Once weekly thyroxine treatment as a strategy to treat non-compliance.

Hypothyroidism is a common disorder, which is mainly treated in primary rather than secondary care. Once daily thyroxine replacement restores euthyroidism in most patients; some patients, however, remain hypothyroid despite adequate thyroxine replacement. Non-compliance is the most common cause of lack of response to thyroxine treatment. We describe two cases of primary hypothyroidism in which daily thyroxine treatment did not restore biochemical euthyroidism but once weekly thyroxine treatment was successful. In addition we review the evidence and discuss the differential diagnosis of lack of response to thyroxine treatment. Once weekly thyroxine treatment can be a safe, well-tolerated, and effective therapy for patients with non-compliance.

An unusual cause of severe hypoglycaemia in type 1 diabetes mellitus. Antepartum pituitary failure: a case report and literature review.

We describe an unusual cause of severe hypoglycaemia, secondary to hypopituitarism as a result of antepartum pituitary failure, in a pregnant patient with type 1 diabetes mellitus (T1DM). Antepartum pituitary failure is a very rare condition, which has been reported only in a very small number of pregnant patients with diabetes and presents with an acute onset headache and a sub-arachnoid haemorrhage-like picture. It is a potentially fatal condition to the mother and the child if not recognised and treated. Our case report highlights the importance of thinking about hypopituitarism, as a cause of recurrent hypoglycaemia in pregnant patients with T1DM as missing the diagnosis could be fatal to the mother and child.

A diagnostic dilemma in diagnosing and managing an incidental phaeochromocytoma.

Incidental adrenal tumours are a common radiological finding. Phaeochromocytomas, though rare, are very important not to be missed, as the consequences could be fatal. Urinary catecholamines and metanephrines measurement is a commonly used method of screening for phaeochromocytomas. We report a patient who had a phaeochromocytoma presented as an incidental adrenal mass on abdominal CT during investigations for recurrent chest infections. The patient had symptoms suggestive of catecholamines excess and hypertension. Repeated urinary catecholamines measurements, plasma catecholamines, 24-hour urinary catecholamines and 24-hour urinary metanephrines all were normal. MIBG scan showed increased uptake in the adrenal mass. Histological examination of the adrenal mass was consistent with phaeochromocytoma. Removal of the adrenal mass resulted in normalisation of blood pressure and abolishing of the patient's symptoms. This case highlights the difficulty in deciding on further management of patients presenting with an adrenal incidentaloma. This case also highlights the difficulty in diagnosing phaeochromocytoma and represents a reminder that plasma and urine catecholamines measurements could be normal in patients with symptomatic phaeochromocytoma. This case also highlights that MIBG scan could reveal a phaeochromocytoma despite absence of biochemical markers.

Outcome on diabetic foot complications in relation to clinical examination and quantitative sensory testing: a case-control study.

A total of 405 diabetic patients who first attended St Thomas' Diabetes Clinic between 1982 and 1985 had a detailed standardized computerized first visit record, including a structured foot examination and toe vibration perception thresholds (VPT, Biothesiometer), were reviewed in 1995. None of the patients had a history of foot ulceration at first visit. Twenty-five patients (6.2%) developed foot ulcers (n = 11, 2.7%) or had an amputation (n = 14, 3.5%) over a mean 12-year period. Twenty of these patients were then individually matched with 3 non-ulcer patients. Statistically significant odds ratios (OR) were found for a baseline abnormal age-adjusted toe VPT (OR 4.38, CI 1.11-17.26; p = 0.01); abnormal clinical examination (at least 1 abnormality out of: ankle jerks, tuning fork or cotton wool sensation; OR 2.3, CI 1.00-5.20; p < 0.01); and HbA1 (OR 1.30, CI 1.01-1.66; P < 0.02) in patients who subsequently developed lower extremity complications. The sensitivity of VPT (70%) was better than that for clinical testing (55 %) in predicting long-term complications, although all tests showed similar specificity (70-72%). The risk of events also doubled for every 10 years of diabetes (OR 2.10, CI 1.11-4.30; p = 0.02). We conclude that age-corrected VPT measurements, which are objective and simple to perform, are better predictors of future foot complications than semi-quantitative tests in diabetes clinics. We encourage their use in the campaign to reduce the morbidity of diabetic peripheral neuropathy.

Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome.

