Oestrogen treatment restores dentate gyrus development in premature newborns by IGF1 regulation.

Prematurely-born infants cared for in the neonatal units suffer from memory and learning deficits. Prematurity diminishes neurogenesis and synaptogenesis in the hippocampal dentate gyrus (DG). This dysmaturation of neurons is attributed to elevated PSD95, NMDR2A, and IGF1 levels. Since oestrogen treatment plays key roles in the development and plasticity of DG, we hypothesized that 17ß-estradiol (E2) treatment would ameliorate neurogenesis and synaptogenesis in the DG, reversing cognitive deficits in premature newborns. Additionally, E2-induced recovery would be mediated by IGF1 signalling. These hypotheses were tested in a rabbit model of prematurity and nonmaternal care, in which premature kits were gavage-fed and reared by laboratory personnel. We compared E2- and vehicle-treated preterm kits for morphological, molecular, and behavioural parameters. We also treated kits with oestrogen degrader, RAD1901, and assessed IGF1 signalling. We found that E2 treatment increased the number of Tbr2+ and DCX+ neuronal progenitors and increased the density of glutamatergic synapses in the DG. E2 treatment restored PSD95 and NMDAR2A levels and cognitive function in preterm kits. Transcriptomic analyses showed that E2 treatment contributed to recovery by influencing interactions between IGF1R and neurodegenerative, as well as glutamatergic genes. ERα expression was reduced on completion of E2 treatment at D7, followed by D30 elevation. E2-induced fluctuation in ERα levels was associated with a reciprocal elevation in IGF1/2 expression at D7 and reduction at D30. ERα degradation by RAD1901 treatment enhanced IGF1 levels, suggesting ERα inhibits IGF1 expression. E2 treatment alleviates the prematurity-induced maldevelopment of DG and cognitive dysfunctions by regulating ERα and IGF1 levels.

Elevated insulin growth factor-1 in dentate gyrus induces cognitive deficits in pre-term newborns.

Prematurely born infants are deprived of maternal hormones and cared for in the stressful environment of Neonatal Intensive Care Units (NICUs). They suffer from long-lasting deficits in learning and memory. Here, we show that prematurity and associated neonatal stress disrupt dentate gyrus (DG) development and induce long-term cognitive deficits and that these effects are mediated by insulin growth factor-1 (IGF1). Nonmaternal care of premature rabbits increased the number of granule cells and interneurons and reduced neurogenesis, suggesting accelerated premature maturation of DG. However, the density of glutamatergic synapses, mature dendritic spines, and synaptic transmission were reduced in preterm kits compared with full-term controls, indicating that premature synaptic maturation was abnormal. These findings were consistent with cognitive deficits observed in premature rabbits and appeared to be driven by transcriptomic changes in the granule cells. Preterm kits displayed reduced weight, elevated serum cortisol and growth hormone, and higher IGF1 expression in the liver and DG relative to full-term controls. Importantly, blocking IGF-1 receptor in premature kits restored cognitive deficits, increased the density of glutamatergic puncta, and rescued NR2B and PSD95 levels in the DG. Hence, IGF1 inhibition alleviates prematurity-induced cognitive dysfunction and synaptic changes in the DG through modulation of NR2B and PSD95. The study identifies a novel strategy to potentially rescue DG maldevelopment and cognitive dysfunction in premature infants under stress in NICUs.

Chitosan modified 5-fluorouracil nanostructured lipid carriers for treatment of diabetic retinopathy in rats: A new dimension to an anticancer drug.

