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Biomedical subjects

M Ryan

Publications and source records attributed to M Ryan.

At least 127 records · Page 7Linked to original sources
PubMed1997

Spontaneous regression of granulomatous mycosis fungoides in an HIV positive patient.

The development of mycosis fungoides in HIV-positive patients is uncommon. We describe the granulomatous type of mycosis fungoides in an HIV-positive patient whose cutaneous lesions regressed without treatment. In addition to HIV seropositivity and mycosis fungoides, he had a long history of pulmonary sarcoidosis. Immunophenotyping of the cutaneous lymphoid infiltrates revealed a predominance of CD4+ T cells, and monoclonality was demonstrated by T-cell gene rearrangement studies. The regression of mycosis fungoides in this patient was associated with a falling peripheral blood CD4 T-cell count.

Adult↗
PubMed1997

Using willingness to pay to value alternative models of antenatal care.

Recent years have seen the development of different models of antenatal care, especially for low risk women. More specifically, there has been a move for more general practitioner and midwifery involvement in such care. Given the current changes that are taking place in the provision of antenatal care, it is becoming increasingly important to carry out economic evaluations of alternative models of care. This paper applies the economic instrument of willingness to pay to assess the benefits of two alternative forms of antenatal care: general practitioner/midwife routine led care versus obstetrician led care. The results suggest a willingness to pay of pounds 2500 for antenatal care, with no significant difference between the types of care provided. It is concluded that before firm policy conclusions can be reached, further studies should be undertaken to address methodological issues around the willingness to pay technique.

Adult↗
PubMed1997

Efficacy of the Tibetan treatment for arthritis.

Tibetans in the refugee communities in Northern India are exposed to both traditional Tibetan and Western medicine. For Tibetans suffering from arthritis (or trung-bo), the Tibetan treatment was compared with the Western treatment in an open randomized controlled trial. On a significance level of 0.0005, this trial demonstrated that for these Tibetans, their indigenous treatment worked better than the Western treatment for improved limb mobility.

Arthritis↗
PubMed1997

Generating ideas for teaching mental health nursing.

University teachers who prepare mental health nurses require a variety of teaching techniques to encourage students to engage with the subject matter and to prepare for unknown future problems and dilemmas that they must resolve. Mental health nursing requires the development of specific discipline knowledge, intellectual skills, such as the ability to think laterally and make ethical decisions, and personal attributes, such as maturity and tolerance, as well as practical experience in collaborative care. This article offers a number of strategies that teachers may use in their classes to promote the development of these mental health nursing skills. Other teachers might use these examples to trigger the development of their own repertoire of teaching skills for beginning mental health nurses.

Art↗
PubMed1997

Bordetella pertussis respiratory infection in children is associated with preferential activation of type 1 T helper cells.

The mechanism of protective immunity against Bordetella pertussis generated following recovery from whooping cough in childhood has not yet been elucidated. Studies with a murine respiratory infection model have indicated that cellular immunity, mediated by Th1 cells, plays a role in the clearance of a primary infection with B. pertussis and in protection against subsequent challenge. In the present study, the induction of B. pertussis-specific Th cell subsets in children was examined. Peripheral blood mononuclear cells from B. pertussis-infected or convalescent children proliferated and secreted cytokines following antigen stimulation in vitro. In contrast, responses were weak or undetectable in the majority of children who had not been infected or vaccinated. In all cases, responding T cells produced interferon-gamma but low or undetectable interleukin-5. The findings suggest that Th1 cells may play a role in protective immunity generated following infection with B. pertussis in children.

Aging↗
PubMed1997

Heat shock protein induction protects human respiratory epithelium against nitric oxide-mediated cytotoxicity.

