Dexamethasone prophylaxis protects from acute high-altitude illness by modifying the peripheral blood mononuclear cell inflammatory transcriptome.

Acute high-altitude (HA) exposure can induce several pathologies. Dexamethasone (DEX) can be taken prophylactically to prevent HA disease, but the mechanism by which it acts in this setting is unclear. We studied the transcriptome of peripheral blood mononuclear cells (PBMCs) from 16 subjects at low altitude (LA, 225 m) and then 3 days after acute travel to HA (3500 m) during the India-Leh-Dexamethasone-Expedition-2020 (INDEX2020). Half of the participants received oral DEX prophylaxis 4 mg twice daily in an unblinded manner, starting 1 day prior to travel to HA, and 12 h prior to the first PBMC collection. PBMC transcriptome data were obtained from 16 subjects, half of whom received DEX. The principal component analysis demonstrated a clear separation of the groups by altitude and treatment. HA exposure resulted in a large number of gene expression changes, particularly in pathways of inflammation or the regulation of cell division, translation, or transcription. DEX prophylaxis resulted in changes in fewer genes, particularly in immune pathways. The gene sets modulated by HA and DEX were distinct. Deconvolution analysis to assess PBMC subpopulations suggested changes in B-cell, T-cell, dendritic cell, and myeloid cell numbers with HA and DEX exposures. Acute HA travel and DEX prophylaxis induce significant changes in the PBMC transcriptome. The observed benefit of DEX prophylaxis against HA disease may be mediated by suppression of inflammatory pathways and changing leukocyte population distributions.

Immune consequences of exercise in hypoxia: A narrative review.

Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type, dose (frequency/duration, intensity), and individual characteristics. Similarly, reduced availability of ambient oxygen (hypoxia) modulates immune functions depending on the hypoxic dose and the individual capacity to respond to hypoxia. How combined exercise and hypoxia (e.g., high-altitude training) sculpts immune responses is not well understood, although such combinations are becoming increasingly popular. Therefore, in this paper, we summarize the impact on immune responses of exercise and of hypoxia, both independently and together, with a focus on specialized cells in the innate and adaptive immune system. We review the regulation of the immune system by tissue oxygen levels and the overlapping and distinct immune responses related to exercise and hypoxia, then we discuss how they may be modulated by nutritional strategies. Mitochondrial, antioxidant, and anti-inflammatory mechanisms underlie many of the adaptations that can lead to improved cellular metabolism, resilience, and overall immune functions by regulating the survival, differentiation, activation, and migration of immune cells. This review shows that exercise and hypoxia can impair or complement/synergize with each other while regulating immune system functions. Appropriate acclimatization, training, and nutritional strategies can be used to avoid risks and tap into the synergistic potentials of the poorly studied immune consequences of exercising in a hypoxic state.

Disparities in COVID-19 incidence and fatality rates at high-altitude.

Background: SARS-CoV-2 has affected every demography disproportionately, including even the native highland populations. Hypobaric-hypoxic settings at high-altitude (HA, >2,500 masl) present an extreme environment that impacts the survival of permanent residents, possibly including SARS-CoV-2. Conflicting hypotheses have been presented for COVID-19 incidence and fatality at HA. Objectives: To evaluate protection or risk against COVID-19 incidence and fatality in humans under hypobaric-hypoxic environment of high-altitude (>2,501 masl). Methods: Global COVID-19 data of March 2020-21, employed from official websites of the Indian Government, John Hopkins University, and Worldometer were clustered into 6 altitude categories. Clinical cofactors and comorbidities data were evaluated with COVID-19 incidence and fatality. Extensive comparisons and correlations using several statistical tools estimated the risk and protection. Results: Of relevance, data analyses revealed four distinct responses, namely, partial risk, total risk, partial protection, and total protection from COVID-19 at high-altitude indicating a mixed baggage and complexity of the infection. Surprisingly, it included the countries within the same geographic region. Moreover, body mass index, hypertension, and diabetes correlated significantly with COVID-19 incidence and fatality rate (P ≤ 0.05). Conclusions: Varied patterns of protection and risk against COVID-19 incidence and fatality were observed among the high-altitude populations. It is though premature to generalize COVID-19 effects on any particular demography without further extensive studies.

The EDN1 Missense Variant rs5370G > T Regulates Adaptation and Maladaptation under Hypobaric Hypoxia.

Endothelin 1 (EDN1) encodes a potent endogenous vasoconstrictor, ET1, to maintain vascular homeostasis and redistribution of tissue blood flow during exercise. One of the EDN1 missense polymorphisms, rs5370 G/T, has strongly been associated with cardiopulmonary diseases. This study investigated the impact of rs5370 polymorphism in high-altitude pulmonary oedema (HAPE) disorder or maladaptation and adaptation physiology in a well-characterized case-control study of high-altitude and low-altitude populations comprising 310 samples each of HAPE-patients, HAPE-free controls and native highlanders. The rs5370 polymorphism was genotyped, and the gene expression and plasma level of EDN1 were evaluated. The functional relevance of each allele was investigated in the human embryonic kidney 293 cell line after exposure to hypoxia and computationally. The T allele was significantly more prevalent in HAPE-p compared to HAPE-f and HLs. The EDN1 gene expression and ET1 bio-level were significantly elevated in HAPE-p compared to controls. Compared to the G allele, the T allele was significantly associated with elevated levels of ET-1 in all three study groups and cells exposed to hypoxia. The in silico studies further confirmed the stabilizing effect of the T allele on the structural integrity and function of ET1 protein. The ET1 rs5370 T allele is associated with an increased concentration of ET-1 in vivo and in vitro, establishing it as a potent marker in the adaptation/maladaptation physiology under the high-altitude environment. This could also be pertinent in endurance exercises at high altitudes.

Sexual Dimorphism of Dexamethasone as a Prophylactic Treatment in Pathologies Associated With Acute Hypobaric Hypoxia Exposure.

Dexamethasone can be taken prophylactically to prevent hypobaric hypoxia-associated disorders of high-altitude. While dexamethasone-mediated protection against high-altitude disorders has been clinically evaluated, detailed sex-based mechanistic insights have not been explored. As part of our India-Leh-Dexamethasone-expedition-2020 (INDEX 2020) programme, we examined the phenotype of control (n = 14) and dexamethasone (n = 13) groups, which were airlifted from Delhi (∼225 m elevation) to Leh, Ladakh (∼3,500 m), India, for 3 days. Dexamethasone 4 mg twice daily significantly attenuated the rise in blood pressure, heart rate, pulmonary pressure, and drop in SaO2 resulting from high-altitude exposure compared to control-treated subjects. Of note, the effect of dexamethasone was substantially greater in women than in men, in whom the drug had relatively little effect. Thus, for the first time, this study shows a sex-biased regulation by dexamethasone of physiologic parameters resulting from the hypoxic environment of high-altitude, which impacts the development of high-altitude pulmonary hypertension and acute mountain sickness. Future studies of cellular contributions toward sex-specific regulation may provide further insights and preventive measures in managing sex-specific, high-altitude-related disorders.

Opioid sparing strategies for perioperative pain management other than regional anaesthesia: A narrative review.

Opioids play a crucial role in pain management in spite of causing increased hospital morbidity and related costs. It may also cause significant risks such as postoperative nausea and vomiting (PONV), sedation, sleep disturbances, urinary retention and respiratory depression (commonly referred to as opioid related adverse effects) in postoperative patients. In order to evade these opioid related side effects and also improve pain management, multimodal analgesia i.e., combination of different analgesics, was introduced more than a decade ago. Both pharmacological and non-pharmacological techniques are available as opioid sparing analgesia. Research from around the world have proved pharmacological techniques ranging from acetaminophen, NSAIDs (non-steroidal anti-inflammatory drugs), N-methyl-D-aspartate receptor antagonists (NDMA), alpha-2 agonists, anticonvulsants such as gamma aminobutyric acid analogues, beta-blockers, capsaicin, lignocaine infusion to glucocorticoids to be effective. On the other hand, non-pharmacological methods include techniques such as cognitive behavioral therapy, transcutaneous electrical nerve stimulation (TENS), electroanalgesia, acupuncture and hypnosis. However, research regarding the effect of these non-pharmacological techniques on pain management is still needed.

Hypertensive Patients Exhibit Enhanced Thrombospondin-1 Levels at High-Altitude.

Thrombospondin-1 (THBS1) levels elevate under hypoxia and have relevance in several cardiovascular disorders. The association of THBS1 with endothelial dysfunction implies its important role in hypertension. To establish the hypothesis, we screened patients with hypertension and their respective controls from the two different environmental regions. Cohort 1 was composed of Ladakhis, residing at 3500 m above sea level (ASL), whereas Cohort 2 was composed of north-Indians residing at ~200 m ASL. Clinical parameters and circulating THBS1 levels were correlated in the case-control groups of the two populations. THBS1 levels were significantly elevated in hypertension patients of both cohorts; however, the levels were distinctly enhanced in the hypertensive patients of HA as compared to normoxia (p < 0.002). The observation was supported by the receiver operating curve analysis with an area under curve of 0.7007 (0.627-0.774) demonstrating the discriminatory effect of hypobaric hypoxia on the levels as compared to normoxia (p < 0.011). Significant correlation of THBS1 and mean arterial pressure was observed with upraised positive correlations in the hypertensive highlanders as compared to the hypertensive patients from sea-level. The prevalence of differential distribution of THBS1 and CD47 genes variants, their interactions, and association with the THBS1 levels were also determined. Genotype-interactions between THBS1 rs2228263 and CD47 rs9879947 were relevant and the regression analysis highlighted the association of risk genotype-interactions with increased THBS1 levels in hypertension. Genetic studies of additional thrombospondin pathway-related genes suggest the complex role of THBS1 in the presence of its family members and the related receptor molecules at HA.

Exposure to air pollutants and risk of congenital anomalies: A systematic review and metaanalysis.

BACKGROUND: Congenital malformations are considered as one of the significant causes of preterm as well as neonatal morbidity and mortality. Literature suggests the association of diverse congenital deformities with maternal exposure to air pollutants. However, the evidence is still inconclusive on the manifestation of these during pregnancy. Thus, systematic review was done on the available epidemiological studies studying the effect of air pollutants on congenital malformations. Furthermore, the meta-analysis was conducted for several combinations of air pollutants and congenital defects. METHODS: Twenty six epidemiological studies were extracted from the databases and examined for association of risk of congenital defects with air pollutant concentrations. Metaanalysis was done if the risk estimates of the same anomaly and pollutant group were reported in at least three studies. RESULTS: Each study reported a statistically significant increased risk of congenital malformation with some air pollutant, amid the several tested combinations. Our meta-analysis reported that nitrogen dioxide and PM2.5 were associated with the risk of pulmonary valve stenosis with OR = 1.74 and OR = 1.42 respectively. The risk of developing tetralogy of Fallot (TOF) was observed to be associated with PM2.5 with OR = 1.52. SO2 exposure was related to a high risk of the ventricular septal defect (VSD) with OR = 1.15 and orofacial defects (OR = 1.27). CONCLUSION: It is evidenced that ambient air pollutants have some effect on congenital malformations. Standard case definitions, improved methods of exposure, and better control of confounders will improve future research in this area.

Vascular homeostasis at high-altitude: role of genetic variants and transcription factors.

High-altitude pulmonary edema occurs most frequently in non-acclimatized low landers on exposure to altitude ≥2500 m. High-altitude pulmonary edema is a complex condition that involves perturbation of signaling pathways in vasoconstrictors, vasodilators, anti-diuretics, and vascular growth factors. Genetic variations are instrumental in regulating these pathways and evidence is accumulating for a role of epigenetic modification in hypoxic responses. This review focuses on the crosstalk between high-altitude pulmonary edema-associated genetic variants and transcription factors, comparing high-altitude adapted and high-altitude pulmonary edema-afflicted subjects. This approach might ultimately yield biomarker information both to understand and to design therapies for high-altitude adaptation.

