Withaferin A Alleviates Inflammation in Animal Models of Arthritis by Inhibiting the NF-κB Pathway and Cytokine Release.

Withaferin A, a steroid lactone from Withania somnifera, exhibits anti-inflammatory, immunomodulatory, and antioxidant properties. This study investigated the effects of withaferin A on collagen-induced arthritis (CIA) rats, focusing on NF-κB p65 regulation and cytokine release. Withaferin A (50 mg/kg b.wt., orally) or methotrexate (0.25 mg/kg b.wt., i.p., as a reference drug) was given to CIA rats daily for 20 days postarthritis induction. Joints were removed from nonarthritic and arthritic rats to assess the levels of NO, MPO, interleukin (IL)-1ß, IL-6, IL-10, TNF-α, COX-2, and NF-κB via ELISA. Furthermore, the mRNA expression of IL-1ß, IL-10, TNF-α, COX-2, iNOS, and NF-κB was also assessed through qPCR. Treatment with withaferin A significantly inhibited the levels of inflammatory cytokines and the transcription factor NF-κB; suppressed the expression of IL-1ß, IL-10, TNF-α, COX-2, iNOS, and NF-κB in the joint tissue of CIA rats; and reduced cartilage and bone destruction, as shown by H&E staining. To confirm the results obtained from biochemical and molecular studies and to determine the molecular target of withaferin A, we performed a molecular simulation of the potential targets of withaferin A, which identified the NF-κB pathway as its target. These results suggested that withaferin A effectively attenuated rheumatoid arthritis progression by inhibiting the activation of the NF-κB pathway and the downstream secretion of inflammatory cytokines.

Estimating the synaptic density deficit in Alzheimer's disease using multi-contrast CEST imaging.

In vivo noninvasive imaging of neurometabolites is crucial to improve our understanding of the underlying pathophysiological mechanism in neurodegenerative diseases. Abnormal changes in synaptic organization leading to synaptic degradation and neuronal loss is considered as one of the primary factors driving Alzheimer's disease pathology. Magnetic resonance based molecular imaging techniques such as chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) can provide neurometabolite specific information which may relate to underlying pathological and compensatory mechanisms. In this study, CEST and short echo time single voxel MRS was performed to evaluate the sensitivity of cerebral metabolites to beta-amyloid (Aß) induced synaptic deficit in the hippocampus of a mouse model of Alzheimer's disease. The CEST based spectra (Z-spectra) were acquired on a 9.4 Tesla small animal MR imaging system with two radiofrequency (RF) saturation amplitudes (1.47 µT and 5.9 µT) to obtain creatine-weighted and glutamate-weighted CEST contrasts, respectively. Multi-pool Lorentzian fitting and quantitative T1 longitudinal relaxation maps were used to obtain metabolic specific apparent exchange-dependent relaxation (AREX) maps. Short echo time (TE = 12 ms) single voxel MRS was acquired to quantify multiple neurometabolites from the right hippocampus region. AREX contrasts and MRS based metabolite concentration levels were examined in the ARTE10 animal model for Alzheimer's disease and their wild type (WT) littermate counterparts (age = 10 months). Using MRS voxel as a region of interest, group-wise analysis showed significant reduction in Glu-AREX and Cr-AREX in ARTE10, compared to WT animals. The MRS based results in the ARTE10 mice showed significant decrease in glutamate (Glu) and glutamate-total creatine (Glu/tCr) ratio, compared to WT animals. The MRS results also showed significant increase in total creatine (tCr), phosphocreatine (PCr) and glutathione (GSH) concentration levels in ARTE10, compared to WT animals. In the same ROI, Glu-AREX and Cr-AREX demonstrated positive associations with Glu/tCr ratio. These results indicate the involvement of neurotransmitter metabolites and energy metabolism in Aß-mediated synaptic degradation in the hippocampus region. The study also highlights the feasibility of CEST and MRS to identify and track multiple competing and compensatory mechanisms involved in heterogeneous pathophysiology of Alzheimer's disease in vivo.