Induction of heat shock proteins (HSPs) confers protection against a variety of cytotoxic agents. We hypothesized that induction of HSPs would protect cultured human respiratory epithelium against nitric oxide (NO)-mediated injury. Incubation of a human bronchial epithelial cell line (BEAS-2B cells) at 43 degrees C for 1.5 h induced expression of several HSPs. Prior induction of HSPs was associated with protection against the NO-donors S-nitroso-N-acetyl penicillamine and 3-morpholinsydnonimine. Protection was evident as improved short term survival and improved ability of cells to recover and proliferate after exposure to NO. Prior induction of HSPs also attenuated NO-mediated decreases in cellular ATP levels, but did not decrease nitrotyrosine formation. Specific overexpression of HSP-70 by plasmid-directed gene transfer protected murine respiratory epithelial cells against S-nitroso-N-acetyl penicillamine. We conclude that in cultured human respiratory epithelium induction of HSPs confers protection against NO-mediated cytotoxicity, possibly by preservation of cellular energetics. We also suggest that HSP-70 may play a specific role in protection.

Adenosine Triphosphate↗
PubMed1997

Selective and transient in vitro effects of heat shock on alveolar type II cell gene expression.

The heat shock response is a highly conserved stress response that can transiently inhibit non-heat shock protein gene expression. Although heat shock protects against acute lung injury, its effects on lung cell gene expression are not known. We studied the in vitro effects of heat shock on the expression of several genes important to alveolar type II cells. Prior induction of heat shock transiently inhibited cytokine-mediated inducible nitric oxide synthase gene expression and cytokine-mediated manganese-superoxide dismutase mRNA expression in murine lung epithelium. In contrast, heat shock had no effect on expression of surfactant protein (SP) A or B mRNA, or SP-B peptide synthesis. Cell survival studies indicated that the inhibitory effects were not secondary to cytotoxicity. Previous heat shock also modestly enhanced the ability of cells to withstand oxidant stress. We conclude that in vitro heat shock has selective and transient inhibitory effects on alveolar type II cell gene expression. Transient inhibition of cytokine-inducible genes, with concomitant conservation of genes required for normal respiratory function (SP) may explain, in part, the mechanism by which heat shock protects during acute lung injury.

Animals↗
PubMed1997

The cost of medicines in the United Kingdom. A survey of general practitioners' opinions and knowledge.

Prescribing costs in general practice continue to grow. Their importance is underlined by the amount of information concerned with costs that general practitioners (GPs) receive, and by the existence of target budgets. In 1986 and 1991, surveys showed that GPs agreed that cost should be borne in mind when choosing medicines, but that their knowledge of drug prices was often inaccurate. This study assessed the current knowledge and attitudes of GPs in the UK in respect of prescribing costs, and examined the influence of various developments in general practice since 1986 on the accuracy of drug price estimation. 1000 randomly selected GP principals (500 in Scotland and 125 in each of 4 English health regions) were sent a postal questionnaire. The GPs' level of agreement with 5 statements concerned with prescribing costs, and the accuracy of their estimates of the basic price of 31 drugs, were analysed. Most GPs (71%) agreed that prescribing costs should be taken into account when deciding on the best treatment for patients. Fundholders were more likely than non-fundholders: (i) to agree that prescribing costs could be reduced without affecting patient care; (ii) to agree that providing more information on costs would lower the cost of prescribing; and (iii) to comment that cost guidelines had changed their prescribing habits. Fundholders were less likely than non-fundholders to reject the principle of fixed limits on prescribing costs. Overall, one-third of the price estimates given were accurate (within 25% of the actual cost). For the most expensive drugs in the survey [those priced over 10 pounds sterling (Pound) per pack], half of the price estimates were accurate. There were significant differences between non-fundholders' and fundholders' estimates of the price of less expensive drugs (those priced at less than 10 pounds per pack). Use of a formulary or computer-displayed drug price information did not affect the accuracy of price estimates. It may be that GPs who were more knowledgeable and concerned about costs were more likely to become fundholders. It is also possible that the expansion of fundholding, or other mechanisms that give GPs responsibility for resource allocation, might improve accurate cost awareness in prescribing. Clinical and economic review of repeat prescribing is recommended.

