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Biomedical subjects

D Simpson

Publications and source records attributed to D Simpson.

At least 55 records · Page 3Linked to original sources
PubMed2001

Individualized heparin and protamine management in infants and children undergoing cardiac operations.

BACKGROUND: Measurements of activated coagulation time do not correlate with plasma concentration of heparin. This study investigated the effects of a patient-specific method to manage anticoagulation and its reversal in pediatric patients undergoing cardiopulmonary bypass. METHODS: Infants and children were randomly assigned to receive either a standard dose of heparin (300 IU/kg; group C, n = 13) or an individualized dose, calculated by an in vitro heparin dose-response test (group HC, n = 13). Protamine dose was based on a 1 mg/l mg ratio of total administered heparin for patients in group C and of the residual heparin concentration in group HC. RESULTS: Administered heparin was significantly higher and total protamine dose was significantly reduced in the HC group (both p < or = 0.001). There was less thrombin generation (p = 0.02) and fibrinolysis (p = 0.05) in group HC. Blood loss and requirement for transfusion of blood and fresh frozen plasma were also lower in group HC (all p < or =0.05). CONCLUSIONS: An individualized management of anticoagulation and its reversal results in less activation of the coagulation cascade, less fibrinolysis, and reduced blood loss and need for transfusions. Further studies are warranted to better define the clinical impact of these findings.

Anticoagulants↗
PubMed2001

Effectiveness of an intervention to reduce HIV transmission risks in HIV-positive people.

BACKGROUND: As many as one in three HIV-positive people continue unprotected sexual practices after learning that they are HIV infected. This article reports the outcomes of a theory-based intervention to reduce risk of HIV transmission for people living with HIV infection. METHODS: Men (n=233) and women (n=99) living with HIV-AIDS were randomly assigned to receive either (1) a five-session group intervention focused on strategies for practicing safer sexual behavior, or (2) a five-session, contact-matched, health-maintenance support group (standard-of-care comparison). Participants were followed for 6 months post-intervention. RESULTS: The intervention to reduce risk of HIV transmission resulted in significantly less unprotected intercourse and greater condom use at follow-up. Transmission-risk behaviors with non-HIV-positive sexual partners and estimated HIV transmission rates over a 1-year horizon were also significantly lower for the behavioral risk-reduction intervention group. CONCLUSIONS: This study is among the first to demonstrate successful HIV-transmission risk reduction resulting from a behavioral intervention tailored for HIV-positive men and women.

Adaptation, Psychological↗
PubMed2001

Peptide phage display library as source for inhibitors of clostridial neurotoxins.

Clostridial neurotoxins are the most powerful toxins known. There are no available antidotes to neutralize neurotoxins after they have been internalized by neuronal cells. Enzymatic domains of clostridial neurotoxins are zinc-endopeptidases specific for protein components of the neuroexocytosis apparatus. Thus, attempts were made to find such antidotes among molecules possessing chelating properties. Subsequently, it was proposed that the process of interaction between clostridial neurotoxins and their substrates might be more complex than viewed previously and may include several separate regions of interaction. Phage display technology is free from bias toward any particular model. This technology in combination with recombinantly produced light chains of botulinum neurotoxins serotypes A, B, and C was used to identify potential inhibitors of clostridial neurotoxins. Identified sequences did not show substantial similarity with substrate proteins of clostridial neurotoxins. Nevertheless, three peptides chosen for further analysis were able to inhibit enzymatic activity of all clostridial neurotoxins tested. This work demonstrates that at least one of these peptides could not be cleaved by clostridial neurotoxin. Attempts to delete amino acid residues from this peptide resulted in dramatic loss of its inhibitory activity. Finally, this work presents a novel approach to searching for inhibitors of clostridial neurotoxins.

Amino Acid Sequence↗
PubMed2001

A rapid flow cytometric assay to detect CD4+ and CD8+ T-helper (Th) 0, Th1 and Th2 cells in whole blood and its application to study cytokine levels in atopic dermatitis before and after cyclosporin therapy.

