Mediators and moderators of functional impairment in adults with obsessive–compulsive disorder

The current study examined correlates, moderators, and mediators of functional impairment in 98 treatment-seeking adults with obsessive–compulsive disorder (OCD). Participants completed or were administered measures assessing obsessive–compulsive symptom severity, functional impairment, resistance against symptoms, interference due to obsessive–compulsive symptoms, depressive symptoms, insight, and anxiety sensitivity. Results indicated that all factors, except insight into symptoms, were significantly correlated with functional impairment. The relationship between obsessive–compulsive symptom severity and functional impairment was not moderated by patient insight, resistance against obsessive–compulsive symptoms, or anxiety sensitivity. Mediational analyses indicated that obsessive–compulsive symptom severity mediated the relationship between anxiety sensitivity and obsessive–compulsive related impairment. Indeed, anxiety sensitivity may play an important contributory role in exacerbating impairment through increases in obsessive–compulsive symptom severity. Depressive symptoms mediated the relationship between obsessive–compulsive symptom severity and obsessive–compulsive related impairment. Implications for assessment and treatment are discussed.     

Spermatogonia differentiation requires retinoic acid receptor γ

Vitamin A is instrumental to mammalian reproduction. Its metabolite, retinoic acid (RA), acts in a hormone-like manner through binding to and activating three nuclear receptor isotypes, RA receptor (RAR)α (RARA), RARβ, and RARγ (RARG). Here, we show that 1) RARG is expressed by A aligned (A(al)) spermatogonia, as well as during the transition from A(al) to A(1) spermatogonia, which is known to require RA; and 2) ablation of Rarg, either in the whole mouse or specifically in spermatogonia, does not affect meiosis and spermiogenesis but impairs the A(al) to A(1) transition in the course of some of the seminiferous epithelium cycles. Upon ageing, this phenomenon yields seminiferous tubules containing only spermatogonia and Sertoli cells. Altogether, our findings indicate that RARG cell-autonomously transduces, in undifferentiated spermatogonia of adult testes, a RA signal critical for spermatogenesis. During the prepubertal spermatogenic wave, the loss of RARG function can however be compensated by RARA, as indicated by the normal timing of appearance of meiotic cells in Rarg-null testes. Accordingly, RARG- and RARA-selective agonists are both able to stimulate Stra8 expression in wild-type prepubertal testes. Interestingly, inactivation of Rarg does not impair expression of the spermatogonia differentiation markers Kit and Stra8, contrary to vitamin A deficiency. This latter observation supports the notion that the RA-signaling pathway previously shown to operate in Sertoli cells also participates in spermatogonia differentiation.     

Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis

Direct evidence for a role of endogenous retinoic acid (RA), the active metabolite of vitamin A in the initial differentiation and meiotic entry of spermatogonia, and thus in the initiation of spermatogenesis is still lacking. RA is synthesized by dedicated enzymes, the retinaldehyde dehydrogenases (RALDH), and binds to and activates nuclear RA receptors (RARA, RARB, and RARG) either within the RA-synthesizing cells or in the neighboring cells. In the present study, we have used a combination of somatic genetic ablations and pharmacological approaches in vivo to show that during the first, prepubertal, spermatogenic cycle (i) RALDH-dependent synthesis of RA by Sertoli cells (SC), the supporting cells of the germ cell (GC) lineage, is indispensable to initiate differentiation of A aligned into A1 spermatogonia; (ii) RARA in SC mediates the effects of RA, possibly through activating Mafb expression, a gene whose Drosophila homolog is mandatory to GC differentiation; (iii) RA synthesized by premeiotic spermatocytes cell autonomously induces meiotic initiation through controlling the RAR-dependent expression of Stra8. Furthermore, we show that RA of SC origin is no longer necessary for the subsequent spermatogenic cycles but essential to spermiation. Altogether, our data establish that the effects of RA in vivo on spermatogonia differentiation are indirect, via SC, but direct on meiotic initiation in spermatocytes, supporting thereby the notion that, contrary to the situation in the female, RA is necessary to induce meiosis in the male.     

A Double-Blind Randomized Controlled Trial (RCT) of Titanium-13Zirconium versus Titanium Grade IV Small-Diameter Bone Level Implants in Edentulous Mandibles - Results from a 1-Year Observation Period

Background: The use of endosseous dental implants has become common practice for the rehabilitation of edentulous patients, and a two‐implant overdenture has been recommended as the standard of care. The use of small‐diameter implants may extend treatment options and reduce the necessity for bone augmentation. However, the mechanical strength of titanium is limited, so titanium alloys with greater tensile and fatigue strength may be preferable. Purpose: This randomized, controlled, double‐blind, multicenter study investigated in a split‐mouth model whether small‐diameter implants made from Titanium‐13Zirconium alloy (TiZr, Roxolid?) perform at least as well as Titanium Grade IV implants. Methods and Materials: Patients with an edentulous mandible received one TiZr and one Ti Grade IV small‐diameter bone level implant (3.3 mm, SLActive®) in the interforaminal region. The site distribution was randomized and double‐blinded. Outcome measures included change in radiological peri‐implant bone level from surgery to 12 months post‐insertion (primary), implant survival, success, soft tissue conditions, and safety (secondary). Results: Of 91 treated patients, 87 were available for the 12‐month follow‐up. Peri‐implant bone level change (?0.3 ± 0.5 mm vs ?0.3 ± 0.6 mm), plaque, and sulcus bleeding indices were not significantly different between TiZr and Ti Grade IV implants. Implant survival rates were 98.9 percent and 97.8 percent, success rates were 96.6 percent and 94.4 percent, respectively. Nineteen minor and no serious adverse events were related to the study devices. Conclusion: This study confirms that TiZr small‐diameter bone level implants provide at least the same outcomes after 12 months as Ti Grade IV bone level implants. The improved mechanical properties of TiZr implants may extend implant therapy to more challenging clinical situations.     

