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recent systematic analysis showed 2011 314 296 331 million children younger 5 years mildly moderately severely stunted 258 240 274 million mildly moderately severely underweight developing countries in iran study among 752 high school girls sistan baluchestan showed prevalence 16.2% 8.6% 1.5% underweight overweight obesity respectively the prevalence malnutrition among elementary school aged children tehran varied 6% 16% anthropometric study elementary school students shiraz revealed 16% suffer malnutrition low body weight snack 300 400 kcal energy could provide 5 10 g protein day nowadays school nutrition programs running national programs world wide national school lunch program united states there also reports regarding school feeding programs developing countries vietnam school base program showed improvement nutrient intakes iran national free food program nffp ) is implemented elementary schools deprived areas cover poor students however program conducted slums poor areas big cities many malnourished children low socio economic situation covered nffp although rate poverty areas known deprived higher areas many students deprived areas actually poor afford food hence nutritional value nffp lower scientific recommended snacks age group furthermore lack variety food packages decreased tendency children toward nffp hand the important one ministry education moe iran responsible selecting providing packages targeted schools the ministry health moh supervising health situation students health needs welfare organizations along charities indirect effect nutritional status students financial support family provincial governors also role coordinating supervising activities organizations parent teacher association community based institution participates school policy nffp in addition organizations nutritional literacy students parents teachers important issue could affect nutritional status school age children therefore present study conducted aim improving nffp resources poor children covered even big cities moreover food packages replaced nutritious diverse packages accessible non poor children according aim study multiple factors could affect problem public health advocacy chosen best strategy deal issue therefore present study determines effects nutrition intervention advocacy process model prevalence underweight school aged children poor area shiraz iran this interventional study carried 2009 2010 shiraz iran this survey approved research committee shiraz university medical sciences coordination education organization fars province two elementary schools one middle school third region urban area shiraz selected randomly schools all students 2897 7 13 years old screened based body mass index bmi nutritionists according convenience method all students divided two groups based economic situation family revenue head household job nutrition situation first group poor malnourished students group well nourished well students for report children height weight entered center disease control prevention cdc calculate bmi bmi age z scores based cdc diseases control prevention growth standards the significance difference proportions calculated using two tailed z tests independent proportions implementing interventions the advocacy process model weight nearest 0.1 kg balance scale model seca scale standing height measured nearest 0.1 cm wall mounted stadiometer advocacy group formation step started stakeholder analysis identifying stakeholders the team formed representatives stakeholders include education organization welfare organization deputy health shiraz university food cosmetic product supervisory office several non governmental organizations charities situation analysis carried use existing data formal report organizations literature review focus group experts the prevalence malnutrition related factors among students determined weaknesses strengths nffp analyzed accordingly three sub groups established research evaluation education justification executive group designing strategies : three strategies identified education justification campaign nutritional intervention providing nutritious safe diverse snacks networking performing interventions interventions implementing selected schools providing diverse nutritious snack package along nutrition education groups first group poor malnourished students utilized package free charge education justification intervention regarding literature review expert opinion educational group affiliated advocacy team prepared educational booklets nutritional information level degree accordingly education booklets integrated regular education students educated justified better nutrition life style it leads educational group hold several meeting student parents justify project benefit children after meetings parental desire participation project illustrated effectiveness justification meeting for educate fifteen talk show programs tv radio 12 published papers local newspaper implemented mobilize community gain support healthy diet importance breakfast snack adolescence wrong food habits among school age children role family improve food habit children main topics media campaign focused nutritional intervention snack basket students replaced traditional nutritious diverse foods general new snack package average provided 380 kcal energy 15 g protein along sufficient calcium iron low economic malnourished children supported executive group affiliated advocacy team rest prepare snack research evaluation step literacy anthropometric indices bmi students assessed interventions the reference anthropometric measures world health organization national center health statistics nchs standards cut offs two standard deviations sd mean each student malnourished poor taken account free food nutritious snacks demographic information height weight knowledge students measured use validated reliable cronbach alpha 0.61 questionnaire this project granted shiraz university medical sciences charities welfare organization education organization fars province statistical analyses performed using statistical package social sciences spss software version 17.0 spss inc the results expressed mean sd proportions appropriated order determine effective variables malnutrition status paired test used compare end values baseline ones group in project z score cut offs used follow using bmi age z scores overweight 1 sd i.e. z score 1 equivalent bmi 25 kg obesity 2 sd equivalent bmi 30 kg thinness 2 sd severe thinness 3 sd this interventional study carried 2009 2010 shiraz iran this survey approved research committee shiraz university medical sciences coordination education organization fars province two elementary schools one middle school third region urban area shiraz selected randomly schools all students 2897 7 13 years old screened based body mass index bmi nutritionists according convenience method all students divided two groups based economic situation family revenue head household job nutrition situation first group poor malnourished students group well nourished well students for report children height weight entered center disease control prevention cdc calculate bmi bmi age z scores based cdc diseases control prevention growth standards the significance difference proportions calculated using two tailed z tests independent proportions implementing interventions weight nearest 0.1 kg balance scale model seca scale standing height measured nearest 0.1 cm wall mounted stadiometer advocacy group formation step started stakeholder analysis identifying stakeholders the team formed representatives stakeholders include education organization welfare organization deputy health shiraz university food cosmetic product supervisory office several non governmental organizations charities situation analysis carried use existing data formal report organizations literature review focus group experts the prevalence malnutrition related factors among students determined weaknesses strengths nffp analyzed accordingly three sub groups established research evaluation education justification executive group designing strategies : three strategies identified education justification campaign nutritional intervention providing nutritious safe diverse snacks networking performing interventions interventions implementing selected schools providing diverse nutritious snack package along nutrition education groups first group poor malnourished students utilized package free charge duration intervention 6 months education justification intervention regarding literature review expert opinion educational group affiliated advocacy team prepared educational booklets nutritional information level degree accordingly education booklets integrated regular education students educated justified better nutrition life style obviously student families remarkable effect children food habit it leads educational group hold several meeting student parents justify project benefit children after meetings parental desire participation project illustrated effectiveness justification meeting educate fifteen talk show programs tv radio 12 published papers local newspaper implemented mobilize community gain support healthy diet importance breakfast snack adolescence wrong food habits among school age children role family improve food habit children main topics media campaign focused nutritional intervention snack basket students replaced traditional nutritious diverse foods general new snack package average provided 380 kcal energy 15 g protein along sufficient calcium iron low economic malnourished children supported executive group affiliated advocacy team rest prepare snack research evaluation step literacy anthropometric indices bmi students assessed interventions the reference anthropometric measures world health organization national center health statistics nchs standards cut offs two standard deviations sd mean each student malnourished poor taken account free food nutritious snacks demographic information height weight knowledge students measured use validated reliable cronbach alpha 0.61 questionnaire this project granted shiraz university medical sciences charities welfare organization education organization fars province advocacy group formation step started stakeholder analysis identifying stakeholders the team formed representatives stakeholders include education organization welfare organization deputy health shiraz university food cosmetic product supervisory office several non governmental organizations charities situation analysis carried use existing data formal report organizations literature review focus group experts the prevalence malnutrition related factors among students determined weaknesses strengths nffp analyzed accordingly three sub groups established research evaluation education justification executive group designing strategies three strategies identified education justification campaign nutritional intervention providing nutritious safe diverse snacks networking performing interventions interventions implementing selected schools providing diverse nutritious snack package along nutrition education groups first group poor malnourished students utilized package free charge education justification intervention regarding literature review expert opinion educational group affiliated advocacy team prepared educational booklets nutritional information level degree accordingly education booklets integrated regular education students educated justified better nutrition life style obviously student families remarkable effect children food habit it leads educational group hold several meeting student parents justify project benefit children after meetings parental desire participation project illustrated effectiveness justification meeting educate fifteen talk show programs tv radio 12 published papers local newspaper implemented mobilize community gain support healthy diet importance breakfast snack adolescence wrong food habits among school age children role family improve food habit children main topics media campaign focused nutritional intervention snack basket students was replaced traditional nutritious diverse foods general new snack package average provided 380 kcal energy 15 g protein along sufficient calcium iron low economic malnourished children supported executive group affiliated advocacy team rest prepare snack research evaluation step literacy anthropometric indices bmi students assessed interventions the reference anthropometric measures world health organization national center health statistics nchs standards cut offs two standard deviations sd mean each student malnourished poor taken account free food nutritious snacks demographic information height weight knowledge students measured use validated reliable cronbach alpha 0.61 questionnaire this project granted shiraz university medical sciences charities welfare organization education organization fars province statistical analyses performed using statistical package social sciences spss software version 17.0 spss inc chicago il usa the results expressed mean sd proportions appropriated order determine effective variables malnutrition status paired test used compare end values baseline ones group two sided p 0.05 considered statistically significant project the z score cut offs used follow using bmi age z scores overweight 1 sd i.e. z score 1 equivalent bmi 25 kg obesity 2 sd equivalent bmi 30 kg thinness 2 sd severe thinness 3 sd study population contains 2897 children 70.8% primary school students 29.2% secondary school students 2336 80.5% total students well 561 children 19.5% indigent 19.5% subjects case group n 561 80.5% control group n 2336 the mean age welfare group 10.0 2.3 10.5 2.5 non welfare group demographic characteristics school aged children shiraz iran table 2 shows frequency subjects different categories bmi age non welfare welfare groups school aged children separately among boys girls nutrition intervention based advocacy process model shiraz iran the frequency subjects bmi lower 2 sd decreased significantly intervention among non welfare girls p 0.01 however significant decreases frequency subjects bmi lower 2 sd boys when assess effect intervention total population without separating sex groups found significant change population table 3 bmi age iranian students aged 7 14 years based gender according growth standards 2007 bmi age iranian students aged 7 14 years according growth standards 2007 non welfare welfare groups total population table 4 shown prevalence normal bmi mild moderate severe malnutrition non welfare welfare groups school aged children separately among boys girls nutrition intervention based advocacy process model according table there significant differences prevalence mild moderate severe malnutrition among girls boys table 4 also shows mean anthropometric indices changed significantly intervention among girls boys the pre- post test education assessment groups showed student average knowledge score significantly increased 12.5 3.2 16.8 4.3 p 0.0001 bmi height weight non welfare welfare groups school aged children separately males females nutrition intervention based advocacy process model shiraz iran according study finding odds ratio sever thinness thinness non welfare compared welfare 3.5 3.5 confidence interval ci 2.5 3.9 p 0.001 furthermore finding showed overweight obesity welfare compared non welfare 19.3 19.3 ci 2.5 3.9 p 0.04 the result community intervention study revealed nutrition intervention based advocacy program successful reduce prevalence underweight among poor girls this study shows determinant factor nutritional status school age children socio economic level according knowledge this first study determines effect community intervention based advocacy process malnutrition indices big city shiraz iran the program iran nffp specified deprived area conducted big cities allocating millions dollars nffp government selecting malnourished students active screening system primary middle schools paying attention policy makers student nutrition provided opportunity combat problem however negligence poverty line providing poor snacks terms nutritional value lack variety main defects program advocacy definition blending science ethics politics comprehensive approaching health issues using advocacy program california among high school students improving nutrition physical activity angeles unified school district participants emphasized nutrition classes families well students addition interventions present study another study revealed evaluability assessment gave stakeholders opportunity reflect project implementation issues it seems iran free food program among students needed deprived areas also performed big cities shiraz baseline no significant difference founded among wealthy students pre- post nutritional status intervention in contrast numbers students malnutrition decreased 44% 39.4% identified significant among impecunious girls students there also significant increase proportion children bmi normal age 2 1 sd published community interventions showed better results among females compared males this difference impact nutritional interventions male female might related different age puberty female population compared male population age range present study female although nffp big cities iran programs improving nutritional status providing free milk schools a recent publication shown school feeding programs focus milk supplementation beneficial effects physical function school performances specifically among girls iran the results mentioned study showed improvement weight children psychological test scores grade point average following school feeding program the intervention present study focused snack intake school time there reports regarding nutrition transition iran shows importance nutrition intervention provide healthy eating dietary habits among welfare groups adolescents hence nutrition intervention especially form nutrition education needed big cities among welfare children adolescents although study among iranian adolescents showed dietary behavior adolescents accord knowledge emphasize necessity community intervention programs recent study regarding major dietary pattern among iranian children showed presence four major dietary patterns fast food pattern sweet pattern two major dietary patterns mentioned among iranian children advocacy program audience analysis accordingly one prominent strategies study working media meeting parent teacher association secondary target audiences also took account policy makers different levels national local primary audiences advocacy team several meetings management planning organization national level education organization fars province well principal targeted schools providing nutritious snacks need contribution private sector food industries factories benefits warranted another choice community involvement achieved female health volunteers working health system advocacy team using support charities female health volunteers could establish local factory produced student snacks based new definition however challenges way expanding program mass production proposed snacks according different desires cultures getting involvement food industries respect marketing issues one challenges moreover providing supportive environment order change food habits students parents among wide range population require sustainable continuous inter sector collaboration although limited number schools study interventions advocacy program successful expanding model another areas around country depends convincing policy makers national level this regard advocacy team prepare evidenced based profile transitional planning convince policy makers improving rule regulation nffp the study studies also emphasized must efforts strengthen capacity within schools deal nutritional problems either overweight obesity malnutrition using educational nutritional intervention assessing dietary adherence important nutrition intervention among population population children adolescents limitation blood sample collection assess subject dietary adherence furthermore intervention focused intake snack school time comprehensive information dietary intake children adolescents school day the investigators propose investigation different areas country based socio cultural differences order make necessary modification adapt model areas regarding nutritional needs school age children provision good platform implementing expanding efficient model whole country based upon socio economic situation region advisable moh moe community nutrition intervention based advocacy process model effective reducing prevalence underweight specifically among female school aged children | background : the present study was carried out to assess the effects of community nutrition intervention based on advocacy approach on malnutrition status among school - aged children in shiraz , iran.materials and methods : this case - control nutritional intervention has been done between 2008 and 2009 on 2897 primary and secondary school boys and girls ( 7 - 13 years old ) based on advocacy approach in shiraz , iran .
the project provided nutritious snacks in public schools over a 2-year period along with advocacy oriented actions in order to implement and promote nutritional intervention . for evaluation of effectiveness of the intervention growth monitoring indices of pre- and post - intervention were statistically compared.results:the frequency of subjects with body mass index lower than 5% decreased significantly after intervention among girls ( p = 0.02 ) .
however , there were no significant changes among boys or total population .
the mean of all anthropometric indices changed significantly after intervention both among girls and boys as well as in total population .
the pre- and post - test education assessment in both groups showed that the student 's average knowledge score has been significantly increased from 12.5 3.2 to 16.8 4.3 ( p < 0.0001).conclusion : this study demonstrates the potential success and scalability of school feeding programs in iran .
