The benefits of hemicraniectomy for malignant middle cerebral artery (MCA) stroke may not be apparent in the 3- to 6-months in which final outcomes are assessed in research studies. We present the case of a 15-year-old who underwent hemicraniectomy for malignant MCA stroke and was significantly disabled 3 and 6 months after event. Over the long-term she was able to graduate from university, play tennis, and live an independent life. Although functional independence with only minor disability is relatively rare in adult hemicraniectomy patients, this outcome may be more easily achieved in children during a longer period of follow-up.

Coumarinic oral-anticoagulants (COAs) are commonly used for treatment of thromboembolic events. However, these medications have a narrow therapeutic range and there are large inter-individual variations in drug response. This is especially important in the initial phases of oral-anticoagulant therapy. Recent advancements in pharmacogenetics have established that clinical outcomes in oral-anticoagulant therapy are affected by genetic factors. The allelic variants of genes like cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are closely associated with maintenance dose of oral anti-coagulants. In addition, GGCX (Gamma-glutamyl carboxylase) polymorphism at position 12970 (rs11676382), CYP4F2 (rs2108622; V433M; 1347 C > T) and Apolipoprotein E (APOE) variants have been shown to explain a small but significant influence on dose requirements. There are large differences in the frequencies of these polymorphisms between different world populations which are also related to the requirements of oral anticoagulants. However, the final drug dosage in an individual is determined by complex sets of genetic and environmental factors and several dosing algorithms which combine clinical and genetic parameters to predict therapeutic COA doses have also been developed. The algorithm based dose prediction shows the importance of pharmacogenetic testing in patients undergoing oral anticoagulant therapies.

Aorto-esophageal fistula (AEF) is a rare and life threatening condition, which can be rapidly fatal. More than half of such cases are secondary to aortic aneurysm rupture. There are only two previous reports describing AEF caused by penetrating atherosclerotic ulcer. We present multidetector computed tomography findings in a case of AEF secondary to penetrating atherosclerotic ulcer.

Objectives

To develop a population specific pharmacogenetic acenocoumarol dosing algorithm for north Indian patients and show its efficiency in dosage prediction.

Methods

Multiple and linear stepwise regression analyses were used to include age, sex, height, weight, body surface area, smoking status, VKORC1 -1639 G>A, CYP4F2 1347 G>A, CYP2C9*2,*3 and GGCX 12970 C>G polymorphisms as variables to generate dosing algorithms. The new dosing models were compared with already reported algorithms and also with the clinical data for various performance measures. Odds ratios for association of genotypes with drug sensitive and resistant groups were calculated.

Results

The pharmacogenetic dosing algorithm generated by multiple regression analysis explains 41.4% (p-value <0.001) of dosage variation. Validation of the new algorithm showed its predictive ability to be better than the already established algorithms based on similar variables. Its validity in our population is reflected by increased sensitivity, specificity, accuracy and decreased rates of over- and under- estimation in comparison to clinical data. The VKORC1-1639 G>A polymorphism was found to be strongly associated with acenocoumarol sensitivity according to recessive model.

Conclusions

We have proposed an efficient north India specific pharmacogenetic acenocoumarol dosing algorithm which might become a baseline for personalised medicine approach for treatment of patients in future.

Background

Doppler ultrasound is the accepted gold standard for assessing direction of flow in the portal vein (PV). Moreover, it is non-invasive; therefore, it is well accepted by the patients and does not interfere with flow hemodynamics.

Objectives

The present study was aimed to evaluate the association between color Doppler findings and the severity of portal hypertension in patients with cirrhosis.

Patients and Methods

The study group included 50 patients referred for ultrasound (US) evaluation over a period of six months from March to August, 2007. The patients were divided into three groups (Child’ A, B and C) based on Child Pugh classification. The direction of flow in the main portal vein (hepatopetal or nonhepatopetal) and peak venous velocity (PVV) in the main portal vein were measured and correlated with the presence or absence of ascites, splenomegaly, splenic and esophageal varices (assessed by Doppler US). These findings were correlated with clinical features and laboratory findings (using Child Pugh’s criteria).

