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Biomedical subjects

M Farrer

Publications and source records attributed to M Farrer.

At least 55 records · Page 3Linked to original sources
PubMed1999

The genetics of disorders with synuclein pathology and parkinsonism.

Despite being considered the archetypal non-genetic neurological disorder, genetic analysis of Parkinson's disease has shown that there are at least three genetic loci. Furthermore, these analyses have suggested that the phenotype of the pathogenic loci is wider than simple Parkinson's disease and may include Lewy body dementia and some forms of essential tremor. Identification of alpha-synuclein as the first of the loci involved in Parkinson's disease and the identification of this protein in pathological deposits in other disorders has led to the suggestion that it may share pathogenic mechanisms with multiple system atrophy, Alzheimer's disease and prion disease and that these mechanisms are related to a synuclein pathway to cell death. Finally, genetic analysis of the synuclein diseases and the tau diseases may indicate that this synuclein pathway is an alternative to the tau pathway to cell death.

Alzheimer Disease↗
PubMed1999

Patient-related outcomes five years after coronary artery bypass graft surgery.

For five years, we prospectively studied 353 consecutive patients undergoing first-time coronary artery bypass graft surgery (CABG) for stable angina in the North of England. Angina was present before surgery in nearly all patients, in 20% 3 months after surgery, and in 48% after 60 months. The Nottingham Health Profile, showed a significant improvement in perceived health status (PHS) 12 and 60 months after surgery compared with preoperation. However, PHS at 60 months was worse than at 12 months in the dimensions 'pain' and 'physical mobility' in part 1, and in 'looking after the home' and 'taking holidays' in part 2. Employment rates were 36%, 34% and 21%, before, and 12 and 60 months after surgery, respectively. Working at 12 and 60 months was associated with age below retirement age, work preoperation and absence of angina, and at 12 months also with male gender and waiting time < 6 months. This study describes everyday clinical practice. The significant improvement in angina symptoms and PHS after CABG persists for at least 5 years. However, only one third of patients in this geographical area return to work, and this is not solely dependent on clinical symptoms.

Aged↗
PubMed1999

Lower cardiac mortality in smokers following thrombolysis for acute myocardial infarction may be related to more effective fibrinolysis.

Smokers have unexplained lower cardiac mortality than non-smokers in the short term following acute myocardial infarction (AMI). We hypothesized that smokers may have enhanced systemic fibrinolysis following thrombolysis. We studied 185 consecutive patients receiving thrombolysis for first AMI. Cardiac mortality at 36 days after thrombolysis was 11.9% (22 deaths). Factors associated with cardiac mortality were: smoking (current 3.4% mortality, previous 11.4%, never 24.2%) (p < 0.001); post-thrombolysis plasma fibrinogen at 60 min (p < 0.05); diabetes (p < 0.005); age (p < 0.01); time to thrombolysis (p < 0.05); and ECG evidence of reperfusion (p < 0.05). In logistic regression analysis, smokers were at significantly lower risk of cardiac death compared with non-smokers: unadjusted odds ratio (OR) 0.3 (95% CI 0.2-0.7) (p < 0.01). This was independent of age, diabetes, ECG evidence of reperfusion and pain to treatment time: OR 0.4 (95% CI 0.3-0.9) (p < 0.05). Smoking was not an independent prognostic factor after adjustment for post-thrombolysis plasma fibrinogen OR 0.5 (95% CI 0.4-1.1) (p = 0.1), although its insignificance may be due to lack of numbers. In non-smokers, there was a subgroup with persistent ST elevation, high post-thrombolysis fibrinogen and 40% short-term mortality. No similar high-risk sub-group was observed in smokers. Smoking was associated with lower mortality in patients receiving thrombolysis for first AMI, and post-thrombolysis fibrinogen concentrations were associated with this beneficial effect. Although patient numbers are small, and the hypothesis should be tested further in a larger group, the higher likelihood of incomplete reperfusion and of incomplete fibrinolysis in non-smokers supports the hypothesis that smokers may have enhanced systemic fibrinolysis following thrombolysis in AMI.

Aged↗
PubMed1999

High apolipoprotein AI concentrations are associated with lower mortality and myocardial infarction five years after coronary artery bypass graft surgery.

