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Biomedical subjects

M Morgan

Publications and source records attributed to M Morgan.

At least 109 records · Page 6Linked to original sources
PubMed1999

The Gal3p-Gal80p-Gal4p transcription switch of yeast: Gal3p destabilizes the Gal80p-Gal4p complex in response to galactose and ATP.

The Gal3, Gal80, and Gal4 proteins of Saccharomyces cerevisiae comprise a signal transducer that governs the galactose-inducible Gal4p-mediated transcription activation of GAL regulon genes. In the absence of galactose, Gal80p binds to Gal4p and prohibits Gal4p from activating transcription, whereas in the presence of galactose, Gal3p binds to Gal80p and relieves its inhibition of Gal4p. We have found that immunoprecipitation of full-length Gal4p from yeast extracts coprecipitates less Gal80p in the presence than in the absence of Gal3p, galactose, and ATP. We have also found that retention of Gal80p by GSTG4AD (amino acids [aa] 768 to 881) is markedly reduced in the presence compared to the absence of Gal3p, galactose, and ATP. Consistent with these in vitro results, an in vivo two-hybrid genetic interaction between Gal80p and Gal4p (aa 768 to 881) was shown to be weaker in the presence than in the absence of Gal3p and galactose. These compiled results indicate that the binding of Gal3p to Gal80p results in destabilization of a Gal80p-Gal4p complex. The destabilization was markedly higher for complexes consisting of G4AD (aa 768 to 881) than for full-length Gal4p, suggesting that Gal80p relocated to a second site on full-length Gal4p. Congruent with the idea of a second site, we discovered a two-hybrid genetic interaction involving Gal80p and the region of Gal4p encompassing aa 225 to 797, a region of Gal4p linearly remote from the previously recognized Gal80p binding peptide within Gal4p aa 768 to 881.

Adenosine Triphosphate↗
PubMed1999

Follow up of workers previously exposed to silver solder containing cadmium.

OBJECTIVES: To study longitudinal biological monitoring data on urinary and blood cadmium collected in a small cohort of nine workers who had been brazing for several years with solders containing cadmium. METHODS: Cadmium was measured by neutron activation analysis in livers and kidneys, and estimates of renal function were carried out in 1983 and 1995. During the intervening period exposure to cadmium was dramatically reduced by local exhaust ventilation control and substitution of the solder containing cadmium. RESULTS: From urinary protein measurements there was evidence within the group of increasing renal tubular damage over the 12 year period, even though exposure to cadmium was dramatically reduced over this period and almost eliminated by 1995. There was no evidence from serum creatinine of decreasing glomerular filtration rate, and the renal tubular handling of calcium, phosphate, or urate had not worsened significantly. Blood and urinary cadmium concentrations reduced significantly over the 12 year period but were still substantial in 1995. Blood cadmium concentrations tended to reflect cadmium body burden in 1995 when exposure had been low for several years, and decreased most significantly during 1983-90. By contrast urinary cadmium concentrations only decreased significantly from about 1990 onwards. Urinary cadmium was not significantly correlated with liver or kidney cadmium concentration in either 1983 or 1995. This may be due to the level of tubular dysfunction in the cohort. Calculated cumulative excretion of cadmium over the 12 year period was substantially greater than the loss of cadmium measured in livers and kidneys and the derived loss in body burden. Reasons for this are discussed. It is possible that in cohorts, where renal damage is apparent, urinary concentrations reflect a substantial component of current exposure rather than stored body losses. CONCLUSIONS: The data reinforce the concept that blood cadmium concentrations may not always reflect recent exposure, but may reflect body burden derived from historical exposure depending on the degree of current exposure; and that the decline in urinary and blood cadmium measurements after removal from, or reduction in, exposure will be slow and depend on the historical body burden.

Adult↗
PubMed1999

Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86.

PURPOSE: The goal of the second German Soft Tissue Sarcoma Study CWS-86 (1985 to 1990) was to improve the prognosis in children and adolescents with soft tissue sarcoma by means of a clinical trial comprising intensive chemotherapy and risk-adapted local therapy. PATIENTS AND METHODS: There were 372 eligible patients. A staging system based on the postsurgical extent of disease was used. Chemotherapy consisted of vincristine, dactinomycin, doxorubicin, and ifosfamide. Radiotherapy was administered early at 10 to 13 weeks simultaneously with the second chemotherapy cycle (32 Gy or 54. 4 Gy). The single dose was reduced to 1.6 Gy and given twice daily (accelerated hyperfractionation). RESULTS: The event-free survival (EFS) and overall survival rates at 5 years were 59% +/- 3% and 69% +/- 3%, respectively. The 5-year EFS rate according to stage was as follows: stage I, 83% +/- 5%; stage II, 69% +/- 6%; stage III, 57% +/- 4%; and stage IV, 19% +/- 6%. The outcome for patients with stage III disease who required radiotherapy was much better in the CWS-86 study compared with the CWS-81 study (5-year EFS, 60% +/- 5% v 44% +/- 6%; P =.053). The most common treatment failure was isolated local relapse, with 14% of patients relapsing at the primary tumor site. CONCLUSION: The improved design of the study incorporating risk-adapted radiotherapy allowed treatment to be reduced for selected groups of patients without compromising survival.

