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Biomedical subjects

S C Clark

Publications and source records attributed to S C Clark.

At least 19 recordsLinked to original sources
PubMed2003

Laser flash photolysis of bismaleimides.

Bismaleimides containing between 2 and 12 methylene spacer units have been synthesized and characterized using laser flash photolysis spectroscopy. In the case of the monofunctional N-methylmaleimide, the 1,4-biradical was observed only at maleimide concentrations high enough to effectively quench the triplet state, indicating that the 1,4-biradical is Formed from self-quenching of the triplet excited state. The transient spectral features and the transient lifetimes of bismaleimides containing 2 and 9 methylene spacer units closely resemble those of N-methylmaleimide and are attributed to triplet-state transients. N,N'-Alkylenebismaleimides with 3 and 6 methylene spacer groups exhibit a transient with a very short lifetime attributed to a singlet 1,4-biradical species formed from intramolecular interaction. The absence of triplet spectra in these latter bismaleimides indicate that the 1,4-biradical is formed directly from the excited singlet state. The large difference in the lifetime of the 1,4-biradical formed in monofunctional maleimide solutions and bismaleimide solutions is reflective of differences in the biradical spin-state multiplicity. The bismaleimide with a 12 methylene spacer group exhibits transient spectra corresponding to both a triplet state of the maleimide and a 1,4-biradical formed by exo interaction of two maleimide groups. As a demonstration of the ability of acrylate monomers to react with the short-lived singlet biradicals, it is shown that the photopolymerization of a multifunctional acrylate monomer is readily initiated by the 1,4-biradical formed from the bismaleimides with 3 and 6 methylene spacer groups, presumably by direct reaction of the biradical with the acrylate.

Journal Article↗
PubMed2002

Effect of WBC reduction of transfused RBCs on postoperative infection rates in cardiac surgery.

BACKGROUND: WBC-replete blood transfusion has been suggested as an independent cause of increased postoperative infection. STUDY DESIGN AND METHODS: A total of 597 patients undergoing elective coronary artery or heart valve surgery were randomly assigned to receive plasma-reduced (PR), buffy coat-depleted (BCD), or WBC-filtered (WCF) RBCs in the event of requiring blood transfusion. Details of postoperative course were recorded. Further information was collected from the patient's general practitioner 3 months after discharge. RESULTS: No significant difference in inpatient infection rates was observed among patients randomly assigned to receive PR, BCD, or WCF RBCs. When only those receiving transfusion were analyzed (n = 509), use of PR RBCs was associated with more events coded as infections (p < or = 0.05) compared with BCD or WCF RBCs. However, when events coded as urinary tract infections were excluded, there was no significant difference among the three groups. Follow-up performed after discharge showed no difference in readmission rates, but a higher reported rate of infection in those randomly assigned to receive WCF RBCs (p < 0.02). CONCLUSION: No evidence has been found, analyzed by intention to treat, that use of WBC-reduced, BCD, or WCF RBCs reduces postoperative inpatient infection in patients undergoing cardiac bypass surgery.

Aged↗
PubMed2000

Effect of low molecular weight heparin (fragmin) on bleeding after cardiac surgery.

BACKGROUND: Fragmin (Dalteparin, Pharmacia Ltd, Milton Keynes, UK), a low molecular weight heparin, is now recommended in the treatment of unstable angina. Due to the greater bioavailability and longer half-life of Fragmin compared with conventional heparin we postulated that this may influence postoperative bleeding after cardiac surgery for unstable angina. METHODS: We investigated the influence of the agent on postoperative bleeding after cardiac surgery. Patients undergoing first-time coronary artery bypass grafting were prospectively studied in four groups: group A (n = 100) were elective patients; group B (n = 60) had unstable angina and received conventional heparin intravenously until operation; group C (n = 115) received Fragmin with the last dose administered more than 12 hours before surgery; and group D (n = 115) received Fragmin within 12 hours of operation. RESULTS: Patients in group D had significantly greater blood loss (p < 0.001) and increased blood transfusion than groups A, B, and C (p = 0.047). Patients receiving Fragmin more than 12 hours before surgery (group C) had similar rates of blood loss and transfusion to group B (p > 0.05) but greater than in group A (p = 0.021). There were no differences in reopening rate. CONCLUSIONS: The risks of bleeding and transfusion must be weighed against the risks of acute ischemic events if Fragmin is stopped more than 12 hours before operation.

