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Biomedical subjects

J Shepherd

Publications and source records attributed to J Shepherd.

At least 145 records · Page 8Linked to original sources
PubMed1995

Metabolism of apolipoprotein B in primary moderate hypercholesterolaemia: effects of acipimox and cholestyramine therapy.

The effects of combined therapy with acipimox (1250 mg/day) and cholestyramine (20 g/day) were examined in a group of 7 subjects with primary moderate hypercholesterolaemia (total cholesterol >=7 mmol/L). Radiolabeled VLDL subfraction turnovers were performed at baseline, during acipimox therapy and during combined therapy. Acipimox and combined therapies lowered plasma low density lipoprotein (LDL)-cholesterol by 20% (P<0.001) and 27% (P<0.001) respectively. The marked fall in LDL-cholesterol associated with acipimox therapy, was due to a reduced production rate of LDL (apolipoprotein) apoB. This is shown to be a result of reduced direct LDL apoB production, reduced IDL to LDL transfer consistent with inhibition of hepatic triglyceride lipase, and with a reduction in the overall throughput of VLDL1 apoB. With combined therapy both reduced production and increased catabolism of apoB containing LDL precursors and of LDL itself have to be invoked to explain the fall in plasma LDL-cholesterol.

Adult↗
PubMed1995

The West of Scotland Coronary Prevention Study: a trial of cholesterol reduction in Scottish men.

The West of Scotland Coronary Prevention Study is a primary prevention trial designed to test the hypothesis that reduction of serum cholesterol with pravastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) over an average of 5 years will reduce the incidence of fatal and nonfatal myocardial infarction. At entry, 6,595 men aged 45-64 years were randomized to treatment with either pravastatin (40 mg/day) or placebo. None of the men at entry had evidence of previous myocardial infarction. All were given smoking and dietary advice throughout the study, which will terminate in 1995. The principal endpoints are: (1) death due to coronary artery disease (CAD) plus nonfatal myocardial infarction; (2) death due to CAD; and (3) nonfatal myocardial infarction.

Anticholesteremic Agents↗
PubMed1995

Exclusion of the 13-kDa rapamycin binding protein gene (FKBP2) as a candidate gene for multiple endocrine neoplasia type 1.

The MEN1 gene is considered to be a tumour suppressor gene and has been localised to a 1-Mb region of 11q13.1. In this study, we report the physical localisation of the 13-kDa FK506 and rapamycin binding protein gene (FKBP2) to the cosmid marker D11S750, which is located inside the MEN1 region of non-recombination. The product of this gene is involved in signal transduction and is thus a candidate cell growth regulator or tumour suppressor gene. Northern studies have revealed that FKBP2 is expressed in those tissues predisposed to hyperplasia in MEN1; however, single-strand conformation polymorphism analysis and direct sequencing of DNAs from affected members of MEN1 kindreds and sporadic tumour DNAs have been performed and no mutations have been found. These studies exclude FKBP2 as a candidate gene for MEN1.

Base Sequence↗
PubMed1995

Danazol and plasma lipoprotein metabolism.

The potential long-term impact of danazol on coronary risk hinges on its effect on lipoprotein metabolism rather than its influence on total plasma lipids. Danazol may exert a regulatory influence on three key processes in lipoprotein metabolism: hepatic lipase activity; low-density lipoprotein receptor function; and lecithin:cholesterol acyl-transferase activity. Danazol decreases plasma fibrinogen and lipoprotein (a) levels, promotes fibrinolysis and causes a rise in plasminogen. Such changes are beneficial as they inhibit the process of thrombosis. Androgenic properties of danazol produce effects of plasma lipids and lipoproteins which oppose estrogen-induced changes. The usual recipients of danazol therapy are premenopausal females, in whom the absolute risk of ischemic heart disease is low. If the drug were shown to increase ischemic heart disease risk, detrimental factors must be weighted against its considerable and proven clinical benefits.

Coronary Disease↗
PubMed1995

Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species and insulin resistance.

We have studied low density lipoprotein (LDL) subclass distribution in a group of male patients with non-insulin-dependent diabetes mellitus (NIDDM) and investigated its relationships to fasting and postprandial triglyceride (TG)-rich lipoproteins, insulin resistance, lipoprotein lipase (EC 3.1.1.3; LPL), hepatic lipase (EC 3.1.1.34; HL), lecithin:cholesterol acyl transferase (EC 2.3.1.43; LCAT) and cholesteryl ester transfer protein (CETP) activities. LDL was subfractionated by density gradient ultracentrifugation. Postprandial lipoproteins were measured after an oral fat load using retinyl palmitate as a marker for intestinal TG-rich lipoproteins. Hypertriglyceridaemic NIDDMs (HTG) had a preponderance of small dense LDL particles present in the plasma and reduced amounts of large buoyant species when compared to normotriglyceridaemic patients (NTG) and controls. Both groups of diabetics were more insulin resistant than the controls (P < 0.05) and had raised concentrations of proinsulin (P < 0.05), although insulin content did not differ significantly. 32-33 split proinsulin (SPI) was the major insulin-like molecule present in HTG and was present in significantly higher amounts in these patients (P < 0.05) than either NTG or control subjects and correlated significantly with the presence of small dense LDL particles. After a test meal, the postprandial chylomicron response was greater in HTG than either NTG diabetics or controls (P < 0.05). Chylomicron remnants were present to a greater extent in HTG than in NTG and controls (P < 0.05), although in this case NTG also contained more chylomicron remnants than control subjects (P < 0.05). There was no difference in the LPL activity, CETP and LCAT between diabetics and controls, whereas an increase in hepatic lipase activity was seen in the HTG diabetics (P < 0.05). Both CETP and LCAT activities increased postprandially. Multivariate analysis showed that TG, HDL content and HL activity were the most important determinants of small dense LDL concentration in the fasting state (R2 = 67%). Postprandially, chylomicron remnant clearance, HL and insulin resistance were the major determinants (R2 = 61%) of LDL-III.

