Antithrombin and first complement protein recognize the same active heparin fraction

Antithrombin (AT) high affinity of unfractionated heparin (UFH) resides in a specific pentasaccharide sequence. Heparin also regulates complement activity on the classical and the alternative pathways. Most experimental pieces of evidence accumulated show that these important activities reside in different segments of the heparin molecule. We demonstrated in previous papers that a low ionic strength and the presence of calcium ions are essential to detect specific interactions between glycosaminoglycans and proteins. Then these very strict conditions were used, and we demonstrated that the first protein complex of the human complement cascade recognizes in the UFH a fraction with very high anticoagulant activity. After isolation from the precipitate of the interaction, this fraction of heparin also contained the pentasaccharide sequence responsible for the great affinity with AT: in fact, it was strongly bound to a resin of AT agarose, and to detach it, an ionic strength of 0.6 M sodium chloride was required. In this way, the heparin regions responsible for the anticoagulant activity and also for the effects over the complement system were identified on the same short segment of the heparin molecule, which includes the active fraction of the glycosaminoglycan. The differences with early results could be explained by our experimental conditions of low ionic strength and the presence of calcium ions used for the interaction of the protein and the glycosaminoglycan.     

Stabilization of mood from below versus above baseline in bipolar disorder: a new nomenclature

Management of bipolar disorder has traditionally emphasized the acute treatment of mania. Although acute treatment of mania is a critical aspect of care, this emphasis has tended to overshadow other important phases of bipolar disorder, such as depression, hypomania, and subsyndromal symptoms. We offer a reconceptualization of bipolar disorder that highlights unmet needs and the importance of differential spectra of efficacy. In this reconceptualization, bipolar disorder can be viewed as an aberration of mood, behavior, and cognition from baseline (euthymia). "Below baseline" is characterized by depression and subsyndromal depression. "Above baseline" is characterized by mania, mixed states, hypomania, and subsyndromal mood elevation. In contrast to the treatment options for mania, the options for depression are limited. This new nomenclature emphasizes the need to develop mood stabilizers that possess the ability to stabilize mood "from below baseline," either alone or in combination with other agents. In this article, the treatment options for bipolar disorder, with a focus on depression and rapid cycling, are discussed according to this new conceptualization of management from below and above baseline.     

Antiepileptic drugs in psychiatry-focus on randomized controlled trial

It is now clear that the class of antiepileptic drugs (AED) constitute a heterogeneous grouping of medications with diverse medical applications. In particular, the spectrum of psychiatric uses of these medications has grown substantially. Valproate and carbamazepine are commonly used in the treatment of bipolar mania, lamotrigine in bipolar depression, and gabapentin in various anxiety disorders. Only divalproex sodium and carbamazepine have received regulatory approval in various countries around the world. This article will review the double-blind, placebo-controlled literature regarding the safety and spectrum of efficacy associated with the use of the above drugs in mood and anxiety disorders.     

Some recovery processes in mutual-help groups for persons with mental illness; I: qualitative analysis of program materials and testimonies

Outcome research is beginning to suggest that mutual-help programs lead to significant improvements in the quality of life and related factors of members who have serious mental illness. This paper is the first in a series that examines recovery processes that may account for these positive outcomes. In Study 1, a content analysis was completed on one dimension of the written program for GROW, a mutual-help program with more than 40 years of experience. Thirteen reliable recovery processes emerged from this analysis; most prominent among these was to be reasonable and to decentralize from self by participating in community. In Study 2, the recovery processes that emerged from this analysis of one aspect of GROW's written program were applied to 22 written testimonies made by Growers. Results of this analysis again showed being reasonable and decentralizing from self by participating in community were essential processes in this mutual-help program. Analysis of the personal testimonies also showed accepting one's personal value as an important element in the GROW program.     

Mast cells in Wallerian degeneration: morphologic and ultrastructural changes

The morphologic and ultrastructural changes of mast cells were followed in degenerating distal and regenerating proximal stumps of frog brachial nerve during Wallerian degeneration. Quantitative analysis included determination of both number and size of mast cells. The mast cell response to injury consisted of an early and a late phase. In the early phase, there was an increase in mast cell numbers in the proximal site of the lesion and a release of Alcian blue material consistent with mediator release. This phase of mast cell activation may be related, through the secretion of biogenic agents such as heparin and histamine, to the increase of endoneurial vessel size and vascular permeability, providing access for macrophages and mast cell precursors. The later phase, which peaked at 40 days after transection in the degenerating distal stump, consisted in the degranulation of the mast cells. These mast cells, closely associated with macrophages and degenerating Schwann cells, released secretory granules into the endoneurial microenvironment. These degranulating mast cells, through the released acid hydrolases, may contribute along with macrophages and Schwann cells, to the degradation of myelin debris. At the same time, mast cells appeared filled with granular content in the regenerating proximal segment. Therefore, we suggest that mast cells in peripheral nerves may play an important role in nerve degenerating and regenerating mechanisms through the secretion of diffusible molecules.     

Cyclosporine-A treatment inhibits the expression of metabotropic glutamate receptors in rat thymus

We have evaluated the expression of metabotropic glutamate receptors (mGluR subtypes 2/3, 4 and 5) in rat thymus under normal and experimental conditions after 2 and 21 days of cyclosporine-A treatment. In normal rats, immunohistochemical analysis showed that expression of mGluRs was high in dendritic cells and lymphocytes of the medulla whereas it was weak in lymphocytes of the cortex. However, there were some differences in the expression of mGluRs subtypes. mGluR5 showed strong expression in lymphocytes of medulla and dendritic cells. mGluR2/3 and mGluR4 were moderately expressed in lymphocytes and dendritic cells of the medulla and weakly in cortical lymphocytes. Immunoblotting showed moderate levels of mGluR2/3 and mGluR4 and strong levels of mGluRS. After 2 days of cyclosporine-A treatment, we observed by immunohistochemistry and immunoblotting a distinct decrease in all mGluRs and their expression had almost completely disappeared after 21 days of treatment. The results clearly indicate that: 1) mGluR2/3, 4 and 5 are widely expressed in thymic cells; 2) the mGluR5 subtype is expressed most strongly in medullary cells; and 3) cyclosporine-A rapidly inhibits expression of all mGluR subtypes after 2 days of treatment and their complete disappearance after prolonged treatment. These findings may indicate a possible mechanism by which cyclosporine-A produces its immunosupressive effects.     

Ethanol and hormesis

This article provides a detailed assessment of the toxicological and pharmacological literature concerning alcohol-induced biphasic dose-response relationships. The assessment reveals that alcohol-induced hormetic-like dose-response relationships are commonly observed, highly generalizeable according to model and endpoint and quantitative feature of the dose response. These findings have important implications affecting study design, animal model, and endpoint selection as well as clinical applications.