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Biomedical subjects

J Shepherd

Publications and source records attributed to J Shepherd.

At least 91 records · Page 5Linked to original sources
PubMed1998

Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals.

Heat shock or stress proteins (Hsp) are typically regarded as being intracellular proteins that have a range of functions including the maintenance of cellular integrity. Members of the Hsp70 family of molecules have been implicated in the processing and presentation of antigen and the cross reactivity of lymphocytes specific for pathogen-derived heat shock proteins with self Hsp70 has been suggested to be an underlying cause of certain autoimmune diseases. This study reports the presence of soluble Hsp70 in the peripheral circulation of normal individuals. Concentrations of soluble Hsp70 in females were approximately twice those in males. Circulating anti-Hsp70 antibodies were detected in all individuals assessed, but there were no differences between males and females. However, there was a significant correlation between soluble Hsp70 concentration and antibody levels in males, but not females. The physiological role for circulating heat shock proteins is intriguing, but currently unknown. These findings extend our previous observations that Hsp60 is present in the peripheral circulation and support the proposition that soluble heat shock proteins may play a regulatory role in either the prevention or protection of pathophysiological processes involving inadvertent immunorecognition or cross-recognition of heat shock proteins.

Adult↗
PubMed1998

A call to action.

Acute myocardial infarction remains the principal cause of death in people aged over 40 years, despite the reductions in coronary heart disease (CHD) mortality that have been observed over the past 25 years in many European countries. Consequently, there is considerable potential to decrease further the risk of cardiovascular morbidity and mortality. This can be achieved through effective lifestyle interventions and appropriate control of blood pressure and blood lipid profiles. Such a multifactorial approach to treatment is warranted because of the complex, and often synergistic relationships between independent risk factors, such as smoking and lipid levels. Guidelines have been introduced to facilitate the application of effective primary and secondary CHD prevention programmes that target multiple risk factors, according to the risk factor profile of the individual. However, it is apparent from recent surveys that physicians have been slow to adopt and implement these guidelines in clinical practice. The extent to which serum cholesterol concentrations are routinely measured is especially poor, and even when hypercholesterolaemia is identified it is frequently undertreated. Since effective lipid-lowering agents are now available and should provide substantial benefits in terms of CHD risk reductions, physicians are urged to consider lipid-lowering therapy as an essential component of both primary and secondary CHD prevention programmes.

Adult↗
PubMed1998

Detection and measurement of hypercholesterolaemia in South Africans attending general practitioners in private practice--the cholesterol monitor.

BACKGROUND: This paper reports data on the detection and management of hypercholesterolaemia in patients attending general practitioners in private practice in South Africa. METHODS: The frequency of cholesterol testing and the level at which active therapeutic intervention occurred at medical practices were monitored over a 2-year period. A sample of 200 medical practitioners was selected from private practices in major cities. Data on patients seen by the selected doctors during a 5-day monitoring period were recorded on a standardised form. RESULTS: 12,842 patients were seen by the 200 private practice GPs. More men (18.7%) than women (10.4%) had coronary heart disease (CHD), and their mean total cholesterol (TC) levels were 5.9 mmol/l and 6.0 mmol/l, respectively. Only 3.1% of the patients were reported to have familial hypercholesterolaemia (FH) and 12.8% were reported to have a family history of CHD. Reported smoking rates were exceptionally high (77.5% of women and 64.4% of men). The most commonly prescribed group of lipid-lowering agents was HMG-CoA reductase inhibitors. CONCLUSIONS: Inadequate management of hypercholesterolaemia leaves many patients with a high risk of CHD mortality in South Africa. Appropriately investigated patients with hypercholesterolaemia should receive treatment to reduce cardiovascular disease using more effective TC control programmes than are currently used in South Africa.

Adult↗
PubMed1997

The West of Scotland coronary prevention study: economic benefit analysis of primary prevention with pravastatin.

