Paleogene Ficus leaves from India and their implications for fig evolution and diversification.

PREMISE: Ficus is a scientifically and economically important genus with abundant fossil records from the Paleocene to Pleistocene, but with an intriguing early evolutionary history that remains unresolved. Here, the foliage of three well-preserved figs is described from the early Paleogene succession of the Gurha mine, Rajasthan, India. These fossils provide new morphological data that strengthens our understanding of the past occurrences of Ficus and, alongside all validly published records of fossil figs, helps to trace the evolutionary history of figs. METHODS: Fossils were identified and described by comparison with their closest modern analogs using the Nearest Living Relative (NLR) technique. Validated fig records are listed and categorized into six geological time frames. Modern precipitation data for the current distributions of NLRs were downloaded from the Climatic Research Unit Timeseries. RESULTS: Fossil leaves assigned to three new species Ficus paleodicranostyla, F. paleovariegata, and F. paleoauriculata closely resemble their modern analogs based on leaf morphology. Reliable fossil records were used to hypothesize historical fig distributions and paleodispersal pathways. Precipitation data suggest higher precipitations at the fossil locality during the early Paleogene than at present. CONCLUSIONS: The fossils described herein supplement fig fossil records known from other regions indicating that figs were widely diverse across low latitudes by the early Paleogene. These data support a Eurasian origin for figs, highlight a pivotal role for the Indian subcontinent during the early phase of fig diversification, and depict a perhumid-to-humid climate with high rainfall concordant with paleoclimate evidence from the Gurha mine.

Risk factors of breast cancer and breast self-examination in early detection: systematic review of awareness among Indian women in community and health care professionals.

BACKGROUND: This review aims at evaluating the awareness of risk factors for breast cancer (BC) and the knowledge of breast self-examination (BSE) among Indian women and health care professionals (HCPs). METHODS: Literature search was conducted on multiple bibliographic databases with restrictions applied to English peer-reviewed journals. RESULTS: We reviewed 37 published articles on this topic. The mean level of awareness for risk factors such as age at menarche (22.3%), age at menopause (27.1%) and late first pregnancy (34.6%) was low in community. The awareness was better among HCPs; however, there was still room for improvement.Knowledge of BSE varied from very poor (2%) to good (69.8%) in the community setting. The practice was similarly negligible (0%) to moderate (34.9%). Mean knowledge and practice of BSE in HCPs were 77.1 and 55.5%, respectively. A significant difference was noted in knowledge and practice of BSE between community and HCPs (P < 0.05). CONCLUSIONS: The present review highlights the low level of awareness regarding risk factors for BC and BSE in the community as well as HCPs. Though BSE is not the ideal modality, this seems to be the best alternative for resource-limited settings.

Association of smokeless tobacco and cerebrovascular accident: a systematic review and meta-analysis of global data.

BACKGROUND: The association of smokeless tobacco (SLT) with stroke has been dealt with in only a few reviews. The present meta-analysis aims to present the updated comprehensive summary risk of stroke in adult SLT users along with sub group analysis. METHODS: A systematic literature search for articles evaluating risk of stroke in SLT users was conducted. The study characteristics and risk estimates were extracted independently by two authors (RG and SG). Random-effect model was used to estimate the summary relative risks. RESULTS: The overall risk of stroke in SLT users was found to be significantly higher (1.17, 95% CI 1.04­1.30) compared to non-users, especially for users in Southeast Asian region. The results remained unchanged even after strict adjustment for smoking (1.18, 95% CI 1.04­1.32). SLT users had 1.34 times or 13.4% higher risk of fatal stroke, though risk of nonfatal stroke was not enhanced. Significantly higher risk of stroke was seen in users of chewing tobacco (1.35, 95% CI 1.20­1.50) in comparison to non-chewers. Gender-based analysis showed enhanced risk of fatal stroke in both male and female users. SLT-attributable fraction of fatal stroke was highest for India at 14.8%. CONCLUSION: The significant higher risk of stroke with SLT use, even after adjustment for smoking, emphasizes the imperative need to include SLT cessation advice for control and prevention of stroke.