BACKGROUND: The immune response in atopic dermatitis (AD) is thought to be driven by T-helper (Th) 2 cytokines. Using flow cytometry, higher frequencies of peripheral blood CD4+ and CD8+ T cells producing interleukin (IL)-4 and correspondingly lower frequencies of CD4+ T cells producing interferon (IFN)-gamma have been found in patients with AD compared with healthy controls. It would be of interest to know whether other Th1 and Th2 cytokines such as IL-5, IL-13 and tumour necrosis factor (TNF)-alpha are similarly skewed in patients with AD and whether this immune skewing, detected via a simple blood assay, can be correlated with other clinical measurements or treatments in AD. OBJECTIVES: To use a rapid (4-h) flow cytometric assay to study a wide range of Th1 and Th2 cytokine patterns in peripheral blood lymphocytes from patients with AD, comparing them with non-atopic healthy controls. To correlate cytokine patterns with the degree of eosinophilia observed and in the case of one patient with severe disease, to observe the effect of cyclosporin therapy on peripheral blood cytokine patterns. METHODS: Peripheral blood from eight patients with AD and 23 healthy controls was examined for the frequencies of CD4+ and CD8+ T cells expressing IL-2, IL-4, IL-5, IL-13, IFN-gamma and TNF-alpha using flow cytometry. RESULTS: Significantly higher frequencies of CD4+/IL-4+ (P < 0.005) and CD4+/IL-13+ (P < 0.0001) and lower frequencies of CD4+/IFN-gamma+ (P < 0.002) and CD8+/TNF-alpha+ (P < 0.05) T lymphocytes were found in patients with AD compared with controls. There were significant positive correlations with the increased percentages of CD4+/IL-4+ and CD4+/IL-13+ T lymphocytes and the degree of eosinophilia observed (P < 0.05, P < 0.001) and a negative correlation between the percentage of CD4+/IFN-gamma+ T lymphocytes and eosinophilia (P < 0.05). In one patient examined before and 8 days after cyclosporin therapy, 50% or greater reductions were observed in percentages of peripheral blood CD8+/IL-5+, CD8+/IL-13+, CD4+/IL-4+ and CD4+/IL-5+ T lymphocytes following cyclosporin therapy. A smaller reduction of 15% after cyclosporin therapy was found in percentages of CD4+/IL-13+ T cells. CONCLUSIONS: These data strongly support a Th2 predominance in the peripheral blood of AD. The results suggest that administration of cyclosporin therapy in patients with AD may help to restore the Th2 cytokine imbalance seen in these patients.

Adult↗
PubMed2001

Characterization and localization of expression of an erythropoietin-induced gene, ERIC-1/TACC3, identified in erythroid precursor cells.

Gene expression profiles during erythropoietin (Epo)-induced differentiation of erythroid progenitor cells derived from the Friend virus anaemia (FVA) and phenylhydrazine (PHZ) murine models have been examined using differential display polymerase chain reaction (PCR). Ten cDNA fragments upregulated by Epo were isolated. The ribonuclease protection assay confirmed differential expression between Epo-stimulated and Epo-deprived cells for one of these, provisionally named ERIC-1. Sequencing of the full-length cDNA predicted a protein of 558 amino acids, 17 amino acids longer than mTACC3, the third member of a novel family of proteins that contain a coiled-coil domain. The human homologue, cloned using rapid amplification of cDNA ends (RACE)-PCR, encodes a larger protein of 838 amino acids that is identical to hTACC3. In addition to erythroid precursor cells, ERIC-1/TACC3 is expressed at high levels in the testes, at moderate levels in the thymus and peripheral leucocytes, and at lower levels in the spleen and intestinal tissue. Immunohistochemical analysis using an antibody to a GST fusion product of the C-terminus of hERIC-1/TACC3 revealed that it is localized to Sertoli cells in the human testes. Confocal microscopy demonstrated hERIC-1/TACC3 protein concentrated in the perinuclear vesicles of dermal microvascular endothelial cells. Although ERIC-1/TACC3 is expressed in a wide range of tissues, its upregulation by Epo in erythroid progenitors implies that it has a role in terminal erythropoiesis.

Amino Acid Sequence↗
PubMed2001

Mallet deformity in sport.

