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Biomedical subjects

D A Morgan

Publications and source records attributed to D A Morgan.

At least 19 recordsLinked to original sources
PubMed2002

Altered frequency responses of sympathetic nerve discharge bursts after IL-1beta and mild hypothermia.

Although interleukin-1beta (IL-1beta) administration produces nonuniform changes in the level of sympathetic nerve discharge (SND), the effect of IL-1beta on the frequency-domain relationships between discharges in different sympathetic nerves is not known. Autospectral and coherence analyses were used to determine the effect of IL-1beta and mild hypothermia (60 min after IL-1beta, colonic temperature from 38 degrees C to 36 degrees C) on the relationships between renal-interscapular brown adipose tissue (IBAT) and splenic-lumbar sympathetic nerve discharges in chloralose-anesthetized rats. The following observations were made. 1) IL-1beta did not alter renal-IBAT coherence values in the 0- to 2-Hz frequency band or at the cardiac frequency (CF). 2) Peak coherence values relating splenic-lumbar discharges at the CF were significantly increased after IL-1beta and during hypothermia. 3) Hypothermia after IL-1beta significantly reduced the coupling (0-2 Hz and CF) between renal-IBAT but not splenic-lumbar SND bursts. 4) Combining IL-1beta and mild hypothermia had a greater effect on renal-IBAT SND coherence values than did mild hypothermia alone. These data demonstrate functional plasticity in sympathetic neural circuits and suggest complex relationships between immune products and SND regulation.

Acute-Phase Reaction↗
PubMed2001

Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein Ib.

Thrombin plays a central role in normal and abnormal hemostatic processes. It is assumed that alpha-thrombin activates platelets by hydrolyzing the protease-activated receptor (PAR)-1, thereby exposing a new N-terminal sequence, a tethered ligand, which initiates a cascade of molecular reactions leading to thrombus formation. This process involves cross-linking of adjacent platelets mediated by the interaction of activated glycoprotein (GP) IIb/IIIa with distinct amino acid sequences, LGGAKQAGDV and/or RGD, at each end of dimeric fibrinogen molecules. We demonstrate here the existence of a second alpha-thrombin-induced platelet-activating pathway, dependent on GP Ib, which does not require hydrolysis of a substrate receptor, utilizes polymerizing fibrin instead of fibrinogen, and can be inhibited by the Fab fragment of the monoclonal antibody LJIb-10 bound to the GP Ib thrombin-binding site or by the cobra venom metalloproteinase, mocarhagin, that hydrolyzes the extracellular portion of GP Ib. This alternative alpha-thrombin pathway is observed when PAR-1 or GP IIb/IIIa is inhibited. The recognition sites involved in the cross-linking of polymerizing fibrin and surface integrins via the GP Ib pathway are different from those associated with fibrinogen. This pathway is insensitive to RGDS and anti-GP IIb/IIIa antibodies but reactive with a mutant fibrinogen, gamma407, with a deletion of the gamma-chain sequence, AGDV. The reaction is not due to simple trapping of platelets by the fibrin clot, since ligand binding, signal transduction, and second messenger formation are required. The GP Ib pathway is accompanied by mobilization of internal calcium and the platelet release reaction. This latter aspect is not observed with ristocetin-induced GP Ib-von Willebrand factor agglutination nor with GP Ib-von Willebrand factor-polymerizing fibrin trapping of platelets. Human platelets also respond to gamma-thrombin, an autoproteolytic product of alpha-thrombin, through PAR-4. Co-activation of the GP Ib, PAR-1, and PAR-4 pathways elicit synergistic responses. The presence of the GP Ib pathway may explain why anti-alpha-thrombin/anti-platelet regimens fail to completely abrogate thrombosis/restenosis in the cardiac patient.

Adenosine Triphosphate↗
PubMed2001

Effect of cervical vagotomy on sympathetic nerve responses to peripheral interleukin-1beta.

Although the vagus nerve is an important neural pathway mediating immune-to-brain communication, the role of the vagus in mediating sympathetic nerve discharge (SND) responses to peripheral cytokines is not well established. In the present study we determined renal, interscapular brown adipose tissue (IBAT), splenic, and lumbar SND responses before and for 60 min after the intravenous administration of interleukin-1beta (IL-1beta, 100 ng) in chloralose-anesthetized, sham-vagotomized and cervical-vagotomized (bilateral) rats. In sham-vagotomized rats, IL-1beta administration increased (P<0.05) splenic and lumbar SND while renal and IBAT SND remained unchanged from control levels. Renal, splenic, and lumbar SND were increased (P<0.05) whereas IBAT SND remained unchanged from control after IL-1beta in vagotomized rats. Renal, splenic, and lumbar SND responses were significantly higher after IL-1beta in vagotomized compared with sham-vagotomized rats. These results demonstrate that regionally-selective SND (renal, splenic, and lumbar) responses to IL-1beta can occur in the absence of the vagus nerve and suggest that the vagus nerve provides a tonic inhibition to the discharges in these nerves in response to peripheral IL-1beta.

