12/15-Lipoxygenase debilitates mitochondrial health in intermittent hypobaric hypoxia induced neuronal damage: An in vivo study.

High altitude cerebral edema does not fall in routine definition of hypoxia and requires alternative therapeutic strategies. 12/15-Lipoxygenase (12/15 LOX), a key proinflammatory lipid peroxidative enzyme which site specifically inserts into cellular and subcellular membranes and plays an instrumental role in hypobaric hypoxia induced neuropathogenesis. Mitochondria, the master regulator organelles for oxygen consumption and ATP generation are sensitive to intracellular oxygen perturbations and are associated with activation of apoptosis based cell death cascades that seal the fate of the cell. The mechanistic involvement of 12/15 LOX in mitochondria mediated cell death in brain microenvironment during hypobaric hypoxia conditions can be an interesting preposition. In the present study, we have investigated underlying involvement of 12/15 LOX in hypobaric hypoxia (HH) induced disturbance in mitochondrial integrity and its relation with neuronal apoptosis. Male Balb/c mice subjected to simulated HH condition for three consecutive days showed robust increase in intra-hippocampal 12(S)HETE (12/15 LOX metabolite), which was significantly reduced following baicalein (12/15 LOX Inhibitor) treatment. The elevated level of 12(S)HETE following hypobaric hypoxia condition correlated with simultaneous increase in expression of 12/15 LOX in neurons and microglia lining the hippocampal CA3 region. Further, 12/15 LOX gets embedded onto the periphery of mitochondria following HH and a strong correlation has been observed with loss of mitochondrial integrity as evident from increased cytochrome-c in the cytosolic compartment and a subsequent upregulated activity of Caspase-3 and Caspase-9 as well as Bax/Bcl-2 expression ratio. The observed effects seen under HH were reversed upon treatment with baicalein suggesting a critical role of 12/15 LOX in HH induced mitochondrial damage Further, the hypobaric hypoxia-mediated increase in hippocampal pAKT and pmTOR protein expression were significantly ameliorated following 12/15 LOX inhibition, suggesting a mitochondrial involvement. We hereby demonstrate the contribution of 12/15 LOX in disorienting mitochondrial integrity with subsequent release of cytochrome-c in cytosol which drives the neuronal cells to intrinsic mode of cell death during hypobaric hypoxia. The protective role of baicalein by inhibition of 12/15 LOX dependent neuronal cell death and preservation of mitochondrial integrity suggests it to be a plausible therapeutic target in CNS related disorders.

Determining the burden of missed opportunities for vaccination among children admitted in healthcare facilities in India: a cross-sectional study.

OBJECTIVES: Children accessing healthcare systems represent a vulnerable population with risk factors for poor health outcomes, including vaccine-preventable diseases. We aimed to quantify missed vaccination opportunities among hospitalised children in India, and identify vaccination barriers perceived by caregivers and healthcare providers. DESIGN: Cross-sectional study. SETTING: Two public-sector tertiary-care hospitals in northern India, during November 2018 and March 2019. PARTICIPANTS: We tracked 263 hospitalised children aged 1-59 months through hospital discharge, to assess vaccination status, and document catch-up vaccinations given during the hospital stay. We interviewed caregivers and healthcare providers to assess their perceptions on vaccination. OUTCOMES: Proportion of hospitalised children considered under-vaccinated for their age; proportion of missed opportunities for vaccination among under-vaccinated children who were eligible for vaccination; and vaccine coverage by antigen. RESULTS: We found that 65.4% (172/263) of hospitalised children were under-vaccinated for their age when they presented to the hospital. Among under-vaccinated children, 61.0% were less than 4 months old, and 55.6% reported prior contact with a health facility for a sick visit. The proportion of under-vaccinated children in hospitals were higher compared with the general population as indicated by regional vaccination coverage data. Among under-vaccinated children who were tracked till discharge, 98.1% (158/161) remained incompletely vaccinated at discharge and were considered 'missed opportunities for vaccination'. Perceived vaccination contraindications that are not part of established contraindications included in national and international guidelines was the most common reason for healthcare providers not to vaccinate children during hospital stay. Among caregivers of under-vaccinated children, 90.1% reported being comfortable having their children vaccinated while they were sick, if recommended by the healthcare provider. CONCLUSION: This pilot study confirmed that hospitalised sick children had substantial missed vaccination opportunities. Addressing these opportunities through concerted actions involving caregivers, healthcare providers and healthcare systems can improve overall vaccination coverage.

