Up-regulation of c-Jun inhibits proliferation and induces apoptosis via caspase-triggered c-Abl cleavage in human multiple myeloma

Here we show the antimyeloma cytotoxicity of adaphostin and carried out expression profiling of adaphostin-treated multiple myeloma (MM) cells to identify its molecular targets. Surprisingly, c-Jun was the most up-regulated gene even at the earliest point of analysis (2 h). We also observed adaphostin-induced c-Abl cleavage in immunoblot analysis. Proteasome inhibitor bortezomib, but not melphalan or dexamethasone, induced similar effects, indicating unique agent-dependent mechanisms. Using caspase inhibitors, as well as caspase-resistant mutants of c-Abl (TM-c-Abl and D565A-Abl), we then showed that c-Abl cleavage in MM cells requires caspase activity. Importantly, both overexpression of the c-Abl fragment or c-Jun and knockdown of c-Abl and c-Jun expression by small interfering RNA confirmed that adaphostin-induced c-Jun up-regulation triggers downstream caspase-mediated c-Abl cleavage, inhibition of MM cell growth, and induction of apoptosis. Finally, our data suggest that this mechanism may not only be restricted to MM but may also be important in a broad range of malignancies including erythroleukemia and solid tumors.     

Comparative assessment of soil contamination by lead and heavy metals in riparian and agricultural areas (southern Québec, Canada)

Soils contaminated with hydrocarbons (C(10)-C(50)), PAHS, lead and other heavy metals were recently found in the banks of two major rivers in southern Québec. Alluvial soils are contaminated over a distance of 100 kilometers. Eight sampling sites, including some located in agriculture areas (farm woodlots) have been selected to compare air pollution (aerosol fallout and rainout) and river pollution values. The concentrations detected in soil profiles for As, Cd and Pb vary between 3.01 to 37.88 mg kg(-1) (As), 0.11 to 0.81 mg kg(-1) (Cd) 12.32 to 149.13 mg kg(-1) (Pb). These metallic elements are considered highly toxic and can harm wildlife and human health at high levels. The maximum concentration of Pb (149.13 mg kg(-1)) in soils of the riparian zone is twelve times higher than the average Pb concentration found in a natural state evaluated at 15.3 mg kg(-1) (SD 17.5). Pb concentrations in soils of agricultural areas (woodland control sites) range between 12 and 22 mg kg(-1), and given that these values are recorded in surrounding cultivated land, the issue of the quality of agricultural products (crops and forage) to feed livestock or destined for human consumption must be further addressed in detail.     

IMMUNOLOGICAL STUDIES IN TWO CHILDREN WITH RECURRENT PAROTITIS

ABSTRACT. In two children with recurrent parotitis, labial salivary gland biopsies showed chronic sialoadenitis. Immunofluorescence studies disclosed deposits of immunoglobulins and complement in juxta-acinar small vessels. Case 1 had gluten enteropathy, IgA deficiency and high titres of antinuclear antibodies (ANA), and in vivo fixation of ANA to nuclei of different cells in lip, skin and jejunum was present. Case 2 showed deposition of IgM in the dermo-epidermal junction of the skin. These findings suggest that autoimmune reactivity and immune complexes may play a role in the pathogenesis of this disorder.     

Recognizing cognitive and psychiatric changes in the post-highly active antiretroviral therapy era

Amid numerous complications that plague the health and quality of life of people living with HIV, neurocognitive and psychiatric illnesses pose unique challenges. While there remains uncertainty with respect to the pathophysiology surrounding these disorders, their adverse implications are increasingly recognized. Left undetected, they have the potential to significantly impact patient well being, adherence to antiretroviral treatment and overall health outcomes. As such, early identification of HIV-associated neurocognitive disorders (HAND) and psychiatric illnesses will be paramount in the proactive management of affected patients. The present review focuses on strategies to ensure optimal screening and detection of HAND, depression and substance abuse in routine practice. For each topic, currently available screening methods are discussed. These include identification of risk factors, recognition of relevant symptomatology and an update on validated screening tools that can be efficiently implemented in the clinical setting. Specifically addressed in the present review are the International HIV Dementia Scale, a novel screening equation and algorithm for HAND, as well as brief, validated, verbal questionnaires for detection of depression and substance abuse. Adequate understanding and usage of these screening mechanisms can ensure effective use of resources by distinguishing patients who require referral for more extensive diagnostic procedures from those who likely do not.     

Neutrophils mediate lipid peroxidation in human red cells

Activated neutrophils (ANs) are known to release reactive oxygen species that may cause oxidative damage to surrounding tissues. We determined if ANs could induce lipid peroxidation (LP) in human red cells and investigated the mechanism involved in this interaction. We studied neonatal glucose-6-phosphate dehydrogenase (G6PD) deficient, and sickle red cells, since each of these are known to be susceptible to oxidant injury. Neutrophils were isolated from whole blood and activated by incubation with opsonized zymosan. Mixtures of such neutrophils and red cells at a ratio of 1:100 were incubated for two hours at 37 degrees C, after which the malonyldialdehyde content in red cells was measured as an index of LP. All red cells underwent LP after AN treatment, and the degree of LP was proportional to the amount of AN in the mixture. Superoxide dismutase and catalase partially inhibited LP. When compared to normal red cells, only sickle cells demonstrated a significant increase in AN-mediated LP. Conversion of hemoglobin to carboxy-hemoglobin increased AN-mediated LP, whereas conversion to met- hemoglobin decreased AN-mediated LP. The protective effect of met- hemoglobin on LP was less in sickle cells than in normal cells. We conclude that AN can induce LP in red cells in vitro and that sickle cells are more susceptible to this process than normal cells. Hemoglobin can serve as an electron trap and protect the cell against peroxidative damage, but this mechanism is impaired in sickle cells. We speculate that the pathogenesis of hemolysis associated with infectious disease may include AN-induced red cell LP.     

Risk stratification for the development of respiratory adverse events following vascular surgery using the Society of Vascular Surgery's Vascular Quality Initiative

Objective

Postoperative respiratory adverse events (RAEs) are associated with high rates of morbidity and mortality in general surgery, however, little is known about these complications in the vascular surgery population, a frail subset with multiple comorbidities. The objective of this study was to describe the contemporary incidence of RAEs in vascular surgery patients, the risk factors for this complication, and the overall impact of RAEs on patient outcomes.