Unraveling the genetic basis of epilepsy: Recent advances and implications for diagnosis and treatment.

Epilepsy, affecting approximately 1% of the global population, manifests as recurring seizures and is heavily influenced by genetic factors. Recent advancements in genetic technologies have revolutionized our understanding of epilepsy's genetic landscape. Key studies, such as the discovery of mutations in ion channels (e.g., SCN1A and SCN2A), neurotransmitter receptors (e.g., GABRA1), and synaptic proteins (e.g., SYNGAP1, KCNQ2), have illuminated critical pathways underlying epilepsy susceptibility and pathogenesis. Genome-wide association studies (GWAS) have identified specific genetic variations linked to epilepsy risk, such as variants near SCN1A and PCDH7, enhancing diagnostic accuracy and enabling personalized treatment strategies. Moreover, epigenetic mechanisms, including DNA methylation (e.g., MBD5), histone modifications (e.g., HDACs), and non-coding RNAs (e.g., miR-134), play pivotal roles in altering gene expression and synaptic plasticity, contributing to epileptogenesis. These discoveries offer promising avenues for therapeutic interventions aimed at improving outcomes for epilepsy patients. Genetic testing has become essential in clinical practice, facilitating precise diagnosis and tailored management approaches based on individual genetic profiles. Furthermore, insights into epigenetic regulation suggest novel therapeutic targets for developing more effective epilepsy treatments. In summary, this review highlights significant progress in understanding the genetic and epigenetic foundations of epilepsy. By integrating findings from key studies and specifying genes involved in epigenetic modifications, we underscore the potential for advanced therapeutic strategies in this complex neurological disorder, emphasizing the importance of personalized medicine approaches in epilepsy management.

Bilateral Renal Hilar Nutcracker Phenomenon in a Male Cadaver.

Nutcracker phenomenon (NCP) typically refers to the entrapment of the left renal vein (LRV) between the aorta and the superior mesenteric artery. Similar to the classic NCP, the renal vein can also get entrapped between the segmental branches of the renal artery at the renal hilum, which has been referred to as 'renal hilar nutcracker phenomenon (RHNP).' During routine dissection of a male cadaver of 67 years, the renal veins of both sides at the renal hilum were seen between the segmental branches of renal arteries, which we identified as the 'renal hilar nutcracker phenomenon.' The disposition of the rest of the perihilar structures was normal. 'Renal hilar nutcracker phenomenon' can have similar clinical presentation like that of the nutcracker phenomenon. Hence, knowledge of such anatomical variation at the renal hilum is desirable.

Yoga and Lifestyle Changes: A Path to Improved Fertility - A Narrative Review.

Infertility, a widespread medical condition affecting numerous couples globally, persists as a challenge despite advances in assisted reproductive technologies (ARTs), often burdened by financial, physical, and emotional strains. Complementary and alternative approaches, notably yoga, have garnered attention for potentially enhancing fertility outcomes. Studies reveal yoga's influence on factors contributing to infertility, including reduced oxidative stress (OS) and oxidative DNA damage (ODD). OS, linked to mutagenic base formation, higher malondialdehyde levels, abnormal methylation, and altered gene expression, can impair sperm genome integrity. Yoga's efficacy is evident in lowering OS, positively affecting signal transmission, gene expression, and physiological systems. Furthermore, yoga has a positive impact on addressing the dysregulation of apoptosis, resulting in improved processes such as spermatogenesis, sperm maturation, and motility, while also reducing DNA fragmentation. OS correlates with genome-wide hypomethylation, telomere shortening, and mitochondrial dysfunction, contributing to genome instability. Yoga and meditation significantly reduce OS and ODD, ensuring proper reactive oxygen levels and preserving physiological systems. The review explores potential mechanisms underlying yoga's positive impact on infertility, including enhanced blood flow, reduced inflammation, relaxation response, and modulation of the hypothalamic-pituitary-adrenal axis. Furthermore, a comprehensive review of the literature reveals substantial evidence supporting the positive effects of yoga on infertility factors. These include oxidative stress (OS), oxidative DNA damage (ODD), epigenetic changes, hormonal balance, ovarian function, menstrual irregularities, and stress reduction. In summary, yoga emerges as a promising adjunctive therapy for infertility, demonstrating the potential to mitigate key factors influencing reproductive success. Although preliminary evidence indicates the positive effects of yoga on infertility, further clinical research is imperative to define specific benefits, molecular mechanisms associated, optimal protocols, and long-term effects in infertility treatment plans.

