Poly-ADP ribose polymerase activates nuclear proteasome to degrade oxidatively damaged histones

The 20S proteasome has been shown to be largely responsible for the degradation of oxidatively modified proteins in the cytoplasm. Nuclear proteins are also subject to oxidation, and the nucleus of mammalian cells contains proteasome. In human beings, tumor cells frequently are subjected to oxidation as a consequence of antitumor chemotherapy, and K562 human myelogenous leukemia cells have a higher nuclear proteasome activity than do nonmalignant cells. Adaptation to oxidative stress appears to be one element in the development of long-term resistance to many chemotherapeutic drugs and the mechanisms of inducible tumor resistance to oxidation are of obvious importance. After hydrogen peroxide treatment of K562 cells, degradation of the model proteasome peptide substrate suc-LLVY-MCA and degradation of oxidized histones in nuclei increases significantly within minutes. Both increased proteolytic susceptibility of the histone substrates (caused by modification by oxidation) and activation of the proteasome enzyme complex occur independently during oxidative stress. This rapid up-regulation of 20S proteasome activity is accompanied by, and depends on, poly-ADP ribosylation of the proteasome, as shown by inhibitor experiments, 14C-ADP ribose incorporation assays, immunoblotting, in vitro reconstitution experiments, and immunoprecipitation of (activated) proteasome with anti-poly-ADP ribose polymerase antibodies. The poly-ADP ribosylation-mediated activated nuclear 20S proteasome is able to remove oxidatively damaged histones more efficiently and therefore is proposed as an oxidant-stimulatable defense or repair system of the nucleus in K562 leukemia cells.     

Nicotine use in suicides: a case-control study.

PURPOSE: Despite of higher rates of substance-related disorders in psychiatric patients and suicides than in the general population, there is no clear specificity to the relationship between nicotine use and other psychiatric disorders for suicide risk. METHODS: One hundred and sixty-three suicides (mean age 49.8 +/- 19.3 years; 64.4% males; using psychological autopsy method) and 396 control persons (mean age 51.6 +/- 17.0 years; 55.8% males) were assessed with a standardised semi-structured interview including SCID-I and SCID-II (for DSM-IV). Suicides and controls were compared in terms of nicotine consumption and psychiatric disorders. Logistic regression was used to evaluate the interactions of tobacco consumption with psychiatric disorders. RESULTS: Suicides were significantly more often current smokers and heavy users of cigarettes (> 20 cigarettes per day; P < 0.001, each). Alcohol dependence, other axis I disorders than substance-related disorders, and cluster B personality disorder(s) remained independent predictors for suicide in both genders, current nicotine consumption only in men (OR = 2.6, 95% CI 1.3-5.2). DISCUSSION AND CONCLUSIONS: In males, but not in females, nicotine consumption contributed to risk of completed suicide after control for psychiatric disorders and has to be considered as independent risk factor for suicide.     

Complications of liver cirrhosis, medical management

Patients with liver cirrhosis bear a considerable risk of a variety of complications that involve virtually all organ systems. They can be addressed with a wide spectrum of drugs for acute interventions as well as for prophylactic purposes. At the same time, treatment of the underlying disease, the identification and treatment of triggering factors, and the possibility of liver transplantation should be kept in mind.     

Oral rehabilitation to maintain independence

A child born with missing or deformed upper extremities must learn to develop alternatives for the activities of daily living (ADL). To assure an independent existence, substitutes for nonfunctioning arms and hands must be developed. Teeth can replace hands for all activities that require pinch and grasp, as well as to support adaptive devices for turning pages, typing, drawing and painting. However, without carefully planned dental care, teeth, particularly incisors and canines, will show excessive wear if used for hands over the years. Loss of teeth threatens independence in self-care and in ADL, and loss of self-esteem. Oral health can be restored and retained to maintain function, independence, and esthetics. This case presentation illustrates a challenge and obligation of dentistry in rehabilitation.     

HIV-1 infection leads to increased HLA-E expression resulting in impaired function of natural killer cells

HIV has evolved several strategies to evade recognition by the host immune system including down-regulation of major histocompatibility complex (MHC) class I molecules. However, reduced expression of MHC class I molecules may stimulate natural killer (NK) cell lysis in cells of haematopoietic lineage. Here, we describe how HIV counteracts stimulation of NK cells by stabilizing surface expression of the non-classical MHC class I molecule, HLA-E. We demonstrate enhanced expression of HLA-E on lymphocytes from HIV-infected patients and show that in vitro infection of lymphocytes with HIV results in up-regulation of HLA-E expression and reduced susceptibility to NK cell cytotoxicity. Using HLA-E transfected K-562 cells, we identified the well-known HIV T-cell epitope p24 aa14-22a as a ligand for HLA-E that stabilizes surface expression of HLA-E, favouring inhibition of NK cell cytotoxicity. These results propose HIV-mediated up-regulation of HLA-E expression as an additional evasion strategy targeting the antiviral activities of NK cells, which may contribute to the capability of the virus in establishing chronic infection.