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Biomedical subjects

C Donovan

Publications and source records attributed to C Donovan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Regulation of CTLA-4 expression during T cell activation.

T cell activation requires at least two distinct signals, including signaling via the Ag-specific TCR and a costimulatory pathway. The best characterized costimulatory pathway involves the CD28 molecule, which is expressed constitutively on T cells and binds the family of B7 counter-receptors on APCs. Inhibition of this costimulatory pathway prevents T cell activation and can lead to long-term T cell unresponsiveness or anergy. In contrast, CTLA4, which is homologous to CD28, has been shown to be a negative regulator of T cell activation. The CTLA4 molecule is not expressed on resting T cells, but is induced after the initial steps of T cell activation. To address the regulation of CTLA4 expression, we have analyzed CTLA4 at the level of cell surface expression, mRNA, rate of transcription, and rate of decay of message. Nuclear runoff results show an increase in the rate of transcription following T cell activation. Our analyses of non-T cells, including B cells, mastocytoma, and fibroblasts, by Northern blot analysis detect only T cell expression of CTLA4. Reporter gene analysis indicates that 335 bp of upstream CTLA4 sequence are sufficient to control inducibility. We have identified important regulatory regions that control inducible and cell-specific CTLA4 expression. These results also suggest that both positive and negative response elements modulate the transcriptional regulation of CTLA4 gene expression. Understanding the regulation of CTLA4 should provide insight into the regulation of T cell activation at the molecular level.

Abatacept↗
PubMed1996

Clinic audit for long-term survivors of childhood cancer.

Follow up for survivors of childhood cancer is considered essential in order to document any continuing impact on growth, fertility and other systems, as well as provide appropriate care and information to individuals themselves. Appropriate follow up needs to take into account the survivors' own views about reasons for attendance and perceived satisfaction with the services provided. Information was sought from 93 survivors (more than five years from diagnosis) and 68 of their parents regarding current attendance, understanding of the purpose of the clinic and satisfaction, and future preferences. Patients' main reasons for attending were to gain reassurance that they were well and information about the disease. There were some discrepancies between the types of information patients would like from clinic attendance and what they remembered being given. Parents were more positive than patients. Our data suggest that (i) knowledge in survivors is poor and (ii) it may be possible to define a subgroup for whom less frequent follow up is appropriate. A key component of care must involve education of patients, both about their past and the implications for future health.

Adolescent↗
PubMed1996

Improving the cancer chemotherapy use process.

PURPOSE: Reports of the tragic consequences of erroneous cancer chemotherapy overdoses at a prominent cancer center and a university hospital prompted a review of our institution's practices and those of 123 other hospitals to ascertain for each the current in-house process to prevent chemotherapy errors. METHODS: A multidisciplinary committee of oncologists, nurses, and pharmacists reviewed the chemotherapy use process and identified opportunities for improvement. A 1-page facsimile survey was answered by 150 of 215 members of the American Society of Clinical Oncology (ASCO) who received it. RESULTS: We further restricted the writing of cytotoxic chemotherapy orders to physicians who were board-certified or -eligible in hematology or medical, pediatric, and gynecologic oncology and their approved fellows. Dispensation of drugs is limited to oncology-certified pharmacists, and administration to chemotherapy-certified nurses. Standard orders are used either on special oncology forms or designated order sets in the computer. Procedures to regulate the ordering of antineoplastic drugs for nonmalignant indications by nononcology specialists are outlined. A process to prevent chemotherapy errors is in place in 95% of hospitals. Dedicated medical oncology units are ubiquitous, and most cancer centers and university hospitals have dedicated gynecologic and pediatric oncology units. Chemotherapy orders are generally written by oncology fellows and countersigned by an attending oncologist in cancer centers and university hospitals, whereas private oncology attending physicians write them in most community hospitals. Drugs are administered by oncology-certified nurses in most institutions. CONCLUSIONS: These recommendations should improve the safety and effective use of chemotherapy and reduce the error rate to as close to zero as human fallibility will allow.

Antineoplastic Agents↗
PubMed1995

A review of the literature examining the relationship between alcohol use and HIV-related sexual risk-taking in young people.

