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2005 detailed polyphasic study reclassification genus thermoactinomyces present the genus laceyella four recognized species namely laceyella putida l. sacchari type species genus laceyella laceyella sediminis laceyella tengchongensis cells aerobic non acid fast produce endospores chemo organotrophic l. sacchari strain gs 1 1 isolated hot spring chumathang leh ladakh india n 32 58 e78 15 height 4600 sea level genomic dna extracted 36 h old culture using zr fungal bacterial dna miniprep per manufacturer instructions the genome l. sacchari strain gs 1 1 sequenced using illumina hiseq 1000 paired end technology produced total 40,874,820 paired end reads paired distance insert size 330 bp 101 bp clc bio workbench v6.0.2 clc bio denmark employed preprocessing data trim remove low quality sequences a total 40,668,128 high quality vector filtered reads 1194 times coverage used assembly clc bio workbench word size 45 bubble size 98 the final assembly contains 42 contigs total size 3,324,316 bp n50 contig length 249,341 bp largest contig assembled measures 698,403 bp this draft genome comprising 3,324,316 bp annotated help rast rapid annotation using subsystem technology system server a total 3429 predicted coding regions cdss 6 rrnas 69 trnas predicted rast indicates strain geobacillus thermodenitrificans strain ng80 2 score 502 geobacillus kaustophilus strain hta426 score 471 geobacillus sp strain g11mc16 score 436 closest neighbors strain gs 1 1 the strain gs 1 1 contains genes glycolysis gluconeogenesis tca cycle pentose phosphate pathway genes alkaline phosphatase ec 3.1.3.1 ferroxidase ec 1.16.3.1 manganese superoxide dismutase ec 1.15.1.1 shikimate kinase ec 2.7.1.7.1 chorismate synthase ec 4.2.3.5 alcohol dehydrogenase 1.1.1.1 superoxide dismutase fe ec 1.15.1.1 pathogenicity islands also present genome annotation strain gs 1 1 we mapped predicted 3429 cdss kegg pathways help kass server the genome essential pathways dna rna metabolism iron sulfur phosphorus acquisition metabolism pathways fig the l. sacchari strain gs 1 1 whole genome shot gun wgs project deposited ddbj embl genbank project accession aszu00000000 project 01 accession numbers aszu00000000 consists sequences aszu01000001aszu01000042 the authors declare conflict interest work published paper

we report the 3.3-mb draft genome of laceyella sacchari strain gs 1 - 1 , isolated from hot spring water sample , chumathang , leh , india . draft genome of strain gs 1 - 1 consists of 3 , 324 , 316 bp with a g + c content of 48.8% and 3429 predicted protein coding genes and 75 rnas . geobacillus thermodenitrificans strain ng80 - 2 , geobacillus kaustophilus strain hta426 and geobacillus sp . strain g11mc16 are the closest neighbors of the strain gs 1 - 1 .

basic fasting protocol transfer fish normal density clean tank withhold food longer term fasting requires rigorous conditions e.g. blood glucose studies see additional considerations discussion for 100 ml volume dissolve following distilled water 725 mg nacl 124.1 mm 38 mg kcl 5.1 mm 41 mg na2hpo4 2.9 mm 24 mg mgso47h2o 1.9 mm 16 mg cacl22h2o 1.4 mm 100 mg nahco3 11.9 mm 4 g polyvinylpyrrolidone pvp 4% 1,000 usp units heparin filter sterilize store 4c cover microscope base plastic wrap protection case spills put paper towel top plastic wrap this eliminate minimize focal adjustment fish surgical table cover microscope base plastic wrap protection case spills put paper towel top plastic wrap pre adjust focus viewing surgical table focusing sponge weigh fish fill 500 ml beaker 1/3 full fish facility water wick excess water away net fish briefly dabbing net paper towels wick excess water away net fish briefly dabbing net paper towels recommend 35 g beveled steel needle 10 l nanofil microsyringe it important remove bubbles syringe tubing filling syringe tubing mount syringe pump program injection volume first fish prepare surgical table cut soft sponge l800-d jaece industries approximately 20 mm height flat face set petri dish sponge suitably sized pipette tip box lid the lid needs large enough hold water help maintain sponge temperature shallow enough get way we use lid p200 tip box 11.4 cm l x 7.7 cm w x 1.5 cm d. three items assembled together sponge petri dish box lid constitute surgical table cut soft sponge l800-d jaece industries approximately 20 mm height flat face make cut 10 15 mm deep set petri dish sponge suitably sized pipette tip box lid the lid needs large enough hold water help maintain sponge temperature shallow enough get way we use lid p200 tip box 11.4 cm l x 7.7 cm w x 1.5 cm d. prepare anesthetic tip using typical ice cube trays take 3 trays anesthetize 10 12 fish put surgical table larger container 2.4 liter rubbermaid food storage container pour facility water warm outer container surgical table put surgical table larger container 2.4 liter rubbermaid food storage container pour facility water warm outer container surgical table important n't go 17c step use net transfer fish outer container slowly add ice chips container bring temperature 12c course several minutes monitor fish behavior 17c slightly lower fish typically spread pectoral fins horizontally gasp rapid operculum movements temperature drops fish swim slowly finally stop swimming surgical plane anesthesia is approached gasping stop operculum movements slow fish ready injection react handled fish as required temperature reached ~12c colder press sponge saturate keep fingers cold water sufficiently warm fish bring anesthesia handling cold fingers gently transfer fish trough sponge position fish abdomen gills trough quickly transfer surgical table microscope stage working quickly carefully insert needle midline pelvic fins needle point cranially inserted closer pelvic girdle anus able feel needle deep body wall inject appropriate volume withdraw needle after injection immediately transfer fish back warm water ~28.5c tank recovery releasing fish sponge tank water tip fish begin swimming immediately help recover gently swirling water towards gills occasionally scale may attached removed prior next injection subsequent injections use warm facility water bring anesthetic chamber water temperature back 17c introducing next fish the basic fasting protocol transfer fish normal density clean tank withhold food longer term fasting requires rigorous conditions e.g. blood glucose studies see additional considerations discussion for 100 ml volume dissolve following distilled water 725 mg nacl 124.1 mm 38 mg kcl 5.1 mm 41 mg na2hpo4 2.9 mm 24 mg mgso47h2o 1.9 mm 16 mg cacl22h2o 1.4 mm 100 mg nahco3 11.9 mm 4 g polyvinylpyrrolidone pvp 4% 1,000 usp units heparin filter sterilize store 4c cover microscope base plastic wrap protection case spills put paper towel top plastic wrap this eliminate minimize focal adjustment fish surgical table cover microscope base plastic wrap protection case spills put paper towel top plastic wrap pre adjust focus viewing surgical table focusing sponge weigh fish fill 500 ml beaker 1/3 full fish facility water wick excess water away net fish briefly dabbing net paper towels wick excess water away net fish briefly dabbing net paper towels recommend 35 g beveled steel needle 10 l nanofil microsyringe it important remove bubbles syringe tubing filling syringe tubing mount syringe pump program injection volume first fish prepare surgical table cut soft sponge l800-d jaece industries approximately 20 mm height flat face set petri dish sponge suitably sized pipette tip box lid the lid needs large enough hold water help maintain sponge temperature shallow enough get way we use lid p200 tip box 11.4 cm l x 7.7 cm w x 1.5 cm d. three items assembled together sponge petri dish box lid constitute surgical table cut soft sponge l800-d jaece industries approximately 20 mm height flat face make cut 10 15 mm deep set petri dish sponge suitably sized pipette tip box lid the lid needs large enough hold water help maintain sponge temperature shallow enough get way we use lid p200 tip box 11.4 cm l x 7.7 cm w x 1.5 cm d. prepare anesthetic tip using typical ice cube trays take 3 trays anesthetize 10 12 fish put surgical table larger container 2.4 liter rubbermaid food storage container pour facility water warm outer container surgical table put surgical table larger container 2.4 liter rubbermaid food storage container pour facility water warm outer container surgical table important n't go 17c step use net transfer fish outer container slowly add ice chips container bring temperature 12c course several minutes monitor fish behavior 17c slightly lower fish typically spread pectoral fins horizontally gasp rapid operculum movements temperature drops fish swim slowly finally stop swimming surgical plane anesthesia is approached gasping stop operculum movements slow fish ready injection react handled fish required temperature reached ~12c colder press sponge saturate keep fingers cold water sufficiently warm fish bring anesthesia handling cold fingers gently transfer fish trough sponge position fish abdomen gills trough quickly transfer surgical table microscope stage working quickly carefully insert needle midline pelvic fins needle point cranially inserted closer pelvic girdle anus able feel needle deep body wall after injection immediately transfer fish back warm water ~28.5c tank recovery releasing fish sponge tank water tip fish begin swimming immediately help recover gently swirling water towards gills occasionally scale may attached removed prior next injection subsequent injections use warm facility water bring anesthetic chamber water temperature back 17c introducing next fish intraperitoneal injection involves five steps fasting weighing anesthetizing injection recovery step there this practice taken fish veterinary literature e.g. brown 1993 longer term fasting found 72-hour fast required decrease blood glucose baseline level prior injection eames et al 2010 we also found glucose studies several procedures required ensure fish fasted properly tanks offline clearly labeled fasting location enthusiastic fish care personnel feed evaluate external environment tank take steps prevent fish stressed disturbances stress known raise blood glucose chavin young 1970 groff et al for example fasting experiment radio operated daily bench holding fish tanks we found blood glucose unusually high concluded fish stressed vibrations fish kept density conforms good fish husbandry practices recommendations we good results fasting fish density 10 12 fish 9 liter tank 3 layers marbles taking volume separating sexes may cause stress recommend maintaining mixed sex population fast this means eggs laid eggs need sequestered eaten a simple way sequester eggs cover tank bottom 2 3 layers marbles water quality needs maintained removing eggs waste replacing 10 15% tank water daily removing eggs waste siphoning works well weighing weighing fish anesthetized care taken minimize water transfer net beaker ensure accurate weighing if net fish blotted paper towels majority excess water removed weight accurately measured it may easier anesthetize fish prior weighing tested possible effects anesthetizing fish twice one day we tested technique weighing fish first netting blotting method weighing fish anesthetized gently blotted dry we found significant difference weight methods p 0.7927 test additionally tested whether netting blotting method affected blood glucose comparison simply transferring fish beaker soon netted blotting we found significant difference blood glucose level two transfer methods p 0.2241 test here demonstrated cold water anesthesia alternative many anesthetics including tricaine ms-222 brown 1993 raise blood glucose previous studies determined cold water raise blood glucose zebrafish eames et al 2010 cold water anesthesia temperature decreased slowly the rate decrease seems depend size fish smaller fish going faster larger fish following injection may observe fish recovering slowly anesthetic see this result either starting temperature low temperature decreased rapidly the starting temperature low fish bends laterally upon entering water it rotate pectoral fins horizontal position gasp rapid operculum movements movements decrease fish lose equilibrium surgical plane anesthesia is reached fish handled without reacting maintain fish surgical anesthesia fingers must cold keep water prior handling fish the sponge must also kept cold temperature water used anesthetizing fish it important saturate sponge water sufficiently cold maintain anesthesia fish placed onto injection prior undertaking injections may want dissect least one fish get sense body wall thickness this help judge far needle needs insert enter abdominal cavity additionally insert needle feel body wall give needle enters abdominal cavity injection make sure sponge saturated correct temperature cold water prevent fish reviving injection a well saturated soft sponge important minimizing damage scales mucus covering skin finally fish anesthetized work quickly minimize time fish recovery fish recover anesthesia virtually upon entering warm tank water fish begin swimming immediately gently swirl water towards gills speed recovery recovery slow fish went quickly adjust anesthesia procedure appropriately

a convenient method for chemically treating zebrafish is to introduce the reagent into the tank water , where it will be taken up by the fish . however , this method makes it difficult to know how much reagent is absorbed or taken up per fish . some experimental questions , particularly those related to metabolic studies , may be better addressed by delivering a defined quantity to each fish , based on weight . here we present a method for intraperitoneal ( ip ) injection into adult zebrafish . injection is into the abdominal cavity , posterior to the pelvic girdle . this procedure is adapted from veterinary methods used for larger fish . it is safe , as we have observed zero mortality . additionally , we have seen bleeding at the injection site in only 5 out of 127 injections , and in each of those cases the bleeding was brief , lasting several seconds , and the quantity of blood lost was small . success with this procedure requires gentle handling of the fish through several steps including fasting , weighing , anesthetizing , injection , and recovery . precautions are required to minimize stress throughout the procedure . our precautions include using a small injection volume and a 35 g needle . we use cortland salt solution as the vehicle , which is osmotically balanced for freshwater fish . aeration of the gills is maintained during the injection procedure by first bringing the fish into a surgical plane of anesthesia , which allows slow operculum movements , and second , by holding the fish in a trough within a water - saturated sponge during the injection itself . we demonstrate the utility of ip injection by injecting glucose and monitoring the rise in blood glucose level and its subsequent return to normal . as stress is known to increase blood glucose in teleost fish , we compare blood glucose levels in vehicle - injected and non - injected adults and show that the procedure does not cause a significant rise in blood glucose .

neuropathic pain defined pain arising direct consequence lesion disease affecting somatosensory system,1 disorder considerably affect quality life patients even though 5% general population could involved treatment neuropathic pain continues challenging due inadequate effectiveness systemic therapies frequent central side effects.2 wide area peripheral neuropathic pain identification specific neuropathic pain syndromes affect circumscribed area body may drive clinical decision use targeted localized treatment(s characterized consistent circumscribed area(s maximum pain associated negative positive sensory signs3 localized neuropathic pain lnp according relevant guidelines,46 5% lidocaine medicated plaster could considered first line treatment option lnp due good efficacy safety profile especially elderly patients comorbidities quite often present polypharmacy poorly tolerated 83% patients post herpetic neuralgia phn complain lnp syndrome,3 5% lidocaine medicated plaster showed better effectiveness versus placebo7,8 substantially better pain relief pregabalin,9,10 fewer systemic side effects even long term treatment.1113 several different mechanisms sustain phn,14 including peripheral inflammation nerve damage denervation peripheral central sensitization lidocaine acts blocking abnormally functioning sensitized nav 1.7 nav 1.8 sodium channels dermal nociceptors,15 thereby reducing ectopic discharges raise peripheral ectopic discharge threshold.15 topical 5% lidocaine plaster affect beta fibers cause paresthesia and/or numbness.16 finally passive protective action plaster reported.810 cohort patients lnp due nerve trauma,17 5% lidocaine medicated plaster showed optimal efficacy reducing pain size painful area knowledge structured trial investigated possible new endpoint phn patients first eight phn patients treated versatis 5% plaster grunenthal germany drug approved italy may 2013 investigated whether could helpful reducing pain allodinic static and/or dynamic areas allodynia phenomenon normally nonpainful stimuli perceived painful clinical sign peripheral central sensitization the two components differentiated using different types stimuli ie peripheral sensitization evoked static mechanical stimulation static mechanical allodynia whereas allodynia dynamic mechanical stimulation result central sensitization while static component found injured area dynamic component also extends halo undamaged tissue surrounding injury.18 consistent literature following approval italy 5% lidocaine medicated plaster used group phn patients untreated lnp lnp inadequately controlled side effects systemic drugs following hospital administrative rules patients signed informed consent allowing anonymous use clinical data research purposes accordance clinical practice patients screened first visit followed 15 30 90 days patients could telephone ask another consultation experienced side effects inadequate analgesia visits recorded daily pain intensity mean least worst using numeric rating scale paresthesia dynamic allodynia scale 0 none 5 worst imaginable static allodynia von frey hair test caliber 0 worst allodynia 18 normal sensation von frey monofilaments perceived painful we used well established von frey hair set touch test sensory evaluators north coast medical inc morgan hill ca usa 5.07 caliper corresponding 10 g applied 1.5 seconds delivers clear mechanical suprathreshold nonpainful stimulus the area statical tactile allodynic area measured cm first visit patients instructed regarding apply 5% lidocaine medicated plaster painful areas intact skin allowed use maximum three plasters 12 hours day depending clinical results seen follow reduced systemic analgesic medication good pain relief least 30% achieved eight patients phn lnp five men three women observed may september 2013 their mean age 77.757.10 range 6989 years mean body mass index bmi 28.15.5 kg the acute episode herpes zoster occurred mean 3.73.6 years earlier the rash affected trunk cases except one patient whose left hand affected all patients polypharmacy taking mean 42 nonanalgesic drugs comorbid conditions all patients reported tried least one systemic drug pain relief antidepressant anticonvulsant and/or opioids inadequate pain control five patients good pain control severe side effects three patients one patient reported accidental fall rib fracture due dizziness anticonvulsant treatment the patients reported good pain relief 45.00%19.75% early 2 weeks start topical therapy improvement treatment continued 52.00%23.87% month 1 60.00%18.70% month 3 reduction cessation systemic treatment six patients table 1 paresthesia dynamic allodynia decreased significantly 3 months 2.881.64 1.201.10 3.750.71 1.801.64 respectively we observed similarly consistent reduction static allodynia 8.633.58 14.000.82 3 months the allodynic static dynamic area measured five eight patients thoracic phn figure 1a the area became progressively smaller baseline measurement 236.38140.34 cm 128.8095.7 cm one month 46% reduction p=0.129 81.3859.19 cm 3 months 66% reduction p=0.02 reduction size area a pronounced reduction observed height 50% length 33% affected area figure 1b neuropathic pain continues challenging clinical problem.2 people neuropathic pain often elderly may several comorbidities high risk drug drug interactions presents serious limitation therapy.19 achieve good pain relief often necessary give combination two drugs,20 increases risk drug drug interactions side effects the mainstay treatment neuropathic pain still adequate personalized therapy based understanding pain pathophysiology patient clinical features.21 majority patients evaluated case series complained limited effectiveness pain treatments and/or side effects systemic treatment phn pain several months years patient refers lnp correctly diagnosed according validated diagnostic algorithm,22 more recent guidelines4,5 suggest topical products first line therapeutic option since better tolerated systemic effects drug drug interactions better patient compliance.9,10,23,24 case series reflects common clinical aspects the main mechanism therapeutic action lidocaine blockade voltage gated sodium channels.15,25 however topical lidocaine may peripheral actions desensitizing effect trpa1 channels contributing nonanesthetic analgesic effects.26 thus reduction peripheral sensitization could attributed blockade pathological sodium channel expression desensitization trpa1 channels a characteristic feature phn presence area primary hyperalgesia static mechanical thermal allodynia within damaged area secondary hyperalgesia dynamic mechanical allodynia surrounds first area).27 static mechanical allodynia mainly mediated sensitized peripheral nociceptors dynamic component probably consequence altered processing large diameter primary afferent inputs central nervous system these alterations least partially maintained barrage nociceptor activity normal abnormal inputs.27 importance ongoing activity maintain secondary hyperalgesia completely elucidated even though patients neuropathic pain secondary hyperalgesia allodynia seen critically dependent continuous afferent input.18 hence 5% lidocaine medicated plaster could act adding blockade pathological sodium trpv1 channels reduction mechanical noxious non noxious inputs via protective action plaster this reduction peripheral inputs could contribute reducing primary secondary sensitization consequently size painful area,28,29 also suggested healthy volunteer study.30 study mean size painful area 236.38140.34 cm agreement data literature.31 regarding reduction static allodynic area noticed much greater reduction height number metameres involved rather length area nerve involved painful area phn the secondary hyperalgesic area mainly distributed primary painful area dermatome overlapping innervation anatomically present it could arguable neural plasticity induced treatment may evident peripheral areas secondary hyperalgesia.18 hence treatment could another important clinical effect reduction allodynic area also suggested study lnp recent onset.17 fact 50% reduction size painful area recorded even though patients complaining phn several months years due small number patients possible evaluate reduction size painful area related time onset phn pronounced reduction static rather dynamic allodynia nevertheless case series highlights possible role chronic topical treatment treating lnp also reducing size painful area these data confirmed appropriately designed controlled trials investigating endpoint well mechanisms activity 5% lidocaine medicated plaster ie whether acts primary rather secondary hyperalgesia whether time onset phn lnp could predictive factor efficacy

post - herpetic neuralgia ( phn ) is neuropathic pain persisting after an acute episode of herpes zoster , and is associated with severe pain and sensory abnormalities that adversely affect the patient s quality of life and increase health care costs . up to 83% of patients with phn describe localized neuropathic pain , defined as a type of neuropathic pain characterized by consistent and circumscribed area(s ) of maximum pain . topical treatments have been suggested as a first - line treatment for localized neuropathic pain . use of 5% lidocaine medicated plaster could reduce abnormal nervous peripheral discharge and via the plaster could have a protective function in the affected area . it has been suggested that use of this plaster could reduce pain as well as the size of the painful area . to evaluate this possible outcome , we retrospectively reviewed eight patients with phn , treated using 5% lidocaine medicated plaster . during a follow - up period of 3 months , we observed good pain relief , which was associated with a 46% reduction in size of the painful area after one month ( from 236.38140.34 cm2 to 128.8095.7 cm2 ) and a 66% reduction after 3 months ( 81.3859.19 cm2 ) . our study cohort was composed mainly of elderly patients taking multiple drugs to treat comorbidities , who have a high risk of drug drug interactions . such patients benefit greatly from topical treatment of phn . our observations confirm the effectiveness of lidocaine plasters in the treatment of phn , indicating that 5% lidocaine medicated plaster could reduce the size of the painful area . this last observation has to be confirmed and the mechanisms clarified in appropriate larger randomized controlled trials .

nephrotic syndrome ns children usually idiopathic may also triggered immunological stimuli like vaccination infection insect sting pollen hypersensitivity humoral cellular immune function studies suggest abnormal immune response probable cause clinical entity bee sting implicated development ns occurrence children rarely reported literature these patients need shorter course steroids show excellent response low risk relapse a 2-year old boy hospitalized generalized edema decreased urine output 4-day duration facial swelling developed initially edema extended legs eventually affecting entire body there history bee sting dorsal aspect right hand 7 days earlier resulted severe pain redness local swelling 48 hours he history atopy similar episodes past physical examination afebrile facial edema pitting pedal edema abdominal distension his blood pressure normal 90/60 mm hg bee sting mark visualized dorsum right hand figure 1 laboratory investigations revealed hemoglobin 13.7 g dl white blood cell count 25 400/ mm 35% neutrophils 58% lymphocytes 5% eosinophils 2% monocytes platelet count 331 000/mm his erythrocyte sedimentation rate 69 mm hr peripheral smear showed normocytic normochromic red blood cells leukocytosis adequate platelets he decreased serum proteins total protein 3.9 g dl albumin 1.5 g dl elevated serum cholesterol 382 mg dl normal renal parameters blood urea 34 mg/ dl creatinine 0.37 mg/ dl urine analysis revealed 3 proteinuria 24-hour urinary protein excretion 0.9 g. complement c3 level 1.16 g dl 0.90 1.80 g dl immunoglobulins profile showed iga 0.32 g dl 0.14 1.59 g dl igm 0.9 g/ dl 0.43 2.07 g dl igg 2.92 g dl 3.45 12.36 g dl ige 245 iu l 230 chest x ray normal ultrasound revealed free fluid abdomen bee sting dorsum right hand admission managed symptomatically diuretics salt fluid restriction laboratory results started oral prednisolone 2 mg kg day the boy progressively improved diuresis set fifth day edema regressed seventh day urine became albumin free 10 day admission corticosteroids changed alternate day regimen tapered gradually 8 weeks withdrawn regular 1-year follow end treatment boy remained well without recurrence ns childhood triggered immunological stimuli including infection vaccination insect bites pollen drug induced hypersensitivity bee stings usually followed minor local allergic reactions rarely anaphylactic delayed hypersensitivity reactions other reported systemic complications following multiple bee stings include acute renal failure arf myocarditis myocardial infarction centrilobular necrosis liver acute encephalopathy guillain barre syndrome vasculitis disseminated intravascular coagulation thrombocytopenia though causal relationship association bee stings development ns long described report demonstrated presence bee venom antigens glomeruli ns develop even single bee sting like case occurred within 7 days the cause effect relationship bee sting renal disease speculative made basis temporal association it postulated components bee venom mediate immunological disturbances involvement lymphocytes cytokine secretion influencing permeability glomerular basal membrane consequent development proteinuria pathologic findings ns following bee sting diverse include minimal change lesions mesangial proliferative glomerulonephritis membranous glomerulonephritis glomerulosclerosis arf following multiple bee stings attributed acute tubular necrosis due hypotension pigment nephropathy resulting rhabdomyolysis intravascular hemolysis acute interstitial nephritis most reported cases favorable clinical course corticosteroid treatment case steroids shortened duration disease relapse chronic renal disease far reported cytotoxic agents may also induce remission occasional steroid resistant cases conclusion though rare children insect stings particularly bee stings must closely followed multiple problems especially immune mediated complications ns

the occurrence of nephrotic syndrome following a bee sting is rarely reported in the literature . hypersensitivity is believed to be the precipitating factor for the renal disease . we report a two - year - old boy , who developed generalized edema and decreased urine output , seven days after a bee sting . physical examination and laboratory findings were consistent with nephrotic syndrome ; and corticosteroid treatment induced prompt remission with resolution of clinical symptoms and normalization of laboratory findings . there was no relapse of the disease during a one - year follow up .

