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Biomedical subjects

K Doherty

Publications and source records attributed to K Doherty.

At least 19 recordsLinked to original sources
PubMed2001

The novel BLM3 gene encodes a protein that protects against lethal effects of oxidative damage.

Mutational alteration of the BLM3 gene in Saccharomyces cerevisiae confers hypersensitivities to lethal effects of ionizing radiation, anticancer bleomycins and structurally-related phleomycins. Bleomycin is used clinically in the treatment of many types of cancers, including Kaposi's sarcoma. The BLM3 gene was cloned from a genomic library by complementing the drug hypersensitivities conferred by the codominant blm3-1 mutation. The nucleotide sequence of BLM3 encodes a predicted integral protein of 1804 amino acids with seven to ten potential transmembrane domains and additional motifs. The blm3 null mutation was created by gene replacement, and found not to be essential for growth in the absence of the bleomycin-phleomycin antibiotics. Sequence analyses suggest the Blm3p could be a potential member of the major facilitator superfamily (MFS) of permeases. Northern dot blot analyses using a human RNA master tissue blot containing RNA from fifty different fetal and adult tissues revealed sequence homology in adult tissues to BLM3, but no sequence homology in fetal tissues. The function of the Blm3p is presently unknown. We propose several functions for the Blm3p in protecting cells against oxidative agents, including roles in detoxification, transport and defending against DNA damage.

Alleles↗
PubMed2000

Effects of nicotine gum dose by level of nicotine dependence.

We used the Heaviness of Smoking Index, a subset of the Fagerstrom Test for Nicotine Dependence, to classify 608 cigarette smokers planning a cessation attempt as low or high in nicotine dependence. Subjects within each level of dependence were then randomly assigned to placebo, 2-mg, or 4-mg nicotine gum treatment. Subjects were also provided brief (5-10 min per visit) behavioral counseling during a 1-year period of follow-up. At 1 year post-cessation, quit rates were 11.2, 19.5, and 18.4% for low-dependence smokers receiving placebo, 2-mg, and 4-mg gum, respectively (plinear trend = 0.20). For high-dependence smokers, quit rates at 1 year were 6.1, 15.7, and 20.7% for the placebo, 2-mg, and 4-mg gum conditions, respectively (plinear trend = 0.002). The interaction of nicotine-gum dose and dependence group was not significant (p = 0.42), nor did the 2-mg and 4-mg doses differ significantly in effectiveness, though both 2-mg and 4-mg gum were significantly more effective than placebo gum. We also found a significant dose-related effect for nicotine gum to moderate post-cessation heart-rate decline. Other variables related to abstinence at 1 year post-cessation were a longer period of abstinence on a prior quit attempt, being married, higher education level, and having a non-smoking spouse or significant other. Results indicate that nicotine gum is a significant aid to smoking cessation, more than doubling the odds of successful cessation compared to the odds for placebo-gum users. The 4-mg dose provided a non-significant increase in cessation rates for high-dependence smokers. Smoking history and demographic variables also have a significant impact on the outcome of a quit-smoking attempt.

Adult↗
PubMed1997

Direct gamete uterine transfer in patients with tubal absence or occlusion.

PURPOSE: Our aim was to examine the potential of the uterine cavity to affect fertilization and early embryo development. DESIGN: A prospective IRB-approved protocol for patients fulfilling study eligibility criteria was used. METHODS: Patients studied included those with primary or secondary infertility, aged less than 38 years, with no history of severe male-factor infertility, and with hysterosalpingogram- and laparoscopic-confirmed bilateral proximal tubal occlusion. Superovulation induction was accomplished with a combination of GnRH agonist and menotropins, with serum hormonal and sonographic monitoring. Within 24 hr prior to, and again at the time of, ovulatory hCG administration, progesterone (P4) was given. Sonographic-guided transvaginal retrieval was performed 35 hr after hCG. Between four and six oocytes were returned to the uterine cavity, admixed with sperm, immediately following retrieval. Luteal support consisted of daily P4 administration. RESULTS: Of the 20 patients recruited for the study, all completed the retrieval and transfer procedure. A total of four clinical pregnancies was achieved, with one early first-trimester loss, one late first-trimester loss (Trisomy 14), and two healthy term infants delivered. IVF of surplus oocytes demonstrated a 82.5% fertilization rate and 66.7% cleavage following cryopreservation. CONCLUSIONS: Human fertilization can be achieved through direct uterine transfer of gametes. Furthermore, administration of P4 prior to the ovulatory dose of hCG is compatible with in vitro or in vivo fertilization and implantation.

