COVID-19 vaccine intercountry distribution inequality and its underlying factors: a combined concentration index analysis and multiple linear regression analysis.

Introduction: Inequitable access to COVID-19 vaccines among countries is a pressing global health issue. Factors such as economic power, political power, political stability, and health system strength contribute to disparities in vaccine distribution. This study aims to assess the inequality in vaccine distribution among countries based on these factors and identify their relationship with COVID-19 vaccine distribution. Methods: A Concentration Index (CI) analysis was conducted to evaluate inequalities in the distribution of COVID-19 vaccines among countries based on four separate variables: GDP per capita, political stability (PS), World Power Index (WPI), and Universal Health Coverage (UHC). Additionally, Multiple Linear Regression (MLR) analysis was employed to explore the relationship between vaccine distribution and these independent variables. Two vaccine distribution variables were utilized for result reliability. Results: The analysis revealed significant inequalities in COVID-19 vaccine distribution according to the countries' GDP/capita, PS, WPI, and UHC. However, the multiple linear regression analysis showed that there is no significant relationship between COVID-19 vaccine distribution and the countries' GDP/capita and that UHC is the most influential factor impacting COVID-19 vaccine distribution and accessibility. Discussion: The findings underscore the complex interplay between economic, political, and health system factors in shaping vaccine distribution patterns. To improve the accessibility to vaccines in future pandemics, Global Health Governance (GHG) and countries should consider working on three areas; enhance political stabilities in countries, separate the political power from decision-making at the global level and most importantly support countries to achieve UHC.

Metabolomic profiling reveals altered phenylalanine metabolism in Parkinson's disease in an Egyptian cohort.

Introduction: Parkinson's disease (PD) is the most common motor neurodegenerative disease worldwide. Given the complexity of PD etiology and the different metabolic derangements correlated to the disease, metabolomics profiling of patients is a helpful tool to identify patho-mechanistic pathways for the disease development. Dopamine metabolism has been the target of several previous studies, of which some have reported lower phenylalanine and tyrosine levels in PD patients compared to controls. Methods: In this study, we have collected plasma from 27 PD patients, 18 reference controls, and 8 high-risk controls to perform a metabolomic study using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Results: Our findings revealed higher intensities of trans-cinnamate, a phenylalanine metabolite, in patients compared to reference controls. Thus, we hypothesize that phenylalanine metabolism has been shifted to produce trans-cinnamate via L-phenylalanine ammonia lyase (PAL), instead of producing tyrosine, a dopamine precursor, via phenylalanine hydroxylase (PAH). Discussion: Given that these metabolites are precursors to several other metabolic pathways, the intensities of many metabolites such as dopamine, norepinephrine, and 3-hydroxyanthranilic acid, which connects phenylalanine metabolism to that of tryptophan, have been altered. Consequently, and in respect to Metabolic Control Analysis (MCA) theory, the levels of tryptophan metabolites have also been altered. Some of these metabolites are tryptamine, melatonin, and nicotinamide. Thus, we assume that these alterations could contribute to the dopaminergic, adrenergic, and serotonergic neurodegeneration that happen in the disease.

Changing roles in global health governance following COVID-19.

Background: The Global Health Governance (GHG) response to the COVID-19 pandemic has been criticized, particularly regarding vaccine management, and changes in the roles of GHG actors have been recommended. Aim: To investigate the perception of experts regarding changes in the roles of different GHG actors following the COVID-19 pandemic. Methods: This study used a 3-round Delphi survey to collect data from 30 global health experts between May and December 2022. The GHG roles investigated were stewardship, production of guidelines and policies, promotion of solidarity and collaboration, and management of global health challenges. Social network analysis was performed and collected data was converted into a 1-mode network. Degree centrality and Eigenvector centrality were calculated using the UCINET 6.757 modelling programme. Results: There were variations between the current and future roles in degree centrality and eigenvector centrality for the 19 GHG actors in each of the 4 functions investigated. For stewardship, WHO, governments and the World Bank had the highest degree centrality and eigenvector centrality during both the current and future periods. In terms of production of guidelines and policies, WHO maintained the highest current and future eigenvector centralities, while research agencies, UNICEF and Gavi upheld their current eigenvector centrality measure. For the promotion of solidarity and collaboration, WHO had the highest centrality measures, followed by UNICEF, governments and Gavi. Regarding the function "management of global health challenges", WHO lost its position to UNICEF as the most central, while UNDP, FHI 360 and research agencies were predicted to have a more central role in the future. Conclusion: The findings position WHO as the current and future top actor in stewardship, production of guidelines and policies, and promoting solidarity and collaboration, and UNICEF as the upcoming most central actor in managing global health challenges. Governments were major actors in all GHG functions except for managing global health challenges. Funding actors were central in all GHG functions, indicating finance as an important factor in obtaining a central role in GHG. Research organizations received a high centrality rating, indicating their importance in GHG.

