Dopamine Gene Polymorphism, Biochemical and Oxidative Stress Parameters in Geriatric Population with and Without Depression: A Pilot Study.

Dopamine transporter takes released dopamine back into presynaptic terminals and has been implicated in several aging disorders including depression. The present study was designed to demonstrate dopamine gene polymorphism, its circulatory levels, biochemical and oxidative stress parameters in geriatric population with and without depression. Thirty geriatric patients with depression and thirty age and sex matched normal controls were genotyped for Dopamine Active Transporter (DAT TaqA1 and DAT VNTR) gene polymorphisms using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method. The frequency of genotypes and alleles were compared in study groups. Biochemical markers, oxidative stress parameters, and dopamine levels were also measured using standard protocols and compared between patients and controls. The frequency distribution of DAT TaqA1 and DAT VNTR genotypes and alleles in patients were not statistically significant as compared to controls. At DAT TaqA1 gene polymorphism we found that the levels of dopamine were significantly high in genotypes A1A2 as compared to A2A2 (p ≤ 0.01). The present study demonstrated elevated levels of Catalase, Lipid Peroxide, and Glutathione Reductase, whereas decreased levels of Superoxide Dismutase, Dehydroepiandrosterone, Glutathione Peroxidase and Melatonin, in depressive patients as compared to controls. Our results clearly suggested that elevated mean levels of Catalase, Lipid Peroxides and Glutathione Reductase and decreased levels of Dehydroepiandrosterone, Superoxide Dismutase, Glutathione Peroxidase and Melatonin in depressed individuals may be a consequence of depression. Moreover, DAT TaqA1 allele A1 has a protective effect with high dopamine levels and DAT VNTR genotype 10R/10R has the highest protective effect followed by 9R/10R and 10R/11R.

Association of Vitamin D Receptor (FokI and BsmI) Gene Polymorphism with Bone Mineral Density and Their Effect on 25-Hydroxyvitamin D Level in North Indian Postmenopausal Women with Osteoporosis.

Osteoporosis is a systemic disease with a strong genetic component. Vitamin D receptor (VDR) has been suggested as a candidate gene for osteoporosis. Therefore the present study was aimed to investigate the pattern of allelic variants of VDR gene polymorphism (FokI and BsmI), its influence on vitamin D levels and bone mineral density (BMD) in North Indian postmenopausal women with osteoporosis for possible genetic association. 254 postmenopausal osteoporotic women and 254 postmenopausal non osteoporotic women were included in the study. VDR FokI and BsmI gene polymorphism gene were assessed by the PCR-RFLP method. Serum 25-hydroxyvitamin D was measured by the ELISA. BMD at the L1-L4 lumbar spine, hip, forearm and femoral neck was assessed by dual energy X-ray absorptiometry. The average BMD at spine and hip in postmenopausal women with bb and spine, hip, femoral neck and forearm with ff genotype had significantly low BMD. The frequency of ff genotype and f allele was significantly higher in postmenopausal osteoporotic women when compared with postmenopausal non osteoporotic women. However, no significant association was found between the genotypes and vitamin D levels. Our study reveals that VDR gene FokI and BsmI polymorphism is significantly associated with low bone mineral density. Therefore the ff genotype and f allele of VDR FokI gene may be used as an important risk factor for osteoporosis.

Osteocalcin HindIII gene polymorphism not associated with bone mineral density­A study in North Indian postmenopausal osteoporotic women.

Osteoporosis is an important health problem in India owing to the prevalence of vitamin D deficiency across all ages, low level of awareness and higher risk of complications. This disease is characterized by decreased bone mass, bone strength and higher risk of bone fracture. Here, we investigated association between osteocalcin HindIII gene polymorphism and bone mineral density (BMD) in postmenopausal osteoporotic and postmenopausal healthy North Indian women, possibly the first study of this kind in the aforesaid population. We investigated Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) of osteocalcin HindIII in 254 postmenopausal osteoporotic (56.12±7.004 years) and 254 postmenopausal healthy (55.27±5.93 years) North Indian women. BMD at lumbar spine (L1-L4), femoral neck, hip and forearm was measured by dual energy X-ray absorptiometry (DEXA). The results showed no significant correlation between osteocalcin HindIII gene polymorphism and BMD and we conclude that osteocalcin HindIII gene polymorphism may not have major effects on BMD variation in postmenopausal North Indian women.

