Influence of outdoor aeroallergens on hospitalization for asthma in Canada

BACKGROUND: The risk of hospitalization for asthma caused by outdoor aeroallergens is largely unknown. OBJECTIVE: The objective of this study was to determine the association between changes in outdoor aeroallergens and hospitalizations for asthma from the Pacific coast to the Atlantic coast of Canada. METHODS: A daily time series analysis was done to test the association between daily changes in aeroallergens and daily changes in hospitalizations for asthma during a 7-year period between 1993 and 2000 in 10 of the largest cities in Canada. Results were adjusted for long-term trends, day of the week, climate, and air pollution. RESULTS: A daily increase, equivalent to the mean value of each allergen, was associated with the following percentage increase in asthma hospitalizations: 3.3% (95% CI, 2.3 to 4.1) for basidiomycetes, 3.1% (95% CI, 2.8 to 5.7) for ascomycetes, 3.2% (95% CI, 1.6 to 4.8) for deuteromycetes, 3.0% (95% CI, 1.1 to 4.9) for weeds, 2.9% (95% CI, 0.9 to 5.0) for trees, and 2.0% (95% CI, 1.1 to 2.8) for grasses. After accounting for the independent effects of trees and ozone, the combination of the 2 was associated with an additional 0.22% increase in admissions averaged across cities (P <.05). CONCLUSION: These findings provide evidence for the hypothesis that aeroallergens are an important cause of severe asthma morbidity across Canada, and in some situations there might be a modest synergistic adverse effect of ozone and aeroallergens combined.     

Current status of live attenuated influenza virus vaccine in the US

The efficacy and effectiveness of cold adapted live attenuated (CAIV-T, FluMist intranasal influenza vaccine is reviewed. CAIV-T consists of approximately 10(7) TCID50 per dose of each influenza A/H1N1, influenza A/H3N2, and influenza B vaccine strain. The exact strains are updated each year to antigenically match the antigens recommended by national health authorities for inclusion in the vaccine. In one year in which the vaccine strain did not well match the epidemic strain, the live attenuated vaccine induced a broad immune response that cross-reacted significantly with the drifted strain. The efficacy of CAIV-T in adults was demonstrated with challenge studies and the effectiveness of the vaccine for reducing febrile upper respiratory illness, days of missed work, and days of antibiotic use was demonstrated in a large field trial. In young children, protective efficacy against culture confirmed influenza was demonstrated in a field trial with overall protective efficacy of 92% during a two year study. Vaccine was also highly protective against a strain not contained in the vaccine, with 86% protective efficacy demonstrated against this significantly drifted virus. Effectiveness measures, including protection against febrile otitis media and visits to the doctor were demonstrated. Live attenuated vaccine provides a significant new tool to help prevent influenza.     

The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy

Vascular dementia appears rarer than previously thought, but the contribution of vascular lesions to cognitive impairment in Alzheimer's disease (AD) affected patients (mixed dementias) is now recognized as frequent. The role of strategic areas of the brain involved in the cognitive decline induced by vascular lesions and their relative contributions to the severity of the dementing process remain poorly understood. We determined the relationship between the severity of clinical dementia and the volume of different brain areas affected by infarcts in a prospective clinicopathological study in elderly patients. A volumetric study of the functional zones of Mesulam's human brain map affected by vascular lesions was made and correlations between quantified neuropathological data and the severity of dementia were performed in cases with large vascular lesions only, pure AD, and both lesions. The severity of cognitive impairment was significantly correlated with the total volume of infarcts but in a multi-variate model the volume destroyed in the limbic and heteromodal association areas, including the frontal cortex and in the white matter explained 50% of the variability in MMSE and GDS. The total volume of ischemic lesions explained only 0.1-5% of the variability in MMSE and GDS. Age only explained an extra of 0.1-1.6%. This study confirms that infarcts located in strategic areas have a role in the mechanism of cognitive impairment and brings a key for their quantification. It may be useful for developing neuropathological criteria in multi-infarct and mixed dementias.     

