Goodpasture disease as a consequence of melioidosis.

We describe a case of anti-glomerular basement membrane (GBM) antibody-mediated disease in association with concomitant Burkholderia pseudomallei (melioidosis) bacteraemia. The temporal profile of the illness and initial absence of circulating anti-GBM antibodies, in light of the subsequent definitive histological diagnosis of anti-GBM disease, makes this case interesting and unusual. Additionally, there have been no prior case reports suggesting melioidosis as a cause of biopsy-proven glomerulonephritis.

Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells.

BACKGROUND: The combination of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib with gemcitabine obtained FDA approval for treating patients with pancreatic cancer. However, duration of response is often limited and there is currently no reliable predictive marker. METHODS: We determined the sensitivity of a panel of human pancreatic tumour cell lines to treatment with afatinib, erlotinib, monoclonal antibody (mAb) ICR62, and gemcitabine, using the Sulforhodamine B colorimetric assay. The effect of these agents on cell signalling and cell-cycle distribution was determined by western blot and flow cytometry, respectively. RESULTS: At 200 nM, ICR62 had no effect on growth of these tumour cells with the exception of BxPC-3 cells. BxPC-3 cells were also sensitive to treatment with afatinib and erlotinib with respective IC(50) values of 11 and 1200 nM. Compared with erlotinib, afatinib was also more effective in inhibiting the growth of the other human pancreatic tumour cell lines and in blocking the EGF-induced phosphorylation of tyrosine, EGFR, MAPK, and AKT. When tested in BxPC-3 xenografts, afatinib induced significant delay in tumour growth. CONCLUSION: The superiority of afatinib in this study encourages further investigation on the therapeutic potential of afatinib as a single agent or in combination with gemcitabine in pancreatic cancer.

Measuring memory impairment in community-based patients with schizophrenia. Case-control study.

BACKGROUND: The majority of memory impairment studies in schizophrenia are cohort studies using laboratory-based tests, which make it difficult to estimate the true extent and relevance of memory impairment in patients with schizophrenia in the community. AIMS: To examine the extent of memory impairment in community-based patients with schizophrenia using a clinically relevant test. METHOD: All patients with schizophrenia (n=190) in one catchment area were identified, of whom 133 were potentially eligible for the study; 73 patients volunteered to take part. They were assessed using the Rivermead Behavioural Memory Test (RBMT), the National Adult Reading Test, the Positive and Negative Syndrome Scale, the Health of the Nation Outcome Scales and the Scales and the Office for National Statistics Classification of Occupation. Their performance on the memory test was compared with that of matched controls (n=71). RESULTS: Patients as a group performed significantly worse (P<0.001) than controls on the RBMT. Using the RBMT normative scores, 81% of patients were found to have impaired memory compared with 28% of controls. CONCLUSIONS: Using a clinically relevant test, the majority of community-based patients with schizophrenia may have memory impairment.

Comparison of prognostic factors in patients in phase I trials of cytotoxic drugs vs new noncytotoxic agents.

The aims of this study were to identify prognostic variables for toxicity and survival in patients with cancer participating in phase I clinical trials and compare characteristics of those treated with cytotoxic chemotherapy (CT) and non-cytotoxic drugs (non-CT). Data were collected from 420 (114 CT, 306 non-CT) patients enrolled in 16 phase I trials (five CT and 11 non-CT trials) in one cancer centre. Analyses of all patients were used to compare treatment groups, identify predictive variables for toxicity and to estimate prognostic factors in overall survival (OS). These were used to develop a prognostic index (PI). Multivariate analysis found those patients with better performance status, fewer sites of metastases, baseline Hb>12 g dl(-1) and WBC or LDH in the normal range had significantly better OS. Male gender, platelet count <450 x 10(9) l(-1), high WBC or treatment with a non-CT phase I agent significantly reduced the chance of grade 3/4 toxicity. Overall survival was not significantly different between the CT and non-CT groups (260 vs 192 days, P=0.47) except for those with liver metastases (228 vs 137 days, P=0.02). Overall tumour response was 4.9% (95% CI: 2.7-7.0%). The PI identified three distinct patient groups with median survival of 321, 257 and 117 days. In conclusion, entry into a phase I trial of a non-CT drug is a safe option for heavily pretreated patients with cancer. The PI generated from these data can estimate the survival probability for patients entering phase I studies.

Prevalence of asthma and wheeze in the Highlands of Scotland.

