The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.

Duchenne muscular dystrophy (DMD), a progressive X-linked neuromuscular disorder, has an estimated worldwide incidence of 1:3500 male births. Currently, there are no curative treatments and the mean age of diagnosis is 5 years. In addition, subsequent pregnancies frequently occur before a diagnosis is made in an index case. An 'opt in' screening programme was introduced in Wales in 1990 with the aim to: reduce the diagnostic delay, permit reproductive choice and allow planning of the care of the affected boy. Newborn bloodspots were collected routinely as part of the Wales newborn screening programme. Specific consent was obtained for this test separately from the other tests. During the 21-year period, 369 780 bloodspot cards were received from male infants, of these 343 170 (92.8%) were screened using a bloodspot creatine kinase (CK) assay following parental consent. A total of 145 cases had a raised CK activity (Z250 U/l) and at follow-up, at 6-8 weeks of age, 79 cases had a normal serum CK (false-positive rate 0.023%) and 66 cases had an elevated serum CK. DMD was confirmed in 56 cases by genotyping/muscle biopsy studies, Becker muscular dystrophy in 5 cases and other rarer forms of muscular dystrophy in 5 cases. This long-term study has so far identified 13 false-negative cases. The incidence of DMD in Wales of 1:5136 during this period is lower than that of 1:4046 before commencement of screening in Wales. Screening has reduced the diagnostic delay enabling reproductive choice for parents of affected boys and earlier administration of current therapies.

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Niacin has recently been demonstrated to lower blood pressure in hypertensive patients and to reduce cardiovascular events when combined with a statin. As a consequence, niacin has been elevated from being of historical interest as the treatment for pellagra, to being a compound with possible relevance to contemporary therapeutics. In spite of this, niacin deficiency leading to pellagra continues to be a health problem in some countries. Characterized by an exposed-site hyperpigmented dermatitis, pellagra is generally accepted to have been the first photosensitivity syndrome described. At its worst, pellagra manifests as one of the most striking examples of systemic photosensitivity. This is the only photosensitivity syndrome where death is included as a cardinal clinical feature (the often quoted four 'Ds': dermatitis, diarrhoea, dementia and death). However, the pathogenetic mechanism for the photosensitivity caused by niacin deficiency has yet to be determined. This review seeks to update the classification and phenotypic characterization of the various forms of niacin-deficient photosensitivity. Previous speculation about possible mechanisms for the pathogenesis of photosensitivity due to niacin deficiency is reviewed in the context of advances in the understanding of the photochemical basis of photosensitivity reactions. The review concludes by highlighting research required to advance the understanding of this photosensitivity syndrome.

Abstract-Hyperhomocysteinemia is associated with endothelial dysfunction, although its mechanism is unknown.Isometric tension recordings and lucigenin chemiluminescence were used to assess the effects of homocysteine exposure on endothelium-dependent and -independent relaxation in isolated rabbit aortic rings and superoxide anion (O 2 Ϫ ) production by cultured porcine aortic endothelial cells, respectively. Homocysteine (0.1 to 10 mmol/L) produced a significant (PϽ0.001) concentration-and time-dependent inhibition of endothelium-dependent relaxation in response to both acetylcholine and the calcium ionophore A23187. Only the intracellular O 2 Ϫ scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron, 10 mmol/L) significantly (PϽ0.001) inhibited the effect of homocysteine on acetylcholine-and A23187-induced relaxation. Incubation of porcine aortic endothelial cells with homocysteine (0.03 to 1 mmol/L for up to 72 hours) caused a significant (PϽ0.001) time-dependent increase in the O 2 Ϫ released by these cells on the addition of Triton X-100 (1% [vol/vol]), with levels returning to values comparable to those of control cells at the 72-hour time point. These changes in O 2 Ϫ levels were associated with a time-dependent increase in endothelial cell superoxide dismutase activity, becoming significant (PϽ0.001) after 72 hours. Furthermore, the homocysteine-induced increase in endothelial cell O 2 Ϫ levels was completely inhibited (PϽ0.001) by the concomitant incubation with either Tiron (10 mmol/L), vitamin C (10 mol/L), or vitamin E (10 mol/L). These data suggest that the inhibitory effect of homocysteine on endothelium-dependent relaxation is due to an increase in the endothelial cell intracellular levels of O 2 Ϫ and provide a possible mechanism for the endothelial dysfunction associated with hyperhomocysteinemia. Key Words: homocysteine Ⅲ endothelial function Ⅲ nitric oxide Ⅲ oxygen-derived free radicals D eficiencies in the enzymes cystathionine ␤ synthase and methylenetetrahydrofolate reductase lead to elevated plasma homocyst(e)ine levels (free and bound homocysteine plus homocystine and homocysteine-cysteine mixed disulfide). 1 Patients with these disorders have much higher plasma concentrations of homocysteine than do normal subjects (Ն80 mol/L compared with Յ10 mol/L, respectively) and are prone to premature cardiovascular disease. 2 Severe hyperhomocysteinemia, arising, for example, from cystathionine ␤ synthase deficiency, is rare among the general population, whereas mild hyperhomocysteinemia (15 to 30 mol/L) is common. A recent epidemiological study confirms that even such modestly elevated homocysteine levels are associated with an increased risk of atherosclerosis 3 and can theoretically be caused by reduced activity of the enzyme methylenetetrahydrofolate reductase or deficiencies in folic acid and vitamin B 12 .The mechanism of the vascular injury seen in hyperhomocysteinemia is not known, although growing evidence suggests that endothelial dysfunction plays a major role. 4,5 Indeed, homocystein...