community nutrition intervention based on the advocacy process model is effective on reducing the prevalence of underweight specifically among female school aged children . |
occurs 50% patients may reach 90% certain types cancers especially patients undergoing chemotherapy and/or radiation therapy.1 anemia defined inadequate circulating level hemoglobin hb hb 12 g dl may arise result underlying disease bleeding poor nutrition chemotherapy radiation therapy preliminary studies suggest survival loco regional control radiation therapy especially head neck cancers may compromised anemia.24 anemia often worsens symptoms fatigue weakness dyspnea thus may negative effect quality life qol performance status patients cancer thus improve physical functioning qol prognosis patients cancer would reasonable take proactive approach identifying populations need treatment cancer associated anemia caa provide timely management blood transfusion effective way replace depleted hb within short period effect unfortunately temporary cause serious adverse risks increased mortality randomized clinical trials patients caa erythropoiesis stimulating agents esas produced significant increases hb level decreased transfusion requirements improved qol.57 however 30%50% patients respond agents in addition use esas often causes concern severe adverse reactions.6,8 several studies esas found shorten overall survival time time tumor progression patients whose hb level reached 12 g dl these studies included patients different primary cancers breast lung head neck cervix lymphomas.911 lack response erythropoietin stimulation patients cancer partly attributed functional iron deficiency state high rate erythropoiesis exceeds delivery usable iron despite adequate iron stores.12 absolute iron deficiency contrast occurs iron delivery impaired iron stores depleted serum ferritin 100 ng ml transferring saturation 20%).13 hepcidin peptide hormone produced liver regulated chronic inflammatory states including cancer hepcidin inhibits iron transport across cell membranes thus decreasing accessibility stored iron gastrointestinal absorption dietary iron leading increased frequency iron restricted erythropoiesis.1416 many randomized trials examined role intravenous iv iron addition esas treatment anemia patients cancer many studies showed improvement esa response time maximal response reduction esa dose improvement qol parameters measured favor combination esas alone the observed benefit independent baseline iron parameters.1721 one study found 36% reduction number patients transfused.21 pilot study assessed efficacy feasibility iv iron monotherapy patients cancer anemia undergoing treatment chemotherapy and/or radiation therapy without use esas patients received study treatment 12 weeks followed 4-week follow period eligible patients least 18 years old start cycle chemotherapy and/or radiation therapy within 1 week inclusion nonmyeloid malignancy hb levels 11.0 g dl less life expectancy 24 weeks eastern cooperative oncology group performance status 02 patients also required serum ferritin level 100 ng ml higher transferrin saturation tsat levels 15% higher received esas iv iron therapy within 30 days oral iron therapy 27 mg day within 7 days enrollment patients excluded leukoerythroblastic features blood film hemolysis gastrointestinal bleeding folate vitamin b12 deficiency elevated serum ferritin 900 ng ml transferrin saturation tsat 35% levels pregnancy lactation liver dysfunction grade 2 higher based national cancer institute common toxicity criteria renal dysfunction serum creatinine levels 2.0 mg dl active infection requiring systemic antibiotics personal family history hemochromatosis comorbidities precluding study participation hypersensitivity iv iron red blood cell transfusion within last 2 weeks investigational agent within 30 days enrollment patients allowed take vitamin mineral herbal supplements containing 27 mg iron per day 100 mg vitamin c per day study follow period blood transfusions permitted primary physician discretion hb levels decreased 8 g dl less patients considered treatment failures written informed consent provided patients study participation protocol supporting documents approved institutional review board king hussein cancer center the study conducted accordance declaration helsinki good clinical practice contained us code federal regulations governs protection human subjects obligations clinical investigators patients received 200 mg ferric hydroxide sucrose diluted 100 ml normal saline infused course 1 hour weekly total 12 weeks first dose given first clinic visit 4 days initiation chemotherapy radiation therapy tsat monitored protocol mandated withholding iron therapy tsat levels higher 50% first clinic visit week 1 baseline blood sample obtained laboratory assessments study treatment started patients attended weekly clinic visits treatment assessment returned follow visits week 14 included complete physical examination complete blood count tsat done every 3 weeks 2 weeks last treatment week 14 complete laboratory assessment hb serum ferritin reticulocyte count transferrin tsat serum iron total iron binding capacity red cell indices white blood cell count differential platelet count serum chemistries done week 1 week 14 end study adverse events assessed clinic visit study completion withdrawal 30 days last study treatment hb test results presented mean median range 12 weeks comparison means hb level made baseline hb hb levels following weeks using test significance criterion p 0.05 used analysis all analyses performed using sas version 9.1 sas institute inc cary nc usa patients received study treatment 12 weeks followed 4-week follow period eligible patients least 18 years old start cycle chemotherapy and/or radiation therapy within 1 week inclusion nonmyeloid malignancy hb levels 11.0 g dl less life expectancy 24 weeks eastern cooperative oncology group performance status 02 patients also required serum ferritin level 100 ng ml higher transferrin saturation tsat levels 15% higher received esas iv iron therapy within 30 days oral iron therapy 27 mg day within 7 days enrollment patients excluded leukoerythroblastic features blood film hemolysis gastrointestinal bleeding folate vitamin b12 deficiency elevated serum ferritin 900 ng ml transferrin saturation tsat 35% levels pregnancy lactation liver dysfunction grade 2 higher based national cancer institute common toxicity criteria renal dysfunction serum creatinine levels 2.0 mg dl active infection requiring systemic antibiotics personal family history hemochromatosis comorbidities precluding study participation hypersensitivity iv iron red blood cell transfusion within last 2 weeks investigational agent within 30 days enrollment patients allowed take vitamin mineral herbal supplements containing 27 mg iron per day 100 mg vitamin c per day study follow period blood transfusions permitted primary physician discretion hb levels decreased 8 g dl less patients considered treatment failures written informed consent provided patients study participation protocol supporting documents approved institutional review board king hussein cancer center the study conducted accordance declaration helsinki good clinical practice contained us code federal regulations governs protection human subjects obligations clinical investigators patients received 200 mg ferric hydroxide sucrose diluted 100 ml normal saline infused course 1 hour weekly total 12 weeks the first dose given first clinic visit 4 days initiation chemotherapy radiation therapy tsat monitored protocol mandated withholding iron therapy tsat levels higher 50% at first clinic visit week 1 baseline blood sample obtained laboratory assessments study treatment started patients attended weekly clinic visits treatment assessment returned follow visits week 14 included complete physical examination complete blood count tsat done every 3 weeks 2 weeks last treatment week 14 complete laboratory assessment hb serum ferritin reticulocyte count transferrin tsat serum iron total iron binding capacity red cell indices white blood cell count differential platelet count serum chemistries done week 1 week 14 end study adverse events assessed clinic visit study completion withdrawal 30 days last study treatment hb test results presented mean median range 12 weeks comparison means hb level made baseline hb hb levels following weeks using test significance criterion p 0.05 used analysis all analyses performed using sas version 9.1 sas institute inc cary nc usa twenty five patients 17 women 8 men eligible consented included study mean age standard deviation sd 56 years 13.0 years chemotherapy varied according primary cancer included anthracycline platinum taxanes cyclophosphamide high dose ifosfamide vincristine vinblastine bleomycin others many included patients chemotherapy treatment second- third line therapy patients characteristics including age primary tumor active anticancer treatment summarized table 1 one patient died study tumor week 2 five patients withdrew study inconvenience three week 3 two week 4 nineteen 76.0% patients completed minimum three treatments 15 60.0% completed nine treatments 14 56.0% completed twelve planned weekly treatments as seen table 2 mean hb level 25 patients baseline 9.6 g dl median 9.9 g dl range 6.9 g dl10.9 g dl 15 patients completed least nine treatments mean change hb level 1.7 g dl median 1.1 g dl range 1.9 g dl 3.2 g dl for 14 patients completed whole treatment period 12 weeks mean hb level change 2.1 g dl median 1.3 g dl range 0.2 g dl 4.6 g dl p 0.0007 eight 42.1% 19 patients completed least three iron infusions 1 g dl increase hb level hemoglobin level changes 14 patients completed twelve iron infusions shown figure 1 no iv iron related adverse events reported among patients study follow period tsat monitored study period patients tsat levels increase 50% the highest ferritin level among patients completed least nine iv iron treatments 1,170 ng ml mean level end study period whole group 379 ng ml five 20.0% patients received blood transfusions considered treatment failures three week 3 transfused hb levels 6.9 g dl 7.8 g dl 5.4 g dl one week 4 transfused hb level 8.2 g dl one week 9 transfused hb level 7.2 g dl low hb levels associated diminished qol possibly decreased overall survival.2 successful treatment anemia undeniable benefits patients often yielding dramatic symptomatic improvement although role esas well established treating caa big concerns recently raised negative effect esas survival patients cancer.911 concerns risk thromboembolism patients cancer higher hb levels receiving esa also addressed many trials.22,23 addition possible immunosuppressive effects blood product transfusions may relevance neoplasia progression addressed before.24 25 pilot study tested feasibility using iron supplementation alone treat anemia patients cancer undergoing chemotherapy without use esas blood transfusion could valid alternative especially patients curable cancers oral iron easier administer relatively inexpensive low patient adherence poor enteral absorption poor tolerance wide range troublesome gastrointestinal adverse effects limit overall effectiveness.26 anemia chronic disease may occur patients cancer associated increase hepcidin levels decreases oral iron absorption bone marrow iron use negating possible effect regular doses oral iron.15 iv iron therapy significantly improves response epoetin alfa compared oral iron iron anemic patients cancer receiving chemotherapy.1721 oral iron supplements esas showed significant benefit esas alone treating caa.21 sodium ferric gluconate iron sucrose appear favorable safety profiles iron dextran a large prospective safety comparison trial failed show serious anaphylactoid reactions,27 confirmed study patients developed reactions patients withdrew study adverse effects given mean hb increase using esas iv iron one large controlled trial 2.4 g dl,21 results obtained study clinically significant these findings confirmed better assessed larger studies questions optimal timing iv iron therapy respect chemotherapy optimal total dose iv iron determined the use iv iron monotherapy recently reviewed group germany studied use ferric carboxymaltose replace esa blood transfusions treatment caa iron deficient patients treated ferric carboxymaltose alone n 233 median 1.4 g dl increase hemoglobin levels compared receiving additional treatment esas n 46 median 1.6 g dl study however peculiar using iron therapy non iron deficiency state.28 iron overload iv iron therapy potential concerns risk developing secondary cancers infection might raised the highest serum ferritin level present study patients completed least 9 weeks iv iron therapy 1,170 ng ml literature addressing cancer infections iron overloaded patients comes patients hemochromatosis patients undergoing hemodialysis published reviews report increase hepatocellular carcinoma patients hemochromatosis develop cirrhosis.29 similarly data supporting association iv iron therapy higher infection rate weak well supported.30 fact anemia risk factor infections patients receiving hemodialysis.31 multivariate analysis associations iron mortality 58,000 patients receiving hemodialysis reported increased death rate serum ferritin levels high 1,200 ng ml.30 increasing cost therapy patients cancer grave concern could additional benefit iv iron use esas patients address many questions raised our team planning bigger trial iv iron patients cancer anemia confirm results discussed pilot trial in addition looking predictors response iv iron serum hepcidin level iv iron therapy alone safe may effective improving hb levels patients cancer undergoing active anticancer therapy further randomized trials needed address many questions raised pilot study | backgroundanemia in patients with cancer who are undergoing active therapy is commonly encountered and may worsen quality of life in these patients . the effect of blood transfusion is often temporary and may be associated with serious adverse events .
erythropoiesis - stimulating agents are not effective in 30%50% of patients and may have a negative effect on overall survival.aimsto assess the efficacy and feasibility of intravenous iron therapy in patients with cancer who have non - iron - deficiency anemia and who are undergoing treatment with chemotherapy without the use of erythropoiesis - stimulating agents.methodsadult patients with solid cancers and non - iron - deficiency anemia were included .
ferric sucrose at a dose of 200 mg was given in short intravenous infusions weekly for a total of 12 weeks .
hemoglobin level was measured at baseline , every 3 weeks , and 2 weeks after the last iron infusion ( week 14 ) .
adverse events related to intravenous iron were prospectively reported.resultsof 25 patients included , 19 ( 76.0% ) completed at least three iron infusions and 14 ( 56.0% ) finished the planned 12 weeks of therapy .
the mean hemoglobin level of the 25 patients at baseline was 9.6 g / dl ( median , 9.9 g / dl ; range , 6.9 g / dl 10.9 g / dl ) . the mean change in hemoglobin level for the 15 patients who completed at least 9 treatments was 1.7 g / dl ( median , 1.1 g / dl ; range , 1.9 g / dl to 3.2 g / dl ) ; it reached 2.1 g / dl ( median , 1.3 g / dl ; range , 0.2 g / dl to 4.6 g / dl ; p = 0.0007 ) for the 14 patients who completed all 12 weekly treatments .
five ( 20.0% ) patients were transfused and considered as treatment failures .
no treatment - related adverse events were reported.conclusionintravenous iron treatment alone is safe and may reduce blood transfusion requirements and improve hemoglobin level in patients with cancer who are undergoing anticancer therapy .
further randomized studies are needed to confirm these findings . |
tardive dystonia td rarer side effect longer exposure antipsychotics characterized local general sustained involuntary contraction muscle muscle group twisting movements generally slow may affect limbs trunk neck face td shown develop 3% patients long term exposure antipsychotics low risk td atypical antipsychotics thought result weak affinity dopamine receptors compared typical atypical antipsychotic agents greater affinity serotonin 5-ht2a dopamine d2 receptors low propensity induce td among olanzapine is thought preferential action mesolimbic nigrostriatal dopaminergic pathways therefore associated low incidence extrapyramidal symptom eps furthermore retrospective analysis controlled multicentric trials suggested olanzapine also improves preexisting symptoms tardive movements we report case 20-year old male belonging lower socioeconomic class educated 2 standard presented severe unilateral dystonic left sided neck movements figure 1 careful history exploration revealed taking risperidone 2 mg irregularly 2 months olanzapine 5 mg another 4 months picture neck dystonia patient 19 years patient presented occasional anger outbursts getting provoked small matters beating family members running away home screaming episodes occasionally fearfulness sleep disturbance 2 days precipitated fever according mother one friend might threatened made fun actually patient stopped going house displayed mentioned symptoms this interpreted psychosis persecutory ideas treated risperidone 2 mg day 2 months olanzapine 5 mg day 4 months last two follow ups patient present mother reported unusual neck movements taken part overall psychopathology taken seriously slight intermittent neck movements reported missed part adolescent behavior problems mimicking hero movies neck dystonia increased patient severe disability patient keep hands behind head support the movement would decrease patient lying absent sleep he even stopped taking food due severe neck movements making chewing swallowing difficult his birth early developmental milestones normal 210 years age patient inattentive mildly hyperactive other siblings educated master degree patient also sent school due inattention restlessness pass 2 standard three attempts he left schooling average executive functioning life skills worked unskilled laborer neighborhood shops helping hand found getting familiar cheerful moody short tempered sometimes patient inappropriate social judgment friends made fun teased mental status assessment routine investigations thyroid function tests electroencephalogram fundus examination cervical x ray magnetic resonance imaging brain normal consulting neurophysician wilson disease secondary causes dystonia ruled the patient treated clonazepam 1 mg total dissolved solid tds tetrabenazine 25 mg tds trihexiphenidyl 2 mg bipolar disorder bd 2 months improvement around 30% baclofen 10 mg added increased 20 mg trihexyphenidyl reduced 2 mg little improvement 4 months treatment dystonia levodopa carbidopa 100 25 added neurophysician increased tablet tds baclofen omitted after 12 months treatment patient improved around 90% tetrabenazine 75 mg levodopa carbidopa 100 25 tablet bd clonazepam 1 mg bd earlier case reports reported td developing high dose atypical antipsychotics olanzapine 20 mg aripiprazole 15 mg longer duration exposure around 1215 months established psychiatric illness like schizophrenia psychotic illness eps general tardive dyskinesia particular extensively studied schizophrenia even though number studies suggest bipolar patients experience higher rates eps parkinsonism dystonia akathisia td compared patients diagnosis schizophrenia research within bd population limited the risk found 3 5 times higher elderly patients compared young patients in addition age risk directly proportional female gender daily total dose antipsychotic drug presence mood disorder use anticholinergics neuroleptics previous physical therapies electroconvulsive therapy presence physical illness diabetes organic disorder younger age exposure presence extrapyramidal symptoms early treatment this patient severe dystonic neck movements developed within short period 6 months exposure atypical antipsychotics risperidone 2 mg olanzapine 5 mg cause minimal extrapyramidal side effects case risk factors developing serious disabling td neuroleptic exposure borderline intellectual functioning externalizing behavior probable misdiagnosis overlooking early indicators side effects this case highlights dangers casually prescribing low dose second generation antipsychotics patient hyperthymic temperament borderline intellectual functioning vague short lasting presenting complaints probably misdiagnosed psychosis leading severe adverse effects patients organic brain damage prone develop adverse effects like td thus judicious use antipsychotics detailed frequent assessments important emergent stereotyped behavior unexplained movements must examined carefully taken seriously the authors certify obtained appropriate patient consent forms form patient(s ) has given consent images clinical information reported journal the patients understand names initials published due efforts made conceal identity anonymity guaranteed the authors certify obtained appropriate patient consent forms form patient(s ) has given consent images clinical information reported journal the patients understand names initials published due efforts made conceal identity anonymity guaranteed | tardive dystonia ( td ) is a serious side effect of antipsychotic medications , more with typical antipsychotics , that is potentially irreversible in affected patients .
studies show that newer atypical antipsychotics have a lower risk of td . as a result , many clinicians may have developed a false sense of security when prescribing these medications .
we report a case of 20-year - old male with hyperthymic temperament and borderline intellectual functioning , who developed severe td after low dose short duration exposure to atypical antipsychotic risperidone and then olanzapine .
