Whole blood NAD and NADP concentrations are not depressed in subjects with clinical pellagra

Population surveys for niacin deficiency are normally based on clinical signs or on biochemical measurements of urinary niacin metabolites. Status may also be determined by measurement of whole blood NAD and NADP concentrations. To compare these methods, whole blood samples and spot urine samples were collected from healthy subjects (n = 2) consuming a western diet, from patients (n = 34) diagnosed with pellagra and attending a pellagra clinic in Kuito (central Angola, where niacin deficiency is endemic), and from female community control subjects (n = 107) who had no clinical signs of pellagra. Whole blood NAD and NADP concentrations were measured by microtiter plate-based enzymatic assays and the niacin urinary metabolites 1-methyl-2-pyridone-5-carboxamide (2-PYR) and 1-methylnicotinamide (1-MN) by HPLC. In healthy volunteers, inter- and intra-day variations for NAD and NADP concentrations were much lower than for the urinary metabolites, suggesting a more stable measure of status. However, whole blood concentrations of NAD and NADP or the NAD:NADP ratio were not significantly depressed in clinical pellagra. In contrast, the concentrations of 2-PYR and 1-MN, expressed relative to either creatinine or osmolality, were lower in pellagra patients and markedly higher following treatment. The use of the combined cut-offs (2-PYR <3.0 micromol/mmol creatinine and 1-MN <1.3 micromol/mmol creatinine) gave a sensitivity of 91% and specificity of 72%. In conclusion, whole blood NAD and NADP concentrations gave an erroneously low estimate of niacin deficiency. In contrast, spot urine sample 2-PYR and 1-MN concentrations, relative to creatinine, were a sensitive and specific measure of deficiency

Low and deficient niacin status and pellagra are endemic in postwar Angola

BACKGROUND: Outbreaks of pellagra were documented during the civil war in Angola, but no contemporary data on the incidence of pellagra or the prevalence of niacin deficiency were available. OBJECTIVE: The objective was to investigate the incidence of pellagra and the prevalence of niacin deficiency in postwar Angola and their relation with dietary intake, poverty, and anthropometric status. DESIGN: Admissions data from 1999 to 2004 from the pellagra treatment clinic in Kuito, Angola, were analyzed. New patients admitted over 1 wk were examined, and urine and blood samples were collected. A multistage cluster population survey collected data on anthropometric measures, household dietary intakes, socioeconomic status, and clinical signs of pellagra for women and children. Urinary excretion of 1-methylnicotinamide, 1-methyl-2-pyridone-5-carboxymide, and creatinine was measured and hemoglobin concentrations were measured with a portable photometer. RESULTS: The incidence of clinical pellagra has not decreased since the end of the civil war in 2002. Low excretion of niacin metabolites was confirmed in 10 of 11 new clinic patients. Survey data were collected for 723 women aged 15-49 y and for 690 children aged 6-59 mo. Excretion of niacin metabolites was low in 29.4% of the women and 6.0% of the children, and the creatinine-adjusted concentrations were significantly lower in the women than in the children (P < 0.001, t test). In children, niacin status was positively correlated with the household consumption of peanuts (r = 0.374, P = 0.001) and eggs (r = 0.290, P = 0.012) but negatively correlated with socioeconomic status (r = -0.228, P = 0.037). CONCLUSIONS: The expected decrease in pellagra incidence after the end of the civil war has not occurred. The identification of niacin deficiency as a public health problem should refocus attention on this nutritional deficiency in Angola and other areas of Africa where maize is the staple