Association of TNF-α promoter gene G-308A polymorphism with metabolic syndrome, insulin resistance, serum TNF-α and leptin levels in Indian adult women.

BACKGROUND: Tumour necrosis factor alpha is a multifunctional proinflammatory cytokine involved in the pathogenesis of metabolic syndrome, insulin resistance, and obesity. Aim of this study is to investigate in a North Indian female population the impact of the G-308A TNF-α variant on various components of the metabolic syndrome, Insulin Resistance, serum TNF-α and Leptin levels. METHODS: The G-308A TNF-α polymorphism has been studied in 269 females with metabolic syndrome (NCEP ATP III criteria) (age 31.91±6.05) and 272 healthy females without metabolic syndrome (age 30.96±7.01). The G-308A variant was detected by PCR amplification and Nco-1 digestion. RESULTS: Homozygous mutant genotype (AA) (p=<0.001: OR=3.24: 95% CI=2.15-4.89) and mutant allele (A) (p=<0.001: OR=3.04: 95% CI=2.08-4.43) of TNF-α was significantly less frequently observed in the control population as compared to study group. Furthermore, on dividing the subjects into two groups according to the absence (TNF-1 allele) or presence of the mutant A (TNF-2) allele, significant results were obtained in most of the metabolic risk factors. CONCLUSIONS: Our results suggest that the G-308A polymorphism of the TNF-α gene may be independently associated with hypertension, leptin level and hypercholesterolemia leading to metabolic syndrome independent of Insulin resistance and hyperglycemia.

MDR-1 gene polymorphisms in steroid-responsive versus steroid-resistant nephrotic syndrome in children.

BACKGROUND: The putative genetic regulation of multidrug resistance gene-1 (MDR-1) gene expression and P-glycoprotein function has not yet been clearly delineated in patients with nephrotic syndrome (NS). We undertook this study to examine the distribution of three most frequent MDR-1 exonic polymorphisms G3435C, G2677T/A and C1236T in patients with NS and control children to investigate their usefulness as markers of responsiveness of the disease to steroids. METHODS: Two hundred and sixteen children with NS and 216 healthy controls were genotyped for three exonic MDR-1 polymorphisms (G3435C, G2677T/A and C1236T) by using the polymerase chain reaction-restriction fragment length polymorphism technique. The frequency distribution of genotypes/alleles was compared between patients with NS and controls and also between steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS) patients. RESULTS: Of the total 216 cases of NS (median age of onset 5 years, 165 males), 137 had SSNS, and 79 had SRNS. Homozygous mutants of C3435T (TT versus CC, P = 0.034) and G2677T/A (TT + AA versus GG), P = 0.030) were significantly higher in patients with NS compared to controls. The frequency distribution of homozygous mutant TT + AA compared to wild genotype GG was significantly higher in SRNS than SSNS patients (P = 0.011) for G2677T/A, while the mutant genotypes for C3435T and C1236T were not different between SRNS and SSNS patients. The combination-bearing mutant genotype either of C3435T or G2677T/A exhibited a significantly higher frequency of mutant genotypes distribution in SRNS patients. MDR-1 haplotypes did not differ significantly between SSNS and SRNS patients. CONCLUSIONS: Patients with NS carrying homozygous mutants of single nucleotide polymorphism (SNP) G2677T/A are prone to develop SRNS. The synergistic effect of mutant genotypes of SNPs G2677T/A and C3435T in different combinations increase the risk of developing steroid resistance in patients with NS.

Blood Lead Levels in Children Living Near an Informal Lead Battery Recycling Workshop in Patna, Bihar.

