Conformational transitions of the sodium-dependent sugar transporter, vSGLT.

Sodium-dependent transporters couple the flow of Na+ ions down their electrochemical potential gradient to the uphill transport of various ligands. Many of these transporters share a common core structure composed of a five-helix inverted repeat and deliver their cargo utilizing an alternating-access mechanism. A detailed characterization of inward-facing conformations of the Na+-dependent sugar transporter from Vibrio parahaemolyticus (vSGLT) has previously been reported, but structural details on additional conformations and on how Na+ and ligand influence the equilibrium between other states remains unknown. Here, double electron-electron resonance spectroscopy, structural modeling, and molecular dynamics are utilized to deduce ligand-dependent equilibria shifts of vSGLT in micelles. In the absence and presence of saturating amounts of Na+, vSGLT favors an inward-facing conformation. Upon binding both Na+ and sugar, the equilibrium shifts toward either an outward-facing or occluded conformation. While Na+ alone does not stabilize the outward-facing state, gating charge calculations together with a kinetic model of transport suggest that the resting negative membrane potential of the cell, absent in detergent-solubilized samples, may stabilize vSGLT in an outward-open conformation where it is poised for binding external sugars. In total, these findings provide insights into ligand-induced conformational selection and delineate the transport cycle of vSGLT.

Improving community ambulation after hip fracture: protocol for a randomised, controlled trial.

INTRODUCTION: After a hip fracture in older persons, significant disability often remains; dependency in functional activities commonly persists beyond 3 months after surgery. Endurance, dynamic balance, quadriceps strength, and function are compromised, and contribute to an inability to walk independently in the community. In the United States, people aged 65 years and older are eligible to receive Medicare funding for physiotherapy for a limited time after a hip fracture. A goal of outpatient physiotherapy is independent and safe household ambulation 2 to 3 months after surgery. Current Medicare-reimbursed post-hip-fracture rehabilitation fails to return many patients to pre-fracture levels of function. Interventions delivered in the home after usual hip fracture physiotherapy has ended could promote higher levels of functional independence in these frail and older adult patients. PRIMARY OBJECTIVE: To evaluate the effect of a specific multi-component physiotherapy intervention (PUSH), compared with a non-specific multi-component control physiotherapy intervention (PULSE), on the ability to ambulate independently in the community 16 weeks after randomisation. DESIGN: Parallel, two-group randomised multicentre trial of 210 older adults with a hip fracture assessed at baseline and 16 weeks after randomisation, and at 40 weeks after randomisation for a subset of approximately 150 participants. PARTICIPANTS AND SETTING: A total of 210 hip fracture patients are being enrolled at three clinical sites and randomised up to 26 weeks after admission. Study inclusion criteria are: closed, non-pathologic, minimal trauma hip fracture with surgical fixation; aged ≥ 60 years at the time of randomisation; community residing at the time of fracture and randomisation; ambulating without human assistance 2 months prior to fracture; and being unable to walk at least 300 m in 6minutes at baseline. Participants are ineligible if the interventions are deemed to be unsafe or unfeasible, or if the participant has low potential to benefit from the interventions. INTERVENTIONS: Participants are randomly assigned to one of two multi-component treatment groups: PUSH or PULSE. PUSH is based on aerobic conditioning, specificity of training, and muscle overload, while PULSE includes transcutaneous electrical nerve stimulation, flexibility activities, and active range of motion exercises. Participants in both groups receive 32 visits in their place of residence from a study physiotherapist (two visits per week on non-consecutive days for 16 weeks). The physiotherapists' adherence to the treatment protocol, and the participants' receipt of the prescribed activities are assessed. Participants also receive counselling from a registered dietician and vitamin D, calcium and multivitamin supplements during the 16-week intervention period. MEASUREMENTS: The primary outcome (community ambulation) is the ability to walk 300 m or more in 6minutes, as assessed by the 6-minute walk test, at 16 weeks after randomisation. Other measures at 16 and 40 weeks include cost-effectiveness, endurance, dynamic balance, walking speed, quadriceps strength, lower extremity function, activities of daily living, balance confidence, quality of life, physical activity, depressive symptoms, increase of ≥ 50 m in distance walked in 6minutes, cognitive status, and nutritional status. ANALYSIS: Analyses for all aims will be performed according to the intention-to-treat paradigm. Except for testing of the primary hypothesis, all statistical tests will be two-sided and not adjusted for multiple comparisons. The test of the primary hypothesis (comparing groups on the proportion who are community ambulators at 16 weeks after randomisation) will be based on a one-sided 0.025-level hypothesis test using a procedure consisting of four interim analyses and one final analysis with critical values chosen by a Hwang-Shih-Decani alpha-spending function. Analyses will be performed to test group differences on other outcome measures and to examine the differential impact of PUSH relative to PULSE in subgroups defined by pre-selected participant characteristics. Generalised estimating equations will be used to explore possible delayed or sustained effects in a subset of participants by comparing the difference between PUSH and PULSE in the proportion of community ambulators at 16 weeks with the difference at 40 weeks. DISCUSSION: This multicentre randomised study will be the first to test whether a home-based multi-component physiotherapy intervention targeting specific precursors of community ambulation (PUSH) is more likely to lead to community ambulation than a home-based non-specific multi-component physiotherapy intervention (PULSE) in older adults after hip fracture. The study will also estimate the potential economic value of the interventions.