emergency department ed use common children adults country without universal health insurance like united states also countries like france virtually residents health insurance 2006 the annual rate ed visits parisian children less 2 years old ranged according district 46.9 91.3 per 100 children many visits true emergencies ed physicians insurers policy makers researchers consider inappropriate nonurgent minor complaints could dealt primary care offices either following day durand colleagues found studies variety countries around world estimates nonurgent visits adults children ranged 4.8% 90% median 32% one reason variation inconsistency defining nonurgent pointed also mistry colleagues pediatric ed visits recent figures pediatric nonurgent visits include 58% united states 57.1% italy 39.9% belgium in many cases parents even try contact primary care physician 79 furthermore go eds even though often long waits children likely undergo testing treatment doctors ed physicians know medical histories usually provide follow many cases costs higher many researchers therefore tried understand parents decide bring children eds they hope find reduce unnecessary ed visits thereby improve continuity care lessen overcrowding eds distraction true emergencies diversion ambulances less crowded distant eds 11 12 decrease health care expenses 6 11 13 14 reasons given parents decisions go pediatric eds peds even without referral children primary care physicians include seek quick convenient solution health issue 1 8 10 1518 view ped best place go better physicians and/or medical equipment 1 5 7 8 10 17 19 dissatisfied primary care physician office physician diagnosis and/or treatment 8 15 20 worried child health 8 15 17 21 financial straits 17 20 habit going ed 1 7 8 access care 1 17 19 the methodologies mentioned studies based broad theory human motivation may result neglected important motives study therefore examined parental motives applying michael apter metamotivational theory mtt 23 24 encompasses systematizes great diversity human motives including theoretically possible categories motives questionnaire could ensure psychologically complete possible parental motive missed objectives study inventory motives going peds b order motives categories motives function importance c find demographic characteristics associated motives the study approved ethics committee children hospital toulouse the participants parents attending ped children hospital tertiary level pediatric hospital toulouse france the research assistant invited parents every child participate informed survey obtained oral consent agreed participate the first questionnaire contained 69 items referring motives going ped table 1 forty eight items created members research team inspired mmt see table 5 medical literature cited personal experience physicians items purposely systematically created correspond mmt categories motives this questionnaire presented focus group parents reformulated items judged ambiguous suggested additional items based personal experiences parents the new questionnaire presented another focus group process repeated saturation occurred the common wording items questionnaireone reasons came ped today childwas chosen acknowledge several motives could operating time the second questionnaire asked demographics previous ed use prior doctor visits illness participants responded individually waiting room children seen parents present one filled questionnaires one could confer the research assistant cases present process order influence they indicated much agreed statement first questionnaire putting mark 10-point response scale one the treating physician subsequently indicated severity child illness scale 1 severe 2 mildly severe 3 severe)and whether child hospitalized the character study exploratory confirmatory exploratory factor analyses using two thirds sample exploratory factor analysis statistical technique used reduce number variables smaller set unobserved factors the variables within factor empirically highly correlated variables if correlation items factor lower 0.30 means low items removed analysis confirmatory factor analysis statistical technique used test whether set factors obtained exploratory factor analysis data one sample fits data observed another sample exploratory factor analysis conducted useable items confirmatory analysis should done representative manageable subset items namely three items highest loadings highest correlations factor within factors found exploratory analysis therefore exploratory factor analysis requires larger sample size confirmatory analysis calculated case 2 1 the sample size 500 determined accordance technical requirements factor analysis maximum expected number factors 10 our choice 10 based analysis previous studies reasons go ed table 1 shows mean ratings scale 1 10 item exploratory factor analysis using first subsample n 332 thirteen 69 items load factor correlation item factor .30 means low six interpretable independent factors emerged namely 1 considered others responsible parents explained 13% variance 2 empathic concern child suffering 8% variance 3 seeking quick diagnosis treatment reassurance 12% 4 dissatisfaction previous consultation 7% 5 ped best place 7% 6 external factors 5% family physician absence impossibility borrowing money recommendation service provides urgent home visits the results confirmatory factor analysis conducted three items highest loadings six factors using second subsample n 168 shown table 3 the mean scores factor final model 10-point scale range 1.79 dissatisfaction previous consultation 6.82 seeking quick diagnosis treatment reassurance ) table 4 shows correlations demographic characteristics severity indices subsequently judged physicians motives seeking quick diagnosis treatment reassurance significantly strongly endorsed parents one child parents one considering ped best place go given higher rating younger fathers older ones empathic concern child suffering given higher rating parents one child being considered others responsible parents stronger motive parents boys girls younger mothers less educated parents parents likely go eds without first consulting regular physician stronger motive cases judged treating physician lesser severity finally external factors strongly endorsed motives parents older children siblings cases symptoms recently appeared the aim study make inventory motives parents bringing children peds using broad theoretical framework we found studies 8 15 17 21 parents endorsed wide variety motives finding factors meant guarantee parents responses meaningful responses sufficiently coherent statistical analysis could reveal clear structure the emergence clear factorial structure also enabled measurement strength motive telic mmt seemed highly goal oriented going ped obtain care saw important this consistent findings countries 8 15 17 26 described guardians worried symptoms represented serious illness important seek medical attention similarly durand colleagues study french adult patients characterized rational consumers contrast abusive irresponsible consumers portrayed ed health professionals interviewed these parents unlikely therefore agree charge large numbers visits peds unwarranted the second highly rated factor ped best place go would called conformist motive mtt their respect ped may stimulated television shows reports media technology specialization available hospitals well united states advertising they may appreciated technology specialized care always beneficial patients empathic concern child suffering received lower overall rating parents strongly endorsed motives labeled sympathy mtt longer able put children suffering they tended parents single child therefore likely less experienced coping sick children it striking however distress child current suffering much less important goal oriented aim obtaining effective treatment the three factors rated quite low overall endorsed parents considered others responsible parents rated highly parents seemed concerned image parents labeled these parents tended younger especially mothers less educated parents go eds frequently their child condition likely judged bad ed physician physicians health services experts especially us often cite structural factors important determinants excessive ed utilization 6 11 13 15 2730 those parents endorsed motives strongly indicated thereby going peds truly personal decision they followed instruction urgent care service could go another medical facility owing absence physician lack money their child illness tended acute child likely others experienced pain and/or fever less 12 hours the lowest average rating dissatisfaction previous consultation negativist motive terminology mmt only parents unhappy care provided family physicians accordance findings countries 8 31 it conducted single site france motives 35% parents declined participate unknown the study results must therefore generalized caution populations children parents sites furthermore even questionnaire based broad theory motivation validated therefore used prospectively confirm results nonetheless findings help illuminate current debate overuse eds access care key issue parents well adult patients therefore focus reform efforts the 2011 national health interview survey united states found among adults went eds admitted hospital 68.9% visiting ed 78.9% least one access issue going ed defined indicating another place go doctor office clinic open ed closest provider and/or clinic open it seems possible reduce ed visits therefore improving access sources care state north carolina without medicaid experience state oregon showed expanding insurance reduce ed use increase accordingly many reformers proposed encouraging pediatric practices expand availability urgent visits 10 30 france tried set primary care units near eds italy requiring primary care offices open 24 hours day 7 days week wang colleagues tested united states pilot ped diversion program children medicaid using extended office hours multiple access locations care coordination reduced ed visits 8 visits per 1000 members per month compared control group diversion program expensive however overall cost care reduced our study demonstrates limits barriers parents perspective success efforts we found parents generally bring children peds serious goal oriented motives similarly united states 2011 national health interview survey found 65.0% adults admitted hospital cited least one acuity issue defined indicating hospital could help advised health provider go ed and/or problem serious doctor office clinic kubicek colleagues found 63% parents bringing children reasons assessed nonurgent perceived visit extremely urgent kalidindi colleagues found parents assessed 94% visits urgent even though 27% urgent visits assessed nonurgent physicians thus even access issues greatly reduced us countries acuity issues would persist consensus population physicians urgent not staff members eds tend define many visits nonurgent label inappropriate feel frustrated 17 31 general eds united states presenting complaints adult patients judged subsequently primary care treatable fact differ judged needing ed care furthermore cresson states speak false urgency situations urgency patient doctors act latter ones capable defining urgency overworked ed physicians well researchers policy makers focus ultimate diagnoses wasted resources forget parents medical knowledge make diagnoses know final diagnoses know illnesses going evolve adams concludes trying discern low acuity conditions putting barriers receiving care denying payment receiving care work better future generations past 38 p. 1174 one logical solution would educate parents better 5 10 17 specifically parents whose characteristics example us study single parents brought eds children medicaid make likely use ed these efforts could involve targeted messaging high utilizers formal instruction far success limited one study 130 families randomly assigned receive educational intervention ped involved reviewing research assistant booklet manage minor illnesses watching 10-minute video 6 months there difference groups ped utilization visits still minor illnesses similarly 90-minute interactive educational activity primary care offices increased 32 parents knowledge fever colds minor trauma increased hours telephone use decrease ed use education may course greater effects groups parents studied done intensively repeatedly yet findings point one possible reason limited impact greater knowledge importance many parents emotional motives anxiety empathetic concern child would expected parents well desire seen caring parent the setting able immediately soothe anxiety distress hospital emergency department it surprising therefore rate ed visits increasing even countries like france extended basic insurance residents when parents france elsewhere think children suffering might seriously ill goal oriented often frightened bring children places immediately available think capable helping children peds thus hendry beattie heaney united kingdom concluded perhaps service design rather patient behavior inappropriate the solution provide anxious parents expanded daytime sick visits 24-hour telephone access even night time home visits currently possible many places the solution may also expand peds provide urgent visit capacity minor illnesses injuries lower cost truly urgent visits places reassurance security peds

parents frequently bring their children to general or pediatric emergency departments ( eds ) , even though many of these visits are judged by others to be nonurgent and inappropriate . this study examined the motives behind parents ' decisions to take their children to a pediatric emergency department ( ped ) . at a ped in toulouse , france , 497 parents rated their level of agreement with each of 69 possible motives representing all categories of human motivation for coming to the ped that day . exploratory and confirmatory factor analyses found evidence for six separable motives , called ( in order of importance ) ( a ) seeking quick diagnosis , treatment , and reassurance ; ( b ) ped as the best place to go ; ( c ) empathic concern for child 's suffering ; ( d ) being considered by others as responsible parents ; ( e ) external factors ; and ( f ) dissatisfaction with previous consultation . conclusions . parents ' motives in bringing their children to the ped are primarily serious and goal - oriented . they are also often emotion based , as would be expected in parents of ill children . the parents would be unlikely to agree that these visits were inappropriate .

south carolina like many cities states historically latinos experienced recent surges immigration small informal enclaves social structures many latinos new communities may lack documentation us residency consequently sampling design took account fact many probability based sampling designs e.g. random digit dialing telephone survey mail survey published list addresses would adequately access hard reach population adult 18 years age latinos attending 2 clinics greater charleston south carolina area serve primarily latino population approached participation face face structured confidential interview names recorded eligible persons included seeking care well accompanying patients since goal collect data latino adults regarding health behavior necessarily linked current illness persons waiting rooms clinic approached interviewer introduced prospective respondent clinic personnel if persons consider latino included study previously used validated surveys designed use latino populations accessed scientific literature consulted question wording relevant present study aims instrument created english pretested initially english flow comprehension following modifications translated spanish spanish the first pretest medical center personnel fluent spanish dealt latino populations following modifications first pretest second pretest conducted latino persons seen clinic different ones used study provide pretest experience instrument similar population after second pretest instrument translated back english wording questions could checked consistency english spanish two trained bilingual interviewers administered survey structured format participant preferred language spanish english reinforced potential respondents anonymous nature survey first questions included assessed acquiring antimicrobial drugs without prescription outside united states corresponding self medication these questions asked get idea health behavior home culture society in addition asked whether respondents believed antimicrobial drugs available united states without prescription second questions included provided assessment importation nonprescription antimicrobial drugs united states context circumstances related behavior third set questions included assessed acquisition nonprescribed antimicrobial drugs within united states we specifically interested scope acquisition nonprescribed antimicrobial drugs bodegas pharmacias stores since behavior suggested study new york city 17 importing nonprescribed antimicrobial drugs acquiring within united states a series questions asked based pretest information gain understanding respondents would engage practices initially descriptive statistics computed gain understanding extent acquisition importation nonprescribed antimicrobial drugs we also computed chi square values examine bivariate relationships importation nonprescribed antimicrobial drugs acquisition nonprescribed antimicrobial drugs united states health beliefs behavior home country access care united states demographic characteristics finally stepwise logistic regression model computed dependent variable acquisition nonprescribed antimicrobial drugs set variables acquired antimicrobial drugs without prescription outside united states believe antimicrobial drugs available united states without prescription health insurance age sex education time united states country birth health status determine best predictors behavior one born united states acquired nonprescribed antimicrobial drugs united states category variable country birth used predictor acquiring nonprescribed antimicrobial drugs instead country birth coded inclusion regression 1 born mexico 2 born elsewhere previously used validated surveys designed use latino populations accessed scientific literature consulted question wording relevant present study aims instrument created english pretested initially english flow comprehension following modifications translated spanish spanish the first pretest medical center personnel fluent spanish dealt latino populations following modifications first pretest second pretest conducted latino persons seen clinic different ones used study provide pretest experience instrument similar population after second pretest instrument translated back english wording questions could checked consistency english spanish two trained bilingual interviewers administered survey structured format participant preferred language spanish english reinforced potential respondents anonymous nature survey first questions included assessed acquiring antimicrobial drugs without prescription outside united states corresponding self medication these questions asked get idea health behavior home culture society in addition asked whether respondents believed antimicrobial drugs available united states without prescription second questions included provided assessment importation nonprescription antimicrobial drugs united states context circumstances related behavior third set questions included assessed acquisition nonprescribed antimicrobial drugs within united states we specifically interested scope acquisition nonprescribed antimicrobial drugs bodegas pharmacias stores since behavior suggested study new york city 17 importing nonprescribed antimicrobial drugs acquiring within united states a series questions asked based pretest information gain understanding respondents would engage practices initially descriptive statistics computed gain understanding extent acquisition importation nonprescribed antimicrobial drugs we also computed chi square values examine bivariate relationships importation nonprescribed antimicrobial drugs acquisition nonprescribed antimicrobial drugs united states health beliefs behavior home country access care united states demographic characteristics finally stepwise logistic regression model computed dependent variable acquisition nonprescribed antimicrobial drugs set variables acquired antimicrobial drugs without prescription outside united states believe antimicrobial drugs available united states without prescription health insurance age sex education time united states country birth health status determine best predictors behavior one born united states acquired nonprescribed antimicrobial drugs united states category variable country birth used predictor acquiring nonprescribed antimicrobial drugs instead country birth coded inclusion regression 1 born mexico 2 born elsewhere four persons initially approached indicated consider latino remaining 273 54 refused provided incomplete information leaving sample 219 a large proportion sample 30.6% believed antimicrobial drugs available united states without prescription the behavior acquiring antimicrobial drugs without prescription outside united states quite common 45.2% indicating done a substantial number persons transported nonprescribed antimicrobial drugs united states 16.4% the primary illnesses bought antimicrobial drugs primarily believe viral respiratory infections among respondents reported bringing back antimicrobial drugs purchased without seeing doctor first reported conditions trying treat included cough 88.9% ear infections 88.9% sore throat 69.4% colds 58.3% when asked whether next trip outside united states would purchase antimicrobial drugs without seeing doctor first bring back country 23.7% sample reported likely likely among persons transported nonprescribed antimicrobial drugs united states primary reason reported mistrust medicines united states comfortable medicines home country 30.6% reasons included following pay less medicines bought home country would bought united states 19.4% avoid going doctor united states 16.7% avoid language barrier care united states 13.9% prepare future illness 13.9% treat someone else medical problem 5.6% acquiring antimicrobial drugs prescribed respondent within united states also common behavior 19.2% among acquired antimicrobial drugs united states without prescription 92.9% reported acquired without prescription stores united states as transportation nonprescribed antimicrobial drugs united states primary illnesses acquired drugs without prescription believe viral respiratory infections among respondents reported acquiring antimicrobial drugs without prescription reported attempting treat gripe flu 97.6% ear infections 97.6% cough 83.3% sore throat 80.9% additionally 97.6% reported acquiring antimicrobial drugs treat diarrhea among persons acquired antimicrobial drugs united states without prescription 64.3% suggested preferable going doctor 26.2% reported cheaper paying doctor visit addition paying prescription only 7.1% group reported acquiring antimicrobial drugs way language barriers tables 2 table 3 show relationship home country behaviors health beliefs access care variables demographic characteristics importing nonprescribed antimicrobial drugs acquiring nonprescribed antimicrobial drugs united states persons acquired nonprescribed antimicrobial drugs united states beliefs practices consistent limited regulations antimicrobial drugs the best predictors acquiring antimicrobial drugs united states without prescription shown table 4 the strongest predictors health beliefs practices consistent limited regulations antimicrobial drugs this study confirms existence large reservoir nonprescription antimicrobial drugs united states used likely inappropriate self medication latino community besides imported many nonprescription drugs are acquired small stores showing organized system nonprescription antimicrobial drug distribution within latino community united states cultural beliefs practice obtaining antimicrobial drugs without prescriptions particularly likely viral respiratory infections reflected antimicrobial drug use patterns latino community united states health beliefs practices instilled countries origin appear maintained even living united states relatively high frequency acquisition nonprescription antimicrobial drugs united states demonstrates previous research has shown persons born united states less likely acquire antimicrobial drugs without prescription within united states 16 fact none latino respondents born united states acquired antimicrobial drugs without prescription united states thus special emphasis patient education made target population instill health beliefs consistent proposed us medical public health communities an additional issue may play role ability encourage appropriate use antimicrobial drugs community problems associated access health care although health insurance distinguishing variable common reasons given respondents importation acquisition nonprescribed antimicrobial drugs united states revolved around economics doctor visits costs medication united states lack health insurance may encourage latinos self medicate antimicrobial drugs first sample recruited single mid sized community thereby limiting generalizability results however many areas united states seen recent large increases latino population these new communities may reflect different practices communities generations latino immigrants e.g. miami new york san antonio second limitation concerns location data collection focusing persons sought treatment health clinic latinos may access care formal health care system would represented study a direction future research would investigate issues antimicrobial drug use broader community sampling frame third results based self reports behavior may somewhat threatening relate interviewer thus reports antimicrobial drug importation acquisition nonprescribed antimicrobial drugs may underreport actual behavior several strategies used try obtain valid reports including multiple pretests clinic staff introduce interviewers potential participants following pretests interview modified contain several instances descriptions antimicrobial drugs names would recognizable latino community moreover each time respondent reported acquiring antimicrobial drugs respondent asked interviewer name drug make sure respondent actually acquired antimicrobial drugs if fact results represent underreporting findings even dramatic nearly 20% acknowledged getting antimicrobial drugs without prescription united states however study one first document problem first knowledge specifically focus importation us acquisition nonprescribed antimicrobial drugs government agencies yet responded problem the south carolina department health environmental control judicious antibiotic use initiative south carolina careful antibiotic use http://www.scdhec.gov/health/disease/sccause their initiatives similar many initiatives focus physician patient education thus far focused latinos nonprescription antimicrobial drug importation local acquisition substantial number persons within us latino community self medicate antimicrobial drugs obtained without prescription inside outside united states adds reservoir drugs united states public health system clinicians aware different health belief systems practices ethnic minority communities patient education materials communicate culturally competent way dangers self medication antimicrobial misuse recent immigrants others latino community us health policies also may need revised consideration given tightening regulations reduce presence nonprescribed antimicrobial drugs increasing access care many latinos

we investigated in a sample of latinos the practices of antimicrobial drug importation and use of nonprescribed antimicrobial drugs . in interviews conducted with 219 adults , we assessed health beliefs and past and present behaviors consistent with acquiring antimicrobial drugs without a prescription in the united states . many ( 30.6% ) believed that antimicrobial drugs should be available in the united states without a prescription . furthermore , 16.4% had transported nonprescribed antimicrobial drugs into the united states , and 19.2% had acquired antimicrobial agents in the united states without a prescription . a stepwise logistic regression analysis showed that the best predictors of having acquired nonprescribed antimicrobial drugs in the united states were beliefs and behavior consistent with limited regulations on such drugs . many persons within the latino community self - medicate with antimicrobial drugs obtained without a prescription both inside and outside the united states , which adds to the reservoir of antimicrobial drugs in the united states .

author receives funding swedish research council ragnar sderbergs stiftelse novonordisk foundation lund university the author also part following strategic research consortia diabetes linnaeus lund university diabetes center ludc funded swedish research council excellence diabetes research sweden exodiab supported swedish government the author responsible conception design drafting manuscript approved final version publication this article distributed terms creative commons attribution noncommercial license permits noncommercial use distribution reproduction medium provided original author(s source credited

common genetic variations in the gene encoding transcription factor 7-like 2 ( tcf7l2 ) reveal the strongest association with type 2-diabetes known to date . these lead to impaired insulin production and output , but the mechanisms of disease remain incompletely known . in this issue of diabetologia , two publications provide new insights into tcf7l2-dependent diabetes .

acquired retinal astrocytoma benign glial intraretinal tumor.1 considered retinal equivalent low grade brain astrocytomas despite benign cytology show progressive growth behave locally aggressive malignant tumor the clinical course complicated exudative retinal detachment vitreous hemorrhage neovascular glaucoma blind painful eye ultimately leading enucleation.23 management acquired astrocytoma remains controversial external beam radiotherapy,2 laser photocoagulation,4 cryotherapy plaque radiotherapy pars plana vitrectomy endoresection5 previously proposed treatment options avoid enucleation.3 however treatments ineffective many patients.234 time studies revealed success verteporfin photodynamic therapy pdt treatment acquired retinal astrocytomas.678 case report present patient symptomatic presumed acquired retinal astrocytoma without evidence tuberous sclerosis showed dramatic regression single session pdt a 42-year old female noted decreased visual acuity right eye 1 month the visual acuity counting fingers one meter right eye 20/20 left eye juxtapapillary amelanotic yellow white lesion circinate exudation exudative inferior hemiretinal including fovea detachment overlying marginal retinal hemorrhages figure 1a the lesion 3.6 mm thickness basal diameter 3 mm optical coherence tomography oct imaging fovea demonstrated serous retinal detachment figure 1b oct lesion showed preservation linear configuration retinal pigment epithelial layer deep optical shadowing suggesting tumor retinal choroidal origin figure 1c fluorescein angiography revealed early hypofluorescence scarce intrinsic vascularity figure 1d diffuse late phase hyperfluorescence subretinal fluorescein leakage figure 1e ultrasonography disclosed solid pedunculated lesion inferior optic disc medium internal reflectivity inferior exudative retinal detachment figure 1f there systemic evidence tuberous sclerosis neurofibromatosis photodynamic therapy color fundus photograph shows juxtapapillary yellow white retinal lesion circinate exudation exudative retinal detachment ( b optical coherence tomography oct fovea demonstrates serous foveal detachment ( c oct lesion shows preservation linear configuration retinal pigment epithelial layer deep optical shadowing suggesting tumor retinal origin ( e diffuse late phase hyperfluorescence subretinal fluorescein leakage note lack typical small well defined fine blood vessels tumor early vascular filling phases ( f ultrasonography reveals non calcified pedunculated retinal mass acoustic solidity inferior retinal detachment patient diagnosed presumed acquired retinal astrocytoma informed consent patient the tumor treated single session pdt using standard treatment parameters 50 j cm light dose 600 mw cm power 83 duration an intravenous injection 6 mg body surface area verteporfin 10 min performed laser emission wavelength 689 nm delivered entire tumor one spot 5400 microns avoiding optic disc much possible following pdt the visual acuity decreased hand motion due dense vitreous hemorrhage developed 1 week treatment figure 2a thereafter visual acuity gradually improved 20/40 complete regression tumor fibrotic scar like tissue 6 months 20/25 complete resolution lipid exudation exudative retinal detachment 14 months 20/20 2 years figure 3 51 months follow visual acuity remained stable complete tumor atrophy recurrence regression tumor photodynamic therapy 1 week b 1 months c 2 months 3 months 2 years photodynamic therapy marked regression tumor ( b optical coherence tomography oct)(fovea shows disappearance serous retinal detachment ( c oct lesion precisely demonstrates intraretinal location tumor overlying epiretinal membrane ( e late phase angiography showing hyperfluorescence staining residual intraretinal fibrotic tissue benign retinal astrocytic lesions include reactive retinal gliosis astrocytic hamartoma acquired astrocytoma.17 retinal gliosis usually occurs trauma inflammation infection astrocytic hamartoma typically stable diagnosed early childhood often associated tuberous sclerosis neurofibromatosis.1 contrast acquired astrocytoma sporadic tumor occurs relatively older individuals associated tuberous sclerosis often symptomatic progressive.13 thus delay diagnosis treatment may result poor visual outcomes increased ocular morbidity the diagnosis acquired retinal astrocytoma depends clinical finding imaging results.1 appears yellow white nodular lesion within sensory retina fluorescein angiography typically shows small well defined fine blood vessels tumor early vascular filling phases rather intense diffuse late staining oct used document intraretinal location tumor highly reflective features fine needle aspiration may required establishing correct diagnosis atypical cases.7 differential diagnosis acquired retinal astrocytoma includes choroidal melanoma solitary idiopathic choroiditis retinoblastoma retinal hemangioblastoma.1 tumor reported current case located sensory retina the confirmation retinal location oct especially images follow figure 2c aided differentiate tumor choroidal origin furthermore color tumor yellow white hypofluorescent without evidence small well defined capillaries early phase angiography in contrast retinal hemangioblastoma typically reddish pink tumor fundus shows rapid hyperfluorescence arterial phase fluorescein angiography finally retinoblastoma comparable size case usually cause lipid exudation exudative retinal detachment the pedunculated architecture acoustic solidity lack calcification b scan ultrasonography also favors diagnosis presumed acquired astrocytoma despite atypical features fluorescein angiography lack histopathologic confirmation case presumably represents example acquired retinal astrocytoma.138 believe presence lipid exudation exudative retinal detachment consistent aggressive behaviour.8 pdt used treatment various intraocular tumors including choroidal hemangioma,9 osteoma,10 melanoma,11 exudative changes nevus combined hamartoma,1213 retinal capillary hemangioma14 retinal vasoproliferative tumors.15 due poor response acquired astrocytoma laser photocoagulation radiotherapy recent studies focused pdt avoid enucleation management lesion.678 2006 mennel et al.6 reported first successful treatment pdt symptomatic retinal astrocytic hamartoma associated tuberous sclerosis they demonstrated complete resolution subretinal fluid disappearance tumor vessels improved vision one session 166 pdt 2008 shields et al.7 described use pdt pigmented variant acquired astrocytoma 18-year old female history tuberous sclerosis they showed minimal involution tumor complete resolution macular exudation edema subretinal fluid improvement visual acuity following one session pdt standard parameters eskelin et al.8 reported similar outcome two cases symptomatic locally aggressive astrocytomas they used pdt successfully secondary treatment failure prior laser photocoagulation juxtapapillary astrocytoma 34-year old male tuberous sclerosis primary treatment macular astrocytoma 68-year old man without tuberous sclerosis following one session pdt standard parameters observed regression tumors complete resolution exudative retinal detachment patients case pronounced effect symptomatic juxtapapillary presumed acquired retinal astrocytoma obtained single session pdt the vitreous hemorrhage pdt presumably occurred due rupture superficial vessels tumor our paper demonstrates dramatic regression symptomatic juxtapapillary presumed acquired retinal astrocytoma complete resolution exudative retinal detachment lipid exudation one session pdt thus pdt considered first line treatment cases acquired retinal astrocytoma

photodynamic therapy ( pdt ) has been used for treatment of various intraocular tumors including choroidal hemangioma , vasoproliferative tumor , amelanotic choroidal melanoma and choroidal neovascular membrane due to choroidal osteoma . this case report documents the effect of pdt for a presumed acquired retinal astrocytoma . a 42-year - old female with a juxtapapillary acquired astrocytoma was treated with a single session of pdt using standard parameters . the tumor showed dramatic regression over 6 months into a fibrotic scar . it remained regressed and stable with 20/20 vision after 51 months of follow - up . we believe that pdt can be used as a primary treatment for acquired retinal astrocytoma .

hemangioblastoma hb central nervous system benign neoplasm central nervous system usually involves brain spinal cord it may occur sporadically association von hippel lindau vhl disease 1 5 sporadic non vhl cases the tumors usually solitary local recurrences seen occasionally surgery 1 2 5 in contrast hbs associated vhl disease usually multiple continue arise course patient life necessitates lifelong surveillance 2 5 7 disseminated hb extremely unusual type recurrence recently called hemangioblastomatosis 10 16 we report case hemangioblastomatosis patient without vhl discuss biological clinical features associated disease in 1996 41-yr old man underwent surgical excision solitary cerebellar mass pathological diagnosis hb fig he family history clinical stigmata suggest presence vhl disease gross total removal tumor possible evidence residual recurrent disease observed magnetic resonance imaging mri performed 1 yr surgery fig ten years surgery returned hospital complaining low back pain hypesthesia right posterior thigh mri brain showed multiple mass lesions suprasellar area anterior aspect upper spinal cord accompanied diffuse leptomeningeal enhancement fig whole spine mri revealed numerous tiny enhancing nodules suggestive leptomeningeal metastasis along spinal cord cauda equina fig genomic dna isolated peripheral blood leukocytes using wizard genomic dna purification kit according manufacturer instructions promega madison wi u.s.a the three exons vhl gene well flanking introns amplified sequenced abi 3730 sequencer ame bioscience toroed norway the patient underwent surgical resection cauda equina lesion subtotal removal tumor histopathological examination confirmed diagnosis hb microscopic findings identical cerebellar hb operated 10 yr earlier fig 2c he subsequently received fractionated radiotherapy total dose 3,600 cgy residual lesion cauda equina brain mri scans obtained 6 months diagnosis recurrence revealed interval growth suprasellar lesion gamma knife radiosurgery performed although treated lesions showed growth condition gradually deteriorated general weakness anorexia frequent vomiting the patient died septic shock respiratory failure 1 yr diagnosis disseminated recurrence hbs account 1 2% primary intracranial tumors 5 15% posterior fossa tumors adults 2 5 7 8) approximately 62% hbs arise sporadically 38% occur association vhl disease 6 the average age presentation sporadic cerebellar hbs approximately 35 yr tumors common men hb thought benign tumor curable microsurgery however several previous studies reported recurrence rate surgical excision 15 27% 9 vhl disease autosomal dominant neoplasia syndrome caused germline mutation deletion short arm chromosome 3 patients vhl tend present neurological symptoms signs younger age sporadic disease the syndrome characterized development multiple visceral central nervous system cns lesions tumors cns include hbs affect 48 80% patients predisposing sites cerebellum 44 73% brainstem 10 25% spinal cord 13 50% retina 25 60% well endolymphatic sac tumors affect 10 15% patients 17 19 the visceral lesions include renal cell carcinoma renal cyst pheochromocytoma pancreatic cyst pancreatic neuroendocrine tumor only 12 cases disseminated hb reported previously 10 16 mohan et al 11 first reported two cases disseminated hb developed several years complete excision bakshi et al 10 reported case diffuse spinal leptomeningeal enhancement mri associated multiple hbs termed condition hemangioblastomatosis all 12 previously reported cases disseminated hb arose patients solid cerebellar hb primary lesion 9 patients association vhl disease 10 16 all patients underwent surgical treatment primary lesion hemangiomatosis developed variable intervals ranging 6 months 22 yr reported cases biopsy specimens primary secondary lesions similar histopathology case tumor infiltration leptomeninges identified five cases mri demonstrating diffuse leptomeningeal enhancement surface brainstem spinal cord 10 12 14 16 the outcomes recurrence poor patients died within 3 yr the common cause death respiratory failure due pontomedullary cervical cord compression the currently available treatment significant effect progression disease eight patients disseminated hb received 13 56 gy irradiation posterior fossa spinal cord however long term tumor control achieved 11 16 advanced radiation techniques radiosurgery may effective conventional fractionated radiotherapy difficult perform high dose radiation therapy radiosurgery numerous lesions scattered throughout entire neuraxis use interferon- thalidomide vascular endothelial growth factor receptor antagonist inhibit angiogenesis 20 21 result remarkable tumor response though vhl gene mutation detected case vhl gene may mutated sporadic cases hb cns 7 molecular genetic analysis four cases hemangioblastomatosis without vhl weil et al ( 14 found evidence germline alterations vhl gene somatic deletion one copy vhl gene these findings implicate monoclonal origin multiple separate deposits tumors patients sporadic hb the results comparative genomic hybridization studies suggest genes addition vhl gene may involved dissemination hbs 15 because case de novo development disseminated hb without previous surgery reported strongly suggested spillage spread tumor cells csf space may origin hemangioblastomatosis patients genetic predisposition condition all previously reported cases showed multiple mass lesions exclusively infratentorial area spinal cord except one case 13 paucity supratentorial lesions may reflect csf flow effect gravity supporting hypothesis tumor spread csf pathway preventive measures reduce tumor cell spillage considered operation study determine biological risk factors disseminated recurrence needed

we report a very rare case of hemangioblastomatosis that developed after surgical removal of a solitary cerebellar hemangioblastoma ( hb ) . a 51-yr - old man presented with back pain 10 yr after undergoing surgery for cerebellar hb . magnetic resonance imaging showed numerous mass lesions along the entire neuraxis accompanied by prominent leptomeningeal enhancement . genomic dna analysis showed no mutation in the von hippel - lindau ( vhl ) genes . a surgical specimen obtained from a lesion in the cauda equina showed pathological findings identical to those of the cerebellar hb that had been resected 10 yr earlier . external beam radiation therapy and radiosurgery were subsequently performed ; however , the patient succumbed one year after receiving the diagnosis of hemangioblastomatosis . the reduction of tumor cell spillage during surgery and regular long - term follow - up are recommended for patients with hbs .

