Association between hereditary predisposition to common cancers and congenital multimalformations

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer-prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer-prone families, the risk for malformations was multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8-21.7] for cancer-prone families but with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.     

Investigating Canadian medical school attrition metrics to inform socially accountable admissions planning

Objective: Attrition from Canadian medical degree programs was never described despite differences in admissions requirements at the 17 faculties of medicine. Knowledge on attrition metrics could help the faculties evaluate new avenues for addressing the Association of Faculties of Medicine’s (AFMC) Future of Medical Education in Canada (FMEC MD) recommendation to enhance admissions practices with the goal to improve social accountability and student diversity.

Method: AFMC databases were used to track medical degree completion of all Canadian M.D. students who enrolled between 2003 and 2007. Students were followed and assigned an M.D. completion status as of by July 1, 2013. Bivariate statistics were used to evaluate if demographic, admission and degree progression variables were associated with medical school attrition.

Results: Of 11,454 students enrolled in Canadian M.D. programs from 2003 to 2007, only 197 (1.7%) did not complete. Québec had significantly higher attrition than other jurisdictions with age, educational attainment at time of enrolment, MCAT completion and struggling academically associated with attrition.

Conclusion: Attrition from Canadian MD programs is rare and associated with differences in admission requirements and possibly suggests an optimum life stage for medical studies. Improved knowledge of attrition-related factors may offer an additional level of evidence for improving the alignment between admissions policies and the social accountability objectives of medical schools.     

Poor Intraoperative Blood Glucose Control Is Associated with a Worsened Hospital Outcome after Cardiac Surgery in Diabetic Patients

Background: Tight perioperative control of blood glucose improves the outcome of diabetic patients undergoing cardiac surgery. Because stress response and cardiopulmonary bypass can induce profound hyperglycemia, intraoperative glycemic control may become difficult. The authors undertook a prospective cohort study to determine whether poor intraoperative glycemic control is associated with increased intrahospital morbidity.

Methods: Two hundred consecutive diabetic patients undergoing on-pump heart surgery were enrolled. A standard insulin protocol based on subcutaneous intermediary insulin was given the morning of the surgery. Intravenous insulin therapy was initiated intraoperatively from blood glucose concentrations of 180 mg/dl or greater and titrated according to a predefined protocol. Poor intraoperative glycemic control was defined as four consecutive blood glucose concentrations greater than 200 mg/dl without any decrease in despite insulin therapy. Postoperative blood glucose concentrations were maintained below 140 mg/dl by using aggressive insulin therapy. The main endpoints were severe cardiovascular, respiratory, infectious, neurologic, and renal in-hospital morbidity.

Results: Insulin therapy was required intraoperatively in 36% of patients, and poor intraoperative glycemic control was observed in 18% of patients. Poor intraoperative glycemic control was significantly more frequent in patients with severe postoperative morbidity (37% vs. 10%; P < 0.001). The adjusted odds ratio for severe postoperative morbidity among patients with a poor intraoperative glycemic control as compared with patients without was 7.2 (95% confidence interval, 2.7-19.0).     

Correlating digit span performance and event-related potentials to assess working memory.

Event-related brain potentials (ERPs) were recorded during a computerized and modified version of the Digit Span Backwards (DB) task from the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III). The modified DB version (ERP-DB task) was divided into two sections of 2, 4, 6 and 8 digits in length (Group 1) and 3, 5 and 7 digits in length (Group 2). Each trial had a study phase and a test phase. For the study phase, a series of digits was presented sequentially and aurally to 20 participants (10 for each group). For the test phase, a second series of digits was also presented sequentially and aurally that either corresponded to the reverse order of the digits in the study phase (correct condition) or had one digit in the sequence replaced by an incorrect digit (incorrect condition). The traditional DB task of the WAIS-III was also administered for comparison purposes. A prolonged positive slow wave (PSW) peaking between 450 and 750 ms was elicited to incorrect condition trials. For each participant, a derived measure was calculated from the ERP differentiation between correct and incorrect conditions. The derived measure was defined as the mean of the t-values obtained from the correct and incorrect waveform comparison, within the temporal interval that encompassed this component. The strongest statistical correlations between the derived measure and the traditional DB test scores were found at the Pz site (Group 1: r=0.79; Group 2: r=0.59). This statistical approach shows that it is possible to adequately relate an individual's performance on a traditional measure of working memory and ERP patterns. Overall, we believe that this kind of ERP approach holds promise as a technique for assessing quantitatively non-communicative patients.     