Results

There was significant association between the decrease of peak portal venous velocity (PVV) and the increase in Child Pugh score. Hepatofugal flow was seen only in patients with more advanced disease. There was also significant association between PVV and splenic varices and ascites, while PVV was not affected by the presence or absence of esophageal varices or splenomegaly. Presence of a recanalized umbilical vein (UV) was associated with increased PVV even in advanced disease.

Conclusions

Color Doppler is an excellent modality for detecting and characterizing the complex hemodynamics of portal hypertension in cirrhosis and they correlate with the clinical stage of disease.

Rationale

Mutations in MYBPC3 encoding cardiac myosin binding protein C are common genetic cause of hereditary cardiac myopathies. An intronic 25-bp deletion in MYBPC3 at 3′ region is associated with dilated (DCM) and hypertrophic (HCM) cardiomyopathies in Southeast Asia. However, the frequency of MYBPC3 25 bp deletion and associated clinical presentation has not been established in an unrelated cohort of left ventricular dysfunction (LVD) secondary to coronary artery disease (CAD) patients.

Objective

We sought to determine the role of MYBPC3 25 bp polymorphism on LVD in two cohorts of CAD patients.

Methods and Results

The study included 265 consecutive patients with angiographically confirmed CAD and 220 controls. MYBPC3 25 bp polymorphism was determined by polymerase chain reaction. Our results showed that carrier status of MYBPC3 25 bp deletion was associated with significant compromised left ventricle ejection fraction (LVEF ≤45) in CAD patients (p value  =  <0.001; OR = 4.49). To validate our results, we performed a replication study in additional 140 cases with similar clinical characteristics and results again confirmed consistent findings (p = 0.029; OR = 3.3). Also, presence of the gene deletion did not have significant association in CAD patients with preserved ejection fraction (LVEF>45) (p value  = 0.1; OR  = 2.3).

Conclusion

The frequency of MYBPC3 DW genotype and D allele was associated with compromised LVEF implying that genetic variants of MYBPC3 encoding mutant structural sarcomere protein could increase susceptibility to left ventricular dysfunction. Therefore, 25 bp deletion in MYBPC3 may represent a genetic marker for cardiac failure in CAD patients from Southeast Asia.

A 40-year-old lady presented with severe endothelial cell loss in both eyes 14 years after angle-supported phakic intraocular lens (AS PIOL) implantation. The left eye had severe corneal edema with bullous keratopathy. The right eye had markedly reduced endothelial cell count (655 cells/mm2) although the cornea was clear. She underwent simultaneous bilensectomy (AS PIOL explantation and phacoemulsification) and Descemet's stripping and endothelial keratoplasty (DSEK) in the left eye. Explanted AS PIOL was identified as ZSAL-4 (Morcher, Stuttgart, Germany) model. Corneal edema cleared completely in 2 months with a best corrected visual acuity (-2.25 D sph) of 20/60. No intervention was done in the right eye. The present case illustrates that AS PIOL-induced endothelial decompensation can be effectively managed by simultaneous bilensectomy and endothelial keratoplasty.

Cysticercosis is endemic in India. Neurocysticercosis most commonly affects the brain parenchyma, which presents as focal lesions with the surrounding edema which later calcify. Rarely, it may affect the ventricular system and subarachnoid spaces and this form is known as racemose cysticercosis. We present magnetic resonance findings in a case of racemose cysticercosis.

BACKGROUND:

The dose requirements for oral anticoagulants in thromboembolic events are influenced by promoter polymorphism in the VKORC1 gene. However, limited data are available on the influence of the polymorphism in various Indian populations. The present study aimed at determining the relationship between the VKORC1-1639 G>A genotypes and maintenance doses of oral anticoagulants for therapeutically stable INR values in patients taking Acitrom after valve replacement surgery.

MATERIALS AND METHODS:

Fifty patients from the northern Indian region were genotyped for VKORC1-1639 G>A by polymerase chain reaction and restriction fragment length polymorphism. Means of the weight-normalized daily Acitrom dose were calculated for every patient.

