Platelet glycoproteins IIb and IIIa as a calcium channel in liposomes

Human platelet membrane glycoproteins IIb and IIIa (GPIIb and IIIa) were incorporated into phospholipid vesicles by the reverse-phase technique to assess the ability of GPIIb and IIIa to function as a Ca2+ channel. Movement of Ca2+ across the lipid bilayer was quantitated by injection of proteoliposomes with encapsulated Fura-2 into Ca2+ buffers and measurement of Fura-2 fluorescence as an indicator of Ca2+ influx. Reciprocally, to assess the function of proteins in an inside-out orientation, Ca2+-loaded vesicles were injected into Ca2+-free buffer and Ca2+ efflux monitored by a calcium electrode. Incorporation of the IIb-IIIa complex produced significant facilitation of Ca2+ movement across the lipid bilayer. No net transmembrane Ca2+ movement was seen with dissociated IIb and IIIa. Movement of Ca2+ was proportional to the transmembrane Ca2+ gradient. Ca2+ movement into the vesicles was inversely proportional to extravesicular NaCl from 25 to 150 mmol/L, analogous to several studies in the intact platelet. Adenosine triphosphate had no effect on Ca2+ movement into or out of the vesicles. Specific inhibition of a Ca2+ shift into the vesicles was seen with M148, a monoclonal antibody to IIb/IIIa, while no inhibition was observed with a panel of other anti-IIb/IIIa monoclonal antibodies. This suggests that a specific site on the complex or orientation of the complex is essential for calcium channel function. These data demonstrate that the GPIIb/IIIa complex can serve as a passive Ca2+ channel across a phospholipid bilayer and has the potential to play a role in Ca2+ flux across the platelet plasma membrane.     

Factor V deficiency in Philadelphia-positive chronic myelogenous leukemia

Factor V deficiency has been identified in 8 of 8 patients 7--20 yr of age, with Philadelphia-positive (Ph1+) chronic myelogenous leukemia (CML). In these 8 patients, factor V deficiency was not due to hepatic dysfunction, factor V inhibitors, or disseminated intravascular coagulation. In 3 patients, factor V activity rose 10%--12% (0.10--0.12 U/ml) after the infusion of 28--31 ml/kg body weight of fresh frozen plasma (FFP). The rise persisted less than 14 hr. The mean measured postinfusion rise in factor V was 18% of the expected rise calculated from the volume of FFP infused in the patients' plasma volume. In 4 patients, a small transient rise in factor V activity occurred after splenectomy or plateletpheresis. Factor V deficiency was completely corrected after a marked reduction in bone marrow cellularity in 2 patients with Ph1+ CML treated with extensive chemotherapy, total body irradiation, and bone marrow transplantation. Factor V deficiency was retrospectively observed in 6 of 20 patients, ages 20--80 yr, with Ph1+ CML and 3 of 6 patients with other myeloproliferative disorders. The factor V deficiency appears to be associated with the large myeloid- megakaryocytic cell mass characteristic of CML and other myeloproliferative disorders.     

Two-decade-long trends (1975-1997) in the incidence,hospitalization, and long-term death rates associated with complete heart block complicating acute myocardial infarction: a community-wide perspective

