Gradual weakening down to complete disappearance of the velocity correlated cluster emission effect in keV collisions of C60 with light metallic targets: Microscopic insights via molecular dynamics simulations.

The so-called velocity correlated cluster emission (VCCE) effect is the recently reported emission of large clusters with nearly the same velocity from an atomically heavy target (such as coinage metals) following a single C60- impact at the keV kinetic energy range. The effect was observed to get weaker for a meaningfully lighter target (Al) down to its complete disappearance for C60-Be impact. Microscopic insight into the subpicosecond evolution and thermalization of the impact induced energy spike (driving the effect) is achieved using molecular dynamics simulations. It is shown that the weakening of the VCCE effect for aluminum (toward its complete disappearance for Be) is due to ultrafast decay of the atomic number density within the spike nanovolume, thus not enabling the buildup of sufficient subsurface pressure as required for driving the correlated emission. For the Be target, an extremely rapid decay of nearly 90% of the initial density within 200 fs from impact is observed. This finding provides further support for the conclusion that the emission of the velocity correlated clusters as observed for the heavier targets takes place within an ultra-short time window of only a few hundreds of femtoseconds, roughly extending from 200 to 500 fs from impact. The lower bound is dictated by the requirement for a relatively slow rate of decay of number density, enabling the buildup of a sufficiently intense pressure spike. The upper bound is dictated by the cooling rate of the spike (still maintaining an extremely high temperature of kT ≥ 1 eV, as experimentally observed) and the onset of the evolution of the impact crater.

Velocity correlated emission of secondary clusters by a single surface impact of a polyatomic ion: a new mechanism of cluster emission and subpicosecond probing of extreme spike conditions.

Emission of secondary clusters off clean solid surfaces following the impact of a projectile ion at kiloelectronvolt (keV) kinetic energies is important from both practical and fundamental points of view. Understanding the underlying emission mechanisms using different types and sizes of projectile ions is therefore of high interest. In this perspective article we provide an up-to-date review of our recently observed new mechanism of velocity correlated cluster emission (VCCE) describing the emission of large clusters off different targets following the impact of a large polyatomic ion (C60-). Due to its large collision cross section and large number of light constituent atoms, the incoming C60- disintegrates completely upon an impact resulting in a rather broad and shallow energy deposition, high subsurface energy density and ultrafast evolution of an extreme nonlinear collision cascade dynamics. It is shown that kinetic energy distributions (KEDs) of the emitted clusters behave very differently from the KEDs of cluster ions emitted following the impact of a heavy monoatomic ion. All the large clusters emitted from a given target (following the keV C60- impact) move with nearly the same velocity and their KEDs could be fairly well described by a shifted Maxwellian. Namely, a thermal distribution superimposed on a center-of-mass velocity of a moving precursor which is the source of the emitted clusters. So far we have measured and analyzed KEDs for NbnCn+, TanCn+,Agn+, Cun+, Aun+ and Aln+ clusters emitted from their respective metallic targets, thus demonstrating the general validity of the VCCE effect as a new sputtering mechanism. We have also proposed a simple model for the initial, subpicosecond emission step of the precursor (and the resulting emitted clusters) and supported it by molecular dynamics (MD) simulations of the thermal behavior of the impact induced spike on the subpicosecond timescale. It is shown that each complete family of measured cluster KEDs (for a given target) can serve as a unique diagnostic tool, probing the extreme temperature and pressure evolving in the impact induced spike. We will discuss our accumulated findings from new perspectives and report new observations and additional analysis aspects.

Emission of velocity-correlated clusters in fullerene-solid single collision and diagnostics of the impact energized subsurface nanovolume.