recent years identification genes involved modulation inflammatory apoptotic processes improved understanding mechanisms linked aberrant activation inflammasome amultiprotein intracytoplasmatic scaffold complex synthesizing biologically active interleukin- il-1 prototypic master cytokine affecting nearly cell types allowed delineation new group diseases called monogenic autoinflammatory syndromes maiss etiopathogenetic point view spite heterogeneity genes responsible various maiss table 1 inflammasome represents ideal point convergence diseases cell structure crucial regulation innate immunity proper assembly allows regular activation caspase-1 physiological production proinflammatory cytokines primis il-1 necessary respond heap different danger signals bacterial peptidoglycans genotoxic stress crystals pathogenesis many maiss erroneous assembly inflammasome leads exaggerated conversion pro il-1 active form subsequent disproportionate overwhelming inflammatory response autoimmune intended highlight spontaneous nature inflammatory attacks occur absence pathogenetic role autoantibodies autoreactive lymphocytes therefore contribution yet unidentified environmental factors potential triggers abnormal inflammatory processes might likely 3 4 clinically speaking a characteristics common maiss identified recurrent nature inflammatory episodes presence fever frequent involvement skin serous membranes eyes joints lymph nodes gastrointestinal tract nervous system each syndromes may manifest less severe inflammatory signs symptoms varying frequency duration associated laboratory point view increased phlogistic parameters 5 6 table 2 date there twelve known maiss familial mediterranean fever fmf tumor necrosis factor receptor associated periodic syndrome traps cryopyrin associated periodic syndrome caps group includes familial cold urticaria syndrome fcas muckle wells syndrome mws chronic infantile neurological cutaneous articular cinca syndrome mevalonate kinase deficiency mkd nlrp12-associated autoinflammatory disorder nlrp12ad granulomatous maiss include blau syndrome bs early onset sarcoidosis eos finally hereditary pyogenic disorders including papa pyogenic arthritis pyoderma gangrenosum acne syndrome majeed syndrome ms deficiency il-1 receptor antagonist dira maiss generally characterized early onset first year life early childhood cases particular fmf traps adult onset also described 7 8 cases the utilization highly sensitive specific score useful guiding diagnosis 911 type aa amyloidosis serious complication maiss due excessive production serum amyloid saa synthesized liver following stimulation certain proinflammatory cytokines il-1 also il-6 tumor necrosis factor- tnf- due persistent activation chronic inflammatory process whether clinically manifested orsubclinically excess saa deposited form fibrils various organs particularly kidneys consequent progressive development severe proteinuria leading nephrotic syndrome kidney failure other areas may involved include autonomous nervous system orthostatic hypotension impotence altered intestinal motility liver spleen hepatosplenomegaly muscles heart contractility circulation abnormalities gastrointestinal tube diarrhea malabsorption therefore close monitoring serum saa levels even healthy periods necessary prevent promptly treat secondary amyloidosis verify efficacy treatment therapeutic point view colchicine proven treatment choice patients fmf nonsteroidal anti inflammatory drugs nsaids corticosteroids utilized treat symptoms maiss varying results the introduction biological agents anti tnf etanercept infliximab adalimumab anti il-1 anakinra canakinumab rilonacept nonetheless opened new interesting possibilities management heterogeneous disorders the purpose paper describe main genetic clinical therapeutic aspects maiss focusing current classification general details shown tables 1 2 ultimate goal increasing awareness conditions among various specialties internal medicine familial mediterranean fever omim 249100 transmitted autosomal recessive inheritance frequent classic phenotype characterized recurrent acute fever episodes polyserositis arthritis erysipelas like erythema due presence mutations among 200 identified date mefv mediterranean fever gene encodes protein pyrin also known european name marenostrin 16 17 table 1 this protein made 781 amino acids expressed mainly neutrophil eosinophil granulocytes monocytes macrophages fibroblasts skin peritoneum synovia pyrin mutations cause altered inflammasome function leads increased synthesis proinflammatory cytokines mainly il-1 activation transcription factor nf-b altered inhibition apoptosis demonstrated subjects fmf 1720 past fmf believed pertain almost exclusively populations living near mediterranean basin today widely held populations also affected still affected populations continue armenians turks arabs non ashkenazi jews rate occurrence oscillates 1 400 1 1.000 turkey around 1 1000 israel 1 500 armenia onset fmf usually occurs first two decades life relatively small number adult onset cases 7 8 clinical point view three different fmf phenotypes identified phenotype 1 characterized recurrent inflammatory episodes lasting 1272 hours sometimes triggered stress physical exercise infections preceded nonspecific symptoms like lack appetite malaise irritability episodes fever abdominal pain abdominal pain due sterile peritonitis may sometimes last days fever ceased about half patients present thoracic pain acute pleuritis almost always monolateral and/or pericarditis 15 24 inflammation tunica vaginalis testis may also occur leading recurrent episodes acute orchiepididymitis subjects skin manifestations also brief duration usually 1248 hours generally associated fever characterized periodic appearance erysipelas like lesions approximately 10 cm diameter usually localized surface legs hip knee and/or tops feet muscular skeletal involvement frequent often form arthralgia myalgia may prolonged crippling significantly reducing patients quality life 27 28 about 30% fmf patients also arthritis especially affecting large joints may last several days fever resolved arthritis rarely erosive generally mono- oligoarticular possible rare aseptic meningitis accompanied headache possibly electroencephalographic alterations convulsions in addition fmf also associated rheumatological diseases spondyloarthritis rheumatoid arthritis systemic lupus erythematosus vasculitis small medium vessels like henoch schenlein purpura polyarteritis nodosa behet disease vasculitis large vessels like takayasu arteritis acute episodes associated increased laboratory phlogosis indicators particularly erythrosedimentation rate esr c reactive protein crp saa fibrinogen laboratory findings may include neutrophil leukocytosis thrombocytosis anemia less frequently increase immunoglobulins particularly classes the increase saa fmf attacks also possible asymptomatic periods clue progression towards amyloidosis saa measurement thus useful parameter highlighting state subclinical inflammation revealing potential secondary systemic amyloidosis 6 12 35 phenotype 2 refers fmf patients proteinuria kidney failure resulting amyloidosis inflammatory attacks typical fmf occur afterwards this phenotype also includes subjects belonging families fmf patients evolve towards systemic amyloidosis sole manifestation disease 3638 phenotype 3 includes subjects carrying one two mutations homozygous heterozygous mefv gene without presenting known clinical manifestations diagnosis fmf primarily clinical based use tel hashomer diagnostic criteria divided major minor signs shown table 2 presence two major criteria one major two minor criteria allows definitive fmf diagnosis presence single major criterion one minor one may point towards probable diagnosis confirmed thereafter presence mutations mefv gene the common mefv gene mutations m694v exon 10 homozygous cases correlated earlier disease onset frequent joint involvement occurrence amyloidosis 41 42 therapeutic point view colchicine recognized drug choice treatment fmf effective almost 95% completely prevents acute episodes 60% patients in addition colchicine also proven effective preventing secondary complications amyloidosis 13 14 4348 unlike case gout colchicine effective aborting established acute episode used prophylaxis initial dose usually 11.2 mg daily increase every 1 2 months depending frequency acute attacks effective response obtained maximal dose 2.02.4 mg per day tolerated optimal dosage determined case case basis achieve maximal efficacy minimal side effects children fmf 0.02 0.03 mg kg day colchicine should given maximum daily dosage 1.82.0 mg day since colchicine treatment often complicated frequent gastrointestinal side effects experts recommend lactose free diet order improve colchicine tolerance colchicine therapy fmf pregnancy reported harm either mother fetus contraindications colchicine include hypersensitivity component formulation severe renal hepatic impairments requiring cautious use elderly renal liver biliary disease nsaids corticosteroids sometimes high doses rarely achieve satisfying clinical results control disease 14 51 52 valid therapeutic alternatives patients fail respond colchicine include il-1 inhibitors anakinra canakinumab rilonacept anti tnf- agents adalimumab etanercept infliximab traps omim 142680 autosomal dominant disease caused prevalently missense mutations tnfrsf1a gene made 10 exons encoding p55 1a receptor tnf tnfr1a vast majority mutations found exons 2 3 4 6 16 55 56 distinguished high- low penetrance ones the former located cysteine rich n terminal domains fundamental assembly receptor three dimensional structure 57 58 characterized early disease onset severe clinical manifestations low penetrance mutations r92q p46l tend associated onset disease adulthood less pronounced atypical clinical characteristics 5965 although biological alteration involves tnf receptor pathogenesis traps also seems associated dysregulation secretion il-1 il-6 well oxidative damage correlated mitochondrial production free radicals 61 66 67 clinically speaking table 2 patients complain inflammatory attacks extremely variable duration intensity 1 2 days 3 4 weeks characterized fever episodes accompanied less constantly sterile peritonitis abdominal pain diarrhea constipation nausea vomiting 55 68 69 mono- bilateral periorbital edema characteristic almost pathognomonic sign disease often associated conjunctivitis periorbital pain also frequent arthralgias muscle cramps and/or centrifugally spreading migratory myalgias chronic fasciitis muscular symptoms may include edema swelling muscular group involved usually localized skin symptoms mostly include serpiginous rash consisting migratory painful patches histologically characterized presence perivascular lymphocytic monocytic infiltrates 70 71 serous membrane inflammation also common usually form polyserositis 6265 7274 pericardial myocardial involvement also reported clinical manifestation traps 911 62 64 71 73 7577 acute episodes and sometimes also asymptomatic periods marked increase phlogosis indicators esr crp saa well neutrophil leukocytes aptoglobin fibrinogen platelets 5 6 25% patients carrying mutations involving cysteine residues 2% carrying low penetrance mutations therefore proteinuria saa serum levels must constantly monitored avoid overlooking occult subclinical amyloidosis progression towards end stage kidney damage dreaded complication disease 56 59 diagnosis requires identification mutation tnfrsf1a thus patients clinical symptoms lead suspicion traps genetic tests indispensible therapeutic point view high doses nsaids corticosteroids may prove useful acute phases though reduce frequency attacks furthermore prevent amyloidosis in addition administered long periods time high dose corticosteroids cause serious systemic side effects colchicine immunomodulating immunosuppressant agents also proven little efficacy traps 14 55 68 72 78 due genetic defect origin pathology clear use anti tnf agents could important effect patients in fact etanercept proven useful reducing intensity duration acute attacks although cases gradually loses efficacy 7881 infliximab adalimumab contrast reasons partially understood may paradoxically evoke typical acute inflammatory attacks disease 81 82 treatment anti il-1 agents hand proven particularly efficacious preventing attacks inducing rapid long lasting remission disease well prevention even regression amyloidosis 77 80 83 84 recently il-6 receptor antagonist tocilizumab used etanercept- anakinra resistant patients good results suggesting possible role il-6 pathogenesis traps cryopyrin associated periodic syndromes group autoinflammatory diseases transmitted autosomal dominant inheritance caused mutations nlrp3 gene also called cias1 pypaf encoding cryopyrin crucial inflammasome protein directly activates il-1. date 90 nlrp3 gene mutations identified exon 3 these mutations induce imbalance il-1 production leading fever attacks associated multiple inflammatory symptoms table 1 16 86 87 the least severe familial cold autoinflammatory syndrome fcas omim 120100 muckle wells syndrome mws omim 191900 clinical phenotype medium severity finally chronic infantile neurological cutaneous articular cinca syndrome omim 607115 also known nomid neonatal onset multisystem inflammatory disease presents decidedly severe overall clinical picture 86 87 while fcas mws may family associated cinca syndrome due seriousness clinical phenotype usually associated sporadic mutations 78 88 fcas generally appears first months life characterized brief recurrent inflammatory episodes usually triggered generalized exposition low temperatures sudden changes temperature recently possible emergence fcas like phenotype adult patients carriers low penetrance mutations described symptoms include fever urticaria like rash responds poorly antihistamines conjunctivitis headache arthralgia and/or arthritis fatigue generally inflammatory attacks fcas decrease spontaneously increase acute phase phlogistic indicators usually seen acute episodes progress amyloidosis rather rare patients fcas contrast caps 12 89 mws characterized variable clinical progression episodic recurrent chronic pattern early childhood onset usually first months life in addition symptoms typical fcas patients often also manifest episcleritis neurosensorial deafness secondary amyloidosis 25% cases 91 92 finally cinca syndrome severe caps appears first weeks life characterized widespread nonpruritic urticaria like skin rash 9396 in addition manifestations seen fcas mws cinca syndrome may also manifest uveitis papilledema optic nerve atrophy leading blindness cerebral atrophy mental retardation increased intracranial pressure ventriculomegaly chronic aseptic meningitis finally characteristic deforming osteoarthropathy large joints hypertrophy growth plates many patients present typical facies characterized prominent frontal eminences saddle nose hypoplasia facial bones also cinca syndrome risk amyloidosis frequent progressive kidney involvement in addition laboratory point view caps characterized persistent elevated neutrophil leukocytosis increased acute phase proteins chronic anemia 5 6 on basis etiopathogenetic mechanisms rooted overproduction il-1 caps treated anti il-1 agents anakinra first drug utilized patients exciting results neurological point view well 97 98 the safety tolerability rilonacept demonstrated group pediatric adult caps patients canakinumab shown safe effective controlling clinical laboratory indicators disease activity controlling amyloidosis related complications 14 99101 also known hyperimmunoglobulinemia syndrome mkd omim 260920 autosomal recessive disease caused mutations mvk gene table 1 encoding enzyme mevalonate kinase involved atp dependent phosphorylation mevalonic acid 5-phosphomevalonate the frequently found mutations v377i i268 h20p n p167l least one found 71.5% patients responsible reduced mevalonate kinase activity leads overproduction proinflammatory isoprenoids reduced synthesis cholesterol accumulation mevalonic acid plasma urine the disease onset usually occurs early childhood generally within first year life case within first 5 years the emergence symptoms 5 years age automatically excludes diagnosis mkd acute episodes generally occur every 46 weeks last 37 days average asymptomatic periods attacks the main clinical manifestations recurrent fever 38.5c headache mouth ulcers abdominal pain vomiting and/or diarrhea table 2 more 60% patients may present joint involvement form arthralgia and/or arthritis especially affecting large joints acute episodes nonspecific maculopapular rash may appear urticaria erythema nodosum purpura less frequently reported attacks generally frequent childhood adolescence disease may persist adulthood half patients amyloidosis may present smaller number patients comparison maiss estimated around 3% cases the possibility macrophage activation syndrome course inflammatory attack observed patient mkd a closely related disease mevalonic aciduria omim 610.377 due near total inactivity enzyme mevalonate kinase condition recurrent fever episodes appear association serious systemic signs delayed growth cranial facial dysmorphism microcephalia cerebellar atrophy ataxia psychomotor retardation retinal dystrophy cataracts terms laboratory findings mkd invariably marked leukocytosis elevated phlogosis indicators fever attacks many patients show increased serum igd concentration levels 100 iu ml less frequently serum iga fever attacks urinary concentration mevalonic acid may increased acute febrile flares may thus sometimes useful diagnosis 5 6 however genetic testing evaluate mvk gene remains essential definite confirmation mkd terms therapy nsaids corticosteroids may bring partial relief symptoms 109 110 statins particular simvastatin seem efficacious reducing duration acute episodes the rationale behind utilization based attempt reduce production mevalonic acid blocking enzyme 3-hydroxy-3-methylglutaryl coenzyme reductase resistant cases treatment anti il-1 110 112 anti tnf 110 113 drugs proven reduce frequency intensity inflammatory attacks this autosomal dominant disease caused mutations nlrp12 gene encoding protein nlrp12 monarch-1 plays crucial role immune system mechanisms pathogenic agents table 1 case caps induced generalized exposure cold characterized recurrent fever episodes lasting 510 days accompanied skin rash headache lymphadenopathy mouth ulcers abdominal pain treatment choice depends seriousness overall clinical picture based use antihistamines nsaids corticosteroids less serious cases administration anakinra serious ones 14 114 115 however loss efficacy anakinra described patients 14 116 raising possibility using anti tnf- anti il-6 agents granulomatous autoinflammatory diseases include blau syndrome bs omim 186580 early onset sarcoidosis eos omim 609464 caused mutations nod2/card15 gene subsequent dysregulation inflammatory response formation noncaseous granulomas table 1 blau syndrome autosomal dominant granulomatous inflammatory disease caused mutations region encoding nucleotide binding domain region nod2/card15 gene table 1 118 119 protein nod2 mainly expressed monocytes plays crucial role clearance bacteria particularly mycobacterium tuberculosis capable interacting peptidoglycan activating nf-b signal route the frequently observed mutations missense substitutions involving arginine residue position 334 within nod2/card15 gene r334w r334q 121 122 the onset generally childhood around age 5 disease affects joints skin eyes common manifestation symmetrical polyarthritis hands feet wrists elbows ankles also lead joint ankylosis 123 124 skin lesions may form dark red macular papular nodular rash lichenoid like lesions generally symmetrical appear trunk and/or limbs under histological examination skin lesions present noncaseous granulomas gigantic multinuclear cells 123 124 eye involvement serious complication bs manifested form recurrent bilateral anterior uveitis bilateral granulomatous panuveitis associated eye pain photophobia blurred vision ocular inflammation often leads chorioretinitis keratopathy cataracts glaucoma retinal detachment may also involve ocular structures conjunctiva tear ducts retina optic nerve additionally bs described association persistent intermittent fevers granulomatous arteritis cranial neuropathies hearing loss 123 124 the familial form bs differentiated eos multiorgan sporadic disease characterized onset first 4 years life joint skin eye lymph node involvement recurrent fevers possible abdominal central nervous system involvement histological point view presence noncaseous epithelioid granulomas observed involved tissues pulmonary parenchyma involved 90% patients adult sarcoidosis usually spared eos 125127 spite notable clinical similarities later genetic analyses demonstrated many patients eos also presented mutations nod2/card15 gene for reason authors proposed bs eos respectively familial sporadic forms disease sporadic bs carriers mutations nod2/card15 gene limiting diagnosis eos pediatric patients sarcoidosis mutations high doses corticosteroids may utilized variable success 130 131 the use anti tnf- anti il-1 biological agents also seems encouraging 132134 the hereditary pyogenic disorders include papa pyogenic arthritis pyoderma gangrenosum acne syndrome majeed syndrome ms deficiency il-1 receptor antagonist dira disorders characterized presence sterile abscesses mainly affect skin joints bones papa syndrome omim 604416 autosomal dominant disease caused mutations pstpip1 gene encoding cd2-binding protein-1 cd2bp1 involved proper assembly cytoskeleton normally inhibits pyrin mediated inflammatory signals activation caspase-1 135138 it appears early childhood characterized joint involvement manifested severe self limiting pyogenic arthritis terms skin involvement the appearance pyoderma gangrenosum nodular cystic acne described early childhood arthritic episodes usually respond readily treatment corticosteroids pyoderma gangrenosum treated topical immunosuppressant drugs 14 134 reports patients papa syndrome responded wonderfully treatment anti tnf- anti il-1 agents 139141 majeed syndrome omim 609628 rare autosomal recessive disease described first time 1989 two brothers cousin childhood onset recurrent chronic multifocal osteomyelitis congenital dyserythropoietic anemia neutrophilic dermatosis also reported two brothers the disease caused homozygous mutations lpin2 gene table 1 encoding lipin 2 role yet clarified clinically syndrome characterized recurrent fever attacks associated multifocal sterile osteomyelitis dyserythropoietic anemia chronic diffuse neutrophilic dermatosis onset early childhood its treatment empirically based use nsaids corticosteroids although excellent results recently described administration anakinra canakinumab 144 145 dira omim 612852 autosomal recessive disease caused missense mutations il1rn gene encoding il-1 receptor antagonist 1 lack endogenous self regulation il-1 activity consequent excessive proinflammatory action il-1 table 1 disease onset first weeks life initial phases may mimic neonatal sepsis multifocal osteomyelitis periostitis pustular skin lesions various sizes skin ungueal alterations hepatosplenomegaly risk multiorgan failure radiological findings may include signs osteolytic lesions bone sclerosis enlargement epiphysis long bones periosteal reaction 147 148 due absence endogenous il-1 receptor antagonist treatment based use anakinra bringing excellent clinical improvement days weeks thus conclusion elucidation molecular basis maiss helped us recognize consequences excessive il-1 signaling proinflammatory isoprenoid production aberrant nk-b activation figure 1 future studies hopefully also evaluate clinical benefit different highly selective biologicals maiss availability new therapeutic options patients previously failed respond conventional treatments nsaids corticosteroids colchicines immunomodulating agents promise patient centered treatment strategies doubtlessly start new era management rare complex disorders

monogenic autoinflammatory syndromes ( maiss ) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin , serous membranes , eyes , joints , gastrointestinal tract , and nervous system , predominantly with a childhood onset . to date , there are twelve known maiss : familial mediterranean fever , tumor necrosis factor receptor - associated periodic syndrome , familial cold urticaria syndrome , muckle - wells syndrome , cinca syndrome , mevalonate kinase deficiency , nlrp12-associated autoinflammatory disorder , blau syndrome , early - onset sarcoidosis , papa syndrome , majeed syndrome , and deficiency of the interleukin-1 receptor antagonist . each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency , associated with findings of increased inflammatory parameters in laboratory investigation . the purpose of this paper is to describe the main genetic , clinical , and therapeutic aspects of maiss and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists .

brain tumors located suprasellar region frequently found childhood include craniopharyngioma germinoma optic nerve glioma histiocytosis 1 following extension tumor intervening procedures surgery chemotherapy radiation considerable damage hypothalamic pituitary axis almost inevitable accordingly children suprasellar tumors suffer endocrinological sequelae even original lesion cured 2 in addition children shown high risk developing morbid obesity recently referred hypothalamic obesity 3,4,5,6 report studied prevalence obesity among children suprasellar tumors treated institute additionally evaluated metabolic aberrations patients tried correlate clinical features endocrinological alterations patients patients remitted suprasellar tumors diagnosed treated institute attended endocrinological unit april 2005 april 2006 enrolled study rathke cleft cyst hypophysitis excluded in addition 28-yr old male craniopharyngioma subjected long term bed rest serious neurological sequela also excluded depicted table 1table 1 profiles 23 patients remitted suprasellar tumors a total 23 patients 10 males 13 females met enrollment criteria including 10 patients craniopharyngioma 43% 7 patients germinoma 30% 4 optic nerve glioma 17% single cases infundibuloma langerhans cell histiocytosis the current ages patients distributed 3 22 yr old median 14 yr old all craniopharyngioma patients near total total tumor removal first line treatment followed additional radiotherapy chemotherapy cases incomplete resection tumor recurrence some cases forced undergo repetitive operations patients germinoma optic nerve glioma radiotherapy chemotherapy mainstay treatment following biopsy partial resection one case germinoma syncytiotrophoblastic giant cells underwent autologous peripheral stem cell transplantation patient a retrospective review regarding contents therapies extent endocrinological dysfunction carried for assessment metabolic alteration degree overweight -overweight determined body fat mass estimated patient the percent overweight expressed quotient excess weight ideal weight female patients less 15 yr age males less 18 ideal weight based auxological data normal japanese children 7 remaining patients weight compatible body mass index 22 body fat mass measured whole body bioelectrical impedance analysis tbf-310 tanita corp in addition blood pressure total cholesterol level triglyceride tg level homeostatic model assessment insulin resistance homa r fasting iri u ml fasting glucose mg dl)/405 determined the diagnosis gh deficiency followed consensus guideline growth hormone research society 8) well national guidelines diagnosis gh deficiency brief gh responses exogenous gh secretagogues less 3 ng ml indicated severe gh deficiency sghd whereas gh responses 36 ng ml considered moderate gh deficiency mghd obesity defined according criteria made national experts 9 follows 20% overweight and/or -body fat exceeding 25% males 30% females younger 11 yr 35% females older 11 yr hyperlipemia defined either elevated fasting total cholesterol level 220 mg dl fasting tg level 140 mg dl 10 presence insulin resistance suggested homa r exceeded 2.5 according guidelines japan diabetes society 11 statistical analysis performed using ystat2000.xls comparison among groups according tumor pathology yates -test non parametric statistical methods kruskal wallis h test applied relatively small samples skewed distribution data comparison groups without gh administration yates -test fisher test applied necessary table 2table 2 endocrinological status 23 patients shows endocrinological status patients time study all patients craniopharyngioma suffered panhypopituitarism diabetes insipidus except case 1 tumor identified chance evaluation head injury all patients germinoma also one defect pituitary hormones on hand none patients optic nerve glioma showed adrenal insufficiency diabetes insipidus treated precocious puberty the condition called growth without gh normal accelerated linear growth despite gh deficiency observed 6 patients these 3 patients chosen take gh supplementation expecting effect improve metabolic aspects table 3table 3 metabolic status 23 patients results investigation metabolic aspects patients summarized obesity judged either -overweight -body fat found 12 23 patients 7 males 5 females fasting blood samples morning could obtained one patient samples an elevated total cholesterol level 220 mg dl identified 4 patients elevated tg 140 mg dl found 6 patients including 2 patients cases 5 13 exhibited strikingly elevated postprandial tg levels 1,200 mg dl in addition another patient case 16 also postprandial hypertriglyceridemia much 1,029 mg dl despite normal fasting tg level homa r exceeding 2.5 found 7 patients 3 males 4 females including one case 9 whose fasting glucose 101 mg dl collectively 23 patients 16 patients least one metabolic aberration obesity hyperlipemia insulin resistance accounted two thirds patients of obesity frequently found 9 12 obese patients either accompanying hyperlipemia insulin resistance relationship obesity hyperlipemia insulin resistance is summarized table 4table 4 summary relationship obesity hyperlipemia insulin resistance n=22 categorization according tumor pathology among 3 major groups tumor pathology craniopharyngioma germinoma optic nerve glioma the incidence obesity significantly different 60% craniopharyngioma 43% germinoma 75% optic nerve glioma p=0.90 in addition -overweight group differ significantly p=0.66 hyperlipemia frequently observed germinoma 71% followed craniopharyngioma 30% optic nerve glioma 0% this order reversed insulin resistance optic nerve glioma 75% craniopharyngioma 30% germinoma 14% these differences showed statistical significance p=0.22 p=0.38 respectively among gh deficient patients 11 patients gh replacement therapy whereas 11 patients time evaluation group likewise incidences hyperlipemia insulin resistance significantly different 3/11 vs. 6/11 p=0.39 4/11 vs. 2/11 p=0.64 respectively these results change fundamentally 2 patients previous gh usage added gh treatment group dose supplemented hydrocortisone mg day correlate degree overweight shown fig 1 relationship supplemented hydrocortisone doses mg day degree overweight patients acth deficiency .. relationship supplemented hydrocortisone doses mg day degree overweight patients acth deficiency all 6 patients growth without gh least one metabolic aberration obesity 4 hyperlipemia 5 insulin resistance 3 conversely 3 patients combined obesity hyperlipemia insulin resistance accompanying growth without gh table 2table 2 endocrinological status 23 patients shows endocrinological status patients time study all patients craniopharyngioma suffered panhypopituitarism diabetes insipidus except case 1 tumor identified chance evaluation head injury all patients germinoma also one defect pituitary hormones on hand none patients optic nerve glioma showed adrenal insufficiency diabetes insipidus treated precocious puberty the condition called growth without gh normal accelerated linear growth despite gh deficiency observed 6 patients these 3 patients chosen take gh supplementation expecting effect improve metabolic aspects in table 3table 3 metabolic status 23 patients results investigation metabolic aspects patients summarized obesity judged either -overweight -body fat found 12 23 patients 7 males 5 females no patients hypertensive time investigation fasting blood samples morning an elevated total cholesterol level 220 mg dl identified 4 patients elevated tg 140 mg dl found 6 patients including 2 patients cases 5 13 exhibited strikingly elevated postprandial tg levels 1,200 mg dl in addition another patient case 16 also postprandial hypertriglyceridemia much 1,029 mg dl despite normal fasting tg level homa r exceeding 2.5 found 7 patients 3 males 4 females including one case 9 whose fasting glucose 101 mg dl collectively 23 patients 16 patients least one metabolic aberration obesity hyperlipemia insulin resistance accounted two thirds patients of obesity frequently found 9 12 obese patients either accompanying hyperlipemia insulin resistance the relationship obesity hyperlipemia insulin resistance summarized table 4table 4 summary relationship obesity hyperlipemia insulin resistance n=22 categorization according tumor pathology among 3 major groups tumor pathology craniopharyngioma germinoma optic nerve glioma incidence obesity significantly different 60% craniopharyngioma 43% germinoma 75% optic nerve glioma p=0.90 in addition -overweight group differ significantly p=0.66 hyperlipemia frequently observed germinoma 71% followed craniopharyngioma 30% optic nerve glioma 0% this order reversed insulin resistance optic nerve glioma 75% craniopharyngioma 30% germinoma 14% these differences showed statistical significance p=0.22 p=0.38 respectively among gh deficient patients 11 patients gh replacement therapy whereas 11 patients time evaluation group likewise incidences hyperlipemia insulin resistance significantly different 3/11 vs. 6/11 p=0.39 4/11 vs. 2/11 p=0.64 respectively these results change fundamentally 2 patients previous gh usage added gh treatment group the dose supplemented hydrocortisone mg day correlate degree overweight shown fig 1 relationship supplemented hydrocortisone doses mg day degree overweight patients acth deficiency .. relationship supplemented hydrocortisone doses mg day degree overweight patients acth deficiency all 6 patients growth without gh least one metabolic aberration obesity 4 hyperlipemia 5 insulin resistance 3 conversely 3 patients combined obesity hyperlipemia insulin resistance accompanying growth without gh hypothalamic obesity refers intractable weight gain following hypothalamic damage described children adults 3,4,5,6 this complication frequently observed treatment craniopharyngioma accounting 50 70% children craniopharyngioma 4 6 dietary modification tends fail leaving patients high risk developing morbid obesity because obesity primary risk factor morbidity general population hypothalamic obesity may serious complication physical fitness psychological aspects excessive hunger due disturbed satiety center postulated 12 13 however demonstrated energy intake children hypothalamic obesity always increased 14 insulin hypersecretion pancreatic beta cells resulting diminished vagal tone due damaged ventromedical hypothalamus promising hypothesis 15 16 in addition increased 11-beta hydroxysteroid dehydrogenase activity demonstrated hypothalamic obesity patients 17 may play additional role pathogenesis assessing obesity three patients case 8 14 19 showed adequate weight despite increased -body fat highlighting importance measuring fat mass addition anthropometric data it may appropriate evaluate visceral fat mass directly ct scan the incidence obesity high 52% figure accordance previous reports 4 6 the identified risk factors developing hypothalamic obesity include presence endocrinopathy tumor infiltration hypothalamus irradiation hypothalamus greater 51 gy younger age diagnosis 4 18 series most craniopharyngiomas extended hypothalamus making post surgical panhypopituitarism inevitable on hand many patients germinoma optic nerve glioma received high dose irradiation caused multiple pituitary hormone deficiency these factors may contributed high incidence obesity series note obese patients optic nerve glioma lacked diabetes insipidus suggesting presence diabetes insipidus always necessary development hypothalamic obesity gh supplementation either previous current decrease incidence obesity this finding accordance report kigs database gh treatment 3 yr influence body mass index craniopharyngioma patients 19 the hydrocortisone dosage given patients acth deficiency merely physiological showed relationship obesity these findings imply endocrinological management gh supplementation hydrocortisone reduction capable ameliorating obesity about one third patients estimated insulin resistance homa r visceral fat accumulation 6 elevated leptin level 20 21 demonstrated hypothalamic obesity elucidates high prevalence insulin resistance series as mentioned insulin hypersecretion resulting hypothalamic damage thought main cause hypothalamic obesity 16 however clarified whether insulin hypersecretion precedes causes visceral fat accumulation whether hypothalamic damage directly increases visceral fat mass case insulin secretion must enhanced compensate insulin resistance would increases visceral fat accumulation therefore cycle established progressive deterioration metabolism may inevitable the effectiveness somatostatin analogue inhibits insulin secretion reported reduction body weight hypothalamic obesity children 16 considering prevalence insulin resistance agent seems promising series especially high iri levels hyperlipemia either hypercholesterolemia hypertriglyceridemia found 9 patients 21 tested particular inordinately elevated postprandial tg found 3 patients the contribution genetic factor may minimal preoperative examinations showed normal tg levels neither parents elevated tg levels reported 6 craniopharyngioma patients higher tg levels control obese group 6 report our finding underlines importance evaluating lipid metabolism hypothalamic obesity particular high tg level gh deficiency must responsible untreated children adolescents adults gh deficiency found elevated tg levels 22 however gh deficiency alone seems insufficient elucidate extremely elevated postprandial tg values effort focused delineating tg metabolism hypothalamic obesity unraveling mechanism establishing pertinent treatment series hyperlipemia frequently found germinoma patients incidence insulin resistance high optic nerve glioma we could explain difference may due small sample size another notable issue found patients growth without gh tended profound metabolic alteration this condition encountered mainly children following surgery suprasellar tumors 23 24 in addition insulin hypersecretion considered major cause growth without gh 24 thus hypothalamic obesity growth without gh arise following hypothalamic damage conditions closely related insulin metabolism we showed patients growth without gh increased incidences obesity 67% hyperlipemia 83% insulin resistance 50% compared whole study group patients presenting growth without gh may regarded particularly increased risk metabolic aberration it demonstrated hyperinsulinemia always present growth without gh patients 6 also true series this finding indicates additional factor(s insulin hypersecretion must involved development growth without gh this unknown factor(s may provide reason high prevalence metabolic aberration growth without gh half patients suprasellar tumors manifested obesity completion therapy irrespective pathohistology gh treatment a high incidence insulin resistance and/or hyperlipemia including inordinately elevated postprandial tg also found growth without gh cases

