Serial measurements of phosphorylated neurofilament-heavy in the serum of subjects with amyotrophic lateral sclerosis.

There is a need for a blood biomarker of disease activity in ALS. This marker needs to measure the loss of motor neurones. Phosphorylated neurofilament heavy chain (pNfH) in the serum is a biomarker of axonal injury. Previous studies have found that levels of pNfH are elevated in ALS. We have performed a serial study of pNfH levels in 98 subjects from our ALS clinic. There was significant elevation of levels of pNfH in subjects with ALS compared to controls, although there was considerable variability. In studies of individuals who had two or more serial samples, we found that the levels of pNfH increased over time in the early stage of disease. Levels were low in subjects with long survival. The rate of rise of pNfH was inversely correlated with survival. We suggest that the initial level of pNfH is a marker of disease severity and that changes in pNfH levels are markers of disease progression.

Modelling 5-year functional outcome in a major traumatic injury survivor cohort.

AIM: To estimate associations between possible predictors of functional disability outcome at 5 years in a working adult population cohort of survivors of major traumatic injury and to develop a prognostic model of outcome. DESIGN: Population based retrospective cohort study. POPULATION: Persons who had experienced major traumatic injury (Injury Seventy Score >15) in the area of the former Yorkshire Regional Health Authority during the period 30 September 1988 to 1 October 1989 and who survived for 5 years (average 5.3 years). METHODS: The same interviewer saw each survivor at their home and used the OPCS Adult Disability Schedule to ascertain levels of functional disability. Disability scores for each survivor were then combined in accordance with the OPCS guidance to calculate a level of disability between 0 (no disability) to 10 (maximum disability). The OPCS level was then dichotomised with a cut-point at 4/5. Possible predictor and confounding variables from pre-injury, injury and post-injury periods were modelled in a logistic regression to identify those that predicted outcome level. Two reduced models were developed to allow early prognosis of late outcome. RESULTS: The full model correctly classified 91% of observed outcomes. Inpatient length of stay OR 1.031 (95% CI 1.014,1.048) per day predicted poorer 5-year outcome; Glasgow Coma Score OR 0.790(0.629,0.992) per 1 point increase; stay in Intensive Care Unit OR 0.931 (0.877,0.987) per day; attainment of degree-level education OR 0.014 (0.000,0.707); single civil status OR 0.110 (0.013,0.908); being taken initially to a hospital with a neurosurgical facility OR 0.064(0.010,0.420); being in paid work during the 2 weeks before index injury OR 0.093(0.009,0.969) predicted better 5-year disability outcome. Two reduced models were constructed that included a simple set of variables, one of these models excluded any rehabilitation variables but still correctly classified 85% of the observed outcomes. CONCLUSION: As well as level of traumatic brain injury (TBI) and total inpatient stay, Pre-injury educational attainment and employment, civil status, immediate care in a hospital with a neurosurgical facility and stay in an Intensive Care Unit determined 5-year outcome. It is possible to efficiently predict outcome at an early stage. Previous work on predictors of disablement have suffered from large selection and attrition biases.

Diabetes UK funded surveys of the structural provision of primary care diabetes services in the UK.