A Comparative Study on the Efficacy of Fractional CO2 Laser and Fractional CO2 Laser with Autologous Platelet-Rich Plasma in Scars.

CONTEXT: Surgical correction of scars may not be an ideal solution in all cases and hence it is desirable to have a nonsurgical option available. Autologous platelet-rich plasma (PRP) and fractional carbon dioxide laser (FCL) offer an alternative treatment modality. AIMS: To compare the efficacy and safety of FCL and intradermal PRP with FCL in the management of postburn and posttraumatic scars. SETTINGS AND DESIGN: A prospective, randomized, observer-blinded, comparative study was conducted at a hospital skin centre from Oct 2016 to Sep 2018. SUBJECTS AND METHODS: A total of 67 patients with scars were randomly divided into two groups; Group I was treated with four sessions of monthly FCL and Group II was treated with four sessions of PRP and FCL. The patients were assessed using the Patient and Observer Scar Assessment Scale (POSAS) at baseline and 4 weeks after each session. STATISTICAL ANALYSIS USED: For continuous variables, the summary statistics of mean ± standard deviation was used; for categorical data, number and percentage were used. Chi-square (χ2) test was used for association between two categorical variables. P value <0.05 was considered to be statistically significant. RESULTS: Thirty cases in each group completed the study. There was a significant improvement in the total score of POSAS (p < 0.001) in both groups, but the final difference between the two groups was not statistically significant (p = 0.793 and P = 0.278, respectively). CONCLUSIONS: Fractional CO2 laser causes significant improvement in scar appearance. PRP in combination with FCL offers no additional advantage.

A Rare Presentation of Posterior Reversible Encephalopathy Syndrome in Recovery Phase of Guillain-Barré Syndrome.

Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological syndrome, in which a patient presents with neurological symptoms, including headache, seizures, altered sensorium, and loss of vision, and accompanied with characteristic magnetic resonance imaging findings which are likely to be reversible. Guillain-Barré syndrome (GBS) is an acute demyelinating polyneuropathy presumably related to immunological mechanisms. Here, we describe a patient who had PRES in recovery phase of GBS while he was neither on any immunomodulator nor was having hypertension. He recovered completely clinically as well as radiologically.

Movement Disorder and Epilepsy in Subependymal Nodular Heterotopia.

CONTEXT: Subependymal nodular heterotopia is a cortical development malformation that is commonly associated with refractory epilepsy. Patients with heterotopia show a wide spectrum of clinical manifestations, from being asymptomatic to presenting with intractable seizures and intellectual impairment. CASE REPORT: We report a case of refractory epilepsy with normal intelligence, having bilateral subependymal heterotopic nodules in brain, presenting to us with a movement disorder in the form of myoclonus of bilateral lower limbs which is an unusual manifestation of gray matter heterotopias. CONCLUSION: Though rare, gray matter heterotopias may present as movement disorder and should be considered in differential diagnosis while work up of movement disorders.

Inhibition of 12/15 LOX ameliorates cognitive and cholinergic dysfunction in mouse model of hypobaric hypoxia via. attenuation of oxidative/nitrosative stress.