Objective The purpose of this study was to investigate the effect of disease modifying therapies on immune response to severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) vaccines in people with multiple sclerosis (MS). Methods Four hundred seventy‐three people with MS provided one or more dried blood spot samples. Information about coronavirus disease 2019 (COVID‐19) and vaccine history, medical, and drug history were extracted from questionnaires and medical records. Dried blood spots were eluted and tested for antibodies to SARS‐CoV‐2. Antibody titers were partitioned into tertiles with people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following the SARS‐CoV‐2 vaccine according to disease modifying therapy. We used regression modeling to explore the effect of vaccine timing, treatment duration, age, vaccine type, and lymphocyte count on vaccine response. Results Compared to no disease modifying therapy, the use of anti‐CD20 monoclonal antibodies (odds ratio = 0.03, 95% confidence interval [CI] = 0.01–0.06, p < 0.001) and fingolimod (odds ratio = 0.04; 95% CI = 0.01–0.12) were associated with lower seroconversion following the SARS‐CoV‐2 vaccine. All other drugs did not differ significantly from the untreated cohort. Both time since last anti‐CD20 treatment and total time on treatment were significantly associated with the response to the vaccination. The vaccine type significantly predicted seroconversion, but not in those on anti‐CD20 medications. Preliminary data on cellular T‐cell immunity showed 40% of seronegative subjects had measurable anti‐SARS‐CoV‐2 T cell responses. Interpretation Some disease modifying therapies convey risk of attenuated serological response to SARS‐CoV‐2 vaccination in people with MS. We provide recommendations for the practical management of this patient group. ANN NEUROL 2021

Background-Homocysteine is a risk factor for coronary artery disease (CAD), although a causal relation remains to be proven. The importance of determining direct causality rests in the fact that plasma homocysteine can be safely and inexpensively reduced by 25% with folic acid. This reduction is maximally achieved by doses of 0.4 mg/d. High-dose folic acid (5 mg/d) improves endothelial function in CAD, although the mechanism is controversial. It has been proposed that improvement occurs through reduction in total (tHcy) or free (non-protein bound) homocysteine (fHcy). We investigated the effects of folic acid on endothelial function before a change in homocysteine in patients with CAD. Methods and Results-A randomized, placebo-controlled study of folic acid (5 mg/d) for 6 weeks was undertaken in 33 patients. Endothelial function, assessed by flow-mediated dilatation (FMD), was measured before, at 2 and 4 hours after the first dose of folic acid, and after 6 weeks of treatment. Plasma folate increased markedly by 1 hour (200 compared with 25.8 nmol/L; PϽ0.001). FMD improved at 2 hours (83 compared with 47 m; PϽ0.001) and was largely complete by 4 hours (101 compared with 51 m; PϽ0.001). tHcy did not significantly differ acutely (4-hour tHcy, 9.56 compared with 9.79 mol/L; PϭNS). fHcy did not differ at 3 hours but was slightly reduced at 4 hours (1.55 compared with 1.78 mol/L; Pϭ0.02). FMD improvement did not correlate with reductions in either fHcy or tHcy at any time. Conclusions-These data suggest that folic acid improves endothelial function in CAD acutely by a mechanism largely independent of homocysteine.

A folate-rich diet including folic acid-fortified foods or low-dose supplements effectively increases folate status. TT homozygotes require higher folate intakes than do individuals with the CT or CC genotype to achieve similar tHcy concentrations but are responsive to folate intervention.