Association of common variants of TCF7L2 and PCSK2 with gestational diabetes mellitus in West Bengal, India.

The genetic etiology of gestational diabetes mellitus (GDM) was suggested to overlap with type-2 diabetes(T2D). Transcription factor 7-like 2 (TCF7L2) and Proprotein Convertase Subtilisin/Kexin type 2 (PCSK2) are T2D susceptibility genes of the insulin synthesis/processing pathway. We analyzed associations of TCF7L2 and PCSK2 variants with GDM risk and evaluated their potential impact on impaired insulin processing in an eastern Indian population. The study included 114 GDM (case) and 228 non-GDM pregnant women (control). rs7903146, rs4132670, rs12255372 of TCF7L2, and rs2269023 of PCSK2 were genotyped by PCR-RFLP, and genotype distributions were compared between case and control. Fasting serum proinsulin and C-peptide levels were measured by ELISA and the Proinsulin/C-peptide ratio was considered an indicator of proinsulin conversion. Significantly higher frequency of risk allele (T) of rs12255372 (p = 0.02, OR = 2.0, 95%CI = 1.11-3.64) and rs4132670 (p = 0.002, OR = 2.26, 95%CI = 1.32-3.87) of TCF7L2 was found in GDM cases than non-GDM controls; TT genotype was associated with significantly increased disease risk. In rs7903146 (TCF7L2) and rs2269023 (PCSK2), although the frequency of risk allele (T) was not significantly higher in cases than controls, an association of TT for both variants remained significant with higher GDM risk in the recessive model. Increased serum pro-insulin and proinsulin:c-peptide ratio was found in GDM than non-GDM women and the phenomenon showed significant association with careers of risk alleles for TCF7L2 variants. In conclusion, TCF7L2 and PCSK2 variants are related to GDM risk in the studied population and hence may serve as potential biomarkers for assessing the disease risk. TCF7L2 variants contribute to impaired insulin processing.

Gestational Diabetes Mellitus in a Tertiary Care Hospital of Kolkata, India: Prevalence, Pathogenesis and Potential Disease Biomarkers.

AIMS: Prevalence of gestational diabetes mellitus (GDM) may vary across a country like India. Risk factors and disease-pathogenesis were also not fully elucidated. This study aimed to examine prevalence of GDM among pregnant women visiting antenatal clinic of a tertiary-care hospital of Kolkata, India; possible mechanism of disease pathogenesis and potency of associated parameters as disease biomarkers were also explored. METHODS: 735 pregnant women were screened for GDM according to DIPSI (Diabetes in Pregnancy Study Group India) guideline and risk-factors were analyzed. Case-control study was conducted with 114 GDM and 114 matched non-GDM control. Blood sample was collected before glucose load for complete blood count, measurement of reactive oxygen species (ROS) and assessment of DNA damage. RESULTS: Prevalence of GDM was found to be 17.2%(127/735). Maternal age, diabetic family history and acanthosis nigricans seemed to be important risk factors. Total ROS, lymphocyte DNA damage (measured by comet-assay) and some inflammatory hematological parameters were significantly higher in GDM compared to control. ROS, comet-tail DNA%, WBC, neutrophil-lymphocyte ratio (NLR) and mean platelet volume (MPV) were established as independent determinants of disease condition after adjustment for pre-gestational body mass index. In receiver operating characteristic analysis, ROS>155.7 arbitrary fluorescent unit, NLR>2.12 and MPV>11.05 fL showed 82.5 & 98.2%, 71.9 & 84.2% and 71.9 & 82.5% sensitivity & specificity respectively in disease prediction. CONCLUSIONS: Prevalence of GDM seemed to be high in Kolkata on Indian scenario. Oxidative-stress, related DNA-damage and inflammation seemed to have important contribution in pathogenesis of GDM independent of obesity. ROS, NLR and MPV with respective cut-off scores might be used as diagnostic and prognostic biomarkers for better management of the disease.

Urological disorders and pregnancy: An overall experience.

