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Background Pulmonary fibrosis is a debilitating condition with limited therapeutic avenues. The pathogenicity of pulmonary fibrosis constitutes involvement of cellular proliferation, activation, and transformational changes of fibroblast to myofibroblasts. It is a progressive lung disease and is primarily characterized by aberrant accumulation of extracellular matrix proteins in the lungs with poor prognosis. The inflammatory response in the pathogenesis of lung fibrosis is suggested because of release of several cytokines; however, the underlying mechanism remains undefined. A genetic model is the appropriate way to delineate the underlying mechanism of pulmonary fibrosis. Methods and results In this report, we have used cc-10 promoter based IκBα mutant mice (IKBM, an inhibitor of NF-κB) which were challenged with bleomycin (BLM). Compared to wild-type (WT) mice, the IKBM mice showed significant reduction in several fibrotic, vascular, and inflammatory genes. Moreover, we have identified a new set of dysregulated microRNAs (miRNAs) by miRNA array analysis in BLM-induced WT mice. Among these miRNAs, let-7a-5p and miR-503-5p were further analyzed. Our data showed that these two miRNAs were upregulated in WT-BLM and were reduced in IKBM-BLM mice. Bioinformatic analyses showed that let-7a-5p and miR-503-5p target for endothelin1 and bone morphogenic receptor 1A (BMPR1A), respectively, and were downregulated in WT-BLM mice indicating a link in pulmonary fibrosis. Conclusion We concluded that inhibition of NF-κB and modulation of let-7a-5p and miR-503-5p contribute a pivotal role in pulmonary fibrosis and may be considered as possible therapeutic target for the clinical management of lung fibrosis.

Extrahepatic duplication of the common bile duct (CBD) is an extremely rare anatomic variation seen in the biliary tract. It represents failure of regression of the primitive duplicated biliary ductal system, resulting in five different subtypes of the duplicated CBD as described by Choi et al. To date, only few such cases have been reported in the literature. Associated variation in branching of intrahepatic bile ducts presenting as combined dual ductal anomaly is even rarer phenomena to be seen. We report a case of a 67-year-old man with chronic kidney disease and obstructive jaundice resulting from choledocholithiasis. Evaluation revealed type IIIa branching of intrahepatic bile ducts with type Va duplication of the CBD.

Spondylo-epi-metaphyseal dysplasias with joint laxity, type 3 (SEMDJL3) is a genetic skeletal disorder characterized by multiple joint dislocations, caused by biallelic pathogenic variants in the EXOC6B gene. Only four individuals from two families have been reported to have this condition to date. The molecular pathogenesis related to primary ciliogenesis has not been enumerated in subjects with SEMDJL3. In this study, we report two additional affected individuals from unrelated families with biallelic pathogenic variants, c.2122+15447_2197-59588del and c.401TG in EXOC6B identified by exome sequencing. One of the affected individuals had an intellectual disability and central nervous system anomalies, including hydrocephalus, hypoplastic mesencephalon, and thin corpus callosum. Using the fibroblast cell lines, we demonstrate the primary evidence for the abrogation of exocytosis in an individual with SEMDLJ3 leading to impaired primary ciliogenesis. Osteogenesis differentiation and pathways related to the extracellular matrix were also found to be reduced. Additionally, we provide a review of the clinical and molecular profile of all the mutation-proven patients reported hitherto, thereby further characterizing SEMDJL3. SEMDJL3 with biallelic pathogenic variants in EXOC6B might represent yet another ciliopathy with central nervous system involvement and joint dislocations.

Background There is limited current knowledge on feasibility and safety of kidney transplantation in COVID-19 survivors. Methods We present a retrospective cohort study of 75 kidney transplants in patients who recovered from polymerase chain reaction (PCR) confirmed COVID-19 performed across 22 transplant centers in India from July 3, 2020 to January 31, 2021. We detail demographics, clinical manifestations, immunosuppression regimen, laboratory findings, treatment and outcomes. Patients with a previous diagnosis of COVID-19 were accepted after documenting 2 negative SARS-CoV-2 PCR tests, normal chest imaging with complete resolution of symptom for at least 28 days and significant social distancing for 14 days prior to surgery. Results Clinical severity in patients ranged from asymptomatic (n=17, 22.7%), mild(n=36,48%), moderate(n=15,20%) and severe(n=7,9.3%) disease. Median duration between PCR positive to transplant was 60 days (overall) and, increased significantly from asymptomatic, mild, moderate and severe disease (49,57,83,94 days, P-value 0.019) respectively. All recipients and donors were asymptomatic with normal creatinine after surgery at a median (interquartile range) follow up of 81 (56-117) days without any complications relating to surgery or COVID-19. Patient and graft survival was 100%, and acute rejection was reported in 6.6%. Conclusions Prospective kidney transplant recipients post-COVID-19 can be considered for transplantation after comprehensive donor and recipient screening before surgery using a combination of clinical, radiologic, and laboratory criteria, careful pre-transplant evaluation, and individualized risk-benefit analysis. Further large-scale prospective studies with longer follow-up will better clarify our initial findings. Till date, this remains the first largest study of kidney transplantation in COVID-19 survivors.Supplemental Visual Abstract; http://links.lww.com/TP/C180.