To establish the prevalence of asthma and wheeze in 12 year old children in a region with low background pollution levels, a population of children resident in the Highland Region of Scotland was studied by questionnaire supported by objective data. A respiratory questionnaire was distributed to the parents of 1919 children aged from 12-13 years and attending secondary schools in the educational divisions of Lochaber, Ross and Cromarty, and Inverness including Skye in Highland Region to ascertain history of wheeze and parental awareness of a diagnosis of asthma. Peak expiratory flow (PEF) measurements were carried out before and after a standardised exercise test. Ozone levels were noted. Questionnaires were completed by 1825 parents (95% of those invited) and 1702 (93%) of those returning questionnaires took part in the exercise test. The overall prevalence of reported asthma was 14% and wheeze 25%. Defined as a fall in PEF of more than 15% with exercise, the overall prevalence of exercise induced bronchospasm was 9%. In Skye the prevalence of reported asthma was 17%, wheeze 28%, and exercise induced bronchospasm 30%. There were no significant differences between areas for reported asthma or wheeze. There was, however, a highly significant difference between areas for exercise induced bronchospasm, most of which was accounted for by the very high incidence in Skye, which is one of the most rural of the areas studied. The results of this study do not support the hypothesis that asthma is commoner in urban than rural areas, whether we compare the Highlands with the rest of the UK or areas within the Highlands, or whether we examine reported symptoms or exercise induced bronchospasm. The results do not support an association between atmospheric pollution and the prevalence of asthma.

UDP-sugar metabolism in Swarm rat chondrosarcoma chondrocytes.

UDP-sugars and adenine nucleotides were extracted from freshly isolated chondrocytes and primary cell cultures and analysed by anion-exchange h.p.l.c. The pool sizes of UDP-N-acetylglucosamine, UDP-N-acetylgalactosamine, UDP-glucose-galactose, UDP-glucuronate and UDP-xylose were 2.9, 1.2, 2.5, 0.6 and 0.03 nmol/10(6) freshly isolated chondrocytes. When chondrocytes were maintained in Dulbecco's modified Eagle medium supplemented with 15% foetal-bovine serum, synthesis of [35S]proteoglycan and [3H]protein decreased over the first 48 h in culture, as did the pools of UDP-glucuronate and ATP. In contrast, the size of the UDP-N-acetylhexosamine pools underwent little change during culture. [35S]Proteoglycan and [3H]protein syntheses were stimulated in cultures supplemented with serum or insulin compared with those maintained in medium alone, in agreement with previous results. However, the UDP-sugar pool sizes were the same in both supplemented and non-supplemented cultures. In cultures maintained in the presence of [1-3H]glucose, the UDP-sugars were labelled to a constant 3H specific radioactivity which was very similar to that of the labelling medium. UDP-N-acetylhexosamines were labelled to constant 3H specific radioactivity with [6-3H]glucosamine as a precursor, but only about 1 in 375 of these UDP-sugars was derived from the amino sugar in the presence of glucose. The half-life (t1/2) for UDP-hexoses, UDP-glucuronate and UDP-N-acetylhexosamines was about 12, 12 and 50 min respectively.

Pharmacological actions of 17 beta-oestradiol on articular cartilage chondrocytes and chondrosarcoma chondrocytes in the absence of oestrogen receptors.

(1) Pharmacological concentrations (greater than 10(-5) M) of 17 beta-oestradiol inhibited 35S-labelled proteoglycan synthesis in bovine articular cartilage explant cultures. They also inhibited 35S-labelled proteoglycan synthesis and 3H-labelled protein synthesis in cell cultures of chondrocytes from bovine articular cartilage and Swarm rat chondrosarcoma. Maximal inhibition was about 30-50%. Physiological concentrations (10(-9)-10(-8) M) of oestradiol had no effect on the synthesis of either protein or proteoglycan. (2) The inhibitory action of high concentrations of oestradiol on these biosynthetic pathways is not common to all steroids since 10(-4) M cortisol had no effect on articular chondrocyte cell cultures. 10(-4) M testosterone had a similar action to oestradiol. (3) Neither physiological nor pharmacological concentrations of 17 beta-oestradiol had any effect on 35S-labelled proteoglycan turnover in the cartilage explant system. (4) 10(-5) M oestradiol inhibited cell division in cultures of articular chondrocytes which had entered the log growth phase. 10(-7) M oestradiol had no effect on articular chondrocyte growth. (5) In male rats implanted with silastic capsules releasing 17 beta-oestradiol, increase in body weight was retarded by about 25% over a period of 6 weeks, compared to control rats. Rat chondrosarcoma grew to the same size in oestrogen-treated rats as it did in controls. (6) Oestrogen receptors could not be detected in freshly isolated bovine articular chondrocytes or in rat chondrosarcoma. (7) In conclusion, neither the mitotic rate of articular chondrocytes nor their proteoglycan metabolism is under the direct physiological control of oestradiol. Growth and biosynthetic activity of the rat chondrosarcoma chondrocytes are independent of either direct control by the hormone or control effected by oestradiol regulation of a second hormone or growth factor.

Change in physician perspective on cholesterol and heart disease. Results from two national surveys.

