Evaluation of the causal relationship between crocidolite asbestos-induced lipid peroxidation and toxicity to macrophages

In vitro, crocidolite asbestos toxicity to macrophages is mediated by the production of reactive oxygen metabolites. We examined whether exposure of macrophages to crocidolite asbestos induced lipid peroxidation as measured by the thiobarbituric acid assay. When elicited mouse peritoneal macrophages were exposed to crocidolite, a dose- and time-dependent increase in lipid peroxidation breakdown products accompanied cell death. Superoxide dismutase plus catalase or deferoxamine prevented both lipid peroxidation and loss of viability caused by crocidolite. We tested whether crocidolite-induced lipid peroxidation was causally responsible for cell death. Macrophages were not killed by crocidolite when incubated with 10 mM 3-aminobenzamide. The level of thiobarbituric acid-reactive material was the same, however, for cells incubated with crocidolite in the presence or absence of 3-aminobenzamide. When macrophagaes were pretreated for 24 h with 25 microM vitamin E and then incubated with crocidolite, no thiobarbituric acid-reactive products were detected. Vitamin E, however, did not prevent crocidolite cytotoxicity. These results suggest that exposure of macrophages to crocidolite asbestos produces lipid peroxidation as measured by thiobarbituric acid-reactive products. This reaction, however, is not directly responsible for irreversible injury in this model system.     

Kir6.2 is required for adaptation to stress

Reaction to stress requires feedback adaptation of cellular functions to secure a response without distress, but the molecular order of this process is only partially understood. Here, we report a previously unrecognized regulatory element in the general adaptation syndrome. Kir6.2, the ion-conducting subunit of the metabolically responsive ATP-sensitive potassium (K(ATP)) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted K(ATP) channel-dependent adjustment of membrane excitability and calcium handling, compromising the enhancement of cardiac performance driven by sympathetic stimulation, a key mediator of the adaptation response. In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade. Thus, this vital function identifies a physiological role for K(ATP) channels in the heart.     

Lack of association between oral contraceptive use and Crohn's disease: a community-based matched case-control study

Previous epidemiologic studies have suggested a weak association between oral contraceptive use and Crohn's disease, specifically Crohn's colitis. To measure a possible etiologic association, 51 women with Crohn's disease who were 18-50 yr old were studied and compared with peer-nominated age- and sex-matched controls. There were no differences between cases and controls with respect to race, religion, marital status, and number of pregnancies. There was no association between oral contraceptive use and Crohn's disease incidence [current use: odds ratio (OR) 0.73, 95% confidence interval (CI) 0.34-1.59; former use: OR 1.80, CI 0.61-5.29; current or former use: OR 1.00, CI 0.46-2.16]. Stratifying by disease location also failed to identify an association. Cigarette smoking was significantly associated with Crohn's disease incidence. Controlling for possible confounding effects of cigarette smoking did not alter the lack of association between oral contraceptive use and Crohn's disease. Similarly, testing for interaction failed to demonstrate any effect modification. Analyzing for duration of current oral contraceptive use or time interval since last use failed to demonstrate a "dose-response" effect. The study was of sufficient size to detect statistical significance for oral contraceptive use for odds ratios of greater than or equal to 2.76. From this community-based matched case-control study, there was no association between oral contraceptive use and Crohn's disease, and women need not be advised to discontinue oral contraceptive use when a diagnosis of Crohn's disease is made.     

