Coaxial laser absorption and optical emission spectroscopy of high-pressure aluminum monoxide.

This work advances laser absorption spectroscopy with measurements of aluminum monoxide (AlO) temperature and column density in extreme pressure (P > 60 bar) and temperature (T > 4000 K) environments. Measurements of the AlO A2Πi-X2Σ+ transition are made using a microelectromechanical system, tunable vertical cavity surface emitting laser (MEMS-VCSEL). Simultaneous emission measurements of the AlO B2Σ+-X2Σ+ transition are made along a line of sight that is coaxial with the laser absorption. Absorption temperature fits agree with emission spectra for a T = 3200 K, P = 9 bar case. In cases with T > 4000 K, P > 60 bar, absorption fits match the ambient temperature while emission fits over-estimate it, owing to high optical depths. These data juxtapose passive and active spectroscopic methods and demonstrate the versatility of AlO laser absorption in high-pressure and high-temperature environments where experimental data remain scarce, and engineering models will benefit from refined measurements.

A pilot study of the safety and effects of the matrix metalloproteinase inhibitor marimastat in gastric cancer.

The aim of this study was to evaluate the safety and tolerability of 4 weeks administration of marimastat, and to seek evidence of biological activity as observed by changes in the endoscopic appearance of the gastric tumours. 35 patients with advanced, inoperable gastric or gastro-oesophageal tumours were recruited. The dose of marimastat was reduced from the starting dose of 50 mg twice daily (6 patients) to 25 mg once daily (29 patients). 31 completed the 28 day study period. Marimastat was generally well tolerated, with the principal treatment-related toxicity being pain and stiffness of the musculoskeletal system. These symptoms occurred more frequently at the higher-dose, and increased to involve a total of 13 patients (37%) with longer-term treatment. The events were usually rapidly reversible on drug discontinuation. 3 patients receiving prolonged treatment experienced more severe symptoms, with the development of skin thickening and contractures in the hands. At endoscopy, 10 patients showed an increased fibrotic cover of the tumour, 8 had decreased haemorrhagic appearance, and in at least 2 cases where comparative tumour histology was assessable, there was evidence of increased stromal fibrotic tissue.

Prediction of recovery for closed-head-injured adults: an evaluation of the MMPI, the Adaptive Behavior Scale, and a "Quality of Life" Rating Scale.

Twenty-five closed-head-injured adults (24 males, 1 female; M age = 28.8 years) were classified as "recovered" if they had returned to work, school, or a sheltered workshop for which pay was received and "non-recovered" if they did not meet these criteria. Current status was compared with MMPI, Adaptive Behavior Scale (ABS), and "Quality of Life" Rating Scale (QLRS) scores at time of entry into a rehabilitation program. The "non-recovered" group was significantly higher on the PD (Psychopathic deviate) scale. No differences were found between groups on the Sc (Schizophrenia) or K (Validity) scales. The "recovered" group was significantly higher on the ABS Economic Activity domain and significantly lower in the Violent & Destructive, Antisocial, Rebelliousness, Untrustworthiness, Stereotyped Behavior & Odd Mannerisms, and Psychological Disturbance behavior domains. The self-ratings (QLRS) of the "nonrecovered" subjects were significantly more distinct from the ratings made by their relatives or significant others than were those of the "recovered" subjects.

Serial echocardiographic assessment of left atrioventricular valve function in young children with ventricular inversion.

BACKGROUND: Regurgitation of the morphologic tricuspid valve (mTV) adversely influences the clinical outcome of patients with ventricular inversion. METHODS AND RESULTS: To evaluate the mTV regurgitation (TR), we reviewed serial echocardiograms for 25 children with ventricular inversion, with and without congenital heart surgery. Patient age was from 6 months to 19.0 (median 5.8) years. Follow-up was from 5 months to 15.0 (median 4.1) years. Initial assessment was at a median 65 days of age; only nine (36%) of 25 had TR. At follow-up, 16 (64%) of 25 had TR, with two requiring valve replacement. The mTV was abnormal in 16 (64%) of 25 patients and in 11 (69%) of 16 TR worsened compared with one (11%) of nine patients with "normal" mTVs. Nine (36%) of 25 had Ebstein's anomaly, three of whom had new TR develop. Of 17 patients who underwent cardiac surgery, 10 (59%) had new or increased TR compared with three (37%) of eight nonoperative patients. After intracardiac repairs, eight (73%) of 11 had increased TR develop compared with two (33%) of six patients after extracardiac surgery. CONCLUSIONS: (1) Young patients with ventricular inversion had TR develop during follow-up, without cardiac surgery. (2) Surgical patients with intracardiac repairs had more TR develop than with extracardiac procedures. (3) Anatomic abnormalities of the mTV were associated with an increased risk of TR developing. These data help elucidate the factors that affect the development of TR in patients with ventricular inversion.

Beta-blockers and sudden cardiac death.