Young people have been targeted as a potentially vulnerable population for the spread of HIV. The influence of alcohol on sexual behaviour is part of popular knowledge. More recently, studies have attempted to illuminate the relationship between alcohol use and sexual risk-taking in relation to HIV transmission. In our review of the literature three important points are highlighted for researchers in this area. First, methodological problems make establishing any relationship extremely difficult. Secondly, the concept of sexual risk-taking has to be developed to include acknowledgement of the context in which sex takes place rather than defining risk only in terms of sexual acts. Finally, populations of gay men and men who have sex with men and lesbians are sufficiently different from heterosexuals, with regard to the influence of alcohol on sexual behaviour, to make generalizations about one population inappropriate for the other.

Adolescent↗
PubMed1994

Combined depletion of O6-alkylguanine-DNA alkyltransferase and glutathione to modulate nitrosourea resistance in breast cancer.

MCF-7 human breast cancer cells possess high levels of O6-alkylguanine-DNA alkyltransferase and moderate levels of glutathione, and are more resistant to chloroethylnitrosoureas (CNUs) than cells with low levels of either molecule. The role of each as a component of CNU resistance was assessed using O6-benzylguanine (O6-bG) or O6-methylguanine (O6-mG) to deplete the alkyltransferase and L-buthionine sulfoxamine (L-BSO) to deplete glutathione. O6-bG and O6-mG potentiated 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) cytotoxicity, resulting in a dose modification factor of 5.4 and 2.3, respectively, which reflected the more potent inhibitory effect of O6-bG. L-BSO alone had little effect on the survival of MCF-7 cells following BCNU exposure, but when combined with O6-mG, BCNU cytotoxicity was additive, yielding a dose modification factor of 3.2. O6-bG or O6-mG and L-BSO acted independently, as neither class of inhibitor affected the other's mechanism of CNU resistance. Furthermore, MCF-7 cells overexpressing GST mu were not more resistant to BCNU than the parent cell line in either the presence or absence of O6-bG or L-BSO. These results indicate that on a relative basis in MCF-7 cells, the alkyltransferase is the cell's first line of defense against CNUs. This suggests that therapeutic trials based on O6-bG-induced biochemical modulation of CNU resistance may increase the efficacy of these chemotherapeutic agents against human malignant cells and that L-BSO may have little additive effect when used with these agents.

Breast Neoplasms↗
PubMed1994

A review of the HIV-related sexual behaviour of gay men and men who have sex with men.

In the last decade studies have identified a myriad of factors associated with continued risky sex in gay men and men who have sex with men. More recently the phenomenon of 'relapse' has been identified among this population. The results of such studies have been fed into the ongoing development of strategies to prevent HIV transmission. This paper critically examines this research--most of which is quantitative--and argues that the usefulness of the research is limited. Because of methodological problems, the evidence is contradictory and indeed, comparison across studies is almost impossible. An examination of the concept of 'relapse' illustrates the problems of relying on quantitative research which, in the main, removes individuals from their social context. The paper concludes that more qualitative research is required to locate individuals within their social milieu and to better understand them as individuals interacting with others and involved in an ongoing decision-making process about sexual pleasure and risk.

Bisexuality↗
PubMed1992

Smoking prevalence and associated risk factors in Canadian adults. Canadian Heart Health Surveys Research Group.

OBJECTIVE: To describe the prevalence and patterns of smoking among Canadian adults, the relation of smoking to other cardiovascular disease risk factors and the awareness of the causes of heart disease. DESIGN: Population-based cross-sectional surveys. SETTING: Nine Canadian provinces, from 1986 to 1990. PARTICIPANTS: A probability sample of 26,293 men and women aged 18 to 74 was selected from the health insurance registries in each province. Of these, 20,585 completed a questionnaire on smoking habits during a home interview. MAIN RESULTS: Approximately 29% of the Canadian population 18 years of age and over were regular cigarette smokers, and over 13% of regular smokers smoked more than 25 cigarettes per day. The proportion of women who had never smoked was higher (37%) than men (24%), except for young women aged 18 to 24. For all participants, there was a lower prevalence of high blood pressure and overweight among smokers than non-smokers. The prevalence of sedentary lifestyle, diabetes and elevated blood cholesterol was positively associated with smoking. The proportion of subjects who identified smoking as a cause of heart disease was higher among smokers, and over 90% believe that heart disease is preventable. CONCLUSION: Because smoking is positively associated with other cardiovascular risk factors, multifactorial and comprehensive approaches are needed in the implementation of cardiovascular disease prevention programs. Knowledge regarding the heart health hazards of smoking is high even among smokers. Motivational approaches that go beyond health risk messages are needed in cessation programs.