Self-reported effectiveness and physician consultation rate in users of over-the-counter histamine-2 receptor antagonists

OBJECTIVE: Decreased physician visits for dyspepsia were predicted with the histamine-2 receptor antagonists (H2RA) release to over-the-counter (OTC) status. The aim of this study was to examine the presentation frequency for dyspeptic complaints before and after the OTC release of the H2RA and the self-reported effectiveness of OTC H2RA. METHODS: Two cross-sectional surveys were used in a community sample. The patients comprised a random age- and sex-stratified sample of 1600 ambulatory adults in 1993 and 1800 in 1997. Self-report, valid mail surveys gathered information on healthcare seeking and gastrointestinal symptoms in 1993 and 1997 and antisecretory use in 1997. RESULTS: Presentation frequency for dyspepsia was 22% in 1993 versus 23.5% in 1997. Only 16% of chronic users of the OTC H2RA obtained complete relief of symptomatic episodes. Use of an OTC H2RA was highly associated with presentation to a physician in the past year. CONCLUSIONS: OTC H2RA infrequently provided the complete relief desired by patients. Presentation frequency to physicians for dyspeptic complaints did not change with availability of H2RA OTC.     

Inflammatory bowel disease in pregnancy

Fertility is affected in ulcerative colitis after surgery and in active Crohn's disease. Adverse fetal outcomes are not increased when IBD is quiescent. Active disease at conception increases the risk of adverse fetal outcomes. Most medications for IBD are safe during pregnancy and breastfeeding, with notable exceptions. Active disease is usually more deleterious than maintaining medical therapy.     

Interrenalectomy and Na-K-ATPase activity in the rectal gland of the skate Raja ocellata.

The rectal gland of elasmobranchs secretes a fluid rich in sodium chloride but the mechanism controlling this secretion is obscure. Interrenalectomy diminishes the rectal gland output of sodium chloride in Raja ocellata. NaK-ATPase of high activity occurs in the rectal gland of R. ocellata, but in the present study no significant difference was found between interrenalectomized and shammed skate.     

Effusive-Constrictive Pericarditis After Pericardiocentesis: Incidence,Associated Findings,and Natural History

Objectives

This study sought to investigate the incidence, associated findings, and natural history of effusive-constrictive pericarditis (ECP) after pericardiocentesis.

Mycobacterium asiaticum as a potential pulmonary pathogen for humans. A clinical and bacteriologic review of five cases

Mycobacterium asiaticum was isolated from pulmonary material from 5 persons residing in Queensland, Australia. All patients had repeated positive specimens, but the organism was considered responsible for pulmonary mycobacteriosis in only 2 of them. This is the first report of disease caused by M. asiaticum. Clinical, bacteriologic, and epidemiologic details are presented.     

Clonal evolution of high‐grade serous ovarian carcinoma from primary to recurrent disease

High‐grade serous carcinoma (HGSC) is the most common and fatal form of ovarian cancer. While most tumours are highly sensitive to cytoreductive surgery and platinum‐ and taxane‐based chemotherapy, the majority of patients experience recurrence of treatment‐resistant tumours. The clonal origin and mutational adaptations associated with recurrent disease are poorly understood. We performed whole exome sequencing on tumour cells harvested from ascites at three time points (primary, first recurrence, and second recurrence) for three HGSC patients receiving standard treatment. Somatic point mutations and small insertions and deletions were identified by comparison to constitutional DNA. The clonal structure and evolution of tumours were inferred from patterns of mutant allele frequencies. TP53 mutations were predominant in all patients at all time points, consistent with the known founder role of this gene. Tumours from all three patients also harboured mutations associated with cell cycle checkpoint function and Golgi vesicle trafficking. There was convergence of germline and somatic variants within the DNA repair, ECM, cell cycle control, and Golgi vesicle pathways. The vast majority of somatic variants found in recurrent tumours were present in primary tumours. Our findings highlight both known and novel pathways that are commonly mutated in HGSC. Moreover, they provide the first evidence at single nucleotide resolution that recurrent HGSC arises from multiple clones present in the primary tumour with negligible accumulation of new mutations during standard treatment.     

TIM family proteins and autoimmunity

Despite their relative novelty, a growing body of literature now demonstrates that T cell immunoglobulin and mucin domain (TIM) family proteins are important regulators of immunity. Not surprisingly, these proteins also play prominent roles in the control of auto-reactive immune responses. Thus, modulation of TIM protein function may prove to be a useful strategy to control autoimmune diseases.