Adolescent↗
PubMed1999

Altered insulin secretion associated with reduced lipolytic efficiency in aP2-/- mice.

Recent studies have shown that genetic deficiency of the adipocyte fatty acid-binding protein (aP2) results in minor alterations of plasma lipids and adipocyte development but provides significant protection from dietary obesity-induced hyperinsulinemia and insulin resistance. To identify potential mechanisms responsible for this phenotype, we examined lipolysis and insulin secretion in aP2-/- mice. Beta-adrenergic stimulation resulted in a blunted rise of blood glycerol levels in aP2-/- compared with aP2+/+ mice, suggesting diminished lipolysis in aP2-/- adipocytes. Confirming this, primary adipocytes isolated from aP2-/- mice showed attenuated glycerol and free fatty acid (FFA) release in response to dibutyryl cAMP. The decreased lipolytic response seen in the aP2-/- mice was not associated with altered expression levels of hormone-sensitive lipase or perilipin. The acute insulin secretory response to beta-adrenergic stimulation was also profoundly suppressed in aP2-/- mice despite comparable total concentrations and only minor changes in the composition of systemic FFAs. To address whether levels of specific fatty acids are different in aP2-/- mice, the plasma FFA profile after beta-adrenergic stimulation was determined. Significant reduction in both stearic and cis-11-eicoseneic acids and an increase in palmitoleic acid were observed. The response of aP2-/- mice to other insulin secretagogues such as arginine and glyburide was similar to that of aP2+/+ mice, arguing against generally impaired function of pancreatic beta-cells. Finally, no aP2 expression was detected in isolated pancreatic islet cells. These results provide support for the existence of an adipo-pancreatic axis, the proper action of which relies on the presence of aP2. Consequently, aP2's role in the pathogenesis of type 2 diabetes might involve regulation of both hyperinsulinemia and insulin resistance through its impact on both lipolysis and insulin secretion.

Adipocytes↗
PubMed1999

Locum doctors in general practice: motivation and experiences.

BACKGROUND: There is evidence of dissatisfaction with locum doctors' performance, but little is known about doctors who work as locums in general practice or about their experiences of this work. AIM: To describe the motivations and experiences of doctors providing locum cover in general practices. METHOD: A postal questionnaire survey distributed to locums through organizations such as locum groups, commercial agencies, and general practices. RESULTS: Questionnaires were returned by 111 doctors currently working as locums in general practice. Four main reasons for working as a locum GP were: as a short-term option while between posts, to gain experience of different practices before commitment to one practice, to balance work and family or other commitments, to continue part-time work after retirement. One-quarter of responders intended to continue working as a locum indefinitely. The drawbacks of locum work included frustration with low status, lack of security, and difficulty accessing structured training and education. CONCLUSION: Locum doctors in general practice are a heterogeneous group that includes those who have chosen this type of work. The doctors who intend to continue as locums indefinitely represent a useful resource in primary care whose ability to provide short-term cover could be maximized. The need to control the quality of 'freelance' doctors should not overshadow the need to control the quality of their working environments.

Attitude of Health Personnel↗
PubMed1999

Elderly people's beliefs about influenza vaccination.

BACKGROUND: Influenza is an important cause of death in the elderly. The uptake of influenza vaccination, despite its effectiveness, is low. AIM: To examine beliefs about influenza vaccination in elderly patients at risk from influenza. METHOD: A qualitative study using semi-structured interviews with 50 patients aged over 75 years at risk from influenza, equally divided between vaccinated and non-vaccinated groups. RESULTS: Although they acknowledged their medical diseases, the patients regarded themselves as healthy in the sense of being independent and active. Few in either the vaccinated or non-vaccinated groups believed themselves at risk of dying from influenza even though they recognized it could be fatal for particular groups of people. Decisions to have the vaccination were based on other considerations, including whether it was thought likely to reduce (or increase) the number and severity of colds and influenza-like illnesses. Although the group with negative views towards vaccination placed more emphasis on the 'side-effects' from the vaccination (including colds and influenza), this was also common in the group who were more positive towards vaccination; however, the side-effects were interpreted in different ways. CONCLUSION: Recommendations to vaccinate according to individual risk status are not in keeping with lay beliefs. The policy to include all people aged 75 years and older as a group requiring influenza vaccination is supported by this study. The evidence that vaccination reduces morbidity from influenza and does not cause colds and influenza needs stressing.