Diabetic retinopathy (DR) is one of the chronic complications of diabetes. It includes retinal blood vessels' damage. If untreated, it leads to loss of vision. The existing treatment strategies for DR are expensive, invasive, and need expertise during administration. Hence, there is a need to develop a non-invasive topical formulation that can penetrate deep to the posterior segment of retina and treat the damaged retinal vessels. In addition, it should also provide sustained release. In recent years, novel drug delivery systems (NDDS) have been explored for treating DR and found successful. In this study, chitosan (CS) modified 5-Fluorouracil Nanostructured Lipid Carriers (CS-5-FU-NLCs) were prepared by modified melt emulsification-ultrasonication method and optimized by Box-Behnken Design. The size, polydispersity index, zeta potential and entrapment efficiency of CS-5-FU-NLCs were 163.2 ± 2.3 nm, 0.28 ± 1.52, 21.4 ± 0.5 mV and 85.0 ± 0.2 %, respectively. The in vitro drug release and ex vivo permeation study confirmed higher and sustained drug release in CS-5-FU-NLCs as compared to 5-FU solution. HET-CAM Model ensured the non-irritant nature of CS-5-FU-NLCs. In vivo ocular studies of CS-5-FU-NLCs confirmed antiangiogenic effect of 5-FU by CAM model and diabetic retinopathy induced rat model, indicating successful delivery of 5-FU to the retina.

Shh activation restores interneurons and cognitive function in newborns with intraventricular haemorrhage.

Premature infants with germinal matrix haemorrhage-intraventricular haemorrhage (GMH-IVH) suffer from neurobehavioural deficits as they enter childhood and adolescence. Yet the underlying mechanisms remain unclear. Impaired development and function of interneurons contribute to neuropsychiatric disorders. Therefore, we hypothesized that the occurrence of IVH would reduce interneuron neurogenesis in the medial ganglionic eminence and diminish the population of parvalbumin+ and somatostatin+ cortical interneurons. Because Sonic Hedgehog promotes the production of cortical interneurons, we also postulated that the activation of Sonic Hedgehog signalling might restore neurogenesis, cortical interneuron population, and neurobehavioural function in premature newborns with IVH. These hypotheses were tested in a preterm rabbit model of IVH and autopsy samples from human preterm infants. We compared premature newborns with and without IVH for intraneuronal progenitors, cortical interneurons, transcription factors regulating neurogenesis, single-cell transcriptome of medial ganglionic eminence and neurobehavioural functions. We treated premature rabbit kits with adenovirus expressing Sonic Hedgehog (Ad-Shh) or green fluorescence protein gene to determine the effect of Sonic Hedgehog activation on the interneuron production, cortical interneuron population and neurobehaviour. We discovered that IVH reduced the number of Nkx2.1+ and Dlx2+ progenitors in the medial ganglionic eminence of both humans and rabbits by attenuating their proliferation and inducing apoptosis. Moreover, IVH decreased the population of parvalbumin+ and somatostatin+ neurons in the frontal cortex of both preterm infants and kits relative to controls. Sonic Hedgehog expression and the downstream transcription factors, including Nkx2.1, Mash1, Lhx6 and Sox6, were also reduced in kits with IVH. Consistent with these findings, single-cell transcriptomic analyses of medial ganglionic eminence identified a distinct subpopulation of cells exhibiting perturbation in genes regulating neurogenesis, ciliogenesis, mitochondrial function and MAPK signalling in rabbits with IVH. More importantly, restoration of Sonic Hedgehog level by Ad-Shh treatment ameliorated neurogenesis, cortical interneuron population and neurobehavioural function in kits with IVH. Additionally, Sonic Hedgehog activation alleviated IVH-induced inflammation and several transcriptomic changes in the medial ganglionic eminence. Taken together, IVH reduced intraneuronal production and cortical interneuron population by downregulating Sonic Hedgehog signalling in both preterm rabbits and humans. Notably, activation of Sonic Hedgehog signalling restored interneuron neurogenesis, cortical interneurons and cognitive function in rabbit kits with IVH. These findings highlight disruption in cortical interneurons in IVH and identify a novel therapeutic strategy to restore cortical interneurons and cognitive function in infants with IVH. These studies can accelerate the development of new therapies to enhance the neurodevelopmental outcome of survivors with IVH.

Multifaceted role of synbiotics as nutraceuticals, therapeutics and carrier for drug delivery.

