Prevention of colorectal cancer by colonoscopic surveillance in families with hereditary colorectal cancer

Objective. In recent years persons at risk for colorectal cancers (CRC) have been subjected to follow-up with colonoscopy in many centres. There is, however, limited knowledge about the effect of such interventions. The objective of this study was to report the results of our observations during the past 15 years. Material and methods. Healthy persons were included in the study according to their family history of CRCs, and prospectively followed with colonoscopies. Results. Altogether, 1133 individuals were included and observed for a total of 3474 follow-up years from the first to the last colonoscopy initiated by our activity. Mismatch repair (MMR) mutations were detected in 6.5% of cases. A total of 1383 polyps were removed, 72% were less than 5 mm in diameter. Findings were scored as hyperplastic polyps (n=887), adenomas with mild to moderate dysplasia (n=460), adenomas with high-grade dysplasia (n=30) and cancers (n=6). Two cancers were observed after the first colonoscopy, compared with 2.6 expected by chance and more than 20 expected under the hypothesis of predominant inherited diseases in the families. Observed annual incidence rates for adenomas were similar in all groups, while in the mutation carriers there was a higher frequency of progression to severe dysplasia or infiltrating cancer. Conclusions. A simple explanation for the combined findings may be that all selected families had a similar tendency to produce adenomas, while mutation carriers more frequently demonstrated dysplasia/cancer in the adenomas. The low annual incidence rates for CRC indicated that the removal of adenomas may have prevented cancers.     

Promotion of Self-directed Learning Using Virtual Patient Cases

Objective. To assess the effectiveness of virtual patient cases to promote self-directed learning (SDL) in a required advanced therapeutics course.Design. Virtual patient software based on a branched-narrative decision-making model was used to create complex patient case simulations to replace lecture-based instruction. Within each simulation, students used SDL principles to learn course objectives, apply their knowledge through clinical recommendations, and assess their progress through patient outcomes and faculty feedback linked to their individual decisions. Group discussions followed each virtual patient case to provide further interpretation, clarification, and clinical perspective.Assessments. Students found the simulated patient cases to be organized (90%), enjoyable (82%), intellectually challenging (97%), and valuable to their understanding of course content (91%). Students further indicated that completion of the virtual patient cases prior to class permitted better use of class time (78%) and promoted SDL (84%). When assessment questions regarding material on postoperative nausea and vomiting were compared, no difference in scores were found between the students who attended the lecture on the material in 2011 (control group) and those who completed the virtual patient case on the material in 2012 (intervention group).Conclusion. Completion of virtual patient cases, designed to replace lectures and promote SDL, was overwhelmingly supported by students and proved to be as effective as traditional teaching methods.     

PRKDC mutations in a SCID patient with profound neurological abnormalities

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs; encoded byPRKDC) functions in DNA non-homologous end-joining (NHEJ), themajor DNA double strand break (DSB) rejoining pathway. NHEJ also functions duringlymphocyte development, joining V(D)J recombination intermediates during antigenreceptor gene assembly. Here, we describe a patient with compound heterozygousmutations in PRKDC, low DNA-PKcs expression, barely detectableDNA-PK kinase activity, and impaired DSB repair. In a heterologous expression system,we found that one of the PRKDC mutations inactivated DNA-PKcs, whilethe other resulted in dramatically diminished but detectable residual function. Thepatient suffered SCID with reduced or absent T and B cells, as predicted fromPRKDC-deficient animal models. Unexpectedly, the patient was alsodysmorphic; showed severe growth failure, microcephaly, and seizures; and hadprofound, globally impaired neurological function. MRI scans revealedmicrocephaly-associated cortical and hippocampal dysplasia and progressive atrophyover 2 years of life. These neurological features were markedly more severe thanthose observed in patients with deficiencies in other NHEJ proteins. Although loss ofDNA-PKcs in mice, dogs, and horses was previously shown not to impair neuronaldevelopment, our findings demonstrate a stringent requirement for DNA-PKcs duringhuman neuronal development and suggest that high DNA-PK protein expression isrequired to sustain efficient pre- and postnatal neurogenesis.     

Innate Immune Activation After Transfusion of Stored Red Blood Cells

The transfusion of red blood cells (RBCs), although necessary for treatment of anemia and blood loss, has also been linked to increased morbidity and mortality. RBCs stored for longer durations and transfused in larger volumes are often cited as contributory to adverse outcomes. The potential mechanisms underlying deleterious effects of RBC transfusion are just beginning to be elucidated. In this narrative review, we explore the hypothesis that prolonged RBC storage results in elaboration of substances which may function as danger associated molecular pattern molecules that activate the innate immune system with consequences unfavorable to healthy homeostasis. The nature of these chemical mediators and the biological responses to them offers insight into the mechanisms of these pathological responses. Three major areas of activation of the innate immune apparatus by stored RBCs have been tentatively identified: RBC hemolysis, recipient neutrophil priming, and reactive oxygen species production. The possible mechanisms by which each might perturb the innate immune response are reviewed in a search for potential novel pathways through which transfusion can lead to an altered inflammatory response.     

Direct and indirect effects of insulin on glucose uptake and storage by the liver

Studies were conducted in conscious 42-h-fasted dogs to determine how much of insulin's effect on hepatic glucose uptake arises from its direct hepatic action versus its indirect (extrahepatic) action. Each experiment consisted of equilibration, basal, and experimental periods. During the latter, somatostatin, basal intraportal glucagon, portal glucose (21.3 micromol x kg(-1) x min(-1)), and peripheral glucose (to double the hepatic glucose load) were infused. During the experimental period, insulin was infused intraportally at a basal rate (BI, n = 6), at a fourfold basal rate (PoI, n = 6), or via a peripheral vein to create a selective increase in the arterial insulin level similar to that in PoI (PeI, n = 6). Arterial and hepatic sinusoidal insulin levels (in picomoles per liter) during the experimental period were 31 +/- 5 and 113 +/- 15 in BI, 97 +/- 11 and 394 +/- 66 in PoI, and 111 +/- 13 and 96 +/- 9 in PeI, respectively. Net hepatic glucose uptake (NHGU) averaged 7.0 +/- 1.1 micromol x kg(-1) x min(-1), 15.7 +/- 2.7 micromol x kg(-1) x min(-1) (P < 0.05 vs. BI), and 12.0 +/- 2.4 micromol x kg(-1) x min(-1) (P < 0.05 vs. BI) in BI, PoI, and PeI, respectively. Net hepatic carbon retention was 4.4 +/- 1.2 micromol glucose equivalents. kg(-1) x min(-1), 12.3 +/- 2.5 micromol glucose equivalents x kg(-1) x min(-1) (P < 0.05 vs. BI, P < 0.05 vs. PeI), and 7.1 +/- 1.0 micromol glucose equivalents x kg(-1) x min(-1) (P < 0.05 vs. BI) in BI, PoI, and PeI, respectively. Both direct and indirect insulin actions increase NHGU, but the rise in hepatic sinusoidal insulin appears critical for efficient storage of glucose as hepatic glycogen.