Emerging novel sequence types of Staphylococcus aureus in Pakistan.

BACKGROUND: Despite an increasing incidence of Staphylococcus aureus infection and dissemination in Pakistan, the epidemiology of different Staphylococcus aureus research clones has been the subject of only a small number of investigations. By analyzing the collected data sequence, this study was designed to study the epidemiology of Staphylococcus aureus in the area using multilocus sequence typing (MLST). METHODS: A total of 1015 staphylococcus strains collected from the city's tertiary care facilities were biochemically screened, followed by antimicrobial susceptibility testing against a panel of 13 antibiotics. Analyzed methicillin-resistant Staphylococcus aureus (MRSA) was subjected to molecular characterization using multilocus sequence typing (MLST), clonal complex analysis, recombination testing, and phylogenetic analysis. RESULTS: Approximately 421 bacteria were verified as Staphylococcus aureus by biochemical analysis. 57% of the isolates exhibited multidrug resistance, of which 89% were found to be methicillin-resistant Staphylococcus aureus (MRSA). MLST results in a total of 39 sequence types (ST) and 5 clonal complexes (CC), out of which twenty-two STs were newly documented worldwide. The most common CC identified was CC8. The direct sequencing data also revealed significant shifts at MLST loci, with point mutations resulting in the aroE-343 and tpi-278 alleles. CONCLUSIONS: This study concludes that there is high diversity in the locally circulating clones of Staphylococcus aureus present in nature and that they are defined by their geographic epidemiology. These findings have practical implications for public health, including the need for tailored infection control strategies, antibiotic stewardship, global surveillance, and a deeper understanding of bacterial evolution.

Randomised controlled trial of adjunctive triamcinolone acetonide in eyes undergoing vitreoretinal surgery following open globe trauma: The ASCOT study.

BACKGROUND/AIMS: To investigate the clinical effectiveness of adjunctive triamcinolone acetonide (TA) given at the time of vitreoretinal surgery following open globe trauma (OGT). METHODS: A phase 3, multicentre, double-masked randomised controlled trial of patients undergoing vitrectomy following OGT comparing adjunctive TA (intravitreal and subtenons) against standard care (2014-2020). The primary outcome was the proportion of patients with at least 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letter improvement in corrected visual acuity (VA) at 6 months. Secondary outcomes included: change in ETDRS, retinal detachment (RD) secondary to PVR, retinal reattachment, macular reattachment, tractional RD, number of operations, hypotony, elevated intraocular pressure and quality of life. RESULTS: 280 patients were randomised over 75 months, of which 259 completed the study. 46.9% (n=61/130) of patients in the treatment group had a 10-letter improvement in VA compared with 43.4% (n=56/129) of the control group (difference 3.5% (95% CI -8.6% to 15.6%), OR=1.03 (95% CI 0.61 to 1.75), p=0.908)). Secondary outcome measures also failed to show any treatment benefit. For two of the secondary outcome measures, stable complete retinal and macular reattachment, outcomes were worse in the treatment group compared with controls, respectively, 51.6% (n=65/126) vs 64.2% (n=79/123), OR=0.59 (95% CI 0.36 to 0.99), and 54.0% (n=68/126) vs 66.7% (n=82/123), OR=0.59 (95% CI 0.35 to 0.98), for TA vs control. CONCLUSION: The use of combined intraocular and sub-Tenons capsule TA is not recommended as an adjunct to vitrectomy surgery following OGT. TRIAL REGISTRATION NUMBER: NCT02873026.

Perturbed neurochemical and microstructural organization in a mouse model of prenatal opioid exposure: A multi-modal magnetic resonance study.