OBJECTIVE: To estimate the economic efficiency of using pravastatin to prevent the transition from health to cardiovascular disease in men with hypercholesterolaemia. DESIGN: Economic benefit analysis based on data from the West of Scotland coronary prevention study. Treatment specific hazards of developing cardiovascular disease according to various definitions were estimated. Scottish record linkage data provided disease specific survival. Cost estimates were based on extracontractual tariffs and event specific average lengths of stay calculated from the West of Scotland coronary prevention study. SUBJECTS: Men with hypercholesterolaemia similar to the subjects in the West of Scotland coronary prevention study. MAIN OUTCOME: Cost consequences, the number of transitions from health to cardiovascular disease prevented, the number needed to start treatment, and cost per life year gained. RESULTS: If 10,000 of these men started taking pravastatin, 318 of them would not make the transition from health to cardiovascular disease (number needed to treat, 31.4), at a net discounted cost of 20m Pounds over 5 years. These benefits imply an undiscounted gain of 2,460 years of life, and thus 8121 Pounds per life year gained, or 20,375 Pounds per life year gained if benefits are discounted. Restriction to the 40% of men at highest risk reduces the number needed to treat to 22.5 (5601 Pounds per life year gained (undiscounted) and 13,995 Pounds per life year gained (discounted)). CONCLUSIONS: In subjects without evidence of prior myocardial infarction but who have hypercholesterolaemia, the use of pravastatin yields substantial health benefits at a cost that is not prohibitive overall and can be quite efficient in selected high risk subgroups.

Anticholesteremic Agents↗
PubMed1997

In vivo metabolism of apo A-I and apo A-II in subjects with apo A-I(Lys107-->0) associated with reduced HDL cholesterol and Lp(AI w AII) deficiency.

Apolipoprotein A-I (apo A-I) and apolipoprotein A-II (apo A-II) represent 80 90% of the protein content of high density lipoproteins (HDL). Previously we have identified a Finnish family with an apo A-I variant (Lys107-->0) associated with reduced plasma HDL cholesterol level and decreased lipoprotein (Lp)(AI w AII) concentration compared to unaffected family members. To determine the in vivo metabolism of apo A-I and apo A-II in the carriers of apo A-I (Lys107-->0) variant we radioiodinated normal apo A-I with 125I and apo A-II with 131I and compared the kinetic data of two heterozygous apo A-I(Lysl07-->0) patients (HDL cholesterol leves 0.31 and 0.69 mmol/l) to that of eight normolipidemic, healthy control subjects. Plasma radioactivity curves of 125I-labelled normal apo A-I of the patients demonstrated accelerated clearance of apo A-I compared to control subjects. In the two patients the fractional catabolic rates (FCR) of apo A-I were 0.347/day and 0.213/day, respectively, while the mean FCR of apo A-I of the control subjects was 0.151 +/- 0.041/day. Similarly, the plasma decay curves of the 131I-labelled apo A-II showed more rapid clearance of apo A-II in the two patients than in control subjects. The FCR of apo A-II in the two patients were 0.470/day and 0.234/day, while the mean FCR of apo A-II in control subjects was 0.154 +/- 0.029/day. The calculated production rates of apo A-I were similar in patients and in control subjects, and the production rates of apo A-II were significantly higher in patients than in control subjects. Our results show that the Lp(AI w AII) deficiency in patients with the apo A-I(Lys107-->0) is associated with increased fractional catabolic rates of normal apo A-I and apo A-II, while the production rates of these apolipoproteins are normal (apo A-I) or slightly increased (apo A-II).

Apolipoprotein A-I↗
PubMed1997

Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM.

