Deficient Individuals Research Articles

The status of early childhood education in Pakistan: Inside stories

This article analyses the status of early childhood education in Pakistan. The education systems in place in Pakistan are mainly framed within a didactic approach to teaching and learning, which addresses certain areas of education but does not teach the child as a whole. Domains of children’s holistic development such as social, ethical, cultural, intellectual, emotional and physical well-being, and some other key academic skills, are not fully covered. In this kind of education, students are taught to follow rules without question and do as instructed, which corresponds to an autocratic view of learning. In the context of early childhood education in Pakistan, teachers occupy dominant roles, which positions them as the imparters and sources of knowledge and children as dependent and the receivers of knowledge, rather than considering them as potential, curious and powerful learners with unlimited capabilities. The literature indicates that this approach to teaching and learning does not privilege the holistic development and well-being of children. In contrast, many developed countries use research-based contemporary approaches to children’s education and development, giving children a more central role in their learning to ensure that every child has the opportunity to develop to their full potential. This kind of approach reminds teachers to view all children not as needy or deficient individuals.

Risk of Venous Thrombosis in Antithrombin Deficiency: A Systematic Review and Bayesian Meta-analysis.

Antithrombin deficiency is a strong risk factor for venous thromboembolism (VTE), but the absolute risk of the first and recurrent VTE is unclear. The objective of this paper is to establish the absolute risks of the first and recurrent VTE and mortality in individuals with antithrombin deficiency. The databases Embase, Medline Ovid, Web of Science, the Cochrane Library, and Google Scholar were systematically searched for case-control and cohort studies. Bayesian random-effects meta-analysis was used to calculate odds ratios (ORs), absolute risks, and probabilities of ORs being above thresholds. Thirty-five publications were included in the systematic review and meta-analysis. Based on 19 studies, OR estimates for the first VTE showed a strongly increased risk for antithrombin deficient individuals, OR 14.0; 95% credible interval (CrI), 5.5 to 29.0. Based on 10 studies, meta-analysis showed that the annual VTE risk was significantly higher in antithrombin-deficient than in non-antithrombin-deficient individuals: 1.2% (95% CrI, 0.8-1.7) versus 0.07% (95% CrI, 0.01-0.14). In prospective studies, the annual VTE risk in antithrombin deficient individuals was as high as 2.3%; 95% CrI, 0.2-6.5%. Data on antithrombin deficiency subtypes are very limited for reliable risk-differentiation. The OR for recurrent VTE based on 10 studies was 2.1; 95% CrI, 0.2 to 4.0. The annual recurrence risk without long-term anticoagulant therapy based on 4 studies was 8.8% (95% CrI, 4.6-14.1) for antithrombin-deficient and 4.3% (95% CrI, 1.5-7.9) for non-antithrombin-deficient VTE patients. The probability of the recurrence risk being higher in antithrombin-deficient patients was 95%. The authors conclude that antithrombin deficient individuals have a high annual VTE risk, and a high annual recurrence risk. Antithrombin deficient patients with VTE require long-term anticoagulant therapy.

Role of CD36 in immune‐mediated thrombocytopenia in Asian populations

It has been suggested that type I cluster of differentiation 36 (CD36)‐deficient individuals are at risk of developing anti‐CD36 isoantibodies (also known as anti‐Naka) after receiving platelet transfusions or during pregnancy. These antibodies are responsible for several immune thrombocytopenic disorders including fetal/neonatal alloimmune thrombocytopenia (FNAIT), post‐transfusion purpura and platelet‐transfusion refractoriness (PTR). In Asian populations, anti‐CD36 isoantibodies are more frequently found in PTR and FNAIT patients compared to alloantibodies against human platelet antigens. In this short review, we illustrate the relevance of CD36 by providing information on the frequency and molecular basis of CD36 deficiency, laboratory diagnostic tests of CD36 antigens/antibodies and treatment of immune‐mediated thrombocytopenia caused by anti‐CD36 antibodies.

