Genetic Insights Into Latent Autoimmune Diabetes In Adults

‘Latent autoimmune diabetes in adults’ (LADA) is a controversial subtype of diabetes characterized by initial insulin independency and the presence of diabetes associated autoantibodies. As a result, LADA is often misclassified and can represent 5-10% of apparent type 2 diabetes (T2D) cases and is potentially more prevalent than childhood-onset type 1 diabetes (T1D). Despite LADA sharing features with the two better characterized classic diabetes subtypes, the genetic etiology of LADA remains largely unknown. Once there is a more accurate definition of LADA, there will be an improvement in diabetes classification and consequently better treatment and therapeutic interventions. The objective of this thesis is to understand the genetic basis of LADA in order to bring clarity to the current definition of LADA by being the first to leverage genome-wide genotype data from a LADA cohort and the subsequent application of statistical genetics approaches. These investigations can be divided into three parts: 1) the role of T1D and T2D loci in LADA 2) the first genome-wide association study (GWAS) of LADA, and 3) searching for genetic discrepancies between LADA and childhood-onset T1D in the human leukocyte antigen (HLA) region. Four out of the five strongest associations from the candidate locus study were known T1D loci (HLA, PTPN22, INS and SH2B3) and reached genome-wide significance in the GWAS meta-analysis. However, a novel independent signal at a known T1D locus was also observed to be genome-wide significant, near the PFKFB3 gene, which had not been implicated in previous T1D or T2D GWAS. Additionally, major T1D-susceptibility HLA haplotypes were observed to be less frequent in LADA. Furthermore, contrary to observations in childhood-onset T1D studies, HLA-B and HLA-A, were not significantly associated with LADA, independent of HLA-DQB1 and HLA-DRB1 haplotypes. Overall, the genetics of LADA point to a strong T1D component, but a positive genetic correlation between LADA and T2D is also evident, strongly suggesting LADA has both a T1D and T2D component. However, it remains unresolved whether LADA is at the genetic intersection of T1D and T2D or simply a mixture of relatively poorly phenotyped individuals who have either T1D or T2D

AN AYURVEDIC AND CONTEMPORARY OVERVIEW OF MENOPAUSE: A CONCEPTUAL APPROACH

Menopause is generally defined as the cessation of menses for period of 12 months or a period equivalent to three previous cycles or the time of cessation of ovarian function resulting in permanent amenorrhea. During the period of menopause the women enters an estrogen deficient phase which leads to the various symptoms. This period is generally associated with manifestation of aging process in women. Other symptoms include hot flushes, sweating, mood changes, loss of libido etc. These symptoms affect the quality of life of the female.Hormone Replacement Therapy (HRT) is the only alternative available for menopausal syndrome in modern medicine. It also has a wide range of side effects on the body of the female.In Ayurveda the context of menopause is depicted as “Jarapakwa avastha†of body and Rajonivrutti. Rajonivrutti janya laksana is a group of symptoms produced by degenerative changes in the body. Degenerative changes are explained in Ayurveda as Dhatukshaya lakshana. Vata dosha dominance is seen in the later stage of life. To combat the degenerative process of the body tissue, Acharyas have described Rasayana Chikitsa. Rasayana includes drugs which promotes longevity and improve the quality of life. Thus an effort is being made here, to study the effect of Rasayana therapy, on Menopausal syndrome, conceptually, based on Available information in Ayurvedic texts and other contemporary resources. The basic Rationale for this study is to establish a reliable platform for further Research on the Said subject

Antifungal Activity of Alcoholic Leaf Extracts of Terminalia Catappa and Terminalia Arjuna on Some Pathogenic and Allergenic Fungi

Abstract Ethanol and methanol leaf extracts of Terminalia catappa and Terminalia arjuna were investigated for in-vitro antifungal activity. Four fungi tested were Aspergillus niger, Alternaria alternata, Curvularia lunata and Trychophyton tonsurans.The in-vitro antifungal activity was evaluated by food poison technique. Both the plants should antifungal activity on comparision with T. arjuna better antifungal efficacy was shown by methanol extract of T. catappa. Methanol extract showed significant antifungal activity against most susceptible mould was Curvularia lunata. The results were compared with standard antifungals. Key words: Terminalia species, medicinal plants, antifungal activity, Aspergillus niger, Alternaria alternata, Curvularia lunata, Trychophyton tonsurans, pathogenic, allergenic in-vivo