the goal of this paper is to alert the reader to be judicious and cautious before using casual low dose second generation antipsychotics in patient with no core psychotic features , hyperthymic temperament , or borderline intellectual functioning suggestive of organic brain damage , who are more prone to develop adverse effects such as td and monitor the onset of td in patients taking atypical antipsychotics . |
lepidoptera include agricultural pests feeding activities negatively affect stored grains food fiber crops 2 3 since single lepidoptera adult produce hundreds eggs primary food source typically plant material cause significant damage agricultural crops although biological agents help manage insect pests insecticides currently essential large scale effective economical pest control these insecticides also affect non target organisms including pollinators application disrupts natural ecosystems also reduces yields crops rely pollination 5 6 the non target effect pesticides part due effects insect immunity necessary insect survival natural environments for example currently used pesticides shown affect cellular 710 humoral 11 12 immune responses interfere grooming behavior 13 14 these effects immunity likely non specific negatively impact health target pest beneficial arthropods therefore need novel target specific approaches control insect pests without affecting beneficial arthropods although immune pathways generally non specifically inhibited pesticides also likely source candidate molecules could inhibited target specific insect control since multiple classes insect immunity genes including signaling pathways strong selection diversification fundamental mechanisms innate immunity comprising cellular humoral pathways conserved throughout animal kingdom controlled signaling pathways activated various stimuli 17 18 including pathogen recognition immune surveillance systems despite overall conservation aspects immune systems subject strong selection evolve response varying pathogen exposure pathogen evolution virulence determinants modulate immunity 15 1921 co evolutionary dynamics promote diversification conserved elements immunity well recruitment novel effectors as investigation insect immune pathways mechanisms pathogen modulation yield insights components may susceptible inhibition for example insect pathogen xenorhabdus nematophila suppresses cellular humoral immunity lepidopteran moths manduca sexta spodoptera exigua 23 24 dipteran fly drosophila melanogaster suggesting stage immunity suppressed x. nematophila may absent d. melanogaster present lepidoptera since dipteran flies serve pollinators 26 27 decomposers food sources animals pest control agents capitalizing possible differences dipteran lepidopteran immune signaling cascades help identification targets pest specific inhibition knowledge hand pest management achieved developing small molecule inhibitors targets suppress pest insect immunity lead increased susceptibility environmental pathogens indeed many insecticides may contribute insect target non target death modulating aspects immunity the feasibility targeted pest control via insect immune inhibition established termites small molecule inhibitor immune surveillance protein led faster termite death upon exposure various pathogens much current knowledge insect immune signaling pathways receptor effector function based premiere model organism d. melanogaster extensive genetic tools several fully sequenced genomes well established lepidopteran insect models silkworm bombyx mori tobacco hornworm m. sexta also widely used study insect immunity these organisms particularly useful investigating hemolymph proteins hemocyte function relatively large larval size hemolymph volume many insects order lepidoptera easy rear laboratory conditions new tools rna interference implemented successfully study genetics immune systems 30 31 also immune signaling pathways gradually revealed genomic transcriptomic data 3238 based model insect systems fairly detailed picture immunity pathogen detection effector function emerging though many gaps remain particularly regard components unique different insect orders here we review aspects insect immunity emphasis similarities distinctions d. melanogaster representative lepidoptera in insects cellular immune response includes phagocytosis nodulation encapsulation 3942 humoral response involves expression antimicrobial peptides amps 43 44 well pro phenol oxidase propo proteolytic cascade results formation melanized nodules toxic reactive compounds 45 46 amps small cationic peptides insert disrupt microbial membranes thereby killing clearing pathogens they synthesized hemocytes greater extent fat body released insect hemolymph rapidly microbial infection 43 47 amps also expressed extra embryonic tissues eggs may help protect developing embryo infection amps conserved component immunity plants animals diverse structures assigned larger families cecropins attacins defensins diptericins their diversity immune effector function well variant representation among insects table 1 made central focus study invertebrate pathology 30 52 d. melanogaster amp synthesis each pathways activated detection microbial components via different pattern recognition receptors prrs trigger complex regulatory cascades nuclear factor kappa b nf-b dependent transcription genes encoding amps after amps translated cytoplasm released hemolymph high concentrations broad activity thought enhance clearance invading microorganisms insect bioinformatic experimental data support existence amp inducing toll imd pathways lepidopterans though components identified model organisms m. sexta 32 35 the conserved presence amps immunity coupled possibility certain elements induction pathways may vary among insects enhances probability microbially induced amp expression could inhibited pest specific manner remainder review focus pathways leading amp gene expression in d. melanogaster transcription amp encoding genes activated nf-b family transcription factors response infection 6569 distinct nf-b family transcription factors responding toll immune deficiency imd signal transduction pathways response toll pathway activation the nf-b inhibitor cactus phosphorylated degraded allowing targets nf-b factors dif dorsal translocated nucleus imd pathway activity culminates nf-b factor relish activated stimulus induced proteolytic cleavage case dif dorsal gram positive bacterial fungal infections primarily serve stimuli induce degradation cactus toll signaling pathway general gram negative bacterial infections d. melanogaster stimulate proteolytic cleavage relish imd pathway nucleus transcription factors drive transcription immune effectors including amp genes whose promoters contain nf-b binding sites 70 72 overall nf-b proteins dna binding specificities conserved among organisms including lepidoptera studied date 73 74 however nfb binding regions inhibitor b ib proteins e.g. cactus conserved suggesting diversification co adaptation ib nfb pairs also recent work indicates nf-b nuclear co regulators may contribute species specific regulation amp gene expression therefore modulation inhibitors nuclear co regulators nf-b dependent transcription may one avenue target specific immune suppression could achieved d. melanogaster nf-b dependent amp induction toll imd pathways activated detection microbial components via different pattern recognition receptors prrs prrs soluble membrane bound proteins bind specific microbe associated molecular patterns mamps lipopolysaccharide lps lipoteichoic acid lta peptidoglycan pgn -1,3-glucan released found cell surfaces bacteria fungi upon interaction mamps prrs directly agglutinate pathogens trigger proteolytic signaling cascades cytokine release turn lead activation downstream cellular humoral pathways including pro po activation amp gene expression 16 65 76 pgn recognition proteins pgrps -1,3-glucanase related proteins grps discovered lepidopteran silkworm b. mori assaying plasma components activate propo cascade pgrps subsequently shown conserved across mammals insects d. melanogaster role induction amp gene expression toll imd pathways response pgn well documented 7983 similarly grps shown induce amp expression toll pathway response fungal infections 79 84 in contrast dearth literature linking specific pgrps grps amp induction lepidoptera such link possible since pgn -1,3-glucan activate amp gene expression m. sexta b. mori 8590 multiple infection induced pgrp- grp encoding genes identified lepidoptera 32 38 54 55 9194 however numerous hints lepidoptera diptera may evolved divergent mechanisms linking pathogen detection conserved toll imd signal transduction cascades first genome comparison b. mori d. melanogaster failed identify 1:1 pgrp orthologs similarly b. mori gram negative binding protein gnbp m. sexta microbe binding protein mbp members -1,3-glucanase related protein superfamily 76 95 appear distantly related d. melanogaster gnbps suggesting divergence group proteins m. sexta mbp expression strongly regulated fat body immune challenge shows specific binding lta lps dap pgn also contrast situation d. melanogaster highly purified lps lta inducers amp gene expression lepidoptera though potently crude lps contaminating pgn purified pgn 85 90 96 97 this raises possibility different mamps combinations mamps efficacious eliciting amp gene expression lepidoptera relative diptera also since purified lps elicit amp expression lepidoptera d. melanogaster lepidoptera either distinct repertoire prrs responsible lps dependent triggering imd toll pathways yet undiscovered pathway links lps amp induction testing ideas awaits identification suite prrs signal transduction pathways responsible transducing lps lta pgn combinatorial microbial signals amp gene expression one class lepidopteran prr may mediate infection dependent induction amps c type lectins ctls ca dependent secreted proteins carbohydrate binding capabilities similar ctls d. melanogaster several ctls m. sexta b. mori 54 99 reported mediate induction cellular responses propo cascade although nomenclature quickly becomes confusing ctls include lipopolysaccharide binding protein lbp m. sexta iml-1 binds gram positive gram negative bacteria well yeast iml-2 shows specific binding lps iml-3 iml-4 show specific binding lps lta iml-3 also bind laminarin -1,3-glucan 103 104 diversity ctl carbohydrate binding specificities may result lineage specific pathogen recognition signal transduction connections of particular relevance theme review prrs present lepidoptera diptera table 1 general orders insects encode grps pgrps however specific representatives class restricted lepidoptera table 1 for example lepidopteran grp-2 binds fungal cell wall -1,3 glucans lta absent diptera such derived grp pgrps may contribute lepidopteran specific transduction signals downstream pathways other lepidoptera specific prrs hemolin hemolymph proteinase-14 precursor prohp14 table 1 like iml c type lectins hemolin lps- lta binding prr roles mediating cellular responses opsonin enhance phagocytosis hp14 shown detect bind broad range mamps may coordinate grp1 grp2 activate propo 60 106 the potential role prrs discussed mediating expression amp genes remains determined study lepidoptera specific immune surveillance proteins divergent activities conserved prrs likely yield novel avenues pest control d. melanogaster mamp dependent mamp independent routes activate toll pathway mamp dependent toll induction bacterial lys pgn typical gram positive bacteria ) is detected pgrp sa pgrp sd presence gnbp-1 yeast fungal -1,3-glucan detected gnbp-3 85 108 109 figure 1 mamp independent stimuli virulence determinants proteases chitinases secreted microbes dubbed
mamps mamp independent stimuli trigger distinct proteolytic cascade culminate cleavage cytokine sptzle serine protease sptzle processing enzyme spe interaction active sptzle c terminal domain c-106 surface localized toll receptor triggers intracellular signal transduction terminating induced expression amps cellular responses some basic components toll pathway present lepidoptera figure 2 m. sexta hemocytes express infection induced toll like receptor genome b. mori encodes 14 genes predicted encode toll like receptors well homologs intracellular components toll dependent signaling 85 114 115 both m. sexta b. mori encode homologs d. melanogaster toll activating cytokine sptzle figure 2 also m. sexta b. mori experimental evidence linking toll pathway amp induction 116118 m. sexta toll pathway results expression several antimicrobial peptides including attacin-1 cecropin-6 moricin lysozyme in addition transcript level hemolin pattern recognition protein exclusive lepidopterans table 1 induced injection activated sptzle c108 larvae despite conservation certain aspects toll pathway extracellular cascades lead sptzle activation may diverged d. melanogaster two lepidoptera figure 1 for example contrast known d. melanogaster m. sexta toll pathway activated gram negative associated mamps 115 118 also genome b. mori lacks 1:1 orthologs grass spirit persephone d. melanogaster serine proteases responsible mamp prr dependent mamp independent cleavage spe figure 1 progress made identifying m. sexta proteolytic cascade results processing pro sptzle active c terminal domain c-108 the direct cleavage mediated hemolymph proteinase hp 8 11 13 homolog d. melanogaster spe turn hp8 processed active form hp6 hp6 similar d. melanogaster persephone protease activates spe response mamp independent stimuli 110 113 this hemolymph proteinase activated response gram positive gram negative bacteria response -1,3-glucan however prrs proteolytic cascade transduce mamp signals amp induction unknown figure 1 the findings reviewed demonstrate overall architecture toll pathway conserved among insects specific identities proteolytic cascade members distinct many gaps remain understanding toll activation lepidoptera filling gaps reveal potential lineage specific molecules serve targets hinder activation toll pathway agricultural pests d. melanogaster the imd pathway also contributes amp gene induction triggered direct interaction dap pgn mamp typical gram negative bacteria transmembrane receptor pgrp lc 82 83 125 126 for example pgrp le act intracellular receptor monomeric pgn truncated form enhance pgrp lc mediated recognition dap pgn pgrp lc interaction activates intracellular imd recruits fas associated death domain fadd death related ced-3/nedd2-like protein dredd form complex 129 130 current evidence supports idea dredd caspase like molecule cleaves nf-b transcription factor relish imd also appears activate phosphorelay transforming growth factor- tgf)-activated kinase 1 tak1 phosphorylates ikb kinase ikk
relish cleavage activated amino terminal transcriptional regulator domain allows translocation nucleus activates amp gene expression the translocation relish nucleus regulated two recently discovered components pathway inhibitor apoptosis 2 iap2 transforming growth factor activated kinase 1 tak1)-binding protein 2 tab2 132 133 both iap2 tab2 act upstream relish downstream imd iap2 functions downstream tak1 132 134 particular importance amp gene expression iap2 knockdown hampers sustained expression amp genes iap2 tab2 necessary imd signal transduction gene product pirk recently characterized gene interacts directly imd pgrp lc pirk overexpression analyses revealed acts negative regulator reducing expression amp genes attacin b cecropin b diptericin b control imd pathway most information available imd pathway lepidoptera comes bioinformatics orthologs intracellular components imd pathway found b. mori 54 137 m. sexta however experiments done characterize molecular mechanisms leading activation imd pathway insects m. sexta several genes imd pathway including encoding imd fadd tak1 dredd relish regulated fat body immune challenged 5th instar larvae midgut b. mori wandering stage genes encoding lysozyme moricin defensin amps also regulated midgut b. mori wandering stage consistent possibility amp induction imd mediated finally lepidopteran beet armyworm spodoptera exigua rnai mediated knockdown relish expression resulted loss cecropin induction upon fungal infection strengthening idea imd pathway may contribute amp gene expression lepidoptera though perhaps triggered distinct signals further study needed elucidate imd mediated amp induction lepidoptera reveal differences pathway diptera lepidoptera in d. melanogaster transcription amp encoding genes activated nf-b family transcription factors response infection 6569 distinct nf-b family transcription factors responding toll immune deficiency imd signal transduction pathways response toll pathway activation the nf-b inhibitor cactus phosphorylated degraded allowing targets nf-b factors dif dorsal translocated nucleus imd pathway activity culminates nf-b factor relish activated stimulus induced proteolytic cleavage case dif dorsal gram positive bacterial fungal infections primarily serve stimuli induce degradation cactus toll signaling pathway general gram negative bacterial infections d. melanogaster stimulate proteolytic cleavage relish imd pathway nucleus transcription factors drive transcription immune effectors including amp genes whose promoters contain nf-b binding sites 70 72 overall nf-b proteins dna binding specificities conserved among organisms including lepidoptera studied date 73 74 however nfb binding regions inhibitor b ib proteins e.g. cactus conserved suggesting diversification co adaptation ib nfb pairs also recent work indicates nf-b nuclear co regulators may contribute species specific regulation amp gene expression therefore modulation inhibitors nuclear co regulators nf-b dependent transcription may one avenue target specific immune suppression could achieved in d. melanogaster nf-b dependent amp induction toll imd pathways activated detection microbial components via different pattern recognition receptors prrs prrs soluble membrane bound proteins bind specific microbe associated molecular patterns mamps lipopolysaccharide lps lipoteichoic acid lta peptidoglycan pgn -1,3-glucan released found cell surfaces bacteria fungi upon interaction mamps prrs directly agglutinate pathogens trigger proteolytic signaling cascades cytokine release turn lead activation downstream cellular humoral pathways including pro po activation amp gene expression 16 65 76 pgn recognition proteins pgrps -1,3-glucanase related proteins grps discovered lepidopteran silkworm b. mori assaying plasma components activate propo cascade pgrps subsequently shown conserved across mammals insects d. melanogaster role induction amp gene expression toll imd pathways response pgn well documented 7983 similarly grps shown induce amp expression toll pathway response fungal infections 79 84 in contrast dearth literature linking specific pgrps grps amp induction lepidoptera such link possible since pgn -1,3-glucan activate amp gene expression m. sexta b. mori 8590 multiple infection induced pgrp- grp encoding genes identified lepidoptera 32 38 54 55 9194 however numerous hints lepidoptera diptera may evolved divergent mechanisms linking pathogen detection conserved toll imd signal transduction cascades first genome comparison b. mori d. melanogaster failed identify 1:1 pgrp orthologs similarly b. mori gram negative binding protein gnbp m. sexta microbe binding protein mbp members -1,3-glucanase related protein superfamily 76 95 appear distantly related d. melanogaster gnbps suggesting divergence group proteins m. sexta mbp expression strongly regulated fat body immune challenge shows specific binding lta lps dap pgn also contrast situation d. melanogaster highly purified lps lta inducers amp gene expression lepidoptera though potently crude lps contaminating pgn purified pgn 85 90 96 97 this raises possibility different mamps combinations mamps efficacious eliciting amp gene expression lepidoptera relative diptera also since purified lps elicit amp expression lepidoptera d. melanogaster lepidoptera either distinct repertoire prrs responsible lps dependent triggering imd toll pathways yet undiscovered pathway links lps amp induction testing ideas awaits identification suite prrs signal transduction pathways responsible transducing lps lta pgn combinatorial microbial signals amp gene expression one class lepidopteran prr may mediate infection dependent induction amps c type lectins ctls ca dependent secreted proteins carbohydrate binding capabilities similar ctls d. melanogaster several ctls m. sexta b. mori 54 99 reported mediate induction cellular responses propo cascade although nomenclature quickly becomes confusing ctls include lipopolysaccharide binding protein lbp m. sexta iml-1 binds gram positive gram negative bacteria well yeast iml-2 shows specific binding lps iml-3 iml-4 show specific binding lps lta iml-3 also bind laminarin -1,3-glucan 103 104 diversity ctl carbohydrate binding specificities may result lineage specific pathogen recognition signal transduction connections particular relevance theme review prrs present lepidoptera diptera table 1 general orders insects encode grps pgrps however specific representatives class restricted lepidoptera table 1 for example lepidopteran grp-2 binds fungal cell wall -1,3 glucans lta absent diptera such derived grp pgrps may contribute lepidopteran specific transduction signals downstream pathways other lepidoptera specific prrs hemolin hemolymph proteinase-14 precursor prohp14 table 1 like iml c type lectins hemolin lps- lta binding prr roles mediating cellular responses opsonin enhance phagocytosis hp14 shown detect bind broad range mamps may coordinate grp1 grp2 activate propo 60 106 the potential role prrs discussed mediating expression amp genes remains determined study lepidoptera specific immune surveillance proteins divergent activities conserved prrs likely yield novel avenues pest control d. melanogaster mamp dependent mamp independent routes activate toll pathway mamp dependent toll induction bacterial lys pgn typical gram positive bacteria ) is detected pgrp sa pgrp sd presence gnbp-1 yeast fungal -1,3-glucan detected gnbp-3 85 108 109 figure 1 mamp independent stimuli virulence determinants proteases chitinases secreted microbes dubbed mamps mamp independent stimuli trigger distinct proteolytic cascade culminate cleavage cytokine sptzle serine protease sptzle processing enzyme spe interaction active sptzle c terminal domain c-106 surface localized toll receptor triggers intracellular signal transduction terminating induced expression amps cellular responses some basic components toll pathway present lepidoptera figure 2 m. sexta hemocytes express infection induced toll like receptor genome b. mori encodes 14 genes predicted encode toll like receptors well homologs intracellular components toll dependent signaling 85 114 115 m. sexta b. mori encode homologs d. melanogaster toll activating cytokine sptzle figure 2 also m. sexta b. mori experimental evidence linking toll pathway amp induction 116118 m. sexta toll pathway results expression several antimicrobial peptides including attacin-1 cecropin-6 moricin lysozyme in addition transcript level hemolin pattern recognition protein exclusive lepidopterans table 1 induced injection activated sptzle c108 larvae despite conservation certain aspects toll pathway extracellular cascades lead sptzle activation may diverged d. melanogaster two lepidoptera figure 1 for example contrast known d. melanogaster m. sexta toll pathway activated gram negative associated mamps 115 118 also genome b. mori lacks 1:1 orthologs grass spirit persephone d. melanogaster serine proteases responsible mamp prr dependent mamp independent cleavage spe figure 1 progress made identifying m. sexta proteolytic cascade results processing pro sptzle active c terminal domain c-108 the direct cleavage mediated hemolymph proteinase hp 8 11 13 homolog d. melanogaster spe turn hp8 processed active form hp6 hp6 similar d. melanogaster persephone protease activates spe response mamp independent stimuli 110 113 this hemolymph proteinase activated response gram positive gram negative bacteria response -1,3-glucan however prrs proteolytic cascade transduce mamp signals amp induction unknown figure 1 findings reviewed demonstrate overall architecture toll pathway conserved among insects specific identities proteolytic cascade members distinct many gaps remain understanding toll activation lepidoptera filling gaps reveal potential lineage specific molecules serve targets hinder activation toll pathway agricultural pests in d. melanogaster imd pathway also contributes amp gene induction triggered direct interaction dap pgn mamp typical gram negative bacteria transmembrane receptor pgrp lc 82 83 125 126 for example pgrp le act intracellular receptor monomeric pgn truncated form enhance pgrp lc mediated recognition dap pgn pgrp lc interaction activates intracellular imd recruits fas associated death domain fadd death related ced-3/nedd2-like protein dredd form complex 129 130 current evidence supports idea dredd caspase like molecule cleaves nf-b transcription factor relish imd also appears activate phosphorelay transforming growth factor- tgf)-activated kinase 1 tak1 phosphorylates ikb kinase ikk
relish cleavage activated amino terminal transcriptional regulator domain allows translocation nucleus activates amp gene expression the translocation relish nucleus regulated two recently discovered components pathway inhibitor apoptosis 2 iap2 transforming growth factor activated kinase 1 tak1)-binding protein 2 tab2 132 133 both iap2 tab2 act upstream relish downstream imd iap2 functions downstream tak1 132 134 particular importance amp gene expression iap2 knockdown hampers sustained expression amp genes iap2 tab2 necessary imd signal transduction gene product pirk recently characterized gene interacts directly imd pgrp lc pirk overexpression analyses revealed acts negative regulator reducing expression amp genes attacin b cecropin b diptericin b control imd pathway most information available imd pathway lepidoptera comes bioinformatics orthologs intracellular components imd pathway found b. mori 54 137 m. sexta however experiments done characterize molecular mechanisms leading activation imd pathway insects m. sexta several genes imd pathway including encoding imd fadd tak1 dredd relish regulated fat body immune challenged 5th instar larvae midgut b. mori wandering stage genes encoding lysozyme moricin defensin amps also regulated midgut b. mori wandering stage consistent possibility amp induction imd mediated finally lepidopteran beet armyworm spodoptera exigua rnai mediated knockdown relish expression resulted loss cecropin induction upon fungal infection strengthening idea imd pathway may contribute amp gene expression lepidoptera though perhaps triggered distinct signals further study needed elucidate imd mediated amp induction lepidoptera reveal differences pathway diptera lepidoptera insecticides necessary guarantee effective insect pest management agricultural settings however cost target effects insecticides directly indirectly increase economic burden latter affecting beneficial arthropods pollinators study insect immunity provide tools development target specific cost effective approaches control agricultural pests directed suppression pest immune defenses predicted render susceptible environmental applied biocontrol pathogens recently demonstrated termites bulmer colleagues the studies summarized suggest many aspects insect immunity including recognition factors serine proteases diverged d. melanogaster lepidoptera continued comparative immunity broad array species diptera lepidoptera and other insect orders reveal possible candidate immunity factors target specific approaches enable effective control insect pests however approaches realized details lepidopteran immune signaling pathways must elucidated the relatively large sizes last instar larvae many lepidopteran species facilitate biochemical approaches studies establishment immune inducible lepidopteran cell lines uga cie1 cell line enable characterization molecular mechanisms leading imd pathway activation contribution amp gene expression finally ongoing investigations immune modulatory mechanisms entomopathogens help identify key steps immunity susceptible manipulation contributing development natural cost effective non toxic alternatives chemical insecticides currently used pest management | many lepidopteran insects are agricultural pests that affect stored grains , food and fiber crops .