Determinants of intrathoracic adipose tissue volume and associations with cardiovascular disease risk factors in Amish.

BACKGROUND AND AIM: Hypothesizing that intrathoracic fat might exert local effects on the coronary vasculature, we assessed the association of intrathoracic fat volume and its two subcomponents with coronary artery calcification (CAC) in 909 relatively healthy Amish adults. METHODS AND RESULTS: Intrathoracic fat, which is comprised of fat between the surface of the heart and the visceral epicardium (epicardial fat) and fat around the heart but outside of the fibrous pericardium (pericardial fat), was measured from electron beam CT scans. We examined the association between intrathoracic fat volume and cardiovascular disease risk factors in multivariate regression model. Fat volume in the epicardial and pericardial compartments were highly correlated with each other and with body mass index. Neither CAC extent nor CAC presence (Agatston score > 0) was associated with increased intrathoracic fat volume in sex-stratified models adjusting for age (p > 0.10). Intrathoracic fat volume was significantly correlated with higher systolic/diastolic blood pressure, pulse pressure, fasting glucose, insulin, triglyceride and lower high-density lipoprotein cholesterol in sex-stratified models adjusting for age (p < 0.05). However, associations were attenuated after further adjustment for body mass index. CONCLUSIONS: These data do not provide support for a significant role for intrathoracic fat in the development of CAC.

Clinical characteristics of patients in a case control study of sarcoidosis.

Sarcoidosis may be affected by sex, race, and age. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled 736 patients with sarcoidosis within 6 mo of diagnosis from 10 clinical centers in the United States. Using the ACCESS sarcoidosis assessment system, we determined organ involvement for the whole group and for subgroups differentiated by sex, race, and age (less than 40 yr or 40 yr and older). The study population was heterogeneous in terms of race (53% white, 44% black), sex (64% female, 36% male), and age (46% < 40 yr old, 54% > or = 40 yr old). Women were more likely to have eye and neurologic involvement (chi(2) = 4.74, p < 0.05 and chi(2) = 4.60, p < 0.05 respectively), have erythema nodosum (chi(2) = 7.28, p < 0.01), and to be age 40 yr or over (chi(2) = 6.07, p < 0.02) whereas men were more likely to be hypercalcemic (chi(2) = 7.38, p < 0.01). Black subjects were more likely to have skin involvement other than erythema nodosum (chi(2) = 5.47, p < 0.05), and eye (chi(2) = 13.8, p < 0.0001), liver (chi(2) = 23.3, p < 0.0001), bone marrow (chi(2) = 18.8, p < 0.001), and extrathoracic lymph node involvement (chi(2) = 7.21, p < 0.01). We conclude that the initial presentation of sarcoidosis is related to sex, race, and age.

Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).

Despite reports of familial clustering of sarcoidosis, little empirical evidence exists that disease risk in family members of sarcoidosis cases is greater than that in the general population. To address this question, we estimated sarcoidosis familial relative risk using data on disease occurrence in 10,862 first- and 17,047 second-degree relatives of 706 age, sex, race, and geographically matched cases and controls who participated in the multicenter ACCESS (A Case-Control Etiology Study of Sarcoidosis) study from 1996 to 1999. Familial relative risk estimates were calculated using a logistic regression technique that accounted for the dependence between relatives. Sibs had the highest relative risk (odds ratio [OR] = 5.8; 95% confidence interval [CI] = 2.1-15.9), followed by avuncular relationships (OR = 5.7; 95% CI = 1.6-20.7), grandparents (OR = 5.2; 95% CI = 1.5-18.0), and then parents (OR = 3.8; 95% CI = 1.2-11.3). In a multivariate model fit to the parents and sibs data, the familial relative risk adjusted for age, sex, relative class, and shared environment was 4.7 (95% CI = 2.3-9.7). White cases had a markedly higher familial relative risk compared with African-American cases (18.0 versus 2.8; p = 0.098). In summary, a significant elevated risk of sarcoidosis was observed among first- and second-degree relatives of sarcoidosis cases compared with relatives of matched control subjects.

Effect of an aggressive lipid-lowering strategy on progression of atherosclerosis in the left main coronary artery from patients in the post coronary artery bypass graft trial.

BACKGROUND: The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of two lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol levels to a mean yearly cholesterol level from 93 to 97 mg/dL compared with a moderate reduction to a level of 132 to 136 mg/dL decreased the progression of atherosclerosis in saphenous vein grafts. Low-dose anticoagulation did not affect progression. This secondary analysis tested the hypothesis that a similar decrease in progression of atherosclerosis would also be present in native coronary arteries as measured in the left main coronary artery (LMCA). METHODS AND RESULTS: A sample of 402 patients was randomly selected from 1102 patients who had baseline and follow-up views of the LMCA suitable for analysis. Patients treated with the aggressive lipid-lowering strategy had less progression of atherosclerosis in the LMCA as measured by changes in minimum (P=0.0003) lumen diameter or the maximum percent stenosis (P=0.001), or the presence of substantial progression (P=0.008), or vascular occlusion (P=0.005) when compared with the moderate strategy. CONCLUSIONS: A strategy of aggressive lipid lowering results in significantly less atherosclerosis progression than a moderate approach in LMCAs.

The late open artery hypothesis--a decade later.

BACKGROUND: Early reperfusion after myocardial infarction has been proved to preserve left ventricular function and reduce mortality. However, a significant number of patients have persistent occlusion of the infarct-related artery late (days to weeks) after myocardial infarction because of ineligibility for thrombolytic therapy, failure of reperfusion, or reocclusion. METHODS: In this report we review the data on the potential mechanisms and benefits of late reperfusion and present prospective data on the incidence of and current practice patterns for the management of persistently occluded infarct-related arteries late after myocardial infarction. RESULTS: Although several studies have associated late patency of the infarct-related artery with improved long-term clinical outcome, they were nonrandomized and reflect selection bias. Furthermore, data on late patency from the largest study, Global Utilization of Steptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO-I), failed to confirm independent benefits of an open infarct-related artery 1 year after myocardial infarction. The randomized data on the effects of percutaneous transluminal coronary angioplasty for occluded infarct-related arteries late after myocardial infarction are limited and inconclusive. CONCLUSIONS: The hypothesis that late reperfusion by percutaneous coronary intervention days to weeks after myocardial infarction results in improved long-term clinical outcomes in asymptomatic patients with occluded infarct-related artery is currently being tested in the randomized, multicenter Occluded Artery Trial.

