A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation.

Selective autophagy of organelles is critical for cellular differentiation, homeostasis, and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathy but is poorly understood beyond a few autophagosomal receptors and remodelers. By using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence human ER-phagy factors. Two pathways were unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ER-phagy, which is opposite of general autophagy and is independent of AMPK. Second, ER-localized UFMylation is required for ER-phagy to repress the unfolded protein response via IRE1α. The UFL1 ligase is brought to the ER surface by DDRGK1 to UFMylate RPN1 and RPL26 and preferentially targets ER sheets for degradation, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the cellular logic of ER-phagy, reveal parallels between organelle autophagies, and provide an entry point to the relatively unexplored process of degrading the ER network.

Fixed Dose Combination Tablets of Aripiprazole and Divalproex Sodium: a Pilot Pharmacokinetic Study in Human Volunteers.

A combination product of aripiprazole (antipsychotic) and divalproex sodium (mood stabilizer) was recently developed to establish their tolerability and safety in fixed dose combination (FDC). A pilot pharmacokinetic (PK) open-labeled parallel study on healthy human volunteers was carried out to assess the PK of FDC of aripiprazole/divalproex sodium in comparison with its individual components with a view to rationalize therapeutic regimen and potentially improve compliance of bipolar patients in future. A total of 24 volunteers were randomized to aripiprazole 5mg, divalproex sodium 500mg, and FDC (aripiprazole/divalproex sodium 5/500 mg) enteric-coated tablets. Peak plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax) of aripiprazole increased, Cmax of valproic acid increased, and Tmax decreased. Half-life (t1/2) of both aripiprazole and valproic acid decreased. Area under the curve (AUC) of both aripiprazole and valproic acid increased while volume of distribution (Vd) and clearance (Cl) decreased when used in fixed combination. Increase in the AUC and decrease in the Vd of aripiprazole in the presence of valproic acid were found statistically significant while rest of the parameters were insignificant at level 0.05. Although not adequately powered, this pilot study gives an idea that FDC of aripiprazole and divalproex sodium has a PK profile comparable to its mono-component products. Thus, concomitant use of aripiprazole and valproate in FDC is possible which may prove to be a cost-effective and result-oriented substitute for conventional individual tablets to improve patients' compliance; however, further evaluation with positive control is required.

Hydroxychloroquine Effects on THP-1 Macrophage Cholesterol Handling: Cell Culture Studies Corresponding to the TARGET Cardiovascular Trial.

Background and Objectives: Cardiovascular (CV) risk is elevated in rheumatoid arthritis (RA). RA patient plasma causes pro-atherogenic derangements in cholesterol transport leading to macrophage foam cell formation (FCF). The TARGET randomized clinical trial compares CV benefits of 2 RA drug regimens. Hydoxychloroquine (HCQ) is a key medication used in TARGET. This study examines effects of HCQ on lipid transport to elucidate mechanisms underlying TARGET outcomes and as an indicator of likely HCQ effects on atherosclerosis in RA. Materials and Methods: THP1 human macrophages were exposed to media alone, IFNγ (atherogenic cytokine), HCQ, or HCQ + IFNγ. Cholesterol efflux protein and scavenger receptor mRNA levels were quantified by qRT-PCR and corresponding protein levels were assessed by Western blot. FCF was evaluated via Oil-Red-O and fluorescent-oxidized LDL. Intracellular cholesterol and efflux were quantified with Amplex Red assay. Results: With the exception of a decrease in the efflux protein cholesterol 27-hydroxylase in the presence IFNγ at all HCQ concentrations, no significant effect on gene or protein expression was observed upon macrophage exposure to HCQ and this was reflected in the lack of change in FCF and oxidized LDL uptake. Conclusions: HCQ did not significantly affect THP1 macrophage cholesterol transport. This is consistent with TARGET, which postulates superior effects of anti-TNF agents over sulfasalazine + HCQ.

Cancer-Related Stigmatization, Quality of Life, and Fear of Death Among Newly Diagnosed Cancer Patients.

