Transforming growth factor-beta1 effects on endothelial monolayer permeability involve focal adhesion kinase/Src.

Transforming growth factor (TGF)-beta1 activity has been shown to increase vascular endothelial barrier permeability, which is believed to precede several pathologic conditions, including pulmonary edema and vessel inflammation. In endothelial monolayers, TGF-beta1 increases permeability, and a number of studies have demonstrated the alteration of cell-cell contacts by TGF-beta1. We hypothesized that focal adhesion complexes also likely contribute to alterations in endothelial permeability. We examined early signal transduction events associated with rapid changes in monolayer permeability and the focal adhesion complex of bovine pulmonary artery endothelial cells. Western blotting revealed rapid tyrosine phosphorylation of focal adhesion kinase (FAK) and Src kinase in response to TGF-beta1; inhibition of both of these kinases using pp2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), ameliorates TGF-beta1-induced monolayer permeability. Activation of FAK/Src requires activation of the epidermal growth factor receptor downstream of the TGF-beta receptors, and is blocked by the epidermal growth factor receptor inhibitor AG1478. Immunohistochemistry showed that actin and the focal adhesion proteins paxillin, vinculin, and hydrogen peroxide-inducible clone-5 (Hic-5) are rearranged in response to TGF-beta1; these proteins are released from focal adhesion complexes. Rearrangement of paxillin and vinculin by TGF-beta1 is not blocked by the FAK/Src inhibitor, pp2, or by SB431542 inhibition of the TGF-beta type I receptor, anaplastic lymphoma kinase 5; however, pp1 (4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), which inhibits both type I and type II TGF-beta receptors, does block paxillin and vinculin rearrangement. Hic-5 protein rearrangement requires FAK/Src activity. Together, these results suggest that TGF-beta1-induced monolayer permeability involves focal adhesion and cytoskeletal rearrangement through both FAK/Src-dependent and -independent pathways.

Cocaine and amphetamine use in patients with psychiatric illness: a randomized trial of typical antipsychotic continuation or discontinuation.

Animal studies indicate that typical antipsychotics (neuroleptics) increase cocaine and amphetamine self-administration. Patients with psychiatric illnesses have high rates of substance abuse and frequently receive chronic typical antipsychotic therapy. This open, pilot study examined the effect of typical antipsychotic discontinuation on cocaine and amphetamine use in patients with psychiatric illnesses. Twenty-four evaluable outpatients were randomized to continue (n = 12) or discontinue (n = 12) chronic typical antipsychotic therapy. The atypical antipsychotic quetiapine was instituted, when necessary, for psychosis in the discontinuation group (n = 8). Participants were assessed weekly over 12 weeks with measures of psychiatric symptoms, drug use, and drug craving. Those discontinuing typical antipsychotics (n = 12) had significant reductions in drug craving compared with those continuing typical antipsychotics. No significant between-group differences in drug use were found. Typical antipsychotic discontinuation combined with a quetiapine switch for those with psychotic symptoms was associated with reduced drug craving. Definitive trials of typical antipsychotic discontinuation in dual-diagnosis patients are warranted.

Drug abuse and bipolar disorder: comorbidity or misdiagnosis?

Bipolar disorder is a common, severe and cyclic psychiatric illness. A strong association between alcohol dependence and bipolar disorder has been reported in numerous studies. The abuse of other drugs including cocaine, amphetamines, opiates, cannabis, and prescription medications in bipolar patients is also an important public health concern and has been less extensively investigated. This review examines the abuse of drugs other than alcohol or nicotine in people with bipolar disorder. The high rates of milder affective symptoms but not mania observed in patients in drug abuse treatment settings suggests the symptoms may in many cases be associated with the drug use. However, such patients presenting in psychiatric settings might be suffering from cyclothymic and related attenuated bipolar disorders (type II). Substance abuse may be associated with medication non-compliance, more mixed or dysphoric mania and possibly an earlier onset of affective symptoms and more hospitalizations. The pharmacotherapy of patients with bipolar disorder and drug abuse is examined, including evidence on the use of mood stabilizers, neuroleptics and the newer atypical antipsychotics in this population.