Deficient inhibition of return in subclinical OCD only when attention is directed to the threatening aspects of a stimulus

Background - Inhibition of return (IOR) is thought to reflect inhibition of previously attended but irrelevant stimuli. Deficient IOR would increase the likelihood of revisiting previously searched locations or objects, thus leading to unproductive perseverations. Method - Therefore, using a novel IOR task, we investigated whether high scoring checkers attentional biases to threat would result in dysfunctional inhibitory functioning compared to low checkers. In two tasks, we compared 53 subclinical high and 49 low checkers regarding IOR effects for stimuli that were concordant with the concerns of high but not of low checkers (electrical kitchen appliances: e.g., toaster, kettle). The difference between the two tasks was the cueing procedure. In one task, an appliance was switched “ON” and “OFF” as an unpredictive cue, drawing attention to the functionality of the stimulus. Results - In this task, IOR was specifically attenuated in high checkers. In the other task, however, the cue was more abstract in form of a yellow outline that appeared around one of two appliances. Although the appliance was either “ON” or “OFF,” this did not seem to matter and high checkers revealed a typical IOR pattern similar to low checkers. Conclusions - We conclude that IOR mechanisms might not be generally deficient in high checkers; rather only when attention is drawn to the threatening aspects of ecologically valid stimuli, then disengagement of attention is deficient in high checkers. We make suggestions on how our task-specific findings may inform cognitive interventions that target attentional control in the treatment of checking/obsessive–compulsive disorder.

Inhibition of object identity in inhibition of return:implications for encoding and retrieving inhibitory processes

Inhibition of return (IOR) effects, in which participants detect a target in a cued box more slowly than one in an uncued box, suggest that behavior is aided by inhibition of recently attended irrelevant locations. To investigate the controversial question of whether inhibition can be applied to object identity in these tasks, in the present research we presented faces upright or inverted during cue and/or target sequences. IOR was greater when both cue and target faces were upright than when cue and/or target faces were inverted. Because the only difference between the conditions was the ease of facial recognition, this result indicates that inhibition was applied to object identity. Interestingly, inhibition of object identity affected IOR both whenencoding a cue face andretrieving information about a target face. Accordingly, we propose that episodic retrieval of inhibition associated with object identity may mediate behavior in cuing tasks.

Long-term inhibition of return of attention

During search of the environment, the inhibition of the return (IOR) of attention to already-examined information ensures that the target will ultimately be detected. Until now, inhibition was assumed to support search of information during one processing episode. However, in some situations search may have to be completed long after it was begun. We therefore propose that inhibition can be associated with an episode encoded into memory such that later retrieval reinstates inhibitory processing and encourages examination of new information. In two experiments in which attention was drawn to face stimuli with an exogenous cue, we demonstrated for the first time the existence of long-term IOR. Interestingly, this was the case only for faces in the left visual field, perhaps because more efficient processing of faces in the right hemisphere than the left hemisphere results in richer, more retrievable memory representations.

Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides

Tissue damage resulting from the extracellular production of HOCl (hypochlorous acid) by the MPO (myeloperoxidase)-hydrogen peroxide-chloride system of activated phagocytes is implicated as a key event in the progression of a number of human inflammatory diseases. Consequently, there is considerable interest in the development of therapeutically useful MPO inhibitors. Nitroxides are well established antioxidant compounds of low toxicity that can attenuate oxidative damage in animal models of inflammatory disease. They are believed to exert protective effects principally by acting as superoxide dismutase mimetics or radical scavengers. However, we show here that nitroxides can also potently inhibit MPO-mediated HOCl production, with the nitroxide 4-aminoTEMPO inhibiting HOCl production by MPO and by neutrophils with IC50 values of approx. 1 and 6 μM respectively. Structure–activity relationships were determined for a range of aliphatic and aromatic nitroxides, and inhibition of oxidative damage to two biologically-important protein targets (albumin and perlecan) are demonstrated. Inhibition was shown to involve one-electron oxidation of the nitroxides by the compound I form of MPO and accumulation of compound II. Haem destruction was also observed with some nitroxides. Inhibition of neutrophil HOCl production by nitroxides was antagonized by neutrophil-derived superoxide, with this attributed to superoxide-mediated reduction of compound II. This effect was marginal with 4-aminoTEMPO, probably due to the efficient superoxide dismutase-mimetic activity of this nitroxide. Overall, these data indicate that nitroxides have considerable promise as therapeutic agents for the inhibition of MPO-mediated damage in inflammatory diseases.

