Aspirin & clopidogrel non-responsiveness & its association with genetic polymorphisms in patients with myocardial infarction

Background & objectives: Cytochrome P450, P2Y 12, cyclooxygenase-1 (COX1) and glycoprotein V1 (GPVI) gene polymorphisms are known to affect patient responsiveness towards aspirin and clopidogrel dual antiplatelet therapy (DAPT). The present study was undertaken to identify aspirin and clopidogrel non-responsiveness and its association with genetic polymorphism in patients with myocardial infarction (MI). Methods: A total of 207 MI patients who were on DAPT, were included. The DAPT non-responsiveness was determined by light transmittance aggregometry using arachidonic acid and adenosine diphosphate and high platelet reactivity by collagen. Platelet activation biomarkers, thromboxane B2 (TxB2)andsoluble CD40 ligand (sCD40L) were measured in plasma. Patient compliance was checked by estimating drug and its metabolite levels (aspirin and clopidogrel) in plasma using liquid chromatography-mass spectrometry/mass spectrometry. Genomic DNA was extracted, amplified by polymerase chain reaction and subsequently sequenced to identify CYP450, P2Y 12, COX1 and GPVI gene polymorphisms. Results: Of the 207 patients, 32 were non-responders. The DAPT non-responsiveness was found in 15.5 per cent patients. The non-responsiveness showed a significant and an independent association with gender [odds ratio (OR)=0.18, 95% confidence interval (CI)=0.01-0.78, P=0.023], TxB2(OR=1.00, 95% CI=1.00-1.01, P=0.013), CYP2C19*2 G>A (OR=3.33, 95% CI=1.04-10.69, P=0.044) and GPVI T>C (OR=0.23, 95% CI=0.08-0.67, P=0.007) after adjusting the demographic, clinical and genetic confounding factors when assessed between non-responder and responder compliant patients. Interpretation & conclusions: The study showed a significant association of genetic polymorphisms (CYP2C19*2 G>A and GPVI T>C) with DAPT non-responsiveness in MI patients. The findings of this study need further validation in a large cohort of patients with clinical follow up.

New genetic players in late-onset Alzheimer's disease: Findings of genome-wide association studies

Late-onset Alzheimer's disease (LOAD) or sporadic AD is the most common form of AD. The precise pathogenetic changes that trigger the development of AD remain largely unknown. Large-scale genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in multiple genes which are associated with AD; most notably, these are ABCA7, bridging integrator 1 (B1N1), triggering receptor expressed on myeloid cells 2 (TREM2), CD33, clusterin (CLU), complement receptor 1 (CRI), ephrin type-A receptor 1 (EPHA1), membrane-spanning 4-domains, subfamily A (MS4A) and phosphatidylinositol binding clathrin assembly protein (PICALM) genes. The proteins coded by the candidate genes participate in a variety of cellular processes such as oxidative balance, protein metabolism, cholesterol metabolism and synaptic function. This review summarizes the major gene loci affecting LOAD identified by large GWASs. Tentative mechanisms have also been elaborated in various studies by which the proteins coded by these genes may exert a role in AD pathogenesis have also been elaborated. The review suggests that these may together affect LOAD pathogenesis in a complementary fashion.

Se-acquisition and reactive oxygen species role in growth, photosynthesis, photosynthetic pigments, and biochemical changes in essential oil(s) monoterpene of geranium ( pelargonium graveolens L.HER.’ EX. AIT.).

Se is an essential element required for various metabolic pathways and act as an antioxidant in the various redox-reactions of primary and secondary plant production of – biomolecules. Geranium is an important essential monoterpene oil(s) bearing plant. Culturing the plant at different doses of Se from 0-1.0 mg Se ml-1 revealed that Se plays an important role as an in antioxidant promoter, apart from its micronutrient essentiality. 0.25 mg Se ml-1 is the critical concentrations for maximum content of (0.21%) total essential monoterpene oil(s). At concentration below and above 0.25 mg Se ml-1, the CO2 assimilation rate, photosynthetic pigments content and ultimately the accumulation of essential monoterpene oil(s) are affected. The maximum peroxidase and SOD activities were obtained at 0.25 mg Se ml-1, with the production of biomolecule geraniol. Results revealed an oxidoreducable reaction of Se in the formation of monoterpene essential oil(s) and possibly for the major constituents Geraniol.

