A three step supercritical process to improve the dissolution rate of eflucimibe.

The aim of this study is to improve the dissolution properties of a poorly-soluble active substance, Eflucimibe by associating it with gamma-cyclodextrin. To achieve this objective, a new three-step process based on supercritical fluid technology has been proposed. First, Eflucimibe and cyclodextrin are co-crystallized using an anti-solvent process, dimethylsulfoxide being the solvent and supercritical carbon dioxide being the anti-solvent. Second, the co-crystallized powder is held in a static mode under supercritical conditions for several hours. This is the maturing step. Third, in a final stripping step, supercritical CO(2) is flowed through the matured powder to extract the residual solvent. The coupling of the first two steps brings about a significant synergistic effect to improve the dissolution rate of the drug. The nature of the entity obtained at the end of each step is discussed and some suggestions are made as to what happens in these operations. It is shown the co-crystallization ensures a good dispersion of both compounds and is rather insensitive to the operating parameters tested. The maturing step allows some dissolution-recrystallization to occur thus intensifying the intimate contact between the two compounds. Addition of water is necessary to make maturing effective as this is governed by the transfer properties of the medium. The stripping step allows extraction of the residual solvent but also removes some of the Eflucimibe which is the main drawback of this final stage.     

Leisure Activities of Individuals With Prader-Willi, Williams, and Down Syndromes

This study extends laboratory-based profiles to participation in leisure activities for persons with three genetic syndromes. Parents of 223 persons with Prader-Willi, Williams, and Down syndromes filled out a newly developed Leisure Activities Questionnaire. Sixteen items loaded onto five distinct factors: social; visual-spatial; visual-strategy; musical; and physical activities. Individuals with Williams syndrome less often participated in visual-spatial activities, those with Prader-Willi syndrome more often performed both visual-spatial and visual-strategy activities, and those with Williams and Down syndromes more often performed musical activities. With increasing chronological ages, all groups increased in their social activities, while those with Williams and Down syndromes decreased in their visual-spatial activities. In both Prader-Willi and Williams syndrome, decreased maladaptive behaviors related to greater amounts of participation in etiology-related activities. Theoretical and practical implications are discussed.     

A complementarity-determining region peptide of an anti-desmosome autoantibody may interact with the desmosomal plaque through molecular mimicry with a cytoplasmic desmoglein 1 sequence

The sera of patients with pemphigus, a group of autoimmune blistering skin diseases, contain autoantibodies directed against components of adhering junctions termed desmosomes. F12, a human monoclonal antibody derived from a pemphigus patient, recognizes an unknown polypeptide of the desmosomal and hemidesmosomal plaques. The third complementarity-determining region of the F12 heavy chain (VH-CDR3) was shown to share a four-amino-acid sequence (GSSG) with the intracellular domains of desmoglein 1 and bullous pemphigoid antigen 2 which interact with components of, respectively, the desmosomal and hemidesmosomal plaques. Computer modeling of F12 showed that the GSSG sequence protudes inside the antigen-combining site and thus might be involved in antigen interactions. The GSSG sequence is essential to F12 function, since a peptide containing the VH-CDR3 inhibited its binding to target antigens while VH-CDR3 peptides with specific modifications of the GSSG sequence did not. These data allow us to hypothesize that certain autoantibodies produced during the course of an autoimmune disease can behave as adhesion molecules, through the molecular mimicry of the motif involved in protein/protein adhesion, and to propose a new self-antigen binding mechanism for some autoantibodies.     

High-resolution ultrasonography of the carpal tunnel

Twenty-eight wrists of 25 patients with carpal tunnel syndrome (CTS) and 28 wrists of 14 normal control subjects were studied with high-frequency real-time ultrasonography. Three general findings could be observed in CTS, regardless of its cause: swelling of the median nerve at the entrance of the carpal tunnel; flattening of the median nerve in the distal carpal tunnel; and increased palmar flexion of the transverse carpal ligament. Quantitative analysis proved these findings to be significant. We conclude that high-resolution sonography is able to diagnose median nerve compression in the carpal tunnel syndrome and to detect some of its potential causes.     

