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C O'Toole

Publications and source records attributed to C O'Toole.

At least 19 recordsLinked to original sources
PubMed1998

Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity.

CONTEXT: Alzheimer disease (AD) susceptibility genes have been identified on chromosomes 1, 14, 19, and 21, and a recent study has suggested a locus on chromosome 12. OBJECTIVE: To confirm or refute the existence of a familial AD susceptibility locus on chromosome 12 in an independent sample of familial AD cases. DESIGN: Retrospective cohort study. DNA data for 6 chromosome 12 genetic markers were evaluated using parametric lod score and nonparametric linkage methods and linkage heterogeneity tests. The latter include the admixture test of homogeneity in the total group of families and the predivided sample test in families stratified by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele among affected members. Parametric analyses were repeated assuming autosomal dominant inheritance of AD and either age- and sex-dependent penetrance or zero penetrance for the analysis of unaffected relatives. SETTING: Clinical populations in the continental United States, Canada, Argentina, and Italy. PATIENTS: Fifty-three white families composed of multiple members affected with AD, from whom DNA samples were obtained from 173 patients with AD whose conditions were diagnosed using established criteria and from 146 nondemented relatives. MAIN OUTCOME MEASURE: Presence of an APOE epsilon4 allele among affected family members. RESULTS: Using parametric methods, no evidence for linkage to the region spanned by the chromosome 12 markers could be detected if familial AD is assumed to arise from the same genetic locus in all 53 families. However, significant evidence for linkage was detected in the presence of locus heterogeneity using the admixture test (odds ratio, 15, 135:1). The estimated proportion of linked families within the 53 families examined varied between 0.40 and 0.65, depending on the genetic model assumed and APOE status. The precise location of the AD gene could not be determined, but includes the entire region suggested previously. Nonparametric linkage analysis confirmed linkage to chromosome 12 with the strongest evidence at D12S96 (P<.001). CONCLUSIONS: Our data provide independent confirmation of the existence of an AD susceptibility locus on chromosome 12 and suggest the existence of AD susceptibility genes on other chromosomes. Screening a larger set of families with additional chromosome markers will be necessary for identifying the chromosome 12 AD gene.

Adult↗
PubMed1998

Absence of association between Alzheimer disease and the -491 regulatory region polymorphism of APOE.

A novel polymorphism (-491 A/T) within the regulatory region on the apolipoprotein E gene has recently been reported to be associated with risk for Alzheimer disease (AD). To test this association in an independent data set, we have examined this polymorphism in a sample of 88 well-characterized AD cases and compared the allele frequency and genotype frequencies for this polymorphism with those observed in 112 cognitively normal subjects drawn from the same ethnic group. These results suggest that in the current data set at least, the -491 A/T polymorphism is not associated with risk for AD, but may be in partial linkage disequilibrium with the APOE epsilon2/epsilon3/epsilon4 polymorphism.

Aged↗
PubMed1997

Site-specific photobiotinylation of immunoglobulins, fragments and light chain dimers.

Herein we report a new method to rapidly photoinsert biotin into a specific and highly conserved site on the Ig structure using a mild photochemical activation step. This site resides in the Fv fragment and involves invariant residues which provide base stacking interactions to the purine ring of ATP (Rajagopalan et al. (1996) Proc. Natl. Acad. Sci. USA 93, 6019-6024). Biotin was coupled to either the phosphate or the ribose of the 8-azidopurine nucleotide or nucleoside photoaffinity probe and shown to insert into the affinity site efficiently. Several monoclonal and polyclonal antibodies, as well as enzymatic and recombinant antibody fragments and light chain dimers were photoaffinity biotinylated and used in ELISA, FACS and Western blots. The selectivity of this site-specific biotinylation method also allows for biotinylation of antibodies in culture supernatants and immune sera without prior purification. Because the biotinylation takes place under physiological conditions and within a short time period, photobiotinylation would be the preferred method for antibodies which are easily damaged by classical non-site specific random biotinylation chemistry.

Animals↗
PubMed1996

The cognitive assessment screening test (CAST) for dementia.

