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1.  Laboratory facilities for investigating lipid disorders in the United Kingdom: results of the British Hyperlipidaemia Association survey. 
Journal of Clinical Pathology  1992;45(2):102-105.
AIMS: To determine the availability of facilities for the investigation of hyperlipidaemia in the United Kingdom. METHODS: A questionnaire was sent to all health districts in the United Kingdom. RESULTS: The response rate was 81%. All laboratories used enzymatic techniques to measure serum triglyceride and cholesterol concentrations, although there were differences in standardisation procedures. Reference ranges for serum lipids were quoted by 58% of laboratories while 50% quoted "desirable limits". Almost half specified that fasting blood samples were required. High density lipoprotein cholesterol concentrations were estimated by 75% and apolipoproteins AI and B by 14% of laboratories; there were differences in specimen type and considerable diversity in procedures used for measurement. CONCLUSIONS: Many laboratories were unaware of current recommendations for screening for hypercholesterolaemia in the community. The present survey indicated an urgent need for the introduction of better reference methods, standardisation, and quality assurance procedures before apolipoproteins become a routine part of coronary heart disease risk assessment.
PMCID: PMC495645  PMID: 1541687
3.  Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia 
The New England journal of medicine  2014;371(8):699-710.
Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.
In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.
A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P = 0.04).
Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.)
PMCID: PMC4195437  PMID: 25140956
4.  Preoperative B-Vitamin Infusion and Prevention of Nitrous Oxide-induced Homocysteine Increase 
Anaesthesia  2010;65(7):710-715.
Nitrous oxide inactivates vitamin B12 with detrimental consequences for folate and methionine metabolism. This inactivation can be clinically detected by an increase in plasma total homocysteine. In a clinical trial, we tested the hypothesis that a preoperative infusion of vitamin B12 and folate prevents the nitrous oxide-induced homocysteine increase. Sixty-three healthy patients scheduled for elective surgery were randomly allocated to receive (a) B-vitamins and nitrous oxide; (b) placebo and nitrous oxide or (c) normal saline and no nitrous oxide. Fifty-nine patients were included in the final study population. After intravenous B-vitamin infusion, plasma vitamin B12 and folate concentrations increased 35-fold and 12-fold on the first postoperative measurement, respectively. Patients who received B-vitamins developed a similar increase (+18%) in homocysteine after nitrous oxide (+ 1.9 μmol.L−1; 95% CI: 0.2 – 3.6 μmol.L−1) as patients who did not receive B-vitamins (+ 22%; + 2.7 μmol/L; 95% CI: 0.6 – 4.8 μmol.L−1). Patients who did not receive nitrous oxide (“air control”) had no change in homocysteine (+ 0.5 μmol.L−1; 95% CI: −0.8 – 1.9 μmol.L−1). This trial indicates that preoperative IV B-vitamins may not prevent nitrous oxide-induced hyperhomocysteinemia.
PMCID: PMC3732777  PMID: 20477781
5.  Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS) 
Neurology  2009;73(3):195-201.
Constraint-induced movement therapy (CIMT) is among the most developed training approaches for motor restoration of the upper extremity (UE).
Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS) was a single-blind phase II trial of CIMT during acute inpatient rehabilitation comparing traditional UE therapy with dose-matched and high-intensity CIMT protocols. Participants were adaptively randomized on rehabilitation admission, and received 2 weeks of study-related treatments. The primary endpoint was the total Action Research Arm Test (ARAT) score on the more affected side at 90 days after stroke onset. A mixed model analysis was performed.
A total of 52 participants (mean age 63.9 ± 14 years) were randomized 9.65 ± 4.5 days after onset. Mean NIHSS was 5.3 ± 1.8; mean total ARAT score was 22.5 ± 15.6; 77% had ischemic stroke. Groups were equivalent at baseline on all randomization variables. As expected, all groups improved with time on the total ARAT score. There was a significant time x group interaction (F = 3.1, p < 0.01), such that the high intensity CIT group had significantly less improvement at day 90. No significant differences were found between the dose-matched CIMT and control groups at day 90. MRI of a subsample showed no evidence of activity-dependent lesion enlargement.
