Oxidative tissue damage following regional intestinal ischemia and reperfusion in the cat

Regional intestinal ischemia in cats resulted in an accumulation of hypoxanthine within 2 h, the concentration of which rose from 0.062 to 1.131 nmol/mg protein. A similar rise in AMP content (from 0.5 to 3.2 nmol/mg protein) was observed, but not in the ADP level. In parallel, ATP content decreased from 7.5 to 2.8 nmol/mg protein. Reperfusion of the ischemic tissue was followed by rapid metabolism of the purine metabolites; after 1 h of reperfusion the tissue level of hypoxanthine was 0.186 nmol/mg protein, of AMP 0.7 nmol/mg protein, and of ATP 4.3 nmol/mg protein. The oxidation of hypoxanthine, mediated by xanthine oxidase, is accompanied by the release of superoxide ions. Consequently, the concentration of oxidized glutathione was doubled upon reperfusion, while marked lipid peroxidation took place, as evidenced by the rise in conjugated diene content from 2.8 mumol/g tissue before reperfusion to 5.6 mumol/g tissue after 10 min of reoxygenation. In line with these findings is the fact that histologically observable damage occurred mainly in the presence of oxygen. These data indicate that, at least in our model, rapid reoxygenation is a major cause of "ischemic" tissue damage.     

Women's angiographic vitamin and estrogen trial: design and methods

The Women's Angiographic Vitamin and Estrogen trial was a randomized, double-blind, placebo-controlled study designed to test the efficacy of estrogen replacement and antioxidant vitamins for preventing angiographic progression of coronary artery disease. Postmenopausal women with one or more angiographically documented coronary stenoses of 15-75% at baseline were assigned in a 2 x 2 factorial randomization to active hormone replacement therapy (conjugated estrogens for women who had had a hysterectomy or conjugated estrogens with medroxyprogesterone for women with intact uteri) or placebo and to active vitamins E and C or their placebos. Seven clinical centers, five in the United States and two in Canada, randomized 423 women between July 1997 and July 1999. Quantitative coronary angiography was performed at baseline and repeated after projected mean follow-up of 3 years.     

Hormone therapy and antioxidant vitamins do not improve endothelial vasodilator function in postmenopausal women with established coronary artery disease: a substudy of the Women's Angiographic Vitamin and Estrogen (WAVE) trial

We measured flow-mediated dilation (FMD) by high-resolution brachial ultrasound in 61 women who participated in the Women's Angiographic Vitamin and Estrogen (WAVE) trial, a randomized controlled trial. There were no significant differences in the baseline demographics of women receiving hormone therapy (0.625 mg/day of conjugated equine estrogen plus 2.5mg of medroxyprogesterone acetate for women who had not had a hysterectomy) or placebo; or vitamins (400 IU of Vitamin E and 500 mg of Vitamin C twice daily) or placebo. Baseline FMD was impaired in all subjects (3.3+/-7.6%). Neither hormone therapy (4.1+/-5.2% at baseline, 4.2+/-5.0% at 3 months, and 4.1+/-6.5% at 34 months) nor antioxidant vitamins (3.0+/-8.3% at baseline; 3.5+/-4.6% at 3 months; 3.1+/-7.6% at 34 months) improved FMD (all p-values=NS). Endothelium-independent vasodilation, induced by nitroglycerin (NTG) was similar at baseline and was not affected by either therapy. In univariate and multivariate analysis, neither hormone therapy nor antioxidant vitamins were associated with FMD. Women with established coronary artery disease have impaired flow-mediated vasodilation of the brachial artery that does not improve after 3 months or up to 34 months of treatment with postmenopausal hormone therapy or antioxidant vitamins.     

Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma

The treatment of patients with relapsed and refractory Hodgkin lymphoma (HL), especially those who relapse after autologous stem cell transplantation, remains challenging. Patients with HL whose disease relapses after stem cell transplantation are rarely cured with current treatment modalities, and have a median survival of less than 3 years. Since no new drugs have been approved by the FDA for HL in more than three decades, there is a clear unmet medical need for drug development for this patient population. New treatment strategies that are based on targeting oncogenic signaling pathways are currently explored. This review will focus on emerging new treatment modalities that are currently under investigation for patients with relapsed classical HL.     

Acinetobacter baumannii-induced lung cell death: role of inflammation, oxidative stress and cytosolic calcium

A growing body of evidence supports the notion that susceptible Acinetobacter baumannii strain ATCC 19606 induces human epithelial cells death. However, most of the cellular and molecular mechanisms associated with this cell death remain unknown, and also the degree of the cytotoxic effects of a clinical panresistant strain compared with a susceptible strain has never been studied. Due to the role of proinflammatory cytokine release, oxidative stress and cytosolic calcium increase in the cell death-induced by other Gram-negative bacteria, we investigated whether these intracellular targets were involved in the cell death induced by clinical panresistant 113-16 and susceptible ATCC 19606 strains.     

