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Biomedical subjects

A Dunn

Publications and source records attributed to A Dunn.

At least 19 recordsLinked to original sources
PubMed2006

Prevention and treatment of musculoskeletal disease in the haemophilia population: role of prophylaxis and synovectomy.

Prophylaxis is defined as primary (started before the onset of joint damage) or secondary (started after the onset of joint damage). The aim of primary prophylaxis is to prevent recurrent bleeding into joints and the development of chronic arthropathy in later life. When started early, and at most after two joint bleeds, the result is predictably excellent if there is compliance with the primary prophylaxis regimen. In order to decrease the need for central venous access devices to assure reliable venous access, a number of centres start primary prophylaxis with once weekly infusions with dose-escalation based on frequency of joint bleeding. A major unanswered question is whether primary prophylaxis can be safely discontinued in adolescents/young adults and if so, when. A promising predictor for the milder bleeding phenotype in persons with severe haemophilia is a later onset of joint bleeding. Once joint damage has occurred as a result of recurrent bleeding, secondary prophylaxis can only retard, but not prevent, ongoing joint damage. Other strategies to decrease recurrent bleeding from target joints include surgical synovectomy (ideally performed using an arthroscopic technique), radionuclide synovectomy and chemical synovectomy. These interventions have very good outcomes when performed by an experienced team. Given the very high cost of factor concentrates required for programmes of prophylaxis prospective studies that document benefits to the child and family, e.g. quality of life are to be encouraged.

Hemarthrosis↗
PubMed2005

Complete genome sequence of Vibrio fischeri: a symbiotic bacterium with pathogenic congeners.

Vibrio fischeri belongs to the Vibrionaceae, a large family of marine gamma-proteobacteria that includes several dozen species known to engage in a diversity of beneficial or pathogenic interactions with animal tissue. Among the small number of pathogenic Vibrio species that cause human diseases are Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus, the only members of the Vibrionaceae that have had their genome sequences reported. Nonpathogenic members of the genus Vibrio, including a number of beneficial symbionts, make up the majority of the Vibrionaceae, but none of these species has been similarly examined. Here we report the genome sequence of V. fischeri ES114, which enters into a mutualistic symbiosis in the light organ of the bobtail squid, Euprymna scolopes. Analysis of this sequence has revealed surprising parallels with V. cholerae and other pathogens.

Aliivibrio fischeri↗
PubMed2003

Threshold effects of glucose transporter-4 (GLUT4) deficiency on cardiac glucose uptake and development of hypertrophy.

The aim of this study was to investigate the metabolic and structural consequences of a decrease in glucose transporter-4 (GLUT4) levels on the heart. The CreLoxP system was utilised to delete GLUT4 in muscle tIssue including heart. The presence of the PGK-neoR cassette in the GLUT4-Lox mice resulted in reduced expression in all tIssues to levels 15-30% of wild-type control mice. In mice expressing Cre recombinase, there was a further reduction of GLUT4 in cardiac tIssue to almost undetectable levels. Cardiac glucose uptake was measured basally and during a euglycaemic/hyperinsulinaemic clamp using 2-deoxy-[1-(14)C]glucose. Insulin-stimulated glucose uptake was normal in hearts expressing 15% of normal GLUT4 levels but markedly reduced in mice with more profound reduction in GLUT4. Cardiac enlargement occurred only when GLUT4 levels were less than 5% of normal values. In heart there is a threshold level of GLUT4 above which insulin-stimulated glucose uptake is maintained. As little as 5% of normal GLUT4 levels expressed in heart is sufficient to prevent the development of cardiac hypertrophy.

Animals↗
PubMed2001

Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure.

This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at scientific sessions of the American Heart Association in November 2000. Clinical studies of particular interest to people caring for patients with heart failure include Val-HeFT, AMIOVIRT and V-MAC. New data from beta-blockers trials are reviewed, highlights from some important developments in post-infarction care, including MIRACL and FLORIDA, discussed and results of some early studies of gene therapy reported.