Methadone-based treatment for pregnant women with opioid use disorder is quite prevalent in the clinical environment. A number of clinical and animal model-based studies have reported cognitive deficits in infants prenatally exposed to methadone-based opioid treatments. However, the long-term impact of prenatal opioid exposure (POE) on pathophysiological mechanisms that govern neurodevelopmental impairment is not well understood. Using a translationally relevant mouse model of prenatal methadone exposure (PME), the aim of this study is to investigate the role of cerebral biochemistry and its possible association with regional microstructural organization in PME offspring. To understand these effects, 8-week-old male offspring with PME (n = 7) and prenatal saline exposure (PSE) (n = 7) were scanned in vivo on 9.4 Tesla small animal scanner. Single voxel proton magnetic resonance spectroscopy (1H-MRS) was performed in the right dorsal striatum (RDS) region using a short echo time (TE) Stimulated Echo Acquisition Method (STEAM) sequence. Neurometabolite spectra from the RDS was first corrected for tissue T1 relaxation and then absolute quantification was performed using the unsuppressed water spectra. High-resolution in vivo diffusion MRI (dMRI) for region of interest (ROI) based microstructural quantification was also performed using a multi-shell dMRI sequence. Cerebral microstructure was characterized using diffusion tensor imaging (DTI) and Bingham-neurite orientation dispersion and density imaging (Bingham-NODDI). MRS results in the RDS showed significant decrease in N-acetyl aspartate (NAA), taurine (tau), glutathione (GSH), total creatine (tCr) and glutamate (Glu) concentration levels in PME, compared to PSE group. In the same RDS region, mean orientation dispersion index (ODI) and intracellular volume fraction (VFIC) demonstrated positive associations with tCr in PME group. ODI also exhibited significant positive association with Glu levels in PME offspring. Significant reduction in major neurotransmitter metabolites and energy metabolism along with strong association between the neurometabolites and perturbed regional microstructural complexity suggest a possible impaired neuroadaptation trajectory in PME offspring which could be persistent even into late adolescence and early adulthood.

GIS based hotspot analysis and health risk assessment of groundwater arsenic from an unconfined deep aquifer of Lahore, Pakistan.

Use of groundwater for drinking purpose poses serious hazards of arsenic contamination particularly in plains of western Himalayan region. Therefore, current study was designed to investigate the level of Arsenic (As) in the water obtained from tubewells in a metropolitan city of Lahore, Pakistan and assess the human health risk. So, a total of 73 tubewells were sampled randomly in the manner that the whole study region was covered without any clustering. The water samples were analyzed for As using atomic absorption spectrophotometer. These samples were also tested for total dissolved solids, chlorides, pH, alkalinity, turbidity, hardness and calcium. GIS based hotspots analysis technique was used to investigate the spatial distribution patterns. Our results revealed that only one sample out of total 73 had arsenic level below the WHO guideline of 10 µg/L. The spatial distribution map of arsenic revealed that the higher concentrations of arsenic are present in the north-western region of Lahore. The cluster and outlier analysis map using Anselin Local Moran's I statistic indicated the presence of an arsenic cluster in the west of River Ravi. Furthermore, the optimized hotspot analysis based on Getis-Ord Gi* statistics confirmed the statistical significance (P < 0.05) and (P < 0.01) of these samples from the vicinity of River Ravi. Regression analysis showed that variables such as turbidity, alkalinity, hardness, chlorides, calcium and total dissolved solids were significantly (all P < 0.05) associated with level of Arsenic in tubewells. Whereas, PH and electrical conductivity and other variables like town, year of installation, depth and diameter of the wells were not significantly associated with Arsenic concentrations in tubewells. Principal component analysis (PCA) exhibited that the random distribution of tubewell samples showed no distinct clustering with towns studied. Health risk assessment based on hazard and Cancer risk index revealed serious risk of developing carcinogenic and non-carcinogenic diseases particularly in children. The health risk due to prevalence of high As concentration in tubewells' water need to be mitigated immediately to avoid worst consequences in future.

Perturbed neurochemical and microstructural organization in a mouse model of prenatal opioid exposure: a multi-modal magnetic resonance study.