The hemostatic effects of warfarin titration in post CABG patients in comparison to placebo treatment.

BACKGROUND: Since coronary artery bypass graft patients remain at risk of coronary artery and bypass graft occlusion after successful surgery, adjunct treatment regimens are under investigation. In a study of the patients of the multicenter Post Coronary Artery Bypass Graft (Post CABG) Trial, 1 mg warfarin was found to have no important effect on coagulation parameters. STUDY DESIGN: The effects of 1, 2 and 3 mg warfarin were evaluated at six-week intervals in 20 Post CABG Trial patients receiving titrated dose increases in comparison to 20 patients of similar age, gender and time from CABG treated with placebo. RESULTS: International normalized ratio (INR) values increased with warfarin dose increments for 1, 2, and 3 mg, respectively (0.95+/-0.16, 1.08+/-0.19, and 1.34+/-0.39) and in comparison to placebo treated patients (dosextreatment p<0.001). Factor VII coagulant activity decreased with warfarin titration (1 mg, 119.0+/-18.3 %; 2 mg, 100.6+/-32.8 %; 3 mg, 95.0+/-27.8 %) and in comparison to placebo (dosextreatment p=0.008). Levels of prothrombin fragment F1.2, tissue plasminogen activator, fibrinogen and von Willebrand factor were unchanged with warfarin dose increments and in comparison to placebo. CONCLUSIONS: At doses up to 3 mg, warfarin acts on the INR through a reduction of factor VII with no effect on the fibrinolytic system, fibrinogen or von Willebrand factor. At these doses F1.2 did not document reduced coagulation activity. The observations of this study were consistent with the decision in the Post CABG Trial to increase the warfarin dose above 1 mg to achieve a distinct effect of warfarin that was less than full anticoagulation.

Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators.

BACKGROUND: The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of 2 lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol (LDL-C) levels to <100 mg/dL compared with a moderate reduction to 132 to 136 mg/dL decreased the progression of atherosclerosis in grafts. Low-dose anticoagulation did not significantly affect progression. METHODS AND RESULTS: Approximately 3 years after the last trial visit, Clinical Center Coordinators contacted each patient by telephone to ascertain the occurrence of cardiovascular events and procedures. The National Death Index was used to ascertain vital status for patients who could not be contacted. Vital status was established for all but 3 of 1351 patients. Information on nonfatal events was available for 95% of surviving patients. A 30% reduction in revascularization procedures and 24% reduction in a composite clinical end point were observed in patients assigned to aggressive strategy compared with patients assigned to moderate strategy during 7.5 years of follow-up, P=0. 0006 and 0.001, respectively. Reductions of 35% in deaths and 31% in deaths or myocardial infarctions with low-dose anticoagulation compared with placebo were also observed, P=0.008 and 0.003, respectively. CONCLUSIONS: -The long-term clinical benefit observed during extended follow-up in patients assigned to the aggressive strategy is consistent with the angiographic findings of delayed atherosclerosis progression in grafts observed during the trial. The apparent long-term benefit of low-dose warfarin remains unexplained.