Morphometric analysis of epithelial thickness and blood vessels in different grades of oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) is a common oral health problem in the Indian subcontinent. It is characterized by a juxtaepithelial inflammatory reaction followed by fibroelastic changes in the lamina propria. Traditionally, it is said to be associated with marked epidermal atrophy and decreased vasculature as the disease advances. OBJECTIVE: To assess the changes in epidermal thickness and mucosal vasculature in various stages of the disease. MATERIAL AND METHODS: Patients with histological diagnosis of OSF were included in the study. Demographic data and oral habits of each patient were collected. The severity of OSF was graded histologically according to Pindborg and Sirsat. Epithelial thickness and subepithelial blood vessel area, diameter and perimeter were measured and analysed using Image analysis software IMAGE PRO PLUS version 6.0. RESULTS: Thirty-five patients with OSF were studied. 25 (71.4%) were males and 10 (28.6%) were females with a male to female ratio of 1.3:1. Most patients were in the 31-40 yrs age group. The majority of patients (40%) chewed areca nut/dohra. Each grade of the disease was found to display either hyperplastic or atrophic epithelial changes. The mean blood vessel area, diameter and perimeter did not show any sustained change with the increasing severity (grade) of the disease. CONCLUSION: These findings question the role of ischaemia in the aetiopathogenesis of oral submucous fibrosis.

Insulin Glargine in Type 1 Diabetes Mellitus: A Review of Clinical Trials and Real-world Evidence Across Two Decades.

BACKGROUND: Over the past two decades, insulin glargine 100 U/mL (Gla-100) has emerged as the "standard of care" basal insulin for the management of type 1 diabetes mellitus (T1DM). Both formulations, insulin glargine 100 U/mL (Gla-100) and glargine 300 U/mL (Gla- 300) have been extensively studied against various comparator basal insulins across various clinical and real-world studies. In this comprehensive article, we reviewed the evidence on both insulin glargine formulations in T1DM across clinical trials and real-world studies. METHODS: Evidence in T1DM for Gla-100 and Gla-300 since their approvals in 2000 and 2015, respectively, were reviewed. RESULTS: Gla-100 when compared to the second-generation basal insulins, Gla-300 and IDeg-100, demonstrated a comparable risk of overall hypoglycemia, but the risk of nocturnal hypoglycemia was higher with Gla-100. Additional benefits of Gla-300 over Gla-100 include a prolonged (>24- hours) duration of action, a more stable glucose-lowering profile, improved treatment satisfaction, and greater flexibility in the dose administration timing. CONCLUSION: Both glargine formulations are largely comparable to other basal insulins in terms of glucose-lowering properties in T1DM. Further, risk of hypoglycemia is lower with Gla-100 than Neutral Protamine Hagedorn but comparable to insulin detemir.

Equitable inclusion of diverse populations in oncology clinical trials: deterrents and drivers.

The burden of cancer exerts a disproportionate impact across different regions and population subsets. Disease-specific attributes, coupled with genetic and socioeconomic factors, significantly influence cancer treatment outcomes. Precision oncology promises the development of safe and effective options for specific ethnic phenotypes and clinicodemographic profiles. Currently, clinical trials are concentrated in resource-rich geographies with younger, healthier, white, educated, and empowered populations. Vulnerable and marginalized people are often deprived of opportunities to participate in clinical trials. Despite consistent endeavors by regulators, industry, and other stakeholders, factors including diversity in trial regulations and patient and provider-related cultural, logistic, and operational barriers limit the inclusiveness of clinical trials. Understanding and addressing these constraints by collaborative actions involving regulatory initiatives, industry, patient advocacy groups, community engagement in a culturally sensitive manner, and designing and promoting decentralized clinical trials are vital to establishing a clinical research ecosystem that promotes equity in the representation of population subgroups.

Legumes from the Paleocene sediments of India and their ecological significance.

During the early Paleogene, greenhouse gases created warm global climates. These warm climates redistributed the habitat of marine and terrestrial biota globally. Understanding the ecology of biotas under extremely warm climates is important to decipher their behavior in future climate warming. Here we report two new legume fossils (Leguminocarpum meghalayensis Bhatia, Srivastava et Mehrotra sp. nov., and Parvileguminophyllum damalgiriensis Bhatia, Srivastava et Mehrotra sp. nov.) from the late Paleocene sediments of Tura Formation of Meghalaya, northeast India. Globally, the Paleocene legume fossil records indicate that legumes most likely immigrated to India from Africa via the Ladakh-Kohistan Arc during the early Paleogene. Moreover, previously reconstructed climate data from the Tura Formation indicate that legumes were well adapted to a warm seasonal climate with monsoon rains.