these insects have negative ecological and economic impacts since they lower crop yield , and pesticides are expensive and can have off - target effects on beneficial arthropods
. a better understanding of lepidopteran immunity will aid in identifying new targets for the development of specific insect pest management compounds .
a fundamental aspect of immunity , and therefore a logical target for control , is the induction of antimicrobial peptide ( amp ) expression .
these peptides insert into and disrupt microbial membranes , thereby promoting pathogen clearance and insect survival .
pathways leading to amp expression have been extensively studied in the dipteran drosophila melanogaster . however , diptera are an important group of pollinators and pest management strategies that target their immune systems is not recommended .
recent advances have facilitated investigation of lepidopteran immunity , revealing both conserved and derived characteristics .
although the general pathways leading to amp expression are conserved , specific components of these pathways , such as recognition proteins have diverged . in this review
we highlight how such comparative immunology could aid in developing pest management strategies that are specific to agricultural insect pests . |
syncope caused transient diffuse cerebral hypoperfusion characterized transient loss consciousness rapid onset followed spontaneous complete recovery clinical features syncope may include myoclonic jerks often multifocal asynchronous convulsions urinary incontinence making difficult differentiate epileptic seizure clinical features alone significant fluctuations cerebral perfusion pressure prevented autoregulation cerebral circulation may conditions mechanism may compensate adequately cough syncope rare form syncope may result transient failure cerebral autoregulatory mechanism cope sudden decrease cerebral blood flow we present unusual case recurrent cough syncope initially diagnosed treated seizures context left sided glomus jugulare tumor benign paraganglioma a 43-year old right handed woman history glomus jugulare tumor left jugular fossa intracranial extension posterior cranial fossa transferred another hospital recurrent seizure like spells she 90% surgical resection tumor done 2011 followed radiation therapy september 2012 her episodes occurred multiple times day 7 per day average wakeful state they triggered coughing usually bout cough characterized staring unresponsiveness well stiffening body mild shaking upper extremities she diagnosed epileptic seizures continued episodes treatment antiepileptic drugs aeds phenytoin levetiracetam lamotrigine escalation aed therapy made increasingly drowsy three aforementioned aeds time presentation her physical examination remarkable excessive drowsiness mild dysarthria right sixth cranial nerve palsy mild hypertonia hyperreflexia lower extremities left right bilateral left right ankle clonus she lumbar puncture done outside hospital opening cerebrospinal fluid csf pressure reported 25 cm blood work also unremarkable except mild anemia hemoglobin 9.4 g dl mild hyponatremia 132 meq l mild hypokalemia 3.1 meq l antiepileptic drug levels within therapeutic range free phenytoin 1.3 g ml levetiracetam 5.9 g ml lamotrigine 2.3 g ml all started bout cough patient lying bed supine lateral position followed brief less minute distal upper extremity tremor subtle proximal upper extremity myoclonic jerks prolonged unresponsiveness 10 min all episodes associated hypotension 7278/3147 mm hg revealed continuous arterial pressure monitoring bradycardia 5459 bpm the eeg spells characterized generalized synchronous asynchronous high amplitude 1- 2-hz delta activity progressed generalized attenuation transitioned generalized delta activity recovery fig 1 a head ct showed recurrence glomus jugulare tumor communicating hydrocephalus external ventricular drain evd ) after placement evd drowsiness gradually started improve episodes decreased frequency one per day 3 showed enhancing t2 hyperintense left skull base mass region left jugular foramen extension posterior cranial fossa base skull brain imaging showed evidence hydrocephalus increased compared previous brain imaging done 2 months back her mental status continued improve one mild episode triggered cough next two days discharge repeat surgical resection tumor recommended otolaryngology team patient declined based clinical features eeg findings episodes observed patient consistent cough syncope the mechanism underlying cough syncope definitively established postulated coughing increases intrathoracic intraabdominal pressures leading transient increase icp increased icp turn causes decrease cerebral perfusion pressure drops critical level may result global cerebral hypoperfusion leading syncope transient cerebral circulatory arrest demonstrated transcranial doppler measurements cough syncope patient also drop blood pressure heart rate probably sufficient cause syncope cough syncope associated posterior fossa mass lesions tonsillar herniation hydrocephalus it may speculated bouts cough caused transient herniation cerebellar tonsils obstructing csf flow contributed increase icp coughing decrease frequency events following placement evd relieve icp lends support notion paragangliomas rare tumors extraadrenal chromaffin cell origin commonly occur head neck region catecholamine hypersecreting paraganglionomas uncommon head neck region patients 95% hypersecreting paraganglionomas hypertension hypotension accompanying syncope observed patient orthostasis related patient always supine spells likely related cough identified subset patients cough syncope lacked blood pressure overshoot expected response relief straining valsalva maneuver the authors postulate cough syncope patients might result delayed recovery hypotension follows paroxysm cough likely contributing global cerebral hypoperfusion patient this case highlights fact cough syncope rare form syncope may associated intracranial mass lesions indirectly exaggerate increase icp response cough glomus caroticum tumor presenting recurrent unexplained syncope posterior fossa meningioma presenting recurrent cough syncope described recurrent cough syncope trigger search factors including brain tumors potential cause transient elevation icp this case also illustrates important role ceeg monitoring video distinguishing syncope seizures cough syncope cases | we present an unusual case of recurrent cough syncope in a 43-year - old woman , which was initially thought to be seizures .
syncopal episodes were triggered by paroxysms of cough and were characterized by unresponsiveness and myoclonic jerks in her extremities .
she had a left - sided glomus jugulare tumor that extended into the posterior cranial fossa with evidence of worsening communicating hydrocephalus on brain imaging .
we postulate that bouts of cough produced increased intracranial pressure both by raising intrathoracic and intraabdominal pressures as well as by transient obstruction to cerebrospinal fluid flow secondary to intermittent tonsillar herniation during cough .
this resulted in diffuse decrease in cerebral blood flow causing syncope .
the patient 's syncopal episodes decreased in frequency once an external ventricular drain was placed followed by a ventriculoperitoneal shunt .
search for factors that can increase intracranial pressure seems warranted in patients with recurrent cough syncope . |
world wide infertility affects 1015% couples trying conceive 15% cases caused male factors affect 1 20 men general population most cases male infertility idiopathic apart several etiologies obstruction deferent duct varicocele sexual dysfunction cryptorchidism although assisted reproductive technology art helped many sterile couples conceive non obstructive azoospermia noa accounts considerable proportion male infertility dramatically lower rate sperm retrieval clinical pregnancy the etiological mechanism noa unknown factors oxidative stress considered effects spermatogenesis antioxidants effective protecting spermatogenesis therefore helpful explore underlying pathogenesis noa patients micrornas class small rnas code amino acid sequences play fundamental roles regulating gene expression transcription lian et al found 154 regulated mirnas 19 regulated mirnas testes noa patients compared fertile males using microarray technologies furthermore mirnas shown affect proliferation apoptosis dna damage germ cells 911 mir-210 one 19 regulated mirnas testes noa patients located within genomic loci transcript ak123483 it induced hypoxia plays essential role cell adaptation hypoxia mir-210 also affects regulation diverse physiological processes angiogenesis cell survival proliferation cell cycle arrest protein modification dna damage repair although mir-210 shown involved regulation physiological processes various diseases regulated mirna testes noa patients remains unknown mir-210 affects spermatogenesis hence aim study investigate underlying mechanisms mir-210 involved pathogenesis spermatogenesis we enrolled 25 patients aged 1841 years azoospermia proven 3 semen analyses testicular biopsies first affiliated hospital anhui medical university pathological examinations performed testicular specimen combined clinical features 4 patients diagnosed sertoli cell syndrome scos 7 patients diagnosed maturation arrest 8 patients diagnosed hypospermatogenesis 6 patients diagnosed obstructive azoospermia oa patients provided informed consent participation study our local medical ethics committee approved study began examine location insulin like growth factor ii ( igf2 human testicular tissues performed immunohistochemistry staining detect igf2 expression tissues cut sections immunoperoxidase staining treated 4% pfa paraffin wax after specific treatment standard procedure immunohistochemistry staining described lian et al sections incubated igf2 antibody abcam overnight 4c biotinylated secondary antibody abcam 2 h room temperature detect expression mir-210 rnas extracted nt-2 cells tissues subjected real time pcr described lian et al briefly rna extraction performed following standard trizol protocol real time pcr carried abi step one system applied biosystems sybr premix ex taq ii kit takara bio inc used primers q rt pcr follows forward primer 5-caataactgtgcgtgtgacagc-3 reverse primer 5-tatggttttgacgactgtgtgat-3 forward primer 5-cagcacatatactaaaattggaacg-3 reverse primer 5-acgaatttgcgtgtcatcc-3 western blot analysis carried detect protein expression igf2 human testicular tissues 3 groups nt2 cells anti igf2 abcam used western blot analysis used -actin loading control detect expression igf2 we supplemented medium 10% fetal bovine serum life technology inc 1% antibiotics 100 units ml penicillin 100 ug ml streptomycin life technology inc cells incubated 37c humidified incubator 5% co2 transfect oligonucleotides plasmids nt-2 cells lipofectamine rnaimax invitrogen fugene hd roche ) all processes performed accordance protocols supplied manufacturers study experiments performed independently least 3 times we enrolled 25 patients aged 1841 years azoospermia proven 3 semen analyses testicular biopsies first affiliated hospital anhui medical university pathological examinations performed testicular specimen combined clinical features 4 patients diagnosed sertoli cell syndrome scos 7 patients diagnosed maturation arrest 8 patients diagnosed hypospermatogenesis 6 patients diagnosed obstructive azoospermia oa patients provided informed consent participation study to examine location insulin like growth factor ii igf2 human testicular tissues performed immunohistochemistry staining detect igf2 expression tissues cut sections immunoperoxidase staining treated 4% pfa paraffin wax after specific treatment standard procedure immunohistochemistry staining described lian et al sections incubated igf2 antibody abcam overnight 4c biotinylated secondary antibody abcam 2 h room temperature rnas extracted nt-2 cells tissues subjected real time pcr described lian et al briefly rna extraction performed following standard trizol protocol real time pcr carried abi step one system applied biosystems sybr premix ex taq ii kit takara bio inc used primers q rt pcr follows forward primer 5-caataactgtgcgtgtgacagc-3 reverse primer 5-tatggttttgacgactgtgtgat-3 forward primer 5-cagcacatatactaaaattggaacg-3 reverse primer 5-acgaatttgcgtgtcatcc-3 western blot analysis carried detect protein expression igf2 human testicular tissues 3 groups nt2 cells anti igf2 abcam used western blot analysis used -actin loading control detect expression igf2 we supplemented medium 10% fetal bovine serum life technology inc 1% antibiotics 100 units ml penicillin 100 ug ml streptomycin life technology inc cells incubated 37c humidified incubator 5% co2 transfect oligonucleotides plasmids nt-2 cells lipofectamine rnaimax invitrogen fugene hd roche ) the igf2 gene part cluster imprinted genes expressing single polypeptide igf2 produced paternal allele the maternal allele transcriptionally silent clarify location igf2 human testicular tissues we found igf2 located spermatocytes testes patients oa figure 1 igf2 located spermatocytes testis detected expression igf2 cases hypospermatogenesis oa scos patients we found igf2 regulated patients hypospermatogenesis compared oa patients considered control group normal spermatogenesis although without significant difference figures 2 3 possibly fewer samples longer preservation times samples quantitative real time pcr performed examined mir-210 expression testis patients hypospermatogenesis oa found mir-210 significantly regulated testis hypospermatogenesis patients compared oa patients figure 4 however due errors rna extraction preliminary experiment 3 testis samples 1 hypospermatogenesis oa patients damaged tested targetscan database 3utr igf2-mrna putative mir-210-binding site igf2 predicted potential target mir-210 identify whether igf2 gene targeted mir-210 directly renilla luciferase reporters include wild type full length 3utr forms mir-210 seeding sites figure 5 shows 60% decrease luciferase activity cotransfection mir-210 mimic renilla luciferase reporters nt2 cells inhibiting mir-210 expression increased activity reporter renilla luciferase expression igf2 protein also significantly lower nt2 cells transfected mir-210 mimics control cells knockdown mir-210 mir-210 inhibitor increased protein expression igf2 figures 6 the igf2 gene part cluster imprinted genes expressing single polypeptide igf2 produced paternal allele the maternal allele transcriptionally silent clarify location igf2 human testicular tissues we found igf2 located spermatocytes testes patients oa figure 1 because igf2 located spermatocytes testis detected expression igf2 cases hypospermatogenesis oa scos patients we found igf2 regulated patients hypospermatogenesis compared oa patients considered control group normal spermatogenesis although without significant difference figures 2 3 possibly fewer samples longer preservation times samples quantitative real time pcr performed examined mir-210 expression testis patients hypospermatogenesis oa found mir-210 significantly regulated testis hypospermatogenesis patients compared oa patients figure 4 however due errors rna extraction preliminary experiment 3 testis samples 1 hypospermatogenesis oa patients damaged tested in targetscan database 3utr igf2-mrna putative mir-210-binding site igf2 predicted potential target mir-210 identify whether igf2 gene targeted mir-210 directly renilla luciferase reporters include wild type full length 3utr forms mir-210 seeding sites used figure 5 shows 60% decrease luciferase activity cotransfection mir-210 mimic renilla luciferase reporters nt2 cells inhibiting mir-210 expression increased activity reporter renilla luciferase expression igf2 protein also significantly lower nt2 cells transfected mir-210 mimics control cells knockdown mir-210 mir-210 inhibitor increased protein expression igf2 figures 6 during recent decades several studies focused effects mirnas spermatogenesis male infertility 911,17 however understood mir-210 one regulated mirnas testes patients noa involved spermatogenesis male infertility the transformation diploid spermatogonia mature haploid cells spermatogenesis complex biological process testes males the insulin igf system takes part processes cell proliferation cell growth differentiation survival affects nearly every organ body also insulin igf plays important role proper function testis males igf2 binds igf1r insr high affinity binds insr igf1r insr b igf1r lower affinity found inactivated insr igf1r 79% reduction daily sperm production adult mouse testes conditional ko approach taken together aforementioned data suggest igf2 might involved process spermatogenesis examine specific mechanism mir-210 associated process spermatogenesis quantitative real time pcr performed detect mir-210 expression we found mir-210 significantly regulated testes subjects hypospermatogenesis patients compared oa these results agree findings lian et al using microarray technologies performed noa normal controls several studies suggested mirna could mediated hypoxia participate various types regulation angiogenesis cell survival proliferation cell cycle arrest protein modification 1214 furthermore researchers even found mir-210 might considered one indicated markers diseases clear cell renal cell carcinoma acute myeloid leukemia present study found igf2 targeted mir-210 directly vitro experiment nt2 cells mir-210 might associated spermatogenesis targeting igf2 male infertility firstly errors occurred rna extraction preliminary experiment mir-210 3 testes samples damaged detected subsequent quantitative real time pcr experiment might affected results secondly investigate functions mir-210 igf2 vitro vivo plan future research we demonstrated mir-210 might associated spermatogenesis targeting igf2 male infertility future mechanistic studies role mir-210/igf2 process spermatogenesis male infertility provide new insights diagnosis management male infertility | backgroundmicrornas ( mirnas ) play pivotal roles in spermatogenesis .