Adipose Tissue, Brown↗
PubMed2001

Massive structural allograft in revision of septic hip arthroplasty.

We reviewed 10 patients who had undergone two-stage reconstruction with massive structural allografts following failure of hip arthroplasty due to infection. The mean follow-up time was more than 5 years (range 3-10 years). There was no case of the infection recurring. The most common pathogen isolated at the time of first-stage surgery was Stalphylococcus epidermnidis. The mean preoperative modified Harris Hip score was 27.4 (range 9-58) and the mean postoperative score was 73.5 (range 53-92) with a mean increase in the score of 46.1 points. One patient required revision of the acetabular cup for aseptic loosening and another had a dislocation, which was stable after manual reduction. We conclude that the use of a massive structural allograft in revision of septic hip arthroplasty is a viable option.

Aged↗
PubMed2001

Does leptin cause functional peripheral sympatholysis?

Leptin is a protein produced by adipocytes. Leptin is known to markedly and rapidly increase sympathetic nerve activity to the kidney and hindlimb of experimental animals. Recent studies suggest that leptin may stimulate endothelial production of nitric oxide, which could oppose sympathetically induced vasoconstriction. We tested the hypothesis that such actions of leptin may produce peripheral functional sympatholysis. In Sprague-Dawley rats, we intermittently stimulated the abdominal sympathetic trunk and measured renal and hindlimb blood flows before and after 3 h of infusion of leptin (1000 microg/kg, n = 7) or vehicle (n = 7). Leptin did not change arterial pressure, heart rate, or renal or hindlimb conductance over the course of 3 h. In addition, leptin did not significantly alter sympathetically mediated vasomotor responses to electrical stimulation, as compared with vehicle. Thus, we conclude that leptin does not change regional blood flows, and that leptin also does not appear to have vascular or neural actions to cause peripheral functional sympatholysis.

Animals↗
PubMed2001

The role of biologically effective dose (BED) in clinical oncology.

There are many clinical situations in which radiobiological considerations can be usefully applied and all clinicians should be aware of the potential benefits of developing a quantitative radiobiological approach to their practice. The concept of biologically effective dose (BED) in particular is useful for quantifying treatment expectations, but clinical oncologists should recognize that careful interpretation of modelling results is required before clinical decisions can be made and that there is a lack of reliable human parameters for application in some situations. Correct use of the BED concept will, in more complex treatment situations, sometimes involve the use of multiple parameters and BED calculations. Examples include: 1. Where the dose per fraction is being altered and it is possible that normal tissue tolerance may be compromised, calculations should include two or more alpha/beta ratio values, some being less than 3 Gy, in order to estimate the 'worst case scenario'. 2. A single one-point BED calculation will not be representative of the biological effect throughout a large planning target volume where there are significant 'hot spots'. Multiple BED evaluations are then indicated. 3. Where there are combinations of radiotherapy treatments or phases of treatments, these can be quantitatively assessed by the addition of BEDs, although the volume of tissue is not inherently included in the BED calculation and any high-dose region needs to be separately assessed as in point 2. 4. Allowance for tumour clonogen repopulation during therapy is required for some tumour types. 5. Different histological classes of cancers require the use of different alpha/beta ratios. Where there is reasonable doubt regarding this parameter, a suitable range should be used. The principles involved are illustrated by worked examples. Attention to detail and the examination of ranges of possible results should offer a safer guide to alternative dose fractionation schedules, although the ultimate choice will be tempered by clinical circumstances.

Dose Fractionation, Radiation↗
PubMed2001

Interleukin-1 beta alters brown adipose tissue but not renal sympathetic nerve responses to hypothermia.