Associations of pretransplant serum albumin with post-transplant outcomes in kidney transplant recipients.

The association between pretransplant serum albumin concentration and post-transplant outcomes in kidney transplant recipients is unclear. We hypothesized that in transplant-waitlisted hemodialysis patients, lower serum albumin concentrations are associated with worse post-transplant outcomes. Linking the 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, we identified 8961 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR]) and logistic regression (Odds ratio [OR]), respectively. Patients were 48 ± 13 years old and included 37% women and 27% diabetics. The higher pretransplant serum albumin was associated with lower mortality, graft failure and DGF risk even after multivariate adjustment for case-mix, malnutrition-inflammation complex and transplant related variable. Every 0.2 g/dL higher pretransplant serum albumin concentration was associated with 13% lower all-cause mortality (HR = 0.87 [95% confidence interval: 0.82-0.93]), 17% lower cardiovascular mortality (HR = 0.83[0.74-0.93]), 7% lower combined risk of death or graft failure (HR = 0.93[0.89-0.97]) and 4% lower DGF risk (OR = 0.96[0.93-0.99]). Hence, lower pretransplant serum albumin level is associated with worse post-transplant outcomes. Clinical trials to examine interventions to improve nutritional status in transplant-waitlisted hemodialysis patients and their impacts on post-transplant outcomes are indicated.

Hypovitaminosis D, neighborhood poverty, and progression of chronic kidney disease in disadvantaged populations.

In the United States, there are significant racial disparities in the incidence and prevalence of end-stage renal disease. The disparities are greatest for the Blacks and the magnitude of disparity is significantly greater than is evident from the incidence and prevalence data of end-stage renal disease - early stage chronic kidney disease is less common in Blacks and during that stage, mortality rate is significantly higher for that racial group. Recent studies have identified a genetic predisposition for non-diabetic renal disease among Blacks. However, genetic factors explain only part of the higher risk and the racial disparities are a result of a complex interplay of biology and sociology. Herein we focus on two factors and their role in explaining the higher risk for progression of chronic kidney disease among Blacks - one biologic (vitamin D deficiency) and one sociologic (neighborhood poverty). A greater Understanding of these factors is important in order to reduce the racial disparities in the United States.

Fixed-dose combination in management of type 2 diabetes mellitus: Expert opinion from an international panel.

Type 2 diabetes mellitus (T2DM) is a progressive disease with multifactorial etiology. The first-line therapy includes monotherapy (with metformin), which often fails to provide effective glycemic control, necessitating the addition of add-on therapy. In this regard, multiple single-dose agents formulated as a single-dose form called fixed-dose combinations (FDCs) have been evaluated for their safety, efficacy, and tolerability. The primary objective of this review is to develop practice-based expert group opinion on the current status and the causes of concern regarding the irrational use of FDCs, in Indian settings. After due discussions, the expert group analyzed the results from several clinical evidence in which various fixed combinations were used in T2DM management. The panel opined that FDCs (double or triple) improve patient adherence, reduce cost, and provide effective glycemic control and, thereby, play an important role in the management of T2DM. The expert group strongly recommended that the irrational metformin FDC's, banned by Indian government, should be stopped and could be achieved through active participation from the government, regulatory bodies, and health ministry, and through continuous education of primary care physicians and pharmacists. In T2DM management, FDCs play a crucial role in achieving glycemic targets effectively. However, understanding the difference between rational and irrational FDC combinations is necessary from the safety, efficacy, and tolerability perspective. In this regard, primary care physicians will have to use a multistep approach so that they can take informed decisions.

Unravelling the utility of modern sulfonylureas from cardiovascular outcome trials and landmark trials: expert opinion from an international panel.

