Is late-onset schizophrenia a subtype of schizophrenia?

OBJECTIVE: To determine whether late-onset schizophrenia (LOS, onset after age 40) should be considered a distinct subtype of schizophrenia. METHOD: Participants included 359 normal comparison subjects (NCs) and 854 schizophrenia out-patients age >40 (110 LOS, 744 early-onset schizophrenia or EOS). Assessments included standardized measures of psychopathology, neurocognition, and functioning. RESULTS: Early-onset schizophrenia and LOS groups differed from NCs on all measures of psychopathology and functioning, and most cognitive tests. Early-onset schizophrenia and LOS groups had similar education, severity of depressive, negative, and deficit symptoms, crystallized knowledge, and auditory working memory, but LOS patients included more women and married individuals, had less severe positive symptoms and general psychopathology, and better processing speed, abstraction, verbal memory, and everyday functioning, and were on lower antipsychotic doses. Most EOS-LOS differences remained significant after adjusting for age, gender, severity of negative or deficit symptoms, and duration of illness. CONCLUSION: Late-onset schizophrenia should be considered a subtype of schizophrenia.

Incidence of liver disease in people with HFE mutations.

BACKGROUND: Most patients with haemochromatosis have mutations of the HFE gene. However, the risk to people with HFE mutations of developing disease manifestations of haemochromatosis is not known. AIMS: To determine the risk of developing cirrhosis and liver cancer in individuals with HFE mutations in a population where few people were being treated for haemochromatosis. METHODS: 215 archive biopsy specimens of liver cancer (n=34) and cirrhosis (n=190) were retrieved from histology archives. Blood samples from 1000 individuals from the normal population were also collected. DNA was extracted from the biopsy specimens and exons 2 and 4 of the HFE gene were amplified using polymerase chain reaction. The products were analysed for the C282Y (845A) and H63D (187G) mutations. RESULTS: Three (8.8%) patients from the liver cancer group were homozygous for the C282Y mutation. Five (2.6%) patients from the cirrhosis group were homozygous for the C282Y mutation. One case fell in both the liver cancer and cirrhosis groups. C282Y homozygosity was thus significantly more frequent in both groups than in the normal population. These 215 cases are representative of a population of about 250 000 over 20 years. During this period we estimate that about 260 births or deaths of C282Y homozygous individuals occurred within this population. CONCLUSIONS: A diagnosis of liver cancer or cirrhosis is rare in the lifetime of individuals from this population who are homozygous for the C282Y mutation (2.5%; upper 95% confidence interval (CI) = 8%). Similarly liver disease is rare among C282Y/H63D compound heterozygotes (1%; upper 95% CI = 3.5%).

Haemochromatosis gene C282Y homozygotes in an elderly male population.

We found that C282Y homozygosity was not under-represented in an elderly male population. This suggests that life-threatening, haemochromatosis-related disease may not occur in many C282Y homozygotes.

The characterisation of the major metabolite of salmeterol in the dog.

Salmeterol xinafoate is the first of a new class of long acting, selective beta2-adrenoceptor agonists introduced for the treatment of asthma. The major metabolite of salmeterol in the dog has been identified as the 3-catechol sulphate of the benzoic acid derivative. This metabolite was isolated from dog bile and was shown to have very similar physiochemical properties to a major endogenous component of bile, the bile acids, creating a complex analytical challenge. Initial experiments, involving hydrolysis with the enzyme sulphatase, suggested that the metabolite was a sulphate conjugate. However, complete identification of the metabolite was complicated in part due to the loss, by metabolism, of deuterium atoms added to the compound, specifically as a marker for mass spectrometry. Subsequently, a synthesis of salmeterol was completed with deuterium labels in different positions. This material was used as a substrate for dog liver slices, a simpler matrix than dog bile, which provided the basis for the metabolite's identification. The metabolite was characterised by the use of spectroscopic techniques, in particular LC/MS, LC/MS/MS and NMR.

A high prevalence of HLA-H 845A mutations in hemochromatosis patients and the normal population in eastern England.

We have examined normal individuals and all the patients currently being treated for hemochromatosis at the Norfolk and Norwich hospital for mutations in the HLA-H gene. We found a gene frequency in 200 normal subjects for teh 845A (C282Y) allele of 0.085, corresponding to a carrier frequency of 17% which is among the highest reported anywhere in the world. The frequency for the less penetrant 187G (H63D) allele was 0.16 among 58 of the normal subjects, which corresponds to a carrier frequency of 32%. All 18 hemochromatosis patients were homozygous for the 845A allele which is not significantly different from other reports in our subset of 12 unrelated patients. These findings present a snapshot of a relatively stable population containing a predicted 3,500 individuals homozygous for the 845A allele but not diagnosed with hemochromatosis. This population will be an excellent model for studies on the penetrance of the 845A homozygous genotype and population screening.

Habitual intake of fruits and vegetables amongst patients at increased risk of colorectal neoplasia.