AIM: To describe diabetes service provision in primary care in the UK. METHODS: Postal questionnaires were sent to all UK primary care organizations (PCOs), and to a sample of general practices in England and all practices in Wales and Scotland. The data collection period ended on 30 April 2001. RESULTS: Seventy-nine per cent of the PCOs and 40% of the practices provided usable information. There is evidence that respondents were not significantly biased in relation to their interest in diabetes care. Diabetes was included as a Health Improvement Programme (or equivalent) priority by 62% of PCOs and had been identified as a clinical governance priority by 27%. Sixty-five per cent had information about the ethnic composition of their general population, 57% had an estimate of the number of people with diabetes. Sixty-nine per cent had a local diabetes register but this was said to cover the entire local population in only 64% of these. At least one audit of diabetes care had been carried out (in the previous 5 years) in 75% and, in 76%, clinical guidelines on diabetes care were made available to practices. In the practices, 80% had a designated lead person for diabetes. Seventy-three per cent had at least one general practitioner with a special interest and 87% at least one nurse. Seventy-two per cent of practices ran specific diabetes clinics and 51% had a screening policy. Eighty-six per cent considered that they had adequate systems in place for the delivery of diabetes care. However, only 6% were able to offer a dedicated diabetes telephone help or advice line and only 9% an evening out of hours clinic. Regular practice meetings were held to discuss diabetes in 35%, whereas 39% had a formal shared care protocol. Fourteen per cent held regular joint meetings with the hospital-based team and in 38% there was membership of Diabetes UK for at least one partner or the practice itself. A third (34%) of responding practices were unsure whether a Local Diabetes Services Advisory Group or equivalent existed in their area. Geographical differences in service provision were identified with, for example, practices in London having fewer components in place that were specifically related to the provision of diabetes care. Single-handed practices, wherever they were situated, had in place fewer staff and facilities specifically for diabetes care.

How to undertake a clinically relevant systematic review in a rapidly evolving field. Magnetic resonance angiography.

OBJECTIVES: The aim was to determine which generations of the evolving technology of magnetic resonance angiography (MRA) are currently of clinical relevance in two clinical applications. Our purpose was to plan a systematic review that would be valuable both to purchasers driven by cost-effectiveness and to practicing clinicians. METHODS: Information was gathered from a search of major bibliographic databases, from a short questionnaire sent to 500 U.K. vascular radiologists and vascular surgeons, and from local clinical experts. We asked which of the MRA techniques were currently used and, assuming availability, what would be their technique of choice. RESULTS: There were 206 published articles that satisfied preliminary inclusion criteria: 69 discussed 2D time of flight (TOF); 47, 3D TOF; and 38, contrast-enhanced techniques. There were 162 questionnaires returned (60 radiologists, 102 surgeons). Of the total respondents, 77/162 (48%) used MRA in the assessment of carotid artery stenosis; 47/77 (61%) used 2D TOF; 32/77 (42%), 3D TOF; and 26/77 (34%), contrast-enhanced techniques. Thirty-five of 162 (22%) respondents used MRA in the assessment of peripheral vascular disease (PVD); 15/35 (43%) used 2D TOF, 4/35 (11%) used 3D TOF, and 22/35 (63%) used contrast-enhanced techniques. For those wishing to use MRA, contrast-enhanced techniques were the method of choice. CONCLUSIONS: The TOF methods that represent earlier generations of the technology remain clinically relevant, and will therefore be included in our systematic review. To ensure complete and relevant coverage in reviews of other evolving technologies, it would be advisable to obtain data for guidance in a similar way.

Use of magnetic resonance angiography to select candidates with recently symptomatic carotid stenosis for surgery: systematic review.

OBJECTIVE: To determine if sufficient evidence exists to support the use of magnetic resonance angiography as a means of selecting patients with recently symptomatic high grade carotid stenosis for surgery. DESIGN: Systematic review of published research on the diagnostic performance of magnetic resonance angiography, 1990-9. MAIN OUTCOME MEASURES: Performance characteristics of diagnostic test. RESULTS: 126 potentially relevant articles were identified, but many articles failed to examine the performance of magnetic resonance angiography as a diagnostic test at the surgical decision thresholds used in major clinical trials on endarterectomy. 26 articles were included in a meta-analysis that showed a maximal joint sensitivity and specificity of 99% (95% confidence interval 98% to 100%) for identifying 70-99% stenosis and 90% (81% to 99%) for identifying 50-99% stenosis. Only four articles evaluated contrast enhanced magnetic resonance angiography. CONCLUSIONS: Magnetic resonance angiography is accurate for selecting patients for carotid endarterectomy at the surgical decision thresholds established in the major endarterectomy trials, but the evidence is not very robust because of the heterogeneity of the studies included. Research is needed to determine the diagnostic performance of the most recent developments in magnetic resonance angiography, including contrast enhanced techniques, as well as to assess the impact of magnetic resonance angiography on surgical decision making and outcomes.

