Preventive use of nitisinone in alkaptonuria

Abstract Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are joint problems, cardiac valve abnormalities and renal problems. Landmark intervention studies with nitisinone 10 mg daily, suppressing an upstream enzyme activity, demonstrated its beneficial effects in AKU patients with established complications, which usually start to develop in the fourth decade. Lower dose of nitisinone in the range of 0.2–2 mg daily will already reduce urinary homogentisic acid (uHGA) excretion by > 90%, which may prevent AKU-related complications earlier in the course of the disease while limiting the possibility of side-effects related to the increase of plasma tyrosine levels caused by nitisinone. Future preventive studies should establish the lowest possible dose for an individual patient, the best age to start treatment and also collect evidence to which level uHGA excretion should be reduced to prevent complications

Relationship between serum B12 concentrations and mortality:experience in NHANES

BACKGROUND: There is conflicting evidence in the literature on the association between (elevated) serum B12 concentrations and subsequent disease or mortality. We evaluated in the NHANES general population the association of serum B12 concentrations as well as vitamin B12 supplement intake with all-cause, cardiovascular, and cancer-related mortality, while taking into account demographic and lifestyle factors and significant other diseases which are known to be associated with poorer outcome. METHODS: The main outcomes of our study were all-cause mortality, cardiovascular mortality, and cancer-related mortality. Mortality status and cause of death were determined by NHANES-linked National Death Index public access files through December 31, 2015. The association of serum B12 concentrations and vitamin B12 supplement intake with mortality was assessed with Cox proportional hazard (PH) models, with adjustment for a number of relevant demographic and lifestyle factors and comorbidity. RESULTS: The final study population of 24,262 participants had a mean age of 48 (SD 19) years; 50.1% were males. The median follow-up duration was 109 months (range 1-201 months). On the census day of December 31, 2015, 3023 participants were determined as deceased (12.5%). The fully adjusted Cox PH model indicated that low serum B12 concentrations  700 pmol/l were associated with an increase in cardiovascular mortality only (HR 1.45, 95% CI 1.01-2.06, p = 0.042). Participants with a diagnosis of hypertension, dyslipidemia, CVD, and cancer more frequently used vitamin B12-containing supplements than those without these diagnoses. We could not demonstrate an association between vitamin B12 supplement intake and mortality, when adjusted for comorbidity. CONCLUSIONS: In the general population of NHANES, low serum B12 concentrations were associated with a moderate increase in all-cause mortality. There was a small but significant increase in cardiovascular mortality in the groups with low or high serum B12. High intake of vitamin B12 in the form of supplements was not associated with any adverse effect on mortality and therefore can be regarded as safe

The Many Faces of Cobalamin (Vitamin B12) Deficiency

Although cobalamin (vitamin B12) deficiency was described over a century ago, it is still difficult to establish the correct diagnosis and prescribe the right treatment. Symptoms related to vitamin B12 deficiency may be diverse and vary from neurologic to psychiatric. A number of individuals with vitamin B12 deficiency may present with the classic megaloblastic anemia. In clinical practice, many cases of vitamin B12 deficiency are overlooked or sometimes even misdiagnosed. In this review, we describe the heterogeneous disease spectrum of patients with vitamin B12 deficiency in whom the diagnosis was either based on low serum B12 levels, elevated biomarkers like methylmalonic acid and/or homocysteine, or the improvement of clinical symptoms after the institution of parenteral vitamin B12 therapy. We discuss the possible clinical signs and symptoms of patients with B12 deficiency and the various pitfalls of diagnosis and treatment.</p

Increased allocation to reproduction reduces future competitive ability in a burying beetle