weight gain is a common sequela of suprasellar tumors , referred to as hypothalamic obesity . we undertook an evaluation of obesity and metabolic aberrations among patients treated at our institute . during the 12 mo from apr . 2005 , 23 patients ( 10 males and 13 females ) with remitted suprasellar tumors attended our clinic : 10 patients with craniopharyngioma , 7 with germinoma , 4 with optic nerve glioma and others . of these , 12 patients ( 52% ) were found to have obesity on the basis of percent overweight and/or percent body fat . elevated cholesterol and/or triglyceride ( tg ) was found in 9 patients ( 39% ) , and insulin resistance was suspected in 7 patients ( 30% ) . three patients exhibited strikingly elevated postprandial tg levels . all 6 patients with the growth without gh phenomenon had at least one metabolic aberration . in conclusion , the prevalence of hypothalamic obesity was nearly half in our series , and hyperlipemia and insulin resistance were also frequently found . the increased risk for metabolic aberration in growth without gh patients was suggested .

mechanical valve thrombosis mvt may cause valve dysfunction onset may acute gradual according nature thrombi rapid slow growth involvement hinge point abrupt insidious edmunds defined mechanical valve thrombosis complication attributable type thrombus without evidence infection attached around mechanical valve deranging hemodynamics interfering valvular function 1 the risk valve thrombosis highest tricuspid position reported rates high 20% 2 incidence left side valve thrombosis varies 4% 8.6% within 5 yr initial valve replacement 3 4 eleven year probability prosthetic valve thrombosis reported 0.01% 0.02% mitral aortic position 5 tilting disc valves commonly reported association complication 6 detection valve thrombosis may easy difficult valve thrombosis suspected transthoracic echocardiographic evaluation used confirm diagnosis 7 transesophageal echocardiographic examination often necessary mitral position thrombi involvement along left atrial side sewing ring 8) several factors inadequate anticoagulation drug interaction pannus overgrowth pregnancy suggested promote valve thrombosis 9 this analysis undertaken evaluate risk factors outcome mechanical valve thrombosis patients undergone valve replacement between january 1981 march 2006 2,908 mechanical valve replacements performed 2,298 patients among these hospital records reviewed retrospectively including preoperative clinical findings initial valve procedures etiologies type event follow anticoagulation diagnostic methods characteristics valve thrombosis perioperative management outcomes several factors evaluated identify risk factors mvt development including sex valve location number valves replaced twenty patients presented mvt 6 30% men 14 70% women valve replacement involved single valve 13 patients 65% double valve replacement done 7 patients 35% table 1 one patient history cerebral embolism another patient history unilateral lower extremity edema left atrial appendage resection performed 4 20% cox maze procedure 4 20% the mean postoperative left ventricular ejection fraction 579.3% mean initial hospital stay 16.96.7 days anticoagulation heparin warfarin started 24 48 hr valvular procedures patients discharged international normalized ratio inr level 2.0 2.5 mitral aortic valve replacement cases 2.5 3.0 tricuspid valve replacement cases the mean age mvt diagnosis 42.014.0 27 66 yr distribution mvts according site valve implantation follows 14 70% mitral 3 15% tricuspid 2 10% aortic 1 5% tricuspid aortic among double valve prosthesis recipients 7 mvts mitral prosthesis 3 aortic prosthesis 3 tricuspid prosthesis 2 the mean time first valve replacement prosthetic valve thrombosis 121.875.4 0.9 284.7 median 96.0)months the mean time diagnosis ofmvt surgical treatment 22.342.5 days range,0 180 days symptoms presentation dyspnea 12 60% patients cardiogenic shock 1 5% patient miscellaneous symptoms myalgia cough fever 2 10% patients table 2 five patients the majority patients 11 55% mvt nyha functional class iii iv time diagnosis the mean duration symptom onset surgical treatment 87.8121.7 days range 0 365 days thromboembolism stroke limb organ ischemia occurred initial valve replacement valve thrombosis 2 10% patients mvt diagnosed transthoracic echocardiography tte 13 65% patients transesophageal echocardiography tee 7 35% patients inr profiles thrombosis diagnosed 1.660.64 1.02 2.68 left sided valves 1.420.53 1.07 2.03 tricuspid valves mvt occurred pregnancy 7 35% patients two patients history denying warfarin fear possible embryopathy one patient experienced thrombosis full term underwent valve replacement 2 days later normal full term baby without adverse event poor compliance anticoagulant treatment leading lower inr recommended responsible mvt another 5 25% patients adding two patients pregnancy poor warfarin compliance responsible 7 patients 35% these patients skipped warfarin distinct reason compliances treatment medication poor 2 10% ) patients mvt thought related drug interaction i.e. one received medication common cold 1 week thrombosis detection patient consumed nutritional supplements without medication one patient bjork shiley convexo concave tilting disc valve take warfarin probably due poor compliance he take medications 285 months could follow he presented clinic due cold sweating dyspnea 3 weeks diagnosis mvt pannus formation present thrombus time operation 45% 9/20 patients two 10% 20 received streptokinase based thrombolytic therapy successful one patient acute mitral valve thrombosis due hemodynamic instability patient received thrombolysis both treated surgical intervention good physical condition all patients underwent surgery redomedian sternotomy consisting mitral valve replacement 14 patients 70.0% tricuspid valve replacement 3 patients 15.0% aortic valve replacement 2 10% tricuspid/ aortic valve replacement one 5% thrombi found around valve hinge points sewing rings valves concerned replaced thrombectomy only one patient received tissue valve 65 yr time diagnosis non compliant warfarin frequent bleeding history the aortic cross clamping time averaged 104.942.8 min range 52 191 min cardiopulmonary bypass time 164.662.7 min range 79 286 min emergent urgent operation done 8 cases 40% due heart failure hemodynamic compromise early complications atrial fibrillation 3 bleeding 1 vocal cord paralysis 1 cerebral infarction 1 atrioventricular conduction block 1 pneumonia 1 oral anticoagulation surgical treatment consisted warfarin alone 16 16/19 83% patients combination warfarin plavix 3 3/19 17% patients the mean hospital stay 18.518.0 range 8 89 days mean intensive care unit stay 3.32.4 days range 1 9 days no late mortality mvt recurrence occurred 63.349.9 0.5 165.1 months mean follow our data show mvt rare complication valve replacement clinical manifestations various the time initial valve replacement diagnosis mvt 121.875.4 months median 96.0 months cases thrombosis occurred insidiously one patient presented acute valve thrombosis one month valve replacement ( 10 reported 39 cases prosthetic valve thrombosis 39.0 42.0-month mean interval occurrence initial operation hospital mortality 41% the difference series durrleman data might due different patient populations some patients might lost possible unknown sudden death ruled clinical course might depend type replaced valves patients bileaflet mechanical valves might stable hemodynamics due well functioning single leaflet unstable vital signs due bileaflet involvement the fact clinical manifestations mvt various follow usually suspect valve thrombosis cases valve click loss skipped warfarin newly appeared symptoms present study tte detected valve thrombosis 75% series found incidental valve thrombosis using modality five patients routine echocardiographic follow ups cases none symptoms could follow urgent operations detection valve thrombosis may difficult series reported many 50% cases diagnosed postmortem 4 recent study the delay first onset symptoms hospitalization found 1 45 days 11 previous studies shown delay diagnosis long duration symptoms result higher mortality 12 however physical examination inadequate diagnostic tool strong clinical suspicion important detect complications any new worsening symptoms patient mechanical valve warrant thorough investigation exclude valve thrombosis present series mvt diagnosed tte 13 65% patients transesophageal echocardiography 7 35% patients follow suggest periodical echocardiographic examination early detection diagnosis may often limited progressive insidious course difference valve thrombosis incidence pattern onset tilting disc bileaflet valve still uncertain another remarkable point present study pregnancy inadequate anticoagulation influenced occurrence complication buttard colleagues 11 found inadequate anticoagulation time diagnosis 45% patients 27% medical reasons ( surgical intervention neurologic events pregnancy 17% poor drug compliance definite relationship already established inadequate anticoagulation valve thrombosis 11 14 anticoagulation pregnancy difficult problem solve pregnancy induces various biophysiologic changes hypercoagulable status the risk warfarinization pregnancy teratogenicity particularly 6th 12th weeks gestation 15 16 therefore obvious mandatory use anticoagulation extremely carefully prevent valve thrombosis thromboembolism our data also demonstrate difficulties maintaining adequate anticoagulation pregnancy however safe reliable protocol anticoagulation therapy pregnancy established 17 pannus formation defined excessive fibrosis around prosthetic valve may occur 25% patients early first postoperative month 11 it plays important role mechanism obstruction could sole cause mechanical valve thrombosis occurrence 9 present series precise role pannus pathogenesis valve thrombosis remains unknown however whether caused valve thrombosis still uncertain include cause valve thrombosis recently roudaut et al 18 conducted retrospective study 110 patients treated fibrinolytic therapy concluded treatment reserved selected patients tricuspid thrombosis critically ill patients patients contraindications surgical intervention thrombolysis appears useful medical bridge operation major curative modality patient medical condition hemodynamics poor present series the present study shows pregnancy inadequate anticoagulation probably influenced occurrence rare complication however knowledge mvt still inadequate efficient ways eradicating complication suggested

in the present study , the authors investigated the management of mechanical valve thrombosis ( mvt ) . from january 1981 through march 2006 , 2,908 mechanical valve replacements were performed in 2,298 patients at our institution . twenty ( 0.87% ) patients presented with mvt , 14 ( 70.0% ) were women , and the mean age of the patients was 42.014.0 ( 27 - 66 ) yr . thrombosis involved mitral in 14 ( 70.0% ) , aortic in 2 ( 10.0% ) , tricuspid / aortic in 1 ( 5% ) , and tricuspid in 3 ( 15% ) . the interval from first operation to valve thrombosis was 121.875.4 ( 0.9 - 284.7 ) months . the most frequent clinical presentation was heart failure ( 13/20 , 65% ) , and predisposing causes of mvt were : poor compliance with warfarin ( 7 ) , pregnancy ( 5 ) , drug interaction ( 2 ) , and unknown ( 6 ) . all 20 patients underwent valve replacement : mitral ( 14 , 70.0% ) , tricuspid ( 3 , 15.0% ) , aortic ( 2 , 10% ) and tricuspid / aortic ( 1 , 5% ) . one early death occurred due to left ventricular failure , but no late mortality occurred during 63.349.9 ( 0.5 - 165.1 ) months of follow - up . mvt was treated successfully , and pregnancy and inadequate anticoagulation were found to influence the occurrence of this rare complication .

squamous cell carcinoma scc thyroid extremely rare disease accounting less 1% thyroid tumors world health organization classification squamous cell carcinoma thyroid defined scc thyroid composed entirely tumor cells squamous differentiation thought arise undifferentiated follicular cells metaplastic follicular epithelium remnant tissue thyroglossal duct primary scc thyroid affects older patients fifth sixth decade life rapidly increasing thyroid mass without cervical lymphadenopathy other symptoms include dysphagia dyspnea hoarseness voice due infiltration adjacent structures time diagnosis tumors usually locally advanced invasion trachea esophagus major vessels although outcome dismal aggressive surgery along adjuvant radiotherapy recommended management rare aggressive cancer optimum outcome here reporting rare case scc thyroid treated palliative radiotherapy a 70-year old male patient noticed rapidly increasing painless mass anterior aspect left side neck 1 month also associated dysphagia stridor 2 weeks he heavy smoker used smoke 1 pack cigarettes day there history previous radiation exposure neck physical examination an 11 cm 7 cm firm lobulated mass found left side anterior aspect neck contrast enhanced computed tomography scan showed evidence well defined large lobulated heterogeneously enhancing solid cystic lesion measuring 11 cm 8.6 cm 7.4 cm relation left lobe thyroid gland the lesion showed multiple thin intervening septae along specks calcification within posteriorly lesion extending vertebral column inferiorly retrosternally brachiocephalic trunk mass effect lesion seen form compression displacement trachea toward right also compression displacement left subclavian carotid vessels left internal jugular vein left sternocleidomastoid figure 1 on positron emission tomography scan large multi lobulated heterogeneously enhancing solid cystic mass 7.8 cm 7.7 cm 5.8 cm seen left side neck arising left lobe thyroid gland intense fluorodeoxyglucose fdg avidity standardized uptake value max 17.7 solid component along peripheral margin cystic component the mass extending anterior mediastinum level d4 vertebra posteriorly prevertebral fascia it seen displace trachea right compressing figure 2 contrast enhanced computed tomography scan showed evidence well defined large lobulated heterogeneously enhancing solid cystic lesion measuring 11 cm 8.6 cm 7.4 cm relation left lobe thyroid gland the lesion showed multiple thin intervening septae along specks calcification within mass effect lesion seen form compression displacement trachea toward right also compression displacement left subclavian carotid vessels left internal jugular vein left sternocleidomastoid positron emission tomography scan revealed large multi lobulated heterogeneously enhancing solid cystic mass 7.8 cm 7.7 cm 5.8 cm seen left side neck arising left lobe thyroid gland intense fluorodeoxyglucose avidity standardized uptake value max 17.7 solid component along peripheral margin cystic component fine needle aspiration cytology fnac revealed scattered malignant epithelial cells showed moderate pleomorphism high nuclear cytoplasmic ratio hyperchromatic nuclei mild moderate cytoplasm aggressive treatment form radical surgery possible particular patient unresectability due encasement major vessels hence delivered palliative radiotherapy 30 gy 10 fractions 2 week period though much regression disease but his pain shortness breath improved reasonably patient leading good quality life last 1 year ( fine needle aspiration cytology smear shows scattered cluster tumor cells moderately pleomorphic hyperchromatic nuclei inconspicuous nucleoli moderate abundant cytoplasm ( b photomicrograph showing fiber cell elongated cytoplasm hyperchromatic nucleus characteristic squamous cell carcinoma most cases reported elderly patients presence local invasion time presentation the overall prognosis tumor poor survival rate less year diagnosis etiology condition clear hypothesis include metaplasia theory ( squamous cells originating remnant ultimobranchial duct thyroglossal duct result metaplasia papillary follicular cells thyroid embryonic remnants metaplasia follicular epithelium thyroglobulin positive variety follicular variable ) may also arise de novo appearance follicular cells without metaplasia thyroglobulin negative variety worse prognosis fnac confirms diagnosis scc mandatory exclude scc spread adjacent upper aero digestive tract sites well metastasis distant sites lung kidney gastrointestinal tract the evaluation therefore usually involves combination endoscopy radiographic examination computed tomography rule neighboring metastatic carcinoma patient could perform biopsy encasement major vessels diagnosis confirmed fnac we excluded possibility tumor arising adjacent structure esophagus representing metastasis primary growth elsewhere different investigative procedures several reports based small series patients scc thyroid the recommended treatment early diagnosis combining best available therapeutic modalities extensive surgery however success rate radical surgery compromised invasive nature tumor poor definition surgical treatment described optimal surgical therapy hemithyroidectomy total thyroidectomy depending upon multifocality followed radiotherapy the addition post operative radiotherapy could lead improved loco regional control date simpson carruthers noted benefit two patients treated adriamycin another treated 5-fluorouracil mitomycin shimaoka tsukada failed achieve response three patients treated nitrogen mustard vincristine ab-132 respectively cisplatin shown benefited patients suffering squamous cell cancers head neck date information available use scc thyroid even optimum treatment aggressive malignancy dire prognosis dismal outcome kind deadly disease survival expected 1 year quality life important particular situation though able deliver optimum treatment patient could achieve effective palliation radiotherapy alone gift patient good quality life

primary squamous cell carcinoma of the thyroid is an extremely rare neoplasm with aggressive behavior . until date , only around 60 cases have been reported in the literature . primary treatment of the patient is radical surgery . with optimum treatment survival is not more than 6 months in this aggressive malignancy . however in our patient surgery it was not possible because of unresectability of the mass due to encroachment of major vessels . hence , we have delivered radiotherapy alone , with which effective palliation could be achieved and patient is leading a good quality - of - life for last 1 year .

although levodopa ld still remains gold standard symptomatic efficacy reducing motor symptoms parkinson disease pd),1 long term use associated development potentially disabling motor complications including response oscillations well drug induced dyskinesias ld induced dyskinesias affecting approximately 30% patients 2 years ld exposure.2 precise underlying pathophysiology ld induced motor complications still incompletely understood however believed pulsatile dopamine receptor stimulation leading neuroplastic changes basal ganglia circuitry plays pivotal role.1,35 dopamine agonists das act directly striatal dopamine receptors preferential effects d2 d1 subfamily generally considerably longer half lives ld table 1).6 first agents class ergolinic compounds affinities multiple non da receptor types newer agents nonergolinic seem lack risk cardiovalvular fibrosis recently reported ergolinic agonists,7 since withdrawn many markets clinical trials involving patients early pd initial monotherapy das was consistently associated significantly reduced risk motor complications compared ld double blind follow periods 5 years table 2),810 das currently recommended first line therapies particularly patients younger age onset.11,12 addition das established first line therapies reduce motor fluctuations ld treated patients.11,12 types clinical benefit das likely related longer half life resulting continuous striatal da receptor stimulation continuous 24-hour delivery daily dosing become possible transdermal formulation short half life agonist rotigotine recently novel extended release er formulations developed nonergolinic oral compounds ropinirole pramipexole the latter principle likely increase convenience possibly adherence particularly patients early disease managed monotherapy the aminobenzothiazole compound highly selective d2 receptor family intragroup preferential affinity d3 receptor subtype.13 agent lacks affinity dopamine receptors d1 d5 displays little affinity d2 d4 receptor subtypes.14 pramipexole er designed prolonged release tablet pramipexole dihydrochloride monohydrate dispersed homogeneously throughout matrix the active substance released proportional square root time15 two different mechanisms diffusion erosion,15 reaching maximum plasma concentration cmax approximately 6 hours oral administration immediate release ir cmax 13 hours respects the pharmacokinetic profile mostly coincides well known ir formulation following oral administration agent shows bioavailability 90%.15 fact pharmacokinetic studies observed increase cmax concomitant intake high fat meal 24% single dose administration 20% multiple dose administrations significant change overall area curve auc024 hours).15,16 protein binding 20% agent metabolized small extent predominantly eliminated renal excretion ~90% renal clearance approximately 400 ml/ min the elimination half life varies 8 hours young 12 hours elderly pramipexole er available five dosage strengths 0.26 0.375 mg 0.52 0.75 mg 1.05 1.5 mg 2.1 mg 3.15 4.5 mg doses expressed terms pramipexole base corresponding dose strengths pramipexole salt given brackets approved use early pd well adjunct therapy advanced pd motor complications two large randomized double blind placebo controlled phase iii trials conducted evaluate clinical efficacy pramipexole er early pd patients.17,18 summarized follows two hundred fifty nine patients early pd hoehn yahr stage 1 3 diagnosed within preceding 5 years randomized 2:2:1 receive pramipexole er 0.263.15 0.3754.5 mg qd pramipexole ir 0.0881.1 0.1251.5 mg tid placebo following 7-week flexible titration phase drug doses maintained additional 26 weeks maximize patient retention trial open label ld rescue medication permitted subjects experiencing insufficient control parkinsonism post ld rescue data censored primary analysis 18 weeks interim analysis subset 253 patients was planned evaluate superiority efficacy pramipexole er placebo unified parkinson disease rating scale updrs ii iii primary endpoint).18 33 weeks study aimed demonstrate noninferiority pramipexole er pramipexole ir combined score updrs ii iii primary endpoint).17 noninferiority predefined treatment group difference lower bound 95% confidence interval ci exceed 3 points this margin chosen conservatively well outside minimally clinically relevant difference updrs suggested 7 points parts ii iii combined.19 18 weeks adjusted mean change updrs ii iii combined scores censoring post ld rescue data 7.4 1.1 pramipexole er group compared 2.7 1.3 placebo group p 0.0010 vs placebo 7.5 1.1 pramipexole ir group p 0.0006 vs placebo).18 including data subjects receiving ld rescue medication adjusted mean change 5.1 1.3 placebo 8.1 1.1 pramipexole er p 0.0282 vs placebo 8.4 1.1 pramipexole ir p 0.0153 vs placebo).18 hence using either approach statistically significant difference pramipexole groups placebo could demonstrated week 4 onward er p 0.0111 ir p 0.0042 vs placebo week 4 either approach).18 33 weeks updrs ii iii change censoring post ld rescue data 8.2 er 8.7 ir the resultant treatment difference 0.5 95% ci 2.3 1.3 thereby establishing noninferiority er formulation including ld rescue data adjusted mean decrease 8.5 versus 9.4 revealing difference 0.9 95% ci 2.7 0.9 still well within predefined margin.17 already demonstrated 18 weeks 33-week analysis confirmed superiority pramipexole er placebo adjusted mean change updrs ii iii score 8.2 er vs 1.2 placebo p 0.0001]).17 consistent symptomatic efficacy pramipexole fewer patients active treatment required ld rescue medication 7.0% er 4.3% ir 21.4% placebo).17 superiority pramipexole formulations could also shown secondary outcome measures including global impression improvement responder rates 41.4% er 45.1% ir vs 20.6% placebo p 0.0003 p 0.0001 patient global impression improvement responder rates 34.4% er 32.4% ir vs 16.5% placebo p 0.0008 p 0.0020 updrs ii iii responder rates 66.7% er 63.8% ir vs 35.0% placebo p 0.0001]).17 summary primary key secondary endpoints week 33 given table 3 rascol et al conducted randomized double blind double dummy parallel group study assess efficacy safety tolerability overnight switch pramipexole ir er early pd patients.20 24-week open label run pramipexole ir tid 156 patients switched overnight either er ir unchanged daily dosage randomized 2:1 subjects allowed one step dose adjustment required efficacy and/or tolerability 4 5 weeks switching the primary efficacy endpoint defined proportion patients successfully switched without dosage adjustment end week 9 determined worsening baseline updrs ii iii score 15% withdrawal due drug related adverse events aes noninferiority predefined 95% ci lower bound exceeding 15% week 9 84.5% patients er versus 94.2% ir group considered successfully switched table 4 the absolute difference groups 9.76% 95% ci 18.81% 1.66% hence noninferiority pramipexole er formally demonstrated however 9 weeks 80.6% er 84.6% ir recipients successfully switched without requiring dose adjustments er group 16.5% had increased 2.9% decreased dosage corresponding percentages ir group 13.5% versus 1.9% table 5 the group difference increased versus unchanged decreased dosage significant p 0.6190 the mean pramipexole dosage 9 weeks 2.75 0.95 mg day 0.12 mg day baseline er compared 2.83 0.86 mg day 0.09 mg day baseline ir group pooled safety data clinical trials early advanced pd comprising information 803 pd patients exposed clinically effective doses pramipexole er show slightly higher rate aes pramipexole ir er compared placebo however significant difference ae profiles found two pramipexole formulations a summary common side effects given table 6.15 safety evaluation 33-week trial early pd17 also identified somnolence gastrointestinal complaints dizziness frequent aes study small numerical increase epworth sleepiness scale score observed pramipexole groups mean values remained cut excessive daytime sleepiness 10 impulse control disorders also slightly common active treatment groups four patients er three ir one placebo group taken whole pramipexole er showed safety tolerability profile pramipexole ir poor compliance identified major issue several disease areas2124 including pd.25,26 irregular intake prescribed medication affects health care many levels including poor symptom control reduced quality life,27 distortion treatment effectiveness28 well increased health care expenditure.29,30 reasons noncompliance manifold include fear side effects complex drug regimens incompatible everyday life dementia one study poorer compliance identified likely among younger patients complex drug regimens depression lower quality life.26 grosset et al demonstrated inverse correlation compliance drug doses per day pd patients31 showed low therapy adherence significantly associated poor motor scores updrs days absent work worse mobility pdq39).31 study measures therapy adherence total number days adherent timing adherence total therapy adherence significantly higher daily medications including das taken versus three times daily.31 therefore availability daily formulations das established efficacy pd represents advantage even added benefit enhanced clinical efficacy safety in addition patient perspective obvious advantage terms convenience ease use particularly early disease monotherapy single dose per day possible due blinding purposes the possible beneficial effects daily formulation convenience adherence possible assess phase iii trials.17,18,20,32 er formulations long acting da pramipexole may also contribute improved symptom control night although formally studied date relevant advanced rather early pd furthermore possibility pharmacokinetic profile slow release formulation may reduce risk peripheral dopaminergic side effects nausea vomiting well central adverse reactions including somnolence daytime sleepiness avoiding rapid plasma level increases high peak concentrations compared ir counterparts this however demonstrated pivotal clinical trials pramipexole er pramipexole widely established symptomatic treatment early well advanced pd the development er formulation stable pramipexole plasma concentration 24 hours offers bioequivalent daily alternative double blind randomized controlled trials early well advanced pd established noninferiority pramipexole er compared ir well superiority formulations placebo overnight switch standard daily formulation was shown successful 80% patients without requiring dose adjustments potential benefits prolonged release daily da formulations include improved compliance potential better symptomatic control day well night however latter along reduced risk dopaminergic side effects formally demonstrated pivotal trial program patient perspective there little doubt daily drugs offer major advantages terms convenience especially initial monotherapy early pd

the aim of this article is to provide a short review of the most relevant pharmacological and clinical data on pramipexole extended release ( er ) as well as to address the clinical utility and potential advantages of a once - daily formulation especially in the treatment of early parkinson s disease ( pd ) . pramipexole is widely established as a symptomatic treatment in early as well as advanced pd . the development of an er formulation , with stable pramipexole plasma concentration over 24 hours , now offers a bioequivalent once - daily alternative . double - blind randomized controlled trials in early and advanced pd , have established noninferiority of pramipexole er compared with immediate release as well as superiority of both formulations over placebo . the overnight switch from the standard to the once - daily formulation was shown to be successful in > 80% of patients without requiring any dose adjustments . potential benefits of the prolonged - release design , which have not yet been formally demonstrated in the pivotal trial program , include improved compliance and a potential for better symptomatic control , particularly in patients with early disease that can be managed with monotherapy .

