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Abstract The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells. We show that integrating chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enables identification of transcription factors and regulatory mechanisms critical for extravillous trophoblast cell development. We elucidate functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of extravillous trophoblast cell development. EPAS1 is identified as an upstream regulator of key extravillous trophoblast cell transcription factors, including ASCL2 and SNAI1 and together with its target genes, is linked to pregnancy loss and birth weight. Collectively, we reveal activation of a dynamic regulatory network and provide a framework for understanding extravillous trophoblast cell specification in trophoblast cell lineage development and human placentation.

This study aims to look at novel variations in TGIF1 gene and explores their potential association with high myopia in an ethnic population from Kashmir (India). Genomic DNA was genotyped for polymorphic variations, and allele frequencies were tested for the Hardy–Weinberg disequilibrium in 240 ethnic Kashmiri cases with high myopia with a spherical equivalent of >−6 diopters (D) and compared with emmetropic controls with spherical equivalent within −0.5D in one or both eyes represented by a sample size of 228. In this study, we found a novel sequence variation G26A (GAT to AAT) in 5′ half of TGIF1 gene (p. aspartic acid >asparagine) at a frequency of 62% (148/240, P ≤ 0.0001). Variation appears to associate with high myopia significantly (P ≤ 0.001) as it happens to be present only in high myopia affected individuals. Further, it shows statistical significance for its association with gender and the degree of myopia (P ≤ 0.05). In addition, in silico predictions show that variation likely has an impact on the structure and functional properties of the protein. The assessment of the I-TASSER protein structure showed higher energy for a wild-type protein (−5820.186 kJ/mol) as compared to mutant protein (−6595.593 kJ/mol).

Introduction The hemochorial placenta provides a critical barrier at the maternal–fetal interface to modulate maternal immune tolerance and enable gas and nutrient exchange between mother and conceptus. Pregnancy outcomes are adversely affected by diabetes mellitus; however, the effects of poorly controlled diabetes on placental formation, and subsequently fetal development, are not fully understood.Research design and methods Streptozotocin was used to induce hyperglycemia in pregnant rats for the purpose of investigating the impact of poorly controlled diabetes on placental formation and fetal development. The experimental paradigm of hypoxia exposure in the pregnant rat was also used to assess properties of placental plasticity. Euglycemic and hyperglycemic rats were exposed to ambient conditions (~21% oxygen) or hypoxia (10.5% oxygen) beginning on gestation day (gd) 6.5 and sacrificed on gd 13.5. To determine whether the interaction of hyperglycemia and hypoxia was directly altering trophoblast lineage development, rat trophoblast stem (TS) cells were cultured in high glucose (25 mM) and/or exposed to low oxygen (0.5% to 1.5%).Results Diabetes caused placentomegaly and placental malformation, decreasing placental efficiency and fetal size. Elevated glucose disrupted rat TS cell differentiation in vitro. Evidence of altered trophoblast differentiation was also observed in vivo, as hyperglycemia affected the junctional zone transcriptome and interfered with intrauterine trophoblast invasion and uterine spiral artery remodeling. When exposed to hypoxia, hyperglycemic rats showed decreased proliferation and ectoplacental cone development on gd 9.5 and complete pregnancy loss by gd 13.5. Furthermore, elevated glucose concentrations inhibited TS cell responses to hypoxia in vitro.Conclusions Overall, these results indicate that alterations in placental development, efficiency, and plasticity could contribute to the suboptimal fetal outcomes in offspring from pregnancies complicated by poorly controlled diabetes.

Organizational commitment is the individual's mental attachment to the organization and is perceived as employees’ eager to contribute in organizational achievements feeling satisfied at work. The study aimed at examining the relationship between the organizational commitment and job satisfaction among the nurses of public and private sectors hospitals in Peshawar. The study used a reliable instrument (Cronbach alpha=0.91), developed from the literature, containing 27 items to measure the components of organizational commitment and job satisfaction. A sample size (N=120) was randomly selected, consists of female nurses employed in public and private hospitals in Peshawar. The primary data was analyzed using descriptive statistics, Pearson correlation and regression analysis. The results showed that the affective commitment and normative commitment are significantly positively associated with job satisfaction, while the continuous commitment was not significantly associated with job satisfaction of the nurses in hospitals of Peshawar. The study revealed that employees who are highly committed to the organization have higher level of job satisfaction. It is concluded from the finding of the study that a caring and conducive work environment may play a vital role in creating organizational commitment among employees.

