Intravegetation antimicrobial distribution in aortic endocarditis analyzed by computer-generated model. Implications for treatment

The distribution of antibiotics into cardiac valvular tissues is incompletely understood. By integrative computer modeling, we have used previously obtained pharmacokinetic data in experimental endocarditis to characterize aminoglycoside distribution within various geographic sectors of aortic vegetations of rabbits and humans in the current study. In rabbits with pseudomonal aortic endocarditis receiving a standard regimen of amikacin (15 mg/kg every eight hours), sub-MBC levels of the drug for the infecting organism were calculated in the center of 0.38-cm vegetations; this occurred despite supra-MBC levels calculated in plasma and more peripheral loci of the vegetation. In contrast, with a high-dose regimen of amikacin (40 mg/kg every eight hours), supra-MBC drug levels were calculated throughout the entire vegetation for at least 50 percent of the dosing interval. Using similar computer-generated approaches, these data in the rabbit were approximately in simulated aminoglycoside penetration of 10-mm human aortic vegetations. Aminoglycoside regimens designed to yield supra-MBC serum levels in both normal and rapid drug eliminators consistently achieved sub-MBC levels in the center of the vegetation. Computer simulations also confirmed that daily doses of aminoglycoside at least two to four times higher than those ordinarily recommended are necessary to consistently achieve uniform supra-MBC intravegetation levels for an entire dosing interval. Such computer-generated data support the concept of maldistribution of aminoglycosides in aortic endocarditis and provide a rationale for investigating the use of high-dose regimens of aminoglycoside in treating experimental endocarditis.     

Experimenter-defined quit dates for smoking cessation: adherence improves outcomes for women but not for men

Aims Smoking cessation treatment trials often require that smokers quit on or before a protocol‐defined date. The goals of this paper were to: (1) identify factors associated with adherence to a protocol‐defined quit date and (2) determine whether such adherence predicts cessation outcome (relapse). Design A quasi‐experimental secondary analysis of data collected from a randomized placebo‐controlled trial of fluoxetine (60 mg or 30 mg) versus placebo for smoking cessation. Setting and participants Clinic‐based smoking cessation treatment program comprising 989 non‐depressed smokers. Intervention Participants received cognitive behavioral therapy for smoking cessation and either study medication or placebo for 10 weeks. They were required to set a quit date within 2 weeks of their second study visit (by visit 4). Findings Significant predictors of quit date adherence were low nicotine dependence and active drug treatment. High‐dose fluoxetine (60 mg) and male gender were protective against relapse. Adherence to quit date was not an independent predictor of relapse; instead there was a significant interaction between quit date adherence and gender. Among non‐adherers to the quit date, women were more than 2.5 times as likely as men to relapse; among adherers to the quit date, women were only 1.3 times as likely as men to relapse. Conclusions Although women were more likely than men to relapse regardless of quit date adherence, adherence was strongly protective against relapse for women.     

Evolution of gastric electrical features and gastric emptying in children with Duchenne and Becker muscular dystrophy