Adult↗
PubMed1997

Differential regulation by protein kinase C isoforms of nitric oxide synthase induction in RAW 264.7 macrophages and rat aortic smooth muscle cells.

1. In RAW 264.7 murine macrophages and rat aortic smooth muscle (RASM) cells lipopolysaccharide (LPS) alone or in combination with interferon gamma (IFN gamma) or forskolin, respectively, stimulated the expression of the 130 kDa inducible isoform of nitric oxide synthase (iNOS) in both a time- and concentration-dependent manner. 2. Incubation with the direct activator of protein kinase C (PKC), phorbol 12-myristate 13-acetate (PMA) alone, did not result in detectable iNOS expression in either cell type. 3. Chronic PMA pretreatment resulted in significant down-regulation of alpha, beta and epsilon isforms of PKC in RAW 264.7 macrophages and corresponded to a 20-30% reduction in LPS-induced iNOS expression. In contrast, IFN gamma alone or in combination with LPS stimulated an approximate 20% and 50% potentiation, respectively. 4. Pre-incubation with PKC inhibitors (calphostin C and H-7) showed similar effects upon stimulated induction of iNOS. 5. In RASM cells chronic PMA pretreatment resulted in down-regulation of alpha and epsilon PKC isoforms and corresponded to potentiation of iNOS expression in response to LPS alone or in combination with forskolin. 6. Co-incubation of RASM cells in the presence of PMA, angiotensin II (AII) or foetal calf serum (FCS) resulted in the inhibition of iNOS expression in response to LPS alone or in combination with forskolin. 7. Differential sensitivity to PKC inhibitors (calphostin C and H-7) was observed in RASM cells and exhibited both negative and positive modulation of stimulated induction. 8. In addition the PKC inhibitor compound Ro-31-8220 abolished stimulated induction in both cell types in response to all treatments. 9. These results suggest that PKC activation is required for induction of the 130 kDa isoform of NOS in both RAW 264.7 macrophages and RASM cells. However, individual PKC isoforms regulate iNOS expression in both a positive and negative manner.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1997

The importance of efficacy and partial agonism in evaluating models of B lymphocyte activation.

Immunologists have developed a range of in vitro techniques for probing the receptor mediated response of cells comprising the immune system. An important and ubiquitous method is the use of antibodies in either soluble or aggregated form to engage cell surface receptors and transmit a signal. Models of cell and molecular interactions, derived from the use of these antibodies, form the basis of our efforts to understand and explain the corresponding in vivo systems. However, interpreting in vitro experiments and distinguishing between alternative models is difficult. This complexity is illustrated here using B cell stimulation by surface immunoglobulin and CD40. The fluorescent cell labelling dye carboxyfluorescein, diacetate, succinimidyl ester (CFSE) is used to show that many anti-Ig and CD40 stimulatory agents, used to assess the role of B cells and lymphokines, are partial agonists. By modelling each step in B cell signalling, activation and division it is possible to show that small changes in signal contributed by a second receptor can generate numerous distinct dose response curves that are highly dependent on the "efficacy" of signal transmission by the primary ligand and the number of cell divisions taken in culture. Differences in dose response curves become particularly striking if the primary activating stimulus is a partial agonist. Although exemplified here with B cell stimulation the conclusions are applicable to other in vitro activation systems and suggest ways to improve both the design and interpretation of in vitro experiments.

Animals↗
PubMed1996

Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy.