Hepatic transcriptional profiling response to fava bean-induced oxidative stress in glucose-6-phosphate dehydrogenase-deficient mice

Favism is an acute hemolytic syndrome caused by the ingestion of fava bean (FB) in glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. However, little is known about the global transcripts alteration in liver tissue after FB ingestion in G6PD-normal and -deficient states. In this study, deep sequencing was used to analyze liver genes expression alterations underlying the effects of FB in C3H (Wild Type, WT) and G6PD-deficient (G6PDx) mice and to evaluate and visualize the collective annotation of a list of genes to Gene Ontology (GO) terms associated with favism. Our results showed that FB resulted in a decrease of glutathione (GSH)-to-oxidized glutathione (GSSG) ratio and an increase of malondialdehyde (MDA) both in the G6PDx and WT-control check (CK) mice plasma. Significantly, liver transcript differences were observed between the control and FB-treated groups of both WT and G6PDx mice. A total of 320 differentially expressed transcripts were identified by comparison of G6PDx-CK with WT-CK and were associated with immune response and oxidation-reduction function. A total of 149 differentially expressed genes were identified by comparison of WT-FB with WT-CK. These genes were associated with immune response, steroid metabolic process, creatine kinase activity, and fatty acid metabolic process. A total of 438 differential genes were identified by comparing G6PDx-FB with G6PD-CK, associated with the negative regulation of fatty acid metabolic process, endoplasmic reticulum, iron binding, and glutathione transferase activity. These findings indicate that G6PD mutations may affect the functional categories such as immune response and oxidation-reduction.

Zinc supplementation plays a crucial role in T helper 9 differentiation in allogeneic immune reactions and non-activated T cells

T helper (Th) 9 cells play a critical role in immune-mediated diseases, including allergic airway inflammation, autoimmune diseases, and cancer development. Thus, the promotion or suppression of Th9 cell differentiation, transcriptional control, and function is very important for a healthy immune system. Interestingly, T cell maturation, differentiation and function are highly dependent on the individuals’ zinc status. This is especially seen in zinc deficient individuals as in the elderly population often suffering of autoimmunity and increased incidence of infections.In this regard, this study examines the impact of zinc supplementation in pharmacological doses on Th9 differentiation in two in vitro models: 1) in mixed lymphocyte cultures (MLC) displaying allogeneic activated T cells in graft versus host disease, and 2) on non-activated resting T cells in peripheral blood mononuclear cells (PBMC).On the one hand, zinc supplementation significantly diminishes IL‐4-induced Th9 differentiation in MLC thereby ameliorating this pro-inflammatory allogeneic immunoreaction. On the other hand, Th9 cells are induced in resting T cells in PBMC hence triggering the immunological defense.Thus, zinc supplementation can be considered as useful additive to dampen unwanted allogeneic immunoreactions. Moreover, the pro-inflammatory immune defense in non-reactive T cells can be strengthened, which is a frequent issue in the elderly population having a weakened immune response against invading pathogens.

Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials.

BackgroundPrimaquine (PQ) actively clears mature Plasmodium falciparum gametocytes but in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals can cause hemolysis. We assessed the safety of low-dose PQ in combination with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in G6PDd African males with asymptomatic P. falciparum malaria.Methods and findingsIn Burkina Faso, G6PDd adult males were randomized to treatment with AL alone (n = 10) or with PQ at 0.25 (n = 20) or 0.40 mg/kg (n = 20) dosage; G6PD-normal males received AL plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. In The Gambia, G6PDd adult males and boys received DP alone (n = 10) or with 0.25 mg/kg PQ (n = 20); G6PD-normal males received DP plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. The primary study endpoint was change in hemoglobin concentration during the 28-day follow-up. Cytochrome P-450 isoenzyme 2D6 (CYP2D6) metabolizer status, gametocyte carriage, haptoglobin, lactate dehydrogenase levels and reticulocyte counts were also determined.In Burkina Faso, the mean maximum absolute change in hemoglobin was -2.13 g/dL (95% confidence interval [CI], -2.78, -1.49) in G6PDd individuals randomized to 0.25 PQ mg/kg and -2.29 g/dL (95% CI, -2.79, -1.79) in those receiving 0.40 PQ mg/kg. In The Gambia, the mean maximum absolute change in hemoglobin concentration was -1.83 g/dL (95% CI, -2.19, -1.47) in G6PDd individuals receiving 0.25 PQ mg/kg. After adjustment for baseline concentrations, hemoglobin reductions in G6PDd individuals in Burkina Faso were more pronounced compared to those in G6PD-normal individuals receiving the same PQ doses (P = 0.062 and P = 0.022, respectively). Hemoglobin levels normalized during follow-up. Abnormal haptoglobin and lactate dehydrogenase levels provided additional evidence of mild transient hemolysis post-PQ.ConclusionsSingle low-dose PQ in combination with AL and DP was associated with mild and transient reductions in hemoglobin. None of the study participants developed moderate or severe anemia; there were no severe adverse events. This indicates that single low-dose PQ is safe in G6PDd African males when used with artemisinin-based combination therapy.Trial registrationClinicaltrials.gov NCT02174900Clinicaltrials.gov NCT02654730