We assessed consumption of fruit and vegetables amongst patients with ulcerative colitis, colorectal polyps or previous carcinoma. The dietary intakes for 119 patients attending a gastroenterology clinic for colonoscopy were assessed using a questionnaire. A single age- and sex-matched control subject was recruited for each patient. The patients consumed 12.8% less energy than the controls (P < 0.02) and 28.9% less fruit and vegetables (P < 0.0001). Patients with neoplastic disease consumed 21% less fruit and vegetables than the controls (n = 60; P < 0.01). This group of patients at increased risk of colorectal cancer selected diets containing significantly less fruit and vegetables than symptomless controls.

Validation of a simple technique for the detection of abnormal mucosal cell replication in humans.

Abnormal intestinal crypt cell proliferation is considered to be an important early risk marker for colorectal cancer but measurement of the rate and spatial distribution of cell division by histochemical localization of DNA synthesis is labour-intensive and expensive. We developed and evaluated a simpler technique for measurement of these parameters using direct visual analysis of mitotic figures in microdissected crypts. The direct crypt analysis technique was applied to colorectal biopsies from patients with ulcerative colitis or no mucosal abnormality. A characteristic shift of cell division toward the intestinal lumen was detected in patients with ulcerative colitis. The direct method was validated using rats fed diets containing cellulose, or guar gum to stimulate mucosal cell proliferation. The crypt cell proliferation rate (CCPR) was measured by the metaphase-arrest technique and the results were compared with direct crypt analysis. There was a fivefold range of CCPR values at three sampling sites across the dietary groups. An excellent linear correlation between the results by the two techniques was obtained (r = 0.98; P < 0.001). In a second experiment the spatial distribution of dividing cells between five zones in colonic crypts, determined by the new method or by staining with BrdU, was compared. Good agreement was again achieved. Visual analysis of intact crypts is a valid technique for the measurement of crypt cell cytokinetics and it is particularly suited for use in a clinical environment.

Treatment of active Crohn's disease by exclusion diet: East Anglian multicentre controlled trial.

Elemental diet is as effective in producing remission of Crohn's disease (CD) as is corticosteroid treatment, but most patients relapse soon after resumption of a normal diet. We have investigated the efficacies of dietary modification and oral corticosteroids in maintaining remission achieved with elemental diet. In a multicentre trial, 136 patients with active CD were started on elemental diet and other treatment was withdrawn. 43 (31%) declined to continue elemental diet for 14 days, but 78 (84%) of the remaining 93 achieved remission and were randomly assigned corticosteroids (38) or diet (40). Corticosteroid treatment started at 40 mg prednisolone daily, which was tapered and stopped after 12 weeks; that group received dietary advice on healthy eating. The diet group received "tapered" placebo and were instructed to introduce one new food daily, excluding any that precipitated symptoms. Assessment of progress for up to 2 years was made by physicians unaware of group assignment. Intention-to-treat analysis showed median lengths of remission of 3.8 (interquartile range 5.0) months in the corticosteroid group and 7.5 (15.3) months on diet, and relapse rates at 2 years, adjusted for withdrawals, of 79% and 62%, respectively (p = 0.048). Clinical improvement in the diet group was associated with significant changes in plasma albumin and alpha 1-antichymotrypsin concentrations and erythrocyte sedimentation rate. Food intolerances discovered were predominantly to cereals, dairy products, and yeast. Diet provides a further therapeutic strategy in active Crohn's disease.

Non-steroidal anti-inflammatory drug-induced jejunal and colonic diaphragm disease: a report of two cases.

Two patients with intestinal submucosal diaphragm disease associated with non-steroidal anti-inflammatory drugs are presented. The jejunum was affected in one, and in the other the ascending colon. Most previously reported cases have shown ileal disease and no case to date has shown involvement of the colon. The reasons for the localisation of these diaphragms remain unclear.

Mapping of von Hippel-Lindau disease to chromosome 3p confirmed by genetic linkage analysis.

Genetic linkage studies were performed in 12 British families with von Hippel-Lindau disease (VHL) using RFLPs at three loci (DNF15S2, THRB, RAF1) on the short arm of chromosome 3. Linkage was detected between the VHL disease locus and RAF1 with a maximum lod score of 3.88 at a recombination fraction of 0.05 (confidence interval 0.003-0.18). Multipoint linkage analysis suggested that the most likely location for the VHL disease locus is telomeric to THRB. These results confirm earlier reports localizing the VHL gene to the short arm of chromosome 3, and provide no evidence for genetic heterogeneity.

Crohn's disease in the city of Derby, 1951-85.

An epidemiological survey of Crohn's disease in the city of Derby showed that the incidence of the condition increased from 0.7/10(5) per year between 1951 and 1955 to 6.67/10(5) per year between 1981 and 1985 but seemed to reach a plateau between 1976 and 1985. Large bowel Crohn's disease was more common in patients presenting aged 60-79 years than in those aged 20-39 years. The increase in incidence was not solely due to the detection of milder disease. There was no evidence that the Asian (Indian subcontinent) population of Derby was resistant to the development of Crohn's disease.

Defect in thermoregulation in malnutrition reversed by weight gain. Physiological mechanisms and clinical importance.