Aged↗
PubMed1999

APOBEC-2, a cardiac- and skeletal muscle-specific member of the cytidine deaminase supergene family.

APOBEC-1, which mediates the editing of apolipoprotein (apo) B mRNA, is the only known member of the C (cytidine)-->U (uridine) editing enzyme subfamily of the cytidine deaminase supergene family. Here we report the cloning of APOBEC-2, another member of the subfamily. Human and mouse APOBEC-2 both contain 224 amino acid residues, and their genes are mapped to syntenic regions of human chromosome 6 (6p21) and mouse chromosome 17. By phylogenetic analysis, APOBEC-2 is shown to be evolutionarily related to APOBEC-1, and analysis of substitution rates indicates that APOBEC-2 is a much better conserved gene than APOBEC-1. APOBEC-2 mRNA and protein are expressed exclusively in heart and skeletal muscle. APOBEC-2 does not display detectable apoB mRNA editing activity. Like other editing enzymes of the cytidine deaminase superfamily, APOBEC-2 has low, but definite, intrinsic cytidine deaminase activity. The identification of APOBEC-2 indicates that APOBEC-1 is not the only member of the C-->U editing enzyme subfamily, which, like the A (adenosine)-->I (inosine) subfamily of editing enzymes, must encompass at least two and possibly more different deaminase enzymes. It suggests that the C-->U editing affecting apoB mRNA and other RNAs is not an isolated event mediated by a single enzyme but involves multiple related proteins that have evolved from a primordial gene closely related to the housekeeping enzyme cytidine deaminase.

APOBEC Deaminases↗
PubMed1999

Modulation of reperfusion injury after single lung transplantation by pentoxifylline, inositol polyanions, and sin-1.

OBJECTIVE: Previous studies have suggested reductions in lung reperfusion injury with pentoxifylline, inositol polyanions, and the nitric oxide donor, SIN-1, but these agents have never been directly compared to ascertain which is superior. We investigated these agents in a porcine model of left single lung transplantation. METHODS: Donor lungs were preserved with modified Euro-Collins solution for a mean ischemic time of 18.4 hours. Neutrophil trapping in the graft, pulmonary vascular resistance, free radical release (measured by malonaldehyde levels) and gas exchange were assessed over a 12-hour period. All groups were reperfused at an initial pulmonary artery pressure of 20 mm Hg. Group A (n = 5) was a control group with no interventions added; group B was reperfused with the addition of intravenous inositol polyanions (0.02 mg/kg/h), and group C was reperfused with intravenous SIN-1 (0.02 mg/kg/h). Group D was reperfused with the addition of intravenous pentoxifylline (2 mg/kg/h). RESULTS: Neutrophil sequestration was observed within 10 minutes of reperfusion in group A. This was attenuated significantly by interventions in groups B, C, and D. In group D, malonaldehyde levels were significantly lower than in other groups and was associated with superior oxygenation. Pulmonary vascular resistance was reduced in groups B, C, and D compared with group A. CONCLUSIONS: Pentoxifylline, when administered only to recipient animals was superior to the other interventions studied. Inositol polyanions are promising as a possible therapeutic intervention but were not as effective as the other agents studied.

Animals↗
PubMed1999

Brain event-related potentials (ERPs) in schizophrenia during a word recognition memory task.

Impairments of recognition memory for words and attenuation of the ERP 'old-new' effect have been found in patients with left medial temporal lobe damage. If left temporal lobe dysfunction in schizophrenia involves medial structures (e.g. hippocampus), then schizophrenic patients might show similar abnormalities of verbal recognition memory. This study recorded ERPs from 30 electrode sites while subjects were engaged in a continuous word recognition memory task. Results are reported for 24 patients having a diagnosis of schizophrenia (n = 16) or schizoaffective disorder (n = 8) and 19 age-matched healthy controls. Both patients and controls showed the expected 'old-new' effect, with greater late positivity to correctly recognized old words at posterior sites, and there was also no significant difference between groups in P3 amplitude. However, accuracy of word recognition memory was poorer in patients than controls, and patients showed markedly smaller N2 amplitude. Reduced amplitudes of N2 and N2-P3 were associated with poorer performance, with highest correlations over the left inferior parietal (N2) and left medial parietal (N2-P3) region. Moreover, patients failed to show significantly greater left than right hemisphere amplitude of N2-P3 at posterior sites, which was seen for healthy controls. These findings suggest that impaired word recognition in schizophrenia may arise from a left lateralized deficit at an early stage of processing, beginning at 200-300 ms after word onset.