We have measured kinetic energy distributions (KEDs) of large clusters emitted from five different solid targets following a single impact of C60 - ion at 14 keV kinetic energy. It was found that all the large clusters emitted from a given target move with nearly the same velocity and that their KEDs can be described by a thermal distribution riding on a common center-of-mass velocity (shifted Maxwellian) of some precursor. This behavior is in sharp contrast to that observed when the incoming projectile ion is monoatomic. Different trends were observed when comparing the behavior of the KED families of group 5 early transition metal elements (Ta and Nb) with those of group 11 late transition metals (Cu, Ag, and Au). We propose a model for the initial phase of formation of the precursor and show that the measured KEDs can serve as both pressure and temperature probes for the impact excited, highly energized subsurface nanovolume, driving the ejection of the clusters. It is also shown that under the proposed impact scenario, thermally equilibrated conditions (of the atomic subsystem) can be established at the subsurface nanovolume on the early subpicosecond time scale relevant for the emission process. This conclusion is demonstrated both experimentally by the KEDs of the emitted large clusters (very high temperatures and center-of-mass velocity) and by molecular dynamics simulation of the temporal evolution of the thermal characteristics of the impact energized subsurface nanovolume.

A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group IND.213.

BACKGROUND: Pelareorep, a serotype 3 reovirus, has demonstrated preclinical and early clinical activity in breast cancer and synergistic cytotoxic activity with microtubule targeting agents. This multicentre, randomized, phase II trial was undertaken to evaluate the efficacy and safety of adding pelareorep to paclitaxel for patients with metastatic breast cancer (mBC). METHODS: Following a safety run-in of 7 patients, 74 women with previously treated mBC were randomized either to paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 4 weeks plus pelareorep 3 × 1010 TCID50 intravenously on days 1, 2, 8, 9, 15, and 16 every 4 weeks (Arm A) or to paclitaxel alone (Arm B). Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate, overall survival (OS), circulating tumour cell counts, safety, and exploratory correlative analyses. All comparisons used a two-sided test at an alpha level of 20%. Survival analyses were adjusted for prior paclitaxel. RESULTS: Final analysis was performed after a median follow-up of 29.5 months. Pelareorep was well tolerated. Patients in Arm A had more favourable baseline prognostic variables. Median adjusted PFS (Arm A vs B) was 3.78 mo vs 3.38 mo (HR 1.04, 80% CI 0.76-1.43, P = 0.87). There was no difference in response rate between arms (P = 0.87). Median OS (Arm A vs B) was 17.4 mo vs 10.4 mo (HR 0.65, 80% CI 0.46-0.91, P = 0.1). CONCLUSIONS: This first, phase II, randomized study of pelareorep and paclitaxel in previously treated mBC did not show a difference in PFS (the primary endpoint) or RR. However, there was a significantly longer OS for the combination. Further exploration of this regimen in mBC may be of interest.

Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators.

BACKGROUND: The role of lipid modification in stroke prevention is controversial, although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease. METHODS AND RESULTS: To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infarction, we followed 4159 subjects with average total and LDL serum cholesterol levels (mean, 209 and 139 mg/dL, respectively) who had sustained an infarction an average of 10 months before study entry and who were randomized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events (CARE) trial. Using prospectively defined criteria, we assessed the incidence of stroke, a prespecified secondary end point, and transient ischemic attack (TIA) over a median 5-year follow-up period. Patients were well matched for stroke risk factors and the use of antiplatelet agents (85% of subjects in each group). Compared with placebo, pravastatin lowered total serum cholesterol by 20%, LDL cholesterol by 32%, and triglycerides by 14% and raised HDL cholesterol by 5% over the course of the trial. A total of 128 strokes (52 on pravastatin, 76 on placebo) and 216 strokes or TIAs (92 on pravastatin, 124 on placebo) were observed, representing a 32% reduction (95% CI, 4% to 52%, P=0.03) in all-cause stroke and 27% reduction in stroke or TIA (95% CI, 4% to 44%, P=0.02). All categories of strokes were reduced, and treatment effect was similar when adjusted for age, sex, history of hypertension, cigarette smoking, diabetes, left ventricular ejection fraction, and baseline total, HDL, and LDL cholesterol and triglyceride levels. There was no increase in hemorrhagic stroke in patients on pravastatin compared with placebo (2 versus 6, respectively). CONCLUSIONS: Pravastatin significantly reduced stroke and stroke or TIA incidence after myocardial infarction in patients with average serum cholesterol levels despite the high concurrent use of antiplatelet therapy.