A Qualitative Survey of Awareness of Health Risks Associated with ALDH2 Deficient Individuals and Alcohol Consumption

Approximately 560 million East Asians have a mutation that results in the impaired activity of aldehyde dehydrogenase 2 (ALDH2), an important enzyme in alcohol metabolism. When alcohol is consumed,...

N-acetylcysteine supplementation increases exercise performance and reduces oxidative stress only in individuals with low levels of glutathione.

Most of the evidence indicates that chronic antioxidant supplementation induces negative effects in healthy individuals. However, it is currently unknown whether specific redox deficiencies exist and whether targeted antioxidant interventions in deficient individuals can induce positive effects. We hypothesized that the effectiveness of antioxidant supplements to decrease oxidative stress and promote exercise performance depends on the redox status of the individuals that receive the antioxidant treatment. To this aim, we investigated whether N-acetylcysteine (NAC) supplementation would enhance exercise performance by increasing glutathione concentration and by reducing oxidative stress only in individuals with low resting levels of glutathione. We screened 100 individuals for glutathione levels and formed three groups with low, moderate and high levels (N = 36, 12 per group). After by-passing the regression to the mean artifact, by performing a second glutathione measurement, the individuals were supplemented with NAC (2 × 600mg, twice daily, for 30 days) or placebo using a double-blind cross-over design. We performed three whole-body performance tests (VO2max, time trial and Wingate), measured two systemic oxidative stress biomarkers (F2-isoprostanes and protein carbonyls) and assessed glutathione-dependent redox metabolism in erythrocytes (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase and NADPH). The low glutathione group improved after NAC supplementation in VO2max, time trial and Wingate by 13.6%, 15.4% and 11.4%, respectively. Thirty days of NAC supplementation were sufficient to restore baseline glutathione concentration, reduce systemic oxidative stress and improve erythrocyte glutathione metabolism in the low glutathione group. On the contrary, the 30-day supplementation period did not affect performance and redox state of the moderate and high glutathione groups, although few both beneficial and detrimental effects in performance were observed. In conclusion, individuals with low glutathione levels were linked with decreased physical performance, increased oxidative stress and impaired redox metabolism of erythrocytes. NAC supplementation restored both performance and redox homeostasis.

Abstract 21310: ApoCIII RX19 Mutation Lowers the Production of ApoCIII and Increases the Clearance of VLDL-TG