Constraint-induced movement therapy (CIMT) was equally as effective but not superior to an equal dose of traditional therapy during inpatient stroke rehabilitation. Higher intensity CIMT resulted in less motor improvement at 90 days, indicating an inverse dose-response relationship. Motor intervention trials should control for dose, and higher doses of motor training cannot be assumed to be more beneficial, particularly early after stroke.
= apparent diffusion coefficient;
= activities of daily living;
= Action Research Arm Test;
= constraint-induced movement therapy;
= diffusion-weighted imaging;
= Functional Independence Measure;
= NIH Stroke Scale;
= Stroke Impact Scale;
= echo time;
= inversion time;
= repetition time;
= upper extremity;
= Very Early Constraint-Induced Movement during Stroke Rehabilitation.
PMCID: PMC2715572  PMID: 19458319
6.  Cancer linked to Alzheimer disease but not vascular dementia 
Neurology  2010;74(2):106-112.
To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD).
Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study–Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer.
The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20–0.84) and pure AD (HR = 0.31, 95% CI = 0.12–0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52–0.997) and pure AD (HR = 0.57; 95% CI = 0.36–0.90) among white subjects after adjustment for demographics, number of APOE ε4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD.
In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.
= modified Mini-Mental State Examination;
= Alzheimer disease;
= Alzheimer Disease Diagnostic and Treatment Centers;
= coronary heart disease;
= Cardiovascular Health Study;
= confidence interval;
= hazard ratio;
= International Classification of Diseases–Ninth Revision;
= mild cognitive impairment;
= National Institute of Neurological and Communicative Diseases and Stroke–Alzheimer's Disease and Related Disorders Association;
= Parkinson disease;
= vascular dementia.
PMCID: PMC2809029  PMID: 20032288
7.  Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk 
Journal of Medical Genetics  2006;43(12):943-949.
To determine the relative frequency of mutations in three different genes (low‐density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK.
Patients and methods
409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single‐strand conformational polymorphism (SSCP) (exons 3, 4, 6–10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP.
Mutations were detected in 253 (61.9%) patients: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post‐statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL‐C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL‐C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03).
The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.
PMCID: PMC2563208  PMID: 17142622
An informant-based screening tool for dementia may be useful in population-based studies of minority populations.
Investigate the feasibility of screening for very mild dementia in a community sample of African Americans using an informant-based screening tool (AD8).
Cohort study
147 persons from the African American Health (AAH) project were screened for dementia; 61 of 93 who were invited had follow-up clinical assessments for dementia diagnosis.
The AD8, Mini-Mental State Examination (MMSE), Short Blessed Test (SBT), Brief Instrument for Dementia Detection (BIDD), and a neuropsychological battery were administered at visit 1. The Clinical Dementia Rating (CDR) was administered at visit 2 by clinicians blinded to visit 1 results; the presence of dementia was determined by a CDR greater than 0.
465 individuals from the AAH cohort were sent a letter describing the study and, among this group, 252 individuals were contacted by phone to request participation in this study. 6% (14 / 252) of participants contacted by phone were unable to identify an informant (required for the AD8). 150 individuals agreed by phone to participate of which 2% (n=3) did not have an informant available at the time of participation. The AD8 alone was effective at discriminating between CDR 0 and CDR 0.5 (area under the curve = .847; p <.001; 95% confidence interval 0.73-0.96).
A brief informant-based instrument, the AD8, has high sensitivity and specificity for distinguishing CDR 0 from CDR 0.5 in the community. Informant availability may not be a barrier to using the AD8 in an African American community sample; however, further study in larger samples with a higher response rate, different community settings (e.g., community clinics), and among older age groups (e.g., age 75+) is warranted to confirm this.
PMCID: PMC2763355  PMID: 19484913
African Americans; Dementia; Screening
9.  Established and emerging coronary risk factors in patients with heterozygous familial hypercholesterolaemia 
Heart  2004;90(12):1431-1437.
