Loss of balancing selection in the βS globin locus

Background  

Probably the best example of the rise and maintenance of balancing selection as an evolutionary trend is the role of S-haemoglobin (HbS - rs334) in protecting from malaria. Yet, the dynamics of such a process remains poorly understood, particularly in relation to different malaria transmission rates and the genetic background of the affected populations.     

Identifying Medical Students Likely to Exhibit Poor Professionalism and Knowledge During Internship

CONTEXT Identifying medical students who will perform poorly during residency is difficult. OBJECTIVE Determine whether commonly available data predicts low performance ratings during internship by residency program directors. DESIGN Prospective cohort involving medical school data from graduates of the Uniformed Services University (USU), surveys about experiences at USU, and ratings of their performance during internship by their program directors. SETTING Uniformed Services University. PARTICIPANTS One thousand sixty-nine graduates between 1993 and 2002. MAIN OUTCOME MEASURE(S) Residency program directors completed an 18-item survey assessing intern performance. Factor analysis of these items collapsed to 2 domains: knowledge and professionalism. These domains were scored and performance dichotomized at the 10th percentile. RESULTS Many variables showed a univariate relationship with ratings in the bottom 10% of both domains. Multivariable logistic regression modeling revealed that grades earned during the third year predicted low ratings in both knowledge (odds ratio [OR] = 4.9; 95%CI = 2.7–9.2) and professionalism (OR = 7.3; 95%CI = 4.1–13.0). USMLE step 1 scores (OR = 1.03; 95%CI = 1.01–1.05) predicted knowledge but not professionalism. The remaining variables were not independently predictive of performance ratings. The predictive ability for the knowledge and professionalism models was modest (respective area under ROC curves = 0.735 and 0.725). CONCLUSIONS A strong association exists between the third year GPA and internship ratings by program directors in professionalism and knowledge. In combination with third year grades, either the USMLE step 1 or step 2 scores predict poor knowledge ratings. Despite a wealth of available markers and a large data set, predicting poor performance during internship remains difficult. This work was presented at the Mid-Atlantic regional SGIM conference at USU on March 9, 2007. It was also presented at the annual SGIM conference as a Lipkin finalist in Toronto, CA on April 27, 2007. It has been accepted for presentation at the USU Research Week conference May 15, 2007 and has been submitted for presentation at the annual Research in Medical Education conference. This was an unfunded research. The opinions expressed in this paper are those of the authors and should not be construed, in any way, to represent those of the US Army or the Department of Defense.     

Toward 21st century blood component replacement therapeutics: artificial oxygen carriers, platelet substitutes, recombinant clotting factors, and others

In this brief overview, recent progress and current status of blood substitute research and development is summarized. Current blood substitute development efforts are focused on red blood cell substitutes but substitutes for platelets and other blood components are also in progress. Red cell substitutes currently in various stages of development are semi-synthetic or synthetic oxygen carriers that include "stealth" or "masked" red cells, hemoglobin-based oxygen carriers and perfluorocarbon-based oxygen carriers. Artificial platelets (or platelet substitutes) are in early stages of development and include human platelet fragments or particles of synthetic/semi-synthetic materials or recombinant human serum albumin coupled with platelet surface receptor fragments. Of note, some recombinant clotting factors (Factors VII, VIII, IX) have already been successfully developed and licensed for treatment of hemophilia. In addition, some future approaches and prospects of blood component replacement therapeutics are discussed.     

Nitrite directly vasodilates hypoxic vasculature via nitric oxide-dependent and -independent pathways

Background and purpose:

It is postulated that nitrite requires reduction to nitric oxide in order to exert its relaxant effect upon isolated hypoxic vessels. Herein, we evaluate the relative contribution of nitric oxide and characterize the downstream mechanisms of nitrite-induced vasorelaxation.

Experimental approach:

Aortic rings were treated with pharmacological agents and exposed to hypoxia (<1% O₂). Following pre-constriction, nitrite (10 µM final) was added to appropriate baths; isometric tension was recorded throughout.

Key results:

Nitrite (under hypoxic conditions at physiological pH) is capable of exerting physiological effects that cannot be completely inhibited by the inhibitor of soluble guanylate cyclase (sGC), 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or a nitric oxide scavenger (carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide). Simultaneous blockade of both sGC and cyclooxygenase (COX) completely inhibited the response to nitrite. With regard to the nitric oxide-dependent component, we confirm that aldehyde oxidase, but not xanthine oxidase or endothelial nitric oxide synthase, was important for the actions of nitrite in our model.

Conclusions and implications:

Nitric oxide generated from nitrite is not exclusively responsible for the physiological actions observed in isolated hypoxic vessels. Nitrite operates via different pathways dependent on the presence or absence of endothelium to produce vasorelaxation. In intact vessels, both sGC and COX enzymes appear to be important. Irrespective of this difference in relaxation mechanism, nitrite is capable of producing the same maximum relaxation, regardless of the presence of endothelium. Having investigated possible nitrite reduction sites, we confirm that aldehyde oxidase is important for the actions of nitrite.     

Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients

BACKGROUND: There is increasing evidence for acute traumatic coagulopathy occurring prior to emergency room (ER) admission but detailed information is lacking. PATIENTS AND METHODS: A retrospective analysis using the German Trauma Registry database including 17,200 multiple injured patients was conducted to determine (a) to what extent clinically relevant coagulopathy has already been established upon ER admission, and whether its presence was associated (b) with the amount of intravenous fluids (i.v.) administered pre-clinically, (c) with the magnitude of injury, and (d) with impaired outcome and mortality. Eight thousand seven hundred and twenty-four patients with complete data sets were screened. RESULTS: Coagulopathy upon ER admission as defined by prothrombin time test (Quick's value) <70% and/or platelets <100,000 microl(-1), was present in 34.2% of all patients. There was an increasing incidence for coagulopathy with increasing amounts of i.v. fluids administered pre-clinically. Coagulopathy was observed in >40% of patients with >2000 ml, in >50% with >3000 ml, and in >70% with >4000 ml administered. Ten percentage of patients presented with clotting disorders although pre-clinical resuscitation was limited to 500 ml of i.v. fluids maximum. The mean ISS score in the coagulopathy group was 30 (S.D. 15) versus 21 (S.D. 12) (p<0.001). Twenty-nine percentage of patients with coagulopathy developed multi organ failure (p<0.001). Early in-hospital mortality (<24h) was 13% in patients with coagulopathy (p<0.001) and overall in-hospital mortality totalled 28% (p<0.001). CONCLUSION: There is a high frequency of established coagulopathy in multiple injury upon ER admission. The presence of early traumatic coagulopathy was associated with the amount of intravenous fluids administered pre-clinically, magnitude of injury, and impaired outcome.