MicroRNAs as a Tool for Differential Diagnosis of Neuromuscular Disorders.

Neuromuscular disorders (NMD) are a class of progressive disorders that are characterized by wasting of the muscles. Some of the disorders like Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophies (CMDs), limb-girdle muscular dystrophies (LGMD), and mild spinal muscular atrophy (SMA) type III share several presenting clinical features, and hence, diagnosis is usually a challenging task. In this study, the diagnostic potential of some species of microRNAs (miRNAs) that are known to play roles in normal and pathological contexts of myocytes (myomiRs) were evaluated to assess their potential in differential diagnosis of NMDs. In this study, seventy-four patients with different neuromuscular disorders along with thirty age-matched healthy control subjects were enrolled. Peripheral blood samples were collected from enrolled subjects followed by miRNA extraction and reverse transcription followed by quantification of the circulating levels of the studied miRNAs (miR-499, miR-206, miR-208a, miR-223, miR-191, miR-103a-3p, miR-103a-5p), by real-time PCR and statistical analysis. The data indicated that miR-499 level showed high circulating levels in DMD patients as well as in patients with other related disorders such as BMD. However, the levels of miR-499 were much higher in DMD patients and it can be used to diagnose DMD. In addition, miR-206 can selectively differentiate between DMD and all other disorders. The results also revealed that miR-208a and miR-223 were significantly dysregulated in SMA patients, and miR-103a-3p could distinguish DMD from BMD. The expression levels of some miRNA species can be utilized in the process of differential diagnosis of NMDs and can serve as a diagnostic biomarker, and such findings will pave the way towards generating targeted therapies.

Global health governance performance during Covid-19, what needs to be changed? a delphi survey study.

BACKGROUND: Covid-19 is not the first pandemic to challenge GHG. Preceding outbreaks and epidemics were sources of continuous debate on GHG leadership and structure resulting in its current structure. However, Covid-19 proved the presence of many deficits in the current GHG. The response to the Covid-19 pandemic is a cumulative result of all policies and actions of different governments and agencies active in global health. Assessing how Covid-19 is being handled globally provides lessons for ensuring better performance in facing upcoming outbreaks. This study has three main objectives: first, to evaluate the performance of GHG during Covid-19 in general and in relation to Covid-19 vaccine equity in particular. Second, to identify the reasons behind this performance; and third, to propose prospective changes in GHG for better performance. METHODS: A cross-sectional research design using the Delphi method was applied. A panel of experts participated in the three-round Delphi surveys. Their scores were used to perform consensus, performance and correlation analysis. RESULTS: GHG performance limited the achievement of Covid-19 vaccines' global equity. GHG performance is a product of the existing GHG system, its actors and legal framework. It is a collective result of individual GHG actors' performance. The most influential actors in decision-making regarding Covid-19 vaccine are the vaccine manufacturers and governments. While the most invoked power to influence decision are economic and political powers. Covid-19 decisions underlying value, although had human right to health at the base, overlooked the concept of health as a global public good and was skewed towards market-oriented values. GHG mal-performance along with its underlying factors calls for four main changes in GHG structure: assigning a clear steward for GHG, enhanced accountability, centralized authority, more equitable representation of actors, and better legal framework. CONCLUSION: GHG structure, actors' representation, accountability system, and underlying priorities and value require future modification for GHG to achieve better future performance and higher health equity levels.

COVID-19 vaccine hesitancy among parents in Low- and Middle-Income Countries: A meta-analysis.

