Components of clinical trials for vasovagal syncope.

The time is ripe for adequately powered, randomized, placebo-controlled clinical trials in vasovagal syncope. Vasovagal syncope is a common syndrome, the symptoms of which can be troublesomely frequent. It is usually diagnosed by tilt-table testing, although this has persistent problems with both sensitivity and specificity. Patients with syncope and positive tilt tests have been the subjects of numerous studies of natural history, risk stratification, and treatment. This paper discusses studies of treatments for vasovagal syncope in the context of a classification of the levels of evidence that can be gleaned from clinical studies. The reasons for placebo-controlled trials are reviewed, as is the evidence for various methods of risk stratification. Data for power calculations are presented for the primary outcome, the time to the first syncope recurrence. Strengths and weakness of the four main types of outcomes for clinical trials are compared.     

HyCoSy--as good as claimed?

Hysterosalpingo contrast sonography (HyCoSy) has been compared favourably in the literature with hysterosalpingography (HSG). It does not require ionizing radiation and demonstrates the uterus and ovaries. HyCoSy is reported as being a safe, well tolerated, quick and easy investigation of Fallopian tube patency. Over a 1-year period HyCoSy was performed by two operators on 118 consecutive women who were thought likely to have patent Fallopian tubes. The examinations were graded using a local scale to assess discomfort and were correlated with tubal patency. HSG was performed on 116 patients by the same operators and discomfort recorded. 15 patients underwent both examinations. The degree of pain or reaction was graded 0 (no pain) to 4 (maximum) according to a locally devised scale. Costs of the two examinations were estimated. 89 patients examined by HyCoSy were graded 0-2. However, 23 had severe protracted pain and/or vasovagal reactions with bradycardia and hypotension. Of these, seven required resuscitation owing to prolonged symptoms, requiring treatment with atropine. 19 of the 23 had bilaterally patent Fallopian tubes. Where subsequent HSG was performed, tubal occlusion was confirmed in 8 of 15 women. Other pathologies were noted in 29 of the HyCoSy patients and there were six technical failures. During the same period no severe adverse reactions occurred in 116 patients having HSG performed by the same operators. Three of the HSG examinations were technically unsuccessful. Discomfort following HyCoSy was much greater than that reported previously. Possible mechanisms are discussed but it does not appear to be related to tubal occlusion. Diagnostic accuracy, costs and discomfort compare unfavourably with HSG.     

Is chromosome radiosensitivity and apoptotic response to irradiation correlated with cancer susceptibility?

PURPOSE: Individuals who have been treated for breast cancer have been reported to have increased lymphocyte chromosomal sensitivity to ionizing radiation and a significantly lower apoptotic response to irradiation compared to controls. We set out to test these findings using a substantial number of cases sampled before treatment (which could alter the parameters measured), compared to age-matched controls with normal mammograms. MATERIAL AND METHODS: We used the G2 chromosome breakage, and apoptotic response assays of peripheral blood lymphocytes to ionizing radiation to compare 211 unselected newly diagnosed and untreated breast cancer patients, with 170 age, sex and ethnically matched controls. RESULTS: We found no significant differences between breast cancer patients and their matched controls in the G2 assay or apoptotic response. However, there was some evidence that both cases and controls with a strong family history of breast cancer had higher radiosensitivity than those without. CONCLUSIONS: This is the largest and best controlled study of its kind, but it has not replicated previous reports of differences between chromosome breakage or apoptotic response in breast cancer cases vs. controls. However there was a suggestion of increased radiosensitivity in patients with a strong family history, which may indicate a heritable cancer susceptibility trait, warranting further study.     

Pain management in the ED

Recent regulatory and legal scrutiny has raised concerns about the over- and undertreatment of pain in the hospital. This debate stems from either the overly aggressive approach to the management of pain with opioids or, alternatively, to the barriers preventing the appropriate prescribing of these medications. The media attention on diversion of controlled substances for illicit purposes has intensified this debate, highlighting the possible overuse of these medications in the treatment of nonmalignant pain. Because pain is a highly common presenting complaint in the ED, EPs are pivotal players in these controversies. Accordingly, they must apprise themselves of pain management skills and continue to help those in need of appropriate medications while thwarting inappropriate prescribing. This review offers a synopsis of the pitfalls associated with ED pain management and provides recommendations for selected conditions.     