Patients with myelodysplastic syndromes (MDS) have refractory cytopenias leading to transfusion requirements and infectious complications. In vitro marrow culture data have indicated that granulocyte colony stimulating factor (G-CSF) synergizes with erythropoietin (EPO) for the production of erythroid precursors. In an effort to treat the anemia and neutropenia in this disorder, MDS patients were treated with a combination of recombinant human EPO and recombinant human G-CSF. Fifty-five patients were enrolled in the study of which 53 (96%) had a neutrophil response. Forty-four patients were evaluable for an erythroid response of which 21 (48%) responded. An erythroid response was significantly more likely in those patients with relatively low serum EPO levels, higher absolute basal reticulocyte counts and normal cytogenetics at study entry. Seventeen (81%) of the patients who responded to combined G-CSF plus EPO therapy continued to respond during an 8-week maintenance phase. G-CSF was then discontinued and all patients' neutrophil responses were diminished, whereas 8 continued to have an erythroid response to EPO alone. In 7 of the remaining 9 patients, resumption of G-CSF was required for recurrent erythroid responses. The median duration of erythroid responses to these cytokines was 11 months, with 6 patients having relatively prolonged and durable responses for 15 to 36 months. Our results also indicate that approximately one half of responding patients require both G-CSF and EPO to maintain an effective erythroid response, suggesting that synergy between G-CSF and EPO exists in vivo for the production of red blood cells in MDS.

Adult↗
PubMed1996

Depression and smoking cessation: characteristics of depressed smokers and effects of nicotine replacement.

Previous research has linked depression to difficulties in smoking cessation. The authors followed 269 smokers who attempted to quit smoking for 3 months. Participants were given nicotine gum (2 or 4 mg) or placebo gum and brief counseling. The study found that 34% of the smokers met the criterion for current depression using the Center for Epidemiological Studies Depression Scale. Depressed smokers relapsed significantly earlier than the nondepressed. Nicotine gum was significantly more effective than placebo gum among all smokers. The benefits of nicotine gum were particularly apparent among the depressed. Only 12.5% of depressed smokers quit successfully with placebo gum for 3 months, whereas 29.5% quit with nicotine gum. Depressed smokers reported more stress, less coping resources, more physical and psychological symptoms, and more frequent smoking in the presence of negative affect than did the nondepressed.

Adaptation, Psychological↗
PubMed1996

Nicotine gum dose and weight gain after smoking cessation.

The authors examined weight gain in 79 abstinent cigarette smokers during treatment with placebo or with 2 mg or 4 mg of nicotine gum. Results indicated that nicotine gum suppressed weight gain in a linear fashion with increasing nicotine dose. At 90 days postcessation, placebo gum users gained 3.7 kg, 2-mg gum users gained 2.1 kg, and 4-mg gum users gained 1.7 kg. Assessment of nicotine replacement by means of pre- and postcessation salivary continue levels revealed that smokers who replaced a greater percentage of their baseline continue levels during treatment gained less weight. Percentage of baseline cotinine replaced remained related to weight gain after the number of pieces of gum used was controlled. Implications for smokers hoping to minimize postcessation weight gain are discussed.

Adult↗
PubMed1995

Urges to smoke during the first month of abstinence: relationship to relapse and predictors.

The urges to smoke reported by 215 former smokers were measured 1 day, 7 days, 14 days and 30 days after they quit to examine: (a) the time course of smoking urges, (b) the relationship of urges to relapse, and (c) predictors of urges to smoke. Urges to smoke were strongest 1 day after quitting, and decreased at each subsequent measurement point. Urges were a powerful predictor of relapse. At each of the four assessment points, abstinent subjects who reported stronger urges to smoke were more likely to relapse by the next measurement point. Urges to smoke at a given day (e.g., day 1) were consistently the best predictors of the persistence of urges at the next assessment (e.g., day 7). Greater negative emotion (e.g., anxiety, sadness, anger, and confusion) and psychosocial stress also predicted stronger urges to smoke. Nicotine gum significantly reduced urges during week 1 post-cessation. Clinical implications of the findings are discussed.

Adult↗
PubMed1994

Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions.

B-cell tolerance to soluble protein self antigens such as hen egg lysozyme (HEL) is mediated by clonal anergy. Anergic B cells fail to mount antibody responses even in the presence of carrier-primed T cells, suggesting an inability to activate or respond to T helper cells. To investigate the nature of this defect, B cells from tolerant HEL/anti-HEL double-transgenic mice were incubated with a membrane preparation from activated T-cell clones expressing the CD40 ligand. These membranes, together with interleukin 4 and 5 deliver the downstream antigen-independent CD40-dependent B-cell-activating signals required for productive T-B collaboration. Anergic B cells responded to this stimulus by proliferating and secreting antibody at levels comparable to or better than control B cells. Furthermore, anergic B cells presented HEL acquired in vivo and could present the unrelated antigen, conalbumin, targeted for processing via surface IgD. In contrast, the low immunoglobulin receptor levels on anergic B cells were associated with reduced de novo presentation of HEL and a failure to upregulate costimulatory ligands for CD28. These defects in immunoglobulin-receptor-mediated functions could be overcome in vivo, suggesting a number of mechanisms for induction of autoantibody responses.