Background: Vaccination is the most effective method to prevent the spread of infectious diseases. Nevertheless, vaccine hesitancy has been an issue. Parental hesitancy toward vaccines is a major part of the problem. COVID-19 vaccine acceptance is no different, it poses another challenge in facing the pandemic. In Low- and Middle-Income Countries (L&MICs) several studies measured parents' acceptance to vaccinate their children against COVID-19 and resulted in different acceptance proportions. Aims: The paper aims at obtaining a precise estimate of the overall proportion of L&MICs' parents accepting to vaccinate their children against COVID-19 and identifying the main determinant of their decisions. Methods: This meta-analysis follows the PRISMA 2020 statement on updated guidelines and the checklist for reporting systematic reviews. Studies published between December till February 2022 were assessed for inclusion. The final effect size (i.e., the proportion of parents in L&MICs accepting to vaccinate their children against COVID-19) was measured using the Arcsine proportions method. Analysis was done using R program. Results: The proportion of parents in L&MICs accepting to vaccinate their children against COVID-19 is 49%. The major reason for their acceptance is their belief that COVID-19 vaccine is fundamental to the fight against the pandemic while the most common factor for parents' hesitancy to vaccinate their children against COVID-19 is their concerns about vaccine efficacy, safety, and possible side effects. Conclusion: The proportion of parents in L&MICs accepting to vaccinate their children against COVID-19 is lower than the global level. To increase parental acceptance, responsible authorities should concentrate on increasing their population's trust in the government and in vaccine manufacturers. As well as concentrating on increasing acceptance of the vaccine idea in general.

Prognostic MicroRNA Panel for HCV-Associated HCC: Integrating Computational Biology and Clinical Validation.

Early detection of hepatocellular carcinoma (HCC) will reduce morbidity and mortality rates of this widely spread disease. Dysregulation in microRNA (miRNA) expression is associated with HCC progression. The objective is to identify a panel of differentially expressed miRNAs (DE-miRNAs) to enhance HCC early prediction in hepatitis C virus (HCV) infected patients. Candidate miRNAs were selected using a bioinformatic analysis of microarray and RNA-sequencing datasets, resulting in nine DE-miRNAs (miR-142, miR-150, miR-183, miR-199a, miR-215, miR-217, miR-224, miR-424, and miR-3607). Their expressions were validated in the serum of 44 healthy individuals, 62 non-cirrhotic HCV patients, 67 cirrhotic-HCV, and 72 HCV-associated-HCC patients using real-time PCR (qPCR). There was a significant increase in serum concentrations of the nine-candidate miRNAs in HCC and HCV patients relative to healthy individuals. MiR-424, miR-199a, miR-142, and miR-224 expressions were significantly altered in HCC compared to non-cirrhotic patients. A panel of five miRNAs improved sensitivity and specificity of HCC detection to 100% and 95.12% relative to healthy controls. Distinguishing HCC from HCV-treated patients was achieved by 70.8% sensitivity and 61.9% specificity using the combined panel, compared to alpha-fetoprotein (51.4% sensitivity and 60.67% specificity). These preliminary data show that the novel miRNAs panel (miR-150, miR-199a, miR-224, miR-424, and miR-3607) could serve as a potential non-invasive biomarker for HCC early prediction in chronic HCV patients. Further prospective studies on a larger cohort of patients should be conducted to assess the potential prognostic ability of the miRNAs panel.

Selective GSK3ß Inhibition Mediates an Nrf2-Independent Anti-inflammatory Microglial Response.