Effects of a late-life suicide risk--assessment training on multidisciplinary healthcare providers

Older adults are among the highest at risk for completing suicide, and they are more likely to seek mental health services from providers outside of traditional mental health care, but providers across the spectrum of care have limited training in suicide risk assessment and management and particularly lack training in suicide prevention for older adults. An educational program was developed to increase awareness and improve suicide risk assessment and management training for a range of healthcare providers who may see older adults in their care settings. One hundred thirty-two participants from two Veterans Affairs Medical Centers participated in a 6.5-hour-long workshop in the assessment and management of suicide risk in older adults. Participants were asked to complete pre- and postworkshop case notes and report on subjective changes in knowledge, attitudes, and confidence in assessment and managing suicide risk in older adults. Participants included social workers, nurses, physicians, psychologists, and occupational therapists from a variety of care settings, including outpatient and inpatient medical, outpatient and inpatient mental health, specialty clinics, home, and community. After the workshop, participants demonstrated improvement in the overall quality of case notes (P = .001), greater ability to recognize important conceptual suicide risk categories (P = .003), and reported heightened awareness of the importance of late-life suicide. The results suggest that educational training may have beneficial effect on the ability of multidisciplinary care providers to identify and manage suicide risk in elderly adults.     

Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF-induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED(50) = 17nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED(50) = 0.5nM) and MM patients. It decreased SDF-1-induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell-induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM.     

Partial plasma cell differentiation as a mechanism of lost major histocompatibility complex class II expression in diffuse large B-cell lymphoma

Loss of major histocompatibility complex class II (MHC II) expression is associated with poor patient outcome in diffuse large B-cell lymphoma (DLBCL). As MHC II molecules are lost with plasmacytic differentiation in normal cells, we asked whether MHC II loss in DLBCL is associated with an altered differentiation state. We used gene expression profiling, quantum dots, and immunohistochemistry to study the relationship between MHC II and plasma cell markers in DLBCL and plasmablastic lymphoma (PBL). Results demonstrate that MHC II(-) DLBCL immunophenotypically overlap with PBL and demonstrate an inverse correlation between MHC II and plasma cell markers MUM1, PRDM1/Blimp1, and XBP1s. In addition, MHC II expression is significantly higher in germinal center-DLBCL than activated B cell-DLBCL. A minor subset of cases with an unusual pattern of mislocalized punctate MHC II staining and intermediate levels of mRNA is also described. Finally, we show that PBL is negative for MHC II. The results imply a spectrum of MHC II expression that is more frequently diminished in tumors derived from B cells at the later stages of differentiation (with complete loss in PBL). Our observations provide a possible unifying concept that may contribute to the poor outcome reported in all MHC II(-) B-cell tumors.     

Glucans from the edible mushroom Pleurotus pulmonarius inhibit colitis-associated colon carcinogenesis in mice

Background

We have recently demonstrated that polysaccharides from fruiting body extract (FBE) or mycelia extract (ME) of the edible mushroom Pleurotus pulmonarius exert antiproliferative effects in intestinal cells and an anti-inflammatory effect in a dextran sulfate sodium (DSS) mouse model of acute colitis. The aim of this study was to assess the role of fungal FBE and ME in colon carcinogenesis.

Methods

In vitro, human colorectal cancer cells were treated with FBE and ME and analyzed for inflammation response, for markers of apoptosis, and for cell-cycle progression. In vivo, FBE and ME were tested in a mouse model of colitis-associated colorectal carcinogenesis induced by cyclic treatments with DSS and azoxymethane. Treated mice were fed a daily diet containing 2 or 20?mg FBE or ME per mouse for 80?days.

Results

In vitro, FBE and ME induced apoptosis in a dose-responsive manner and modulated the expression of Bcl-2, Bax, and cytochrome c, and blocked tumor necrosis factor (TNF)-α-induced inhibitor of nuclear factor (NF) (Iκ)-Bα degradation and NF-κB nuclear translocation. In vivo, dietary administration of FBE and ME significantly reduced the formation of aberrant crypt foci, which precedes colorectal cancer, and of microadenomas. The treatments significantly lowered the expression of proliferating cell nuclear antigen and increased the number of cells undergoing apoptosis in the colon. Additionally, FBE and ME inhibited the expression of the proinflammatory cytokine TNF-α in colonic tissue.

Conclusions

We conclude that P. pulmonarius FBE and ME inhibit colitis-associated colon carcinogenesis induced in mice through the modulation of cell proliferation, induction of apoptosis, and inhibition of inflammation.