Insulin administration to healthy subjects inhibits the production of very low density lipoprotein (VLDL)1 (Svedbergs flotation (Sf) rate 60-400) without affecting that of VLDL2 (Sf 20-60) sub-class. This study was designed to test whether this hormonal action is impaired in non-insulin-dependent diabetes mellitus (NIDDM). We studied six men with NIDDM (age 53 +/- 3 years, body mass index 27.0 +/- 1.0 kg/m2, plasma triglycerides 1.89 +/- 0.22 mmol/l) during an 8.5 h infusion of saline (control) and then in hyperinsulinaemic (serum insulin approximately 540 pmol/l) conditions during 8.5 h infusions of glucose and insulin to give either hyper- and normoglycaemic conditions. [3-2H]-leucine was used as tracer and kinetic constants derived using a non-steady-state multicompartmental model. Compared to the control study, patients with NIDDM reduced VLDL1 apo B production by only 3 +/- 8% after 8.5 h of hyperinsulinaemia (701 +/- 102 vs 672 +/- 94 mg/day respectively, NS) in hyperglycaemic conditions and by 9 +/- 21% under normoglycaemic conditions (603 +/- 145 mg/day). In contrast, in normal subjects insulin induced a 50 +/- 15% decrement in VLDL1 apo B production (p < 0.05). Direct synthesis of VLDL2 apo B in patients with NIDDM was not markedly affected by insulin. We conclude that a contributory factor to hypertriglyceridaemia in NIDDM is the inability of insulin to inhibit acutely the release of VLDL1 from the liver, despite efficient suppression of serum nonesterfied fatty acids.

Apolipoproteins B↗
PubMed1997

Lipoprotein subfraction concentrations in preeclampsia: pathogenic parallels to atherosclerosis.

OBJECTIVE: To determine whether large triglyceride-rich lipoproteins, very-low-density lipoprotein1 (VLDL1), and small, dense low-density lipoprotein (LDL-III), are significantly increased in women with preeclampsia compared with concentrations seen in normal pregnancy. METHODS: Plasma concentrations of very-low-density and low-density lipoprotein subfractions and pre-heparin hepatic lipase activity were measured in eight women with preeclampsia and in eight healthy pregnant controls matched for age, gestational age, and weight. RESULTS: Women with preeclampsia exhibited higher median plasma triglyceride concentrations (3.68 versus 1.93 mmol/L, P = .004) compared with controls. This was reflected in an almost threefold increase in median VLDL1 (184 versus 68 mg/dL, P = .002) and a twofold increase in very-low-density lipoprotein2 (VLDL2) (146 versus 76 mg/dL, P = .014), whereas total plasma cholesterol, intermediate-density lipoprotein, and total LDL concentration were the same in subjects and controls. Furthermore, women with preeclampsia demonstrated significantly lower concentrations of the large, buoyant LDL subfractions, LDL-I and LDL-II, and markedly elevated median plasma concentrations of small, dense LDL, LDL-III (170 versus 55 mg/dL, P = .024). High-density lipoprotein-cholesterol concentration also was significantly lower (P = .021), and pre-heparin hepatic lipase activity was significantly elevated (29 versus 18 mumol fatty acids/mL/hour, P = .041) in the preeclamptic group. The concentration of small, dense LDL correlated positively with plasma triglyceride concentration (r2 = 0.504, P = .002). CONCLUSION: Women with preeclampsia exhibit markedly elevated concentrations of triglyceride-rich lipoproteins in the circulation. These particles are potential contributors to endothelial dysfunction and the expression of preeclampsia, both directly and, indirectly, through the generation of small, dense LDL.

Adult↗
PubMed1997

Tomorrow's world: atherosclerosis in the year 2000.

