Comparison of the Disposition of Hepatically-Generated Morphine-3-glucuronide and Morphine-6-glucuronide in Isolated Perfused Liver from the Guinea Pig

Purpose. Humans and guinea pigs metabolise morphine extensively, forming the isomers morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs. Methods. Livers were perfused at 30 ml/min in a non-recirculating manner with Krebs bicarbonate buffer containing morphine (6 to 7 M). Perfusing medium, venous perfusate and bile were collected at regular intervals and concentrations of morphine, M3G and M6G determined by reversed-phase HPLC. Results. Concentrations of morphine, M3G and M6G in perfusate and the rates of biliary excretion of M3G and M6G were consistent between 20 and 50 min of perfusion. The mean (±s.d.) ratio for the rate of formation of M3G relative to M6G was 3.7 ± 1.5. A mean 33 ± 3% of morphine extracted by the liver was recovered as summed M3G and M6G. Of the M3G and M6G formed during a single passage, 19 ± 11% and 9 ± 9%, respectively, was excreted into bile; the values were significantly different (P = 0.002). Conclusions. A greater fraction of hepatically-generated M3G excreted into bile compared to that for M6G reflects differences in their relative transport across sinusoidal and canalicular membranes of hepatocytes, possibly via carrier-mediated systems.     

Screening for somatization and hypochondriasis in primary care and neurological in-patients: a seven-item scale for hypochondriasis and somatization

The aim of this study was to investigate the internal and external validity of the Whiteley Index as a screening instrument for somatization illness. A 14-item version of the Whiteley Index for hypochondriacal traits was given to 99 of 191 consecutive primary care patients, aged 18-65 years, and to 100 consecutive patients, aged 18-60 years, admitted for the first time to a neurological ward. The primary care sample was, in addition, interviewed by means of the SCAN (Schedules for Clinical Assessment in Neuropsychiatry) psychiatric interview. The GPs and the neurologists were asked to rate various characteristics of the patients that might indicate somatization. The internal validity of the Whiteley Index was tested by means of latent structure analysis. On this basis, a reduced seven-item scale (Whiteley-7 scale) and two subscales (i.e., an Illness Conviction and Illness Worrying scale, each with three items) were constructed. All three had a high internal validity fitting into the very restricted Rasch statistical model (p>0.05) and an acceptable transferability between most of the subpopulations investigated. In the primary care population, the Whiteley-7 and the Illness Conviction scales at cut-point 0/1 showed 1.00 and 0.87 sensitivity and 0.65 and 0.87 specificity, respectively, using as "gold standard" the fulfillment of criteria for at least one ICD-10 somatoform disorder, and 0.71 and 0.63 sensitivity and 0.62 and 0.87 specificity, respectively, as gold standard for the fulfillment of criteria for at least one DSM-IV somatoform disorder, excluding the NOS diagnostic group. The Illness Worrying subscale showed less impressive performance in this respect. The agreement between the Whiteley-7 scale including the two subscales and neurologists' rating and the GPs' rating and the somatization subscale on the SCL-90 was modest or worse. It may be concluded that the Whiteley-7 scale and the Illness Conviction subscale had acceptable psychometric profiles, and both seem to be promising screening tools for not only hypochondriasis but also for somatoform disorders in general.     

On the mechanism of kidney stone disintegration by acoustic shock waves

In the present study we have, by theoretical and experimental investigations, especially concentrated on the importance of acoustic streaming, transient cavitation and microstreaming in the fluid close to the stone. Artificial stones, round stones 20 mm in diameter made of Plaster of Paris or rectangular flat stones, 25 x 25 x 15 mm, were suspended in a water bath at the focus of an EDAP LT01 lithotripter. "Unprotected" stones were disintegrated while stones surrounded by a layer of silicone showed no or very small disintegration. For successful destruction of the calculus, it seems to be essential that the stones are surrounded by a liquid, i.e., water.     

Expression of activated extracellular signal-regulated kinases 1/2 in malignant melanomas: relationship with clinical outcome.