RESULTS AND DISCUSSION:

The VKORC1 1639G>A minor allele frequency in the study population (n = 50) was found to be 22%. The patients with a wild type genotype required the maximum drug dose as suggested for full functionality of the enzyme. Heterozygous patients were found to have an intermediate drug dose and the patients with a variant homozygous genotype had the minimum maintenance drug dose requirement. These findings are in concurrence with the effect of the promoter polymorphism on vitamin K epoxide reductase activity.1639G>A minor allele frequency in the study population (n = 50) was found to be 22%. The patients with a wild type genotype required the maximum drug dose as suggested for full functionality of the enzyme. Heterozygous patients were found to have an intermediate drug dose and the patients with a variant homozygous genotype had the minimum maintenance drug dose requirement. These findings are in concurrence with the effect of the promoter polymorphism on vitamin K epoxide reductase activity.

CONCLUSION:

The VKORC1-1639 G>A status can be indicative of establishing the therapeutic dose of oral anticoagulants in Indian patients.

Introduction

Prostate cancer is common around the world, but rates of advanced disease differ substantially by race and geography. Although a major health issue, little is known about prostate cancer presentation in West Africa and India compared to the United States (US).

Objective

The aim of this study was to compare prostate tumor characteristics in four populations of men from the US, Senegal and India.

Materials and methods

We recruited prostate cancer patients from four hospital-based populations. The sample included 338 African-Americans, 1265 European-Americans, 222 Asian Indians, and 72 Senegalese. Questionnaire and medical record data were collected on each participant.

Results

We found significant differences in age at diagnosis, BMl, and PSA levels across the groups. Senegalese and Indian men had a higher probability of high stage (T3/T4) disease compared to US men. Gleason grade was significantly higher in Asian Indians compared to other populations. African-Americans, Senegalese, and Asian Indians had a significantly higher probability of metastatic disease compared to European Americans. The odds ratios (OR) for metastasis were consistently higher in Asian Indians compared to American cases. As only 19/72 Senegalese were assessed for metastasis, OR could not be determined for metastasis.

Conclusions

These results suggest that there are significant geographical and ethnic differences in the presentation of prostate cancer. Men in developing countries lend to present with advanced disease compared to US men. Identifying risk factors for advanced disease may help to decrease the rate of poor prostate cancer outcomes and associated mortality worldwide.

Combined clinical presentation of hemifacial spasm and ipsilateral trigeminal neuralgia is also known as painful tic convulsif (PTC). It is a rare condition and the most common cause is vascular compression. Vertebrobasilar dolichoectasia (VBD) is characterized by dilated and tortuous vertebral and basilar arteries. VBD is an uncommon and rarely reported cause of PTC. Magnetic resonance imaging (MRI), due to its inherent excellent contrast resolution, is an excellent modality for demonstrating the nerve compression by dilated and tortuous vessels seen in this condition. For this purpose, 3D MRI sequences are especially useful like constructive interference in steady state (CISS) and MR angiography. Both of these have been reported to be helpful in the diagnosis of this condition. We report a case of PTC in which we were able to document facial and trigeminal nerve compression by VBD on MRI, using CISS and time-of-flight MR angiography.

A 44-year-old man presented 28 days after cataract surgery (phacoemulsification) in right eye with multiple pinpoint infiltrates in posterior stroma at cataract surgery wound site. Visual acuity was 20/60. Corneal scraping from the floor of the corneal tunnel revealed fungus which was later identified to be Aspergillus flavus. The patient was started on oral voriconazole 200 mg twice daily and topical voriconazole 1% every hour. Two intracameral injections of voriconazole (50 micrograms/ 0.1 ml) were given 72 h apart, five days after starting initial therapy. Infiltrates increased in size and density in spite of 20 days of voriconazole therapy. Full-thickness patch graft was done to arrest progressive necrosis. Four months after surgery, patient had 20/60 best-corrected visual acuity. There was no recurrence in one-year follow-up. Present case illustrates the therapeutic challenge in fungal tunnel infections and possibility of voriconazole-resistant Aspergillus species.