12/15 Lipoxygenase has recently been described as potent propagator of oxidative stress and is closely associated with cognitive decline in neurodegenerative diseases. The mechanism/s behind 12/15 LOX involvement in cognitive deficits remain obscure. The current study has been designed to investigate the underlying role of 12/15LOX and effect of 12/15 LOX inhibition on hypobaric hypoxia-induced memory impairment and cholinergic deficits. Male Balb/c mice subjected to simulated hypobaric hypoxia/reoxygenation condition for 3days showed marked working memory impairment concomitant with hippocampal neuronal damage and malondialdehyde production which were significantly attenuated by baicalein, a specific inhibitor of 12/15LOX. Hypobaric hypoxia-exposed mice had consistently increased expression of 12/15LOX and elevated 12(S) HETE levels in the hippocampus as well as plasma which were significantly mitigated following baicalein treatment. 12/15LOX inhibition also reduced hypobaric hypoxia-mediated upregulation of hippocampal HIF-1α protein expression along with reduction in expression of inflammatory genes. The inhibition of 12/15 LOX resulted in a significant decrease in NO levels in the hippocampal homogenate associated with downregulated iNOS, nNOS transcription but not eNOS speculating that 12/15 LOX is critically involved in HIF-1α, mediated by nitric oxide-induced neurotoxicity. We also observed a similar effect of 12/15 LOX inhibition on hippocampal COX2 expression. 12/15LOX inhibition could effectively modulate central cholinergic indices during hypobaric hypoxia by restoring mAChR-1, α7NAChR expression and AChE, ChAT activity in the hippocampus comparable to normal mice. We report here the mechanistic involvement of 12/15LOX in orchestrating hypoxia-associated neuronal damage and HIF-1α-dependent neuroinflammation resulting in cognitive decline.

Lactate clearance as the predictor of outcome in pediatric septic shock.

CONTEXT: Septic shock can rapidly evolve into multiple system organ failure and death. In the recent years, hyperlactatemia has been found to be a risk factor for mortality in critically ill adults. AIMS: To evaluate the predictive value of lactate clearance and to determine the optimal cut-off value for predicting outcome in children with septic shock. SETTINGS AND DESIGN: A prospective observational study was performed on children with septic shock admitted to pediatric Intensive Care Unit (PICU). SUBJECTS AND METHODS: Serial lactate levels were measured at PICU admission, 24 and 48 h later. Lactate clearance, percent decrease in lactate level in 24 h, was calculated. The primary outcome measure was survival or nonsurvival at the end of hospital stay. We performed receiver operating characteristic analyses to calculate optimal cut-off values. RESULTS: The mean lactate levels at admission were significantly higher in the nonsurvivors than survivors, 5.12 ± 3.51 versus 3.13 ± 1.71 mmol/L (P = 0.0001). The cut-off for lactate level at admission for the best prediction of mortality was determined as ≥4 mmol/L (odds ratio 5.4; 95% confidence interval [CI] =2.45-12.09). Mean lactate clearance was significantly higher in survivors than nonsurvivors (17.9 ± 39.9 vs. -23.2 ± 62.7; P < 0.0001). A lactate clearance rate of <10% at 24 h had a sensitivity and specificity of 78.7% and 72.2%, respectively and a positive predictive value of 83.1% for death. Failure to achieve a lactate clearance of more than 10% was associated with greater risk of mortality (likelihood ratio + 2.83; 95% CI = 1.82-4.41). CONCLUSIONS: Serial lactate levels can be used to predict outcome in pediatric septic shock. A 24 h lactate clearance cut-off of <10% is a predictor of in-hospital mortality in such patients.

Griscelli syndrome subtype 2 with hemophagocytic lympho-histiocytosis: A case report and review of literature.

Griscelli syndrome (GS) is a rare autosomal recessive disorder resulting in pigmentary dilution of the skin and hair with variable phenotypes depending upon subtypes. Mutations in 3 distinct genes MYO5A, RAB27A, MLPH are responsible for 3 subtypes (GS1, GS2, and GS3) of GS respectively. GS subtype 2 commonly develops hemophagocytic lymphohistiocytosis (HLH) and recurrent infections due to immunodeficiency. We hereby report a 20 month old male child presenting with silvery gray hair, hypomelanosis and features of hemophagocytosis. The diagnosis of a type 2 GS was made in response to a set of clinical features: hypopigmentation of skin and the silvered reflection of the hair, absence of psychomotor retardation, the occurrence of an accelerated phase (hemophagocytosis) and, above all, a pathognomonic appearance by microscopic examination of a hair. The absence of giant granules in the nucleated cells made it possible to eliminate Chediak-Higashi syndrome, which shares a close clinical spectrum with GS. This case promotes awareness about this rare case of GS as a high indicator of suspicion about this potentially fatal condition and aids in prompt diagnosis and foresees complications. Early bone marrow transplant is the only curative treatment for GS-2.