AIM: The primary objective of this review is to develop practice-based expert group opinions on the cardiovascular (CV) safety and utility of modern sulfonylureas (SUs) in cardiovascular outcome trials (CVOTs). BACKGROUND: The United States Food and Drug Administration issued new guidance to the pharmaceutical industry in 2008 regarding the development of new antihyperglycemic drugs. The guidance expanded the scope for the approval of novel antihyperglycemic drugs by mandating CVOTs for safety. A few long-term CVOTs on dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors have been completed, while others are ongoing. SUs, which constitute one of the key antihyperglycemic agents used for the management of type 2 diabetes mellitus (T2DM), have been used as comparator agents in several CVOTs. However, the need for CVOTs on modern SUs remains debatable. In this context, a multinational group of endocrinologists convened for a meeting and discussed the need for CVOTs of modern SUs to evaluate their utility in the management of patients with T2DM. At the meeting, CVOTs of modern SUs conducted to date and the hypotheses derived from the results of these trials were discussed. REVIEW RESULTS: The expert group analyzed the key trials emphasizing the CV safety of modern SUs and also reviewed the results of various CVOTs in which modern SUs were used as comparators. Based on literature evidence and individual clinical insights, the expert group opined that modern SUs are cardiosafe and that since they have been used as comparators in other CVOTs, CVOTs of SUs are not required. CONCLUSION: Modern SUs can be considered a cardiosafe option for the management of patients with diabetes mellitus and CV disease; thus CVOTs among individuals with T2DM are not required.

Utility of Precision Medicine in the Management of Diabetes: Expert Opinion from an International Panel.

AIM: The primary objective of this review is to develop a practice-based expert group opinion on the role of precision medicine with a specific focus on sulfonylureas (SUs) in diabetes management. BACKGROUND: The clinical etiology, presentation and complications of diabetes vary from one patient to another, making the management of the disease challenging. The pre-eminent feature of diabetes mellitus (DM) are chronically elevated blood glucose concentrations; however, in clinical practice, the exclusion of autoimmunity, pregnancy, pancreatic disease or injury and rare genetic forms of diabetes is crucial. Within this framework, precision medicine provides unique insights into the risk factors and natural history of DM. Precision medicine goes beyond genomics and encompasses patient-centered care, molecular technologies and data sharing. Precision medicine has evolved in the field of diabetology. It has helped improve the efficacy of SUs, a class of drugs, which have been effectively used in the management of diabetes mellitus for decades, and it has enabled the expansion of SUs use in diabetes patients with genetic mutations. REVIEW RESULTS: After due discussions, the expert group analyzed studies that focused on the use of SUs in diabetes patients with genomic variations and rare mutations. The expert group opined that SUs are important glucose-lowering drugs and that precision medicine helps in improving the efficacy of SUs by matching them to those patients who will benefit most. CONCLUSION: Precision medicine opens new vistas for the effective use of SUs in unexpected patient populations, such as those with genetic mutations.

Oral cytology revisited.

During the last decade, oral cytology has once again become the focus of scientific research. This new interest is due to the introduction of a cytobrush for cell collection as well as a computer-assisted analysis (Oral CDx). Although promising, the sensitivity and specificity of conventional oral brush cytology remains limited. To circumvent the problems and improve the accuracy, various adjunctive analytical methods have been attempted. DNA analysis, immunocytochemical and molecular analysis are suggested methodological cytology approaches to improve the validity of oral brush cytology. An increase in sensitivity (up to 100%) and specificity (up to 100%) of oral brush biopsy has been reported on localized pre-malignant and malignant lesions. Oral brush biopsy probably will not replace histopathology in the definitive diagnosis of oral cancer, but it might be valuable for the prevention of misdiagnosis of clinically doubtful oral lesions and for the monitoring of lesions that might proceed on to oral cancer.

Low Framingham risk score despite high prevalence of metabolic syndrome in asymptomatic North-Indian population.