Yoga and its effect on sperm genomic integrity, gene expression, telomere length and perceived quality of life in early pregnancy loss.

Achieving successful pregnancy outcomes is a delicate interplay between the maternal and the fetal counterparts. Paternal factors play a critical role in health and disease of offspring. Early pregnancy loss (EPL) is a psychologically devastating condition affecting the quality of life (QOL). Thus, it needs to be managed by a mind body integrated approach like yoga.The prospective single arm exploratory studyincluded male partners of couples experiencing recurrent pregnancy loss (RPL, n = 30), and recurrent implantation failure (RIF, n = 30) and semen samples wereassessed at the beginning and completion of yoga (6 weeks) (WHO 2010).A significant increase in the sperm concentration, motility, decrease in seminal ROS, DFI and increase in relative sperm telomere length was found at the end of yoga. The relative expression of genes critical for early embryonic developmentnormalized towards the levels of controls. WHOQOL-BREF questionnaire scores to assess QOL also showed improvement.Integration of regular practice yoga into our lifestyle may help in improving seminal redox status, genomic integrity, telomere length, normalizing gene expression and QOL, highlighting the need to use an integrated, holistic approach in management of such cases. This is pertinent for decreasing the transmission of mutation and epimutation load to the developing embryo, improving pregnancy outcomes and decreasing genetic and epigenetic disease burden in the next generation.

A Comprehensive Analysis of Y-Chromosome Microdeletions and Their Relationship to Male Infertility and Lifestyle Variables.

BACKGROUND: Male infertility is the inability of a male to conceive a fertile female during at least a year of unprotected sexual activity. A variety of medical conditions and treatments cause male infertility. Y chromosome microdeletion is an important cause of infertility among males. Various epidemiological factors also play a role in the occurrence of infertility. Our study aims to determine the association between Y-chromosome microdeletion and age, sperm count, body mass index (BMI), alcohol, and tobacco consumption. METHODS: This study was conducted in 70 male infertility cases. Data was collected from 2018 to 2023 at the Genetic Lab, Department of Anatomy, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India. Demographic profiles, including age, sperm count, weight and height, and history of smoking and drinking, were collected from individuals. BMI was calculated, and chromosome analysis was done for Y chromosome microdeletion. Both multiplex and singleplex methods were used to determine the microdeletion using a thermocycler (Applied Biosystems, VeritiTM 96-well Fast Thermal Cycler, 0.2 ml USA) in AZF, and the association between age, sperm count, BMI, alcohol, and tobacco was determined. RESULTS: The number of regions deleted among individuals varies from one to seven. Regions Sy746, Sy143, and Sy145 were found to be commonly deleted. We found a positive, but not statistically significant, correlation between age and microdeletion (point biserial correlation coefficient (r) = 0.2, p-value = 0.097). When comparing age with sperm count, the results showed a negative correlation, highlighting the influence of age on sperm count (r (68) = 0.284, p = 0.017). In comparing BMI and microdeletion, no significant relationship (χ² = 3.7, p = 0.296) indicated independence between them. According to our observations, microdeletion affects all smokers and 45% of non-smokers. We found a significant association between smoking and microdeletion (χ2 = 4.49, P = 0.034). There was no statistically significant relationship between microdeletion and drinking (χ²(3) = 5.65, p = 0.13). CONCLUSION: We discovered a significant positive association between smoking and a positive, but not statistically significant, correlation between age, BMI, and drinking, as well as a microdeletion. There are probably a lot of unidentified variables that affect successful fertilization and implantation. These could include variables that affect fertility and the success of reproduction on an environmental, genetic, and epigenetic level. The study reveals that Y chromosome microdeletion and other epidemiological factors coexist concurrently in cases of infertility. Assessing these variables is crucial for infertile patients. A community-based, comprehensive survey is required to assess the overall consequences of various epidemiological factors on infertility.