Cost-Benefit Analysis↗
PubMed1997

Bordetella pertussis-specific Th1/Th2 cells generated following respiratory infection or immunization with an acellular vaccine: comparison of the T cell cytokine profiles in infants and mice.

In an investigation of cell-mediated immunity against Bordetella pertussis, we found that B. pertussis infection in infants and in mice was associated with the induction of antigen-specific T cells that secrete IFN-g and IL-2, but not IL-4 or IL-5. This cytokine profile is characteristic of Th1 cells that mediate cellular immune responses against a range of intracellular pathogens. An examination of cytokine production following immunization with a three-component acellular vaccine, comprising inactive PT, FHA and pertactin adsorbed to alum, demonstrated that spleen cells from vaccinated mice produced high levels of IL-5, but no detectable IFN-g and low levels of IL-2. In contrast, peripheral blood mononuclear cells from vaccinated infants produced IL-2, IL-5 and IFN-g. These findings highlight significant differences in the immune responses generated by vaccination and natural infection with B. pertussis and demonstrate that the T-cell response induced with an acellular vaccine, although dominated by type 2 cytokines in mice, is more heterogeneous in infants with a Th0 or mixed Th1/Th2 cytokine profile.

Adult↗
PubMed1996

Synthesis, structure-activity relationships, and the effect of polyethylene glycol on inhibitors of phosphatidylinositol-specific phospholipase C from Bacillus cereus.

Substrate analog inhibitors of Bacillus cereus phosphatidylinositol-specific phospholipase C (PI-PLC) were synthesized and screened for their suitability to map the active site region of the enzyme by protein crystallography. Analogs of the natural substrate phosphatidylinositol (PI) were designed to examine the importance of the lipid portion and the inositol phosphate head group for binding to the enzyme. The synthetic compounds contained pentyl, hexyl, or hexanoyl and octyl lipid chains at the sn-1 and sn-2 positions of the glycerol backbone and phosphonoinositol, phosphonic acid, methyl phosphonate, phosphatidic acid, or methyl phosphate at the sn-3 position. The most hydrophobic compound, dioctyl methyl phosphate 14, was also the best inhibitor with an IC50 of 12 microM. In a series of dihexyl lipids, compounds with phosphonoinositol head groups inhibited more strongly than those that do not contain inositol but are otherwise identical. Compound 29, a short-chain lipid with a phosphonoinositol head group, was found to be a competitive inhibitor and the most potent in this series with an IC50 of 18 microM (Ki = 14 microM). Analogs with dihexyl chains were better inhibitors than those with dihexanoyl chains, presumably because the ether-linked lipids are more hydrophobic than the ester-linked lipids. No appreciable difference in inhibition was found between a phosphonoinositol lipid and the corresponding difluorophosphonoinositol lipid. Inositols and inositol derivatives that do not contain lipid moieties show IC50s about 3 orders of magnitude above those of the short-chain lipids. In this group, glucosaminyl(alpha 1-->6)-D-myo-inositol inhibited more strongly than myo-inositol, which in turn is a better inhibitor than inositol phosphate. The addition of polyethylene glycol (PEG-600) resulted in a marked decrease in inhibition by the short-chain lipids, but had little effect on the water-soluble head group analogs. This is accounted for in terms of solubilization of the amphipathic inhibitors by PEG. Since PEG is required in the crystallization, these data indicate that the best strategy for obtaining enzyme inhibitor complexes is to start by cocrystallizing PI-PLC with the head group analogs. The next step is to synthetically add the shortest possible hydrophobic moieties to the analogs and cocrystallize these with the enzyme. This strategy may be applicable to other lipolytic enzymes.

Bacillus cereus↗
PubMed1996

Crystal structure of phosphatidylinositol-specific phospholipase C from Bacillus cereus in complex with glucosaminyl(alpha 1-->6)-D-myo-inositol, an essential fragment of GPI anchors.