Glycogen synthase kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with nuclear factor kappa B (NF-κB). GSK3 is also a suppressor of nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. Agreeing with the oxidative paradigm of aging, Nrf2 is often deregulated in parainflammatory and neurodegenerative diseases. In this study, we aimed to explore a multimodal disease-modifying utility of GSK3 inhibition, beyond neuronal proteopathologies. Furthermore, we aimed to underscore the difference in therapeutic value between the two GSK3 paralogs by isoform-selective chemical inhibition. The anti-inflammatory effects of paralog-selective GSK3 inhibitors were evaluated as a function of the reductive capacity of each to mitigate LPS-induced activation of SIM-A9 microglia. The Griess method was employed to detect the nitrate-lowering capacity of selective GSK3 inhibition. Real-time PCR was used to assess post-treatment expression levels of pro-inflammatory markers and antioxidant genes; pro-inflammatory cytokines were assayed by ELISA. Nuclear lysates of treated cells were examined for Nrf2 and NF-κB accumulation by immunoblotting. Finally, to infer whether the counter-inflammatory activity of GSK3 inhibition was Nrf2-dependent, DsiRNA-mediated knockdown of Nrf2 was attempted. Results from our experiments reveal a superior anti-inflammatory and anti-oxidative efficacy for GSK3ß-selective inhibition, compared to GSK3α-selective and non-selective pan-inhibition; hence, use of selective GSK3ß inhibitors is likely to be more propitious than non-selective dual inhibitors administered at comparable doses. Moreover, our results suggest that the anti-inflammatory effects of GSK3 inhibition are not Nrf2 dependent.

Global Health Governance and Health Equity in the Context of COVID-19: A Scoping Review.

BACKGROUND: Health equity is an important aspect of responsible governance. COVID-19 exposed existing shortfalls of Global Health Governance (GHG). A considerable amount of related literature is produced. This scoping review aims at mapping the present knowledge and at identifying research gaps. METHODS: This scoping review is based on the Joanna Briggs Institute's guideline for standardized methods and PRISMA-ScR guidelines for reporting. Documents published from December 2019 to October 2021 were searched using PubMed, Scopus, Google Scholar, World cat, and WHO-Global Index Medicus. Two reviewers screened and reviewed eligible studies in three stages: duplicates identification and elimination, title and abstract screening, and full-text assessment. Data was charted and results were classified into conceptual categories. Analysis was done in three stages: open descriptive coding, focused thematic analysis, and frequency, commonality and significance analysis. RESULTS: forty-nine studies met the inclusion criteria. Areas of research were grouped into seven themes: "human rights and inequities", "solidarity, collaboration and partnership", "GHG structure change", "political and economic power and finance", "approaches to address inequity", "law and regulations", and "private investment and public-private partnerships (PPPs) in GHG". The highest number of papers were in the first theme, "human rights and inequities". However, the themes are interrelated. Authors who contributed to research were mostly affiliated to developed countries indicating a gap in knowledge and expertise in developing countries. CONCLUSION: Through this scoping review we found that the seven themes are interconnected. Disciplinary collaboration in research relating GHG to health inequities is solicited. Collaboration in research, information sharing, and research capacity development are in needed in developing countries.

Effects of Metformin Combined With Antifolates on HepG2 Cell Metabolism and Cellular Proliferation.

Hepatocellular carcinoma (HCC), one of the most prevalent types of cancers worldwide, continues to maintain high levels of resistance to standard therapy. As clinical data revealed poor response rates, the need for developing new methods has increased to improve the overall wellbeing of patients with HCC. Furthermore, a growing body of evidence shows that cancer metabolic changes are a key feature of many types of human malignancies. Metabolic reprogramming refers to cancer cells' ability to change their metabolism in order to meet the increased energy demand caused by continuous growth, rapid proliferation, and other neoplastic cell characteristics. For these reasons, metabolic pathways may become new therapeutic and chemopreventive targets. The aim of this study was to investigate the metabolic alterations associated with metformin (MET), an anti-diabetic agent when combined with two antifolate drugs: trimethoprim (TMP) or methotrexate (MTX), and how metabolic changes within the cancer cell may be used to increase cellular death. In this study, single drugs and combinations were investigated using in vitro assays including cytotoxicity assay (MTT), RT-qPCR, annexin V/PI apoptosis assay, scratch wound assay and Seahorse XF analysis, on a human HCC cell line, HepG2. The cytotoxicity assay showed that the IC50 of MET as single therapy was 44.08 mM that was reduced to 22.73 mM and 29.29 mM when combined with TMP and MTX, respectively. The co-treatment of both drugs increased p53 and Bax apoptotic markers, while decreased the anti-apoptotic marker; Bcl-2. Both combinations increased the percentage of apoptotic cells and halted cancer cell migration when compared to MET alone. Furthermore, both combinations decreased the MET-induced increase in glycolysis, while also inducing mitochondrial damage, altering cancer cell bioenergetics. These findings provide an exciting insight into the anti-proliferative and apoptotic effects of MET and anti-folates on HepG2 cells, and how in combination, may potentially combat the aggressiveness of HCC.

