Acute alcohol modulates cardiac function as PI3K/Akt regulates oxidative stress.

BACKGROUND: Clinical manifestations of alcohol abuse on the cardiac muscle include defective contractility with the development of heart failure. Interestingly, low alcohol consumption has been associated with reduced risk of cardiovascular disease. Although several hypotheses have been postulated for alcoholic cardiomyopathy and for the low-dose beneficial cardiovascular effects, the precise mechanisms and mediators remain largely undefined. We hypothesize that modulation of oxidative stress by PI3K/Akt plays a key role in the cardiac functional outcome to acute alcohol exposure. METHODS: Thus, acutely exposed rat cardiac tissue and cardiocytes to low (LA: 5 mM), moderate (MA: 25 mM), and high (HA: 100 mM) alcohol were assessed for markers of oxidative stress in the presence and absence of PI3K/Akt activators (IGF-1 0.1 µM or constitutively active PI3K: Ad.BD110 transfection) or inhibitor (LY294002 1 µM or Akt-negative construct Ad.Akt(K179M) transfection). RESULTS: Acute LA reduced Akt, superoxide dismutase (SOD-3) and NFκB, ERK1, and p38 MAPK gene expression. Acute HA only increased that of SOD-3 and NFκB. These effects were generally inhibited by Ad.Akt(K179M) and enhanced with Ad.BD110 transfection. In parallel, LA reduced but HA enhanced Akt activity, which was reversed by IGF-1 and inhibited by Ad.Akt(K179M), respectively. Also, LA reduced caspase 3/7 activity and oxidative stress, while HA increased both. The former was blocked, while the latter effect was enhanced by Ad.Akt(K179M). The reverse was true with PI3K/Akt activation. This translated into reduced viability with HA, with no effect with LA. On the functional level, acute LA improved cardiac output and ejection fraction, mainly through increased stroke volume. This was accompanied with enhanced end-systolic pressure-volume relationship and preload recruitable stroke work. Opposite effect was recorded for HA. LA and HA in vivo functional effects were alleviated by LY and enhanced by IGF-1 treatment. CONCLUSIONS: Acute LA and HA seem to oppositely affect cardiac function through modulation of oxidative stress where PI3K/Akt plays a pivotal role.

Inotropic and lusitropic effects of calcitonin gene-related peptide in the heart.

Previous studies have demonstrated positive-inotropic effects of calcitonin gene-related peptide (CGRP), but the mechanisms remain unclear. Therefore, two experiments were performed to determine the physiological correlates of the positive-inotropic effects of CGRP. Treatments designed to antagonize the effects of physiologically active CGRP1₋37 included posttreatment with CGRP8₋37 and pretreatment with LY-294002 (LY, an inhibitor of phosphatidylinositol 3-kinase), 17ß-estradiol (E), and progesterone (P) were also used to modulate the effects of CGRP1₋37. Experiment 1 was in vitro studies on sarcomeres and cells of isolated adult rat cardiac myocytes. CGRP1₋37, alone and in combination with E and P, decreased sarcomere shortening velocities and increased shortening percentages, effects that were antagonized by CGRP8₋37, but not by LY. CGRP1₋37 increased resting intracellular calcium ion concentrations and Ca(2+) influxes, effects that were also antagonized by both CGRP8₋37 and LY. Experiment 2 was in vivo studies on left ventricular pressure-volume (PV) loops. CGRP1₋37 increased end-systolic pressure, ejection fraction, and velocities of contraction and relaxation while decreasing stroke volume, cardiac output, stroke work, PV area, and compliance. After partial occlusion of the vena cava, CGRP1₋37 increased the slope of the end-systolic PV relationship. CGRP8₋37 and LY attenuated most of the CGRP-induced changes. These findings suggest that CGRP-induced positive-inotropic effects may be increased by treatments with estradiol and progesterone and inhibited by LY. The physiological correlates of CGRP-induced positive inotropy observed in rat sarcomeres, cells, and intact hearts are likely to reveal novel mechanisms of heart failure in humans.

The good, the bad, and the ugly with alcohol use and abuse on the heart.

Since its advent, alcohol has been utilized throughout history socially, for rituals, worship, and for its therapeutic, antibacterial, and analgesic properties. In moderation, alcohol consumption and its use are generally viewed as clinically beneficial. Excessive alcohol consumption on the other hand has been recognized as having several adverse implications. Excessive use increases the risk of liver and heart disease, metabolic disturbances, nutritional deficiencies, certain cancers, brain damage, dementia, neuropathy, as well as other facets of morbidity and mortality. This review targets the sequelae of alcohol consumption on the heart, specifically on myocardial contractility, calcium channel signaling, and intracellular signaling pathways. With the incidence of alcohol-induced cardiac abnormalities being higher than previously thought, it is of increasing importance to elucidate the mechanisms behind them. Here, the cardiac effects of alcohol were not discussed in isolation but in conjunction with other important factors, such as high- and low-density lipoprotein levels and vascular dilatory influences. We explore these mechanisms, in particular, the oxidative stress as the major contributor, as well as pathways that may prove to be cardioprotective. As such, we demonstrate the involvement of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/NRF2) as well as AKT that act as regulators of oxidative balance during oxidative stress responses. Thus, alcohol consumption may confer a cardioprotective effect when used in moderation through an AKT/NRF2-dependent mechanism.

In vitro antibacterial activity of doripenem against clinical isolates from French teaching hospitals: proposition of zone diameter breakpoints.

