admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

http://www.hmphanmi.com.cn/hmp/upload/event/study_4/16.pdf

Treatment of Relapsing Mild-to-Moderate Ulcerative Colitis With the Probiotic VSL#3 as Adjunctive to a Standard Pharmaceutical Treatment: A Double-Blind, Randomized, Placebo-Controlled Study

Background and purpose In 2006, a life-threatening 'cytokine storm', not predicted by pre-clinical safety testing, rapidly occurred in all six healthy volunteers during the phase I clinical trial of the CD28 superagonist monoclonal antibody (mAb) TGN1412 To date, no unequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release in vitro or in vivo in species used for pre-clinical safety testing has been established Here, we have identified a species difference almost certainly responsible for this disparate immunopharmacology Experimental approach Polychromatic flow cytometry and intracellular cytokine staining were employed to dissect the in vitro immunopharmacology of TGN1412 and other therapeutic mAbs at the cellular level to identify differences between humans and species used for pre-clinical safety testing Key results In vitro IL-2 and IFN-γ release from CD4+ effector memory T-cells were key indicators of a TGN1412-type response This mechanism of cytokine release differed from that of other therapeutic mAbs, which can cause adverse reactions, because these other mAbs stimulate cytokine release primarily from natural killer cells In contrast to humans, CD28 is not expressed on the CD4+ effector memory T-cells of all species used for pre-clinical safety testing, so cannot be stimulated by TGN1412 Conclusions and implications It is likely that activation of CD4+ effector memory T-cells by TGN1412 was responsible for the cytokine storm Lack of CD28 expression on the CD4+ effector memory T-cells of species used for pre-clinical safety testing of TGN1412 offers an explanation for the failure to predict a 'cytokine storm' in humans

/pdf/monoclonal-antibody-tgn1412-trial-failure-explained-by-4nu0s4y2cj.pdf

Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells.

In 2006, a life-threatening ‘cytokine storm’, not predicted by pre-clinical safety testing, rapidly occurred in all six healthyvolunteers during the phase I clinical trial of the CD28 superagonist monoclonal antibody (mAb) TGN1412. To date, nounequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release

Monoclonal antibody TGN1412 trial failure explained by species differences in CD28

CD4+NKG2D+ T Cells in Crohn’s Disease Mediate Inflammatory and Cytotoxic Responses Through MICA Interactions

In a previous study we found an expansion of circulating memory (CD45RO(+)) CD4(+) T cells in patients with Crohn's disease (CD). The aim of this work was to investigate the phenotypic and functional characteristics of this T-cell subset in CD. We analyzed in peripheral blood CD4(+)CD45RO(+) T cells from CD patients the expression of surface markers associated to immune activation, costimulation, and apoptosis. In sorted CD4(+)CD45RO(+) T cells apoptosis was quantified by fluorescent annexin V binding. Healthy subjects and patients with ulcerative colitis and acute bacterial enterocolitis served as control groups. An increased percentage of memory CD4(+)CD45RO(+) T cells lacking the expression of costimulatory receptor CD28 was detected in patients with active CD when compared to the other groups evaluated. This expanded CD4(+)CD45RO(+)CD28(null) T-cell subset expressed mostly the effector-cell marker CD57(+). Both CD28 downregulation and CD57 expression correlated to CDAI and surrogate markers of disease activity. These phenotypic changes observed on CD4(+)CD45RO(+) T cells from active CD returned to values similar to healthy controls after clinical remission. Moreover, this memory CD28(null) T-cell subset might express more intracytoplasmic TNF and IFN-gamma than their CD28(+) counterpart. Significantly lower frequencies of memory CD4(+)CD45RO(+) T cells expressing CD95 apoptosis receptor were found in patients with active CD. Moreover, sorted CD4(+)CD45RO(+)and CD4(+)CD45RO(+) CD28(null) T cells from patients with active CD exhibited a lower apoptotic rate than that found in healthy controls and inactive CD patients. According to our data, circulating T lymphocytes from active CD patients show distinctive phenotypic and functional changes, characterized by an expansion of memory CD4(+)CD45RO(+)CD28(null) T cells expressing effector-associated cell surface molecules and displaying enhanced resistance to apoptosis.

Active Crohn's disease patients show a distinctive expansion of circulating memory CD4+CD45RO+CD28null T cells.

Novel risk factors related to cancer in scleroderma.

