Cytomorphological alterations of thyroid gland consequent upon fluorosis

Background: Study aimed at assessing the impact of elevated fluoride from drinking water on thyroid gland structure and function in fluorosis prone areas. Iodine is incorporated in the thyroid synthesis by thyroid gland but in the presence of low Iodine levels fluoride is likely to interfere with the concentrating capacity of thyroid of iodine in thyroid production, consequently reflecting changes in thyroid parameters and also cytomorphological features manifesting hypothyroidism in association with different pathological entities.Methods: Prakasam district in Andhra Pradesh is fluorosis prone zone and subjects are picked up from highly vulnerable zone in this district and their specimens are collected to study cytomorphological changes of the thyroid gland and biochemical parameters of blood samples for thyroid function test were considered. Cytological study by way of Fine Needle Aspiration Cytology (FNAC) of thyroid gland, biochemical parameters pertaining to function of thyroid gland namely Free triiodothyronine (FT3), Free Thyroxine (FT4) and Thyroid stimulating hormone (TSH) were assessed in the subjects from fluorosis prone zone.Results: The results were statistically significant with concurrent association of different cytological alterations of thyroid gland in these subjects like Hashimoto’s thyroiditis of hypothyroidism, adenomatous goitre, colloid goitre and few of follicular adenoma/neoplasm. FNAC makes cytological changes evident showing different morphological features that comprise different pathological entities largely with an evidence of hypothyroidism in most of the cases in the given study.Conclusions: The results of the study strongly suggest assessing the magnitude of the problem of fluorosis and also magnitude of its influence on thyroid structure and function that warrants assessment of the thyroid function by biochemical and cytological studies

Application of machine learning tools for evaluating the impact of premenopausal hysterectomy on serum anti-mullerian hormone levels

245-251Women who have had premenopausal total hysterectomy at a young age could probably experience partial or total loss of ovarian function. The purpose of this retrospective cross-sectional study is to investigate the ovarian function in women underwent hysterectomy at an early age. A total of 1165 subjects comprised of 685 hysterectomised women and 480 age matched controls were enrolled in the study. We found that there is a steady decline in serum Anti Mullerian Hormone (AMH) levels, a marker of ovarian function after every five years post - hysterectomy in early age groups (20-30 yr and 31-40 yr) followed by loss of ovarian function in the age group of 40-50 yr. The application of multiple linear regression and machine learning tools has revealed that AMH is positively correlated with LH and estradiol and negatively correlated with age, FSH, years since hysterectomy and vitamin D. Serum AMH level of <0.08 ng/ml is associated with the increased of FSH, decreased LH and estradiol. The decreased ovarian function is associated with lower calcium levels, which are likely to influence the bone health. In conclusion, by utilizing multiple linear regression and machine learning tools, we found that serum FSH is the most important in predicting the AMH-mediated ovarian function

Application of machine learning tools for evaluating the impact of premenopausal hysterectomy on serum anti-mullerian hormone levels

Women who have had premenopausal total hysterectomy at a young age could probably experience partial or total loss of ovarian function. The purpose of this retrospective cross-sectional study is to investigate the ovarian function in women underwent hysterectomy at an early age. A total of 1165 subjects comprised of 685 hysterectomised women and 480 age matched controls were enrolled in the study. We found that there is a steady decline in serum Anti Mullerian Hormone (AMH) levels, a marker of ovarian function after every five years post - hysterectomy in early age groups (20-30 yr and 31-40 yr) followed by loss of ovarian function in the age group of 40-50 yr. The application of multiple linear regression and machine learning tools has revealed that AMH is positively correlated with LH and estradiol and negatively correlated with age, FSH, years since hysterectomy and vitamin D. Serum AMH level of &lt;0.08 ng/ml is associated with the increased of FSH, decreased LH and estradiol. The decreased ovarian function is associated with lower calcium levels, which are likely to influence the bone health. In conclusion, by utilizing multiple linear regression and machine learning tools, we found that serum FSH is the most important in predicting the AMH-mediated ovarian function

Association of brain-derived neurotrophic factor (Val66Met) polymorphism with the risk of Parkinson’s disease and influence on clinical outcome

