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Biomedical subjects

D A Morgan

Publications and source records attributed to D A Morgan.

At least 55 records · Page 3Linked to original sources
PubMed1997

Role of nitrosyl factors in the hemodynamic adjustments to heat stress in the rat.

The present study examined the mechanisms responsible for the hindlimb vasodilation produced by elevating core body (colonic) temperature (Tco) of alpha-chloralose-anesthetized rats from 37 to 39 degrees C. Elevating Tco to 39 degrees C produced equivalent decreases in hindlimb vascular resistance in sham-operated (-48 +/- 2%) and sinoaortic baroreceptor-denervated rats (-44 +/- 3%) rats. There were no changes in mean arterial blood pressure, heart rate, or lumbar sympathetic nerve activity in either group. The prior administration of the alpha 1-adrenoceptor antagonist prazosin (100 micrograms/kg i.v.) did not prevent the heat-induced decrease in hindlimb resistance in sham-operated rats (-52 +/- 7% vs. baseline). In contrast, the fall in hindlimb resistance was markedly attenuated (-20 +/- 5% vs. baseline) in sham-operated rats that had received a prior injection of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (100 mumol/kg i.v.). Dexamethasone (1 mg/kg i.v.), administered to prevent the possible induction of inducible NOS, did not modify the heat-induced hindlimb vasodilation in sham-operated rats (-41 +/- 5%). These results demonstrate that the elevation of Tco to 39 degrees C in alpha-chloralose-anesthetized rats produces a relative vasodilation in the hindlimb that is not obviously linked to an alteration in lumbar sympathetic nerve activity. Because the vasodilation occurred in the presence of prazosin, it is unlikely that the decline in resistance is due to the loss of the vasoconstrictor potency of neurally derived catecholamines. The findings that NG-nitro-L-arginine methyl ester, but not dexamethasone, diminished the heat-induced hindlimb vasodilation suggests that the fall in resistance is due in part to constitutive NOS and supports a role for NOS as a mediator of thermoregulatory active vasodilation.

Acclimatization↗
PubMed1997

Oxygen-derived free radicals contribute to neural stunning in the canine heart.

Oxygen-derived free radicals (ODFR) contribute to delayed recovery of myocardial function after brief ischemia. We examined the effect of ODFR scavengers on ischemia-induced dysfunction of cardiac sympathetic nerves. Mongrel dogs were anesthetized and instrumented for recording heart rate, arterial pressure, systolic wall thickening, and left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCX) flow velocities. Bilateral stellate stimulation was performed, measuring changes in an index of coronary vascular resistance (% delta CVR) before and after 15 min of LAD occlusion. Superoxide dismutase (SOD) and catalase (CAT) were infused intravenously for 30 min beginning 10 min before occlusion. With vehicle (n = 13), % delta CVR was significantly attenuated in LAD after ischemia and 30-min reperfusion [39 +/- 3 to 13 +/- 2%, P < 0.05; for LCX, 42 +/- 4 to 45 +/- 7%, P = not significant (NS)]; however, no attenuation was seen in dogs in which SOD and CAT were infused (n = 10; for LAD, 39 +/- 5 to 41 +/- 5%; for LCX, 46 +/- 7 to 47 +/- 6%; P = NS). Baseline and stimulated changes in hemodynamics were similar between groups. The % delta CVR in the LCX (control) bed was not affected by SOD and CAT. Recovery of myocardial function (percent of baseline) was greater in SOD and CAT after reperfusion (26 +/- 16% vs. -30 +/- 11% at 90 min of reperfusion, P < 0.05). We conclude that ODFR contribute not only to myocardial stunning but also to neural stunning of sympathetic cardiac innervation after brief ischemia.

Animals↗
PubMed1997

Sympathetic and cardiorenal actions of leptin.