The purpose of the study is to investigate the gender differences among newly diagnosed cancer patients from the cultural perspective of Pakistan. The data comprised two equal groups: men (50%) and women (50%). Most participants were 31-45 years old, and the duration of the cancer diagnosis was less than 6 months (74.6%). The data was collected on the following scales: the discrimination and stigma scale, the internalized stigma scale, the WHO-quality of life scale, and the fear of death scale. Data was analyzed using SPSS v.25; descriptive statistics, an independent sample t-test, and simple linear regression were applied to the data. The results revealed that men and women are both experiencing cancer-related stigmatization in Pakistan. However, women face a higher level of stigmatization, lower quality of life, and higher fear of death than men. Furthermore, the regression analysis result confirms that the cancer-related stigma faced by the diagnosed patients decreases the patient's quality of life and induces the fear of death.

The role of interferon-γ in cardiovascular disease: an update.

PURPOSE: Cardiovascular disease (CVD) is the leading cause of death, globally, and its prevalence is only expected to rise due to the increasing incidence of co-morbidities such as obesity and diabetes. Medical treatment of CVD is directed primarily at slowing or reversing the underlying atherosclerotic process by managing circulating lipids with an emphasis on control of low-density lipoprotein (LDL) cholesterol. However, over the past several decades, there has been increasing recognition that chronic inflammation and immune system activation are important contributors to atherosclerosis. This shift in focus has led to the elucidation of the complex interplay between cholesterol and cellular secretion of cytokines involved in CVD pathogenesis. Of the vast array of cytokine promoting atherosclerosis, interferon (IFN)-γ is highly implicated and, therefore, of great interest. METHODS: Literature review was performed to further understand the effect of IFN-γ on the development of atherosclerotic CVD. RESULTS: IFN-γ, the sole member of the type II IFN family, is produced by T cells and macrophages, and has been found to induce production of other cytokines and to have multiple effects on all stages of atherogenesis. IFN-γ activates a variety of signaling pathways, most commonly the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, to induce oxidative stress, promote foam cell accumulation, stimulate smooth muscle cell proliferation and migration into the arterial intima, enhance platelet-derived growth factor expression, and destabilize plaque. These are just a few of the contributions of IFN-γ to the initiation and progression of atherosclerotic CVD. CONCLUSION: Given the pivotal role of IFN-γ in the advancement of CVD, activation of its signaling pathways is being explored as a driver of atherosclerosis. Manipulation of this key cytokine may lead to novel therapeutic avenues for CVD prevention and treatment. A number of therapies are being explored with IFN-γ as the potential target.

Design, Construction and Testing of IoT Based Automated Indoor Vertical Hydroponics Farming Test-Bed in Qatar.

Growing plants in the gulf region can be challenging as it is mostly desert, and the climate is dry. A few species of plants have the capability to grow in such a climate. However, those plants are not suitable as a food source. The aim of this work is to design and construct an indoor automatic vertical hydroponic system that does not depend on the outside climate. The designed system is capable to grow common type of crops that can be used as a food source inside homes without the need of large space. The design of the system was made after studying different types of vertical hydroponic systems in terms of price, power consumption and suitability to be built as an indoor automated system. A microcontroller was working as a brain of the system, which communicates with different types of sensors to control all the system parameters and to minimize the human intervention. An open internet of things (IoT) platform was used to store and display the system parameters and graphical interface for remote access. The designed system is capable of maintaining healthy growing parameters for the plants with minimal input from the user. The functionality of the overall system was confirmed by evaluating the response from individual system components and monitoring them in the IoT platform. The system was consuming 120.59 and 230.59 kWh respectively without and with air conditioning control during peak summer, which is equivalent to the system running cost of 13.26 and 25.36 Qatari Riyal (QAR) respectively. This system was circulating around 104 k gallons of nutrient solution monthly however, only 8-10 L water was consumed by the system. This system offers real-time notifications to alert the hydroponic system user when the conditions are not favorable. So, the user can monitor several parameters without using laboratory instruments, which will allow to control the entire system remotely. Moreover, the system also provides a wide range of information, which could be essential for plant researchers and provides a greater understanding of how the key parameters of hydroponic system correlate with plant growth. The proposed platform can be used both for quantitatively optimizing the setup of the indoor farming and for automating some of the most labor-intensive maintenance activities. Moreover, such a monitoring system can also potentially be used for high-level decision making, once enough data will be collected. This work presents significant opportunities for the people who live in the gulf region to produce food as per their requirements.

Development of fixed dose combination tablets of aripiprazole plus divalproex sodium and their simultaneous determination using HPLC-UV.