Peripheral clonal deletion of antiviral memory CD8+ T cells

Antiviral cytotoxic memory CD8⁺ T cells adoptively transferred to mice which are persistently infected with lymphocytic choriomeningitis virus WE or DOCILE initially proliferated extensively; they either caused the death of the recipient or, alternatively, disappeared within a few days. Apparently, the complete and coordinated induction and stimulation by widely distributed viral antigen caused these memory T cells to die before virus had been eliminated from the host. Thus memory T cells are as susceptible to peripheral exhaustion/deletion as unprimed T cells. These results indicate possible limitations of exclusively CD8⁺ T cell-mediated adoptive immunotherapy against viral infections or tumors.     

High susceptibility of human dendritic cells to invasion by the intracellular pathogens Brucella suis, B. abortus, and B. melitensis

Bacteria from the Brucella genus are able to survive and proliferate within macrophages. Because they are phylogenetically closely related to macrophages, myeloid dendritic cells (DCs) constitute potential targets for Brucella bacteria. Here we report that DCs display a great susceptibility to Brucella infection. Therefore, DCs might serve as a reservoir and be important for the development of Brucella bacteria within their host.     

Epidermal T lymphocytes--ontogeny, features and function.

Conclusions The murine epidermis contains a network of Thy-1⁺ dendritic T cells. These T cells arise from early fetal stem cells and differentiate in the fetal or neonatal thymic or epidermal microenvironment. Their lack of expression of CD5, CD4, and CD8 antigens, as well as their virtually exclusive expression of a CD3/TCR V3/V1 complex, distinguishes DETC from the bulk of peripheral T cells.The early appearance of TCR / cells in ontogeny, the lack of expression of CD4 and CD8 antigens, and the relative paucity of and genes compared to and genes, indicates that / T cells provide a phylogenetically primitive, broadly acting, and poorly discriminating immunologic defense system. In this system, recognition of antigen is not restricted by classical MHC class I and class II antigens, but may occur in the context of relatively nonpolymorphic restricting elements, such as Qa [82], Tla [10] or CD1 [62]. This rather primitive immune system provided by DETC may serve to protect the epidermal integrity. Upon recognition of self proteins released following epidermal injury, DETC may become activated and assist in the removal of altered cells. In this limited fashion, the epidermis may be an independently competent immunologic system. However, the fact that the TCR repertoire of DETC does not allow for the recognition of antigenic peptides in conjunction with MHC moieties excludes the possibility that the diverse immune response elicited by topical contact with foreign antigens is mediated by DETC.Whether this statement also applies to the human epidermis cannot be answered at the present time. Let us consider a few plausible concepts concerning derivation and function of human epidermal T cells. First, one could postulate that in early ontogeny, the human epidermis harbors a small, indigenous population of naive T lymphocytes with monomorphic TCR representing an analogue to murine DETC. These cells could function in a manner similar to that proposed for murine DETC. They may even persist into adult life, so far undetected because they would be outnumbered by immigrating polymorphic T cells from peripheral lymphoid organs. Second, it is conceivable that the human epidermis contains an indigenous population of naive T lymphocytes with a polymorphic TCR repertoire representing a phylogenetically advanced analogue to murine DETC. Although equipped with TCR allowing antigen recognition in the context of MHC, their density is probably too low to make them an effective host defense system against the multitude of environmental antigens presented by Langerhans cells. One could rather assume that they proliferate upon recognition of self antigens occurring in a perturbed epidermis. The autoreactivity of these cells may not necessarily be beneficial. Finally, the fact that the entry of circulating HECA-452⁺ memory cells into the skin is dependent upon the injury-induced ELAM-1 expression by endothelial cells of the dermal microvasculature could indicate that all T cells present in adult human epidermis are recruited upon alteration of the skin. Following this reasoning, the human epidermis should not be regarded as a complete, self-sustaining immunologic organ but rather as a homing site for and a target of lymphocytes antigenically sensitized in peripheral lymphoid organs.