Background The purpose of this community-wide study was to describe a >2-decade-long experience (1975-97) in the incidence and death rates associated with complete heart block (CHB) in patients with acute myocardial infarction (AMI). Limited population-based data exist describing recent, and changes with time therein, incidence and case-fatality rates associated with CHB complicating AMI. Methods We conducted an observational study of 9082 metropolitan Worcester, Mass, residents (1990 census = 437,000) hospitalized with validated AMI in all greater Worcester hospitals during 11 1-year periods between 1975 and 1997. Results Overall, CHB developed in 5.0% of patients with AMI. The incidence rates of CHB declined in the periods studied (6.0% in 1975/78 vs 3.1% in 1997). Declines in the occurrence of CHB were noted in patients with anterior or inferior/posterior MI. These trends remained after adjustment for other factors that might affect the risk of CHB. Patients in whom CHB developed experienced significantly higher hospital death rates than patients in whom CHB did not develop (46.8% vs 14.6%). However, improving trends in the hospital survival rate of patients with CHB were observed between 1975/78 (47.4% surviving) and 1997 (61.3% surviving). Patients in whom CHB developed during hospitalization were not at increased risk for dying after hospital discharge. Conclusions Our findings indicate that the incidence of CHB complicating AMI has declined with time. The hospital prognosis of patients in whom CHB developed has improved, but these patients remain at an increased risk of hospital mortality. The long-term prognosis of patients with inferior MI and CHB is similar to that of patients in whom CHB did not develop. Patients with anterior MI and CHB may be at an increased risk of long-term mortality. (Am Heart J 2003;145:500-7.)     

Individual and Composite Study Endpoints: Separating the Wheat from the Chaff

We provide an overview of the individual and combined clinical endpoints and patient-reported outcomes typically used in clinical trials and prospective epidemiological investigations. We discuss the strengths and limitations associated with the utilization of aggregated study endpoints and surrogate measures of important clinical endpoints and patient-centered outcomes. We hope that the points raised in this overview will lead to the collection of clinically rich, relevant, measurable, and cost-efficient study outcomes.     

Changing clinico-laboratory profile of encephalitis patients in the eastern Uttar Pradesh region of India

A cross-sectional study was done on 100 consecutive paediatric patients presenting with acute encephalitis syndrome. The clinico-laboratory features of all patients were recorded in a prestructured performa. Cerebrospinal fluid and serum samples were tested for: Japanese encephalitis (JE) virus; Chandipura virus; coxsackie virus; dengue virus; enterovirus 76; and West Nile virus. Twenty-two (22.0%) patients were confirmed JE cases and 17% had parasitic or bacteriological aetiology. The remaining 61 cases (61.0%) in which no viral aetiological agent was found were grouped as non-JE cases. Peripheral vascular failure, splenomegaly and hypotonia were distinguishing clinical features found in the non-JE patients. A high mortality of 26.5% was seen in patients with confirmed or presumptive viral encephalitis (22/83). A fatal outcome was independently associated with peripheral vascular failure and pallor at the time of admission. Early recognition of these signs may help clinicians to manage these cases.     

Risk-Prediction Model for Ischemic Stroke in Patients Hospitalized With an Acute Coronary Syndrome (from the Global Registry of Acute Coronary Events [GRACE])

The risk of stroke in patients hospitalized with an acute coronary syndrome (ACS) ranges from <1% to ≥2.5%. The aim of this study was to develop a simple predictive tool for bedside risk estimation of in-hospital ischemic stroke in patients with ACS to help guide clinicians in the acute management of these high-risk patients. Data were obtained from 63,118 patients enrolled from April 1999 to December 2007 in the Global Registry of Acute Coronary Events (GRACE), a multinational registry involving 126 hospitals in 14 countries. A regression model was developed to predict the occurrence of in-hospital ischemic stroke in patients hospitalized with an ACS. The main study outcome was the development of ischemic stroke during the index hospitalization for an ACS. Eight risk factors for stroke were identified: older age, atrial fibrillation on index electrocardiogram, positive initial cardiac biomarkers, presenting systolic blood pressure ≥160 mm Hg, ST-segment change on index electrocardiogram, no history of smoking, higher Killip class, and lower body weight (c-statistic 0.7). The addition of coronary artery bypass graft surgery and percutaneous coronary intervention into the model increased the prediction of stroke risk. In conclusion, the GRACE stroke risk score is a simple tool for predicting in-hospital ischemic stroke risk in patients admitted for the entire spectrum of ACS, which is widely applicable to patients in various hospital settings and will assist in the management of high-risk patients with ACS.