A vast majority of psychiatric patients are effectively treated with combination of drugs to improve efficacy and adherence, but due to limited research and development in fixed dose combination (FDC) in psychiatry, these products are not commonly available. The aim of this study is to prepare cost effective FDC tablets containing aripiprazole and divalproex sodium. Two batches of fixed dose combination tablets, FDC1 and FDC2, were successfully prepared using wet granulation technique. Furthermore, aripiprazole tablets A1 and A2 and divalproex tablets D1 were also formulated as reference to compare the in vitro availability profile. An accurate and simple isocratic HPLC method was established and validated for the simultaneous quantification of aripiprazole and valproic acid in the FDC tablets. A reversed-phase C18 (250 × 4.6 mm) column in isocratic mode was used. The mobile phase consisted of acetonitrile and 0.32% KH2PO4 (60:40, v/v), flow rate was set at 1.0 mL/min and the detection was performed at 210 nm. Average percent recoveries of aripiprazole and valproic acid were 96.0 and 95.5%, respectively, meeting the official requirements. The newly developed FDC product may be used for the better therapeutic outcomes of combined use of aripiprazole and valproic acid, which may improve patient adherence.

Pilot feasibility and efficacy of a strategy to sustain A1C improvement among diverse adults with type 2 diabetes completing a diabetes care management program.

INTRODUCTION: Evidence-based strategies are needed to sustain improvements in outcomes following diabetes care management (DCM) programs. We examined the impact of Boot Camp-Plus (BC-Plus), an innovative sustaining strategy, on A1C among adults with type 2 diabetes completing a 3-month Diabetes Boot Camp (DBC). This health system sponsored program consisted of diabetes self-management education and support, medical nutrition therapy and antihyperglycemic medications management. RESEARCH DESIGN AND METHODS: From March 2019 to July 2021, adult DBC completers with Medicare or a health system Medicaid or employee commercial plan were enrolled in BC-Plus for 9 months. DBC completers not meeting insurance eligibility or who declined to participate in BC-Plus acted as controls. During the first 3 months, BC-Plus participants received ongoing daily remote blood glucose (BG) monitoring; and during all 9 months, they received monthly check-in calls with BG review by a medical assistant who addressed needs for supplies/drugs, whether participants were checking BGs, and self-care encouragement. Escalation to a nurse practitioner occurred if the monthly BG trend was >200 mg/dL and/or several BG <80 mg/dL and/or new A1C >9.0% were identified. A1C was followed for an additional 9 months post-BC-Plus. A longitudinal mixed effects analysis was used to assess change in A1C from month 0 to month 21 of follow-up between BC-Plus participants versus controls. RESULTS: A total of 838 DCM completers were identified, among whom 281 joined the BC-Plus intervention and 557 acted as controls. Mean age was 55.9 years; 58.2% were women; 66.2% were black; and 30.6% insured by Medicare. BC-Plus participants experienced significantly lower A1C compared with controls and remained below 8.0% to month 18. CONCLUSIONS: Among completers of a 3-month DCM program, a low intensity 9-month sustaining strategy maintained A1C under 8.0% (HEDIS (Healthcare Effectiveness Data and Information Set) threshold for diabetes control) compared with controls for 15 months after completion of the initial DCM intervention.

Cholesterol deficiency as a mechanism for autism: A valproic acid model.

Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.

Spontaneous coronary artery dissection (SCAD) and takotsubo cardiomyopathy (TCM) - A potential association.

Background: Spontaneous coronary artery dissection and takotsubo cardiomyopathy are increasingly recognized in the last two decades. Case reports have shown both entities can present concomitantly - however, little is known about their association. Methods: In this retrospective study we aimed to explore a potential association between SCAD and TCM using the Nationwide Inpatient Sample. The odds of having TCM among patients with SCAD compared with those who did not have SCAD were calculated as an odds ratio. Conversely, the odds of having SCAD among patients with TCM compared with those who did not have TCM were also calculated. The primary outcome was the odds of TCM among patients with a primary diagnosis of SCAD and vice versa. The secondary endpoint was the odds of in-hospital mortality among patients with SCAD, and/or TCM. Results: Hospitalized patients who had SCAD were 7.12 (95 % CI: 6.28-8.08) times more likely to also have TCM than those who did not have SCAD (p < 0.0001).), while patients with TCM were 6.91 (95 % CI: 6.07-7.85) times more likely to have SCAD compared to those who didn't have TCM adjusted for age, gender, race, hypertension, hyperlipidemia, and diabetes mellitus (p < 0.0001). Conclusion: This data indicate that patients with either SCAD or TCM are seven times more likely to be diagnosed concomitantly with both, compared to the patients without either diagnosis [after adjusting for age, gender, race, hypertension, hyperlipidemia, and diabetes mellitus]. Our data are consistent with the growing body of evidence supporting an association between SCAD and TCM and raise the question of a common pathophysiologic mechanism.