Adult↗
PubMed1992

Diagnosis of congenital antral web by ultrasound.

Historically, the first case of congenital prepyloric membrane in an infant was documented in 1933 [1]. Since then cases have been reported only sporadically in the literature [2-8]. This is a case of congenital antral web which was identified by real-time ultrasonography, confirmed by barium meal study, and proven at gastrotomy.

Humans↗
PubMed1992

Expression of monocyte activation antigen Mo3 on the surface of peripheral blood monocytes from patients with multiple sclerosis.

Exposure of human peripheral blood monocytes (PBM) to phorbol esters, bacterial products, and cyclic adenosine monophosphate agonists is known to stimulate expression of a plasma membrane antigen ([Ag]; Mo3). Mo3 is recognized by two monoclonal antibodies, Mo3e (IgM), and Mo3f (IgG). Surface Mo3 is barely detectable by indirect immunofluorescence flow cytometry in nonstimulated monocytes. Mo3-positive monocytes have been found in inflammatory tissues, but increased surface expression of Mo3 in PBM has not been seen in any patient group. We report that PBM from patients with chronic progressive MS (CPMS) express increased Mo3. PBM from patients with other neurologic diseases and healthy controls express little measurable Mo3. No difference was seen in class II major histocompatibility complex Ag expression and in Mo2 (CD14) expression. Exposure of PBM to lipopolysaccharide (10 mg/ml) enhanced Mo3 expression in both MS patients and controls. Mo3 expression on CPMS PBM was not dependent on culture conditions. Taken together, our observations suggest that monocytes from patients with MS are stimulated in vivo to express activation Ag Mo3, but that Mo3-positive monocytes need not be upregulated for HLA-DR.

Cell Separation↗
PubMed1991

Torsion of a wandering spleen in a one month old, with a confusing ultrasound examination.

Torsion of a wandering spleen is an uncommon diagnosis and rare in children. The entity is commonly misdiagnosed. In our case, a one month old infant presented with an abdominal mass. Ultrasound identified a large heterogeneous mass but also revealed what appeared to be normal splenic tissue below the left hemidiaphragm. The ultrasound findings steered us away from the diagnosis of wandering spleen or splenic infarction. Differential diagnosis of the mass included twisted hemorrhagic ovarian cyst, neoplastic mass, or inflammatory abscess. Postoperative histologic analysis demonstrated splenic infarction.

Diagnosis, Differential↗
PubMed1991

Functional desensitization of monocytes from patients with multiple sclerosis due to prostaglandin E.

We previously showed that monocytes from patients with multiple sclerosis (MS) produce increased prostaglandin E (PGE) in tissue culture. In this paper we show that monocytes from patients with chronic progressive MS are less sensitive to agents which stimulate PGE synthesis than healthy controls. MS cells are equally sensitive to PG inhibitors. MS monocytes have increased levels of cellular cyclic AMP and are less sensitive to PGE-mediated increases in cAMP. Depressed monocyte natural cytotoxicity was found to be correlated with cellular cAMP. Functional desensitization of monocytes and decreased sensitivity to PGE signals may be related to chronic exposure to prostaglandin E.

Aspirin↗
PubMed1991

Cerebrospinal fluid eicosanoid levels: endogenous PGD2 and LTC4 synthesis by antigen-presenting cells that migrate to the central nervous system.

We analyzed CSF from patients with multiple sclerosis, patients with other neurologic diseases, and healthy controls for the presence of prostaglandin (PG) E2, F2 alpha, D2, I, A, and leukotriene (LT) C4. Control CSF had little measurable PGs or LTs. CSF eicosanoids from patients with progressive MS were increased. We found PGD2 only in MS CSF. CSF monocytes from patients in active disease produced significantly increased PGD, PGE, and LTC4 than paired peripheral blood monocytes and monocytes from healthy controls. We saw no significant difference in LTC4 production between MS and control peripheral blood monocytes.