192-201Parkinson’s disease (PD) is a common neurodegenerative disease. Motor symptoms of rigidity, tremor, and bradykinesia and non-motor symptoms like the cognitive deficit, autonomic dysfunction, dementia, anxiety and depression all contribute to morbidity. Emerging shreds of evidence suggest the role of BDNF (Val66Met) polymorphism in PD risk and associated cognitive deficit. Hence, the current study is aimed to investigate the role of BDNF Val66Met in the risk of PD development and associated cognitive abnormalities. A total of 269 PD cases and 271 healthy, age, ethnicity and gender matched controls were recruited in the study. Genomic DNA was isolated, amplified and SNP was identified using the RFLP method and validated by Sanger’s sequencing. There was a significant association of BDNF Val66Met with PD risk in both Dominant and recessive models (GG vs GA+AA: OR: 1.47, CI: 1.04-2.09, P =0.03, GG+GA vs AA: OR: 2.32, CI: 1.07-5.00, P =0.02). The main nonmotor symptom i.e. cognitive impairment was significantly associated with the variant genotype of BDNF Val66Met Polymorphism (GG vs GA+AA: OR: 1.47, CI: 1.04-2.09, P =0.03, GG+GA vs AA: OR: 2.32, CI: 1.07-5.00, P =0.02).We found a significant association of variant genotype with disease severity, the activity of daily living as assessed by S & E score as it was found to better with wild genotype and a significant decrease in quality of life with homozygous mutant genotype. We did not find significant differences in disease duration, absolute levodopa response among the genotypes. Our results implicate BDNF Val66Met polymorphism is associated with the risk of PD, cognitive impairment, poor quality of life and greater disease severity in PD

Association of brain-derived neurotrophic factor (Val66Met) polymorphism with the risk of Parkinson’s disease and influence on clinical outcome

Parkinson’s disease (PD) is a common neurodegenerative disease. Motor symptoms of rigidity, tremor, and bradykinesia and non-motor symptoms like the cognitive deficit, autonomic dysfunction, dementia, anxiety and depression all contribute to morbidity. Emerging shreds of evidence suggest the role of BDNF (Val66Met) polymorphism in PD risk and associated cognitive deficit. Hence, the current study is aimed to investigate the role of BDNF Val66Met in the risk of PD development and associated cognitive abnormalities. A total of 269 PD cases and 271 healthy, age, ethnicity and gender matched controls were recruited in the study. Genomic DNA was isolated, amplified and SNP was identified using the RFLP method and validated by Sanger’s sequencing. There was a significant association of BDNF Val66Met with PD risk in both Dominant and recessive models (GG vs GA+AA: OR: 1.47, CI: 1.04-2.09, P =0.03, GG+GA vs AA: OR: 2.32, CI: 1.07-5.00, P =0.02). The main nonmotor symptom i.e. cognitive impairment was significantly associated with the variant genotype of BDNF Val66Met Polymorphism (GG vs GA+AA: OR: 1.47, CI: 1.04-2.09, P =0.03, GG+GA vs AA: OR: 2.32, CI: 1.07-5.00, P =0.02).We found a significant association of variant genotype with disease severity, the activity of daily living as assessed by S &amp; E score as it was found to better with wild genotype and a significant decrease in quality of life with homozygous mutant genotype. We did not find significant differences in disease duration, absolute levodopa response among the genotypes. Our results implicate BDNF Val66Met polymorphism is associated with the risk of PD, cognitive impairment, poor quality of life and greater disease severity in PD

Association of SLC6A3 gene polymorphisms with the pharmacokinetics of Levodopa and clinical outcome in patients with Parkinson’s disease

202-212Levodopa (LD) is the gold standard for the treatment of Parkinson’s disease (PD). Genetic polymorphisms in the SLC6A3 gene (Solute carrier family 6 member 3/DAT-Dopamine Transporter gene) are shown to have a functional impact on levodopa therapeutic response, motor complications of PD and adverse events. Hence the present study was carried out to investigate the association of SLC6A3 polymorphisms with the pharmacokinetics of levodopa and clinical response. A total of 150 PD patients were recruited in the study. Plasma levodopa was analysed by HPLC at 0, 1, 2, 3 and 4 h post levodopa administration and AUC was calculated. Genotyping of SLC6A3 40 bp VNTR and SLC6A3 rs393795 (G>T) polymorphisms was done by the PCR-RFLP method. The result shows that AUC of levodopa was significantly higher in patients carrying homozygous10/10 genotype (P =0008) compared to 9/9 genotype of SLC6A3 40 bp VNTR polymorphism. A similar difference was also observed in early-onset Parkinson’s disease (EOPD) and late-onset Parkinson’s disease (LOPD) groups. SLC6A310/10 genotype was found to be significantly associated with disease severity (P =0.05) compared with the 9/10 genotype in the EOPD group, however, there was no significant association with dyskinesia. To conclude, patients carrying SLC6A3 40VNTR 10/10 genotype were found to have higher levodopa exposure, disease severity and prone to further neurodegeneration