Excess dietary iodine intake in long-term African refugees

Abstract Objective To assess the iodine status of long-term refugees dependent on international food aid and humanitarian assistance. Design A series of cross-sectional two-stage cluster or systematic random sample surveys which assessed urinary iodine excretion and the prevalence of visible goitre. Salt samples were also collected and tested for iodine content by titration. Setting Six refugee camps in East, North and Southern Africa. Subjects Male and female adolescents aged 10-19 years. Main results The median urinary iodine concentration (UIC) ranged from 254 to 1200 μg l−1 and in five of the camps exceeded the recommended maximum limit of 300 μg l−1, indicating excessive iodine intake. Visible goitre was assessed in four surveys where it ranged from 0.0 to 7.1%. The camp with the highest UIC also had the highest prevalence of visible goitre. The iodine concentrations in 11 salt samples from three camps were measured by titration and six of these exceeded the production-level concentration of 20 to 40 ppm recommended by the World Health Organization (WHO), but were all less than 100 ppm. Conclusions Excessive consumption of iodine is occurring in most of the surveyed populations. Urgent revision of the level of salt iodisation is required to meet current WHO recommendations. However, the full cause of excessive iodine excretion remains unknown and further investigation is required urgently to identify the cause, assess any health impact and identify remedial actio

Monocyte NOTCH2 expression predicts interferon-beta immunogenicity in multiple sclerosis patients

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-β is an established treatment for MS; however, up to 30% of IFN-β–treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14+ monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-β. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-β administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-β administration

Peripheral blood biomarkers in multiple sclerosis.

Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system. The heteroge-neity of pathophysiological processes in MS contributes to the highly variable course of the disease and unpre-dictable response to therapies. The major focus of the research on MS is the identification of biomarkers inbiologicalfluids, such as cerebrospinalfluid or blood, to guide patient management reliably. Because of the diffi-culties in obtaining spinalfluid samples and the necessity for lumbar puncture to make a diagnosis has reduced,the research of blood-based biomarkers may provide increasingly important tools for clinical practice. However,currently there are no clearly established MS blood-based biomarkers. The availability of reliable biomarkerscould radically alter the management of MS at critical phases of the disease spectrum, allowing for interventionstrategies that may prevent evolution to long-term neurological disability. This article provides an overview ofthis researchfield and focuses on recent advances in blood-based biomarker researc

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: Recommendations of the innovative medicines initiative ABIRISK consortium

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies, and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry, and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk, and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices, and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium (Anti-Biopharmaceutical [BP] Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu), was formed by leading clinicians, academic scientists, and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation, and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp). This article is protected by copyright. All rights reserved

Non-imaging concentrators and their application to multispectral radiometry

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Electrophilic additions to functionalised alkenes : the chemistry and synthesis of heterocyclic compounds

The electrophilic addition of organosulphur compounds to alkenes is reviewed. The oxidative electrophilic addition of diphenyl disulphide [using manganese (III) acetate as the oxidant] to a series of alkenes carrying a range of remote nucleophilic groups is described. For example the alkenes investigated carry either amide, urea, thiourea, carbamic acid, carbamimidothioic acid, carbondithioic acid, carbontrithioic acid, guanidine, and sulphonamide functionalities. On the addition of diphenyl disulphide these alkenes afford a number of novel cyclic and acyclic sulphur substituted compounds. A review is made of the literature background to the electrophilic addition-cyclisation reaction of iodine with alkenes carrying remote nucleophiles. A number of novel iodosubstituted heterocyclic compounds are efficiently synthesised via the addition of iodine to alkenes carrying either thiourea, carbamimidothioic acid, carbontrithioic acid, and guanidine functionalities. The principle factors determining the mode of these cyclisations are discussed. Dehydroiodination of these compounds affords a variety of novel unsaturated heterocycles. A route through to 5-methylenedihydrothiaxolamines, 6-methylenedihydrothiaxinamines, and 6-methylenetetrahydropyrimidines, and related compounds, having synthetic potential as both nucleophiles, and electrophiles is established. Related reactions with anaolgous methylene lactones, methylenethiaxoles, methylenedihydro-oxazoles, and methylene cyclic carbonates are noted. Further elaboration of the iodosubstituted heterocycles by the substitution of iodine with carbon, nitrogen, oxygen, and sulphur nucleophiles is reported. Examples are given of carbon-carbon bond formation, via free radical substitution reactions, using organotin chemistry.</p