Antigen-Presenting Cells↗
PubMed1990

High level, regulated expression of the chimeric P-enolpyruvate carboxykinase (GTP)-bacterial O6-alkylguanine-DNA alkyltransferase (ada) gene in transgenic mice.

Transgenic animals expressing genes capable of repairing DNA may be a valuable tool to study the effect of DNA-damaging agents on tissue-specific carcinogenesis. For this reason, we constructed a chimeric gene consisting of the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) gene linked to the Escherichia coli ada gene coding for O6-alkylguanine-DNA alkyltransferase and the polyadenylate region from the bovine growth hormone gene. The PEPCK promoter results in gene expression in liver and kidney and is induced by hormones, and its transcription is regulated by diet. The chimeric PEPCK ada gene was injected into the male pronucleus of fertilized eggs to produce transgenic mice. Six of 65 developing mice contained 5-10 copies of the intact trans gene per genome. Two founders transmitted the trans gene in a heterozygous manner, whereas 3 transmitted as germ line mosaics and 1 did not transmit to F1 offspring. All F1 offspring carrying the PEPCK ada trans gene expressed ada mRNA in liver and kidney and produced a functional alkyltransferase with a protein molecular weight of 39,000 originating from the bacterial gene. Total alkyltransferase activity was increased in the liver of F1 offspring from all founder mice, but offspring of only one founder had elevated renal alkyltransferase levels. A diet high in protein markedly increased ada mRNA and alkyltransferase activity within 1 week in both liver and kidney, whereas a high carbohydrate diet for 1 week markedly reduced expression of PEPCK ada and alkyltransferase levels. Nontransgenic animals were unaffected by these dietary manipulations. During induction with a high protein diet, hepatic alkyltransferase in transgenic mice was 16.6 +/- 1.5 units/micrograms DNA (mean +/- SE) compared to 5.3 +/- 0.6 units/micrograms DNA in control animals. This level of alkyltransferase is higher than that in any mammalian tissue noted previously except human liver. Transgenic animals expressing high levels of alkyltransferase should help define the role of DNA repair in protection from carcinogenesis induced by N-nitroso compounds.

Animals↗
PubMed1989

Modulation of O6-alkylguanine-DNA alkyltransferase in rats following intravenous administration of O6-methylguanine.

The purine analogue O6-methylguanine is an effective biochemical modulator of the DNA repair protein O6-alkylguanine-DNA alkyltransferase. Inactivation of the alkyltransferase by O6-methylguanine sensitizes tumor cells to nitrosoureas in vitro. The pharmacokinetics of O6-methylguanine were evaluated in female Sprague-Dawley rats following administration of a single 40 mg/kg i.v. bolus dose. Two-compartment pharmacokinetic analysis revealed a terminal elimination half-life of 2.3 +/- 0.68 h, a total body clearance of 6.0 +/- 0.53 ml/min/kg, and a volume of distribution at steady state of 948 +/- 186 ml/kg. To inactivate the alkyltransferase, 80 mg/kg O6-methylguanine was given at 0 and 2 h. Alkyltransferase decreased in bone marrow, kidney, lung, spleen, and intestine by 20-90%. Regeneration of alkyltransferase activity was observed 22-70 h after the first bolus dose of O6-methylguanine. A continuous infusion protocol, which achieved a steady state serum concentration of 10.3 +/- 1.5 micrograms O6-methylguanine/ml at 15 h, resulted in a similar degree of inactivation of tissue alkyltransferase to that observed following bolus drug infusion. O6-Methylguanine tissue concentrations, including that determined in brain, were 1.7- to 4-fold higher than that in serum, indicating that O6-methylguanine is concentrated in most if not all tissues. These studies establish pharmacokinetic parameters of O6-methylguanine in rats and suggest that effective biochemical modulation of alkyltransferase can be achieved in vivo. Further studies are indicated to assess the extent to which biochemical modulation of alkyltransferase reduces tumor nitrosourea resistance in vivo.

Animals↗