Atherosclerosis is an increasing problem, largely due to lifestyle changes. Lipid accumulates in artery walls throughout life, and infiltration into the subintimal space of cholesterol and cholesterol esters and of inflammatory cells can lead to narrowing, clotting, thrombosis and death. Lipid-lowering agents, particularly statins [(3-hydroxy-3-methylglutarate coenzyme A (HMG-CoA) reductase inhibitors] represent one important approach to treatment. They work by blocking the conversion of 3-hydroxy-3-methylglutarate into mevalonate, a precursor of cholesterol. The West Of Scotland Coronary Prevention Study (WOSCOPS) was a large prospective randomised study comparing the effects of pravastatin versus that of placebo in 6595 middle-aged men. In the pravastatin group the rate of fatal or non-fatal myocardial infarction was reduced by one-third over 5 years, the rate of cardiovascular deaths by one-third, and overall deaths by 22% relative to the placebo group. Implications of the results are considered and the results of the US-CARE study are compared. Discussion of relative and absolute risk, and continuous and discrete risk factors leads to the formulation of rational cost/beneficial strategies for decreasing cardiovascular risk by targeting high-risk individuals with lipid-lowering drugs.

Anticholesteremic Agents↗
PubMed1997

Clinicopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1.

Thymic carcinoid is part of the multiple endocrine neoplasia type 1 (MEN1) syndrome occurring predominantly in male patients who were heavy smokers, presenting most commonly in middle age. In contrast with metastatic midgut carcinoids, MEN1-related thymic carcinoid is not associated with carcinoid syndrome, nor is it associated with Cushing syndrome, in contrast with sporadic thymic carcinoids. Local invasion and metastasis are common. Prognosis is poor because of late detection, lack of effective treatment, and the aggressive nature of the tumor. All patients with thymic carcinoids should be investigated for MEN1, including thorough clinical evaluation and family studies. Anterior mediastinal lesions in MEN1 male patients should be considered thymic carcinoids until proven otherwise. All male MEN1 patients and asymptomatic gene carriers should be warned of the risk of thymic carcinoids and the possible link to smoking. Computed tomography (CT) of the chest is recommended on first screening for MEN1 in male patients more than 25 years of age, followed by yearly chest X-rays and chest CT every 3 years. Prophylactic thymectomy should be carried out during subtotal or total parathyroidectomy on MEN1 patients.

Adult↗
PubMed1997

Serum concentrations of cancer antigen 125, placental alkaline phosphatase, cancer-associated serum antigen and free beta human chorionic gonadotrophin as prognostic markers for epithelial ovarian cancer.

OBJECTIVE: To investigate the prognostic significance of elevated levels of cancer antigen 125 (CA125), placental alkaline phosphatase (PLAP), free beta human chorionic gonadotrophin (hCG) and cancer-associated serum antigen (CASA) in women with primary epithelial ovarian carcinoma. DESIGN: A two year follow up study of survival. SETTING: A tertiary care gynaecological oncology unit. PARTICIPANTS: One hundred and eleven women with histologically confirmed epithelial ovarian cancer. MAIN OUTCOME MEASURES: Survival over a two year period. RESULTS: Stage corrected log-rank chi 2 tests demonstrated a significant effect on survival for all four tumour markers (CA125 P = 0.0142; PLAP P < 0.0001; CASA P = 0.0098; hCG P = 0.0002). This was confirmed when each variable was fitted together with disease stage in Cox proportional hazard models. When fitted as multiple variables in a Cox proportional hazard model, the addition of free beta-hCG and CASA to disease stage, PLAP concentrations and CA125 levels did not demonstrate further prognostic value. CONCLUSIONS: Levels of all four markers correlate with survival in patients with epithelial ovarian cancer. The combination of PLAP and CA125 concentrations together with disease stage may be used to predict survival but the addition of hCG and CASA levels do not give additional prognostic information.

Adult↗
PubMed1997

Violence: the relation between seriousness of injury and outcome in the criminal justice system.

OBJECTIVE: To investigate the relation between injury severity in assault, offence seriousness, and outcome in the criminal justice system. METHODS: Prospective random sample of 93 assault victims who attended hospital were interviewed and examined and followed through the criminal justice system. Patient and police interviews were carried out at Bristol Royal Infirmary accident and emergency and outpatient departments, wards, and in Avon police stations and criminal courts. Severity of injury (injury severity score [ISS] assessed by the major trauma outcome study group), offence seriousness (Delphi panel of criminologists), and outcome in the criminal justice system were recorded. RESULTS: Median ISS was 4 (range 1-17). There was no significant correlation between ISS and outcome in the CJS (rs = 0.07). There was a weak correlation between offence seriousness and outcome (rs = -0.24, P = 0.019). CONCLUSIONS: Outcome in the criminal justice system was not predictable from injury severity scores and was only weakly linked to offence seriousness. Contacts with medical services are opportunities for protecting those at risk of violence.