Body weight is tightly regulated physiologically. The recent discovery of the peptide hormone leptin has permitted more detailed evaluation of the mechanisms responsible for control of body fat. Leptin is almost exclusively produced by adipose tissue and acts in the CNS through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback mechanism to control adipose tissue mass. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, and endocrine function. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Studies from our laboratory suggest that leptin also increases sympathetic nerve activity to kidney, hindlimb, and adrenal gland. However, systemic administration of leptin does not acutely increase arterial pressure or heart rate in anesthetized animals. Thus, longer-term exposure to hyperleptinemia may be necessary for full expression of the expected pressor effect of renal sympathoexcitation. Alternatively, leptin may have additional cardiovascular actions to oppose sympathetically mediated vasoconstriction. Leptin in high doses increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin appears to increase systemic insulin sensitivity, even in the absence of weight loss. Although we are at an early stage of understanding, we speculate that abnormalities in the actions of leptin may have implications for the sympathetic, cardiovascular, and renal changes associated with obesity.

Adipose Tissue↗
PubMed1997

Effects of leptin on insulin sensitivity in normal rats.

To determine whether leptin has insulin sensitizing effects in normal rodents, we measured plasma glucose and insulin concentrations in male Sprague-Dawley rats treated with leptin or vehicle by continuous s.c. infusion for 48 h. In additional experiments, we examined the acute effect of i.v. leptin upon insulin sensitivity under conditions of clamped glycemia. Subcutaneous leptin was administered at 10.0 and 1.0 microg/h. To avoid confounding effects of differences in food intake, both leptin- and vehicle-treated rats were fasted during the 48-h period of infusion. Infusion of leptin, 10 microg/h, significantly reduced both plasma glucose and insulin. Leptin, 1.0 microg/h, also decreased plasma glucose and insulin, although the effects on insulin did not achieve statistical significance. Leptin at either dose did not alter body weight or epididymal fat mass compared with vehicle treated controls. Leptin, 10 microg/h, decreased circulating insulin-like growth factor-1 levels. No differences in GLUT-4 content in either in brown or epididymal fat were observed as a result of leptin-treatment. Leptin, 10 microg/h, significantly decreased urine osmolality, increased water intake, and reduced renal potassium excretion compared with vehicle-infused rats. In additional rats, we measured the acute effect of i.v. leptin on insulin sensitivity determined as whole body glucose utilization during hyperinsulinemic glucose clamps performed at glucose targets of 60 and 90 mg/100 ml. Glucose utilization was increased by 29% during the last 135 min of glycemia clamped at 60 mg/100 ml (P < 0.05) and by 30% during the last 135 min of glycemia clamped at 90 mg/dl (P < 0.01) in rats infused with leptin compared with vehicle. In summary, leptin increased insulin sensitivity in normal rats both under fasting conditions and in the presence of hyperinsulinemia at clamped glucose. These effects did not appear dependent on altered body weight. Leptin also altered salt and water metabolism under fasting conditions resulting in increased water intake and more dilute urine.

Adipose Tissue, Brown↗
PubMed1997

Cytokine-mediated erythroid maturation in megakaryoblastic human cell line HU-3.

