TLR-3 receptor activation protects the very immature brain from ischemic injury

Abstract Background We have shown that preconditioning by lipopolysaccharide (LPS) will result in 90% reduction in ischemic brain damage in P7 rats. This robust LPS neuroprotection was not observed in P3 or P5 pups (corresponding to human premature infant). LPS is a known Toll-like receptor 4 (TLR-4) ligand. We hypothesized that TLRs other than TLR-4 may mediate preconditioning against cerebral ischemic injury in the developing brain. Methods TLR-2, TLR-3, TLR-4, and TLR-9 expression was detected in brain sections from P3, P5, and P7 rats by immuno-staining. In subsequent experiments, P5 rats were randomly assigned to TLR-3 specific agonist, poly I:C, or saline treated group. At 48 h after the injections, hypoxic-ischemic (HI) injury was induced by unilateral carotid artery ligation followed by hypoxia for 65 min. Brains were removed 1 week after HI injury and infarct volumes were compared in H&E stained sections between the two groups. Results TLR-2 and TLR-3 were highly expressed in brains of P3 and P5 but not in P7 rats. The number of TLR-4 positive cells was lower in P3 and P5 compared to P7 brains (P <0.05). TLR-3 was predominately expressed in P5 pups (P <0.05). There was no significant difference in TLR-9 expression in the three age groups. There was a significant reduction in infarct volume (P = 0.01) in poly I:C compared to saline pre-treated P5 pups. Pre-treatment with poly I:C downregulated NF-κB and upregulated IRF3 expression in P5 rat ischemic brains. Pre-treatment with poly I:C did not offer neuroprotection in P7 rat brains. Conclusion TLRs expression and function is developmentally determined. Poly I:C-induced preconditioning against ischemic injury may be mediated by modulation of TLR-3 signaling pathways. This is the first study to show that TLR-3 is expressed in the immature brain and mediates preconditioning against ischemic injury

Coagulation test understanding and ordering by medical trainees: Novel teaching approach

Abstract Background Coagulation testing provides a prime opportunity to make an impact on the reduction of unnecessary laboratory test ordering, as there are clear indications for testing. Despite the prothrombin time/international normalized ratio and activated partial thromboplastin time being validated for specific clinical indications, they are frequently ordered as screening tests and often ordered together, suggesting a gap in understanding of coagulation. Methods Based on a needs assessment, we developed an online educational module on coagulation for trainees, incorporating education on testing cost, specificity, and sensitivity. Fifty participating resident physicians and medical students completed a validated premodule quiz, postmodule quiz after completion of the module, and a latent quiz 3 to 6 months after to assess longer‐term knowledge retention. Trainees provided responses regarding their subjective laboratory test‐ordering practices before and after module completion. Results The median premodule quiz score was 67% (n = 50; range, 24%‐86%) with an increase of 24% to a median postmodule quiz score of 91% (n = 50; range, 64%‐100%). There was evidence of sustained knowledge acquisition with a latent quiz median score of 89% (n = 40; range, 67%–100%). Trainees were more likely to consider the sensitivity, specificity, and cost of laboratory investigations before ordering them following completion of the educational module. Conclusions Using the expertise of medical educators and incorporating trainee feedback, we employed a novel approach to the teaching of coagulation to maximize its approachability and clinical relevance. We found sustained knowledge retention regarding coagulation and appropriate coagulation test ordering, and a subjective change to trainee ordering habits following participation in our educational intervention

Risk Associated With Valvular Regurgitation During Pregnancy

Background: Pregnancies in women with regurgitant valve lesions are generally considered low risk, but this has not been well studied. Objectives: This study determined the frequency of adverse cardiac events (CEs) in pregnant women with moderate or severe regurgitant valve lesions. Methods: Maternal and fetal outcomes in women with moderate or severe chronic valve regurgitation enrolled in a prospective multicenter study on pregnancy outcomes were examined. Adverse CEs included heart failure, sustained arrhythmias, cardiac arrest, or death. A multivariate logistic regression model was used to identify determinants of CEs in women at the highest risk. Results: Outcomes of 430 pregnancies in women with moderate or severe regurgitant lesions were examined: 145 with mitral regurgitation (MR), 101 with pulmonary regurgitation (PR), 71 with multivalve disease, 73 with tricuspid regurgitation (TR), and 40 with aortic regurgitation (AR). Most women had associated congenital or acquired heart disease. Adverse CEs occurred in 13% of pregnancies: 27% of pregnancies with multivalve disease; 15% with MR; 15% with TR; 5% with AR; and 3% with PR. Maternal mortality was rare. In women with MR, TR, or multivalve disease (n = 289), left ventricular systolic dysfunction (p = 0.001), pulmonary hypertension (p = 0.005), and cardiac events before pregnancy (p \u3c 0.001) were important determinants of CEs during pregnancy. Conclusions: Women with AR and PR are at low risk for cardiac complications during pregnancy. While many women with MR, TR, and multivalve regurgitation do well during pregnancy, additional clinical variables help stratify those at highest risk. This new information will enhance the quality and precision of preconception counseling and pregnancy planning