Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients

Purpose: Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity. Methods: We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients during therapy. Results: We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that patients. Conclusions: Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrexate- induced neurotoxic effects

Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect

No abstract available

Analysing the Security of Google's implementation of OpenID Connect

Many millions of users routinely use their Google accounts to log in to relying party (RP) websites supporting the Google OpenID Connect service. OpenID Connect, a newly standardised single-sign-on protocol, builds an identity layer on top of the OAuth 2.0 protocol, which has itself been widely adopted to support identity management services. It adds identity management functionality to the OAuth 2.0 system and allows an RP to obtain assurances regarding the authenticity of an end user. A number of authors have analysed the security of the OAuth 2.0 protocol, but whether OpenID Connect is secure in practice remains an open question. We report on a large-scale practical study of Google's implementation of OpenID Connect, involving forensic examination of 103 RP websites which support its use for sign-in. Our study reveals serious vulnerabilities of a number of types, all of which allow an attacker to log in to an RP website as a victim user. Further examination suggests that these vulnerabilities are caused by a combination of Google's design of its OpenID Connect service and RP developers making design decisions which sacrifice security for simplicity of implementation. We also give practical recommendations for both RPs and OPs to help improve the security of real world OpenID Connect systems

Effects of switching to PI monotherapy on measures of lipoatrophy: meta-analysis of six randomized HIV clinical trials

Background: Switching from triple combination treatment to protease inhibitor (PI) monotherapy may prevent or reverse adverse events related to long-term nucleoside analogues. Lipoatrophy is associated with long-term use of thymidine analogues (zidovudine and stavudine). Methods: A detailed MEDLINE search was conducted to identify randomised clinical trials of triple combination treatment versus PI monotherapy. Summary results from analysis of changes in body composition (DEXA analysis) were collected: the mean change in limb fat and trunk fat to Week 48 or 96, and the percentage of patients with lipoatrophy (20% reduction from baseline in limb fat) or lipohypertrophy (20% rise from baseline in trunk fat). Results: Six randomised trials of PI monotherapy versus triple therapy with data on body composition changes, measured by DEXA scanning at baseline and Week 48 or 96, were identified: Abbott-613 (LPV/r vs ZDV/3TC/EFV, induction-maintenance trial, n=105), Monark (LPV/r vs ZDV/3TC/LPV/r, first-line trial, n=63), Kalesolo (LPV/r vs LPV/r +2NRTIs, switch trial, n=42), MONOI (DRV/r vs DRV/r + 2NRTIs, switch trial, n=156), MONARCH (DRV/r vs DRV/r + 2NRTIs, switch trial, n=30) and KRETA (LPV/r vs LPV/r + ABC/3TC, switch trial, n=74). In the meta-analysis, there were greater rises in limb fat in the PI monotherapy arms than the triple therapy arms (mean difference =277g, 95% CI=+36 to+517g, p=0.024). The percentage of patients with lipoatrophy was significantly lower in the PI monotherapy arms (4%) than the triple therapy arms (20%), (p=0.0005). There was no difference between PI monotherapy and triple therapy for mean change in trunk fat (mean difference=−73g, 95% CI = −621 to +475g, p=ns). There was also no significant difference in the risk of lipohypertrophy between the PI monotherapy arms (32%) and the triple therapy arms (27%) (p=ns). In each of the four analyses, there was no evidence for heterogeneity of treatment effects between the trials (Cochran's Q tests, p=ns for each comparison). Conclusions: In this meta-analysis, the risk of lipoatrophy was significantly lower for patients taking PI monotherapy, compared to triple therapy. There was no significant difference between the arms for lipohypertrophy. However, several of the trials included zidovudine in the control arm, which carries a higher risk of lipoatrophy than tenofovir and abacavir, which are now more widely used

Literatuuronderzoek naar analysemethodieken voor de bepaling van thallium

Naast hoofdzakelijk aandacht voor gevoelige detectiemethoden wordt ingegaan op monsterontsluitingsmethoden voor de bepaling van het zeer toxische element thalliu

Literatuuronderzoek naar het gebruik, gedrag en voorkomen van organotin bevattende bestrijdingsmiddelen