Cost-effectiveness of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) demonstrated the efficacy of hydroxyurea in reducing the rate of painful crises compared to placebo. We used resource utilization data collected in the MSH to determine the cost-effectiveness of hydroxyurea. The MSH was a randomized, placebo-controlled double-blind clinical trial involving 299 patients at 21 sites. The primary outcome, visit to a medical facility, was one of the criteria to define occurrence of painful crisis. Cost estimates were applied to all outpatient and emergency department visits and inpatient hospital stays that were classified as a crisis. Other resources for which cost estimates were applied included hospitalization for chest syndrome, analgesics received, hydroxyurea dosing, laboratory testing, and clinic visits for management of patient care. Annualized differential costs were calculated between hydroxyurea- and placebo-receiving patients. Hospitalization for painful crisis accounted for the majority of costs in both arms of the study, with an annual mean of $12,160 (95% CI: $9,440, $14,880) for hydroxyurea and $17,290 (95% CI: $13,010, $21,570) for placebo. The difference in means was $5,130 (95% CI: $60, $10,200; P = 0.048). Chest syndrome was the next largest cost with a mean difference of $830 (95% CI: $-340, $2,000; P = 0.16). The hydroxyurea arm was also associated with lower costs for emergency department visits, transfusion, and use of opiate analgesics. In total, the annual average cost per patient receiving hydroxyurea was $16,810 (95% CI: $13,350, $20,270) and the annual average costs per patient receiving placebo was $22,020 (95% CI: $17,340, $26,710). The difference in means was $5,210 (95% CI: $-610, $11,030; P = 0.21). The cost of hydroxyurea with the more intensive monitoring required when using this drug appears to be more than offset by decreased costs for medical care of painful crisis and analgesic use. Although the total cost difference was not significant statistically, these results suggest that hydroxyurea therapy is cost-effective compared to placebo in the management of adult patients with sickle cell anemia. If hydroxyurea can prevent development of chronic organ damage, long-term savings may be even greater.

Hemostatic effects of 1 mg daily warfarin on post CABG patients. Post CABG Studies Investigators.

Although coronary bypass graft surgery has increased the survival and quality of life of many individuals, patients remain at risk of restenosis and thrombotic occlusion of the coronary arteries and bypass grafts. In the screening period for participation in the multicenter Post Coronary Artery Bypass Graft (Post CABG) trial, the effects of 1 mg daily warfarin were evaluated using paired patient samples collected prior to and after at least 21 days of treatment. In stable patients (n = 40; 39 males 1 female; 51-74 years old) who previously had undergone coronary artery revascularization (1-10 years), no alterations in prothrombin time, international normalized ratio (INR), prothrombin fragment 1.2, or the hemostatic risk factors factor VII antigen and coagulant activity, von Willebrand's factor, fibrinogen, tPA, or PAI-1 were associated with the 1 mg daily warfarin treatment. The observations reported here supported the Post CABG Studies Steering Committee decision to treat patients with 1-4 mg warfarin daily adjusted to achieve INRs not to exceed 2. 0 consistent with low-intensity therapy.

Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. ACCESS Research Group. A Case Control Etiologic Study of Sarcoidosis.

BACKGROUND: Sarcoidosis is a multiorgan granulomatous disease of unknown cause. Lack of an objective system for assessment of sarcoidosis to evaluate disease course and effectiveness of therapy is a major problem. METHODS: The sarcoidosis assessment instrument was developed by the Steering Committee of A Case Control Etiologic Study of Sarcoidosis (ACCESS) which included investigators at the ten ACCESS Clinical Centers, the Clinical Coordinating Center, and representatives of the National Heart, Blood, and Lung Institute. This system was developed to assess sarcoidosis organ involvement in ACCESS patients who would be followed over a two-year period. The system represents a consensus of opinions of members of the Steering Committee based on review of their experience and the medical literature. RESULTS: Criteria for involvement in patients with biopsy-confirmed sarcoidosis are presented for organs and systems that are commonly involved (lung, skin, eyes, liver, calcium metabolism), unusual but clinically important (nervous system, kidney, heart) and other sites (non-thoracic lymph nodes, bone marrow, spleen, bone/joint, ear/nose/throat, parotid/salivary glands, muscles). CONCLUSION: The proposed instrument is partially subjective in that it depends upon the clinician's diligence in pursuing evidence for sarcoidosis involvement of various organs. It is hoped that this instrument will lead to increased standardization in the definition of sarcoidosis organ involvement to help clinicians and researchers better characterize patients with sarcoidosis.

