Double-blind placebo-controlled comparison of enoximone and dobutamine infusions in patients with moderate to severe chronic heart failure

Few data exist on the safety of transferring patients to standard oral therapy for chronic heart failure (CHF) after acute management with inotropic agents. This study compares hemodynamic responses and cardiac dysrhythmic effects of continuous infusion of enoximone, dobutamine, or placebo in patients with moderate to severe CHF. The authors enrolled 136 patients who were randomly assigned to either open-label dobutamine or double-blind enoximone vs placebo. After 24 hours of treatment, the study was unblinded. Patients receiving placebo completed the study. Patients receiving enoximone or dobutamine received the infusion for an additional 24 hours and were then switched to standard oral therapy for 72 hours. Compared with placebo, both enoximone and dobutamine increased cardiac index and decreased pulmonary capillary wedge pressure (PCWP). Compared with dobutamine, enoximone significantly increased cardiac index after the first 24 hours of infusion and significantly decreased PCWP throughout the infusion period. There was no difference in the incidence of arrhythmias between enoximone and dobutamine. More patients (65%) tolerated the switch to oral therapy in the enoximone group compared with dobutamine (49%; P =.12). Enoximone is effective in improving the hemodynamics in patients with moderate to severe CHF and is tolerated at least as well as dobutamine.     

Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF–IGFBP axis

The IGF axis is critical for the regulation of apoptosis in many human cancer cell lines. Recently, potent anti-tumorigenic effects of pomegranate juice and extracts have been reported. Consequently, pomegranate has potential not only as a treatment but also as a preventative measure against certain types of cancer, including prostate. In this study, we investigated the relationship between pomegranate-induced apoptosis in human prostate cancer cells and the IGF/IGFBP system. Treatment of LAPC4 prostate cancer cells with 10 μg/ml POMx, a highly potent pomegranate extract prepared from skin and arils minus seeds and standardized to ellagitannin content (37% punicalagins by HPLC), resulted in inhibition of cell proliferation and induction of apoptosis. Interestingly, co-treatment with POMx and IGFBP-3 revealed synergistic stimulation of apoptosis and additive inhibition of cell growth. Western blot analysis revealed that treatment with POMx or POMx/IGFBP-3 combination resulted in increased JNK phosphorylation, and decreased Akt and mTOR activation, consistent with a growth inhibitory, pro-apoptotic function. We also investigated the relationship between IGF-1 and pomegranate-induced apoptosis in 22RV1 prostate cancer cells. Co-treatment with 100 ng/ml IGF-1 completely blocked apoptosis induction by POMx. In contrast, IGF-I failed to inhibit POMx-induced apoptosis in R^? cells, suggesting the importance of IGF-IR. POMx-treatment decreased Igf1 mRNA expression in a dose-dependent manner indicating that its actions also involve tumor-specific suppression of IGF-1. These studies revealed novel interactions between the IGF system and pomegranate-induced apoptosis.     

Heterologous expression in transgenic mosquitoes

Arthropod-borne diseases such as malaria and dengue virus afflict billions of people worldwide imposing major economic and social burdens. Control of such pathogens is mainly performed by vector management and treatment of affected individuals with drugs. The failure of these conventional approaches due to emergence of insecticide-resistant insects and drug-resistant parasites demonstrate the need of novel and efficacious control strategies to combat these diseases. Genetic modification (GM) of mosquito vectors to impair their ability to be infected and transmit pathogens has emerged as a new strategy to reduce transmission of many vector-borne diseases and deliver public health gains. Several advances in developing transgenic mosquitoes unable to transmit pathogens have gained support, some of them attempt to manipulate the naturally occurring endogenous refractory mechanisms, while others initiate the identification of an exogenous foreign gene which disrupt the pathogen development in insect vectors. Heterologous expression of transgenes under a native or heterologous promoter is important for the screening and effecting of the transgenic mosquitoes. The effect of the transgene on mosquito fitness is a crucial parameter influencing the success of this transgenic approach. This review examines these two aspects and describes the basic research work that has been accomplished towards understanding the complex relation between the parasite and its vector and focuses on recent advances and perspectives towards construction of transgenic mosquitoes refractory to vector-borne disease transmission.     

Effect of Punica granatum peel extract on learning and memory in rats

ObjectiveTo evaluate potential memory enhancing effect of Punica granatum peel extract on rats.MethodsHealthy adult male albino rats of Wistar strain were used. Each group of 6 rats were administered either distilled water or 50 mg/kg of extract or 100 mg/kg of extract for 15 days and subjected to passive avoidance test or T-maze test. In the next phase rats were administered distilled water or 100 mg/kg of extract for 15 days and the rats were given injection diazepam before subjecting them to the tests.ResultsThe overall performance was better in test groups compared to control groups. Among the test groups, 100 mg/kg rats performed better than 50 mg/kg. The effect on spatial learning parameters like mean number of alternations and mean percentage bias was more marked compared to retention testing parameters like latency. 100 mg/kg Punica extract treated group also improved performance of diazepam treated rats.ConclusionsThere is a definite trend of memory improvement by Punica granatum peel with effects being more marked on spatial learning tendency and long term memory than on retention capacity.     

