Sepsis and organ dysfunction: an ongoing challenge.

In recent years the problem of infection has become increasingly significant, especially in intensive care hospital wards such as Intensive Care Units (ICU), emergency medicine, surgery and critically ill patient care departments. Sepsis is a complex, multifactorial syndrome that can develop into conditions of different severity, described as severe sepsis or septic shock. In these conditions the triggering event may coincide with the functional impairment of one or more vital organs or systems, thus leading to poorer prognosis in patients with overt signs of sepsis or systemic inflammation syndromes. The available data are quite alarming, as most prevention and treatment is performed empirically and requires considerable human and technological resources. Clinical signs are often misleading and, in some circumstances, it may be difficult or even impossible to identify the source of the infection which might otherwise be removed relatively simply, using proper antimicrobial treatment or a less invasive surgical removal of the area from which the infection originates based on needle-guided radiology. In addition, the complex pathophysiological mechanisms involved can be an obstacle to gaining a full understanding of the various biohumoral interactions or mediators action mechanisms. It may not be easy to enroll patients belonging to homogeneous groups in terms of age, underlining disease, immune profile or genetic predisposition, although the use of specific severity indexes has proved helpful also to establish the prognosis. Although the interpretation of generalised inflammation as a warning sign also in the absence of clear signs of infection or a state of overt inflammation has to rely largely on simple intuition, it has helped to drive experimental and clinical research work towards the investigation of interaction between different factors such as infection and sepsis, or inflammation and coagulation. An additional useful tool is the possibility of modulating the endothelial response which may support the process of disseminated thrombosis typical of sepsis evolution. In this context the improvement of standards of care can shed light on the efficacy of different treatments.

Furanocoumarins from the aerial parts of Dorstenia contrajerva.

A new glycosylated furanocoumarin, alpha-L-rhamnopyranosyl-(1-->6)-beta-D-glucopyranosyl-bergaptol (1), has been isolated from Dorstenia contrajerva together with three known furanocoumarins, catechin and epicatechin. Their structures were established using high field 2D NMR techniques.

Impairment of cardiac autonomic function in patients with Duchenne muscular dystrophy: relationship to myocardial and respiratory function.

BACKGROUND: Previous studies reported an impairment of nervous autonomic activity in patients with Duchenne muscular dystrophy (DMD). However, the relationship of the autonomic dysfunction to the impairment of cardiac mechanical function and of respiratory failure is not completely understood. METHODS: We evaluated cardiac autonomic function by time- and frequency-domain heart rate variability (HRV) analysis on 24-hour Holter recordings in 60 patients with DMD (16.8 +/- 4.8 years) and 28 healthy control patients (15.2 +/- 4.6 years, P = not significant). The circadian rhythm of R-R interval, low frequency, high frequency, and low-frequency/high-frequency ratio was also assessed. In all patients, left ventricular ejection fraction was measured by 2D echocardiography; respiratory function was assessed by spirometry. RESULTS: All HRV parameters were lower in patients with DMD than in control subjects, with the percentage of differences between adjacent R-R intervals >50 ms (11.6% +/- 8.5% vs 27.3% +/- 14.1%, P =.00001) and high frequency (23.9 +/- 10.3 ms vs 36.1 +/- 12.2 ms, P =.0001) showing the strongest differences. A significant circadian rhythm of HRV variables was present in both groups, but it was considerably flattened in patients with DMD. There was no correlation between left ventricular ejection fraction and HRV indexes except for a weak correlation with high frequency (r = 0.30, P =.02) and with low-frequency to high-frequency ratio (r = -0.29, P <.03). Similarly modest correlations were found between forced vital capacity and high frequency (r = 0.4, P =.007) and low-frequency/high-frequency ratio (r = -0.32, P =.026). Multiple regression analysis did not show any independent predictive variable for the autonomic impairment. CONCLUSIONS: Our data show a marked impairment of cardiac autonomic function in patients with DMD, which appears to mainly involve the parasympathetic branch and appears to have a multifactorial origin.

Clinical, electrocardiographic and electrophysiological predictors of atrial fibrillation development in different cardiac substrates.

We performed a review of the current literature in order to evaluate clinical, electrocardiographic and electrophysiologic parameters predictive of atrial fibrillation development. Clinical parameters were obtained from two large observational studies (the Framingham heart study and the Cardiovascular health study). Different laboratoristic predictors were also reviewed: ECG-derived predictors, among which we separately evaluated those derived from the 12-lead surface ECG and those derived from the signal averaged P-wave, and other electrophysiologic predictors as atrial monophasic action potential analysis. We also evaluated the clinical value of these different parameters in atrial fibrillation in patients with no overt structural heart disease and in the most common clinical conditions known to be related to atrial fibrillation development such as hypertension, heart failure, cardiovascular surgery.

Computer-assisted design, synthesis and biological evaluation of novel pyrrolyl heteroaryl sulfones targeted at HIV-1 reverse transcriptase as non-nucleoside inhibitors.

Three pyrrolyl heteroaryl sulfones (ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxyla te, ethyl 1-[(1H-benzimidazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate and ethyl 1-[(1H-benzotriazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate) were designed as novel HIV-1 reverse transcriptase non-nucleoside inhibitors using structure-based computational methods. Although these compounds were inactive in the cell-based assay, they inhibited the target enzyme with micromolar potency (IC50s = 2 microM, 3 microM and 9 microM, respectively).