microrna-210 ( mir-210 ) expression was up - regulated in the testes of sterile men with non - obstructive azoospermia ( noa ) .
however , the underlying mechanisms of mir-210 involved in the spermatogenesis in patients with noa are unknown.material/methodsexpression of mir-210 and insulin - like growth factor ii ( igf2 ) in the testes of noa cases ( only including maturation arrest and hypospermatogenesis ) were detected in this study .
we carried out in vitro experiments to determine if igf2 was directly targeted by mir-210 in nt2 cells.resultscompared with obstructive azoospermia ( oa ) as normal control , our results suggest that mir-210 was significantly up - regulated in testis of patients with noa ( p<0.05 ) , and igf2 was down - regulated , but without a significant difference .
the results also indicated that igf2 was directly targeted by mir-210 in nt2 cells.conclusionsthe results showed that mir-210 was involved in spermatogenesis by targeting igf2 in male infertility . |
midwife led primary delivery care low risk pregnant women labor reported various advantages increased odds high maternal satisfaction decrease unnecessary medical interventions 18 although maternity care system low risk pregnant women peculiar one country easily compared countries consumer demands humanization obstetric care arisen various countries 18 date found evidence midwife led primary obstetric care unsafe low risk pregnant women comparison obstetric care favorable cooperation obstetricians midwives japan 912 in addition 85% low risk pregnant women request give birth receiving midwife led primary delivery care therefore safe midwife led delivery care backup obstetricians may also required low risk pregnant women japan complications occur threaten occur primary midwife led delivery care midwives refer woman obstetricians neighboring hospital private obstetric clinic soon possible this deliveries managed independent midwives japan many intervention measures oxytocin infusion epidural anesthesia episiotomy suture instrumental delivery available based japanese legal restrictions institute one main tokyo city perinatal centers 3 japanese systems midwife led delivery care follows 1 intending give birth home managed midwives belong hospital 2 planning give birth futons
( i.e. japanese style bedding japanese tatami mat delivery rooms hospital managed midwives belong hospital 3 planning give birth japanese tatami mat delivery rooms managed midwives belong hospital the objective study describe trends transfers perinatal outcomes among labors using 3 japanese systems midwife led primary delivery care the protocol analysis approved ethics committee japanese red cross katsushika maternity hospital addition informed consent analysis retrospective database obtained subject hospital visit hospital pregnant women initially considered low risk 3436 weeks gestation choose freely 3 systems midwife led care obstetric shared care in midwife led care units midwives practice autonomously fully accountable practice unsupervised obstetricians factors used exclude women low risk group comprise following 912 1 medical history pregnancy induced hypertension chronic hypertension diabetes mellitus renal disease idiopathic thrombocytopenia systemic illnesses 2 gynecological history history infertility therapies vitro fertilization congenital uterine anomalies uterine myomatosis adnexal anomaly 3 obstetric history narrowing pelvic outlet cephalopelvic disproportion previous cesarean section previous anal sphincter injury previous postpartum hemorrhage 1,000 ml blood transfusion previous manual removal placenta previous gestational diabetes history severe preeclampsia 4 complications present pregnancy multiple pregnancy nonvertex presentation obesity maternal body mass index pregnancy 25 and/or third trimester 28 anemia hemoglobin 9.0 g dl epilepsy treatment polyhydramnios oligohydramnios low set placenta placenta previa fetal growth restriction heavy date fetus gestational diabetes pregnancy induced hypertension risk factors present women managed obstetricians midwives 5 complications labor intrauterine infection thick meconium staining prolongation labor active phase dilation 1 cm hour duration second stage labor 2 hours prolonged rupture membranes 24 hours uterine inertia arrest labor fetal heart rate abnormality nonreassuring fetal status factors present women transferred managed mainly obstetricians obstetric shared care standard western style delivery room surgery room hospital a retrospective study performed examine trends transfers perinatal outcomes among labors started using 3 systems midwife led primary delivery care study student test used continuous variables test categorical variables odds ratios ors 95% confidence intervals cis also calculated differences p between 2009 2012 total 678 low risk women placed 3 forms midwife led primary delivery care onset labor pains and/or rupture membranes 3741 weeks gestation 123 18% intended give birth home 88 13% planned give birth japanese tatami mat rooms hospital managed midwives belong hospital 467 59% planned give birth managed midwives belonging hospital
table 1 shows clinical descriptions 678 pregnant women initially considered low risk receiving midwife led primary delivery care systems significant differences maternal age parity among 3 groups
table 2 shows rate transfers 3 groups midwife led primary delivery care systems the total rate transfers system run midwives belonging hospital 56% higher 2 systems run independent midwives 31% planned home birth 1.87 95% ci 1.23.0 p 0.01 38% planned hospital birth 2.51 95% ci 1.73.8 p 0.01 in addition timing transfers system run midwives belonging hospital second stage labor 52% earlier 2 systems 21% planned home birth 4.12 95% ci 2.66.6 p 0.01 20% planned hospital birth 4.29 95% ci 2.57.4 p 0.01 however classified nulliparous parous women significant differences rate transfers among 3 groups shown table 1 in addition among 3 groups significant differences rate main 2 indications transfer fetal heart rate abnormality failure progress the main indications transfer delivery maternal postpartum hemorrhage neonatal respiratory distress associated asphyxia
table 3 shows obstetric neonatal outcomes pregnant women initially considered low risk receiving midwife led primary delivery care systems significant differences outcomes among 3 groups our obstetric care system involves division women labor low- high risk groups 912 the women initially considered low risk choose freely midwife led care obstetric shared care complications occur risk factors arise labor primary midwife led care transferred obstetric shared care this may first report concerning differences timing transfers midwife led care obstetric shared care among 3 systems midwife led primary delivery care japan study evidence primary midwife led care unsafe low risk pregnant women 3 midwife led delivery care systems however significant differences timing referrals midwife led care obstetric shared care system led midwives belong hospital hospital midwifery system systems led midwives belong hospital hospital midwifery system timing transfers seemed earliest due ease transfer within hospital administrator setting hand the rate transfers delivery 2 systems higher hospital midwifery care period main indications transfers maternal postpartum hemorrhage and/or neonatal respiratory distress associated asphyxia fortunately difference associated adverse obstetric neonatal outcomes however unfortunately led early mother child separation especially cases planned home birth healthy puerperal women newborns transferred home hospital according japanese law although home birth might comfortable involved must prepared mother child separation cases referrals delivery the major limitations study small sample size lack long term follow mothers children consider potential findings based context there cases fetal neonatal death midwife led delivery care the evaluated outcome midwife led delivery satisfaction pregnant women development mother child relationships delivery in addition might bias related backgrounds selection systems randomized trial study therefore large prospective study long term follow may needed there significant differences perinatal outcomes among 3 systems however differences status transfers obstetric shared care |
objective .
the objective of this study was to describe the recent clinical characteristics of labor using 3 systems of japanese midwife - led primary delivery care , as follows : ( 1 ) those intending to give birth at home managed by midwives who do not belong to our hospital , ( 2 ) those planning to give birth in our hospital managed by the same midwives , and ( 3 ) those planning to give birth managed by midwives who belong to our hospital .
methods . a retrospective cohort study was performed .
results .
there were no significant differences in the obstetric or neonatal outcomes among the 3 groups .
the rate of transfers during labor with the system involving midwives belonging to our hospital was higher than those with the other 2 systems .
in addition , the timing of transfers in the system with the midwives belonging to our hospital was earlier than with the other 2 systems . among the 3 groups ,
there were no significant differences in the rate of the main 2 indications for transfers : fetal heart rate abnormality and failure to progress . conclusion .
there were no significant differences in perinatal outcomes among the 3 systems ; however , there were some differences in the status of transfers to obstetric shared care . |
diabetes decreases overall life expectancy cause heavy burden public health 1 moreover asia pacific region considered verge emerging diabetes epidemic 2 the development type 2 diabetes affected genetic environmental determinants 3 recently one study investigated whether common variants functional positional candidate genes including adrb3 pparg enpp1 capn10 determinants type 2 diabetes 4 enpp1 also called k121q glutamine substitution lysine codon 121 5 type 2 diabetes characterized insulin resistance 6 enpp1 plays important role insulin resistance 7 8) enpp1 interacts -subunit insulin receptor interrupt signaling 9 previous studies k121q polymorphism human pc-1 gene strongly associated insulin resistance 1 3 7 10 12 however association insulin resistance k121q variant 13 14 in addition discrepancies impact enpp1 polymorphism obesity ethnic groups 5 10 13 15 19 obesity increases concentration insulin plasma major contributor insulin resistance 20 obesity appears effect modifier type 2 diabetes d1057 carriers 21 the association obesity genetic variant insulin receptor substrate identified studies 21 22 chinese han population the pc-1 q121 allele associated insulin resistance women carriers q allele had increased risk obesity development 3 caucasians african americans 121q carriers association increased body mass index bmi 23 three allele risk type haploid qdeltg q allele increased risk obesity 24 ) however danish population differences distribution frequencies dominant types kk wild type kq qq variant type alleles 19 the complexity type 2 diabetes related factors genetic heterogeneity interactions genes modulating role played environment 4 spite limitations studies type 2 diabetes genetic factors obesity can predict risks development type 2 diabetes obesity order assist primary prevention korea appropriate country studies homogeneity racial composition lifestyle 25 therefore aim study analyze presence enpp1 polymorphism studied yet korean population identify association genotypes allele type 2 diabetes obesity this company electric power company located kori yonggwang ulchin wolsung seoul korea there 195 male workers age 48.26.7 yr bmi 24.672.64 kg diagnosed diabetics medical examinations conducted march 2004 october the 1,750 male workers age 45.27.7 yr bmi 24.772.64 kg control group selected randomly subjects included met one criteria onset age older 20 yr old exclude type 1 diabetes 1 blood sugar level meal exceeded 126 mg dl twice 2 blood sugar level meal exceeded 126 mg dl blood sugar level two hours meal exceeded 200 mg dl 3 reported history diabetes questionnaire taken oral hypoglycemic agents the workers included obesity group whose bmi 25 kg collecting blood sample vein fasting 8 hr status measured blood sugar level insulin lipid profile also measured height weight calculate bmi fasting glucose levels greater 126 mg dl checked 2 hr post prandial plasma glucose level site within 1 month height weight measured autoanalyzer health guard fanics seoul korea the fasting blood level analyzed glucose oxidase assay using autochemistry analyzer determine lipid profile total cholesterol analyzed enzyme assay using cholesterol oxidase cod high density lipoprotein hdl cholesterol glycerol phosphate oxidase assay low density lipoprotein ldl cholesterol direct surfactant assay we carried study approval ethnics committee asan medical center obtained written consent subjects providing subjects sufficient explanation obtain informed consent we extracted genomic dna buffy coats using generall blood sv kit general biosystem seoul korea following instructions suggested manufacturer the method genotyping used identify k121q polymorphism enpp1 exon 4 polymerase chain reaction restriction fragment length polymorphism pcr rflp using dna treated restriction enzyme pcr based paper reported abate et al we carried student test analyze effects genotypes biochemical parameters using genotypes factors the hardy weinberg equilibrium computed based goodness fit test we also investigated differences frequencies genotypes type 2 diabetic normal groups obesity normal groups fisher exact test the spss 12.0 window statistical software package used statistical analysis this company electric power company located kori yonggwang ulchin wolsung seoul korea there 195 male workers age 48.26.7 yr bmi 24.672.64 kg diagnosed diabetics medical examinations conducted march 2004 october the 1,750 male workers age 45.27.7 yr bmi 24.772.64 kg control group selected randomly subjects included met one criteria onset age older 20 yr old exclude type 1 diabetes 1 blood sugar level meal exceeded 126 mg dl twice 2 blood sugar level meal exceeded 126 mg dl blood sugar level two hours meal exceeded 200 mg dl 3 reported history diabetes questionnaire taken oral hypoglycemic agents the workers included obesity group whose bmi 25 kg collecting blood sample vein fasting 8 hr status measured blood sugar level insulin lipid profile also measured height weight calculate bmi fasting glucose levels greater 126 mg dl checked 2 hr post prandial plasma glucose level site within 1 month height weight measured autoanalyzer health guard fanics seoul korea the fasting blood level analyzed glucose oxidase assay using autochemistry analyzer determine lipid profile total cholesterol analyzed enzyme assay using cholesterol oxidase cod high density lipoprotein hdl cholesterol glycerol phosphate oxidase assay low density lipoprotein ldl cholesterol direct surfactant assay we carried study approval ethnics committee asan medical center obtained written consent subjects providing subjects sufficient explanation obtain informed consent we extracted genomic dna buffy coats using generall blood sv kit general biosystem seoul korea following instructions suggested manufacturer the method genotyping used identify k121q polymorphism enpp1 exon 4 polymerase chain reaction restriction fragment length polymorphism pcr rflp using dna treated restriction enzyme pcr based paper reported abate et al we carried student test analyze effects genotypes biochemical parameters using genotypes factors the hardy weinberg equilibrium computed based goodness fit test we also investigated differences frequencies genotypes type 2 diabetic normal groups obesity normal groups fisher exact test the spss 12.0 window statistical software package used statistical analysis the frequencies kk type kq type qq type enpp1 k121q 82.1% 17% 0.9% respectively the homozygous type q carrier qq type added heterozygous type kq type frequency qq type low 0.9% we investigated differences age blood pressure bmi results clinical examinations according genotypes enpp1 k121q type 2 diabetic non diabetic groups table 1 type 2 diabetics non diabetics pooled n=1,945 significant differences bmi systolic pressure diastolic pressure glucose value fasting status total cholesterol ldl cholesterol hdl cholesterol triglyceride c reactive protein homa ir kk type kq+qq type in addition significant differences characteristics type 2 diabetic group non diabetic groups table1 obese group non obese groups table2 the frequencies genotypes accordance hardy weinberg equilibrium p=0.85 the odds ratio kq+qq genotype 0.85 diabetics versus non diabetics the odds ratio q allele 0.91 diabetics versus non diabetics however significant difference genotypic allelic distribution type 2 diabetics non diabetics table3 the odds kq+qq genotype 0.93 obese versus non obese subjects furthermore odds q allele 0.96 obese versus non obese subjects however significant difference genotypic allelic distribution obese non obese table4 the frequency kk type enpp1 k121q genotypes 82.1% kq+qq type 17.9% q allele 9.4% there statistically significant difference distribution among genotypes alleles p=0.81 p=0.89 respectively although 121q carrier q allele obese and/or diabetics seemed differ slightly non obese non diabetics reference group determining prevalence q allele carriers kq qq subjects q allele significant differences genotypic allelic distribution respect phenotypes data shown after adjusting effects obesity probability type 2 diabetes kq+qq type 0.858 data shown q allele 1.095 showing significant difference table 5 moreover adjusting effects type 2 diabetes probability developing obesity kq+qq type 0.936 data shown q allele 1.038 showing significant difference table 6 the results studies association enpp1 k121q variants type 2 diabetes obesity several races disparate we carried study investigate association k121q variants type 2 diabetes obesity korean male workers insulin resistance major component pathogenesis type 2 diabetes 27 insulin receptor kinase activity impaired muscle insulin sensitive tissue many type 2 diabetic patients 28 potential inhibitor insulin receptor tyrosine kinase identified plasma cell membrane differentiation antigen-1 pc-1 29 therefore significant analyze enpp1 pc-1 polymorphism previous studies association type 2 diabetes polymorphism enpp1 k121q missense mutation increased odds ratio type 2 diabetes dominican 10 south asian caucasian 16 finnish 18 french populations 24 moreover according meta analysis association enpp1 k121q variant type 2 diabetes odds ratios 1.30 95% confidence interval ci 1.13 1.50 16 1.17 95% ci 1.10 1.25 19 showing significant association study 121q associated type 2 diabetes showing consistent results japanese population 5 danish caucasians 13 oji cree population 17 finnish population 18 danish white subjects 19 most type 2 diabetes koreans characterized non obesity thus enpp1 k121q mutant relevant insulin resistance possibly could candidate gene appropriate explain susceptibility type 2 diabetes this possible explanation lack association enpp1 121q carrier type 2 diabetes study obesity main risk factor development type 2 diabetes 20 linear association obesity type 2 diabetes 3 previous studies association obesity polymorphism enpp1 121q carriers and/or q allele associated obesity chinese han population bmi obesity group 27 kg 3 caucasians bmi obesity group 90th percentile african american adults bmi obesity group 80th percentile 23 french population bmi obesity group 95th percentile 24 dominican population bmi obesity group 30 kg 10 however study bmi obesity group 25 kg difference distribution obesity 121q carriers presence q allele this result consistent study 7,333 danes 19 spanish population 14 bmi obesity group 25 kg higher hand matsuoka study the percentage subjects whose bmi 30 kg higher low 2.5% investigate effect k121q genotype obesity the results present study showed frequencies q allele 8.7% type 2 diabetic group 9.2% obesity group lower finnish swedish populations 12.9 15.1% 11 danish caucasians 14 16% 13 south asians chennai 14% caucasians dallas 16% south asians dallas 19% 16 dominican population 54.2% 10 black children 77% 30 the frequencies q allele investigated study might smaller statistical power explain association either type 2 diabetes obesity 121q carriers kq+qq and/or q allele conclusion present study suggests enpp1 k121q polymorphism associated type 2 diabetes obesity the results negative associations study might attributable low prevalence obesity relatively younger age low frequencies 121q carriers large prospective studies needed confirm preliminary observation korean population | type 2 diabetes is characterized by insulin resistance , and enpp1 plays an important role in insulin resistance .