OBJECTIVE: To examine mortality and myocardial infarction five years after coronary artery bypass graft (CABG) surgery and the association with different lipid fractions and haemostatic, glycaemic, and demographic risk factors. SETTING: A regional cardiothoracic centre, Freeman Hospital, and the University Clinical Investigation Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK. DESIGN: 353 consecutive patients (297 male, mean age 57.2 years) undergoing first time CABG for stable angina were recruited to a prospective cohort study and studied to five years. MAIN OUTCOME MEASURES: All cause mortality, late cardiac mortality (beyond 30 days) alone and in combination with non-fatal myocardial infarction. Risk factor assessments before operation and 3, 6, 12, 24, and 60 months after surgery. For each laboratory variable a weighted mean for the period of exposure was calculated from the concentration at each time interval and the time between measurements. The distribution was divided into tertiles. RESULTS: 41 patients died (16 late cardiac deaths) and eight had a myocardial infarct. An adverse outcome occurred more frequently in the lower tertile of weighted apolipoprotein AI compared with the upper tertile. An adverse outcome was also more common in patients in the upper tertile of weighted total white blood cell count and less consistently so in patients in the upper tertile of the haemostatic covariates, factor VIIc and factor VIIIc. There was no association with other lipid fractions except for total mortality and apolipoprotein B (owing to low levels in five patients with carcinoma). CONCLUSIONS: Low apolipoprotein AI concentrations, but no other markers of an adverse lipid profile, were associated with mortality and myocardial infarction five years after CABG. Apolipoprotein AI is associated with paraoxonase, an enzyme located on high density lipoprotein, which may limit the oxidation of low density lipoprotein. An association between outcome and other covariates such as white cell count provides a credible pointer to inflammation mediating a component of cardiovascular risk.

Apolipoprotein A-I↗
PubMed1999

An audit on access to coronary artery surgery within a health district using New Zealand priority criteria as a benchmark.

A professional advisory group in New Zealand, consisting of cardiologists, cardiac surgeons and general practitioners have recommended priority criteria for access to Coronary-Artery Bypass Graft (CABG). They used published outcome studies in developing the criteria, and numerical scores were assigned to both biological and social dimensions of ischaemic heart disease. The New Zealand criteria were used to investigate access to services for patients in the UK in Sunderland, Tyne and Wear. Case notes of 229 Sunderland residents who underwent coronary angiography in the 1995 96 financial year were reviewed. The clinical threshold for access to CABG was much higher in Sunderland than in New Zealand. After controlling for the severity of disease, there was no evidence of inequity of access based on age, gender, smoking status or the deprivation indices of the patients' ward of residence. The correlation between the New Zealand Priority Criteria scores and the waiting time for coronary angiography, CABG and Percutaneous Transluminal Coronary Angioplasty (PTCA) was present, but weak (r = -0.22, -0.1 and -0.54 respectively). The New Zealand consensus criteria proved a useful benchmark both to assess access for patients with ischaemic heart disease to coronary artery surgery in a local Health District and to prioritise patients on the waiting list for coronary artery surgery. They allowed a realistic assessment of access according to age, gender, smoking status and deprivation by taking disease severity into account.

Benchmarking↗
PubMed1998

Exclusion of genetic linkage to 4q21-23 and 17q21 in a family with Lewy body parkinsonism.

Genetic analysis of markers from chromosomes 4q21-23 and 17q21 in a family with apparently autosomal dominant Lewy body parkinsonism is presented. This analysis shows that the locus leading to this disease is not allelic with that previously shown to lead to Lewy body parkinsonism on chromosome 4 or to the locus on chromosome 17 leading to frontotemporal dementia with parkinsonism. A brief clinical comparison of this family with families showing linkage to these loci is presented. The data suggest that at least one other major genetic determinant for Lewy body parkinsonism remains to be identified.

Adult↗
PubMed1998

Low frequency of alpha-synuclein mutations in familial Parkinson's disease.