AIM: Pregnancy is an anatomical and physiological altered state and the presence of various urological problems not only aggravates the disease itself, but also results in unfavourable pregnancy outcome. Aim is to highlight obstetric outcome in pregnant women with urological problems. MATERIALS AND METHODS: Longitudinal prospective cohort study conducted in tertiary care hospital, IPGME and R, Kolkata from Jan 2011 to Dec 2012. All pregnant women with urological problems were included as subjects. RESULTS: A total of 33 subjects were followed up throughout their antenatal period. Among them majority (72.72%) presented with hydro nephrosis followed by hydroureter (60.6%), PUJ obstruction and pyelonephritis each with incidence of 15.15%, then urolithiasis (12.12%), nephrolithiasis (6.06%) and renal abscess (12.12%). Interventions required were DJ stenting (72.72%), pyeloplasty (15.15%) and others were RURSL, abscess drainage and ATT. The pregnancy outcome was complicated with preterm labor in majority of patients (45.45%), oligohydramnious (18.18%), PIH (9.09%) and still birth (6.06%). Twenty four live birth were there. Majority required NICU admissions as predominantly prematurity was an important concern. Majority women with hydronephrosis underwent DJ stenting. CONCLUSION: Preterm labor is an important obstetric concern. Vaginal delivery is the choicest mode of termination and LSCS can be reserved for obstetric reason. DJ stenting is safe and practical approach for continuation of pregnancy with hydronephrosis. Regular follow up, vigilant antenatal care and multidisciplinary approach from urologist, obstetrician and neonatologist will bring out successful pregnancy outcome.

Menstrual and Gonadal Function Alterations in Women with Systemic Lupus Erythematosus.

PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune disorder and may affect the reproductive health status of the women. Objective is to analyze the types, incidence of various menstrual disturbances in these women, to identify risk factors and to assess the gonadal function. METHODS: The prospective cohort study was conducted in the SLE clinic of the Rheumatology Department of IPGMEandR, Kolkata from April 2010 to April 2011. Out of 152 females attending clinic, 110 patients fulfilling criteria were included in the study. RESULTS: Mean age of the study population was 27.25±3.4 years. Sixty six cases had menstrual abnormalities (12.72% amenorrhea, 44.45% oligomenorrhea, 2.7% premature ovarian failure, 10.9% menorrhogia). When comparative analysis of demographic, hormonal, ovarian Doppler and therapeutic variables of normal and abnormal cycles was carried out, following parameters were significantly more related to patients with abnormal cycle ; SLEDAI score (12.48±5.53 vs 8.69±4.9; p=0.00), disease duration (6.46±3.08 vs 4.3±1.36; p< 0.05), TSH (7.73±8.64 vs 3.07±2.06; p=0.00.), LH (6.55±4.38 vs 4.56±3.29; p=0.02), a high normal prolactin (12.57±7.75 vs 8.73±3.07; p=0.02), peak systolic velocity (6.53±2.17 vs 9.12±2.1; p=0.00), end-diastolic volume (4.21±2.9 vs 9.35±2.32; p=0.00) and cumulative dose of steroid (24.02±41.44 vs 9.32±9.96; p=0.01).Cyclophosphamide with cumulative dose ≥10 gm was related to amenorrhea and affected gonadal function. Gonadal insufficiency was evident in 33.63% and 2.72% had ovarian failure. CONCLUSIONS: Reduced menstruation is a major health concern in women with SLE as it is frequent and can result in depressed and failed gonadal function later. Doppler study of ovaries is a novel way of depiction of gonadal status in these women. Certain risk factors and revolving treatment part can be preventable.

Symptomatic sick sinus syndrome requiring permanent pacemaker implantation in a patient uwith mirror image dextrocardia with situs inversus and infertility.