Case-Control Studies↗
PubMed1995

Carcinosarcoma of the ovary: incidence, prognosis, treatment and survival of patients.

BACKGROUND: Carcinosarcomas (also known as malignant mixed mullerian tumours) are rare malignant neoplasms that histologically contain both epithelial and stromal components. METHODS AND MATERIALS: All cases of carcinosarcoma of the ovary presenting to the Royal Marsden Hospital from January 1975 to August 1993 were retrospectively analysed and the histological sections reviewed. RESULTS: There were 37 cases of carcinosarcoma of the ovary representing 1.12% of the ovarian neoplasms seen at this institution. The median age of presentation was 65 years (range 26-85 years) and 70% of patients had advanced disease (FIGO stage III and IV). Clinical features at presentation were similar to those encountered in patients with epithelial ovarian cancer. The overall median survival was 247 days with 40% 1-year survival and 6% 5-year survival for all stages. Early FIGO stage was the only independent prognostic factor for survival. Histology (homologous/heterologous subtypes; grade, type or percentage of the epithelial component) had no significant impact on survival. Adjuvant radiotherapy may have a role and single agent platinum compounds are active, giving a response rate of 35%. CONCLUSIONS: The management of this tumour is difficult and randomised trials are needed to accrue sufficient patient numbers to demonstrate optimal therapy.

Adult↗
PubMed1995

Current concepts in the treatment of familial hypercholesterolaemia.

Molecular biological studies in familial hypercholesterolaemia have indicated that the severity of the disease, at least in terms of circulating LDL-cholesterol levels, varies depending on the kind of structural defect found in the LDL receptor gene. This may well influence individual risk and signal that more aggressive therapeutic intervention is required. The discovery of the statins has revolutionized therapy for the familial hypercholesterolaemia heterozygote, but the prognosis for the rare homozygote, who fails to respond adequately to therapy, remains poor unless extreme measures are taken.

Anticholesteremic Agents↗
PubMed1995

Genetic mapping of the multiple endocrine neoplasia type 1 locus at 11q13.

Oncogenesis of tumours related to multiple endocrine neoplasia type 1 (MEN1) is associated with somatic deletions involving the MEN1 locus at chromosomal region 11q13, suggesting inactivation of a tumour-suppressor gene in this region. Here we describe the localization of the MEN1 gene to a 900-kb region, based on linkage analysis in affected families and deletion mapping of MEN1-associated tumours. In addition, a set of microsatellite markers mapped to the 11q11-13 region were used for linkage analysis in a large Tasmanian MEN1 pedigree, demonstrating the usefulness of these markers for presymptomatic testing in affected families.

Adult↗
PubMed1995

Fully automatic determination of soil bacterium numbers, cell volumes, and frequencies of dividing cells by confocal laser scanning microscopy and image analysis.

We describe a fully automatic image analysis system capable of measuring cell numbers, volumes, lengths, and widths of bacteria in soil smears. The system also determines the number of cells in agglomerates and thus provides the frequency of dividing cells (FDC). Images are acquired from a confocal laser scanning microscope. The grey images are smoothed by convolution and by morphological erosion and dilation to remove noise. The background is equalized by flooding holes in the image and is then subtracted by two top hat transforms. Finally, the grey image is sharpened by delineation, and all particles above a fixed threshold are detected. The number of cells in each detected particle is determined by counting the number of local grey-level maxima in the particle. Thus, up to 1,500 cells in 10 fields of view in a soil smear are analyzed in 30 min without human intervention. Automatic counts of cell numbers and FDC were similar to visual counts in field samples. In microcosms, automatic measurements showed significant increases in cell numbers, FDC, mean cell volume, and length-to-width ratio after amendment of the soil. Volumes of fluorescent microspheres were measured with good approximation, but the absolute values obtained were strongly affected by the settings of the detector sensitivity. Independent measurements of bacterial cell numbers and volumes by image analysis and of cell carbon by a total organic carbon analyzer yielded an average specific carbon content of 200 fg of C (mu)m(sup-3), which indicates that our volume estimates are reasonable.

Journal Article↗
PubMed1995

Relations between plasma lipids and postheparin plasma lipases and VLDL and LDL subfraction patterns in normolipemic men and women.