The APOCIII R19X mutation (rs76353203), has been found in ~5% of the Lancaster Old Order Amish. It is a C ->T substitution at the 55th nucleotide in human aolipoprotein C-III mRNA that prevents translation of mature apoC-III protein. The mutation decreases apoC-III levels by ~50% and confers favorable lipid profiles and less coronary artery calcification, providing evidence that ApoC-III deficiency is cardioprotective. This conclusion is supported by recent data in Danish and U.S. cohorts showing a 40% reduction in myocardial infarction rates in people with this mutation. The mechanisms whereby apoc-III deficiency exerts its effects are not fully understood. The aim of this study was to describe the fractional clearance rates (FCR) and production rates (PR) of apoB containing lipoproteins, apoCIII, and very low density lipoprotein (VLDL) tryglyceride (TG) in five Amish sibling pairs (CT vs. CC) discordant for the APOC3 R19X mutation and matched for age and sex. Methods: Sib pairs completed a 24-hr stable isotope kinetic study using leucine and glycerol. Blood samples were collected over 24-hr period. We measured plasma lipids and apoCIII by Elisa. We determined the FCR and PR of VLDL apoB, apoCIII, and VLDL-TG. Results: The CT subjects had a 38% decrease in baseline TG levels compared to CC. ApoCIII levels were reduced by 42% in the CT vs. CC. We observed reductions in VLDL-Chol (49%), IDL-Chol (52%), VLDL-TG(44%), and IDL-TG(39%) in the CT when compared to CC. The changes in plasma levels were due to an increase in the VLDL apoB FCR (p = 0.001) without significant changes in production. VLDL-TG FCR increased by 76% in the CT when compared to CC (p=0.03). We observed no differences in post-heparin plasma levels of hepatic and lipoprotein lipase activity in the CT vs. CC. The plasma changes in apoCIII were due to and increased FCR in the CT compared to CC. Conclusions: Reductions in plasma TG levels in heterozygous apoC-III deficient individuals is due to enhanced FCRs of VLDL-apoB and VLDL-TG.

The rachitic tooth: The use of radiographs as a screening technique

This study investigates morphological changes in pulp chambers of living and archaeological individuals with past vitamin D deficiency. Living individuals (n=29), four with detailed medical and dental records and three groups of archaeological individuals (n=25) were radiographed; selected individuals were further evaluated histologically for the presence of incremental interglobular dentin (IIGD), indicative of deficiency (28 living; 17 archaeological). Measurements of pulp horns/chambers from radiographs were conducted to quantify morphological observations. One group had clear skeletal evidence of rickets from St. Matthew, Quebec (n=1) and St. Jacques, France (n=4); a second group had slight skeletal indicators from Bastion des Ursulines, Quebec (n=6); and a third group lacked both skeletal and radiological evidence of deficiency from St. Antoine (n=6) and Pointe-aux-Trembles (n=4). Results showed archaeological individuals with clear and slight skeletal evidence of past deficiency displayed constricted or chair shaped pulp horns. Living individuals with deficiency exhibited similar pulp chamber morphology. Radiographic pulp horn/chamber measurements corroborated morphological findings and significant differences were found in pulp horn/chamber measurements between those with and without deficiency. Results suggest that radiograph assessment of teeth can be used as a screening technique to elucidate patterns of deficiency and select individuals for microCT or histological assessment.

Alpha-1 antitrypsin augmentation therapy decreases miR-199a-5p, miR-598 and miR-320a expression in monocytes via inhibition of NF\u03baB

Alpha-1 antitrypsin (AAT) augmentation therapy involves infusion of plasma-purified AAT to AAT deficient individuals. Whether treatment affects microRNA expression has not been investigated. This study’s objectives were to evaluate the effect of AAT augmentation therapy on altered miRNA expression in monocytes and investigate the mechanism. Monocytes were isolated from non-AAT deficient (MM) and AAT deficient (ZZ) individuals, and ZZs receiving AAT. mRNA (qRT-PCR, microarray), miRNA (miRNA profiling, qRT-PCR), and protein (western blotting) analyses were performed. Twenty one miRNAs were differentially expressed 3-fold between ZZs and MMs. miRNA validation studies demonstrated that in ZZ monocytes receiving AAT levels of miR-199a-5p, miR-598 and miR-320a, which are predicted to be regulated by NFκB, were restored to levels similar to MMs. Validated targets co-regulated by these miRNAs were reciprocally increased in ZZs receiving AAT in vivo and in vitro. Expression of these miRNAs could be increased in ZZ monocytes treated ex vivo with an NFκB agonist and decreased by NFκB inhibition. p50 and p65 mRNA and protein were significantly lower in ZZs receiving AAT than untreated ZZs. AAT augmentation therapy inhibits NFκB and decreases miR-199a-5p, miR-598 and miR-320a in ZZ monocytes. These NFκB-inhibitory properties may contribute to the anti-inflammatory effects of AAT augmentation therapy.