Cr-acquisition and reactive oxygen species role in growth, photosynthesis, photosynthetic pigments, and biochemical changes in essential oil(s) monoterpene of geranium (pelargonium graveolens L.HER.’ EX. AIT.)

Cr is an essential element required for various metabolic pathways and act as an antioxidant in the various redox-reactions of primary and secondary plant production of – biomolecules. Geranium is an important essential monoterpene oil(s) bearing plant. Culturing the plant at different doses of Cr from 0-1.0 g Cr ml-1 revealed that Cr plays an important role as an in antioxidant promoter, apart from its micronutrient essentiality. 0.25 m g Cr ml-1 is the critical concentrations for maximum content of (0.21%) total essential monoterpene oil(s). At concentration below and above 0.25 g Cr ml-1, the CO2 assimilation rate, photosynthetic pigments content and ultimately the accumulation of essential monoterpene oil(s) are affected. The maximum peroxidase and SOD activities were obtained at 0.25 g Cr ml-1, with the production of biomolecule geraniol. Results revealed an oxido-reducable reaction of Cr in the formation of monoterpene essential oil(s) and possibly for the major constituents Geraniol.

A case-control study on insulin resistance, metabolic co-variates & prediction score in non-alcoholic fatty liver disease.

Background & objectives: Asian Indians have a high prevalence of insulin resistance and the metabolic syndrome. Currently, non-alcoholic fatty liver disease (NAFLD) is considered to be an integral part of the metabolic syndrome with insulin resistance as a central pathogenic factor. We studied anthropometric parameters, insulin resistance and metabolic co-variates in subjects with NAFLD as compared to those without NAFLD, and also developed a prediction score for NAFLD. Methods: Thirty nine subjects with NAFLD and 82 controls were selected for the study after ultrasonography of 121 consecutive apparently healthy subjects. Anthropometric profile [body mass index (BMI), waist circumference (WC) etc,], lipid profile, hepatic aminotransferases, fasting blood glucose (FBG), insulin were recorded and value of homeostasis model assessment of insulin resistance (HOMA-IR) was analysed. Step-wise logistic regression analysis and area under the receiver operator curve (aROC) were analysed to arrive at a prediction score. Results: Overall, prevalence of NAFLD was 32.2 per cent and prevalence of metabolic syndrome was seen in 41 per cent among cases and 19.5 per cent in controls (P<0.01). Subjects with NAFLD had significantly higher values of BMI, WC, hip circumference, FBG, fasting insulin, total cholesterol and serum triglycerides. Step-wise logistic regression analysis showed odds ratio (OR) and 95 per cent confidence interval (CI) for BMI [ 4.3 (1.6, 11.3)], FBG [5.5 (1.5, 19.8)] and fasting insulin [ 2.4 (1.0, 5.8)] as independent predictors of NAFLD. The prediction score for NAFLD was; 1 (fasting insulin) +1.6 (BMI) + 1.9 (FBG) (sensitivity of 84.6%, specificity of 51.2% and aROC 76%). Interpretation & conclusion: In this study, presence of NAFLD indicated close relationship with multiple features of metabolic syndrome. The prediction score developed could be used as a screening tool to predict NAFLD among Asian Indians in north India.

Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for asian indians and recommendations for physical activity, medical and surgical management.

