Mammalian reovirus, a nonfusogenic nonenveloped virus, forms size-selective pores in a model membrane

During cell entry, reovirus particles with a diameter of 70-80 nm must penetrate the cellular membrane to access the cytoplasm. The mechanism of penetration, without benefit of membrane fusion, is not well characterized for any such nonenveloped animal virus. Lysis of RBCs is an in vitro assay for the membrane perforation activity of reovirus; however, the mechanism of lysis has been unknown. In this report, osmotic-protection experiments using PEGs of different sizes revealed that reovirus-induced lysis of RBCs occurs osmotically, after formation of small size-selective lesions or "pores." Consistent results were obtained by monitoring leakage of fluorophore-tagged dextrans from the interior of resealed RBC ghosts. Gradient fractionations showed that whole virus particles, as well as the myristoylated fragment mu1N that is released from particles, are recruited to RBC membranes in association with pore formation. We propose that formation of small pores is a discrete, intermediate step in the reovirus membrane-penetration pathway, which may be shared by other nonenveloped animal viruses.     

Observational study of patients switched to the fixed travoprost 0.004%/timolol 0.5% combination in Croatia

The purpose of this study was to assess both the benefits of a 3-month travoprost 0.004%/timolol 0.5%fixed combination (trav/tim) regimen in comparison with previous medications for the control of intraocular pressure (IOP) and the tolerability of these drug regimens in glaucoma patients. An observational, non-interventional, open-label study of 406 eyes with primary open angle glaucoma and ocular hypertension was thus undertaken. One drop of trav/tim fixed combination was administered in the evening for 3 months. Patients were divided into five groups according to previous drug regimens: timolol 0.5% monotherapy; betaxolol 0.5% monotherapy; latanoprost 0.005% monotherapy; travoprost 0.004% monotherapy; and dorzolamide 2%/timolol 0.5% fixed combination. Upon medication substitution, the trav/tim fixed combination provided better IOP control and tolerability in all five patient groups. At the 3-month follow up, the mean IOP changes from previous therapy were as follows: 5.2 ± 2.7 mmHg (20.8% change) in timolol 0.5% group; 5.7 ± 2.2 mmHg (22.5% change) in betaxolol 0.5% group; 3.8 ± 2.6 mmHg (24.5% change) in latanoprost 0.005% group; 4.4 ± 2.8 mmHg (20% change) in travoprost 0.004% group; and 3.4 ± 4.1 mmHg (14.5% change) in dorzolamide 2%/timolol 0.5% fixed combination group. The difference between baseline and trav/tim combination patient satisfaction at the 3-month follow-up was significant. Thus, the trav/tim fixed combination provided better IOP control and tolerability than previous mono- or polytherapies.     

Neurohumoral and hemodynamic effects of the selective endothelin antagonist darusentan in advanced chronic heart failure.

BACKGROUND: Endothelin antagonists represent a new approach to neurohumoral treatment in patients with chronic heart failure. In this study, the new selective endothelin-A receptor antagonist, darusentan, was compared with placebo for 3 weeks in patients with severe heart failure on top of standard treatment that included angiotensin-converting enzyme (ACE) inhibitors and beta-blockers. Effects on neurohormones and hemodynamics were evaluated. METHODS: Consecutive patients with severe heart failure (New York Heart Association [NYHA] Grade III) were included in this neurohumoral sub-study of an international, multi-center, double-blind, placebo-controlled study of darusentan, and randomized to darusentan (n = 23) or placebo (n = 8). The mean left ventricular ejection fraction was 19 +/- 6% at the beginning of the study. Patients were randomized to different dosage levels of darusentan (30, 100, or 300 mg) for 3 weeks. Hemodynamics were obtained by right heart Swan-Ganz catheterization at entry and end of study. Serial assessment of plasma brain natriuretic peptide (BNP), big-endothelin, and pro-atrial natriuretic peptide (pro-ANP) was performed. In the active treatment group, 1 patient died due to worsening heart failure, 1 patient received elective heart transplantation, and 2 patients stopped taking the medication due to vertigo. In the placebo group, 1 patient was excluded due to non-compliance. RESULTS: Overall, the mean dose of darusentan was 144 +/- 125 mg/day (30 mg: n = 8; 100 mg: n = 4; 300 mg: n = 7). Significant benefits in hemodynamic variables were found after 3 weeks only in patients receiving darusentan (baseline vs end of study: cardiac index: 2.0 +/- 0.3 vs 2.6 +/- 0.5 liters/min m(2), p < 0.0001; mean pulmonary artery pressure: 35 +/- 9 vs 33 +/- 8 mm Hg, p < 0.05; heart rate: 79 +/- 16 vs 71 +/- 10 beats/min, p < 0.01). A significant reduction in mean arterial blood pressure was observed with the endothelin antagonist (baseline 80 +/- 8 vs end 73 +/- 8 mm Hg, p < 0.01). BNP decreased significantly in patients with darusentan (90 +/- 87 at entry vs 63 +/- 67 fmol/ml after 3 weeks, p < 0.01), whereas big-endothelin remained unchanged. Pro-ANP tended to decrease in the active treatment group, but did not reach statistical significance. CONCLUSION: Significant hemodynamic and neurohumoral benefits were observed in patients with severe heart failure receiving the selective endothelin antagonist darusentan.     