glutaric aciduria type caused deficiency enzyme glutaryl coa dehydrogenase gcdh metabolic pathway lysine hydroxylysine tryptophan leading accumulation glutaric acid ga derivative 3-hydroxy glutaric acid 3ohga funk et al 2005 harting et al 2-hydoxyglutaric 2ohga acidurias characterized presence elevated concentrations either l-2ohga enantiomer d-2ohga -ketoglutarate kg body fluids read et al 2007 whereas l-2ohga aciduria caused mutations fad dependent l-2ohga dehydrogenase rzem et al 2004 underlying metabolic defects d-2ohga aciduria due mutations enzyme d-2-hydroxyglutarate dehydrogenase struys et al 2005 we recently identified sodium dependent dicarboxylate transporter 3 nadc3 organic anion transporter 1 oat1 responsible uptake ga derivatives blood renal proximal tubular cells hagos et al whereas oat1 involved efflux various neurotransmitter metabolites cerebrospinal fluid blood across choroid plexus alebouyeh et al 2006 possibly choroid plexus pajor et al 2001 besides nadc3 another electrogenic sodium dependent di- tricarboxylate transporter hnact identified brain nact preferentially located neurons especially hippocampus cerebellum cerebral cortex olfactory bulb inoue et al since neuropathological findings observed patients suffering glutaric aciduria type 1 well d- l-2ohga aciduria occur neurons investigated impact ga derivatives hnact expressed xenopus laevis oocytes in vitro transcription hnact- hnadc3-crna capped crna human nact genbank accession plasmids linearized vitro crna transcription performed using t7 mmessage mmaschine kit ambion austin tx usa according manufactor instructions the resulting crna suspended purified rnase free water final concentration 1 g/l solutions standard oocyte ringer solution ori used oocyte preparation storage uptake well electrophysiologic measurements ori contained mm 110 nacl 3 kcl 2 cacl2 5 hepes tris adjusted ph 7.5 citrate succinate glutarate ga derivatives 3-hydroxyglutarate 3ohga d- d-2ohga l-2-hydroxyglutarate l-2ohga glutamate added ori concentrations indicated figure legends ph adjusted 7.5 all chemicals including ori oocyte preparation storage well uptake electrophysiologic experiments purchased sigma aldrich taufkirchen germany 3ohga obtained c. mhlhausen uke hamburg germany oocyte preparation storage stage v vi oocytes xenopus laevis nasco fort atkinson wi usa separated overnight treatment collagenase typ cls ii biochrom berlin germany subsequent washings calcium free ori maintained 1618c ori containing calcium concentration 2 mm one day removal frog oocytes injected 23 nl crna coding either hnact hnadc3 equivalent amount water mocks maintained 1618c ori supplemented 50 gentamycin 2.5 mm sodium pyruvate after 34 days incubation daily medium changes oocytes used tracer uptake studies transport experiments uptake c]citrate ccitric acid ge health care freiburg germany c]glutarate cglutaric acid mp biomedicals heidelberg germany hnact- c]succinate csuccinic acid perkin elmer rodgau germany hnadc3-expressing oocytes assayed room temperature inhibition citrate uptake determined simultaneous application 12 c citrate ori containing 1 mm ga 3ohga d- l-2ohga respectively 30 min c glutarate used concentration 20 inhibition succinate uptake determined simultaneous application 18 c succinate plus 40 sodium succinate ori containing 1 mm glutamate after incubation respective solutions radioactivity aspirated oocytes washed twice ice cold ori oocytes dissolved gently shaking 2 h 100 l 1 n naoh neutralized 100 l 1 n hcl c contents determined liquid scintillation counting tricarb 2900tr perkin elmer inhibition experiments performed least duplicate 810 oocytes experimental condition electrophysiologic analysis studies carried 34 days crna injection room temperature oocytes placed 0.5-ml chamber stage microscope impaled direct view borosilicate glass microelectrodes filled 3 kcl biomedical instruments zllnitz germany current voltage v recordings performed using two electrode voltage clamp device oc725a warner hambden ct usa voltage clamp mode substrate associated currents obtained subtraction currents presence absence substrate interest paired student test used show statistically significant difference citrate uptake absence presence ga derivatives succinate uptake absence presence glutamate michaelis menten constants km 3ohga d- l-2ohga determined sigmaplot software systat software point richmond ca usa using michaelis menten equation imax s]/(km current imax maximum current observed saturating substrate concentrations km substrate concentration half maximal current substrate concentration in hnact expressing oocytes 5 oocytes 4 donors application 1 mm citrate led potential dependent inward currents showing larger current amplitudes 90 mv depolarizing potentials fig the inward currents abolished upon substitution sodium n methyl glucamine data shown in contrast citrate ga derivatives 3ohga d-2ohga l-2ohga ga evoke potential dependent inward currents the individual currents induced compounds similar hnact expressing oocytes fig did change result data shown indicating ga ga derivatives either transported hnact transport electroneutral discriminate possibilities uptake c]citrate compared uptake c]glutarate within 30 min batch hnact expressing oocytes fig 1c whereas citrate uptake increased factor 3.76 0.63 three independent experiments compared mocks uptake ga hnact expressing oocytes mocks virtually identical current voltage v relations substrate associated currents hnact expressing oocytes shown c mocks b oocytes superfused first ori subsequently ori 1 mm respective ga derivative added subtraction currents obtained presence absence respective substrate revealed substrate associated currents oocytes first tested current induced prototypical substrate citrate test successful expression oocytes showing citrate associated currents 20 na 90 mv used study afterwards 3ohga d- l-2ohga kg ga applied random order a b means sem 5 oocytes 4 donors 3 oocytes 3 donors respectively c comparison uptake labeled citrate glutarate batch oocytes whereas hnact expressing oocytes 3 independent experiments 10 oocytes experimental condition took citrate 12 current voltage v relations substrate associated currents hnact expressing oocytes shown c mocks b oocytes superfused first ori subsequently ori 1 mm respective ga derivative added subtraction currents obtained presence absence respective substrate revealed substrate associated currents oocytes first tested current induced prototypical substrate citrate test successful expression oocytes showing citrate associated currents 20 na 90 mv used study afterwards 3ohga d- l-2ohga kg ga applied random order a b means sem 5 oocytes 4 donors 3 oocytes 3 donors respectively c comparison uptake labeled citrate glutarate batch oocytes whereas hnact expressing oocytes 3 independent experiments 10 oocytes experimental condition took citrate 12 no uptake glutarate 20 observed hnadc3-expressing oocytes 4 oocytes four donors succinate 1 mm evoked substrate dependent inward currents potentials tested fig 2a closed circles subsequent application glutamate 1 mm give rise currents fig 2a open circles neither succinate- glutamate associated currents observed mocks data shown in addition succinate uptake marginally inhibited 1 mm glutamate incubation time 15 min fig 2effect succinate glutamate hnadc3 current voltage v relations function membrane potential vc hnadc3-expressing oocytes obtained substraction currents presence 1 mm succinate ori 1 mm glutamate ori measured ori alone data present mean values sem 4 oocytes 4 donors b succinate uptake absence presence 1 mm glutamate hnadc3-expressing oocytes black columns mocks grey columns obtained two independent experiments 810 oocytes experimental condition effect succinate glutamate hnadc3 current voltage v relations function membrane potential vc hnadc3-expressing oocytes obtained substraction currents presence 1 mm succinate ori 1 mm glutamate ori measured ori alone b succinate uptake absence presence 1 mm glutamate hnadc3-expressing oocytes black columns mocks grey columns obtained two independent experiments 810 oocytes experimental condition uptake succinate absence presence glutamate significantly different 60 mv hnadc3 mediates translocation 3ohga d- l-2ohga low affinity hagos et al these kinetic measurements extended broader potential range 90 0 mv disease astrocytes might lower membrane potentials transporter may change affinity ga derivatives potentials tested km 3ohga larger km d- l-2ohga whereas km values d- l-2ohga similar decreased depolarizing membrane potential km 3ohga increased depolarization fig the largest current amplitudes observed d-2ohga 3 oocytes 3 donors amplitudes measured 3ohga 7 oocytes 3 donors l-2ohga 6 oocytes 5 donors similar magnitude potentials tested fig 3michaelis menten constants km mm maximal substrate inducible currents imax na b ga derivatives function membrane potential vc hnadc3-expressing oocytes subsequently superfused increasing substrate concentrations 3ohga 0.1 0.2 0.5 1 2 5 mm d- l-2ohga 0.01 0.05 0.1 0.5 1 mm ori ph 7.5 data obtained end 10-s perfusion respective solution indicated vc calculated 7 oocytes 3 donors 3ohga d-2ohga 3 oocytes 3 donors l-2ohga 5 oocytes 4 donors michaelis menten constants km mm maximal substrate inducible currents imax na b ga derivatives function membrane potential vc hnadc3-expressing oocytes subsequently superfused increasing substrate concentrations 3ohga 0.1 0.2 0.5 1 2 5 mm d- l-2ohga 0.01 0.05 0.1 0.5 1 mm ori ph 7.5 data obtained end 10-s perfusion respective solution indicated vc calculated 7 oocytes 3 donors 3ohga d-2ohga 3 oocytes 3 donors l-2ohga 5 oocytes 4 donors to date brain mammalian tissue nact cloned inoue et al subsequent studies shown expression restricted neurons wada et al therefore reasoned hnact might able accept ga derivatives suggested induce neuronal damage observed patients suffering glutaric aciduria type 1 l hydroxyglutaric aciduria however compounds neither induced substrate associated currents inhibit uptake citrate prototypical substrate hnact hnact expressing oocytes in addition found interaction hnact kg compound recently described taken neurons shank bennett 1993 consequently uptake ga derivatives neurons nact cause observed neurodegeneration particularly glutaric aciduria type 1 suggested glutaryl coa ga 3ohga accumulating synaptic cleft involved pathogenesis disease klker et al because compounds readily cross blood brain barrier accumulate within brain klker et al 2004 wajner et al 2004 gerstner et al 2005 sauer et al 2006 may inhibit delivery neurometabolic precursors due absence pyruvate carboxylase cesar hamprecht 1995 hassel 2001 neurons lack capacity perform de novo synthesis tricarboxylic cycle constitutents tca therefore depend extracellular sources tca intermediates replenish intracellular pools neurotransmitters glutamate -aminoisobutyrate gaba astrocytes contrast neurons express pyruvate carboxylase shank et al 1985 play major role feeding tca constituents neurons since nact localized neurons assumed nact responsible uptake citrate also uptake tri- dicarboxylic acid derivatives neurons this however case ga kg accepted nact the synaptic action glutamate terminated uptake astrocytes presynaptic neurons uptake glutamate astrocytes occurs distinct excitatory amino acid transporters eaats possibly low affinity sodium dependent transport systems danboldt 2001 holten et al one candidate transporter may nadc3 recently localized astrocytes yodoya et al however glutamate neither induced inward currents inhibited succinate uptake hnadc3-expressing oocytes 1 mm glutamate reduced succinate uptake 19.9 8.5 n.s therefore hnadc3 excluded transporter facilitating glutamate uptake astrocytes opposed recent speculation frizzo et al 2008 60 mv hnadc3 carries kg ga high ga derivatives moderate affinity hagos et al 2008 in present study found affinities d- l-2ohga increased whereas 3ohga decreased depolarized potentials besides km the different ga derivatives also differ imax largest d-2ohga indicating d-2ohga taken astrocytes high rates may interfere uptake kg needed astrocytes synthesis glutamine peng et al although findings elucidate mechanisms ga derivatives induce neuronal damage observed affected patients definitely exclude nact transporter facilitating uptake d- l-2ohga well 3ohga neurons the impaired uptake kg due efficient interactions d- l-2ohga nadc3 could interfere astrocytes ability produce tca derivatives feed neurons compounds needed synthesis neurotransmitters brain development energy requirements increasing harting et al 2009 metabolic support astrocytes may limited due accumulating ga derivatives synaptic cleft this turn may induce observed neuronal damage due shortage fuels brain vulnerable phase recently discussed strauss et al

concentrations of glutarate ( ga ) and its derivatives such as 3-hydroxyglutarate ( 3ohga ) , d- ( d-2ohga ) and l-2-hydroxyglutarate ( l-2ohga ) are increased in plasma , cerebrospinal fluid ( csf ) and urine of patients suffering from different forms of organic acidurias . it has been proposed that these derivatives cause neuronal damage in these patients , leading to dystonic and dyskinetic movement disorders . we have recently shown that these compounds are eliminated by the kidneys via the human organic anion transporters , oat1 and oat4 , and the sodium - dependent dicarboxylate transporter 3 , nadc3 . in neurons , where most of the damage occurs , a sodium - dependent citrate transporter , nact , has been identified . therefore , we investigated the impact of ga derivatives on hnact by two - electrode voltage clamp and tracer uptake studies . none of these compounds induced substrate - associated currents in hnact - expressing xenopus laevis oocytes nor did ga derivatives inhibit the uptake of citrate , the prototypical substrate of hnact . in contrast , d- and l-2ohga , but not 3ohga , showed affinities to nadc3 , indicating that d- and l-2ohga impair the uptake of dicarboxylates into astrocytes thereby possibly interfering with their feeding of tricarboxylic acid cycle intermediates to neurons .

fibromyalgia chronic pain syndrome unknown origin estimated affect 25% populations studied raspe 1992 wolfe et al 1995 ; fibromyalgia characterized widespread pain fatigue poor sleep dyscognition wolfe et al 2010 often also associated mood disorders depressive episodes anxiety although underlying pathophysiology entirely understood fibromyalgia associated augmented central nervous system cns processing nociceptive stimuli using quantitative sensory testing qst functional neuroimaging ( gracely et al 2002 desmeules et al 2003 petzke et al 2003 smith et al context notion dysfunctional endogenous pain inhibition proposed play pivotal role genesis chronic widespread pain this supported studies demonstrating impaired absent conditioned pain modulation cpm patients lautenbacher rollman 1997 vierck et al 2001 julien et al 2005 chalaye et al functional gracely et al 2002 giesecke et al 2004 jensen et al 2012 structural kuchinad et al 2007 schmidt wilcke et al 2007 ; 2013 brain imaging studies shed light possible central mechanisms might play role genesis chronic pain fibromyalgia one approach investigation fluctuations blood oxygenation level dependent bold signals rest termed resting state functional connectivity rs fc only recently changes rs fc demonstrated fibromyalgia hyper connectivity default mode network dmn constellation brain regions involved self referential thought insular cortex ic brain region known play pivotal role pain perception napadow et al 2010 interestingly hyper connectivity may marker chronic pain intensity two independent trials shown decreases connectivity dmn ic following treatment associated reductions clinical pain napadow et al 2012 harris et al 2013 treatment fibromyalgia terms clinically relevant reduction widespread pain often challenging pharmacological non pharmacological approaches bernardy et al 2013 food drug administration treatment pain fibromyalgia pregabalin compound binds 2 subunit voltage dependent presynaptic calcium channel two selective serotonin 5-ht norepinephrine ne reuptake inhibitors milnacipran mln duloxetine goldenberg et al 2010 schmidt wilcke clauw 2010 schmidt wilcke clauw 2011 other drugs tricyclic compounds tca e.g. amitryptiline viewed non selective 5-ht ne reuptake inhibitors also repeatedly shown efficacious treatment fibromyalgia frequently used pharmacological treatment regimens the way 5-ht ne reuptake inhibitors act reduce pain still matter debate spinal subcortical cortical mechanisms proposed however overall effect individual treatments modest huser et al 2013 moreover key limitation treatment fibromyalgia chronic pain general reliable tools guide treatment assignment individual patients such recently group shown chemical functional imaging fibromyalgia used predict treatment response pregabalin fibromyalgia harris et al 2013 here sought identify rs fc patterns might predict treatment response fibromyalgia selective 5-ht ne reuptake inhibitor mln since preclinical studies indicated dual reuptake inhibitors thought favorable effect endogenous pain inhibition believed dysfunctional fibromyalgia lautenbacher rollman 1997 julien et al 2005 ) specifically focused rs fc brain regions involved antinociception pain modulation periaqueductal gray pag rostral part anterior cingulate cortex acc dorsolateral prefrontal cortex dlpfc amygdala inclusion criteria 1 meeting 1990 american college rheumatology criteria fm chronic widespread pain least 6 months 2 1870 years age 3 non lactating non pregnant 4 right handed 5 score 40 90 mm inclusive 100 mm pain visual analogue scale vas 6 willing withdraw cns active therapies marketed antidepressants monoamine oxidase inhibitors tricyclics tetracyclics selective serotonin reuptake inhibitors norepinephrine reuptake inhibitors snris 7 willing withdraw stimulant medications used treat attention deficit disorder attention deficit hyperactivity disorder e.g. mixed amphetamine salts methylphenidate dextroamphetamine fatigue associated sleep apnea shift work e.g. modafinil 8) willing withdraw anorectic agents diethylpropion sibutramine phentermine 9 currently taking pregabalin and/or gabapentin remain stable dosage throughout duration study major exclusion criteria 1 significant risk suicide 2 medical conditions including cardiac diseases glaucoma autoimmune disease systemic infections e.g. human immunodeficiency virus hepatitis active cancer pulmonary disease dysfunction unstable endocrine disease must stable least 3 months prior study enrollment unstable diabetes unstable thyroid disease 3 pregnant lactating 4 severe acute chronic medical psychiatric conditions could increase risk interfere trial results 5 body mass index greater 36 6 treatment experimental agent including mln within 30 days screening 7 contraindications mri procedures all study participants gave written informed consent study protocol informed consent documents approved university michigan institutional review board ann arbor michigan forest laboratories new york ny all imaging data stored validated analyzed assessed quality university michigan independent forest personnel patient demographics medications identification inclusion analysis listed table 1 all patients randomized double blind two period crossover study mln versus placebo fig potential participants underwent initial visit prior first neuroimaging session wherein evaluated study criteria after meeting inclusion exclusion criteria consenting patients randomized either mln first placebo first period 1 followed 14 week washout period withdraw excluded medications could interfere efficacy neuroimaging measures this washout period included 1-week single blind placebo run period reduce possibility placebo effects first double blind treatment period following placebo run period participants underwent first neuroimaging scan pretreatment period 1 involved functional connectivity magnetic resonance imaging fcmri following initial scan subjects randomized receive mln first period underwent dose escalation mln 200 mg day course 2 weeks maintained fixed dose 4 weeks time identical post treatment fcmri session conducted those subjects randomized placebo period 1 took matching placebo pills course 6 weeks undergoing identical post treatment fcmri session all participants entered 1 week taper 2 weeks placebo washout time placebo sugar pill consumed daily once washout period completed patients crossed study drug period 2 i.e. mln period 1 received placebo period 2 vice versa placebo data included analyses came either period 1 period 2 depending treatment order included subjects regardless treatment order all subjects informed would dosed mln placebo various times throughout study told transferred one treatment we assessed treatment response clinical pain well evoked experimental pain participants prior following study period clinical pain assessed short form brief pain inventory bpi captures pain severity bpi sev interference due pain bpi int cleeland ryan 1994 measured course previous week changes components post minus pre used measures treatment response clinical pain changes pain following mln placebo assessed spss version 20 performing paired tests further specifically investigated whether changes following mln treatment differed significantly changes following placebo treatment performing paired samples tests change scores behavioral measures also spss version 20 assessing responders compared non responders treatment period defined patient responder 30% improvement behavioral measure treatment period patients 30% improvement treatment period categorized non responders evoked experimental pain data also collected outside mri scanner treatment period pressure pain administered left thumbnail three distinct conditions using multi modal automated sensory testing mast system harte et al 2013 : 1 equal pressure condition 1.5 kg cm 2 amount pressure required elicit pain50 0100 nrs 3 faint touch rest condition both behavioral bold fmri response data analyzed reported subsequent manuscript investigation we primarily interested identifying baseline neuroimaging parameters could predict changes clinical evoked pain specifically following treatment mln resting state fmri data were acquired using t2 -weighted spiral sequence tr 2.0 te 30 ms fa 90 matrix size 64 64 43 slices fov 20 cm 3.12 3.12 3 mm voxels using 3 tesla general electric signa scanner 9.0 vh3 16 rod birdcage transmit receive radio frequency coil 6 min resting state fmri acquisition period 180 scans subjects asked remain awake eyes open stare motionless cross presented screen minimal cognitive tasks staring cross thought disrupt resting state networks greicius et al 2003 the first 6 images resting state scan discarded data set analyzed order avoid equilibration effects t-1 weighted structural gradient echo data set tr 1400 ms te 1.8 ms flip angle 15 fov 256 256 yielding 124 sagittal slices defined voxel size 1 1 1.2 mm also acquired subject data pre processed analyzed using fsl http://www.fmrib.ox.ac.uk/fsl statistical parametric mapping software packages spm version 8 functional imaging laboratories london uk well functional connectivity toolbox conn cognitive affective neuroscience laboratory massachusetts institute technology cambridge usa running matlab 7.5b mathworks sherborn usa upon collection functional data cardiorespiratory artifacts corrected using retroicor hu et al pre processing steps included motion correction realignment first image time series normalization standard spm epi template generating 2 2 2 mm resolution images smoothing convolution 8 mm fwhm gaussian kernel subject head motion assessed evaluating three translations three rotations scan translational thresholds set 2 mm rotational thresholds limited 1. subject excluded analysis head motion exceeded either thresholds one six dimensions as snris thought augment antinociceptive mechanisms particularly interested rs fc brain regions known involved descending antinociceptive pain modulatory system the following regions chosen based current literature suggesting involvement antinociception pain modulation bingel 2010 three seeds covering rostral acc ventral vacc pre genual pgacc subgenual sgacc regions bilateral seeds dorsolateral prefrontal cortex dlpfc amygdala periaqueductal gray pag seed regions created using spm extension tool marsbar all seed regions created spheres information including size location seed regions time series extracted white matter cerebrospinal fluid realignment parameters entered analysis covariates interest band pass filter frequency window 0.010.1 hz ) first level analyses performed correlating seed region signal voxel signal throughout whole brain thereby creating seed region voxel connectivity maps one map per seed per individual group analyses focused pre- mln rs fc predictor subsequent change pain resulting drug our primary approach enter pre treatment connectivity maps multiple regression analysis changes pain post mln minus pre mln spm results deemed significant using family wise error fwe cluster corrected threshold p 0.05 within priori brain regions including ic posterior cingulate cortex pcc precuneus inferior parietal lobule ipl dlpfc small volume correction using sphere radius 5 mm performed results deemed significant fwe cluster level corrected threshold p 0.05 these regions selected priori regions specifically interested rs fc changes regions known involved pain processing allowed small volume correction analysis based previously published results significant results extracted entered spss version 20 assess outliers determine results specific mln identical analyses performed placebo period using significant regions identified predicting response mln order rule chance differences treatment period baseline compared mln placebo correlations two cross periods separately i.e. mln first placebo first correlations performed spss version 20 results found significant p 0.05 finally sought incorporate multiple functional connectivity measures regression analysis explore collinearity amongst rs fc outcomes improve prediction treatment response simultaneously controlling pre treatment pain levels harris et al a multiple linear regression model created pre treatment pain measures rs fc correlation values serving independent variables post treatment pain dependent variable a model first constructed rs fc measure individually combination multiple rs fc values predicted pain outcome way forward selection eight excluded analysis following reasons six withdrew prior completing neuroimaging sessions two prematurely stopped taking mln two side effects drug prevented participation trial two terminated due personal reasons two additional participants excluded reach pre specified dose mln imaging the drop rate due adverse events medication 9% 2 23 participants thus fifteen subjects mean age 40.7 10.2 included present analysis multiple dimensions clinical pain found show significant decreases trends towards decreased pain treatment mln placebo bpi sev change mln mean 0.88 1.8 p 0.076 pbo mean 0.17 2.3 p 0.78 bpi int change mln mean 1.1 1.7 p 0.03 pbo mean 0.56 2.1 p 0.31 comparing effects treatment periods significant differences mln placebo treatment observed bpi sev p 0.39 bpi int p 0.50 according priori definition responders 5 15 patients 33% responders mln 3 15 patients 20% responders placebo treatment bpi sev whereas 7 15 patients 47% responders mln treatment 4 15 patients 27% responders placebo bpi int scores table 2 we found strong associations baseline rs fc values i.e. rs fc correlation values pre specified antinociceptive brain regions brain regions involved pain processing modulation changes clinical experimental pain measures treatment periods table 3 a significant association found rs fc right pag seed right mid ic subsequent reduction clinical pain severity bpi sev mln r 0.885 p 0.001 placebo r 0.216 p 0.440 table 3 fig less rs fc activity associated greater reductions clinical pain following mln treatment placebo we also observed significant association connectivity right dlpfc left ipl changes bpi sev mln placebo mln r 0.873 p 0.001 placebo r 0.030 p 0.917 table 3 fig 3b respect limbic system connectivity left amygdala precuneus posterior cingulate cortex pcc found negative correlation change bpi sev response mln placebo mln r 0.916 p 0.001 placebo r 0.389 p 0.152 table 3 fig low levels connectivity pgacc right posterior ic found associated greater reduction clinical pain interference bpi int following mln placebo mln r 0.900 p 0.001 placebo r 0.082 p 0.771 table 3 fig 4a placebo lower levels connectivity pgacc left dlpfc were associated greater pain reduction i.e. patients less connectivity two structures baseline would showed greater response clinical pain interference bpi int placebo treatment placebo r 0.869 p 0.001 mln r 0.050 p 0.859 table 3 fig 5 when assessing treatment period separately found order treatment mln placebo administered first period impact results two linear regression models predicting changes bpi sev mln period constructed the first model measure included pre mln bpi sev values adjusted r square 0.34 p 0.014 right pag right mid ic connectivity adjusted r square 0.50 p 0.001 right dlpfc left ipl connectivity adjusted r square 0.10 p 0.001 independent predictors explained 94% variance post mln pain severity a second model explained 95% variance post mln bpi sev scores included pre mln bpi sev values adjusted r square 0.34 p 0.014 right pag right mid ic connectivity adjusted r square 0.51 p 0.001 left amygdala right pcc precuneus adjusted r square 0.10 p 0.001 independent predictors table 4 independent predictors including pre mln bpi int scores adjusted r square 0.58 p 0.001 pre mln connectivity pgacc right posterior ic adjusted r square 0.32 p 0.001 explained 90% variance post mln pain interference table 4 we investigated rs fc cortical subcortical structures involved pain modulation determine parameters would predict treatment response treatment mln patients fibromyalgia importantly find acc ic well pag ic connectivity baseline predictive treatment response patients displayed lower pgacc ic connectivity pag ic connectivity respectively showed greater reductions clinical pain following mln treatment other rs fc measures also predictive clinical response mln treatment dlpfc ipl amygdala precuneus pcc connectivity less pgacc dlpfc connectivity predictive placebo response we hypothesize subgroup fibromyalgia patients poor connectivity pro- antinociceptive brain regions profits snri treatment pattern reflects dysfunctional endogenous antinociceptive system viewed biomarker thereof a dysfunctional endogenous antinociceptive system suggested contributor genesis pain fm lautenbacher rollman 1997 vierck et al there indeed evidence cns levels two key neurotransmitters within antinociceptive system 5-ht ne lowered fm indicated decreased levels corresponding metabolites cerebrospinal fluid russell et al 1992 ; snris thought support antinociceptive system increasing synaptic 5-ht ne levels turn reduce nociceptive input brain snris well characterized respect molecular mechanisms targeting presynaptic transporter proteins e.g. sert thereby raising synaptic 5-ht ne levels however since 5-ht ne bind different receptor subtypes different effects concentrations different cns sites overall effect 5-ht ne reuptake inhibition highly complex context pain pain modulation however predominantly spinal mechanisms are discussed account analgesic effects yoshimura furue 2006 burnham dickenson 2013 5-ht this via binding 5-ht1a 5-ht1b 5-ht1d receptors lead pre- post synaptic hyperpolarization pain transmitting neurons furthermore 5-ht increases inhibitory transmitter release e.g. gaba interneurons via 5-ht3 possibly 5-ht2 ne hand thought act via presynaptic 1 receptors leading suppression glutamate release c afferent fibers well via 2 receptors increasing inhibitory transmitter release interneurons importantly mechanisms seem play beneficial role variety chronic pain conditions diabetic neuropathy boyle et al 2012 osteoarthritis chappell et al 2009 well fibromyalgia goldenberg et al 2010 huser et al 2012b thought specific one particular pain condition interestingly fibromyalgia recently published study investigating spinal effects mln via assessment nociceptive flexion reflex r iii came conclusion mln must also supraspinal effects based observation dose dependent analgesic effect absence mln associated modulation nociceptive flexion reflex matthey et al 2013 the study date aware directly test whether diminished descending analgesic activity predictive treatment response classes drugs study yarnitsky colleagues showing neuropathic pain patients impaired descending activity baseline qst likely respond duloxetine yarnitsky et al 2012 our choice seed regions rs fc connectivity analyses based current literature highlighting role key structures pain inhibition pain modulation i.e. pag rostral acc dlpfc amygdala petrovic et al 2002 wager et al 2004 bingel et al 2007 our strongest findings also well line priori hypotheses acc ic connectivity pag ic connectivity predictive treatment response within endogenous antinociceptive system pag plays central role coordinating via rostroventromedial medulla rvm moreau fields 1986 heinricher et al 2009 activity descending 5-ht ne pathways project spinal cord decrease nociceptive routing periphery the pag receives input spinal nociceptive neurons variety cortical structures it hypothesized two cortical systems mediate cortical top modulation one pathway involves descending input rostral acc prefrontal cortex pag second pathway arrives pag ic via amygdala schweinhardt bushnell 2010 said needs acknowledged evidence stems animal research fields 2004 precise mapping pathways humans currently unknown however notion rostral acc pag connectivity hardy leichnetz 1981 interacting regard recently supported functional petrovic et al 2002 bingel 2010 kong et al 2010 structural stein et al 2012 imaging studies the interaction rostral acc ic antinociception pain modulation hand remains elucidated both structures part cortical opioidergic network petrovic et al 2002 ) rostral acc might exert direct antinociceptive activity ic cortex structures modulate pag either interactively independently rs fc reflects coordinated activity two systems when looking resting state networks bilateral ic together dorsal acc mcc supplementary motor area make called salience network connectivity within network influences perceptual decisions pain the vacc pgacc sgacc part salience network rather belong executive control network vacc dmn pgacc sgacc beckmann et al as one would expect highly correlated bold activity rostral acc ic even healthy subjects intriguingly negative correlation resting state activity two regions predictive mln response recently performed study found increased rostral acc ic rs fc young patients temporomandibular disorder interpreted early compensatory mechanism group young patients developing chronic pain condition ichesco et al 2012 effort tempting hypothesize break mechanism associated pain chronification based increasingly dysfunctional antinociceptive system the rs fc patterns predicted response mln treatment right dlpfc left ipl well amygdala posterior cingulate cortex the ipl well posterior cingulate cortex part dmn the role dmn chronic pain beginning investigated previous work fibromyalgia suggesting ic connectivity dmn associated increased pain napadow et al 2010 interestingly present work show lowered dmn connectivity antinociceptive regions dlpfc predictive response mln other dmn regions pcc also highlighted involved pain functional structural imaging studies erpelding et al another interesting finding study pgacc left dlpfc connectivity predicted response placebo treatment fibromyalgia patients lower pgacc left dlpfc connectivity showed greater pain reductions undergoing placebo treatment the placebo effect fibromyalgia patients recently investigated meta analyses based randomized placebo controlled trials studies 1830% patients have shown placebo responders magnitude placebo responders drug trials fibromyalgia similar seen chronic pain conditions huser et al 2011 the neural mechanisms underlying clinical observation cognitive factors beliefs expectations modulate pain perception investigated using various brain imaging methods petrovic et al 2002 bingel 2010 mostly using short term interventions the role dlpfc cortex placebo research underlined fmri studies wager et al 2004 ; wager et al 2011 well transcranial magnetic stimulation tms studies describing significant impairment placebo analgesia associated tms induced functional lesions left dlpfc krummenacher et al 2010 as dlpfc viewed key region initiating placebo related changes pain perception implementation requires interaction cortical subcortical brain regions rostral acc pag increases rostral acc activity acc pag connectivity placebo analgesia likely mediated opioidergic transmission petrovic et al 2002 ) dlpfc playing key role placebo analgesia also extend clinical setting baseline rs fc predicts placebo effects visible 6 weeks treatment initiation despite significant progress made understanding pathophysiology fibromyalgia advances yet translated pharmacological treatment it generally thought underlying pathophysiology fibromyalgia heterogeneous leading similar phenotype chronic widespread pain subgroup patients diminished synaptic 5-ht ne levels responding drugs augment activity despite small sample size the rates drug placebo responders well line larger randomized studies consistent idea effect one united states food drug administration approved drugs examined isolation modest 30% improvement pain occurring 3040% patients huser et al 2012b also case chronic pain states nsaids opioids example modest efficacy conditions osteoarthritis chronic low back pain clauw 2010 this stresses need develop tools predict treatment response order design individually tailored therapies woolf 2010 recently studies indicated brain imaging might suited perform predictions harris et al 2013 ; resting state fmri might particularly interesting tool easy safe perform little demands patients cognition cooperation first study based rather small study sample i.e. findings might representative larger fibromyalgia population may apply subgroup fibromyalgia patients also drop rates well treatment response mln placebo comparable seen larger randomized placebo controlled trials results need reproduced larger study sample as rs fc analyses allow assumptions causality directedness influence conceivable connectivity two regions could driven third region identified analysis furthermore necessity direct causal relationship brain connectivity patterns identified study clinical response dual reuptake inhibitors likely act first foremost spinal level context pain inhibition connectivity measures forebrain structures might thus relate indirectly site action scenario connectivity measures would need viewed surrogate markers however would detract potential clinical usefulness finally four snris used clinical practice including venlafaxine desvenlafaxine duloxetine mln mln blocks 5-ht ne reuptake equal extent whereas greater selectivity 5-ht sites described venlafaxine duloxetine regard it uncertain whether results generalized snris even tcas besides confirmation studies larger sample sizes research is needed extent findings snri non selective reuptake inhibitors e.g. tcas overall able show rs fc patterns brain structures involved antinociception pain modulation might useful parameters prediction treatment response snri mln fibromyalgia patients as clinical practice subset patients respond pharmacological treatment approaches might turn useful tools identify subgroups patients likely respond one approach moving towards individualized medicine

