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

Evaluatie van het, in 1988 in het kader van het VREK-programma uitgevoerde onderzoek naar de cadmium-, lood-, kwik- en arseengehalten in vlees en organen van runderen, varkens, schapen, kalveren en pluimvee

De in 1988 in het kader van het LAC-signaleringsprogramma VREK gevonden lood-, cadmium-, kwik- en arseengehalten zijn gepresenteerd en vergeleken met de resultaten van voorgaande jaren. Voorts zijn de gevonden gehalten getoetst aan de geldende aktiegrenzen en normen. De in 1988 gevonden cadmium-, lood-, kwik- en arseengehalten in dierlijke produkten zijn in het algemeen vergelijkbaar met de onderzoeksresultaten van voorgaande jaren. De over de afgelopen jaren waargenomen licht dalende trend in de loodgehalten in organen van schapen, runderen en kalveren zijn mogelijk het gevolg van een daling van de atmosferische looddepositie t.o.v. voorgaande jaren. De dalende trend is het meest duidelijk bij schapen (intensieve beweiding). In de verdelingen van de in 1988 gevonden loodgehalten in vlees, levers en nieren van varkens is nauwelijks een verdere verandering opgetreden t.o.v. de resultaten van 1987. Hierbij dient te worden opgemerkt dat de gevonden loodgehalten de bepalingsgrens van de toegepaste analysemethode zeer dicht naderen. In 1988 werden in 2 monsters kalfslever de voor runderlever geformuleerde aktiegrens en norm voor cadmium overschreden. In 3 monsters rundernier werd de voor cadmium geldende aktiegrens overschreden. De norm werd hierbij niet overschreden. In 2 monsters schapenleren werden extreem hoge cadmiumgehalten (2.20 resp. 2.24 mg/kg) aangetroffen. Voor schapen zijn echter geen aktiegrenzen of normen vastgesteld

Disparities in kidney transplantation accessibility among immigrant populations in Europe: A systematic review and meta-analysis

Background and objectives: Disparities in access to healthcare for patients with an immigration background are well-known. The aim of this study was to determine whether disparities among immigrant populations translate into a relative difference in the number of kidney transplants (KT) performed in documented immigrant patients (first and second generation) relative to native-born patients in Europe. Methods: A literature search was performed in PubMed from inception to 11-10-2022. Studies were eligible if: (1) written in English, (2) included immigrant and native-born KT patients, (3) performed in countries registered as Council of Europe members, (4) focused on documented first- and second-generation immigrant populations [1]. Systematic reviews, literature reviews, and case reports or articles about emigration, non-KT, and undocumented immigrants were excluded. The outcome measurement was a relative percentage of KTs to the total population per 100.000 residents. By dividing the immigrant percentages by the native-born resident percentages, the odds ratio (OR) was calculated in a meta-analysis. The risk of bias was assessed; articles with high risk of bias were excluded in a second meta-analysis. Results: Out of 109 articles, 5 were included (n = 24,614). One Italian study (n = 24,174) had a ratio below 1, being 0.910 (95%CI 0.877-0.945). The other four articles (n = 196, n = 283, n = 77, n = 119) had ratios above 1: 1.36 (95%CI 0.980-1.87), 2.04 (95%CI 1.56-2.68), 2.23 (95%CI 1.53-3.25) and 2.64 (95%CI 1.68-4.15). After performing a meta-analysis, the OR did not show a significant difference: 1.68 (95%CI 1.03-2.75). After bias correction, this remained unchanged: 1.78 (95%CI 0.961-3.31). Conclusions: In our meta-analysis we did not find a significant difference in the relative number of KTs performed in immigrant versus native-born populations in Europe. However, a lesser likelihood for immigrants to receive a pre-emptive kidney transplantation was found. Large heterogeneity between studies (e.g. different sample size, patient origins, study duration, adult vs children patients) was a shortcoming to our analysis. Nevertheless, our article is the first review in this understudied topic. As important questions (e.g. on ethnicity, living donor rate) remain, future studies are needed to address them

A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation

Like Bcl-2, Mcl-1 is an important survival factor for many cancers, its expression contributing to chemoresistance and disease relapse. However, unlike other prosurvival Bcl-2–like proteins, Mcl-1 stability is acutely regulated. For example, the Bcl-2 homology 3 (BH3)–only protein Noxa, which preferentially binds to Mcl-1, also targets it for proteasomal degradation. In this paper, we describe the discovery and characterization of a novel BH3-like ligand derived from Bim, BimS2A, which is highly selective for Mcl-1. Unlike Noxa, BimS2A is unable to trigger Mcl-1 degradation, yet, like Noxa, BimS2A promotes cell killing only when Bcl-xL is absent or neutralized. Furthermore, killing by endogenous Bim is not associated with Mcl-1 degradation. Thus, functional inactivation of Mcl-1 does not always require its elimination. Rather, it can be efficiently antagonized by a BH3-like ligand tightly engaging its binding groove, which is confirmed here with a structural study. Our data have important implications for the discovery of compounds that might kill cells whose survival depends on Mcl-1