Numerous proteins on the external surface of the plasma membrane are anchored by glycosylated derivatives of phosphatidylinositol (GPI), rather than by hydrophobic amino acids embedded in the phospholipid bilayer. These GPI anchors are cleaved by phosphatidylinositol-specific phospholipases C (PI-PLCs) to release a water-soluble protein with an exposed glycosylinositol moiety and diacylglycerol, which remains in the membrane. We have previously determined the crystal structure of Bacillus cereus PI-PLC, the enzyme which is widely used to release GPI-anchored proteins from membranes, as free enzyme and also in complex with myo-inositol [Heinz, D.W., Ryan, M. Bullock, T.L., & Griffith, O. H. (1995) EMBO J. 14, 3855-3863]. Here we report the refined 2.2 A crystal structure of this enzyme complexed with a segment of the core of all GPI anchors, glucosaminyl(alpha 1-->6)-D-myo-inositol [GlcN-(alpha 1-->6)Ins ]. The myo-inositol moiety of GlcN(alpha 1-->6)Ins is well-defined and occupies essentially the same position in the active site as does free myo-inositol, which provides convincing evidence that the enzyme utilizes the same catalytic mechanism for cleavage of PI and GPI anchors. The myo-inositol moiety makes several specific hydrogen bonding interactions with active site residues. In contrast, the glucosamine moiety lies exposed to solvent at the entrance of the active site with minimal specific protein contacts. The glucosamine moiety is also less well-defined, suggesting enhanced conformational flexibility. On the basis of the positioning of GlcN(alpha 1-->6)Ins in the active site, it is predicted that the remainder of the GPI-glycan makes little or no specific interactions with B. cereus PI-PLC. This explains why B. cereus PI-PLC can cleave GPI anchors having variable glycan structures.

Bacillus cereus↗
PubMed1996

Heat-resistant factors in human erythrocyte membranes mediate CD4-dependent fusion with cells expressing HIV-1 envelope glycoproteins.

It has been shown that human CD4 expressed in nonhuman cells does not support HIV-1 entry into those cells and that components from human cells in addition to CD4 are required to overcome the block. We have used human red blood cells (huRBC) as a source for the accessory components since their membrane composition is less complex than that of nucleated cells and they are well characterized. Components were transferred by fusion of huRBC to nonhuman CD4(+) cells mediated by influenza hemagglutinin or polyethylene glycol. The RBC-modified nonhuman CD4(+) cells were labeled with fluorescent markers and incubated with gp 120-gp41-expressing cells labeled with a different fluorescent probe. Fusion between RBC- modified nonhuman CD4(+) cells and gp 120--gp41-expressing cells was quantified by fluorescence video microscopy. Human erythrocyte components transferred to nonhuman CD4+ cells conferred HIV-1 envelope glycoprotein-mediated fusion susceptibility to those cells. The fusion was enhanced by pretreatment of the erythrocytes for 10 min at 56 degrees. No gp 120--gp41-mediated fusion was observed when components from nonhuman RBC were transferred to nonhuman CD4+ cells. Human cell lines with pre-RBC characteristics (K562-CD4) also supported HIV-1 envelope glycoprotein-mediated fusion.

Animals↗
PubMed1996

Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome.