VLDL1, VLDL2, IDL, and LDL and its subfractions (LDL-I, LDL-II, and LDL-III) were quantified in 304 normolipemic subjects together with postheparin plasma lipase activities, waist/hip ratio, fasting insulin, and glucose. Concentrations of VLDL1 and VLDL2 rose as plasma triglycerides (TGs) increased across the normal range, but the association of plasma TGs with VLDL1 showed a steeper slope than that of VLDL2 (P < .001). Plasma TG level was the most important determination of LDL subfraction distribution. The least dense species, LDL-I, decreased as the level of this plasma lipid rose in the population. LDL-II in both men and women exhibited a positive association with plasma TG level in the range 0.5 to 1.3 mmol/L, increasing from about 100 to 200 mg/dL. In contrast, within this TG range the LDL-III concentration was low (approximately equal to 30 mg/dL) and changed little. As plasma TGs rose from 1.3 to 3.0 mmol/L there was a significant fall in LDL-II concentration in men (r = .45, P < .001) but not in women (r = .1, NS). Conversely, above the TG threshold of 1.3 mmol/L there was a steeper rise in LDL-III concentrations in men than in women (P < .001); 42% of the men had and LDL-III in the range associated with high risk of heart disease ( > 100 mg lipoprotein/dL plasma) compared with only 17% of the women. Other influences on the LDL subfraction profile were the activities of lipases and parameters indicative of the presence of insulin resistance. Men on average had twice the hepatic lipase activity of women. This enzyme was not strongly associated with variation in the LDL subfraction profile in men, but in women it was correlated with LDL-III (r = 39, P = .001) and remained a significant predictor in multivariate analysis. Increased waist/hip ratio, fasting insulin, and glucose were correlated negatively with LDL-I and positively with LDL-III, primarily, at least in the case of LDL-III, through raising plasma TGs. On the basis of these cross-sectional observations we postulate the following model for the generation of LDL-III. Subjects develop elevated levels of large TG-rich VLDL1 for a number of reasons, including failure of insulin action. The increase in the concentration of VLDL1 expands the plasma TG pool, and this, via the action of cholesteryl ester transfer protein (which facilitates neutral lipid exchange between lipoprotein particles), promotes the net transfer of TGs into LDL-II, the major LDL species.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia.

The apoB arginine-to glutamine change at codon 3500 has become established as a cause of failure of binding of the LDL particle to its receptor and the consequent hypercholesterolemia of familial defective apoB 100. A search for further similar mutations was undertaken by systematic screening of a candidate region of the apoB gene from individuals with hypercholesterolemia. Polymerase chain reaction and denaturing gradient gel electrophoresis were used. We describe two families in which a different mutation in the codon 3500 causes an arginine-to-tryptophan substitution. Most adults in these families who have this mutation have hypercholesterolemia. LDL derived from all who have inherited the mutation is dysfunctional in that it allows only poor growth of an LDL cholesterol-dependent cell line. We conclude that this arginine 3500 is essential to the function of apoB and that its loss and replacement by glutamine or tryptophan is responsible for the hypercholesterolemia of familial defective apoB 100.

Adolescent↗
PubMed1995

The demand for primary dental care at a dental teaching hospital, 1989 and 1993.

The demand for, and provision of, primary dental care was investigated in a teaching hospital setting in 1989 and 1993 - a period which saw the introduction of the new dental contract and the publication of the Poswillo report on general anaesthesia and sedation. Five hundred patients who attended the primary care department for the first time at the University of Wales Dental Hospital were interviewed in May/June 1989, and a further 520 patients were interviewed in May/June 1993. Self-referrals increased from 260 patients (52%) in 1989 to 352 patients (68%) in 1993. The proportion of patients who did not have a general dental practitioner (GDP) increased from 32% (160) in 1989 to 39% (202) in 1993. More patients registered with a dentist self-referred in 1993 compared to those in 1989, reportedly because of inability to obtain an appointment with their own GDP (88), rather than because of cost (17). Over the four-year period there was an increase in demand for treatment of early stage (pulpitic) dental infection from 32% to 40%, and a decrease in relation to end-stage infection (dentoalveolar abscess) from 11% to 6%. This 'safety net' role of dental hospitals needs to be taken into account when contracting for services.

Adolescent↗
PubMed1995

The relevance of health state utilities to lower third molar surgery.

A study of the attitudes of 102 arts and science undergraduate students was carried out to establish relative utility values, that is the participants own assessments, for possible outcomes of surgical intervention and non-intervention in lower third molar management. Using a standardised visual analogue scale, respondents were asked to rate 17 outcomes of treatment presented to them by means of short descriptions (vignettes). Ranking of mean utility values showed that post operative complications were considered to be a greater handicap than the sequelae of leaving third molars in situ. The respondents considered that the effects of irreversible lingual and inferior dental nerve damage reduced health to a major degree, and that normally encountered post operative complications such as moderate pain, swelling and trismus were a greater handicap than recurrent mild/moderate pericoronitis.

Adult↗