Methadone-based treatment for pregnant women with opioid use disorder is quite prevalent in the clinical environment. A number of clinical and animal model-based studies have reported cognitive deficits in infants prenatally exposed to methadone-based opioid treatments. However, the long-term impact of prenatal opioid exposure (POE) on pathophysiological mechanisms that govern neurodevelopmental impairment is not well understood. Using a translationally relevant mouse model of prenatal methadone exposure (PME), the aim of this study is to investigate the role of cerebral biochemistry and its possible association with regional microstructural organization in PME offspring. To understand these effects, 8- week-old male offspring with PME (n=7) and prenatal saline exposure (PSE) (n=7) were scanned in vivo on 9.4 Tesla small animal scanner. Single voxel proton magnetic resonance spectroscopy ( 1 H-MRS) was performed in the right dorsal striatum (RDS) region using a short echo time (TE) Stimulated Echo Acquisition Method (STEAM) sequence. Neurometabolite spectra from the RDS was first corrected for tissue T1 relaxation and then absolute quantification was performed using the unsuppressed water spectra. High-resolution in vivo diffusion MRI (dMRI) for region of interest (ROI) based microstructural quantification was also performed using a multi-shell dMRI sequence. Cerebral microstructure was characterized using diffusion tensor imaging (DTI) and Bingham-neurite orientation dispersion and density imaging (Bingham-NODDI). MRS results in the RDS showed significant decrease in N-acetyl aspartate (NAA), taurine (tau), glutathione (GSH), total creatine (tCr) and glutamate (Glu) concentration levels in PME, compared to PSE group. In the same RDS region, mean orientation dispersion index (ODI) and intracellular volume fraction (VF IC ) demonstrated positive associations with tCr in PME group. ODI also exhibited significant positive association with Glu levels in PME offspring. Significant reduction in major neurotransmitter metabolites and energy metabolism along with strong association between the neurometabolites and perturbed regional microstructural complexity suggest a possible impaired neuroadaptation trajectory in PME offspring which could be persistent even into late adolescence and early adulthood.

Presenting clinical characteristics of open globe injuries in ocular trauma: baseline analysis of cases in the ASCOT national clinical trial.

BACKGROUND/OBJECTIVES: The Adjunctive Steroid Combination in Ocular Trauma (ASCOT) trial is a unique pragmatic, multi-centre, patient and assessor masked, randomised controlled trial. We evaluate the clinical characteristics and pathology of this large trial cohort of patients with open globe injuries undergoing vitreoretinal surgery, including the associations between patient characteristics and their baseline vision. SUBJECTS/METHODS: We (i) summarise demographics, injury history and ocular history of the 280 participants recruited into the ASCOT trial using descriptive statistics; (ii) analyse the national and seasonal variation across England and Scotland in these participant characteristics; and (iii) explore the associations between participant demographic, trauma history, ocular history and presenting baseline visual acuity (measured using the Early Treatment Diabetic Retinopathy Study, ETDRS) using multivariable regression analyses. RESULTS: The majority of participants with open globe penetrating injuries were of white ethnicity (233, 84%), male (246, 88%), with a median age of 43 years (IQR 30-55 years). There was considerable variability in presenting visual acuity with 75% unable to read any letters on the ETDRS chart, whilst the median ETDRS letter score was 58 (IQR 24-80) for those who could read ≥1 letter. The most common causes of injury were workplace related (31%) or interpersonal violence (24%). Previous eye surgery, visual axis corneal scar, lens status, hyphaemia and vitreous haemorrhaging were found to be associated with presenting vision as measured by the ETDRS chart. CONCLUSION: The ASCOT trial provides valuable insights into the spectrum of pathology of patients with open globe eye injuries undergoing vitreoretinal surgery. The identified causes of injury and clinical presentation of the cases will help in training and resource planning to deal with these often challenging surgical cases. TRIAL REGISTRATION: EudraCT No. 014-002193-37. HTA Project 12/35/64.

Health risk assessment and geospatial analysis of arsenic contamination in shallow aquifer along Ravi River, Lahore, Pakistan.

