Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise

BACKGROUND: Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials. METHODS AND RESULTS: We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction < or = 0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n = 145) or carvedilol (n = 133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P = .014) or by a global assessment of progress judged either by the patient (P = .002) or by the physician (P < .001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (P < .001) and a significant decrease in the combined risk of morbidity and mortality (P = .029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure. CONCLUSIONS: These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.     

Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction

Pediococcus sp. is a nonpathogenic heat-resistant spoilage organism that has been used as a test organism in milk pasteurization studies. These characteristics make this bacterium an attractive test organism to study the mode of bacterial thermal inactivation in a food pilot plant. We report here the effect of growth medium on the thermal D value of this organism in skim milk, whole liquid egg, 10% glucose solution, pineapple juice, apple juice, tomato juice, and water at 60 degrees C. Thermal inactivation was done in a submerged coil; D values were calculated from the linear portion of the survival curves by linear regression analysis. The range of D values of stationary-phase cells grown at 28 degrees C in tryptone glucose yeast extract (TGY) or tryptic soy broth (TSB) was 0.14 to 12.05 min in all heating menstrua tested. The TSB-grown cells exhibited the highest thermal resistance with skim milk and 10% glucose solution as the heating menstrua. Survival curves of the TGY-grown cells indicated the presence of a cell population heterogeneous in thermal resistance. The TSB-grown cells exhibited a cell population uniform in thermal resistance and with a lag time for thermal inactivation. When compared to TGY-grown cells, Pediococcus sp. grown in TSB showed a significant (P < 0.05) increase in D values by up to eightfold in all heating menstrua. Results from this study suggested that thermal inactivation of Pediococcus sp. was dependent on the growth medium and on the heating menstruum with respect to both pH and composition.     

Hormonal protection from cyclophosphamide-induced inactivation of rat stem spermatogonia

Studies of protection of testicular function from cyclophosphamide with hormonal pretreatment have been limited by the lack of a convenient model for cyclophosphamide-induced inactivation of stem spermatogonia. In the rat, the mortality from cyclophosphamide had prevented the administration of sufficient dosages to produce detectible damage to stem spermatogonia. To overcome this problem, we used bone marrow transplantation and sodium 2-mercaptoethanesulfonate (Mesna) treatment to raise the lethal dose for 50% of the animals (LD50) for cyclophosphamide from 275 to > 400 mg/kg body weight. In addition we used irradiation, 2 weeks prior to injection of cyclophosphamide, to greatly enhance the measured toxicity of cyclophosphamide towards stem spermatogonia. Whereas sperm counts at 9 weeks after a 300 mg/kg cyclophosphamide dose were reduced by only a factor of 1.6 without prior irradiation, they were reduced by a factor of 60 when 2.5 Gy of irradiation had been given. Dramatic protection against this toxicity was produced by hormone treatment with a gonadotropin-releasing hormone (GnRH) antagonist (Nal-Glu) and an antiandrogen (flutamide) following the radiation but prior to cyclophosphamide. This hormone treatment did not modify the stem cell toxicity of the radiation and it therefore must be protecting stem cells against cyclophosphamide-induced damage. Because GnRH antagonist-antiandrogen treatment can protect stem spermatogonial survival and/or function in the rat from cyclophosphamide-induced damage, if the same principles are applicable in human, hormonal pretreatment should be useful for preventing the prolonged azoospermia caused by chemotherapy with cyclophosphamide-containing protocols.     

