Disubstituted indazoles as potent antagonists of the integrin alpha(v)beta(3)

A new series of indazole-containing alpha(v)beta(3) integrin antagonists is described. Starting with lead compound 18a, variations in a number of structural features were explored with respect to inhibition of the binding of beta(3)-transfected 293 cells to fibrinogen and to selectivity for alpha(v)beta(3) over GPIIbIIIa, another RGD-binding integrin. Indazoles attached to a 2-aminopyridine or 2-aminoimidazole by a propylene linker at the indazole 1-position and to a diaminopropionate derivative via a 5-carboxylate amide provided the best potency with moderate selectivity. Several differences in the SAR of the diaminopropionate moiety were observed between this series and a series of isoxazoline-based selective GPIIbIIIa antagonists. Compound 34a (SM256) was a potent antagonist of alpha(v)beta(3) (IC(50) 2.3 nM) with 9-fold selectivity over GPIIbIIIa.     

Bioactive polymethyl methacrylate-based bone cement: comparison of glass beads, apatite- and wollastonite-containing glass-ceramic, and hydroxyapatite fillers on mechanical and biological properties

A new bioactive bone cement (designated GBC) consisting of polymethyl methacrylate (PMMA) as an organic matrix and bioactive glass beads as an inorganic filler has been developed. The bioactive beads, consisting of MgO-CaO-SiO(2)-P(2)O(5)-CaF(2) glass, have been newly designed, and a novel PMMA powder was selected. The purpose of the present study was to compare this new bone cement GBC's mechanical properties in vitro and its osteoconductivity in vivo with cements consisting of the same matrix as GBC and either apatite- and wollastonite-containing glass-ceramic (AW-GC) powder (designated AWC) or sintered hydroxyapatite (HA) powder (HAC). Each filler added to the cements amounted to 70 wt %. The bending strength of GBC was significantly higher than that of AWC and HAC (p < 0.0001). Cements were packed into intramedullar canals of rat tibiae in order to evaluate osteoconductivity as determined by an affinity index. Rats were sacrificed at 2, 4, and 8 weeks after operation. An affinity index, which equaled the length of bone in direct contact with the cement expressed as a percentage of the total length of the cement surface, was calculated for each cement. At each time interval studied, GBC showed a significantly higher affinity index than AWC or HAC up to 8 weeks after implantation (p < 0.03). The value for GBC increased significantly with time up to 8 weeks (p < 0.006). The handling property of GBC was comparable with that of PMMA bone cement. Our study revealed that the higher osteoconductivity of GBC was due to the higher bioactivity of the bioactive glass beads at the cement surface and the lower solubility of the new PMMA powder to MMA monomer. In addition, it was found that the smaller spherical shape and glassy phase of the glass beads gave GBC strong enough mechanical properties to be useful under weight-bearing conditions. GBC shows promise as an alternative with improved properties to the conventionally used PMMA bone cement.     

Extra-pulmonary tuberculosis in patients with fever of unknown origin: clinical features and diagnosis

One hundred twenty-nine patients with extra-pulmonary tuberculosis admitted at the Abbassia Fever Hospital, NAMRU-3 during a seven year period (1991 to 1997) are described. Tuberculous peritonitis was diagnosed in 35 patients, tuberculous lymphadenitis in 32, intestinal tuberculosis in 19, genito-urinary tuberculosis in 14, skeletal tuberculosis in 13, disseminated miliary tuberculosis in 11, and splenic tuberculosis in 5 patients. The clinical picture included fever, and weight loss accompanied by anaemia and an elevated erythrocyte sedimentation rate in all patients.     

IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis

Cytokines are considered important factors in the modulation of various immune responses. Among them, interleukin (IL)-21 is one of the major immune modulators, adjusting various immune responses by affecting various immune cells. It has been suggested that IL-21 may enhance autoimmunity through different mechanisms, such as development and activation of helper T (T_H)-17 and follicular helper T (T_FH) cells, activation of natural killer (NK) cells, enhancing B-cell differentiation and antibody secretion and suppression of regulatory T (T_reg) cells. Moreover, IL-21 has also been suggested to be an inducer of autoimmunity when following treatment of MS patients with some therapeutics such as alemtuzumab. This review will seek to clarify the precise role of IL-21/IL-21R in the pathogenesis of MS and, in its animal model, experimental autoimmune encephalomyelitis (EAE).     

Altered microRNA Expression and Immunosuppressive Cytokine Production by Regulatory T Cells of Ulcerative Colitis Patients

Regulatory T (Treg) cells are essential for maintenance of peripheral tolerance and prevention of autoimmune diseases in part by producing immunosuppressive cytokines. Recently, microRNAs (miRNAs) have also been involved in autoimmune disorders, not least for their crucial role in the regulation of Treg biology and function. We simultaneously investigated the concentration of IL-35, IL-10, TGF-β, and sCD25 in supernatant of cell culture and the expression patterns of several miRNAs in CD4⁺CD25⁺ CD127^?/low FoxP3⁺ Tregs of ulcerative colitis (UC) patients. Significantly lower levels of IL-10 and IL-35 were observed in Treg cultures of UC patients. miR-21, miR-146a, and miR-155 levels were downregulated and miR-31 level was upregulated in Tregs of patients. Our results suggest that microRNAs may serve as a novel regulator in function and homoeostasis of UC Treg cells, providing a key role for them in pathophysiology of UC.     

Co-expression of beta-endorphin with adhesion molecules in a model of inflammatory pain

Opioid-containing immunocytes migrate to inflamed sites where they release beta-endorphin which activates peripheral opioid receptors and produces analgesia. The immigration of immunocytes to sites of inflammation is mediated by adhesion molecules. In this study, the expression of L-, P-, E-selectin and platelet-endothelial adhesion molecule-1 (PECAM-1) in relation to beta-endorphin expression was analyzed by immunohistochemistry in inflamed tissues. The proportion of immunocytes expressing L-selectin was increased in inflamed lymph nodes and subcutaneous paw tissue. P-selectin and PECAM-1 were constitutively expressed on endothelia of noninflamed lymph nodes and subcutaneous tissue and were upregulated in inflammation. beta-endorphin positive cells expressed L-selectin in lymph nodes and subcutaneous tissue. Upregulation of P-selectin and PECAM-1 and the co-localization of L-selectin and beta-endorphin in immunocytes suggest an important role of these adhesion molecules for the recruitment of immunocytes containing beta-endorphin to sites of painful inflammation.