There has been growing interest in recent years in the extraosseous effects of vitamin D. In this article, we review the physiology of vitamin D, the physiopathological effects associated with vitamin D deficit and the available evidence on its etiopathogenic role in respiratory diseases. Given the pleiotropic actions of vitamin D, it is biologically plausible that the deficit of this vitamin could play a pathogenic role of in the development of various respiratory diseases. However, the many epidemiological studies that have shown an association between low vitamin D levels and a higher risk of developing various respiratory diseases or a poorer prognosis if they do appear, were unable to show causality. Post-hoc analyses of some clinical trials, particularly in chronic obstructive pulmonary disease (COPD) and asthma, appear to suggest that some patient subtypes may benefit from correction of a vitamin D deficit. In this respect, it would be interesting to determine if the interindividual differences found in the effect of vitamin D deficit and responses to correcting this deficit could be explained by the genetic variants involved in vitamin D metabolism. Ultimately, only appropriately designed clinical trials will determine whether 25-OHD supplements can prevent or improve the course of the various respiratory diseases in which an epidemiological association between prognosis and vitamin D deficit has been described.

The role of vitamin D in chronic obstructive pulmonary disease, asthma and other respiratory diseases.

Resumen En los ultimos anos existe un creciente interes por las acciones extraoseas de la vitamina D. En este articulo revisamos la fisiologia de la vitamina D, los aspectos fisiopatologicos asociados a su deficit y la evidencia existente sobre su papel etiopatogenico en enfermedades respiratorias. Teniendo en cuenta las acciones pleiotropicas de la vitamina D, existe plausibilidad biologica sobre un potencial papel patogenico del deficit de esta vitamina en el desarrollo de diversas enfermedades respiratorias. Sin embargo, los numerosos estudios epidemiologicos que han encontrado asociacion entre niveles bajos de vitamina D y mayor riesgo de desarrollar diversas enfermedades respiratorias o de conllevar un peor pronostico no permiten demostrar causalidad. Los analisis post hoc de algunos ensayos clinicos, especialmente en enfermedad pulmonar obstructiva cronica (EPOC) y asma, parecen demostrar que ciertos subtipos de pacientes podrian beneficiarse de la correccion del deficit de vitamina D. En este sentido, resultara interesante averiguar si las variantes geneticas implicadas en el metabolismo de la vitamina D pueden explicar las diferencias interindividuales encontradas en cuanto al efecto del deficit de vitamina D y la respuesta a su correccion. En ultimo termino, solo los ensayos clinicos adecuadamente disenados permitiran determinar si los suplementos de 25-OH D pueden tener un efecto preventivo o mejorar la evolucion de las distintas enfermedades respiratorias en las que se ha descrito asociacion epidemiologica entre su pronostico y el deficit de esta vitamina.

Papel de la vitamina D en enfermedad pulmonar obstructiva crónica, asma y otras enfermedades respiratorias

Background Heart-type fatty acid-binding protein (H-FABP) is a cytosolic protein that is released into the bloodstream when the myocardium is injured. The aim was to determine the diagnostic and prognostic value of H-FABP in patients with suspected acute myocardial infarction (AMI) within the fi rst 3-6 hours after the onset of chest pain.Methods and results A consecutive series of 165 patients with chest pain lasting less than 6 hours were enrolled in a forward observational design in the emergency department. The diagnostic validity of H-FABP was evaluated according to sensitivity, specifi city, and predictive values, likelihood ratios, ROC curves, and multivariate logistic regression analyses. The prognostic value of H-FABP at 6 months was checked using survival curves and the multivariate Cox proportional hazards model.The sensitivity of H-FABP was 81% (95% CI: 69.2-92.9). Its area under the ROC curve: 0.729 (95% CI: 0.63-0.83) and negative likelihood ratio (0.38; 95% CI: 0.22-0.65) were signifi cantl...

Jaime García de Tena

Papers

Active Crohn's disease patients show a distinctive expansion of circulating memory CD4+CD45RO+CD28null T cells.

Novel risk factors related to cancer in scleroderma.

The role of vitamin D in chronic obstructive pulmonary disease, asthma and other respiratory diseases.

Papel de la vitamina D en enfermedad pulmonar obstructiva crónica, asma y otras enfermedades respiratorias

Diagnostic and prognostic value of heart-type fatty acid-binding protein in the early hours of acute myocardial infarction.