Treatment of endothelium with the chemotherapy agent vincristine affects activated protein C generation to a greater degree in newborn plasma than in adult plasma

INTRODUCTION: Activated protein C (APC) is well-established as a physiologically important anticoagulant. During development, plasma concentrations of protein C and alpha(2)macroglobulin, factors involved in APC generation, differ from adult levels. Chemotherapy drugs can perturb endothelial expression of PC-activating receptors. This study examines the effect of chemotherapy treatment of endothelium on APC generation in newborn and adult plasma. MATERIALS AND METHODS: APC generations were initiated on endothelial cells treated with vincristine or media by recalcifying defibrinated plasma with buffer containing thromboplastin. APC generation was terminated by mixing timed subsamples into FFRCMK-EDTA or heparin, followed by EDTA. APC-PCI and APC-alpha(1)AT were assayed by ELISA. APC-alpha(2)M was measured chromogenically. Since heparin converts free APC to APC-PCI, the difference between APC-PCI detected in heparin subsamples and APC-PCI detected in FFRCMK-EDTA subsamples gave the free APC. Cellular expression of EPCR and TM were measured by flow cytometry and Western blot. RESULTS: Vincristine-treated endothelium decreased free APC generation in newborn plasma to a greater degree than in adult plasma. APC-PCI levels in both adult and newborn plasma were unaffected by chemotherapy. Vincristine treatment reduced levels of APC-alpha(1) AT and APC-alpha(2) M to a greater degree in newborn plasma versus adult plasma. Expression of EPCR was reduced in cells treated with vincristine. Conversely, TM was reduced on the cell surface, but increased in whole cell lysates. CONCLUSIONS: The differential response of newborn and adult plasma PC components to chemotherapy-mediated changes in cell surface components may be a factor in the increased risk of thrombosis in children receiving chemotherapy.     

Stroke in rural areas and small communities

The management of stroke in rural and regional areas is variable in both the developed and developing world. Informed by best-practice guidelines and recommendations for systems of stroke care, adaptable models of care that are appropriate for local needs should be devised for rural and regional settings. This review addresses the issue of the provision of appropriate services in rural and regional settings, with particular attention to the barriers involved, according to the classification of Low Human Development Country (LHDC), Medium Human Development Country (MHDC) and High Human Development Country (HHDC). We discuss the need and feasibility of developing implementing stroke care in rural settings according to best-practice recommendations, within models of care adapted to local conditions.     

Effects of hydrogen sulfide on erectile function and its possible mechanism(s) of action

IntroductionThe current pharmacotherapy for erectile dysfunction (ED) relies significantly on the use of phosphodiesterase type 5 (PDE5) inhibitors, but quite a proportion of ED patients are resistant to this therapy, necessitating a search for an alternative treatment. We reviewed available published data to analyze current evidence of hydrogen sulfide (H₂S) as a novel pharmacotherapeutic agent with supportive role in sexual function.AimTo discuss the role of H₂S in erectile function, its possible mechanism of action, and how this knowledge may be exploited for therapeutic use.MethodsPubmed and Medline search was conducted to identify original articles and reviews.Main Outcome MeasuresData from peer‐reviewed publications.ResultsAnimal studies using different species, including in vitro study done in humans, show evidence of H₂S's pro‐erectile effects. The mechanism behind is still unclear, but evidence in literature points out the involvement of K⁺_ATP channel, modulation of protein with anti‐erectile effects, as well as involvement of the nitrergic pathway through a complex cross‐talk. A new drug called H₂S‐donating sildenafil (ACS6), which incorporated an H₂S‐donating moiety in sildenafil, has been developed. While more studies are still needed, this heralded a new pharmacotherapeutical approach, which is multipronged in nature.ConclusionsGiven the mounting evidence of H₂S's role in erectile function and how it appears to achieve its pro‐erectile effects through different mechanisms, H₂S represents a potentially important treatment alternative or adjunct to PDE5 inhibitors. Liaw RL, Srilatha B, and Adaikan PG. Effects of hydrogen sulfide on erectile function and its possible mechanism(s) of action. J Sex Med 2011;8:1853–1864.     

