kappa -opioid receptor agonists modulate visceral nociception at a novel, peripheral site of action.
(25/1019)
kappa-opioid receptor agonists (kappa-ORAs) have been shown to modulate visceral nociception through an interaction with a peripheral, possibly novel, kappa-opioid-like receptor. We used in the present experiments an antisense strategy to further explore the hypothesis that kappa-ORA effects in the colon are produced at a site different from the cloned kappa-opioid receptor (KOR). An antisense oligodeoxynucleotide (ODN) to the cloned rat KOR was administered intrathecally (12.5 microg, twice daily for 4 d) to specifically knock-down the cloned KOR. Efficacy of the KOR antisense ODN treatment was behaviorally evaluated by assessing the antinociceptive effects of peripherally administered kappa- (EMD 61, 753 and U 69,593), mu- (DAMGO) and delta- (deltorphin) ORAs in the formalin test. Intrathecal antisense, but not mismatch ODN blocked the actions of EMD 61,753 and U 69,593 without affecting the actions of DAMGO or deltorphin; a complete recovery of antinociceptive actions of the kappa-ORA EMD 61,753 was observed 10 d after the termination of antisense ODN treatment. In contrast, the ability of EMD 61,753 to dose-dependently attenuate responses of pelvic nerve afferent fibers to noxious colonic distension was unaffected in the same rats in which the antisense ODN effectively knocked-down the KOR as assessed in the formalin test. Additionally, Western blot analysis demonstrated a significant downregulation of KOR protein in the L4-S1 dorsal root ganglia of antisense, but not mismatch ODN-treated rats. The present results support the existence of a non-kappa-opioid receptor site of action localized in the colon. (+info)
Hemoglobin adducts from acrylonitrile and ethylene oxide in cigarette smokers: effects of glutathione S-transferase T1-null and M1-null genotypes.
(26/1019)
Acrylonitrile (ACN) is used to manufacture plastics and fibers. It is carcinogenic in rats and is found in cigarette smoke. Ethylene oxide (EO) is a metabolite of ethylene, also found in cigarette smoke, and is carcinogenic in rodents. Both ACN and EO undergo conjugation with glutathione. The objectives of this study were to examine the relationship between cigarette smoking and hemoglobin adducts derived from ACN and EO and to investigate whether null genotypes for glutathione transferase (GSTM1 and GSTT1) alter the internal dose of these agents. The hemoglobin adducts N-(2-cyanoethyl)valine (CEVal), which is formed from ACN, and N-(2-hydroxyethyl)valine (HEVal), which is formed from EO, and GST genotypes were determined in blood samples obtained from 16 nonsmokers and 32 smokers (one to two packs/day). Smoking information was obtained by questionnaire, and plasma cotinine levels were determined by immunoassay. Glutathione transferase null genotypes (GSTM1 and GSTT1) were determined by PCR. Both CEVal and HEVal levels increased with increased cigarette smoking dose (both self-reported and cotinine-based). CEVal and HEVal levels were also correlated. GSTM1 and GSTT1 genotypes had little effect on CEVal concentrations. GSTM1 null genotypes had no significant impact on HEVal. However, HEVal levels were significantly elevated in GSTT1-null individuals when normalized to smoking status or cotinine levels. The ratio of HEVal:CEVal was also elevated in GSTT1-null smokers (1.50 +/- 0.57 versus 0.88 +/- 0.24; P = 0.0002). The lack of a functional GSTT1 is estimated to increase the internal dose of EO derived from cigarette smoke by 50-70%. (+info)
Antibodies to both ICAM-1 and LFA-1 do not protect the kidney against toxic (HgCl2) injury.
(27/1019)
BACKGROUND: The role of inflammatory leukocytes in acute renal failure (ARF) remains controversial and appears largely uninvestigated in toxic (in contrast to ischemic) ARF. METHODS: Female Wistar rats were injected with monoclonal antibodies (mAbs) directed to both the leukocyte function-associated antigen 1 (LFA-1) and the intercellular adhesion molecule 1 (ICAM-1). Doses (6 mg/kg of each mAb) were given 24 hours prior to the induction of acute tubular necrosis (ATN) by mercuric chloride administration (2 mg/kg, subcutaneously, day 0) and subsequently every 48 hours. Control rats similarly received either control antibody (12 mg/kg) or vehicle prior to and following the induction of ATN. Renal function was also measured from male Lewis rats that were similarly treated with anti-adhesion antibodies during exposure to 30 minutes of unilateral renal ischemia. RESULTS: Injected antibodies were demonstrated on peripheral blood leukocytes (flow cytometrical detection of mouse anti-LFA-1) and on endothelium (immunohistochemical staining of mouse anti-ICAM-1) and were measured in serum (enzyme-linked immunosorbent assay). Macrophages and T cells were prominent in the kidney of control treatment rats after HgCl2 injection, but anti-adhesion treatment clearly had prevented their infiltration. Notwithstanding, renal tubular injury was equally pronounced in all mercuric chloride treatment groups and so was the decline in renal function (serum creatinine, proteinuria). Tubular epithelial cell proliferation seemed slightly less pronounced and delayed in anti-adhesion treated rats. Kidneys from ischemia exposed rats were, however, functionally protected by identical anti-ICAM-1/anti-LFA-1 treatment. CONCLUSION: Prevention of cellular infiltration by mAbs to LFA-1 and ICAM-1 has no effect on renal morphology, function, or regeneration following mercuric chloride-induced ARF in the rat. This result contrasts with the functional protection of the rat kidney to ischemia/reperfusion injury by virtue of an identical antibody treatment protocol. Resolving that controversy should bring better insight in fundamental processes underlying different types of ARF, and will be the subject of further study. (+info)
Nephrin in experimental glomerular disease.