During a four month period 851 patients presented to the Edinburgh Orthopaedic Trauma Unit with an acute sporting injury. Eighteen (2%) patients had either a soft tissue or bony mallet deformity. Six different sports were identified with rugby accounting for eight of the 18 mallet deformities. All patients were treated with splintage. Fourteen patients returned questionnaires regarding subjective digit function following treatment and nine patients claimed excellent function. The average splinting time for this group was 6 weeks and sports were avoided for an average of 5 weeks. Mallet deformity accounts for a minority of sporting injuries, but excellent functional outcome can be achieved with splintage and avoidance of the causative sport while splinted.

Adolescent↗
PubMed2001

Dermal injection of radioactive colloid is superior to peritumoral injection for breast cancer sentinel lymph node biopsy: results of a multiinstitutional study.

OBJECTIVE: To determine the optimal radioactive colloid injection technique for sentinel lymph node (SLN) biopsy for breast cancer. SUMMARY BACKGROUND DATA: The optimal radioactive colloid injection technique for breast cancer SLN biopsy has not yet been defined. Peritumoral injection of radioactive colloid has been used in most studies. Although dermal injection of radioactive colloid has been proposed, no published data exist to establish the false-negative rate associated with this technique. METHODS: The University of Louisville Breast Cancer Sentinel Lymph Node Study is a multiinstitutional study involving 229 surgeons. Patients with clinical stage T1-2, N0 breast cancer were eligible for the study. All patients underwent SLN biopsy, followed by level I/II axillary dissection. Peritumoral, subdermal, or dermal injection of radioactive colloid was performed at the discretion of the operating surgeon. Peritumoral injection of isosulfan blue dye was performed concomitantly in most patients. The SLN identification rates and false-negative rates were compared. The ratios of the transcutaneous and ex vivo radioactive SLN count to the final background count were calculated as a measure of the relative degree of radioactivity of the nodes. One-way analysis of variance and chi-square tests were used for statistical analysis. RESULTS: A total of 2,206 patients were enrolled. Peritumoral, subdermal, or dermal injection of radioactive colloid was performed in 1,074, 297, and 511 patients, respectively. Most of the patients (94%) who underwent radioactive colloid injection also received peritumoral blue dye injection. The SLN identification rate was improved by the use of dermal injection compared with subdermal or peritumoral injection of radioactive colloid. The false-negative rates were 9.5%, 7.8%, and 6.5% (not significant) for peritumoral, subdermal, and dermal injection techniques, respectively. The relative degree of radioactivity of the SLN was five- to sevenfold higher with the dermal injection technique compared with peritumoral injection. CONCLUSIONS: Dermal injection of radioactive colloid significantly improves the SLN identification rate compared with peritumoral or subdermal injection. The false-negative rate is also minimized by the use of dermal injection. Dermal injection also is associated with SLNs that are five- to sevenfold more radioactive than with peritumoral injection, which simplifies SLN localization and may shorten the learning curve.

Breast Neoplasms↗
PubMed2001

Defining the optimal surgeon experience for breast cancer sentinel lymph node biopsy: a model for implementation of new surgical techniques.

OBJECTIVE: To determine the optimal experience required to minimize the false-negative rate of sentinel lymph node (SLN) biopsy for breast cancer. SUMMARY BACKGROUND DATA: Before abandoning routine axillary dissection in favor of SLN biopsy for breast cancer, each surgeon and institution must document acceptable SLN identification and false-negative rates. Although some studies have examined the impact of individual surgeon experience on the SLN identification rate, minimal data exist to determine the optimal experience required to minimize the more crucial false-negative rate. METHODS: Analysis was performed of a large prospective multiinstitutional study involving 226 surgeons. SLN biopsy was performed using blue dye, radioactive colloid, or both. SLN biopsy was performed with completion axillary LN dissection in all patients. The impact of surgeon experience on the SLN identification and false-negative rates was examined. Logistic regression analysis was performed to evaluate independent factors in addition to surgeon experience associated with these outcomes. RESULTS: A total of 2,148 patients were enrolled in the study. Improvement in the SLN identification and false-negative rates was found after 20 cases had been performed. Multivariate analysis revealed that patient age, nonpalpable tumors, and injection of blue dye alone for SLN biopsy were independently associated with decreased SLN identification rates, whereas upper outer quadrant tumor location was the only factor associated with an increased false-negative rate. CONCLUSIONS: Surgeons should perform at least 20 SLN cases with acceptable results before abandoning routine axillary dissection. This study provides a model for surgeon training and experience that may be applicable to the implementation of other new surgical technologies.