we investigated the association of the enpp1 k121q polymorphism with both diabetes and obesity ( body mass index [ bmi ] ) in korean male workers .
the study design was case - control .
subjects were 1,945 male workers ( type 2 diabetes , 195 ; non - diabetes , 1,750 ) of nuclear power plants who received examinations from march to october in 2004 .
we collected venous blood samples under fasting ( 8 hr ) conditions , calculated bmi by height and weight , and assessed relevant biochemical factors .
the results of this study demonstrated that the enpp1 121q genotype ( kq+qq types ) was not associated with type 2 diabetes ( odds ratios [ or ] , 0.854 ; 95% confidence interval [ ci ] , 0.571 - 1.278 ) or obesity ( or , 0.933 ; 95% ci , 0.731 - 1.190 ) .
in addition , the frequency of the q allele was not related to type 2 diabetes ( or , 0.911 ; 95% ci , 0.630 - 1.319 ) or obesity ( or , 0.962 ; 95% ci , 0.767 - 1.205 ) .
we concluded that the enpp1 121q allele is not a critical determinant for either diabetes or obesity in korean males .
the discordance between the results of this study and those derived from studies of dominican , south asian , caucasian , finnish , and french populations might be due to differences in genetic backgrounds between these populations . |
lipid apheresis provides safe effective means treating patients severe hyperlipidemia it functions first separating plasma blood cells cell separator using either adsorption apolipoprotein b affinity columns containing anti apolipoprotein b antibodies dextran sulphate precipitation low ph heparin lipid apheresis allows patients attain lower levels low density lipoprotein ldl usually attainable traditional drug therapy alone leaving high density lipoprotein hdl levels generally unaffected used conjunction statins lipid lowering drugs lipid apheresis may also induce regression coronary atherosclerotic plaque familial hypercholesterolemia fh patients fh group autosomal dominant genetic defects resulting elevated serum ldl cholesterol levels heterozygous state fh relatively common serious genetic disorder incidence 1 500 persons general population fh associated increased risk atherosclerosis premature coronary heart disease heart failure 3 4 fh caused mutation affecting apolipoprotein b proprotein convertase subtilisin kexin type 9 pcsk9 enzyme involved ldl receptor degradation commonly ldl receptor gene resulting defective ldl receptors and/or diminished number ldl receptors 7 8 these mutations cause ldl catabolized slower rate thus accumulate circulation currently fh treated using variety cholesterol lowering drugs notably statins hmg coa reductase inhibitors many patients however statins viable treatment option either intolerance ineffectiveness lipid apheresis alternative form treatment fh patients well persistently elevated ldl levels despite treatment because apheresis performed highly specialized centers relatively low volume little literature discussing effectiveness lipid apheresis reduction lipid profiles prevention future cardiac events this study therefore reports experience single metropolitan center treating patients hyperlipidemia lipid apheresis retrospective chart reviews performed questionnaire surveys given active lipid apheresis patients minneapolis heart institute mhi abbott northwestern hospital anw minneapolis minnesota mhi anw divisions allina health large healthcare provider minnesota western wisconsin patients identified electronic health record ehr screen ambulatory patients representing patients seen allina health metro area regional locations 2009 2012 epic systems verona wi patients criteria qualify apheresis based united states food drug administration fda approval recommendations currently fda supports ldl apheresis patients six months adequate response diet therapy maximum drug therapy due either ineffectiveness intolerance meet following criteria functional homozygotes ldl cholesterol 500 mg dl without cad functional heterozygotes ldl cholesterol 300 mg dl without cad functional heterozygotes ldl cholesterol 200 mg dl documented coronary heart disease functional homozygotes ldl cholesterol 500 mg dl without cad functional heterozygotes ldl cholesterol 300 mg dl without cad functional heterozygotes ldl cholesterol 200 mg dl documented coronary heart disease the date birth gender date apheresis initiation lipid disorder diagnosis apheresis frequency family history cardiac events recorded patients noted fh active problem list contained diagnosis fh determine patients fh used national lipid association nla criteria 80% probable fh diagnosis using highest ldl recorded patient chart follows age 20 ldl 190 mg dl age 2029 ldl 220 mg dl age 30 ldl 250 mg dl potential homozygous fh hofh patients defined untreated ldl 500 mg dl treated statin ldl 300 mg dl addition clinical evidence xanthomas age 10 years two parents heart disease high lipids identifiable secondary causes marked hyperlipidemia excluded analysis examining ehr chart potential homozygote current cholesterol lowering medications also recorded focusing use statins colesevelam welchol ezetimibe zetia niacin aspirin a significant cardiovascular event defined myocardial infarction mi percutaneous transluminal coronary angioplasty ptca stenting procedure coronary artery bypass graft cabg using ehr documented icd-9 criteria cardiac events separated occurrence patient began apheresis total number events recorded group multiple cardiac events occurring hospitalization mi followed ptca counted single event cardiac event rate calculation pre- postapheresis cardiac event rates calculated adding total number cardiac events dividing total person years time period the preapheresis time period describes time first documented ehr visit date apheresis initiation the postapheresis time period describes time date apheresis initiation study date unverifiable events noted ehr occurring prior first documented ehr visit noted excluded cardiac event rate calculation mean acute ldl reductions calculated averaging recorded ldl values prior immediately treatment sessions mean acute total cholesterol hdl cholesterol triglyceride reductions calculated using lipid profile recent treatment session ldl apheresis performed abbott northwestern hospital using kaneka liposorber la-15 system kaneka medical products the system consists kaneka ma-03 machine integrated sulflux kp-05 plasma separator consists porous hollow fibers separate plasma whole blood two disposable liposorber la-15 adsorption columns adsorb apolipoprotein b containing lipoproteins patient plasma patients confirmed information ehr risk factors answered questions relating awareness fh family previously tested provided level satisfaction apheresis program indicated interest learning alternative treatments the data questionnaires cross referenced data patient charts ensure accuracy descriptive statistics displayed means sds continuous variables number percentage characteristic given categorical variables categorical variables analyzed using pearson chi square fisher exact tests continuous variables analyzed using student test value p 0.05 considered significant p values two sided possible all statistical calculations plots done stata 11.2 college station tx institutional review board approval obtained data collection follow data analysis of 8 72.7% male 10 90.9% caucasian 1 9.1% african american 10 90.9% carried diagnosis fh 2 18.2% patients identified probable homozygotes 1 9.1% diagnosed familial combined hyperlipidemia the average age patients 65.6 9.3 years patients apheresis average 6.2 7.0 years four 36.4% patients currently statins 7 63.6% history statin intolerance five 11 45.5% patients nonstatin cholesterol lowering medications including 1 9.1% colesevelam welchol 3 27.3% ezetimibe zetia 1 9.1% niacin maximum ldl levels ranged 211 448 mg dl mean sd value 298 80.7 mg dl study group since ehr implemented 2005 possible may underestimating highest lifetime ldl patient of 11 participants 9 completed questionnaire entirety 1 patient provided answers questions disclose risk factors 1 patient complete questionnaire all patients indicated aware likely fh 7 patients indicated immediate family tested fh the patients self reported total 44 cardiac events apheresis 8 cardiac events apheresis of 10 patients completed questionnaire 4 patients currently statins 6 statin intolerant eight patients 72.7% cardiac event documented ehr 43 cardiac events occurring overall table 4 self reported events unable verified via ehr excluded cardiac event rate analysis thirty four cardiac events documented apheresis 8 patients compared 9 events 5 patients apheresis excluding cardiac events unverifiable 14 cardiac events documented preapheresis time period 7 documented postapheresis time period the cardiac event rates calculated 0.23 0.13 0.39 events per person year preapheresis group 0.10 0.041 0.21 events per person year postapheresis group p 0.064 patients observed average 7.6 5.9 years apheresis 6.2 4.7 years apheresis 60.6 total patient years apheresis 67.8 patient years apheresis this study conducted gain information lipid apheresis evaluate effectiveness lowering lipid values addition chart review patient survey attempted gain greater understanding patient population terms traditional risk factors family awareness screening statin cholesterol medication uses desire additional treatment options ultimately cardiac events our study shows apheresis markedly lowers total cholesterol ldl cholesterol triglycerides much lesser degree hdl cholesterol there small statistically significant reduction hdl values apheresis many patients statin intolerant using nonstatin cholesterol medications importantly 10/11 90.9% participants indicated desire learn potential treatment options indicating population may indeed experience fatigue procedure although taken small study population data suggests reduction cardiac event rate apheresis statistically significant data shows strong trend towards event rate reduction this statistical insignificance likely explained study small sample size larger population it also important note risk cardiac events increases age ldl apheresis shown improve endothelium dependent vasodilation 11 12 microvascular flow myocardial perfusion some studies 2 15 16 also shown significant reduction angiographic cad others these studies small primarily nonrandomized trials ldl apheresis atherosclerosis regression study laars ) looked change plaque characteristics patients undergoing apheresis compared drug therapy period two years in period 7 21 patients apheresis cardiac event compared 3 21 medication study found apheresis arrested progression atherosclerosis the fh regression study found ldl apheresis combined simvastatin effective colestipol plus simvastatin reducing ldl cholesterol lipoprotein less effective influencing coronary atherosclerosis another study found 18 patients 3 myocardial infarctions 1 underwent cabg 12 needed coronary angioplasties within two years beginning combination therapy apheresis statins probucol beginning combination therapy 11 experienced mi 5 undergone cabg 13 undergone angioplasty the heparin induced extracorporeal ldl precipitation help study found help suitable reducing ldl concentrations may work reduce burden atherosclerosis myocardial infarctions low coronary intervention rate patients began apheresis due expensive nature apheresis randomized controlled clinical trial needed truly gauge effectiveness apheresis reducing occurrence cardiac events if apheresis deemed effective minimally effective studies suggest types treatment lomitapide mipomersen pcsk9 inhibitors pursued satisfaction generally high survey patients specifically cited satisfaction based results apheresis process many patients complained invasive nature apheresis citing bruises procedure inconvenience reporting treatment every two weeks additionally almost patients interested learning alternative treatments suggesting would prefer alternative treatment could match results provided apheresis this study several limitations since lipid apheresis advanced treatment uncommon genetic disease limited number patients available participate study led small sample size the event rate reduction statistically significant showed strong trend toward cardiac event rate reduction apheresis defining observational period initial time point first documented ehr visit excluded 20 events apheresis 2 events apheresis cardiac event rate calculation the lipid lowering effects apheresis best expressed reductions interval means although lipid apheresis performed every two weeks ldl values measured ever two weeks due clinical practices this inconsistency measurement intervals prevents use advanced measures accurately track effect apheresis ldl measurements finally study focused active apheresis patients therefore include patients stopped apheresis deceased lipid apheresis reliably reduce ldl non hdl cholesterol triglyceride total cholesterol levels fh patients our data suggest lipid apheresis shows strong statistically significant trend towards reduction cardiac events apheresis viable treatment fh patients especially statin intolerant due lipid lowering nature apparent reduction cardiac events however need alternative treatments less invasive provide easier patient access | lipid apheresis is used to treat patients with severe hyperlipidemia by reducing low - density lipoprotein cholesterol ( ldl - c ) .
this study examines the effect of apheresis on the lipid panel and cardiac event rates before and after apheresis .
an electronic health record screen of ambulatory patients identified 11 active patients undergoing lipid apheresis with 10/11 carrying a diagnosis of fh .
baseline demographics , pre- and postapheresis lipid levels , highest recorded ldl - c , cardiac events , current medications , and first apheresis treatment were recorded .
patients completed a questionnaire and self - reported risk factors and interest in alternative treatment .
there were significant reductions in mean total cholesterol ( 58.4% ) , ldl - c ( 71.9% ) , triglycerides ( 51% ) , high - density lipoprotein ( hdl ) cholesterol ( 9.3% ) , and non - hdl ( 68.2% ) values .
thirty - four cardiac events were documented in 8 patients before apheresis , compared with 9 events in 5 patients after apheresis .
our survey showed a high prevalence of statin intolerance ( 64% ) , with the majority ( 90% ) of participants indicating an interest in alternative treatment options .
our results have shown that lipid apheresis primary effect is a marked reduction in ldl - c cholesterol levels and may reduce the recurrence of cardiac events .
apheresis should be compared to the newer alternative treatment modalities in a randomized fashion due to patient interest in alternative options . |
agenesis inferior vena cava ivc cause recurrent deep vein thrombosis dvt uncommon a 33-year old male family history thrombophilia experienced multiple recurrent episodes dvt 15-year period unknown cause admitted hospital cellulitis right leg congenital absence ivc could rare risk factor idiopathic dvt especially young individuals venous thromboembolism vte includes deep vein thrombosis dvt pulmonary embolism incidence 1 3 per 1000 individuals per year western populations.1 congenital anomalies inferior vena cava ivc uncommon associated development venous thrombosis lower limbs.2 congenital anomalies ivc reported risk factor dvt especially individuals 30 years old concomitant thrombophilic disorder found individuals.3 report case recurrent dvt 33-year old man agenesis ivc the patient experienced recurring episodes idiopathic dvt right leg 15 years a 33-year old man admitted internal medicine department holy family hospital nazareth israel cellulitis right leg one week prior admission complained pain increased local heat left ankle thumb right leg the patient history previous trauma surgery insect bites dysuria joint symptoms family history thrombophilia he reported rheumatic fever without complications 19 years old treated penicillin b hospitalized 23 years old infected skin ulcers right calf treated parenteral antibiotics c recurrent episodes idiopathic dvt last 15 years he also reported treated warfarin prophylactic enoxaparin therapy dvt years ago since stopped recently treated allopurinol colchicine presumed diagnosis gout he investigated several times primary hypercoagulability state results negative examination outstanding clinical findings swelling ankles mild edema redness increased temperature right ankle calf trophic skin changes skin discoloration ulcers superficial varicose veins lower abdomen figure 1 the clinical laboratory findings erythrocyte sedimentation rate leukocyte platelet counts plasma hemoglobulin plasma protein c plasma protein fibrinogen antithrombin iii levels results kidney liver function tests resistance activated protein c normal polymorphisms genes encode methylenetetrahydrofolate reductase detected factor v leiden prothrombin mutations g20210a absent results clinical immunological studies complement c3 c4 rheumatoid factor negative circulating titers antinuclear antibody antineutrophil cytoplasmic antibody cardiolipin antibody found cultures infected skin ulcers right leg positive methicillin resistant staphylococcus aureus mrsa ultrasound imaging leg veins showed previous dvt right common femoral vein dilated superficial inguinal veins computer tomography contrast abdomen showed agenesis infrarenal segment ivc figure 2 dilated azygos hemiazygos veins figure 3 there also varicose veins abdominal wall right groin associated dilated superficial collateral veins figure 4 transthoracic echocardiography patient heart revealed mild atrial enlargement good systolic function left ventricle pathological valvular flows the patient diagnosed agenesis infrarenal segment ivc dvt right leg without concomitant risk factors vte since attributed agenesis ivc underlying cause recurrent episodes dvts patient started anticoagulant therapy subcutaneous enoxaparin 160 mg day dvt antibiotic therapy intravenous vancomycin 1.5 g day mrsa skin infection referred vascular surgeon specialist patient refused follow internal medicine clinic the outstanding clinical findings swelling left ankle redness trophic skin changes mild improvement skin ulcers despite several phone calls follow up the normal ivc composed 4 segments hepatic suprarenal renal infrarenal since many transformations occur formation ivc such anomalies occur 0.3% otherwise healthy individuals 0.6% 2% patients cardiovascular anomalies.4 ruggeri et al reported 10 years ago 4 cases congenital absence ivc 75 young patients idiopathic dvt 5-year period estimated 5% young patients dvt anomaly ivc.5 venous thrombosis caused presence isolated combined risk factors almost 150 years ago nineteenth century pathologist rudolf virchow described 3 critically important causes venous thrombosis venous damage coagulation defect(s venous stasis.6 individuals congenital anomaly ivc typically asymptomatic anomaly usually detected incidentally radiological abdominal procedures congenital absence ivc infrequently associated thromboembolic events.5 patients suffer congenital anomalies ivc usually develop compensatory circulation azygos veins collateral abdominal veins order keep venous return near normal levels.7 reported cases congenital anomalies ivc cases linked thrombophilia disorders.3,5,7 however true prevalence thrombophilia congenital anomalies ivc unknown screening thrombophilia patients ivc anomaly usually incomplete.3 anticoagulants thrombolytic therapy usually prescribed venous thrombosis duration anticoagulant therapy well established hence anticoagulant therapy indefinite duration probably prescribed unless vascular reconstructive surgery done anomalous ivc such surgery rarely reported long term outcome undetermined.8 congenital anomalies ivc may cause recurrent dvt especially young individuals | background : agenesis of the inferior vena cava ( ivc ) as a cause of recurrent deep vein thrombosis ( dvt ) is uncommon.case:a 33-year - old male with no family history of thrombophilia , who had experienced multiple recurrent episodes of dvt over a 15-year period of unknown cause , was admitted into our hospital because of cellulitis in the right leg .
