Rising mortality from motor neurone disease in Sweden 1961–1990: the relative role of increased population life expectancy and environmental factors

Recent studies of mortality from motor neurone disease (MND) in Sweden have demonstrated rising levels of mortality from the disease, especially amongst older age groups. Case-control investigations have suggested that certain environmental factors are significantly related to variations in mortality from the disease, and are associated with a probable individual susceptibility to MND. This study applies an innovative epidemiological technique to longitudinal and cohort analysis of Swedish mortality from MND during the period 1961 to 1990. Survival modelling shows that a subpopulation susceptible to MND exists in Sweden, as has been demonstrated in other countries. The increased life expectancy of the Swedish population since 1961 has resulted in more of that susceptible population living to the ages at which MND is expressed, explaining the majority of the increase in mortality from the disease. However, environmental factors may play a role in accelerating the course of MND and may affect the timing of death within the susceptible sub-population.     

Dorsal root ganglia cocultured with macrophages: an in vitro model to study experimental demyelination

The present investigation introduces an in vitro model to study macrophage properties during demyelination. Rat dorsal root ganglia (DRG) were cultured for obtaining myelinated peripheral nerve fibers. These cultures were exposed to non-resident macrophages. In untreated control cultures, there was no indication of myelin removal by the added macrophages. DRG were exposed to enzymatically generated oxygen radicals using the xanthin/xanthin oxidase or the glucose/glucose oxidase system. Assessment of Schwann cell viability and ultrastructural morphology revealed different patterns of cell cytotoxicity and morphological changes in different experiments. High concentrations caused complete tissue necrosis of the DRG, while low concentrations did not affect either cell viability or ultrastructural morphology. Under intermediate experimental conditions, oxygen radicals caused non-lethal Schwann cell damage leading to Schwann cell retraction and myelin sheath rejection. Myelin lamellae were disrupted and decompacted. These changes were followed by a selective macrophage attack on myelin sheats, resulting in demyelination. Axons, Schwann cells and sensory ganglion cells survived this attack. The specificity of the oxygen radical effects was tested in experiments using the oxygen radical scavengers catalase and superoxide dismutase. Catalase prevented the described effects on cell morphology and subsequently blocked demyelination by non-resident macrophages.Supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) (Br 1274/1-1)     

Diabetes prevalence in England, 2001--estimates from an epidemiological model.

AIMS: To estimate the total prevalence of diabetes mellitus (diagnosed and undiagnosed) at national, regional and local level in England to support health-care planning and delivery. METHODS: An epidemiological model was constructed by applying age-sex-ethnic-specific reference prevalence rates from epidemiological studies to resident populations (2001 census) of England at national, regional, and local authority/Primary Care Trust levels. RESULTS: Estimated prevalence of total diabetes for all persons in England was 4.41% in 2001, equating to 2 168 000 persons. Type 2 diabetes was estimated to affect 2 002 000 persons (92.3%) and Type 1 diabetes 166 000 persons (7.7%). Diabetes prevalence was estimated to be higher in women (5.17%) than men (3.61%). People from ethnic minority groups had higher crude prevalence than White Europeans (4.29, 5.69, 6.63 and 2.13% among White Europeans, Black African/Caribbeans, South Asians and 'other' groups, respectively). Prevalence increased sharply with age (0.33, 3.37 and 13.92%, respectively, in those aged 0-29, 30-59 and 60+ years). The model allows use of user-defined population denominator estimates to derive numbers and prevalence of people with diabetes for a given local population group, such as at ward or general practice level. CONCLUSIONS: Self-reported diabetes prevalence estimates from community surveys underestimate the true burden of diabetes. The model can be used to derive the expected total prevalence of diabetes in health areas that lack reliable data to facilitate the implementation of the National Service Framework for diabetes. It will also allow estimates of future diabetes prevalence to be derived, and can potentially be used for prevalence estimates in all of the UK.     

Role of intercellular adhesion molecule-1 in a murine model of toluene diisocyanate-induced asthma

BACKGROUND: Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) are thought to contribute to the airway inflammation and airway hyper-responsiveness (AHR) of allergic asthma. Some differences from allergic asthma have been noted, including airway neutrophilia, and the involvement of ICAM-1 in toluene diisocyanate (TDI) asthma is currently unclear. OBJECTIVE: We utilized mice lacking ICAM-1 expression (ICAM-1(-/-)) to investigate the role of ICAM-1 in airway inflammation and AHR in TDI-induced asthma. METHODS: Male C57BL/6J mice (ICAM-1(+/+)) and ICAM-1(-/-) mice were intranasally sensitized to TDI solution or solvent alone. Airway inflammation, AHR and cytokine secretion were assessed 24 h after challenge by TDI or solvent. The production of antigen-specific IgG and IgE by TDI sensitized and non-sensitized mice was determined. RESULTS: TDI challenge to ICAM-1(+/+) mice induced an increase in airway inflammatory cell numbers, AHR and cytokine secretion of TNF-alpha, macrophage inflammatory protein-2 (MIP-2), IL-4, IL-5 and IFN-gamma into the bronchoalveolar lavage fluid. All these pathophysiological changes were reduced in ICAM-1(-/-) mice. Serum levels of TDI-specific IgG and IgE of ICAM-1(-/-) and ICAM-1(+/+) mice were comparable. CONCLUSION: These results suggest that ICAM-1 plays an essential role in airway inflammation and AHR in TDI-induced asthma.     