Vaccination with outer membrane complexes elicits rapid protective immunity to multidrug-resistant Acinetobacter baumannii

Acinetobacter baumannii causes pneumonias, bacteremias, and skin and soft tissue infections, primarily in the hospitalized setting. The incidence of infections caused by A. baumannii has increased dramatically over the last 30 years, while at the same time the treatment of these infections has been complicated by the emergence of antibiotic-resistant strains. Despite these trends, no vaccines or antibody-based therapies have been developed for the prevention of A. baumannii infection. In this study, an outer membrane complex vaccine consisting of multiple surface antigens from the bacterial membrane of A. baumannii was developed and tested in a murine sepsis model. Immunization elicited humoral and cellular responses that were able to reduce postinfection bacterial loads, reduce postinfection proinflammatory cytokine levels in serum, and protect mice from infection with human clinical isolates of A. baumannii. A single administration of the vaccine was able to elicit protective immunity in as few as 6 days postimmunization. In addition, vaccine antiserum was used successfully to therapeutically rescue naïve mice with established infection. These results indicate that prophylactic vaccination and antibody-based therapies based on an outer membrane complex vaccine may be viable approaches to preventing the morbidity and mortality caused by this pathogen.Acinetobacter baumannii causes different types of infections, including, among others, pneumonia, bacteremia, meningitis, and skin and soft tissue infections (24).Over the last 3 decades, A. baumannii has emerged as a pathogen of increasing clinical importance due to the global increase in the incidence of infections caused by this organism. A. baumannii was shown to be the causative agent in 6.9% of nosocomial pneumonias in 2003 in a national surveillance study performed in the United States, which represents a 72% increase compared to data collected in 1986 (14). In addition, A. baumannii was the causative agent in 2.4% of bacteremias and 6.2% of bacteremias in intensive care units (14, 39). Infections caused by this pathogen have been especially problematic in patients receiving mechanical ventilation, in burn patients, and in military personnel sustaining war-related trauma in Iraq and Afghanistan. A. baumannii can cause outbreaks in intensive care units and trauma/burn units, which are presumably caused by passage of the organism from infected or colonized individuals and contaminated hospital equipment to uninfected patients. Although A. baumannii causes primarily nosocomial infections, recent reports have described community-acquired pneumonias caused by this pathogen (16, 25). Mortality rates associated with A. baumannii infection have been reported to be between 35 and 70% for nosocomial pneumonias (37) and between 20 and 60% for bacteremic infections (14, 39).The treatment of infections caused by A. baumannii has become difficult due to the emergence of multidrug-resistant strains. A. baumannii has demonstrated the ability to acquire resistance to diverse classes of antibiotics via multiple resistance mechanisms (40). Carbapenems have been the standard treatment for A. baumannii infections; however, increasing resistance rates have limited their efficacy. Surveillance studies performed in 2007 showed that resistance rates to imipenem were between 38 and 71%, whereas 20 years ago resistance to imipenem was exceedingly rare (37). Due to increasing resistance to commonly used antibiotics, clinicians have relied increasingly upon the use of the polymyxin antibiotic colistin (15). However, the emergence of strains resistant to colistin has now been reported (1, 5). Of particular concern are recent reports describing outbreaks of panresistant strains, which are resistant to all standard antimicrobials (33, 34). Given these trends, the development of new strategies for preventing and treating infections caused by this pathogen is necessary.Immunization represents a potentially effective strategy for preventing infections caused by A. baumannii; however, to date, there have been no vaccines developed for this pathogen. Vaccines that elicit antibodies against bacterial outer membrane proteins are attractive candidates due to the role of these proteins in interacting with the host and their availability for antibody neutralization due to their localization on the cell surface.Vaccines based on inactivated whole cells and attenuated strains are able to elicit antibodies against multiple surface proteins; however, the administration of whole organisms raises potential safety concerns. One approach that has been used to elicit antibodies against multiple bacterial surface proteins without the administration of whole organisms is the development of vaccines based on proteins extracted from the bacterial outer membrane, termed outer membrane complex (OMC) vaccines (4, 10, 17). OMC vaccines have been shown to elicit antibodies against multiple proteins of the bacterial outer membrane and to induce protective immunity against infection and have given promising results in early human clinical trials (4, 10, 17-19). The objective of the present study was to develop an OMC vaccine against A. baumannii and to characterize its efficacy in a murine sepsis model. In addition, the ability of antisera from vaccinated mice to passively protect and treat naïve mice was tested.