OBJECTIVES: To 1) consider the problem of sudden death from heart disease and the role of beta-blockers and other agents in preventing sudden death and 2) review perceived problems with beta-blocker therapy, such as effects on blood lipids, complications in diabetes, and adverse effects on heart failure and quality of life. DATA SOURCES: MEDLINE and EMBASE searches done from July 1994 on, and recognized texts. STUDY SELECTION: More than 400 original and review articles were evaluated, of which the most relevant were selected. DATA EXTRACTION: Data were extracted and reviewed by two authors. Accuracy was confirmed, when necessary, by the other authors. DATA SYNTHESIS: Of all of the therapies currently available for the prevention of sudden cardiac death, none is more established or more effective than beta-blockers. Indeed, the evidence that beta-blockers have a cardioprotective effect is compelling. They probably reduce the rate of atheroma formation; they reduce the risk for ventricular fibrillation in animal models of myocardial ischemia; they appear to reduce cardiac mortality in primary prevention trials; and they reduce mortality, particularly from sudden death, in patients who have had infarction. Moreover, withholding beta-blockers because of problems perceived to be associated with them is usually not warranted and may frequently prevent their use in those who will benefit most from them. CONCLUSION: Clinicians should reappraise the evidence for the significant effect of beta-blockers on morbidity and mortality, and they should recognize the importance of initiating and maintaining beta-blocker therapy when the less well-informed might suggest otherwise.

Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers.

AIMS: To assess the tolerability and pharmacokinetic profile of single and repeat doses of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. METHODS: A total of 31 subjects participated in two placebo-controlled, rising-dose studies. The first study assessed the pharmacokinetics and tolerability of single doses of marimastat of 25, 50, 100, 200, 400 and 800 mg. In the second study, continuous dosing over 6.5 days with three incremental dose levels of 50, 100 and 200 mg twice daily was assessed. Full pharmacokinetic profiles were obtained on days 0 and 6, and trough concentrations were measured on all days. For each pharmacokinetic profile in the studies, summary measures including Cmax, tmax, elimination half-life and AUC were calculated. Urinary drug weights were also measured. All adverse events were documented, and haematological and biochemical variables, vital signs and ECGs were monitored throughout the study. RESULTS: Peak plasma concentrations were observed at 1.5-3 h for all subjects at all doses. Peak levels were approximately proportional to dose, as was drug exposure as calculated by AUC. Data from both studies indicate that the terminal elimination half-life is of the order of 8-10 h, and that there is no unexpected drug accumulation. Marimastat was well-tolerated, with adverse effects being mild and occurring with similar frequency to placebo. Small but reversible elevations in liver transaminases were noted with repeat dosing of marimastat, the most significant of these occurring at a dose of 200 mg twice daily. CONCLUSION: Single and repeat oral doses of marimastat in healthy male subjects appear to be well-tolerated. The drug is rapidly absorbed with high peak levels achieved. It has a terminal elimination half-life of 8-10 h which would support twice daily dosing in further clinical trials.

Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen.

Marimastat is a specific inhibitor of matrix metalloproteinases that has been shown to be effective in cancer models. A pilot, escalating-dose study of oral marimastat was performed in patients with recurrent colorectal cancer, in whom evaluation of serological response was made by measurement of carcinoembryonic antigen (CEA) levels. The study assessed the safety and tolerability of 4 weeks administration of marimastat, and determined a dose range producing detectable serological effects. Patients were recruited with a serum CEA level greater than 5 ng ml(-1), and rising by more than 25% over a 4-week screening period. Patients were treated for 28 days and entered into a continuation protocol if a serological response or clinical benefit was observed. Pharmacokinetic and safety data determined that groups of patients were recruited sequentially at 25 mg and 50 mg twice daily, and, thereafter, 10 mg twice daily, 10 mg once daily, 5 mg once daily and 20 mg once daily. A biological effect (BE) was defined as a CEA value on day 28 no greater than on day 0; a partial biological effect (PBE) was defined as a rise in CEA over the 28-day treatment period of less than 25%. Of 70 patients recruited, 63 completed the 28-day treatment period, and 55 were eligible for cancer antigen analysis. Examination of the dose-effect relationships provides evidence for a causal relationship between marimastat and biological effects: the proportion of patients with BE or PBE was higher with twice daily dosing (16 out of 25, 64%) than with once daily dosing (11 out of 30, 37%) (P = 0.043, chi2 test). Furthermore, the median rates of rise of CEA fell markedly during treatment compared with the screening period for patients receiving twice daily marimastat (P<0.0001), but not for patients receiving marimastat once daily (P = 0.25). Musculoskeletal adverse events emerged as the principal drug-related toxicity of marimastat, occurring in a dose- and time-dependent fashion. It was concluded that marimastat was associated with dose-dependent biological effects in cancer patients. The occurrence of musculoskeletal side-effects define 25 mg twice daily as the upper limit of the dose range for continuous use in further studies. Therefore, a dose range of 20 mg once daily to 25 mg twice daily seems appropriate for further studies, which should aim to demonstrate the efficacy of the drug in terms of conventional clinical end points and describe the long-term tolerability of this novel agent.