Wolfram syndrome is the association of diabetes mellitus and optic atrophy, and is sometimes called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Incomplete characterisation of this autosomal recessive syndrome has relied on case-reports, and there is confusion with mitochondrial genome disorders. We therefore undertook a UK nationwide cross-sectional case-finding study to describe the natural history, complications, prevalence, and inheritance of the syndrome. We identified 45 patients with Wolfram syndrome--a prevalence of one per 770,000. Non-autoimmune, insulin-deficient diabetes mellitus presented at a median age of 6 years, followed by optic atrophy (11 years). Cranial diabetes insipidus occurred in 33 patients (73%) with sensorineural deafness (28, 62%) in the second decade; renal-tract abnormalities (26, 58%) presented in the third decade followed by neurological complications (cerebellar ataxia, myoclonus [28, 62%]) in the fourth decade. Other abnormalities included gastrointestinal dysmotility in 11 (24%), and primary gonadal atrophy in seven of ten males investigated. Median age at death (commonly central respiratory failure with brain-stem atrophy) was 30 years (range 25-49). The natural history of Wolfram syndrome suggests that most patients will eventually develop most complications of this progressive, neurodegenerative disorder. Family studies indicate autosomal recessive inheritance with a carrier frequency of one in 354, an absence of a maternal history of diabetes or deafness, and an absence of the mitochondrial tRNA Leu (3243) mutation. Juvenile-onset diabetes mellitus and optic atrophy are the best available diagnostic criteria for Wolfram syndrome, the differential diagnosis of which includes other causes of neurodegeneration.

A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population.

A cross-sectional multicentre study of randomly selected diabetic patients was performed using a standardised questionnaire and examination, to establish the prevalence of peripheral neuropathy in patients attending 118 hospital diabetes clinics in the UK. Vibration perception threshold was performed in two centres to compare with the clinical scoring systems. A total of 6487 diabetic patients were studied. 53.9% male, median age 59 years (range 18-90 years). 37.4% Type 1 (insulin-dependent) diabetes mellitus, with a median duration of diabetes 8 years (0-62 years). The overall prevalence of neuropathy was 28.5% (27.4-29.6%) (95% confidence interval) in this population. The prevalence in Type 1 diabetic patients was 22.7% (21.0-24.4%) and in Type 2 (non-insulin-dependent) diabetic patients it was 32.1% (30.6-33.6%). The prevalence of diabetic peripheral neuropathy increased with age, from 5% (3.1-6.9%) in the 20-29 year age group to 44.2% (41.1-47.3%) in the 70-79 year age group. Neuropathy was associated with duration of diabetes, and was present in 20.8% (19.1-22.5%) of patients with diabetes duration less than 5 years and in 36.8% (34.9-38.7%) of those with diabetes duration greater than 10 years. Mean vibration perception threshold measured at the great toe was 21.1 +/- 13.5 SD volts and correlated with the neuropathy disability score, r = 0.8 p < 0.001. In conclusion, diabetic peripheral neuropathy is a common complication associated with diabetes. It increases with both age and duration of diabetes, until it is present in more than 50% of Type 2 diabetic patients aged over 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)

A restaurant-associated outbreak of E. coli O157 infection.

An outbreak of haemorrhagic colitis due to Escherichia coli O157 and associated with a restaurant in Lothian, occurred in September 1990. There were 16 symptomatic cases, four of whom (all children) required dialysis. Notable features of the outbreak were the wide range of incubation periods (1-14 days), the occurrence of secondary spread through asymptomatic carriers and the prolonged period (at least seven days) during which the restaurant appears to have been the source of infection. Despite careful investigation, no single source within the restaurant was identified. The implications for public health are discussed.

A multicentre trial of the aldose-reductase inhibitor tolrestat, in patients with symptomatic diabetic peripheral neuropathy. North European Tolrestat Study Group.