A mutation in exon 4 of the alpha-synuclein (NACP) gene has been reported to explain the chromosome 4 linkage to autosomal dominant Parkinson's disease. We developed primers and methods for exonic sequencing of this gene and sequenced the entire coding region of the gene in 6 families with autosomal dominant disease and in 2 cases of lytico and bodig from Guam. In addition, we have sequenced exon 4 of this gene in 5 cases of familial disease and have screened for the specific mutation (A53T) in a 40 cases of idiopathic Parkinson's disease, 3 cases of multisystem atrophy, and 15 cases of Lewy body dementia. We have found no genetic variation in the gene. We discuss these findings with respect to both the epidemiology of Parkinson's disease and the possibility that NACP is not the chromosome 4 locus for disease.

Adult↗
PubMed1998

A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.

We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.

Age of Onset↗
PubMed1997

Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21-22.

An Australian family with autosomal dominant presenile nonspecific dementia was recently described. The disease results in behavioral changes, usually disinhibition, followed by the onset of dementia accompanied occasionally by parkinsonism. Twenty-eight affected individuals were identified with an age of onset of 39 to 66 years (mean, 53 +/- 8.9 years). We mapped the disease locus to an approximately 26-cM region of chromosome 17q21-22 with a maximum two-point LOD score of 2.87. Affected individuals share a common haplotype between markers D17S783 and D17S808. This region of chromosome 17 contains the loci for several neurodegenerative diseases that lack distinctive pathological features, suggesting that these dementias, collectively referred to as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in the same gene. The entire coding region of five genes, mapped to the FTDP-17 candidate region, were also sequenced. This analysis included the microtubule-associated protein tau that is the major component of the paired helical filaments observed in Alzheimer's disease. No pathogenic mutations were identified in either the tau gene or in any of the other genes analyzed.

Adult↗
PubMed1997

Outcome after coronary artery surgery in women and men in the north of England.

We prospectively studied, for 1 year initially, 353 consecutive patients (297 male 56 female, 57.2 +/- 7.32 years) with chronic stable angina admitted for coronary artery bypass graft (CABG) surgery in the North East of England. Patients generally had severe anginal symptoms (median 36 months duration) despite anti-anginal therapy (90% taking two or more anti-anginal drugs). Women were more severely symptomatic than men prior to surgery, despite a similar severity of angiographically-defined coronary artery disease, suggesting possible referral bias. Women were given fewer grafts than men in operations carrying similar risks. After surgery, clinical outcome was generally good but women had a higher mortality (12-month mortality 14% in women vs. 6% in men), and higher morbidity in terms of readmissions, angina symptoms, antianginal drug use and effort tolerance. This series describes clinical practice in an area of high coronary disease morbidity and mortality. It identifies the real risks for women with severe symptomatic disease undergoing coronary artery surgery. We believe it highlights the need for improved risk stratification in the treatment of women with angina, and a consideration of alternative treatment strategies for those women destined to have a poor outcome from CABG.

Angina Pectoris↗
PubMed1997

Serum Lp(a) lipoprotein concentration is not associated with clinical and angiographic outcome five years after coronary artery bypass graft surgery.

OBJECTIVE: To examine the association between serum Lp(a) lipoprotein concentration and clinical and angiographic outcomes five years after coronary artery bypass graft (CABG) surgery. SETTING: A regional cardiothoracic centre, Freeman Hospital, and the University Clinical Investigation Unit, Royal Victoria Infirmary, Newcastle upon Tyne. PATIENTS AND DESIGN: 353 consecutive patients (56 female, 297 male, mean age 57-2 years) undergoing first time CABG surgery for stable angina were studied prospectively. MAIN OUTCOME MEASURES: Late cardiac death (beyond 30 days) and non-fatal myocardial infarction; prevalence of angina five years after surgery in 291 (94%) survivors and vein graft patency (evaluated by patient) in 118 survivors five years after surgery. Serum Lp(a) concentration and lipid profiles were measured before operation, and 3, 6, 12, and 60 months after surgery. Lipid profiles were also measured 24 months after surgery. RESULTS: Weighted Lp(a) concentration (by tertile) was not associated with late cardiac death or with the combination of late cardiac death and non-fatal myocardial infarction, with the presence of angina, or with vein graft occlusion. The association remained non-significant if analysis was restricted to the upper tertile of LDL cholesterol (> 4.1 mmol/l) or to patients under the age of 55 years at the time of surgery. CONCLUSIONS: Serum Lp(a) concentration did not predict late cardiac death, the combination of late cardiac death and non-fatal myocardial infarction, or the prevalence of angina or vein graft occlusion five years after CABG surgery.