Background: Corona Virus Disease (COVID-19) was declared as Global Pandemic by W.H.O. on 11th March 2020. As nationwide lockdown was imposed from 21st March 2020 in India, teleconsultation project known as eSanjeevani: Stay Home OPD” was launched by Honourable Union Health Minister. This facility was also started by the Department of Health & Family Welfare, Govt. of Himachal Pradesh at our center; Dr. Rajendra Prasad Govt. Medical College (Dr. RPGMC), Kangra at Tanda from 20th April 2020 onwards. Aim & Objective: To analyse the parameters influencing teleconsultation service from the perspective of patients during Covid-19 pandemic. Materials and Methods: This cross-sectional descriptive study was conducted through a semi-structured 10-point feedback questionnaire. The feedback was collected telephonically. A total of 131 responses were noted and analysed accordingly. Results: Out of 131 patients, 71 (54%) were males and 60 (46%) were females. All of them 131 (100%) accepted the legibility of e-prescription, and the majority (91%) of them were comfortable in procuring (downloading) the same. (83%) respondents preferred teleconsultation services over conventional OPD based services and (98%) patients also recommended teleconsultation platform to others. Conclusion: Mean rating score was 8.9±1.04 out of 10 which clearly shows that majority of patients were satisfied with teleconsultation services availed by them through Dr. RPGMC Tanda hub. Keywords: COVID- 19, Pandemics, Remote Consultation, Patient Satisfaction, Electronic Prescribing, eSanjeevni OPD.

Objectives: To analyse the utilization of outpatient eSanjeevani Telemedicine Service during COVID pandemic in a public healthcare institution in North India by profiling the attributes of patients availing online video consultation in terms of gender, age, urban-rural, organ-system involvement, speciality of OPD service given and prescription analysis. Materials and Methods: This is a descriptive, cross sectional study done at Dr. Rajendra Prasad Govt. Medical College which served as a hub in a hub & spoke type model for rendering online OPD consultations; on a software platform “eSanjeevani” developed by Centre for Development of Advanced Computing (C-DAC) Mohali. Data from 206 audio+video based online tele-OPD consultations & their prescriptions were analysed. Results: Out of a total 206, 114 (55%) were males and 92 (45%) were females. Mean ± S.D. age of patients was 42 ±19.6 years. 146 (71%) connected from rural area and 60 (29%) from urban area. 38 (18%) patients required to be referred to the health-care centre and 46 (22%) patients required a review after blood biochemistry investigations. 76 (37%) were from district Kangra of Himachal Pradesh. The most common organ system involved was musculoskeletal system (19%) followed by skin (18.4%) and gastrointestinal system (16%). The most commonly prescribed class of drugs were NSAIDs & analgesics (36%) antimicrobials (23%) and antihistaminics (18%). Conclusion: Telemedicine is an innovative solution to many of the challenges posed by COVID-19 pandemic. It can help substantially in decreasing the OPD workload in hospitals & decreasing infection chances for both patients & hospital staff. Keywords: COVID- 19, Remote Consultation, Teleconsultation, Telemedicine.

Study question Do use of fertility drugs increase the risk of ovarian cancer among infertile women Summary answer Use certain types of fertility drugs may modify the risk of ovarian cancer among infertile women, primarily for serous ovarian tumors and among parous women. What is known already Even though most previous studies on the association between fertility treatment and ovarian cancer have not been able to show a convincing association, some studies have found an increased risk of this malignancy among women undergoing fertility treatment. However, many of the previous studies have had methodological limitations including selection bias and potential confounding due to missing information of important factors, such as parity status and hormonal contraceptive use, small sample size as well as short- and incomplete follow-up time. Furthermore, only few studies have assessed the association between fertility treatment and ovarian cancer according to histological type. Study design, size, duration This retrospective register-based cohort study included virtually all 20-45 year old infertile women in Denmark between 1971 and 2017 as identified in the Danish Infertility Cohort. All women were followed from entry in the cohort (i.e. the date of first infertility diagnosis) to occurrence of ovarian cancer, any other cancer (except non-melanoma skin cancer), death, emigration, bilateral oophorectomy or end of follow-up (December 31, 2017), whichever occurred first. The median follow-up length was 10.3 years Participants/materials, setting, methods In total, 332 women were diagnosed with ovarian cancer during the follow-up period. Information on the use of specific fertility drugs (clomiphene citrate, gonadotropins, hCGs, GnRH receptor modulators and progesterone), ovarian cancer, covariates and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs for ovarian cancer overall and for serous ovarian tumors. Main results and the role of chance After adjustment for attained age (as the underlying time scale), calendar year of study entry, highest obtained level of education, maternal age at first childbirth, number of childbirths, hormonal contraceptive use as well as mutual adjustment for treatment with any other specific fertility drugs, ever use of hCG (HR 0.62, 95% CI 0.44-0.89) and GnRH receptor modulators (HR 0.63, 95% CI 0.40-1.00) were associated with a decreased risk of overall ovarian cancer. In contrast, ever use of gonadotropins (HR 1.43; 95% CI 0.91-2.24) and especially progesterone (HR 1.81; 95% CI 1.18-2.78) increased the risk of overall ovarian cancer. No marked association was observed for clomiphene citrate (HR 1.07, 95% CI 0.80-1.44)). The rates for serous ovarian cancer generally resembled those observed for overall ovarian cancer; however only the association for progesterone reached statistical significance (HR 2.89; 95% CI 1.67-4.99). The observed associations existed mainly among parous women and did not vary with time since first use of the fertility drug in question and no statistically significant associations were observed with cumulative dose of the specific fertility drugs. Limitations, reasons for caution The median age at the end of follow-up was only 42.5 years, which is markedly lower than the usual peak age for ovarian cancer in Denmark (mid 60s). Hence, we were not able to capture the true, potential long-term association between use of fertility drugs and ovarian cancer. Wider implications of the findings Use of certain specific types of fertility drugs in fertility treatment may modify the risk of ovarian cancer among subgroups of women. However, although this study is by far the largest to date, additional large epidemiological studies with longer follow-up time are needed to further clarify the observed associations. Trial registration number Not applicable.