BACKGROUND: Lead can cause significant biological and neurologic damage, even at small concentrations, and young children are at higher risk. Informal recycling of lead batteries and lead-based workshops/industries have increased the burden of lead toxicity in developing countries, including India. Many informal recycling lead battery workshops have been established by the local people of Patna, Bihar as self-employment opportunities. However, most of the residents are not aware of the risk factors associated with lead poisoning. OBJECTIVES: The present pilot study aimed to assess blood lead levels (BLLs) and hemoglobin levels among children aged between 3 to 12 years in the settlement of Karmalichak near Patna, India. MATERIALS AND METHODS: Children residing near the informal lead battery manufacturing unit were selected for BLL assessment. A total of 41 children were enrolled in the questionnairebased survey. RESULTS: All the children in the present study had detectable lead concentrations in their blood. Only 9% of the studied children had a BLL ≤5 µg/dl, while 91% children had a BLL above >5 µg/dl. CONCLUSIONS: The present study carried out in children of Karmalichak region of Patna, India was an attempt to better understand the problem of lead toxicity, describe the epidemiology of its adverse effects, identify sources and routes of exposure, illustrate the clinical effects and develop strategies of prevention so that remedial measures may be taken by government agencies and regulatory bodies. In view of the high lead levels in children in the study area, attempts are being made to develop strategies for future prevention by relocating the informal battery recycling workshops from the area. Moreover, parents have been advised to increase nutritional supplementation of children by providing calcium-, iron- and zinc-rich foods, including milk and vegetables. PARTICIPANT CONSENT: Obtained. ETHICAL APPROVAL: The study was approved by the ethical committee of Era's Lucknow Medical College & Hospital, Era University, Lucknow (India). COMPETING INTERESTS: The authors declare no competing financial interests.

Case of Lead Poisoning Associated with Herbal Health Supplements.

BACKGROUND: Lead poisoning is a chronic health condition arising from prolonged ingestion and exposure to lead above permissible limits. Although reported globally, developing countries like India and neighboring countries are amongst the most affected by lead. OBJECTIVES: The aim of the present study was to evaluate lead poisoning associated with herbal health supplements in a suspected case. MATERIALS AND METHODS: A 31-year-old male reported consuming sixteen different herbal health supplements. The case and supplements were assessed for lead levels. The patient came from one of the metro cities of Uttar Pradesh state, India. RESULTS: The blood lead level of the case was found to be 78.40 µg/dL, which was much higher than the permissible limit of ≤5 µg/dL. Moreover, one of the supplements was found to have a very high lead content. CONCLUSIONS: The present study demonstrated a case of lead poisoning which was very likely due to high lead content present in one of the supplements. The case had typical neurological signs of lead toxicity such as irritability, frequent headache, mental dullness, generalized pain, muscle weakness, numbness and tingling, and twitching and shaking of the legs while sleeping. PATIENT CONSENT: Obtained. COMPETING INTERESTS: The authors declare no competing financial interests.

Induction of apoptosis by piperine in human cervical adenocarcinoma via ROS mediated mitochondrial pathway and caspase-3 activation.

Piperine (1-piperoylpeperdine), a nitrogenous pungent substance, is present in the fruits of black pepper (Piper nigrum Linn.) and long pepper (Piper longum Linn.). It possesses several pharmacological properties and has been extensively explored for its anti-cancerous activities. The mechanism underlying its anti-cancer potential in human cervical adenocarcinoma (HeLa) cells is not well interpreted. The anti-proliferative effect and the mode of action of piperine were investigated through some potent markers of apoptosis viz.reactive oxygen species (ROS) generation, cellular apoptosis and loss of mitochondrial membrane potential (MMP). DNA fragmentation, cell cycle kinetics, caspase-3 activity and cell migration assays were also conducted to observe the efficacy of piperine against HeLa cells. The results showed that piperine exposure induces apoptosis significantly in a dose-dependent manner and inhibits the growth of HeLa cells with an increase in ROS generation, nuclear condensation and delayed wound healing. In addition, piperine also encourages cell death by the loss of MMP, DNA fragmentation and the activation of caspase-3. Growth inhibition of HeLa cells was found to be associated with G2/M phase arrest and sub-G1 accumulation. The present study provides useful insight into the apoptotic potential of piperine and further in vivo and clinical studies will be needed for its validation and in the finding of more effective and least toxic regimens against cervical cancer.

