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.

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.

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.

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.

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.

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.

Reduced Hippocampal Dendrite Branching, Spine Density and Neurocognitive Function in Premature Rabbits, and Reversal with Estrogen or TrkB Agonist Treatment.

Preterm-born children suffer from neurological and behavioral disorders. Herein, we hypothesized that premature birth and non-maternal care of preterm newborns might disrupt neurobehavioral function, hippocampal dendritic arborization, and dendritic spine density. Additionally, we assessed whether 17ß-estradiol (E2) replacement or the TrkB receptor agonist, 7,8-dihydroxyflavone (DHF), would reverse compromised dendritic development and cognitive function in preterm newborns. These hypotheses were tested by comparing preterm (E28.5) rabbit kits cared and gavage-fed by laboratory personnel and term-kits reared and breast-fed by their mother doe at an equivalent postconceptional age. Neurobehavioral tests showed that both premature-birth and formula-feeding with non-maternal care led to increased anxiety behavior, poor social interaction, and lack of novelty preference compared with term-kits. Dendritic branching and number of total or mushroom dendritic spines were reduced in the CA1 field of preterm-kits compared with term controls. While CDC42 and Rac1/2/3 expression levels were lower, RhoA-activity was higher in preterm-kits compared with term controls. Both E2 and DHF treatment reversed prematurity-induced reduction in spine density, reduced total RhoA-GTPase levels, and enhanced cognitive function. Hence, prematurity and non-maternal care result in cognitive deficits, and reduced dendritic arbors and spines in CA1. E2 replacement or DHF treatment might reverse changes in dendritic spines and improve neurodevelopment in premature infants.

Changes in Protein Expression and Lysine Acetylation Induced by Decreased Glutathione Levels in Astrocytes.

Astrocytes and neurons form a highly specialized functional unit, and the loss or gain of astrocytic functions can influence the initiation and progression of different neurodegenerative diseases. Neurons depend on the antioxidant protection provided by neighboring astrocytes. Glutathione (γ-l-glutamyl-l-cysteinyl-glycine) is a major component of the antioxidant system that defends cells against the toxic effects of reactive oxygen/nitrogen species. A decline in glutathione levels has been observed in aging and neurodegenerative diseases, and it aggravates the pathology in an amyotrophic lateral sclerosis-mouse model. Using a SILAC-based quantitative proteomic approach, we analyzed changes in global protein expression and lysine acetylation in primary astrocyte cultures obtained from wild-type mice or those deficient in the glutamate-cysteine ligase modifier subunit (GCLM). GCLM knockout astrocytes display an ∼80% reduction in total glutathione levels. We identified potential molecular targets and novel sites of acetylation that are affected by the chronic decrease in glutathione levels and observed a response mediated by Nrf2 activation. In addition, sequence analysis of peptides displaying increased acetylation in GCLM knockout astrocytes revealed an enrichment of cysteine residues in the vicinity of the acetylation site, which suggests potential crosstalk between lysine-acetylation and cysteine modification. Regulation of several metabolic and antioxidant pathways was observed at the level of protein expression and lysine acetylation, revealing a coordinated response involving transcriptional and posttranslational regulation.

Effect of wrist cooling on aerobic and anaerobic performance in elite sportsmen.

BACKGROUND: Body cooling has been used to increase sporting performance and enhance recovery. Several studies have reported improvement in exercise capacities using forearm and hand cooling or only hand cooling. Wrist cooling has emerged as a portable light weight solution for precooling prior to sporting activity. The Astrand test for aerobic performance and the Wingate test for anaerobic performance are reliable and accurate tests for performance assessment. This study conducted on elite Indian athletes analyses the effects of wrist precooling on aerobic and anaerobic performance as tested by the Astrand test and the Wingate test before and after wrist precooling. METHODS: 67 elite sportsmen were administered Wingate and Astrand test under standardised conditions with and without wrist precooling using a wrist cooling device (dhamaSPORT). Paired t-test was applied to study effect on aerobic [VO2 (ml/min/kg)] and anaerobic performance [peak power (W/kg) and average power (W/kg)] and Cohen's d was used to calculate effect size of wrist precooling. RESULTS: After wrist precooling, significant increase of 0.22 (p = 0.014, 95% CI: 0.047, 0.398) in peak power (W/kg) and 0.22 (p < 0.0001, 95% CI: 0.142, 0.291) was observed in average power (W/kg). Although, an increase of 1.38 (p = 0.097, 95% CI: -0.225, 3.012) was observed in VO2 (ml/min/kg), wrist precooling was not significantly effective in aerobic performance. Wrist cooling effect size was smaller in VO2 (Cohen's d = 0.21), peak power (Cohen's d = 0.31) and it was larger in average power (Cohen's d = 0.71). CONCLUSION: Results show wrist precooling significantly improves anaerobic than aerobic performance of elite sportsmen.