Resting Echocardiography for the Early Detection of Acute Coronary Syndromes in Chest Pain Unit Patients

Aim: The purpose of this study is to assess the ability of resting echocardiography to detect an acute coronary syndrome (ACS) before the occurrence of ischemic electrocardiogram (ECG) changes or troponin‐T elevations. Methods: Four hundred and three patients who presented to the emergency room (ER) with chest pain, normal ECGs, and normal troponin‐T levels were admitted to the cardiologist‐run Chest Pain Unit (CPU) for further monitoring. They underwent serial resting echocardiography for monitoring of left ventricle wall motion (LVWM), ECG telemetry monitoring, and serial troponin‐T measurements. Results: An ACS was detected in 49 patients (12.1%). These 49 patients were then subdivided into three different groups based on the initial mode of detection of their ACS. In group A, 16 of 49 (32.6%) patients had ACS shown by echocardiographic detection of LVWM abnormalities. In group B, 24 of 49 (48.9%) patients had an ACS detected by ischemic ECG changes. In group C, 9 of 49 (18.3%) patients had an ACS detected by troponin‐T elevations. The shortest time interval between CPU‐admission and ACS‐detection occurred in group A (A vs. B, P < 0.003; A vs. C, P < 0.0001). In group A, cardiac angiogram showed that the culprit coronary lesion was more frequent in the circumflex artery (11 out of 16; 68.7%) (LCx vs. LAD, P < 0.02; LCx vs. RCA, P < 0.001) and of these 11 patients with circumflex lesions, the ECG was normal in eight (72.7%) patients. Conclusion: This study demonstrates the utility of LVWM monitoring by serial echocardiography as part of a diagnostic protocol that can be implemented in a CPU. Furthermore, echocardiography could become an essential tool used in the diagnosis of ACS secondary to circumflex lesions. (Echocardiography 2010;27:597‐602)     

Acute myocardial infarction in the young— The University of Michigan experience

Background The purpose of this study was to assess frequency, risk factors, treatment, and complications of very young patients with acute myocardial infarction (MI) at the University of Michigan Medical Center (UMMC). Methods From a database of 976 consecutive patients admitted to the UMMC with acute MI between 1995 and 1998, we compared care and outcomes of patients divided into 3 age categories: <46 years, 46-54 years, and >54 years. Risk factors, presenting symptoms, type of MI, management, complications, and hospital outcomes of the 3 groups were evaluated. Results Young patients represented >10% of all patients with acute MI, and >25% of these individuals were women, a number considerably higher than seen in previous studies. This group of young patients was more likely to have Q-wave MI and risk factors such as family history and tobacco use and less likely to have a history of angina. Although all 3 groups received similar inpatient treatment, there was more attention paid to risk factor modification such as smoking cessation and referral to cardiac rehabilitation in younger individuals. Young patients had fewer in-hospital complications and a lower mortality rate. Conclusions At the University of Michigan, >1 in 10 with acute MI is <46 years old. Data suggest that current management and aggressive risk factor modification are quite good in this particular group, and overall the mortality rate is very low. (Am Heart J 2002;143:56-62.)     

Reassessing the definition of myeloid engraftment after autotransplantation: it is not necessary to see 0.5 x 10(9)/l neutrophils on 3 consecutive days to define myeloid recovery

The time to myeloid recovery after autologous hematopoietic stem cell transplantation (HSCT) is usually defined as the first of 3 consecutive days with an absolute neutrophil count (ANC) of >or=0.5 x 10(9)/l (ANC500). Universal documentation of ANC500 for 3 consecutive days, historically required to ensure robust myeloid recovery, has become difficult with a trend towards early discharge and outpatient HSCT. We studied 90 autografted patients to see how frequently ANC declined after having reached >or=0.5 x 10(9)/l. ANC500 was documented on 2 and 3 consecutive days in 14 and 63 patients, respectively. ANC increased by a median of 213% from the 1st to the 2nd day (rise in 75 and unchanged in two), and by a median of 142% from the 2nd day to the 3rd (rise in 60, unchanged in one, and decline in two; higher than the 1st day in the latter three). The increase from the 1st to the 3rd day was 13-3433% (median, 557%). Thus, in all 63 patients, no decline below ANC500 was seen, and the first day with ANC500 was also the first of 3 consecutive days with ANC500. The remaining 13 patients had repeat counts 2-7 days after the 1st day with ANC500 documenting further increase in ANC with no evidence of failed engraftment. These data show that the first day with ANC500 is also consistently the first of 3 consecutive days with ANC500 in autografted patients. Therefore, the traditional definition of myeloid engraftment should be changed to consider the first day with ANC500 as the day of engraftment without necessarily documenting ANC500 on the subsequent 1-2 days. This simple change in definition has significant implications for how data are reported to transplant registries and how peer-review organizations such as the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) define completeness of data.     

