two cases. In the remaining patients who received analgesia no delay in definitive management occurred. Of equal importance was the observation that the surgical registrar's confidence in diagnosing and in deciding on management was not affected by previous administration of papaveretum.The correct management of patients presenting with acute abdominal pain includes diagnosis, resuscitation, and early operative intervention when indicated. Re Objective-To study the dose related response of salmon calcitonin (salcatonin) given intranasaily on bone mass and bone turnover and the effect of salcatonin on rates of fracture in elderly women with moderate osteoporosis.Design-Double blind, placebo controlled, randomised group comparison.Setting-Outpatient clinic for research into osteoporosis.Subjects-208 healthy women aged 68-72 years who had a bone mineral content of the distal forearm on average 30% below the mean value for healthy premenopausal women.Interventions-The 208 women were allocated randomly in blocks of four to two years of treatment with either salcatonin 50 IU, 100 IU, or 200 IU given intranasally or placebo. All groups received a calcium supplement of 500 mg. 32 of the women left the study before its end and 164 women complied with the study criteria throughout.Main outcome measures-Bone mineral content of the distal forearm and lumbar spine and rates of vertebral and peripheral fractures after two years of treatment.Results-The average changes in bone mineral content of the spine showed positive outcomes of 1% (95% confidence interval -0-1% to 1-5%) in the group treated with calcium (placebo) and 3% (1-8% to 4.2%) in the group treated with salcatonin 200 IU. There was a significant dose related response to salcatonin, manifested by an increase of 1-0%/100 IU (0-2% to 1-7%, p=0 008). The rate of patients with new fractures was reduced significantly in the women treated with salcatonin to about one third of that in the non-salcatonin treated women (relative risk 0-23 (0.07 to 0.77)).Conclusion-The results suggest that, compared with calcium alone, salcatonin given intranasally reduces the rates of fracture by two thirds in elderly women with moderate osteoporosis. Furthermore, it increases spinal bone mass in a dose dependent manner.

The nuclear hormone 1alpha,25-dihydroxyvitamin D(3) induces cell cycle arrest, differentiation, or apoptosis depending on target cell type and state. Although the antiproliferative effect of 1alpha,25-dihydroxyvitamin D(3) has been known for years, the molecular basis of the cell cycle blockade by 1alpha,25-dihydroxyvitamin D(3) remains largely unknown. Here we have investigated the mechanisms underlying the G(1) arrest induced upon 1alpha,25-dihydroxyvitamin D(3) treatment of the human breast cancer cell line MCF-7. Twenty-four-hour exposure of exponentially growing MCF-7 cells to 1alpha,25-dihydroxyvitamin D(3) impeded proliferation by preventing S phase entry, an effect that correlated with appearance of the growth-suppressing, hypophosphorylated form of the retinoblastoma protein (pRb), and modulation of cyclin-dependent kinase (cdk) activities of cdk-4, -6, and -2. Time course immunochemical and biochemical analyses of the cellular and molecular effects of 1alpha,25-dihydroxyvitamin D(3) treatment for up to 6 d revealed a dynamic chain of events, preventing activation of cyclin D1/cdk4, and loss of cyclin D3, which collectively lead to repression of the E2F transcription factors and thus negatively affected cyclin A protein expression. While the observed 10-fold inhibition of cyclin D1/cdk 4-associated kinase activity appeared independent of cdk inhibitors, the activity of cdk 2 decreased about 20-fold, reflecting joint effects of the lower abundance of its cyclin partners and a significant increase of the cdk inhibitor p21(CIP1/WAF1), which blocked the remaining cyclin A(E)/cdk 2 complexes. Together with a rapid down-modulation of the c-Myc oncoprotein in response to 1alpha,25-dihydroxyvitamin D(3), these results demonstrate that 1alpha,25-dihydroxyvitamin D(3) inhibits cell proliferation by targeting several key regulators governing the G(1)/S transition.

SummaryThe clinical use of dendritic cells (DCs) to induce antigen-specific immune tolerance has been hampered by the lack of a widely acknowledged method for generating human regulatory DCs but even more so by the non-existence of reliable markers. Thus, we set out to find reliable markers that can be measured with simple methods to identify regulatory DCs that are applicable for future clinical studies. Human DCs were generated from peripheral blood monocytes in the presence of 1a,25-dihydroxyvitamin D3 (VD3), which gave rise to a phenotype that resembles immature DCs, with the exception of high CD14 and reduced CD1a on the cell surface. These VD3-treated DCs exert a long-lasting inefficient T cell stimulation and induce T cell hyporesponsiveness with regulatory potential. Importantly, such VD3-treated DCs were readily distinguishable from untreated DCs by low levels of interleukin-23 secretion and low expression of miR-155 upon exposure to maturation stimuli. Furthermore, VD3-treated DCs showed over-expression of miR-378. All these features can be used as robust markers for quality control of VD3-treated regulatory DCs in future clinical studies.