HU-3 is a bipotential cell line derived from the bone marrow of a patient with megakaryoblastic leukemia. Continuously proliferating cells evolved from cultures supplemented with nutrient medium containing human serum and granulocyte-macrophage (GM) colony-stimulating factor (CSF). Growth and viability of the HU-3 cell line was strictly dependent on the presence of GM-CSF, interleukin-3, or thrombopoietin (Tpo). Independent of the cytokine, the cells constitutively expressed a well-defined megakaryocyte phenotype, with 70-95% of the cells positive for CD4, CD34, and platelet glycoproteins Ib, IIb, and IIIa. Fewer than 10% of the cells had detectable erythroid glycophorin A. Erythropoiesis was induced in HU-3 parental cells and five clones harvested from culture medium containing GM-CSF by replacement of the growth-promoting cytokine with stem cell factor (SCF) and erythropoietin (Epo). During the first week of induction, the proliferating cells slowly acquired erythroid markers. Concomitant with a maturational growth arrest during the second week, there was a rapid accumulation of gamma and beta globin chains and benzidine reactive hemoglobin, as well as a distinct erythroid morphology. The culture declined after 12 days because of the transient effect of SCF in maintaining viability. Parental and cloned cells cultured for 7 days in Tpo-supplemented medium responded to the synergistic growth effect of SCF and Epo but were markedly suppressed in their yield of hemoglobinized cells. Recycling of the cells in GM-CSF for 4 days did not reverse the suppressive effect of Tpo. These results suggest a role for Tpo in the lineage commitment of erythromegakaryocytic progenitors by suppressing the erythroid potential. With its constitutive megakaryocyte phenotype and inducible erythroid potential, the self-renewing bipotential HU-3 cell line may represent one of the earliest stages in megakaryocytopoiesis before irreversible lineage commitment. The suppressive effect of Tpo on the erythroid potential of cloned HU-3 cells enhances the value of this cell line for deciphering the molecular and cellular events during lineage commitment of progenitor cells.

Cell Division↗
PubMed1996

Locally advanced breast cancer: long-term results of a randomized trial comparing primary treatment with tamoxifen or radiotherapy in post-menopausal women.

We have previously reported the early results of a randomized cross-over study of radical radiotherapy vs tamoxifen in patients with locally advanced breast cancer. This study has now recruited 143 patients with a median time from randomization of almost 10 years for both groups. Seventy-three patients received 20 mg tamoxifen twice daily, and 70 had primary radiotherapy at a dose of 40 Gy, which is a lower dose than currently administered. The treatment groups were similar in age, size of tumour and oestrogen receptor status. There was no significant difference between the two treatment groups for the combined initial response and static disease rates (89% for radiotherapy and 78% for tamoxifen, P = 0.15). The median duration of initial response was 12 months for both groups. When patients crossed over to the alternative therapy on local relapse, there was no difference in response/static disease rates (P = 0.34) and duration of response (P = 0.76). A non-significant prolongation of the metastatic-free interval in favour of tamoxifen (P = 0.08) was identified, although there was no difference in survival outcome (P = 0.38). This study shows that in this group of patients primary tamoxifen offers a similar clinical benefit to primary radiotherapy at a dose of 40 Gy, and is therefore an acceptable alternative primary treatment.

Aged↗
PubMed1996

Carcinoma of the larynx and hypopharynx in the elderly.

The outcome of a series of 68 patients over 75 years old with carcinoma of the larynx, and 33 patients over 75 years old with hypopharyngeal carcinoma managed by a single oncological team during a 10-year period was studied. Sixty-one of the patients with laryngeal carcinoma were treated with curative intent. The actuarial 3-year survival rate of the whole group was 45%. This contrasts with hypopharyngeal carcinoma in which we found a 3-year survival of 11% with only 17 of the 33 patients suitable for treatment with curative intent. In view of the anticipated poor prognosis of hypopharyngeal carcinoma in the elderly we conclude that treatment should be directed towards palliation without radical surgery whenever possible.

Aged↗
PubMed1996

Analysis of p53 and mdm-2 expression in 18 patients with Sézary syndrome.

Sézary syndrome is a leukaemic form of cutaneous T-cell lymphoma which presents with multiple cytogenetic abnormalities and responds poorly to chemotherapy. Because of the importance of the p53 tumour suppressor in maintaining genomic stability and in sensitizing transformed cells to DNA damaging agents, we looked for alternations which may affect p53 functions in 18 patients with Sézary syndrome. Cytogenetic analysis suggested frequent p53 gene inactivation since 6/18 patients had loss of one copy of 17p. However, single-strand conformational polymorphism (SSCP) revealed that p53 gene mutations are relatively rare, occurring in only two of 18 Sézary patients. Neither of these two patients was missing a copy of 17p. Possible abnormalities of p53 pathway function through mdm-2 over-expression were also investigated. Although all 18 patients had normal levels of mdm-2 RNA 4/18 over-expressed mdm-2 protein. One patient with advanced disease and the highest percentage of malignant cells overexpressed mdm-2 protein and possessed a nonsense p53 gene mutation. The five patients with abnormalities of p53 or mdm-2 were found to have significantly highest absolute lymphocyte counts and higher absolute numbers of Sézary cells (P=0-021 and 0.027 respectively). In summary, molecular alternations of 17p and potential p53 pathway abnormalities are a common event in Sézary syndrome and appear to be associated with more advanced disease.