computer tomography with contrast of the abdomen showed an absence of ivc.conclusion:congenital absence of the ivc could be a rare risk factor for idiopathic dvt , especially in young individuals . |
exponential rise alzheimer disease ad prevalence rates predicted parallel aging baby boomers creating potentially unsustainable economic burden healthcare system delaying onset progression ad even modestly earlier pharmacological intervention could substantially reduce economic psychosocial impact illness 1 2 unfortunately many ad patients remain undiagnosed go undetected later stages disease
insights underlying pathological mechanisms involving beta amyloid plaque deposition within brain led development host antiamyloid agents various stages clinical investigation there scientific consensus pathological events ad initiate decades clinical symptoms become apparent disease modification realized coming decades need improved methods early detection prior overt clinical signs accentuated traditionally neuropsychological measures particularly tap cognitive abilities subsumed hippocampal formation episodic memory shown usefulness identifying cognitively normal elders subsequently develop ad 4 5
decrements semantic memory concept formation shown occur nearly decade development ad
performance visual spatial verbal memory measures midlife also shown predict later memory loss
however individuals high premorbid intellectual abilities experiencing incipient cognitive decline may go undetected false positives possible individuals low level intellectual abilities also appropriate interpretation extensive neuropsychological testing requires high degree expertise training limits use routine clinical settings advancement molecular imaging tracers bind amyloid pittsburgh compound b pib longer lived probes e.g. fddnp offers non invasive vivo method detect quantify brain amyloid deposition 8 9 however approach presymptomatic detection economically impractical routine use given current costs restrictions medically necessary use similarly biomarkers including a142 phosphorylated tau also implicated ad pathology cerebral spinal fluid csf predict subsequent cognitive decline 10 11 lumbar puncture carries risks inconvenient wide scale use cognitively impaired elderly subjects
blood based biomarkers practical applicability routine use likely cost effective csf imaging procedures consequently measurement a140 a142 blood increasingly explored shows potential identifying individuals preclinical stage ad 1214
it reported csf levels subject high diurnal fluctuations extremely high variability reported 12 hours days weeks furthermore serum contains plasma possibly due release bound clotting process
hence serum appears suitable use predicting mci ad optimal sensitivity specificity probably achievable combined current diagnostic procedures brief neuropsychological testing study examined usefulness brief neuropsychological tests combination blood a140 a142 predictive test detecting mci ad risk older adults pre symptomatic stage
such approach practical clinical use germane designing large scale prevention trials participants included subset subjects enrolled alzheimer disease anti inflammatory prevention trial adapt adapt randomized placebo controlled multicenter primary prevention trial sponsored national institute aging subjects randomly assigned one three groups celecoxib 200 mg b.i.d naproxen sodium 220 mg b.i.d placebo full details data collection measurements study procedures available http://www.jhucct.com/adapt/manall43.pdf described elsewhere inclusion criteria adapt subjects age 70 older enrollment self reported family history ad like dementia normal cognitive performance brief battery neuropsychological tests
recruitment adapt began 2002 study completed 2007
in 2005 roskamp institute initiated proteomic ancillary study f. crawford pi involving blood draw subjects
the inclusion criteria ancillary study stipulated subject active adapt participant met adapt inclusion exclusion criteria
a separate consent also obtained subject participated ancillary study
two hundred fifteen subjects roskamp adapt cohort enrolled proteomic ancillary study time blood draw subjects maintained cognitively normal status determined performance annual cognitive assessment battery
blood collected semi annual followup visits cognitive assessments performed baseline visit annual visits
the time baseline cognitive testing diagnosis mci ad 4.06 years 1.3 sd timeframe baseline cognitive testing blood draw 2.25 years 0.71 sd blood draw diagnosis 1.79 years 1.2 sd the cognitive measures completed baseline annual followup included modified mini mental state examination 3ms hopkins verbal learning test revised hvlt r digit span forward backward wechsler adult intelligence scale revised wais r generative verbal fluency test supermarket items narratives rivermead behavioral memory test rbmt brief visuospatial memory test revised bvmt r
the mini mental state examination mmse extracted 3ms
alternate forms utilized annually hvlt r rbmt bvmt r subsequent annual visit
subjects also completed 30-item geriatric depression scale self rating scale memory functions
collateral respondents completed dementia severity rating scale dsrs due significant intercorrelations tests analyses described below are limited baseline cognitive tests sensitive early changes i.e. verbal learning memory associated mci ad tests similar previously shown associated levels normative data cache county study used develop standardized cut scores utilized adapt individuals scored cut scores annual cognitive assessments underwent dementia workup including physical neurological examinations laboratory studies i.e. cbc chemistry count sedimentation rate vitamin b12 folic acid levels thyroid test syphilis serological test neuroimaging i.e. mri ct applicable a comprehensive neuropsychological assessment also administered neuropsychologist part dementia work this battery tests consisted expanded consortium establish registry alzheimer disease cerad battery logical memory ii wechsler memory scale revised benton visual retention test benton generative fluency test animals control oral word association test cowat cfl trail making test symbol digit modalities test smdt shipley vocabulary following completion components dementia work consensus team determined cognitive status using published diagnostic criteria the diagnosis ad made using nincds adrda amnestic mild cognitive impairment mci using petersen criteria all mci patients considered amnestic mci memory impairment maintained normal activities daily living overall well preserved cognition cognitive domains ample evidence indicates amnestic mci patients may transitional stage normal aging ad 85% subjects converting ad 7-year period additional evidence comes imaging study demonstrated pattern brain atrophy amnestic mci patients typical observed ad patients it reasonable combine diagnoses single category thus allowing large enough numbers supply statistical power 215 subjects gave blood ancillary study two developed non ad dementia and of remaining subject pool 208 used analyses 28 subjects met criteria either ad n 10 mci n 18 two years following blood draw the serum content determined per manufacturer instructions using elisa kits human a140 a142 inter assay cv intraassay cv reported 10% invitrogen calif
dna extracted whole blood apoe genotyping using pure gene kits gentra systems calif apoe genotyping performed using previously established methods described elsewhere
apoe genotypes unavailable 4 individuals included analyses the data set range checked prior analyses dependent independent variables examined missing data outliers violations normalcy assumption differences among groups demographic variables neuropsychological variables serum a140 levels examined using either student test analyses depending type variable measurement
time updated cox regression modeling used test whether neuropsychological test scores combination predict conversion mci ad individuals cognitively normal baseline
potential confounding variables shown impact risk cognitive decline included age education gender apoe status serum creatinine triglycerides presence apoe 4 allele history vascular disease determined treatment statins antihypertensive medication entered covariates latter variables coded dichotomously previously shown impact levels
because previous analyses revealed nonsignificant increase ad risk naproxen cohort also controlled effect
logistic regression modeling employed construct receiver operator curves roc examine predictive performance neuropsychological measures baseline visit serum levels diagnoses mci ad
roc curve comparisons based area curve auc se associated 95% confidence interval ci we subsequently calculated sensitivity various models using predicted probability subject logistic regression modeling specificity least eighty percent post hoc power calculations using g power software multivariate regression analyses utilized suggest power nearly 100% alpha value 0.05 current sample size total number predictors observed effect size the mean age education sample 76.7 sd 3.9 14.6 sd 2.8 years respectively the majority sample caucasian 98.1% 51.9% male despite cohort self report enriched family history less one third total sample 31.7% carried least one apoe 4 allele frequency similar general population comparisons variables subjects remained cognitively normal declined short follow period reported table 1 although subjects enrollment performed within normal limits based established cut scores ultimately declined generally poorer scores 3ms mmse memory measures the two groups also significantly different serum a142 levels a142/a140 ratios prior diagnoses mci ad only 23% cognitively normal individuals serum a142 lowest quartile compared nearly 50% diagnostic group 44% mci subjects 50% ad subjects
time dependent cox regression analyses performed examine relationship cognitive tests prediction subsequent conversion mci ad all neuropsychological analyses adjusted age gender education adjustment study medications required baseline scores
cox regression analyses show model using neuropsychological tests predicted mci ad 2 log likelihood 206.51 52.11 df 8 p .001
significant individual neuropsychological measures 3ms 0.25 0.06 wald 17.78 p .001 generative verbal fluency 0.12 0.04 wald 8.09 p < .004 hvlt r scores 0.24 0.11 wald 4.58 p .032
cox regression analysis showed a142 measured lowest two quartiles compared highest quartile significant individual predictor conversion mci ad model 2 log likelihood 197.47 38.41 df 15 p .001
the regression analysis utilizing a142/a140 ratio found similarly significant results 2 log likelihood 204.69 36.10 df 14 p .001 lowest ratios predictive subsequent conversion mci ad final full model adjusting confound study medications included hvlt r fluency 3ms a142 levels a142 quartiles 2 log likelihood 166.25 74.55 df 18 p .001 fluency 3ms a142 lowest two quartiles significant individual predictors mci ad model similar results observed a140 levels a142 quartiles substituted model a142/a140 ratios 2 log likelihood 168.49 72.90 df 17 p .001
baseline values 3ms hvlt r generative verbal fluency scores subtracted obtained 12-month repeat testing determine changes measures differ a142 a142/a140 ratios unadjusted analyses among subjects converted mci ad greatest decline hvlt r observed among individuals lowest quartile a142 1.17 2.33 sd a142/a140 ratios 0.75 2.63 sd individuals highest quartile a142 1.33 1.86 sd a142/a140 ratios improved nearly one point 0.6 1.82 sd
however differences statistically significant p .05 3ms scores among subjects converted mci ad a142 lowest quartile declined 1.83 1.28 sd compared highest quartile 4.83 1.35 sd difference statistically significant f 3.42 p .033 mci ad subjects lowest quartile a142/a140 ratios 3ms values remained ultimately unchanged 0.16 1.20 sd while scores improved among highest quartile a142/a140 ratios 4.33 1.20 sd differences also statistically significant f 3.10 p .046 generative verbal fluency test decline noted lowest quartile 4.17 1.40 sd highest quartile 1.17 2.13 sd a142 differences marginally significant f 2.63 p .073 a142/a140 ratios a similar pattern observed difference statistically significant among individuals remained cognitively normal while similar pattern observed lowest quartile a142 a142/a140 ratios larger decline highest quartile hvlt r 0.28 0.27 sd versus 0.14 0.33 sd respectively 3ms 1.02 0.51 sd versus 0.39 0.44 sd
however due small magnitude change scores differences statistically significant no change observed generative verbal fluency test data shown
examination sensitivity specificity using roc analysis revealed auc neuropsychological testing age education gender covariates 0.83 95% ci 0.750.91 p .001 a142 ( adjusted presence apoe 4 allele vascular risk factors associated medications auc 0.79 95% ci 0.700.88 p .001 neuropsychological testing 3ms hvlt r generative verbal fluency a142 combined auc increased 0.91 95% ci 0.860.95 p .001 adjusted a142/a140 ratios alone .001 combined neuropsychological measures auc 0.91 95%ci 0.870.96 p .001
optimal sensitivities specificity least 80% predicted probabilities shown table 2 highest sensitivity specificity was achieved using combination cognitive scores a142/a140 ratio finding driven a142 the pathogenesis ad initiated clinical symptoms cognitive impairment functional decline become apparent victims a simple pragmatic method identifying older adults increased risk mci ad may benefit targeted prevention therefore importance reducing burden ad the combination brief neuropsychological tests along blood based biomarkers ad represents reasonable approach potential wide scale use
our findings provide support notion demonstrate early prediction risk developing mci ad may feasible via combination brief neuropsychological tests biomarkers risk cohort subcohort adapt measures global cognitive function 3ms episodic memory hvlt r trial 4 language fluency serum a142/a140 ratio achieved excellent accuracy 91% furthermore sensitivity specificity least 80% combined measures superior neuropsychological measures serum levels alone we recently shown levels alone predict mci ad levels influenced vascular disease associated medications require adjustment observe full impact predictive modeling we also shown subjects diagnosed ad association measures language tests fluency object naming a140 memory performance associated serum a142
an association serum a140 cognitive measures memory language also reported cognitively normal older adults high baseline a142 a140 stable a142 time shown associated diminishing cognition more recently yaffe colleagues demonstrated low a142/a140 ratios predict cognitive decline 9 years study demonstrate low a142 a142/a140 ratios associated cognitive decline even within one year this extremely valuable clinical perspective ability identify risk individuals within year prior onset significantly improve quality care recruitment strategy prevention trials redirecting individuals may benefit preventive therapies towards suitable clinical intervention
this demonstrated recent adapt findings suggest individuals low baseline cognitive scores converted soon trial initiated neither naproxen celecoxib intervention beneficial individuals collectively findings suggest combining cognitive tests blood may useful predicting future mci ad date explored particularly either cognitive tests alone may desired sensitivity specificity prediction future mci ad
this current work presented provides evidence combination brief neuropsychological tests blood potential utility predicting mci ad least 2 4 years prior clinical classification mci diagnosis ad in addition findings also demonstrate importance accounting factors apoe vascular risk factors medications using predicting mci ad although present studies reported sensitivity specificity csf a142 predicting mci ad conversion normal cognition large multicenter study shown csf a142 predicts transition mci ad tau alone achieved high sensitivity 83% acceptable specificity 72% it interesting note findings using blood cognitive tests far less invasive method resulted higher sensitivities specificities predicting cognitive decline risk cognitively normal older adults despite limitation blood sampling conducted time point cognitive testing our data provide strong support evaluation approach particularly seen significant fluctuations levels one year period pers our study provides support blood based levels may diagnostic utility combined neuropsychological measures proposed method warrants investigation determine practical applicability specialized clinic setting allied health personal routine primary care clinics | we examined the usefulness of brief neuropsychological tests and serum a as a predictive test for detecting mci / ad in older adults .
serum a levels were measured from 208 subjects who were cognitively normal at enrollment and blood draw .
twenty - eight of the subjects subsequently developed mci ( n = 18 ) or ad ( n = 10 ) over the follow - up period .
baseline measures of global cognition , memory , language fluency , and serum a142 and the ratio of serum a142/a140 were significant predictors for future mci / ad using cox regression with demographic variables , apoe 4 , vascular risk factors , and specific medication as covariates . an optimal sensitivity of 85.2% and specificity of 86.5% for predicting mci / ad was achieved using roc analyses .
brief neuropsychological tests and measurements of a142 obtained via blood warrants further study as a practical and cost effective method for wide - scale screening for identifying older adults who may be at - risk for pathological cognitive decline . |
we compared serum polychlorinated dibenzo - p - dioxins ( pcdds ) and polychlorinated dibenzofurans ( pcdfs ) among residents of two homes to levels among age- and sex - matched comparison subjects .
the residents of the two homes consumed contaminated eggs and beef from animals raised at the homes .
the animals had greater soil contact than those raised with conventional commercial husbandry practices .
the comparison subjects were from a similar rural area , but did not consume home - produced beef and eggs .
serum levels of 2,3,7 , 8-substituted tetra- , penta- , and hexacdds and penta- , hexa- , and heptacdfs were increased between 2- and 6-fold in residents from one home ; contaminated eggs and beef were consumed by residents for 2 - 15 years .
elevations were less for those in the other index home , where only home - produced eggs were consumed for 2 years ; a 3-fold elevation of 1,2,3,7,8,9-hexacdd as compared to controls was most apparent .
very strong bivariate correlations among all of the 2,3,7 , 8 penta- and hexacdds / cdfs were observed .
the elevations observed verify that pcdd / pcdf - contaminated food contributed to the body burden of these compounds .
the blood levels among the highest exposed participants are generally higher than those observed in other studies of u.s .
contaminated - fish consumers and higher than average adipose tissue levels observed in u.s . urban populations .
there are sufficient animal toxicologic and human epidemiologic data to recommend that exposures be reduced . in the study area ,
pentachlorophenol and pentachlorophenol incineration sources have been identified , and the animal contamination and blood elevations probably reflect these sources .