Synbiotics, are a combination of probiotics and prebiotics. They play an important role in metabolizing different nutritional substrates and thus helps in the maintenance of human health. Any disbalance in the gut microflora, known as dysbiosis, is known to lead to a number of diseased conditions. It can be reverted by the administration of synbiotics. Present review highlights various mechanistic pathways through which synbiotics act as therapeutics. The dual role of synbiotics as nutraceutical and excipient in developing oral formulations are entailed with case studies. The findings entailed that there exist numerous studies on prebiotics as well as probiotics have been carried out to show their effects in several diseases. However, the concept of combining together them for prevention and treatment of various pathological conditions accruing from dysbiosis is relatively new. Synbiotics, however, face challenge of low stability during their sojourn in the GIT, which is generally overcome by various encapsulation techniques. Various studies also showed potential role of synbiotics in drug delivery. However, it is an emerging area and lacks clinical correlation. It is important to focus on clinical trials of formulations wherein synbiotics have been used as therapeutic moiety as well as pharmaceutical carrier for treating various diseases.

Synthesis, Self-Aggregation, Surface Characteristics, Electrochemical Property, Micelle Size, and Antimicrobial Activity of a Halogen-Free Picoline-Based Surface-Active Ionic Liquid.

We present a new approach toward the design of a halogen-free picoline-based surface-active ionic liquid (SAIL) (1-octyl-4-methyl pyridinium dodecyl sulfate) [C8γPic]DS consisting of long dodecyl sulfate (DS) as an anion. The surface properties, micellization behavior, and antimicrobial activity in an aqueous solution were investigated using tensiometry, conductometry, and ultraviolet (UV) spectroscopy. Incorporating the DS group in SAIL leads to lower critical micellar concentration (CMC) and enhanced adsorption at the air/water interface of the functionalized ionic liquid compared to the C8-alkyl chain-substituted pyridine ionic liquids. The antimicrobial activity was evaluated against a representative Gram-negative and Gram-positive bacteria panel. Antibacterial activities increased with the alkyl chain length, C8 being the homologous most effective antimicrobial agent. The micelle size of [C8γPic]DS was determined by the dynamic light-scattering (DLS) study. Cyclic voltammetry (CV) measurements have been employed to evaluate the interaction between the SAIL micelle and working electrode, diffusion coefficient, and micelle size of the SAIL solution. The diffusion coefficient explored the correlation of surface properties and the antimicrobial activity of [C8γPic]DS. This halogen-free SAIL is the future of wetting agents and emulsion studies in agriculture due to its small micelle size and surface characteristics.

Cerebral gray matter injuries in infants with intraventricular hemorrhage.

While intraventricular hemorrhage (IVH) predominantly damages the periventricular white matter, it induces substantial injury to the cerebral gray matter. IVH destroys the germinal matrix, suppresses neurogenesis, and disrupts corticogenesis, thereby reducing the number of neurons in the upper cortical layer and volume of the cerebral gray matter. The pathogenesis of gray matter injury is attributed to IVH-induced oxidative stress, inflammation, and mass effect damaging the germinal matrix as well as to post-hemorrhagic ventricular dilation (PHVD). The IVH-induced cerebral gray matter injury and PHVD contribute to cognitive deficits and neurobehavioral disorders. Neuroimaging has enhanced our understanding of cerebral gray matter injury and is a valuable predictor of neurodevelopmental outcomes. Evidence from therapies tested in preclinical models and clinical trials suggests that strategies to promote neurogenesis, reduce cerebral inflammation and oxidative stress, and remove blood clots from the ventricles might enhance the outcome of these infants. This review offers an integrated view of new insights into the mechanisms underlying gray matter injury in premature infants with IVH and highlights the imminent therapies to restore neurodevelopmental dysfunction in IVH survivors.

Survey of antidoping knowledge, attitudes and practices amongst elite Indian sportsmen and the way forward.

BACKGROUND: Indian sportspersons have reported several antidoping rule violations with several cases suggesting inadvertent use of prohibited substances. This study was designed to evaluate the anti-doping knowledge, attitudes and practices amongst elite Indian sportsmen to suggest future interventions. METHODS: This study conducted at a Sports institute used an anonymized questionnaire to survey 181 male (18-35 years old) elite young athletes' attitudes toward performance-enhancing substances and anti-doping rules. RESULTS: Athlete awareness regarding antidoping agencies and antidoping rule violations was poor. 40% or less reported receiving antidoping updates. All reported improvement in antidoping knowledge and attitude changes after attending updates. Health is more important than sporting performance for 80% or more. Very low percentage reported consumption of banned substances amongst themselves and team mates. One-third of these athletes reported not having being tested for banned substances. Athletes who have attended antidoping sessions exhibit significantly higher knowledge levels and a significantly higher 80% reported consulting their Team doctor before any therapeutic drug use as compared with non-attendees. CONCLUSION: Indian elite athletes report low awareness about anti-doping rules and prohibited substances with low proportion of athletes reporting doping and being tested for doping. Grass root level education, supplement regulation, trained athlete support personnel and accessible reference material seems to be the way forward.