The exposure variation of arsenic from different ground and surface water sources has remained unpredictable which may cause severe human health problems. The current study is, therefore, designed to analyze the spatial variability of arsenic contamination in shallow aquifer and assess the potential human health risks. For this purpose, a total of 55 groundwater, 10 drain water, 4 river water, and 6 sediment samples were collected along zero to 5 km stretch of the River Ravi, Lahore. All water samples were tested for As, pH, and total dissolved solids (TDS), whereas sediments were only tested for As. Health risk models were used to predict cancer and non-cancer risk in adults and children. Among water samples, highest median (minimum-maximum) concentrations (µg/L) of As were recorded 53.32 (1.98-1555) in groundwater, followed by 53.04 (1.58-351.5) in drain water, and 4.80 (2.13-8.67) in river water, respectively, whereas As concentration (mg/kg) in river sediments was 6.03 (5.56-13.92). Variation of As in groundwater was non-significant (P > 0.05) among every 1-km stretch from the Ravi River. However, maximum median concentrations (µg/L) of 60.18 and 60.08 were recorded between 2-3 and 0-1 km from River Ravi, respectively, reflecting possible mixing of river water with shallow aquifers. A very high cancer and non-cancer risk (HI > 1.0 × 10-4) through groundwater As exposure was predicted for both children and adults. The current study concluded that prevalence of As above WHO prescribed limits in shallow aquifer along the urban stretch of the River Ravi is posing serious health risk to the exposed population.

Bassoon contributes to tau-seed propagation and neurotoxicity.

Tau aggregation is a defining histopathological feature of Alzheimer's disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer's disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.

Alterations of brain microstructures in a mouse model of prenatal opioid exposure detected by diffusion MRI.

Growing opioid use among pregnant women is fueling a crisis of infants born with prenatal opioid exposure. A large body of research has been devoted to studying the management of opioid withdrawal during the neonatal period in these infants, but less substantive work has explored the long-term impact of prenatal opioid exposure on neurodevelopment. Using a translationally relevant mouse model of prenatal methadone exposure (PME), the aim of the study is to investigate the cerebral microstructural differences between the mice with PME and prenatal saline exposure (PSE). The brains of eight-week-old male offspring with either PME (n = 15) or PSE (n = 15) were imaged using high resolution in-vivo diffusion magnetic resonance imaging on a 9.4 Tesla small animal scanner. Brain microstructure was characterized using diffusion tensor imaging (DTI) and Bingham neurite orientation dispersion and density imaging (Bingham-NODDI). Voxel-based analysis (VBA) was performed using the calculated microstructural parametric maps. The VBA showed significant (p < 0.05) bilateral alterations in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), orientation dispersion index (ODI) and dispersion anisotropy index (DAI) across several cortical and subcortical regions, compared to PSE. Particularly, in PME offspring, FA, MD and AD were significantly higher in the hippocampus, dorsal amygdala, thalamus, septal nuclei, dorsal striatum and nucleus accumbens. These DTI-based results suggest widespread bilateral microstructural alterations across cortical and subcortical regions in PME offspring. Consistent with the observations in DTI, Bingham-NODDI derived ODI exhibited significant reduction in PME offspring within the hippocampus, dorsal striatum and cortex. NODDI-based results further suggest reduction in dendritic arborization in PME offspring across multiple cortical and subcortical regions. To our best knowledge, this is the first study of prenatal opioid exposure to examine microstructural organization in vivo. Our findings demonstrate perturbed microstructural complexity in cortical and subcortical regions persisting into early adulthood which could interfere with critical neurodevelopmental processes in individuals with prenatal opioid exposure.

Multimodal magnetic resonance imaging reveals distinct sensitivity of hippocampal subfields in asymptomatic stage of Alzheimer's disease.