Objectives: To assess the clinical and biochemical factors associated with inter-individual variation in susceptibility to coronary artery disease (CAD) in treated heterozygous familial hypercholesterolaemia.
Design: A cross sectional study was conducted of 410 patients recruited from six lipid clinics in the UK.
Results: CAD was documented in 104 of the 211 men and in 55 of the 199 women with mean ages of onset of 43.1 and 46.5 years, respectively. CAD was significantly more common in men (49% v 28%, p < 0.001) and in patients who had smoked cigarettes versus patients who had never smoked (51% v 28%, p < 0.001). After adjusting for age, sex, and current smoking status, there were no significant differences between patients with or without CAD in lipoprotein(a), homocysteine, fibrinogen, plasminogen activator inhibitor-1, white blood cell count, body mass index, glucose, triglyceride or total cholesterol. However, high density lipoprotein (HDL) cholesterol concentrations were significantly lower in those with CAD (6%, 95% confidence interval (CI) 1% to 11%, p  =  0.03) and this difference was greater in women than men (12% v 2%, p  =  0.041).
Conclusions: These results indicate that emerging coronary risk factors appear not to be associated with CAD in adults with treated familial hypercholesterolaemia, but the strong association with smoking suggests that patients should be identified early in childhood and discouraged from ever starting to smoke.
PMCID: PMC1768595  PMID: 15547022
familial hypercholesterolaemia; coronary artery disease; coronary risk factors; cigarette smoking; coronary risk factors
11.  Improved survival of patients with homozygous familial hypercholesterolaemia treated with plasma exchange. 
Plasma exchange was undertaken in five patients with homozygous familial hypercholesterolaemia at intervals of two weeks for a mean of 8.4 years. These patients had survived an average of 5.5 years longer than their five respective homozygous siblings (p = 0.3), each of whom must have had a matching genetic defect but who died untreated. The 37% decrease in peak serum cholesterol concentrations maintained by plasma exchange presumably reduced progression of atherosclerosis in the treated patients and thus lessened their risk of premature death.
PMCID: PMC1418783  PMID: 3935235
12.  Hypobetalipoproteinaemia--a variant of the Bassen-Kornzweig syndrome. 
Gut  1979;20(2):163-168.
A patient is reported with hypobetalipoproteinaemia and clinical features resembling the Bassen-Kornzweig syndrome (abetalipoproteinaemia) more completely than previously described. This supports a link between hypobetalipoproteinaemia and abetalipoproteinaemia and it is suggested that the Bassen-Kornzweig syndrome has a wide spectrum with serum betalipoprotein ranging from absent to normal. It is likely that there are different genetic entities with similar end results.
PMCID: PMC1419446  PMID: 428829
14.  Association between anaemia and hypolipidaemia. 
British Medical Journal  1972;4(5838):492.
PMCID: PMC1786735  PMID: 4653898
16.  Relationship of hepatic iron concentration to histochemical grading and to total chelatable body iron in conditions associated with iron overload 
Gut  1971;12(12):1011-1014.
A simple method based on atomic absorption spectrophotometry and using protein concentration as the reference standard was used for measuring the total tissue iron concentration in needle liver biopsy specimens from 47 patients with varying levels of body iron stores. The values obtained showed a close correlation over a wide range with measurements of total chelatable body iron stores. A comparison with the histochemical assessment of iron deposition showed that only those with grades 3 and 4 had significant increases in iron concentration which is in accord with other clinical observations in such patients. A liver biopsy can thus be of value in the quantitative determination of total body iron overload as well as in the diagnosis of underlying liver disease.
PMCID: PMC1411991  PMID: 5157130
17.  Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia 
BMJ : British Medical Journal  2000;321(7275):1497.
To assess the feasibility of detecting new cases of heterozygous familial hypercholesterolaemia by using a nurse led genetic register.
Case finding among relatives of patients with familial hypercholesterolaemia.
Two lipid clinics in central and south Manchester.
259 (137 men and 122 women) probands and 285 first degree relatives.