Tunneling with dissipation and decoherence for a large spin

We present rigorous solution of problems of tunneling with dissipation and decoherence for a spin of an atom or a molecule in an isotropic solid matrix. Our approach is based upon switching to a rotating coordinate system coupled to the local crystal field. We show that the spin of a molecule can be used in a qubit only if the molecule is strongly coupled with its atomic environment. This condition is a consequence of the conservation of the total angular momentum (spin + matrix), that has been largely ignored in previous studies of spin tunneling.Comment: 4 page

Superfluids and Supersolids on Frustrated 2D Lattices

We study the ground state of hard-core bosons with nearest-neighbor hopping and nearest-neighbor interactions on the triangular and Kagom\'e lattices by mapping to a system of spins ($S={1\over2}$), which we analyze using spin-wave theory. We find that the both lattices display superfluid and supersolid (a coexistence of superfluid and solid) order as the parameters and filling are varied. Quantum fluctuations seem large enough in the Kagom\'e system to raise the interesting possibility of a disordered ground state.Comment: Latex format, 24 figures available by email upon request. Submitted to Physical Review

Evaluatie van het, in 1987 in het kader van het VREK-programma uitgevoerde onderzoek naar de cadmium-, lood-, kwik- en arseengehalten in vlees en organen van runderen, varkens, schapen, kalveren en pluimvee

De in 1987 in het kader van het LAC-signaleringsprograrruna VREK gevonden lood-, cadmium-, kwik- en arseengehalten zijn gepresenteerd en vergeleken met de resultaten van voorgaande jaren. Voorts zijn de gevonden gehalten getoetst aan de geldende aktiegrenzen en ontwerpnormen. In de verdelingen van de gevonden loodgehalten in vlees, levers en nieren van zowel runderen als varkens is in de loop van de jaren een verschuiving naar lagere waarden waarneembaar. De range waarbinnen de loodgehalten worden gevonden is echter nagenoeg konstant. De in 1987 gevonden loodgehalten in schapelevers liggen op een vergelijkbaar niveau als in 1986, maar op een beduidend lager niveau dan in de jaren daarvoor. Een mogelijke relatie tussen deze abrupte daling van de loodgehalten in schapelevers en de sterke toename van loodvrije benzine met een hiermee samenhangende vermeende daling in de atmosferische looddepositie zal nader worden onderzocht. In 1987 werden in kalfslevers meer lagere en in schapenieren daarentegen meer hogere cadmiumgehalten waargenomen. In 1987 werden in 1 monster varkensvlees en in 1 monster rundvlees de aktiegrens en de ontwerpnorm voor cadmium overschreden. Voorts werd in 2 monsters rundernier de voor cadmium geldende aktiegrens overschreden. In 1 monster van een rund werden in het vlees, de nier en de lever verhoogde arseengehalten waargenomen. Alleen de voor nieren geldende aktiegrens van arseen werd hierbij overschreden, terwijl de respectievelijke richtnormen niet werden overschreden

Formulae for zero-temperature conductance through a region with interaction

The zero-temperature linear response conductance through an interacting mesoscopic region attached to noninteracting leads is investigated. We present a set of formulae expressing the conductance in terms of the ground-state energy or persistent currents in an auxiliary system, namely a ring threaded by a magnetic flux and containing the correlated electron region. We first derive the conductance formulae for the noninteracting case and then give arguments why the formalism is also correct in the interacting case if the ground state of a system exhibits Fermi liquid properties. We prove that in such systems, the ground-state energy is a universal function of the magnetic flux, where the conductance is the only parameter. The method is tested by comparing its predictions with exact results and results of other methods for problems such as the transport through single and double quantum dots containing interacting electrons. The comparisons show an excellent quantitative agreement.Comment: 18 pages, 18 figures; to appear in Phys. Rev.

Magnetic Field Dependence of Macroscopic Quantum Tunneling and Coherence of Ferromagnetic Particle

We calculate the quantum tunneling rate of a ferromagnetic particle of $\sim 100 \AA$ diameter in a magnetic field of arbitrary angle. We consider the magnetocrystalline anisotropy with the biaxial symmetry and that with the tetragonal symmetry. Using the spin-coherent-state path integral, we obtain approximate analytic formulas of the tunneling rates in the small $\epsilon (=1- H/H_c)$-limit for the magnetic field normal to the easy axis ($\theta_H = \pi/2$), for the field opposite to the initial easy axis ($\theta_H = \pi$), and for the field at an angle between these two orientations ($\pi/2 << \theta_H << \pi$). In addition, we obtain numerically the tunneling rates for the biaxial symmetry in the full range of the angle $\theta_H$ of the magnetic field ($\pi/2 < \theta_H \leq \pi$), for the values of \epsilon =0.01 and 0.001.Comment: 25 pages of text (RevTex) and 4 figures (PostScript files), to be published in Phys. Rev.