Exosomes in Cardiovascular Disease: From Mechanism to Therapeutic Target.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent decades, clinical research has made significant advances, resulting in improved survival and recovery rates for patients with CVD. Despite this progress, there is substantial residual CVD risk and an unmet need for better treatment. The complex and multifaceted pathophysiological mechanisms underlying the development of CVD pose a challenge for researchers seeking effective therapeutic interventions. Consequently, exosomes have emerged as a new focus for CVD research because their role as intercellular communicators gives them the potential to act as noninvasive diagnostic biomarkers and therapeutic nanocarriers. In the heart and vasculature, cell types such as cardiomyocytes, endothelial cells, vascular smooth muscle, cardiac fibroblasts, inflammatory cells, and resident stem cells are involved in cardiac homeostasis via the release of exosomes. Exosomes encapsulate cell-type specific miRNAs, and this miRNA content fluctuates in response to the pathophysiological setting of the heart, indicating that the pathways affected by these differentially expressed miRNAs may be targets for new treatments. This review discusses a number of miRNAs and the evidence that supports their clinical relevance in CVD. The latest technologies in applying exosomal vesicles as cargo delivery vehicles for gene therapy, tissue regeneration, and cell repair are described.

Implications of Ramadan Fasting in the Setting of Gastrointestinal Disorders.

Intermittent fasting is an increasingly popular dieting technique with many well-studied benefits, such as permitting weight loss in obese patients, lowering low-density lipoprotein cholesterol (LDL-C) levels and triglyceride levels, and optimizing circadian rhythms. A special type of intermittent fasting occurs during Ramadan, when Muslims worldwide fast daily from dawn to sunset for a month. Ramadan fasting has demonstrated several health benefits, including improving the gut microbiome, modifying gut hormone levels, and lowering proinflammatory markers such as cytokines and blood lipids. Although fasting has many health benefits, fasting during Ramadan may aggravate chronic medical conditions. We aim to review the literature devoted to Ramadan fasting and its effects on Muslim patients with gastrointestinal (GI) disorders, such as Inflammatory bowel disease (IBD), peptic ulcer disease (PUD), upper GI bleeding (UGIB), gastroesophageal reflux disease (GERD), and liver conditions. We will discuss recommendations for diet and medication compliance during Ramadan in the recommended pre-Ramadan counseling sessions. In this study, we used PubMed to research journals using the key terms "Ramadan," "intermittent fasting," and "gastrointestinal diseases." The current literature studying the impact of Ramadan on gastrointestinal disorders shows that patients with IBD have a minimal risk of disease exacerbation, although older men with ulcerative colitis (UC) were more prone to exacerbation during fasting. Patients with duodenal ulcers were at a higher risk of hemorrhage after Ramadan fasting. Although with mixed results, studies show patients with liver disease demonstrated improvements in liver enzymes, cholesterol, and bilirubin after Ramadan. Physicians should offer pre-Ramadan counseling to educate patients on the risks of fasting and encourage shared decision-making. To facilitate more definitive discussions between the physician and a Muslim patient, clinicians should seek a deeper understanding of how Ramadan fasting affects certain health conditions and offer accommodations, such as diet and medication adjustments.

Assessment of hepatitis-related knowledge, attitudes, and practices on quality of life with the moderating role of internalized stigma among hepatitis B-positive patients in Pakistan.