From microbes to medicine: harnessing the gut microbiota to combat prostate cancer.

The gut microbiome (GM) has been identified as a crucial factor in the development and progression of various diseases, including cancer. In the case of prostate cancer, commensal bacteria and other microbes are found to be associated with its development. Recent studies have demonstrated that the human GM, including Bacteroides, Streptococcus, Bacteroides massiliensis, Faecalibacterium prausnitzii, Eubacterium rectale, and Mycoplasma genitalium, are involved in prostate cancer development through both direct and indirect interactions. However, the pathogenic mechanisms of these interactions are yet to be fully understood. Moreover, the microbiota influences systemic hormone levels and contributes to prostate cancer pathogenesis. Currently, it has been shown that supplementation of prebiotics or probiotics can modify the composition of GM and prevent the onset of prostate cancer. The microbiota can also affect drug metabolism and toxicity, which may improve the response to cancer treatment. The composition of the microbiome is crucial for therapeutic efficacy and a potential target for modulating treatment response. However, their clinical application is still limited. Additionally, GM-based cancer therapies face limitations due to the complexity and diversity of microbial composition, and the lack of standardized protocols for manipulating gut microbiota, such as optimal probiotic selection, treatment duration, and administration timing, hindering widespread use. Therefore, this review provides a comprehensive exploration of the GM's involvement in prostate cancer pathogenesis. We delve into the underlying mechanisms and discuss their potential implications for both therapeutic and diagnostic approaches in managing prostate cancer. Through this analysis, we offer valuable insights into the pivotal role of the microbiome in prostate cancer and its promising application in future clinical settings.

Cancer risk and male Infertility: Unravelling predictive biomarkers and prognostic indicators.

In recent years, there has been a global increase in cases of male infertility. There are about 30 million cases of male infertility worldwide and male reproductive health is showing rapid decline in last few decades. It is now recognized as a potential risk factor for developing certain types of cancer, particularly genitourinary malignancies like testicular and prostate cancer. Male infertility is considered a potential indicator of overall health and an early biomarker for cancer. Cases of unexplained male factor infertility have high levels of oxidative stress and oxidative DNA damage and this induces both denovo germ line mutations and epimutations due to build up of 8-hydroxy 2 deoxygunaosine abase which is highly mutagenic and also induces hypomethylation and genomic instability. Consequently, there is growing evidence to explore the various factors contributing to an increased cancer risk. Currently, the available prognostic and predictive biomarkers associated with semen characteristics and cancer risk are limited but gaining significant attention in clinical research for the diagnosis and treatment of elevated cancer risk in the individual and in offspring. The male germ cell being transcriptionally and translationally inert has a highly truncated repair mechanism and has minimal antioxidants and thus most vulnerable to oxidative injury due to environmental factors and unhealthy lifestyle and social habits. Therefore, advancing our understanding requires a thorough evaluation of the pathophysiologic mechanisms at the DNA, RNA, protein, and metabolite levels to identify key biomarkers that may underlie the pathogenesis of male infertility and associated cancer. Advanced methodologies such as genomics, epigenetics, proteomics, transcriptomics, and metabolomics stand at the forefront of cutting-edge approaches for discovering novel biomarkers, spanning from infertility to associated cancer types. Henceforth, in this review, we aim to assess the role and potential of recently identified predictive and prognostic biomarkers, offering insights into the success of assisted reproductive technologies, causes of azoospermia and idiopathic infertility, the impact of integrated holistic approach and lifestyle modifications, and the monitoring of cancer susceptibility, initiation and progression. Comprehending these biomarkers is crucial for providing comprehensive counselling to infertile men and cancer patients, along with their families.