Situs inversus with dextrocardia is a congenital condition in which the heart is a mirror image of the anatomically normal heart on the right side. A patient presented with the sick sinus syndrome accompanying mirror image dextrocardia which was associated with double superior vena cava and a left sided inferior vena cava A permanent transvenous demand pacemaker was inserted because of repeated episodes of dizziness and a single episode of syncope with ECG showing bradycardia with junctional escape rhythm. Precise knowledge of the venous system and the location of the apex of the right ventricle were necessary prior to permanent pacemaker implantation. Without such knowledge pacing may be technically challenging.

Obstetric patients requiring high-dependency unit admission in a tertiary referral centre.

AIM: To analyze the HDU requirement in an obstetric population in terms of utilization rate, indications for admission, interventions required and gestational outcome. SETTING AND DESIGN: A retrospective observational study was carried out from May 2007 to May 2011 in the Dept. of Obstetrics and Gynecology and HDU of IPGME and R, Kolkata. MATERIALS AND METHODS: Data related to obstetric history, pre-existing medical problems, indications for HDU admission, interventions required, length of stay and outcome were collected and results were analyzed. RESULTS: Our obstetric HDU utilization rate was 11.2 per 1000 deliveries. Out of total 57 subjects 48 had no prior antenatal care. Majority (68.42%) admitted in HDU with only obstetric reasons, while 31.57% required HDU for pre-existing medical diseases. The major obstetric indications were septicemia (35.08%), PPH (29.08%) and hypertension was observed in 21.05% of women. Other less common causes included post surgical acute kidney injury, APH, chrioamnionitis and pyelonephritis. Half of the women with pre-existing medical disease had cardiovascular problems. Patients with medical diseases had more pre-term labor (10 vs 5; P ≤ 0.05), respiratory failure (9 vs 2; P ≤ 0.05), cardiac failure (7 vs 1; P ≤ 0.05), duration of stay more than 10 days (15 vs 6; P ≤ 0.05), fetal growth restriction (6vs 3; P ≤ 0.05) and prolonged recovery time. Maternal mortality was 12.28% and fetal mortality was 17.54%. CONCLUSION: Early screening of high risk mothers, vigilant antenatal care and proper maintenance of asepsis during delivery and postpartum period can reduce HDU utilization rate and can result in healthier outcome.

Peripartum cardiomyopathy coexistent with human immunodeficiency virus: a substantial obstetric jeopardy.

Peripartum cardiomyopathy (PPCM) is a rare cause of pregnancy-related heart failure, which affects a woman during the last months of pregnancy or first months of parturition. Its etiopathogenesis is still unclear. Coexistence of PPCM with human immunodeficiency virus (HIV) has been scarcely analyzed. A low CD4 count is proposed to be one of the predictors of dilated cardiomyopathy in HIV. Here, a pregnant woman with HIV presented with signs of congestive heart failure for the first time during her last trimester. Echocardiography revealed a dilated cardiomyopathy with ejection fraction of 34% which proved the diagnosis of PPCM. She underwent cesarean section for impending previous scar rupture. Her status deteriorated subsequently in spite of all efforts and she succumbed due to ventricular tachycardia. This case necessitates an awareness regarding coexistence of HIV with PPCM and dreaded clinical sequences. Patients suffering from HIV should be treated well and their CD4 count should be improved before conception to avoid such complications in pregnancy.

Is pregnancy safe with extrahepatic portal vein obstruction? An analysis.

INTRODUCTION: We aimed to analyse the pregnancy outcome of women with extrahepatic portal vein obstruction. METHODS: This was a retrospective observational analysis conducted at the Institute of Postgraduate Medical Education and Research, Kolkata, India, between January 2007 and September 2009. A total of 41 pregnancies in 24 women were evaluated. RESULTS: All women conceived spontaneously (maternal age 20-35 years). 17 women had moderate-to-severe anaemia, and five women had pancytopenia. Variceal bleeding occurred in ten women during pregnancy, which was managed successfully with endoscopic sclerotherapy in eight women and endoscopic variceal ligation in two women. Preterm labour (14.63%), postpartum haemorrhage (7.31%), abortion (4.87%) and pregnancy-induced hypertension (4.87%) were observed in the 41 pregnancies. There were 39 live births and almost all mothers delivered vaginally, except for four who underwent Caesarean section for obstetric indications. Prematurity (15.38%), low birth weight (10.25%), admission to the neonatal intensive care unit (12.82%), stillbirth (2.56%) and neonatal death (2.56%) were noted in the newborns. CONCLUSION: Variceal bleeding during pregnancy coincided with unfavourable outcomes. Although endoscopic obliteration of varices is a safe and effective method for antenatal management of varices in women, prenatal obliteration results in less morbidity. On rare occasions, obliterated varices can bleed in subsequent pregnancies. Therefore, preconception evaluation of the state of varices prior to each pregnancy and their ligation are important aspects of counselling. A successful foetomaternal outcome is achievable with multidisciplinary backup in a tertiary care centre.

