Biomedical subjects
J M Kelso
Publications and source records attributed to J M Kelso.
An age-associated correlation between cellular bioenergy decline and mtDNA rearrangements in human skeletal muscle.
Post-mitotic tissues such as skeletal muscle develop a tissue bioenergy mosaic during the process of normal aging that eventually culminates into a bioenergetically diverse tissue containing cells ranging in their oxidative phosphorylation capacity from normal to grossly defective. The mosaic is postulated to develop continuously from birth with the relative proportions of cytochrome c oxidase (COX) proficient (positive) and COX deficient (negative) muscle fibers differing dramatically as a function of age. Generally, young individuals only display the rare fiber deficient in COX activity while aged individuals show a significantly higher proportion of negative fibers. There appears to be a random element governing which cells will be affected. Consequently, adjacent cells within a given tissue may exhibit vastly differing COX activities. Multiple mitochondrial DNA (mtDNA) deletions also appear to accumulate in skeletal muscle, similarly displaying a dramatic disparity as a function of age. Our previous findings have indicated that the accumulation of multiple mtDNA deletions, along with a concurrent decrease in wild-type mtDNA, strongly correlates with the age-associated decrease in COX activity observed in skeletal muscle. Although no definitive associations were established at the cellular level, an important prediction arose from this study. Cells that accumulate large numbers of mitochondrial mutations and have reduced levels of full-length mtDNA would be expected to be severely affected and show reduced COX activity as a consequence. Cells that accumulate fewer mutations or retain adequate amounts of wild-type mtDNA would be predicted to be less affected or even retain normal oxidative metabolism. In order to establish a link associating COX activity to the status of mtDNA within individual fibers, we developed single cell extra-long PCR (XL-PCR). The procedure was used to assess the relative concentration of full-length mtDNA with respect to any mtDNA deletions detected in individual human skeletal muscle fibers of 'pre-established' COX activity. Single cell XL-PCR analysis of COX positive fibers dissected from a 5-year old and 90-year old individual showed that 80% or more of the fibers contained full length mtDNA and few, if any, mtDNA rearrangements. COX deficient or COX intermediate fibers taken from the same individuals, by contrast, depicted a heterogeneous population of rearranged mtDNA species with no detectable full-length mtDNA. The data presented here indicates that COX deficient muscle fibers extracted from individuals, regardless of age, were accompanied by extensive mtDNA rearrangements and reduced levels of full-length mtDNA. This provides compelling evidence linking mtDNA mutations to COX activity decline in skeletal muscle and has important implications when considering the molecular basis of the aging process.
Anaphylaxis after initial ingestion of rambutan, a tropical fruit.
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Astemizole use in pregnancy.
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Deltoid human muscle mtDNA is extensively rearranged in old age subjects.
Extra long PCR analysis of mitochondrial DNA (mtDNA) isolated from skeletal muscle of humans of different ages revealed three phenomena: (i) the amount of normal length mtDNA (16.5 kb) was progressively reduced with age, such that the cells of old age individuals (about 90 years) contained little, or undetectable amounts of normal length mtDNA; (ii) the total amount of mtDNA did not appear to be greatly decreased rather the extent of mtDNA deletions greatly increased; (iii) in old age subjects, considerable amounts of over-sized mtDNA (more than 16.5 kb) was observed. Enzyme histochemical analysis of cytochrome-c oxidase (COX) activity in the muscle tissue of all subjects evidenced a cellular bioenergy mosaic with cells ranging from high to zero detectable enzyme activity in the muscle samples. The frequency of COX deficient muscle fibres was highly dependent on the age of the subject. We have found that the extent of the mtDNA mutational changes strongly correlate with the observed progressive decrease in COX activity. Therefore, it was suggested that the total extent of mtDNA mutation is very large in old age subjects and is sufficient to account for the decline in cellular COX activity with age and for a progressive decrease of overall mitochondrial bioenergetic capacity.
In vitro effects of MOCA and dapsone on rat hepatic and splenic immune cells.
The industrial curing agent 4,4'-methylene-bis(2-chloroaniline) (MOCA) and the structurally related medicinal agent 4,4'-sulphonyldianiline (dapsone), are two commonly used aromatic amine compounds and documented animal carcinogens. In this study the effects of in vitro exposure to MOCA and dapsone (over a dose range of 1-200 microM on spleen and liver immune cell functions were investigated. MOCA exposure caused a dose-dependent inhibition of natural immune activities (i.e. natural killer, NK and natural P815 killer, NPK) and mitogen-stimulated proliferation of T- and B-lymphocytes, with 50% inhibition (IC50) of splenic-cell activities occurring at 145, 85, 21 and 31 microM, respectively. Liver NK and NPK activities were less sensitive to MOCA exposure and exhibited higher IC50's of 165 and 160 microM, respectively. Dapsone exposure slightly enhanced both T- and B-cell mitogenesis at low doses (1 microM) but decreased B-cell mitogenesis at high doses (IC50 = 130 microM). Natural tumouricidal activities were generally unaffected by dapsone, whilst natural cytotoxic (NC) activity was unaffected by both compounds. These results indicate that MOCA is generally immunotoxic in vitro, and may have the potential to enhance the carcinogenic effects of its genotoxic metabolite by inhibiting the tumour surveillance activities of the immune system. The relationship between immune effects and the carcinogenicity of dapsone remains unclear.
Study protocol on azelastine.
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Successful desensitization for treatment of a fixed drug eruption to allopurinol.
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Monospecific allergy to swordfish.