Evaluation of hypothesis testing for comparing two populations using NONMEM analysis

In a simulation study of inference on population pharmacokinetic parameters, two methods of performing tests of hypotheses comparing two populations using NONMEM were evaluated. These two methods are the test based upon 95% confidence intervals and the likelihood ratio test. Data were simulated according to a monoexponential model and, in that context, power curves for each test were generated for (i)the ratio of mean clearance and (ii)the ratio of the population standard deviations of clearance. To generate the power curves, a range of these parameters was employed; other pharmacokinetic parameters were selected to reflect the variability typically present in a Phase II clinical trial. For tests comparing the means, the confidence interval tests had approximately the same power as the likelihood ratio tests and were consistently more faithful to the nominal level of significance. For comparison of the standard deviations, and when the volume of information available was relatively small, however, the likelihood ratio test was more able to detect differences between the two groups. These results were then compared to results on parameter estimation in order to gain insight into the question of power. As an example, the nonnormality of estimates of the ratio of standard deviations plays an important role in explaining the low power for the confidence interval tests. We conclude that, except for the situation of modeling standard deviations with only sparse information, NONMEM produces tests of significance that are effective at detecting clinically significant differences between two populations.Partial support from the Upjohn Company, NIH-BRSG SO RR 07066, and the Burroughs Wellcome Foundation.     

Laying the Cytotaxonomic Foundations of a New Model Grass, Brachypodium distachyon (L.) Beauv.

Brachypodium distachyon is a ubiquitous, temperate grass species which is being developed and exploited as an alternative model to rice, in order to gain access to important syntenic regions of the genomes of less tractable relatives such as wheat. As part of this initiative, this paper describes for the first time the cytotaxonomy of members of the polyploid series of this species, and challenges the assumption that the series evolved simply by chromosome doubling. In situ hybridization using genomic DNA probes and rDNA markers uncovers a hybrid origin of several of the polyploid ecotypes, and sheds light upon the complex evolution of this species and its close relatives.     

Deep brain stimulation for Parkinson''s disease: electropermeabilization and activation

Deep brain stimulation, DBS, is an accepted technique for the treatment of Parkinson's disease. DBS affects the electrical functions of neurons, but exactly how it alters those functions is not clearly explained. An electrical model is determined to simulate treatment with DBS of the sub thalamic nucleus. This model shows the difference in electrical fields between the inside and the outside the neurons. The generated electrical field near the electrodes is high enough to perform an electropermeabilization of the cell membranes, which most likely blockade normal nerve pulses or reduce the nerve impulse speed. Further away from the electrodes activation of large axons is performed.     

Unsupervised fuzzy clustering analysis supports behavioral cutoff criteria in an animal model of posttraumatic stress disorder.

BACKGROUND: Unsupervised fuzzy clustering (UFC) analysis is a mathematical technique that groups together objects in the multidimensional feature space according to a specified similarity measurement, thereby yielding clusters of similar data points that can be represented by a set of prototypes or centroids. METHODS: Since clinical studies of mental disorders distinguish between affected and unaffected individuals, we designed an inclusion/exclusion criteria (cutoff behavioral criteria [CBC]) approach for animal behavioral studies. The effect of classifying the study population into clearly affected versus clearly unaffected individuals according to behaviors on two behavioral paradigms was statistically significant. RESULTS: Here the raw data from previous studies were subjected to UFC algorithms as a means of objectively testing the validity of the concept of the CBC for our experimental model. The first UFC algorithm yielded two clearly discrete clusters, found to consist almost exclusively of the exposed animals in the one and unexposed animals in the other. The second algorithm yielded three clusters corresponding to animals designated as clearly affected, partially affected, and clearly unaffected. The algorithm for physiological data in addition to behavioral data failed to elicit discrete clusters. CONCLUSIONS: The UFC analysis yielded data that support the conceptual contention of the CBC and lends additional validity to our previous behavioral studies.     

A corneal model for slit-scanning elevation topography

Computerised videokeratography is increasing in sophistication and accuracy. The Orbscan II Videokeratographer combines the advantages of Placido derived and slit-scanning derived topography, to acquire shape information on the posterior surface of the cornea. The purpose of this paper is to construct a model of slit-scanning elevation topography and highlight potential sources of variation in this methodology. Ray tracing calculations were performed on a defined, theoretical, spherical model to obtain a pachymetric measurement. These calculations were tested by comparing the pachymetry measurement derived from the model, over a refractive index shift from 1.376 to 1.400 with the pachymetry measurement obtained by Orbscan II, of a human eye, with an identical alteration in refractive index. The two methods of measurement differed by only 0.157 microm, suggesting that the model is a good representation of slit-scanning elevation topography, and that refractive index variations have only a minimal effect on Orbscan II pachymetry measurement.