Adult↗
PubMed1996

Shared care: a review of the literature.

This review examines broad issues of concern regarding the primary/secondary care interface. The main purpose was to identify areas of good practice which could be adapted for more general use. One of the most fundamental aspects identified was communication, which is discussed in some detail. Also covered are shared prescribing and disease management. The data suggest that the most effective system(s) of shared care has yet to be established. Further qualitative and economic evaluations are required, taking into account patient preferences. Although the literature does describe certain practice exemplars, it is clear that inter- and intra-professional communication continues to be a problem. Whilst information technology may provide some of the solutions, it is concluded that a culture change, which compels health professionals to make sharing of patient information a much higher priority, is required.

Continuity of Patient Care↗
PubMed1996

Aging is not accompanied by sympathetic hyperresponsiveness to air-jet stress.

It has been postulated that sympathetic nervous system reactivity to acutely applied stress is increased with age. We investigated the autonomic and hemodynamic adjustments to air-jet stress in 9 mature (12-mo-old) and 11 senescent (24-mo-old) Fischer 344 rats. Rats were instrumented with arterial and venous catheters, flow probes around the renal artery, and nerve electrodes on the ipsilateral renal nerve. After the rats recovered from surgery, blood pressure, heart rate, renal blood flow, and renal sympathetic nerve activity were recorded during control conditions and during an 8-min continuous air-jet application. Renal resistance and the low (0.01-0.20 Hz)- and mid-frequency (0.20-0.50 Hz) power of blood pressure were computed off-line. The air jet induced an increase in blood pressure, heart rate, renal resistance, renal nerve activity, and blood pressure power in the low- and mid-frequency ranges in both groups. Blood pressure and low-frequency blood pressure power increased less, and the elevations in renal resistance and renal nerve activity were of shorter duration in senescent compared with mature rats. These data suggest that sympathetic responsiveness to air-jet stress is not enhanced with increasing age.

Aging↗
PubMed1996

Nonuniform sympathetic nerve responses after sustained elevation in arterial pressure.

We tested the hypothesis that sustained increases in mean arterial pressure (MAP) produce nonuniform changes in regional sympathetic nerve discharges (SND) after the return of MAP to control levels. Renal, adrenal, splanchnic, and lumbar SND were recorded before, during, and after a 30-min elevation in MAP produced by phenylephrine (PE) infusion in alpha-chloralose-anesthetized spontaneously hypertensive (SH) rats. SND remained reduced from control values after PE infusion, despite the return of MAP to control levels. Importantly, the duration of poststimulus sympathoinhibition was significantly less in adrenal and splanchnic SND compared with renal and lumbar SND. In sinoaortic-denervated SH rats, SND remained at control levels during and after PE infusion. Simultaneous recordings of aortic depressor nerve (ADN) activity and SND demonstrated that prolonged renal and lumbar sympathoinhibition occurred even when ADN activity fell below control levels after PE infusion. We conclude that poststimulus responses of efferent SND in SH rats are regionally nonuniform and that renal and lumbar sympathoinhibitory responses are not mediated solely by prolonged increases in afferent baroreceptor nerve activity.

Adrenal Glands↗
PubMed1996

Genetic characterization of the "new" Harlan Sprague Dawley Dahl salt-sensitive rats.