Asian Indians exhibit unique features of obesity; excess body fat, abdominal adiposity, increased subcutaneous and intra-abdominal fat, and deposition of fat in ectopic sites (liver, muscle, etc.). Obesity is a major driver for the widely prevalent metabolic syndrome and type 2 diabetes mellitus (T2DM) in Asian Indians in India and those residing in other countries. Based on percentage body fat and morbidity data, limits of normal BMI are narrower and lower in Asian Indians than in white Caucasians. In this consensus statement, we present revised guidelines for diagnosis of obesity, abdominal obesity, the metabolic syndrome, physical activity, and drug therapy and bariatric surgery for obesity in Asian Indians after consultations with experts from various regions of India belonging to the following medical disciplines; internal medicine, metabolic diseases, endocrinology, nutrition, cardiology, exercise physiology, sports medicine and bariatric surgery, and representing reputed medical institutions, hospitals, government funded research institutions, and policy making bodies. It is estimated that by application of these guidelines, additional 10-15% of Indian population would be labeled as overweight/obese and would require appropriate management. Application of these guidelines on countrywide basis is also likely to have a deceleration effect on the escalating problem of T2DM and cardiovascular disease. These guidelines could be revised in future as appropriate, after another large and countrywide consensus process. Till that time, these should be used by clinicians, researchers and policymakers dealing with obesity and related diseases. ©

Whole grains and health: Perspective for Asian Indians.

Grains are a part of human diet for about 10,000 years . Grains are the most important food source of Indian population, due to this carbohydrate consumption constitute approx. 60-70% of total food intake. Variety of grains are available in India , and different grains form staple diets of people in different part of the country. Whole grains are now recognized as an important source of fiber and other nutrients like trace minerals a vitamins. Grains have shown to have a role in prevention and reducing the risk of Type 2 Diabetes, Coronary Heart Disease, Cancer and Obesity. ©

Distribution and cutoff points of fasting insulin in Asian Indian adolescents and their association with metabolic syndrome.

AIM: To evaluate the levels and appropriate cutoff points of fasting insulin, and their association with the metabolic syndrome (MS) in Asian Indian adolescents. METHODS: This cross-sectional, population based study included 948 (527 males & 421 females) adolescent subjects aged 14-19 years selected randomly from New Delhi, India. Cutoff points of fasting insulin were defined using Receiver Operating Characteristics curve analysis against overweight, abdominal obesity and high subscapular skinfold thickness. The MS was defined according to NCEP, ATP III and IDF criteria using age-, gender- and ethnicity-specific cutoff points. RESULTS: Fasting insulin levels peaked at 16 y and reduced subsequently in both genders. The derived cutoff points for fasting insulin (pmol/L) were: 14-15 y- 128.5 and 164.8; 16-17 y- 126.1 and 152.8; 18-19 y- 121.2 and 162.4 in males and females, respectively. Prevalence of fasting hyperinsulinemia (39.1%) and MS (NCEP 2.2%, IDF 1.5%) was highest in age group 16-17 years. CONCLUSION: The data from this first study describing the distribution and cutoff points of fasting insulin in Asian Indian adolescents may be helpful for detection of and application of primary prevention strategies for fasting hyperinsulinemia and the metabolic syndrome in this population.

Comparison of definitions of the metabolic syndrome in adult Asian Indians.