Aged↗
PubMed1999

WMS-R and MAS correlations in a neuropsychological population.

The present study was an attempt to examine the relationship between the Wechsler Memory Scale-Revised (WMS-R; Wechsler, 1987) and the Memory Assessment Scale (MAS; Williams, 1991). The sample consisted of 51 patients referred for neuropsychological examination. Average age was 55.29 (SD = 20.94). Average education was 11.94 years (SD = 3.18). Average Full Scale IQ was 94.75 (SD = 15.44). The results showed that no MAS index correlated higher than.60 with any of the WMS-R indices. There was minimal specific prediction between instruments across each memory domain. Agreement between the tests clinically was low as well. Corrections for such factors as age, education, intelligence or diagnosis lowered the relationships between the tests although not significantly. Corrections to the correlations for the inherent reliability of each test increased correlations between the tests but still resulted in a maximum common variance of 56% (for the visual measures) down to 40% (for General Memory). These results are consistent with the argument that "general memory" is not as useful a construct as that of "general intelligence" and that these tests of general memory measure different underlying constructs. This has important impact on how we conceive and report memory test results.

Journal Article↗
PubMed1998

Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors.

Recombinant adeno-associated virus (AAV) vectors have been used to transduce murine skeletal muscle as a platform for secretion of therapeutic proteins. The utility of this approach for treating alpha-1-antitrypsin (AAT) deficiency was tested in murine myocytes in vitro and in vivo. AAV vectors expressing the human AAT gene from either the cytomegalovirus (CMV) promoter (AAV-C-AT) or the human elongation factor 1-alpha promoter (AAV-E-AT) were examined. In vitro in C2C12 murine myoblasts, the expression levels in transient transfections were similar between the two vectors. One month after transduction, however, the human elongation factor 1 promoter mediated 10-fold higher stable human AAT expression than the CMV promoter. In vivo transduction was performed by injecting doses of up to 1.4 x 10(13) particles into skeletal muscles of several mouse strains (C57BL/6, BALB/c, and SCID). In vivo, the CMV vector mediated higher levels of expression, with sustained serum levels over 800 micrograms/ml in SCID and over 400 micrograms/ml in C57BL/6 mice. These serum concentrations are 100,000-fold higher than those previously observed with AAV vectors in muscle and are at levels which would be therapeutic if achieved in humans. High level expression was delayed for several weeks but was sustained for over 15 wk. Immune responses were dependent upon the mouse strain and the vector dosage. These data suggest that recombinant AAV vector transduction of skeletal muscle could provide a means for replacing AAT or other essential serum proteins but that immune responses may be elicited under certain conditions.

Animals↗
PubMed1998

Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior.

Catechol-O-methyltransferase (COMT) is one of the major mammalian enzymes involved in the metabolic degradation of catecholamines and is considered a candidate for several psychiatric disorders and symptoms, including the psychopathology associated with the 22q11 microdeletion syndrome. By means of homologous recombination in embryonic stem cells, a strain of mice in which the gene encoding the COMT enzyme has been disrupted was produced. The basal concentrations of brain catecholamines were measured in the striatum, frontal cortex, and hypothalamus of adult male and female mutants. Locomotor activity, anxiety-like behaviors, sensorimotor gating, and aggressive behavior also were analyzed. Mutant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex. In addition, homozygous COMT-deficient female (but not male) mice displayed impairment in emotional reactivity in the dark/light exploratory model of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited increased aggressive behavior. Our results provide conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggest a role for COMT in some aspects of emotional and social behavior in mice.

Amino Acid Sequence↗
PubMed1998

Sodium butyrate upregulates Kupffer cell PGE2 production and modulates immune function.