One hundred and ninety patients with symptomatic diabetic peripheral neuropathy took part in a double blind multicentre trial of either placebo or tolrestat 200 mg once daily for 6 months. Painful and paraesthetic symptoms, vibration sensory threshold, and nerve conduction velocity (NCV) were assessed as efficacy end-points during the trial. There was an equally marked improvement of painful symptoms during the trial in the tolrestat and placebo groups. A difference in the improvement of paraesthetic symptoms was found however in favour of the placebo group at 24 weeks (p less than 0.02). The deterioration in mean vibration threshold of the tolrestat group was less than placebo at 24 weeks at all 3 sites measured, and reached significance at the carpal site (p less than 0.05). Significant improvements in median motor NCV and in the mean NCV of the four motor nerves were also seen in tolrestat treated patients at 24 weeks compared to placebo (p less than 0.05). In addition, significant changes in favour of tolrestat were seen when the number of motor nerves per patient with NCV increased during the trial was analysed (p less than 0.001). Concordance analysis of patients with increased mean motor NCV and improvement in painful symptoms demonstrated a positive effect for tolrestat compared to placebo (p less than 0.02). Mild reversible elevations of hepatic transaminases were seen in a few patients treated with tolrestat, with no other significant adverse effects. Tolrestat may therefore be helpful in diabetic peripheral neuropathy, where there is little opportunity for therapeutic intervention apart from effort to achieve normoglycaemic control.

Comparison of the real-time use of glycosylated haemoglobin and plasma fructosamine in the diabetic clinic.

The within-clinic use of glycosylated haemoglobin (HbA1) and plasma fructosamine results in assessing blood glucose control and clinical management was compared in 1030 diabetic patients. The physician initially reviewed the patient with one randomly allocated measure (HbA1 or fructosamine) and completed a questionnaire concerning perception of blood glucose control, alteration to diet, alteration to medication, referral for diabetes education, and follow-up interval. The patient was then re-assessed using the second measure and the questionnaire repeated. Discordance rates for the study end-points, judged as binary outcomes, were: blood glucose control 15%; alteration to diet 7%; alteration to medication 9%; referral for education 3%; follow-up interval 4%. A significantly greater number of patients were rated as poorly controlled with HbA1 than with fructosamine (p less than 0.001) and were, in consequence, more frequently recommended alteration to diet and medication, referral for education and shorter follow-up interval; the rate of discordance for at least one of the management decisions was 16%. Multifactorial analysis showed that discordant management was dependent on the reviewing physician (p less than 0.001) and a history of cardiovascular disease (p less than 0.01); but neither type of diabetes, nor presence of nephropathy or variant haemoglobins, nor plasma glucose concentration, significantly influenced the likelihood of a discordance. Replacing HbA1 with fructosamine in the diabetic clinic may result in significant differences in the physician's perception of blood glucose control and in the management of patients.

Non-cardiac autonomic tests in diabetes: use of the galvanic skin response.

Diabetic peripheral neuropathy affects both large myelinated and small unmyelinated nerve fibres. It has been proposed that the small unmyelinated fibres, responsible for pain and temperature sense, and autonomic function, are involved early, particularly in subjects with painful symptoms, and may be important in foot ulceration. The sympathetic skin response has been used to investigate the function of small unmyelinated sympathetic fibres in the limbs of diabetic subjects. Changes in skin resistance at the fingers and toes have been measured simultaneously after a sound stimulus. These procedures were controlled using a microcomputer. Data collected from 55 diabetic subjects, randomly selected from the diabetic clinic, have been compared with results from conventional tests of large motor and sensory fibres and autonomic function. The ratio of the change in skin resistance for toes to fingers correlated with sural and posterior tibial nerve conduction velocity (correlation coefficients 0.54 and 0.42, p less than 0.001 and p less than 0.01, respectively), with the expired to inspired ratio (correlation coefficient 0.51, p less than 0.01), and inversely with vibration perception threshold in the feet (correlation coefficient 0.50, p less than 0.001). Correlation with the dark adapted pupil diameter, however, only just achieved statistical significance (correlation coefficient 0.27, p = 0.043). We propose that this simple test may elucidate the role of the peripheral autonomic system in diabetic neuropathy.

Effect of long-term inhibition of gonadotrophin secretion by the gonadotrophin-releasing hormone agonist, buserelin, on sex steroid secretion and ovarian morphology in polycystic ovary syndrome.

In order to investigate the effect of long-term suppression of the gonadotrophin axis in polycystic ovary syndrome, eight affected subjects were given s.c. infusions of gonadotrophin-releasing hormone (GnRH) agonist buserelin for 12 weeks. Hormone measurement and ultrasound studies were carried out weekly, from 6 weeks before to 12 weeks after administration of buserelin. An overnight dexamethasone-suppression test was carried out before and after treatment. Maximal suppression of LH to below the lower limit of that in normal subjects occurred after 6 weeks of treatment with buserelin. Plasma testosterone and androstenedione fell to normal levels during the infusion but reached pretreatment levels during the follow-up period. There was no effect of buserelin on plasma dehydroepiandrosterone sulphate or sex hormone-binding globulin. Ovarian size decreased significantly during the infusion with the disappearance of cysts in six subjects. After cessation of buserelin therapy, there was rapid and spontaneous ovulation which occurred within 3 weeks in all subjects. The results suggest that treatment with this GnRH agonist facilitates ovulation in this condition.

