males individual number correct responses submitted 2 3 repeated measures anova assessed shapiro
wilk test data normally distributed factors gender female male emotional expression knocking happy neutral angry this analysis revealed lack main effect gender f(1,32 0.21 p 0.648 ns however main effect emotional expression f(2,32 82.94 p 0.0001 interaction factors gender emotional expression f(2,32 6.23 p 0.003 highly significant planned pair wise comparisons indicated males outperformed recognition happy knocking t32 2.58 p 0.015 one tailed bonferroni corrected multiple comparisons 0.84 whereas females tended perform recognition angry knocking t32 1.87 p 0.07 one tailed excelled recognition neutral knocking t32 2.54 p 0.016 one tailed 0.88 the data therefore reveals lack advantage females recognition accuracy instead findings indicate sex effects recognition accuracy modulated emotional contents actions error analysis figure 2b indicated females males happy knocking mistaken neutral knocking 80% wrong responses error rate 0.84 0.86 females males respectively gender difference t32 0.42 p 0.68 two tailed ns error rate calculated average ratio number errors particular type overall number errors made display type turn lack gender differences neutral knocking misperceived happy actions 70% error responses ( error rate 0.68 0.67 females males respectively gender differences t32 0.02 p 0.99 two tailed ns 80% error trials response angry knocking females males mistook angry knocking neutral knocking error rate 0.79 0.8 females males respectively gender difference t32 0.14 p 0.88 two tailed ns the lack gender differences error rate suggests gender effects recognition accuracy emotional content knocking observed present study caused gender related bias mistaking one emotion another response time analyses a 2 3 repeated measures anova performed individual values assessed shapiro
wilk test data normally distributed factors gender female male emotional expression happy neutral angry this analysis reveal effect gender f(1,32 1.56 p 0.22 ns well interaction factors gender emotional expression response time f(2,32 1.42 p 0.25 ns figure 2c however main effect emotional expression significant f(2,32 35.16 p 0.0001 fastest response angry knocking slowest response neutral knocking figure 2b this shows recognition neutral knocking difficult angry happy knocking post hoc pair wise comparisons showed gender difference response time happy t32 0.09 p 0.93 two tailed ns average 2.00 0.39 1.99 0.28 stimulus onset females males respectively neutral t32 1.21 p 0.24 two tailed ns average 2.15 0.33 2.28 0.3 females males respectively angry knocking t32 0.14 p 0.89 two tailed ns average 1.84 0.32 1.85 0.28 females males respectively taken together findings suggest gender affect speed body language reading females males however swiftness response body language depends emotional content actions since difficult interpret negative findings within relatively small sample size might considered limitation study lack sex differences error rate response time explored the outcome study indicates gender affects accuracy rather speed body language reading best knowledge the gender effect however modulated emotional content actions females tend excel recognition accuracy angry knocking whereas males perform recognition happy actions the lack gender differences error rate suggests gender effects recognition accuracy caused gender related bias based popular wisdom one expect women possess soft skills social perception including high sensitivity positive emotional signals subtle details men might outperform recognition negative menacing expressions this assumption based different evolutionary socio cultural roles genders e.g. biele grabowska 2006 proverbio et al 2008 high sensitivity women positive emotions related role primary offspring care providers social cognition men presumably connected active interactions immediate reactions therefore emotion perception likely associated motor programs anger detection usually associated need act example escape person prepare confront person these data agree findings showing men appear exhibit stronger brain activation response positive pictures depicting landscapes sport activities families erotic scenes women wrase et al moreover males equally responsive happiness conveyed static dynamic happy faces males rate intensity dynamic static expressions happiness equally high whereas females less responsive happiness static faces biele grabowska 2006 presumably indicates males better tuned subtle expressions happiness faces actions this might hold true least population young men high social status educational level participated present study the prominent outcome study females clear advantage recognition neutral knocking this suggests women better tuned lack emotional content body actions future research clarify whether gender effects body language reading occur repertoires actions arrays emotions one possibility gender differences neurobiological sources cahill 2006 jazin cahill 2010 brain mechanisms underpinning body language reading sex specific the social cognition network commonly referred social brain primarily involves parieto temporal junction temporal cortices including fusiform face area sts orbitofrontal cortices amygdala adolphs 2003 left lateral cerebellum sokolov et al 2010 right sts cornerstone processing meaningful body motion grossman blake 2002 pavlova et al studies sex effects social brain limited investigation face expressions body actions represented still photographs brain activation females reported bilaterally distributed presumably providing greater contribution hemispheres identification facial affect bourne 2005 proverbio et al 2010 females show stronger event related potential erp response emotional faces orozco ehlers 1998 however findings controversial sex effects found blood oxygen level dependent bold response amygdala happy fearful faces killgore yurgelun todd 2001 hand significant correlation functional magnetic resonance imaging fmri activity amygdala behavioral response fearful faces both behavioral amygdala responses threat related face expressions correlated testosterone level derntl et al in accordance widespread belief reported female brain responsive social stimuli represented still images proverbio et al 2009 recent erp findings indicate females processing actions goals occurs earlier proverbio et al 2010 neuroimaging reveals gender effects evident neural circuitry underpinning visual processing social interaction rather regions engaged perceptual decision making neuromagnetic gamma response left prefrontal cortex peaks earlier females pavlova et al 2010a gender effects behavioral level necessarily imply sex related difference brain activation subserving body language reading moreover gender differences performance social cognition tasks impacted socio cultural stereotypes pavlova et al 2010b several types interrelations behavioral measures brain mechanisms engaged social perception taken account sex differences behavioral brain responses ii sex differences detectable either behavioral level brain activation iii absence sex differences behavioral brain levels pavlova 2009 noteworthy gender related dimorphism brain may elicit also prevent behavioral differences maladaptive de vries 2004 future research directed uncovering sex differences brain activity body language reading such investigation would also shed light sex differences neuropsychiatric conditions characterized impairments social cognition asd depression schizophrenia it known males commonly affected asd females ratio 4:1 newschaffer et al 2007 females however affected much severely therefore high functioning autistic individuals ratio even much higher although behavioral evidence individuals asd difficulties revealing information emotions point light body movements moore et al 1997 hubert et al 2007 parron et al 2008 unclear whether females males asd differ body language reading lack studies females asd calls thorough investigation profile the important issue future research sex differences visual social cognition survivors premature birth males 1420% higher risk premature birth melamed et al 2010 complications brain cognition adolescents born prematurely likely exhibit difficulties visual social cognition pavlova et al 2008 gender effects largely unknown clarification gender impact body language reading underlying brain networks would provide novel insights understanding gender vulnerability neuropsychiatric neurodevelopmental impairments visual social cognition the authors declare research conducted absence commercial financial relationships could construed potential conflict interest | body motion is a rich source of information for social cognition . however , gender effects in body language reading are largely unknown . here
we investigated whether , and , if so , how recognition of emotional expressions revealed by body motion is gender dependent .