While hippocampal atrophy and its regional susceptibility to Alzheimer's disease (AD) are well reported at late stages of AD, studies of the asymptomatic stage of AD are limited but could elucidate early stage pathophysiology as well as provide predictive biomarkers. In this study, we performed multi-modal magnetic resonance imaging (MRI) to estimate morphometry, functional connectivity, and tissue microstructure of hippocampal subfields in cognitively normal adults including those with asymptomatic AD. High-resolution resting-state functional, diffusion and structural MRI, cerebral spinal fluid (CSF), and neuropsychological evaluations were performed in healthy young adults (HY: n = 40) and healthy older adults with negative (HO-: n = 47) and positive (HO+ : n = 25) CSF biomarkers of AD. Morphometry, functional connectivity, and tissue microstructure were estimated from the structural, functional, and diffusion MRI images, respectively. Our results indicated that normal aging affected morphometry, connectivity, and microstructure in all hippocampal subfields, while the subiculum and CA1-3 demonstrated the greatest sensitivity to asymptomatic AD pathology. Tau, rather than amyloid-ß, was closely associated with imaging-derived synaptic and microstructural measures. Microstructural metrics were significantly associated with neuropsychological assessments. These findings suggest that the subiculum and CA1-3 are the most vulnerable in asymptomatic AD and tau level is driving these early changes.

COVID-19 Lockdown in New Zealand: Perceived Stress and Wellbeing among International Health Students Who Were Essential Frontline Workers.

This study examined the stresses and wellbeing of international postgraduate health and nursing students at a tertiary education institute in New Zealand who were mainly essential frontline healthcare workers during the COVID-19 lockdown. Quantitative and qualitative data were collected by purposeful sampling (n = 43). The study utilised a cross-sectional survey, along with the Short Form of Cohen's Perceived Stress Scale (PSS-10), adapted for the COVID-19 lockdown, and followed by semi-structured individual interviews. This study is the first in New Zealand to demonstrate that, with a mean PSS-10 score of 21.7 (±7.1), international health students experienced higher than optimal levels of stress, with supporting qualitative data identifying four themes for the sources of stress: (1) familial relationships, (2) essential work, (3) finances, and (4) study. However, these students coped because of the extensive support provided by their education institute and employers. These students played a critical role in the pandemic's response and made a significant public health contribution by working in the frontline of the COVID-19 outbreak. Considering the global shortage of healthcare workers and understanding the key challenges, means of coping and support provisions, as we have here, offer insights for building and maintaining a resilient and resourceful health workforce through international health and nursing students in New Zealand and elsewhere.

Barriers and drivers in mental health services in New Zealand: current status and future direction.

In New Zealand, mental health issues have created a 'silent epidemic' with diverse consequences in mental health outcomes. Poor mental health state along with inequities to access services are persistent. Key areas of mental health promotion in New Zealand that require constant attention are appropriate policymaking, reaching out to all communities, interventions at the individual level, and the complexity of the mental health system. This commentary evaluates the inadequacies faced by the public in accessing mental health services and the directions to improve in the future. It also reviews the New Zealand government's 'Like Mind, Like Mine' program, aiming to provide socially inclusive services to people to live a life free from mental health-related stigma or discrimination.

A multi-tissue biomonitoring investigation of toxic trace elements and their trophic transfer potential in a semi aquatic bird species, the Cattle Egret (Bubulcus ibis).

The constant exposure of toxic trace elements can elicit adverse health effects particularly in birds and species residing higher at the food web. The current study is designed to evaluate the tendency of toxic trace elements viz. Cd, Cr, Pb, Cu, As and Hg to bioaccumulate in liver, kidney, blood, pelvic and pectoral muscles of cattle egret (Bubulcus ibis) collected from premises of a metropolitan city, Lahore, Pakistan. Further, the Trophic Transfer Potential of these elements was also estimated using prey/food samples of cattle egret. All of the selected toxic trace elements except Hg and As were detected with varying concentrations in different tissues of cattle egret. In general, toxic trace elements followed the pattern as Cu > Pb > Cd > Cr in tissues of cattle egret. The maximum mean (Min-max) concentrations (µg/g) of Cu 0.58 (0.11-0.93) and Pb 0.46 (0.40-0.54) in blood and Cd at 0.46 (0.40-0.54) were observed in liver. Similarly, the highest mean (min-max) concentration (µg/g) of Cr 0.17 (0.09-0.25) was recorded in pectoral muscle. In general, blood and liver were found as the most contaminated tissues followed by kidney, pectoral and pelvic muscles. Differences of trace elements were found non-significant (all P > 0.05) among tissues of cattle egret reflecting their homogenous distribution in body. Principal Component Analysis (PCA) corroborated lack of strong association between any of the trace elements and tissues. All the toxic trace elements except Cr showed higher tendency of trophic transfer potential through food chain in all the tissues of Cattle Egret (TTF >1). Although the current study revealed decreasing trends of toxic trace elements, yet their still presence in the local environment and greater likelihood of trophic transfer can undoubtedly cause some severe health effects to the already declining bird populations.