Systemic interleukin 2 therapy for human prostate tumors in a nude mouse model

Once the regional lymph nodes become involved in prostate carcinoma, 85% of patients develop distant metastases within 5 years, and metastatic disease is difficult to treat. We have investigated the effect of systemic interleukin 2 (IL-2) treatment on metastatic prostate carcinoma using a xenograft tumor model. Cells from a PC-3/IF cell line, produced by intrafemoral injection of human PC-3 prostate carcinoma cells, were injected in the prostate of Balb/c nude mice. Prostate tumors and para-aortic lymph nodes were resected, and tumor cells were recultured and passaged in the prostate in vivo to produce new cell lines. On day 6 following prostatic injection of these cell lines, mice were treated with i.p. injections of IL-2 at 25,000-50,000 units/ day for 5 consecutive days. The effect of IL-2 on tumor progression was assessed, and histological studies were performed on prostate tumor and lymph node sections. The tumor cell lines generated by serial prostate injection were tumorigenic and metastasized to regional para-aortic lymph nodes. Tumors of 0.4 cm were obtained by day 16 and grew to 1-1.5 cm by day 40 with metastasis to para-aortic lymph nodes. Following two to three weekly courses of 5 days of 25,000-40,000 units/day of IL-2, the growth of prostate tumors was inhibited by 94%. Higher doses of 50,000 units/ day were toxic. Histologically, prostate sections showed vascular damage manifested by multifocal hemorrhages and an influx of lymphocytes and polymorphonuclear cells into disintegrating tumors and areas of necrosis containing numerous apoptotic cells. In contrast to control mice, para-aortic lymph nodes were not enlarged in responding mice. These findings suggest that systemic IL-2 therapy can induce an antitumor response in prostate tumors and control their growth and metastasis.     

Cutaneous leishmaniasis in the Libyan Arab Republic: distribution of the disease and identity of the parasite

When mammalian sperm cells are exposed to solutions of albumin there are changes in the membranes of some species that resemble those that normally occur in the uterus prior to fertilization. We have shown that albumin molecules absorb on to the membranes of ejaculated rabbit sperm cells, and that the equilibrium binding constant, K, (1) varies inversely with the albumin concentration, (2) is independent of the sperm cell concentration in the range of 10(6)--10(7) per ml, (3) is independent of the time of exposure of the sperm cells to the albumin solution, and (4) decreases in the presence of Ca++ and Mg++ ions. An unusual aspect of the adsorption is that if the albumin concentration is given the symbol [A], K[A] is a constant in our measurements. This means that for virtually the entire range of [A] studied, the sperm cells bind albumin so that half of the available surface is coated and half remains uncoated. This situation is rather remarkable and it suggests a role that adsorption could play in the physical processes preceding fertilization. In purely physical systems, the optimum for the bridging and flocculation of particles that are coated with adsorbed macromolecular films occurs when half of the available surface is covered. The sperm cell appears to provide the optimal situation for interacting with itself or with another surface.     

Conservative surgical management of tubal pregnancy

In an attempt to maintain optimal fertility in the patient treated for midtubal pregnancy, an investigation of conservative surgical procedure was made. The technic developed utilizes tubal excision, reanastomosis, and a single hydrotubation with Dextran. Tubal patency was maintained without the use of stents that may damage the fimbria. The procedure is compared to other conservative technics and its advantages discused. Thus far 2 patients have undergone this excision and reanastomosis, and both patients successfully established intrauterine gestations within 2 months of returning to normal active coital frequency. Both were in the midtrimester of pregnancy at the time of this report.     

Pneumomediastinum following a surgical renal biopsy

A case of pneumomediastinum, which appeared after a biopsy of the right kidney by minimal lumbotomy, is reported. The anatomicopathological condition of the renal fragment obtained was judged to be focal and segmental hyalinosis. We wish to emphasize the rarity of such a complication, the type of electrocardiographic changes observed, and the rapid and spontaneous recuperation of the patient without further repercussions.     

A comparative analysis of four protocols for maximal treadmill stress testing

The purpose of this investigation was to compare the results from four commonly used maximal treadmill stress tests: Balke, Bruce, Ellestad, and a continuous multistage running protocol. The results compared serial and maximal heart rate, metabolic demands, and ECG determinations. Fifty-one healthy men, 35 to 55 years of age, volunteered for this study and were dichotomized into trained and untrained subjects. Regression analyses showed all the tests to correlate highly. No significant differences were found between tests at maximum for V02, heart rate, and blood pressure, except for V02 for the Balke as compared to the running protocol (39 vs. 41 ml./Kg-min). The Balke protocol showed lower values at maximum in VE and RP than the other three tests as well as the most gradual rate of progression in MET cost (0.5 METS per minute). The increase for the Bruce and Ellestad tests was from 1 to 1.5 METS per minute, and a rapid initial increase (9 METS in the first 3 minutes) made the running test undesirable as a screening method. Although serial plots of heart rate and MET costs were similar to those previously reported for different population samples, the present data further refined these values. Finally, a nomograph comparing treadmill time and V02, max. for the Balke, Bruce, and Ellestad tests was developed from these data.