The Effect of Insulin on the Intracellular Distribution of 14(R,S)-[18F]Fluoro-6-thia-heptadecanoic Acid in Rats

Purpose The aim of this study was to determine the effect of hyperinsulinemia on myocardial and hepatic distribution and metabolism of 14(R,S)-[¹⁸F]fluoro-6-thia-heptadecanoic acid ([¹⁸F]FTHA).Procedures Mitochondrial retention and intracellular lipid incorporation of [¹⁸F]FTHA were compared to that of [¹⁴C]-2-bromopalmitate or [¹⁴C]palmitate during hyperinsulinemic clamp vs. saline infusion in male Wistar rats.Results Mitochondrial ¹⁸F activity was increased in the heart (1.7 ± 0.4 vs. 0.5 ± 0.1% ID/g, P < 0.05), whereas it was reduced in the liver (1.1 ± 0.3 vs. 1.8 ± 0.4% ID/g, P < 0.05) during insulin vs. saline infusion, respectively. Mitochondrial [¹⁴C]-2-bromopalmitate activity was affected by insulin in a similar way in both tissues. The fractional esterification of [¹⁸F]FTHA into triglycerides was impaired compared to [¹⁴C]palmitate in both tissues, and [¹⁸F]FTHA was insensitive to the shift of esterification of fatty acids into complex lipids in response to insulin.Conclusions [¹⁸F]FTHA is sensitive to insulin-induced modifications of free fatty acid oxidative metabolism in rats but is insensitive to changes in nonoxidative fatty acid metabolism.     

Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study

Graefe's Archive for Clinical and Experimental Ophthalmology - To report the effectiveness of intravitreal aflibercept (IVT-AFL) treatment for diabetic macular edema (DME) in French clinical...     

Oncological patterns of care and outcomes for 265 elderly patients with newly diagnosed glioblastoma in France

The incidence of glioblastoma (GBM) has increased in patients aged 70 years or older, and will continue to grow. Elderly GBM patients have been excluded from most clinical trials; furthermore, optimal care management as well as benefit/risk ratio of GBM treatments are still being debated. This study describes oncological patterns of care, prognostic factors, and survival for patients ≥70 years in France. We identified patients over 70 with newly diagnosed and histologically confirmed GBM on data previously published by the French Brain Tumor DataBase. We included 265 patients. Neurological deficits and mental status disorders were the most frequent symptoms. The surgery consisted of resection (RS _n?=?95) or biopsy (B _n?=?170); 98 patients did not have subsequent oncological treatment. After surgery, first-line treatment consisted of radiotherapy (RT _n?=?76), chemotherapy (CT _n?=?52), and concomitant radiochemotherapy (CRC _n?=?39). The median age at diagnosis was 76, 74, and 73 years, respectively, for the untreated, B?+?RT and/or CT, RS?±?RT and/or CT groups. Median survival (in days, 95 % CI) with these main strategies, when analyzed according to surgical groups, was: B-CT _n?=?41, 199_[155–280]; B-CRC _n?=?21, 318_[166–480]; B-RT _n?=?37, 149_[130–214]; RS-CT _n?=?11, 245_[211–na]; RS-CRC _n?=?18, 372_[349–593]; RS-RT _n?=?39, 269_[218–343]. This population study for elderly GBM patients is one of the most important in Europe, and could be considered as a historical cohort to compare future treatments. Moreover, we can hypothesize that elderly patients (versus patients <70 years) are undertreated. Karnofsky performance status seems to be the most relevant clinical predictive factor, and RS and CRC have a positive impact on survival for elderly GBM patients in the general population, at least when feasible.     

TMPRSS2-ERG Fusions Are Strongly Linked to Young Patient Age in Low-grade Prostate Cancer

Based on next-generation sequencing of early-onset prostate cancer (PCa), we earlier demonstrated that PCa in young patients is prone to rearrangements involving androgen-regulated genes—such as transmembrane protease, serine 2 (TMPRSS2)–v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion—and provided data suggesting that this situation might be caused by increased androgen signaling in younger men. In the same study, an accumulation of chromosomal deletions was found in cancers of elderly patients. To determine how age-dependent molecular features relate to cancer phenotype, an existing data set of 11 152 PCas was expanded by additional fluorescence in situ hybridization analyses of phosphatase and tensin homolog (PTEN), 6q15 and 5q21. The results demonstrate that the decrease in TMPRSS2–ERG fusions with increasing patient age is limited to low-grade cancers (Gleason ≤3 + 4) and that the significant increase in the deletion frequency with age was strictly limited to ERG-negative cancers for 6q15 and 5q21 but to ERG-positive cancers for PTEN. These data suggest that the accumulation of non–androgen-linked genomic alterations with advanced patient age may require an appropriate microenvironment, such as a positive or negative ERG status. The strong link of ERG activation to young patient age and low-grade cancers may help to explain a slight predominance of low-grade cancers in young patients.     

