Decreased baroreflex sensitivity is linked to sympathovagal imbalance, low-grade inflammation, and oxidative stress in pregnancy-induced hypertension.

Pregnancy-induced hypertension (PIH) has been reported as a cardiovascular (CV) risk. We assessed the sympathovagal imbalance (SVI) and the association of inflammation and oxidative stress (OS) with CV risks in PIH. A total of 125 pregnant women having a risk factor for PIH were followed till term and the incidence of PIH was observed. Retrospectively, they were divided into two groups: Group I (those who did not develop PIH, n = 82) and Group II (those who developed PIH, n = 43). Blood pressure variability (BPV) parameters including baroreflex sensitivity (BRS), spectral heart rate variability (HRV), autonomic function tests (AFTs), inflammatory markers (interleukin-6, TNF-α, interferon-γ), and OS markers were measured in both the groups. Alterations in parasympathetic and sympathetic components of AFTs were analyzed. Link of various parameters to BRS was assessed by correlation and multiple regression analysis. Parasympathetic components of AFTs were decreased from the early part of pregnancy and sympathetic components were increased toward the later part of pregnancy. Decreased BRS, the marker of CV risk, was more prominent in Group II subjects. Independent contribution of interleukin-6 (ß = 0.276, P = 0.020), TNF-α (ß = 0.408, P = 0.002), interferon-γ (ß = 0.355, P = 0.008), and thiobarbituric-acid reactive substance (ß = 0.287, P = 0.015) to BRS was found to be significant. It was concluded that sympathetic overactivity that develops more in the later part (third trimester) of pregnancy contributes to SVI and genesis of PIH. In PIH women, CV risks are present from the beginning of pregnancy that intensifies in the later part of pregnancy. Retrograde inflammation and oxidative stress contribute to the decreased BRS in PIH.

Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population.

BACKGROUND: The antiplatelet activity of clopidogrel is variable among patients suffering from ischemic heart disease. Variation in the cytochrome P450 2C19 (CYP2C19) gene coding for the CYP2C19 enzyme is one of the major determinants of this variable response to clopidogrel. The activity of the CYP2C19 enzyme, which plays a role in the conversion of the prodrug clopidogrel to its active metabolite, is genetically influenced by polymorphisms in its gene. The aim of our study was to evaluate the association of CYP2C19 polymorphisms and the antiplatelet effect of clopidogrel in the South Indian Tamilian population. MATERIALS AND METHODS: Genotyping and platelet aggregation results of 149 ischemic heart disease patients on clopidogrel maintenance therapy (75 mg daily dose) were analyzed in this study. CYP2C19 polymorphisms were genotyped by the PCR-restriction fragment length polymorphism method. We measured residual platelet activities in these patients on clopidogrel therapy in terms of impedance (expressed as ohms). The study subjects were divided into two metabolizer phenotype groups [group 1: poor/intermediate metabolizers (PM/IM); group 2: extensive/ultra-rapid metabolizers (EM/URM)] based on CYP2C19 genotype, and the residual platelet activities were compared. Higher values of impedance denote increased residual platelet activity. RESULTS: Poor/intermediate metabolizers had significantly higher impedance values than EM/URM [(median; range) 4.0; 0-13 vs. 2.0; 0-11, respectively; p = 0.04]. These higher impedance values denote higher residual platelet activities among the carriers of loss-of-function alleles (CYP2C19*2,*3) than among non-carriers. However, residual platelet activities were lower among the carriers of the gain-of-function allele (CYP2C19*17) than among non-carriers, although this difference was not significant. CONCLUSION: Patients with CYP2C19 (*2 or *3) genetic polymorphisms had higher residual platelet activities and were associated with a reduced antiplatelet response to clopidogrel. As the South Indian Tamilian population is characterized with higher frequencies of these genetic polymorphisms, our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy.

Distribution of CYP2C19*17 allele and genotypes in an Indian population.