(28/1019)
BACKGROUND: The recently identified gene NPHS1 with its mutations causing congenital nephrotic syndrome of the Finnish type (CNF) is highly promising in providing new understanding of pathophysiology of proteinuria. Earlier we cloned a rat NPHS1 homologue, as well as characterized and raised antibodies to the respective protein product nephrin. METHODS: Changes in the expression levels of nephrin-specific mRNA in commonly used experimental models of proteinuria were examined using semiquantitative reverse transcription-polymerase chain reaction, immunofluorescence, and immunoelectron microscopy (IEM) of nephrin. RESULTS: Notably, a 40% down-regulation of the nephrin-specific mRNA of cortical kidney was seen already at day 3 after induction of the puromycin aminonucleoside nephrosis (PAN), while no major elevation of urinary protein secretion was seen at this stage. A further decrease of 80% of nephrin message was seen at the peak of proteinuria at day 10. A similar decrease of up to 70% from the basal levels was seen in mercuric chloride-treated rats. Changes in the protein expression paralleled those of the mRNA in indirect immunofluorescence. Interestingly, a remarkable plasmalemmal dislocation from the normal expression site at the interpodocyte filtration slits could be observed in IEM. CONCLUSIONS: Nephrin appears to be an important causative molecule of proteinuria and shows a remarkable redistribution from the filtration slits to the podocyte plasma membrane, especially in PAN. (+info)
Relation between stillbirth and specific chlorination by-products in public water supplies.
(29/1019)
During water treatment, chlorine reacts with naturally occurring organic matter in surface water to produce a number of by-products. Of the by-products formed, trihalomethanes (THMs) are among the highest in concentration. We conducted a retrospective cohort study to evaluate the relationship between the level of total THM and specific THMs in public water supplies and risk for stillbirth. The cohort was assembled from a population-based perinatal database in the Canadian province of Nova Scotia and consisted of almost 50,000 singleton deliveries between 1988 and 1995. Individual exposures were assigned by linking mother's residence at the time of delivery to the levels of specific THMs monitored in public water supplies. Analysis was conducted for all stillbirths and for cause-of-death categories based on the physiologic process responsible for the fetal death. Total THMs and the specific THMs were each associated with increased stillbirth risk. The strongest association was observed for bromodichloromethane exposure, where risk doubled for those exposed to a level of [greater and equal to] 20 microg/L compared to those exposed to a level < 5 microg/L (relative risk = 1. 98, 95% confidence interval, 1.23-3.49). Relative risk estimates associated with THM exposures were larger for asphyxia-related deaths than for unexplained deaths or for stillbirths overall. These findings suggest a need to consider specific chlorination by-products in relation to stillbirth risk, in particular bromodichloromethane and other by-product correlates. The finding of a stronger effect for asphyxia deaths requires confirmation and research into possible mechanisms. (+info)
Survey of symptoms, respiratory function, and immunology and their relation to glutaraldehyde and other occupational exposures among endoscopy nursing staff.