to this end , females and males were presented with point - light displays portraying knocking at a door performed with different emotional expressions .
the findings show that gender affects accuracy rather than speed of body language reading .
this effect , however , is modulated by emotional content of actions : males surpass in recognition accuracy of happy actions , whereas females tend to excel in recognition of hostile angry knocking .
advantage of women in recognition accuracy of neutral actions suggests that females are better tuned to the lack of emotional content in body actions .
the study provides novel insights into understanding of gender effects in body language reading , and helps to shed light on gender vulnerability to neuropsychiatric and neurodevelopmental impairments in visual social cognition . |
aripiprazole third generation atypical antipsychotic dopamine serotonin system stabilizer dss effective positive negative symptoms schizophrenia it low propensity extrapyramidal side effects causes minimal weight gain sedation produces elevation serum prolactin levels cause prolongation qtc interval it partial agonist d2 5ht1a blocks 5ht2a receptors.[13 common adverse reactions adult patients reported clinical trials dosage 1015 mg per day fatigue insomnia headache nausea vomiting tremors rigidity akathisia constipation overall incidence acute dystonic reactions antipsychotic medications 2.55% majority due typical high potency antipsychotics the following case report aripiprazole induced oculogyric crisis acute dystonia a 28-year old single female brought relatives psychiatry outpatient clinic last 89 months interacting less family per history suspicious towards family members would poison also feared strangers would come kill in addition talking occasionally irritable sleep disturbance after psychiatric evaluation mental status examination revealed delusion persecution primary well systematized complete intermittent associated intense fear harmed palpitations irritability she also auditory hallucinations unknown male commenting day day work occasionally criticizing associated patient replying voice her weight 70 kg family history mother diabetes mellitus her baseline investigations hemogram liver function renal function tests chest x ray electrocardiogram within normal range she prescribed aripiprazole 10 mg orally two divided dosages per day eszopiclone 2 mg orally nighttime dosage advised follow 2 weeks first follow visit showed improvement sleep improvement psychotic symptoms aripiprazole increased 20 mg orally two divided dosages advised follow 2 weeks after 5 days dose increment brought complaints upward rolling eye balls suddenly unexpected occurring five seven times day difficult bring back original position patient after evaluation conversion disorder tardive dystonia epileptic encephalopathy anti epileptic drug intake diagnosed oculogyric crisis acute dystonia patient admitted psychiatry ward aripiprazole withdrawn immediately injection promethazine 50 mg intramuscularly given repeated half hour her symptoms improved next 1 hour patient prescribed 25 mg promethazine orally night time dosage within 3 days admission put aripiprazole 10 mg orally two divided dosages psychotic symptoms continuing eszopiclone promethazine 25 mg nocte the patient advised follow week repeat challenge aripiprazole 20 mg orally two divided dosages resulted oculogyric crisis within 4 days the patient advised cap ziprasidone 20 mg orally two divided doses per day i.e. 40 mg per day food asked follow 2 weeks later electrocardiogram done later uptitration cap ziprasidone 20 mg orally three divided doses per day i.e. 60 mg per day food done she improved psychotic symptoms 2 months extrapyramidal symptoms normal electrocardiogram baseline investigations various case reports aripiprazole induced acute dystonia report symptoms neck extension torticollis rigidity tongue movements.[810 addition various studies describe medications causing acute dystonic reactions management described table 1 case reports acute dystonic reactions patients medications antimalarials chloroquinone hydroxychloroquine amodiaquine antivertigo agents cinnarizine flunarizine cocaine buspirone diazepam sumatriptan phenylpropanolamine ecstasy 3,4-methylenedioxymethamphetamine also reported drugs causing acute dystonia management case oculogyric crisis symptom attention this case female patient third generation antipsychotic medicine aripiprazole least propensity dystonia.[13 risk factor developing acute dystonia case history acute dystonia acute dystonia occurred 5 days increasing aripiprazole 10 mg 20 mg per day orally two divided dosage it regressed completely stopping aripiprazole administration promethazine repeat challenge reappeared severity hence causality assessment scale naranjo et al score 7 numerous studies report mechanisms acute dystonia dopamine hypofunction resulting relative overactivity cholinergic mechanisms since aripiprazole lacks protective anticholinergic action potential precipitate dystonia this supported fact case dystonia resolved promethazine antihistaminic anticholinergic property in addition aripiprazole action d3 receptor antagonism 5-ht6 5-ht7 receptors still unknown hence may play role oculogyric crisis preclinical studies found inhibitory action aripiprazole serotonin transporter may potential alter dopamine balance basal ganglia region studies mention paradoxical dopaminergic hyperfunction either preferentially blocking presynaptic receptors exposing postsynaptic receptors natural release dopamine presynaptic terminals dba levels drop may result dystonia this justifies judicious use medications treatment prophylaxis acute dystonia due antipsychotics this case outlines significant side effect aripiprazole practitioner vigilant initiating medication | aripiprazole is the third generation atypical antipsychotic and a dopamine serotonin system stabilizer ( dss ) effective against positive and negative symptoms of schizophrenia .
it has a low propensity for extrapyramidal side effects , causes minimal weight gain or sedation , produces no elevation in serum prolactin levels , and does not cause prolongation of qtc interval .
this case report is of a patient suffering from schizophrenia ( paranoid ) .
the patient developed oculogyric crisis ( acute dystonia ) with aripiprazole dose uptitration .
dystonic reaction resolved with promethazine administration .
naranjo 's causality assessment reveals probable association of aripiprazole with oculogyric crisis .