Aim: This study aimed to assess the Pakistani hepatitis B patients' knowledge, attitudes, and practices towards hepatitis management and the impact of self-management on the quality of life of hepatitis B patients as well as the moderating role of stigmatization. Methods: A cross-sectional study design was used, and the data was collected from a total of 432 hepatitis B positive patients through a self-designed questionnaire. The studied subjects consisted of men (n = 205, 47%), women (n = 165, 38%), and transgender (n = 62, 14%). The obtained data were statistically analyzed using SPSS software version 26.0 for Windows. Results: The mean age of the study participants was 48. Knowledge has a significant positive relationship with hepatitis self-management and quality of life, whereas knowledge has a negative relationship with stigmatization. Furthermore, multivariate analysis revealed that men were more knowledgeable about the disease than women and transgender people (6.14 ± 2.08 vs. 3.23 ± 1.61 vs. 1.03 ± 0.73, F = 8.2**, p = .000). On the scale of attitude and practice, significant gender differences were found. Women had more experience with hepatitis self-management than men or transgender (4.21 ± 13.0 vs. 2.17 ± 6.02 vs. 0.37 ± 0.31, F = 6.21**, p = .000). The regression analysis showed that self-management has a positive association with quality of life (B = 0.36, p = .001). The moderation analysis revealed that stigmatization negatively moderates the relationship between self-management and quality of life (B = -0.53, p = .001). Conclusion: Generally, patients had good knowledge about the disease and its self-management. However, a societal and community-level awareness campaign should be organized on the quality of life and stigmatization of people with chronic illness regarding their human rights, dignity, and physical, mental, and social well-being.

Therapeutic Potential of P110 Peptide: New Insights into Treatment of Alzheimer's Disease.

Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer's disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-ß accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-ß generation and improving neuronal health by maintaining mitochondrial function in neurons.

Methotrexate effects on adenosine receptor expression in peripheral monocytes of persons with type 2 diabetes and cardiovascular disease.

The Cardiovascular Inflammation Reduction Trial (CIRT) was designed to assess whether low-dose methotrexate (LD-MTX) would reduce future cardiac events in patients with metabolic syndrome or type 2 diabetes (T2DM) who are post-myocardial infarction (MI) or have multivessel disease. Our previous work indicates that MTX confers atheroprotection via adenosine A2A receptor (A2AR) activation. In order for A2AR ligation to reduce cardiovascular events, A2AR levels would need to be preserved during MTX treatment. This study was conducted to determine whether LD-MTX alters peripheral blood mononuclear cell (PBMC) adenosine receptor expression in persons at risk for cardiovascular events. Post-MI T2DM CIRT patients were randomized to LD-MTX or placebo (n=10/group). PBMC isolated from blood drawn at enrollment and after 6 weeks were evaluated for expression of adenosine receptors and reverse cholesterol transporters by real-time PCR. Fold change between time points was calculated using factorial analyses of variance. Compared with placebo, the LD-MTX group exhibited a trend toward an increase in A2AR (p=0.06), while A3R expression was significantly decreased (p=0.01) after 6 weeks. Cholesterol efflux gene expression did not change significantly. Persistence of A2AR combined with A3R downregulation indicates that failure of MTX to be atheroprotective in CIRT was not due to loss of adenosine receptors on PBMC (ClinicalTrials.gov identifier: NCT01594333).

Organic amendment plus inoculum drivers: Who drives more P nutrition for wheat plant fitness in small duration soil experiment.

Functioning of ecosystems depends on the nutrient dynamics across trophic levels, largely mediated by microbial interactions in the soil food web. The present study investigated the use of phosphate solubilizing bacteria (PSB) and poultry manure (PM) for maintaining labile P in the soil for an extensive fertility enhancement and as a substitution of chemical fertilizers. Based on the different P solubilizing capabilities of Bacillus and Pseudomonas, a quadruple consortium of Bacillus subtilis, Bacillus cereus, Bacillus thuringiensis and Pseudomonas fluorescens, and their grazer nematodes (soil free living) supplemented with PM were studied. This study was carried out on the trophic levels of soil communities to assess the growth and availability of P to the wheat plants. Experiment was performed for 90 days. Comparing the unamended and amended predator results showed that nematode addition beyond bacterial treatment substantially increased the net available P by ≈2 times, and alkaline phosphatase (ALP) activity by 3.3 times. These results demonstrated the nematodes association with increasing nutrient availability or P mineralization. The interactive effect of PM as substrate and biological drivers was more noticeable on plant dry biomass (1.6 times) and plant P concentration (3.5times) compared to the similar unamended treatment. It is concluded that the biological drivers significantly enhanced the soil ALP and available P while the substrate and biological drivers enhanced dry biomass and plant P concentration. Bacterivore nematodes enhanced the effect of PSB for P mineralization via microbial loop and could be used for the enhancement of wheat production.

The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell. METHODS: Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD. RESULTS: This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD. CONCLUSIONS: There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.

Severe malaria in children: factors predictive of outcome and response to Quinine.