Effects of nebulized diethylenetetraamine-NONOate in a mouse model of acute Pseudomonas aeruginosa pneumonia

OBJECTIVE: Endogenous and exogenous nitric oxide (NO) may have important antibacterial effects in patients with pneumonia. NO administration has been limited to the continuous inhalation of gas-phase NO (ie, inhaled NO [iNO]). Intermittent nebulization of NONOates, novel NO donors, may permit the continuous intrapulmonary delivery of NO. Thus, we assessed the effects of nebulized diethylenetetraamine-NONOate (DETA-NO) in a model of acute Pseudomonas aeruginosa pneumonia. DESIGN: Randomized, controlled study. SUBJECTS: Male C57Bl/6 mice. INTERVENTIONS: Pneumonia was induced by intratracheal instillation of P aeruginosa (3 x 10(7) CFU in 50 microL). Pneumonia and sham mice were randomized to receive no treatment, nebulized DETA-NO (12.5 or 125 micromol) at 4 h and 12 h, or continuous iNO for 24 h (10 or 40 ppm) until they were killed at 24 h. MAIN RESULTS: The nebulization of DETA-NO was associated with a marked increase in mean (+/- SEM) exhaled NO levels (after nebulization, 484 +/- 34 parts per billion [ppb]; baseline, 13.4 +/- 0.4 ppb; p < 0.01) and plasma levels of nitrites/nitrates (after nebulization, 73 +/- 28 microM; at baseline, 14 +/- 3 microM; p < 0.05). Nebulized DETA-NO decreased the pulmonary bacterial load in mice with pneumonia by 65 +/- 19% (p < 0.05 vs untreated mice) but had no effect on pulmonary leukocyte infiltration. Although the growth of P aeruginosa colonies in vitro was impaired on exposure to DETA-NO, growth was similarly impaired by exposure to DETA nucleophile/backbone alone. CONCLUSIONS: The nebulization of DETA-NO provides a method for the prolonged intrapulmonary delivery of NO. The antibacterial effect of DETA-NO in vivo and in vitro is due, in large part, to the DETA nucleophile moiety and is independent of NO, suggesting a limited therapeutic role for exogenous NO in pneumonia.     

Hemodynamic Studies in Acute-on-Chronic Liver Failure

Background Patients with decompensated cirrhosis and acute liver failure have circulatory dysfunctions leading to high portal pressure and cardiac output (CO) and low systemic vascular resistance (SVR). Circulatory changes in acute-on-chronic liver failure (ACLF) patients have not been studied. We studied the portal, systemic, and pulmonary hemodynamics in patients with ACLF and compared them with compensated and decompensated cirrhotics. Patients and Methods Clinical features and hemodynamic profile were studied in patients with ACLF and compared with age- and sex-matched compensated and decompensated cirrhotics with portal hypertension. Results The study cohort comprised 144 patients categorized into one of three groups (ACLF, compensated cirrhosis, and decompensated cirrhosis), with 48 (33%) patients in each group. All values are given as the mean ± standard deviation, except for frequencies (%). The mean arterial pressure (MAP) and SVR were lower in the ACLF than the compensated group and were similar to those of the decompensated group (MAP 90 ± 16 vs. 99 ± 15 vs. 96 ± 16 mmHg; SVR 912 ± 435 vs. 1350 ± 449 vs. 891 ± 333 dyn s/cm⁵). The mean CO of the ACLF patients was higher than that of the compensated group and similar to that of the decompensated group (CO 8.9 ± 3.5 vs. 6.1 ± 1.7 vs. 9.0 ± 3.0 l/min). The pulmonary vascular resistance (PVR) and pulmonary capillary wedge pressures (PCWP) were similar in all the three groups (PVR 78 ± 48 vs. 109 ± 70 vs. 61 ± 47 dyn s/cm⁵; PCWP 8 ± 4 vs. 8 ± 4 vs. 10 ± 5 mmHg). The mean hepatic venous pressure gradient (HVPG) in the ACLF group was 15.1 ± 6.3 mmHg, which was significantly higher than that of the compensated group (11.7 ± 6.3 mmHg), but lower than that of the decompensated cirrhosis group (20.2 ± 6.0 mmHg). When patients of ACLF were categorized on the basis of their variceal size, the mean HVPG in ACLF patients with small varices was similar to that of compensated cirrhotics (13.7 ± 5.7 vs. 11.7 ± 6.3 mmHg; P = 0.146), while in the ACLF patients with large varices, the HVPG was comparable to that of the decompensated cirrhotics (18.7 ± 6.6 vs. 20.2 ± 6.0 mmHg; P = 0.442). Conclusions The systemic hemodynamics in patients with ACLF is similar to that in decompensated cirrhotics. The portal pressure in these patients is higher than that in the compensated cirrhotics, and in the subgroup with large varices, it becomes similar to that of decompensated cirrhotics.