WHAT IS KNOWN AND OBJECTIVE: CYP2C19*17 allele increases the metabolic activity of CYP2C19 resulting in decreased therapeutic levels of CYP2C19 substrates. There exist inter-ethnic differences in the distribution of this allele. The present study was aimed at establishing the allele and genotype frequencies of CYP2C19*17 in a South Indian Tamilian population. Furthermore, we describe the haplotype structure of the three common variant alleles of CYP2C19 in the Tamilian population. METHODS: Two hundred and six subjects of South Indian Tamilian origin were genotyped for CYP2C19*17 allele by nested polymerase chain reaction and restriction fragment length polymorphism. A subset of 87 subjects were also genotyped for CYP2C19*2 and CYP2C19*3 alleles. After ascertaining linkage disequilibrium (LD), haplotypes were constructed. Allele and genotype frequencies, LD pattern and haplotype frequency were compared with those of the HapMap populations. RESULTS AND DISCUSSION: The CYP2C19*17 allele frequency in the Tamilian population (n = 206) was found to be 19·2% (95% CI: 15·4 - 20·3). The CYP2C19*2 allele frequency (n = 87) was found to be 40·2% (95% CI: 32·9 - 47·5), whereas the CYP2C19*3 allele was not detected in the study subjects (n = 97). The high frequency of the CYP2C19*17 allele in the study population has resulted in a revision of frequencies for CYP2C19*1/*2 (31·0%) and CYP2C19*1/*1 (16·1%) genotypes in the Tamilian population. We also observed significant differences in haplotype structure and frequencies of these variant alleles in the HapMap population compared to Tamilian population. WHAT IS NEW AND CONCLUSION: CYP2C19*17 allele is present at high frequency in the Tamilian population. This study also demonstrates the need for reassessment of wild-type allele frequencies in view of CYP2C19*17 allele. The estimated high frequency of CYP2C19*17 allele will aid in genotype-phenotype association studies in the Tamilian population. Further genotype-phenotype association studies are required to evaluate the clinical utility of this allele in South Indians.

Effect of lesion of nucleus septal medialis on energy homeostasis in Wistar rats.

Mesolimbic areas such as nucleus accumbens, amygdala and septal nuclei are known to influence food intake and body weight. However, the reports on gender difference in the neural regulation of obesity and energy homeostasis are incomplete. Therefore, the present study was conducted to assess the effect of lesions of nucleus septal medialis (NSM) and the gender difference of lesion on food intake (FI), body weight (BW), serum lipid profile, thyroid profile, glucose and insulin levels and glucose-insulin ratio (GIR) in Wistar albino rats. Twenty-four rats were divided equally into control and experimental groups having 6 male and 6 female rats in each group. In the experimental group, bilateral electrolytic lesion of NSM was performed by stereotaxy and post-lesion parameters were recorded. In the control group, sham-lesions of NSM were produced. Following lesion, blood glucose and serum insulin levels were decreased and GIR was increased significantly in female rats, but not in male rats. It was concluded that NSM is involved in energy homeostasis, especially in female rats.

Role of ventromedial hypothalamus on energy homeostasis in albino rats: effect of gender.

Various brain areas like the ventromedial hypothalamus (VMH) are known to influence food intake and body weight. Though obesity is more common in females, the reports on gender difference in the neural regulation of energy homeostasis are not adequate. Therefore, the present study was conducted to assess the gender difference in the effect of VMH lesion on food intake (FI), body weight (BW), serum lipid profile, thyroid profile, glucose and insulin levels and glucose-insulin ratio (GIR) in Wistar albino rats. Twenty-four Wistar albino rats were divided equally into control and experimental groups with 6 male and 6 female rats in each. In the experimental group, bilateral electrolytic lesion of VMH was performed by stereotaxy and post-lesion parameters were recorded. In the control group, VMH sham lesion was made. Male-female difference in each parameter was determined. Following VMH lesion, FI was increased (females, P < 0.01) and BW (males, P < 0.05) and GIR decreased in males (P < 0.001), which was significantly correlated with BW. T3 was more significantly correlated with FI and BW in females (P < 0.000 and P < 0.001). Following VMH lesion, male rats exhibited significant weight gain in the absence of proportionate hyperphagia indicating that weight-gain was mainly metabolic in nature. Also, the male rats developed more susceptibility to insulin resistance. The female rats developed resistance to weight-gain inspite of hyperphagia, which could be due to the higher T3 level.