Failure to produce conditioning with low-dose trimethylthiazoline or cat feces as unconditioned stimuli

Trimethylthiazoline (TMT), a derivative of fox feces, has been reported to fail to produce aversive conditioning as an unconditioned stimulus (UCS) when presented in large amounts (I. S. McGregor, L. Schrama, P. Ambermoon, & R. A. Dielenberg, 2002). Experiment I evaluated very low TMT levels that nonetheless produced defensive behaviors in rats during exposure. Although each level (0.01, 0.05, and 0.10 microl TMT) produced significant change in defensiveness, none resulted in significant changes the following day in the absence of TMT. Experiment 2 evaluated cat urine, cat feces, and cat fur/skin odor against a no-odor control. Urine produced no significant changes, but feces and fur/skin odors elicited virtually identical changes in defensive behaviors during exposure. When tested the next day in the absence of odor, the fur/skin odor-exposed group showed significant differences on the same behaviors as during exposure, but the feces-exposed group showed no differences on any measure. Results suggest that lack of conditioning to TMT may relate to the type of predator odor rather than the amount, predator species, or possible lack of odor components in TMT that are present in natural feces. Predator feces may also be less effective as a UCS because they are poorly predictive of the actual presence of the predator, suggesting the need for a reevaluation of UCS functions in aversive conditioning.     

A flattening filter for brachytherapy skin irradiation

Radioactive sources in close contact offer an alternative to superficial radiation in the treatment of skin lesions. A flattening filter was designed for a lead surface applicator to improve the skin dose distribution of a high dose rate (HDR) brachytherapy unit (Nucletron). At three heights from the opening (10, 15 and 25 mm) of the cylindrical applicator, the 192Ir source can be driven into the centre of the applicator. Thin sheets of lead foil (0.2 mm) were cut into circular shapes and placed in the opening to build a cylindrical cone that acts as a flattening filter. The shape of the cone was optimized in an iterative process using a spreadsheet and the resulting dose distribution under the applicator was determined using radiosensitive film. The use of the filter improved the dose distribution in a plane perpendicular to the beam axis to be within +/- 5% of the central axis dose. The present applicator and flattening filter together with an HDR brachytherapy unit offer an alternative for skin irradiation where a superficial unit is not available or will be replaced with a more flexible device. As the depth dose characteristics can be modified using different source-to-surface distances, the dose throughout the patient's skin can be shaped as desired by the radiation oncologist using a compensator design type approach.     

"Discordant" increases in CD4 cell count relative to plasma viral load in a closely followed cohort of patients initiating antiretroviral therapy

BACKGROUND: In HIV-positive persons receiving antiretroviral therapy, CD4 cell responses are associated with optimal suppression of viral replication. However, increases in CD4 cell counts in the absence of viral suppression have been reported. We characterized plasma viral load (pVL) and CD4 cell count increases in closely followed patients to evaluate determinants and the prevalence of CD4 cell responses at a populational level. METHODS: All HIV-positive patients in the province of British Columbia, Canada, who were antiretroviral naive and initiated therapy between August 1996 and May 1998 were eligible for the study. The selection criteria were that patients had to have CD4 cell counts and pVLs measured at baseline and at least once during eight 16-week periods after the initiation of therapy. We characterized CD4 cell responses and sought patients who had a "discordant" increase at 1 year, which was defined as an increase in CD4 cell count of >or=50/mm3 with a <1 log10 decrease in pVL. We also evaluated adherence and antiretroviral use. RESULTS: Overall, when baseline and 1-year pVLs and CD4 cell counts were compared, 6.2% of patients had CD4 cell count increases without pVL decreases of >or=1 log10. However, when all pVLs before 1 year were considered, 92% of the discordant increases could be attributed to prior transient or partial viral suppression. Furthermore, although substantial increases in CD4 cell counts were observed in transient virologic responders, the cumulative number of antiretroviral agents used by this group was significantly higher than that used by full virologic responders (p <.001). CONCLUSIONS: Our results demonstrate that virtually all CD4 cell count increases can be attributed to transient or partial pVL suppression. Unmeasured pVL suppression likely explains discordant responses that have been previously reported. Similarities between transient and full virologic responders also appear to be time limited and are often associated with greater cumulative use of antiretroviral therapy by transient virologic responders.     

The mutational spectrum of brachydactyly type C

Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.