Association of SLC6A3 gene polymorphisms with the pharmacokinetics of Levodopa and clinical outcome in patients with Parkinson’s disease

Levodopa (LD) is the gold standard for the treatment of Parkinson’s disease (PD). Genetic polymorphisms in the SLC6A3 gene (Solute carrier family 6 member 3/DAT-Dopamine Transporter gene) are shown to have a functional impact on levodopa therapeutic response, motor complications of PD and adverse events. Hence the present study was carried out to investigate the association of SLC6A3 polymorphisms with the pharmacokinetics of levodopa and clinical response. A total of 150 PD patients were recruited in the study. Plasma levodopa was analysed by HPLC at 0, 1, 2, 3 and 4 h post levodopa administration and AUC was calculated. Genotyping of SLC6A3 40 bp VNTR and SLC6A3 rs393795 (G&gt;T) polymorphisms was done by the PCR-RFLP method. The result shows that AUC of levodopa was significantly higher in patients carrying homozygous10/10 genotype (P =0008) compared to 9/9 genotype of SLC6A3 40 bp VNTR polymorphism. A similar difference was also observed in early-onset Parkinson’s disease (EOPD) and late-onset Parkinson’s disease (LOPD) groups. SLC6A310/10 genotype was found to be significantly associated with disease severity (P =0.05) compared with the 9/10 genotype in the EOPD group, however, there was no significant association with dyskinesia. To conclude, patients carrying SLC6A3 40VNTR 10/10 genotype were found to have higher levodopa exposure, disease severity and prone to further neurodegeneration

Molecular mechanism of interaction of mitocurcumin-1 with Akt1 and STAT3: An <i>In silico</i> approach

308-313The bioavailability of curcumin is the limiting factor for its effective use in anti-cancer therapy. Recently, we reported a novel approach to enhance the cellular uptake by conjugating curcumin with triphenyl phosphonium, named mitocurcumin-1. We found that such conjugation significantly increased the uptake of curcumin in various cancer cells and caused cancer cell death by inducing apoptosis by decreasing the phosphorylation of Akt1 (Thr308) and STAT3 (Tyr705). In this study, a molecular mechanistic model deciphering the regulation of phosphorylation of Akt1 and STAT3 by mitocurcumin-1 was investigated and compared with curcumin. The protein structures were obtained from protein data bank data base and protein-ligand interaction studies were performed with mitocurcumin-1 and curcumin. Docking interaction studies of mitocurcumin-1 with Akt1 and STAT3 active sites showed a strong binding affinity of -60.4107 Kcal/mol and -51.1734 Kcal/mol respectively, suggesting mitocurcumin-1 interacted with the residues at the active sites of phosphorylation of these molecules. Further, a Chi rotationary root mean square deviation of 1.468 Å and 3.965 Å at the active sites in Akt1 and STAT3, respectively indicated that changes in the conformation of protein structure at the active site resulted in the inhibition of phosphorylation of these molecules. To conclude, by using molecular modeling approaches for the first time, we demonstrated the inhibition of Akt1 and STAT3 phosphorylation by mitocurcumin-1

Association of GSTT1 and GSTM1 polymorphisms in South Indian Epilepsy Patients

783-787Experimental studies suggest that oxidative stress is one of the contributing factors in the onset of epileptic seizures. Glutathione S-transferases (GSTs) are able to conjugate electrophilic compounds, and thus possess neuroprotective role by removing exogenous and endogenous oxidants, detoxifying therapeutic drugs, environmental toxins through conjugation with glutathione (GSH). Several studies from different ethnic groups showed that polymorphisms of the GST gene have been associated with Epilepsy. In the present study, we investigated the association of GST polymorphism in the South Indian epilepsy patients population. A total 371 samples (110 cases and 261 controls) were genotyped for the GST1 and GSTM1 polymorphism by multiplex PCR method. We observed a significant association of GSTT1 null polymorphism in patients with epilepsy. The frequency of the GSTT1 null genotype was found to be significantly higher in cases (35.45 %) than the controls (18.39 %) (OR: 2.44, 95%CI: 1.4-4.02, P <0.0001). In contrast, the frequency of the GSTM1 null variant was significantly lower in cases (11.81%) than controls (32.95%) (OR: 0.27, 95%CI: 0.14-0.51, P <0.001) indicating a protective role. These results indicated that individuals who have GSTT1 null variant are at higher risk for developing seizure than those of GSTT1 wild genotype. On the other hand, individuals carrying GSTM1 null variant showed protective role against seizure. Further, these two null variants did not show any significant association with antiepileptic drug-induced skin rash