OBJECTIVE: The optimum definition of the metabolic syndrome (MS) is not known. We compared international definitions of MS [recently proposed modified definition of National Cholesterol Education Programme, Adult Treatment Panel III (NCEP, ATP III) and International Diabetes Federation (IDF)] with two proposed candidate definitions in adult Asian Indians. DESIGN: Data from three previous cross-sectional studies carried out in North India were analyzed. SUBJECTS: The study included 2050 adult (mean age: 40 +/- 18 years) Asian Indian subjects residing two metropolitan cities. MEASUREMENTS: Candidate definitions of MS were proposed by modifying the NCEP, ATP III and IDF definitions by including the following modified variables into two combinations (MS-ATP1 and MS-IDF1); waist circumference cut-off points as >90 cm in males and >80 cm in females, body mass index (BMI) cut-off point as >23 kg/m2, impaired fasting glucose (IFG) cut-off point >100 mg/dl and waist circumference as an obligatory criterion. RESULTS: Maximum overall and gender-specific prevalence of the MS (49.2% overall; 41.4% in males; 55.3% in females) was observed using the definition which included modified cut-off points of WC (non-obligatory), BMI, and IFG (>100 mg/dl) in addition to other defining parameters. Compared to other definitions this proposed candidate definition maximally detected presence of MS in subjects with IFG and T2DM [Percentage prevalence: 78.1% (73.0-82.7) and 91.1% (84.2-95.6)]. Even in subjects without abdominal obesity, a high prevalence of other abnormal defining parameters of the metabolic syndrome; hypertension (> or = 130 or > or = 85 mmHg), 35.7%; BMI >23 kg/m2, 15.3%; hypertriglyceridemia (>150 mg/dl), 20.2% and low levels of HDL-C (<40 in males; <50 mg/dl in females), 55% were seen. Further, 10.5% of subjects who did not have abdominal obesity had presence of at least 3 risk variables of the metabolic syndrome. These data indicate that by making abdominal obesity a mandatory criterion would lead to missing of some cases of the metabolic syndrome. CONCLUSION: By including BMI and making waist circumference as a non-obligatory criterion, more cases of the metabolic syndrome is detected. For Asian Indians, making waist circumference as mandatory variable in the definition of the metabolic syndrome would lead to non-inclusion of nearly 11% cases who would otherwise be diagnosed as metabolic syndrome according to modified NCEP, ATP III definition.

Limbic encephalitis--an uncommon presentation of systemic malignancy.

A 46 years, nondiabetic, nonhypertensive woman presented with headache, vomiting, low grade intermittent fever, behavioral abnormality and seizures for last three months. Clinically she had meningism with bilateral papilloedema. Based on CSF analysis, normal CT scan of brain and suspicious lesion in X-ray chest, she was put on anti-tuberculosis therapy. As the patient further deteriorated clinically, MRI of brain was carried out and revealed bilateral increased signal intensities in both medial temporal lobes in T2 and flair sequences. Inj. acyclovir was added considering the diagnosis of herpes simplex encephalitis. In spite of receiving treatment patient gradually became more drowsy and repeat X-ray chest with CT guided FNAC showed picture of adenocarcinoma of lung. So finally, we concluded it to be a case of limbic encephalitis.

Response surface optimization of effective medium constituents for the production of alkaline protease from a newly isolated strain of Pseudomonas aeruginosa.

Optimization of the fermentation medium for maximum alkaline protease production was carried out with a new strain of Pseudomonas aeruginosa (B-2). Replacing the protein source/inducer (albumin in place of casein) brought about significant increase in yield after 48 hr of inoculation. Three most effective medium constituents identified by initial screening method of Plackett-Burman were albumin, (NH4)2SO4 and glucose. Central Composite Design (CCD) and Response Surface Methodology (RSM) were used in the design of the experiment and in the analysis of the results. Optimum levels of the effective medium constituents were albumin (6.586%); (NH4)2SO4, 0.164%; and glucose, 6.72%. The alkaline protease production increased from 533460 to 793492 Ul(-1).

Gastroduodenal dysmotility in patients with gallbladder carcinoma: frequency of occurrence and clinical importance.