Enhancing NAD+ Salvage Pathway Reverts the Toxicity of Primary Astrocytes Expressing Amyotrophic Lateral Sclerosis-linked Mutant Superoxide Dismutase 1 (SOD1).

Nicotinamide adenine dinucleotide (NAD(+)) participates in redox reactions and NAD(+)-dependent signaling pathways. Although the redox reactions are critical for efficient mitochondrial metabolism, they are not accompanied by any net consumption of the nucleotide. On the contrary, NAD(+)-dependent signaling processes lead to its degradation. Three distinct families of enzymes consume NAD(+) as substrate: poly(ADP-ribose) polymerases, ADP-ribosyl cyclases (CD38 and CD157), and sirtuins (SIRT1-7). Because all of the above enzymes generate nicotinamide as a byproduct, mammalian cells have evolved an NAD(+) salvage pathway capable of resynthesizing NAD(+) from nicotinamide. Overexpression of the rate-limiting enzyme in this pathway, nicotinamide phosphoribosyltransferase, increases total and mitochondrial NAD(+) levels in astrocytes. Moreover, targeting nicotinamide phosphoribosyltransferase to the mitochondria also enhances NAD(+) salvage pathway in astrocytes. Supplementation with the NAD(+) precursors nicotinamide mononucleotide and nicotinamide riboside also increases NAD(+) levels in astrocytes. Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Superoxide dismutase 1 (SOD1) mutations account for up to 20% of familial ALS and 1-2% of apparently sporadic ALS cases. Primary astrocytes isolated from mutant human superoxide dismutase 1-overexpressing mice as well as human post-mortem ALS spinal cord-derived astrocytes induce motor neuron death in co-culture. Increasing total and mitochondrial NAD(+) content in ALS astrocytes increases oxidative stress resistance and reverts their toxicity toward co-cultured motor neurons. Taken together, our results suggest that enhancing the NAD(+) salvage pathway in astrocytes could be a potential therapeutic target to prevent astrocyte-mediated motor neuron death in ALS.

Cell cycle activation in p21 dependent pathway: An alternative mechanism of organophosphate induced dopaminergic neurodegeneration.

In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G0/G1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.

Comparison between Standing Broad Jump test and Wingate test for assessing lower limb anaerobic power in elite sportsmen.

BACKGROUND: Lower limb explosive power is an important motor quality for sporting performance and indicates use of anaerobic energy systems like stored ATP and Creatine phosphate system. Weightlifting, Fencing and Wrestling use it for monitoring and identification of potential sportsmen. The Wingate test and Standing Broad Jump (SBJ) test are reliable and accurate tests for its assessment. This study conducted on elite Indian sportsmen tries to analyse feasibility of use of the SBJ test in sports and military medicine when Wingate test is impractical. METHODS: 95 elite sportsmen (51 Fencers, 17 Weight lifters and 27 Wrestlers) of a sports institute were administered Wingate cycle ergometer test and SBJ under standardised conditions. The results were analysed for mass and inter-discipline correlation. RESULTS: Analysis using Pearson's correlation showed significant positive correlation between Peak power (r = 0.446, p < 0.0001) and SBJ (distance) in all sportsmen. Inter-sport correlation showed positive correlation between SBJ and peak power (r = 0.335, p < 0.016) in Fencers and between SBJ, peak power (r = 0.686, p < 0.002) in Weightlifters. Bland-Altman plot analysis showed that about 94% pairs of peak power and SBJ were within limits of agreement for each discipline as well as among all sportsmen. CONCLUSION: The test results show definite correlation and SBJ test can be used as a field test in performance monitoring, talent identification, military recruit screening and injury prevention.

Hidden Obesity in Dialysis Patients: Clinical Implications.