Prevalence of FSH-R Asn680Ser and Ala307Thr receptor polymorphism and their correlation with ART outcomes among infertile Indian-Asian women-a prospective cohort study.

The present prospective cohort study evaluated the prevalence of FSH-R receptor Asn680Ser and Ala307Thr among infertile Indian women and the correlation of these polymorphisms with ART outcomes. Total 804 infertile and 209 fertile controls were enrolled for FSH-R analysis. Correlation of different genotypes with ovarian reserve markers, IVF parameters, and cumulative live birth rates (CLBR) was done among women undergoing IVF. In fertile controls, at 680 position GG (Ser/Ser) was the most common genotype; but among infertile women, all the genotypes were equally distributed. There was no significant difference in ovarian response parameters, oocyte yield, and CLBR among the three genotype groups. Empty follicle syndrome (EFS) was highest in women with AA or AG type at both positions. On categorisation of unexpected poor responders according to POSEIDON stratification; GG genotype at both positions had the lowest risk ratio of low-oocyte yield in ART cycles, but these differences were not statistically significant. This is the largest study from Indian ethnicity showing GG (Ser/Ser) genotype is most common among fertile women. The effect of FSH-R genotypes is very marginal on IVF parameters and is not reflected in CLBR. More prospective data may be required on the correlation of these genotypes with genuine EFS, thus stratifying the next cycles with self or donor oocytes. Routine genetic testing of FSH-R polymorphism should not be done except in a research setting. As both 680 and 307 positions are in linkage disequilibrium, only 680 position analysis may be done in a research setting.

Beyond the optic nerve: Genetics, diagnosis, and promising therapies for glaucoma.

Glaucoma stands as a leading global cause of blindness, affecting millions. It entails optic nerve damage and vision loss, categorized into open-angle and closed-angle glaucoma with subtypes like POAG, ACG, XFG, PCG, PDG, and developmental glaucoma. The pathophysiological and genetic factors behind glaucoma remain partially understood, with past studies linking intraocular pressure (IOP) levels to retinal ganglion cell death. Open-angle glaucoma involves elevated resistance to aqueous outflow via the trabecular meshwork, while angle-closure glaucoma typically sees drainage pathways obstructed by the iris. Genes have been identified for POAG, ACG, XFG, PCG, PDG, and developmental glaucoma, allowing for early-onset detection and the emergence of gene therapy as an effective treatment. Nevertheless, diagnostic and treatment options have their constraints, necessitating large-scale, well-designed studies to deepen our grasp of genetics' role in glaucoma's pathogenesis. This review delves into glaucoma's risk factors, pathophysiology, genetics, diagnosis, and available treatment options, including gene therapy. Additionally, it suggests alternative therapies like yoga and meditation as adjunct treatments for glaucoma prevention. Overall, this review advances our comprehension of the pathophysiology and genetic associations of glaucoma while highlighting the potential of gene therapy as a treatment avenue. Further research is imperative to fully elucidate the genetic mechanisms underpinning glaucoma and to devise effective treatments.

Yoga maintains Th17/Treg cell homeostasis and reduces the rate of T cell aging in rheumatoid arthritis: a randomized controlled trial.

