Quantitative kinetic modelling and mapping of cerebral glucose transport and metabolism using glucoCESL MRI

Chemical-exchange spin-lock (CESL) MRI can map regional uptake and utilisation of glucose in the brain at high spatial resolution (i.e sub 0.2 mm³ voxels). We propose two quantitative kinetic models to describe glucose-induced changes in tissue R_1ρ and apply them to glucoCESL MRI data acquired in tumour-bearing and healthy rats. When assuming glucose transport is saturable, the maximal transport capacity (T_max) measured in normal tissue was 3.2 ± 0.6 µmol/min/mL, the half saturation constant (K_t) was 8.8 ± 2.2 mM, the metabolic rate of glucose consumption (MR_glc) was 0.21 ± 0.13 µmol/min/mL, and the cerebral blood volume (v_b) was 0.006 ± 0.005 mL/mL. Values in tumour were: T_max = 7.1 ± 2.7 µmol/min/mL, K_t = 14 ± 1.7 mM, MR_glc = 0.22 ± 0.09 µmol/min/mL, v_b = 0.030 ± 0.035 mL/mL. T_max and K_t were significantly higher in tumour tissue than normal tissue (p = 0.006 and p = 0.011, respectively). When assuming glucose uptake also occurs via free diffusion, the free diffusion rate (k_d) was 0.061 ± 0.017 mL/min/mL in normal tissue and 0.12 ± 0.042 mL/min/mL in tumour. These parameter estimates agree well with literature values obtained using other approaches (e.g. NMR spectroscopy).     

COVID-19 vaccine effectiveness against SARS-CoV-2 infection during the Delta period,a nationwide study adjusting for chance of exposure,the Netherlands,July to December 2021

BackgroundDifferential SARS-CoV-2 exposure between vaccinated and unvaccinated individuals may confound vaccine effectiveness (VE) estimates.AimWe conducted a test-negative case–control study to determine VE against SARS-CoV-2 infection and the presence of confounding by SARS-CoV-2 exposure.MethodsWe included adults tested for SARS-CoV-2 at community facilities between 4 July and 8 December 2021 (circulation period of the Delta variant). The VE against SARS-CoV-2 infection after primary vaccination with an mRNA (Comirnaty or Spikevax) or vector-based vaccine (Vaxzevria or Janssen) was calculated using logistic regression adjusting for age, sex and calendar week (Model 1). We additionally adjusted for comorbidity and education level (Model 2) and SARS-CoV-2 exposure (number of close contacts, visiting busy locations, household size, face mask wearing, contact with SARS-CoV-2 case; Model 3). We stratified by age, vaccine type and time since vaccination.ResultsVE against infection (Model 3) was 64% (95% CI: 50–73), only slightly lower than in Models 1 (68%; 95% CI: 58–76) and 2 (67%; 95% CI: 56–75). Estimates stratified by age group, vaccine and time since vaccination remained similar: mRNA VE (Model 3) among people ≥ 50 years decreased significantly (p = 0.01) from 81% (95% CI: 66–91) at < 120 days to 61% (95% CI: 22–80) at ≥ 120 days after vaccination. It decreased from 83% to 59% in Model 1 and from 81% to 56% in Model 2.ConclusionSARS-CoV-2 exposure did not majorly confound the estimated COVID-19 VE against infection, suggesting that VE can be estimated accurately using routinely collected data without exposure information.     

Educational objectives and requirements of an undergraduate clerkship in general practice. The outcome of a consensus procedure

OBJECTIVES: The main aim of this study was to reach consensus between students, faculty and general practice teachers on the educational objectives and requirements of the clerkship in general practice. METHOD: The consensus procedure consisted of four steps and all active general practice teachers (n = 116) were asked to participate in the study. RESULTS: We identified 189 educational objectives: 127 complaints (problems, symptoms, syndromes), 29 clinical skills and 37 objectives concerning the theoretical dimensions of general practice. Educational requirements crystallized to 16 essential preconditions of a teaching practice and 35 didactic activities to be performed by the general practice teachers. CONCLUSIONS: These consensus results will be used to structure the medical curriculum and as guidelines for the educational process during the clerkship.      

Chemopreventive effects of 2-(allylthio)pyrazine on hepatic lesion, mutagenesis and tumorigenesis induced by vinyl carbamate or vinyl carbamate epoxide

2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a hepatoprotective agent, has been found to selectively inhibit rat hepatic cytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261- 269, 1997), while it enhances the activities of phase II detoxification enzymes such as glutathione S-transferase and epoxide hydrolase. As part of a program in evaluating the chemopreventive potential of 2-AP, we have determined its effects on hepatotoxicity, mutagenicity and tumorigenicity of vinyl carbamate (VC), a prototypic hepatocarcinogen preferentially activated by P450 2E1 to the ultimate carcinogenic metabolite vinyl carbamate epoxide (VCO), which undergoes detoxification by glutathione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male Sprague-Dawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of these compounds as determined by decreased serum aspartate aminotransferase and alanine aminotransferase activities. Furthermore, 2-AP pre-treatment significantly suppressed the VC-induced hepatocarcinogenesis in infant male B6C3F1 mice. In a separate experiment, the multiplicities of skin tumors formed in female ICR mice treated with 5.8 micromol of VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncogene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inhibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreventive agent.      

Normal and disrupted lumbar longitudinal ligaments: correlative MR and anatomic study

The posterior and anterior longitudinal ligaments of the lumbar spine appear on magnetic resonance (MR) images as thin lines of very low signal intensity in all spin-echo sequences. They cover the periphery of the outer fibers of the anulus fibrosus on sagittal images. The lumbar spine of 17 patients with 19 disk herniations was prospectively evaluated with MR imaging, and these findings were correlated with surgical findings. At surgery the posterior ligament was found to be disrupted in eight cases and intact in 11. Absence of a low-signal peripheral line around the herniated nucleus pulposus (HNP) was the most reliable sign of ligament rupture (no false-negative or false-positive findings). The peripheral line appeared to be interrupted in four cases, two of which were falsely positive. The two false-positive cases were related to a chemical shift artifact between epidural fat and the HNP. Presence of a normal and continuous peripheral line outlining the HNP excluded ligament disruption. The overall sensitivity for detecting disruption was 100%, and the specificity was 78%.