fibromyalgia is a chronic pain syndrome characterized by widespread pain , fatigue , and memory and mood disturbances . despite advances in our understanding of the underlying pathophysiology , treatment is often challenging . new research indicates that changes in functional connectivity between brain regions , as can be measured by magnetic resonance imaging ( fcmri ) of the resting state , may underlie the pathogenesis of this and other chronic pain states . as such , this parameter may be able to be used to monitor changes in brain function associated with pharmacological treatment , and might also be able to predict treatment response.we performed a resting state fcmri trial using a randomized , placebo - controlled , cross - over design to investigate mechanisms of action of milnacipran ( mln ) , a selective serotonin and norepinephrine reuptake inhibitor ( snri ) , in fibromyalgia patients . our aim was to identify functional connectivity patterns at baseline that would differentially predict treatment response to mln as compared to placebo . since preclinical studies of mln suggest that this medication works by augmenting antinociceptive processes , we specifically investigated brain regions known to be involved in pain inhibition.15 fibromyalgia patients completed the study , consisting of 6 weeks of drug and placebo intake ( order counterbalanced ) with an interspersed 2 week wash out period . as a main finding we report that reductions in clinical pain scores during mln were associated with decreased functional connectivity between pro - nociceptive regions and antinociceptive pain regions at baseline , specifically between the rostral part of the anterior cingulate cortex ( acc ) and the insular cortex ( ic ) , as well as between the periaqueductal gray ( pag ) and the ic : patients with lower preexisting functional connectivity had the greatest reduction in clinical pain . this pattern was not observed for the placebo period . however a more robust placebo response was associated with lower baseline functional connectivity between the acc and the dorsolateral prefrontal cortex.this study indicates that acc ic connectivity might play a role in the mechanism of action of mln , and perhaps more importantly fcmri might be a useful tool to predict pharmacological treatment response .

several malignant tumours metastasize colon including stomach breast ovary cervix kidney lung prostate skin clinical symptoms signs may suggest diagnosis one third patients asymptomatic diagnosis may incidental finding autopsy therapeutic options include resection intent cure primary secondary tumours resection palliative interventions colonic resection colostomy non surgical treatment if metastases resected prognosis reportedly primary tumour two years previously 49-year old male caucasian patient chronic smoker diagnosed small cell carcinoma lung ct scan thorax revealed mediastinal lymphadenopathy ct scans abdomen pelvis brain essentially normal the patient received chemotherapy 3 months partial response thoracic changes ct followed three months radiotherapy including prophylactic radiotherapy brain one year later residual tumour ct scan thorax bronchoscopy follow chest department year later showed significant progression lung cancer lung lymphatic metastases follow chest ct scan abdomen scanned further chemotherapy given patient health deteriorated received several blood transfusions normochromic normocyctic anaemia six months later attended emergency department anorexia asthenia generalized abdominal pain 3 days obstipation 8 days without nausea vomiting he looked pale tender right lower abdomen rebound tenderness mcburney point blumberg sign normal bowel sounds abdominal ultrasound us revealed area liquid right lower quadrant containing elongated structure suggestive acute appendicitis mcburney incision surgical exploration revealed mass right colon a midline incision made two tumours identified one right colon mobile second one sigmoid colon fixed sacrum deemed irresectable right hemicolectomy ileocolic side side stapled anastomosis performed together sigmoid loop colostomy the appendix normal macroscopically also histology resected bowel confirmed right colonic tumour secondary small cell carcinoma lung immunohistochemistry showed immunoreactivity tumour cells cytokeratin cam 5,2 dot like chromogranin synaptofisin cd56 secondary cancer confirmed intense diffuse immunoreactivity thyroid transcription factor-1 ttf-1 consistent metastatic lung cancer he discharged 11th post operative day died 12 weeks surgery colonic metastases rare usually secondary malignant tumours stomach breast ovary cervix kidney lung prostate skin the published reports suggest colon metastases lung cancer tend giant cell carcinoma squamous cell carcinoma although third colonic metastases asymptomatic found autopsy often present clinically ochsner debakey found gastrointestinal involvement 4.3% 3047 autopsies usually colonic metastases diagnosed later primary tumour however cases synchronous prior diagnosis exuberant symptoms rare signs symptoms bowel obstruction lower gastrointestinal haemorrhage macroscopic occult intestinal perforation gastrointestinal fistula anaemia weight loss transfusion dependent anaemia described literature normochromic normocytic anaemia frequent chronic oncologic diseases current availability positron emission tomography pet scanning colonic metastases may diagnosed frequently previously even patients without mediastinal lymph node involvement pet scans may come major role evaluation lung cancer a pathological diagnosis crucial case confirmation right colonic lesion metastatic lung cancer came intense diffuse immunoreactivity ttf-1 expressed primary colonic cancer immunoreactivity tumour cells cytokeratin cam 5,2 dot like chromogranin synaptofisin cd56 the prognosis lung cancer intestinal metastases poor mean survival 4 8 weeks maximum 16 weeks found patient survived 12 weeks post operatively if resection colonic metastases possible prognosis primary tumour cases complicated bowel obstruction haemorrhage intestinal perforation managed emergency laparotomy resection metastases reported mean survival 6 months maximum 13 months chemotherapy patients primary secondary non resectable lesions may prolong survival 23 weeks reported chemotherapy induce intestinal perforation patients known intestinal metastases therapy must individualized three surgical options resection curative intent primary secondary lesions palliative therapy colon resection colostomy intervention selected cases given poor general health patient non resectability primary secondary lesions management decisions appear appropriate metastatic lesions colon rare may raise difficult problems management survival reports treatment options vary dilemma lesion treat first primary secondary needs considered case case gastrointestinal metastatic disease considered differential diagnosis patients lung cancer presenting acute abdomen aggressive surgical management provides best chance palliation decrease duration hospitalization improves quality life resecting secondary colonic lung primary tumours may increase survival chemotherapy though treatment must individualised written informed consent obtained patient publication case report.a copy written consent available review editor chief journal request ceca data collection manuscript writing manuscript review lsr data collection cmca manuscript review

introductioncolonic metastases are rare , and usually secondary from malignant tumours of the stomach , breast , ovarian , cervix , kidney , lung , prostate , or skin . around one third are asymptomatic or found only at autopsy.case reporta middle - aged male smoker , who had a small cell carcinoma of the lung diagnosed two years previously and treated with radiotherapy and chemotherapy , was admitted to the emergency room with intense abdominal pain and constipation . with the suspicion of an acute appendicitis he was submitted to surgery . at laparotomy he was found to have a normal appendix but two hard colonic lesions : a mobile one in the right colon and the other fixing the sigmoid colon to the sacrum . a right hemicolectomy and a sigmoid loop colostomy were performed . pathology showed those lesions to be colonic metastases from small cell carcinoma of the lung.discussioncolonic secondaries are most frequently diagnosed in patients who have had a known primary tumour , and may present with bowel obstruction , lower gastrointestinal haemorrhage , gastrointestinal fistula , or intestinal perforation . presentation with acute abdomen is rare , and survival is usually limited.conclusioncolonic metastatic disease should be considered in any patient presenting with an acute abdomen and past history of lung malignancy .

use dental implants revolutionized prosthodontics fixed treatment options offered patients high survival rates long term predictability clinically loaded endosseous implants consistently reported resulting one successful treatment modalities dentistry 14 however despite early characterization factors related implant fixture success noticeable understanding prosthetic related failures less explored typically implant supported rehabilitation comprised endosseous implant connects transmucosal abutment 2-piece receives single multiple unit prosthetic restoration the location connection either submerged bone crest level nonsubmerged regardless location type connection internal external important best implant abutment interface fit achieved order favor stress distribution connecting components biological response hindering microorganism colonization interface 68 the commonly used internal external connections involve use screw clamp implant fixture abutment the stability connection secured clamping force challenged unclamping forces derived occlusal function according bolted joint mechanics achieve maintain stability screw type connection it important gap size minimum decrease likelihood screw loosening it demonstrated gaps minimized chances screw loosening also decreased 911 thus showing positive relationship gap size screw loosening clinically absence gap free implant abutment interface induce biological mechanical complications jeopardizing implant long term success an intense host immunological response acute inflammatory process found near gaps around implant abutment interface leading potential bone loss 1214 the bacterially contaminated interface may elicit maintain inflammatory process peri implantitis 15 16 such bacterial colonization may initiate surgical placement implant reopening installation intermediary misfit prosthetic connection 7 12 13 17 thus interface gap allows fluid bacterial microleakage 6 1820 implant well may serve bacterial reservoir allows microorganisms seep perpetuating peri implantitis disease however implant design junctions changed time providing predictability bone stability displayed one piece implant switching platform concept 2125 these positive reports may intensify clinical negative impact provided marginal misfit implant abutment interface located alveolar crest mechanical perspective it identified systematic review common technical complication single unit implant supported reconstruction abutment occlusal screw loosening cumulative incidence 12.7% 5 years followup one potential reason type failure could ill fitted implant abutment interface destabilizing implant abutment connection 2832 despite outstanding success rates modern implantology one crucial factor maintenance bone level long term negatively affected mechanical biological complications since establishment peri implant bone level healing period somewhat predictable stability time affected inherent issues implant abutment connection 33 34 mechanical 911 29 31 32 biological perspective 12 17 3540 studies commonly investigated sealing capability bacterial 7 8 14 41 color marker migration towards implant well direct observations implant abutment interface also performed x ray scanning electron microscopy sem 43 44 optical microscopy another possibility cross sectional analysis evaluation misfit made function implant radius allows comprehensive observation adaptation along implant abutment interface however evaluation implant abutment sealing capability followed sem direct observation addressed date this study sought compare sealing capability marginal fit two external hexagon implant systems spectrophotometric quantification microleakage several incubation times followed sem observation implant abutment interface two external hexagon implant systems 4.1 mm diameter used study n 10 per system tryon sin sistema de implantes nacional paulo sp brazil osseotite biomet 3i palm beach fla usa implants proprietary abutments first subjected sealing capability testing direct sem observation interface in order quantify amount color marker 1% acid red propylene glycol hydrosoluble pigment caries detector kuraray medical incorporation okayama japan dissolved distilled water calibration curve determined linear regression best line fit using fraction color marker volume water seven color marker increments 0.1 l 0.7 l added using automated pipette eppendorf research pro westbury usa 1.3 ml distilled water placed 2.5 ml vials the absorbance color marker increments dissolved water figure 1 quantified spectrophotometer calibrated wavelength 560 nm fluostar optima the maximum amount 0.7 l determined pilot study indicated volume enough fill implant well remained free contact torqued abutment screw apical portion samples increment n 5 per increment analyzed spectrophotometer calibrated wavelength 560 nm acquire absorbance values used compose absorbance curve starting point formulate absorbance curve pure distilled water without color marker apical portion implant well 0.7 l amount color marker dispensed means automated pipette subsequently implants held vise connected bench vertical position abutments assembled onto implants torqued 20 ncm per manufacturers recommendations using hand torque wrench tmec sin sistema de implantes paulo brazil the connected implants placed 2.5 ml vials eppendorf research pro westbury usa filled 1.3 ml distilled water assuring implant abutment interface remained immersed interface abutment screw the capped vials containing implants water kept room temperature using automated pipette samples 100 l n 3 implant acquired 1 3 6 24 48 72 96 144 hrs incubation time room temperature each sample transferred respective vial microplate costar 96 costar the arithmetic average three absorbance values determined used statistical analyses two way anova 95% level significance tukey test multiple comparisons utilized specimens subjected marginal fit evaluation sem model 3500s hitachi ltd osaka japan 15 kv acceleration voltage 750x magnification the calibration curve generated 0.1 l increments color marker 0.7 l dissolved water linear presenting r 0.9974 figure 2 the color marker release quantification showed statistical difference p .05 groups however groups increased amount color marker release function incubation time figure 3 the highest amount color marker release observed 144 hours relative previous incubation times p .000001 groups although results showed presence gaps sem marginal observation interface caution must taken technique considered method evaluate fit joint since variations gap sizes shown occur along implant radius cross sectional observations interface in addition whereas knowledge interface size allow understanding potential bacterial colonization limited providing insight possibility fluid passage implant abutment interface when compared results sealing capability testing internal connecting systems present data shows leakage also occurring investigated external connection systems the external hexagon connection chosen long history use plethora data concerning application 30 47 although efforts reduce leakage use polymeric components interface hindered eliminated bacterial colonization screw less interference fit implant abutment connection shown restrain bacterial passage along interface besides alteration connection designs positive outcomes bone level maintenance compared matching implant abutment dimensions noticed clinical prospective studies two distinct approaches the first involves positioning implant abutment interface inward away outer edge implant platform switching concept 21 22 24 25 49 second comprises absence connection use one piece implants the results first may mainly attributed distance increase abutment interface bone level perhaps decreasing bone response consequently bone loss one piece implants however application platform switching concept seems limited larger diameter implants 5.0 6.0 mm prosthetic platform diameter considering relationship extension bone loss magnitude inflammatory process suggested likely associated presence microorganism implant abutment interface 15 16 seems direct relationship peri implant disease interface gap 7 15 therefore alterations connection designs always gained attention implant supported prosthodontics considerable effort devoted improve stability minimize implant abutment interface gap 7 35 39 46 51 imperfections related machining implants components excessive torque abutment placement may allow distortion parts addition misfit implant abutment factors related interface gap origin therefore new studies involving sealing capability different connection systems combined fatigue testing evaluate effect misfit systems mechanical performance may bring insight development new connection designs evaluation sealing capability two different systems showed passage fluids groups groups presented implant abutment gaps sem micrographs

to evaluate the sealing capability of external hexagon implant systems and assess the marginal fit , two groups ( n = 10 each ) were employed : sin ( sistema de implantes nacional , brazil ) and osseotite , ( biomet 3i , usa ) . sealing capability was determined by placing 0.7 l of 1% acid - red solution in the implant wells before the torque of their respective abutments . specimens were then placed into 2.5 ml vials filled with 1.3 ml of distilled water with the implant - abutment interface submerged . three samples of 100 l water were collected at previously determinate times . the absorbance was measured with a spectrophotometer , and the data were analyzed by two - way anova ( p < .05 ) and tukey 's test . marginal fit was determined using sem . leakage was observed for both groups at all times and was significantly higher at 144 hrs . sem analysis depicted gaps in the implant - abutment interface of both groups . gaps in the implant - abutment interface were observed along with leakage increased at the 144 hrs evaluation period .

postmenopausal osteoporosis systemic skeletal condition affects many millions women around world the national institutes health consensus conference defined osteoporosis disease increased skeletal fragility accompanied microarchitectural deterioration low bone mineral density score bone mineral density 2.5 osteoporosis prevention treatment relied hormonal treatments estrogens selective estrogen receptor modulators anticatabolic drugs bone resorption inhibitors including bisphosphonates . compounds potent suppressor osteoclast activity improve trabecular cortical architecture increase bone mineral density thereby reducing risk fracture women osteoporosis since 2003 numerous reports proposed association bisphosphonate use osteonecrosis jaw bone long term side effect class agents according american association oral maxillofacial surgeons position paper patients may considered bisphosphonates related osteonecrosis jaw bronj following three characteristics present 1 current previous treatment bisphosphonate 2 exposed necrotic bone maxillofacial region persisted eight weeks 3 history radiation therapy jaws although bronj dose related side effect common cancer patients recent paper showed frequency osteoporosis patients oral bps affected bronj higher previously reported n 470 7.8% purpose longitudinal study present data 76 female patients treated bisphosphonates postmenopausal osteoporosis referred unit oral diagnosis day surgery university milano diagnosis treatment starting 2005 female osteoporotic patients treated bps referred unit oral diagnosis day surgery evaluation management visit treatment this study approved director clinic accordance declaration helsinki each tooth probed four sites three buccally one lingually using north carolina probe measure probing pocket depth recession periodontitis based measures presence extent cal least 20% sites probed cal 4 mm relevant clinical data regarding bps treatment comorbidities oral findings dental treatment plan past present dental therapies assessed patients followed every three months routine clinical examination oral hygiene instructions debridement restorative care periodontal dentoalveolar procedures provided needed according american association oral maxillofacial surgeons guidelines individuals included stage group asymptomatic exposed bone without evidence infection finally patients included stage iii group exposed necrotic bone evidence infection pain one following pathologic fracture extraoral fistula osteolysis extending inferior border mandible sinus floor the management bronj aimed reduce lesion size soft hard tissue inflammation alleviate pain nonsurgical treatment included wide spectrum antibiotics antifungal agents mouthwashes antimicrobial solution surgical treatment included debridement without mucosal elevation removal loose segments bony sequestra we described distribution participants characteristics including demographics smoking status medical history prevalence clinical features bronj we performed logistic regression analysis estimate odds ratios ors 95% ci exposures interest diabetes hypertension dental periodontal abscess multiple dental decays periodontitis dental extraction presence onj a total 76 caucasian women included analysis time enrollment patients ranged age 51 91 years median age 69 years interquartile range 6274 table 1 in addition 34.2% suffered hypertension 21.1% cardiovascular disease 5.3% patients reported diabetes 5.3% treatment immunosuppressant agent 3.9% previously underwent chemo- radiotherapy multiple dental decays periodontitis present 61.8% 77.6% individuals respectively 61.8% patients receiving alendronate 21.1% clodronate 3.9% ibandronate 13.2% risedronate patients received bps consecutively mean duration time 191 weeks 95% ci 150.9230.7 76 patients seven 9.2% active onj first visit treated clinics table 1 three patients classified stage four individuals stage ii among majority 85.7% mandible 14.3% onj maxilla the triggering events onj identified previous dentoalveolar surgery n 2 local trauma dentures all bronj patients received wide spectrum antibiotic therapy four patients underwent surgical debridement closure exposure complete remission obtained 4 cases 7 present none non onj patients submitted invasive dental treatments developed onj signs and/or symptoms individuals dental periodontal abscess significantly likely develop onj table 2 women positive history diabetes significant increase odds onj 3.7 95% ci 0.340.9 patients underwent dental extraction receiving bps therapy three times likely develop onj 2.9 95% ci 0.515.9 no significant associations observed following variables age smoking status type bps used hypertension cardiovascular disease immunosuppressant previous radio- chemotherapy multiple dental decays bisphosphonates widely prescribed drugs treatment osteoporosis 190 million prescriptions dispensed worldwide the results analysis showed incidence onj attributable use bisphosphonates 9% our findings agreement otto et al conducted large multicenter trial relationship onj use bps showed 7.8% cases ( n 470 associated oral bps therapy due osteoporosis the risk increased also patients underwent dental alveolar procedures women periodontal disease dental periodontal abscess our results also consistent paper m. d. anderson cancer center group reported patients dental periodontal abscess taking bisphosphonates seven fold increased risk developing bronj individuals dental extractions three times likely diagnosed bronj showed cancer patients positive history dental extractions associated significant increase odds detecting onj 13.2 95% ci 3.747.3 p .0001 however odds ratios lower reported hoff colleagues it may suggested cancer patients slower healing process cancer free osteoporotic patients radiation therapy chemotherapy affect ability cells reproduce slows healing process mouth in addition chemotherapy may reduce number white blood cells weaken immune system making easier patient develop infection though small numbers limited ability fully evaluate risk factors onj associations observed tobacco use presence multiple decays previous radiotherapy and/or chemotherapy concomitant use immunosuppressant medications another limitation note study study population hospital based therefore results may generalizable population large order overcome sample size issues our findings indicate patients osteoporosis receiving bps may develop osteonecrosis mandible especially presence active infectious process mouth periodontal disease suppuration in addition management condition requires use prolonged medical treatment may require oral surgical procedures urgent need fill knowledge gap better characterizing condition identifying main cause determining individual susceptibility intervention prevention bronj follow findings additional large clinical trials aim find overcome bisphosphonate associated onj predict may benefit bisphosphonate treatment without accompanying risk onj warranted meantime patients receiving bisphosphonates therapy followed carefully avoid occurrence extended osteonecrotic lesions

the aim of this longitudinal study is to present data from 76 female patients treated with bisphosphonates ( bps ) for postmenopausal osteoporosis and referred to the unit of oral diagnosis and day surgery of the university of milano for diagnosis and treatment . all patients received a thorough oral examination . the diagnosis of osteonecrosis of the jaw bone ( onj ) was made from radiographic and clinical findings . 9% of individuals had bronj at first visit . patients with dental or periodontal abscess were significantly more likely to develop bronj ( or : 2.9 , 95% ci 0.515.9 ) . patients with osteoporosis receiving bps may develop bronj , especially in the presence of an active infectious process in the mouth . clinicians should carefully follow up on individuals receiving bisphosphonates therapy to avoid the occurrence of osteonecrotic lesions .