OBJECTIVES: Although muscular dystrophy (MD) affects primarily striated muscles, smooth muscle cells of the gastrointestinal tract may also be involved. We recorded gastric electrical activity and gastric emptying time (GET) in children with MD at initial presentation and at 3-yr follow-up in order to detect gastric motor abnormalities and study their evolution along the clinical course. METHODS: Twenty children with MD (median age: 4.6 yr; range age: 3-7 yr) were investigated by means of ultrasonography, for measuring GET, and by electrogastrography (EGG); 70 children served as controls. RESULTS: Ten patients had Duchenne muscular dystrophy (DMD) and 10 Becker muscular dystrophy (BMD). GET was significantly more delayed in MD patients (DMD, median: 195 min; range 150-260 min; BMD, median: 197 min; range: 150-250 min) than in controls (median: 150 min; 110-180 min; p < 0.05); it markedly worsened at the follow-up in DMD (median: 270 min; range 170-310 min; p < 0.001 vs controls) but not in BMD patients (median: 205 min; 155-275 min; p < 0.05 vs DMD). Baseline EGG showed a significantly lower prevalence of normal rhythm and significantly higher prevalence of dysrhythmias in both groups of patients as compared to controls (% of normal rhythm: DMD 66.7 +/- 8.2, BMB 67.2 +/- 11.5, controls 85.3 +/- 7.2, p < 0.001; % of tachygastria: DMD 28.4 +/- 8.0, BMB 29.8 +/- 12.3, controls 10.6 +/- 5.1, p < 0.001; % of dominant frequency instability coefficient: DMD 36.1 +/- 6.0, BMB 33.2 +/- 2.9, controls 17.9 +/- 7.1, p < 0.001); furthermore, no difference in fed-to-fasting ratio of the dominant EGG power was found between the two groups and controls (DMD 2.84 +/- 1.27, BMB 2.82 +/- 0.98, controls 3.04 +/- 0.85, ns). However, at the follow-up no significant change in the prevalence of normal rhythm and dysrhythmias occurred in both groups (ns vs baseline values), whereas only DMD patients showed a marked reduction in fed-to-fasting power ratio (0.78 +/- 0.59; p < 0.001 vs controls and BMD; p < 0.05 vs baseline), which correlated with the progressive neuromuscular weakness occurring in DMD subjects (r, 0.75; p < 0.001). CONCLUSIONS: In children with MD, there is an early abnormality in gastric motility that is due to deranged regulatory mechanisms, whereas contractile activity of smooth muscle cells seems to be preserved. At the follow-up, DMD patients exhibited a progressive failure in neuromuscular function, which was accompanied by a gastric motility derangement with worsening in GET and in EGG features suggesting an altered function of gastric smooth muscle cells.     

ST segment elevations: Always a marker of acute myocardial infarction?

Chest pain is one of the chief presenting complaints among patients attending Emergency department. The diagnosis of acute myocardial infarction may be a challenge. Various tools such as anamnesis, blood sample (with evaluation of markers of myocardial necrosis), ultrasound techniques and coronary computed tomography could be useful. However, the interpretation of electrocardiograms of these patients may be a real concern. The earliest manifestations of myocardial ischemia typically interest T waves and ST segment. Despite the high sensitivity, ST segment deviation has however poor specificity since it may be observed in many other cardiac and non-cardiac conditions. Therefore, when ST–T abnormalities are detected the physicians should take into account many other parameters (such as risk factors, symptoms and anamnesis) and all the other differential diagnoses. The aim of our review is to overview of the main conditions that may mimic a ST segment Elevation Myocardial Infarction (STEMI).     

Flavodilol: a new antihypertensive agent

Flavodilol, a new antihypertensive drug, was evaluated in a variety of test systems for better understanding of its biologic properties and the nature of its mechanism of action. Oral administration of the drug to spontaneously hypertensive rats (SHR) lowered arterial blood pressure (ABP) in a dose-related manner, and doses greater than 35 mg/kg increased duration but not magnitude of the response. In contrast, oral administration of flavodilol to normotensive rats did not significantly alter ABP at 35 mg/kg, although larger doses of 75 or 150 mg/kg significantly lowered ABP. In rats with DOCA/salt hypertension, flavodilol effectively lowered ABP to a degree similar to that observed in SHR. At antihypertensive doses, flavodilol did not alter blood pressure responses to a 90 degrees head-up tilt in SHR and did not influence cardiac output in conscious SHR. In addition, flavodilol did not appear to manifest its antihypertensive activity through an interaction with beta-adrenoceptors, dopamine (DA) receptors or prostaglandin synthetase. Daily oral administration of flavodilol to SHR for 4 days resulted in augmented vasopressor responses to exogenously administered epinephrine (EPI) or norepinephrine (NE) and attenuated responses to exogenously administered tyramine. In addition, flavodilol treatment attenuated in a dose-related manner ABP and heart rate (HR) responses of pithed SHR to electrical stimulation of sympathetic nerves. We conclude that flavodilol is an effective antihypertensive drug which decreases the release of NE from postganglionic sympathetic nerves, resulting in attenuation of peripheral noradrenergic function.