An industrial hygiene methodology developed in support of a retrospective morbidity case-control study.

An industrial hygiene methodology that was developed in support of an epidemiologic case-control study is described. This study was conducted to investigate a potentially increased incidence of colorectal cancer among employees who worked at a unit that manufactured polypropylene by a heavy diluent process. Retrospective epidemiologic case-control studies typically have exposure assessment problems because industrial hygiene monitoring data are often not available. Misleading job titles are another problem that can provide a poor framework for estimating exposures. In addition, a job title-based exposure assessment assumes individual work patterns are not important in assessing worker exposures, although this is contradictory to industrial hygiene experience. The design of the case-control study provided an innovative industrial hygiene approach to circumvent these typical exposure estimating problems. The industrial hygiene methodology of the case-control study included assessing historical exposures, developing an exposure estimating matrix, selecting candidate etiologic agents based on a joint toxicologic and industrial hygiene review, administering a work activity questionnaire, calculating exposure scores, and conducting a statistical analysis. The study design also provided an additional exposure measurement independent of the toxicologic and industrial hygiene review. This provided an opportunity to compare the likelihood of exposure misclassification and, as expected, showed that a more detailed exposure estimate resulted in less misclassification.     

Sleep hypoxia in myotonic dystrophy and its correlation with awake respiratory function.

BACKGROUND--Tiredness and daytime respiratory failure occur frequently in myotonic dystrophy. Sleep hypoxaemia was studied in 12 patients with myotonic dystrophy and correlations were sought with their daytime lung and respiratory muscle function. METHODS--All patients underwent overnight sleep studies, clinical assessment, measurement of flow-volume loops and carbon monoxide transfer factor, arterial blood gas analysis, and physiological assessment of both thoracic muscle function and upper airways obstruction. RESULTS--The mean nadir of oxygen saturation during sleep was 75% (95% confidence interval 69% to 81%). A mean of 3.4% of total sleep duration was spent at an oxygen saturation level below 85%. Five of the 12 patients had an apnoea index of > 5, the group mean apnoea/hypopnoea index being 15.8 events/sleep hour. The mean awake arterial oxygen tension (PaO2) was 10.7 kPa. There was a trend to hypercapnoea with a mean awake arterial carbon dioxide tension of 6.1 kPa; carbon dioxide retention worsened during sleep. Respiratory muscle dysfunction was mainly evident as a low maximum expiratory mouth pressure. Upper airway obstruction assessed by physiological criteria was found in four of the 12 patients. The proportion of total sleep duration with oxygen saturation levels below 85% was directly related to body mass index (weight/height2) and inversely related to the awake PaO2. Body mass index was inversely related to the overnight nadir of oxygen saturation. CONCLUSIONS--Patients with myotonic dystrophy are often hypoxic during sleep and the subgroup that are obese, or have symptoms of sleep apnoea, or both, are particularly at risk. Sleep studies should be considered in this subgroup of patients with myotonic dystrophy.     

Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo.

An experimental drug, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine, that facilitates glutamatergic transmission in brain after systemic administration was tested for its effects on the induction of long-term potentiation in the hippocampus of rats. Intraperitoneal injections of the drug markedly increased the degree and duration of long-term potentiation; similar results were obtained with an analogue of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine that was also found to improve retention of memory in a radial maze task and in an odor-matching problem. These results define tools for enhancing long-term potentiation in vivo and confirm an important prediction from the hypothesis that long-term potentiation is a substrate of memory.     

Regional preferences of AMPA receptor modulators determined through agonist binding autoradiography

Autoradiographic techniques were used to test if positive modulators of AMPA-type glutamate receptors have regionally differentiated effects on ligand binding. Cyclothiazide, a drug with ten fold greater effects on `flip' than `flop' splice variants of the receptors, had unequal effects across the subdivisions of hippocampus; i.e., it reduced [³H]AMPA binding in field CA3 with an EC₅₀ of 24 μM and in field CA1 and dentate gyrus with EC₅₀s between 60 and 100 μM. The EC₅₀ for the drug's influence on binding was also significantly lower in the superficial than in the deeper layers of the neocortex, though these differences were not as pronounced as those in the hippocampus. The ampakine CX614, a compound with a modest preference for flop variants, had a slightly lower EC₅₀ for its effects on [³H]AMPA binding in CA1 than in CA3. This result was confirmed with [³H]fluorowillardiine binding. The effects of the ampakine in neocortex tended to be greater in the deeper than superficial layers but this did not reach statistical significance. These results indicate that differential effects of modulators on AMPA receptor subunits are reflected in their relative potency across brain subdivisions. This raises the possibility that subclasses of positive modulators will exhibit a measurable degree of selectivity in their physiological and behavioral influences.     

Persistent loss of thermoregulation in the rat induced by 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”) but not by fenfluramine

Using radio-biotelemetry, the timecourse of recovery and sensitivity to ambient temperature (Ta) of the thermogenic response of methylenedioxymethamphetamine (MDMA or “Ecstasy”) was examined. Ambient temperatures of 17 and 22°C produced very different response profiles, with the lower temperature producing a hypothermic response to 10 and 15 mg/kg doses of MDMA, and the higher temperature producing a profound hyperthermia to the same doses. Although the peak responses to the drug had subsided within 5 h of administration, residual effects, in the form of an elevation of body temperature during the “low” phase of the diurnal cycle, were present for a further 48 h. Long-lasting disruption of the thermoregulatory system following a short series of MDMA administrations (10 mg/kg once per day for 4 days) was shown by exposing the rats in the undrugged state to a thermoregulatory challenge, consisting of 60-min exposure to a Ta of 30°C, at 1 week before, and at 4 weeks and 14 weeks after the drug administration. MDMA-treated rats showed a prolonged hyperthermic response to the challenge at both post-drug intervals compared with fenfluramine-treated rats and saline-treated controls. Thus, the results indicate both that MDMA’s thermogenic effects are more sensitive to Ta than previously demonstrated, and that the serotonergic neurotoxicity of the drug may produce long-lasting changes in thermoregulatory mechanisms. Received: 7 December 1997/Final version: 23 January 1998     

Predicting cholangiocarcinoma in patients with primary sclerosing cholangitis before transplantation.

Patients with primary sclerosing cholangitis are at an increased risk of developing cholangiocarcinoma, which is difficult to diagnose because the biliary tree is already distorted. Eleven patients with primary sclerosing cholangitis who underwent orthotopic liver transplantation at this hospital were evaluated. Four patients had coincidental histologically proved cholangiocarcinoma. Patients with cholangiocarcinoma in contrast to patients without tumour presented with rapid onset of persistent jaundice, pruritus, and weight loss associated with an appreciable rise in bilirubin (8x v 2x) and alkaline phosphatase (3.5x v 1.2x) over one year. Cholangiography and computed tomography showed appreciably dilated intrahepatic bile ducts (3/4 v 0/7). The diagnosis of cholangiocarcinoma could only be established before operation in one patient by fine needle aspiration cytology. Tumour was recognised at operation in one other. Histological examination of hepatectomy specimens showed that patients with cholangiocarcinoma had less advanced histological features of primary sclerosing cholangitis. Multiple areas of carcinoembryonic antigen positive epithelial atypia and carcinoma in situ were found in all patients with cholangiocarcinoma. Cholangiocarcinoma recurred in two patients at 14 and 39 months after transplantation. Superimposed cholangiocarcinoma can be predicted in most patients with cholangitis before transplantation, although a definitive diagnosis is difficult to make. Their prognosis after successful transplantation is guarded.