A proteasome-sensitive connection between PSD-95 and GluR1 endocytosis

Synaptic transmission at excitatory synapses can be regulated by changing the number of synaptic glutamate receptors (GluRs) through endocytosis and exocytosis. The endocytosis of GluRs has recently been shown to require the activity of the ubiquitin-proteasome system (UPS): proteasome inhibitors or dominant negative forms of ubiquitin block the ligand-stimulated internalization of GluRs. We have examined whether PSD-95 is a potential target of the UPS. Following neurotransmitter stimulation, PSD-95 levels are negatively correlated with the magnitude of internalized GluR1 in individual neurons. Neurotransmitter stimulation also results in a proteasome-dependent decrease in dendritic PSD-95. Consistent with the idea that PSD-95 degradation is important for GluR internalization, overexpression of PSD-95 can inhibit neurotransmitter-stimulated GluR1 endocytosis. If PSD-95 is a direct target for proteasomal degradation, then the polyubiquitination of PSD-95 is expected. Using experimental conditions that favor the detection of polyubiquitination, however, no ubiquitination of PSD-95 was detected. It is possible that the polyubiquitination of PSD-95 is short-lived and thus difficult to detect. Alternatively, the regulation of PSD-95 levels by the proteasome important for ligand-stimulated GluR endocytosis may be accomplished via an intermediate protein.     

Comparison of effects of cyclooxygenase inhibitors on myometrial contraction and constriction of ductus arteriosus in rats

The aim of this study was to compare the tocolytic effect of a selective cyclooxygenase-2 inhibitor, DFU (5,5-dimethyl-3(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone), indomethacin and nimesulide on myometrial strips isolated from rats in both lipopolysaccharide-induced preterm labour and term labour. We also compared the constrictor effects of DFU and indomethacin on the fetal ductus arteriosus. Myometrial strips were obtained from preterm and term labour Wistar albino rats and were mounted in organ baths for the recording of isometric tension. DFU, nimesulide and indomethacin significantly inhibited KCl-, oxytocin-, prostaglandin E(2)- and prostaglandin F(2 alpha)-stimulated contractions of myometrial strips isolated from rats in preterm and term labour. The E(max) value of indomethacin was significantly lower than those for DFU and nimesulide (P<0.05), with no change-log (10) EC(50) values. There was no significant difference between in -log (10) EC(50) and E(max) values of DFU and nimesulide for any of the tissues (P>0.05). In addition, there was no significant difference between -log (10) EC(50) and E(max) values for each of these three agents in myometrial tissues isolated from rats in preterm and term labour (P>0.05). Fetal ductus arteriosus was significantly constricted by DFU (10 or 100 mg/kg) in preterm and term rats, although DFU (10 or 100 mg/kg)-induced constriction ratios were significantly lower than those for indomethacin (P<0.05). These data demonstrate that DFU, a specific cyclooxygenase-2 inhibitor, could be considered as a new therapeutic agent for preterm labour. However, careful attention should be given to constriction of the fetal ductus arteriosus.     

Residential exposure to magnetic fields: an empirical examination of alternative measurement strategies

OBJECTIVES: To investigate the impact of measuring a single home then imputing information from another home among subjects who lived in two homes in a subset of the National Cancer Institute/Children's Cancer Group (NCI/CCG) investigation of residential exposure to magnetic fields and risk of childhood leukaemia. METHODS: Each subject's summary time weighted average (TWA) exposure was derived from measurements of two homes, weighted by the fraction of the reference period lived in the residence. The three cost efficient field work strategies examined were measuring: (a) the longer lived in home; (b) the currently lived in home; and (c) the former lived in home. Two different methods were used for imputing the missing values: (a) control mean imputation, (b) status specific mean imputation. The subject's summary exposure to magnetic fields estimated with each approach was compared with the subject's TWA calculated from measurements in both homes. The association between estimated exposure to magnetic fields and the risk of leukaemia under different approaches was examined with unconditional logistic regression analysis. RESULTS: The Pearson correlation coefficient between the two measurements within subjects was 0.31 (p < 10(-4), indicating a lack of independence of measurements. Differences were found between mean exposures in current and former homes of cases, and between longer and shorter lived in homes of controls. All methods with measurements from one of the homes in conjunction with imputation of measurements for the second home led to marked attenuation of risk estimates at the highest exposure category, particularly when measurements from current homes were used and those from former homes were imputed. CONCLUSION: Results argue against attempting to estimate lifetime magnetic field exposure from imputed values derived from current residences to fill in gaps caused by unmeasured residences previously lived in.     

Agricultural use of DDT and risk of non-Hodgkin's lymphoma: pooled analysis of three case-control studies in the United States

OBJECTIVES: The objective of this pooled analysis was to examine whether exposure to DDT was associated with the risk of non-Hodgkin's lymphoma among male farmers. METHODS: Data from three case-control studies from four midwestern states in the United States (Nebraska, Iowa, Minnesota, Kansas) were pooled to carry out analyses of 993 cases and 2918 controls. Information on use of agricultural pesticides and other risk factors was based on interviews. Non-farmers (people who had never lived or worked on a farm) were used as a reference category. RESULTS: There were 161 cases and 340 controls who reported use of DDT on animals or crops, or on both, yielding an odds ratio (OR) of 1.2 (95% confidence intervals (95% CI) 1.0 to 1.6). Farmers who had used DDT for > or = 15 years had an OR of 1.5 (95% CI 1.0 to 2.3). Adjustment for respondent status and use of other pesticides resulted in slightly reduced ORs. Analyses by the number of days of use a year was limited to the Nebraska data. The most notable increase was found among farmers who used DDT for > or = 5 days a year (OR 2.6, 95% CI 1.1 to 5.9); however, additional adjustment for use of organophosphates, phenoxyacetic acids, and the individual pesticides lindane, malathion, and atrazine reduced the ORs to 1.0, 0.9, 1.1, 1.6, and 1.9 respectively. CONCLUSIONS: No strong consistent evidence was found for an association between exposure to DDT and risk of non-Hodgkin's lymphoma. It seems that the excess risk initially found may be explained by use of other pesticides.