In 1994, it was reported that Dahl salt-sensitive SS/Jr rats supplied by Harlan Sprague Dawley were genetically contaminated and resistant to the pressor effects of a high salt diet. Harlan Sprague Dawley subsequently developed new pedigree expansion and production colonies from their foundation colony to supply new, purportedly inbred, Harlan Sprague Dawley SS/Jr (S(HSD)). To evaluate the genetic integrity and salt sensitivity of thse new S(HSD), we performed genotyping (microsatellite DNA markers) and phenotyping (radiotelemetric arterial pressure) of 12 S(HSD), 16 "authentic" SS/Jr from the inbred colony of John Rapp (S(Rapp)), 9 Harlan Sprague Dawley salt-resistant SR/Jr (R(HSD)), and (genotyping only) 6 known "contaminated" Harlan Sprague Dawley Dahl SS/Jr (S*). In the genotyping studies, 20 of 22 markers revealed polymorphisms between S(Rapp) and S* and 18 were polymorphic between S(Rapp) and R(Rapp), but none of the 22 markers revealed polymorphisms between S(Rapp) and the new S(HSD). The phenotyping studies showed that during an ultra-low salt diet, mean arterial pressure was higher (P < .05) in both authentic S(Rapp) (129 +/- 2 mm Hg; mean +/- SE) and new S(HSD) (120 +/- 2 mm Hg) than in R(HSD) (93 +/- 1 mm Hg). A high salt diet increased mean arterial pressure in every S(HSD) and S(Rapp). Increases in mean arterial pressure after 4 weeks of a high salt diet were significantly (P < 0.05) greater in authentic S(Rapp) (+51 +/- 3 mm Hg) than in new S(HSD) (+39 +/- 3 mm Hg). In addition, salt-induced mortality was significantly greater in S(Rapp) (62.5%) than S(HSD) (8.3%) after 8 weeks (P < 0.01). S(HSD) were genotypically indistinguishable from S(Rapp), had an elevated arterial pressure on a low salt diet, and had a pressor response to salt. Thus, the new S(HSD) supplied to us had several characteristics of inbred Dahl SS/Jr and did not have evidence of the previously detected genetic contamination. However, phenotypic characteristics such as body weight, salt-induced hypertension, and mortality were significantly different in S(HSD) compared with S(Rapp). This may reflect genetic differences between these two strains or differences in environmental factors and suggests that the S(HSD) and S(Rapp) may now constitute distinct substrains of Dahl SS/Jr.

Animals↗
PubMed1995

Core and comprehensive health care services: 2. Quality-of-care issues.

Health care services are being evaluated and redefined. Terms such as "medically necessary" and "comprehensive" are being supplanted by "core", "basic" and "optional." Quality-of-care concepts and analysis can assist decision making about which services should be insured, core services. A service is more likely to remain or become insured, and core to the system if it satisfies the key dimensions of high quality: effectiveness, appropriateness, efficiency, patient acceptance and safety. Quality of care, combined with ethical and economic considerations, provides an analytic framework for deciding whether services should be insured.

Comprehensive Health Care↗
PubMed1995

Safe selection criteria for breast conservation without radical excision in primary operable invasive breast cancer.

In a previous series from this unit of 263 women with primary operable breast cancer treated by macroscopic lumpectomy and breast irradiation, local recurrence was high. An audit at a median follow up of 36 months showed 56 (21%) ipsilateral breast recurrences. Eighteen of these recurrences were aggressive and uncontrolled. Multivariate analysis shows patient age, lymphovascular invasion, tumour size and nodal status to be predictive of local recurrence (Locker AP, et al., Br J Surgery 1989, 76, 890-894). New selection criteria for breast conservation were defined based on these data and also on securing an adequate clear margin of excision. In a subsequent prospective series of 275 women fulfilling these criteria, 6 women (2.2%) developed ipsilateral breast recurrence at the same median follow up of 36 months. In none was this uncontrolled and aggressive. Breast conservation, without radical excision, is safe as long as the selection criteria described are followed.

Adult↗
PubMed1995

Differential sympathetic nerve responses to nitric oxide synthase inhibition in anesthetized rats.