In December 2019, novel coronavirus (SARS-CoV-2) infection started in Wuhan and resulted in a pandemic within a few weeks' time. Organ transplant recipients being at a risk for more severe COVID-19 if they get SARS CoV-2 viral infection, COVID-19 vaccine has a significant role in these patients. The vaccine is a safer way to help build protection and would either prevent COVID-19 infection or at least diminish the severity of the disease. It would also reduce the risk of the continuing transmission and enhance herd immunity. Immuno-compromised patients should not receive live vaccines as they can cause vaccine-related disease and hence the guidelines suggest that all transplant recipients should receive age-appropriate 'inactivated vaccine' as recommended for general population. Though trials have not been undertaken on transplant recipients, efficacy and safety of COVID-19 vaccine have been scientifically documented for few vaccines among the general population.

Alcohol use and alcohol use disorders (AUDs) are an increasing concern among veterans, particularly those from recent conflicts in Iraq and Afghanistan. The study of biomarkers in alcohol use and AUD has moved to enhancing the understanding of the development and maintenance of AUDs, as well as investigating its association with clinical severity and potential predictors of treatment response. Cortisol, a glucocorticoid known as a stress hormone, has been linked with both stress and trauma, as well as increased alcohol suppression effects. The present review summarizes existing literature and presents suggestions for future research to evaluate whether cortisol may be a possible biomarker of alcohol use disorder risk in combat veterans. Specifically, aspects of combat deployments and high levels of PTSD, coupled with the stress of reintegration may dysregulate cortisol and increase risk to AUD. There may also be bidirectional impacts, such that alcohol is used as a coping mechanism and can dysregulate hypothalamic pituitary adrenal (HPA) axis functioning and cortisol. In the context of this framework, cortisol may serve as a biomarker for the development of AUD, as well as a biomarker of risk or relapse. This review ends with both theoretical and clinical implications, as well as directions for future research.

Posttraumatic stress disorder (PTSD) is a common psychiatric disorder for military Veterans, characterized by hyperarousal, intrusive thoughts, flashbacks, hypervigilance, and distress after experiencing traumatic events. Some of the known physiological effects of PTSD include hypothalamic-pituitary-adrenal (HPA)-axis imbalance, a cortical function resulting in neuronal deficit and changes in behavior. Moreover, excessive discharge of inflammatory molecules and a dysregulated immune system are implicated in the pathophysiology of PTSD. Due to complex nature of this disorder, the biological underpinnings of PTSD remain inexplicable. Investigating novel biomarkers to understanding the pathogenesis of PTSD may reflect the underlying molecular network for therapeutic use and treatment. Circulatory microRNAs (miRNAs) and exosomes are evolving biomarkers that have shown a key role in psychiatric and neurological disorders including PTSD. Given the unique nature of combat trauma, as well as evidence that a large portion of Veterans do not benefit from frontline treatments, focus on veterans specifically is warranted. In the present review, we delineate the identification and role of several miRNAs in PTSD among veterans. An association of miRNA with HPA-axis regulation through FKBP5, a key modulator in PTSD is discussed as an emerging molecule in psychiatric diseases. We conclude that miRNAs may be used as circulatory biomarker detection in Veterans with PTSD.

Kidney Disease: Improving Global Outcomes (KDIGO) engaged an evidence review team and convened a work group to produce a guideline to evaluate and manage candidates for living kidney donation. The evidence for most guideline recommendations is sparse and many “ungraded” expert consensus recommendations were made to guide the donor candidate evaluation and care before, during, and after donation. The guideline advocates for replacing decisions based on assessments of single risk factors in isolation with a comprehensive approach to risk assessment using the best available evidence. The approach to simultaneous consideration of each candidate’s profile of demographic and health characteristics advances a new framework for assessing donor candidate risk and for defensible shared decision making., One of the most important tasks we have to undertake is to evaluate and then care for living donors. This paper provides a summary of the KDIGO Guidelines and encapsulates what you will find in the guidelines themselves, which are published in full in a separate supplement. Care of our living kidney donors is not an evidence free void for personal opinion and practice to fill–there are data.

The 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors is intended to assist medical professionals who evaluate living kidney donor candidates and provide care before, during and after donation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach and guideline recommendations are based on systematic reviews of relevant studies that included critical appraisal of the quality of the evidence and the strength of recommendations. However, many recommendations, for which there was no evidence or no systematic search for evidence was undertaken by the Evidence Review Team, were issued as ungraded expert opinion recommendations. The guideline work group concluded that a comprehensive approach to risk assessment should replace decisions based on assessments of single risk factors in isolation. Original data analyses were undertaken to produce a “proof-in-concept” risk-prediction model for kidney failure to support a framework for quantitative risk assessment in the donor candidate evaluation and defensible shared decision making. This framework is grounded in the simultaneous consideration of each candidate's profile of demographic and health characteristics. The processes and framework for the donor candidate evaluation are presented, along with recommendations for optimal care before, during, and after donation. Limitations of the evidence are discussed, especially regarding the lack of definitive prospective studies and clinical outcome trials. Suggestions for future research, including the need for continued refinement of long-term risk prediction and novel approaches to estimating donation-attributable risks, are also provided. In citing this document, the following format should be used: Kidney Disease: Improving Global Outcomes (KDIGO) Living Kidney Donor Work Group. KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors. Transplantation. 2017;101(Suppl 8S):S1–S109.