Influence of CYP2C9 gene polymorphisms on response to glibenclamide in type 2 diabetes mellitus patients.

PURPOSE: The antidiabetic drug glibenclamide is metabolized by the enzyme cytochrome P450 2C9 (CYP2C9) encoded by the polymorphic gene CYP2C9. Previous studies involving healthy volunteers have shown a significant influence of variant CYP2C9 genotypes on glibenclamide metabolism. The aim of this study was to investigate the influence of genetic polymorphisms of CYP2C9 on the response to glibenclamide and on glibenclamide plasma levels in type 2 diabetes mellitus patients. METHODS: The study cohort consisted of type 2 diabetes mellitus patients (n = 80) on regular therapy with glibenclamide either alone or with concomitant metformin. Plasma levels of glibenclamide were estimated by reverse phase high pressure liquid chromatography. The variant alleles of CYP2C9, namely CYP2C9 *2 and *3, were identified by PCR-restricted fragment length polymorphism. The plasma levels of glibenclamide and occurrences of hypoglycemic adverse effects with their severity were compared between the genotype groups. RESULTS: Of the 80 patients (61 males, 19 females), 78 were on concomitant treatment with two drugs, namely, glibenclamide and metformin, and two were on monotherapy with glibenclamide. There was a significant association (p < 0.001) between genotype status of CYP2C9 and the control of diabetes in patients receiving treatment with glibenclamide. There were no statistically significant differences in hypoglycemic adverse effects between the genotype groups. CONCLUSION: The type 2 diabetes mellitus patients participating in this study with variant genotypes of CYP2C9 were found to respond better to treatment with glibenclamide than those with the normal genotype. The variant genotype CYP2C9 *1/*3 did not significantly influence the hypoglycemic adverse effects among those patients on long-term glibenclamide treatment.

Assessment of sympathovagal imbalance by spectral analysis of heart rate variability in prehypertensive and hypertensive patients in Indian population.

Though the incidence of hypertension has increased considerably in recent years, the pathophysiologic mechanism that causes progression from stage of prehypertension to hypertension has not been fully elucidated. Therefore, the present study was conducted to assess the sympathovagal imbalance in prehypertensives and hypertensives by spectral analysis of heart rate variability (HRV) to understand the nature of change in autonomic balance in this common dysfunction of mankind. Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), and spectral indices of HRV such as total power (TP), normalized low frequency power (LFnu), normalized high frequency power (HFnu), ratio of low frequency power to high frequency power (LF-HF ratio), mean heart rate (mean RR), square root of the mean squared differences of successive normal to normal intervals (RMSSD), the number of interval differences of successive NN intervals greater than 50 ms (NN50), and the proportion derived by dividing NN50 by the total number of NN intervals (pNN50) were assessed in three groups of subjects: normotensives (n = 32), prehypertensives (n = 28), and hypertensives (n = 31). Sympathovagal balance was analyzed and correlated with BMI, BHR, and BP in all the groups. It was observed that autonomic imbalance in prehypertensives was due to proportionate increased sympathetic activity and vagal inhibition, whereas in hypertensives, vagal withdrawal was more prominent than sympathetic overactivity. The LF-HF ratio, the sensitive indicator of sympathovagal balance, was significantly correlated with BMI, BHR, and BP. It was concluded that vagal inhibition plays an important role in the critical alteration of sympathovagal balance in the development of clinical hypertension in prehypertensive subjects.

Study of sympathovagal imbalance by spectral analysis of heart rate variability in young prehypertensives.