Tobacco consumption is the leading preventable cause of disease, disability, and premature death but little is known about its deleterious effect on the ocular health of workers handling tobacco. The goal of this study was to identify probable effects of occupational tobacco exposure among south Indian bidi- industry workers. This study included 310 females (mean age, 34.8 ± 10.9 years) actively involved in bidi-rolling presenting with eye symptoms to a tertiary eye care hospital. Results suggested that a wide spectrum of ocular complications exist among these workers. Common ocular symptoms were defective vision, dull- aching headache and eye irritation. The main ocular findings were papillary conjunctival hyperplasia, hyperpigmentation of ocular surface, punctate epithelial erosion or superficial punctate keratitis, cataract or pseudophakia and segmental optic atrophy. Abstaining from work, supplementation of Vitamin B complex rich in B 12 and appropriate surgical or medical management reversed visual loss due to corneal disease or cataract but was not effective in optic neuropathy.

The main adverse consequences of excess bodyweight are cardiovascular disease, type II diabetes, and several cancers, IL-1Ra serum concentration has been reported earlier to increase in human obesity and it is therefore assumed that the polymorphism of IL-1Ra may influence cytokine production. We designed this study to investigate whether the IL-1Ra polymorphism was associated with obesity. A total number of 103 individuals; 19 lean (BMI<25 Kg/m2), 51 overweight (BMI 25–29.9 Kg/m2) and 33 obese (BMI≥30.0 Kg/m2) were enrolled in this study. Genotyping was performed using a polymerase chain reaction PCR amplification of the intron-2 fragment harboring a variable number of tandem repeat (VNTR) nucleotide sequences 86 pb of tandem repeat. The PCR products were separated on 2% agarose gel. Statistical analysis was performed using SPSS software (version 11.5). We found no significant difference in genotype and allele frequencies between the three groups; lean vs. overweight and lean vs. obese (p=0.323; 0.202; 0.123 and 0.068 resp). However, an increased risk for obesity had a propensity to be higher in those having genotype II/II. This genotype has been reported to be a ‘high producer’ of IL-1Ra. Although no statistically significant relationship between IL-1Ra polymorphism and BMI was observed, however, a trend towards an increase of allele*II in overweight and obese group was observed. This may suggest that IL-1Ra appears to be induced by inflammatory stimuli as well as obesity-associated factors. This is relatively a pilot study: but nevertheless, may assist in identifying the pathophysiological cause for obesity.

Microsatellite instability (MSI) characterized by alterations at simple repetitive genomic sequences is a distinct mechanism in tumorogenesis. Central nervous system (CNS) tumors have been reported to exhibit MSI, indicator of defective mismatch repair system with controversies. The present study was undertaken to examine sixteen primary brain and two spinal tumors for MSI at six mono: BAT-26, BAT-40, BAX, TGFßRII, IGFIIR and hMSH3 and four dinucleotide loci: D2S123, D9S1851, D9S283 and D18S58. Polymerase chain reaction (PCR) was done to amplify tumour and blood DNA, analyzed on 8% denaturing Polyacrylamide gel followed by autoradiography. Out of 18 CNS tumors examined, 39% exhibited MSI at BAT-26, BAT-40, D9S1851, D9S283 and D18S58 in tumoral DNA. However, no alteration was observed at BAX, TGFßRII, IGFIIR, hMSH3 and D2S123 loci. Low incidence of MS1-high hypothesizes role of MSI in evolution of CNS tumors but not in cancer initiation or progression.

Background

Carcinoma of urinary bladder is one of the leading causes of death in India. Successful treatment of bladder cancer depends on the early detection & specific diagnostic approaches. In the present study, microsatellite instability (MSI) has been evaluated as a prognostic marker in patients with superficial urinary bladder cancer in lower urinary tract for determining risk of recurrence.

Methods

A total of 44 patients with bladder tumors diagnosed with Transitional Cell Carcinomas [TCC] from lower urinary tract were selected for the study. Tumors were staged and graded according to AJCC-UICC (1997) classification and patients were followed with cystoscopy as per the protocol. Polymerase chain reaction (PCR) was done to amplify microsatellite sequences at mononucleotide BAT – 26, BAT – 40, TGFβ RII, IGFIIR, hMSH3, BAX and dinucleotide D2S123, D9S283, D9S1851 and D18S58 loci in blood (control) and tumor DNA. PCR products were separated on 8% denaturing polyacrylamide gel and visualized by autoradiography.