The role of psychopathology in the parenting of drug-dependent women.

This paper explores the parenting of drug-dependent women and the contributions of comorbid psychopathology to their parenting. A sample of 32 children whose mothers were dependent on opioid drugs during pregnancy and 37 children whose mothers were not drug users were followed from birth to middle childhood. Multivariate regression analyses were conducted contrasting whether maternal substance abuse or psychopathology was more closely linked to parenting behaviors and continuity in parenting over time. Maternal drug dependence was related to whether mothers were able to remain primary caregivers for their children over time, even after controlling for psychopathology. Maternal drug use was related to unresponsive and negative parenting behavior during mother-infant interaction, but this relation was largely accounted for by the effects of comorbid maternal psychopathology on parenting, particularly symptoms of antisocial and related personality disorders. For those children whose mothers continued to care for them into middle childhood, perceptions of their mothers as rejecting were related to maternal antisocial personality and maternal depression. Substance-abuse treatment for women should be integrated with interventions addressing their mental health and parenting needs.

Angiotensin-converting enzyme inhibition in myocardial infarction--Part 1: Clinical data.

There is an increasing body of clinical trial evidence to support the use of angiotensin-converting enzyme (ACE) inhibitors in the management of patients following myocardial infarction (MI). Enthusiasm for the use of ACE inhibitors in the acute phase of MI had previously been tempered by the adverse results of an early trial. However, exciting new information is available from several large, randomized studies that has not only quelled those initial concerns but also attests to the efficacy of using this class of medication in the first 24 h after an acute MI. A Canadian National Opinion Leader Symposium was held in November 1995 to review the results of the major ACE inhibitor clinical trials and to discuss key issues and controversies surrounding their use in acute MI. The focus of this paper, the first of two parts, is on the results of the major ACE inhibitor clinical trials.

Angiotensin-converting enzyme inhibition in myocardial infarction--Part 2: Clinical issues and controversies.

Over the past 10 years, several clinical studies have concluded that, in patients already receiving conventional therapies, angiotensin-converting enzyme (ACE) inhibitors further reduce the risk of death following myocardial infarction (MI). Post-MI ACE inhibitors have proven to be effective as long term therapy in high risk patients as well as when used for much shorter periods in a broad patient population. However, while considerable mortality data have been collected, the effects of ACE inhibitors post-MI on other cardiovascular outcomes have not been as well documented. In addition, a number of issues regarding the most effective use of these agents remain unresolved. This paper, the second of two parts, focuses on the clinical issues and controversies surrounding the use of ACE inhibitors following acute MI. The effects of ACE inhibitors on the outcomes of sudden death, nonsudden death, recurrent angina, mitral regurgitation and left ventricular dysfunction are reviewed and potential mechanisms of action are proposed. In addition, ACE inhibitor therapy is discussed in terms of patient selection criteria, choice of agent, optimal dosing regimen, concomitant use of other therapies and relative costs of treatment. Finally, potential mechanisms of action of ACE inhibitors are proposed for each of the outcomes examined.

Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. SAVE investigators. Survival and Ventricular Enlargement.

BACKGROUND: There is increasing evidence of a link between conduit vessel stiffness and cardiovascular events, although the association has never been tested in a large post-myocardial infarction patient population. METHODS AND RESULTS: We evaluated the relationship between baseline pulse pressure, measured by sphygmomanometry 3 to 16 days after myocardial infarction, and subsequent adverse clinical events in the 2231 patients enrolled in the SAVE Trial. Increased pulse pressure was associated with increased age, left ventricular ejection fraction, female sex, history of prior infarction, diabetes, and hypertension and use of digoxin and calcium channel blockers. Over a 42-month period, there were 503 deaths, 422 cardiovascular deaths, and 303 myocardial infarctions. Pulse pressure was significantly related to each of these end points as a univariate predictor. In a multivariate analysis, pulse pressure remained a significant predictor of total mortality (relative risk, 1.08 per 10 mm Hg increment in pulse pressure; 95% CI, 1.00 to 1.17; P<.05) and recurrent myocardial infarction (relative risk, 1.12; 95% CI, 1.01 to 1.23; P<.05) after control for age; left ventricular ejection fraction; mean arterial pressure; sex; treatment arm (captopril or placebo); smoking history; history of prior myocardial infarction, diabetes, or hypertension; and treatment with beta-blockers, calcium channel blockers, digoxin, aspirin, or thrombolytic therapy. CONCLUSIONS: These data provide strong evidence for a link between pulse pressure, which is related to conduit vessel stiffness, and subsequent cardiovascular events after myocardial infarction in patients with left ventricular dysfunction.