A novel nucleotide-containing antigen for human blood γδ T lymphocytes

The stimulation of human γδ T cells by mycobacteria occurs through recognition of four distinct nonpeptide phosphorylated antigens termed TUBag1–4. Among these latter, TUBag4 has already been biochemically characterized as a γ-X derivative of 5′-deoxythymidine triphosphate (Constant, P., Davodeau, F., Peyrat, M. A., Poquet, Y., Puzo, G., Bonneville, M. and Fournié, J.-J., Science 1994. 264: 267). However, despite chemical synthesis of weakly stimulatory nucleotide-containing analogs, these mycobacterial compounds remained the sole nucleotide-containing antigens actually isolated from natural sources. Here, we present the complete isolation of the TUBag3 antigen from Mycobacterium fortuitum and demonstrate that this nonpeptide molecule contains a 5′-UTP nucleotide moiety. On selected Vγ9/Vδ2 clones, T cell responses can be triggered with nanomolar concentrations of TUBag3. Like crude mycobacterial extracts, this purified nucleotide conjugate elicits a strong polyclonal response of γδ PBL from healthy donors. Furthermore, we present evidence that this compound is distinct from the recently synthesized γ-isopentenyl 5′-UTP, a nucleotide conjugate of isopentenyl pyrophosphate that was found to be stimulatory for human γδ T cells (Tanaka, Y., Morita, C. T., Tanaka, Y., Nieves, E., Brenner, M. B. and Bloom, B. R., Nature 1995. 375: 155). Since it appears that both mycobacterial nucleotide antigens are molecules structurally related to peculiar precursors of nucleic acid synthesis, we propose that TUBag-reactive T cells might be specifically devoted to surveillance of proliferating cells.     

Hormonal and metabolic adaptation in professional cyclists during training.

The aim of this study was to examine hormonal and metabolic changes in a group of 18 professional male cyclists ((.)VO(2)max 69.9 [95 % CI 64.9 to 74.9] mL x kg(-1) x min(-1) ) during two successive periods of adapted intensive training. The second training period included 4 days of cycling competition. Intensity was increased while volume was decreased in the second training. Anthropometric data were collected before and at the end of the two training periods. Venous blood samples were taken in a basal state before the two training sessions and after each training session. Serum concentrations of cortisol (C), testosterone (T), dehydroepiandrosterone sulfate (DHEAs), and catecholamines were determined as well as branched-chain amino acids (valine, leucine, isoleucine) (BCAA) and free fatty acids (FFAs). At the end of the two training periods, the subjects lost fat mass whereas mean body mass was unchanged. The T/C ratio was reduced transiently after the first training session (45.90 %), while DHEAs/C remained unchanged. T/C and DHEAs/C were significantly increased after the second training session compared to the first (48.40 and 97.18 %, respectively). Catecholamines and FFAs were unchanged. The significant increase in BCAA levels after the second training session was of note as it might constitute a "store shape" of amino acids in anticipation of future intense training loads. Based on the responses of testosterone, DHEAs, and cortisol, and on the training-induced increase in BCAA, there appeared to be hormonal and metabolic adaptation despite the inherent psychological stress of competition.     

Hormonal responses to training and its tapering off in competitive swimmers: relationships with performance

During a winter training season, the effects of 12 weeks of intense training and 4 weeks of tapering off (taper) on plasma hormone concentrations and competition performance were investigated in a group of highly trained swimmers (n = 8). Blood samples were collected and the swimmers performed their speciality in competition at weeks 10 (mid-season), 22 (pre-taper) and 26 (post-taper). No statistically significant changes were observed in the concentrations of total testosterone (TT), non-sex hormone binding globulin-boundtestosterone (NSBT), cortisol (C), luteinising hormone, thyroid stimulating hormone, triiodothyronine, thyroxine plasma catecholamines, creatine kinase and ammonia during training and taper. Mid-season NSBT: C ratio and the amount of training were statistically related (r = 0.82,P < 0.05). Competition performance slightly declined during intense training [0.52 (SD 2.51) %, NS] and improved during taper [2.32 (SD 1.69)%,P < 0.01]. Changes in performance during training and taper correlated with changes in ratios TT: C (r = 0.86,P < 0.01andr = 0.81,P < 0.05, respectively) and NSBT: C (r = 0.77,P < 0.05 andr = 0.76,P < 0.05, respectively). In summary, these results showed that the monitored plasma hormones and metabolic indices were unaltered by 12 weeks of intense training and 4 weeks of taper. The TT: C and NSBT: C ratios, however, appeared to be effective markers of the swimmers' performance capacities throughout the training season.     

Intracerebroventricular infusion of neuropeptide Y up-regulates synthesis and accumulation of luteinizing hormone but not follicle stimulating hormone in the pituitary cells of prepubertal female lambs

Neuropeptide Y (NPY) is a putative neuroregulator of the reproductive axis in the central nervous system. In this study we evaluated the effects of central infusion of exogenous NPY on the secretory activity of pituitary gonadotrophic cells in prepubertal lambs. Immature female Merino sheep (n=12) were infused of Ringer solution (control) or 50 microg of NPY to the third ventricle for 5 min and then slaughtered 3 h later. Immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) cells were localised by immunohistochemistry using antibody raised against LHbeta and FSHbeta. Messenger RNA analyses were performed by in situ hybridisation using sense and antisense riboprobes produced from beta subunits of LH and FSH cDNA clones. The results were generated by computer image analysis to determine the area fraction occupied by immunoreactive and/or hybridising cells and optical density for immunostaining and hybridisation signal. LH in the blood plasma was determined by radioimmunoassay. It was found, that in the lambs infused with NPY the area fraction and optical density for immunoreactive LH cells and mRNA LHbeta-expressing cells increased significantly (P<0.001), compared to the vehicle-infused animals. The concentration of LH in the blood plasma did not differ between control and treated groups. The NPY infusions had no effect on the immunoreactivity of FSH cells or on expression of mRNA for FSHbeta. In conclusion we suggest that NPY may be an important component of mechanisms stimulating the synthesis and storage but not the release of LH in the pituitary gonadotrophs from prepubertal female sheep. In addition, this effect is specific for LH, no such effect was apparent on FSH.