The pathogenesis of rheumatoid arthritis (RA) is characterized by a Th17/Treg cell imbalance. A pro-inflammatory cytokine milieu that promotes the continued proliferation of Th17 cells is related to the development of autoinflammation. In RA, T cells have several hallmarks of cellular aging, and they accumulate DNA damage, predisposing to the occurrence of mutations and epigenetic alterations. Since the onset, progression, and treatment response are influenced by a variety of external stressors and environmental factors, this study aimed to evaluate the impact of 8-week yoga practice on disease severity, T cell subsets, markers of T cell ageing and inflammation, epigenetic alterations and gene expression patterns in active RA patients on standard disease-modifying anti-rheumatic drugs (DMARDs). A total of 64 participants with active RA were randomized into 2 groups, yoga group (n = 32) or non-yoga group (n = 32); that were assessed for disease severity, at baseline and after 8 week duration, for Disease Activity Score (DAS28-ESR), T cell subsets [Th17 (CD3+ CD4+ IL17+ RORγt+) cells and Treg (CD3+ CD4+ CD25+ CD127-Foxp3+) cells], markers of T cell aging [aged Th17 cells (CD3+ CD4+ IL17+ RORγt+ CD28-) and aged Treg cells (CD3+ CD4+ CD25+ CD127-Foxp3+ CD28-)], pro-inflammatory markers [IL-6, and IL-17], anti-inflammatory markers [TGF-ß, and IL-10], epigenetic alterations [5-methyl cytosine, 5-hydroxymethyl cytosine, and HDAC1] and gene expression patterns [RORγt, FoxP3, IL-17, IL-6, TGF-ß, CXCL2, CXCR2, and JUN]. In yoga group, there was a significant improvement in DAS28-ESR scores at the end of 8-weeks of yoga program. The Th17 cells and aged T cell subsets showed a significant decline whereas Treg cell population showed a significant elevation in yoga group. There were significant improvements observed in epigenetic markers as well as inflammatory markers post 8-weeks of yoga practice. The yoga group showed downregulation of RORγt, IL-17, IL-6, CXCL2, CXCR2, and upregulation of FoxP3 and TGF-ß transcripts. Yoga enables the maintenance of immune-homeostasis as evident by increased Treg cell population and reduced Th17 cell population. Yoga reduces the rate of immunological aging in T cells, as seen by the reduction in population of aged Th17 cells and aged Treg cells. Yoga positively modifies transcriptome and epigenome by normalization of various inflammatory markers, gene expression patterns and epigenetic alterations. Taken together, yoga reduces RA severity, and aids in immune-modulation and hence can be beneficial as an adjunct therapy.

Unilateral Versus Bilateral Vasoepididymal Anastomosis for Idiopathic Obstructive Azoospermia: A Randomised Controlled Trial.

Background: Men with idiopathic obstructive azoospermia (OA) are candidates for surgical reconstruction with a vasoepididymal anastomosis (VEA) performed on one or both testis. There are no randomised trials comparing the success of unilateral versus bilateral VEA. Objective: We conducted a randomised trial to compare the two surgical options. Design setting and participants: Between April 2017 and March 2022, men with infertility due to idiopathic OA were randomised to a unilateral (group 1) or bilateral (group 2) VEA in an ethics committee-approved clinical trial, registered with the Clinical Trials Registry. Outcome measurements and statistical analysis: The primary outcome was successful surgery, defined as appearance of sperm in the ejaculate, evaluated at 3 mo intervals after surgery. Additional outcomes were pregnancy rates and complications between the two groups. Men with successful surgery were compared with those without patency to identify the predictors of success. Results and limitations: Fifty-four men fulfilled the criteria and 52 who completed follow-up were included in the analysis. The overall patency rate was 36.5% (19/52 individuals). This was higher in men with bilateral surgery (12/26 patients, 46%) than in those with unilateral surgery (7/26 patients, 27%) but was not statistically significant (p = 0.1). The overall pregnancy rate with ejaculated sperm was significantly higher in the bilateral surgery group (4 vs 0, p = 0.037), while the spontaneous conception rate was higher but not statistically significant (3 vs 0, p = 0.074). The complication rates in the two groups were similar (p = 0.7), and all complications were Clavien-Dindo grade 1. Although bilateral surgery and presence of sperm in epididymal fluid were higher in men with patency, these were not statistically significant. Conclusions: A bilateral VEA was associated with higher patency and spontaneous pregnancy rates than unilateral surgery, but the results were not statistically significant. However, the overall pregnancy rate with ejaculated sperm, spontaneous and assisted, was significantly higher in the bilateral surgery group. Patient summary: In this study, we compared between unilateral and bilateral reconstructive surgery in azoospermic men and found better overall success with bilateral surgery. However, these results were not statistically significant.