Of the 200 first degree relatives tested, 121 (60%) had inherited familial hypercholesterolaemia. The newly diagnosed patients were younger than the probands and were generally detected before they had clinically overt atherosclerosis. Concentrations of serum cholesterol were, respectively, 8.4 (1.7 SD) mmol/l and 8.1 (1.9 SD) mmol/l in affected men and women and 5.6 (1.0 SD) mmol/l and 5.6 (1.1 SD) mmol/l in unaffected men and women. Screening for risk factors as recommended in recent guidelines for coronary heart disease prevention would have failed to identify most of the affected relatives in whom hypertension, diabetes mellitus, cigarette smoking, and obesity were uncommon.
By performing cholesterol tests on 200 relatives, 121 new patients with familial hypercholesterolaemia were discovered. Because 1 in 500 people in the UK are affected by this condition, to detect a similar number by population screening over 60 000 tests would be required, and only a few of these patients would have been detected had cholesterol testing been restricted to those with other risk factors for coronary heart disease. A case exists for organising a genetic register approach, linking lipid clinics nationally.
PMCID: PMC27551  PMID: 11118175
20.  Three novel brain tropomyosin isoforms are expressed from the rat alpha-tropomyosin gene through the use of alternative promoters and alternative RNA processing. 
Molecular and Cellular Biology  1990;10(4):1729-1742.
cDNA clones encoding three novel tropomyosins, termed TMBr-1, TMBr-2, and TMBr-3, were isolated and characterized from a rat brain cDNA library. All are derived from a single gene, which was previously found to express striated muscle alpha-tropomyosin and a number of other tropomyosin isoforms via an alternative splicing mechanism (N. Ruiz-Opazo and B. Nadal-Ginard, J. Biol. Chem. 262:4755-4765, 1987; D. F. Wieczorek, C. W. J. Smith, and B. Nadal-Ginard, Mol. Cell. Biol. 8:679-694, 1988). The derived amino acid sequences revealed that TMBr-1 contains 281 amino acids, TMBr-2 contains 251 amino acids, and TMBr-3 contains 245 amino acids. All three proteins contain a region that is identical to amino acids 81 through 258 of skeletal muscle alpha-tropomyosin. TMBr-1 is identical to striated muscle alpha-tropomyosin from amino acids 1 through 258 but contains a novel COOH-terminal region from amino acids 259 through 281. TMBr-2 and TMBr-3 both contain identical NH2-terminal sequences from amino acids 1 through 44 which were found to be expressed from a novel promoter. TMBr-3 contains the same COOH-terminal region as TMBr-1, whereas TMBr-2 contains a second novel COOH-terminal region. The genomic organization of the exons encoding TMBr-1, TMBr-2, and TMBr-3 were determined. These studies revealed a previously uncharacterized promoter located in the internal region of the alpha-TM gene as well as two novel COOH-terminal coding exons. The alpha-TM gene is a complex transcription unit containing 15 exons including two alternative promoters, two internal mutually exclusive exon cassettes, and four alternatively spliced 3' exons that encode four different COOH-terminal coding regions. A total of nine distinct mRNAs are known to be expressed from the alpha-TM gene in a cell type-specific manner in tissues such as striated muscle, smooth muscle, kidney, liver, brain, and fibroblasts. The mRNAs encoding TMBr-1, TMBr-2, and TMBr-3 were found to be expressed only in brain tissue, with TMBr-3 being expressed at much greater levels than TMBr-1 and TMBr-2. The individual structural characteristics of each brain alpha-tropomyosin isoform and their possible functions are discussed.
PMCID: PMC362279  PMID: 2320008
21.  Antacid maintenance therapy in the prevention of duodenal ulcer relapse. 
Gut  1988;29(12):1748-1754.