Prognostic role of heart rate variability in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: The aim of this study was to investigate whether heart rate variability may predict the outcome in patients with idiopathic dilated cardiomyopathy. METHODS: Time-domain and frequency-domain heart rate variability was analyzed on 24-hour Holter recordings of 56 patients with idiopathic dilated cardiomyopathy (70% males, mean age 49 +/- 16 years; left ventricular ejection fraction 28 +/- 6%). RESULTS: There were 8 cardiac deaths (14.3%) and 11 arrhythmic events (19.6%, either sudden death or sustained ventricular tachycardia) at a follow-up of 18.5 months (range 3-50 months). Furthermore, 6 patients were included in the list for cardiac transplantation, leading to a prevalence of total cardiac events of 37.5 % (21 patients). All time-domain and most frequency-domain heart rate variability parameters did not show any significant relationship with the end points. However, a low frequency to high frequency (LF/HF) ratio < 1.2 was associated with cardiac death (relative risk-RR 6.8, p < 0.03), arrhythmic events (RR 11.0, p < 0.004), and total cardiac events (RR 4.8, p < 0.002). On the multivariate Cox analysis, no variable showed an independent association with cardiac death, but an LF/HF ratio < 1.2 was the only variable independently predictive of arrhythmic events (RR 8.2, p < 0.02), and the most powerful predictor of total cardiac events (RR 3.8, p < 0.009). CONCLUSIONS: Our data show that, in patients with idiopathic dilated cardiomyopathy, a low LF/HF ratio, as assessed on 24-hour Holter recordings, is a powerful predictor of cardiac events.

Evaluation of analgesic and anti-inflammatory activity of novel beta-lactam monocyclic compounds.

We have examined the in vivo anti-inflammatory and analgesic activity of a new series of monocyclic beta-lactams (azetidinones), similar to others which have been demonstrated to be inhibitors of human leukocyte elastase (HLE), an enzyme involved in degradation processes of connective tissue. Our new compounds have been administered orally (15 mg/kg) to albino rats 30 min before injecting carrageenin in the plantar aponeurosis. Tested compounds have demonstrated a certain activity and stability to gastric hydrolysis, in particular two of them markedly reduced paw edema formation, even if slightly less effectively than indomethacin (reference compound, 5 mg/kg). To evaluate the analgesic activity we carried out the acetic acid writhing test, pretreating rats orally with our compounds 30 min before injecting the acid solution i.p. The same two molecules which showed the anti-inflammatory activity demonstrated a very light analgesic activity. These results suggest the possibility of carrying out further studies, particularly in vitro, on the mechanism of action of our compounds, mechanism which could be the HLE inhibition.

Amide derivatives with H1-antihistaminic effect.

The synthesis and the structure-activity correlation of a series of N-aminoalkylacetamides as H1-antihistaminic agents have been carried out. The compounds were tested in vitro by measurement of the inhibition of histamine-induced contractions on isolated guinea pig ileum; the results are expressed as pA2.

A new class of pyrrolidin-2-ones: synthesis and pharmacological study. II.

The anticonvulsant activity of a second series of pyrrolidin-2-ones (1-2a, 1-4b, 1-9c) was tested on pentylenetetrazole (PTZ) treated mice. The compounds were obtained by acylation of N-(3'-aminopropyl)-2-pyrrolidinone with the suitable acid chloride.

Synthesis and pharmacological activities of some 2,3,4,5-tetrahydro[1,5]benzo[f]thiazepines.

In search of new biological active agents in the series of [1,5]benzothiazepines, some 2,3,4,5-tetrahydro-N-(5-morpholinopentanoyl)-[1,5]benzo[f] thiazepines were synthesized and examined in vitro for their calcium antagonist activity compared to the Diltiazem one.

Detection of coronary artery disease by digital stress echocardiography: comparison of exercise, transesophageal atrial pacing and dipyridamole echocardiography.

OBJECTIVES: This study assessed and compared the diagnostic potential of exercise, transesophageal atrial pacing and dipyridamole stress echocardiography in a clinical setting. BACKGROUND: Although they have been widely studied, no data exist with regard to comparisons of these procedures in a head-to-head study in different clinical settings. METHODS: One hundred four consecutive patients with suspected coronary artery disease undergoing coronary angiography and with no previous myocardial infarction or rest left ventricular wall motion abnormalities underwent digital posttreadmill, transesophageal atrial pacing and dipyridamole echocardiography. RESULTS: Feasibility of digital exercise echocardiography was 84%; 8 of 88 remaining patients had a nondiagnostic exercise echocardiographic test (inadequate exercise or imaging). In 80 patients with feasible and diagnostic digital exercise echocardiography, sensitivity, specificity and accuracy were, respectively, 89%, 91% and 90%. Eighty of the 104 patients underwent transesophageal atrial pacing and dipyridamole echocardiography. Feasibility of the alternative stress procedures was 77% for transesophageal atrial pacing and 96% for dipyridamole. In 60 patients successfully undergoing both alternative stress procedures, sensitivity and specificity were 83% and 76% for atrial pacing and 43% and 92% for dipyridamole echocardiography, respectively. In the group of 24 patients with nondiagnostic exercise echocardiography and consequent indication to alternative stress procedures, accuracy of transesophageal atrial pacing was higher than that of dipyridamole echocardiography (73% vs. 45%, p = 0.06). CONCLUSIONS: Because of its higher diagnostic potential and additional functional information, exercise is the stress of choice when stress echocardiography is used to detect the presence of coronary artery disease. Alternative stresses can be used in patients with nondiagnostic exercise echocardiography. Transesophageal and dipyridamole echocardiography differ in feasibility and diagnostic reliability (higher sensitivity of transesophageal atrial pacing, higher specificity of dipyridamole). These characteristics must be considered when selecting procedures to be used as alternatives to exercise.