Significantly elevated foetal haemoglobin levels in individuals with glucose 6-phosphate dehydrogenase disease and/or sickle cell trait: a cross-sectional study in Cape Coast, Ghana

BackgroundPreviously published data have demonstrated that sickle red blood cells produce twice as much reactive oxygen species (ROS) suggesting that co-inheritance of sickle cell disease (SCD) and glucose 6-phosphate dehydrogenase (G6PD) enzymopathy could lead to more severe anaemia during sickling crises. Elevated foetal haemoglobin (Hb F) levels have been shown to have positive modulatory effects on sickling crises and disease outcomes. This study sought to assess how inheritance of G6PD enzymopathy affects the level of Hb F and haemoglobin concentration in adults in steady state.MethodsThis cross-sectional study selected 100 out-patients (41 males and 59 females) visiting the University of Cape Coast hospital, between January, 2016 and May, 2016. Cellulose acetate electrophoresis (pH 8.2–8.6), methaemoglobin reductase test, modified Betke alkaline denaturation methods were used to investigate haemoglobin variants, qualitative G6PD status, and %Hb F levels in venous blood samples drawn from these participants. Data was analysed with GraphPad Prism 6 and SPSS and significance set at p < 0.05.ResultsForty one percent of the participants demonstrated qualitative G6PD enzymopathy whereas only 10% demonstrated Hb AS type (Sickle cell trait, SCT). 5% of the participants co-inherited SCT and G6PD enzymopathy. %Hb F levels in G6PD deficient males was significantly higher than in G6PD deficient females [(p = 0.0003, 2.696% (males) vs 1.975% (females)], although the %Hb F levels was comparable in non-G6PD deficient individuals. %Hb F levels were significantly elevated in males with SCT only (p < 0.05), or G6PD enzymopathy only (p < 0.0001), or SCT + G6PD enzymopathy (p < 0.0001) compared to males with none of these pathologies even though their respective haemoglobin levels were comparable. Male participants with G6PD enzymopathy + SCT co-inheritance had significantly elevated %Hb F when compared to their counterparts with only G6PD enzymopathy (p < 0.001). Male gender [(p = 0.001, OR: 6.912 (2.277–20.984)] partial defective G6PD enzyme [(p = 0.00, OR: 7.567E8 (8.443E7–6.782E9)] SCT [(p = 0.026, OR: 4.625 (1.196–17.881)] were factors associated with raised %Hb F levels ≥2.5.ConclusionThe inheritance of G6PD defect and/or SCT significantly elevate %Hb F levels in the steady state even though haemoglobin levels are not affected.

IgA and IgG Antitransglutaminase 2 Antibodies in the Diagnosis of Celiac Disease

Screening for celiac disease (CD) dramatically improved when techniques able to measure blood autoantibodies against tissue transglutaminase 2 (TTG) were developed. Although typically increased in CD, these antibodies are not pathognomonic since they are also detected in several other autoimmune processes. IgA deficiency among celiac patients is more frequent than in general population (up to 25% vs 1-3%). This led to develop kits able to measure IgG-TTG, which until today represent a helpful diagnostic tool during diagnosis of CD in IgA deficient individuals. Today, commercial kits measuring IgG- TTG (and other) antibodies are widely available, are frequently used and create confusion in diagnosing CD in IgA-sufficient individuals. This is attributed to the fact that sensitivity and specificity of IgG-TTG is lower when applied to IgA-sufficient persons, and also because IgG-TTG is detected in several autoimmune disorders, with variable frequency and isotypes depending on the condition. Evidence analyzed indicate that to date available data: i) is insufficient to understand the difference of classes and subclasses detected in CD and other autoimmune conditions; ii) does not support the use of IgG-TTG for diagnosing CD in IgA-sufficient individuals and therefore iii) IgG should not be used in the routine diagnostic process of CD.

