Peroxynitrite increases the degradation of aconitase and other cellular proteins by proteasome

We report that exposure of aconitase to moderate concentrations of peroxynitrite, 3-morpholinosydnonimine (SIN-1; a superoxide- and nitric oxide-liberating substance), or hydrogen peroxide, inhibits the enzyme and enhances susceptibility to proteolytic digestion by the isolated 20 S proteasome. Exposure to more severe levels of oxidative stress, from these same agents, causes further inhibition of the enzymatic activity of aconitase but actually decreases its proteolytic breakdown by proteasome. It should be noted that the superoxide and nitric oxide liberated by SIN-1 decomposition react to form a steady flux of peroxynitrite. S-Nitroso-N-acetylpenicillamine, a compound that liberates nitric oxide alone, causes only a small loss of aconitase activity (25% or less) and has no effect on the proteolytic susceptibility of the enzyme. Proteasome also seems to be the main protease in cell lysates that can degrade aconitase after it has been oxidatively modified by exposure to peroxynitrite, SIN-1, or hydrogen peroxide. Using cell lysates isolated from K562 cells treated for several days with an antisense oligodeoxynucleotide to the initiation codon region of the C2 subunit of proteasome (a treatment which diminishes proteasome activity by 50-60%), the enhanced degradation of moderately damaged aconitase was essentially abolished. Other model proteins as well as complex mixtures of proteins, such as cell lysates, also exhibit enhanced proteolytic susceptibility after moderate SIN-1 treatment. Therefore we conclude that peroxynitrite reacts readily with proteins and that mild modification by peroxynitrite results in selective recognition and degradation by proteasome.     

Insulin management and metabolic control of type 1 diabetes mellitus in childhood and adolescence in 18 countries. Hvid?re Study Group on Childhood Diabetes

Insulin regimens and metabolic control in children and adolescents with Type 1 diabetes mellitus were evaluated in a cross-sectional, non-population-based investigation, involving 22 paediatric departments, from 18 countries in Europe, Japan, and North America. Blood samples and information were collected from 2873 children from March to August 1995. HbA1c was determined once and analysed centrally (normal range 4.4-6.3%, mean 5.4%). Year of birth, sex, duration of diabetes, height, body weight, number of daily insulin injections, types and doses of insulin were recorded. Average HbA1c in children under 11 years was 8.3 +/- 1.3% (mean +/- SD) compared with 8.9 +/- 1.8% in those aged 12-18 years. The average insulin dose per kg body weight was almost constant (0.65 U kg(-1) 24 h(-1)) in children aged 2-9 years for both sexes, but there was a sharp increase during the pubertal years, particularly in girls. The increase in BMI of children with diabetes was much faster during adolescence compared to healthy children, especially in females. Sixty per cent of the children (n = 1707) used two daily insulin injections while 37% (n = 1071) used three or more. Of those on two or three injections daily, 37% used pre-mixed insulins, either alone or in combination with short- and intermediate-acting insulin. Pre-adolescent children on pre-mixed insulin showed similar HbA1c levels to those on a combination of short- and long-acting insulins, whereas in adolescents significantly better HbA1c values were achieved with individual combinations. Very young children were treated with a higher proportion of long-acting insulin. Among adolescent boys, lower HbA1c was related to use of more short-acting insulin. This association was not found in girls. We conclude that numerous insulin injection regimens are currently used in paediatric diabetes centres around the world, with an increasing tendency towards intensive diabetes management, particularly in older adolescents. Nevertheless, the goal of near normoglycaemia is achieved in only a few.     