Background Cardiac fibrosis occurs because of disruption of the extracellular matrix network leading to myocardial dysfunction. Angiotensin II (Ang II ) has been implicated in the development of cardiac fibrosis. Recently, micro RNA s have been identified as an attractive target for therapeutic intervention in cardiac pathologies; however, the underlying mechanism of micro RNA s in cardiac fibrosis remains unclear. Next‐generation sequencing analysis identified a novel characterized microRNA, miR‐1954, that was significantly reduced in AngII‐infused mice. The finding led us to hypothesize that deficiency of miR‐1954 triggers cardiac fibrosis. Methods and Results A transgenic mouse was created using α‐MHC (α‐myosin heavy chain) promoter and was challenged with AngII infusion. AngII induced cardiac hypertrophy and remodeling. The in vivo overexpression of miR‐1954 showed significant reduction in cardiac mass and blood pressure in AngII‐infused mice. Further analysis showed significant reduction in cardiac fibrotic genes, hypertrophy marker genes, and an inflammatory gene and restoration of a calcium‐regulated gene (Atp2a2 [ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2]; also known as SERCA 2), but no changes were observed in apoptotic genes. THBS 1 (thrombospondin 1) is indicated as a target gene for miR‐1954. Conclusions Our findings provide evidence, for the first time, that miR‐1954 plays a critical role in cardiac fibrosis by targeting THBS 1. We conclude that promoting the level of miR‐1954 would be a promising strategy for the treatment of cardiac fibrosis.

Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RARα signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RARα deletion (RARαKO) mice were utilized. Echocardiographic and cardiac catheterization studies showed significant diastolic dysfunction after 16 wks of gene deletion. However, no significant differences were observed in left ventricular ejection fraction (LVEF), between RARαKO and wild type (WT) control mice. DHE staining showed increased intracellular reactive oxygen species (ROS) generation in the hearts of RARαKO mice. Significantly increased NOX2 (NADPH oxidase 2) and NOX4 levels and decreased SOD1 and SOD2 levels were observed in RARαKO mouse hearts, which were rescued by overexpression of RARα in cardiomyocytes. Decreased SERCA2a expression and phosphorylation of phospholamban (PLB), along with decreased phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase II δ (CaMKII δ) was observed in RARαKO mouse hearts. Ca2+ reuptake and cardiomyocyte relaxation were delayed by RARα deletion. Overexpression of RARα or inhibition of ROS generation or NOX activation prevented RARα deletion-induced decrease in SERCA2a expression/activation and delayed Ca2+ reuptake. Moreover, the gene and protein expression of RARα was significantly decreased in aged or metabolic stressed mouse hearts. RARα deletion accelerated the development of diastolic dysfunction in streptozotocin (STZ)-induced type 1 diabetic mice or in high fat diet fed mice. In conclusion, myocardial RARα deletion promoted diastolic dysfunction, with a relative preserved LVEF. Increased oxidative stress have an important role in the decreased expression/activation of SERCA2a and Ca2+ mishandling in RARαKO mice, which are major contributing factors in the development of diastolic dysfunction. These data suggest that impairment of cardiac RARα signaling may be a novel mechanism that is directly linked to pathological stimuli-induced diastolic dysfunction.

Thymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tβ4 in cardiomyocyte hypertrophy is currently unknown. The purpose of this study was to determine the cardio-protective effect of Tβ4 in angiotensin II (Ang II)-induced cardiomyocyte growth. Neonatal rat ventricular cardiomyocytes (NRVM) were pretreated with Tβ4 followed by Ang II stimulation. Cell size, hypertrophy marker gene expression and Wnt signaling components, β-catenin, and Wnt-induced secreted protein-1 (WISP-1) were evaluated by quantitative real-time PCR, Western blotting and fluorescent microscopy. Pre-treatment of Tβ4 resulted in reduction of cell size, hypertrophy marker genes and Wnt-associated gene expression, and protein levels; induced by Ang II in cardiomyocyte. WISP-1 was overexpressed in NRVM and, the effect of Tβ4 in Ang II-induced cardiomyocyte growth was evaluated. WISP-1 overexpression promoted cardiomyocytes growth and was reversed by pretreatment with Tβ4. This is the first report which demonstrates that Tβ4 targets Wnt/WISP-1 to protect Ang II-induced cardiomyocyte growth. J. Cell. Physiol. 231: 1737-1744, 2016. © 2015 Wiley Periodicals, Inc.

Pneumocephalus is a rare condition characterized by the presence of gas within the cranial cavity. This gas arises either from a trauma, tumor, surgical procedure, or occasionally from infection. Pneumocephalus secondary to chronic otitis media is an extremely rare phenomenon. We describe here a 70-year-old male, a known case of chronic suppurative otitis media who presented with sudden onset severe thunderclap headache and was eventually diagnosed as pneumocephalus.

Two new fossil woods resembling Eucalyptus L’ H’erit of the family Myrtaceae are described from the Palaeocene and Eocene successions of Gujarat and Rajasthan, respectively. They are characterized by diffuse-porous wood, heavily tylosed vessels arranged in echelon, vasicentic tracheids, simple perforations, thin rays and non septate fibres with bordered pits. Eucalyptus is considered native to Australia as most of its species are found there. The fossil records of Eucalyptus are hitherto known from the Cenozoic successions of Argentina, New Zealand, Australia and India. The genus is phytogeographically important as it has a wide range of distribution in the geologic past which suggests its long history affiliated with different Gondwanaland continents. A warm and humid coastal environment is inferred in western India during the Palaeogene on the basis of the earlier records of the genus.