While body-mass index (BMI) is used to diagnose obesity in the general population, its application in the end-stage renal disease (ESRD) population is fraught with difficulty. A major limitation is its inability to distinguish muscle mass from fat mass, thereby leading to misclassification of individuals with poor muscle mass but excess adipose tissue as non-obese (i.e. BMI <30 kg/m(2) ). As muscle wasting is common among ESRD patients, this is an important problem. A substantial proportion of ESRD patients have levels of BMI in the normal range, yet excess adiposity based on other measures. The importance of this "hidden" obesity remains to be determined, but it must be recognized in order for obesity interventions to be appropriately targeted and tested in the ESRD population.

Dichlorvos-induced cell cycle arrest and DNA damage repair activation in primary rat microglial cells.

Dichlorvos, an organophosphate (OP), is known to cause oxidative stress in the central nervous system (CNS). Previously we have shown that dichlorvos treatment promoted the levels of proinflammatory molecules and ultimately induced apoptotic cell death in primary microglial cells. Here we studied the effect of dichlorvos on crucial cell cycle regulatory proteins and the DNA damage sensor ataxia-telangiectasia mutated (ATM). We found a significant increase in p53 and its downstream target, p21, levels in dichlorvos-treated microglial cells compared with control cells. Moreover, dichlorvos exposure promoted the levels of different cell cycle regulatory proteins. These results along with flow cytometry results suggested that primary microglial cells were arrested at G1 and G2/M phase after dichlorvos exposure. We have shown in a previous study that dichlorvos can induce DNA damage in microglia; here we found that microglial cells also tried to repair this damage by inducing a DNA repair enzyme, i.e., ATM. We observed a significant increase in the levels of ATM after dichlorvos treatment compared with control.

Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression.

The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and its downstream targets i.e. Nuclear respiratory factor-1(NRF-1), Nuclear respiratory factor-2(NRF-2) and Mitochondrial transcription factor A (Tfam) in mitochondrial biogenesis. Aluminium lactate (10mg/kgb.wt./day) was administered intragastrically to rats for 12 weeks. After 12 weeks of exposure, we found an increase in ROS levels, mitochondrial DNA oxidation and decrease in citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain. On the other hand, there was a decrease in the mRNA levels of the mitochondrial encoded subunits-NADH dehydrogenase (ND) subunits i.e. ND1, ND2, ND3, Cytochrome b (Cytb), Cytochrome oxidase (COX) subunits i.e. COX1, COX3, ATP synthase (ATPase) subunit 6 along with reduced expression of nuclear encoded subunits COX4, COX5A, COX5B of Electron transport chain (ETC). Besides, a decrease in mitochondrial DNA copy number and mitochondrial content in both regions of rat brain was observed. The PGC-1α was down-regulated in aluminium treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α in aluminium treated rats. Electron microscopy results revealed a significant increase in the mitochondrial swelling, loss of cristae, chromatin condensation and decreases in mitochondrial number in case of aluminium treated rats as compared to control. So, PGC-1α seems to be a potent target for aluminium neurotoxicity, which makes it an almost ideal target to control or limit the damage that has been associated with the defective mitochondrial function seen in neurodegenerative diseases.

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.

Dichlorvos exposure results in activation induced apoptotic cell death in primary rat microglia.

Dichlorvos [2,2-dichlorovinyl dimethyl phosphate] is one of the most common in-use organophosphate (OP) in developing nations. Previous studies from our lab have shown chronic Dichlorvos exposure leads to neuronal cell death in rats. However, the extent of damage caused by Dichlorvos to other cells of the central nervous system (CNS) is still not clear. Microglial cells are the primary threat sensors of CNS which become activated in many pathological conditions. Activation of microglial cells results in reactive microgliosis, manifested by increased cellular damage in the affected regions. Using rat primary microglial cultures, here we show that Dichlorvos exposure can activate and induce apoptotic cell death in microglia. We observed significant up-regulation of pro-inflammatory molecules like nitric oxide, TNF-α, and IL-1ß when microglia were treated with Dichlorvos (10 µM). Significant up-regulation of CD11b, microglial specific activation marker, was also observed after 24 h of Dichlorvos treatment. The activated microglial cells eventually undergo cell death after 48 h of Dichlorvos treatment. The DNA fragmentation pattern of Dichlorvos treated microglia along with increased expression of Bax in mitochondria, cytochrome c release from mitochondria, and caspase-3 activation led us to assume that microglia were undergoing apoptosis. Thus, the present study showed that Dichlorvos can induce microglial activation and ultimately apoptotic cell death. These findings gave new perspective to the current knowledge of Dichlorvos (OPs) mediated CNS damage and presents microglial activation as a potential therapeutic target for preventing the OP induced neuronal damage.

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.

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.