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%–5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.     

Changes in Medical Students’ Attitudes Towards End-of-Life Decisions Across Different Years of Medical Training

BACKGROUND  Decisions to forgo life-sustaining medical treatments in terminally ill patients are challenging, but ones that all doctors must face. Few studies have evaluated the impact of medical training on medical students’ attitudes towards end-of-life decisions and none have compared them with an age-matched group of non-medical students. OBJECTIVE  To assess the effect of medical education on medical students’ attitudes towards end-of-life decisions in acutely ill patients. DESIGN  Cross-sectional study. PARTICIPANTS  Four hundred and two students at The Chinese University of Hong Kong. MEASUREMENTS  Completion of a questionnaire focused on end-of-life decisions. MAIN RESULTS  The number of students who felt that cardiopulmonary resuscitation must always be provided was higher in non-medical students (76/90 (84%)) and medical students with less training (67/84 (80%) in year 1 vs. 18/67 (27%) in year 5) (p < 0.001). Discontinuing life-support therapy was more accepted among senior medical students compared to junior medical and non-medical students (27/66 (41%) in year 5 vs. 18/83 (22%) in year 1 and 20/90 (22%) in non-medical students) (p = 0.003). An unexpectedly large proportion of non-medical students (57/89 (64%)) and year 1 medical students (42/84 (50%)) found it acceptable to administer fatal doses of drugs to patients with limited prognosis. Euthanasia was less accepted with more years of training (p < 0.001). When making decisions regarding limitation of life-support therapy, students chose to involve patients (98%), doctors (92%) and families (73%) but few chose to involve nurses (38%). CONCLUSIONS  Medical students’ attitudes towards end-of-life decisions changed during medical training and differed significantly from those of non-medical students.     

A2 gene of Old World cutaneous <Emphasis Type="Italic">Leishmania</Emphasis> is a single highly conserved functional gene

Background  

Leishmaniases are among the most proteiform parasitic infections in humans ranging from unapparent to cutaneous, mucocutaneous or visceral diseases. The various clinical issues depend on complex and still poorly understood mechanisms where both host and parasite factors are interacting. Among the candidate factors of parasite virulence are the A2 genes, a family of multiple genes that are developmentally expressed in species of the Leishmania donovani group responsible for visceral diseases (VL). By contrast, in L. major determining cutaneous infections (CL) we showed that A2 genes are present in a truncated form only. Furthermore, the A2 genomic sequences of L. major were considered subsequently to represent non-expressed pseudogenes [1]. Consequently, it was suggested that the structural and functional properties of A2 genes could play a role in the differential tropism of CL and VL leishmanias. On this basis, it was of importance to determine whether the observed structural/functional particularities of the L. major A2 genes were shared by other CL Leishmania, therefore representing a proper characteristic of CL A2 genes as opposed to those of VL isolates.     

Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men

The present study examined the associations between a major adipokine, adiponectin, and adiposity indices as well as metabolic risk variables in a sample of 190 untreated asymptomatic men. Anthropometric measurements and a complete fasting plasma lipoprotein and lipid profile were obtained, and subjects underwent an oral glucose tolerance test. Fasting plasma adiponectin concentrations were determined by an ELISA. Although all adiposity and adipose tissue (AT) distribution indices were negatively correlated with plasma adiponectin levels (-0.14 /=30 kg/m(2)) but who markedly differed in their level of visceral AT (< vs. >/=130 cm(2); n = 15) revealed significant differences in adiponectin levels (7.0 +/- 3.0 vs. 11.1 +/- 4.9 microg/ml; P < 0.02 for men with high vs. low visceral AT, respectively). Finally, when men were stratified into tertiles of visceral AT and further classified on the basis of the 50th percentile of adiponectin levels (8.8 microg/ml), a 3 x 2 ANOVA revealed an independent contribution of adiponectin on the variation of high-density lipoprotein cholesterol levels (P < 0.002) and of the glucose area (P < 0.02). These results support the notion that adiponectin concentration is influenced to a greater extent by visceral than sc obesity. Furthermore, adiponectin predicts glucose tolerance and plasma high-density lipoprotein cholesterol levels in a manner that is partly independent from the contribution of visceral adiposity.