a thorough workup and vigilance is required prior to initiation of aripiprazole in the case of schizophrenia . |
venous thromboembolism vte occurs one serious complications undergoing total joint arthroplasty.1 generally pulmonary thromboembolism generated secondary product deep vein thrombosis dvt emergence may possibly trigger chronic thromboembolic pulmonary hypertension well post thrombotic syndrome.2 patent foramen ovale pfo residue fetal circulation found approximately 25 30% among adults also known thrombus venous circulation rarely causes arterial thromboembolism right left shunt.3 case authors experienced patient pfo several thrombotic disease pulmonary thromboembolism dvt right atrial thrombus along cryptogenic ischemic stroke total knee arthroplasty tka a 64-year old female presented emergency room shortness breath she taking antiplatelet drugs aspirin 100 mg day clopidogrel 75 mg day treatment right posterior temporal lobe infarction detected brain magnetic resonance imaging disorientation third day operation fig 1 carotid brain computed tomography ct angiography showed evidence atherosclerosis afterwards experienced dyspnea second week operation performed transthoracic echocardiography tte showed right atrial thrombi treated low molecular weight heparin lmwh the symptoms nonetheless remained transferred hospital medical history her blood pressure 127/79 mm hg heart rate 89 bpm physical pitting edema left lower leg noted neurologic examination unremarkable chest x rays show signs cardiomegaly well pulmonary edema both dimer n terminal pro brain natriuretic peptide increased respectively 2686 ng ml 3310 pg ml hand cardiac enzymes creatinine kinase mb troponin within normal range tte demonstrated normal left ventricular systolic function ejection fraction 63% right atrium two highly mobile masses 1.67 2.18 cm 0.69 0.80 cm suggesting possible thrombi observed the echocardiogram also revealed right atrium right ventricle enlargement severe pulmonary hypertension pulmonary artery systolic pressure 102 mm hg shaped left ventricle fig her chest ct showed pulmonary thromboembolism found main pulmonary arteries dvt observed left femoral vein fig holter ecg reveal arrhythmia except rare atrial premature complex ventricle premature complex the patient administered warfarin target inr 2 3 using lmwh follow up tte 3 weeks later two previous thrombi right atrium ra disappeared along improvement ra also positive change extent pulmonary hypertension the follow ct taken 4 weeks hospitalization reveal pulmonary thromboembolism dvt fig 3 since cause cerebral infarction unclear additional evaluation needed order examine intracardiac shunt the results confirmed transference microbubble right atrium left atrium without showing atrial septal defect therefore diagnosed patient pfo fig currently patient taking warfarin continuously without signs abnormalities outpatient clinic we recommended treatment pfo including device closure patient refused poor general condition as vte one fatal complications undergoing tka dvt pulmonary embolism pe known occur approximately around 13% 3% respectively.4 occurrence period vte tka reported 3 9 days operatio5 mostly cases accompany dvt pe occasionally thrombi observed several organs particularly reported patients pfo even might develop arterial thromboembolism cryptogenic stroke.3)6 present case authors suspected cryptogenic stroke 3 days operation might possibly caused vte changed arterial thromboembolism pfo pfo one congenital heart diseases observed even adulthood typically symptom nonetheless affect risk factor several conditions including ischemic stroke platypnea orthodeoxia syndrome decompression sickness.7 pfo cause cryptogenic stroke uncommon hence occurrence ischemic stroke either pe dvt considered possible example paradoxical embolism right left shunt.8 among treatments prevention frequent strokes within patient pfo medical options invasive methods.9 medical options include use antiplatelet agents well prescription warfarin patients hypercoagulable state venous thrombosis terms invasive methods it used operation past application device closure used recently.10 case cryptogenic stroke took place within 3 days tka right atrial thrombus dvt pe present way passage right left shunt speculated result subsequent echocardiography led diagnosis positive reaction agitated saline test pfo the patient treated lmwh administered warfarin patient discharged recovered conditions conclusion occurrence pulmonary thromboembolism dvt patient pfo trigger development cryptogenic stroke right left shunt therefore further evaluation cause essential patients occurrence cryptogenic stroke associated high risk vte total joint arthroplasty also anticoagulation treatment necessary patient right left shunt pfo | patients undergoing total joint arthroplasty frequently develop post - operative complication , such as deep vein thrombosis and pulmonary thromboembolism .
however , it is not common coexisting deep vein thrombosis , pulmonary thromboembolisms , right atrial thrombus and acute cerebral infarction raised by thrombus through patent foramen ovale .
we reported the patient who had multiple thrombi which were accompanied with a cryptogenic ischemic stroke and associated with patent foramen ovale after operation . |
non alcoholic fatty liver disease nafld hepatic manifestation metabolic syndrome includes spectrum diseases ranging simple steatosis steatohepatitis nash fibrosis ultimately cirrhosis 1 2 disease definition modalities used diagnosis epidemiology studies standardized 3 the prevalence nafld increased rapidly affects 20% 30% population western countries 4 15% china 5 lipid metabolism disorder nafld strong genetic component a recent gwas genetics obesity related liver disease consortium identified lyplal1 rs12137855 nafld 7177 adults european ancestry 6 lyplal1 encodes lysophospholipase like protein 1 26 kda cytosol protein belongs subclass lysophospholipase family 7 recently several single nucleotide polymorphisms snps near human lyplal1 gene revealed significantly associated fat distribution relatively sex specific pattern 8) 3 snps including rs4846567 9 rs2605100 10 rs2820443 11 near lyplal1 gene associated increased waist hip ratio whr adjusted bmi women men snp rs11118316 lyplal1 associated visceral adipose tissue subcutaneous adipose tissue ratio men women 12 snp rs12137855 near lyplal1 gene strongly associated nafld 13 subsequent studies showed lyplal1 plays important role fat distribution lipid metabolism lyplal1 rs12137855 susceptibility gene nafld widely studied results inconsistent research performed association polymorphism lyplal1 nafld chinese han population the aim study investigate association nafld lyplal1 chinese han population assess effect gene serum lipid profiles the study performed accordance principles declaration helsinki appendices 14 this study approved ethical committee qingdao municipal hospital qingdao china written informed consent form obtained patients participation study may 2010 may 2014 selected total 298 unrelated adult subjects including 184 unrelated chinese patients genders different ages 85 males 97 females mean age 43.18 11.53 years diagnosed nafld 114 healthy controls matched sex age 57 males 57 females mean age 40.77 11.47 years b type ultrasonography 15 the subjects collected department gastroenterology medical center qingdao municipal hospital the diagnosis nafld performed standard clinical evaluation conditions according aasid criteria other causes liver disease excluded including increased alcohol intake 210/140 g wk males females confirmed least one family member friend carboxydesialylated transferrin determination viral autoimmune hepatitis hereditary hemochromatosis alphal antitrypsin deficiency 16 we excluded related disease subjects type 1 diabetes mellitus coronary atherosclerotic disease cad the controls confirmed healthy medical history general examinations laboratory examinations hospital blood samples subject biochemical analyses collected ethylene diamine tetraacetic acid containing tubes 12-hour overnight fast following information subject gathered height body mass waist hip circumference calculating body mass index bmi equals mass kg)/height environmental factors diet physical activity recorded study the blood sample tested total cholesterol tc triglycerides tg high density lipoprotein hdl low density lipoprotein ldl using routine enzymatic methods serum alanine aminotransferase alt aspartate aminotransferase ast -glutamyltransferase ggt concentrations measured previously described 17 the genomic dna purification kit bioteke biotechnology beijing china used extracting dna peripheral blood following manufacturer instructions stored 20c use genotyping lyplal1 rs12137855 performed polymerase chain reaction pcr analysis using following primers lyplal1 polymorphism 5'-tcctaagttcctattgtcccttca-3 5'-tgctgtggggtgagtca-3 pcr amplification labnet united states performed follows initial step 95c 10 minutes followed 35 cycles denaturation 94c 1 minute annealing 