Characterization of fluoroelastomer networks. I. Infrared analysis

Fluorocarbon compounds based on vinylidene fluoride copolymers and dihydroxy nucleophiles were prepared to determine the network forming structures of the cured materials. Previous attempts to achieve this goal consisted of model compound reactions, of prevulcanization events, and of materials cured under conditions only approaching industrial vulcanization conditions. The proposed structures derived from these studies could be different from the entities that will come in contact with alternate fuels such as methanol/gasoline blends when used in automotive applications. The evolution of the solid-state chemistry during cure and the final network structure needed to be defined. Thus, infrared vibrational spectra for 25-μm thick sections from key stages of processing were recorded. These spectra established directly, for the first time, that bisphenol-AF (BPAF) serves as the crosslinker during cure. Additionally, persistent unsaturation is formed on the elastomer backbone after crosslinking. Curing for extended periods of time produces no observable effect on the network. Furthermore, postcuring reduces residual hydrofluoric acid in the compound and results in two new absorptions at 2851 and 2920 cm^?1, indicative of amorphous regions of polyvinylidene fluoride (PVF₂). Although these findings help define the final network structure, there remain uncertainties about the pathway leading to the final structure. The data serve as input to understanding the fracture behavior and long term performance of this class of materials. It also could serve as a starting point for studies dealing with the enhancement of certain fluorocarbon properties such as low temperature behavior. © 1993 John Wiley & Sons, Inc.     

The initial results of lumbar dual-energy x-ray absorptiometry (DEXA) compared to double-energy quantitative computed tomography (DE-QCT)

Bone density measurements were performed on 51 patients with suspected osteoporosis. We used DE-QCT and DEXA. The methods were compared with regard to deviation from normal. In 29 of the 51 patients there was more than half standard deviation and in 12 of the 51 cases there was more than a full standard deviation.     

A phase II evaluation of oral tamoxifen and intermittent intravenous vinblastine in hormone-refractory adenocarcinoma of the prostate

Hormone refractory prostate carcinoma is an incurable disease. Therapy affecting the tissue matrix at the level of the cytoskeleton has been demonstrated to inhibit prostate cancer growth. In vivo and in vitro evidence demonstrated vinblastine and tamoxifen to be agents that would interact to inhibit prostate cancer growth by microtubule inhibition. This study evaluated the effectiveness of these agents in combination in 22 patients with metastatic hormone refractory prostate cancer. Patients received tamoxifen 20 mg twice daily continuously plus vinblastine 4 mg/m2 on days 1, 8, 15, 22, 28, and 35 every 49 days. Disease response was assessed after the first two cycles of therapy. No partial or complete responses were definitively identified. Only 23% of participants received two or more full cycles of therapy. Major toxicities included grade 1-3 leukopenia (73%), grade 2-3 anemia (64%), and two participants experienced a grade 3/4 thrombocytopenia. Only two participants experienced a greater than 50% decrease in serum PSA, one of which may have been attributed to a flutamide withdrawal syndrome. We conclude that the dosage and schedule of vinblastine and tamoxifen used in this study is inactive in the treatment of metastatic hormone refractory prostate cancer.     

Body mass index in young adults: Associations with parental body size and education in the CARDIA Study

OBJECTIVES: Associations of parental education, parental body size, and offspring's education with body mass index and 7-year change in body mass index were examined among participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: CARDIA is a study of coronary artery disease risk factors in 5115 Black and White persons aged 18 to 30 at baseline. Analyses of covariance were carried out with body mass index and change in body mass index as the dependent variables, and with parental education, parental body size, and participant education as the major independent variables. RESULTS: Father's body size was positively associated with participant's baseline body mass index among Black men, White men, and White women. Mother's body size was positively associated with baseline body mass index among all race-sex groups, and with change in body mass index among White women. Father's education was inversely associated with baseline body mass index among Black men and White women, and with change among White women. CONCLUSIONS: Parental education may influence body mass index and changes in young adulthood, especially among White women. Such associations may be both genetic and environmental and may be important for obesity prevention efforts.     

A matter of trust [data security]

Larger amounts of information are being exchanged by electronic means. This has many advantages, including speed and convenience, but is by no means problem free. Most forms of electronic communication (not least the Internet) are not inherently secure. Security needs vary between applications, but common requirements include ensuring the information is not changed in transit and protecting the information against unauthorised disclosure. Ensuring security for electronic information exchange is far from straightforward and there is a danger that this problem could form a significant barrier to the growth of electronic commerce. Cryptography is one method of addressing the security weaknesses, but there is a difficulty in the management of the various keys. As the demand for secure electronic communications has grown, especially in the domain of electronic commerce, new institutions, often known as trusted third parties are emerging to meet this need. Trusted third parties could become key players in ensuring the security of electronic communications. The author explains the nature of these novel organisations and discusses some of the issues associated with their development