PURPOSE: The purpose of the present work was to analyze the protein expression of activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) in a panel of superficial spreading (SSM) and nodular (NM) primary and metastatic melanomas, and to correlate the expression level with clinicopathological parameters. EXPERIMENTAL DESIGN: Expression of activated ERK1/2 was examined by immunohistochemistry in 172 primary melanomas (108 SSM and 64 NMs), 67 metastatic lesions, and in 41 benign nevi. RESULTS: Fifty four percent of primary and 33% of metastatic melanomas expressed variable levels of activated ERK1/2. No immunoreactivity was detected in benign nevi. In 21% of the primaries only cytoplasmic expression was detected, whereas 3% and 30% showed positive immunoreactivity in either nucleus or cytoplasm and nucleus, respectively. Activated ERK1/2 expression varied significantly with the thickness of superficial spreading melanomas, with lower expression in thinner lesions (P = 0.016). A significant correlation between activated ERK1/2 and cyclin D1 (P = 0.031) in nodular, as well as between activated ERK1/2 and cyclin D3 (P = 0.030) in SSMs were observed. The protein level of p27(Kip1) correlated with activated ERK1/2 (P = 0.048) in the nucleus. Furthermore, a strong inverse correlation between activated ERK1/2 and membrane-bound beta-catenin (P = 0.004) in nodular melanomas was revealed. Activation of ERK1/2 did not have any impact on relapse-free or overall survival. CONCLUSION: Our results suggest that activation of ERK1/2 may be involved in cell cycle regulation in SSMs. Moreover, the inverse association between membrane-bound beta-catenin and ERK1/2 in NMs suggest that ERK1/2 activation may play a role in decreasing homotypic interactions through destabilization of beta-catenin.     

Auditing paediatric diabetes care and the impact of a specialist nurse trained in paediatric diabetes

AIMS: To define outcome measures for auditing the clinical care of children and adolescents with insulin dependent diabetes mellitus (IDDM) and to assess the benefit of appointing a dedicated paediatric trained diabetes specialist nurse (PDSN). METHODS: Retrospective analysis of medical notes and hospital records. Glycaemic control, growth, weight gain, microvascular complications, school absence, and the proportion of children undergoing an annual clinical review and diabetes education session were assessed. The effect of the appointment of a PDSN on the frequency of hospital admission, length of inpatient stay, and outpatient attendance was evaluated. RESULTS: Children with IDDM were of normal height and grew well for three years after diagnosis, but grew suboptimally thereafter. Weight gain was above average every year after diagnosis. Glycaemic control was poor at all ages with only 16% of children having an acceptable glycated haemoglobin. Eighty five per cent of patients underwent a formal annual clinical review, of whom 16% had background retinopathy and 20% microalbuminuria in one or more samples. After appointing the PDSN the median length of hospital stay for newly diagnosed patients decreased from five days to one day, with 10 of 24 children not admitted. None of the latter was admitted during the next year. There was no evidence of the PDSN affecting the frequency of readmission or length of stay of children with established IDDM. Non-attendance at the outpatient clinic was reduced from a median of 19 to 10%. CONCLUSIONS: Outcome measures for evaluating the care of children with IDDM can be defined and evaluated. Specialist nursing support markedly reduces the length of hospital stay of newly diagnosed patients without sacrificing the quality of care.     

Serum leptin concentrations in relation to pubertal development

OBJECTIVES: The amount of adipose tissue influences pubertal development and fertility in girls. A candidate for mediating this is the hormone leptin, derived from adipocytes. This work was carried out to determine whether the leptin concentration in serum is regulated during pubertal development. SUBJECTS AND METHODS: Serum concentrations of leptin were determined by radioimmunoassay in a sample of 252 healthy children representing all pubertal stages. RESULTS: Serum leptin concentrations correlated directly with age (r = 0.53), body mass index (BMI) (r = 0.71), and weight for height SD score (r = 0.44) in girls and with BMI (r = 0.33) and weight for height SD score in boys (r = 0.36). Leptin concentrations increased with pubertal development in girls, resulting in significantly higher concentrations at pubertal stages 4 and 5 than at the prepubertal stage, whereas there was no change in the boys. CONCLUSIONS: Serum leptin concentrations increased during pubertal development in the girls, but remained constant in the boys. Whether the increase in serum leptin concentrations in girls is of importance for, or a consequence of, pubertal development is still to be determined.