Animals↗
PubMed2001

Clinical trials update: Highlights of the Scientific Sessions of Heart Failure 2001, a meeting of the Working Group on Heart Failure of the European Society of Cardiology. CONTAK-CD, CHRISTMAS, OPTIME-CHF.

This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at Scientific Sessions of Heart Failure 2001, a meeting of the Working Group on Heart Failure of the European Society of Cardiology. Clinical studies of particular interest to people caring for patients with heart failure include CONTAK-CD, CHRISTMAS and further updates on OPTIME-CHF. A brief review of the current status of cardiac resynchronisation therapy is included.

Cardiology↗
PubMed2001

A placebo controlled evaluation of the antifibrillatory effects of carvedilol.

This article evaluates the antifibrillatory effects of carvedilol 5 mg/kg and vehicle (dimethyl-formamide) over time. Sprague-Dawley rats were anesthetized and intubated. They underwent baseline ventricular fibrillation threshold (VFT) determination and then received 1 of the 2 treatments (n = 10/group) over 8 minutes. VFT and determinations were performed at 2, 7, 15, 30, 45, and 60 minutes postinfusion. Carvedilol significantly increased the VFT at 2, 7, 15, 30 minutes versus baseline and the vehicle control group. Carvedilol significantly reduced the heart rate and the mean arterial pressure at every evaluable time point versus baseline and vehicle control. Carvedilol showed significant antifibrillatory effects versus baseline and vehicle for the first 30 minutes but not thereafter, even though the heart rate and mean arterial pressure remain significantly reduced.

Adrenergic beta-Antagonists↗
PubMed2000

Gene inactivation by multiphoton-targeted photochemistry.

Multiphoton-targeted photochemistry was used to selectively inactivate the expression of genes in vertebrate cells. A membrane permeable DNA-associating vital dye, ethidium bromide monoacetate (visible wavelength single photon absorption peak at 530 nm) was used to photosensitize chromosomes in dividing cells. A 100-ps infrared laser beam operating at 1.06 microns was focused onto a selected region of a mitotic chromosome corresponding to the sites of the nucleolar (ribosomal) genes. Individual cells followed through mitosis demonstrated a reduction in the number of nucleoli formed in daughter cells that corresponded to the number of nucleolar genes sites irradiated. These results demonstrate the ability to selectively manipulate genes by using the focal point specificity characteristic of multiphoton microscopy. This technique should have wide biotechnology applications both in vitro and in vivo.

Animals↗
PubMed2000

Identification of an HLA-B7 serological variant and its characterization by sequencing based typing.

We have identified an HLA-B*07 variant allele, B*0716, in a Caucasoid cadaver kidney donor. The HLA class I type by polymerase chain reaction using sequence-specific primers (PCR-SSP) was A*01, 32; B*07, 08; Cw*07. Serological typing, using monoclonal and polyclonal anti-HLA antisera, gave disparate results for the B antigens. Monoclonal antibodies identified B7 and B8 antigens but polyclonal antisera recognised only the B8 antigen. PCR using sequencing based typing (PCR-SBT) confirmed the presence of both B*0703 and B*0801 alleles but with a mutation in one of the alleles. The HLA-B*07 allele was isolated by allele-specific PCR and was shown to have a mutation, G-->T, at 292 in exon 2. This mutation changes codon 74, which encodes aspartic acid (GAC) present in all previously identified B*07 alleles, to tyrosine (TAC) in the variant. The serological results suggest that codon 74 is a crucial part of a B7 antigen-specific epitope recognised by tissue typing polyclonal antisera.

Alleles↗
PubMed2000

Oral heparin (Emisphere).