Does cytokine gene polymorphism affect steroid responses in idiopathic nephrotic syndrome?

BACKGROUND: Immunological responses may be possibly involved in the pathogenesis of idiopathic nephrotic syndrome (INS). Cytokines act as a potent immunomodulator. Pathogenesis of INS is associated with Th1 and Th2 cytokines imbalance. AIMS, SETTINGS AND DESIGN: We have investigated the association of IL-4, IL-6, and TNF-alpha gene polymorphisms and analyzed the data to evaluate the effect of these polymorphisms on the pathogenesis and clinical course of INS. MATERIALS AND METHODS: One hundred fifty children with INS were selected. Children were analyzed for IL-4, IL-6, and TNF-alpha gene polymorphisms by using polymerase chain reaction and restriction fragment length polymorphism. STATISTICAL ANALYSIS USED: Chi-square test was used for different comparisons. The synergistic effects of IL-4, IL-6, and TNF-alpha gene polymorphisms were evaluated by using logistic regression analysis. RESULTS AND CONCLUSIONS: We compared the steroid-resistant (SR) and steroid-responsive (SS) groups. Our results showed strong association of IL-6 -G174C, and IL-4 -C590T at genotypic level (P = 0.0121, OR = 14.71, 95% CI = 1.59-136.46; and P = 0.0386, OR = 7.29, 95% CI = 1.26-41.69). TNF-alpha revealed a strong association at genotypic level (P = 0.0121, OR = 14.71, 95% CI = 1.59-136.46), as well as at allelic level (P = 0.0433, OR = 2.251, 95% CI = 1.09-4.66), demonstrating that it may be considered one of the genetic risk factors affecting the steroid response in INS patients. The GG genotype of IL-6 -G174C, TT genotype of IL-4 -C590T, and AA genotype of TNF-alpha -G308A cytokine gene polymorphisms may be causative factors for nonresponsiveness towards steroid therapy among INS children.

Association of vitamin D receptor gene polymorphism (TaqI and Apa1) with bone mineral density in North Indian postmenopausal women.

Vitamin D receptor (VDR) gene has an important role as a candidate gene for the regulation of bone mass in osteoporosis. However, its association with bone mineral density (BMD) is controversial and has not been established in different ethnic populations. To enhance the understanding of VDR gene polymorphism in the context of BMD, we investigated the plausible genetic association of TaqI and ApaI polymorphism with BMD in North Indian postmenopausal women with osteoporosis.254 osteoporotic women (Age 55.82 ±â€¯6.91) and 254 postmenopausal non osteoporotic women (Age 54.76 ±â€¯6.26) were included in the study. VDR TaqI and ApaI polymorphism were determined by PCR (polymerase chain reaction) and RFLP (restriction fragment length polymorphism). BMD was assessed by dual energy X-ray absorptiometry (DXA) at the lumbar spine (L1-L4), hip, forearm and femoral neck. The average BMD with TT genotype was significantly lower at lumbar spine, hip and forearm. The Frequency of TT genotype and t allele was significantly high in osteoporotic women when compared with controls. The average BMD with Aa genotype was higher in ApaI. Furthermore, comparison of frequency distribution of genotype and allele for VDR ApaI between osteoporotic patients and controls did not show any significant difference. Our findings revealed that TaqI gene TT genotype was associated with low BMD in North Indian osteoporotic women. Moreover, TT genotype and t allele associated significantly with osteoporosis in postmenopausal women. Therefore, VDR TaqI gene is an important determinant of risk factor for osteoporosis.

Cytokine gene polymorphism in idiopathic nephrotic syndrome children.