Previous studies in infants and in the elderly have shown that a low body weight is associated with a defect in thermoregulation and an increased risk of hypothermia. In the present study, thermoregulatory responses to a cooling stimulus were measured in 10 young and middle-aged patients who lost at least 10 per cent of their body weight during illness. Investigations were performed before and after restoration of body weight (mean weight gain 7.2 kg, SE 1.2 kg, p less than 0.001). The cooling stimulus was provided by a special suit perfused with water at 28 degrees C and then at 23 degrees C. Before weight gain, there was no increase in metabolic rate in response to cooling, despite a fall in core temperature. Following weight gain, the thermogenic response to cooling was restored towards normal. Peripheral vasoconstriction, the principal mechanism for heat conservation, was similar before and after weight gain. The thermogenic response to an infusion of adrenaline (25 ng/kg/min) was not abolished by weight loss, suggesting that the defect in cold-induced thermogenesis following weight loss is due to a change in central control mechanisms of thermoregulation, and not to tissue unresponsiveness. The phenomenon of abnormal thermoregulation following weight loss and the return to normal with subsequent weight gain may be clinically important, particularly in the elderly, since quite small falls in core temperature may impair both neuromuscular coordination and cerebral function.

Carcinoid tumour of the common bile duct--a novel complication of von Hippel-Lindau syndrome.

A 30 year old man with von Hippel-Lindau syndrome presented with obstructive jaundice caused by a carcinoid tumour of the mid- and upper common bile duct. This association is probably causally related in view of the propensity for patients with von Hippel-Lindau syndrome to develop neuroendocrine tumours.

Enhanced thermogenic response to epinephrine after 48-h starvation in humans.

The effects of 48-h starvation on the physiological responses to a 30-min infusion of epinephrine at 25 ng.min-1.kg body wt-1 were studied in 11 normal-weight healthy young subjects. Starvation led to considerable alterations in basal metabolism including a significant (mean 3.6%) increase in resting metabolic rate. During the infusions, plasma epinephrine concentration rose less in the starved state (+1.47 nmol/l) than in the normally fed state (+1.73 nmol/l) (SE 0.06 nmol/l; P less than 0.05). The maximum increments (mean +/- SE) in heart rate induced by epinephrine were 11.9 +/- 1.3 beats/min in the normally fed state and 20.1 +/- 2.0 beats/min in the starved state (P less than 0.001); the corresponding mean increments in blood glycerol concentration were 0.07 and 0.14 mmol/l (SE 0.01 mmol/l; P less than 0.01). The increase in the metabolic rate above base line during the final 10 min of the epinephrine infusion was 0.58 +/- 0.18 kJ/min in the normally fed state and 0.78 +/- 0.14 kJ/min in the starved state (P less than 0.01). The chronotropic, lipolytic, and thermogenic effects of infused epinephrine were therefore enhanced by prior starvation, despite the lower plasma epinephrine levels.

Nature and time-course of piroxicam-induced injury to human gastric mucosa.

The nature and time-course of acute piroxicam-induced gastric mucosal injury was determined in ten healthy volunteers treated with 10 mg piroxicam twice daily by mouth for 21 days. Mucosal injury was measured endoscopically by visual analogue scales and by the method of Lanza, and luminal blood loss by haemoglobin measurements in gastric washings, 10 h after the first drug dose and then after 5, 10 and 21 days. Acute mucosal injury, consisting mainly of haemorrhagic lesions in the gastric body, developed to a maximum extent within 10 h of the first dose of piroxicam, and did not increase thereafter. By contrast intraluminal bleeding increased little for 10 days and then rose significantly at 21 days, when plasma piroxicam levels reached values likely to affect platelet function. We conclude that gastric mucosal injury and bleeding may be dissociated and may constitute different targets for prophylaxis. Gastric mucosal injury is probably exerted topically as it is maximal at low plasma drug concentrations, whereas bleeding may arise because of interference with platelet-dependent mechanisms.

The metabolic and cardiovascular effects of intravenous infusion of glucose or intralipid in normal humans.

This study was performed to determine whether the administration of intravenous fluids, isosmolar with plasma, activated the sympathetic nervous system, thereby causing changes in cardiovascular variables. On four separate occasions, six young, healthy men were studied for 30 min before and, for 40 min after a 60 min period of either (a) intravenous infusion of 500 ml of 5% dextrose, (b) intravenous infusion of 500 ml of a mixture of 10% Intralipid and saline (154 mmol NaCl 1(-1)), (c) intravenous infusion of 500 ml of saline (154 mmol NaCl 1(-1)) or (d) no intravenous infusion. Venous plasma noradrenaline and adrenaline concentrations did not change significantly during any of these interventions. The venous plasma insulin level rose during infusion of 5% dextrose (p<0.001). The respiratory exchange ratio rose during the dextrose infusion and fell during the infusion of the Intralipid and saline mixture (p<0.01). Hand and calf blood flows and vascular resistances were not significantly affected by any procedure. Similar, small, changes in heart rate, arterial blood pressure, metabolic rate, core temperature and mean skin temperature were observed during the four protocols. The provision of small amounts of metabolic substrate, as either glucose or fat, led to rapid changes in fuel utilisation. However, under the conditions of the present experiments, there was no evidence of activation of the sympathetic nervous system.