BACKGROUND: Fish allergy is a relatively common and potentially fatal condition. Most fish allergic subjects are allergic to multiple fish species. We encountered a patient clinically allergic only to swordfish. OBJECTIVE: To characterize the in vivo and in vitro IgE antibody responsiveness of this patient solely allergic to swordfish. METHODS: Prick skin tests, as well as immunoassay and protein immunoblotting for IgE antibody were performed using commercial fish extracts and fresh swordfish. A more typical multiple fish-allergic subject and a subject not allergic to food were also studied for comparison. RESULTS: The multiple fish-allergic subject demonstrated IgE antibody to a 13-kD protein in all fish tested (probably Gad c 1 and its analogues in other fish). The swordfish-allergic subject did not recognize this 13-kD band but did demonstrate IgE directed against a 25-kD band only in swordfish. The negative control showed no IgE binding to either the 13 or 25 kD bands. CONCLUSIONS: It is possible to be allergic to a single fish species, such as swordfish, and such monospecific allergy may be due to the presence of species-specific allergens, in this case a 25-kD allergen in swordfish.
Allergy to penicillin and cephalosporins.
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Skin test results in related and unrelated persons with allergic rhinitis.
BACKGROUND: First degree relatives of patients with allergic rhinitis are at increased risk of having the disorder. It is not yet clear whether or not two such related persons with allergic rhinitis are more likely to be skin test positive to the same specific allergic extracts than unrelated persons with allergic rhinitis. OBJECTIVE: To determine whether or not first degree relatives (parent and child or full siblings) with allergic rhinitis are more likely to be skin test positive to the same allergen extracts than unrelated persons with the disease. METHODS: A retrospective chart review of Allergy Clinic patients was performed. Skin test results for 12 common aeroallergen extracts were compared in 32 pairs of genetically related subjects and 32 pairs of age-matched and sex-matched unrelated subjects, all with allergic rhinitis. The percent of concordant results (both members of a pair skin test positive or both negative) and discordant results (one member of a pair positive and the other negative) were calculated and compared for related and unrelated groups. Also, the expected rates of positive concordance (both skin tests positive) based on the prevalence of skin test positively in the two groups were calculated and compared with the corresponding observed rates. RESULTS: Results were concordant in 242 of 384 skin tests (63%) in related pairs versus 233 of 384 skin tests (61%) in unrelated pairs (P = .28, not significant). The expected and observed rates of positive concordance were not significantly different in the related (P = .38) or unrelated (P = .49) groups. When the groups were subdivided into parent-child pairs and sibling pairs, a similar lack of significant differences between the groups was found. CONCLUSIONS: It is concluded that first degree relatives, both with allergic rhinitis, are no more likely to be skin test positive to the same allergen extracts than unrelated persons with this disease. Further, it seems appropriate to advise patients with allergic rhinitis that their first degree relatives who also have the disorder will not necessarily have the same specific allergies.
Oral allergy syndrome successfully treated with pollen immunotherapy.
BACKGROUND: Some patients with allergic rhinitis have oral allergic reactions to fresh fruits and vegetables. This phenomenon has been termed "oral allergy syndrome" and is proposed to be due to cross-reacting allergens in the foods and pollens. METHODS: We report a patient with allergic rhinitis and oral allergy syndrome treated with pollen immunotherapy. Prior to immunotherapy, eating any fresh fruit or vegetable caused immediate itching and swelling of his tongue and throat. Prick skin test titration with pollens and foods was performed before and after 13 months of immunotherapy. Specific IgE immunoassay was performed with the same extracts on serum obtained before and after 7 and 13 months of immunotherapy. IgE immunoblots were performed on the same extracts separated by polyacrylamide gel electrophoresis using sera from the same time periods. RESULTS: After 1 year on immunotherapy, the patient's allergic rhinitis symptoms resolved, and he was able to eat fresh fruits and vegetables without reaction. Skin testing and specific IgE immunoassay demonstrated a marked reduction in sensitivity to not only the pollens but the foods as well. Immunoblots revealed that the intensity of IgE binding to most components of the extracts, some common to pollens and foods, declined during immunotherapy. CONCLUSIONS: These results support the notion that oral allergy syndrome is due to cross-reacting allergens in foods and pollens and may be amenable to treatment with pollen immunotherapy.
Extractable latex allergens and proteins in disposable medical gloves and other rubber products.
BACKGROUND: IgE-mediated sensitization to rubber proteins is being reported with increasing frequency in health care workers. To explore the relative importance of various sources of allergen exposure, we measured the total rubber allergen and protein levels in extracts of disposable rubber gloves and compared the allergen levels with those in extracts of other medical and consumer rubber products. METHODS: Rubber allergens were measured by inhibition immunoassay with a rubber glove extract as the solid-phase allergen and pooled plasma from five rubber-sensitized health care workers as the IgE antibody source. Proteins were measured by Ninhydrin assay. RESULTS: Among 71 lots of gloves tested, the extractable allergen and protein levels were significantly correlated and were appreciably higher in powdered gloves than in powder-free gloves. Allergen levels varied 3000-fold among gloves from different manufacturers and were higher in examination gloves than in surgical or chemotherapy gloves. Measurable allergen was found in 11 of 24 lots of "hypoallergenic" gloves tested. Allergen levels in toy balloons were comparable to those in powdered gloves; much lower allergen levels were measured in condoms and anesthesia rebreathing bags. CONCLUSIONS: The allergen content of disposable rubber gloves varies widely and is higher in powdered gloves than in powder-free gloves and higher in examination gloves than in surgical gloves. Hypoallergenic gloves may contain substantial amounts of IgE-binding proteins. Gloves and toy balloons appear to be more important sources of rubber allergens than the other rubber products tested.