A pilot randomized trial comparing symptomatic vs. hemoglobin-level-driven red blood cell transfusions following hip fracture.

BACKGROUND: The indications for transfusion have never been evaluated in an adequately sized clinical trial. A pilot study was conducted to plan larger clinical trials. STUDY DESIGN AND METHODS: Hip fracture patients undergoing surgical repair who had postoperative hemoglobin levels less than 10 g per dL were randomly assigned to receive 1) symptomatic transfusion: that is, transfusion for symptoms of anemia or for a hemoglobin level that dropped below 8 g per dL or 2) threshold transfusion: that is, patients receive 1 unit of packed RBCs at the time of random assignment and as much blood as necessary to keep the hemoglobin level above 10 g per dL. Outcomes were 60-day mortality, morbidity, functional status, and place of residence. RESULTS: Among 84 eligible patients enrolled, mean (+/- SD) prerandomization hemoglobin was 9.1 (+/- 0.6) g/ dL. The median number of units transfused in the threshold transfusion group was 2 (interquartile range, = 1-2), and that in the symptomatic transfusion group was 0 (6; interquartile range, = 0-2) (p < 0.001). Mean hemoglobin levels were approximately 1 g per dL higher in the threshold group than in the symptomatic group: for example, on Day 2, 10.3 (+/- 0.9) g per dL versus 9.3 (+/- 1.2) g per dL, respectively (p < 0.001). At 60 days, death or inability to walk across the room without assistance occurred in 16 (39.0%) of the symptomatic transfusion group and 19 (45.2%) of the threshold transfusion group. Death occurred by 60 days in 5 (11.9%) of the symptomatic transfusion group and 2 (4.8%) in the threshold transfusion group (relative risk = 2.5; 95% CI, 0.5-12.2). Other outcomes were similar for the two groups. CONCLUSIONS: Symptomatic transfusion may be an effective blood-sparing protocol associated with the transfusion of appreciably fewer units of RBCs and lower mean hemoglobin levels than are associated with the threshold transfusion policy. However, it is unknown whether these two clinical strategies have comparable mortality, morbidity, or functional status. A definitive trial is needed.

Individual subject random assignment is the preferred means of evaluating behavioral lifestyle modification.

Of the three most important approaches to evaluating lifestyle and health outcomes--observational studies, individual subject random assignment clinical trials, and community random assignment clinical trials--individual subject random assignment clinical trials provide the most useful information and the most certain inferences. Observational studies are limited by the collection of information on association of lifestyle instead of change in lifestyle with health outcomes, as well as by individual lifestyle selection that may be associated with particular outcomes. Community randomized trials may be the best way to decide such public health policy issues as whether or not to add fluoride to a water supply or to use a community-wide anti-smoking program. The limited amount of individual-specific data collected in community randomized trials, difficulties in accounting for missing data, and problems in data analysis because people move into or out of communities that are under study limit the value of community randomized trials for advising individuals whether or not to embark on a lifestyle modification program. Clinical trials of pharmacologic agents have successfully addressed challenges to individual subject random assignment clinical trials of lifestyle modification, such as long duration of study, access to study intervention(s) by individuals not assigned them, and cost.

An extension of stochastic curtailment for incompletely reported and classified recurrent events: the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH).

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), a double-blind randomized clinical trial, compared the frequency of acute vaso-occlusive (painful) crises during 2 yr of follow-up in 299 patients randomly assigned to hydroxyurea or placebo. Most patients had more than one crisis; all crises reported were included in the primary outcome analysis. A total of 7,229 follow-up medical contact reports were classified as crises/not crises by a Crisis Review Committee. Because of the time required to report, document, and classify contacts, interim analyses were prepared with incomplete data. If a stopping boundary were crossed, early termination could be advised only after assessing the potential impact of the incomplete data. In an extension of stochastic curtailment methods, simulation procedures were used to estimate the probability of detecting differences when group crisis rates projected to the end of the study were compared using a rank test. To account for medical contacts not yet reported and the future occurrence of crises, Poisson process models assuming no treatment effect on crisis rates were used for these simulations. The number of unclassified contacts that would be classified as crises was simulated as a binomial random variable. These methods may be useful for interim monitoring in other studies of recurrent events with ongoing event reporting and classification.