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BackgroundDendritic cells (DC) are main gate-keepers of the immune system, bridging the innate and adaptive immune system. DCs are able to mature into inflammatory DCs at sites of inflammation in both autoimmune and allergic disease, thereby sustaining a continuous activation of the adaptive immune system at sites of inflammation. This function of DCs makes them attractive target cells for therapeutic intervention in inflammatory diseases. We have designed a DC-based screening model by which drug candidates can be evaluated for their ability to suppress DC maturation into an inflammatory and disease promoting phenotype.MethodsHuman monocyte derived DCs were differentiated using IL-4 and GM-CSF to immature DCs (imDCs). The imDCs were treated with various combinations of TLR-agonists and pro-inflammatory cytokines to identify cocktails with ability to mature imDCs into inflammatory DCs. The effect of the cocktails on DC maturation was evaluated using ELISA and cytokine arrays to measure secreted cytokines and chemokines. FACS analysis was used to assess expression of maturation markers, and functional studies were carried out using naïve allogeneic T-cells to assay for a Th1-promoting DC phenotype.ResultsNine cocktails were designed with potent ability to induce secretion of the Th1-promoting cytokines IL-12p70 and TNFα from imDCs, and three were able to induce the Th17-promoting cytokine IL-23. The cocktails were further characterized using cytokine arrays, showing induction of inflammation related cytokines and chemokines like CXCL10, CCL2, CCL4, CCL8, CCL15, CCL20 and IL-8, of which some are present in a range of autoimmune pathologies. Prostaglandin E2 secretion was identified from DCs treated with TLR agonists poly I:C and peptidoglycan, but not LPS. The cocktails were able to induce DC maturation markers like HLA-DR, CD40, CD80, CD83 and CD86, except the TLR7/8 agonist R848. Functional end-points made by co-culture of allogeneic CD4+ T cells with the cocktail treated DCs, showed that five cocktails in particular could induce a classical Th1-phenotype with ability to secrete high amounts of the hall-mark cytokine IFNγ. The model was validated using dexamethasone and two COX-inhibitors, which were able to suppress the cocktail driven pro-inflammatory DC maturation.ConclusionsThe identification of novel Th1-promoting cocktails allows screening of anti-inflammatory drug candidates by assessing the ability to suppress the activation and differentiation of imDCs into inflammatory DCs with a specific Th1-promoting phenotype. The model thus provides a screening tool, which can identify potential anti-inflammatory effects on the natural regulator of the immune response, the dendritic cell.

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Sexual dysfunction is a well-known complication of chronic somatic illness. Eighty-six consecutive epileptic outpatients, 38 men and 48 women, without accompanying disorders, were studied. The frequency and symptoms of sexual dysfunction were compared with results from previous studies using identical sexological methodology. The previous studies were of diabetic patients and healthy controls. Eight percent of the epileptic men reported a sexual dysfunction compared to 44% of the diabetics and 13% of the controls. Epileptic women, diabetic women, and controls showed no significant differences in sexual dysfunction (29%, 28%, and 25%, respectively). In both sexes, the sexual function measured by frequencies of coitus and masturbation was normal. Most patients had good control of epileptic attacks on a treatment of monotherapy. Hormonal status was generally within normal limits in both men and women; only a few minor differences were found and they showed no correlation with sexual dysfunction. Psychologically and socially the patients did not differ appreciably from normals, and they exhibited a high degree of disease acceptance. This study, using a biopsychosocial approach in understanding sexual dysfunctions, is in contrast with previous, mainly uncontrolled, studies of epileptic patients that reported high frequencies of "hyposexuality" in males. We conclude that epilepsy does not necessarily increase the risk of sexual dysfunction in male or female.

Testimony as a ritual both of healing and of condemnation of injustice would seem to be a universal phenomenon. The concept of testimony contains both connotations of something subjective or private, and of something objective, judicial, or political. When political refugees give testimony to the torture to which they have been subjected, the trauma story can be given a meaning, can be reframed: private pain is transformed into political dignity. In the context of testimony, shame, and guilt connected with the trauma can be confessed by the victim and reframed. In the transcultural meeting between the political refugee and the Western therapist, the common goal of creating evidence against repression becomes both a meeting place and a joint point of departure. The testimony method is demonstrated by two case histories.