The purpose of this study was to assess the usefulness, the sensitivity, and the specificity of the Cognitive Assessment. Screening Test (CAST), a paper-and-pencil self-administered cognitive test designed to screen elderly people for possible dementia, for use in general physicians' offices, requiring little expertise or staff time. CAST consists of three parts: part A (relatively easy), part B (more demanding), and part C (self-report of concerns). CAST was administered in two studies to: (1) 19 patients known to be mildly to moderately demented versus 24 age-matched normal controls (to establish cutoff standards); and (2) a "real world" sample of 26 elderly patients not known to be demented, attending a general medicine clinic. The sensitivity and specificity of CAST were compared with the Mini-Mental State Examination (MMSE) and the Blessed Dementia Scale cognitive portion (BDS-cog). In study 1, controls were given a detailed neuropsychological battery; in study 2, all patients were given the neuropsychological battery, which served as the "gold standard" to identify individuals with cognitive impairment. In study 1, the cutoff scores for dementia using CAST (Parts A and B) were established. CAST discriminated demented patients from controls with a sensitivity of 95% and a specificity of 88%; the MMSE had a sensitivity of 74% and a specificity of 100%; and the BDS-cog had a sensitivity of 100% and a specificity of 96%. In study 2, CAST discriminated cognitive impairment with a sensitivity of 88% and a specificity of 100%, the MMSE had a sensitivity of 38% and a specificity of 100%; and the BDS-cog had a sensitivity of 50% and a specificity of 94%. Part C was not used to discriminate demented from normal elderly individuals, but to screen for those concerned about their cognitive functioning. CAST is highly useful as a dementia screening test, with sensitivity and specificity equal to or better than the MMSE and BDS-cog, yet requiring minimal examiner time and little training or experience to administer.

Aged↗
PubMed1994

Effect of pentoxifylline and progesterone on human sperm capacitation and acrosomal exocytosis.

The effects of pentoxifylline and progesterone on human sperm capacitation and acrosomal exocytosis were investigated using chlortetracycline (CTC) fluorescence. Continuous exposure to 3.60 mM pentoxifylline caused significant changes in distribution of the three CTC patterns (F, B and AR) compared with control suspensions. Initially, the main effect was promotion of the F to B transition, followed by increases in acrosome-reacted (AR) pattern cells as well. Such responses would be consistent with a pentoxifylline-mediated inhibition of cAMP phosphodiesterase leading to increased availability of cAMP. When continuous and short-term exposure to pentoxifylline were compared, very similar responses were observed: both pentoxifylline-treated groups had significantly more capacitated cells (B and AR patterns) than controls. Progesterone tested at 1, 10 and 100 micrograms ml-1 elicited a similar response to that observed with pentoxifylline, with both capacitation and acrosomal exocytosis being stimulated. Cells incubated in 2 x Ca2+ (3.6 mM) medium were even more responsive to progesterone treatment than those in standard 1 x Ca2+ (1.8 mM) medium, with a threefold decrease in cells exhibiting the F pattern (characteristic of uncapacitated, acrosome-intact cells) and a marked increase in AR cells. These responses are consistent with a progesterone-mediated rise in intracellular Ca2+ that could promote completion of capacitation and initiation of acrosomal exocytosis. Used in combination, pentoxifylline followed by progesterone treatment produced significantly more AR pattern cells than either compound individually.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrosome↗
PubMed1991

Vocal cord dysfunction presenting as asthma.

A 14 year old boy presented with deteriorating asthma and marked stridor. Neither asthma nor stridor responded to an increase in anti-asthma medication, including high dose oral steroids. Indirect laryngoscopy revealed adduction of the vocal cords throughout the respiratory cycle, a phenomenon previously identified as a psychosomatic conversion reaction. When gently confronted with these findings and offered psychological assistance the boy's symptoms abated totally. After two sessions of hypnotherapy he has had better control of both his physical (asthma) and psychological problems.

Adolescent↗
PubMed1990

Hepatic copper metabolism in a mouse model for Menkes' kinky hair syndrome.