The pathogenesis of idiopathic nephrotic syndrome is not completely understood. We postulate that cytokine gene polymorphisms may influence susceptibility or clinical course in Idiopathic Nephrotic Syndrome. Polymorphisms of IL-4, IL-6, and TNF-α cytokines were investigated in 150 children with Idiopathic Nephrotic Syndrome and 569 healthy controls by using polymerase chain reaction and restriction fragment length polymorphism. On comparing patient with controls strong association were found for IL-6, TNF-α and IL-4 at allelic level (IL-6-G174C (G vs. C): P = <0.001; OR = 6.33, TNF-α-G308A (G vs. A): P = <0.001; OR = 1.99, IL-4-C590T (C vs. T): P = 0.048; OR = 1.38). Further when SR group was compared with SS group significant association was found at genotypic level in all the studied genetic polymorphisms. Studied cytokine gene polymorphisms may influence susceptibility to idiopathic nephrotic syndrome and might affect steroid response in INS patients.

Genetic risk factors for renal failure among north Indian ESRD patients.

OBJECTIVES: Angiotensin converting enzyme (ACE), G-Protein couple receptor (G-Prot), endothelial nitric oxide synthase (ecNOS), Leptin -2548G/A and uncoupling protein (UCP2) are potent regulators of intra renal hemodynamics and may be the causative factors contributing to the deterioration of renal functions. In recent years few studies have been published to show the association of these markers with the end stage renal disease (ESRD). Our study was designed to see the role of different genetic factors individually and synergistically in the progression of renal failure. DESIGN AND METHODS: The genotypes of these markers were determined by PCR and RFLP. The gene frequencies of ACE, G-protein, ecNOS, Leptin and UCP2 in 184 ESRD patients and 569 healthy controls from North India were compared. RESULTS: There was a significant difference between ESRD patients and control groups both in the biochemical parameters and genotype frequencies. The genotype distribution of ACE in patients was significantly different from the controls (p=0.0001; OR=9.428; 95% CI=4.56-19.492). There was no difference observed for the GNB3-825 TT genotype and for ecNOS aa genotype in patient and control groups. The distribution of Leptin -2548G/A genotype and UCP2 genotype in patients were significantly different from that of controls (p=0.0013; OR=2.804; 95% CI=1.501-5.237 and p=0.0001; OR=8.853; 95% CI=3.458-22.667 respectively). CONCLUSIONS: Our results propose that the ACE-DD, Leptin AA and UCP2-DD genotype may be potential genetic markers for predicting the causation and progression of chronic renal failures.

Do glutathione-S-transferase polymorphisms influence response to intravenous cyclophosphamide therapy in idiopathic nephrotic syndrome?

The response to cyclophosphamide (CP) is variable and difficult to predict in children with idiopathic nephrotic syndrome (INS). The polymorphic expression of glutathione-S-transferase (GST) may affect the remission rate after CP therapy. In this study, we evaluated the correlation of GST polymorphism and response to CP in INS. We studied GST polymorphism in 74 children with steroid-sensitive (44) and steroid-resistant (30) INS receiving intravenous cyclophosphamide (IVCP) therapy. We correlated GSTM1, GSTT1, and GSTP1 genotypes with response to IVCP. Thirty-seven (50%) out of 74 children responded to CP therapy. A synergistic effect of three genotypic combinations showed significant correlation with remission in the steroid-sensitive group. These combinations were GSTP1 and GSTM1 null genotype (p = 0.013) and GSTP1 together with GSTM1 and GSTT1 null genotypes (p = 0.026). Further, a significant difference was observed with a combination of GSTM1 and GSTT1 null genotypes and Val105 polymorphism. No association was observed among steroid-resistant patients. Our results indicate that among children with steroid-sensitive NS, there is an association with response to IVCP therapy and combination of GSTP1 Val105 polymorphism and the null genotypes of GSTT1 and GSTM1. GST polymorphism may be of significance in the management of children with INS receiving CP therapy.