The immunosuppressive effect of portal venous blood transfusions in organ transplantation has been well established and may be mediated by increased Kupffer cell production of the immunosuppressive arachidonic acid metabolite prostaglandin E2 (PGE2). In this study, butyrate, a short-chain fatty acid known to enhance gene transcription, is hypothesized to enhance Kupffer cell PGE2 production by altering cyclooxygenase or phospholipase A2 (PLA2) activity, thus augmenting the immunosuppressive effect of portal venous transfusion. Lewis rats were given a portal venous transfusion of Wistar-Firth blood or saline 1 h prior to Kupffer cell harvest. The in vitro effects of butyrate on Kupffer cell PGE2 production, cyclooxygenase, and PLA2 activity were assessed. Kupffer cell tumor necrosis factor-alpha (TNFalpha) production was also assessed due to its sensitivity to PGE2 and its proinflamatory effects. Kupffer cells from portally transfused animals produced significantly more PGE2 than saline-transfused controls. Addition of butyrate to the culture medium further increased PGE2 production by as much as sevenfold in Kupffer cells of portally transfused animals. Other short-chain fatty acids, propionate and hexanoate, did not increase PGE2 production. Butyrate added to Kupffer cells from transfused animals slightly upregulated inducible cyclooxygenase (COX-2) mRNA levels as measured by both Northern blot and reverse-transcriptase polymerase chain reaction and increased PLA2 activity fivefold as measured by Western blot. Kupffer cell immune function was also affected by in vitro butyrate treatment with a significant decrease in the production of TNFalpha. Thus, butyrate may be a useful immunoregulatory agent in organ transplantation protocols which seek to enhance transcription of immunosuppressive molecules.

Animals↗
PubMed1998

Expression of metalloproteinases and their inhibitors in human trophoblast continuous cell lines.

Trophoblasts cells which are derived from the outer layer of the blastocyst have developed mechanisms by which they can invade the uterus and tap into the maternal circulation. In contrast to tumor cell invasion trophoblast invasion is precisely regulated, being confined spatially to the uterus and temporally to early pregnancy. The invasive properties manifested by trophoblasts are made possible by the secretion of proteolytic enzymes which can degrade components of the extracellular matrix (ECM). A number of investigators have shown that the matrix metalloproteinases (MMPs) are important mediators of trophoblast invasion. The two type IV collagenases, MMP-2 and MMP-9, which specifically degrade type IV collagen and gelatins have been of particular interest in this respect. In this paper we examine the expression and regulation of MMPs and their inhibitors in a series of trophoblast continuous cell lines. These cell lines, ED27, ED31, ED77, and a choriocarcinoma cell line, BeWo, were initially characterized with respect to various properties, including cytokeratin, hCG, and hPL expression. We have looked at the expression of MMPs and their inhibitors in these cell lines and their in vitro invasive behavior. Using zymography and RT-PCR we show that the trophoblast cell lines produce both MMP-2 and MMP-9, while the BeWo produce only MMP-2. Using an in vitro invasion assay the trophoblast cell lines were shown to be capable of invading while the BeWo were unable to invade. These results suggest that expression of MMP-9 in these cells is crucial for invasion. We have also examined the regulation of MMP expression by cytokines and found that MMP-9 expression could be modulated by IL-1 beta in these cell lines. The data presented in this paper suggest that these trophoblast cell lines present an ideal model system to investigate the regulation of metalloproteinases in trophoblast invasion.

Cell Line↗
PubMed1998

Selective targeting of Kupffer cells with liposomal butyrate augments portal venous transfusion-induced immunosuppression.

BACKGROUND: Enhanced Kupffer cell production of the immunosuppressive arachidonic acid metabolite prostaglandin E2 (PGE2) has been shown to be a mechanism of the immunosuppressive effect of portal venous transfusions (PVT). Butyrate, a four-carbon short-chain fatty acid, has received increased attention because of its ability to enhance gene transcription. This study tested the hypothesis that the intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production and thus augments the immunosuppressive effect of PVT. METHODS: Butyrate was incorporated into liposomes and administered intravenously to Lewis rats. Control rats were administered liposomes without butyrate. Twenty-four hours after liposome injection, rats were administered a PVT of 1 ml of Wistar-Furth blood. Kupffer cells were isolated, and PGE2 and tumor necrosis factor-alpha levels were measured in the culture medium after 24 hr. Additionally, Kupffer cells from butyrate-treated and control animals were added to one-way mixed lymphocyte reaction cultures. RESULTS: Intrahepatic delivery of butyrate via liposomes increased Kupffer cell PGE2 (3800+/-1220 vs. 1010+/-119 pg/ml, P<0.05) and decreased tumor necrosis factor-alpha (1670+/-81 vs. 3360+/-415 pg/ml, P<0.01) production as compared with controls. Butyrate also augmented the Kupffer cell-mediated immunosuppression as demonstrated by significant depression of the mixed lymphocyte reaction (690+/-119 vs. 3850+/-148 cpm, P<0.01). CONCLUSION: The results support the hypothesis that intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production, and specific targeting of Kupffer cells with liposomes containing immunomodulating agents such as butyrate may be a useful means of augmenting immunosuppression protocols in organ transplantation.