Recent studies have suggested that the interaction between the sympathetic nervous system and nitric oxide (NO) or nitrosyl factors may be an important means by which arterial blood pressure is regulated. We investigated whether NO synthase (NOS) inhibition modulates basal sympathetic nerve discharge (SND) in baroreceptor-innervated and -denervated, chloralose-anesthetized Sprague-Dawley rats. We recorded mean arterial pressure (MAP), renal SND, and lumbar SND before and after administration of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg iv). Two minutes after L-NAME administration in baroreceptor-innervated rats, MAP increased (+23 +/- 3 mmHg), whereas renal (-45 +/- 6%, n = 7) and lumbar (-35 +/- 2%, n = 6) SND significantly decreased from control levels. These changes persisted for up to 20 min after L-NAME administration. In baroreceptor-denervated rats, L-NAME increased MAP (+40 +/- 6 mmHg) and decreased lumbar SND (n = 7) (-37 +/- 10% from control at 20 min post-L-NAME). In contrast, renal SND progressively increased (+33 +/- 8% at 20 min post-L-NAME) from control after L-NAME administration in baroreceptor-denervated rats (n = 7). These results demonstrate that NOS inhibition can produce nonuniform changes in SND in baroreceptor-denervated rats and suggest that endogenous nitrosyl factors provide tonic excitation to lumbar SND, whereas they provide a tonic restraint to renal SND.

Animals↗
PubMed1995

Renal sympathetic nerve activity is increased in obese Zucker rats.

A low level of sympathetic nerve activity (SNA) to brown adipose tissue has been found in genetically obese Zucker rats and may promote obesity through decreased thermogenesis. In contrast, acquired obesity is reportedly associated with increased SNA. To determine whether low SNA levels in obese Zucker rats extend to the kidney, we compared baseline levels of renal SNA in obese and lean conscious unrestrained Zucker rats fed for 2 weeks on low salt (0.4% NaCl) and high salt (8.0% NaCl) diets. Baseline renal SNA was calculated from multifiber recordings obtained before death under conscious, resting conditions and after death. Body weight averaged 490 +/- 12 g (mean +/- SEM) in obese rats (n = 17) and 339 +/- 7 g in lean rats (n = 19). Mean arterial pressure did not differ in obese and lean Zucker rats fed the low salt diet. However, on the high salt diet, mean arterial pressure was significantly higher in obese rats (n = 8) than in lean rats (n = 9) (113 +/- 3 and 101 +/- 3 mm Hg, respectively; P < .05). Baseline renal SNA was approximately 2 to 2.5 times higher (P < .05) in obese rats than in lean rats in all groups. These studies suggest that obese Zucker rats have heightened levels of SNA to the kidney in contrast to reduced SNA to brown adipose tissue.

Animals↗
PubMed1995

Role of adenosine in postischemic dysfunction of coronary innervation.

We sought to determine the role of adenosine in the sustained but reversible decrease in cardiac neurotransmission that occurs after brief ischemia. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, and left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCX) flow velocities. Changes in coronary vascular resistance were measured during bilateral stimulation of the stellate ganglia. After beta-adrenergic blockade and bilateral vagotomy, stellate stimulation increased coronary vascular resistance in the LAD and LCX beds 28 +/- 2% and 30 +/- 3%, respectively. After a 15-minute infusion of adenosine into the LAD, the peak increase in LAD resistance was significantly reduced (18 +/- 2%) compared with LCX (34 +/- 5%) and control (P < .05, n = 6) resistance. The LAD response after infusion of the vasodilator papaverine was unchanged (n = 6). Intracoronary infusion of adenosine deaminase (n = 10) but not vehicle (n = 5) into the LAD during a 15-minute LAD occlusion prevented the attenuation in constriction to stellate stimulation. We conclude that adenosine, exogenously infused or endogenously produced, is capable of reducing cardiac neurotransmission.

Adenosine↗