PPAR-γ activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage.

Intraventricular hemorrhage (IVH) results in periventricular inflammation, hypomyelination of the white matter, and hydrocephalus in premature infants. No effective therapy exists to prevent these disorders. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists reduce inflammation, alleviate free radical generation, and enhance microglial phagocytosis, promoting clearance of debris and red blood cells. We hypothesized that activation of PPAR-γ would enhance myelination, reduce hydrocephalus, and promote neurological recovery in newborns with IVH. These hypotheses were tested in a preterm rabbit model of IVH; autopsy brain samples from premature infants with and without IVH were analyzed. We found that IVH augmented PPAR-γ expression in microglia of both preterm human infants and rabbit kits. The treatment with PPAR-γ agonist or PPAR-γ overexpression by adenovirus delivery further elevated PPAR-γ levels in microglia, reduced proinflammatory cytokines, increased microglial phagocytosis, and improved oligodendrocyte progenitor cell (OPC) maturation in kits with IVH. Transcriptomic analyses of OPCs identified previously unrecognized PPAR-γ-induced genes for purinergic signaling, cyclic adenosine monophosphate generation, and antioxidant production, which would reprogram these progenitors toward promoting myelination. RNA-sequencing analyses of microglia revealed PPAR-γ-triggered down-regulation of several proinflammatory genes and transcripts having roles in Parkinson's disease and amyotrophic lateral sclerosis, contributing to neurological recovery in kits with IVH. Accordingly, PPAR-γ activation enhanced myelination and neurological function in kits with IVH. This also enhanced microglial phagocytosis of red blood cells but did not reduce hydrocephalus. Treatment with PPAR-γ agonist might enhance myelination and neurological recovery in premature infants with IVH.

Concurrent Presentation of Emphysematous Pyelonephritis, Emphysematous Osteomyelitis, and Psoas Abscesses.

Emphysematous pyelonephritis (EPN) is an uncommon necrotizing infection commonly seen in people with diabetes. Emphysematous osteomyelitis (EOM) is a rare form of pyogenic osteomyelitis characterized by the presence of air in the bones. A combination of both these infections has been reported only thrice in the literature. We present the case of a middle-aged diabetic woman who had both these rare infections along with psoas abscesses, a phenomenon that has been described only once previously. The patient required prolonged hospitalization, surgical debridement and drainage, a double-J stent, and meropenem, and she subsequently achieved full recovery.

Entrustable Professional Activities (EPAs) and milestones for MD sports medicine: A proposed portfolio.

BACKGROUND: Sports Medicine is an upcoming postgraduate speciality in India. A MD Sports Medicine specialist is expected to contribute in the prevention of sports injuries, sportsmen training and enhancement of performance apart from being involved in planning of conduct of sports events amongst many other roles and responsibilities. This requires hands-on training and acquisition of skill sets required to perform these roles. The National Medical Council of India highlights the need for a competency based curriculum and has laid down guidelines for the course. There was a felt need to develop Entrustable Professional Activities (EPAs) and milestones based on the prescribed curricula and develop a portfolio for continuous monitoring of the achievement of these EPAs. METHODS: A five step model was done by experts in the field to prepare the EPAs, milestones and portfolio. This consisted of faculty development, identification of the EPAs and milestones and portfolio preparation. RESULTS: 114 EPAs and 961 milestones were identified by the subject experts. The portfolio was developed with the help of specialists and faculty of the field of sports medicine, and medical educationists. CONCLUSION: Post graduate medical education is mandated to be competency based. A portfolio has been developed in the current exercise for use in a competency based post-graduate curriculum in sports medicine. This will help in the better implementation of CBME in the country.

