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Biomedical subjects

S O'Toole

Publications and source records attributed to S O'Toole.

17 recordsLinked to original sources
PubMed2000

Polymorphisms of the human IFNG gene noncoding regions.

Interferon gamma (IFN-gamma) is a multifunctional cytokine that is essential in the development of Th1 cells and in cellular responses to a variety of intracellular pathogens including human immunodeficiency virus (HIV-1). We screened genomic DNA samples from a predominately Caucasian male population of HIV-infected and healthy donors for polymorphisms in the human IFNG gene from -777 to +5608 by single-stranded conformational polymorphism. Surprisingly, the proximal promoter (-777 to transcription start) is invariant as no polymorphisms were found in over 100 samples tested. However, further screening revealed polymorphisms in other regions of the gene including a single base insertion in a poly-T tract in the first intron, three single base pair substitutions in the third intron, and another single base pair substitution in the 3' untranslated region (UTR). Electrophoretic mobility shift assay was used to investigate whether these variants have altered DNA-binding abilities, since intronic enhancer elements have been reported for the IFNG gene. Oligonucleotides constructed for two third intron variants showed no difference in DNA-binding abilities as compared with wild-type sequences. However, the 3'UTR variant showed the formation of unique DNA-binding complexes to radiolabeled oligonucleotide probes as compared with the wild-type sequence. The influence of a CA-repeat microsatellite on AIDS disease progression in HIV-1 seroconverters was tested by a Cox proportional hazards model. There is no evidence of an association between alleles and infection with HIV-1 or progression to AIDS. We report an invariant proximal human IFNG promoter and the existence of multiple intronic variants and a potentially functional 3'UTR polymorphism.

3' Untranslated Regions↗
PubMed1999

Pituitary-adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration in normal women and men.

Animal studies indicate that central cholinergic neurotransmission stimulates CRH secretion, but several human studies suggest that the hypothalamo-pituitary-adrenal cortical (HPA) axis may be activated only by doses of cholinergic agonists that produce noxious side effects and, by inference, a nonspecific stress response. Physostigmine (PHYSO), a reversible cholinesterase inhibitor, was administered to normal women and men at a dose that elevated plasma ACTH1-39, cortisol, and arginine vasopressin (AVP) concentrations but produced few or no side effects. Exogenous AVP also was administered alone and following PHYSO, to determine if it would augment the effect of PHYSO on the HPA axis. Fourteen normal women and 14 normal men matched to the women on age and race underwent four test sessions 5 to 7 days apart: PHYSO (8 micrograms/kg i.v.), AVP (0.08 U/kg i.m.), PHYSO plus AVP, and saline control. Serial blood samples taken before and after pharmacologic challenge were analyzed for ACTH1-39, cortisol, and AVP. PHYSO and AVP administration produced no side effects in about half the subjects and mild side effects in the other half, with no significant female-male differences overall. There also were no significant female-male differences in ACTH1-39 or cortisol responses to AVP. In contrast, the men had significantly greater ACTH1-39 responses to PHYSO administration than did the women. The endogenous AVP response to PHYSO also was significantly greater in the men than in the women, and the ACTH1-39 and AVP responses to PHYSO were significantly correlated in the men (both = +0.70) but not in the women. None of the hormone responses was significantly correlated with the presence or absence of side effects in either group of subjects. These results indicate a greater sensitivity of the HPA axis to low-dose PHYSO in normal men than in normal women, which likely is mediated by increased secretion of AVP. The lack of difference in side effects between the two groups of subjects and the lack of significant correlations between presence or absence of side effects and hormone responses in either group suggest that the increased hormone responses in the men were due to increased responsivity of central cholinergic systems and not to a nonspecific stress response.

Adrenocorticotropic Hormone↗
PubMed1998

Temperature measurement devices.

Nurses should gain an understanding of the physiological mechanisms involved in thermoregulation and be aware of the many variables that affect temperature measurement. The rectum, mouth, axilla and tympanic membrane may be used for temperature measurement. To ensure accurate readings, measurements for each individual should be obtained in a consistent manner.

Axilla↗
PubMed1997

The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects.

Recent studies have suggested that theophylline, a nonspecific phospho-diesterase inhibitor, has useful anti-inflammatory actions in asthma. Phosphodiesterase 4 (PDE4) represents the predominant PDE isoenzyme present in inflammatory cells. PDE4 inhibitors might, therefore, have beneficial effects in asthma. Side-effects, specifically nausea, have limited the use of existing agents. CDP840 is an orally active, potent and selective PDE4 inhibitor. We have examined the effect of CDP840 on the allergen-induced asthmatic response, its possible modes of action, and its tolerability at therapeutic doses. A total of 54 patients were recruited to three double-blind, placebo-controlled studies. The first study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on the allergen-induced asthmatic response in patients with known dual response to allergen. A second study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on airway responsiveness to histamine. A third study examined whether single dose CDP840 (15 and 30 mg) had significant bronchodilatory effects. In all studies, CDP840 was well-tolerated, with no patients reporting nausea. CDP840 did not lead to changes in baseline forced expiratory volume in one second (FEV1) as compared to placebo. The late asthmatic response (LAR) to allergen, expressed as area under the curve at 3-8 h (AUC3-8h), was inhibited by 30% (p=0.016), an effect which persisted to the end of the observation period. The early asthmatic response (EAR) was unaffected, and there was no bronchodilatory effect at the doses used. Treatment with CDP840 did not affect bronchial hyperresponsiveness to histamine. In conclusion, CDP840 significantly attenuated the late asthmatic response to allergen challenge in the absence of any bronchodilatory or histamine antagonist effect. This suggests that CDP840 may exert its effects via an anti-inflammatory mechanism.