OBJECTIVE: To identify clinical features of severe malaria and their association with adverse outcomes according to recently proposed WHO guidelines and observe treatment failure to Quinine. METHODS: This descriptive study was performed at Civil Hospital Karachi from September 2007 to January 2008. Various clinical features and laboratory parameters were analyzed according to t WHO guidelines and treatment failure to anti-malarial drugs was recorded. Mean, frequencies, percentages and chi-square test were used for analysis. Statistical significance was defined as p-value < 0.05. RESULTS: Total of 81 patients were enrolled in the study. Mean age of children was 5.5 +/- 3.4 years. Type of malaria infections that were seen included falciparum 46 (57%), mixed infection 26 (32%) and vivax 9 (11%). Frequent clinical features included splenomegaly (74%), multiple organ dysfunction (MOD) (70%), cerebral malaria (31%) and malnutrition (27%). Thrombocytopenia (86%) and severe anaemia (42%) were the common laboratory findings. Shock (p < 0.001), renal failure (p < 0.001), hepatic involvement (p < 0.002) and cerebral malaria (p < 0.002) emerged as strong predictors of complications. Fourteen out of 81 cases showed early treatment failure to Quinine. CONCLUSION: Shock, renal failure, hepatic involvement and cerebral malaria are strongly associated with complications in severe malaria. MOD and malnutrition were identified as significant new clinical features present in severe malaria in this study.

Non-traumatic coma in paediatric patients: etiology and predictors of outcome.

OBJECTIVE: To determine the common etiological features of non-traumatic coma in children and evaluate possible predictors of morbidity and mortality in these patients. METHOD: A cross sectional study was carried out at the Paediatric Department of Civil Hospital Karachi from February 2008 to February 2009. In total 100 children, up to 14 years of age having history of non-traumatic coma were included. At the time of enrolment demographic data, clinical features, laboratory parameters and radiological workup were recorded. Data was entered and analyzed with SPSS version 16. Descriptive statistics were generated for all variables. Relationships between categorical variables were evaluated by examining cross-tabulations, chi2 test and Fisher's exact tests. P-values < 0.05 were considered statistically significant. RESULTS: Mean age of the patients in months were 45 months. Male female ratio was 1.45:1. Among 65 survivors 38 (58%) showed no disability and 27 (41%) showed disability. Infections emerged as major cause of mortality (n=23, 79%). Clinical features that showed association with mortality included hypothermia (P = 0.032), hypotension (P = 0.002), altered breathing pattern (P = 0.0001), non reactive pupils (P = 0.001), low Glasgow coma scale (GCS) (P = 0.038), hypotonia (P = 0.002), hyporeflexia (P = 0.0001) and muscle power score of two (P = 0.043). CONCLUSION: Infections were the leading cause of non-traumatic coma as well as the leading cause of mortality in our study. Hypothermia, hypotension, altered breathing pattern, non reactive pupils, low GCS, hypotonia, hyporeflexia and low muscle power score were significantly associated with mortality in children presenting with non-traumatic coma.

Understanding Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Toward Better Treatment and Prevention.

Systemic lupus erythematosus (SLE) carries a significant risk of cardiovascular disease (CVD). The prevalence of premature CVD is especially noteworthy because it occurs in premenopausal women with SLE who would otherwise have very low rates of CVD. While traditional risk factors likely play a role in development of CVD in the setting of SLE, they do not fully explain the excess risk. The pathogenesis of CVD in SLE is not fully understood, but the inflammatory nature of SLE is believed to be a key factor in accelerating atherosclerosis. Systemic inflammation may lead to an abnormal lipid profile with elevated triglycerides, total cholesterol, and low-density lipoprotein cholesterol and dysfunctional high-density lipoprotein cholesterol. Additionally, the inflammatory milieu of SLE plasma promotes endothelial dysfunction and vascular injury, early steps in the progression of atherosclerotic CVD. Despite the overall headway that has been achieved in treating lupus, innovative therapeutics specifically targeting the progression of atherosclerosis within the lupus population are currently lacking. However, there have been advancements in the development of promising modalities for diagnosis of subclinical atherosclerosis and detection of high CVD risk patients. Due to the significant impact of CVD on morbidity and mortality, research addressing prevention and treatment of CVD in SLE needs to be prioritized. This review explores the intricate interplay of SLE-specific properties that contribute to atherosclerosis and CVD within this population, as well as screening methods and possible therapies.