Takayasu arteritis in pregnancy: an analysis from eastern India.

OBJECTIVE: Takayasu's Arteritis (TA) is a rare inflammatory disease of medium and large size arteries that affects women of reproductive age. This study aims to highlight the antenatal management and analyze the obstetric outcome in women with TA. METHODS: This retrospective study was carried out in the Department of O&G, Cardiology and Rheumatology--IPGME&R, Kolkata from June 2002 to July 2010. Sixteen patients with 29 pregnancy events were compared with 60 matched controls. RESULTS: Clinical presentation of study population at admission included unequal or absent pulse, hypertension, congestive cardiac failure, retinopathy, aortic regurgitation and cerebrovascular accident (CVA). Mode of delivery was cesarean in 20 pregnancies (71.49%) and vaginal in nine pregnancies (31.03%). Significant maternal complications included pregnancy induced hypertension (100 vs. 1.66%; P < 0.001), preeclampsia (92.85 vs. 0%; P < 0.001), postpartum hemorrhage (17.24 vs. 1.66%; P < 0.001) and preterm labor (17.24 vs. 3.33%; P < 0.001). One maternal mortality was present due to CVA. Neonatal outcome showed 26 live births with increased incidence of intrauterine growth restriction (51.72 vs. 1.66%; P < 0.001) and neonates requiring NICU admissions (58.62 vs. 5.0%; P < 0.001). CONCLUSION: Although conception was spontaneous in all these pregnancies, antenatal and intrapartum control of blood pressure played a pivotal role in pregnancy outcome. High rate of operative interference was present. All subsequent pregnancies had similar outcome due to slow progression of the disease. Although pregnancy was complicated by hypertension and its sequelae, successful outcome could be achieved with timely admission, judicious medication and multidisciplinary approach.

Maternal obesity and pregnancy outcome: a prospective analysis.

OBJECTIVE: To analyze whether the obese women have an increased risk of pregnancy complications and adverse fetal outcome. METHODS: The longitudinal prospective study was carried out in the Obst and Gynae department, IPGME and R, Kolkata. The study enrolled 422 pre-pregnant obese women with pregnancy as study population and equal number of non obese pregnant mothers as controls. Body mass index (BMI) was > or = 30.0 kg/m2 and 20-22 kg/m2 in obese and control group respectively. RESULTS: In comparison to average weight pregnant women, obese pregnant women were at increased risk of gestational diabetes mellitus (19.43 vs 3.79%; p < 0.001), pregnancy induced hypertension (12.32 vs 2.36%; p < 0.001), pre-eclampsia (8.76 vs 3.31%; p < 0.001), preterm labor in less than 34 week gestation (7.58 vs 3.55%; p < 0.001), cesarean section (36.72 vs 17.53%; p < 0.001), instrumental deliveries (12.32 vs 5.21%; p < 0.001) and postpartum infection morbidities (9.95 vs 3.79%; p < 0.001). These women were more prone to develop overt diabetes (2.36% vs 0) and chronic hypertension (5.21 vs .47% ) in future as well. Neonates of obese women were mostly large for gestational age, macrosomic and they had high incidences of birth injuries, shoulder dystocia, premature deliveries, late fetal deaths and congenital malformations particularly spina bifida, cleft lip, cleft palate and heart defect. CONCLUSION: As obesity is considered to be a modifiable risk factor, preconception counseling and creating awareness regarding health risks associated with over weight and obesity should be encouraged.

Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome.

BACKGROUND & AIMS: The intestinal microbiomes of healthy children and pediatric patients with irritable bowel syndrome (IBS) are not well defined. Studies in adults have indicated that the gastrointestinal microbiota could be involved in IBS. METHODS: We analyzed 71 samples from 22 children with IBS (pediatric Rome III criteria) and 22 healthy children, ages 7-12 years, by 16S ribosomal RNA gene sequencing, with an average of 54,287 reads/stool sample (average 454 read length = 503 bases). Data were analyzed using phylogenetic-based clustering (Unifrac), or an operational taxonomic unit (OTU) approach using a supervised machine learning tool (randomForest). Most samples were also hybridized to a microarray that can detect 8741 bacterial taxa (16S rRNA PhyloChip). RESULTS: Microbiomes associated with pediatric IBS were characterized by a significantly greater percentage of the class γ-proteobacteria (0.07% vs 0.89% of total bacteria, respectively; P < .05); 1 prominent component of this group was Haemophilus parainfluenzae. Differences highlighted by 454 sequencing were confirmed by high-resolution PhyloChip analysis. Using supervised learning techniques, we were able to classify different subtypes of IBS with a success rate of 98.5%, using limited sets of discriminant bacterial species. A novel Ruminococcus-like microbe was associated with IBS, indicating the potential utility of microbe discovery for gastrointestinal disorders. A greater frequency of pain correlated with an increased abundance of several bacterial taxa from the genus Alistipes. CONCLUSIONS: Using 16S metagenomics by PhyloChip DNA hybridization and deep 454 pyrosequencing, we associated specific microbiome signatures with pediatric IBS. These findings indicate the important association between gastrointestinal microbes and IBS in children; these approaches might be used in diagnosis of functional bowel disorders in pediatric patients.

Pregnancy and subsequent pregnancy outcomes in peripartum cardiomyopathy.

AIM: To study the clinical profile and management of peripartum cardiomyopathy, and to analyze the pregnancy outcomes of pregnant women with this disorder as well as its effect on subsequent pregnancies. METHODS: All patients admitted with peripartum cardiomyopathy from July 2006 to June 2009 by the Departments of Cardiology and Obstetrics and Gynecology from the Institute of Post Graduate Medical Education and Research, Kolkata, India, were considered for this observational study. Thirty-six women with 42 pregnancies (36 first pregnancies and six second pregnancies in the same patients) were evaluated. RESULTS: Primiparas constituted 39% (14/36) of the total study population. Twenty-six women (72%) were clinically improved and in 17 (48%) the left ventricular functional status returned to normal. Five cases (14%) developed persistent cardiomyopathy (persistent left ventricular dysfunction beyond six months of presentation), and five women (14%) presented with thromboembolic events and anticoagulation was used as secondary prophylaxis. Maternal mortality was 14% (5/36). Among all live babies two had intrauterine growth restriction (IUGR) and another two died during the neonatal period. Of the six women with subsequent pregnancies, the patient with persistent cardiomyopathy died after delivering a stillborn baby. The remaining five cases with normal left ventricular functional status had favorable fetal outcomes; however, the mothers experienced morbidities such as symptoms of heart failure (two cases) and one of them progressed to persistent cardiomyopathy. CONCLUSIONS: Subsequent pregnancies should be discouraged as it increases the risk of recurrence of left ventricular dysfunction. Anticoagulation may be considered as a primary prevention of thromboembolism in pregnant mothers with peripartum cardiomyopathy.

RETRACTED: REDOX regulation of IL-13 signaling in intestinal epithelial cells: usage of alternate pathways mediates distinct gene expression patterns.