Angina Pectoris↗
PubMed1997

Change in ST segment elevation 60 minutes after thrombolytic initiation predicts clinical outcome as accurately as later electrocardiographic changes.

OBJECTIVE: To compare prospectively the prognostic accuracy of a 50% decrease in ST segment elevation on standard 12-lead electrocardiograms (ECGs) recorded at 60, 90, and 180 minutes after thrombolysis initiation in acute myocardial infarction. DESIGN: Consecutive sample prospective cohort study. SETTING: A single coronary care unit in the north of England. PATIENTS: 190 consecutive patients receiving thrombolysis for first acute myocardial infarction. INTERVENTIONS: Thrombolysis at baseline. MAIN OUTCOME MEASURES: Cardiac mortality and left ventricular size and function assessed 36 days later. RESULTS: Failure of ST segment elevation to resolve by 50% in the single lead of maximum ST elevation or the sum ST elevation of all infarct related ECG leads at each of the times studied was associated with a significantly higher mortality, larger left ventricular volume, and lower ejection fraction. There was some variation according to infarct site with only the 60 minute ECG predicting mortality after inferior myocardial infarction and only in anterior myocardial infarction was persistent ST elevation associated with worse left ventricular function. The analysis of the lead of maximum ST elevation at 60 minutes from thrombolysis performed as well as later ECGs in receiver operating characteristic curves for predicting clinical outcome. CONCLUSION: The standard 12-lead ECG at 60 minutes predicts clinical outcome as accurately as later ECGs after thrombolysis for first acute myocardial infarction.

Aged↗
PubMed1995

Patients undergoing coronary artery bypass graft surgery are at high risk of impaired glucose tolerance and diabetes mellitus during the first postoperative year.

This study demonstrates that patients who have undergone coronary artery bypass graft (CABG) surgery have a high prevalence of abnormal glucose tolerance 3 months and 1 year later. Although only 6% were known to have diabetes mellitus (DM) preoperatively, a further 4% were classified DM at two oral glucose tolerance tests (OGTTs) over the subsequent year and a further 18% were classified as having impaired glucose tolerance (IGT) at 12 months. Reproducibility of the 120-minute plasma glucose level in the 75-g OGTT was estimated from a repeat test performed within 10 days. The coefficient of variation (CV) of 120-minute glucose was between 14% and 18%. The observed changes in class of glucose tolerance observed at OGTTs repeated 6 and 12 months after surgery differed from the predicted changes based purely on the estimated variability of 120-minute glucose measurement. There was evidence of regression to the mean for the IGT group. However, there was also evidence of deteriorating glucose tolerance in some subjects. Between 4% and 9% of those with IGT 3 months after CABG surgery developed DM by 12 months, and 26 (13%) of those with initially normal glucose tolerance (NGT) developed IGT. Insulin and glucose responses in the OGTT and estimates of insulin resistance and beta-cell function from fasting samples show that insulin resistance was the principal abnormality in IGT subjects, whereas in DM subjects, both insulin resistance and beta-cell dysfunction contributed. Analysis of preoperative patient characteristics showed that the presence of either a systolic blood pressure of 140 mm Hg or body mass index (BMI) of more than 25 kg/m2 identified 51% of the subjects who would at 1 year after surgery include all those who would be classified DM and 67% of those who would have IGT. Further analyses including insulin levels identified groups at particularly high risk of DM, but no combination of readily available preoperative measures identified all those destined to be classified IGT.

Blood Glucose↗
PubMed1995

Assessing the impact of blood sample type on the estimated prevalence of impaired glucose tolerance and diabetes mellitus in epidemiological surveys.

