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Biomedical subjects

C O'Toole

Publications and source records attributed to C O'Toole.

At least 19 recordsLinked to original sources
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↗
PubMed1978

Ultrastructure, karyology and immunology of a cell line originated from a human transitional-cell carcinoma.

A cell line (J82) was derived from a poorly differentiated, invasive, transitional-cell carcinoma, Stage T3. The cells have been propagated in vitro for 5 years and showed 100% aneuploidy and a mixed epithelial-fibroblastic morphology. The majority of cells contained 2Y chromosomes and several distinctive markers. Peripheral-blood lymphocytes from the donor of the J82 cells were tested sequentially for cytotoxicity toward autologous and allogeneic tumour cells. Autologous cytotoxicity was detected against J82 cells in early in vitro passage. Allogeneic lymphocytes from some patients with transitional-cell carcinoma were also cytotoxic to J82 cells in primary culture. However, selective cytotoxicity by lymphoid cells from bladder-carcinoma patients was not detected against J82 cells in long-term tissue culture.

Carcinoma, Transitional Cell↗
PubMed1978

Effect of a low protein diet on in vitro protein synthesis in thymus, spleen, and bone marrow in young adult rats.

Young adult rats (body weight 90 g) were given a low protein (3% casein) diet for 6 days. Under these conditions, thymus and spleen organ wet weights and DNA content decreased as compared with control rats given a high protein (20% casein) diet. The in vitro incorporation of amino acids into protein was followed using leucine as the radioactive precursor. Ribosomes of tissues from the dietary rats were incubated together with soluble enzymes from liver of rats fed a stock diet, and cofactors. Ribosomal capacity for leucine incorporation into protein diminished in thymus by 33% per mg ribosomal RNA, 77% per total ribosomal RNA, and 43% per mg DNA. In spleen the corresponding reductions were 29%, 81%, and 31%; in bone marrow the decrease was 29% per mg ribosomal RNA, 56% per total ribosomal RNA, and 19% per mg DNA. A reduction in physiological activity is thus evident in these tissues soon after protein restriction.

Amino Acids↗
PubMed1978

Anti-squamous tumor antibodies in patients with squamous cell carcinoma.

Patients with advanced squamous cell carcinomas were shown to have serum antibodies directed towards cultured squamous tumor cells as shown by quantitative membrane immunofluorescence. The sera of these same patients did not react with a variety of other cultured tumor cells. Serum obtained from normals or from patients with other forms of cancer (transitional cell carcinoma, adenocarcinoma, and melanoma) did not give positive reactions. When the sera of squamous carcinoma patients were chromatographed on Sephadex G-150, tumor-reactive antibodies were recovered solely in the 19 S fraction, suggesting immunoglobulin M as the immunoglobulin isotype involved. Identification of the squamous tumor cell-reactive immunoglobulin as ijmunoglobulin M was confirmed by quantitative immunofluorescence with the use of class monospecific antisera to human immunoglobulins.

Adult↗
PubMed1977

A 51chromium isotope release assay for detecting cytotoxicity to human bladder carcinoma.

A 51chromium isotope release assay is described for measuring in vitro cytotoxicity reactions against allogenetic target cells. Lymphoid cells from some patients with localized transitional cell carcinoma (TCC) were shown to selectively lyse targets derived from two long-term cell lines of TCC. The effector cells in this reaction did not form E rosettes. Cytotoxicity was successfully recovered after cryopreservation.

Carcinoma, Transitional Cell↗