Results

MSI was observed in 72.7% of tumors at BAT – 26, BAT – 40, D2S123, D9S283, D9S1851 and D18S58 loci. Good association of MSI was seen with tumor stage and grade. MSI – High (instability at > 30% of loci) was frequently observed in high stage (40.6%) and high grade (59.4%) tumors. Of 24 tumors of Ta-T1 stage with different grades, 11 (9/18 high grade and 2/6 low grade tumors) recurred in the mean duration of 36 months. MSI positivity was significantly high in patients who had one or more recurrences (p = 0.02 for high grade and 0.04 for low grade tumors).

Conclusions

MSI may be an independent prognostic marker for assessing risk of recurrence in superficial tumors irrespective of the grade. Further studies on progression would help in stratifying the patients of T1G3 for early cystectomy vs bladder preservation protocol.

The present study was undertaken to investigate the relation of retinol with lipid profile of patients with cancers of breast, stomach, oesophagus, colon, gallbladder, pancreas, lung and cervix. Serum retinol was assayed in 120 patients and 40 healthy normal control by reverse phase HPLC using CLC-ODS C-18 columns and retinyl acetate as an internal standard.

Significant decease in serum cholesterol and LDL was observed in patients with cancers of esophagus, colon, stomach, pancreas and gallbladder respectively.

Retinol was reduced in all forms of cancers but pronounced decrease was observed in oesophagus, gallbladder, pancreas, stomach and colon. Serum Retinol in all patients was directly correlated with total cholesterol and LDL. These findings suggest that therapeutic modalities of this vitamin could be planned for these patients, as vitamin A is known to act as an antioxidant for prevention of certain cancers.

Metabolic abnormalities were investigated in 44 stone patients with first time (group 1) and 56 with 2 times stone formation (group 2), and in 25 normal individuals. 24hr urine was analysed spectrophotometrically for oxalate, calcium, magnesium, citrate, uric acid, phosphate and creatinine. Hypocitraturia and hyperoxaluria were the common abnormalities in the stone formers. Stone patients had significantly higher urinary oxalate, calcium and uric acid and lower phosphate than normal individuals. Citrate/calcium and magnesium/calcium ratio were significantly high in normal individuals than stone formers. Patients in group 2 excreted significantly higher urinary calcium and lower citrate that patients in group 1. Citrate/calcium ratio was higher in group 1 than group 2. Hypocitraturia, hyperoxaluria, hypercalciuria and increased citrate/calcium and magnesium/calcium ratio seem to be an essential risk factor for stone formation. Patients with recurrent stone formation could be distinguished from patients with first time stone formation on the basis of urinary calcium and citrate.

Eight weeks of latent iron deficiency in weaned female rats of Sprague Dawley strain maintained on experimental low-iron diet (18–20 mg/kg) did not significantly change the gross body, weight and tissue weights of brain and liver. Packed cell volume (PCV) and hemoglobin concentration remained unaltered. However, non-heme iron content in liver and brain decreased significantly (p<0.001). The activities of glutamate dehydrogenase, glutamic acid decarboxylase, and GABA-transaminase (GABA-T) in brain decreased by 15%, 11.4% and 25.7% respectively. However, this decrease was not statistically significant. Binding of3H Muscimol at pH 7.5 and 1 mg protein/assay increased by 143% (p<0.001) in synaptic vesicular membranes from iron-deficient rats as compared to the controls.3H glutamate binding to the synaptic vesicles was also carried out under similar condition. However, the L-glutamate binding was reduced by 63% in the vesicular membranes of iron deficient animals. These studies indicate that iron plays important functional role in both excitatory and inhibitory neurotransmitter receptors.