The epidemiology of disability and occupation handicap resulting from major traumatic injury.

PURPOSE: To assess the prevalence of disability and handicap among survivors of major traumatic injury (injury severity score > 15) using a prospective population based cohort study design. The study was set in the former Yorkshire Health Region. SUBJECTS/METHODS: A cohort of 367 individuals identified as having received and survived major traumatic injury during the 12 month period October 1988-September 1989. OPCS disability scores and employment status at 5 years post injury were established through structured face-to-face interviews. RESULTS: Three hundred and four (84% response. 89% adjusted response) individuals were interviewed. Seventy-seven percent of these were male and they had a mean age (SEM) of 30.8 (1.06) years. Injuries were caused by road traffic accidents in 68% of the cases and were primarily orthopaedic and neurological in nature. At 5 years post injury 81.2% of individuals had some form of measurable disability principally relating to locomotion, behaviour, continence and intellectual functioning consistent with injury type. A third had an OPCS disability score of 5 or greater and approximately 1 in 12 were in the most severe categories of OPCS scores of 9-10 necessitating dependency on formal or informal carer assistance. Whilst five of the eight sub-scales of the SF36 showed correlation in severity proportion, general health perception and energy/vitality were higher in those with increasing disability as measured by the OPCS scale. Of those between the ages of 16-64 nearly half (49%) were not in paid employment at the time of follow up. CONCLUSION: A high prevalence of severe permanent disability, work disability and occupation handicap has been identified in a cohort of mainly young adult males following major traumatic injury resulting from road traffic accidents. Progress in accident prevention, injury reduction and the management of patients with serious injuries should be measured not only in terms of reduced mortality from such events but also in the long term disability and quality of life sequelea of survivors.

Hypoglycaemia induced by exogenous insulin--'human' and animal insulin compared.

AIMS: A systematic review of the literature was carried out to examine whether published evidence suggests a difference in the frequency and awareness of hypoglycaemia induced by 'human' and animal insulin. METHODS: The review identified randomized controlled trials and studies of other designs including observational comparisons, case series and case reports in which the use of 'human' insulin was compared to animal insulin in people with diabetes. These were identified from bibliographic databases and hand-searches of key journals. The main outcome measures were frequency, severity, awareness and symptoms of insulin induced hypoglycaemia. RESULTS: Fifty-two randomized controlled trials, 37 of double-blind design, were identified which included one or more of the relevant outcome measures. Of these, 21 specifically investigated hypoglycaemic frequency and awareness as primary outcomes (six in people with previously reported reduced hypoglycaemic awareness). The remainder of the identified trials reported hypoglycaemic outcomes as a secondary or incidental outcome during comparative investigations of efficacy or immunogenicity. Seven of the double-blind studies reported differences in frequency of hypoglycaemia or awareness of symptoms, although none of the studies which selected subjects on the basis of previously reported impaired awareness demonstrated significant differences between insulin species. Four of the unblinded trials reported differences in hypoglycaemia. This reached statistical significance in two of the studies. A further 56 studies of other designs and case reports were considered. In addition to the 10 case reports describing individuals with impaired hypoglycaemic awareness, nine studies reported differences in the incidence and manifestation of hypoglycaemia during 'human' insulin treatment. Notably, none of the four population time trend studies found any relationship between the increasing use of 'human' insulin and hospital admission for hypoglycaemia or unexplained death among those with diabetes. The largest case series could find no support for the hypothesis that an influence of treatment with 'human' insulin on hypoglycaemia had contributed to any of the 50 deaths investigated. When all types of studies considered are ranked in order of rigour (according to the accepted 'hierarchy of evidence'), it is the least rigorous which lend most support to the notion that treatment with 'human' insulin has an effect on the frequency, severity or symptoms of hypoglycaemia. CONCLUSIONS: Evidence does not support the contention that treatment with 'human' insulin per se affects the frequency, severity or symptoms of hypoglycaemia. However, a number of studies, mainly those of less rigorous design, describe an effect when people are transferred from animal insulin to 'human' insulin. It is not possible to state how common this is or whether the phenomenon is specific to 'human' insulin or an effect resulting from stricter glycaemic control (perhaps compounded, in some cases, by neurological complications in long-standing diabetes). This remaining uncertainty makes it essential that insulin from animal sources continues to be available so that clinicians and patients may retain this choice of treatment.