Hippocampal-subfield microstructures and their relation to plasma biomarkers in Alzheimer's disease.

Hippocampal subfields exhibit differential vulnerabilities to Alzheimer's disease-associated pathology including abnormal accumulation of amyloid-ß deposition and neurofibrillary tangles. These pathological processes extensively impact on the structural and functional interconnectivities of the subfields and may explain the association between hippocampal dysfunction and cognitive deficits. In this study, we investigated the degree of alterations in the microstructure of hippocampal subfields across the clinical continuum of Alzheimer's disease. We applied a grey matter-specific multi-compartment diffusion model (Cortical-Neurite orientation dispersion and density imaging) to understand the differential effects of Alzheimer's disease pathology on the hippocampal subfield microstructure. A total of 119 participants were included in this cross-sectional study. Participants were stratified into three categories, cognitively normal (n = 47), mild cognitive impairment (n = 52), and Alzheimer's disease (n = 19). Diffusion MRI, plasma biomarkers and neuropsychological test scores were used to determine the association between the microstructural integrity and Alzheimer's disease-associated molecular indicators and cognition. For Alzheimer's disease-related plasma biomarkers, we studied amyloid-ß, total tau and neurofilament light; for Alzheimer's disease-related neuropsychological tests, we included the Trail Making Test, Rey Auditory Verbal Learning Test, Digit Span and Montreal Cognitive Assessment. Comparisons between cognitively normal subjects and those with mild cognitive impairment showed significant microstructural alterations in the hippocampal cornu ammonis (CA) 4 and dentate gyrus region, whereas CA 1-3 was the most sensitive region for the later stages in the Alzheimer's disease clinical continuum. Among imaging metrics for microstructures, the volume fraction of isotropic diffusion for interstitial free water demonstrated the largest effect size in between-group comparisons. Regarding the plasma biomarkers, neurofilament light appeared to be the most sensitive biomarker for associations with microstructural imaging findings in CA4-dentate gyrus. CA 1-3 was the subfield which had stronger correlations between cognitive performance and microstructural metrics. Particularly, poor performance on the Rey Auditory Verbal Learning Test and Montreal Cognitive Assessment was associated with decreased intracellular volume fraction. Overall, our findings support the value of tissue-specific microstructural imaging for providing pathologically relevant information manifesting in the plasma biomarkers and neuropsychological outcomes across various stages of Alzheimer's disease.

Trends and projections of land use land cover and land surface temperature using an integrated weighted evidence-cellular automata (WE-CA) model.

Land use land cover (LULC) change has become a major concern for biodiversity, ecosystem alteration, and modifying the climatic pattern especially land surface temperature (LST). The present study assessed past and predicted future LULC and LST change in the Swabi District of Pakistan. LULC maps were generated from satellite data for years 1987, 2002, and 2017 using supervised classification. Mean LST and its areal change were estimated for different LULC classes from thermal bands of satellite images. LULC and LST were projected for the year 2047 using the integrated weighted evidence-cellular automata (WE-CA) model and a regression equation developed in this study, respectively. LULC change revealed an increase of > 5% in the built-up while a decrease in the agricultural area by ~ 9%. There was an increase of ~ 63% area in the LST class ≥ 27 °C which may create urban heat island (UHI). Simulation results indicated that the built-up area will further be increased by ~ 3% until 2047. Area associated with LST class > 30 °C indicated a further increase of ~ 38% till 2047 with reference to year 2017. Findings of this study suggested proper utilization of LULC in order to mitigate the creation of UHIs associated with urbanization and built-up areas.