This study reports a new fossil leaf of Kleinhovia L., Kleinhovia bikanerensis sp. nov., from the Eocene clay mine of the Marh Formation of Bikaner, Rajasthan. The leaf resembling Kleinhovia hospita L. of the family Malvaceae is described for the first time from India. The leaf is characterized by very wide ovate shape, basal actinodromous venation with seven primary veins and cordate base. The presence of this leaf fossil indicates tropical warm and humid climatic conditions prevailing in the area during the Eocene and throws light on its past and present distribution.

Diabetic cardiomyopathy (DCM), a significant contributor to morbidity and mortality in diabetic patients, is characterized by ventricular dysfunction, in the absence of coronary atherosclerosis and hypertension. There is no specific therapeutic strategy to effectively treat patients with DCM, due to a lack of a mechanistic understanding of the disease process. Retinoic acid, the active metabolite of vitamin A, is involved in a wide range of biological processes, through binding and activation of nuclear receptors: retinoic acid receptors (RAR) and retinoid X receptors (RXR). RAR/RXR-mediated signaling has been implicated in the regulation of glucose and lipid metabolism. Recently, it has been reported that activation of RAR/RXR has an important role in preventing the development of diabetic cardiomyopathy, through improving cardiac insulin resistance, inhibition of intracellular oxidative stress, NF-κB-mediated inflammatory responses and the renin-angiotensin system. Moreover, downregulated RAR/RXR signaling has been demonstrated in diabetic myocardium, suggesting that impaired RAR/RXR signaling may be a trigger to accelerate diabetes-induced development of DCM. Understanding the molecular mechanisms of retinoid receptors in the regulation of cardiac metabolism and remodeling under diabetic conditions is important in providing the impetus for generating novel therapeutic approaches for the prevention and treatment of diabetes-induced cardiac complications and heart failure.

Climate has played a crucial role in assigning a different kind of topography to Rajasthan and Gujarat since the Cenozoic time. Evidently, three genera, namely, Dipterocarpus Gaert. f., Hopea Roxb. and Shorea Roxb. of the Dipterocarpaceae are described from the Neogene sediments of western India (Rajasthan and Gujarat). These taxa are marked by their complete absence in the region today. The presence of Dipterocarpaceae in western India has been noticed from the Early Eocene up to the Plio-Pleistocene in deep time. The family is usually a dominant component of the humid tropical and subtropical flora of the Indo-Malayan region and its discovery, along with earlier described fossils from western India indicates existence of ancient tropical rain forests in western India. A change in the climate affected warm and humid conditions occurring there during the Cenozoic resulting in arid to semi-arid climate at present which is responsible for the ultimate extinction of Dipterocarpaceae in the region. In addition, the palaeobiogeography of Dipterocarpaceae is reviewed.

Diabetic cardiomyopathy (DCM) is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. Retinoids, through activation of retinoic acid receptor (RAR) and retinoid×receptor (RXR), have been linked to control of glucose and lipid homeostasis, with effects on obesity and diabetes. However, the functional role of RAR and RXR in the development of DCM remains unclear. Zucker diabetic fatty (ZDF) and lean rats were treated with Am580 (RARα agonist) or LGD1069 (RXR agonist) for 16 weeks, and cardiac function and metabolic alterations were determined. Hyperglycemia, hyperlipidemia and insulin resistance were observed in ZDF rats. Diabetic cardiomyopathy was characterized in ZDF rats by increased oxidative stress, apoptosis, fibrosis, inflammation, activation of MAP kinases and NF-κB signaling and diminished Akt phosphorylation, along with decreased glucose transport and increased cardiac lipid accumulation, and ultimately diastolic dysfunction. Am580 and LGD1069 attenuated diabetes-induced cardiac dysfunction and the pathological alterations, by improving glucose tolerance and insulin resistance; facilitating Akt activation and glucose utilization, and attenuating oxidative stress and interrelated MAP kinase and NF-κB signaling pathways. Am580 inhibited body weight gain, attenuated the increased cardiac fatty acid uptake, β-oxidation and lipid accumulation in the hearts of ZDF rats. However, LGD1069 promoted body weight gain, hyperlipidemia and cardiac lipid accumulation. In conclusion, our data suggest that activation of RAR and RXR may have therapeutic potential in the treatment of diabetic cardiomyopathy. However, further studies are necessary to clarify the role of RAR and RXR in the regulation of lipid metabolism and homeostasis.

Shukla, A., Mehrotra, R.C. & Guleria, J.S. iFirst article. African elements (fossil woods) from the upper Cenozoic sediments of western India and their palaeoecological and phytogeographical significance. Alcheringa, 1–20. ISSN 0311-5518. Fossil woods resembling tropical African taxa are described from late Neogene–Pleistocene sediments of western India. They resemble the extant representatives of Baphia Afzel., Brachystegia Benth., Erythrophleum Afzel. (Fabaceae), Entandrophragma C. DC., Khaya A. Juss. (Meliaceae) and Milicia Sim (Moraceae). The discovery of these taxa indicates the invasion of African elements into the Indian subcontinent during the Plio-Pleistocene and palaeogeographic connections between the two continents. All these genera include both evergreen and deciduous representatives and grow mainly in the tropical forests of Africa. On this basis, the presence of semi-evergreen to deciduous forest is inferred in western India during the Neogene in contrast to the semi-arid to arid climate wi...