Multi-objective probabilistic fractional programming problem involving two parameters Cauchy distribution

The paper presents the solution methodology of a multi-objective probabilistic fractional programming problem, where the parameters of the right hand side constraints follow Cauchy distribution. The proposed mathematical model can not be solved directly. The solution procedure is completed in three steps. In first step, multi-objective probabilistic fractional programming problem is converted to deterministic multi-objective fractional mathematical programming problem. In the second step, it is converted to its equivalent multi-objective mathematical programming problem. Finally, ε -constraint method is applied to find the best compromise solution. A numerical example and application are presented to demonstrate the procedure of proposed mathematical model.

Urinary tract infections at first antenatal check-up: a single centre prospective study

Background: Pregnant women with asymptomatic bacteriuria (ASB) are more likely to develop acute pyelonephritis, postpartum UTI, hypertensive disease, anemia, prematurity, low birth weight babies and prenatal death if untreated.Methods: Total 780 pregnant women attending for first antenatal check-up in a medical college were enrolled for the study. Those with any symptoms of UTI, like burning micturition, frequency, urgency, dysuria or fever were excluded from the study. All were subjected to undergo urine culture and sensitivity to the commonly used antibiotics in that area, irrespective of period of gestation, age and parity. Prevalence of ASB, most common infecting organism and antibiotic sensitivity pattern were analyzed.Results: The prevalence of ASB in 25 years age group (26.06% versus 18.80%; p = 0.020). Out of the 780 culture samples, 52 had more than 3 type colonies indicating contamination and 22 had budding yeast colonies, thus excluded from the study. No growth was found in 551 samples (78.05%). The prevalence of ASB was 21.95%. The most common organism isolated was ESBL-ve E coli (32.25%), followed by ESBL +ve E coli (21.29%) and Enterococcus (15.48%) respectively. E coli were mostly sensitive to nitrofurantoin, amikacin and cotrimoxazole whereas enteroccocus was sensitive to vancomycin.Conclusions: ASB is more common during pregnancy even in first antenatal check-up. We suggest routine urine culture and sensitivity during first antenatal check-up to detect ASB and treat with proper antibiotic to prevent the complications and development of resistance

Microgravity induces proteomics changes involved in endoplasmic reticulum stress and mitochondrial protection

On Earth, biological systems have evolved in response to environmental stressors, interactions dictated by physical forces that include gravity. The absence of gravity is an extreme stressor and the impact of its absence on biological systems is ill-defined. Astronauts who have spent extended time under conditions of minimal gravity (microgravity) experience an array of biological alterations, including perturbations in cardiovascular function. We hypothesized that physiological perturbations in cardiac function in microgravity may be a consequence of alterations in molecular and organellar dynamics within the cellular milieu of cardiomyocytes. We used a combination of mass spectrometry-based approaches to compare the relative abundance and turnover rates of 848 and 196 proteins, respectively, in rat neonatal cardiomyocytes exposed to simulated microgravity or normal gravity. Gene functional enrichment analysis of these data suggested that the protein content and function of the mitochondria, ribosomes, and endoplasmic reticulum were differentially modulated in microgravity. We confirmed experimentally that in microgravity protein synthesis was decreased while apoptosis, cell viability, and protein degradation were largely unaffected. These data support our conclusion that in microgravity cardiomyocytes attempt to maintain mitochondrial homeostasis at the expense of protein synthesis. The overall response to this stress may culminate in cardiac muscle atrophy

Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation

Abstract Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing V max and K m. Pharmacological activation of AMP‐activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF‐1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF‐1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia

Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC

OBJECTIVE The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS The strongest associations in the MHC class II region (rs3957146, beta [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (beta [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, beta [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.Peer reviewe

Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes

Background: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. Methods: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 nondiabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls. Results: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted. Conclusion: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes