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With the advent of antibiotics, bacterial infections were supposed to be a thing of past. However, this instead led to the selection and evolution of bacteria with mechanisms to counter the action of antibiotics. Antibiotic efflux is one of the major mechanisms, whereby bacteria pump out the antibiotics from their cellular interior to the external environment using special transporter proteins called efflux pumps. Inhibiting these pumps seems to be an attractive strategy at a time when novel antibiotic supplies are dwindling. Molecules capable of inhibiting these pumps, known as efflux pump inhibitors (EPIs), have been viewed as potential therapeutic agents that can rejuvenate the activity of antibiotics that are no longer effective against bacterial pathogens. EPIs follow some general mechanisms of efflux inhibition and are derived from various natural as well as synthetic sources. This review focuses on EPIs and identifies the challenges that have kept these futuristic therapeutics away from the commercial realm so far.

Avoidable blindness is a significant public health problem in India. Nationally representative RAAB surveys (Rapid Assessment of Avoidable Blindness) are being conducted periodically in the country to know the current status of blindness in the country. The current study describes the findings from the RAAB survey conducted during 2015-19 in India. A cross-sectional, population-based survey was conducted across the entire country among persons aged 50 years and above using RAAB version 6 methodology. Presenting and pinhole visual acuity was recorded followed by lens examination using a torchlight. In order to estimate the prevalence of blindness and visual impairment in overall population in India, district weights were assigned to each of the 31 surveyed districts and the prevalence was standardized using the RAAB software. The overall weighted, age-gender standardized, prevalence of blindness (presenting visual acuity <3/60 in better eye) in population aged ≥50 years was 1.99% (95% CI 1.94%, 2.13%) and of visual impairment (VI) (presenting visual acuity <6/12 in better eye) was 26.68% (95% CI 26.57-27.17%). On multivariate analysis, adjusted odds ratio showed that blindness was associated with age ≥ 80 years (OR = 20.3, 95% CI: 15.6-26.4) and being illiterate (OR = 5.6, 95% CI: 3.6-8.9). Blindness was not found to be significantly associated with either gender or locality. The results of the survey demonstrate that currently more than one fourth of persons aged 50 years and above are visually impaired (PVA<6/12 in better eye) in India. The prevalence of blindness among them is 1.99%, and older age and illiteracy are significantly associated with blindness. Major causes of blindness included cataract (66.2%), corneal opacity (CO) (8.2%), cataract surgical complications (7.2%), posterior segment disorders (5.9%) and glaucoma (5.5%). The proportion of blindness and visual impairment that is due to avoidable causes include 92.9% and 97.4% respectively.

Food and feeds contaminated with mycotoxins have been a threat to the rearing industry by causing some of the most fatal toxic reactions not only in the farm animals but also in humans who consume them. Toxicity to juvenile goats was induced by feed contamination with T-2 toxin (at 10 and 20 ppm dosage; group I and II, respectively). The toxicity impact was assessed on days 15 and 30 post treatment with respect to growth performance, oxidative stress, apoptotic studies and detailed pathomorphology. The study revealed that apart from the obvious clinical toxicosis (weakness, lethargy, and retardation in growth), the toxin fed groups also exhibited significant haematological (reduced hemoglobin, total leukocyte and thrombocyte counts) and biochemical changes (increased levels of oxidative stress markers with concomitant decrease in levels of serum and tissue catalase and superoxide dismutase). The pathomorphological and histological alterations suggested that the liver and intestine were the most affected organs. Ultra-structurally, varying degrees of degeneration, cytoplasmic vacuolations and pleomorphic mitochondria were observed in the hepatocytes and the enterocytes of the intestine. Kidney also revealed extensive degeneration of the cytoplasmic organelles with similar condensation of the heterochromatin whereas the neuronal degeneration was characterized by circular, whirling structures. In addition, the central vein and portal triad of the hepatocytes, cryptic epithelial cells of the intestine, MLNs in the lymphoid follicles, PCT and DCT of the nephronal tissues and the white pulp of the spleen exhibited extensive apoptosis. In this study, it was also observed that the expression of HSPs, pro-apoptotic proteins and pro-inflammatory cytokines were significantly upregulated in response to the toxin treatment. These results suggest that the pathogenesis of T-2 toxicosis in goats employs oxidative, apoptotic and inflammatory mechanisms.

Vascular endothelium offers a variety of therapeutic targets for the treatment of cancer, cardiovascular diseases, inflammation, and oxidative stress. Significant research has been focused on developing agents to target the endothelium in diseased tissues. This includes identification of antibodies against adhesion molecules and neovascular expression markers or peptides discovered using phage display. Such targeting molecules also have been used to deliver nanoparticles to the endothelium of the diseased tissue. Here we report, based on in vitro and in vivo studies, that the specificity of endothelial targeting can be enhanced further by engineering the shape of ligand-displaying nanoparticles. In vitro studies performed using microfluidic systems that mimic the vasculature (synthetic microvascular networks) showed that rod-shaped nanoparticles exhibit higher specific and lower nonspecific accumulation under flow at the target compared with their spherical counterparts. Mathematical modeling of particle–surface interactions suggests that the higher avidity and specificity of nanorods originate from the balance of polyvalent interactions that favor adhesion and entropic losses as well as shear-induced detachment that reduce binding. In vivo experiments in mice confirmed that shape-induced enhancement of vascular targeting is also observed under physiological conditions in lungs and brain for nanoparticles displaying anti–intracellular adhesion molecule 1 and anti-transferrin receptor antibodies.