Exploring arterial tissue microstructural organization using non-Gaussian diffusion magnetic resonance schemes.

The purpose of this study was to characterize the alterations in microstructural organization of arterial tissue using higher-order diffusion magnetic resonance schemes. Three porcine carotid artery models namely; native, collagenase treated and decellularized, were used to estimate the contribution of collagen and smooth muscle cells (SMC) on diffusion signal attenuation using gaussian and non-gaussian schemes. The samples were imaged in a 7 T preclinical scanner. High spatial and angular resolution diffusion weighted images (DWIs) were acquired using two multi-shell (max b-value = 3000 s/mm2) acquisition protocols. The processed DWIs were fitted using monoexponential, stretched-exponential, kurtosis and bi-exponential schemes. Directionally variant and invariant microstructural parametric maps of the three artery models were obtained from the diffusion schemes. The parametric maps were used to assess the sensitivity of each diffusion scheme to collagen and SMC composition in arterial microstructural environment. The inter-model comparison showed significant differences across the considered models. The bi-exponential scheme based slow diffusion compartment (Ds) was highest in the absence of collagen, compared to native and decellularized microenvironments. In intra-model comparison, kurtosis along the radial direction was the highest. Overall, the results of this study demonstrate the efficacy of higher order dMRI schemes in mapping constituent specific alterations in arterial microstructure.

Effect of salicylic acid supplementation on blood glucose, lipid profile and electrolyte homeostasis in gentamicin sulphate induced nephrotoxicity.

This study was designed to investigate effect of salicylic acid supplementation in gentamicin- induced nephrotoxicity. For this purpose, twenty four male albino rabbits were divided into 4 groups (n=6); control group, healthy untreated rabbits; gentamicin group, received only gentamicin (80mg/kg); gentamicin + salicylic acid group, received gentamicin (80mg/kg) + salicylic acid (80mg/kg) and salicylic acid group, received only salicylic acid (80mg/kg) through intra peritoneal route for 21 consecutive days. Biochemical evaluation was carried out by assessment of body weights and by estimating plasma glucose, lipid profile and electrolyte homeostasis. Gentamicin sulphate induction resulted in increased plasma glucose, plasma TG, plasma cholesterol, plasma LDL, and plasma sodium and in decreased plasma HDL and plasma potassium with significant reduction in body weights in GS-treated group, which were restored by supplementation with salicylic acid in GS+SA treated group. Therefore, these findings confirm the protective role of salicylic acid in gentamicin- induced nephrotoxicity in rabbits.

LATE PRESENTATION OF RETINAL DETACHMENT: CLINICAL FEATURES AND SURGICAL OUTCOMES.

PURPOSE: To describe and evaluate demographic, clinical features, prognostic factors, and rate of success of surgery and visual outcomes in patients with late presentation of retinal detachment. METHODS: A retrospective, comparative, observational case series of patients with late presentation retinal detachment, defined as retinal detachment with the loss of central vision for 4 weeks or more, over a period of 12 months. RESULTS: The mean of onset of central visual loss was 12.7 weeks (SD, 21.3). Proliferative vitreoretinopathy at the first operation was identified in 69% of eyes. The overall primary success rate was 69.2%, significantly less than that was found in outcomes for nonselected retinal detachment (primary success rate, 86%; P = 0.006). The initial best-corrected visual acuity was 20/500, and the final was 20/160 (P = 0.0027). There were no identifiable statistically significant socioeconomic factors related to late presentation. CONCLUSION: A high rate of established proliferative vitreoretinopathy on presentation was identified, and although cases can be treated with good anatomical results, visual outcomes are often less favorable. Primary surgical success is lower, and more reoperations are required compared with standard retinal detachments.