Eight weeks of latent iron deficiency in weaned female rats of Sprague Dawley strain maintained on experimental low-iron diet (18–20 mg/Kg) did not significantly change the gross body weight and tissue weights of brain and liver. Packed cell volume (PCV) and hemoglobin concentration remained unaltered. However, non-heme iron content in liver and brain decreased significantly (P<0.001). The activities of glutamate dehydrogenase, glutamic acid decarboxylase, and GABA-transaminase (GABA-T) in brain decreased by 15%, 11.4% and 25.7% respectively. However, this decrease was not statistically significant. Binding of3H Muscimol at pH 7.5 and 1 mg protein/assay increased by 143% (P<0.001) in synaptic vesicular membranes from iron-deficient rats as compared to the controls.3H glutamate binding to the synaptic vesicles was also carried out under similar condition. However, the L-glutamate binding was reduced by 63% in the vesicular membranes of iron deficient animals. These studies in dicate that iron plays an important functional role in both excitatory and inhibitory neurotransmitter receptors.

Objective

Intra-amniotic and systemic infection/inflammation have been causally linked to preterm parturition and fetal injury. An emerging theme is that adipose tissue can orchestrate a metabolic response to insults, but also an inflammatory response via the production of adipocytokines, and that these two phenomenon are interrelated. Adiponectin, an insulin-sensitizing, anti-inflammatory adipocytokine, circulates in multimeric complexes including low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. Each of these complexes can exert differential biological effects. The aim of this study was to determine whether spontaneous preterm labor (PTL) with intact membranes and intra-amniotic infection/inflammation (IAI) is associated with changes in maternal serum circulating adiponectin multimers.

Study design

This cross-sectional study included patients in the following groups: 1) normal pregnant women (n=158); 2) patients with an episode of preterm labor and intact membranes without IAI who delivered at term (n=41); 3) preterm labor without IAI who delivered preterm (n=27); and 4) preterm labor with IAI who delivered preterm (n=36). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analyses.

Results

1) Preterm labor leading to preterm delivery or an episode of preterm labor which does not lead to preterm delivery, was associated with a lower median maternal serum concentration of total and HMW adiponectin, a lower median HMW/total adiponectin ratio, and a higher median LMW/total adiponectin ratio than normal pregnancy; 2) among patients with preterm labor, those with IAI had the lowest median concentration of total and HMW adiponectin, as well as the lowest median HMW/total adiponectin ratio; 3) The changes in maternal adiponectin and adiponectin multimers remained significant after adjusting for confounding factors such as maternal age, BMI, gestational age at sampling, and parity.

Conclusion

1) Preterm labor is characterized by a change in the profile of adiponectin multimers concentrations and their relative isoforms. These changes were observed in patients with an episode of preterm labor not leading to preterm delivery, in patients with intra-amniotic inflammation, or in those without evidence of intra-amniotic inflammation; 2) The changes in adiponectin multimer concentrations reported in preterm labor are different from those previously reported in spontaneous labor at term, suggesting that there is a fundamental difference between preterm labor and labor at term; 3) The findings reported herein, provide the first evidence for the participation of adiponectin multimer in preterm parturition. We propose that adiponectins and adipokines in general provide a mechanism to organize the metabolic demands generated by the process of preterm parturition regardless of the nature of the insult (intra-amniotic inflammation or not).

Objective

To determine the pregnancy outcome of asymptomatic patients in the second trimester with a non-measurable cervical length (“0 mm”).

Methods

This retrospective cohort study included 78 patients with singleton pregnancies and a sonographic non-measurable cervix detected at 14–28 weeks’ gestation. Patients with cervical cerclage were excluded.

Results

1) 75.3% of the patients delivered before 32 weeks; 2) the median diagnosis-to-delivery interval was 20.5 days; the delivery rate within 7 and 14 days was 28.2% and 35.6%, respectively; 3) patients with a non-measurable cervix diagnosed <24 weeks had a shorter median diagnosis-to-delivery interval than those diagnosed at 24–28 weeks (17.5 vs. 41 days; p=0.009).

Conclusions

1) Asymptomatic women with a non-measurable cervix in the second trimester have a median diagnosis-to-delivery interval of ~3 weeks; 2) almost 65% of these patients will not deliver within two weeks, yet 75% deliver before 32 weeks; 3) the earlier a non-measurable cervix is identified the shorter the diagnosis-to-delivery interval.