1. The existence of a trade-off between current and future reproduction is a fundamental prediction of life-history theory. Support for this prediction comes from brood size manipulations, showing that caring for enlarged broods often reduces the parent's future survival or fecundity. However, in many species, individuals must invest in competing for the resources required for future reproduction. Thus, a neglected aspect of this trade-off is that increased allocation to current reproduction may reduce an individual's future competitive ability. 2. We tested this prediction in the burying beetle, Nicrophorus vespilloides, a species where parents care for their offspring and where there is fierce competition for resources used for breeding. 3. We manipulated reproductive effort by providing females with either a small brood of 10 larvae or a large brood of 40 larvae and compared the ability of these females, and virgin females that had no prior access to a carcass, to compete for a second carcass against a virgin competitor. 4. We found that increased allocation to current reproduction reduced future competitive ability, as females that had cared for a small brood were more successful when competing for a second carcass against a virgin competitor than females that had cared for a large brood. In addition, the costs of reproduction were offset by the benefits of feeding from the carcass during an initial breeding attempt, as females that had cared for a small brood were better competitors than virgin females that had no prior access to a carcass, whilst females that had cared for a large brood were similar in competitive ability to virgin females. 5. Our results add to our understanding of the trade-off between current and future reproduction by showing that this trade-off can manifest through differences in future competitive ability and that direct benefits of reproduction can offset some of these costs. 16-Apr-2020Read me for "Data from RichardsonStephensSmiseth_JournalofAnimalEcology.csv" This data file consists of a comma separated values spreadsheet (.csv), which provides data for the effects of allocation to reproduction via brood size manipulation on future competitive ability in contests for a carcass. Each line in the spreadsheet represents an individual, experimental female. female_id – individual ID of the female. eclosion – date of eclosion. death – date of death. lifespan – number of days lived from eclosion to death. treatment_code – experimental treatment (control = no breeding attempt, ten = brood of ten larvae, forty = brood of forty larvae). won – outcome of the contest (Y = female won, N = female lost, NA = unclear). outcome_clear – was the outcome of the contest clear? (Y = yes, N = no). size – size of the female, measured as pronotum width (mm). competitor_size – size of the virgin female competitor measured as pronotum width (mm). size_difference – absolute difference in size between focal female and her competitor (mm). brood_size – number of larvae in the experimental brood at dispersal. dot – number and placement of identifying marks (1 or 2 = number of dots, L or R = left or right elytra). female_pre_mass – female mass prior to initial reproductive attempt (g). female_post_mass – female mass after initial reproductive attempt (g). female_mass_change – female mass change during initial reproductive attempt (g). brood_mass_pre – mass of the brood of larvae when cross fostered and given to the female (g). brood_mass_post – mass of the brood of larvae at dispersal from the carcass (g). breeding_carcass_mass – mass of the mouse carcass used for breeding (g). competition_carcass_mass – mass of the mouse carcass females competed for (g). Funding provided by: Natural Environment Research CouncilCrossref Funder Registry ID: http://dx.doi.org/10.13039/501100000270Award Number: NE/L002558/

Why we need systematic reviews and meta-analyses in the testing and assessment literature

Multivariate analysis of psychological dat

Sea buckthorn berries <i>Hippophae rhamnoides</i> L. predict size and composition of a great tit population <i>Parus major</i> L.

In seasonal environments variation in food abundance in the non-breeding season is thought to affect songbird population dynamics. In a unique tit-sea buckthorn berry system we can estimate the berry abundance and both the tit consumption and population dynamics. Six hundred nest boxes were available to great and blue tits Cyanistes caeruleus for breeding in spring and roosting in winter. We followed the dynamics including the recapture histories of individually marked great tits from 2008 to 2014. In each year we estimated 1) the winter sea buckthorn berry availability, 2) an index of berry consumption in December based on the colour of the faeces of roosting birds, 3) the number of breeding great and blue tits, 4) both recapture probability and the return rate of the great tits and 5) immigration rates. December berry abundance positively predicted the number of breeding pairs of both species in the subsequent season and great tit return rates in the second half of the winter. There was support for a sex specific berry effect on the adult return rate in the great tit: female return rate was associated less strongly to berry abundance than male return rate. This skewed the sex ratio of the local breeders in the following breeding season. Intriguingly, annual berry consumption in December was not related to berry abundance, and individuals consuming more berries tended to have slightly lower return rates. Reproductive rate was not related to berry abundance. There was hardly support for a relation between immigration rates of first year breeders and berry abundance. Taken together these results imply that berry stock not only affected population size but also the population composition through sex specific exchange with the surroundings. Since population density covaried with berry abundance, density dependent effects provide an alternative explanation for the patterns observed