The prevalence of multiple sclerosis in the Leeds Health Authority.

OBJECTIVES: To determine the prevalence of multiple sclerosis in the Leeds Health District. METHODS: Multiple sources of case ascertainment were used-namely, neurology departments, hospital episode statistics, general practitioners, the Leeds branch of the Multiple Sclerosis Society, the West Yorkshire Multiple Sclerosis Therapy Centre, community physiotherapists and occupational therapists, the Leeds Wheelchair Centre, and the Young Disabled Unit. Data collection was from retrospective analysis of hospital and primary care case records. A population based incidence register was established by prospectively registering all new patients with diagnoses of multiple sclerosis. RESULTS: On prevalence day, 30 April 1996, 712 people with multiple sclerosis were identified living in Leeds (population 732,061), giving a prevalence of 97/10(5). The prevalence for definite and probable multiple sclerosis was 84/10(5), and for suspected multiple sclerosis it was 13/10(5). The sex ratio of prevalent people with multiple sclerosis was 2.79 to 1 women to men. The mean age of prevalent cases was 51 years, the mean age at symptom onset was 34 years, and the mean duration of disease was 16 years. Forty cases were prospectively reported as incident cases from 1 November 1995 to 1 February 1996. CONCLUSIONS: The prevalence of multiple sclerosis in Leeds was found to be similar to that in the south of the United Kingdom but lower than that in Scotland. There is no evidence of a latitudinal gradient of increasing prevalence of multiple sclerosis from the south to the north of England.

Major trauma workload within an English Health Region.

The incidence, distribution and clinical patterns of life-threatening and multiple injuries were evaluated within an English Regional Health Authority area. Cases of major injury were identified retrospectively for the 12 month period October 1988 to September 1989 using data from the 16 Accident and Emergency (A&E) units within the Yorkshire Health Region, and coroners' records. There were 968 cases of fatal and serious injury, meeting the criterion of an injury severity score greater than 15, 67 per cent (645) being due to road traffic incidents. Thirty-five per cent (337) died at the scene or before reaching hospital, whilst 65 per cent (631) survived to reach an A&E unit (0.082 per cent of the Region's annual A&E case load), 75 per cent arriving outside of normal office hours. Eleven per cent (72) died prior to ward admission and 34 per cent (213) were immediately transferred to a secondary medical referral centre. Three hundred and sixty-seven patients (38 per cent) survived to be discharged from acute hospital care whilst 188 (19 per cent) died as in-patients. Major injuries were found to be distributed throughout the Authority area in rough proportion to district population density with a regional incidence of 27 cases per 100,000. This study has quantified a group of patients with very specific and specialized needs, but further research and debate is required to decide how these needs are best met.

Etoposide-related myocardial infarction.

The occurrence of a myocardial infarction is reported after chemotherapy containing etoposide, in a man with no risk factors for coronary heart disease. Possible causal mechanisms are discussed.

The effect of aldose reductase inhibition on erythrocyte polyols and galactitol accumulation in diabetic patients.

