Evaluating risk factors associated with severe hypoglycaemia in epidemiology studies—what method should we use?

AIMS: To determine the most appropriate regression models to use when assessing risk factors for severe hypoglycaemia and to investigate the impact of model misspecification and its clinical implications. METHODS: A total of 1229 children with Type 1 diabetes (mean age 11.7 years sd 4.1), of which 605 (49.2%) were males, were studied. Prospective assessment of severe hypoglycaemia (an event leading to loss of consciousness or seizure) was made over the 9-year period, 1992-2001. Patients were seen every 3 months and episodes of hypoglycaemia along with clinical data were recorded. Over 70% of children never experienced a severe hypoglycaemic event. Data were analysed using the Poisson regression, negative binomial, zero-inflated Poisson (ZIP) and zero-inflated negative binomial (ZINB) models. The over-dispersion and likelihood ratio statistics were calculated and the analytical methods compared. RESULTS: The Poisson regression model did not fit the data well. The negative binomial and the zero inflated Poisson and negative binomial models fitted the data better than Poisson. CONCLUSIONS: The commonly used Poisson regression models to analyse hypoglycaemia epidemiology may lead to biased parameter estimates and incorrect determination of risk factors for hypoglycaemia. We recommend the use of the negative binomial or zero inflated models to examine any risk factors associated with severe hypoglycaemia. Careful consideration must be given to the interpretation of hypoglycaemia surveys and their analysis.     

Elevation of cell adhesion molecule immunoreactivity in the anterior cingulate cortex in bipolar disorder.

BACKGROUND: Neuroimaging reports of increases in signal hyperintensities in white and deep gray matter and other work indicate that there might be an inflammatory response in affective disorders. METHODS: The microvascular immunoreactivity of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 was measured with image analysis in postmortem tissue from the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) from 15 unipolar and 15 bipolar subjects and compared with each other and with 15 subjects with schizophrenia and 15 control subjects. RESULTS: Intercellular adhesion molecule-1 immunoreactivity in gray and white matter of the ACC in bipolar subjects was increased compared with control subjects (gray: p =.001; white: p <.001) and schizophrenic subjects (gray: p =.016; white: p =.025) and modestly increased in white matter compared with unipolar subjects (p =.049). No such differences were found in the DLPFC. CONCLUSIONS: These findings are consistent with the presence of an inflammatory response in the ACC in bipolar disorder.     

Importance of dosimeter calibration method on nebulizer output.

BACKGROUND: We have observed that dosimeter-run nebulizers have a much smaller output when manually activated than when breath activated; however, this has not been adequately investigated. OBJECTIVE: To evaluate the effect of different calibration methods on nebulizer output. METHODS: Six healthy subjects performed all calibrations. The nebulizers were operated by 2 different dosimeters and were calibrated to produce 9 microL per actuation by breath activation followed by exhalation to the room. The nebulizers were then operated at these identical settings, and the output determined in 3 ways: (1) breath activation followed by exhalation to the room, (2) breath activation with exhalation into the nebulizer, and (3) manual activation (with no subject using the nebulizer). These 3 methods were termed regular, rebreathe, and manual, respectively. RESULTS: There was a large and statistically significant difference in nebulizer output among the 3 methods. The measured rebreathe outputs (5.6 and 5.7 microL per actuation) were approximately two thirds and the manual outputs (3.2 and 3.9 microL per actuation) were approximately one third of the regular calibration outputs (8.6 and 8.9 microL per actuation); the 2 values are for the 2 dosimeters. The results were highly statistically significant (P < .001). CONCLUSIONS: The method by which a nebulizer-dosimeter system is calibrated results in different nebulizer outputs. This has a high likelihood of influencing the concentration of methacholine causing a 20% decrease in volume in the first second of forced expiration.     

Systematic review of the treatment of cancer-associated anorexia and weight loss.

PURPOSE: We systematically assessed the efficacy and safety of appetite stimulants in the management of cancer-related anorexia. Literature databases were searched for randomized controlled trials of appetite stimulants in the treatment of cancer anorexia. MATERIALS AND METHODS: Studies were graded according to quality. Fifty-five studies met inclusion criteria. RESULTS: Only two drugs have evidence to support their use for anorexia (progestins and corticosteroids). There is strong evidence against the use of hydrazine sulfate. The outcomes of these trials have been mixed and patient population heterogeneous. CONCLUSION: The optimal dose, time to start, and duration of treatment for many appetite stimulants for cancer anorexia is still unknown. A more systematic approach to research methodology with universal outcome measure and prospective randomized studies are need. Combination regimens are needed but this cannot at the present time be supported by the data presented.     

Studies on the properties of some peripheral MAO inhibitors

1. Studies were carried out on three monoamine oxidase (MAO) inhibitors, two of which, debrisoquine and para- hydroxyphenelzine, are purported to be peripheral inhibitors and one, phenelzine, is a peripherally acting inhibitor, which has been included for comparitive purposes. 2. All three showed varying degrees of specificity towards MAO type A. 3. The action of debrisoquine was very rapid as was that of para- hydroxyphenelzine. 4. The inhibition caused by debrisoquine was competitive and reversible, while that caused by both phenelzine and para- hydroxyphenelzine was irreversible. 5. The inhibition caused by debrisoquine appeared to be unaffected by the pH of the medium.     

Regulation of ketogenesis, gluconeogenesis, and glycogen synthesis by insulin and proinsulin in rat hepatocyte monolayer cultures

The metabolic actions of porcine insulin and biosynthetic human proinsulin on fatty acid and glucose metabolism were studied in rat hepatocytes cultured in monolayer for 24 h. Our aim was to establish whether proinsulin action in the liver is similar to insulin action and whether the relative potencies of the two hormones are the same for different metabolic processes. Proinsulin and insulin exerted a similar maximal inhibitory effect on ketone body formation from palmitate and on gluconeogenesis from pyruvate. The half-maximal effective concentration of proinsulin was 11-13 times that of insulin. The antiketogenic effects of insulin and proinsulin were associated with an increased glycerol 3-phosphate content and a decreased affinity of carnitine palmitoyltransferase for its substrate palmitoyl-CoA. When the basal rate of ketogenesis was increased with isobutyl methylxanthine, the half-maximal effective concentrations of both proinsulin and insulin were decreased, but the relative potency of the two hormones was unchanged. Proinsulin and insulin exerted similar maximal stimulatory effects on glycogen synthesis and on the activities of pyruvate kinase, glucose 6-phosphate dehydrogenase, phosphogluconate dehydrogenase, and malic enzyme. The half-maximal effective concentration of proinsulin was 10-30 times that of insulin. These findings are consistent with receptor binding studies on liver membranes that suggest that proinsulin interacts with insulin-specific and not proinsulin-specific receptors. Our findings also suggest that proinsulin action does not differ from insulin action at a postreceptor site.