Though prehypertension has recently been considered as a risk factor for cardiovascular accidents, the pathophysiological mechanism that causes the development of prehypertension in normotensive subjects has not been fully elucidated. Therefore, the present study was conducted to assess the sympathovagal imbalance in prehypertensives and normotensives by spectral analysis of heart rate variability (HRV) to understand the nature of change in autonomic balance in this dysfunction. Body mass index (BMI), waist-hip ratio (WHR), basal heart rate (BHR), blood pressure (BP), rate-pressure product (RPP) and spectral indices of HRV such as total power (TP), normalized low frequency power (LFnu), normalized high frequency power (HFnu), ratio of low frequency power to high frequency power (LF-HF ratio), mean heart rate (mean RR), square root of the mean squared differences of successive normal to normal intervals; (RMSSD), the number of interval differences of successive NN intervals greater than 50 ms (NN50) and the proportion derived by dividing NN50 by the total number of NN intervals (pNN50) were assessed in two groups of young subjects: normotensives (n=68) and prehypertensives (n=66). Sympathovagal balance (SVB) was analyzed and correlated with BMI, WHR, BHR, BP and RPP in both the groups. It was observed that autonomic imbalance in prehypertensives was due to increase in both sympathetic activity and vagal inhibition. LF-HF ratio, the sensitive indicator of SVB was significantly correlated with BMI, WHR, BHR, BP and RPP in prehypertensive subjects. It was concluded that vagal inhibition might be important in the critical alteration of sympathovagal balance in the development of prehypertension in young normotensive subjects.

Association of aldosterone synthase (CYP11B2 C-344T) gene polymorphism & susceptibility to essential hypertension in a south Indian Tamil population.

BACKGROUND & OBJECTIVE: Renin-angiotensin aldosterone system (RAAS) plays an important role in the regulation of blood pressure. Aldosterone, synthesized by aldosterone synthase in the adrenal cortex is encoded by the CYP11B2 gene. In this case-control study we examined the association between CYP11B2 C-344T polymorphism and essential hypertension in south Indian Tamil population. METHODS: The study was conducted in 406 hypertensive cases and 424 healthy controls from Tamil population. Genotyping was performed by PCR-restriction fragment length polymorphism method. Statistical analysis was performed by logistic regression analysis. RESULTS: The 344TT homozygous variant genotype (OR-1.8; 95% CI: 1.1-2.8; P=0.02) and T allele (P=0.007) were found to be significantly associated with hypertension. In gender based analysis, the risk was significantly higher in male hypertensives (OR-1.8; 95% CI: 1.0-3.6, P=0.05) but not in female subjects. INTERPRETATION & CONCLUSION: A significant association between CYP11B2 gene polymorphism and essential hypertension was observed and the risk was confined to male subjects in south Indian Tamil population.

Polymorphic variants of beta1 adrenergic receptor gene (Ser49Gly & Arg389Gly) in healthy Tamilian volunteers.

BACKGROUND & OBJECTIVES: Several studies reported the polymorphisms of beta1-adrenergic receptor gene in healthy volunteers and its influence on cardiovascular disorders. We investigated the genotype and allele frequencies of Ser49Gly and Arg389Gly polymorphism in healthy volunteers of South Indian Tamilian population vis-à-vis other major ethnic groups. METHODS: The genetic variants were determined by using Taqman 5' nuclease assay- real time PCR analysis in 533 normal healthy volunteers (18-60 yr; M=290; F=243). The allelic discrimination analysis was done by 7700 SDS software. RESULTS: The estimated genotype and allele frequencies of Ser49Gly and Arg389Gly polymorphism were compared with other major populations. The frequencies of the variant alleles Gly49 and Gly389 were 15.1 and 25.8 per cent respectively. INTERPRETATION & CONCLUSIONS: Our study shows that interethnic variation exists in the polymorphisms of beta1-adrenergic receptor gene and the results generated in this study might serve as a genetic marker for further studies in Tamilian (South India) population.

Atropine-induced rhabdomyolysis: an uncommon and potentially fatal adverse drug reaction.

A 25 year old woman received daily injection of 0.6 mg atropine for seven days by the intra-venous route. In addition to fever, incomprehensible speech and alteration of sensorium she developed albuminuria, hemoglobinuria and myoglobinuria. A diagnosis of atropine-induced rhabdomyolysis was made on the basis of clinical presentations and investigations. Although, datura poisoning and intoxication with wild mushrooms are known to result in rhabdomyolysis, this can be considered to be the first case of atropine-induced rhabdomyolysis and myoglobinuria.

Gly460Trp polymorphism of the ADD1 gene and essential hypertension in an Indian population: A meta-analysis on hypertension risk.