Safety of primaquine given to people with G6PD deficiency: systematic review of prospective studies

BackgroundHaemolysis risk with single dose or short course primaquine was evaluated in glucose-6-phosphate dehydrogenase (G6PD) deficient people.MethodsMajor electronic databases (to August 2016) were searched for single or short course 8-aminoquinolines (8-AQ) in (1) randomized comparisons against placebo in G6PD deficient people; and (2) observational comparisons in G6PD deficient compared to replete people. Two authors independently assessed eligibility, risk-of-bias, and extracted data.ResultsFive randomized controlled trials and four controlled observational cohorts were included. In G6PD deficient individuals, high-dose (0.75 mg/kg) PQ resulted in lower average haemoglobin levels at 7 days (mean difference [MD] −1.45 g/dl, 95% CI −2.17 to −0.74, 2 trials) and larger percentage fall from baseline to day 7 (MD −10.31%, 95% CI −17.69 to −2.92, 3 trials) compared to placebo. In G6PD deficient compared to replete people, average haemoglobin was lower at 7 days (MD −1.19 g/dl, 95% CI −1.94 to −0.44, 2 trials) and haemoglobin change from baseline to day 7 was greater (MD −9.10%, 95% CI −12.55 to −5.65, 5 trials). One small trial evaluated mid-range PQ dose (0.4–0.5 mg/kg) in G6PD deficient people, with no difference detected in average haemoglobin at day 7 compared to placebo. In one cohort comparing G6PD deficient and replete people there was a greater fall with G6PD deficiency (MD −4.99%, 95% CI −9.96 to −0.02). For low-dose PQ (0.1–0.25 mg/kg) in G6PD deficient people, haemoglobin change from baseline was similar to the placebo group (MD 1.72%, 95% CI −1.89 to 5.34, 2 trials). Comparing low dose PQ in G6PD deficient with replete people, the average haemoglobin was lower in the G6PD deficient group at 7 days (−0.57 g (95% CI −0.97 to −0.17, 1 trial)); although change from baseline was similar (MD −1.45%, 95% CI −5.69 to 2.78, 3 trials).ConclusionsFalls in average haemoglobin are less marked with the 0.1 to 0.25 mg/kg PQ than with the 0.75 mg/kg dose, and severe haemolytic events are not common. However, data were limited and the evidence GRADE was low or very low certainty.

Field Trial of the CareStart Biosensor Analyzer for the Determination of Glucose-6-Phosphate Dehydrogenase Activity in Haiti.

Throughout many developing and tropical countries around the world, malaria remains a significant threat to human health. One barrier to malaria elimination is the ability to safely administer primaquine chemotherapy for the radical cure of malaria infections in populations with a high prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency. In the current study, a field trial of the world's first quantitative, point-of-care assay for measuring G6PD activity was conducted in Haiti. The performance of the CareStart Biosensor Analyzer was compared with the gold standard spectrophotometric assay and genotyping of the G6PD allele in schoolchildren (N = 343) from the Ouest Department of Haiti. In this population, 19.5% of participants (67/343) had some form of G6PD deficiency (< 60% residual activity) and 9.9% (34/343) had moderate-to-severe G6PD deficiency (< 30% residual activity). Overall, 18.95% of participants had the presence of the A-allele (65/343) with 7.87% (27/343) considered at high risk for drug-induced hemolysis (hemizygous males and homozygous females). Compared with the spectrophotometric assay, the sensitivity and specificity to determine participants with < 60% residual activity were 53.7% and 94.6%, respectively; for participants with 30% residual activity, the sensitivity and specificity were 5.9% and 99.7%, respectively. The biosensor overestimated the activity in deficient individuals and underestimated it in participants with normal G6PD activity, indicating the potential for a systematic measurement error. Thus, we suggest that the current version of the biosensor lacks adequate sensitivity and should be improved prior to its use as a point-of-care diagnostic for G6PD deficiency.