Molecular genetics of primary open-angle glaucoma.

Glaucoma is a series of linked optic diseases resulting in progressive vision loss and total blindness due to the acquired loss of retinal ganglion cells. This harm to the optic nerve results in visual impairment and, ultimately, total blindness if left untreated. Primary open-angle glaucoma (POAG) is the most frequent variety within the large family of glaucoma. It is a multifaceted and heterogeneous condition with several environmental and genetic variables aiding in its etiology. By 2040, there will be 111.8 million glaucoma patients globally, with Asia and Africa accounting for the vast majority. The goal of this review is to elaborate on the role of genes (nuclear and mitochondrial) as well as their variants in the pathogenesis of POAG. PubMed and Google Scholar databases were searched online for papers until September 2022. Prevalence and inheritance patterns vary significantly across different ethnic and geographic populations. Numerous causative genetic loci may exist; however, only a few have been recognized and characterized. Further investigation into the genetic etiology of POAG is expected to uncover novel and intriguing causal genes, allowing for a more precise pathogenesis pattern of the disease.

Novel Osteo Refurbishment Method and Choice of Colouring Materials for Anatomy Specimens.

Objective: The introduction of competency-based medical education curriculum and a shifted focus towards self-directed learning (SDL) in medical schools across the world has necessitated a reduction of didactic teaching hours. Museum specimens are an indispensable tool in anatomy teaching and can play a pivotal role in fostering and reinforcing SDL. Coloring of specimens makes it attractive and facilitates understanding anatomy. The aims of this study were: (1) weigh up the two commonly used coloring materials in anatomy viz. acrylic paint and nail polish; and (2) to assess the perception of anatomy students towards a Novel Osteo Refurbishment Method (NORM) for restoration of partially damaged osteology specimens. Methods: Undergraduate and postgraduate students of anatomy were recruited in the study. Participants responded to a 5-point Likert scale questionnaire. Obtained data were analyzed using Microsoft Excel version 2019. For a comparison of the two coloring agents Mann-Whitney U test was applied to the responses toward the Likert scale-based questionnaire. P-value <0.05 was considered significant. Results: Out of 318 study participants, 63.7% and 36.3% of the respondents were male and female, respectively. 90.5 % were new entrants to university and the remainder 9.5% had a prior university degree. Students found the acrylic paint to be a better coloring agent and they also opined that NORM generated refurbished osteology specimens could serve as a useful self-learning tool. Acrylic paint was found to be more suitable as compared to nail polish with significant p-value in most of the parameters tested. Conclusions: Acrylic colour holds a good place in coloring both specimens and models in anatomy. Nail polish can be an alternative but with some noted disadvantages. The initial experience with NORM yielded encouraging results with potential practical utility.

Role of Gut Microbiota in Neurological Disorders and Its Therapeutic Significance.

In humans, the gut microbiota (GM) are known to play a significant role in the metabolism of nutrients and drugs, immunomodulation, and pathogen defense by inhabiting the gastrointestinal tract (GIT). The role of the GM in the gut-brain axis (GBA) has been documented for different regulatory mechanisms and associated pathways and it shows different behaviors with individualized bacteria. In addition, the GM are known as susceptibility factor for neurological disorders in the central nervous system (CNS), regulating disease progression and being amenable to intervention. Bidirectional transmission between the brain and the GM occurs in the GBA, implying that it performs a significant role in neurocrine, endocrine, and immune-mediated signaling pathways. The GM regulates multiple neurological disorders by supplementing them with prebiotics, probiotics, postbiotics, synbiotics, fecal transplantations, and/or antibiotics. A well-balanced diet is critically important for establishing healthy GM, which can alter the enteric nervous system (ENS) and regulate multiple neurological disorders. Here, we have discussed the function of the GM in the GBA from the gut to the brain and the brain to the gut, the pathways associated with neurology that interacts with the GM, and the various neurological disorders associated with the GM. Furthermore, we have highlighted the recent advances and future prospects of the GBA, which may require addressing research concerns about GM and associated neurological disorders.