The National Heart, Lung, and Blood Institute sponsored national telephone surveys of practicing physicians in 1983 (N = 1610) and 1986 (N = 1277) to assess attitudes and practices regarding elevated serum cholesterol levels. The 1983 survey was conducted just before the release of the results of the Lipid Research Clinics Coronary Primary Prevention Trial, which showed that a reduction in the blood cholesterol level reduced coronary heart disease. In 1986, 64% of physicians thought that reducing high blood cholesterol levels would have a large effect on heart disease, up considerably from 39% in 1983. Whereas in 1983, physicians attributed considerably less preventive value to reducing the cholesterol level than to reducing blood pressure or smoking, this disparity was substantially smaller in 1986. The median range of blood cholesterol at which diet therapy was initiated was 6.21 to 6.70 mmol/L (240 to 259 mg/dL) in 1986, down from 6.72 to 7.21 mmol/L (260 to 279 mg/dL) in 1983; the median for drug therapy was 7.76 to 8.25 mmol/L. (300 to 319 mg/dL) in 1986 and 8.79 to 9.28 mmol/L (340 to 359 mg/dL) in 1983. In 1986, 87% of physicians surveyed felt that medical evidence warranted the recommended treatment levels set forth in the 1984 National Institutes of Health Consensus Conference on Lowering Blood Cholesterol. These changes indicate that by 1986, physicians were more convinced of the benefit of lowering high blood cholesterol levels and were treating patients accordingly. The data also suggest areas for continued educational initiatives.

Is carbamazepine an alternative maintenance therapy for neonatal seizures?

The absorption and elimination of a hospital pharmacy preparation of carbamazepine suspension have been investigated in a group of 6 new-born and 2 older infants. The results indicate that carbamazepine is adequately absorbed from the gastrointestinal tract and that blood carbamazepine levels which are therapeutic in older children or adults are maintained with doses of 5-8 mg/kg twice daily. Elimination half-lives in this group of infants, who were each receiving other anti-epileptic drugs, varied from 7.2 to 15.2 h. Carbamazepine may provide a useful alternative to phenytoin and phenobarbitone as maintenance oral therapy in the management of neonatal seizures. Further investigation of efficacy and safety in this age group is required.

Effects of prenatal glucocorticoids on renal maturation in newborn infants.

The effect of prenatally administered glucocorticoids on tubular reabsorption of beta 2-microglobulin and elimination half-life gentamicin have been investigated in newborn infants. beta 2-Microglobulin:creatinine ratio was significantly higher in preterm (4.43 +/- 0.88) than in full-term infants (0.89 +/- 0.42), but did not differ between infants exposed to betamethasone in utero and those who were not. Gentamicin pharmacokinetics did not differ between preterm infants who had or had not been exposed to betamethasone. It is therefore concluded that whilst prenatally administered glucocorticoids influence both pulmonary and hepatic maturation, they do not alter either renal tubular reabsorption of beta 2-microglobulin or glomerular filtration rate as estimated by gentamicin half-life.

Glycaemia, arterial pressure and micro-albuminuria in type 1 (insulin-dependent) diabetes mellitus.

Plasma glucose control and arterial pressure were assessed in 28 Type 1 (insulin-dependent) diabetic patients with different degrees of micro-albuminuria. They were divided into two groups according to their urinary albumin excretion rate: a low micro-albuminuria group (n = 16) with albumin excretion ranging between 12.1 and 28.9 micrograms/min and a high micro-albuminuria group (n = 12) with albumin excretion between 32.4 and 91.3 micrograms/min. The groups were matched for age, sex and duration of diabetes with the same number of normo-albuminuric (2.0-10.4 micrograms/min) diabetic control subjects. Both the low and high micro-albuminuria groups had significantly higher glycosylated haemoglobin levels and mean plasma glucose concentrations during a 24-h profile than their respective normo-albuminuric control subjects. A correlation between glycosylated haemoglobin level and urinary albumin excretion rate was found in the whole study group (r = 0.48; p less than 0.001). Arterial pressure (both systolic and diastolic) was significantly higher in the high micro-albuminuria group than in either the control group or the low micro-albuminuria group. A significant correlation was found between arterial pressure and albumin excretion rate in the whole study population (r = 0.49; p less than 0.001) as well as in the pooled micro-albuminuria groups (r = 0.43; p less than 0.05). Multiple regression analysis showed that glycosylated haemoglobin and arterial pressure levels were independently correlated with albumin excretion rates. Diabetic patients with micro-albuminuria of any degree have worse glycaemic control than normo-albuminuric patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in response to metrazole during fever in juvenile rats; a new model for febrile convulsions?

Previous models for febrile convulsions have used environmentally induced hyperthermia as the stimulus to induce convulsions. Changes in response to metrazole during yeast-induced fever in juvenile rats are reported here. Animals were more susceptible to metrazole during the rising phase of fever but showed some resistance to its convulsant effects once the fever was established and following defervescence. It is suggested that this may form the basis of a physiologically more appropriate model for the study of the pathogenesis of febrile convulsions.