Adult↗
PubMed1999

A new porcine model of reperfusion injury after lung transplantation.

Rodent models have been described to investigate lung preservation and reperfusion injury but have significant disadvantages. In large animals single lung transplant studies are probably optimal but problems remain over the ability to rigorously separate the lungs for assessment while promoting medium to long-term animal survival for meaningful investigation. Our aim was to develop a novel and refined large animal model to assess reperfusion injury in the transplanted lung, overcoming the difficulties associated with existing models. Specifically, small animal models of lung transplantation usually have short perfusion times (often one hour) and include extracorporeal circuits while larger animal models often require the contralateral lung to be excluded after transplantation-an unphysiological situation under which to evaluate the graft. A porcine model of left lung allotransplantation was developed in which native and donor lungs are individually ventilated. Sampling catheters placed within the graft lung allowed specimen withdrawal without mixing of blood from the contralateral lung after reimplantation. The model permits a variety of clinical scenarios to be simulated with the native lung supporting the animal irrespective of function in the graft. This model has been used in over 60 transplant procedures with a postoperative survival time of 12 h being readily achieved. The mean operating time was 2.6 h. The mortality rate is 4% in our series. We have found the model to be reliable, reproducible and flexible. We propose this model as an adaptable investigation for evaluating lung reperfusion injury and preservation.

Animals↗
PubMed1998

A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia.

PURPOSE: The cause of fibromyalgia (FM) is not known. Low levels of insulin-like growth factor 1 (IGF-1), a surrogate marker for low growth hormone (GH) secretion, occur in about one third of patients who have many clinical features of growth hormone deficiency, such as diminished energy, dysphoria, impaired cognition, poor general health, reduced exercise capacity, muscle weakness, and cold intolerance. To determine whether suboptimal growth hormone production could be relevant to the symptomatology of fibromyalgia, we assessed the clinical effects of treatment with growth hormone. METHODS: Fifty women with fibromyalgia and low IGF-1 levels were enrolled in a randomized, placebo-controlled, double-blind study of 9 months' duration. They gave themselves daily subcutaneous injections of growth hormone or placebo. Two outcome measures--the Fibromyalgia Impact Questionnaire and the number of fibromyalgia tender points-were evaluated at 3-monthly intervals by a blinded investigator. An unblinded investigator reviewed the IGF-1 results monthly and adjusted the growth hormone dose to achieve an IGF-1 level of about 250 ng/mL. RESULTS: Daily growth hormone injections resulted in a prompt and sustained increase in IGF-1 levels. The treatment (n=22) group showed a significant improvement over the placebo group (n=23) at 9 months in both the Fibromyalgia Impact Questionnaire score (P <0.04) and the tender point score (P <0.03). Fifteen subjects in the growth hormone group and 6 subjects in the control group experienced a global improvement (P <0.02). There was a delayed response to therapy, with most patients experiencing improvement at the 6-month mark. After discontinuing growth hormone, patients experienced a worsening of symptoms. Carpal tunnel symptoms were more prevalent in the growth hormone group (7 versus 1); no other adverse events were more common in this group. CONCLUSIONS: Women with fibromyalgia and low IGF-1 levels experienced an improvement in their overall symptomatology and number of tender points after 9 months of daily growth hormone therapy. This suggests that a secondary growth hormone deficiency may be responsible for some of the symptoms of fibromyalgia.

Double-Blind Method↗
PubMed1998

Controlled reperfusion and pentoxifylline modulate reperfusion injury after single lung transplantation.