BACKGROUND: Gastric stasis, common in patients with gall-bladder carcinoma (GBC), results from anatomical obstruction or motor abnormalities. We studied patients with GBC for antroduodenal motor dysfunction using manometry. METHODS: Forty-one patients with GBC without endoscopic gastric outlet obstruction and 10 healthy controls were evaluated using a symptom scoring system for gastric stasis, saline load test and water perfusion antroduodenal manometry. Fasting, post-prandial and post-octreotide motility were recorded and analysed on a computer using GiPC manometry software. RESULTS: Sixteen of 41 patients (39%) with GBC reported recurrent vomiting; patients with vomiting had a higher symptom score (13 [11-17] v. 6 [4-10], p<0.0001] and higher volume of aspirate on the saline load test (460 ml [210-650] v. 160 ml [70-260], p<0.0001) as compared with those without vomiting. Healthy subjects more often had spontaneous fasting migratory motor complex than patients with GBC (9/10 v. 13/41, p=0.002). The amplitudes of contractions in the antrum and duodenum were significantly lower in patients with GBC than in healthy subjects. Patients with GBC had lower fasting (157 [68-284] v. 190.5 [150-284], p=0.01) and post-prandial (200 [96-395] v. 284 [178-395], p<0.0001) antral motor indices than healthy subjects. Patients with GBC and vomiting had significantly lower contraction amplitude and motility indices than those without vomiting. Motility indices correlated inversely with the symptom score and volume of aspirate on the saline load test (Spearman correlation, p = 0.01 for all). CONCLUSION: Antroduodenal motor abnormalities are common in patients with GBC. These may explain the symptoms of gastric stasis and abnormal results of the saline load test in the absence of anatomical obstruction in such patients.

Increasing access to cataract surgery in a rural area--a support strategy.

The objectives of the study were to elicit the reasons for not undergoing cataract surgery from those having cataract, aged 50 years and above, in a village community and, develop, implement and assess a support strategy for getting cataract surgery done. The leading reasons identified were monetary constraints (18.8%), transport difficulty (17.4%), lack of awareness about cataract in the eyes (17.4%) and lack of escort (14.5%). Based on the identified reasons, patients were transported in groups to a government eye hospital for free surgery after completion of required pre operative formalities at the village health center itself. Out of 65 eligible individuals, 66.2% underwent surgery. The success of the approach was evident by perceived improvement in vision in 88.4% operated patients, occurrence of only few minor complications and a satisfactory hospital experience being reported by all.

Involuntary jerking of lower half of the body (spinal myoclonus).

A 55 years old, hypertensive, diabetic lady presented with sudden onset jerky movement of lower trunk and legs. It was present both in awake and sleep and got aggravated by mental stress as well as sensory stimulation. Examination revealed rhythmic jerks affecting muscles of lower abdomen and legs. The lower limbs had normal muscle bulk and power, increased tone, exaggerated deep tendon reflexes, bilateral flexor plantar response with normal sensory autonomic and cerebellar function. Investigations including CSF study, MRI of dorsal spine and NCV were normal. A combination therapy with tizanidine, baclofen and clonazepam induced gradual improvement within 6 weeks.

Henoch-Schonlein purpura with intracerebral haemorrhage.

Henoch-Schonlein purpura is a leucocytoclastic vasculitis commonly seen among children and young adults. Neurological complications, though rare, include focal cerebral deficit, coma, convulsion, subarachnoid hemorrhage and chorea. We are reporting a 12 years boy with Henoch-Schonlein purpura who developed a large intracerebral hematoma in right occipital lobe. He made an uneventful recovery with conservative treatment and one year follow up revealed no major neurological sequelae.

Arthropathic presentation of Wilson's disease.

A patient is described who presented with polyarthritis involving small and large joints of limbs with later onset of tremors affecting all four extremities. Investigations including genetic study confirmed the diagnosis of Wilson's disease (WD). The case highlights the importance of considering the possibility of WD in young patient presenting with repetitive unexplained joint symptoms with or without tremor.

Dyslipidemia in Asian Indians: determinants and significance.

Data suggest that lipid fractions other than total cholesterol, i.e. serum triglycerides (TG) and high-density lipoprotein (HDL) cholesterol are important for the pathogenesis of atherosclerosis. A combination of hypertriglyceridemia, low levels of HDL-cholesterol and high levels of small dense low-density lipoprotein, termed as "atherogenic dyslipidemia', is particularly seen in Asian Indians. Although precise reason for such dyslipidemia is unknown, genetic predisposition and characteristic body composition (excess truncal subcutaneous fat and intraabdominal fat) may be important contributors. A common interface between such body composition and dyslipidemia in Asian Indians is high tendency to develop insulin resistance, more than the other ethnic groups. The general guidelines for the management of dyslipidemia in Asian Indians should be according to National Cholesterol Education Program, Adult Treatment Panel III. However, optimal management requires consideration of ethnic-specific dietary, lifestyle and management factors to formulate individual treatment guidelines.