The aims of the study were to determine the in vitro activity of doripenem, a new carbapenem, against a large number of bacterial pathogens and to propose zone diameter breakpoints for clinical categorization in France according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) minimum inhibitory concentration (MIC) breakpoints. The MICs of doripenem were determined by the broth microdilution method against 1,547 clinical isolates from eight French hospitals. The disk diffusion test was performed (10-µg discs) according to the Comité de l'Antibiogramme de la Société Française de Microbiologie (CASFM) method. The MIC(50/90) (mg/L) values were as follows: methicillin-susceptible Staphylococcus aureus (MSSA) (0.03/0.25), methicillin-resistant Staphylococcus aureus (MRSA) (1/2), methicillin-susceptible coagulase-negative staphylococci (MSCoNS) (0.03/0.12), methicillin-resistant coagulase-negative staphylococci (MRCoNS) (2/8), Streptococcus pneumoniae (0.016/0.25), viridans group streptococci (0.016/2), ß-hemolytic streptococci (≤0.008/≤0.008), Enterococcus faecalis (2/4), Enterococcus faecium (128/>128), Enterobacteriaceae (0.06/0.25), Pseudomonas aeruginosa (0.5/8), Acinetobacter baumannii (0.25/2), Haemophilus influenzae (0.12/0.25), and Moraxella catarrhalis (0.03/0.06). According to the regression curve, the zone diameter breakpoints were 24 and 19 mm for MICs of 1 and 4 mg/L, respectively. This study confirms the potent in vitro activity of doripenem against Pseudomonas aeruginosa, Acinetobacter, Enterobacteriaceae, MSSA, MSCoNS, and respiratory pathogens. According to the EUCAST MIC breakpoints (mg/L) ≤1/>4 for Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter, and ≤1/>1 for streptococci, pneumococci, and Haemophilus, the zone diameter breakpoints could be (mm) ≥24/<19 and ≥24/<24, respectively.

[Activity of doripenem against anaerobic bacteria]. / Activité du doripénème sur les bactéries anaérobies strictes.

AIMS OF THE STUDY: This study examines the activity of doripenem, a new carbapenem compound compared with amoxicillin-clavulanic acid, piperacillin+tazobactam, imipenem, clindamycin and metronidazole against 316 anaerobes. METHODS: Inoculum preparation and agar dilution method were performed according to the CLSI method for anaerobes (M11A7). RESULTS: At a concentration of 4µg/ml doripenem and imipenem (IMP) inhibited 122 (96 %) and 126 (99 %) strains of the Bacteroides fragilis group, respectively. In contrast, doripenem appeared more potent than IMP against Gram-positive anaerobes inhibiting at the same concentration of 4µg/ml 145/145 strains (100 %) versus 115/145 for IMP (79.3 %). Against 316 anaerobic strains, the carbapenem doripenem had an MIC(50) of 0.25µg/ml and an MIC(90) of 2µg/ml. Results were similar to those for imipenem (MIC(50) of 0.125µg/ml and MIC(90) of 4µg/ml). If we consider the resistant breakpoints of the two carbapenems as defined by EUCAST, the resistance rate for doripenem (MIC>4µg/ml) 1.6 % is similar to that of imipenem (MIC>8µg/ml) 1.3 %. CONCLUSION: Thus independently of the PK/PD parameters the two carbapenems demonstrated very close activity; doripenem was more potent on Gram-positive anaerobes and slightly less potent against Gram-negative anaerobes mainly the B. fragilis group. Further clinical studies are needed to assess its usefulness in patients.

In vitro antibacterial activity of ceftobiprole against clinical isolates from French teaching hospitals: proposition of zone diameter breakpoints.

The aims of this study were to determine the in vitro activity profile of ceftobiprole, a pyrrolidinone cephalosporin, against a large number of bacterial pathogens and to propose zone diameter breakpoints for clinical categorisation according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) minimum inhibitory concentration (MIC) breakpoints. MICs of ceftobiprole were determined by broth microdilution against 1548 clinical isolates collected in eight French hospitals. Disk diffusion testing was performed using 30 µg disks according to the method of the Comité de l'Antibiogramme de la Société Française de Microbiologie (CA-SFM). The in vitro activity of ceftobiprole, expressed by MIC(50/90) (MICs for 50% and 90% of the organisms, respectively) (mg/L), was as follows: meticillin-susceptible Staphylococcus aureus, 0.25/0.5; meticillin-resistant S. aureus (MRSA), 1/2; meticillin-susceptible coagulase-negative staphylococci (CoNS), 0.12/0.5; meticillin-resistant CoNS, 1/2; penicillin-susceptible Streptococcus pneumoniae, ≤ 0.008/0.03; penicillin-resistant S. pneumoniae, 0.12/0.5; viridans group streptococci, 0.03/0.12; ß-haemolytic streptococci, ≤ 0.008/0.016; Enterococcus faecalis, 0.25/1; Enterococcus faecium, 64/128; Enterobacteriaceae, 0.06/32; Pseudomonas aeruginosa, 4/16; Acinetobacter baumannii, 0.5/64; Haemophilus influenzae, 0.03/0.12; and Moraxella catarrhalis, 0.25/0.5. According to the regression curve, zone diameter breakpoints could be 28, 26, 24 and 22 mm for MICs of 0.5, 1, 2 and 4 mg/L respectively. In conclusion, this study confirms the potent in vitro activity of ceftobiprole against many Gram-positive bacteria, including MRSA but not E. faecium, whilst maintaining a Gram-negative spectrum similar to the advanced-generation cephalosporins such as cefepime. Thus ceftobiprole appears to be well suited for the empirical treatment of a variety of healthcare-associated infections.