Emisphere (formerly in collaboration with Elan) is developing an oral heparin formulation for the potential treatment of deep vein thrombosis (DVT). The formulation uses Emisphere's proprietary carrier molecule, P-414, and had started phase III trials by January 2000 [353372]. The protocol for the trials was finalized in December 1999, and aims to demonstrate the safety and superior efficacy of oral heparin dosed for 30 days post-operatively compared to injectable enoxaparin sodium for 10 days, in the prevention of DVT following hip-replacement surgery. The studies will take place in 95 centers in the US, UK and Canada, and are expected to enroll 2250 patients [350778]. The two trials involved are expected to be completed by mid-2001 [353372]. In May 1998, Emisphere initiated a phase II study for its oral heparin product for the prevention of DVT. The study had three arms of approximately 40 patients each, who had undergone surgery for hip replacement, and was conducted at approximately 20 sites in the US and Canada. Two different doses of oral heparin were compared to subcutaneous heparin. The objective was to demonstrate that the orally administered heparin is well tolerated and comparable to subcutaneous heparin in preventing DVT [288267]. Positive preliminary results were reported in January 1999, showing that the oral formulations were comparable to injectable heparin [311218]. Final results, reported in August 1999, demonstrated that heparin administered orally via a novel carrier system (P-414; SNAC) was comparable, in both safety and activity, to subcutaneous heparin when used to prevent venous thromboembolic events following elective hip arthroplasty [337262,337712]. The heparin formulation was developed as part of a collaboration between Emisphere and Elan investigating oral formulations of heparin and heparinoids. By January 1998, the lead product had completed four phase I trials in patients following knee and hip surgery [274905]. Results from phase I trials showed that the product was successfully absorbed after oral administration and changed blood clotting times, serum levels of antifactors IIa and Xa, and lipoprotein-associated coagulation inhibitor concentrations [254869,226042]. The study also showed that the dosing volume could be reduced to 15 ml/dose [274905]. P-414 was one of number of novel non-alpha-amino acids evaluated by Emisphere for potential use in the oral delivery of heparin. The compounds, which were mixed with heparin in the ratio 2:1 for oral administration, achieved therapeutic levels when administered to rats and primates [244542]. Emisphere also evaluated the use of these compounds for the oral delivery of low molecular weight (LMW) heparin in primates. One study used two carriers: SNAC and SNAD (sodium-N-amino decanoate), and showed that a combination of LMW heparin and SNAD could be delivered orally with a bioavailability of 38% relative to subcutaneous injection. SNAD was also 4-fold more effective than SNAC for oral heparin delivery [268737]. The technologies combine the CADDSYS and PODDS transmembrane delivery systems from Emisphere, with Elan's broad delivery technologies [194787]. Emisphere aims to enter a partnership in the first half of 2000 to explore the potential of the heparin formulation in other indications, such as cancer [353372]. In March 1997, Emisphere received a notice of allowance from the USPTO, for a composition of matter patent (US-05650386) for P- 414, the carrier used for the oral formulation of heparin [236336]. The joint venture agreement between Elan and Emisphere was established in 1996 to develop oral heparin formulations [302729]. However, in July 1999, Emisphere assumed full ownership of the technology and marketing rights for products arising from the collaboration, with complete responsibility for phase III development. Elan will receive future royalties based on product sales and has also committed to provide Emisphere with up to US 15 million dollars in loans as financial support for phase III studies [330658]. In April 2000, analysts at Chase H&Q predicted that Emisphere would sign a major profit-split partnership by mid-2000. It was also predicted that the drug would be launched in 2003, with first year sales of US 100 million dollars, rising to US 2.1 billlion dollars by 2012 [370980].

Journal Article↗
PubMed1999

Cost-effectiveness of amiodarone for prophylaxis of atrial fibrillation in coronary artery bypass surgery.