Breast cancer is a complex heterogeneous disease involving genetic and epigenetic alterations in genes encoding proteins that are components of various signaling pathways. Candidate gene approach have identified association of genetic variants in the Wnt signaling pathway genes and increased susceptibility to several diseases including breast cancer. Due to the rarity of somatic mutations in key genes of Wnt pathway, we investigated the association of genetic variants in these genes with predisposition to breast cancers. We performed a case-control study to identify risk variants by examining 15 SNPs located in 8 genes associated with Wnt signaling. Genotypic analysis of individual locus showed statistically significant association of five SNPs located in β-catenin, AXIN2, DKK3, SFRP3 and TCF7L2 with breast cancers. Increased risk was observed only with the SNP in β-catenin while the other four SNPs conferred protection against breast cancers. Majority of these associations persisted after stratification of the cases based on estrogen receptor status and age of on-set of breast cancer. The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni's correction. Apart from these five variants, rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. This is the first study to utilize pathway based approach to identify association of risk variants in the Wnt signaling pathway genes with breast cancers. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of Wnt pathway as well as screening markers for early detection of breast carcinomas.

Genome-wide association studies (GWAS) have revealed many single nucleotide polymorphisms (SNPs) associated with complex traits. Although these studies frequently fail to identify statistically significant associations, the top association signals from GWAS may be enriched for true associations. We therefore investigated the association of alcohol dependence with 43 SNPs selected from association signals in the first two published GWAS of alcoholism. Our analysis of 808 alcohol-dependent cases and 1,248 controls provided evidence of association of alcohol dependence with SNP rs1614972 in the ADH1C gene (unadjusted p = 0.0017). Because the GWAS study that originally reported association of alcohol dependence with this SNP [1] included only men, we also performed analyses in sex-specific strata. The results suggest that this SNP has a similar effect in both sexes (men: OR (95%CI) = 0.80 (0.66, 0.95); women: OR (95%CI) = 0.83 (0.66, 1.03)). We also observed marginal evidence of association of the rs1614972 minor allele with lower alcohol consumption in the non-alcoholic controls (p = 0.081), and independently in the alcohol-dependent cases (p = 0.046). Despite a number of potential differences between the samples investigated by the prior GWAS and the current study, data presented here provide additional support for the association of SNP rs1614972 in ADH1C with alcohol dependence and extend this finding by demonstrating association with consumption levels in both non-alcoholic and alcohol-dependent populations. Further studies should investigate the association of other polymorphisms in this gene with alcohol dependence and related alcohol-use phenotypes.

Objective

Several mechanisms of disease have been implicated in the pathophysiology of SGA including an anti-angiogenic state, failure of physiologic transformation of spiral arteries, and an exaggerated intravascular pro-inflammatory response. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine circulates in oligomeric complexes including low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. Adiponectin plays a role in a wide range of biological activities including those that have been implicated in the pathophysiology SGA. Thus, the aim of this study was to determine if third trimester adiponectin concentrations differed between women with normal weight infants and those with an SGA neonate.

Study design

This cross-sectional study included women with: 1) a normal pregnancy (n=234); and 2) an SGA neonate (n=78). The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Maternal serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analyses.

Results

1) The median maternal serum concentrations of total, HMW and MMW adiponectin were significantly lower in patients with an SGA neonate than in those with normal pregnancies; 2) patients with an SGA neonate had a significantly lower median HMW/total adiponectin ratio and higher median MMW/total adiponectin and LMW/total adiponectin ratios than those with a normal pregnancy; 3) among patients with an SGA neonate, neither maternal serum concentrations of adiponectin multimers, nor their relative distribution differ between normal weight and overweight/obese patients.

Conclusion

1) Pregnancies complicated by an SGA neonate are characterized by a alterations in the maternal serum adiponectin multimers concentrations and their relative abundance; 2) in contrast to normal pregnancies, those complicated by an SGA neonate are not associated with low circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in the presence of an SGA neonate; 3) collectively, the findings reported herein suggest that maternal adipose tissue may play a role, in the pathogenesis of SGA.