BACKGROUND: Conflicting data exists regarding relationship between the Framingham risk score (FRS) and presence of metabolic syndrome (MS). Strong influence of age on FRS may further modify this relationship as prevalence of MS at younger age increases in South-Asian countries including India. However, only limited information is available about the prevalence of MS and its relationship with FRS in such populations at present. METHODS: Clinical examination and biochemical investigations were performed in 1905 asymptomatic office executives who underwent routine health check-up at a tertiary care centre in India during the year 2005. Diagnosis of MS and FRS were based on the modified National Cholesterol Education Program-Adult Treatment Panel III guidelines. RESULTS: Mean age of the subjects was 45.2 +/- 10.3 years and 71.8% were males. MS was present in 47.5% (905 of 1905) subjects. Overall, 76.8% patients with MS had 10-year cardiovascular (CV) risk < 10%, 20.6% had 10-20% risk and only 2.7% had > 20% risk according to FRS. In the lowest age-quartile, 95.9% patients had 10-year risk < 10%, 4.1% patients had 10-20% risk and none had > 20% risk. In contrast, in the highest age-quartile, less than half of the patients had 10-year risk <10% and nearly half had 10-20% risk of CV events. CONCLUSIONS: Although the prevalence of MS is markedly high in young asymptomatic Indians, majority have low 10-year risk of CV events as estimated by FRS. These findings necessitate continued emphasis on detection of MS in these populations as reliance on FRS alone may result in underestimation of CV risk in them.

Fine needle aspiration cytology of the testis as the first-line diagnostic modality in azoospermia: a comparative study of cytology and histology.

OBJECTIVES: Male factors are responsible for about half of all infertility cases. Until recently, testicular biopsy was the standard method to ascertain the aetiology of azoospermia. Fine needle aspiration cytology has gained increasing popularity as a simple and minimally invasive procedure that can help in assessing testicular function accurately. This study was aimed at addressing the question whether testicular fine needle aspiration (FNA) may be used as a first-line diagnostic modality in azoospermia and to assess its usefulness in the diagnostic protocol. METHODS: The FNA was performed in 78 consecutive azoospermic patients. To obviate sampling errors both testes were aspirated, except when contraindicated. Routine haematoxylin and eosin as well as Romanowsky staining was performed on the smears. RESULTS: The smears were categorized on cytological examination into normal spermatogenesis in 35 (50%) patients, Sertoli cells only syndrome in 22 (31.4%) and maturation arrest at the spermatocyte/spermatid level was seen in 13 (18.4%) patients. There were eight (10.2%) cases with scant smears where cytological diagnosis could not be made. A good correlation between cytological smears and histological sections was found in 54 of 58 testes (93.1%) in which histopathological confirmation was available. CONCLUSIONS: Testicular FNA may be utilized as a first-line investigative modality in patients with azoospermia, provided the procedure is performed and interpreted by experts.

Efficacy of teriparatide in increasing bone mineral density in postmenopausal women with osteoporosis--an Indian experience.

BACKGROUND AND OBJECTIVE: Osteoporosis is emerging as a leading cause of substantial morbidity in India, particularly in postmenopausal women. Teriparatide (recombinant human parathyroid hormone [1-34]) increases bone formation and improves bone microarchitecture, thereby reducing the risk of fractures. This study was conducted to evaluate the efficacy of teriparatide in increasing bone mineral density (BMD) in postmenopausal women with osteoporosis. MATERIAL AND METHODS: A randomised, prospective, multicentre, open-label, controlled study was conducted on 82 postmenopausal women with established osteoporosis. Patients were randomly divided into control and teriparatide groups, each group consisting of 41 patients. All the patients were supplemented with 1000 mg of elemental calcium and 500 IU of vitamin D throughout the study period of 180 days. Besides, teriparatide group patients were administered teriparatide 20 microg daily subcutaneously. Lumbar spine, femoral neck and total hip BMD, bone mineral content (BMC) and bone area were measured by dual energy x-ray absorptiometry (DXA) at baseline and at the end of 6 months of treatment. Bone biomarkers, such as serum bone specific alkaline phosphatase (BSAP) and serum osteocalcin (OC), representing bone formation, and urinary deoxypyridinoline (DPD), representing bone resorption were assessed at baseline, and at 3 and 6 months of treatment. RESULTS: During the study period, 9 patients (11%) were lost to follow-up--6 in control group (7.3%) and 3 in teriparatide group (3.7%). There was an excellent compliance to both oral and injectable medication. The investigational product teriparatide was well tolerated and there were no serious adverse events. In addition, there were no significant differences between the groups in the incidence of adverse events. The percentage of increase in lumbar spine BMD, which is the primary endpoint, was significantly (P < 0.001) higher in teriparatide group compared to that in control group (6.58% vs. 1.06%). Further, teriparatide significantly increased percentage of change in lumbar spine T-score (P < 0.001), BMC (P < 0.001) and bone area (P < 0.028) compared to control group at 6 months. Administration of teriparatide resulted in a significant percentage of increase in all the bone biomarkers in teriparatide group compared to control group patients at 3 and 6 months over baseline, thereby showing that there was a significant increase in bone turnover in teriparatide group of patients. CONCLUSION: These results show that teriparatide is an effective and safe drug in increasing the BMD and therefore, teriparatide provides yet another new therapeutic option for reducing the risk management of osteoporosis in postmenopausal women (clinicaltrials.gov number, NCT00500409).