(30/1019)
OBJECTIVES: To find the nature and incidence of symptoms experienced by a large sample of hospital endoscopy nurses. To find whether nurses in endoscopy units develop asthma under current working conditions in endoscopy units. To obtain analytically reliable data on exposure concentrations of glutaraldehyde (GA) vapour in endoscopy units, and to relate them to individual hygiene and work practices. To characterise any exposure-response relations between airborne GA and the occurrence of work related symptoms (WRSs). Due to the growing concern about the perceived increase in WRSs among workers regularly exposed to biocides, all of whom work within a complex multiexposure environment, a cross sectional study was designed. METHODS: Current endoscopy nurses (n=348) from 59 endoscopy units within the United Kingdom and ex-employees (who had left their job for health reasons (n=18) were surveyed. Symptom questionnaires, end of session spirometry, peak flow diaries, skin prick tests (SPTs) to latex and common aeroallergens, and measurements of total immunoglobulin E (IgE) and IgE specific to GA and latex were performed. Exposure measurements included personal airborne biocide sampling for peak (during biocide changeover) and background (endoscopy room, excluding biocide changeover) concentrations. RESULTS: All 18 ex-employees and 91.4% of the current nurses were primarily exposed to GA, the rest were exposed to a succinaldehyde-formaldehyde (SF) composite. Work related contact dermatitis was reported by 44% of current workers exposed to GA, 56.7% of those exposed to SF composite, and 44.4% of ex-employees. The prevalence of WRSs of the eyes, nose, and lower respiratory tract in current workers exposed to GA was 13.5%, 19.8%, and 8.5% respectively and 50%, 61.1%, and 66.6% in the ex-employees. The mean percentage predicted forced expired volume in 1 second (ppFEV(1)) for ex-employees (93.82, 95% confidence interval (95% CI) 88.53 to 99.11) was significantly lower (p<0.01) than that of current workers exposed to GA (104.08, 95% CI 102.35 to 105.73). Occupational peak flow diaries completed by current workers with WRSs of the lower respiratory tract showed no evidence of bronchial asthma (<15% variation). Six per cent of the population had positive latex SPTs. Positive indications of one GA specific IgE and 4.1% latex specific IgE occurred. There was no conformity between the latex specific IgE and positive SPTs. Positive SPTs to latex were associated with WRSs of dermatitis and ocular WRSs, but no other WRSs. Exposures were above the current maximum exposure limit (MEL) of 0.2 mg/m(3) (0.05 ppm) in eight of the units investigated. A significant relation existed between peak GA concentrations and work related chronic bronchitis and nasal symptoms (after adjustment for types of local ventilation) but not to other WRSs. Peak GA concentrations were significantly higher in units that used both negative pressure room and decontaminating unit ventilation. CONCLUSION: This study documents a significant level of symptoms reported in the absence of objective evidence of the physiological changes associated with asthma. Ex-employees and current workers with WRSs warrant further study to elucidate the cause and mechanisms for their symptoms. Ventilation systems used for the extraction of aldehydes from the work area may be less effective than expected and due to poor design may even contribute to high peak exposures. (+info)
Laryngeal and hypopharyngeal cancers and occupational exposure to formaldehyde and various dusts: a case-control study in France.
(31/1019)
OBJECTIVES: A case-control study was conducted in France to assess possible associations between occupational exposures and squamous cell carcinomas of the larynx and hypopharynx. METHODS: The study was restricted to men, and included 201 hypopharyngeal cancers, 296 laryngeal cancers, and 296 controls (patients with other tumour sites). Detailed information on smoking, alcohol consumption, and lifetime occupational history was collected. Occupational exposure to seven substances (formaldehyde, leather dust, wood dust, flour dust, coal dust, silica dust, and textile dust) was assessed with a job exposure matrix. Exposure variables used in the analysis were probability, duration, and cumulative level of exposure. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were estimated by unconditional logistic regression, and were adjusted for major confounding factors (age, smoking, alcohol, and when relevant other occupational exposures). RESULTS: Hypopharyngeal cancer was found to be associated with exposure to coal dust (OR 2.31, 95% CI 1.21 to 4.40), with a significant rise in risk with probability (p<0.005 for trend) and level (p<0.007 for trend) of exposure. Exposure to coal dust was also associated with an increased risk of laryngeal cancer (OR 1.67, 95% CI 0.92 to 3.02), but no dose-response pattern was found. A significant relation, limited to hypopharyngeal cancer, was found with the probability of exposure to formaldehyde (p<0.005 for trend), with a fourfold risk for the highest category (OR 3.78, 95% CI 1.50 to 9.49). When subjects exposed to formaldehyde with a low probability were excluded, the risk also increased with duration (p<0.04) and cumulative level of exposure (p<0.14). No significant association was found for any other substance. CONCLUSION: These results indicate that exposure to formaldehyde and coal dust may increase the risk of hypopharyngeal cancer. (+info)
Environmental control to reduce transmission of Clostridium difficile.
(32/1019)
Restrictive antibiotic policies and infection control measures have been shown to reduce the incidence of Clostridium difficile-associated diarrhea (CDAD) among hospitalized patients. To date, the role of environmental disinfectants in reducing nosocomial CDAD rates has not been well studied. In a before-and-after intervention study, patients in 3 units were evaluated to determine if unbuffered 1:10 hypochlorite solution is effective as an environmental disinfectant in reducing the incidence of CDAD. Among 4252 patients, the incidence rate of CDAD for bone marrow transplant patients decreased significantly, from 8.6 to 3.3 cases per 1000 patient-days (hazard ratio, 0.37; 95% confidence interval, 0.19-0.74), after the environmental disinfectant was switched from quaternary ammonium to 1:10 hypochlorite solution in the rooms of patients with CDAD. Reverting later to quaternary ammonium solution increased the CDAD rate to 8.1 cases per 1000 patient-days. No reduction in CDAD rates was seen among neurosurgical intensive care unit and general medicine patients, for whom baseline rates were 3.0 and 1.3 cases per 1000 patient-days, respectively. Unbuffered 1:10 hypochlorite solution is effective in decreasing patients' risk of developing CDAD in areas where CDAD is highly endemic. Presumed mechanisms include reducing the environmental burden and the potential for C. difficile transmission among susceptible patients. (+info)