Menkes' kinky hair syndrome (KHS) is a lethal x-linked neurodegenerative disorder of copper metabolism, with low serum copper concentrations, tissue-specific copper sequestration, and decreased activities of cuproenzymes in a number of cell types. Although liver copper accumulation is abnormal in KHS, the actual defect in hepatic copper metabolism has not been elucidated. Our studies of liver copper metabolism were conducted in the mottled (blotchy) mouse, an animal model of KHS. After implantation of central venous and biliary catheters in both blotchy and control mice, we measured biliary copper excretion, hepatic copper uptake, and tissue copper contents over an 8-h period after i.v. bolus administration of radioactive 64Cu. Under the experimental conditions used, bile flow and biliary bile acid excretion were held constant, and control and blotchy hepatic 64Cu concentrations were similar in the face of the expected differential in control and mutant kidney 64Cu contents. Biliary excretion of radiocopper was 24.7 +/- 1.5% of injected 64Cu over 8 h in control animals, whereas heterozygotes excreted 6.5 +/- 1.3% and a single hemizygote excreted less than 2%. The pattern of biliary copper excretion was different, with sharp increase and steady decline in control biliary 64Cu excretion but consistently low excretion in mutant mice. No differences were observed in control or mutant hepatic uptake of 64Cu. These data show a reduced biliary excretion of copper in the blotchy mouse, in the absence of a defect in hepatic copper uptake. We suggest that defective copper transport from hepatocyte to bile represents the hepatic expression of the mottled mutation and speculate that a similar defect occurs in human KHS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Metallothionein messenger RNA regulation in the mottled mouse and Menkes kinky hair syndrome.

Menkes kinky hair syndrome is an X-linked neurodegenerative disorder, causing tissue-specific increases in copper and metallothionein content. A mouse model is provided by hemizygotes for mutant alleles at the X-linked mottled locus. Herein we test the possibility that the primary defect in both species is in metallothionein gene regulation. We show that metallothionein-I messenger RNA (mRNA) (mouse) and metallothionein-II mRNA (human) are elevated in mutant fibroblasts. However, comparable dose-response curves in mutant and control cells are generated when mouse metallothionein-I mRNA concentrations are measured in cells exposed to varying concentrations of cadmium or copper (metallothionein inducers). Furthermore, when mutant and control cells are grown to achieve overlapping intracellular copper concentrations in the two cell types, metallothionein-I (mouse) and metallothionein-II (human) mRNA levels are proportional to the intracellular copper concentrations. Finally, in paired determinations in blotchy hemizygote and littermate kidneys containing comparable copper levels, metallothionein-I mRNA contents are very similar. The observations suggest that elevated intracellular copper in these mutants induces metallothionein synthesis by normal regulatory mechanisms.

Alleles↗
PubMed1984

Copper utilization in cultured skin fibroblasts of the mottled mouse, an animal model for Menkes' kinky hair syndrome.

An animal model for Menkes' kinky hair syndrome is provided by mice mutant at the X-linked mottled locus. Two mechanisms have been invoked to explain disease manifestations in mottled and in kinky hair syndrome: relative tissue copper deficiencies and corresponding reductions in cuproenzyme activities; or defective intracellular copper utilization, with impaired intracellular translocation to cuproenzymes or to copper-dependent processes. We addressed the second possibility through measurements of soluble superoxide dismutase (SOD-1) in cytosol extracts of confluent mottled (blotchy) cultured skin fibroblasts. At comparable intracellular copper concentrations over a broad range, SOD-1 specific activities in the mutant cells were not distinguishable from those in controls, or, in some instances, were actually higher. These data suggest that the excess copper anomalously sequestered in a cell expressing the mutation remains available for binding to a cytosolic cuproenzyme. When taken together with data in other systems, the results are consistent with the thesis that the basic lesion in blotchy may primarily affect copper transport or delivery to specific copper transport systems.

Animals↗
PubMed1984

Trace metal metabolism in cultured skin fibroblasts of the mottled mouse: response to metallothionein inducers.

Menkes' kinky hair syndrome is a lethal X-linked disorder marked by tissue-specific increases in copper content. An animal model of kinky hair syndrome is provided by mice mutant at the X-linked mottled locus. The basic defect is unknown. In order to discriminate among potential etiologies, we asked whether the expression of the mottled mutation causes abnormalities in the metabolism of trace metals other than copper in hemizygous mottled (blotchy) cultured skin fibroblasts, and whether we can differentiate mutant and normal cells according to their response to metal inducers of metallothionein. Blotchy fibroblasts accumulated up to 12 times more 64Cu than control (littermate) cells, over time and over a range of 64Cu concentrations. A saturable high affinity component to 64Cu accumulation over a fixed time interval was revealed in these studies. While 64Cu uptake kinetics were indistinguishable in mutant and control cells, the patterns of 64Cu exit differed. In both cell types, the rate of release of a rapidly exchangeable fraction of newly acquired 64Cu was similar. However, in mutant cells, a larger fraction of recently accumulated 64Cu is retained. In contrast to the results for 64Cu, accumulation and exit of 65Zn and 109Cd were not distinguishable in mutants and controls. With exposure to either a strong (cadmium) or weaker (zinc) inducer of metallothionein, 64Cu accumulation was increased in normal cells, while there was no change from the already elevated level of 64Cu accumulation in blotchy cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Histocompatibility testing in patients with carcinoma of the bladder.