Pulmonary functions in patients with type 2 diabetes mellitus & correlation with anthropometry & microvascular complications.

BACKGROUND & OBJECTIVES: The purpose of this study was to evaluate pulmonary functions including respiratory muscle strength in patients with type 2 diabetes mellitus (T2DM) and to determine their correlations with anthropometric profile, glycaemic control, and microangiopathic diabetic complications. METHODS: Twenty nine patients with T2DM and 11 healthy control subjects were divided into the following three groups; (i) T2DM patients with any or a combination of microangiopathy(ies) (retinopathy, nephropathy, and peripheral neuropathy) (group 1, n=12); (ii) T2DM patients without any complications (group 2, n = 17); and (iii) a healthy control group (group 3, n=11). All patients were assessed with anthropometry, glycosylated haemoglobin (HbA1C), and lipid profile. Pulmonary functions were measured by spirometry. Pulmonary diffusion capacity for carbon monoxide (DLco) was measured by the steady state method. The presence of diabetic nephropathy was determined by 24 h protein excretion. RESULTS: A significant reduction of DLco was observed in group 1 (P<0.001), as compared to the other groups. There were no differences among the three groups for other pulmonary functions; forced vital capacity, forced expired volume in one second, peak expiratory flow rate, and maximal static inspiratory and expiratory pressures. Significant correlations were observed between DLco and the following parameters in group 1; HbA1c (r=0.62, P<0.05), total cholesterol level (r = -0.44, P<0.05) and creatinine clearance (r=0.42, P<0.05). INTERPRETATION & CONCLUSION: The present study shows that the impairment of pulmonary diffusion capacity for carbon monoxide was common in T2DM Asian Indian patients having microangiopathy. Pathophysiologically, it could be related to glycaemic control or dyslipidaemia. Correlation of % BF with DLCo needs to be explored further.

Receiver operating characteristics curve analysis of body fat & body mass index in dyslipidaemic Asian Indians.

BACKGROUND & OBJECTIVES: Optimal limit of body mass index (BMI) for Asian Indians remains to be defined. In this study, we describe the anthropometric and lipid profiles and determine the appropriate cut-offs of BMI for defining obesity in dyslipidaemic patients. METHODS: Correlations were carried out between lipid profile and anthropometric variables in 217 dyslipidaemic Asian Indians and the data were compared to those of 123 healthy historical controls. Receiver operating characteristics (ROC) curve analysis was carried out to determine the appropriate cut-offs of BMI for defining obesity taking the percentage of body fat (% BF) as the standard. RESULTS: Dyslipidaemic patients had high waist-hip ratio (W-HR) and percentage of BF. The prevalence of obesity as measured by percentage of BF was significantly (P < 0.05) higher as compared to obesity defined by the BMI cut-off. W-HR was the most important independent predictor (odds ratio: 2.8; 95% CI: 1.02-7.83) of atherogenic dyslipidaemia on multivariate logistic regression analysis. On ROC curve analysis the suggested appropriate cut-offs of BMI were; males 24.0 kg/m2 (sensitivity, 74.7%, and specificity, 79.7%), and females 23.0 kg/m2 (sensitivity, 85.7% and specificity, 62.5%). According to the suggested lower limits of BMI, an additional 15 per cent dyslipidaemic patients will be diagnosed as obese. INTERPRETATION & CONCLUSION: The observations in dyslipidaemic Asian Indians suggest high prevalence rates of generalized and abdominal obesity, and that high values of W-HR alone predisposes to atherogenic dyslipidaemia. Further, obesity may be optimally defined by a lower cut-off of BMI. The revised criteria for the BMI-based diagnosis of obesity will lead to a more rational management of dyslipidaemia in Asian Indians.