Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ12,14PGJ2

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ^12,14PGJ₂ a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ^12,14PGJ₂ production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ₂ and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.     

How Do Students Source and Supply Drugs? Characteristics of the University Illegal Drug Trade

Background: It is widely known that a proportion of university students use drugs. However, much less is known about how they source and supply their drugs. Objectives: In this article, we investigate student drug trading activity, including how they obtained their drugs, whether they sold drugs, and the extent to which their drug trading might be described as a form of “social supply”. Methods: A survey was conducted of all students across seven of the nine universities of Wales. In total, 7855 students submitted a questionnaire and 1877 of these reported drug use in the current academic year. All students who reported using one or more illegal drugs in the current academic year were asked how they obtained their drugs, how they funded their drug use, whether they had sold, traded or given away illegal drugs, along with their motives for drug trading. Results: The results showed that about half of users obtained drugs solely from friends and associates and one-fifth obtained them solely from external dealers. One-quarter used friends and associates as well as external markets. In many cases, supplying drugs amounted to sharing them or giving them away. However, over one-third of students said that they had sold drugs. Conclusions: Overall, the methods of sourcing and supplying drug among university students shares features of both “social supply” and “traditional” drug markets. We conclude that the student drug market investigated is best described as a “hybrid” combination of both.     

'Reprofessionalization' or 'occupational imperialism'?: some reflections on pharmacy in Britain

Drawing upon preliminary research findings, this paper considers whether pharmacists in Britain face a crisis in their occupational status and identity as a result of changes in their work and market situations. It further examines some of the ways in which they are responding to the challenges and opportunities presented. The paper also comments on the utility of the concepts of 'reprofessionalization' and 'occupational imperialism' in the study of British pharmacy.     

Genetic association studies of interleukin-13 receptor alpha1 subunit gene polymorphisms in asthma and atopy.

Interleukin (IL)-13 plays a central role in asthma pathogenesis by binding to the IL-13 receptor, which is a heterodimer composed of the IL-13 receptor alpha1 subunit (IL-13Ralpha1) and IL-4Ralpha. The genetic diversity at the IL-13Ralpha1 gene (IL13RA1) locus on chromosome Xq24 was characterised and the association of identified polymorphisms with asthma and atopy phenotypes examined. The promoter and coding region of IL13RA1 were screened for common genetic variants, and polymorphisms found were genotyped in a large cohort of 341 asthmatic Caucasian families (each containing at least two asthmatic siblings) and 182 nonasthmatic control subjects. Genetic association was determined using case-control and transmission disequilibrium test analyses. Two common polymorphisms were identified, a newly found thymidine (T) to guanine (G) transition of nucleotide -281 (-281T>G) single nucleotide polymorphism in the IL13RA1 promoter and the previously described 1365A>G variant in the IL13RA1 proximal 3' untranslated region. No significant association of either -281T>G or 1365A>G with risk of asthma or atopy phenotypes was found, apart from a suggestive association between the IL13RA1 -281T/1365A haplotype and raised total serum immunoglobulin E levels in adult female asthmatics. These findings indicate that the interleukin-13 receptor alpha1 subunit gene -281T>G and 1365A>G polymorphisms do not contribute to asthma susceptibility or severity, although the interleukin-13 receptor alpha1 subunit gene locus might be involved in the control of immunoglobulin E production.     

Percutaneous decompression: treatment for respiratory distress secondary to multicystic dysplastic kidney

Multicystic dysplastic kidney is a common renal anomaly in the newborn. Long-term problems, such as pain, infection, hypertension and neoplasm, although infrequent, have been reported. Acute, life-threatening complications resulting from the size of the affected kidney are rare and emergency nephrectomy has been the only reported effective therapy. We present a case of ultrasound-guided percutaneous cyst decompression used as definitive treatment of respiratory failure associated with multicystic dysplastic kidney.     

IUD insertion forces: effects of recent childbirth and lactation

This investigation compared the force required to insert an IUD in women who were breastfeeding and who had recently delivered a child with that required in control women who were not breastfeeding and who had not recently delivered. Twenty-eight women who had recently delivered and who were breastfeeding were compared with twenty-eight controls. The women were matched for age and parity and for the type of IUD used. The mean IUD insertion force in the breastfeeding, recently-delivered women was 1.75 newtons (N) as compared to 2.80 N in the controls. The difference was statistically highly significant (pairedt-test,p<0.01). Recent childbirth and lactation are associated with a reduction in IUD-related insertion pain, probably due to a reduction in the force required for insertion. This reduction in IUD insertion force is not necessarily related to lower uterine perforation rates in IUD insertion in this group. A number of physiological mechanisms may be responsible for this finding.

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Resumen Esta investigacion comparó la fuerza requerida para insertar un DIU en mujeres amamantando y que habían parido recientemente, con mujeres de control que no amamantaban ni habían parido recientemente. Veintiocho mujeres que habían parido recientemente y amamantando fueron comparadas con veintiocho controles. Las mujeres fueron apareadas por edad y paridad y por el tipo de DIU usado. La fuerza media de inserción de un DIU en la mujer que había parido recientemente y estaba amamantando, fué de 1.75 newtons (N) comparada con 2.80 N en los controles. La diferencia fué estadísticamente altamente significativa (t-test apareado,p<0.01). Lactancia y reciente paridad están asociadas con la reducción en el dolor relacionado a la inserción del DIU. Esta reducción en la fuerza de inserción no está necesariamente relacionada con las tasas de perforación uterina baja en la inserción de un DIU en este grupo. Un número de mecanismos fisiológicos podrían ser responsables de este hallazgo.