BACKGROUND: Essential hypertension is a complex genetic trait. Genetic variant of alpha adducin (ADD1) gene have been implicated as a risk factor for hypertension. Given its clinical significance, we investigated the association between ADD1 Gly460Trp gene polymorphism and essential hypertension in an Indian population. Further, a meta-analysis was carried out to estimate the risk of hypertension. METHODS: In the current study, 432 hypertensive cases and 461 healthy controls were genotyped for the Gly460Trp ADD1 gene polymorphism. Genotyping was determined by real time PCR using Taqman assay. Multiple logistic regression analysis was used to detect the association between Gly460Trp polymorphism and hypertension. RESULTS: No significant association was found in the genotype and allele distribution of Gly460Trp polymorphism with hypertension in our study. A total of 15 case-control studies were included in the meta-analysis. There was no evidence of the association of Gly460Trp polymorphism with hypertension in general or in any of the sub group. CONCLUSIONS: We found that the Gly460Trp polymorphism is not a risk factor for essential hypertension in a south Indian Tamilian population. However, the role of ADD1 polymorphism may not be excluded by a negative association study. Further, large and rigorous case-control studies that investigate gene-gene-environment interactions may generate more conclusive claims about the molecular genetics of hypertension.

Corrigendum: Global Text Mining and Development of Pharmacogenomic Knowledge Resource for Precision Medicine.

[This corrects the article DOI: 10.3389/fphar.2019.00839.].

Genetic variants of beta(1)-adrenoceptor gene polymorphisms (Ser49Gly and Arg389Gly) and essential hypertension in a south Indian Tamil population.

1. Essential hypertension is a complex polygenic disorder, the pathogenesis of which is dependent on an interplay between genetic and environmental factors. Various studies suggest an association between beta(1)-adrenoceptor gene polymorphisms (Ser49Gly and Arg389Gly) and cardiovascular disorders, including hypertension, cardiomyopathy and congestive heart failure. 2. The genetic profile of the beta(1)-adrenoceptor gene has not yet been documented for any Indian population. Thus, the aim of the present study was to investigate the association between beta(1)-adrenoceptor gene polymorphisms and essential hypertension in a south Indian Tamil population. 3. The present case-control study included 438 patients with essential hypertensives and 444 healthy volunteers from the Tamil population. Genotyping was performed using real-time polymerase chain reaction. 4. Genotype and allele frequencies of Ser49Gly and Arg389Gly polymorphism were compared between hypertensive patients and healthy volunteers. The homozygous variant genotype Gly49Gly of the Ser49Gly polymorphism was higher in hypertensive patients compared with controls (12.3 vs 7.4%, respectively). After adjusting for confounding variables (odds ratio (OR) 2.0; 95% confidence interval (CI) 1.2-2.9; P < 0.01) by multilogistic regression analysis, the gene was found to be associated with hypertension. A significant interaction was observed in hypertensive patients carrying the Ser49Gly/Gly49Gly x Arg389Gly/Gly389Gly genotypes (OR 1.9; 95% CI 1.1 2.7). 5. In conclusion, the Ser49Gly polymorphism is associated with essential hypertension in a south Indian Tamil population. The results of the present study deviate from those of previous studies, implying that marked interethnic difference exist in beta(1)-adrenoceptor gene polymorphisms.

Novel applications of nanotechnology in medicine.

Current modalities of diagnosis and treatment of various diseases, especially cancer have major limitations such as poor sensitivity or specificity and drug toxicities respectively. Newer and improved methods of cancer detection based on nanoparticles are being developed. They are used as contrast agents, fluorescent materials, molecular research tools and drugs with targeting antibodies. Paramagnetic nanoparticles, quantum dots, nanoshells and nanosomes are few of the nanoparticles used for diagnostic purposes. Drugs with high toxic potential like cancer chemotherapeutic drugs can be given with a better safety profile with the utility of nanotechnology. These can be made to act specifically at the target tissue by active as well as passive means. Other modalities of therapy such as heat induced ablation of cancer cells by nanoshells and gene therapy are also being developed. This review discusses the various platforms of nanotechnology being used in different aspects of medicine like diagnostics and therapeutics. The potential toxicities of the nanoparticles are also described in addition to hypothetical designs such as respirocytes and microbivores. The safety of nanomedicine is not yet fully defined. However, it is possible that nanomedicine in future would play a crucial role in the treatment of human diseases and also in enhancement of normal human physiology.