OBJECTIVE: Rodent models have suggested that initial low-pressure reperfusion of transplanted lungs reduces injury after ischemia. We investigated this phenomenon and the use of pentoxifylline in a porcine model of left single lung transplantation. METHODS: Donor lungs were preserved with Euro-Collins solution for a mean ischemic time of 18.4 hours. Neutrophil trapping in the graft, pulmonary artery pressure, and gas exchange were assessed over a 12-hour period. Partial occlusion of the contralateral pulmonary artery allowed manipulation of the pulmonary artery pressure in the transplanted lung. Group A (n = 5) was perfused at a mean pulmonary artery pressure of 20 mm Hg, group B was reperfused at a mean pulmonary artery pressure of 45 mm Hg for 10 minutes before reducing the pressure to the same as group A, and group C was reperfused at a mean pressure of 20 mm Hg for 10 minutes, then increased to a mean of 45 mm Hg for the remainder of the experiment. Group D was reperfused as in group A with the addition of intravenous pentoxifylline. RESULTS: Leukocyte sequestration was observed in the first 10 minutes after reperfusion in groups A, B, and C, with maximal sequestration at 2 minutes. Significantly more sequestration was observed in the first 6 minutes in group B than in groups A and C, which were similar. Pentoxifylline significantly reduced leukocyte sequestration. Pulmonary venous oxygen tension in the allograft lung was worst in group B. Groups A and C were similar, but group D was superior to all other groups (p < 0.001). CONCLUSIONS: Low-pressure reperfusion, even when limited to the first 10 minutes, modulates reperfusion injury possibly through a leukocyte-dependent mechanism. The addition of pentoxifylline in the recipient confers significant additional benefit.

Animals↗
PubMed1997

Crucial role of the residue R280 at the F'-G' loop of the human granulocyte/macrophage colony-stimulating factor receptor alpha chain for ligand recognition.

The receptor for granulocyte/macrophage colony-stimulating factor (GM-CSF) is composed of two chains, alpha and betac. Both chains belong to the superfamily of cytokine receptors characterized by a common structural feature, i.e., the presence of at least two fibronectin-like folds in the extracellular domain, which was first identified in the growth hormone receptor. The GM-CSF receptor (GMR)-alpha chain confers low affinity binding only (5-10 nM), whereas the other chain, betac, does not bind GM-CSF by itself but confers high affinity binding when associated with GMR-alpha (25-100 pM). The present study was designed to define the assembly of the GMR complex at the molecular level through site-directed mutagenesis guided by homology modeling with the growth hormone receptor complex. In our three-dimensional model, R280 of GMR-alpha, located in the F'-G' loop and close to the WSSWS motif, is in the vicinity of the ligand Asp112, suggesting the possibility of electrostatic interaction between these two residues. Through site directed mutagenesis, we provide several lines of evidence indicating the importance of electrostatic interaction in ligand-receptor recognition. First, mutagenesis of GMR-alphaR280 strikingly ablated ligand binding in the absence of beta common (betac); ligand binding was restored in the presence of betac with, nonetheless, a significant shift from high (26 pM) toward low affinity (from 2 to 13 nM). The rank order of the dissociation constant for the different GMR-alphaR280 mutations where Lys > Gln > Met > Asp, suggesting the importance of the charge at this position. Second, a mutant GM-CSF with charge reversal mutation at position Asp112 exhibited a 1,000-fold decrease in affinity in receptor binding, whereas charge ablation or conservative mutations were the least affected (10-20-fold). Third, removal of the charge at position R280 of GMR-alpha introduced a 10-fold decrease in the association rate constant and only a 2-fold change in the dissociation rate constant, suggesting that R280 is implicated in ligand recognition, possibly through interaction with Asp112 of GM-CSF. For all R280 mutants, the half-efficient concentrations of GM-CSF required for membrane (receptor binding) to nuclear events (c-fos promoter activation) and cell proliferation (thymidine incorporation) were in the same range, indicating that the threshold for biologic activity is governed mainly by the affinity of ligand-receptor interaction. Furthermore, mutation of other residues in the immediate vicinity of R280 was less drastic. Sequence alignment and modeling of interleukin (IL)-3R and IL-5R identified an arginine residue at the tip of a beta turn in a highly divergent context at the F'-G' loop, close to a conserved structural element, the WSXWS motif, suggesting the possibility of a ligand association mechanism similar to the one described herein for GMR.

3T3 Cells↗