The problem of autonomic neuropathy in diabetic pregnancy.

The hazards of pregnancy for both the mother and the fetus in diabetic women with severe retinopathy and nephropathy are well reported. We wish to highlight a poorly recognized problem in the obstetric management of the diabetic mother, that of pregnancy in a patient with autonomic neuropathy. Two such cases are reported where the presence of autonomic neuropathy severely jeopardized the health of the mother, with the loss of the fetus in one, due to occurrence of severe and intractable vomiting. The presence of moderate to severe symptomatic diabetic autonomic neuropathy, particularly with evidence of gastroparesis, may be a relative contraindication to pregnancy.

Maternal and cord blood plasma. Comparative analyses by 1H NMR spectroscopy.

Normal and 'Hahn' spin-echo 500 MHz 1H NMR spectra of 21 pairs of plasma from mother and cord taken at the time of delivery are reported. The concentrations of 'NMR-visible' lactate, alanine, and valine in the cord plasma significantly exceed those in the maternal plasma. In both maternal and cord plasma, measured lactate levels appear to increase with the length of the second stage of labour. Ethanol was unexpectedly detected in five samples of cord plasma. Lipoprotein--CH3 and--(CH2)n--resonances are more intense in the spectra of maternal plasma compared to cord plasma, and are unusual in composition. The intensities of N-acetyl signals from 'acute-phase' plasma glycoproteins are greater in spin-echo spectra of maternal plasma compared to those of cord plasma (mean ratio 2.1 (SD 0.8]. These results suggest that high resolution NMR spectroscopy may provide a useful new insight into the comparative biochemistry of maternal and cord plasma.

Treatment of acromegaly by external irradiation.

Despite the place of hypophysectomy as the primary treatment in acromegaly, external radiotherapy maintains a role as a relatively slow but effective therapy for inadequately treated patients or those unsuitable for operation. Over the last 25 years our radiotherapy regimen has differed from the published series in that we give a larger dose per fraction, with fewer treatments. We have analysed the efficacy and side-effects of this regimen in 27 subjects with acromegaly. Growth hormone levels have fallen by, on average, 27% per year in the first five years, 83% of subjects achieving a basal growth hormone of less than 10 mU/l. The acute and chronic side-effects of irradiation are discussed, including the relevance of estimates of biological potency, for example the Time Dose Fraction (TDF). One patient suffered visual loss that was most likely to be secondary to the radiotherapy. We also report the histological appearances of the pituitary fossa in five subjects previously treated with radiotherapy.

Food poisoning in hospitals in Scotland, 1978-87.

During the 10-year period 1978-87 there were 48 outbreaks of food poisoning in Scottish hospitals affecting a total of 2287 persons of whom 12 died. This compared with 50 outbreaks during the previous 5 years (1973-77) when over 1500 persons and 7 deaths were recorded. Although the incidence of outbreaks has decreased the average number of persons affected in outbreaks has increased. A marked reduction was seen in the incidence of outbreaks due to Clostridium perfringens, in contrast to foodborne salmonellosis which remains a problem. Thirty-four hospitals, of which 10 reported two or more outbreaks, were involved. The type of hospitals most frequently affected were general (14), psychiatric (13), geriatric (9) and hospitals for the mentally subnormal (7). Meat, including poultry meat, was incriminated in over 90% of outbreaks where a food vehicle was identified. In modern or re-equipped kitchens cooking in advance with subsequent reheating is being progressively discontinued as more food is being cooked on the day of consumption, a practice which may readily explain the decreasing incidence of outbreaks due to Cl. perfringens. Bacterial cross-contamination from poultry-meat and other raw foods, compounded by inadequate temperature control, however, continues to be a problem in some hospitals. It is too early as yet to determine whether the removal of Crown immunity will have any effect on the future incidence of hospital 'food poisoning'.

Costing of a hospital-based outbreak of poultry-borne salmonellosis.