A number of disease states have been found to have a positive association with certain HLA antigens. Weak associations have been described for a number of cancers. Seventy patients with transitional cell carcinoma of the bladder underwent serotyping for HLA, A, B, C, and DR antigens. There were 54 men and 16 women patients with a mean age of 65.3 years. Noninvasive lesions (Ta and T1) were present in 50 and 20 were invasive (T2, T3, and T4). Low grade tumors (G1 and G4) were found in 53 and 17 were moderately or poorly differentiated (G3 and G4). Gene frequencies for the HLA determinants in the cancer patients were compared to those for normal English caucasoids. No significant differences were found at either the A, B, C, or DR loci. DR4 was the commonest antigen expressed in bladder cancer patients with an allelic frequency of 39% compared to 28% in the normal population. The presence or absence of the DR4 antigen was not related to the stage or grade of the tumor.

Aged↗
PubMed1983

Cadmium, zinc, and copper metabolism in the mottled mouse, an animal model for Menkes' kinky hair syndrome.

Studies of uptake and release of 64Cu, 109Cd, and 65Zn in suckling C57BL/6J male mice revealed kinetics and distributions that differed for each metal both within and among the organs analyzed, suggesting distinct, albeit overlapping, mechanisms for transport and binding of each metal. In mutants, there were tissue-specific increases in copper-binding capacity. In hemizygotes (Moblo/y) accumulation of 64Cu was increased in kidney, lung, and duodenum. In heterozygotes (Moblo/+), 64Cu content was increased in kidney, with a smaller increase in lung, and no change in duodenal Cu. Decreased 64Cu accumulation was seen in liver in both hemi- and heterozygotes. In contrast, 64Zn and 109Cd accumulation in organs of heterozygote mice was not significantly distinguishable from normal. In skin and connective tissues there is excessive accumulation of 64Cu in Moblo/+ and Moblo/y, no abnormality in heterozygote 65Zn accumulation, but a clear decrease in heterozygote 109Cd content. In both mutant kidney and liver, there was an aberrant subcellular distribution of 64Cu, with the major fraction of sequestered 64Cu in the cytosol. Our studies establish that in spite of the ubiquity of metallothioneins and the structural similarities of those that have been characterized, there is specificity and functional heterogeneity in metal binding among tissues. The aggregate data suggest that there are unique regulatory mechanisms for the metabolism of copper and zinc, while there exists, in part, an inverse relationship between the binding of copper and cadmium. Our data further suggest that the blotchy mutation involves a specific cytosolic copper storage or transport protein also capable of binding cadmium.

Animals↗
PubMed1981

Antibody-dependent cytotoxicity to transitional cells in cystitis cystica.

Serum from 20 children with urinary tract infections and proved cystitis cystica has been examined for antibody to a panel of established cell lines derived from normal urothelium and transitional cell carcinomas of the bladder. Antibody-dependent cytotoxicity was measured with serial dilutions of patient serum and lymphocytes from normal healthy adults as effector cells. The reaction was quantitated by the release of 51chromium from labeled target cells. The patients were grouped according to the duration of symptoms, the presence or absence of reflux, and the presence or absence of upper tract changes or scarring. No differences between test and control subjects were detected.

Antibodies↗
PubMed1979

Clinical status and rate of recovery of blood lymphocyte levels after radiotherapy for bladder cancer.

Peripheral blood lymphocytes and leukocyte levels were monitored in 34 patients with bladder carcinoma before, during, and up to 5 years after radiotherapy. Radiotherapy in doses 6500 to 8500 rads caused a marked decline in the numbers of circulating leukocytes and particularly lymphocytes. In patients clinically free of disease for 5 years, lymphocyte counts returned to pretherapy levels within 3 years after radiotherapy. In contrast, in patients with recurrent or residual tumors lymphocyte counts failed to reach pretherapy levels within 3 years after therapy. The rate of recovery from radiation-induced lymphopenia was significantly different for patients who were free of disease as compared to those with recurrent or residual tumor (p less than 0.05). No correlation was found between posttherapy leukocyte levels and clinical status.

Aged↗