60c 1 minute elongation 70 c 1 minute all pcr products resolved using 2% agarose gel electrophoresis 110 v 30 minutes 237-base pair product size the lyplal1 genotypes detected direct dna sequencing using abi prism sequence detection system abi3730 foster city ca usa the genotyping call rate 95% completion rate 99% statistical analyses performed using spss statistical software version 17.0 window spss inc hardy weinberg equilibrium expected observed genotype distributions assessed using test genotype alleles estimated chi square test dna distributions nafld patients controls analyzed pearson test fisher exact test appropriate differences characteristics different groups examined using student test paired samples test test the strength association polymorphism nafld evaluated logistic regression analysis adjusted confounders age sex smoking hypertension considered continuous variables the study performed accordance principles declaration helsinki appendices 14 this study approved ethical committee qingdao municipal hospital qingdao china written informed consent form obtained patients participation study may 2010 may 2014 selected total 298 unrelated adult subjects including 184 unrelated chinese patients genders different ages 85 males 97 females mean age 43.18 11.53 years diagnosed nafld 114 healthy controls matched sex age 57 males 57 females mean age 40.77 11.47 years b type ultrasonography 15 the subjects collected department gastroenterology medical center qingdao municipal hospital the diagnosis nafld performed standard clinical evaluation conditions according aasid criteria other causes liver disease excluded including increased alcohol intake 210/140 g wk males females confirmed least one family member friend carboxydesialylated transferrin determination viral autoimmune hepatitis hereditary hemochromatosis alphal antitrypsin deficiency 16 we excluded related disease subjects type 1 diabetes mellitus coronary atherosclerotic disease cad the controls confirmed healthy medical history general examinations laboratory examinations hospital blood samples subject biochemical analyses collected ethylene diamine tetraacetic acid containing tubes 12-hour overnight fast following information subject gathered height body mass waist hip circumference calculating body mass index bmi equals mass kg)/height environmental factors diet physical activity recorded study the blood sample tested total cholesterol tc triglycerides tg high density lipoprotein hdl low density lipoprotein ldl using routine enzymatic methods serum alanine aminotransferase alt aspartate aminotransferase ast -glutamyltransferase ggt concentrations measured previously described 17 the genomic dna purification kit bioteke biotechnology beijing china used extracting dna peripheral blood following manufacturer instructions stored 20c use genotyping lyplal1 rs12137855 performed polymerase chain reaction pcr analysis using following primers lyplal1 polymorphism 5'-tcctaagttcctattgtcccttca-3 5'-tgctgtggggtgagtca-3 pcr amplification labnet united states performed follows initial step 95c 10 minutes followed 35 cycles denaturation 94c 1 minute annealing 60c 1 minute elongation 70 c 1 minute all pcr products resolved using 2% agarose gel electrophoresis 110 v 30 minutes 237-base pair product size the lyplal1 genotypes detected direct dna sequencing using abi prism sequence detection system abi3730 foster city ca usa the genotyping call rate 95% completion rate 99% statistical analyses performed using spss statistical software version 17.0 window spss inc chicago il usa hardy weinberg equilibrium expected observed genotype distributions assessed using test genotype alleles estimated chi square test dna distributions nafld patients controls analyzed pearson test fisher exact test appropriate differences characteristics different groups examined using student test paired samples test test the strength association polymorphism nafld evaluated logistic regression analysis adjusted confounders age sex smoking hypertension considered continuous variables abbreviations alt alanine aminotransferase ast aspartate aminotransferase bmi body mass index ggt gamma glutamyl transpeptidase glu glucose hdl high density lipoprotein ldl low density lipoprotein nafld non alcoholic fatty liver disease patients tc total cholesterol tg triglyceride data presented mean sd genotypes distribution lyplal1 accordance hardy weinberg equilibrium nafld control groups pnafld 0.323 pcontrol 0.230 respectively ensure accuracy genotyping randomly repeated dna sequencing 100 subjects reverse sequencing the genotype allele distribution shown table 2 indicates significant difference two groups p 0.05 the gene lyplal1 increase risk developing nafld 0.622 95% ci 0.334 1.159
p nafld patients vs. control explore whether gene polymorphism affect laboratory parameters we compared non carriers carriers variant allele rs12137855 subjects nafld patients healthy controls respectively table 3 results showed significant difference weight bmi ldl
abbreviations alt alanine aminotransferase ast aspartate aminotransferase bmi body mass index ggt gamma glutamyl transpeptidase glu glucose hdl high density lipoprotein ldl low density lipoprotein nafld non alcoholic fatty liver disease patients tc total cholesterol tg triglyceride abbreviations alt alanine aminotransferase ast aspartate aminotransferase bmi body mass index ggt gamma glutamyl transpeptidase glu glucose hdl high density lipoprotein ldl low density lipoprotein nafld non alcoholic fatty liver disease patients tc total cholesterol tg triglyceride the genotypes distribution lyplal1 accordance hardy weinberg equilibrium nafld control groups pnafld 0.323 pcontrol 0.230 respectively ensure accuracy genotyping randomly repeated dna sequencing 100 subjects reverse sequencing the genotype allele distribution shown table 2 indicates significant difference two groups p 0.05 the gene lyplal1 increase risk developing nafld 0.622 95% ci 0.334 1.159
to explore whether gene polymorphism affect laboratory parameters compared non carriers carriers variant allele rs12137855 subjects nafld patients healthy controls respectively table 3 results showed significant difference weight bmi ldl
abbreviations alt alanine aminotransferase ast aspartate aminotransferase bmi body mass index ggt gamma glutamyl transpeptidase glu glucose hdl high density lipoprotein ldl low density lipoprotein nafld non alcoholic fatty liver disease patients tc total cholesterol tg triglyceride in recent years gene widely studied results inconsistent 6 18 speliotes et al observed significant associations histologic nafld ct nafld variants near lyplal1 6 our study first time investigated association lyplal1 rs12137855 nafld chinese han population selected 184 nafld patients 114 controls observe association lyplal1 rs12137855 nafld however find significant association gene nafld accordance previous findings 18 23 multiple factors involved development progression nafld insulin resistance obesity oxidative stress 24 study diagnosed nafld using routine blood testing liver ultrasonography lack direct measurement hepatic fat content gold standard liver biopsy reduced accuracy diagnosis observed metabolism indicators change obviously alt ast used markers liver fat accumulation 25 27 commonly used clinical practice 28 ) observe significant differences plasma concentrations transaminases nafld healthy controls contrary independent genetic variation lyplal1 these results accordance paola leon mimila speliotes study confirmed lyplal1 rs12137855 associated increased tg content 6 29 interestingly lyplal1-related proteins predicted play role consecutive steps triglyceride breakdown 30 31 pnpla3 confirmed increase hepatic steatosis preventing breakdown triglyceride 32 whether lyplal1 function knowing mechanism triglyceride breakdown need investigations for chinese subjects bmi 28 kg index obesity 16 study kg controls 23.04 3.47kg p 0.05 also higher variant carrier 25.29 3.51 independent gene nafld group control group difference reach statistical significant our study suggested lyplal1 influence bmi reflects association obesity indirectly our findings first time found significant difference variant carriers non carriers regarding ldl mechanism clear needs research as far studies asian population negative 18 19 reasons doubt correlation gene nafld asian population obtain precise results larger studies multiple ethnic groups asian indian korean performed our results may also due small sample size ethnic differences linkage disequilibrium ld patterns ethnic specific association gene environment interactions this study provided preliminary evidence association lyplal1 rs12137855 polymorphism development nafld chinese han origin first time further studies large study samples different ethnicity needed investigate influence gene nafld | background : recent genome - wide association studies ( gwas ) identified that gene lysophospholipase - like 1 ( lyplal1 ) rs12137855 associated with non - alcoholic fatty liver disease ( nafld ) .