Ocular manifestations of central insulin resistance.

Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer's disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance may lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.

Exome sequencing and functional analyses revealed CETN1 variants leads to impaired cell division and male fertility.

Human spermatogenesis requires an orchestrated expression of numerous genes in various germ cell subtypes. Therefore, the genetic landscape of male infertility is highly complex. Known genetic factors alone account for at least 15% of male infertility. However, ~40% of infertile men remain undiagnosed and are classified as idiopathic infertile men. We performed exome sequencing in 47 idiopathic infertile men (discovery cohort), followed by replication study (40 variants in 33 genes) in 844 infertile men and 709 controls using Sequenom MassARRAY® based genotyping. We report 17 variants in twelve genes that comprise both previously reported (DNAH8, DNAH17, FISP2 and SPEF2) and novel candidate genes (BRDT, CETN1, CATSPERD, GMCL1, SPATA6, TSSK4, TSKS and ZNF318) for male infertility. The latter have a strong biological nexus to human spermatogenesis and their respective mouse knockouts are concordant with human phenotypes. One candidate gene CETN1, identified in this study, was sequenced in another independent cohort of 840 infertile and 689 fertile men. Further, CETN1 variants were functionally characterized using biophysical and cell biology approaches. We demonstrate that CETN1 variant- p.Met72Thr leads to multipolar cells, fragmented nuclei during mitosis leading to cell death and show significantly perturbed ciliary disassembly dynamics. Whereas CETN1-5' UTR variant; rs367716858 leads to loss of a methylation site and increased reporter gene expression in vitro. We report a total of eight novel candidate genes identified by exome sequencing, which may have diagnostic relevance and can contribute to improved diagnostic workup and clinical management of male infertility.

From Inner Balance to Visual Health: Unraveling the Therapeutic Role of Yoga in Optic Neuropathy and Ocular Manifestations - Narrative Review.

The optic nerve comprises approximately 1.2 million axons of retinal ganglion cells and is vulnerable to degeneration due to a myriad of causes. While traditional treatments have been the cornerstone of ocular care, emerging evidence highlights the benefits of integrative approaches, which can be used as an adjunct in the management of optic neuropathy. Yoga is a mind-body energy medicine encompasses physical postures, breath control, and meditation. Currently, it has gained attention for its holistic effects on well-being, by promoting health, preventing onset of diseases, adjunct in disease management, and for its rehabilitative potential. In addition, the underlying mechanisms through which yoga exerts its therapeutic influence, evaluates clinical outcomes, and explores potential synergistic effects with conventional treatments remain largely unexplored. Neuroprotective mechanisms of yoga, such as enhancing retinal ganglion cell function, reducing oxidative stress, coupled with its ability to modulate inflammatory processes and improve circulation, contribute to its potential benefits in visual health. Analysis of clinical studies reveals promising outcomes, including improvements in visual acuity, visual fields, quality of life, and functional outcomes in individuals with optic neuropathy and ocular manifestations who undergo yoga intervention (especially dhyaan) with awareness of breath. Furthermore, the integration of yoga with conventional treatments and complementary modalities unveils the possibilities of multidisciplinary approaches in ocular care that need evaluation. By unraveling the role of yoga intervention in ocular health, this review provides valuable insights for clinicians and researchers, fostering a deeper understanding of the mind-body connection and paving the way for enhanced visual health outcomes. Embracing yoga as an adjunctive therapy may has the potential to revolutionize the management of optic neuropathy and ocular manifestations, offering individuals a holistic approach to optimize visual well-being, reduce comorbid depression and caregiver burden, and improve overall quality of life.

Anti-seizure medications and quality of life in person with epilepsy.