De succesvolle toepassing van organotinverbindingen voor ver uiteenlopende doeleinden heeft geleid tot de huidige hoge wereldproduktie van deze verbindingen. De meest belangrijke en oudste toepassing is de verwerking van di- en mono-organotinverbindingen als stabilisatoren in kunststoffen, zoals PVC . De laatste decennia is echter in het bijzonder het gebruik van tri-organotin-bevattende bestrijdingsmiddelen sterk toegenomen. Zo worden tributyltin- en trifenyltin verbindingen in aangroeiwerende verven voor schepen, pleziervaartuigen etc. verwerkt. In de land- en tuinbouw zijn de fungiciden trifenyltinhydroxide en -acetaat en de acaraciden tricyclohexyltinhydroxide en fenbutatinoxide de belangrijkste organotin-bevattende middelen, die worden toegepast voor gewasbescherming . Op basis van deze literatuurstudie moet gesteld worden dat nog onvoldoende onderzoeksgegevens beschikbaar zijn om een eventueel verbod op het gebruik van deze middelen te onderbouwen cq . af te wijzen. Het name bestaat nog onduidelijkheid omtrent de belasting van het aquatisch milieu, de werkelijke accumulatie in de bodem en de afbraaksnelheid van deze verbindingen onder veldcondities

Nonsaturating magnetoresistance and nontrivial band topology of type-II Weyl semimetal NbIrTe4

Weyl semimetals, characterized by nodal points in the bulk and Fermi arc states on the surface, have recently attracted extensive attention due to the potential application on low energy consumption electronic materials. In this report, the thermodynamic and transport properties of a theoretically predicted Weyl semimetal NbIrTe4 is measured in high magnetic fields up to 35 T and low temperatures down to 0.4 K. Remarkably, NbIrTe4 exhibits a nonsaturating transverse magnetoresistance which follows a power-law dependence in B. Low-field Hall measurements reveal that hole-like carriers dominate the transport for T $>$ 80 K, while the significant enhancement of electron mobilities with lowering T results in a non-negligible contribution from electron-like carriers which is responsible for the observed non-linear Hall resistivity at low T. The Shubnikov-de Haas oscillations of the Hall resistivity under high B give the light effective masses of charge carriers and the nontrivial Berry phase associated with Weyl fermions. Further first-principles calculations confirm the existence of 16 Weyl points located at kz = 0, $\pm$0.02 and $\pm$0.2 planes in the Brillouin zone.Comment: 5 figures, 1 tabl

Bodemontwikkeling voor natuur - het uitmijnexperiment voor de Westelijke Langstraat

Het verlagen van de fosfaatgehaltes in het profiel van de landbouwgrond in de Westelijke Langstraat kan twee doelen dienen: • Voorkomen dat de bodem fosfaat afgeeft aan het grondwater (en dus oppervlaktewater) waardoor er fosfaat arm oppervlaktewater wordt aangevoerd naar de Natura 2000 natuurgebieden binnen de WL. • Verschralen van de bouwvoor waardoor de soortensamenstelling van de vegetatie verandert, toeneemt en bijzonder kan worden

Optimalisatie van parameters, kalibratie en toepassing van een interne standaard bij multi-elementanalyses m.b.v. ICP-AES

ICP-AES heeft als belangrijkste voordeel dat meerdere elementen tegelijkertijd gemeten kunnen worden. Uit voorgaand onderzoek is gebleken dat matrix- interferenties kunnen leiden tot foutieve analyseresultaten. Om voor deze matrix-effecten te corrigeren zou standaardadditie toegepast moeten worden. Deze methode is echter zeer bewerkelijk, vooral bij multi-elementanalyses. In het huidige onderzoek is nagegaan of deze matrix-effecten geëlimineerd kunnen worden door een optimale instelling van de meetcondities, eventueel in combinatie met toepassing van een interne standaard (scandium). In het onderzoek is tevens aandacht besteed aan de kalibratie en aan de invloed van de zoutconcentratie. Bij de optimalisatie van een aantal apparatuur-parameters is de invloed van meethoogte en verstuiverdruk op o.a. de gevoeligheid onderzocht