Spontaneous pulmonary hemorrhage after thrombolytic therapy for acute myocardial infarction.

We report a case of 63-year-old man who developed massive pulmonary hemorrhage following intravenous streptokinase for acute myocardial infarction. Pulmonary hemorrhage was diagnosed by the triad of hemoptysis, a drop in hematocrit, and a new unilateral infiltrate on chest radiograph. This diagnosis was confirmed by autopsy findings. Pulmonary hemorrhage has rarely been reported following thrombolytic therapy. We believe that pulmonary hemorrhage is a rare but a potentially life-threatening complication of thrombolytic therapy and should be considered in the differential diagnosis of pulmonary infiltrates or falling hemoglobin after thrombolytic therapy for acute myocardial infarction with no obvious site of bleeding.

Diagnosis and management of heart failure. Canadian Cardiovascular Society.

Many of the recommendations presented in this consensus report are summarized in Figure 2. All patients with known or suspected heart failure should undergo a detailed history and physical examination. Other causes for the symptoms and/or clinical signs indicative of heart failure should be excluded. Routine biochemical tests, as well as a standard chest x-ray and ECG, should be performed on all patients with heart failure. Precipitating or aggravating causes of heart failure should be eliminated. Patients with potentially surgically correctable lesions, such as constrictive pericarditis, valvular disease or left ventricular aneurysm, should be referred for cardiological evaluation and the appropriate surgery. Patients with ischemic induced heart failure should be assessed for possible revascularization by either angioplasty or bypass surgery. Pending clinical findings and the degree of systolic or diastolic dysfunction present, determined by noninvasive tests, the panel made recommendations concerning the choice of various therapeutic agents. These clinical guidelines have been developed for practising physicians who manage patients with heart failure. The process by which consensus recommendations were developed by the Canadian Cardiovascular Society was based on the principle that guidelines have the best chance of succeeding if they are developed by those who will be using them. Strategies that ensure physicians are aware of the current guidelines, and that their implementation leads to measurable improvement in the diagnosis and management of patients with heart failure must be developed. Consensus reports represent an ongoing process which is subject to revision when further conclusive evidence is obtained by ongoing and future clinical trials.

A comparison of management patterns after acute myocardial infarction in Canada and the United States. The SAVE investigators.

BACKGROUND: There are major differences in the organization of the health care systems in Canada and the United States. We hypothesized that these differences may be accompanied by differences in patient care. METHODS: To test our hypothesis, we compared the treatment patterns for patients with acute myocardial infarction in 19 Canadian and 93 United States hospitals participating in the Survival and Ventricular Enlargement (SAVE) study, which tested the effectiveness of captopril in this population of patients after a myocardial infarction. RESULTS: In Canada, 51 percent of the patients admitted to a participating coronary care unit had acute myocardial infarctions, as compared with only 35 percent in the United States (P < 0.001). Despite the similar clinical characteristics of the 1573 U.S. patients and 658 Canadian patients participating in the study, coronary arteriography was more commonly performed in the United States than in Canada (in 68 percent vs. 35 percent, P < 0.001), as were revascularization procedures before randomization (31 percent vs. 12 percent, P < 0.001). During an average follow-up of 42 months, these procedures were also performed more commonly in the United States than in Canada. These differences were not associated with any apparent difference in mortality (22 percent in Canada and 23 percent in the United States) or rate of reinfarction (14 percent in Canada and 13 percent in the United States), but there was a higher incidence of activity-limiting angina in Canada than in the United States (33 percent vs. 27 percent, P < 0.007). CONCLUSIONS: The threshold for the admission of patients to a coronary care unit or for the use of invasive diagnostic and therapeutic interventions in the early and late periods after an infarction is higher in Canada than in the United States. This is not associated with any apparent difference in the rate of reinfarction or survival, but is associated with a higher frequency of activity-limiting angina.