Adolescent↗
PubMed1997

Alternatives to mercury thermometers.

Training is essential to ensure the effectiveness of most temperature measurement devices. There are a number of factors that need to be considered when choosing a temperature measurement device for a particular clinical setting. There are currently four main alternatives to the mercury thermometer.

Choice Behavior↗
PubMed1997

Disposable gloves.

Disposable gloves are available in latex and synthetic materials, in sterile and non-sterile forms and with and without powder. Sterile disposable gloves should be worn during invasive procedures and when the hands are in contact with wounds. Non-sterile disposable gloves are recommended when the hands are in contact with blood and other body fluids and for indirect contact with wounds.

Disposable Equipment↗
PubMed1996

Biochemical characterization of a mitomycin C-resistant human bladder cancer cell line.

This study describes characteristics of a mitomycin C (MMC)-resistant human bladder cancer cell line, J82/MMC-2, which was established by repeated in vitro exposures of a 6-fold MMC-resistant variant (J82/MMC) to 18 nM MMC. A 9.6-fold higher concentration of MMC was required to kill 50% of the J82/MMC-2 sub-line compared with parental cells (J82/WT). NADPH cytochrome P450 reductase and DT-diaphorase activities were significantly lower in J82/MMC-2 cells compared with J82/WT, suggesting that reduced sensitivity of J82/MMC-2 cells to MMC resulted from impaired drug activation. Consistent with this hypothesis, the formation of MMC-alkylating metabolites was significantly lower in J82/MMC-2 cells compared with J82/WT. Furthermore, DT-diaphorase activity in J82/MMC-2 cells was significantly lower compared with the 6-fold MMC-resistant variant. Glutathione (GSH) levels were comparable in all 3 cell lines. Although GSH transferase (GST) activity was significantly higher in the J82/MMC-2 cells compared with J82/WT, this enzyme activity did not differ between 6- and 9.6-fold MMC-resistant variants. Whereas DNA polymerase alpha mRNA expression was comparable in these cell lines, levels of DNA ligase I mRNA were slightly lower in both MMC-resistant variants relative to J82/WT. However, the DNA polymerase beta mRNA level was markedly higher in the J82/MMC-2 cell line compared with either J82/WT or J82/MMC. Thus, emergence of a higher level of resistance to MMC in J82/MMC-2 cells compared with J82/MMC may be attributed to (i) impaired drug activation through further reduction in DT-diaphorase activity and (ii) enhanced DNA repair through over-expression of DNA polymerase beta.

Antibiotics, Antineoplastic↗
PubMed1995

Community study of role of viral infections in exacerbations of asthma in 9-11 year old children.

OBJECTIVE: To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. DESIGN: Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. SUBJECTS: 108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire. SETTING: Southampton and surrounding community. MAIN OUTCOME MEASURES: Upper and lower respiratory viral infections detected by polymerase chain reaction or conventional methods, reported exacerbations of asthma, computer identified episodes of respiratory tract symptoms or peak flow reductions. RESULTS: Viruses were detected in 80% of reported episodes of reduced peak expiratory flow, 80% of reported episodes of wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow. The median duration of reported falls in peak expiratory flow was 14 days, and the median maximum fall in peak expiratory flow was 81 l/min. The most commonly identified virus type was rhinovirus. CONCLUSIONS: This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children.

Asthma↗
PubMed1995

Prostaglandin D2-induced bronchoconstriction is mediated only in part by the thromboxane prostanoid receptor.

Prostaglandin D2 (PGD2) is a potent bronchoconstrictor, and is thought to have a role in the pathogenesis of asthma. PGD2 causes vasodilation acting via the prostaglandin (DP) receptor on vascular smooth muscle, and myocontraction acting via the thromboxane (TP) receptor on bronchial smooth muscle. To determine the relative contribution of these mechanisms we have studied the degree to which a potent TP receptor antagonist inhibits PGD2-induced bronchoconstriction. Twelve atopic asthmatic subjects underwent baseline PGD2 bronchial challenges to determine the cumulative concentration of PGD2 required to reduce forced expiratory volume in one second (FEV1) by 20%. At four subsequent randomized visits, subjects received this concentration of PGD2 90 min after dosing with placebo or 20, 50 or 100 mg of BAY u 3405, a potent competitive TP receptor antagonist. Serum was taken for drug assay at 90 min. After each dose of PGD2, FEV1 was measured for 30 min, and the area under the percentage fall in the FEV1/time curve (AUC) was calculated. The mean +/- SEM AUC for placebo was 414 +/- 68, and for the 20, 50 and 100 mg doses of BAY u 3405 was 169 +/- 33, 173 +/- 59 and 135 +/- 63, respectively. There were no significant differences between the AUCs for any of the drug doses, whilst all three doses were significantly different from placebo. The plateau response achieved with increasing doses of the antagonist suggests complete blockade of the TP receptor. These data demonstrate that thromboxane receptor blockade only partially inhibits the airway narrowing response to PGD2, and support the existence of a vascular component to PGD2-induced acute airway narrowing in asthma.