We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-κB and RA signaling. HG induced a sustained phosphorylation of IKK/IκBα and transcriptional activation of NF-κB in cardiomyocytes. Activated NF-κB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG-mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-κB activation was mediated through inhibition of IKK/IκBα phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IκBα were blocked by okadaic acid or silencing the expression of PP2Ac-subunit, indicating that the inhibitory effect of RA on NF-κB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IκBα. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IκBα and gene expression of MCP-1, IL-6, and TNF-α in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF-κB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-κB-mediated signaling and downstream targets.

The biological actions of retinoids are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We have recently reported that decreased expression of RARα and RXRα has an important role in high glucose (HG)-induced cardiomyocyte apoptosis. However, the regulatory mechanisms of HG effects on RARα and RXRα remain unclear. Using neonatal cardiomyocytes, we found that ligand-induced promoter activity of RAR and RXR was significantly suppressed by HG. HG promoted protein destabilization and serine-phosphorylation of RARα and RXRα. Proteasome inhibitor MG132 blocked the inhibitory effect of HG on RARα and RXRα. Inhibition of intracellular reactive oxidative species (ROS) abolished the HG effect. In contrast, H(2)O(2) stimulation suppressed the expression and ligand-induced promoter activity of RARα and RXRα. HG promoted phosphorylation of ERK1/2, JNK and p38 MAP kinases, which was abrogated by an ROS inhibitor. Inhibition of JNK, but not ERK and p38 activity, reversed HG effects on RARα and RXRα. Activation of JNK by over expressing MKK7 and MEKK1, resulted in significant downregulation of RARα and RXRα. Ligand-induced promoter activity of RARα and RXRα was also suppressed by overexpression of MEKK1. HG-induced cardiomyocyte apoptosis was potentiated by activation of JNK, and prevented by all-trans retinoic acid and inhibition of JNK. Silencing the expression of RARα and RXRα activated the JNK pathway. In conclusion, HG-induced oxidative stress and activation of the JNK pathway negatively regulated expression/activation of RAR and RXR. The impaired RAR/RXR signaling and oxidative stress/JNK pathway forms a vicious circle, which significantly contributes to hyperglycemia induced cardiomyocyte apoptosis.

A new fossil fruit wing of Shorea Roxb. belonging to the family Dipterocarpaceae is described from the Early Miocene sediments of Kachchh, Gujarat. It resembles best the extant species Shorea macroptera Dyer, which is a prominent member of the tropical evergreen forests of the Malayan Peninsula. The present finding, along with the other megafossil records described from the same area, indicates a typical tropical vegetation with a warm and humid climate at the time of deposition in contrast to the present day xeric vegetation in the area. As the family Dipterocarpaceae no longer exists in western India, it is essential to discuss the time of its extinction and possible causes, which may include drastic changes in the climate of the region. The present finding also supports the theory of a Malaysian origin for the family in contrast to the hypothesis of a Gondwanan origin.

It is well recognized by orthopedic surgeons that fractures of alcoholics are more difficult to heal successfully and have a higher incidence of non-union, but the mechanism of alcohol's effect on fracture healing is unknown. In order to give direction for the study of the effects of alcohol on fracture healing, we propose to identify gene expression and microRNA changes during the early stages of fracture healing that might be attributable to alcohol consumption. As the inflammatory stage appears to be the most critical for successful fracture healing, this paper focuses on the events at day three following fracture or the stage of inflammation. Sprague–Dawley rats were placed on an ethanol-containing or pair-fed Lieber and DeCarli diet for four weeks prior to surgical fracture. Following insertion of a medullary pin, a closed mid-diaphyseal fracture was induced using a Bonnarens and Einhorn fracture device. At three days' post-fracture, the region of the fracture calluses was harvested from the right hind-limb. RNA was extracted and microarray analysis was conducted against the entire rat genome. There were 35 genes that demonstrated significant increased expression due to alcohol consumption and 20 that decreased due to alcohol. In addition, the expression of 20 microRNAs was increased and six decreased. In summary, while it is recognized that mRNA levels may or may not represent protein levels successfully produced by the cell, these studies reveal changes in gene expression that support the hypothesis that alcohol consumption affects events involved with inflammation. MicroRNAs are known to modulate mRNA and these findings were consistent with much of what was seen with mRNA microarray analysis, especially the involvement of smad4 which was demonstrated by mRNA microarray, microRNA and polymerase chain reaction.

Diabetes mellitus (DM) is a primary risk factor for cardiovascular diseases and heart failure. Activation of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) has an anti-diabetic effect; but, a role in diabetic cardiomyopathy remains unclear. Using neonatal and adult cardiomyocytes, we determined the role of RAR and RXR in hyperglycemia-induced apoptosis and expression of renin-angiotensin system (RAS) components. Decreased nuclear expression of RARα and RXRα, activation of apoptotic signaling and cell apoptosis was observed in high glucose (HG) treated neonatal and adult cardiomyocytes and diabetic hearts in Zucker diabetic fatty (ZDF) rats. HG-induced apoptosis and reactive oxygen species (ROS) generation was prevented by both RAR and RXR agonists. Silencing expression of RARα and RXRα, by small interference RNA, promoted apoptosis under normal conditions and significantly enhanced HG-induced apoptosis, indicating that RARα and RXRα are required in regulating cell apoptotic signaling. Blocking angiotensin type 1 receptor (AT(1) R); but, not AT(2) R, attenuated HG-induced apoptosis and ROS generation. Moreover, HG induced gene expression of angiotensinogen, renin, AT(1) R, and angiotensin II (Ang II) synthesis were inhibited by RARα agonists and promoted by silencing RARα. Activation of RXRα, downregulated the expression of AT(1) R; and RXRα silencing accelerated HG induced expression of angiotensinogen and Ang II synthesis, whereas there was no significant effect on renin gene expression. These results indicate that reduction in the expression of RARα and RXRα has an important role in hyperglycemia mediated apoptosis and expression of RAS components. Activation of RAR/RXR signaling protects cardiomyocytes from hyperglycemia, by reducing oxidative stress and inhibition of the RAS.