Vitamin D for Depression with a Seasonal Pattern: an Effective Treatment Strategy

Background: Low level of vitamin D is often associated with major depression with a seasonal pattern, formerly known as seasonal affective disorder under the DSM IV classification. Major depressive disorder is commonly observed during the fall and winter seasons in countries away from the tropical zone and is referred to as depression with a seasonal pattern under the DSM V classification. Here, we conduct a review of literature to address the factors highlighting the association between vitamin D level and depression with a seasonal pattern. Objective: 1) Review the epidemiology, etiology and pathogenesis associating vitamin D level and depression. 2) Provide treatment recommendations and practice guidelines for addressing vitamin D deficiency associated with depression with a seasonal pattern. Methods: Literature review on human studies published in English language from 2000-2017 using PubMed, EBSCO, and Google Scholar was performed. Results: Majority of published studies have associated low level of vitamin D to depression with a seasonal pattern. A high prevalence of major depressive disorder is observed in Northern latitude countries with severe, prolonged winter that experience little or no sunshine available within the wavelength that is necessary for cutaneous synthesis of vitamin D. A review of literature indicated that reduced exposure to sunlight is associated with low levels of vitamin D, decreased serotonin activity, an increased production of melatonin, and changes in circadian rhythm. Associated factors include socio-demographic (older age, female, higher BMI>25Kg/m2 , geographical location), and clinical correlates including chronic pain, comorbid neuropsychiatric conditions, chronic diseases (hypertension, diabetes mellitus, autoimmune disorder), and musculoskeletal disorders. Treatment recommendations include light therapy, antidepressant treatment, psychotherapy, melatonin and vitamin D supplementation. Among all the modalities, vitamin D supplementation is an effective preventative and treatment strategy for the management of depression with a seasonal pattern. Conclusion: Sunlight exposure within the recommended wavelength promotes vitamin D synthesis from cholesterol in the skin. Vitamin D deficiency is observed among adults especially those residing in sunlight deficient geographical locations. Among vitamin D deficient individuals suffering from major depression with a seasonal pattern, early detection and vitamin D supplementation can be a simple, convenient, and cost-effective treatment strategy for improving symptoms and mental health outcomes associated with major depression.

Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency.

2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, also known as beta-ketothiolase deficiency, is an inborn error of ketone body utilization and isoleucine catabolism. It is caused by mutations in the ACAT1 gene and may present with metabolic ketoacidosis. In order to obtain a more comprehensive view on this disease, we have collected clinical and biochemical data as well as information on ACAT1 mutations of 32 patients from 12 metabolic centers in five countries. Patients were between 23months and 27years old, more than half of them were offspring of a consanguineous union. 63% of the study participants presented with a metabolic decompensation while most others were identified via newborn screening or family studies. In symptomatic patients, age at manifestation ranged between 5months and 6.8years. Only 7% developed a major mental disability while the vast majority was cognitively normal. More than one third of the identified mutations in ACAT1 are intronic mutations which are expected to disturb splicing. We identified several novel mutations but, in agreement with previous reports, no clear genotype-phenotype correlation could be found. Our study underlines that the prognosis in MAT deficiency is good and MAT deficient individuals may remain asymptomatic, if diagnosed early and preventive measures are applied.

G6PD deficiency alleles in a malaria-endemic region in the Western Brazilian Amazon

BackgroundPlasmodium vivax parasites are the predominant cause of malaria infections in the Brazilian Amazon. Infected individuals are treated with primaquine, which can induce haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals and may lead to severe and fatal complications. This X-linked disorder is distributed globally and is caused by allelic variants with a geographical distribution that closely reflects populations exposed historically to endemic malaria. In Brazil, few studies have reported the frequency of G6PD deficiency (G6PDd) present in malaria-endemic areas. This is particularly important, as G6PDd screening is not currently performed before primaquine treatment. The aim of this study was to determine the prevalence of G6PDd in the region of Alto do Juruá, in the Western Brazilian Amazon, an area characterized by a high prevalence of P. vivax infection.MethodsFive-hundred and sixteen male volunteers were screened for G6PDd using the fluorescence spot test (Beutler test) and CareStart™ G6PD Biosensor system. Demographic and clinical-epidemiological data were acquired through an individual interview. To assess the genetic basis of G6PDd, 24 SNPs were genotyped using the Kompetitive Allele Specific PCR assay.ResultsTwenty-three (4.5%) individuals were G6PDd. No association was found between G6PDd and the number of malaria cases. An increased risk of reported haemolysis symptoms and blood transfusions was evident among the G6PDd individuals. Twenty-two individuals had the G6PDd A(−) variant and one the G6PD A(+) variant. The Mediterranean variant was not present. Apart from one polymorphism, almost all SNPs were monomorphic or with low frequencies (0–0.04%). No differences were detected among ethnic groups.ConclusionsThe data indicates that ~1/23 males from the Alto do Juruá could be G6PD deficient and at risk of haemolytic anaemia if treated with primaquine. G6PD A(−) is the most frequent deficiency allele in this population. These results concur with reported G6PDd in other regions in Brazil. Routine G6PDd screening to personalize primaquine administration should be considered, particularly as complete treatment of patients with vivax malaria using chloroquine and primaquine, is crucial for malaria elimination.