Adolescent↗
PubMed1997

Interaction of very-low-density, intermediate-density, and low-density lipoproteins with human arterial wall proteoglycans.

The specific interaction of lipoproteins with arterial wall constituents, particularly proteoglycans (APG), is believed to play an important role in the development of atherosclerosis. The objective of this study was to examine the interaction of apolipoprotein B (apoB) containing lipoprotein subfractions (VLDL1, Sf 60 to 400; VLDL2, Sf 20 to 60; IDL1, Sf 16 to 20; IDL2, Sf 12 to 16; LDLA, Sf 8 to 12; and LDLB, Sf 0 to 8) prepared by cumulative density gradient centrifugation with chondroitin sulfate-rich APG. Eighteen subjects were studied, and a similar pattern of interaction between the lipoprotein species and APG was found in all. The order of reactivity (as measured by increased turbidity due to insoluble complex formation) was IDL Sf 12 to 16 > or = LDL Sf 8 to 12 > LDL Sf 0 to 8 > IDL Sf 16 to 20 >> VLDL Sf 20 to 60 > VLDL Sf 60 to 400. When the subjects were divided on the basis of their LDL subfraction profile, the extent of insoluble complex formation was highest in the group in which small, dense LDLIII was predominant; intermediate in the group whose LDL was mainly LDLII; and lowest in the group with a high proportion of LDLI (the mean reactivity, AU at 600 nm. of APG with IDL Sf 12 to 16 and LDL Sf 8 to 12 was 0.66; 0.62 and 0.46, 0.43 and 0.20, and 0.21 for the three groups, respectively). Fibrate lipid-lowering treatment decreased the percentage of LDLIII and increased the percentage of LDLI within total LDL and reduced the reactivity of all apoB-containing lipoprotein fractions toward APG. Sialic acid content varied in different lipoprotein subfractions, being the highest in VLDL and lowest in LDL. However, across lipoprotein species, it did not significantly correlate with APG-binding reactivity, suggesting that other factors are important in determining the interaction of lipoproteins with APG. Modification of LDL arginine and lysine residues abolished the ability of the lipoprotein to interact with APG, a finding that supports the hypothesis that the interaction is dependent on key positively charged amino acids on apoB. These findings demonstrate that (1) the overall reactivity of apoB-containing lipoproteins is greatest in individuals with small, dense LDL and (2) within an individual, IDL of Sf 12 to 16 is the most reactive species, and this may in part explain the positive correlation between IDL and risk of coronary heart disease.

Adult↗
PubMed1997

Lipoprotein heterogeneity and apolipoprotein B metabolism.

The apolipoprotein B containing lipoproteins VLDL, IDL, and LDL exhibit variation in their structure, function, and metabolism. These major lipoprotein classes can be fractionated into apparently discrete components by density gradient centrifugation or affinity chromatography. Examination of the behavior of subfractions in vivo reveals the presence of metabolic channels within the VLDL-LDL delipidation cascade so that the pedigree of a lipoprotein in part determines its metabolic fate. Evidence from VLDL and LDL apoB turnovers together with epidemiological data allows the construction of a quantitative model for the generation of small, dense LDL. This lipoprotein subspecies is one component of the dyslipidemic syndrome known as the atherogenic lipoprotein phenotype, a common disorder in those at risk for coronary heart disease. Understanding lipoprotein heterogeneity is an essential step in the further discovery of the pathogenesis of atherosclerosis and in the tailoring of pharmacologic treatment for subjects at risk.

Apolipoproteins B↗