no research has been performed regarding the association between lyplal1 and nafld in china.objectives:the aim of the present study was to investigate the association between the gene lyplal1 rs12137855 and nafld , and the effect on serum lipid profiles in a chinese han population.patients and methods : lyplal1 rs12137855 gene was genotyped in 184 patients with nafld and 114 healthy controls using sequencing and polymerase chain reaction analysis ( pcr ) .
we tested serum lipid profiles using biochemical methods.results:no significant differences in genotype and allele frequencies of lyplal1 rs12137855 was found between the nafld group and the controls group ( p > 0.05 ) .
subjects with the variant lyplal1 rs12137855 cc genotype had a higher mean weight , body mass index ( bmi ) and low density lipoprotein ( ldl).conclusions : our results showed for the first time that lyplal1 gene is not associated with a risk of nafld development in the chinese han population .
the variant carriers of overall subjects significantly increased weight , bmi and ldl . |
2-year old boy transferred emergency department approximately 4 hours severe head trauma loss consciousness physical examination right temporoparietal scalp laceration subgaleal hematoma child status decerebrate rigidity brain ct showed intraventricular hemorrhage subarachnoid hemorrhage figure 1a head computed tomography ct illustrating intraventricular hemorrhage b postoperative intraventricular external drainage resulted significant decrease intraventricular hemorrhage c enlargement lateral ventricles surrounding white matter edema consistent communicating hydrocephalus f axial sagittal ct images showing severe bilateral thickening inner table frontal bone cortex compression i outer table frontal bone intact external ventricular drain performed one week surgery cranial ct revealed ventricle hemorrhage disappeared figure 1b drain tube removed one month later repeat head ct showed dilation entire ventricular system associated communicating hydrocephalus figure 1c his consciousness gradually recovered awakened 2 months later patient discharged 2-year follow showed hypophrenia dysphasia diagnosed according diagnosis criterion mental retardation established world health organization 1985 checkup list dysphasia
the neuroimaging findings revealed lateral ventricles smaller figure 1e five years surgery child readmitted department due headache vomiting imbalance inappropriate behavior loss interest the patient developed frontal extra axial hemorrhage past 5 years there bilateral optic disc swelling hemorrhages optic nerve head surrounding retina figure 2a serum cortisol prolactin progesterone estradiol t3 t4 thyroid stimulating hormone glucose tolerance test within normal limits brain ct showed severe bilateral thickening inner table frontal bone cortex compression figure 1f the inner table honeycombed red figure 2b c intracranial pressure elevated achieve decompression complete resection mass performed dura opened star fashion three dimensional image formation used shape titanium mesh skull neoplasty the mass immersed formalin study histological appearance mass mineralized lamellar bone the forehead good contour postoperative radiographs demonstrated bone grafts remained intact evidence recurrence mass baseline radiography skeletal system performed showed additional foci hyperostosis figure 3a c a c postoperative brain computed tomography ct demonstrating frontal bone removed replaced titanium mesh relieve brain compression hyperostosis frontalis interna overgrowth bony tissue inner plate frontal bone documented medical literature 300 years the estimated incidence hyperostosis frontalis interna general population 5% 12% hyperostosis frontalis interna reported asymptomatic patient younger 10 years age hence present patient first case medline database the acceptable hypothesis regarding hyperostosis frontalis interna etiology hormonal influence bone growth for example estrogen stimulation could play part emergence hyperostosis frontalis interna explain predominance among females case the hormone levels normal interestingly hyperostosis frontalis interna found severe trauma existing findings difficult address whether trauma related hyperostosis frontalis interna best knowledge there previous reports literature associating hyperostosis frontalis interna brain trauma the associated signs symptoms generally nonspecific benign cluster together cases giving rise various syndromes the frequently presented complaints morgagni syndrome headache obesity virilism hypertrichosis stewart morel syndrome obesity neuropsychiatric symptoms troell junet syndrome acromegaly toxic goiter diabetes mellitus our patient imbalance knowledge mentioned previously severe cases hyperostosis frontalis interna leads compression soft tissue dural irritation brain atrophy thickening skull decrease intracranial volume it established hyperostosis frontalis interna cause diverse psychiatric disturbances aggressiveness paranoia depression our case tends confirm due extensive hyperostosis frontalis interna frontal lobe compression lead cognitive impairment psychiatric disorders the clinical symptoms signs indicated elevated intracranial pressure described previous reports hyperostosis frontalis interna commonly incidental finding x ray ct mri studies computed tomography scans provide radiologist enough information distinguish hyperostosis frontalis interna bony growth better diagnostic tools hyperostosis frontalis interna case authors found bilateral frontal inner tables diffuse uneven thickening histologically process hyperostosis frontalis interna thought deposition new bone primarily inner table progressive development diploe hyperostosis frontalis interna characterized remodeling inner table frontal bone cancellous phenotype hyperostosis frontalis interna benign process majority patients appear asymptomatic thus conservative observation used cases if hyperostosis frontalis interna leads headaches neurologic symptoms psychiatric disorders cognitive impairment surgical excision thickened portion bone method treatment relieve symptoms postoperatively patient uneventful recovery cognitive impairment improved hyperostosis frontalis interna currently regarded independent entity starts appear much younger age the authors described case 7-year old boy presenting imbalance cognitive impairment headache vomiting papilledema hemorrhages first case reported literature the etiology however remains unclear difficult prove correlation hyperostosis frontalis interna brain injury present surgical decompression effective treatment method our case confirms clinical presentation elicited due compression involved cortex area | hyperostosis frontalis interna is an unexplained irregular thickening of the inner table of the frontal bone .
hyperostosis frontalis interna was first identified in 1719 by morgagni as a symptom of a more generalized syndrome characterized by virilism and obesity .