soil reference values and site - specific risk assessments should include estimates of exposures to contamination in home - produced animal products .
such estimates can be verified with limited pcdd / pcdf sampling of animals and humans.imagesfigure 1figure 2 |
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wnt/-catenin pathway implicated development progression melanoma wide range cancer types including colorectal cancer breast cancer esophageal carcinoma liver cancer 13 normal conditions increases expression binding certain wnt ligands frizzled receptor mutations specific components -catenin degradation assembly deactivate regulatory mechanism nuclear -catenin stimulates transcription large number tcf/-catenin responsive genes include cyclin d1 c myc 5 6 melanocyte specific gene microphthalmia associated transcription factor mitf thus accumulation nuclear -catenin observed several cancer types considered marker canonical wnt/-catenin pathway deregulation unfavorable prognosis 3 8 previous studies reported association nuclear -catenin accumulation melanoma progression suggested nuclear -catenin marker poor prognosis 1 7 however recent studies shown contrary breast colon cancer metastatic progression melanoma associated decreases nuclear cytoplasmic -catenin expression 9 10 moreover clinical genetic histological studies suggest nuclear cytoplasmic -catenin may used biomarkers good prognosis melanoma 1114 recently hhr6 human homologue yeast rad6 gene principal component postreplication dna repair pathway identified important regulator canonical wnt/-catenin signaling 15 16 hhr6 referred hereafter rad6 stabilizes -catenin polyubiquitin modifications render -catenin resistant 26s proteasomal degradation furthermore rad6 transcriptional target -catenin thus revealing positive feedback loop -catenin mediated activation rad6 gene expression rad6-induced -catenin stabilization rad6 expression low normal breast tissues however increases rad6 protein expression detected hyperplastic ductal carcinoma situ dcis invasive breast carcinomas we previously demonstrated role rad6 breast cancer progression regulatory effect canonical wnt/-catenin pathway since decrease loss nuclear -catenin 9 10 rather increases breast cancer is linked melanoma progression known whether rad6 -catenin work concert promote melanoma pathogenesis furthermore rad6 expression skin investigated data role rad6 pathogenesis benign nevi malignant melanoma melanocytic lesions it important address gap knowledge unmet medical need new effective antimelanoma therapies rad6 -catenin identified therapeutic targets 19 20 study examined rad6 -catenin expressions serial sections nevi primary metastatic melanomas determine potential roles melanoma development metastatic progression our data suggest membranous relocation -catenin upregulation rad6 independent markers melanoma development progression we also offer hypothesis explains role membranous -catenin relocation decreasing cytoplasmic -catenin melanoma development phenomenon linked unfavorable prognosis 9 21 22 cases retrieved files pinkus dermatopathology laboratory pdl private dermatopathology laboratory located monroe mi preserved paraffin embedded tissue specimens collected case assigned accession code excluded patient identifier information nevus primary melanoma cases selected study using random numbers generated uniform random number generator stata mp 13.1 the study groups consisted 30 cases melanocytic nevi 29 cases primary cutaneous melanoma 29 cases metastatic cutaneous melanoma the study includes metastatic cutaneous melanoma samples archived 2010 2012 the number cases nevus primary melanoma subtype determined reflect lesion relative representation cases obtained pdl period atypical nevi diagnosed using criteria originally proposed clark lesion architecture reviewed roth et al primary antibodies used study follows anti--catenin is702 purchased dako glostrup denmark used undiluted form ii anti rad6 ab31917 purchased abcam cambridge used 1 500 dilution humans yeast homologous rad6 gene duplicated proteins encoded two genes hhr6a rad6a hhr6b rad6b chromosomes xq24-q25 5q23-q31 respectively share 95% identical amino acid residues neither ab31917 rad6 antibody commercially available anti rad6 antibody currently able distinguish rad6a rad6b proteins therefore rather referring rad6a rad6b refer protein detected antibody rad6 briefly five micrometer sections deparaffinized xylene rehydrated graded ethanol antigen retrieval sections microwaved citrate buffer ph 6.0 biogenex san ramon ca usa 12 min 95c cooled 30 min prior immunostaining sections incubated 3% hydrogen peroxide 15 min followed incubation primary antibody 60 min an automated immunostainer i6000 biogenex utilized subsequent incubation steps sections incubated multilink biotinylated anti igg 20 min horseradish peroxidase conjugated secondary antibody 20 min followed development 3-amino-9-ethyl carbazole 10 min biogenex all incubation steps performed room temperature sections washed tris buffered saline incubations lung colon cancer tissues included positive controls immunostaining anti--catenin antibody breast cancer tissues included positive controls staining anti rad6 antibody stained sections independently enumerated two coauthors d. r. mehregan m. campbell blinded patient medical records case blinded enumeration performed light microscopy 400x magnification ocular grid consisting simple square lattice 100 test points utilized count number positively negatively stained melanomas nevus cells section per section total number positively negatively stained cells counted three sequential horizontal fields the mean value three fields used estimate relative density cells specimen increase assessment accuracy positively negatively stained melanomas nevus cells visual field when independent readings positively stained cells differed 20% given section evaluators reviewed section together establish consensus reading a specimen considered negative less 4% cells immunostained rad6 -catenin a tumor considered stained high intensity 50% cells specimen expressed rad6 -catenin similar criteria used mineta et al kruskal wallis tests used compare groups basis continuous variables age percent positive cells chi square tests differences proportions used compare groups basis categorical variables gender -catenin localization spearman rank correlation used assess pairwise association age percent rad6 positive -catenin positive cells multinomial logistic regression used assess simultaneous association rad6 age diagnostic group adjustments made multiple comparisons using wilcoxon rank sum tests bonferroni correction pairwise comparisons our analysis included 30 individuals diagnosed nevi 29 primary melanoma 29 metastatic melanoma table 1 these groups differed marginally respect gender p 0.08 significantly age p 0.0001 significant age differences observed individuals nevi either primary melanomas p 0.02 metastatic melanomas p 0.0001 in contrast age difference observed individuals primary metastatic melanomas p 0.27 significant differences age also observed groups defined -catenin localization p 0.007 individuals -catenin localized cytoplasm significantly younger individuals -catenin localization cell membrane p 0.02 marginally younger individuals -catenin localization cytoplasm cell membrane p 0.05 age categorized 50 5060 60 years statistically significant differences rad6 expression groups p 0.0008 although substantial variability table 2 median rad6 greater group people older 60 years compared 5060 years old group p 0.04 50 years old group p 0.001 a 20% discrepancy positively stained cells two evaluators observed fewer 5% cases cases evaluated together establish consensus reading melanoma development progression associated significant changes percentage specimens expressing -catenin -catenin staining observed 97% nevi primary metastatic melanomas also percentages nevi 93% primary melanoma 97% metastatic melanoma 93% expressed -catenin 50% cells differ significantly figures 1 2 3 however significant differences observed percentages nevi 59% primary melanoma 90% metastatic melanoma 56% expressed -catenin 90% cells p 0.02 figure 2 these differences greatly impacted percentage primary melanomas 48% expressed -catenin 100% cells approximately twofold higher percentages nevi 21% metastatic melanoma 26% data shown none nevi melanomas expressed -catenin nucleus figure 1 the percentage tumors expressed membranous -catenin increased dramatically nevi 10% primary metastatic melanomas 83% 93% resp ; concurrently increase percentage tumors expressed cytoplasmic -catenin decreased nevi 90% primary metastatic melanomas 45% 38% resp ; in contrast significant differences observed percentages primary metastatic melanomas expressed -catenin either membrane 83% 93% resp ; p 0.289 cytoplasm 45% 38% resp p 0.633 figure 4 four nevi types junctional intradermal compound atypical expressed -catenin cytoplasm junctional atypical nevi expressed -catenin plasma membrane as opposed nevi types three primary melanoma types examined superficial spreading nodular lentigo maligna differ -catenin localization -catenin localized plasma membrane cytoplasm figure 4 conversely primary melanomas 100% majority metastatic melanomas 96% exhibited greater 50% rad6 expression the increase tumor populations expressing rad6 37% nevi 100% primary metastatic melanomas significant p 0.0001 figures 1 2 3 melanoma progression primary metastatic disease associated changes percentage melanomas expressing rad6 100% primary metastatic melanomas ii percentage melanomas expressing rad6 50% tumor cells 100% 96% primary metastatic melanomas resp the increase proportion tumor populations expressing rad6 50% cells primary melanoma 67% versus metastatic melanoma 79% significant p 0.37 figure 2 this study designed test whether distribution tumor cells positive rad6 subtypes nevi however percentages benign tumors lacked rad6 similar atypical nevi 62% group three nevi types 59% interestingly one 30 nevi atypical nevus 3% expressed rad6 80% cells none primary metastatic melanomas expressed rad6 40% cells figure 2 these results prompted us examine whether rad6 expression serve marker histological diagnosis melanoma using multiple logistic regression model found strength rad6 expression strong predictor melanoma p 0.001 even age group p 0.65 gender p 0.24 included model the model predicts every 1% increase rad6 expression results 9% increase probability lesion melanoma if assume predicted probability 0.5 indicates melanoma model rad6 sensitivity 93% specificity 80% these results encouraging however need validated larger study expression profiles -catenin rad6 differed considerably nevi approximately 93% nevi expressed -catenin 50% cells whereas 27% population nevi expressed rad6 figure 2 -catenin rad6 expressions nevi significantly correlated r 0.06 p 0.77 there 2.7-fold difference percentage primary melanomas 100% expressing rad6 compared nevi 37% virtually difference -catenin expression primary metastatic melanomas 100% accordingly rad6 -catenin expressions primary melanoma correlated r 0.001 p 0.99 significant correlation rad6 -catenin positive cells however association diminished r 0.40 p 0.05 following exclusion two observations disproportionally influential one 50% positive rad6 one 50% positive -catenin this first study characterize rad6 expression cutaneous benign malignant melanocytic tumors study examined association rad6 -catenin expressions benign malignant melanocytic tumors determine whether rad6 works concert -catenin influence melanoma development progression rad6 -catenin positively regulate breast cancer 15 18 however -catenin implicated pathogenesis melanoma cancer types data role rad6 cancer pathogenesis mostly limited breast cancer therefore hypothesized comparison rad6 -catenin expressions nevi melanoma tumors would help determine whether two signals collaborate promote melanoma development progression breast cancer 15 28 accumulation nuclear cytoplasmic -catenin implicated driving development progression several cancer types e.g. colon ovarian cancers 2931 however results show expression levels -catenin contribute melanoma initiation progression since difference -catenin levels found nevi primary melanoma metastatic melanoma 93%97% samples expressed -catenin 50% tumor cells the high expression levels -catenin line crucial role -catenin differentiation proliferation normal melanocytes metastatic melanoma cells also findings agreement previous reports positive -catenin staining nevi 100% primary melanoma 95% 94% higher reported metastatic melanoma 75% 68% 9 21 variation expression -catenin levels metastatic melanomas studies while studied melanoma metastases skin studies either obtained 58% specimens lymph nodes tonsil liver identify anatomical site metastases 9 21 furthermore different anatomical sites may regulate dissimilar antigen expressions metastases originate primary tumor patient 33 34 previous studies shown higher percentages nuclear -catenin nevi melanoma 84% versus 33% 44% versus 15% 9 22 those observations provided basis currently held concept loss nuclear cytoplasmic -catenin suggest poor prognosis decreased overall survival melanoma patients 12 22 light data absence nuclear -catenin nevi melanomas analyzed study surprising usage different anti--catenin antibodies may explain part discrepancy nuclear -catenin expression observed studies however results consistent lack nuclear -catenin reported four studies comprised 57 nevi 55 primary melanomas 20 metastatic melanomas 21 3537 moreover nuclear -catenin found either nevus portion melanoma portion 15 cutaneous lesions absent additional 42 primary melanomas another study 70 primary melanomas nuclear -catenin reported 6.4% melanomas finally study 230 primary metastatic melanomas nuclear -catenin reported 13 cases 5.6% therefore cases excluded analysis taken together absence negligible amount nuclear -catenin detected aforementioned studies well suggests possible extranuclear roles -catenin nevi melanoma this notion supported role cytoplasmic -catenin execute functions require nuclear translocation e.g. activation map kinase p38 nf kb 37 40 a major finding study association melanoma development intracellular redistribution -catenin the percentage cases expressed -catenin cell membrane increased dramatically 10% nevi 83% 93% primary metastatic melanomas respectively concurrently percentage cases expressed cytoplasmic -catenin decreased 90% nevi 45% 39% primary metastatic melanomas respectively figure 4 we hypothesize relocation -catenin cytoplasm cell membrane may serve deactivating mechanism canonical wnt/-catenin signaling resulting reduction cytoplasmic -catenin level may contribute malignant transformation melanocytic nevi the proposed hypothesis supported following observations study bachmann et al also reported association nevus melanoma development relocation -catenin cell membrane nevertheless authors study offer explanation observation ii analysis data kagashita et al showed -catenin decrease cytoplasm increase cell membrane changes -catenin distribution corresponded malignant transition nevi iii wnt4 signal identified mechanism drive -catenin relocation cytoplasm cell membrane iv -catenin relocation cytoplasm cell membrane reported block -catenin signaling human embryonic kidney hek293 cell line of note hypothesis explain despite abundant -catenin expression melanoma 1 7 cytoplasmic -catenin selectively decreased phenomenon associated unfavorable melanoma prognosis 9 21 22 our current efforts directed towards determining increases membranous -catenin observed primary metastatic melanomas result relocation existing molecules cytoplasm deposition newly generated -catenin membranous site rad6 implicated early breast cancer development since increase rad6 levels observed adenosis benign hyperplasias compared normal tissue in contrast findings support rad6 play similar role nevus formation benign breast neoplasia since 63% nevi negative rad6 rad6 also implicated breast cancer progression rad6 levels increase progression ductal carcinoma situ invasive primary carcinoma metastatic cancer 15 28 accordance upregulation rad6 early stages breast cancer development compared benign hyperplasia 15 17 observed striking increase rad6 expression primary melanoma compared nevi while primary melanomas displayed strong rad6 staining 50% tumor cells rad6 negative 63% nevi these findings suggest rad6 may play role malignant transformation nevi breast cancer progression melanoma primary metastatic disease significantly associated changes percentage tumors expressing rad6 rad expression intensity 50% tumor cells stained positively 100% 96% primary melanomas metastatic melanomas respectively these findings suggest rad6 may play sustained role melanoma metastasis melanoma development benign malignant breast tumors rad6 stabilizes -catenin turn -catenin positively upregulates rad6 transcription 1517 however direct positive correlation -catenin rad6 expression appear conserved melanoma expression profiles -catenin rad6 differed considerably nevi approximately 93% nevi expressed -catenin compared 27% nevi expressed rad6 50% cells figure 2 these observations suggest high -catenin expression nevi likely driven regulators rad6 first glance would appear -catenin rad6 expressions correlated primary melanoma proteins coexpressed approximately primary melanomas also findings correspond 80% correlation rad6 -catenin expressions primary breast cancer however unlikely high rad6 expression primary melanoma driven concurrent high -catenin expression rad6 expression low nevi despite presence high cytoplasmic -catenin expression comparable primary melanoma this notion confirmed lack statistical correlation rad6 -catenin expressions primary melanoma -catenin activator rad6 instance rad6 activated nerve growth factor nervous tissue therefore conceivable primary melanoma rad6 expression regulated yet unidentified activators we also demonstrated progression melanoma primary metastatic disease associated correlation -catenin rad6 expressions taken together study support direct positive interaction -catenin rad6 either benign malignant melanocytic tumors we characterized first time rad6 expression cutaneous benign malignant melanocytic tumors we showing striking upregulation rad6 negative expression benign melanocytic tumors 100% primary metastatic melanomas these findings strongly suggest role rad6 development primary melanoma metastatic disease we show contrast rad6 -catenin expressed 50% tumor cells almost nevi melanoma tumors taken together contrast rad6 -catenin positive relationship breast cancer 1517 study support similar positive interaction -catenin rad6 benign malignant melanocytic tumors finally findings suggest role cytoplasmic membrane translocation -catenin development primary melanoma future studies determine whether newly generated -catenin membranous site coincide -catenin translocation cytoplasm | we have previously demonstrated that rad6 and -catenin enhance each other 's expression through a positive feedback loop to promote breast cancer development / progression . while -catenin has been implicated in melanoma pathogenesis , rad6 function has not been investigated . here
, we examined the relationship between rad6 and -catenin in melanoma development and progression .
eighty - eight cutaneous tumors
, 30 nevi , 29 primary melanoma , and 29 metastatic melanomas , were immunostained with anti--catenin and anti - rad6 antibodies . strong expression of rad6 was observed in only 27% of nevi as compared to 100% of primary and 96% of metastatic melanomas .
-catenin was strongly expressed in 97% of primary and 93% of metastatic melanomas , and unlike rad6 , in 93% of nevi .
none of the tumors expressed nuclear -catenin .
-catenin was exclusively localized on the cell membrane of 55% of primary , 62% of metastatic melanomas , and only 10% of nevi .
cytoplasmic -catenin was detected in 90% of nevi , 17% of primary , and 8% of metastatic melanoma , whereas 28% of primary and 30% of metastatic melanomas exhibited -catenin at both locations .
these data suggest that melanoma development and progression are associated with rad6 upregulation and membranous redistribution of -catenin and that -catenin and rad6 play independent roles in melanoma development . |
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