Erythrocyte sorbitol level has previously been used as a measure of the efficacy of aldose reductase inhibitors, but its value is limited by fluctuations related to variations in blood glucose concentration. The aim of the study was to compare sorbitol content with the ability to accumulate galactitol during ex vivo incubation with galactose, of erythrocytes taken from diabetic patients following administration of a single 600 mg dose of the aldose reductase inhibitor, ponalrestat. Twelve patients were studied in a placebo-controlled crossover trial. Blood glucose levels were not statistically different during the placebo and ponalrestat treatment periods except at 1 h after the dose was taken (10.6 +/- 6.7 vs 7.7 +/- 4.6 mmol l-1 (+/- SD), p less than 0.05). Ponalrestat reduced erythrocyte sorbitol concentrations compared with placebo at 3, 5 and 7 h (0.82 +/- 0.36, 0.69 +/- 0.23, and 0.83 +/- 0.35 mg l-1 vs 1.79 +/- 0.67, 1.68 +/- 0.65, and 1.57 +/- 0.59 mg l-1 respectively, p less than 0.005) and 24 h post-dose (1.57 + 0.45 vs 2.01 + 0.73 mg l-1, p less than 0.05). Ponalrestat also reduced erythrocyte galactitol accumulation at 3, 5 and 24 h post-dose from 5.53 +/- 2.41, 5.43 +/- 1.89, and 5.42 +/- 1.96 mg l-1 2-h-1 to 1.47 +/- 0.30, 1.76 +/- 0.41, and 4.12 +/- 0.72 mg l-1 2-h-1 respectively, p less than 0.01. Galactitol accumulation rate appeared to be a less variable parameter than erythrocyte sorbitol and was not influenced by fluctuations in blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of aldose reductase inhibition on nerve conduction velocity and resistance to ischemic conduction block in experimental diabetes.

The relationships between nerve polyol levels and both nerve conduction velocity (NCV) and resistance to ischemic conduction block (RICB) in streptozocin-induced diabetic rats were examined in two studies. In the first study, sciatic NCV and RICB of the tail nerve, assessed by measuring the time to disappearance of the nerve action potential after the tail was rendered ischemic, were measured in nondiabetic rats, untreated diabetic rats, and diabetic rats given Statil, an aldose reductase inhibitor (ARI). Sciatic NCV was lower in the untreated diabetic animals than in control animals (P less than .05), and RICB of the tail nerve was greater (P less than .001). Treatment with the ARI completely prevented the slowing of NCV but had no significant effect on the increase in RICB. In the second study, similar groups of rats were treated with either ARI, insulin, or myo-inositol. Sciatic NCV was lower in the untreated diabetic rats than in the nondiabetic rats (P less than .001). In diabetic rats treated with the ARI and in those treated with insulin, NCV was greater than in the untreated diabetic rats (P less than .05 and P less than .001, respectively) and was not significantly different from the nondiabetic rats. NCV in the myo-inositol-treated rats was not significantly different from that in the untreated diabetic rats. RICB was assessed by measuring the decline in sciatic nerve action potential amplitude at minute intervals after death.(ABSTRACT TRUNCATED AT 250 WORDS)

Red cell sorbitol levels during hyper and hypoglycaemic clamp studies in insulin-dependent diabetic patients.

The red cell sorbitol concentration has been suggested as a measure of polyol pathway activity. Red cell sorbitol levels were higher in 53 patients having insulin-dependent diabetes mellitus (IDDM) than in 16 control subjects. Six patients having IDDM underwent hyperglycaemic 'clamp' studies; the red cell sorbitol level returned to the normal range when the blood glucose was clamped at 5 mmol/l for 1 h and rapidly increased when it was clamped at 15 and 25 mmol/l for a further hour at each level. Seven patients with IDDM were rendered hypoglycaemic; red cell sorbitol levels rapidly fell to a level less than, but not significantly different from normal. The results of these studies suggest that in IDDM red cell sorbitol levels are a reflection of prevailing blood glucose concentration and do not indicate long-term sorbitol accumulation in other tissues.

Changes in skinfold thickness with increasing age.

Skinfold thickness measurements on 626 normal subjects of both sexes between the ages of 5 months and 73 years demonstrated a tri-phasic relationship between loss of skin thickness and age. Measurements for infants of either sex were indistinguishable and high, falling rapidly to levels which only changed slightly over the period 20-60 years. Thereafter, massive loss of skin-thickness occurred in both sexes. Throughout the major portion of adult life the values obtained for females were significantly lower than those for males. It is suggested that the three phases may be associated with progressive dehydration, failure to synthesize collagen and frank degradation of the collagen of the dermis.