most current studies have shown hyperostosis frontalis interna to be a sex- and age - dependent phenomenon , and females manifest a significantly higher prevalence of hyperostosis frontalis interna than males . in this article , the authors report the clinical case of hyperostosis frontalis interna in a 7-year - old child who had severe traumatic brain injury in the past ; review the related literature ; and discuss the clinical , radiological , and therapeutic features of this condition . |
since seminal report lung protective strategy published amato et al new england journal medicine 1998 whether ways different strategies mechanical ventilation affect clinical outcome ards patients remains controversial topic among physicians researchers this concise review article focuses lessons surviving sepsis campaign guidelines sscg 2012 report imparts regarding optimized strategy mechanically ventilating ards patients lung protective strategy ards patients includes following 7 recommendations tidal volume targeted 6 ml kg predicted body weight pbw plateau pressures passively inflated lung limited 30 cm h2o positive end expiratory pressure peep applied avoid alveolar collapse end expiration higher levels peep strategically used patients moderate severe sepsis induced ards even though difficult specify absolute values
higher levels peep think ardsnet standard
peep strategy reasonable choice peep setting
much higher peep strategy adopted alveoli trial higher peep group show significant improvement
survival they set peep high possible
without increasing maximum inspiratory plateau pressure
28 30 cmh2o keeping tidal volume 6 ml kg recruitment maneuvers used sepsis patients severe refractory hypoxemia prone positioning used sepsis induced ards patients pao2/fio2 ratio 100 mmhg facilities experience practices a short term course 48 h neuromuscular blocking agents nmbas along sedatives prescribed early sepsis induced ards pao2/fio2 150 mm hg a serious question must answered whether strict implementation 7 recommendations proposed sscg 2012 report reduce mortality rate ards patients despite recent advances medical treatment technologies mortality rate among ards patients still remains high ~40% 3 4 one plausible explanations despite introduction lung protective strategies patient populations included old 5 6 new 3 4 studies might comparable thereby introducing misclassification bias older studies 5 6 tended use relatively low levels peep fio2 patients classified suffering ards might meet current ards criteria therefore older studies might included less severe cases potentially estimating true mortality rate among ards afflicted patients
another possible explanation could decrease incidence ards population based study li et al reported lower incidence ards despite increase patients severity illness comorbidities although ards mortality rate changed time mortality rate patients risk ards reduced fuller et al reported systematic review mechanically ventilated patients manifest ards time endotracheal intubation use lower tidal volume ventilation reduced progression ards prophylactic use lung protective strategies patients risk yet manifested ards might help avoid progression however mortality rate among patients suffer ards still high needham et al revealed prospective cohort study lung protective strategies used 41% eligible cases confirmed compared non adherence lung protective strategies estimated absolute mortality risk reduction two years patient half adherence strategies 4.0% perfect adherence resulted 7.8% risk reduction
second limiting tidal volume 6 ml kg pbw plateau pressure 30 cmh2o may sufficient minimize lung injury certain severe ards patients showed patients large dependent non aerated compartment tidal volume 6 ml kgpbw resulted increasing number hyper inflated compartments decreasing number normally aerated compartments in cases tidal volume reduced low 4 ml kg pbw according ardsnet protocol
third ards heterogeneous syndrome optimization ventilator settings individual would required mechanically ventilating ards patients for example among patients recruitable lung increasing peep may help avoid cyclic opening closing alveoli without increasing distention alveolar strain however among patients no- little recruitable lung increasing peep may prevent cyclic opening closing also cause distention therefore raising peep might cause harm patients may benefit others alveolar recruitability may assessed bedside near future computed tomography ct electrical impedance tomography eit thereby making possible individually optimize ventilator settings ards patients fourth high frequency oscillation hfo considered alternative conventional ventilation cv compared cv hfo hypothesized superior ventilatory strategy could avoid cyclic collapse hyperinflation alveoli however two recent randomized controlled trials rcts comparing hfo cv ards adult patients hfo prevented severe hypoxemia improve hospital mortality rates 12 13 trials mean airway pressure higher hfo group cv group 5 cmh2o guervilly et al demonstrated recent prospective study using high mean airway pressure subjects hfo worsened right ventricular function compared cv ards patients sedative agents nmba frequently used hfo groups may negatively affected patients prognosis furthermore many physicians less clinical experience hfo cv malhorta et al commented editorial hfo hfo protocols management strategies used clinical trials less effective established lung protective strategy using cv context might room hfo protocols better optimized individual ards patients in addition ct eit pleural pressure transpulmonary pressure must taken account optimizing ventilator settings individual ards patients transpulmonary pressure stress airway pressure per se determines alveolar size lung volume ventilation transpulmonary pressure alveolar pressure pleural pressure delta transpulmonary pressure lung elastance reported overstretch induced lunginjury occurs alveoli stretched specific threshold level 16 17 animal study protti et al demonstrated lung damage develops strain ratio delta volume functional residual capacity frc > 2 strain delta volume frc delta transpulmonary pressure lung elastance x frc delta transpulmonary pressure specific lung elastance specific lung elastance delta transpulmonary pressure delta lung volume frc lung elastance x frc cmh2o delta lung volume lung volume change frc specific lung elastance transpulmonary pressure makes delta volume b fig 1 chiumello et al elucidated specific lung elastance around 13.5 cmh2o subgroups surgical patients medical patients ali patients ards patients affected peep tidal volume as results transpulmonary pressure greater 13.5 x 2 may represent upper threshold overstretch induced lung injury occurs fig this number 27 cmh2o close recommended upper transpulmonary pressure limit grasso et al showed overinflation starts plateau transpulmonary pressure around 25 cmh2o for example transpulmonary pressure far less 27 cmh2o airway pressure than30 cmh2o physicians increase peep avoid cyclic alveolar collapse permit proper ventilation lungs grasso et al reported patients influenza h1n1)-associated ards ventilatory strategy raising peep plateau pressure maintaining transpulmonary pressure 25 cmh2o lessened possibility respiratory failure patients recovered without use extracorporeal membrane oxygenation ecmo hand patients transpulmonary pressure > 25 cmh2o subsequently deteriorated required ecmo support cases raising peep might resulted overstretch induced lung injury one study proposed optimizing ventilator settings individual ards patients peep adjusted based esophageal pressure measurements patients exhibit excessively high pleural pressures inadequately low peep for example 10 cmh2o peep applied patient 15 cmh2o pleural pressure end expiration transpulmonary pressure would -5 cmh2o level incapable sustaining patency alveoli therefore peep must increased level would result positive transpulmonary pressure end expiration observational study talmor et al showed optimization ventilator settings basedon transpulmonary pressure values significantly improve oxygenation respiratory system compliance one must aware onset spontaneous breathing mechanical ventilation harmful ards patients spontaneous breathing lung protective mechanical ventilation patients ards could induce large negative deflection pleural pressure this large negative pleural pressure could turn increase transpulmonary pressure potentially inducing lung injury yoshida et al demonstrated animal study spontaneous breathing superimposed cv could induce lung injury even plateau pressure kept 30 cmh2o large negative pleural pressure could also increase transcapillary pressure gradient thereby causing pulmonary edema increased work breathing due large increase negative pleural pressure may associated elevated inflammatory cytokine levels
administration nmbas may advisable ease patient inspiratory effort way thus reducing transpulmonary pressure papazian et al demonstrated randomized controlled trial rct short term treatment nmbas 48 hours reduced mortality rates patients early sepsis induced severe ards using animal ards model yoshida et al demonstrated whereas spontaneous breathing could worsen severely injured lungs could alleviate mildly injured lungs since lung recruitment possible latter it worth noting two identical tidal volume settings could result different outcomes depending whether spontaneous breathing permitted yoshida et al suggested cases severe lung injury strong spontaneous breathing efforts high transpulmonary pressure lead increased rate cyclic alveolar opening collapse affected regions surrounding diaphragm however distributionof pleural pressure could inhomogeneous unpredictable expansion lungs inhomogenous rabbits positive pressure ventilation egan showed larger amount closed areas higher regional overdistension ratio inflated volume frc remaining open ones this study implies considerable part lung suffers collapse transpulmonary pressure area adjacent collapsed tissue may become high vacuum effect may produced inside chest wall collapsed tissue therefore must aware imposing positive airway pressure patient imhomogenous lung patient paralyzed nmbas cause much larger transpulmonary pressure pressure predicted healthy lung it technically difficult insert catheter esophagus properly position calibrate when critically ill patients supine position measurements esophageal pressure might result artifacts associated body position pathologic conditions thus rendering less accurate reliable canine ards model pelosi et al found vertical gradient pleural pressure supine position the esophageal pressures closely matched actual pleural pressures surface mid lung animal placed supine position however pleural pressures nondependentand dependent lung legions 7 cmh2o lower 4 cmh2o higher respectively esophageal pressures however airway pressure increased measured pleural pressure regions changed similar fashion this suggests one could estimate precision variations pleural pressure using measured variation esophageal pressure summary authors believe protective ventilatory strategy recommended sscg 2012 report sub optimal ards patients patients individual optimizations ventilator settings the authors would also propose reduce tidal volume use nmbas necessary possible determine peep settings based transpulmonary pressure ards patients failed improve using sscg 2012-recommended ventilatory protocol | the mortality rate among patients suffering acute respiratory distress syndrome ( ards ) remains high despite implementation at clinical centers of the lung protective ventilatory strategies recommended by the international guidelines for management of severe sepsis and septic shock , 2012 .