This study was designed to determine the effect of all- trans retinoic acid (RA) on the development of cardiac remodeling in a pressure overload rat model. Male Sprague-Dawley rats were subjected to sham operation and the aortic constriction procedure. A subgroup of sham control and aortic constricted rats were treated with RA for 5 mo after surgery. Pressure-overloaded rats showed significantly increased interstitial and perivascular fibrosis, heart weight-to-body weight ratio, and gene expression of atrial natriuretic peptide and brain natriuretic peptide. Echocardiographic analysis showed that pressure overload induced systolic and diastolic dysfunction, as evidenced by decreased fractional shortening, ejection fraction, stroke volume, and increased E-to-Earatio and isovolumic relaxation time. RA treatment prevented the above changes in cardiac structure and function and hypertrophic gene expression in pressure-overloaded rats. RA restored the ratio of Bcl-2 to Bax, inhibited cleavage of caspase-3 and -9, and prevented the decreases in the levels of SOD-1 and SOD-2. Pressure overload-induced phosphorylation of ERK1/2, JNK, and p38 was inhibited by RA, via upregulation of mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-2. The pressure overload-induced production of angiotensin II was inhibited by RA via upregulation of expression of angiotensin-converting enzyme (ACE)2 and through inhibition of the expression of cardiac and renal renin, angiotensinogen, ACE, and angiotensin type 1 receptor. Similar results were observed in cultured neonatal cardiomyocytes in response to static stretch. These results demonstrate that RA has a significant inhibitory effect on pressure overload-induced cardiac remodeling, through inhibition of the expression of renin-angiotensin system components.

Nineteen isolates of Rhizoctonia solani collected from different rice varieties grown in various regions of Pun-jab were studied for their morphological and pathological characterization. Majority of the isolates were fast growing with raised and fluffy colonies and hyphal width of 9.6 μm while four exhibited moderate growth rate. Colony colour in all except two isolates was light yellowish brown. While sclerotial number per 5.0 mm culture disc of the test isolates ranged between 2.1 and 11.2 mm, their size varied between 1.31 and 2.08 mm. Sclerotial colour in all except two isolates was dark brown and most of these were found scattered in the colony. There was no relationship between morphologically similar isolates and their pathogenic behaviour. Majority of the isolates produced lesion length between 45.6 and 58.2 mm on detached rice leaves (cv. PR116). Molecular characterization of genetic diversity in the test isolates was studied by using 10 inter simple sequence repeats (ISSR) and eight random amplified polymorphic DNA (RAPD) markers. The size of amplified DNA bands ranged from 0.25-3.0 to 0.5-4.0 kb with ISSR and RAPD markers, respectively. Combined data set of 155 DNA markers were analysed with UPGMA resulting five clusters with 49-89% genetic similarity. Most of the isolates showed grouping specific to the host variety. Out of these two types of DNA markers, RAPD markers were able to detect more genetic variability when compared to ISSR markers.

Causes of retinoid resistance often observed in neuroblastomas are unknown. We studied all trans-retinoic acid (RA) signaling in neuroblastoma cells differing in N-myc levels in terms of neurite formation, expression of tissue transglutaminase, neuronal marker proteins, matrix metalloproteinases (MMPs), and activation of Rac1 and Cdc42. Poor invasiveness observed in SH-SY5Y, LA-N-5, and SMS-KCNR cells was associated with RA-induced neurite formation, Cdc42 activation and N-myc down regulation; expression of constitutively active Cdc42 down regulated N-myc expression and reduced invasion in RA-resistant SK-N-BE(2) and IMR32 cells. RA treatment for 24 h transiently increased invasion and expression of MMP9 in SH-SY5Y, LA-N-5 and MMP2 in SMS-KCNR cells. MMP inhibition prevented RA-induced neurite formation indicating a role in differentiation. Variation in RA signaling thus follows a defined pattern and relates to invasive potential. A defective RA signaling might result in retinoid resistance and unpredictable clinical outcome observed in some neuroblastomas.

Integrins are the principle mediators of molecular dialog between a cell and its extracellular matrix environment. The unique combinations of integrin subunits determine which extracellular matrix molecules are recognized by a cell. Recent studies have demonstrated that remodeling in heart and vasculature is linked to alterations in extracellular matrix and integrin expression. The roles of integrins in controlling cellular behavior have made these molecules highly attractive drug targets. New insights into mechanisms whereby the extracellular matrix takes part in the control of smooth muscle cell proliferation and cardiac growth suggest a number of putative targets for future therapies that can be applied to increase plaque stability, prevent the clinical consequences of atherosclerosis and improve outcomes after interventional procedures such as cardiac transplantation. Therapeutic candidates include antibodies, cyclic peptides, peptidomimetics and small molecules. The integrin inhibitors Integrilin and ReoPro have been approved as blood thinners in cardiovascular disease, and newer agents are undergoing testing. Although integrin function is important in the cardiovascular system, there are wide gaps in knowledge. In this review, we discuss the primary mechanisms of action and signaling of integrins in the cardiac and vascular system in normal and pathological states, as well as therapeutic strategies for targeting these molecules in the cardiovascular system.