The effectiveness of antacid maintenance therapy in preventing duodenal ulcer (DU) relapse was investigated. Two hundred and fifty one asymptomatic patients with healed DU were stratified into smokers and non-smokers and randomised to receive for one year either placebo, or Maalox TC three tablets (81 mmol) at bedtime (hs), or Maalox TC three tablets in the morning plus three tablets at bedtime (bd) (162 mmol), or cimetidine 400 mg at bedtime. A double dummy technique was used to render the study double blind. In 176 patients evaluable for efficacy, the cumulative relapse at one year was: placebo 57%; Maalox TC hs 39%; Maalox TC bd 23%; cimetidine 25%. Maalox TC bd and cimetidine were equally effective and superior to placebo (p less than 0.01) and bedtime Maalox TC (p less than 0.04). The benefit of treatment was significant for the overall sample and for the subgroup of smokers. The results for the non-smokers also supported efficacy for these two treatments but, perhaps because of small sample sizes, these comparisons were not significant. All 251 patients were assessed for safety. Approximately half the patients in each treatment group had adverse events, leading to withdrawal in three, seven, 12, and four patients on placebo, Maalox hs, Maalox bd, and cimetidine respectively. Diarrhoea occurred in 12 patients in Maalox TC bd and eight in each other group. Serum magnesium concentrations were unchanged; aluminium concentrations were higher than baseline at six and 12 months in both antacid groups and at 12 months in the cimetidine group but the differences were not significant. Maalox TC three tablets bd are as effective as cimetidine 400 mg at bedtime in reducing DU relapse and both are superior to placebo.
PMCID: PMC1434100  PMID: 3065157
23.  Computed tomographic appearances of cardiac amyloidosis. 
British Heart Journal  1984;51(5):519-522.
Computed tomography was used to identify the characteristic appearances of histologically confirmed cardiac amyloidosis in two patients. Mean myocardial density and 95% confidence limits in one of these patients (30.6 +/- 3.4 Hounsfield units (HU) ) were significantly lower than in patients with diffuse hypertrophic cardiomyopathy (range from 38.8 +/- 5.7 HU to 45.9 +/- 4.4 HU) and normal myocardium (range from 41.9 +/- 4.3 HU to 44.8 +/- 4.4 HU) on pre-contrast computed tomograms. Although only an approximate myocardial density was obtained in the second patient with amyloidosis, a similar result (30 HU) was noted on pre-contrast tomograms. Diffuse thickening of the interventricular septum and left ventricular free wall was found in both patients. Myocardial density on post-contrast computed tomograms was 102.8 +/- 5.2 HU in one patient and approximately 100 HU in the other. A pericardial effusion was noted in the first patient. A low myocardial density on pre-contrast tomograms and diffuse myocardial thickening on post-contrast tomograms are considered to be important features of cardiac amyloidosis.
PMCID: PMC481542  PMID: 6721947
24.  Development of a Computer-Assisted Follow-Up Methodology for Clinical Research 
One major goal of a clinical research project was to follow a large group of survivors of myocardial infarction over a seven-year period in order to obtain information about patient survival and/or circumstances of death. A computerized data-management system was used to assist in the procurement of consistent, complete data. We succeeded in completing follow-up on 98.4% of our population in this program. Our experience suggests that follow-up can be computer-directed, and a strategy for this approach is presented.
PMCID: PMC2203787
25.  Use of a modified shell vial technique to quantitate cytomegalovirus viremia in a population of solid-organ transplant recipients. 
Journal of Clinical Microbiology  1992;30(10):2620-2624.
A quantitative modification of the shell vial assay was used to investigate cytomegalovirus viremia in solid-organ transplant recipients. The level of viremia detected in 109 of 407 specimens ranged from 0.02 to 28 infectious foci per 100,000 leukocytes. By using a Poisson model, a technique was developed to determine 95% confidence limits for the measured levels of viremia. These confidence limits were used to determine the level of viremia that could be excluded by culturing a given number of cells. Longitudinal assessment of two transplant recipients revealed different patterns of viremia and demonstrated that significant disease sometimes occurred with low-level viremia. On the basis of the results of the studies, culture of at least 4 x 10(6) leukocytes is recommended for the sensitive detection of cytomegalovirus viremia.
PMCID: PMC270488  PMID: 1328280

Results 1-25 (28)