BACKGROUND: The genetic basis of Gilbert's syndrome is ill-defined. This common mild hyperbilirubinaemia sometimes presents as an intermittent jaundice. A reduced hepatic bilirubin UPD- glucuronosyltransferase (UGT) is associated with this syndrome. We have examined variation in the gene encoding the UGT1*1 enzyme and serum bilirubin levels in a Scottish population. METHODS: Blood was collected from 12 patients with confirmed or suspected Gilbert's syndrome, from 6 members of a family with 4 Gilbert members, and from 77 non-smoking, alcohol-free, drug-free volunteers recruited from the staff of a teaching hospital in Dundee. Polymerase chain reaction amplification was used to examine sequence variation of the promoter upstream of the UGT1*1 exon I. Genotypes were assigned as follows: 6/6 (homozygous for a common allele bearing the sequence [TA](6)TAA), 7/7 (homozygous for a rarer allele with the sequence [TA](7)TAA), and 6/7 (heterozygous with one of each allele). FINDINGS: Individuals in the population with the 7/7 genotype had significantly higher bilirubin concentrations than those who had the 6/7 or 6/6 genotype. 14 volunteers underwent a 24 h fasting test to see if they had Gilbert's syndrome, and all four positives had the 7/7 genotype. One confirmed Gilbert's patient, two recurrent jaundice patients (with suspected Gilbert's syndrome), and nine clinically diagnosed cases had the 7/7 genotype. Segregation of the 7/7 genotype with the Gilbert phenotype was also demonstrated in the family with four affected members. The frequency of the 7/7 genotype in this eastern Scottish population was 10-13%. INTERPRETATION: In a healthy population there was an association between variation in bilirubin concentration and a mutation within the gene encoding the enzyme bilirubin UGT. This and other findings suggest the existence of a mild and a more severe form of Gilbert's syndrome, depending on whether the gene defect lies in the promoter sequence upstream of UGT1*I exon I, as here (mild), or in the coding sequence (severe) of the gene.

Adult↗
PubMed1996

Dependence of tissue oxygen on oxygen delivery.

The viability of tissue flaps depends on adequate blood flow and oxygenation. To help ensure oxygen delivery, increased inspired oxygen is often provided. This study uses a porcine model to measure tissue oxygen (TPO2) in a muscle flap, in response to varying levels of inspired oxygen concentration (FiO2). Six swine underwent the creation of a latissimus dorsi island flap. An ultrasonic flow probe was used to monitor afferent flow through the thoracodorsal artery, and a 20-ga fluorescence-quenching optode was employed to monitor TPO2. Additional optodes were inserted in muscle of an ipsilateral hindlimb, and in the terminal ileum. Inspired oxygen concentration was varied from 15 to 100%, and oxygen delivery variables measured. Analysis of variance and multiple linear regression were used to determine which variables had the greatest effect on TPO2. All three sites varied directly with inspired oxygen concentration. Flap TPO2 had a strong dependence on FiO2 and local oxygen delivery (r2 = 0.54). PaO2 and hemoglobin were the most significant determinants of ileal submucosal TPO2 (r2 = 0.65). A correlation between average submucosal and flap TPO2 was observed (r > 0.9, P < 0.05). We conclude that (1) muscle flap and bowel TPO2 vary directly with inspired FiO2, (2) changes in ileal submucosal TPO2 correlate with those observed in muscle, and (3) monitoring of readily accessible muscle TPO2 merits further investigation to evaluate the status of TPO2 in critical visceral beds.

Animals↗
PubMed1996

Surgical outcome in acquired immunodeficiency syndrome patients with non-Hodgkin's lymphoma of the gastrointestinal tract.

PURPOSE: Incidence of non-Hodgkin's lymphoma (NHL) has shown a dramatic increase, concurrent with the epidemic of acquired immunodeficiency syndrome (AIDS). In terms of surgical intervention, management of the patient with AIDS-NHL remains unclear. Purpose of this paper was to determine the role and outcome of surgical intervention in patients with AIDS-NHL of the gastrointestinal (GI) tract. METHODS: Data were obtained by retrospective chart review. RESULTS: From 1980 to 1993, charts of 22 patients with diagnosis of AIDS-NHL of the GI tract who underwent either biopsy or surgical procedure were reviewed. All patients were male, with a mean age of 35.7 years. Sixty-seven biopsies were performed in the 22 patients identified. No morbidity or mortality was associated with any of the biopsy procedures. Major intra-abdominal operations were performed in eight patients, including seven who underwent primary resections of lymphomas. Mean survival for the group as a whole was 18 months, although that for the seven patients undergoing resection was 20.4 months. CONCLUSIONS: Diagnosis of AIDS-NHL of the GI tract should not discourage performance of otherwise appropriate surgical procedures.

Adult↗