In a prospective study of 353 patients who had undergone coronary artery bypass graft surgery a 75 g oral glucose tolerance test was performed at 3 months and 12 months after surgery. Venous whole blood glucose and venous plasma glucose samples were assayed on a bench-top analyser. The World Health Organization diagnostic criteria for impaired glucose tolerance and diabetes mellitus were applied to venous whole blood glucose and venous plasma glucose measurements. The difference between the plasma and whole blood concentration of glucose was 0.79-0.86 mmol l-1 at a plasma glucose of 7.8 mmol l-1 and 1.22-1.24 mmol l-1 at a plasma glucose of 11.1 mmol l-1 (compared to 1.1 mmol l-1 by World Health Organization criteria at both cut-points). Despite this, in our subject population with a high prevalence of impaired glucose tolerance (20.3% at 3 months, 15.3% at 12 months) and diabetes mellitus (10.1% at 3 months and 12 months), there was no significant difference in the proportion classified impaired glucose tolerance or having diabetes mellitus using venous whole blood glucose compared to venous plasma glucose. We conclude that despite the minor anomaly between WHO diagnostic criteria based on venous whole blood glucose and venous plasma glucose measurements, these criteria are robust and give broadly comparable population prevalence of diabetes mellitus and impaired glucose tolerance irrespective of blood sample choice.

Autoanalysis↗
PubMed1994

Reduced serum lipoprotein(a) levels in patients with primary biliary cirrhosis.

Lipoprotein(a) (Lp(a)) is a unique lipoprotein, elevated serum levels of which are independently associated with an increased risk of coronary heart disease (CHD). Primary biliary cirrhosis (PBC) is often associated with high serum cholesterol, itself a risk factor for CHD. Despite this, patients with PBC are thought to have a lower than expected incidence of CHD. We hypothesised that this may be related to low serum levels of Lp(a) in PBC patients. This was investigated by collecting fasting blood samples from 42 patients with PBC, 39 age- and sex-matched subjects with non-PBC liver disease and 432 community control subjects. Serum was analysed for total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol and apolipoproteins A1 and B (apo A1 and apo B). Lp(a) was measured by an enzyme-linked immunosorbent assay (ELISA) technique. There was a significant reduction of Lp(a) concentrations in the PBC group compared with the healthy controls (median value 28.5 mg/l vs. 75.0 mg/l, P < 0.005) and between the non-PBC liver disease group (median value 52.0 mg/l) and control group (P = 0.001). Within both the liver disease and PBC patient groups there were significant negative correlations between Lp(a) levels and bilirubin (R = -0.564, P < 0.001 and R = -0.395, P = 0.010 respectively). This preliminary study has demonstrated reduced Lp(a) levels in PBC patients which may be a contributory factor to explain a possible cardioprotective effect in such patients, despite elevated LDL cholesterol levels.

Bilirubin↗
PubMed1994

Simvastatin in non-insulin-dependent diabetes mellitus: effect on serum lipids, lipoproteins and haemostatic measures.

The clinical efficacy of the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMGCoA) reductase inhibitor simvastatin in the treatment of hypercholesterolaemia in non-insulin-dependent diabetes (NIDDM), was examined in a double-blind placebo-controlled study of 6 months in 70 patients with NIDDM (age 25-70 years), of whom 57 were randomised to placebo (29 patients) or simvastatin for 6 months, following a 3-month run-in on diet. Patients were hypercholesterolaemic (7.8 (7.6-8.0) (mean (95% confidence intervals)) mmol/l simvastatin vs. 8.0 (7.7-8.5) mmol/l placebo) and mildly hypertriglyceridaemic (2.6 (2.2-3.0) simvastatin vs. 2.9 (2.3-3.5) placebo). Other lipid measures and estimates of glycaemic control and haemostasis were similar in both groups. There were no significant changes in lipids, haemostatic factors, or measures of glycaemic control in the placebo treatment group. Conversely by the end of 24 weeks, simvastatin produced a 28% reduction in cholesterol (to 5.6 (5.0-6.2) mmol/l (P < 0.001)), a 38% reduction in LDL cholesterol (from 5.5 (5.4-5.6) mmol/l to 3.4 (2.8-4.0) mmol/l, P < 0.001), a 15% reduction in triglyceride (to 2.2 (1.8-2.6) mmol/l, P < 0.05, and a 9% rise in HDL (from 1.16 (1.07-1.25) to 1.23 (1.14-1.32) mmol/l, P < 0.05). Improvements in apolipoprotein B (apo B) (-28%, P < 0.001), the LDL cholesterol to apo B ratio (-20%, P < 0.001), and apo A1 (+15%, P < 0.001) were recorded. There were no effects upon fibrinogen, factor VII activity, factor VIII activity, or measures of glycaemic control (fasting glucose, insulin, C-peptide, or HbA1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