Breast Neoplasms↗
PubMed2001

Short report: Hyperammonaemia in critically ill septic infants.

Three infants with subphrenic abscess, pyonephrosis, and obstructive ureterocoele respectively had grossly increased concentrations of plasma ammonia. This was considered to be a result of infections with urea splitting organisms. All died in spite of intensive care support, including specific measures to reduce plasma ammonia.

Ammonia↗
PubMed2001

Tresperimus: a new agent for transplant tolerance induction.

Tresperimus is a novel agent that induces allogeneic transplant tolerance. It is structurally related to deoxyspergualin (DSG) but has been modified to resist rapid hydrolysis in aqueous solution, which simplifies administration. Despite this modification, tresperimus's actions in experimental models seem almost identical to DSG. Initially, DSG was developed as an antitumour agent. Its antitumour efficacy appears limited but DSG and tresperimus have favourable effects on transplant rejection. A short course of tresperimus has been shown to have similar or greater quantitative effects to cyclosporin in bone marrow, cardiac and skin transplant models. However, qualitatively the effects are different. Prevention of rejection is due to induction of donor-specific tolerance without affecting immunity to third party antigens. In addition, CD4+ T-cells from tresperimus-treated animals can transfer donor specific tolerance to naïve animals, an effect not seen with cyclosporin or other traditional immunosuppressive drugs. The mechanism by which tolerance is induced is not clear. Tresperimus (like DSG) binds to Hsc70, which among other effects inhibits nuclear localisation of NF-kappa B. NF-kappa B nuclear localisation is induced by CD40 ligation in antigen-presenting cells, an important early step in T-cell co-stimulation. NF-kappa B is also required for CD28 ligation signalling, important in late co-stimulation. It also is involved in B-cell activation, via CD40 ligation and kappa light chain production. Hsc70 is also required for efficient cytosolic peptide chaperoning to MHC class I molecules. Presumably, it is disruption of T-cell/dendritic cell interaction that leads to induction of T-cell anergy. Tresperimus is well-tolerated. The main dose limiting side effects are orthostatic hypotension and peri-oral numbness. These effects are dependant on blood drug levels and, due to its short half-life, correspond to the rate of infusion. Phase II/III clinical studies are accruing patients and results have not yet been reported. Tresperimus shows promise in the move from immunosuppression to tolerance induction as the way to prevent transplant rejection and graft versus host disease (G v HD). However, its role in tolerance induction and effect in combination with other tolerance inducing agents e.g., CTLA-4-Ig and anti-CD40L antibodies remains unclear.

Animals↗
PubMed2001

New developments in the prophylaxis and treatment of graft versus host disease.

Graft versus host disease (GVHD) remains the major obstacle to successful allogeneic bone marrow transplantation. Cyclosporin with methotrexate is the most common prophylactic regimen. Tacrolimus is associated with less GVHD and is gaining ground especially in unrelated donor transplants where current regimens are unsatisfactory. Mycophenolate mofetil (MMF) and rapamycin have not yet shown benefit in acute GVHD prophylaxis. In vivo T-cell depletion with Campath 1H or thymoglobulin used during transplant conditioning are increasingly used in place of ex vivo T-cell depletion, where results remain disappointing. Steroids remain first choice for therapy of GVHD but anti-CD25 antibodies, daclizumab or basiliximab are gaining popularity as second-line therapy ahead of ATG. Chronic GVHD is increasing with greater use of peripheral blood stem cell grafts and older patients. The combination of tacrolimus and MMF is promising for patients with extensive disease. Tolerance induction using CTLA-4-Ig, anti-CD40L, tresperimus and/or rapamycin may revolutionise GVHD therapy. However, due to the desirability of tumour intolerance, tolerance is likely to be developed in organ transplantation before bone marrow transplantation for traditional indications. Bone marrow transplants performed to induce organ tolerance may see increasing use of these agents. TNF blockade using infliximab or etanercept (Enbrel) is promising but the role of these agents is not yet defined.

Abatacept↗