A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumours: a phase 1 and pharmacokinetic study

The aim of this phase I study was to assess feasibility, pharmacokinetics and toxicity of methoxymorpholino doxorubicin (MMRDX or PNU-152243) administered as a 3 h intravenous infusion once every 4 weeks. Fourteen patients with intrinsically anthracycline-resistant tumours received 37 cycles of MMRDX. The first cohort of patients was treated with 1 mg m−2of MMRDX. The next cohorts received 1.25 mg m−2and 1.5 mg m−2respectively. Common toxicity criteria (CTC) grade III/IV nausea and vomiting were observed in 1/18 cycles at 1.25 mg m−2and in 2/11 cycles at 1.5 mg m−2. Transient elevation in transaminases up to CTC grade III was observed in 2/16 cycles at 1.25 mg m−2and 4/11 cycles at 1.5 mg m−2. No cardiotoxicity was observed. At 1.25 mg m−2CTC grade IV neutropenia occurred in 1/17 cycles. At 1.5 mg m−2CTC grade III neutropenia was seen in 2/7 and grade IV in 3/7 evaluable cycles. Thrombocytopenia grade III was observed in 2/9 and grade IV in 1/9 evaluable cycles. One patient treated at 1.5 mg m−2died with neutropenic fever. Therefore, dose-limiting toxicity was reached and 1.25 mg m−2was considered the maximum tolerated dose for MMRDX as 3 h infusion. No tumour responses were observed. Pharmacokinetic parameters showed a rapid clearance of MMRDX from the circulation by an extensive tissue distribution. Renal excretion of the drug and its metabolite was negligible. In conclusion, prolongation of MMRDX infusion to 3 h does not improve the toxicity profile as compared with bolus administration. © 2000 Cancer Research Campaig

Fast screening of N-glycosylation disorders by sialotransferrin profiling with capillary zone electrophoresis

Background Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most frequently used screening method is sialotransferrin profiling using isoelectric focusing (IEF). Capillary zone electrophoresis (CZE) may be a simple and fast alternative. We investigated the Capillarys CDT assay (Sebia, France) to screen for N-glycosylation disorders, using IEF as gold standard. Methods Intra- and inter-assay precision were established, and analyses in heparin-anticoagulated plasma and serum were compared. Accuracy was assessed by comparing IEF and CZE profiles of 153 samples, including 49 normal, 53 CDG type I, 2 CDG type II, 1 combined CDG type I and type II and 48 samples with a Tf-polymorphism. Neuraminidase-treated plasma was analysed to discriminate CDG and Tf-polymorphisms using samples of 52 subjects (25 had a confirmed Tf-polymorphism). Age-dependent reference values were established using profiles of 312 samples. Results Heparin-plasma is as suitable as serum for CDG screening with the Capillarys CDT assay. The precision of the method is high, with a limit of quantification (LOQ) of 0.5%. All profiles, including CDG and Tf-polymorphisms, were correctly identified with CZE. Forty-nine of 52 neuraminidase-treated samples correctly identified the presence/absence of a Tf-polymorphism. Interferences in 3/52 samples hampered interpretation. Sialo-Tf profiles were dependent of age, in particular in the first three months of age. Conclusions CZE analysis with the Capillarys CDT kit (Sebia) is a fast and reliable method for screening of N-glycosylation defects. Tf-polymorphisms could be excluded after overnight incubation with neuraminidase