 

     

Different glomerulopathies accompanying non-small-cell lung cancer

The coexistence of lung cancer and glomerular lesion is not commonly reported. Malignancy-related glomerulopathy is commonly membranous glomerulonephritis. Other glomerulopathies are seldom reported. We report two cases presenting with non-small-cell lung cancer, acute renal failure and nephrotic syndrome secondary to membranoproliferative glomerulonephritis and amyloidosis.     

Environmental fiber-induced pleuro-pulmonary diseases in an Anatolian village: an epidemiologic study

This study was designed to determine the prevalence of pleural mesothelioma and other malignancies in the Anatolian village of Tuzk?y, where neither asbestos nor any environmental carcinogen has been detected. Another village (Kizilk?y) located 12 km from Tuzk?y was selected as a control. Three hundred twelve subjects from Tuzk?y who were at least 25 yr of age and 95 subjects from Kizilk?y were studied. Analysis of X-rays of the Tuzk?y group revealed that subjects had calcified pleural plaques (17%), pleural thickening (10.5%), obscured costophrenic angles (15%), and diffuse interstitial pulmonary fibrosis (12.1%). Sixty-seven deaths were records in Tuzk?y during the previous 3 yr, 41 of which resulted from malignant diseases. There were no X-ray abnormalities or deaths resulting from malignancies in the control group. Because of the high incidence of mesothelioma and lung cancer which usually results from asbestos exposure, the presence of asbestos in Tuzk?y was investigated, but none was detected in spite to Tuzk?y's volcanic location. Nevertheless, zeolite, an asbestiform mineral, was detected in the stones of buildings and in the village soil, as well as in the lung and pleura of the patients during biopsy. Thus, this mineral was considered to be responsible for the fiber-induced pleuro-pulmonary diseases in Tuzk?y. No zeolite was found in the soil and stones of the control village.     

The Heartfile Lodhran CVD prevention project--end of project evaluation

Mainstream preventive interventions often fail to reach poor populations with a high risk of cardiovascular diseases (CVDs) in Pakistan. A community-based CVD primary prevention project aimed at developing approaches to reduce risk factors in such populations was established by Heartfile in collaboration with the National Rural Support Program in the district of Lodhran. The project implemented a range of activities integrated with existing social and health service mechanisms during a three year intervention period 2000/01-03/04. These were targeted in 4 key settings: community health education, mass media interventions, training of health professionals and health education through Lady Health Workers. The project received support from the Department for International Development, U.K. At the community level, a pre-test-post-test quasi-experimental design was used for examining project outcomes related to the community component of the intervention. Pre and post-intervention (training) evaluations were conducted involving all health care providers in randomly selected workshops in order to determine baseline levels of knowledge and the impact of training on knowledge level. In order to assess practices of physician and non-physician health care providers patient interviews, with control comparisons were conducted at each health care facility. Significant positive changes were observed in knowledge levels at a community level in the district of intervention compared with baseline knowledge levels particularly in relation to a heart healthy diet, beneficial level of physical activity, the causes of high blood pressure and heart attack and the effects of high blood pressure and active and passive smoking on health. Significant changes in behaviors at a practice level were not shown in the district of intervention. However the project played a critical role in spurring national action for the prevention and control of non-communicable diseases and introducing sustainable public health interventions for poor communities in Pakistan.     

Risk for prostate cancer by occupation and industry: A 24-state death certificate study

Current knowledge of the etiology of prostate cancer is limited. Numerous studies have suggested that certain occupations and industries may be associated with the occurrence of prostate cancer. Information on occupation and industry on death certificates from 24 states gathered from 1984 to 1993 was used in case control study on prostate cancer. A total of 60,878 men with prostate cancer as underlying cause of death was selected and matched with controls who died of all other causes except cancer. Similar to the findings of our parallel large case control study of prostate cancer, we observed excess risks in some white-collar occupations, such as administrators, managers, teachers, engineers, and sales occupations. However, some blue-collar occupations, such as power plant operators and stationary engineers, brickmasons, machinery maintenance workers, airplane pilots, longshoreman, railroad industry workers, and other occupations with potential exposure to PAH also showed risk of excess prostate cancer. Risk was significantly decreased for blue-collar occupations, including farm workers, commercial fishermen, mechanics and repairers, structural metal workers, mining, printing, winding, dry cleaning, textile machine operators, cooks, bakers, and bartenders. Although we observed excess risks of prostate cancer among some low socioeconomic status (SES) occupations, the overall results suggest that the effects of higher SES cannot be ruled out in associations between occupational factors and the risk of prostate cancer. Am. J. Ind. Med. 34:413–420, 1998. © 1998 Wiley-Liss, Inc.