Tension-free left ITA graft -- the pericardial strip technique

Emphysematous lung occupying the whole dome of the left pleural cavity and expanding well over the midline may occasionally present a significant problem for positioning of the left internal thoracic artery, although the graft has been mobilized up to its origin. To avoid an undue tension on it, we combined a well known technique of the pericardial incision with the pericardial strip technique, enabling the lung to expand freely.     

The loss of circadian heart rate variations in patients undergoing mitral valve replacement and Corridor procedure--comparison to heart transplant patients

We have presently demonstrated that when added to mitral valve replacement (MVR) the corridor procedure is 75% efficient in restoring and maintaining sinus rhythm in patients with chronic atrial fibrillation (AF), caused by rheumatic mitral valve disease, (follow up 13.9months). In the same patient population, we observed that the typical day-night cycle heart rate (HR) variations were lost and our present study concentrates on this subject. Heart rate variability analysis based on 24-h Holter ECG recording (StrataScan 563 DelMar Avionics) or hospital discharge (12th-14th postoperative days) was performed in 3 patient groups: Group I: Patients with a Corridor procedure added to MVR (12pts, m/f 10/2, mean age 47.3+/-7.5yr); Group II (control): with patients MVR performed through the left atrial approach, without additional antiarrhythmic procedures (10pts, m/f 3/7 mean age 51.5+/-6.7yr), and Group III: heart transplant recipients (5pts, mean age 46.4+/-11.22yr). We analyzed the hourly heart rate over 24-h period divided into three 8-h segments (07-14h; 15-22h and 23-06h). Statistical comparison of mean hourly heart rate values was made between the three time periods of Holter monitoring. The Corridor procedure performed with mitral valve replacement resulted in conversion of sinus rhythm in 75% of patients (Group I), but postoperative heart rate variability analyses based on Holter monitoring disclosed that the mean heart rate was not statistically significantly difficult between the three 8-h segments of the day-night (P>0.05). The same results were found in the group of patients after heart transplant (P>0.05). The same results were found in the group of patients after heart transplant (P>0.05). In the second group (classical MVR), statistically significant differences in mean HR variation existed between the three 8-h intervals (P<0.05), and although atrial fibrillation occurred postoperatively physiologic circadian heart rate variations were preserved.With the Corridor procedure, both atria were surgically and electrically isolated and chronotropic function of the ventricles was restored by creating a small strip of atrial tissue with isolated sinus node and atrio-ventricular node, connected to the ventricles. This technique produced heart denervation nervous system influence, producing the loss of circadian HR variations, similar to the transplanted heart.     

Prognostic factors for intensive care unit admission, intensive care outcome, and post-intensive care survival in patients with de novo acute myeloid leukemia: a single center experience

Background

Acute myeloid leukemia is a life-threatening disease associated with high mortality rates. A substantial number of patients require intensive care. This investigation analyzes risk factors predicting admission to the intensive care unit in patients with acute myeloid leukemia eligible for induction chemotherapy, the outcome of these patients, and prognostic factors predicting their survival.

Design and Methods

A total of 406 consecutive patients with de novo acute myeloid leukemia (15–89 years) were analyzed retrospectively. Markers recorded at the time of diagnosis included karyotype, fibrinogen, C-reactive protein, and Charlson comorbidity index. In patients requiring critical care, the value of the Simplified Acute Physiology Score II, the need for mechanical ventilation, and vasopressor support were recorded at the time of intensive care unit admission. The independent prognostic relevance of the parameters was tested by multivariate analysis.

Results

Sixty-two patients (15.3%) required intensive care, primarily due to respiratory failure (50.0%) or life-threatening bleeding (22.6%). Independent risk factors predicting intensive care unit admission were lower fibrinogen concentration, the presence of an infection, and comorbidity. The survival rate was 45%, with the Simplified Acute Physiology Score II being the only independent prognostic parameter (P<0.05). Survival was inferior in intensive care patients compared to patients not admitted to an intensive care unit. However, no difference between intensive care and non-intensive care patients was found concerning continuous complete remission at 6 years or survival at 6 years in patients who survived the first 30 days after diagnosis (non-intensive care patients: 28%; intensive care patients: 20%, P>0.05).

Conclusions

Ongoing infections, low fibrinogen and comorbidity are predictive for intensive care unit admission in acute myeloid leukemia. Although admission was a risk factor for survival, continuous complete remission and survival of patients alive at day 30 were similar in patients who were admitted or not admitted to an intensive care unit.     

Impairment of cardiac insulin signaling in fructose-fed ovariectomized female Wistar rats

Background  

Fructose consumption produces deleterious metabolic effects in animal models. The sites of fructose-induced insulin resistance are documented to be the liver, skeletal muscle, and adipose tissue, but effects of fructose-rich diet on cardiac insulin signaling and action were not investigated.