The cost-effectiveness of amiodarone prophylaxis of atrial fibrillation (AF) in patients undergoing coronary artery bypass grafting (CABG) was determined. A decision analysis using current hospital data and values from the literature was conducted. Under the base-case scenario, CABG patients received usual care (no prophylaxis) or 2 g of oral amiodarone hydrochloride over one to three days before surgery and 400 mg daily for seven days after surgery. Costs of hospitalization in the intensive care unit (ICU) and the cardiac step-down unit (SDU), cardioversion costs, electrocardiogram costs, drug costs, nursing administration charges, and pharmacy i.v. admixture charges were included. A sensitivity analysis using a Monte Carlo simulation and a one-way sensitivity analysis were performed. The mean cost per AF event avoided was lower in the amiodarone group ($15,750, 95% confidence interval [CI]: $15,591-$15,999) than the control group ($17,426,95% CI: $17,252-$17,600). A majority of the cost difference was due to the cost of hospitalization for patients without AF, the frequency of AF, and the cost of hospitalization in the SDU for patients with AF. For patients treated with amiodarone who did not develop AF, the cost difference was sensitive to changes in the cost of hospitalization and the efficacy of amiodarone. For patients who did develop AF, the cost difference was robust. Prophylaxis of AF with amiodarone in CABG patients was more cost-effective than usual care in the short term from a hospital perspective; the results were sensitive to changes in the cost of hospitalization of patients who did not develop AF and the efficacy of amiodarone.

Amiodarone↗
PubMed1999

An assessment of the safety of short-term amiodarone therapy in cardiac surgical patients with fentanyl-isoflurane anesthesia.

UNLABELLED: In previously published case reports and a retrospective study, investigators have noted that amiodarone may cause substantial hemodynamic instability when combined with fentanyl-containing anesthesia regimens. We performed the present study to evaluate the safety of short-term amiodarone therapy when combined with a fentanyl-containing anesthesia regimen in a randomized, double-blinded, placebo-controlled format. After institutional approval and written informed consent, patients scheduled to undergo coronary artery bypass grafting or valvular surgery were randomly allocated to receive amiodarone (3.4 g over 5 days or 2.2 g over 24 hours) or placebo before surgery. Four indicators for hemodynamic instability were assessed: 1) a net increase in fluid balance during surgery of >2 L; 2) use of dopamine at a rate >10 microg x kg(-1) x min(-1); 3) use of other vasopressive catecholamines; and 4) use of a phosphodiesterase inhibitor or intraaortic balloon pump. Systolic, diastolic, and central venous pressures were measured before fentanyl administration, before cardiopulmonary bypass (CPB), and after separation from CPB. Overall, 84 patients (45 patients in the amiodarone group, 39 in the placebo group) were enrolled and completed the study. There were no significant differences between the two groups in any indicator for hemodynamic instability or the indicators of instability combined. After CPB, there was a significantly lower systolic blood pressure in the amiodarone group compared with the placebo group (112 +/- 12 vs 117 +/- 14 mm Hg; P = 0.049). However, there was a trend toward smaller IV fluid requirements during surgery in the amiodarone group compared with the placebo group (438 +/- 867 vs 907 +/- 1640 mL; P = 0.09). We found no increased risk of hemodynamic compromise after short-term amiodarone therapy among patients receiving a fentanyl-containing anesthesia regimen during open heart surgery. IMPLICATIONS: In previous retrospective studies and case reports, investigators have identified a possible risk of hemodynamic compromise when patients receiving chronic amiodarone therapy are given anesthesia regimens containing fentanyl. We performed a prospective, randomized, double-blinded study to evaluate the hemodynamic effects of short-term amiodarone therapy during fentanyl-isoflurane anesthesia for open heart surgery. No adverse hemodynamic effects of amiodarone were identified.

Adjuvants, Anesthesia↗
PubMed1999

Transfer of behavioral intervention technology to a sexually transmitted disease clinic.

This article describes the authors' approach to introducing a behavioral counseling intervention into a local health department STD clinic setting. The goal of the intervention was to change the sexual practices of clients with STDs. The project was a collaborative effort with a local health department, school of public health, and a community training organization. The authors used an organizational change framework for implementing the intervention.

Adult↗
PubMed1999

An exploratory study of undergraduates' attributions of success or failure on spatial tests.