The relative and absolute reliability of two balance performance measures in chronic stroke patients

PURPOSE: To examine the relative reliability and absolute reliability of the Berg Balance Scale (BBS) and the Postural Assessment Scale for Stroke Patients (PASS) in chronic stroke patients. METHOD: A total of 52 mild to moderate stroke patients, who had a stroke more than 6 months previously, participated in the study. Both balance measures were administered twice, seven days apart, to the patients. A relative reliability index (intra-class correlation coefficient, ICC2,1) was used to examine the level of agreement between test and retest. Absolute reliability indices, including the Bland and Altman method, the standard error of measurement (SEM), and the smallest real differences (SRD), were used to define the extent to which a balance score varies on test-retest measurements. RESULTS: Test-retest agreements were high (ICC2,1: BBS = 0.98; PASS = 0.97), indicating excellent agreement from a relative perspective. The SEM of the BBS and PASS, representing the smallest change threshold that indicates a real improvement for a group of individuals, were 2.4 and 1.1, respectively. The SRD of the BBS and PASS were 6.7 and 3.2, respectively, exhibiting the smallest change threshold that indicates a real improvement for a single individual. CONCLUSIONS: The test-retest agreements of the BBS and PASS were high in mild to moderate chronic stroke patients. The thresholds of both measures to detect real change are acceptable in research and clinical settings.     

Gene gun bombardment with DNA-coated gold particles is a potential alternative to hydrodynamics-based transfection for delivering genes into superficial hepatocytes

Although in vivo nonviral gene delivery to the liver is critical for hepatic gene therapy, there are a number of technical obstacles. Enhanced green fluorescent protein (EGFP)-encoding DNA was coated onto gold particles (gold-DNA), dissolved in phosphate-buffered saline (pure DNA), and prepared as a polymer adjuvant (jetPEI)-galactosidase solution (polymer-DNA). Murine liver transfection was attempted by nonviral approaches, which included hydrodynamics-based transfection (HBT) of pure DNA, transport and transhepatic injection of polymer-DNA, and gene gun bombardment with pure DNA, gold-DNA, and polymer-DNA. Only HBT and gene gun bombardment yielded significant numbers of EGFP(+) hepatocytes. With the exception of the edge of the liver, HBT had a whole-liver transfection rate of 20% under optimized conditions. HBT resulted in marked hepatic infarctions, most prominently at the edge of the liver. For gene gun bombardment, the transfection rate was pressure dependent and limited to 15% for gold-DNA. Triple or quadruple bombardment at 30 psi resulted in a transfection rate comparable to that of a single bombardment at higher pressure, but was associated with minimal scattered hepatic necrosis. The EGFP(+) hepatocytes were located mainly in the superficial layers. We conclude that both HBT and gene gun bombardment yielded efficient murine hepatocyte transfection in vivo. Severe hepatic infarction impedes foreign gene expression in the superficial hepatocytes after HBT. Repeated bombardment with gold-DNA, using an accelerated particle gene gun at 30 psi, is a potential alternative to HBT for delivering genes to superficial hepatocytes in vivo, although gold-related hepatic necrosis is a persistent problem.     

Sonographic septation: a useful prognostic indicator of acute thoracic empyema.

The aim of this study was to identify sonographic predictors of patient outcomes or need for surgical intervention of acute thoracic empyema. All patients with a clinical diagnosis of thoracic empyema underwent transthoracic ultrasonographic examination and thoracentesis at admission. According to the presence or absence of septa in sonographic images, the patients were classified into two groups: septated and nonseptated. Sonographic findings were analyzed with respect to duration of hospital stay, chest tube drainage, and treatment efficacy. A total of 163 consecutive patients were included in the study (83 patients with septated and 80 with nonseptated sonographic images). The mean duration of hospital stay (35.4 versus 27.0 days, P = 0.009) and chest tube drainage (13.1 versus 7.6 days, P < 0.001) for the patients with septa were significantly longer than for those without septa. The patients with septa were more likely to undergo intrapleural fibrinolytic therapy (63.8% versus 38.8%, odds ratio 2.79, P = 0.001) and surgical intervention (24.3% versus 7.5%, odds ratio 3.92, P = 0.004). We concluded that sonographic septation is a useful sign to predict the need for subsequent intrapleural fibrinolytic therapy and surgical intervention in cases of acute thoracic empyema. Early fibrinolytic therapy or even surgical intervention may be indicated in patients with sonographic septations.