Poultry-borne salmonellosis is the most common form of foodborne infection in Scotland for which the vehicle can be identified, yet little is known about the costs imposed on society by this disease, or the costs of preventing it. The present study identifies and values the costs of a hospital based outbreak of poultry-borne salmonellosis. Account is taken of costs falling on individuals, the health services and society as a whole. Depending on assumptions made about the value of 'intangibles', the cost of the outbreak is estimated to be between pounds 200,000 and pounds 900,000.

Prevention of poultry-borne salmonellosis by irradiation: costs and benefits in Scotland.

Poultry-borne salmonellosis is the most common foodborne infection in Scotland for which the vehicle can be identified. The cost of the disease to society in terms of health service use, absence from work, morbidity, and mortality is substantial. The study estimates the total cost of poultry-borne salmonellosis in Scotland and compares it with the cost of a single preventive measure: the irradiation of poultry meat. The results suggest that the public health benefits exceed irradiation costs. This conclusion is, however, sensitive to assumptions made in the analysis, particularly those related to the cost of unreported cases of salmonellosis.

1H NMR studies of human blood plasma. Assignment of resonances for lipoproteins.

Single-pulse and Hahn spin-echo 500 MHz 1H NMR spectra of human blood plasma and isolated chylomicrons, VLDL, LDL and HDL are reported. The comparison has enabled specific assignments to be made for the resonances of individual lipoproteins in the CH2 and CH3 (fatty acid), and NMe+3 (phospholipid choline head group) regions of the spectra of plasma (0.8-1.3 and approximately 3.25 ppm, respectively). Fasting, and freeze-thawing of plasma samples led to marked changes in the intensities and linewidths of lipid resonances. Analysis of lipid resonances in the spectra of plasma in terms of individual lipoproteins may shed new light on many conditions of clinical and biochemical interest.

Resolution of hypergastrinaemia after parathyroidectomy in multiple endocrine neoplasia syndrome type I (MEN type I).

The treatment of choice for gastric acid hypersecretion in MEN type I has now changed from total gastrectomy to the long-term administration of H2 receptor blockers or similar agents. However, the importance of parathyroidectomy for the concomitant hypercalcaemia is not fully realized. A case is reported of a subject with MEN type I, who was initially treated with parathyroidectomy and H2 receptor blockade. Following parathyroidectomy, there was a rapid fall of the markedly elevated gastrin levels to the upper limit of the normal range. During follow-up of 2.5 years, there has been no increase in serum gastrin, and the subject's gastric symptoms have resolved, despite the cessation of H2 blockade. Infusion of calcium to pre-operative levels and superimposed secretin stimulation after this period of time closely reproduced the pre-operative hypergastrinaemia. On screening, the subject's only child was found to have hypercalcaemia but normal serum gastrin levels and pituitary function; parathyroidectomy has been carried out. No abnormality of gastrin secretion has been found during follow-up. This case highlights the importance of early parathyroidectomy in this syndrome.

High resolution proton nuclear magnetic resonance studies of human cerebrospinal fluid.

One- and two-dimensional (correlated shift spectroscopy) high resolution proton n.m.r. spectra of human cerebrospinal fluid (CSF) are reported. The merits of water suppression by freeze drying or irradiation, and spectral simplification by spin-echo methods, are discussed. Well-resolved resonances for a range of low molecular weight metabolites such as lactate, 3-D-hydroxybutyrate, alanine, acetate, citrate, glucose, valine and formate were observed. Resonances for glutamine were observed only from freeze dried samples. Concentrations determined by n.m.r. were in reasonable agreement with those from conventional methods. The n.m.r. spectra of CSF were related to the clinical conditions of the subjects. No resonances for citrate were present in spectra of CSF from subjects (three infants) with bacterial meningitis; high lactate and lowered glucose levels were observed. Strong resonances for glucose and glycine were observed for mildly diabetic subjects. Both the aromatic and the aliphatic regions of the CSF spectra from subjects suffering from liver failure contained distinctive features characteristic for hepatic coma: Intense resonances for lactate, alanine, valine, methionine, tyrosine, phenylalanine and histidine. In some cases guanine was also present, which does not appear to have been reported previously. The two-dimensional spectrum suggested the presence of abnormally high levels of a number of endogenous metabolites. Such assignments were not possible using one-dimensional spectra alone because of signal overlap.