Oral squamous cell carcinoma: etiology, pathogenesis and prognostic value of genomic alterations.

Tumours of the head and neck comprise an important group of neoplasia, the incidence of which is increasing in many parts of the world. This increase remains high, despite all the advances in modern medicine. This malignancy is more prevalent in the developing world and unfortunately, has not received satisfactory attention as the more prevalent cancers of the developed world, like lung, breast, or colon cancer. Recent advances in diagnosis and therapeutic techniques of these lesions have yielded novel molecular targets, uncovered signal pathway dominance and advanced early cancer detection. This review covers recent advances in our understanding of the etiology, molecular changes and the possible role that genomic and proteomic research might play in the diagnosis and effective cure of this modern-day scourge.

Contribution of aflatoxin B1 and hepatitis B virus infection in the induction of liver tumors in ducks.

The study of two major risk factors in the development of hepatocellular carcinoma, namely persistent hepatitis virus infection and exposure to dietary aflatoxins, has been hampered by lack of an experimental system. To this end we have used a Pekin duck model to examine the effect of congenital duck hepatitis B virus (DHBV) infection and aflatoxin B1 (AFB1) exposure in the induction and development of liver cancer. AFB1 was administered to DHBV infected or noninfected ducks at two doses (0.08 and 0.02 mg/kg) by i.p. injection once a week from the third month posthatch until they were sacrificed (2.3 years later). Two control groups of ducks not treated with AFB1 (one of which was infected with DHBV) were observed for the same period. Each experimental group included 13-16 ducks. Higher mortality was observed in ducks infected with DHBV and treated with AFB1 compared to noninfected ducks treated with AFB1 and other control ducks. In the groups of noninfected ducks treated with high and low doses of AFB1, liver tumors developed in 3 of 10 and 2 of 10 ducks; in infected ducks treated with the high dose 3 of 6 liver tumors were observed and none in the low dose of AFB1. No liver tumors were observed in the two control groups. Ducks infected with DHBV and treated with AFB1 showed more pronounced periportal inflammatory changes, fibrosis, and focal necrosis compared to other groups. All DHBV carrier ducks showed persistent viremia throughout the observation period. An increase of viral DNA titers in livers and sera of AFB1 treated animals compared to infected controls was frequently observed. No DHBV DNA integration into the host genome was observed, although in one hepatocellular carcinoma from an AFB1 treated duck, an accumulation of viral multimer DNA forms was detected. The metabolism of AFB1 in infected and noninfected duck liver was also examined. The study on the role of DHBV infection and AFB1 in the etiopathogenesis of liver tumors may help to clarify some of the basic mechanisms of carcinogenesis.

A slow obligatory proton release step precedes hydride transfer in the liver glutamate dehydrogenase catalytic mechanism.

We have used the stopped-flow indicator dye method to measure proton release and product formation simultaneously in the initial transient-state portion of the glutamate dehydrogenase-catalyzed oxidative deamination of L-glutamate. We observe a measurably slow release of a proton from the enzyme-NADP-L-glutamate complex. This proton release precedes the hydride transfer step, as indicated by the distinct lag in the product formation signal. We show that the proton release step corresponds to an obligatory intermediate in the reaction sequence. We also find that compounds which are competitive inhibitors of L-glutamate are capable of inducing this phenomenon. We prove that this unanticipated prehydride transfer event cannot be due to the release of an alpha-amino group proton from the substrate.