this suggests that such strategies are still sub - optimal for some ards patients . for these patients ,
tailored use of ventilator settings should be considered , including : further reduction of tidal volumes , administration of neuromuscular blocking agents if the patient s spontaneous breathing is incompatible with mechanical ventilation , and adjusting positive end - expiratory pressure ( peep ) settings based on transpulmonary pressure levels . |
head neck cancer sixth common type cancer world representing 6% cancer cases worldwide more half million head neck cancer cases 320,000 deaths due head neck cancer estimated occur year eighth cause cancer mortality world head neck cancer higher incidence older people primarily due relationship chronic exposure tobacco smoking alcohol drinking fifty seven per cent newly diagnosed malignancies 71% cancer deaths occur 65 years age more 40% head neck cancers occur patients older 65 years increasing life expectancy it estimated 2030 nearly 70% cancer cases would diagnosed adults age 65 years older india 30,831,190 males 33,998,613 females age group 65 years accounting 5.5% nation population one challenging tasks practicing oncologist today care elderly cancer patient recent years management cancer elderly population adequately addressed patients often represented clinical trials new cancer treatments clinical cancer trials arbitrary upper age limits majority elderly cancer patients less likely receive definitive adequate cancer directed therapy this seen head neck cancers also common malignancies advancing age may associated progressive loss stress tolerance decline functional reserve multiple organ systems high prevalence co morbid conditions limited socioeconomic support reduced cognition higher prevalence depression however aging highly individualized chronologic age may reflect functional reserve life expectancy individual compliance elderly patients intensive multimodality cancer therapy challenging due significant treatment related toxicities logistical demands involved treatments unplanned treatment gaps introduced treatments all factors decrease treatment compliance prolong overall treatment time known detriment therapeutic outcomes cancer directed therapy the present study evaluated compliance elderly hnscc cancer directed therapy knowledge this study one first studies evaluating compliance overall treatment time elderly hnscc patients cancer directed therapy developing nation our study included total forty seven elderly hnscc patients age 65 years older referred radiotherapy various multi disciplinary clinics institute one unit department radiotherapy july 2010 june 2011 the patients assessed per stage site disease general condition performance status pre existing co morbidities purpose study compliance defined patients able complete stipulated treatment intended primary clinic the key factors evaluated compliance overall treatment time included date registration cancer centre radiotherapy registration date surgery date radiation start completion date treatment completion date compliance evaluated regard age stage general condition performance status presence co morbidity intention treatment possible factors affecting compliance statistical analysis done using stata 9.1 software chi square fischer exact test used see strength association two categorical variables for compliant patients overall treatment time calculated day initiation cancer directed therapy completion treatment further study pattern non compliance patients divided early non compliance patients non compliant investigation staging work period mid course non compliance patients non compliant complete diagnostic work treatment decision radiation delivery late non compliance patients non compliant radiation delivery in cohort 47 patients treatment decision taken multi disciplinary clinic radical treatment 68% 32/47 patients whereas remaining 32% 15/47 patients planned receive palliative treatment radical treatment included either radical radiation without chemotherapy 55% 26/47 patients surgery followed postoperative radiotherapy 13% 6/47 patients retrospective analysis patient treatment characteristics the salient features majority 42/47 elderly hnscc presented loco regionally advanced stage iii iv common site malignancy oropharynx 21/47 followed oral cavity 11/47 larynx 9/47 hypopharynx 6/47 regard age distribution 72% 34/47 patients were age group 6574 years whereas 13/47 28% 75 older general condition fair elderly patients 38/47 5/47 elderly patients good general condition remaining 4/47 poor general condition out 47 elderly patients analysis compliance treatment decision revealed 62% 29/47 elderly hnscc patients compliant cancer directed therapy whereas 38% 18/47 patients able complete stipulated treatment for compliant patients overall treatment time calculated day initiation cancer directed therapy completion treatment the median overall treatment time patients subjected radical radiation therapy 52 range 4799 days radical surgery adjuvant radiotherapy 109 95190 days twenty two per cent elderly patients one associated co morbidities factors affecting compliance association categorical variables using statistical analysis chi square fischer exact test mentioned table 2 compliance treatment decreased stage disease increased 80% early stage versus 62% loco regionally advanced stage compliance better elderly patients good fair general condition 63% versus 50% patients poor general condition fifty seven per cent patients one co morbidity compliant treatment whereas compliance increased 63% patients co morbidity p value ns compliance similar regard intention treatment radical 63% vs. palliative 60% advancing age age group 6574years 62% vs. 75 older 62% a analysis pattern non compliance revealed early non compliance therapy seen 5% 1/18 patients whereas majority 14/18 elderly patients showed mid course non compliance only 17% 3/18 patients non compliant treatment course radiation delivery non compliance treatment reported determent parameters disease control survival the assessment patients receiving definitive concurrent chemoradiation either locally advanced medically inoperable nsclc treated rtog studies revealed prolongation ott associated significantly poorer survival 2% increase risk death day treatment prolongation interruptions one week post operative irradiation breast cancer adversely affected overall survival patients head neck cancer analysis treatment compliance radiation therapy oncology group rtog prospective randomized trials 1978 1991 reported significantly reduced three year loco regional control 13% vs. 27% three year absolute survival 13% vs. 26% patients prolongation treatment 14 days similarly numerous studies demonstrated non compliance treatment protocols impedes local control head neck cancers these studies describe loss local control 0.4% 2.9% day treatment course prolonged average 1.7% per day recent analysis critical impact radiotherapy compliance treatment advanced head neck cancers trans tasman radiation oncology group trog 02.02 trial revealed patients major deficiencies treatment plans markedly inferior outcome(i.e deviations versus compliance regards treatment results2 years overall survival 50% vs. 70% freedom loco regional failure 78% vs. 54% head neck squamous cell carcinoma may geographical variation regard site stage presentation treatment compliance survival amidst pre existing geographical variation inferior treatment compliance survival asian population compliance elderly hnscc patients is utmost importance advancing age may construed progressive loss stress tolerance ii decline functional reserve multiple organ systems iii high prevalence co morbid conditions iv limited socioeconomic support v reduced cognition vi higher prevalence depression may reasons poor treatment compliance present study elderly hnscc patient compliance study comparable overall treatment compliance hnscc patients previously reported subcontinent overall treatment time prolonged patients subjected radical surgery adjuvant radiotherapy median ott 109 days whereas delays patients receiving radical radiotherapy median ott 52 days elderly patients cancer may often preexisting medical co morbidities especially related chronic exposure tobacco smoke alcohol the secondary aim study see burden co morbidities elderly hnscc patients associated co morbidities present 23% elderly hnscc patients burden co morbidity less compared reported literature presence co morbidity patients associated decreased compliance however difference compliance statistically significant similarly study find statistical significant association compliance age stage performance condition general condition intent treatment the factors influencing compliance elderly patients remain complex need elucidated the highlights study
pattern elderly hnscc patient non compliance revealed majority elderly patients 83% non compliant treatment initiation radiation therapy this bit surprising result elderly patients expected non compliant treatment course radiation therapy development increased acute radiation morbidity worsening performance status poor tolerance.to knowledge present study first study report early mid course non compliance cancer directed therapy elderly hnscc patients per available records reasons early mid course non compliance finding the probable explanation could long median radiation waiting two months cancer center elderly patients may preferred early cancer directed therapy cancer centers further possibility upstaging disease progression radiation waiting period ignored majority patients already loco regionally advanced stage this aspect early mid course non compliance cancer directed treatment emerged predominant factor study needs evaluated especially developing countries much load available machines cancer patient population probably outnumbered available resources the pattern elderly hnscc patient non compliance revealed majority elderly patients 83% non compliant treatment initiation radiation therapy this bit surprising result elderly patients expected non compliant treatment course radiation therapy development increased acute radiation morbidity worsening performance status poor tolerance knowledge the present study first study report early mid course non compliance cancer directed therapy elderly hnscc patients per available records reasons early mid course non compliance finding could evaluated the probable explanation could long median radiation waiting two months cancer center elderly patients may preferred early cancer directed therapy cancer centers further possibility upstaging disease progression radiation waiting period ignored majority patients already loco regionally advanced stage this aspect early mid course non compliance cancer directed treatment emerged predominant factor study needs evaluated especially developing countries much load available machines cancer patient population probably outnumbered available resources limitations study include
retrospective nature study small number patients.in view retrospective nature study factors non compliance could elicited other factors could influence non compliance available include poor socio economic status b lack social family support c distance treatment centre.elderly patients subjected comprehensive geriatric assessment treatment decisions.while medical record documented non compliance underlying reasons behind non compliance could determined retrospective nature study small number patients view retrospective nature study other factors could influence non compliance available include poor socio economic status b lack social family support c distance treatment centre elderly patients subjected comprehensive geriatric assessment treatment decisions medical record documented non compliance underlying reasons behind non compliance could determined in recent years improvements treatment modalities techniques made delivery cancer directed therapy safe feasible elderly hnscc patients non compliance treatment patients could pose obstacle delivery effective health care our findings india small cohort elderly hnscc patients showing issues early mid course non compliance pattern need evaluated a larger prospective study performing comprehensive geriatric assessment evaluating role comprehensive interventions combining cognitive behavioural affective components improve compliance elderly patients warranted | backgroundtreatment compliance of elderly patients to intensive multi - modality cancer therapy can be challenging and has not been adequately addressed in developing countries .
the present study evaluated compliance of elderly head and neck carcinomas patients to cancer - directed therapy.methodsforty-seven elderly hnscc patients were evaluated in the present study .
patients were assessed as per stage and site of disease , general condition , performance status , and any pre - existing co - morbidities .
compliance was defined as patients who were able to complete cancer therapy as intended at primary clinic .
non - compliance to therapy was stratified as early , mid- and late - course non - compliance .
statistical analysis was done using stata 9.1 software , chi - square / fischer s exact test to see strength of association between two categorical variables that could possibly affect compliance in elderly patients.resultssixty-eight per cent of elderly patients were subjected to radical treatment , majority ( 42/47 ) presented in loco - regionally advanced stage ( iii iv ) , most common site of malignancy was oropharynx ( 21/47 ) .
sixty - two per cent of elderly hnscc patients were compliance to cancer therapy .
median overall treatment time for patients subjected to radical radiation therapy was 52 ( range 4799 ) days , and for radical surgery and adjuvant radiotherapy was 109 ( 95190 ) days .
compliance to therapy for elderly hnscc patients was not significantly associated with advanced stage , poor general condition , intent of treatment or presence of co - morbidity .
as regards to non - compliance , majority ( 14/18 ) of elderly patients showed mid - course treatment non-compliance.conclusionsnearly two - thirds of elderly head and neck carcinoma patients were compliant to cancer - directed therapy . |
service authors readers journal provides supporting information supplied authors such materials peer reviewed may reorganized online delivery copyedited typeset technical support issues arising supporting information missing files addressed authors | abstractmacrocyclization can be used to constrain peptides in their bioactive conformations , thereby supporting target affinity and bioactivity . in particular , for the targeting of challenging protein
protein interactions , macrocyclic peptides have proven to be very useful .
available approaches focus on the stabilization of helices , which limits their general applicability . here
we report for the first time on the use of ringclosing alkyne metathesis for the stabilization of an irregular peptide secondary structure .
a small library of alkynecrosslinked peptides provided a number of derivatives with improved target affinity relative to the linear parent peptide .
in addition , we report the crystal structure of the highestaffinity derivative in a complex with its protein target 1433. it can be expected that the alkynebased macrocyclization of irregular binding epitopes should give rise to new scaffolds suitable for targeting of currently intractable proteins . |