Apolipoprotein AI and Apolipoprotein B gene polymorphisms and lipid profile in Tamilian population.

Apolipoprotein (ApoAI) is the major protein constituent of high density lipoproteins (HDL). Apolipoprotein (apo) B-100, a component of low density lipoprotein (LDL), serves as a ligand for the removal of LDL from the circulation by the LDL receptor. Genotyping of ApoAI and ApoB polymorphisms was carried out in 185 healthy Tamilian volunteers of south India after clinical examination. Lipid profile was estimated and polymorphisms were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The frequency of the rare M1-, M2- and R- alleles were 21%, 4.3% and 5.4%, respectively. An increase of 9.1 mg dL(-1) (0.23 mmol L(-1)) in HDL-cholesterol (HDL-C) levels was observed with M1-/- genotype when compared to M1+/+ genotype, which was not found after adjustments were made for confounding risk factors. A paradoxical increase in levels of total cholesterol and LDL-cholesterol (LDL-C) was observed with M2+/- genotype when compared to M2+/+ genotype. Analysis of combination of genotypes of ApoAI revealed no influence on the lipid parameters. ApoB EcoRI in contrast to ApoAI polymorphisms had no significant effect on lipid profile..

Association of polymorphisms in apolipoprotein A1 and apolipoprotein B genes with lipid profile in Tamilian population.

To study the influence of ApoAI and ApoB gene polymorphisms on lipid profile in healthy Tamilian volunteers of south India. Genotyping of ApoAI and ApoB polymorphisms was done in 185 subjects by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method.The frequency of the M1-, M2- and R- alleles were 21%, 4.3% and 5.4% respectively and were similar to that reported from Asian Indians. An increase of 9.1mg/dl in HDL-C levels was observed with M1-/- genotype when compared to M1+/+. A paradoxical increase in levels of total cholesterol and LDL-C was observed with M2+7divide;- genotype when compared to M2+/+ genotype. Analysis of combination of genotypes of ApoAI revealed no influence on the lipid parameters. ApoB EcoRI had no significant effect on lipid profile. For the first time genotype distribution of ApoAI and ApoB polymorphisms and their effect on lipid profile was established in Tamilians. Only -75G/A polymorphism of ApoAI was significantly associated with HDL7ndash;C levels.

Global Text Mining and Development of Pharmacogenomic Knowledge Resource for Precision Medicine.

Understanding patients' genomic variations and their effect in protecting or predisposing them to drug response phenotypes is important for providing personalized healthcare. Several studies have manually curated such genotype-phenotype relationships into organized databases from clinical trial data or published literature. However, there are no text mining tools available to extract high-accuracy information from such existing knowledge. In this work, we used a semiautomated text mining approach to retrieve a complete pharmacogenomic (PGx) resource integrating disease-drug-gene-polymorphism relationships to derive a global perspective for ease in therapeutic approaches. We used an R package, pubmed.mineR, to automatically retrieve PGx-related literature. We identified 1,753 disease types, and 666 drugs, associated with 4,132 genes and 33,942 polymorphisms collated from 180,088 publications. With further manual curation, we obtained a total of 2,304 PGx relationships. We evaluated our approach by performance (precision = 0.806) with benchmark datasets like Pharmacogenomic Knowledgebase (PharmGKB) (0.904), Online Mendelian Inheritance in Man (OMIM) (0.600), and The Comparative Toxicogenomics Database (CTD) (0.729). We validated our study by comparing our results with 362 commercially used the US- Food and drug administration (FDA)-approved drug labeling biomarkers. Of the 2,304 PGx relationships identified, 127 belonged to the FDA list of 362 approved pharmacogenomic markers, indicating that our semiautomated text mining approach may reveal significant PGx information with markers for drug response prediction. In addition, it is a scalable and state-of-art approach in curation for PGx clinical utility.