Interaction of cytokines and growth factor in the regulation of verotoxin-induced apoptosis in cultured human endothelial cells

The role of CD77, inflammatory cytokines and endothelial cell growth factor (ECGF) in verotoxin (VT)-induced apoptosis in human umbilical vein endothelial cells (HUVECs) was studied. Apoptosis was detected using annexin V and propidium iodide staining. The expression of CD77 antigen was measured on a FACStar flow cytometer using specific monoclonal antibodies. Our experiments showed that HUVECs had very low initial levels of CD77 and were resistant to VT. Treatment with tumour necrosis factor alpha (TNF-alpha) resulted in a significant upregulation of CD77 expression and sensitized endothelial cells to VT-mediated apoptosis. HUVECs incubated with a combination of cytokines [TNF-alpha and interferon gamma (IFN-gamma), both 500 U/ml] showed more pronounced upregulation of CD77 expression (> sixfold at 48 h) and underwent apoptosis, suggesting that TNF-alpha and IFN-gamma have a synergistic effect on CD77 expression in HUVECs and can induce apoptosis without VT. Cells pretreated with TNF-alpha and IFN-gamma and incubated with VT showed the most pronounced (14-fold) increase in CD77 expression. ECGF had a partial protective effect against cytokine- and VT-induced apoptosis. Taken together, our data suggest that CD77 antigen is involved in the regulation of endothelial cell apoptosis.     

Noncardiac surgery in long-term implantable left ventricular assist-device recipients.

OBJECTIVE: The authors describe their experience with left ventricular assist-device (LVAD) recipients undergoing noncardiac surgery and delineate surgical, anesthetic, and logistic factors important in the successful intraoperative management of these patients. SUMMARY BACKGROUND DATA: Left ventricular assist-devices have become part of the armamentarium in the treatment of end-stage heart failure. As the numbers of patients chronically supported with long-term implantable devices grows, general surgical problems that are commonly seen in other hospitalized patients are becoming manifest. Of particular interest is the intraoperative management of patients undergoing elective noncardiac surgical procedures. METHODS: The anesthesia records and clinical charts were reviewed for eight ventricular assist-device recipients undergoing general surgical procedures between August 1, 1990 and August 31, 1994. RESULTS: A total of 12 procedures were performed in 6 men and 2 women averaging 52.7 years of age. Mean time elapsed from device implantation to operation was 68 +/- 35 days. Conventional inhalational and intravenous anesthetic techniques were well tolerated in these patients undergoing diverse surgical procedures. No perioperative mortality was observed. Five of eight patients went on to successful cardiac transplantation. CONCLUSIONS: Hemodynamic recovery after LVAD insertion has defined a new group of patients who develop noncardiac surgical problems often seen in other critically ill patients. Recognition of the unique potential problems that the LVAD recipient may encounter in the perioperative period--in particular patient positioning, device limitations, and fluid and inotropic management--will ensure an optimal surgical outcome for LVAD recipients undergoing noncardiac surgery.     

Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells

The transmembrane ubiquitin ligase K5/MIR2 of Kaposi sarcoma herpesvirus (KSHV) mediates internalization and lysosomal degradation of glycoproteins involved in antigen presentation and co-stimulation. In endothelial cells (ECs), K5 additionally reduced expression of CD31/platelet-endothelial cell adhesion molecule (PECAM), an adhesion molecule regulating cell-cell interactions of ECs, platelets, monocytes, and T cells. K5 also reduced EC migration, a CD31-dependent process. Unlike other K5 substrates, both newly synthesized and pre-existing CD31 molecules were targeted by K5. K5 was transported to the cell surface and ubiquitinated pre-existing CD31, resulting in endocytosis and lysosomal degradation. In the endoplasmic reticulum, newly synthesized CD31 was degraded by proteasomes, which required binding of phosphofurin acidic cluster sorting protein-2 (PACS-2) to acidic residues in the carboxyterminal tail of K5. Thus, CD31, a novel target of K5, is efficiently removed from ECs by a dual degradation mechanism that is regulated by the subcellular sorting of the ubiquitin ligase. K5-mediated degradation of CD31 is likely to affect EC function in KS tumors.