Ischemic cerebral infarction after rt-PA and heparin therapy for acute myocardial infarction. The TIMI-II pilot and randomized clinical trial combined experience.

BACKGROUND AND PURPOSE: Ischemic cerebral infarction (CI) is a serious complication of acute myocardial infarction (MI). Little information exists on CI after thrombolytic therapy for MI. METHODS: Of 3924 MI patients treated with recombinant tissue plasminogen activator (rt-PA) and heparin, 29 (0.7%) developed CI after treatment. All CI patients had detailed neurological evaluations, and 27 (93%) had CT scans centrally reviewed. RESULTS: Age range was 40 to 74 years (mean, 60 years); 25 patients (86%) were men, and 22 (76%) were white. The electrocardiographic location of MI was anterior in 22 (76%) and nonanterior in 7 (24%). Five CIs occurred within 6 hours, 4 between 6 to 24 hours, 8 during the remainder of the first week, 10 during the second week, and 2 others distributed over the 4 weeks after study entry. Six of 29 CIs did not involve the cerebral cortex; 9 patients (31%) had multiple CIs. Of 28 CIs thought to be embolic in origin, 17 showed strong evidence for at least one cardiac abnormality (mural clot, wall-motion abnormality, aneurysm, or atrial fibrillation) known to be associated more specifically with embolism than MI. Eight of 27 CIs (30%) with CT scans had hemorrhagic transformation of varying degrees; 5 were symptomatic. CONCLUSIONS: The time of occurrence and sites of CI after rt-PA and heparin therapy for acute MI are similar to those reported during the prethrombolytic era.

Comparison of preoperative characteristics of men and women undergoing coronary artery bypass grafting (the Post Coronary Artery Bypass Graft [CABG] Biobehavioral Study).

A cohort of 759 coronary artery bypass grafting (CABG) patients (269 women and 490 men) was enrolled in the prospective POST CABG Biobehavioral Study at 5 clinical centers in the United States and Canada. Sociodemographic and medical data were obtained by interview and from medical charts. Health-related quality of life and psychosocial data were ascertained preoperatively by interview and questionnaire for those patients whose condition allowed preoperative assessment and was compared among patients from hospitals enrolling both male and female patients (143 women and 267 men). Women enrolled in the Biobehavioral Study were older than men (65.4 +/- 9.0 vs 61.8 +/- 9.7 years, p < 0.001) and more likely to have a preoperative medical condition which precluded biobehavioral evaluation (47% vs 34%, p < 0.001). Women were less likely to be high school graduates (59% vs 74%, p < 0.001), were less likely to be earning > or = $25,000 per year (39% vs 69%, p < 0.001), and were married less often at the time of surgery (59% vs 85%, p < 0.001). Fewer women than men were able to perform basic self-care activities (p < 0.001) and social activities (p < 0.001). Women were also less able to perform the more demanding activities required for independent living, recreation, and maintaining a household (p < 0.001). Women were also more anxious (p = 0.01) and reported more depressive symptoms (p < 0.001) than men. These data suggest that plans for perioperative and convalescent care for women undergoing CABG should take into account their less favorable medical and psychosocial status relative to men.

Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea.