A unique bone-like variant of alkaline phosphatase.

The authors describe an unusual variant of alkaline phosphatase (ALP) discovered in a patient with a 90-fold increase in serum ALP. The variant ALP was indistinguishable from the bone isoenzyme when subjected to chemical inhibition, heat inactivation, lectin precipitation, and routine electrophoresis. However, treatment with neuraminidase produced a marked decrease in the ALP variant's electrophoretic mobility and a reduction in its molecular weight. A bone marrow biopsy revealed metastatic infiltration of the bone marrow by adenocarcinoma of the prostate accompanied by a remarkable amount of new bone formation, suggesting a bone origin for the unusual isoenzyme. The authors believe this to be the first report of an ALP variant with these properties.

Low concentration galactose determination in plasma adapted to the Cobas-Bio.

Galactose elimination at blood concentrations lower than 2.22 mmol/L has been advocated as a measure of functional liver blood flow. We have adapted an assay employing galactose dehydrogenase (EC 1.1.1.48) to the Cobas-Bio to measure low galactose concentrations in plasma. The collection of blood in sodium fluoride/potassium oxalate anticoagulant tubes eliminated the necessity for the plasma deproteinization step required in similar, manual methods. The between run CV's for plasma samples spiked with galactose to concentrations of 0.13-0.5 mmol/L were 3.6% and 3.2%, respectively. Our automated assay was more precise and had a greater range of linearity than a manual galactose oxidase (EC 1.1.3.9) method set up in our laboratory (0.04-1.10 mmol/L as compared to 0.06-0.56 mmol/L). The total assay time was 20 min.

Efficacy of the calcium antagonist isradipine in angina pectoris.

Thirty-six patients with chronic, stable angina pectoris were studied during 2-week treatment periods in which they received, in a randomized double-blind, crossover study, a new calcium entry blocking agent, isradipine, 7.5 mg three times daily or placebo. Antianginal efficacy was determined by treadmill exercise testing carried out 3 and 9 hours after drug administration on the final day of each treatment period. During placebo therapy, treadmill exercise time to the onset of angina (P1) and to the development of moderate angina (P2) was similar at 3 and 9 hours and similar to the placebo run-in period. During isradipine therapy, treadmill exercise time 3 hours after dosing was greater than with placebo therapy (P1 312 +/- 23.0 vs. 267 +/- 19.5 seconds, p less than 0.001; P2 410 +/- 20.2 vs. 355 +/- 18.8 seconds, p less than 0.002). Nine hours after drug administration, the results of exercise testing were similar to placebo.

Sex and age differences in lifestyle risk: implications for health promotion programming.

We analyzed data from the 1982 Texas Behavioral Risk Factor Survey by sex and age to suggest strategies for the design and implementation of risk reduction programs. Men were more likely than women to report heavy drinking (76 percent versus 62 percent), drinking and driving (11 percent versus 3 percent), smoking (34 percent versus 27 percent), being overweight (42 percent versus 32 percent), and not using seat belts (63 percent versus 58 percent). Women were slightly more likely to report insufficient physical activity (64 percent versus 60 percent). A larger percentage of women than men reported using eating to cope with stress (31 percent versus 15 percent), while smoking (26 percent versus 22 percent), alcohol use (8 percent versus 3 percent), and exercise (21 percent versus 14 percent) were coping mechanisms reported by a greater proportion of men than women. These differences in risk behaviors by sex and age suggested that worksite programs addressing weight control and smoking for men and women and alcohol use and driving for men, along with community-based programs emphasizing fitness and hypertension control for older adults, would be most effective.