Animals↗
PubMed1994

The triangle model of responsibility.

Responsibility acts as a psychological adhesive that connects an actor to an event and to relevant prescriptions that should govern conduct. People are held responsible to the extent that (a) a clear, well-defined set of prescriptions is applicable to an event (prescription-event link); (b) the actor is perceived to be bound by the prescriptions by virtue of his or her identity (prescription-identity link); and (c) the actor is connected to the event, especially by virtue of appearing to have personal control over it (identity-event link). Studies supported the model, showing that attributions of responsibility are a direct function of the combined strengths of the 3 linkages (Study 1) and that, when judging responsibility, people seek out information that is relevant to the linkages (Study 2). The model clarifies prior multiple meanings of responsibility and provides a coherent framework for understanding social judgment.

Analysis of Variance↗
PubMed1994

Induction of Lyt-2+ cytotoxic T lymphocytes following primary and secondary Salmonella infection.

Investigations of the cytotoxic activity of T cells induced following one or two intraperitoneal doses of live Salmonella revealed that cytotoxicity was restricted to the Lyt-2+ T-cell subset and was enhanced following secondary infection with Salmonella. Initial studies using the lectin-dependent cellular cytotoxicity (LDCC) assay detected Lyt-2+ cytotoxic T cells in peritoneal cell suspensions of S. enteritidis 11RX (11RX)-infected mice, with the peak of activity occurring 5 days after infection. This did not correlate with the proliferative activity of these cells, which peaked 10-12 days after infection. Secondary challenge with 11RX or S. typhimurium C5 (C5) induced a rapid increase in the cytotoxic activity of Lyt-2+ peritoneal T cells and was detected even 21 days later. The antigen specificity of some of these cells was confirmed in cytotoxicity assays using P815 tumour cells infected with 11RX organisms as targets. No cytotoxic activity was detected in the spleen cell suspensions of infected (and normal) mice unless the cells were first activated by in vitro culture with concanavalin A (Con A). Both types of activated spleen cells showed LDCC but Salmonella-specific cytotoxic Lyt-2+ T cells were detected only in spleen cell (SC) cultures prepared from mice challenged with a second dose of Salmonella.

Animals↗
PubMed1993

Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin.

We treated myelodysplastic syndrome patients (MDS) with both recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human erythropoietin (EPO) to determine whether such combination therapy resulted in improvement of their anemias. Twenty-four of 28 patients begun on study completed the protocol and were evaluable for erythroid responses. Therapy was initiated with G-CSF at 1 micrograms/kg administered by daily subcutaneous injection and adjusted to either normalize or double the neutrophil count. EPO was then administered by daily subcutaneous injection at a dose of 100 U/kg and dose-escalated to 150 and 300 U/kg every 4 weeks while continuing the G-CSF. Changes in absolute reticulocyte count, hematocrit level, and need for RBC transfusions were compared with pretreatment values as well as other blood cell counts. Ten of 24 patients (42%) had erythroid responses, whereas all patients had neutrophil responses. Six previously transfused patients no longer required RBC transfusions during the treatment period. Erythroid responses were found to be independent of patient age, French-American-British subtype, duration of disease, prior RBC transfusion requirements, or cytogenetic abnormalities at presentation. Pretreatment serum EPO levels were lower in erythroid-responding as compared with nonresponding patients (median 157 v 600 U/L; P = .05). The combined treatment modality was generally well tolerated. We conclude that a substantial percentage of MDS patients had both erythroid and myeloid responses when treated with the combination of G-CSF and EPO.

Adult↗
PubMed1992

Phase I/II trial and pharmacokinetics of intrathecal diaziquone in refractory meningeal malignancies.