The study is designed to identify the determinants of profitability in the insurance industry of Pakistan. The panel data set of 41 insurance companies (life, non-life, and takaful insurance) from 2007-2017 was employed. Hausman's specification and Breusch-Pagan Lagrange multiplier (LM) tests have selected the most appropriate test i.e. fixed effect and pooled OLS model for this study. The results of pooled OLS and fixed effect model reveal that insurancespecific and macroeconomic factor like leverage, business risk, and inflation rate are negative but significantly affect the profitability of the insurance sector. However, size and GDP rate has a positive and statistically significant influence on profitability. Liquidity and growth are insignificant determinants of the study. This is the first study that covers the entire insurance industry, which is also composed of the takaful industry, along with firm-specific and country-specific attributes and applies the most suitable models for the study. Thus, this study is very important for top-echelon and policy- makers of the insurance sector of Pakistan regarding the profitability of the firm and wealth of the shareholders.

Amongst the illicit drugs cocaine, amphetamines and cannabis have been studied and documented well to cause myocardial infarction by different mechanisms but there is very sparse data available on myocardial involvement after heroin abuse. We report a young man who developed acute myocardial injury after heroin inhalation and alcohol binge drinking. Heroin induced cardio toxic effect and vasospasm compounded by alcohol were suspected to be the cause of this. [ABSTRACT FROM AUTHOR]

Injection of linearized DNA constructs into the pronuclei of fertilized mammalian eggs is a standard method for producing transgenic embryos and animals. Here, we show that injection of covalently closed circular (ccc) plasmids into the cytoplasm of fertilized bovine and murine eggs is a highly efficient and simple alternative for ectopic expression of foreign DNA in embryos. A broad range of plasmids could be successfully expressed in preimplantation stages, including plasmids and minicircles with a scaffold/matrix attachment region (S/MAR), conventional plasmids, and bacterial artificial chromosomes (BACs). Although the foreign DNA plasmids are mainly maintained as episomal entities during preimplantation development, they accurately behave like nuclear DNA. Onset of transcription of an Oct4 promoter–controlled marker gene coincided with the species-specific time points of major embryonic genome activation, and could be modulated by in vitro DNA-methylation. This approach allows an experimental access to reprogramming events in early mammalian embryos.

Introduction: Dengue viral infections are among the most important mosquito-borne diseases of the Indian subcontinent and have become a major global public health concern. Spread of disease has led to increased recognition of atypical manifestations apart from the classical clinical features of dengue infection. Methodology: A cross-sectional study of admitted patients suspected to have dengue infection was conducted during the monsoon and post-monsoon seasons in the year 2010. Patients who had serological confirmation of dengue infection were classified according to World Health Organization definitions of dengue fever and dengue hemorrhagic fever. Clinical and biochemical parameters were compared between the two groups. Results: Out of 356 patients with suspected dengue fever enrolled in the study, 138 (39%) had serologically confirmed dengue infection. Eighty (58%) patients were males and 58 (42%) were females. Ninety-six (70%) patients had classical dengue fever while 42 (30%) had dengue hemorrhagic fever. The most common symptoms were headache (105, 76%), abdominal pain (87, 63%), vomiting (80, 58%), rash (36, 26%), and cutaneous hypersensitivity (22, 16%). Hemorrhagic manifestations were present in 55 (40%) patients. Atypical manifestations were recorded. Notably, 14% of patients had neurological involvement and 4% had acute hepatic failure. Overall mortality was 6% and all fatal cases were due to multi-organ failure. Conclusion: Dengue infection poses a huge burden to the health-care system; its spectrum ranges from mild self-limiting illness to severe fatal disease. It can have varied and multi-systemic manifestations which can go unrecognized. Clinicians should have a high index of suspicion for atypical manifestations. [ABSTRACT FROM AUTHOR]