eukaryotic cells depend vesicle mediated endocytosis secretion interact communicate environment such membrane based cellular processes dynamic well closely interconnected thus require complex cellular logistics small vesicles example cycle endoplasmic reticulum er golgi larger spherical compartments termed endosomes these endosomes actively transported along polarized microtubules action kinesin dynein motor proteins cover long distances kinesins mainly transport cargo plus ends microtubules whereas dynein mediates transport opposite direction simple eukaryotes as membrane trafficking necessary support fast expansion growth cones hyphal tip apex a particular active zone secretion visible spitzenkrper proposed act vesicle supply center adjacent structure polarisome assembles actin cables likely anchors microtubules membrane thereby directing cytoskeleton dependent membrane traffic toward tip they also deliver biosynthetic enzymes chitin glucan synthases sustain formation cell walls well hydrolytic enzymes nutrient acquisition cell wall remodelling in addition pathogenic fungi secrete battery effector proteins interact animal plant host trafficking reverse direction endocytosis required uptake membranes membrane associated proteins trans membrane receptors protein cargo either recycled plasma membrane directed vacuole degradation fungi the basidiomycete ustilago maydis established fungal model system particularly well suited study mechanism biological function microtubule dependent membrane dynamics important infection developmental switch saprophytic yeast cells proliferate budding fig the key transcriptional regulator triggers filamentous growth heterodimeric transcription factor bw constitute active heterodimer subunits thus wild type cells plasmogamy mates prerequisite generating active transcription factor however monokaryotic lab strains established express active bw heterodimer control regulated promoters induced either arabinose nitrate haploid strains hyphal growth closely resembles wild type filaments elicited synchronously reproducibly switching carbon nitrogen source medium fig ( yeast b filamentous form strain ab33rab5ag expressing active bw2/be1 variant control nitrogen source regulated promoter green fluorescent protein gfp fused n terminus rab5a filamentous growth induced changing nitrogen source medium size bars 10 rab5ag positive endosomes arrowheads inverted image detecting gfp fluorescence shuttle bi directionally along microtubules kymograph lower panel kymograph time thus motion rab5ag visible defined tracks note highly processive movement reversal shuttling poles ( c model depicting motor dependent mechanism three motor system endosome transport endosomes carry small g protein rab5a snare yup1 symbols explained inlay u. maydis microtubule dependent transport endosomes important various steps life cycle triggering cell separation budding receptor recycling pheromone signaling maintenance polarity filamentous growth review recent advances detailed transport mechanism well biological function endosomes signaling endocytosis mrna transport information microtubule transport u. maydis biology as mentioned processes involving membrane trafficking tightly interwoven highly complex a common concept investigating endosomal compartments identification characteristic marker proteins differentiate endosomes present two different classes endosomes known u. maydis mcs1- rab5a positive endosomes mcs1 fungal class 17 myosin consists two domains n terminal myosin motor domain c terminal chitin synthase domain transport mcs1-positive endosomes depend myosin motor domain mcs1 mediated actin- microtubule dependent motors the integral motor domain mcs1 thought tether membrane units hyphal tip membrane based mcs1 trafficking needed secretion exocytosis process apparently required cell wall remodelling virulence rab5a small g protein belonging family rab proteins serve specific markers distinct classes endosomes u. maydis rab5a positive endosomes suggested early endosomes also stained styryl dye fm464 used study endocytic pathway however fm464 specific endocytosis also stains secretory vesicles fungal spitzenkrper well secretory vesicles downstream trans golgi network plant cells moreover far reported rab5a positive endosomes maturate late endosomes u. maydis second rab5 protein rab5b encoded genome therefore use generic term rab5a positive endosomes throughout review important component rab5a positive endosomes snare like protein yup1 related vam7p s. cerevisiae proposed function fusing endocytic vesicles endosomes its precise role yet unclear loss yup1 results altered cell morphology reduced endocytic recycling pheromone receptor pra1 see moreover yup1 important endosome movement motility drastically impaired temperature sensitive yup1 mutants restrictive conditions last decade endosomal transport u. maydis studied great detail yeast form filaments rab5a positive endosomes shuttle along microtubules throughout cell moving highly processive fashion poles change direction without extensive pause fig each cell contains two four microtubule bundles consist single microtubules oriented antiparallel fashion near poles filaments i.e. 10 ends microtubules arranged antiparallel bundles form single unidirectional extensions plus ends facing poles fig - end directed movement endosomes along antiparallel bundled well single microtubules mediated kin3 fig 1c kinesin-3 type motor related unc104 kif1a nematodes mammals respectively the motor contains c terminal pleckstrin homology ph domain interaction phosphatidylinositol lipid containing membranes the ph domain essential unc104-dependent transport neurons c. elegans kin3-driven movements endosomes filaments u. maydis each endosome contains three six kin3 responsible highly processive bidirectional movement along antipolar bundles filaments fig minus end directed transport endosomes mediated dynein motor dyn1/2 fig this becomes important poles filaments unidirectional region microtubule cytoskeleton minus end directed transport option endosomes return antiparallel array this nicely seen temperature sensitive mutants dyn2 rab5a positive endosomes accumulate poles restrictive conditions dyn1/2 also move minus end direction independently rab5a positive endosomes if minus end directed dyn1/2 motor meets oncoming endosome dyn1/2 able reverse direction moving endosome toward minus end this process proposed protect endosomes falling track motors recycled reach ends microtubules kin3 associates rab5a positive endosomes directions transport this holds true even poles unidirectional microtubules longer antiparallel bundles present area dyn1/2 mediates minus end directed transport endosomes kin3 cargo specific recycling system kin3 needed in contrast dynein actively transported back plus ends microtubules conventional kinesin therefore endosomes accumulate poles absence conventional kinesin dynein required minus end directed transport missing poles summary tripartite motor system consisting kin3 dynein conventional kinesin manages complex logistics long distance transport endosomes along highly organized array microtubules fig interestingly rab5a positive endosomes exhibit rather diverse functions throughout life cycle u. maydis yeast cells play important role septum formation cell separation 2a reminiscent mutants don1 don3 originally identified owing striking colony morphology the explanation mutant phenotype failure form secondary septum essential cell separation cytokinesis fig don1 encodes guanine nucleotide exchange factor gef specific small gtp binding protein cdc42 don3 ste20-like protein kinase acting parallel signaling module don1 carries c terminal fyve domain specific recognition phosphatidylinositol-3-phosphate lipids thus targets don1 rab5a positive endosomes kin3-mediated transport don1-loaded endosomes critical cell separation order synchronize cdc42-triggered secondary septum formation accumulation vesicles involved lysis fragmentation zone fig 2c ( colony b yeast cell morphology strain ab33kin3 comparison progenitor strain size bar 10 ( c model depicting function rab5a positive endosomes delivery don1 site septation process essential formation secondary septum red rectangle shown middle panel c enlarged d. mating rab5a positive endosomes involved endocytic recycling pheromone receptor pra1 pra1 accumulates endocytic vesicles inside cell temperature sensitive yup1 mutants restrictive conditions thus missing plasma membrane conjugation tubes this correlates reduced recognition compatible mating partners results fusion defect conjugation tubes thus endocytic recycling pra1 mediated rab5a positive endosomes appears important polarized accumulation receptor growth cones mating hyphae orient growth toward pheromone sources filamentous growth microtubule dependent motor function is important maintaining unidirectional growth tip cell concomitant formation retraction septa distal end hyphae 3a predominantly bipolar filaments lacking retraction septa indicating unipolar growth disturbed fig 3b c similar observations made absence functional dynein conventional kinesin filaments treated microtubule inhibitor benomyl ( colony b c cell morphology kin3 filaments the edges colonies growing filament inducing conditions shown monokaryotic filament carrying wild type allele kin3 b compared bipolarly growing filament kin3 c strain grown filament inducing conditions size bars 10 ( e model depicting function rab5a positive endosomes transport mrnps red rectangle shown growth cone enlarged e symbols explained inlay it noteworthy loss rna binding protein rrm4 causes similar growth defect mutant filaments grow mainly bipolar fail insert retraction septa this rrm type rna recognition motif rna binding protein constitutes integral part transport machinery mediating microtubule dependent long distance transport mrnas rrm4 binds distinct sets target mrnas encoding cytotopically related proteins including polarity factors rho3 ribosomal proteins ubi1 natural fusion protein ubiquitin rpl40 large ribosomal subunit rrm4-mediated mrna transport believed promote subcellular accumulation rho3 retraction septum local translation fig co transport observed throughout whole filament co localization endosomes depend presence kin3 in absence rrm4 endosomal movement drastically impaired suggesting rab5a positive endosomes shuttle independently rrm4 mrna cargo nevertheless loss rrm4 causes defects filamentous growth resembling mutants defects microtubule function thus mrna transport appears important function trafficking rab5a positive endosomes particularly filamentous growth fig this novel function endosomes broad implications mrna transport general u. maydis we could demonstrate unambiguously microtubule dependent mrna transport mainly endosome dependent fig it observed mrna transport tightly linked membrane trafficking s. cerevisiae actin dependent transport mrnas achieved hitchhiking er development d. melanogaster endosomal marker rab11 well components escrt ii endosomal sorting complex required transport important correct subcellular localization mrnas encoding morphogens therefore speculated endosomes might directly involved short range mrna transport research recent years revealed endosome action lot complex previously anticipated this well supported recent findings variety endosomal functions fungal model system u. maydis along function endocytosis rab5a positive endosomes important cell separation pheromone signaling mrna transport the connection mrna transport particular adds novel aspect growing list endosomal functions thus substantiating current views endomembrane compartments function multipurpose platforms if example mrnas encoding proteins involved endocytosis transported endosomes alterations endosome function might disturb endocytosis directly also indirectly via mrna transport future joint efforts scientists focusing mrna membrane trafficking needed explain mechanistic functional aspects complex interlaced molecular sorting machinery

long - distance trafficking of membranous structures along the cytoskeleton is crucial for secretion and endocytosis in eukaryotes . molecular motors are transporting both secretory and endocytic vesicles along polarized microtubules . here , we review the transport mechanism and biological function of a distinct subset of large vesicles marked by the g - protein rab5a in the model microorganism ustilago maydis . these rab5a - positive endosomes shuttle bi - directionally along microtubules mediated by the unc104/kif1a - related motor kin3 and dynein dyn1/2 . rab5a - positive endosomes exhibit diverse functions during the life cycle of u. maydis . in haploid budding cells they are involved in cytokinesis and pheromone signaling . during filamentous growth endosomes are used for long - distance transport of mrna , a prerequisite to maintain polarity most likely via local translation of specific proteins at both the apical and distal ends of filaments . endosomal co - transport of mrna constitutes a novel function of these membrane compartments supporting the view that endosomes function as multipurpose platforms .

regards selection criteria post system clinicians often succumb marketing tactics opposed clinical evidence this study attempts bridge gap using finite element analysis model analyze effect oblique loading forces stress concentration entire assembly incorporated tooth structure the likelihood survival pulpless tooth directly related quantity quality remaining dental tissue post commonly placed attempt strengthen tooth however vitro vivo studies demonstrated post reinforce endodontically treated teeth despite improving retention less 3 4 mm vertical height around 25 50% clinical crown remaining recent developments esthetic dentistry supported use fiber post restore endodontically treated teeth the need light translucent composite resins ceramics mimic natural tooth requires use translucent posts replace metal posts esthetic zone oral cavity the presence metal post cause shadowing soft tissues adjacent root surface adversely affects esthetic results required bonded resin ceramic restorations anterior region when fiber reinforced post bonded within root canal dissipates functional parafunctional forces reducing stress root acute consequences forces assembly anticipated gradual build destructive stresses finally cause failure assembly catastrophic force placed crown tooth the crown fracture instead post transmitting energy force root creating vertical root fracture consequently post system able dissipate function energy even overcome moderate trauma fiber reinforced posts demonstrated ability fracture coronal portion tooth restoration presence catastrophic forces without root fracture permitting scope retreatment remaining root structure thus structural integrity clinical longevity post- core restored teeth therefore strongly dependent state stress created different regions due occlusal loads in addition magnitude direction loads stress state given point within restored tooth also influenced factors like design material post quantity quality remaining root tissue as extensive loss root dentin increases risk radicular fracture appropriate mechanical behavior post considered case fundamental success rehabilitating restored teeth earlier various methods used study stress concentration tooth structures namely photo elastic studies photomechanical investigations strain gauge studies etc finite element analysis fea ) is one commonly used techniques stress analysis.[36 basic concept technique visualization actual structure assembly finite number elements three post systems different manufacturers used maxillary central incisors virtual model subjected forces elicit data regarding tensile strength varied biomechanical behavior different stresses expected post systems used significantly dissimilar design taper modulus elasticity a maxillary central incisor created virtually using computer aided designing cad 2-dimensional model figure 1a mesial view this design parts endodontically treated tooth i.e. enamel dentin cementum alveolar bone gutta percha fiber post luting cement full coverage crown material properties like young modulus poisson ratio provided design the design one variation shape three brands group dt light post rdt bisco france group b luscent anchor dentatus usa group c relyx 3 espe germany according taper due design patent modulus elasticity dt light post double tapered luscent anchor comparison parallel shape taper last 1.8 mm apical end contrast relyx uni taper 8% middle third post shape tables 1 2 ( shows virtual model b shows meshed assembly c shows comparative results lowest value force generated shows parallelism glass fibers relyx post modulus elasticity post systems used study elastic properties materials involved fem calculation virtual model rendered meshing figure 1b represents division virtual model smaller elements constrained four nodes show dimensional changes individual units entire design assembly subjected finite element analysis software ansys oblique loading forces 25 n 80 n 125 n 60 degrees lingual surface incisor a maxillary central incisor created virtually using computer aided designing cad 2-dimensional model figure 1a mesial view this design parts endodontically treated tooth i.e. enamel dentin cementum alveolar bone gutta percha fiber post luting cement full coverage crown material properties like young modulus poisson ratio provided design the design one variation shape three brands group dt light post rdt bisco france group b luscent anchor dentatus usa group c relyx 3 espe germany according taper due design patent modulus elasticity dt light post double tapered luscent anchor comparison parallel shape taper last 1.8 mm apical end contrast relyx uni taper 8% middle third post shape tables 1 2 ( shows virtual model b shows meshed assembly c shows comparative results lowest value force generated shows parallelism glass fibers relyx post modulus elasticity post systems used study elastic properties materials involved fem calculation virtual model rendered meshing figure 1b represents division virtual model smaller elements constrained four nodes show dimensional changes individual units entire design assembly subjected finite element analysis software ansys oblique loading forces 25 n 80 n 125 n 60 degrees lingual surface incisor when three groups subjected analysis group c showed maximum stress distribution entire structure least forces generated stress concentration apical third tooth model significantly different two groups the results figure 1c model presented terms von misses stress values decides likelihood failure structure material analyzed when oblique forces applied structure design showed movement direction force applied i.e. buccal flexion transferring compression interface crown core dentin coronal near cej cemento enamel junction similar change shades colors occurred gutta percha post dentin radicular interface confirming stress concentrations junction act potential site bond failure colored bar bottom analysis showed maximum force red minimum force blue generated analysis conducted ansys software minimal changes colors observed apical third tooth structure signifies complete dissipation occlusal load predicting potential absence vertical fractures result using metal post vivo vitro experiments conducted past the structure tooth remains endodontic treatment usually undermined previous episodes caries fracture tooth preparation it established many detrimental effects produced rehabilitative procedures due lack understanding biomechanical principles underlying treatment the purpose using products mechanical properties closer dentin enamel always obtain best resistance retention restoration done application dislodging occluding forces thus protecting remaining tooth structure when occlusal forces act tooth surface divide two components vectors such forces create stresses dentin dynamic structure stress escapes dentin form crack propagation ultimately resulting crazing fiber post systems popular choice modern dentists replacing restoring missing tooth structure grossly mutilated teeth this vogue fiber post due ease handling manipulation impeccable esthetic value especially anterior teeth fea mathematical analysis designs demonstrate amount stress generated application forces site fracture application technology dentistry important reduce operator bias sample preparation vitro studies all variables eliminated due cad product desired study acted variable conducting fem study poisson ratio young modulus elasticity components taken previous studies.[916 variety products genre always adds dilemma choosing rightly anterior teeth subjected oblique forces angulated 60 degrees form long axis lingual surface mandibular incisors contact maxillary teeth angulation three different amounts forces chosen observe behavior post system mild forces 25 n biting heavy bruxism forces 125 n near mean average forces 80 n relyx subjected forces within parameters study resulted least amount forces stress concentration reached gutta percha cement post interface figure 1c apical third endodontically treated tooth this result attributed parallel fibers present post unique modulus elasticity provided better resistance applied forces figure 1d for superior mechanical properties glass fibers parallel orientation distributed equally surface area additionally manufacturing process glass fibers pretensioned enhanced post stability therefore clinical application relyx fiber posts cut diamond disc according manufacturer specifications provided product brochure restored tooth loading angle kept fixed increasing load found increase von misses stress applying data real model one suggest loading tooth subjected may create immediate failure tooth may create cracks tooth assembly may duration time cause catastrophic failure a virtual model completely mimic vivo model subjected types occlusal forces a 2-d model never represent actual 3-dimensional tooth structure also accuracy entire analysis depends software model created elemental values given study incorrect values inputs inaccurate design lead varying results vulnerable wrong results accurate estimation results obtained increase anticipation better clinical performance mechanical testing failure conducted improves predictability data available literature indicating better performance fiber post probably result use adhesive cementation longevity bonding procedures involving radicular dentin uncertain long term clinical follow necessary confirm effectiveness glass fiber posts restorative solution endodontically treated teeth disclaimer author abovementioned article affirm neither financial affiliation e.g. employment direct payment stock holdings retainers consultant ships patent licensing arrangements honoraria involvement commercial organization direct financial interest subject materials discussed manuscript arrangements existed past three years within confined limitations fea given framework fiber post relyx 3 best choice among competitive products available resulting longevity restoration final goal grossly decayed teeth it conclusive results study fiber post system components higher modulus enable better stress distribution additional observations suggest oblique load tensile applied tooth restored fiber post high stress concentration gutta percha cement post interface also stress concentration present immediate vicinity apical end post found inversely proportional young modulus value post system used mechanical testing products larger sample sizes required support result studies conducted using fea

aims and objectives : to study the stress concentrations in endodontically treated maxillary central incisor teeth restored with 3 different fiber post systems subjected to various oblique occlusal loads.materials and methods : fem analysis was used to analyze stress concentrations generated in maxillary anterior teeth . computer aided designing was used to create a 2-d model of an upper central incisor . post systems analyzed were the dt light post ( rdt , bisco ) , luscent anchor ( dentatus ) & relyx ( 3m - espe ) . the entire design assembly was subjected to analysis by ansys for oblique loading forces of 25n , 80n & 125 nresults : the resultant data showed that the relyx generated the least amount of stress concentration.conclusions:minimal stress buildups contribute to the longevity of the restorations . thus relyx by virtue of judicious stress distribution is the better option for restoration of grossly decayed teeth .

peer review publications late 17 century authorship papers generally used autonomous attributed sponsors 1 however readers wish know paid research work problems authorship persist everywhere despite international committee medical journal editors icmje criteria 2 authorship considered currency field biomedical sciences researchers open first publication account either undergraduate postgraduate studies continue add acquire faculty positions 2 someone impressive research publications curriculum vitae cv much better chances selection also helps academic promotions strong publication record also leads publications providing great career opportunities preferred considered tenure status appointments grants funding in addition also earn respect admiration community research scientists 3 publish perish popular west many years developing third world countries recognition credit published research work academic appointments medical institutions started two decades ago result faculty members compulsion write publish hence times quality research good there also temptation get gift authorship menace spreading everywhere it generally felt manuscripts many authors certainly include whose names added without intellectual contribution recipients gift authorship order overcome problem renie proposed contributor ship system many years ago 4 listing contributor ship european medical writers association emwa guidelines state medical writes statistician qualify authorship role acknowledged 5 issues related authorship consist almost 25% cases discussed cope meetings 6 issue discussed almost every peer review congress medical editors conferences held different parts world just like everywhere else pakistan medical editors faced issue authorship many times even details contribution demanded journals enable listed bylines authors editors much regard the objective study assess knowledge ascertain views researchers icmje criteria authorship current practice choosing authors scientific papers views gift authorship experience authorship problems it cross sectional survey 218 faculty members 180 males 38 females various medical universities dow university health sciences karachi baqai medical university karachi liaquat university medical sciences hyderabad avicenna medical college lahore king edward medical university the main outcome measures awareness use icmje criteria authorship awareness contributions research merit authorship perceptions gift authorship the participants also asked problems faced deciding authorship strategies wish adopted eliminate gift authorship majority respondents 105 48.2% 218 faculty members participated study senior registrars one hundred twenty eight 58.7% surgery allied disciplines principal investigator surgeon ninety six 44.0% one five publications 60 27.5% six ten published papers credit table 1 demographic profile respondents n 218 one hundred eleven participants 50.9% said aware existence guidelines criteria authorship however twenty two 19.8% could name document four 1.8% could correctly state criteria authorship suggested icmje table 2 knowledge icmje criteria authorship n 218 responding thought icmje authorship criteria 201 92.7% agreed first criteria regards substantial contribution conception design acquisition data analysis interpretation 186 85.3% also agreed drafting article revising critically almost similar number 179 82.1% agreed final approval version published however 120 55.0% said three criteria must met eligible authorship table 3 views participants regards contributions merit authorship scientific publications given table 4 attitude icmje criteria authorship(n 218 faculty view criteria alone contribution merits author scientific publication n 218 34 19.7% respondents felt authorship based contributions 98 45.0% felt decided main author also decide order authorship table 5 ninety three 42.7% stated included authors study though deserved sixty three said included authors though merit strangely 42 19.3% said aware listed authors 52 two said assigned inappropriate co authorship number perception incorrect placing authorship order table 6 faculty current trend co -authorship order authorship n 218 faculty perception problems authorship n 218 ) fifty percent respondents study knowledge existence guidelines regarding criteria authorship only19.8% could name whereas four 218 1.8% could state icmje authorship criteria dismal picture hence participants claimed aware forgotten could easily picked since could ( 7 study fifty sixty respondents supported criteria authorship though knew used five people could specify three criteria one knew three criteria met 55% study felt three criteria must met authorship they also reported gift authorship quite common promoted pressure publish motivate research team maintain working relationship they view signed statement could justify authorship besides contributions author could help tackle issue gift authorship their conclusions gap editor criteria authorship researchers practice they believe future criteria authorship agreed researchers imposed editors french study pignatell et al interviewed 39 investigators submitted 48 proposals 1994 96 half respondents said aware authorship criteria also knew icmje but most disagreed obligation meet three criteria justifying co authorship found rigid inapplicable similar findings study again 59% french study recipients gift authorship felt need french guidelines authorship french researchers serious reservations regarding third criteria i.e. approval final version published few people question ghost gift authorship consider normal serious problem requiring depth debate discussions they also suggested guidelines authorship prepared professionals learned societies representatives biomedical journals besides public research institutes national organizations 8) survey india among teaching faculty 9 39% respondents 77 reported conflict authorship issues like pressure gift authorship academic competition personality differences intellectual passion besides ownership data they also suggested training ethical concerns research undergraduate level though authors understand authorship issues stated dr it sufficiently considered men require often reminded informed debate authorship issues bmj scot tim remarked present authorship system continue slow evolution since reflects real power relations science 10 richard smith editor bmj reported authorship influenced power departmental politics 11 currie opined authors saw fraud misconduct unfairness junior staff culprits often senior researchers those applying specialists registrars asked choose two best publications inclusion cv prepared discuss one two publications submitted previous year consultants merit awards cme points related quality relevance number publications 11 tramara bates colleagues study reported per authors published contributions number honorary authors highest annals internal medicine 21.5% followed bmj 9.5% jama 0.5% the number articles honorary authors 60% annals 215 mbj 4% jama 12 out 6,686 researches 68% fulfilled icmje criteria per author contributions lists radiology articles published 1998 2000 13 these criteria fulfillment decreased number authors increased 2,316 researchers 35% contributed one two categories this study showed total 2,172 32.5% 6,686 authors appearing bylines fulfill icmje criteria authorship 13 study 80% respondents opined designing study collection data important followed conceiving research idea besides literature search review regards eligibility authorship goodman reported one third 84 authors meet authorship criteria analysis twelve articles 14 shapiro survey 184 articles multiple authors ten medical journals reported 268 26% 1014 authors insufficient contributions research meet authorship criteria 15 ana marusic colleagues single blind randomized trial of1462 authors 232 manuscripts general medical journal answered one three different contribution disclosure forms they asked respondents decide words contribution submitted manuscripts they found structure contribution disclosure form significantly influenced number contributions reported authors compliance icmje criteria they concluded editors journals take existing contribution disclosure authorship forms face value 16 more half major papers published american journal roentgenology ajr five co authors 17 the incidence undeserved co authors increased 9% papers three authors 30% papers six authors mean authors manuscript chances gift authorship gift authorship primarily attributed control first author fear obligation moreover temporary staff member found likely gift authorship permanent faculty 17 conception design analysis interpretation drafting articles recognized important icmje criteria 18 final approval critical revision taught important authorship criteria future scientists 18 vesnailakovac colleagues study included 919 authors 201 articles submitted general medical journal found two third corresponding authors 67.9% differed least one contribution choice two disclosure statements made contributions 19 some others studies report giving medical students clear guidelines exposing high ethical standards long term solution problem authorship abuses field medical research 20 a recent study iran reported 89% published bio medical articles iran least one honorary author more 50% article authors meet authorship criteria according icmje about 20% authors confessed colleagues omitted authors list final manuscript the author iranian study concluded regardless authorship criteria recommended icmje followed many journals still cases authorship criteria followed 21 it shows yet found answer acceptable editors authors well researches regards authorship debate still continues perhaps continue time various suggestions put forward redefine criteria authorship final word yet spoken it also evident fact authorship important topic comes discussion various forums icmje bodies science editors well representatives research institutions researchers need come authorship guidelines acceptable stakeholders finding hundred percent consensus neither possible aimed since people continue view point issue majority participants study junior faculty members i.e. registrars assistant professors begun academic career overwhelming majority one hundred eighty two hundred eighteen participants male most junior faculty either written one five papers hence either aware existence guidelines familiar icmje this also main reason 98% could correctly state icmje criteria authorship yet another limitation self administered questionnaire based survey participants tend provide information may 100% correct medical students exposed art medical writing beginning institutions yet included subject medical writing research methodology curriculum must advised similarly regular workshops particularly junior faculty members postgraduates medical writing guidance plan conduct study highlighting existing guidelines authorship various bodies including icmje help expose scientific publishing world thus improving quality studies well majority participants study junior faculty members i.e. registrars assistant professors begun academic career overwhelming majority one hundred eighty two hundred eighteen participants male most junior faculty either written one five papers hence either aware existence guidelines familiar icmje this also main reason 98% could correctly state icmje criteria authorship yet another limitation self administered questionnaire based survey participants tend provide information may 100% correct medical students exposed art medical writing beginning institutions yet included subject medical writing research methodology curriculum must advised similarly regular workshops particularly junior faculty members postgraduates medical writing guidance plan conduct study highlighting existing guidelines authorship various bodies including icmje help expose scientific publishing world thus improving quality studies well a vast majority young faculty members aware existence authorship criteria icmje gift authorship quite common pakistan ethical issues including plagiarism informed consent misconduct data fabrication and/or falsification double publication and/or submission redundancy etc completely observed authors

abstractbackgroundthe objective of this study was to assess the knowledge and views of faculty members on criteria for authorship by international committee of medical journal editors ( icmje ) , their current practice of choosing the authors , views on gift authorship and problems they had faced concerning authorship.methodsit was a cross sectional survey from january 2011 to july 2011 among faculty members of various private and public sector medical institutions of pakistan through a self - administered questionnaire . main outcome measures included awareness and use of icmje criteria , which contribution to research merit authorship and their perceptions about gift authorship.resultstwo hundred eighteen faculty members ( 180 males , 38 females ) participated in the study . one hundred twenty eight ( 58.7% ) were from surgery and allied disciplines . ninety six percent had published between one to five papers while 60(27.5% ) had six to ten papers to their credit . one hundred eleven ( 50.9% ) claimed they were aware about the authorship criteria , only twenty two ( 19.8% ) could name this document . only four ( 1.8% ) could correctly state this . only one hundred twenty ( 55.0% ) said that all three criteria s must be met to be eligible for authorship . ninety three ( 42.7% ) said that they were not included as authors though they deserved it while sixty three said they did not merit but were still included . forty two ( 19.3% ) said that they were not aware when they were listed as authors.conclusiona vast majority of young faculty members are not aware of the existence of authorship criteria and gift authorship is quite common .