Bioinformatics Analysis of Allele Frequencies and Expression Patterns of ACE2, TMPRSS2 and FURIN in Different Populations and Susceptibility to SARS-CoV-2.

The virus responsible for the COVID-19 global health crisis, SARS-CoV-2, has been shown to utilize the ACE2 protein as an entry point to its target cells. The virus has been shown to rely on the actions of TMPRSS2 (a serine protease), as well as FURIN (a peptidase), for the critical priming of its spike protein. It has been postulated that variations in the sequence and expression of SARS-CoV-2's receptor (ACE2) and the two priming proteases (TMPRSS2 and FURIN) may be critical in contributing to SARS-CoV-2 infectivity. This study aims to examine the different expression levels of FURIN in various tissues and age ranges in light of ACE2 and TMPRSS2 expression levels using the LungMAP database. Furthermore, we retrieved expression quantitative trait loci (eQTLs) of the three genes and their annotation. We analyzed the frequency of the retrieved variants in data from various populations and compared it to the Egyptian population. We highlight FURIN's potential interplay with the immune response to SARS-CoV-2 and showcase a myriad of variants of the three genes that are differentially expressed across populations. Our findings provide insights into potential genetic factors that impact SARS-CoV-2 infectivity in different populations and shed light on the varying expression patterns of FURIN.

Mercury and Alzheimer's disease: a look at the links and evidence.

This review paper investigates a specific environmental-disease interaction between mercury exposure and Alzheimer's disease hallmarks. Alzheimer's disease is a neurodegenerative disorder affecting predominantly the memory of the affected individual. It prevails mostly in the elderly, rendering many factors as possible causative agents, which potentially contribute to the disease pathogenicity cumulatively. Alzheimer's disease affects nearly 50 million people worldwide and is considered one the most devastating diseases not only for the patient, but also for their families and caregivers. Mercury is a common environmental toxin, found in the atmosphere mostly due to human activity, such as coal burning for heating and cooking. Natural release of mercury into the atmosphere occurs by volcanic eruptions, in the form of vapor, or weathering rocks. The most toxic form of mercury to humans is methylmercury, to which humans are exposed to by ingestion of fish. Methylmercury was found to exert its toxic effects on different parts of the human body, with predominance on the brain. There is no safe concentration for mercury in the atmosphere, even trace amounts can elicit harm to humans in the long term. Mercury's effect on Alzheimer's disease hallmarks formation, extracellular senile plaques and intracellular neurofibrillary tangles, has been widely studied. This review demonstrates the involvement of mercury, in its different forms, in the pathway of amyloid beta deposition and tau tangles formation. It aims to understand the link between mercury exposure and Alzheimer's disease so that, in the future, prevention strategies can be applied to halt the progression of this disease.

Biocompatible PCL-nanofibers scaffold with immobilized fibronectin and laminin for neuronal tissue regeneration.

Recent advances in regenerative medicine have given hope in overcoming and rehabilitating complex medical conditions. In this regard, the biopolymer poly-ε-caprolactone (PCL) may be a promising candidate for tissue regeneration, despite lacking the essential bioactivity. The present study used PCL nanofibers (NFs) scaffold decorated with the extracellular matrix proteins fibronectin and laminin combined for neuronal regeneration. The potential for the dual proteins to support neuronal cells and promote axonal growth was investigated. Two NFs scaffolds were produced with PLC concentrations of 12% or 15%. Under scanning electron microscopy, both scaffolds evidenced uniform diameter distribution in the range of 358 nm and 887 nm, respectively, with >80% porosity. The Brunauer-Emmett-Teller (BET) test confirmed that the fabricated NFs mats had a high surface area, especially for the 12% NFs with 652 m2/g compared to 254 m2/g for the 15% NFs. The proteins of interest were successfully conjugated to the 12% PCL scaffold through chemical carbodiimide reaction as confirmed by Fourier-transform infrared spectroscopy. The addition of fibronectin and laminin together was shown to be the most favorable for cellular attachment and elongation of neuroblastoma SH-SY5Y cells compared to other formulations. Light microscopy revealed longer neurite outgrowth, higher cellular projected area, and lower shape index for the cells cultured on the combined proteins conjugated fibers, indicating enhanced cellular spread on the scaffold. This preliminary study suggests that PCL nanoscaffolding conjugated with matrix proteins can support neuronal cell viability and neurite growth.

Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma.

Hepatocellular carcinoma is the fifth most common cancer worldwide and the second most lethal, following lung cancer. Currently applied therapeutic practices rely on surgical resection, chemotherapy and radiotherapy, or a combination thereof. These treatment options are associated with extreme adversities, and risk/benefit ratios do not always work in patients' favor. Anomalies of the epigenome lie at the epicenter of aberrant molecular mechanisms by which the disease develops and progresses. Modulation of these anomalous events poses a promising prospect for alternative treatment options, with an abundance of felicitous results reported in recent years. Herein, the most recent epigenetic modulators in hepatocellular carcinoma are recapitulated on.

Circulating MicroRNAs in Duchenne Muscular Dystrophy.

OBJECTIVE: The diagnosis of Duchenne Muscular Dystrophy (DMD) currently depends on non-specific measures such as Creatine kinase (CK) levels. MicroRNAs (miRNAs) are a class of small, endogenous RNAs of 21-25 nucleotides, that are important regulators for numerous physiological and pathological processes. The aim of the current study is to assess the potential of miRNAs as non-invasive biomarker for the diagnosis of DMD and for identifying carriers. PATIENTS AND METHODS: Thirty healthy subjects and 29 families with one member diagnosed with DMD were enrolled in the study. Peripheral blood samples were collected from all subjects where microRNAs were extracted from plasma followed by the quantification of miR-499, miR-103a-3p, miR-103a-5p, miR-206, miR-208a, miR-223 and miR-191-5p. MLPA and NGS were carried out as a gold standard technique to identify the mutations in the participants. RESULTS: Our data revealed that miR-499 was significantly upregulated in all DMD patients, and true carriers (mothers), while 78 % of potential carriers (sisters) exhibited high levels of this miRNA. Similarly, miR-103a-3p showed an increase in the patients' families although to a lesser extent. On the other hand, miR-206 and miR-191-5p were significantly downregulated in the majority of the DMD patients and the tested female family members. MicroRNA miR-103a-5p and miR-208a followed a comparable trend in patients and mothers. CONCLUSIONS: Ourresults suggest that the plasma levels of miRNAs have the capability to diagnose DMD patients and more importantly, miRNAs can be used to identify female carriers.

Date (Phoenix dactylifera) Polyphenolics and Other Bioactive Compounds: A Traditional Islamic Remedy's Potential in Prevention of Cell Damage, Cancer Therapeutics and Beyond.

This review analyzes current studies of the therapeutic effects of Phoenix dactylifera, or date palm fruit, on the physiologic system. Specifically, we sought to summarize the effects of its application in preventing cell damage, improving cancer therapeutics and reducing damage caused by conventional chemotherapy. Phoenix dactylifera exhibits potent anti-oxidative properties both in vitro and in vivo. This allows the fruit to prevent depletion of intrinsic protection from oxidative cell damage and assist these defense systems in reducing cell damage. Macroscopically, this mechanism may be relevant to the prevention of various adverse drug events common to chemotherapy including hepatotoxicity, nephrotoxicity, gastrotoxicity, and peripheral neuropathy. While such effects have only been studied in small animal systems, research suggests a potential application to more complex mammalian systems and perhaps a solution to some problems of chemotherapy in hepato-compromised and nephro-compromised patients.

Effect of Vitamin D Supplementation on Glucose Control and Inflammatory Response in Type II Diabetes: A Double Blind, Randomized Clinical Trial.