Cytokine storm (CS) refers to the spontaneous dysregulated and hyper-activated inflammatory reaction occurring in various clinical conditions, ranging from microbial infection to end-stage organ failure. Recently the novel coronavirus involved in COVID-19 (Coronavirus disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has been associated with the pathological phenomenon of CS in critically ill patients. Furthermore, critically ill patients suffering from CS are likely to have a grave prognosis and a higher case fatality rate. Pathologically CS is manifested as hyper-immune activation and is clinically manifested as multiple organ failure. An in-depth understanding of the etiology of CS will enable the discovery of not just disease risk factors of CS but also therapeutic approaches to modulate the immune response and improve outcomes in patients with respiratory diseases having CS in the pathogenic pathway. Owing to the grave consequences of CS in various diseases, this phenomenon has attracted the attention of researchers and clinicians throughout the globe. So in the present manuscript, we have attempted to discuss CS and its ramifications in COVID-19 and other respiratory diseases, as well as prospective treatment approaches and biomarkers of the cytokine storm. Furthermore, we have attempted to provide in-depth insight into CS from both a prophylactic and therapeutic point of view. In addition, we have included recent findings of CS in respiratory diseases reported from different parts of the world, which are based on expert opinion, clinical case-control research, experimental research, and a case-controlled cohort approach., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Regeneration is a rare occurrence in the animal kingdom, but the earthworm stands out as a remarkable example of this phenomenon. Recent research has highlighted the promising wound healing properties of extracts derived from earthworms. Therefore, we propose that earthworm granulation tissue extract (EGTE) may facilitate wound healing by regulating immune responses in a rabbit diabetic wound model. Electron microscopy reveals that 70 % EGTE possesses noteworthy porosity with spherical to irregularly oval configuration. Gas chromatography-mass spectrometry (GC-MS) Characterization of EGTE revealed higher levels of ergosta-5,7,22-trien-3-ol, (3. beta.,22E). In-Vitro studies revealed significant anti-oxidant, anti-inflammatory and anti-bacterial properties in dose dependent manner. Likewise, cytotoxicity assessments reveal that 70 % EGTE exhibits minimal harm to cells while displaying substantial antioxidant and anti-inflammatory activities. For In-Vivo studies excision wounds were created on the dorsal regions of the experimental animals and were divided as Group I (50 % EGTE), Group II (70 % EGTE), Group III (vehicle) and Group IV (distilled water). Over a 21-day observation period 70 % EGTE facilitated the early healing of wounds in the experimental animals, evident through prompt wound closure, granulation tissue formation, increased DNA content, enhanced tensile strength of the wound area and enhanced the expression/synthesis of wound healing markers/proteins. From these results it can be postulated that EGTE accelerates wound healing by immune modulation, dampening of inflammatory pathway and enhanced expression of growth markers. Henceforth making it promising candidate for therapeutic use in diabetic wound healing., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Diabetes mellitus (DM) is characterized by an absolute decline in insulin secretion and peripheral resistance and is the most prevalent metabolic and endocrine disorder. However, the pathogenesis of DM also includes adipocyte insulin resistance, increased glucagon secretion, increased renal glomerular glucose absorption, and neurotransmitter dysfunction. Although there is a wide spectrum of therapeutics available for glycemic control, owing to the identification of various pathogenic determinants of DM, management of DM remains challenging and complex. Current therapeutic interventions against DM focus mostly on glycemic control without considering the other pathological determinants that eventually lead to treatment failure and the progression of DM. Furthermore, long-term use of these conventionally available anti-diabetic drugs leads to various side effects, henceforth development of novel drugs against DM remains an unending search strategy for researchers. Various studies conducted in various parts of the world have proposed that these novel therapeutic interventions target multiple and alternate pathogenic hotspots involved in DM. The current review article discusses novel therapeutic options that hold particular promise to support their safety and discuss the side effects resulting from their use so that these novel candidate drugs can be effectively fabricated into potential drugs for the treatment of DM.