Adult↗
PubMed1992

Attenuation of exercise induced asthma by local hyperthermia.

BACKGROUND: Prior treatment with local hyperthermia has been shown to prevent mast cell degranulation and leucocyte histamine release, and to reduce mortality and cellular infiltrates in a model of acute lung injury. Local hyperthermia is effective in reducing the symptoms of the common cold and perennial and seasonal allergic rhinitis, nasal patency also being improved in rhinitis. It is possible that these effects are mediated by common anti-inflammatory mechanisms, and that this treatment may be effective in the treatment of asthma. The effect of prior local hyperthermia on the response to exercise challenge and histamine bronchoprovocation was therefore examined. METHODS: In a randomised, double blind, placebo controlled, crossover study, 10 asthmatic subjects with exercise induced asthma used machines delivering 40 1/minute of fully humidified air at either 42 degrees C (active treatment) or 31 degrees C (placebo treatment) for 30 minutes' tidal breathing. For each pretreatment, at two week intervals they underwent exercise challenges starting one and 24 hours after starting the inhalations. After a further two weeks the protocol was repeated with histamine substituted for the exercise challenges. RESULTS: The mean (SE) maximum percentage fall in forced expiratory volume in one second (FEV1) was significantly lower one hour after treatment with air at 42 degrees C (30.8% (3.1%)) than after treatment with air at 31 degrees C (22.3% (2.9%)). There was no significant effect on exercise challenge at 24 hours, or on histamine challenge at either time point, though there were nonsignificant trends towards protection with exercise at 24 hours and with histamine at one hour. CONCLUSION: In asthmatic subjects the response to exercise challenge is significantly attenuated one hour after treatment with local hyperthermia. This treatment warrants further investigation in the treatment of clinical asthma and other inflammatory disorders.

Adolescent↗
PubMed1988

Childhood adrenoleukodystrophy. Failure of intensive immunosuppression to arrest neurologic progression.

Cyclophosphamide in a dosage of 350 to 700 mg/m2/d was administered for five to 11 days to four patients with childhood adrenoleukodystrophy (ALD) and to one patient with the adult cerebral form of the disease. The rate of neurologic progression in the four patients with childhood ALD did not differ from that of 167 untreated patients with childhood ALD surveyed previously.

Adrenoleukodystrophy↗
PubMed1985

Identification of the inflammatory cells in the central nervous system of patients with adrenoleukodystrophy.

Adrenoleukodystrophy is a disorder of long-chain fatty acid metabolism associated with adrenal cortical insufficiency and central nervous system demyelination. The central nervous system disease is unusual in that it is abrupt in onset and accompanied by a considerable infiltration of mononuclear inflammatory cells. To determine the nature of these inflammatory cells, immunocytochemical staining was carried out on the mononuclear cells in the brain and cerebrospinal fluid of patients with adrenoleukodystrophy. Monoclonal antibodies to T lymphocytes (T11), the helper/inducer (T4) and cytotoxic/suppressor (T8) subsets of T lymphocytes, B lymphocytes (B1), and monocyte/macrophages (M1 or esterase) were used. Mononuclear cells in the perivascular cuffs of autopsy material from 4 patients were, on average, 59% T cells, 34% T4 cells, 16% T8 cells, 24% B cells, and 11% monocyte/macrophages. Cerebrospinal fluid from 8 of 10 patients had increased IgG concentrations. Mononuclear cells in the cerebrospinal fluid of 6 patients with active disease were, on average, 61% T cells, 40% T4 cells, 16% T8 cells, 3% B cells, and 18% monocyte/macrophages. This distribution of cells is similar to that found in the central nervous system during a cellular immune response and suggests the possibility that one component of this disease is immunologically mediated.

Adolescent↗
PubMed1983

Detection of leukemia-related karyotypes in granulocyte/macrophage colonies from a patient with acute myelomonocytic leukemia.

We performed cytogenetic analysis of 11 normal-appearing granulocyte/macrophage colonies derived from cultures of the marrow of a child with acute myelomonocytic leukemia in relapse. We found diploid karyotypes and two abnormal ones--both hyperdiploid and containing the translocation t(1q-;11q+). A clonal origin of the karyotypic differences was suggested by the absence of variation within individual colonies. The evidence suggests that in this patient, the cytogenetic abnormality originated at or before the stage of granulocyte/macrophage progenitor.

Chromosome Aberrations↗