Seven spatial tests from the CTY Spatial Test Battery and four subscales of an attribution scale were administered to 23 female and 28 male undergraduates. Three hypotheses were tested. The seven spatial tests and three of the attribution subscales were found reliable; sex differences were found for the spatial tests but not the attribution scales; and subjects' attributions did not predict spatial performance.

Achievement↗
PubMed1998

Predicting graft-versus-host disease in HLA-identical bone marrow transplant: a comparison of T-cell frequency analysis and a human skin explant model.

BACKGROUND: Graft-versus-host disease (GVHD) occurring after HLA-identical sibling bone marrow transplantation (BMT) is considered to be mainly caused by minor histocompatibility antigen (mHag) disparities between the recipient and donor. In our laboratory, a human skin explant model has been successfully used to predict acute GVHD in HLA-identical sibling BMT. More recently, the frequency analysis of host-reactive helper and cytotoxic T lymphocyte precursors (HTLp and CTLp, respectively) has been shown to have potential application for predicting GVHD. In the present study, HTLp and CTLp frequency analysis and the skin explant model were directly compared for their ability to predict acute GVHD in HLA-identical sibling BMT. METHODS: Host-reactive HTLp and CTLp frequencies were determined using a combined limiting dilution assay. A human skin explant model was used to detect graft-versus-host reactions in vitro. The results from the skin explant model (graft-versus-host reaction grades I-IV) and T cell frequency analysis (>/< 1:100,000) were correlated with posttransplant GVHD outcome, respectively. RESULTS: The skin explant model correctly predicted GVHD outcome in 77% of cases (P=0.03). HTLp frequencies were very low in all patient/donor pairs tested. None of them exceeded 1:100,000, although 9/18 recipients developed GVHD (> or =clinical grade II) after transplant. In all patients tested, the relationship between either high (>1:100,000) or low (<1:100,000) CTLp frequency and occurrence of GVHD appeared to be random (P=1.0). CONCLUSIONS: HTLp and CTLp frequency analysis did not predict the occurrence of acute GVHD after HLA-identical sibling BMT. The human skin explant model, however, remained an accurate indicator of acute GVHD and probably detects mHag disparities.

Acute Disease↗
PubMed1998

Comparison of the allosteric properties of the Co(II)- and Zn(II)-substituted insulin hexamers.

The positive and negative cooperativity and apparent half-site reactivity of the Co(II)-substituted insulin hexamer are well-described by a three-state allosteric model involving ligand-mediated interconversions between the three states: T3T3' right harpoon over left harpoon T3o R3o right harpoon over left harpoon R3R3' [Bloom, C. R., Heymann, R., Kaarsholm, N. C., and Dunn, M. F. (1997) Biochemistry 36, 12746-12758]. Because of the low affinity of the T state for ligands, this model is defined by four parameters: LoA and LoB, the allosteric constants for the T3T3' to T3o R3o and the T3o R3o to R3R3' transitions, respectively, and the two dissociation constants for ligand binding to T3o R3o and to R3R3'. The d-d electronic transitions of the Co(II)-substituted hexamer give optical signatures of the T to R transition which can be quantified, but the "spectroscopically silent" character of Zn(II) has made previous attempts to describe the Zn(II) species difficult. This work shows that the T to R state conformational transitions of the Zn(II) hexamer can be easily quantified using the chromophore 4-hydroxy-3-nitrobenzoate (4H3N). When the chromophore is bound to the HisB10 sites of the R state, the absorption spectrum of 4H3N is red-shifted, exhibiting strong absorbance and CD signals, whereas 4H3N does not bind to the T state. Hence, 4H3N can be employed as a sensitive indicator of conformation under conditions that do not significantly disturb the T to R state equilibrium. Using 4H3N as an indicator, these studies show that both LoA and LoB are made less favorable by the substitution of Co(II) for Zn(II); LoA is increased by 10-fold while LoB by 35-fold, whereas the ligand affinities of the phenolic pockets are unchanged.

Allosteric Site↗