Animals↗
PubMed1998

"Depression" increases "craving" for sweet rewards in animal and human models of depression and craving.

This study consisted of two experiments, one in rats and one in human volunteers, that used the identical progressive ratio (PR) operant procedure. In both experiments, responding was reinforced under a progressively increasing work requirement, and different groups of subjects received reinforcers that varied in sweetness. In experiment 1, rats were subjected to chronic mild stress, a well-validated animal model of depression. Performance under the PR schedule increased in subjects reinforced with conventional precision pellets (which contain 10% sucrose) or very sweet pellets, but not in subjects reinforced with sugar-free pellets. In experiment 2, volunteers were subjected to a depressive musical mood induction. Performance under the PR schedule increased in subjects reinforced with chocolate buttons, but not in subjects reinforced with with buttons made from the relatively unpalatable chocolate substitute carob. In experiment 2, depressive mood induction also increased chocolate craving, as measured by a novel questionnaire, and there were significant correlations between chocolate craving and chocolate-reinforced PR performance. These results suggest that performance under the PR schedule provides a measure of craving rather than reward, and that craving for sweet rewards is increased by depressive mood induction in both animal and human models. Implications for the interpretation of pharmacological studies using the PR procedure are also discussed.

Adult↗
PubMed1998

Insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 in women with premenstrual syndrome.

OBJECTIVE: To determine whether women with premenstrual syndrome (PMS) have aberrations of the GH axis as has been demonstrated in individuals with depression. DESIGN: Prospective trial. SETTING: Department of Obstetrics and Gynecology, University of California, Los Angeles. PATIENT(S): After prospective screening, 32 healthy women with PMS and 32 asymptomatic controls completed the study. INTERVENTION(S): Subjects completed a daily PMS symptom diary and a Beck Depression Inventory. They underwent phlebotomy 5 days and 12 days after the LH midcycle surge, which was identified with the use of a urinary LH detection kit. MAIN OUTCOME MEASURE(S): Serum levels of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein-3 (IGFBP-3), E2, and progesterone. RESULT(S): Levels of IGF-1, IGFBP-3, E2, and progesterone did not differ between women with prospectively documented PMS and control subjects. CONCLUSION(S): Premenstrual syndrome and affective disorder share common symptoms and possibly a common cause. Biochemical markers such as alterations in the somatotropic system often are associated with major depression. Levels of IGF-1 and IGFBP-3 did not differ between women with PMS and control subjects, supporting the concept that PMS and endogenous depression are biologically distinct entities.

Adult↗
PubMed1998

Unilateral asymptomatic carotid disease does not require surgery.

BACKGROUND AND PURPOSE: The efficacy of carotid endarterectomy (CEA) in symptomatic patients with > 70% stenosis is accepted. The stroke risk of asymptomatic patients may not justify surgical intervention. The aim of this study is to use natural history data from a single unit to identify asymptomatic patients who would benefit from CEA. METHODS: Five hundred and sixty-four patients attending for duplex ultrasound assessment of the internal carotid artery between 1986 and 1993 were retrospectively identified as focally asymptomatic with > 40% ipsilateral stenosis. Patients were traced using hospital records, family practitioner databases and the Office of Population of Census and Surveys. The number of strokes, transient ischaemic attacks and cause of death were determined. Exclusions were 15 (2.7%) asymptomatic occlusions and 49 patients (8.7%) who underwent surgery for asymptomatic disease. RESULTS: Thirteen patients (2.6%) were not traced, leaving 487 study patients. The average follow-up was 41 months (range, 1-120 months). Mean presentation age was 69 years (S.D. 8.9), and the male to female ratio was 3:2. One hundred and fifty-six (32%) patients died. Forty-three patients suffered strokes, of whom two had bilateral strokes. In total there were 16 (i/p) strokes, 25 (c/l) strokes and four strokes undetermined. The average yearly stroke rate was 2.74 per 100 person years and the (i/p) rate 1.02 per hundred person years. There was no effect of age, sex or degree of stenosis on stroke. The presence of bilateral disease did increase the risk of stroke (rel risk 2.35, p = 0.029) but not ipsilateral stroke (rel risk 1.6, p = 0.39). Patients with unilateral asymptomatic carotid disease had an all stroke rate of less than 5% in the first year after presentation and this was unaffected by degree of stenosis. In patients with bilateral disease the stroke rate in the first year after presentation increased with degree of stenosis to a stroke rate of 9.6 per 100 person years in patients with > 90% contralateral stenosis. CONCLUSIONS: This data suggests that CEA will not benefit patients with unilateral asymptomatic disease. Patients with bilateral disease warrant inclusion in clinical trials.

Aged↗