Objective: The goal of this study was to determine the effects of mono-, bi-, and polytherapy anti-seizure medications (ASMs) in terms of seizure reduction and quality of life (QOL) in persons with epilepsy (PWE). Methods: A cross-sectional observational study was conducted. All PWE with age <75 years were recruited and further classified into two groups: responders and non-responders, based on the response of the ASMs to the treatments for reduced seizure frequency since the last one year. Other demographic and clinical data such as seizure frequency, type of seizures, age at onset of seizures, and information about ASMs with their daily doses were assessed for the descriptive analysis. The quality of life was assessed in randomly selected PWE (n = 100) using the quality of life in epilepsy inventory-31 (QOLIE-31) in adults. Results: With a total of 486 PWE, the median age (years) was comparable in both groups. Out of these the non-responders group was found to be significantly higher (77.8%) than the responders group (22.2%). In the responders group, the percentage of PWE who were on monotherapy was significantly higher (51.85 %) than those who were on polytherapy (17.59%), whereas in the non-responders group, 21.16% of PWE were on monotherapy and 44.86% were on polytherapy. The duration of epilepsy was similar in both groups, but the average seizure frequency was significantly higher in the non-responders. In QOL assessments, 43% of PWE were observed in the responders group, whereas 57% of PWE were found in the non-responders group. The overall comparative QOL scores were also significantly higher (p < 0.0001) in the responders group as compared to the non-responders group. Conclusion: Our findings revealed that those PWE who were on monotherapy showed better reduction in seizure frequency and improved QOL in responder groups as compared to non-responder groups.

Identification of novel genes by targeted exome sequencing in Retinoblastoma.

BACKGROUND: Retinoblastoma (RB) is initiated by mutation in both alleles of RB1 gene. However, few cases may occur even in the absence of RB1 mutation suggesting the role of genes other than RB1. METHODOLOGY: The current study was planned to utilize targeted exome sequencing in Indian RB patients affected with unilateral non-familial RB. 75 unilateral RB patients below 5 years of age were enrolled. Genomic DNA was extracted from blood and tumor tissue. From peripheral blood DNA, all coding and exon/intron regions were amplified using PCR and direct sequencing. Cases which did not harbor pathogenic variants in peripheral blood DNA were further screened for mutations in their tumor tissue DNA using targeted exome sequencing. Three pathogenicity prediction tools (Mutation Taster, SIFT, and PolyPhen-2) were used to determine the pathogenicity of non-synonymous variations. An in-house bioinformatics pipeline was devised for the mutation screening by targeted exome sequencing. Protein modeling studies were also done to predict the effect of the mutations on the protein structure and function. RESULTS: Using the mentioned approach, we found two novel variants (g.69673_69674insT and g.48373314C>A) in RB1 gene in peripheral blood DNA. We also found novel variants in eight genes (RB1, ACAD11, GPR151, KCNA1, OTOR, SOX30, ARL11, and MYCT1) that may be associated with RB pathogenesis. CONCLUSION: The present study expands our current knowledge regarding the genomic landscape of RB and also highlights the importance of NGS technologies to detect genes and novel variants that may play an important role in cancer initiation, progression, and prognosis.

Evaluation of cell-free seminal mRNA for the diagnosis of obstruction as the cause of azoospermia in infertile men: A prospective cohort study.

Differentiating obstructive (OA) from non-obstructive (NOA) azoospermia is clinically important in managing infertile men. Classically, the differentiation has been based on clinical, hormonal and histological analysis. Histological tests are invasive and may miss spermatogenic areas. Seminal fluid can serve as a medium to assess the status of spermatogenesis and presence or absence of certain markers can help diagnosing and differentiating azoospermia. We evaluated the role of cell-free seminal markers: DDX4, PRM1 and PRM2 in diagnosing and differentiating between OA and NOA and classifying their subtypes. We observed DDX4 was more sensitive for NOA compared with OA. Among various subtypes of NOA, DDX4 positivity was higher in patients with maturation arrest and hypospermatogenesis compared with Sertoli cell only syndrome. PRM1 and PRM2 had very low positivity rate for any meaningful comparison. Seminal cell-free markers can serve as non-invasive tests in diagnosing and differentiating etiologies of azoospermia but their validity needs to be proved in long-term trials with more refined molecular techniques.