PURPOSE: Because there is a compelling need to develop new agents for intrathecal use, we investigated the safety, efficacy, and CSF pharmacokinetics of diaziquone (AZQ) following intrathecal administration in patients with refractory meningeal malignancies. PATIENTS AND METHODS: Thirty-nine patients received 45 courses of intrathecal AZQ. Two schedules were studied; twice-weekly administration of a 1- or 2-mg dose and "concentration times time" (C x T) administration of 0.5 mg every 6 hours for three doses, administered once weekly. RESULTS: Dose-limiting toxicity consisting of headache, nausea, or vomiting occurred in only three patients and only at the 2-mg, twice weekly dose. The schedules of 1 mg twice-weekly and 0.5 mg every 6 hours for three doses were well tolerated. Thirty-seven courses were assessable for response. The overall response rate was 62%. Complete responses (CRs) occurred in 14 of 37 courses (38%) and partial responses (PRs) occurred in nine of 37 courses (24%). Among patients with meningeal leukemia, CRs were observed in 11 of 26 courses (42%) and PRs in nine of 26 courses (35%). There was no difference in response rate related to dose or schedule. The pharmacokinetic behavior of intrathecally administered AZQ was characterized by biexponential disappearance from ventricular CSF, with mean half-lives of 18.2 and 78.6 minutes. The mean clearance rate was 0.37 mL/min. CONCLUSION: Intrathecal AZQ is safe, well tolerated, and highly active against refractory meningeal malignancies.

Adolescent↗
PubMed1992

General practice estimates of the prevalence of common chronic conditions.

This study measured the prevalence of chronic medical conditions in 4,549 middle aged persons attending three large general practices in Dublin over the course of a calender year. The prevalence of the following conditions were measured: coronary heart disease, hypertension, stroke, diabetes, asthma, chronic bronchitis, rheumatic disorders, dyspepsia, depression, anxiety disorders, psychoses, and cancer. In order to obtain a valid denominator for the study a second community based study was carried out in the same areas to determine what proportion of persons visit their general practitioner over the course of a year. Overall 40.5% of males and 44% of females suffered from a least one of the twelve conditions, with rheumatic disorders having the highest prevalence (14.5%) and psychotic disorders the lowest (0.75%).

Adult↗
PubMed1992

An explanation for the difference in general practitioner consultation rates between GMS and non-GMS patients.

This study compares annual consultation rates between 3,111 General Medical Services and private patients, and their family doctors in three large general practices in Dublin. Visiting rates were substantially different between practices and between GMS and private patients. However, GMS patients were older and had 50% more chronic illnesses. When the effects of age and illness were controlled in a multiple regression model, GMS status accounted for less than 5% of the variation in visiting rates. GMS patients consult their practitioners in proportion to their medical need.

Adult↗
PubMed1990

Inhibition of phosphoglucomutase by vanadate.

Phosphoglucomutase is inhibited by a complex formed from alpha-D-glucose 1-phosphate (Glc-1-P) and inorganic vanadate (Vi). Both the inhibition at steady state and the rate of approach to steady state are dependent on the concentrations of both Glc-1-P and Vi. Inhibition is competitive versus alpha-D-glucose 1,6-bisphosphate (Glc-P2) and is ascribed to binding of the 6-vanadate ester of Glc-1-P (V-6-Glc-1-P) to the dephospho form of phosphoglucomutase (E). The inhibition constant for V-6-Glc-1-P at pH 7.4 was determined from steady-state kinetic measurements to be 2 x 10(-12) M. The first-order rate constant for approach to steady state increases hyperbolically with inhibitor concentration. The results are consistent with rapid equilibrium binding of V-6-Glc-1-P to E, with dissociation constant 1 x 10(-9) M, followed by rate-limiting conversion of the E.V-6-Glc-1-P complex to another species, E*.V-6-Glc-1-P, with first-order rate constant 4 x 10(-2)s-1. The rate constant determined for the reverse reaction, conversion of E*.V-6-Glc-1-P to E.V-6-Glc-1-P, is 2.5 x 10(-4)s-1. Formation of E*.V-6-Glc-1-P can also occur via binding of glucose 6-vanadate to the phospho form of phosphoglucomutase (E-P) followed by phosphoryl transfer and rearrangement of the enzyme-product complex.

Glucose-6-Phosphate↗