Background: Diverse strategies are employed globally to integrate medical curricula. Nevertheless, a gap exists in assessing the role of medical instructors in meaningful integration. We developed and used a tool to explore the current level of integration, score medical instructors' individual practices for integration, and investigate contextual elements minimizing integration., Methodology: This cross-sectional study, conducted in September-November-2020, used convenience-sampling. The study participants were basic-sciences and clinical instructors at two private-sector medical colleges in Karachi-Pakistan (with a response rate of 53.5%, n = 107). We validated a paper-based questionnaire through a pilot study on five participants. This tool with 11 close-ended questions on a 5-point Likert scale generated instructors' integration scores, and six open-ended questions probed instructors' perspectives., Results: The mean integration score was 37.4±6.7. Participants' perspectives indicated a need for participation of clinical faculty in teaching initial undergraduate years, involving lecturers in curriculum meetings, and integration of assessment. The questionnaire Cronbach-alpha was 0.732 with satisfactory principal-component-analysis., Conclusion: Medical instructors facilitated integration mainly through concurrent timetabling of similar topics. Moreover, formal consultation through committee meetings, with discipline-based and integrated approaches complementing each other, were in practice to achieve curricular goals., (© 2022 Baig, Siddiqui, Baig, Khursheed, Meah; licensee Synergies Partners.)

Objectives: To measure the students' perceptions of educational environment of a medical school, to compare the perceptions of high, average and low academic achievers, and to explore the relation between these perceptions and their academic achievements in order to identify specific problem areas., Methods: The cross-sectional study was conducted at Ziauddin University, Karachi, during the mid of the 2010-11 academic year using Dundee Ready Education Environment Measure inventory. Data was collected from 200 undergraduate medical students of all five years. Analysis was performed using both Inventory guidelines on SPSS19.0., Results: Of the 200 students initially enrolled, completed forms were received from 168 (84%). The overall mean score was 117+/-8.3. Mean comparison of their perceptions on the overall score was significantly less (p<0.001) for the low achievers across all 5 years. Moderate positive correlation (r= 0.417) was found between perceptions and academic achievements., Conclusions: Students' perceptions of their educational environment were reasonably positive, indicating adequate satisfaction in most areas. Emphasis needs to be paid on the implementation of strong student support system across all medical schools to initiate timely remedial measures where needed. The learning environment should be evaluated regularly for quality improvement purposes.

Background: Accurate working length determination is a pre-requisite for a successful endodontic treatment. Even with improved systems of working length measurement, different readings may be recorded in different electrolytes present in the canal. The purpose of this in vivo/ex vivo comparative study was to determine the accuracy in measuring the working length of root canal using Direct Digital Radiographic Method (Radiovisiography or RVG) and ProPex electronic apex locator in the presence of three different irrigating solutions: 0.9% normal saline, 2% chlorhexidine, 3% NaOCl solutions., Materials and Methods: Forty single-rooted human teeth scheduled for extraction with mature apices were selected for this study. Measurements were performed by using RVG and ProPex in the presence of irrigating solutions. After extraction of the teeth, light microscope was used to confirm visually the relationship of the tip of the endodontic file to the apical foramen, and actual lengths were determined by reducing 0.5 mm from this length. The statistical analysis was performed by one-way ANOVA test and Tukey-HSD post hoc procedure. P < 0.05 was considered as significant., Results: No significant difference was found between overall mean electronic working length and digital radiographic length; however, prediction error (P < 0.05) was significant with respect to different irrigants. Among the irrigating solutions, chlorhexidine gluconate had the smallest distance to the actual lengths, whereas NaOCl had the greatest., Conclusion: Electronic apex locator ProPex yielded best result in the presence of chlorhexidine, whereas the largest error was demonstrated with NaOCl indicating that higher electroconductive irrigating solutions affect the precision of multi-frequency apex locators.

The aim of the study was to evaluate undergraduate students' perceptions regarding Objectively Structured Clinical Examination (OSCE) to be used as a feedback to improve the assessment technique. At the end of OSCE, students were provided with a feedback questionnaire related to OSCE to obtain their views and comments. The feedback was obtained from two consecutive batches of third year medical students and was utilized to incorporate the improvements in the process, wherever possible. A great majority of students (93% from group 'A' and 95% from group 'B') regarded OSCE as a practical and useful assessment tool in early years of medical education. In this study, students appreciated OSCE and offered constructive feedback on structure and organization of the process. However, at some stations they felt that instructions were ambiguous and time allocation was inadequate for the assigned tasks. The overall feedback was very useful and facilitated a critical review of the process.