Integrin-αvβ3 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells

Throughout life, one's blood supply depends on sustained division of hematopoietic stem cells (HSCs) for self-renewal and differentiation. Within the bone marrow microenvironment, an adhesion-dependent or -independent niche system regulates HSC function. Here we show that a novel adhesion-dependent mechanism via integrin-β3 signaling contributes to HSC maintenance. Specific ligation of β3-integrin on HSCs using an antibody or extracellular matrix protein prevented loss of long-term repopulating (LTR) activity during ex vivo culture. The actions required activation of αvβ3-integrin "inside-out" signaling, which is dependent on thrombopoietin (TPO), an essential cytokine for activation of dormant HSCs. Subsequent "outside-in" signaling via phosphorylation of Tyr747 in the β3-subunit cytoplasmic domain was indispensable for TPO-dependent, but not stem cell factor-dependent, LTR activity in HSCs in vivo. This was accompanied with enhanced expression of Vps72, Mll1, and Runx1, 3 factors known to be critical for maintaining HSC activity. Thus, our findings demonstrate a mechanistic link between β3-integrin and TPO in HSCs, which may contribute to maintenance of LTR activity in vivo as well as during ex vivo culture.     

Molecular-based haplotype analysis of the beta 2-adrenergic receptor gene (ADRB2) in Japanese asthmatic and non-asthmatic subjects.

BACKGROUND: The beta2-adrenergic receptor gene (ADRB2) is a target molecule of beta2-agonists. Single nucleotide polymorphisms (SNPs) in the ADRB2 are related to the effectiveness of beta2-agonists. However, there are some discrepancies in the results of pharmacogenetic studies of ADRB2 among different ethnic groups. The aims of this study were to determine the ADRB2 haplotypes and diplotypes in Japanese asthmatic and non-asthmatic subjects and to examine their relation to asthma and to compare these results with previous studies done in other ethnic groups. METHODS: Complete sequences for 3 kb promoter and 1.2 kb structural regions of ADRB2 were analyzed in 48 Japanese asthmatics and 100 controls, and haplotypes and diplotypes of SNPs were analyzed. RESULTS: Fifteen SNPs including a novel one in -839 were observed. Allele frequencies for all SNPs were similar between asthmatics and controls. We also identified 42 haplotypes and 54 diplotypes of ADRB2 in a Japanese population. The frequencies were similar between the two groups. They were classified into 17 and 23 types, respectively, according to Drysdale's haplotype-organization system, and a significant ethnic difference was observed between the Japanese and Caucasian populations. CONCLUSIONS: The frequencies of SNPs and ADBR2 haplotypes in Japanese are different from those in Caucasians and African Americans. These divergences might imply the need for independent pharmacogenetic studies for ADBR2 in each ethnic group.     

Histamine H2-receptor antagonistic action of N-(3-[3-(1-piperidinylmethyl)phenoxy]propyl)acetoxyacetamide hydrochloride (TZU-0460)

The antagonism of histamine H2-receptor by N-(3-[3-(1-piperidinylmethyl)phenoxy)propyl)acetoxyacetamide hydrochloride (TZU-0460) was estimated on isolated guinea-pig right atrium and rat uterus in vitro and on gastric acid secretion in dog with Heidenhain pouch. The concentration-response curves for the positive chronotropic effect of histamine and dimaprit (S-[3-(N,N-dimethylamino) propyl]isothiourea) on atrium were displaced to the right in parallel without change in the maximum response by TZU-0460 with pA2 values of 6.56 and 6.74 and also for the relaxant effect on uterus with pA2 values of 6.81 and 6.65, respectively. There was no significant difference between the estimated pA2 values for TZU-0460 on the different tissues against the same agonist, and also between the pA2 values on the same tissue against the different agonists. The slope of the regression line of log (DR-1) against log TZU-0460 concentration on either tissue was not significantly different from unity; 0.98 (95% confidence limits, 0.81-1.14) on atrium, 0.95 (0.56-1.34) on uterus. These results indicate that TZU-0460 is a competitive antagonist of histamine and dimaprit in vitro. In Heidenhain pouch dog, TZU-0460 also competitively antagonized the stimulation of acid secretion by histamine with pA2 of 6.59 and by dimaprit with pA2 of 6.52, calculated on infused rates. These results indicate that TZU-0460 was about 6 times more potent than cimetidine.     

Hemorrhagic cyst of the mandible associated with a retained root apex of the lower third molar

An unusual case of hemorrhagic cyst of the mandible, associated with a retained root of the lower right third molar, is reported. The cyst was revealed by routine radiologic examination as part of treatment of the lower right second molar. Radiologically, a faintly outlined cavity with radiopaque mass was found in the third molar region. A final diagnosis of this condition was made after surgical intervention and histologic examination. A nonepithelial lining cavity was found, and the radiopaque mass was identified as a root apex.     

Cementless Tapered-Wedge Stem Length Affects the Risk of Periprosthetic Femoral Fractures in Direct Anterior Total Hip Arthroplasty

Background

Although the popularity of the direct anterior approach for total hip arthroplasty has increased, the femoral procedure in this approach is considered technically challenging, and one of the most frequent complications reported was periprosthetic femoral fractures. The present study aimed to identify factors for predicting the risk of periprosthetic femoral fractures after using stems with a cementless tapered-wedge design through the direct anterior approach.

Gastrointestinal Graft-versus-Host Disease Is a Risk Factor for Postengraftment Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.