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Résumé On a cherché à comparer la force nécessaire pour insérer un DIU chez des femmes qui allaitaient et avaient récemment mis au monde un enfant et chez des femmes qui n'allaitaient pas et qui n'avaient pas récemment accouché. La comparaison portait sur vingt-huit femmes dans un cas comme dans l'autre. On a veillé à faire corresponde les deux séries du point de vue de l'âe, du nombre de grossesses antérieures et du type de DIU utilisé. Chez les femmes allaitant et ayant récemment accouché, la force nécessaire pour insérer un stérilet était en moyenne de 1,75 newton (N), au lieu de 2,80 N chez les sujets témoins. Cette différence est très significative du point de vue statistique (t test sur séries appariées, p<0,0.1). Un accouchement récent et l'allaitement sont associés à une réduction des douleurs causées par l'insertion d'un DIU, probablement du fait que la force nécessaire pour pratiquer cette opération est moindre. Cette réduction de la force d'insersion n'est pas forcément liée à des taux inférieurs de perforation utérine lors de l'insersion d'un DIU dans ce groupe. Il est possible qu'un certain nombre de mécanismes physiologiques soient responsables des faits ainsi constatés.

     

Follow up study of children born elsewhere but attending schools in Seascale, West Cumbria (schools cohort)

Records on 1546 children who were identified as having attended schools in Seascale up to November 1984 and were born since 1950 but not in the civil parish were studied. These children lived in or near Seascale for a period of time while they were attending one or more of three local schools and are an additional group to the 1068 children who were identified as born to mothers resident in Seascale in an accompanying study. Even though some of the schoolchildren apparently remained in the village for a short period only all but 7% were followed up through the National Health Service Central Register. Mortality among these children to 30 June 1986 is comparable to that expected at national rates. From all causes there were 10 observed deaths compared with 12.69 expected--a ratio of 0.79 (95% confidence interval 0.38 to 1.45)--and from cancer one observed death compared with 2.04 expected--a ratio of 0.49 (95% CI 0.01 to 2.73). No deaths from leukaemia or lymphoma were reported, but only 0.83 was expected. Since 1971 (the year when cases of cancer were first notified to the NHS Central Register) three non-fatal cases of cancer were reported, including two lymphomas, compared with 2.04 expected and two cases of carcinoma in situ of the cervix compared with 1.79 expected. In addition, there was a case of leukaemia among the schoolchildren which was known previously and had been diagnosed in 1968. There is an interesting difference between the results of this study and the results of the study of children born to mothers who were resident in Seascale. In the latter study there was an excess of leukaemia and of other cancers, but a similar finding is not apparent among children who spent some time at schools in Seascale but were born elsewhere. This raises the question of whether one or more aetiological factors in childhood cancer were acting on a locality specific basis before birth or early in life. This cannot be answered from these cohort studies, but it is hoped that the case-control study that is under way in West Cumbria will provide relevant information.     

Micro1-opioid antagonist naloxonazine alters ethanol discrimination and consumption.

The endogenous opioid system is implicated in excessive ethanol-drinking behavior. However, the role of individual opioid receptor subtypes in the mechanism underlying excessive ethanol-drinking behavior is not yet well understood. Therefore, we investigated the ability of a selective micro1-opioid antagonist, naloxonazine, to modulate ethanol-drinking behavior and ethanol discrimination in a rat model with the use of ethanol self-administration and drug discrimination paradigms. The effects of naloxonazine (0.001-10 mg/kg) on ethanol intake were examined in Sprague-Dawley rats under conditions of limited access to 10% (wt./vol.) ethanol and ad libitum access to food and water. Pretreatment with high doses of naloxonazine (1-10 mg/kg) significantly reduced ethanol consumption. When the effects of naloxonazine on food intake in free-feeding male rats were examined, naloxonazine (1.8-10 mg/kg) significantly suppressed 24-h food intake. Another group of rats was trained to discriminate ethanol (1.25 g/kg, i.p.) from saline on a fixed-ratio schedule (FR 10), and ethanol dose-response tests were conducted once rats had acquired ethanol-saline discrimination. Injections were given 15 min before ethanol dose-response tests were conducted, and after characterization of the ethanol dose-response curve, the effects of naloxonazine on ethanol discrimination were assessed by administering naloxonazine (0.001-10 mg/kg, i.p.) 15 min before ethanol administration. Treatment with naloxonazine (0.001-1.8 mg/kg, i.p.) before the ED(100) dose of ethanol partially antagonized the discriminative stimulus of ethanol without having any effect on the response rate. The results support the suggestion of involvement of micro1-opioid receptors in the discriminative effects of ethanol and ethanol-drinking behavior.