Objectives: We have previously demonstrated that the expression/activation of retinoic acid receptor (RAR) is inhibited in diabetic hearts, and that activation of RARα prevents diabetes-induced diastolic heart failure, suggesting that impairment of RARα signaling may be a critical mechanism in heart failure. Methods and Results: Cardiac RARα gene deletion (KO) was achieved by tamoxifen injection at 6-weeks old RARαfl/fl α-MHC-MerCreMer mice, RARαfl/fl mice were used as control (WT). Heart function was monitored by echocardiograph for 64 wks. Mice were sacrificed at 20 or 64 wks post gene deletion, respectively. A significant decrease in E/A ratio and TDI E’ and increase in IVRT (isovolumic relaxation time) and DT (deceleration time) suggested diastolic dysfunction after 16 wks of gene deletion in KO mice, which was confirmed by cardiac catheterization (decreased dP/dtmin and increased tau). Concentric hypertrophy developed in KO mice after 56 wks of gene deletion, as confirmed by increased thickness of left ventricular wall and interventricular septum and elevated heart weight/tibia length ratio. However, no significant difference was observed in LVEF (LV ejection fraction), FS (fraction shortening) and dP/dtmax between KO and WT mice. Significantly increased gene expression of NOX2 (NADPH oxidase 2) and NOX4, decreased SOD1 and SOD2 levels and increased intracellular reactive oxygen species (ROS) were observed in KO mouse hearts, along with a significantly decreased protein expression of SERCA2a and CaMKIIδ, decreased phosphorylation of PLB, Akt and CaMKIIδ. Overexpression of RARα in cardiomyocytes rescued RARα deletion-induced changes in SERCA2a, PLB, Akt and CaMKIIδ. Deletion of RARα in cardiomyocytes impaired intracellular calcium reuptake into SR and cardiomyocyte relaxation. Inhibition of ROS by N-acetyl cysteine abolished RARα deletion-induced calcium mishandling and cardiomyocyte relaxation. Conclusion: Cardiac specific deletion of RARα induces diastolic heart failure with preserved ejection fraction (HFpEF), by promoting intracellular ROS and disrupting SERCA2a-mediated calcium reuptake and cardiomyocyte relaxation. Our study suggests that deficiency in RARα signaling is a novel mechanism leading to HFpEF.

Thymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tβ4 in cardiomyocyte hypertrophy is currently unknown. The purpose of this study was to determine the cardio-protective effect of Tβ4 in angiotensin II (Ang II)-induced cardiomyocyte growth. Neonatal rat ventricular cardiomyocytes (NRVM) were pretreated with Tβ4 followed by Ang II stimulation. Cell size, hypertrophy marker gene expression and Wnt signaling components, β-catenin, and Wnt-induced secreted protein-1 (WISP-1) were evaluated by quantitative real-time PCR, Western blotting and fluorescent microscopy. Pre-treatment of Tβ4 resulted in reduction of cell size, hypertrophy marker genes and Wnt-associated gene expression, and protein levels; induced by Ang II in cardiomyocyte. WISP-1 was overexpressed in NRVM and, the effect of Tβ4 in Ang II-induced cardiomyocyte growth was evaluated. WISP-1 overexpression promoted cardiomyocytes growth and was reversed by pretreatment with Tβ4. This is the first report which demonstrates that Tβ4 targets Wnt/WISP-1 to protect Ang II-induced cardiomyocyte growth. J. Cell. Physiol. 231: 1737-1744, 2016. © 2015 Wiley Periodicals, Inc.

Catastrophic antiphospholipid antibody syndrome (CAPS) resembles severe sepsis in its acute presentation, with features of systemic inflammatory response syndrome (SIRS) leading to multiple organ dysfunction. Infections are the best known triggers of CAPS. This emphasizes the need for early diagnosis and aggressive treatment as the mortality is as high as 50%. We present a 42-year-old woman who developed SIRS postoperatively and was eventually diagnosed as CAPS.

The present study has been undertaken to monitor the extent of oxidative stress in mice infected with M. tuberculosis and the role of crude green tea extract in repairing the oxidative damage. The mice were divided into three groups of 9 each; normal, infected-untreated and infected-treated. The infected group of animals exhibited significant enhancement of erythrocytic catalase and glutathione peroxidase activities along with elevated levels of erythrocytic total thiols and plasma lipid peroxidation as compared to normal animals. The infected group also exhibited significantly decreased activity of superoxide dismutase and levels of glutathione in erythrocytes. Upon oral administration of green tea extract for seven days the oxidative stress parameters were reverted back to near normal levels as evidenced by a fall in catalase, glutathione peroxidase, total thiol and extent of lipid peroxidation with concomitant increase in the levels of SOD and reduced glutathione in infected animals. The findings thus, portray that there is a high oxidative stress during early stages of tuberculosis and antioxidants such as green tea extract, can play a vital role by reducing stress through adjuvant therapy.

Shrinking lung syndrome (SLS) is a infrequently reported manifestation of systemic lupus erythematosus (SLE). Reported prevalence of SLS is about 0.5% in SLE patients. Pathogenesis is not fully understood and different therapeutic modalities have been employed with variable results, as only 77 cases of SLS have been documented in literature. SLS in SLE-Scleroderma overlap has not been reported yet. We report a patient of SLE - scleroderma overlap presenting with dyspnea, intermittent orthopnea and pleuritic chest pain. Evaluation revealed elevated hemidiaphragms and severe restrictive defect. She was eventually diagnosed as a case of SLS. This case report is a reminder to the medical fraternity that SLS although a rare complication must be thought of in the special subset of patients of SLE having respiratory symptoms.