Identification of potential snow drought (SD) hotspots is critical, especially considering seasonal snow imbalances in the recent years, with snow being one of the significant water resource in the Hindu Kush Himalayas (HKH). The critical linkage between the spatio-temporal anomalies of snow cover days (SCD) and SD remains under-observed in the HKH region. To investigate this linkage, we identified the SD at basin (11 basins) using the snow water equivalent index (SWEI) based on the High Mountain Asia Snow Reanalysis (HMASR) data from 1999 to 2016 water cycle. The declined snow cover days (DSCD) and snow cover persistence anomalies (SCPA) at sub-km spatial resolution from 2002 to 2018 were estimated from the improved MOYDGL06 snow cover data, respectively. Our basin scale findings indicate moderate to severe snow droughts were observed in 2008, 2011, 2015 and 2016 in the North-West (NW), Amu-Darya (AD), Indus (IN), and Salween (SA) and Mekong (MK) basins with strong linkages to DSCD and SCPA. The observed frequencies of snow-droughts were 25, 16, 14, 5, and 3 in the NW, AD, IN, MK, SA basins, respectively. These basins also exhibit significant DSCD, approximately 12, 11, 12 in NW, AD, IN, respectively, and 14 days in MK and SA basins each. Further, it is noted that significantly higher negative SCPA coincides with the SD episodes in drought years. Both SD and DSCD were more prominent between 3000 and 6000 m elevations in the HKH, which are often considered under elevation dependent warming (EDW) scenarios in various studies. Overall, we observed that a higher frequency of drought events corresponds to a greater DSCD and higher negative magnitudes of SCPA. These insights indicate the urgent need for snow-conservation strategies and development and enforcement of strong policies.

To evaluate the incidence and progression of myopia and factors associated with progression of myopia in school going children in Delhi. Prospective longitudinal study of 10,000 school children aged 5 to 15 years screened after an interval of 1 year to identify new myopes (Spherical Equivalent≤ -0.5D) and progression of myopia in previously diagnosed myopic children. Association between risk factors and progression was analyzed using adjusted odds ratio. Of the 9,616 children re-screened (97.3% coverage), annual incidence of myopia was 3.4%with mean dioptric change of -1.09 ± 0.55. There was a significant higher incidence of myopia in younger children compared to older children (P = 0.012) and among girls compared to boys (P = 0.002). Progression was observed in 49.2%children with mean dioptric change of -0.27 ± 0.42 diopters. The demographic and behavioral risk factors were analyzed for children with progression (n = 629) and adjusted odds ratio values were estimated. Hours of reading-writing/week (p<0.001), use of computers/ video games (P<0.001) and watching television (P = 0.048) were significant risk factors for progression of myopia. Outdoor activities / time spent outdoors> 2 hours in a day were protective with an inverse association with progression of myopia (P< 0.001). Myopia is an important health issue in India and is associated with long hours of reading and screen time with use of computers and video games. An annual eye vision screening should be conducted, and outdoor activities be promoted to prevent the increase of myopia among school children.

Alzheimer’s disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ 42 ) forms and novel intraneuronal Aβ oligomers (AβOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aβ uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aβ 42 , S100 calcium-binding protein B + macrogliosis, and atrophy correlated with severity of brain Aβ pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aβ 42 , far-peripheral AβOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.

Abstarct Glaucoma is a chronic disease that shares many similarities with other neurodegenerative disorders of the central nervous system. This study was designed to evaluate the association between glaucoma and other neurodegenerative disorders by investigating glaucoma-associated protein changes in the retina and vitreous humour. The multiplexed Tandem Mass Tag based proteomics (TMT-MS3) was carried out on retinal tissue and vitreous humour fluid collected from glaucoma patients and age-matched controls followed by functional pathway and protein network interaction analysis. About 5000 proteins were quantified from retinal tissue and vitreous fluid of glaucoma and control eyes. Of the differentially regulated proteins, 122 were found linked with pathophysiology of Alzheimer’s disease (AD). Pathway analyses of differentially regulated proteins indicate defects in mitochondrial oxidative phosphorylation machinery. The classical complement pathway associated proteins were activated in the glaucoma samples suggesting an innate inflammatory response. The majority of common differentially regulated proteins in both tissues were members of functional protein networks associated brain changes in AD and other chronic degenerative conditions. Identification of previously reported and novel pathways in glaucoma that overlap with other CNS neurodegenerative disorders promises to provide renewed understanding of the aetiology and pathogenesis of age related neurodegenerative diseases.

India is the second most populated country in the world with 41% of the population (492 million) under 18 years of age. While numerous studies have shown an increasing prevalence of myopia worldwide, there continues to be uncertainty about the magnitude of myopia in Indian school going population. Systematic review and meta-analysis. We systematically identified published literature of last four decades from 1980 to March 2020 and assessed them for methodological quality. Data were gathered into 5-year age groups from 5-15, in urban or rural populations, and standardized to definition of myopia as refractive error ≥ -0.50 dioptre. Random effects meta-analysis was done. We included data from 59 quality assessed studies, covering nearly 1,66,000 urban and 1,20,000 rural children. The overall crude prevalence of myopia over last four decades is 7.5% (95% CI, 6.5-8.5%) in 5-15-year age group. The prevalence of myopia is 8.5% (95% CI, 7.1-9.9%) in urban and 6.1% (95% CI, 4.5-7.7%) in rural children, with highest prevalence in urban 11-15-year age group [15.0% in last decade]. A significant increment in prevalence is noted in the last decade in rural children from 4.6% to 6.8%, reflecting changing rural environment. Myopia is an emerging public health problem in both urban and rural school going adolescents in India requiring urgent efforts.

Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod- or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration. The transitional link from robust clearance of intravenously injected nanoparticles by strategically placed macrophages in systemic circulation to adverse haemodynamic reactions can be overcome by changing nanoparticle geometry or by prior nanoparticle attachment to erythrocytes