Chewable Tablets of Acacia catechu Extract, an Alternative to Betel (Paan) for Mouth Ulcers: Formulation and In vitro Evaluation.

OBJECTIVE: The objective of the current research work was to prepare chewable tablets having Acacia catechu extract useful for mouth ulcers using a 32 factorial design. METHODS: Acacia catechu heartwood extract was prepared using a reported method with some modifications. The extract was characterized using TLC against the catechin marker. Then, drug-excipient interaction studies were carried out. The mixture of drug and excipients was evaluated for pre-compression parameters. With the application of 32 factorial design, chewable tablets were prepared using direct compression technique. Prepared tablets were evaluated for post-compression parameters. RESULTS: In vitro drug release study of the developed formulations was investigated both in intact and crushed form of tablets. Based on the in vitro performance, the best formulations were selected (F6, F7 & F8 from intact and F1, F5 & F9 from the crushed group) and subjected to various kinetic models and evaluated for Chewing Difficulty Index (CDI). CONCLUSION: The overall results revealed that the formulated chewable tablets complied with the standards and exhibited the satisfactory performance in terms of drug release, chewing difficulty index and other related parameters.

Recent advances in intraocular and novel drug delivery systems for the treatment of diabetic retinopathy.

Introduction: Diabetic retinopathy (DR) is associated with damage to the retinal blood vessels that lead eventually to vision loss. The existing treatments of DR are invasive, expensive, and cumbersome. To overcome challenges associated with existing therapies, various intraocular sustained release and novel drug delivery systems (NDDS) have been explored.Areas covered: The review discusses recently developed intraocular devices for sustained release of drugs as well as novel noninvasive drug delivery systems that have met a varying degree of success in local delivery of drugs to retinal circulation.Expert opinion: The intraocular devices have got very good success in providing sustained release of drugs in patients. The development of NDDS and their application through the ocular route has certainly provided an edge to treat DR over existing therapies such as anti-VEGF administration but their success rate is quite low. Moreover, most of them have proved to be effective only in animal models. In addition, the extent of targeting the drug to the retina still remains variable and unpredictable. The toxicity aspect of the NDDS has generally been neglected. In order to have successful commercialization of nanotechnology-based innovations well-designed clinical research studies need to be conducted to evaluate their clinical superiority over that of the existing formulations.

Diagnosis and management of tumor lysis syndrome.

Tumor lysis syndrome (TLS) is an oncological emergency characterized by a classic tetrad of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Risk assessment and prophylactic therapy is critical in preventing this oncological emergency. Treatment of established TLS involves aggressive hydration, electrolyte management, and the use of hypouricemic agents.

Characteristics, Outcomes and 60-Day Hospital Mortality of ICU Patients with COVID-19 and Acute Kidney Injury.

Background: AKI has been reported in patients with COVID-19 pneumonia and it is associated with higher mortality. The aim of our study is to describe characteristics, outcomes, and 60-day hospital mortality of patients with COVID-19 pneumonia and AKI in the intensive care unit (ICU). Methods: We conducted a retrospective study in which all adult patients with confirmed COVID-19 who were admitted to ICUs of Montefiore Medical Center and developing AKI were included. The study period ranged from March 10 to April 11, 2020. The 60-day follow-up data through June 11, 2020 were obtained. Results: Of 300 adults admitted to the ICUs with COVID-19 pneumonia, 224 patients (75%) presented with AKI or developed AKI subsequent to admission. A total of 218 (97%) patients required invasive mechanical ventilation for moderate to severe acute respiratory distress syndrome (ARDS). A total of 113 (50%) patients had AKI on day 1 of ICU admission. The peak AKI stages observed were stage 1 in 49 (22%), stage 2 in 35 (16%), and stage 3 in 140 (63%) patients, respectively. Among patients with AKI, 114 patients (51%) required RRT. The mortality rate of patients requiring RRT was 70%. Of the 34 patients who were survivors, 25 (74%) were able to be weaned off RRT completely before hospital discharge. Nonsurvivors were older and had significantly higher admission and peak creatinine levels, admission hemoglobin, and peak phosphate levels compared with survivors. The 60-day hospital mortality was 67%. Conclusions: COVID-19 requiring ICU admission is associated with high incidence of severe AKI, necessitating RRT in approximately half of such patients. The majority of patients with COVID-19 and AKI in ICU developed moderate to severe ARDS, requiring invasive mechanical ventilation. Timing or severity of AKI did not affect outcomes. The 60-day hospital mortality is high (67%). Patients with AKI requiring RRT have high mortality, but survivors have good rates of RRT recovery. Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/K360/2020_12_31_KID0004282020.mp3.

