Antipsychotics activate the TGFß pathway effector SMAD3.

Although effective in treating an array of neurological disorders, antipsychotics are associated with deleterious metabolic side effects. Through high-throughput screening, we previously identified phenothiazine antipsychotics as modulators of the human insulin promoter. Here, we extended our initial finding to structurally diverse typical and atypical antipsychotics. We then identified the transforming growth factor beta (TGFß) pathway as being involved in the effect of antipsychotics on the insulin promoter, finding that antipsychotics activated SMAD3, a downstream effector of the TGFß pathway, through a receptor distinct from the TGFß receptor family and known neurotransmitter receptor targets of antipsychotics. Of note, antipsychotics that do not cause metabolic side effects did not activate SMAD3. In vivo relevance was demonstrated by reanalysis of gene expression data from human brains treated with antipsychotics, which showed altered expression of SMAD3 responsive genes. This work raises the possibility that antipsychotics could be designed that retain beneficial CNS activity while lacking deleterious metabolic side effects.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.

Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms (P < 0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls (P < 0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain.

Supporting multi-level multi-perspective dynamic decision making in medicine.

Most medical decision problems are exceedingly complex and contain a large number of variables. Abstraction facilitates the process of building a decision model by allowing a model builder to work at a level of detail that he is most comfortable with; it is also useful in time-critical situations or when there is insufficient data to support complete specification of probabilities of the uncertain events. In this paper, we identify and formalize abstraction and refinement operations commonly used in model construction. We illustrate the use of these mechanisms with an example on the follow-up management of colorectal cancer patients after surgery.

Decision analytic approach to severe head injury management.

Severe head injury management in the intensive care unit is extremely challenging due to the complex domain, the uncertain intervention efficacies, and the time-critical setting. We adopt a decision analytic approach to automate the management process. We document our experience in building a simplified influence diagram that involves about 3000 numerical parameters. We identify the inherent problems in structuring a model with unclear domain relationships, numerous interacting variables, and real-time multiple inputs. We analyze the effectiveness and limitations of the decision analytic approach and present a set of desiderata for effective knowledge acquisition in this setting. We also propose a semi-qualitative approach to parameter elicitation.