Hydroxyurea (HU) can increase fetal hemoglobin (HbF) in sickle cell anemia (HbSS). To identify determinants of the HbF response, we studied 150 HU-treated patients grouped by quartiles of change in HbF from baseline to 2 years. Half of the HU-assigned patients had long-term increments in HbF. In the top two quartiles, HbF increased to 18.1% and 8.8%. These patients had the highest baseline neutrophil and reticulocyte counts, and largest treatment-associated decrements in these counts. In the lower two quartiles, 2-year HbF levels (4.2% and 3.9%) and blood counts changed little from baseline. In the highest HbF response quartile, myelosuppression developed in less than 6 months, compliance was best, and final doses of HU were 15 to 22.5 mg/kg. All four quartiles had substantial increases of F cells in the first year. This was maintained for 2 years only in the top three quartiles. Leukocyte and reticulocyte counts decreased initially in all quartiles, but drifted back toward baseline levels in the lowest HbF response quartile. Initial HbF level and phenotype of the F-cell production (FCP) locus were not associated with HbF response, but absence of a Central African Republic (CAR) haplotype was. Bone marrow ability to withstand HU treatment may be important for sustained HbF increases during HU treatment of HbSS.

Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

Painful crises in patients with sickle cell anemia are caused by vaso-occlusion and infarction. Occlusion of blood vessels depends on (at least) their diameter, the deformability of red cells, and the adhesion of blood cells to endothelium. Deoxygenated sickle cells are rigid because they contain linear polymers of hemoglobin S (Hb S); polymerization is highly concentration dependent, and dilution of Hb S by a nonsickling hemoglobin such as fetal hemoglobin (Hb F) would be expected to lead ultimately to a decrease in the frequency of painful crises. It might also be expected to decrease the severity of anemia, although the pathogenesis of anemia in sickle cell anemia (SS disease) is not clearly understood. Reversion to production of fetal rather than adult hemoglobin became practical with the discovery that HU was an orally effective and relatively safe "switching agent." Preliminary dose-ranging studies led to a double-blind randomized controlled clinical trial, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), designed to test whether patients treated with HU would have fewer crises than patients treated with placebo. The MSH was not designed to assess the mechanism(s) by which a beneficial effect might be achieved, but it was hoped that observations made during the study might illuminate that question. The 2 MSH treatment groups were similar to each other and were representative of African-American patients with relatively severe disease. The trial was closed earlier than expected, after demonstration that median crisis rate was reduced by almost 50% (2.5 versus 4.5 crises per year) in patients assigned to HU therapy. Hospitalizations, episodes of chest syndrome, and numbers of transfusions were also lower in patients treated with HU. Eight patients died during the trial, and treatment was stopped in 53. There were no instances of alarming toxicity. Patients varied widely in their maximum tolerated doses, but it was not clear that all were taking their prescribed treatments. When crisis frequency was compared with various clinical and laboratory measurements, pretreatment crisis rate and treatment with HU were clearly related to crisis rate during treatment. Pretreatment laboratory measurements were not associated with crisis rates during the study in either treatment group. It was not clear that clinical improvement was associated with an increase in Hb F. Crisis rates of the 2 treatment groups became different within 3 months. Mean corpuscular volumes (MCVs) and the proportion of Hb F containing red cells (F cells) rose, and neutrophil and reticulocyte counts fell, within 7 weeks. When patients were compared on the basis of 2-year crisis rates, those with lower crisis rates had higher F-cell counts and MCVs and lower neutrophil counts. Neutrophil, monocyte, reticulocyte, and platelet counts were directly associated, and F cells and MCV were inversely associated, with crisis rates in 3-month periods. In multivariable analyses, there was strong evidence of independent association of lower neutrophil counts with lower crisis rates. F-cell counts were associated with crisis rate only in the first 3 months of treatment; MCV showed an association over longer periods of time. Overall, the evidence that decreased neutrophil counts played a role in reducing crisis rates was strong. Increased F cells or MCV and evidence of cytoreduction by HU were also associated with decreased crisis rates, but no definitive statement can be made regarding the mechanism of action of HU because the study was not designed to address that question. Future studies should be designed to explore the mechanism of action of HU, to identify the optimal dosage regimen, and to study the effect of HU when combined with other antisickling agents.