Alpha-1 antitrypsin supplementation improves alveolar macrophages efferocytosis and phagocytosis following cigarette smoke exposure.

Cigarette smoking (CS), the main risk factor for COPD (chronic obstructive pulmonary disease) in developed countries, decreases alveolar macrophages (AM) clearance of both apoptotic cells and bacterial pathogens. This global deficit of AM engulfment may explain why active smokers have worse outcomes of COPD exacerbations, episodes characterized by airway infection and inflammation that carry high morbidity and healthcare cost. When administered as intravenous supplementation, the acute phase-reactant alpha-1 antitrypsin (A1AT) reduces the severity of COPD exacerbations in A1AT deficient (AATD) individuals and of bacterial pneumonia in murine models, but the effect of A1AT on AM scavenging functions has not been reported. Apoptotic cell clearance (efferocytosis) was measured in human AM isolated from patients with COPD, in primary rat AM or differentiated monocytes exposed to CS ex vivo, and in AM recovered from mice exposed to CS. A1AT (100 μg/mL, 16 h) significantly ameliorated efferocytosis (by ~50%) in AM of active smokers or AM exposed ex vivo to CS. A1AT significantly improved AM global engulfment, including phagocytosis, even when cells were simultaneously challenged with apoptotic and Fc-coated (bacteria-like) targets. The improved efferocytosis in A1AT-treated macrophages was associated with inhibition of tumor necrosis factor-α converting enzyme (TACE) activity, decreased mannose receptor shedding, and markedly increased abundance of efferocytosis receptors (mannose- and phosphatidyl serine receptors and the scavenger receptor B2) on AM plasma membrane. Directed airway A1AT treatment (via inhalation of a nebulized solution) restored in situ airway AM efferocytosis after CS exposure in mice. The amelioration of CS-exposed AM global engulfment may render A1AT as a potential therapy for COPD exacerbations.

The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial.

Disruption of vitamin D signaling in rodents causes activation of the rennin-angiotensin system (RAS) and development of hypertension. Observational studies in humans found lower circulating 25-hydroxyvitamin D [25(OH)D] is associated with increased RAS activity and blood pressure (BP). We performed the first randomized control trial to investigate the effects of vitamin D supplementation on the RAS in humans. Vitamin D deficient, [25(OH)D ≤20 ng/ml), overweight individuals without hypertension were randomized into a double-blind, placebo-controlled trial of 8-weeks treatment with ergocalciferol or placebo. Kidney-specific RAS activity, measured using renal plasma flow response to captopril in high sodium balance, was assessed at baseline and 8 weeks, as was systemic RAS activity and 24-h ambulatory BP. In total, 84 participants completed the study. Mean 25[OH]D levels increased from 14.7 to 30.3 ng/ml in the ergocalciferol group, P value < 0.0001, and from 14.3 to 17.4 ng/ml in the placebo group, P value = 0.3. The renal plasma flow response to captopril was 33.9 ± 56.1 ml/min per 1.73 m at baseline and 35.7 ± 47.7 ml/min per 1.73 m at 8 weeks in the ergocalciferol group (P value = 0.83); and was 37.3 ± 46.9 ml/min per 1.73 m at baseline and 35.9 ± 26.2 ml/min per 1.73 m at 8 weeks in the placebo group (P value = 0.78). Ergocalciferol had no effect on PRA, AngII, or 24-h BP measurements. This trial found no benefit from correcting vitamin D deficiency on RAS activity or BP after 8 weeks. These findings are not consistent with the hypothesis that vitamin D is a modifiable target for lowering BP in vitamin D deficient individuals.