Sex-derived attributes contributing to SARS-CoV-2 mortality.

Epidemiological data in COVID-19 mortality indicate that men are more prone to die of SARS-CoV-2 infection than women, but biological causes for this sexual dimorphism are unknown. We discuss the prospective behavioral and biological differences between the sexes that could be attributed to this sex-based differentiation. The female sex hormones and the immune stimulatory genes, including Toll-like receptors, interleukins, and micro-RNAs present on X-chromosome, may impart lesser infectivity and mortality of the SARS-CoV-2 in females over males. The sex hormone estrogen interacts with the renin-angiotensin-aldosterone system, one of the most critical pathways in COVID-19 infectivity, and modulates the vasomotor homeostasis. Testosterone on the contrary enhances the levels of the two most critical molecules, angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine-type 2 (TMPRSS2), transcriptionally and posttranslationally, thereby increasing viral load and delaying viral clearance in men as compared with women. We propose that modulating sex hormones, either by increasing estrogen or antiandrogen, may be a therapeutic option to reduce mortality from SARS-CoV-2.

Development, validation and evaluation of a novel self-instructional module in patients with chronic non-specific low back pain.

BACKGROUND: Low back pain (LBP) is ranked highest in terms of disability-adjusted life-years lived. Patient education and self-management have shown to play a crucial role in the overall pain management. However, the literature on the same with respect to Indian context is still lacking. The study was aimed to develop, validate and assess the acceptability and effectiveness of self-instructional educational module among Indian chronic LBP (CLBP) patients. METHODS: A prospective single-arm open-label study was conducted in a pain clinic of a tertiary care public hospital in North India with 'Backcare booklet-self-instructional module (SIM)' as an intervention in patients with CLBP. SIM was developed with the intent to provide up-to-date evidence-based information in an easy understanding way to patients with CLBP. 132 patients were administered SIM with a single session of verbal explanation. Pain intensity (numeric rating scale [NRS]), disability, fear-avoidance belief Questionnaire (FABQ), quality of life (EQ5D) and knowledge level were assessed at baseline and after 3 months of intervention. Student's paired t-test and Chi-square test were used. Data were analysed using SPSS version 15.0. RESULTS: 120 patients successfully completed the 3 months' follow-up. Significant reductions were observed in pain intensity (76[12] vs 55 [15, P < 0.01); disability (51[14] vs 43 [10], P < 0.01); FABQ (46[12] vs 41 [10], P < 0.01); EQ5D (0.35 [0.27] vs 0.18 [0.26], P < 0.01). CONCLUSION: Backcare booklet as an intervention, along with usual pharmacological care is a cost-effective educational medium to promote self-management of CLBP in the clinical outpatient settings.

ORP150-CHIP chaperone antagonism control BACE1-mediated amyloid processing.

BACE1, a key protein involved in Alzheimer's progression, initiates Aß42 generation that induce senile plaques in brain. However, the role of chaperone synergy or antagonism on BACE1-mediated amyloid processing is unknown. We have discovered that BACE1 as well as Aß42 are antagonistically controlled by ER chaperone ORP150 and cellular chaperone CHIP. We have shown ORP150 as a chaperone interacts with and stabilizes BACE1 at post-translational level. Furthermore, ORP150 enhances BACE1-mediated amyloid processing thus masking CHIP-mediated BACE1 degradation. Conversely, siORP150 reversed the chaperone function of ORP150 resulting in BACE1 degradation. ORP150 and CHIP demonstrate antagonism under normal and stress conditions wherein they inversely regulate each other thus affecting BACE1 level. In conclusion, we have uncovered for the first time a phenomenon of chaperone antagonism on BACE1-mediated Aß42 generation. Future strategy would require both suppression of ORP150 as well as activation of E3-ligase activity of CHIP that might prevent Aß42 in Alzheimer's disease.