Proinflammatory cytokines and acute physical stress influence sympathetic nerve discharge (SND). Because interleukin-1 beta (IL-1 beta) produces physiological responses that require central neural integration and because the sympathetic nervous system mediates physiological responses to environmental stress, we hypothesized that IL-1 beta modulates SND responses to acute physical stress. Therefore, this study examined the effects of IL-1 beta (290 ng/kg iv) and mild hypothermia on renal and interscapular brown adipose tissue (IBAT) SND regulation in chloralose-anesthetized rats. IBAT SND did not change after IL-1 beta administration but was significantly increased during acute mild hypothermia, which was induced 60 min after IL-1 beta treatment. Renal SND was unchanged after IL-1 beta administration and during hypothermia. Acute hypothermia, without prior IL-1 beta administration, did not alter IBAT and renal SND. Increases in IBAT SND during sustained (120 min) hypothermia were significantly higher in IL-1 beta-treated rats compared with saline-treated rats, whereas renal SND responses to sustained hypothermia did not differ among groups. Exposure to acute cold stress after sustained hypothermia produced greater increases in IBAT SND in IL-1 beta-treated rats compared with saline-treated controls. These data suggest that IL-1 beta alters IBAT SND responses to acute and sustained hypothermia.

Acute Disease↗
PubMed2001

Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure.

Systemic leptin increases energy expenditure through sympathetic mechanisms, decreases appetite, and increases arterial pressure. We tested the hypothesis that the pressor action of leptin is mediated by the central nervous system. The interaction of dietary salt with leptin was also studied. Leptin was infused for 2 to 4 weeks into the third cerebral ventricle of Sprague-Dawley rats. Arterial pressure was measured by radiotelemetry. To control for the effects of leptin on body weight, vehicle-treated rats were pair-fed to the leptin group. Intracerebroventricular infusion of leptin at 200 ng/h in salt-depleted rats caused a reduction in food intake, weight loss, tachycardia, and decreased arterial pressure. Leptin at 1000 ng/h caused further reduction in food intake, weight loss, and tachycardia and prevented the hypotensive effect of weight loss observed in pair-fed, vehicle-treated animals. Intracerebroventricular leptin at 1000 ng/h in high-salt-fed rats also caused a sustained pressor response (+3+/-1 mm Hg), but high-salt intake did not potentiate the pressor effect of leptin. Intracerebroventricular leptin potentiated the pressor effect of air-jet stress. Intravenous administration of the same dose of leptin (1000 ng/h) did not change weight or arterial pressure, suggesting a direct central nervous system action. In contrast, a high dose of intravenous leptin (18 000 ng/h) caused weight loss and prevented the depressor effect of weight loss. In conclusion, this study demonstrates that high-dose leptin increases arterial pressure and heart rate through central neural mechanisms but leptin does not enhance salt sensitivity of arterial pressure. Leptin appears to oppose the depressor effect of weight loss.

Animals↗
PubMed2001

Role of corticotrophin-releasing factor in effects of leptin on sympathetic nerve activity and arterial pressure.

Leptin and corticotrophin-releasing factor increase sympathetic nervous activity to interscapular brown adipose tissue, kidneys, and adrenal glands. Leptin is known to increase hypothalamic corticotrophin-releasing factor. In this study, we tested the hypothesis that leptin-dependent increases in sympathetic nervous activity are mediated through increases in central nervous system corticotrophin-releasing factor activity. We examined the effects of intracerebroventricular administration of corticotrophin-releasing factor and intravenous leptin on sympathetic nervous activity to interscapular brown adipose tissue through multifiber neurography in anesthetized Sprague-Dawley rats pretreated with intracerebroventricular alpha-helical corticotrophin-releasing factor(9-41) (corticotrophin-releasing factor receptor antagonist) or vehicle. Centrally administered corticotrophin-releasing factor substantially increased interscapular brown adipose tissue sympathetic nervous activity. The responses to corticotrophin-releasing factor were substantially attenuated in animals pretreated with alpha-helical corticotrophin-releasing factor(9-41). Leptin-dependent increases in interscapular brown adipose tissue sympathetic nervous activity were significantly inhibited by pretreatment with alpha-helical corticotrophin-releasing factor(9-41). Interestingly, leptin also significantly increased arterial pressure over 6 hours, but this pressor action was not attenuated by the corticotrophin-releasing factor receptor antagonist. These results suggest that corticotrophin-releasing factor may mediate the sympathoexcitatory effect of leptin on thermogenic tissue without altering its cardiovascular actions.

Adipose Tissue, Brown↗
PubMed2001

Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation?