BACKGROUND: Diabetes mellitus (DM) and vitamin D deficiency are major health concerns around the world. Evidence suggests a possible role of vitamin D in improvement of insulin secretion and sensitivity. OBJECTIVES: We assessed whether vitamin D supplementation could be used in vitamin D deficient-type II diabetes to improve glucose metabolism, components of metabolic syndrome (MetS) and specific inflammatory biomarkers. PATIENTS AND METHODS: A double blind, randomized clinical trial was conducted in King Khalid University Hospital, Saudi Arabia to evaluate the effect of cholecalciferol supplementation on glycemic control, MetS components and specific inflammatory biomarkers including tumor necrosis factor-alpha (TNF-α), Interleukin (IL-6), leptin, adiponectin and vascular cell adhesion molecule-1 (VCAM-1). Twenty-two patients with type II diabetes with insulin resistance, glycated hemoglobin (HbA1c) ≥ 6 (42 mmol/mol) and serum 25(OH)D < 50 nmol/L were randomized using a computer program to receive either supplementation with cholecalciferol (5000 IU/day) or placebo for 12 weeks. The primary outcome was change in HbA1c levels from baseline. RESULTS: Median [IQR] 25(OH)D levels increased significantly in the vitamin D group as 58.1 [48, 67.3] nmol/L (P = 0.002). There was no significant difference in the change of HbA1c between the groups (P = 0.5) with a decrease of -0.1% [-1, 0.5] in the vitamin D group and an increase of 0.15% [0.1, 0.2] in the placebo group. A significant improvement was observed in the homeostasis model of assessment of ß-cell activity (HOMA-%B) (P = 0.03) with vitamin D supplementation compared to baseline. CONCLUSIONS: Vitamin D repletion for 12 weeks increased serum vitamin D concentrations and improved ß-cell activity in vitamin D-deficient type II diabetes with no significant changes in HbA1c or insulin sensitivity.

Autoantibodies associated with prenatal and childhood exposure to environmental chemicals in Faroese children.

Methylmercury, polychlorinated biphenyls (PCBs), and perfluorinated compounds (PFCs) are ubiquitous and persistent environmental chemicals with known or suspected toxic effects on the nervous system and the immune system. Animal studies have shown that tissue damage can elicit production of autoantibodies. However, it is not known if autoantibodies similarly will be generated and detectable in humans following toxicant exposures. Therefore, we conducted a pilot study to investigate if autoantibodies specific for neural and non-neural antigens could be detected in children at age 7 years who have been exposed to environmental chemicals. Both prenatal and age-7 exposures to mercury, PCBs, and PFCs were measured in 38 children in the Faroe Islands who were exposed to widely different levels of these chemicals due to their seafood-based diet. Concentrations of IgM and IgG autoantibodies specific to both neural (neurofilaments, cholineacetyltransferase, astrocyte glial fibrillary acidic protein, and myelin basic protein) and non-neural (actin, desmin, and keratin) antigens were measured and the associations of these autoantibody concentrations with chemical exposures were assessed using linear regression. Age-7 blood-mercury concentrations were positively associated with titers of multiple neural- and non-neural-specific antibodies, mostly of the IgM isotype. Additionally, prenatal blood-mercury and -PCBs were negatively associated with anti-keratin IgG and prenatal PFOS was negatively associated with anti-actin IgG. These exploratory findings demonstrate that autoantibodies can be detected in the peripheral blood following exposure to environmental chemicals. The unexpected association of exposures with antibodies specific for non-neural antigens suggests that these chemicals may have toxicities that have not yet been recognized.

Neuroantibody biomarkers: links and challenges in environmental neurodegeneration and autoimmunity.

The majority of neurodegenerative (ND) and autoimmune diseases (AID) remain idiopathic. The contribution of environmental chemicals to the development of these disorders has become of great interest in recent years. A convergence of mechanism between of ND and AID development has also emerged. In the case of ND, including neurotoxicity, the focus of this review, work over the last two decade in the realm of biomarker development, indicates that the immune response provides a venue whereby humoral immunity, in the form of autoantibodies to nervous system specific proteins, or neuroantibodies (NAb), may provide, once validated, a sensitive high throughput surrogate biomarker of effect with the potential of predicting outcome in absence of overt neurotoxicity/neurodegeneration. In addition, NAb may prove to be a contributor to the progression of the nervous system pathology, as well as biomarker of stage and therapeutic efficacy. There is a compelling need for biomarkers of effect in light of the introduction of new chemicals, such as nanoengineered material, where potential neurotoxicity remains to be defined. Furthermore, the convergence of mechanisms associated with ND and AID draws attention to the neglected arena of angiogenesis in defining the link between environment, ND, and AID.