reveal registry longitudinal registry involving 54 pulmonary hypertension centers united states e appendix 1 diagnosis defined date diagnostic right sided heart catheterization rhc occurring date enrollment patients new diagnoses defined whose diagnostic rhc occurred within 90 days enrollment all consecutive patients opinion enrolling investigator clinical diagnosis pah group 1 met following inclusion criteria eligible enrollment 1 mean pulmonary artery pressure 25 mm hg rest 30 mm hg exercise 2 mean pulmonary capillary wedge pressure left ventricular end diastolic pressure 18 mm hg 3 pvr 240 dynes cm divide 80 wood units wu 4 3 months age data reveal registry collected prospectively analyses study performed retrospectively the database 3,515 patients locked february 4 2013 current analyses we developed algorithm fig 1 exclude patients exercise induced pah accordance dana point classification criteria pulmonary capillary wedge pressure 15 mm hg shown differ many respects meeting traditional hemodynamic definition pah included patients ctd apah we also excluded evidence significant interstitial lung disease ild defined evidence severe fibrosis high resolution ct scan chest we divided patients ctd apah ssc apah ssc group non ssc ctd apah non ssc group strobe diagram registry evaluate early long term pah management reveal registry patients used analysis we included patients ctd apah met strict criteria world health organization group 1 pulmonary arterial hypertension ctd apah pulmonary arterial hypertension associated connective tissue disease hrct high resolution ct scan chest ild interstitial lung disease non ssc ctd connective tissue disease systemic sclerosis pcwp pulmonary capillary wedge pressure ssc systemic sclerosis tlc total lung capacity baseline characteristics time enrollment compared ssc non ssc groups using student wilcoxon test compare continuous variables fisher exact test compare categorical variables bnp levels highly skewed variables log transformed comparison continuous variables cumulative probabilities survival 3 years calculated using kaplan meier estimator previously newly diagnosed populations differences ssc non ssc groups compared using log rank test cox regression models identified significant predictors mortality ssc non ssc populations all variables identified previously candidate predictors mortality overall reveal registry population evaluated univariate multivariate models stepwise selection used determine final model retaining variables p .05 sas version 9.1 sas institute inc statistical software used analyses the reveal registry longitudinal registry involving 54 pulmonary hypertension centers united states e appendix 1 diagnosis defined date diagnostic right sided heart catheterization rhc occurring date enrollment patients new diagnoses defined whose diagnostic rhc occurred within 90 days enrollment all consecutive patients opinion enrolling investigator clinical diagnosis pah group 1 met following inclusion criteria eligible enrollment 1 mean pulmonary artery pressure 25 mm hg rest 30 mm hg exercise 2 mean pulmonary capillary wedge pressure left ventricular end diastolic pressure 18 mm hg 3 pvr 240 dynes cm divide 80 wood units wu 4 3 months age the data reveal registry collected prospectively analyses study performed retrospectively the database 3,515 patients locked february 4 2013 current analyses we developed algorithm fig 1 exclude patients exercise induced pah accordance dana point classification criteria pulmonary capillary wedge pressure 15 mm hg shown differ many respects meeting traditional hemodynamic definition pah included patients ctd apah we also excluded evidence significant interstitial lung disease ild defined evidence severe fibrosis high resolution ct scan chest we divided patients ctd apah ssc apah ssc group non ssc ctd apah non ssc group strobe diagram registry evaluate early long term pah management reveal registry patients used analysis we included patients ctd apah met strict criteria world health organization group 1 pulmonary arterial hypertension ctd apah pulmonary arterial hypertension associated connective tissue disease hrct high resolution ct scan chest ild interstitial lung disease non ssc ctd connective tissue disease systemic sclerosis pcwp pulmonary capillary wedge pressure ssc systemic sclerosis tlc total lung capacity baseline characteristics time enrollment compared ssc non ssc groups using student wilcoxon test compare continuous variables fisher exact test compare categorical variables bnp levels highly skewed variables log transformed comparison continuous variables cumulative probabilities survival 3 years calculated using kaplan meier estimator previously newly diagnosed populations differences ssc non ssc groups compared using log rank test cox regression models identified significant predictors mortality ssc non ssc populations all variables identified previously candidate predictors mortality overall reveal registry population evaluated univariate multivariate models stepwise selection used determine final model retaining variables p .05 sas version 9.1 sas institute inc statistical software used analyses of 3,515 patients enrolled reveal registry 815 identified ctd apah fig 1 804 500 ssc 304 non ssc significant ild selected analyses the majority patients non ssc group systemic lupus erythematosus apah mixed ctd apah table 1 patients ssc older shorter time diagnostic rhc enrollment database patients non ssc ctd apah table 2 patients ssc apah severe disease overall higher nyha fc shorter 6mwd higher borg dyspnea index lower dlco higher bnp level patients ssc apah also likely renal insufficiency pericardial effusions patients non ssc ctd apah although strong trend toward higher mrap ssc group significant differences hemodynamics pah specific therapies time enrollment ssc vs non ssc groups apah associated pulmonary arterial hypertension ctd connective tissue disease non ssc ctd connective tissue disease systemic sclerosis ssc systemic sclerosis characteristics hemodynamics cardiac pulmonary function enrollment p value calculation uses test categorical data fisher exact test categorical data small cell counts 5% student test continuous data 6mwd 6-min walk distance bnp brain natriuretic peptide bpm beats per min ccb calcium channel blocker dlco diffusion capacity lung carbon monoxide era endothelin receptor agonist fc functional class fco fick cardiac output mpap mean pulmonary arterial pressure mrap mean right atrial pressure nyha new york heart association pah pulmonary arterial hypertension pcwp pulmonary capillary wedge pressure pde-5 phosphodiesterase type-5 pvr pulmonary vascular resistance rhc right sided heart catheterization see table 1 legend expansion abbreviations cardiac output fco fco missing cardiac output thermodilution cardiac output pvr wood units mean pulmonary arterial pressure rest pcwp rest)/cardiac output cardiac output fco fco missing cardiac output thermodilution cardiac output predicted value based hankinson et al computation three year survival ssc group worse non ssc group previously newly diagnosed populations 61.4% 2.7% vs 80.9% 2.7% 51.2% 4.0% vs 76.4% 4.6% respectively p < three year survival curves patients ssc non ssc ctd apah a three year survival enrollment newly diagnosed ssc group 51.2% 4.0% compared 76.4% 4.6% non ssc ctd group p .001 b three year survival enrollment previously diagnosed ssc group 61.4% 2.7% compared 80.9% 2.7% non ssc ctd group p .001 figure 3 shows univariate analyses previously identified predictors mortality overall reveal registry cohort ssc non ssc groups the following variables predictive mortality groups age 60 years nyha fc iii iv status 6mwd 165 bnp 180 pg ml unique predictors mortality ssc group non ssc group included male sex systolic bp sbp 110 mm hg pericardial effusion dlco 32% predicted mrap 20 mm hg within 1 year pvr 32 wu newly diagnosed status bnp levels 50 pg ml protective patients ssc hazard ratio hr 0.34 95% ci 0.16 0.72 p .005 non ssc group hr 0.68 95% ci 0.36 1.29 p .24 figure 3 also shows univariate analyses additional variables relevant ctd apah population mild moderate ild feature increased mortality patients non ssc ctd apah patients ssc apah hr 2.19 95% ci 1.14 4.23 p .02 vs hr 0.84 95% ci 0.55 1.30 p .44 compared ipah mrap > 20 mm hg within 1 year pvr 32 wu newly diagnosed status remained unique predictors death ssc apah group predictors mortality patients ssc apah non ssc ctd apah using univariate cox regression analyses unique predictors mortality ssc group non ssc group included male sex sbp 110 mm hg pericardial effusion dlco 32% predicted mrap 20 mm hg within 1 pvr 32 wu newly diagnosed status bnp levels 50 pg ml protective patients ssc non ssc group mild moderate ild feature increased mortality non ssc group patients ssc 6mwd 6-min walk distance bnp brain natriuretic peptide dlco diffusion capacity lung carbon monoxide fc functional class gfr glomerular filtration rate hr hazard ratio mrap mean right atrial pressure nyha new york heart association pvr pulmonary vascular resistance sbp systolic bp world health organization wu wood units following variables remained predictive mortality ssc non ssc groups nyha fc iii iv status bnp 180 pg ml table 3 unique predictors mortality ssc group included men 60 years sbp 110 mm hg 6mwd 165 mrap 20 mm hg within 1 year pvr 32 wu 6mwd 440 m protective non ssc group ssc group whereas bnp 50 pg ml protective ssc group non ssc group of 3,515 patients enrolled reveal registry 815 identified ctd apah fig 1 804 500 ssc 304 non ssc significant ild selected analyses the majority patients non ssc group systemic lupus erythematosus apah mixed ctd apah table 1 patients ssc older shorter time diagnostic rhc enrollment database patients non ssc ctd apah table 2 patients ssc apah severe disease overall higher nyha fc shorter 6mwd higher borg dyspnea index lower dlco higher bnp level patients ssc apah also likely renal insufficiency pericardial effusions patients non ssc ctd apah although strong trend toward higher mrap ssc group significant differences hemodynamics pah specific therapies time enrollment ssc vs non ssc groups apah associated pulmonary arterial hypertension ctd connective tissue disease non ssc ctd connective tissue disease systemic sclerosis ssc systemic sclerosis characteristics hemodynamics cardiac pulmonary function enrollment p value calculation uses test categorical data fisher exact test categorical data small cell counts 5% student test continuous data 6mwd 6-min walk distance bnp brain natriuretic peptide bpm beats per min ccb calcium channel blocker dlco diffusion capacity lung carbon monoxide era endothelin receptor agonist fc functional class fco fick cardiac output mpap mean pulmonary arterial pressure mrap mean right atrial pressure nyha new york heart association pah pulmonary arterial hypertension pcwp pulmonary capillary wedge pressure pde-5 phosphodiesterase type-5 pvr pulmonary vascular resistance rhc right sided heart catheterization see table 1 legend expansion abbreviations cardiac output fco fco missing cardiac output thermodilution cardiac output pvr wood units mean pulmonary arterial pressure rest pcwp rest)/cardiac output cardiac output fco fco missing cardiac output thermodilution cardiac output predicted value based hankinson et al computation three year survival ssc group worse non ssc group previously newly diagnosed populations 61.4% 2.7% vs 80.9% 2.7% 51.2% 4.0% vs 76.4% 4.6% respectively p .001 fig 2 three year survival curves patients ssc non ssc ctd apah a three year survival enrollment newly diagnosed ssc group 51.2% 4.0% compared 76.4% 4.6% non ssc ctd group p .001 b three year survival enrollment previously diagnosed ssc group 61.4% 2.7% compared 80.9% 2.7% non ssc ctd group p .001 see figure 1 legend expansion abbreviations figure 3 shows univariate analyses previously identified predictors mortality overall reveal registry cohort ssc non ssc groups the following variables predictive mortality groups age 60 years nyha fc iii iv status 6mwd 165 bnp 180 pg ml unique predictors mortality ssc group non ssc group included male sex systolic bp sbp 110 mm hg pericardial effusion dlco 32% predicted mrap 20 mm hg within 1 year pvr 32 wu newly diagnosed status bnp levels 50 pg ml protective patients ssc hazard ratio hr 0.34 95% ci 0.16 0.72 p .005 non ssc group hr 0.68 95% ci 0.36 1.29 p .24 figure 3 also shows univariate analyses additional variables relevant ctd apah population mild moderate ild feature increased mortality patients non ssc ctd apah patients ssc apah hr 2.19 95% ci 1.14 4.23 p .02 vs hr 0.84 95% ci 0.55 1.30 p .44 when compared ipah mrap 20 mm hg within 1 year pvr 32 wu newly diagnosed status remained unique predictors death ssc apah group predictors mortality patients ssc apah non ssc ctd apah using univariate cox regression analyses unique predictors mortality ssc group non ssc group included male sex sbp 110 mm hg pericardial effusion dlco 32% predicted mrap 20 mm hg within 1 pvr 32 wu newly diagnosed status bnp levels 50 pg ml protective patients ssc non ssc group mild moderate ild feature increased mortality non ssc group patients ssc 6mwd 6-min walk distance bnp brain natriuretic peptide dlco diffusion capacity lung carbon monoxide fc functional class gfr glomerular filtration rate hr hazard ratio mrap mean right atrial pressure nyha new york heart association pvr pulmonary vascular resistance sbp systolic bp world health organization wu wood units following variables remained predictive mortality ssc non ssc groups nyha fc iii iv status bnp 180 pg ml table 3 unique predictors mortality ssc group included men 60 years sbp 110 mm hg 6mwd 165 mrap 20 mm hg within 1 year pvr 32 wu 6mwd 440 m protective non ssc group ssc group whereas bnp 50 pg ml protective ssc group non ssc group our study provides evidence patients ssc apah experience higher mortality rates patients ctd apah incident prevalent populations our results validate usefulness risk score calculator patients ctd apah including patients ssc apah we identified several baseline risk factors significantly associated mortality ssc apah population comparison non ssc ctd apah population including elderly man low sbp poor exercise capacity severe hemodynamic indices including elevated mrap pvr identifying patients ssc apah high mortality risk based on the presence unique predictors mortality enable physicians monitor patients closely escalate therapy indicated three year survival newly diagnosed ssc apah population 51% similar survival rates found cohorts assessed modern treatment era other studies found better survival rates 75%-81% patients ssc apah rates similar survival rate 77% others observed patients non ssc ctd apah this survival discrepancy could related early detection algorithms implemented ssc apah cohorts goal initiate pah specific therapy disease less severe survival patients non ssc ctd apah appears similar ipah ssc apah despite similar baseline hemodynamics pah specific therapies whether initiating aggressive pah treatment patients ssc apah particular high mortality risk may improve outcomes remains important question answered overall predictors identified multivariate model ssc apah similar core predictors pah whole including subtypes our results concur studies patients ssc apah male sex older age fc iii iv status significant predictors death our results confirmed single center study identified high pvr strong predictor mortality unlike studies find low dlco glomerular filtration rate predictive mortality ssc apah group multivariate analyses although significant univariate analyses lefvre et al identified additional poor prognostic factors patients ssc pulmonary hypertension meta analysis including patients groups ii iii pulmonary hypertension pericardial effusion low 6mwd high mean pulmonary arterial pressure poor cardiac index elevated mrap poor prognostic factors although pericardial effusion lost significance multivariate analysis patients ssc apah poor exercise capacity elevated mrap remained significant predictors death m protective non ssc ctd apah group multivariate analyses a potential explanation discrepancies patients ssc suffer presence contractures tendon friction rubs significantly limit mobility particularly diffuse skin disease addition factors limit exercise capacity anemia joint muscle inflammation patients ctds however including variables multivariate model without stepwise selection 6mwd 165 significant predictor death non ssc group hr 2.03 95% ci 1.01 4.12 p .05 6mwd 440 showed trend toward protective effect ssc group hr 0.62 95% ci 0.33 1.15 p .13 in addition evaluated effect 6mwd mortality risk various cutaneous subgroups ssc increase distance 100 significantly protective three groups p < .001 diffuse hr 0.53 95% ci 0.38 0.75 limited 0.59 95% ci 0.51 0.68 unclassified 0.54 95% ci 0.40 0.71 study bnp 180 pg ml increased risk death ssc non ssc apah groups twofold also shown patients ipah we others shown patients ssc apah markedly elevated bnp n terminal pro bnp nt pro bnp levels compared patients ipah patients non ssc ctd apah williams et al found uk ssc apah cohort every order magnitude increase baseline nt pro bnp level fourfold increased risk death p .002 in addition several studies found nt pro bnp useful screening early detection pah patients ssc biomarker integrated novel screening algorithms knowledge study first show bnp independent predictor mortality patients ctd apah ssc apah particular unfortunately nt pro bnp levels available 89% ctd apah cohort therefore could included regression models to knowledge first study identify low baseline sbp 110 mm hg independent predictor death patients ssc apah other studies shown low sbp peak exercise upon admission hospital right sided heart failure independent risk factor death pah a potential pathophysiologic explanation finding presence high right ventricular pressure results pronounced effect low sbp coronary perfusion in addition low sbp may sign low cardiac output reduced stroke volume neurohormonal activation unless complicated renal disease patients ssc relatively low baseline bp mean sbp 119 19 mm hg patients ssc apah study given bp monitored easily identification low baseline sbp risk factor ssc apah important finding we find mild moderate ild predictive death patients ssc apah although significant predictor non ssc apah group univariate analysis longer significant multivariate analysis we attempted exclude patients substantial ild defined previously precise measurements regarding degree fibrosis imaging the ssc apah non ssc ctd apah cohorts smaller overall cohort thus differences significant multivariable predictors may caused loss power opposed true differences predictors different subtypes the majority reveal registry patients particularly patients previous diagnoses receiving phosphodiesterase-5 inhibitors endothelin receptor antagonists prostacyclins combination although 86% patients ctd apah enrolled sites routinely involve rheumatologist diagnosis care patients misclassification patients may occurred finally analysis assessed variables available reveal registry database may additional factors particular patients ctd apah autoantibody status could impact results in conclusion patients ssc apah higher mortality rates patients non ssc ctd apah our results validate usefulness pah risk score patients ssc apah we identified unique predictors mortality patients ssc apah including older man low baseline sbp poor exercise capacity elevated mrap pvr used identify high risk patients may benefit closer monitoring aggressive treatment

background : patients with pulmonary arterial hypertension ( pah ) associated with systemic sclerosis ( ssc - apah ) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases ( ctd - apah ) . we sought to identify unique predictors of mortality associated with ssc - apah in the ctd - apah population.methods:the registry to evaluate early and long - term pah management ( reveal registry ) is a multicenter , prospective us - based registry of patients with previously and newly diagnosed ( enrollment within 90 days of diagnostic right - sided heart catheterization ) pah . cox regression models evaluated all previously identified candidate predictors of mortality in the overall reveal registry population to identify significant predictors of mortality in the ssc - apah ( n = 500 ) vs non - ssc - ctd - apah ( n = 304 ) populations.results:three-year survival rates in the previously diagnosed and newly diagnosed ssc - apah group were 61.4% 2.7% and 51.2% 4.0% , respectively , compared with 80.9% 2.7% and 76.4% 4.6% , respectively , in the non - ssc - ctd - apah group ( p < .001 ) . in multivariate analyses , men aged > 60 years , systolic bp ( sbp ) 110 mm hg , 6-min walk distance ( 6mwd ) < 165 m , mean right atrial pressure ( mrap ) > 20 mm hg within 1 year , and pulmonary vascular resistance ( pvr ) > 32 wood units remained unique predictors of mortality in the ssc - apah group ; 6mwd 440 m was protective in the non - ssc - ctd - apah group , but not the ssc - apah group.conclusions:patients with ssc - apah have higher mortality rates than patients with non - ssc - ctd - apah . identifying patients with ssc - apah who are at a particularly high risk of death , including elderly men and patients with low baseline sbp or 6mwd , or markedly elevated mrap or pvr , will enable physicians to identify patients who may benefit from closer monitoring and more aggressive treatment.trial registry : clinicaltrials.gov ; no . : nct00370214 ; url : www.clinicaltrials.gov

cerebral palsy nonprogressive central nervous system disorder results physical impairments functional limitations change children grow older among large number instruments 24 measuring physical ability children cp gross motor function classification system gmfcs introduced palisano et al 1997 widely applied clinical research settings the gmfcs five level classification system identifies abilities functional limitations based need assistive devices cerebral palsy child self initiated movements walking sitting the system application quick easy gives brief description level child resembles based current gross motor function the reliability validity gmfcs differentiating cerebral palsy children different functional levels reported similarly stability system time proved consistent suggesting gmfcs could used routinely clinical practice follow children cerebral palsy however due heterogeneous nature cerebral palsy overlap levels ii observed indeed anticipated authors 2 5 7 gmfcs level associated children persistent neuromotor abnormalities severe children level ii overlap levels occurred often deciding child limitations walking outdoors going stairs jumping running many studies aimed determine outcome tools could assist clinicians researchers improve classification levels ii gmfcs 1 4 8 correct classification clinical settings corroborated tests gmfm-66 gait velocity weefim mobility 8 9 child cerebral palsy often develops changes muscle length time common hip knee flexors ankle dorsiflexors 10 11 kilgour colleagues 2005 using passive range motion tests reported diplegic children levels ii gmfcs minimal loss hip extension compared matched control group since gmfcs classification based functional activities would interesting obtain measurements dynamic activities in addition expected muscle shortness advanced diplegic children level ii level gmfcs therefore range motion comparison levels ii also relevant these muscles changes might affect range amplitude lower limb dynamic activities gait however date none studies tried discriminate gmfcs levels ii according angular displacement pelvis hip knee ankle foot complex gait instrumented gait analysis complex procedure highly costly diagnostic tool however kinematic data obtained provides quantitative information gait abnormalities detected visual observation raising knowledge gait biomechanical differences child cerebral palsy level ii gmfcs improve observational gait analysis skills time improve classification accuracy coherent physical therapy approaches based functional status children cerebral palsy therefore research questions study 1 differences kinematics gait profiles pelvis lower limb joints gait diplegic cerebral palsy children classified gmfcs levels ii 2 differences kinematics found ones would discriminatory groups ? a cross sectional observational study conducted diplegic cerebral palsy children classified trained physical therapist gmfcs levels ii the intra rater reliability physical therapist assessing gmfcs levels excellent icc 0.941 all children community ambulates outpatient clinics together parents guardians invited participate study the temporal spatial gait parameters kinematics pelvis hip knee ankle foot joints collected one day laboratory the present study received approval ethics committee universidade federal de minas gerais process number etic 088/04 prior participation procedures explained child parent guardian informed written consent obtained twenty two 22 diplegic cerebral palsy children included study 15 male 7 females ages 7 12 could ambulate independently without assistive devices minimum 6 meters without resting patients excluded neurological diseases botulin injections history orthopedic surgery past six months characteristics participants age years height body mass index bmi kg obtained order describe anthropometrics groups three dimensional kinematics right lower limb hip knee ankle foot joints pelvis stance phase gait cycle obtained six camera motion analysis system motion capture unit qualisys medical ab 411 12 gothenburg sweden the children walked barefoot 6-meter walkway average 9 sd 3.1 trials natural speed reflective markers clusters tracking markers used determine coordinate systems motions pelvis thigh shank ankle foot segments according recommendations minimizing soft tissue artifacts footswitch synchronized motion system was fixed children foot determine contact loss contact walking surface consequently delimiting stance swing phases gait cycle the resulting data processed visual 3d motion analysis software c motion inc rockville maryland rigid segments corresponding pelvis shank thigh ankle foot segments first created the position reflective anatomical markers used attributing coordinate systems segment located left right iliac crest left right greater trochanter medial lateral epicondyle femur medial lateral malleoli 1st 5th head metatarsus calcaneal tuberosity one rigid cluster 4 noncollinear markers placed base sacrum two nonrigid clusters 3 noncollinear markers placed medial side thigh shank data smoothed using zero lag fourth order butterworth low pass filter cut frequency 6 hz three dimensional angular motion calculated using cardan sequence defined orientation coordinate system one segment relation orientation coordinate system adjacent segment the hip knee ankle foot joint angles obtained using reference pelvis thigh shank segments respectively sign convention used defining clinical rotation angles were follows 1 flexion hip knee anterior tilt pelvis ankle dorsiflexion occur lateral medial x axis positive angles 2 adduction hip knee pelvic obliquity meaning height iliac crest stance foot higher relation height iliac crest opposite foot internal rotation ankle foot complex occur anterior posterior axis considered positive angles 3 internal rotation pelvis hip knee joints adduction ankle foot complex occurs distal proximal z axis positive angles gait velocity stride length cycle time entire gait cycle swing stance time also obtained baseline characteristics participants presented values means standard deviations sd the mean difference groups 95% ci subject characteristics temporal spatial gait parameters also obtained principal component analysis pca ) was applied stance phase gait waveforms reduce data explore profiles characterizing typical functions levels ii gmfcs 15 16 pca this technique determines linear combination original variables used summarize new set variables called principal components uncorrelated ordered first component retains variation present original data therefore principal component represents specific feature waveform data criteria choose number principal components 90% total sample variance for pc extracted score calculated subject aids describing meaning variation component according characteristics group the higher score correlated subject waveform specific pc to interpret components two waveforms created based mean waveform one standard deviation pc scores times loading vector pc the principal component scores analyzed using student test bonferroni correction difference groups the pcs retained discriminant analysis described according discriminant function coefficient determine relative importance separating groups group gmfcs level 11 children average age 9.1 years sd 2.3 average height 1.3 sd 0.1 bmi 16.7 kg sd 0.2 group level ii also 11 children average age 9.8 years sd 2.1 height 1.3 sd 0.1 bmi 17.2 kg sd 3.8 table 1 table 2 describes temporal spatial parameters groups 95% confidence interval showing significant difference groups principal component analyses carried three dimensional angular displacement pelvis hip knee ankle foot complex the pc scores generated subject component tested differences groups the results showed scores first component pc1 pelvis hip joint frontal plane statistically different groups table 3 p .05 no difference found curve profiles knee joint ankle foot complex pelvis figure 1(a shows angular displacement pelvis stance phase normalized 100% level ii groups gmfcs the coefficient pc1 positive values figure 1(b therefore captures magnitude pelvic obliquity angle frontal plane stance figure 1(c shows mean waveform high low curves created based mean waveform one standard deviation pc1 score times loading vector pc1 the results confirm average diplegic pc children level ii stance phase gait walked reduced pelvic obliquity comparison children group level i. average range pelvic obliquity stance phase gait cycle group level 6.2 level ii 3.3. figure 1(d shows average angular displacement hip joint frontal plane groups stance phase gait cycle hip joint two pcs extracted pc1 explaining 86.1% pc2 8.5% total 94.6% variance explained pc1 positive values measured magnitude adduction angle hip figure 1(e the mean waveform high low waveforms shown figure 1(f confirm children gmfcs level ii presented reduced hip adduction stance phase compared cerebral palsy children level i. average range hip adduction abduction stance phase gait cycle group level 11.3 level ii 8.9. stepwise discriminant analysis conducted pc1s pelvis hip frontal plane wilk lambda score significant .217 2 n 22 29.002 p .000 showed pelvic obliquity hip abduction angle stronger discriminant variables 95.5% cross validation the magnitude coefficients pcs standardized canonical discriminant function showed pelvic obliquity higher impact separating groups 0.711 followed hip abduction angle 0.654 stance phase gait to knowledge first study compared angular displacement pelvis lower limb joints diplegic cerebral palsy children classified according gmfcs levels ii the results demonstrated children diplegia level ii gmfcs significantly reduce amplitude pelvic obliquity hip adduction angles stance phase gait cycle gait velocity stride length stance swing cycle time similar outcome groups children classified gmfcs level ages 7 12 years expected walk independently inside outside homes go stairs run jump however gait velocity balance motor coordination may reduced compared paired child normal development difference children gmfcs levels ii included limitations walking outdoors community uneven surfaces crowded places children level ii may hold onto rail climb stairs may require wheeled mobility traveling long distances ability perform gross motor skills running jumping minimal compared children level studies showing disagreement levels ii reported suggesting difficulty classifying child functional limitation perform gross motor skills 5 7 normal gait strike hemipelvis stance limb aligned contralateral hemipelvis beginning loading response mid stance contralateral hemipelvis drops frontal plane stance hemipelvis higher around 4 7 the effect pelvic drop adjust length support lower limb helped degree knee flexion avoiding excessive lower vertical displacement center mass the hip abduction adduction displacement moment dependent pelvis movement femur hemipelvis elevation favors adduction stance limb hemipelvis drop favors contralateral side hip abduction movement besides saving body energy preventing greater inferior displacement center mass hip adduction stance limb also shifts body center mass towards center rotation hip loaded the result would decrease external adductor moment force favoring mechanical advantage hip abductor muscles stance the summation actions prevents excessive pelvic drop trendelenburg gait well support limb begins terminal stance preswing phases opposite occur the pelvis begin drop favoring hip abduction important assist release foot ground permitting body swing forward 22 24 therefore pelvic obliquity hip adduction two mechanisms work synchronously maintain stability forward movement body diplegic children cerebral palsy reduced pelvic obliquity could result abductor muscles weakness bilaterally adductor muscles spasticity another explanation could reducing pelvic elevation supported limb stance phase cycle children cerebral palsy probably trying decrease leg length facilitate next initial contact foot however strategy would increase inferior displacement center mass cycle resulting less efficient gait 25 27 hip joint reduced hip adduction stance phase increases internal abductor moment support limb since children cerebral palsy normally show weakness hip abductor muscles gait pattern would unstable forcing increase base support spend less time unipodal phase 14 22 the decreased hip adduction could also response alterations pelvic obliquity loaded hemipelvis lower normal challenging hip mechanics generate hip adduction the combination reduced pelvic obliquity hip adduction stance phase gait cycle reinforce evidence children cerebral palsy gmfcs level ii unstable gait compared children level i. threatening situations walking uneven inclined surfaces greater instability children gmfcs level ii could justify need assistive devices it also justifies use rail walk stairs since reduced pelvic obliquity would decrease hip abduction could also affect hip flexion although kinematic analysis tool used assist development gmfcs classification system findings present study support differences levels ii gmfcs recently revised authors the discriminant model revealed pelvic obliquity higher impact discriminating children gmfcs level level ii clinically result shows pelvic obliquity frontal plane explains better mechanical difference children level ii the importance pelvic obliquity gait introduced 1953 saunders coworkers one important gait marker minimizes vertical displacement center mass 2001 della croce coworkers confirmed pelvic obliquity single support knee flexion second important gait determinants reducing center mass dislocation consequently improving gait efficiency the present study demonstrated gait velocity similar cp children level ii in multicentre study conducted 562 children cerebral palsy classified levels iii gmfcs determined gait velocity discriminant factor levels ii similar results reported oeffinger et al in addition damiano abel reported temporal spatial parameters important indicators severity level cerebral palsy children the classification levels ii proposed palisano et al based primarily limitation child execute movements involved velocity stability walking jumping going stairs therefore would expect significant difference levels ii gait spatial temporal markers it likely different instruments used capture temporal spatial gait markers fact sample composed diplegic cerebral palsy children probably justify different results found present study gait alterations children cerebral palsy may also occur planes motion rodda graham proposed classification system diplegic children based kinematic kinetic analyses focused sagittal plane however authors agreed important alterations may also occur frontal transverse planes for example excessive internal pelvic rotation initial contact contributes higher range hip abduction motion observed gait strike hand increased pelvic obliquity may secondary decrease hip knee sagittal motions the lack significant findings sagittal plane could related nature movement sagittal plane the range motion greater compared planes variability normally smaller compared movements smaller range motions 33 34 one option would increase sample size attempt identify subtle variances could occur sagittal plane nevertheless present study even relatively small sample size results could discriminate groups showing fact difference levels ii although subtle could detected multivariate analysis technique applied the present study offers new information angular displacement three planes gait stance children cerebral palsy classified gmfcs levels ii clinical observation reduced pelvic obliquity hip adduction gait difficult task the literature observational gait analysis shown training experience important consistent observation pelvic hip movements gait therefore kinematic idiosyncrasy gmfcs level could added one important clinical parameter help classification process mild moderate children diplegia in addition prior knowledge biomechanical differences gmfcs levels ii may guide physical therapy strategies focused regaining pelvic obliquity hip adduction range motion support limb strategies may promote gait stability cerebral palsy children level ii less energy expenditure free assistive devices

objective . to determine if gait waveform could discriminate children with diplegic cerebral palsy of the gmfcs levels i and ii . patients . twenty - two children with diplegia , 11 classified as level i and 11 as level ii of the gmfcs , aged 7 to 12 years . methods . gait kinematics included angular displacement of the pelvis and lower limb joints during the stance phase . principal components ( pcs ) analyses followed by discriminant analysis were conducted . results . pc1s of the pelvis and hip in the frontal plane differ significantly between groups and captured 80.5% and 86.1% of the variance , respectively . pc1s captured the magnitude of the pelvic obliquity and hip adduction angle during the stance phase . children gmfcs level ii walked with reduced pelvic obliquity and hip adduction angles , and these variables could discriminate the groups with a cross - validation of 95.5% . conclusion . reduced pelvic obliquity and hip adduction were observed between children gmfcs level ii compared to level i. these results could help the classification process of mild - to - moderate children with diplegia . in addition , it highlights the importance of rehabilitation programs designed to improve pelvic and hip mobility in the frontal plane of diplegic cerebral palsy children level ii of the gmfcs .