Leptin decreases appetite and increases sympathetic nerve activity and arterial pressure. Recent reports suggest that leptin may also have peripheral vasodilator actions that would tend to reduce arterial pressure. We tested the hypothesis that the direct vascular actions of leptin oppose sympathetically mediated vasoconstriction. We evaluated the effects of intravenous leptin (1 mg/kg over 3 hours) on arterial pressure and mesenteric, hindlimb, and renal blood flows in conscious rats. We then tested whether blockade of nitric oxide or the sympathetic nervous system would unmask a pressor or depressor effect of leptin, consistent with direct vascular actions. Acute intravenous administration of leptin alone did not change arterial pressure or regional blood flows. This was despite a significant increase in lumbar sympathetic nerve activity. Administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester significantly increased arterial pressure and caused vasoconstriction. However, leptin did not have any significant effect on hemodynamics in the presence of N(G)-nitro-L-arginine methyl ester despite continued sympathoactivation. alpha-Adrenoceptor blockade with prazosin alone or combined with yohimbine significantly decreased arterial pressure and caused vasodilation. Again, leptin did not have any effect on arterial pressure or regional blood flow in the presence of sympathetic blockade. These data demonstrate that leptin does not have vasodilator actions in vivo at concentrations that are sufficient to increase sympathetic nerve activity. The absence of a pressor effect of leptin-induced sympathetic activation may merely reflect the brief duration of leptin administration. These data support the concept that the chronic hemodynamic actions of leptin are likely to be related to sympathetic activation.

Adrenergic alpha-Antagonists↗
PubMed2001

Effect of acute and antecedent hypoglycemia on sympathetic neural activity and catecholamine responsiveness in normal rats.

Adrenergic responsiveness to acute hypoglycemia is impaired after prior episodes of hypoglycemia. Although circulating epinephrine responses are blunted, associated alterations in adrenal sympathetic nerve activity (SNA) have not been reported. We examined adrenal nerve traffic in normal conscious rats exposed to acute insulin-induced hypoglycemia compared with insulin with (clamped) euglycemia. We also examined adrenal SNA and catecholamine responses to insulin-induced hypoglycemia in normal conscious rats after two antecedent episodes of hypoglycemia (days -2 and -1) compared with prior episodes of sham treatment. Acute insulin-induced hypoglycemia increased adrenal sympathetic nerve traffic compared with insulin administration with clamped euglycemia (165 +/- 12 vs. 118 +/- 21 spikes/s [P < 0.05]; or to 138 +/- 8 vs. 114 +/- 10% of baseline [P < 0.05]). In additional experiments, 2 days of antecedent hypoglycemia (days -2 and -1) compared with sham treatment significantly enhanced baseline adrenal SNA measured immediately before subsequent acute hypoglycemia on day 0 (180 +/- 11 vs. 130 +/- 12 spikes/s, respectively; P < 0.005) and during subsequent acute hypoglycemia (229 +/- 17 vs. 171 +/- 16 spikes/s; P < 0.05). However, antecedent hypoglycemia resulted in a nonsignificant reduction in hypoglycemic responsiveness of adrenal SNA when expressed as percent increase over baseline (127 +/- 5% vs. 140 +/- 14% of baseline). Antecedent hypoglycemia, compared with sham treatment, resulted in diminished epinephrine responsiveness to subsequent hypoglycemia. Norepinephrine responses to hypoglycemia were not significantly altered by antecedent hypoglycemia. In summary, prior hypoglycemia in normal rats increased adrenal sympathetic tone, but impaired epinephrine responsiveness to acute hypoglycemia. Hence, these data raise the intriguing possibility that increased sympathetic tone resulting from antecedent hypoglycemia downregulates subsequent epinephrine responsiveness to hypoglycemia. Alternatively, it is possible that the decrease in epinephrine responsiveness after antecedent hypoglycemia could be the result of reduced adrenal sympathetic nerve responsiveness.

Adrenal Glands↗
PubMed2000

Comparison of wet combing with malathion for treatment of head lice in the UK: a pragmatic randomised controlled trial.

BACKGROUND: Concern about the effectiveness and toxicity of insecticide lotions has led to promotion of mechanical methods to remove head lice. We compared the effectiveness of "bug-busting" (wet combing with a fine-toothed comb) and malathion lotion. METHODS: We screened 4037 schoolchildren in two counties in Wales, UK (intermediate resistance to malathion). Of 167 found to have head lice, 81 (aged 3-14 years) were eligible to participate in a randomised controlled trial that compared mechanical removal of lice by a commercial kit every 3-4 days for 2 weeks with two applications of 0.5% malathion lotion 7 days apart; parents carried out both treatments. The outcome measure was the presence of live lice 7 days after the end of treatment. Analyses were by intention to treat. FINDINGS: 74 children completed the study and 72 were included in the analysis. The cure rate was 38% (12 of 32) for bug-busting and 78% (31 of 40) for malathion. Children assigned bug-busting were 2.8 (95% CI 1.5-5.2) times more likely than those assigned malathion to have lice at the end of treatment (p=0.0006). INTERPRETATION: Malathion lotion was twice as effective as bug-busting, even in an area with intermediate resistance. Policies advocating bug-busting as first-line treatment for head lice in the general population are inappropriate. Assessment of the outcome of treatment 1-2 weeks after completion is essential for successful management. Only about 50% of participants complied fully with treatment, so future trials should be pragmatic in design, avoid false incentives, and study representative samples of children.