In the classic view interleukin-13 (IL-13) binds to a heterodimer protein complex of the IL-13Ralpha1 and IL-4Ralpha chains and signals through a Janus kinase 1 (JAK1)-signal transducer and activator of transcription 6 (STAT6) mechanism. We recently reported that IL-13 also signals through the IL-13Ralpha2 chain initiating all three mitogen activated protein kinase (MAPK) pathways, and the relative expression of IL-13Ralpha1 and IL-13Ralpha2 modulates one another's transduction pathway. Therefore we investigated whether generation of reactive oxygen species (ROS) as second messengers may serve as a common nexus between these two pathways emanating from the individual IL-13 receptor chains in intestinal epithelial cells (IEC). IL-13 stimulates intracellular ROS synthesis within 5min via IL-13Ralpha1-JAK1-STAT6- and IL-13Ralpha2-MEK1/2-ERK1/2-dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 (NOX-1). IL-13-induced ROS generation in turn positively regulates phosphorylation of ERK1/2 and STAT6, yielding a feed forward amplification loop. IL-13 also stimulates the stable, long-term gene expression of two other NADPH oxidases, NOX-4 and DUOX-2, which along with constitutive NOX-1, might facilitate elevated, continuous production of ROS in IL-13-activated IEC. The contribution of each signal transduction pathway initiated by IL-13 engagement to such biological functions as wound healing, inflammation, and apoptosis was mapped for representative, responsive genes. Distinct usage patterns were observed, demonstrating not only that IL-13 signal transduction through STAT6, MAPK, and ROS is regulated in both an antagonistic and cyclic fashion, but also that each pathway plays a specific role in modulating the wound healing and anti-apoptotic capabilities of the intestinal epithelium.

Elevated IL-13Ralpha2 in intestinal epithelial cells from ulcerative colitis or colorectal cancer initiates MAPK pathway.

BACKGROUND: Chronic inflammation in ulcerative colitis (UC) is a sizeable risk factor for colorectal cancer (CRC). Interleukin-13 (IL-13) is elevated in the UC mucosa and may induce dysregulated signaling in neighboring intestinal epithelial cells (IECs) and thus function as a tumorogenic cytokine. METHODS: Expression of IL-13 receptor chains on IECs obtained from control or chronically inflamed mucosa and colonic tumors was quantified by flow cytometry and immunoblot. IL-13Ralpha1 and IL-13Ralpha2 expression was significantly increased on IEC from UC and CRC patients compared to control and Crohn's disease (CD) subjects. Purified IEC from these subjects and cell lines expressing varying ratios of IL-13Ralpha1 and IL-13Ralpha2 chains were stimulated with IL-13 in vitro to investigate by immunoblot the activation of the signal transducer and activator of transcription 6 (STAT6) and mitogen activated protein kinase (MAPK) signaling pathways. RESULTS: Despite similarly elevated receptor expression in UC and CRC, IL-13 does not activate the STAT6 or MAPK pathways in UC, while in colonic tumors only the STAT6 pathway is activated. Using neutralizing antibodies and cell lines expressing a range of surface densities for IL-13Ralpha1 and IL-3Ralpha2, we demonstrate that IL-13Ralpha2 serves a dual role, initiating MAPK signaling at low concentrations and as an inhibitory, decoy receptor at high IL-13Ralpha2 to IL-13Ralpha1 ratios. CONCLUSIONS: IL-13Ralpha2 is both a decoy receptor and induces MAPK signal transduction, depending on its relative expression and the local concentration of IL-13, which together modulate the balance and intensity of the signaling pathways initiated in UC and CRC.

Successful pregnancy outcome among women with end-stage renal disease requiring haemodialysis.

Pregnancy is rare in women with end-stage renal disease, and perinatal outcome remains suboptimal because of prematurity and foetal growth restriction. Successful obstetrical outcome in two women presented with chronic renal failure requiring serial haemodialysis and multiple blood transfusions during pregnancy is reported. Both women had vaginal delivery of low birth weight neonates--2100 g and 1540 g at 33 and 37 weeks' gestations respectively. With specialised neonatal care, both neonates survived, and the mothers were counselled for renal replacement therapy.