Application of the Lower Extremity Functional Scale and Its Correlation with Lymphedema Health-Related Quality of Life on Lower Limb Filarial Lymphedema Patients.

Introduction: This study carried out as a part of the lymphedema (LE)-osteoarthritis project to know the feasibility and applicability of lower extremity functional scale (LEFS) and LE health-related quality of life (LEHRQoL) among filarial LE patients of the lower extremity. Materials and Methods: Following inclusion and exclusion criteria 30 LE patients and 30 controls were recruited in the study. After obtaining informed written consent, Tamil version of the two "self-reporting assessment tools" LEFS and LEHRQoL were applied to all the participants by two examiners independently. Feasibility was assessed by the time schedule. Internal consistency and the correlation between two examiners was assessed by calculating Cronbach's alpha and Karl Pearson correlation coefficient and Spearman rank correlation respectively. Results: The mean time taken for completing the LEFS and LEHRQoL questionnaire was 5 minutes and 2 seconds and 12 minutes and 8 seconds respectively. Internal consistency reliability assessment showed good internal consistency for both the examiners (Cronbach's alpha 0.816 and 0.812). There was a strong positive correlation for the cases (r = 0.956, p < 0.001; r = 0.908, p < 0.001) and controls (r = 0.992, p < 0.001; r = 0.985, p < 0.001) between the two examiners. Conclusions: LEFS and LEHRQoL were well accepted among filarial LE patients and the patients with low literacy were able to respond without any difficulty to both assessment tools. LEFS was found suitable for the assessment of lower extremity functions of the LE patients as in other diseases affecting the lower limb and it also indirectly brought out the impact on the QoL.

Treatment Strategies Against Psoriasis: Principle, Perspectives and Practices.

BACKGROUND: Psoriasis is a genetically predisposed autoimmune disease mediated by cytokines released by the activated immune cells. It manifests inflammatory, scaly red or white silvery flaky skin which may be a fluid-filled lesion with soreness and itchiness. The prevalence rate of psoriasis is increasing day by day. Despite having such a high prevalence rate, the treatment of psoriasis is still limited. Hence, there is a need to rethink the various treatment strategies available in the allopathic as well as in the alternative systems of medicine. METHODS: Various bibliographic databases of previously published peer-reviewed research papers were explored and systematic data culminated in terms of various treatment strategies used for the management of psoriasis. The prime focus is given towards modern as well as alternative systems of medicine such as phototherapy, a combination of phototherapy with pharmacotherapy such as Ayurveda, Yoga and naturopathy, Unani, Siddha, and Homeopathy to treat psoriasis. RESULTS: A comprehensive review of 161 papers, including both research and review articles, was carried out to make the article readily understandable. The pathogenesis including inflammatory mediators and type of psoriasis is discussed before the treatment strategies to understand the pathophysiology of the disease. The uniqueness, procedure, advantages, and limitations of conventional, advanced, and traditional systems of medicine to treat psoriasis are discussed in detail. Emphasis has also been given towards marine sources such as fish oil, marine sponges, and algae. CONCLUSION: Although there are many modern and alternative treatment strategies available to treat psoriasis, none of them have been proven to provide complete relief to patients. Moreover, they are associated with certain side effects. In order to overcome them, novel drug delivery systems have been utilized and found effective; however, their stability and safety become the major impediments towards their successful positioning. Traditional and alternative treatment strategies have found to be safe and effective but their use is localized to certain areas. In a nutshell, to achieve successful treatment of psoriasis, there is a need to focus on the development of stable and non-toxic novel drug delivery systems or the promotion of traditional systems to treat psoriasis.