Adolescent↗
PubMed2000

Contamination of banked femoral head allograft: incidence, bacteriology and donor follow up.

BACKGROUND: Allograft donations are not uncommonly found to be contaminated. The issue of contaminated donations from live donors at the time of surgery, and the significance of this to the patient in terms of subsequent sepsis of the arthroplasty, were examined. METHODS: The donations of femoral heads to the Queensland Bone Bank over a 9-year period were reviewed, and the incidence and bacteriology of contamination were detailed. Clinical outcomes were determined for donors who had positive cultures at the time of retrieval and they were compared with those of culture-negative donors. RESULTS: Between March 1987 and February 1996, 232 femoral heads were donated to the Queensland Bone Bank. Four specimens were sent for culture with each femoral head (surface swab of femoral head, acetabular swab, bone biopsy and capsule). In 51 cases, one or more positive cultures were obtained (22% contamination rate). The majority of organisms cultured were Staphylococcus epidermidis. One hundred and seventy donations came from surgery performed at the Princess Alexandra Hospital, and 40 femoral heads were considered contaminated. Deep infection was recorded in one of the 40 cases with contaminated donations and three out of 130 non-contaminated donations had subsequent septic episodes. CONCLUSION: The contamination rate detailed in the present report is higher than in most series. This may be due to the fact that four bacteriological specimens are taken to assess contamination. Two of these specimens are tissue samples which yielded more positive results than did the two swabs. All other series take no more than two bacteriological specimens, which are usually bone swabs. These are shown to have a poor yield of positive cultures. Therefore there is a significant underestimation of contamination rates by other bone banks. This has implications for the recipients of bone from those banks, particularly when the allograft material is not secondarily sterilized. This is important given increasing allograft usage, and the increasing numbers of revision joint arthroplasty and impaction grafting procedures being performed. Sterilization of all bone by irradiation to 25 kGy is recommended.

Acetabulum↗
PubMed2000

Poor results of the Freeman uncemented metal-backed acetabular component. Five-to-nine-year results.

We reviewed 120 consecutive primary total hip replacements in 109 patients in whom a Freeman uncemented metal-backed component had been used. Acetabular components were used with a Freeman neck-retaining stem in one of three configurations: cemented smooth stem, uncemented smooth stem or uncemented ridged stem. After a mean follow up of 72 months (62 to 113) there were nine cases of aseptic loosening; a survivorship at eight years of 83%. In addition, more than one-third of the remaining surviving cups showed loosening radiologically. The Freeman acetabular component demonstrated a characteristic pattern of loosening on radiographs. The high incidence of aseptic loosening can be explained by poor design and material failure.

Acetabulum↗
PubMed2000

The medium-term results of a cemented Freeman femoral neck-retaining prosthesis.

We have reviewed 202 consecutive primary hip replacements using a Freeman cemented femoral component after a mean period of follow-up of 64 months (23 to 113). There was only one revision for aseptic loosening. Retention of the femoral neck may act to reduce the torsional and shear forces at the implant-cement interface and may provide a seal against the migration of polyethylene-laden joint fluid in the potential joint space. The cemented Freeman femoral component with retention of the femoral neck was successful for up to nine years.

Adult↗
PubMed1999

Bacterial contamination rates during bone allograft retrieval.

A retrospective study of allograft bone retrieved from 401 donors between January 1987 and March 1996 was performed to determine the incidence of bacterial contamination. Contamination according to type of donor (live, multiorgan, cadaveric) was also determined. Live donors donating a femoral head demonstrated a contamination rate of 13%; multiorgan donors, 24%; and cadaveric donors, 35%. Donor contamination by type of bone (hemipelvis, femur, tibia) showed no significant difference in the multiorgan donors. In cadaveric donors, there was a significant increase in contamination of the hemipelves as compared to the femur and tibias. Recommendations for contamination control in allograft retrieval are given. Our findings are of great significance for musculoskeletal banks that do not secondarily irradiate and rely on screening of allograft bone for contamination alone.

Bacteria↗