Effect of poly(acrylic acid) end-group functionality on inhibition of calcium oxalate crystal growth

A number of series of poly(acrylic acids) (PAA) of differing end-groups and molecular weights prepared using atom transfer radical polymerization were used as inhibitors for the crystallization of calcium oxalate at 23 and 80°C. As measured by turbidimetry and conductivity and as expected from previous reports, all PAA series were most effective for inhibition of crystallization at molecular weights of 1500–4000. However, the extent of inhibition was in general strongly dependent on the hydrophobicity and molecular weight of the end-group. These results may be explicable in terms of adsorption/desorption of PAA to growth sites on crystallites. The overall effectiveness of the series didn't follow a simple trend with end-group hydrophobicity, suggesting self-assembly behavior or a balance between adsorption and desorption rates to crystallite surfaces may be critical in the mechanism of inhibition of calcium oxalate crystallization.

Inhibition of integrative cartilage repair by proteoglycan 4 in synovial fluid

To determine the effects of the articular cartilage surface, as well as synovial fluid (SF) and its components, specifically proteoglycan 4 (PRG4) and hyaluronic acid (HA), on integrative cartilage repair in vitro. Methods. Blocks of calf articular cartilage were harvested, some with the articular surface intact and others without. Some of the latter types of blocks were pretreated with trypsin, and then with bovine serum albumin, SF, PRG4, or HA. Immunolocalization of PRG4 on cartilage surfaces was performed after treatment. Pairs of similarly treated cartilage blocks were incubated in partial apposition for 2 weeks in medium supplemented with serum and 3 H-proline. Following culture, mechanical integration between apposed cartilage blocks was assessed by measuring adhesive strength, and protein biosynthesis and deposition were determined by incorporated 3 H-proline. Results. Samples with articular surfaces in apposition exhibited little integrative repair compared with samples with cut surfaces in apposition. PRG4 was immunolocalized at the articular cartilage surface, but not in deeper, cut surfaces (without treatment). Cartilage samples treated with trypsin and then with SF or PRG4 exhibited an inhibition of integrative repair and positive immunostaining for PRG4 at treated surfaces compared with normal cut cartilage samples, while samples treated with HA exhibited neither inhibited integrative repair nor PRG4 at the tissue surfaces. Deposition of newly synthesized protein was relatively similar under conditions in which integration differed significantly. Conclusion. These results support the concept that PRG4 in SF, which normally contributes to cartilage lubrication, can inhibit integrative cartilage repair. This has the desirable effect of preventing fusion of apposing surfaces of articulating cartilage, but has the undesirable effect of inhibiting integrative repair.

Inhibition of p38 pathway leads to OA-like changes in a rat animal model

Objectives The p38 mitogen-activated protein kinase (MAPK) signal transduction pathway is involved in a variety of inflammatory responses, including cytokine generation, cell differentiation proliferation and apoptosis. Here, we examined the effects of systemic p38 MAPK inhibition on cartilage cells and osteoarthritis (OA) disease progression by both in vitro and in vivo approaches. Methods p38 kinase activity was evaluated in normal and OA cartilage cells by measuring the amount of phosphorylated protein. To examine the function of p38 signaling pathway in vitro, normal chondrocytes were isolated and differentiated in the presence or absence of p38 inhibitor; SB203580 and analysed for chondrogenic phenotype. Effect of systemic p38 MAPK inhibition in normal and OA (induced by menisectomy) rats were analysed by treating animals with vehicle alone (DMS0) or p38 inhibitor (SB203580). Damage to the femur and tibial plateau was evaluated by modified Mankin score, histology and immunohistochemistry. Results Our in vitro studies have revealed that a down-regulation of chondrogenic and increase of hypertrophic gene expression occurs in the normal chondrocytes, when p38 is neutralized by a pharmacological inhibitor. We further observed that the basal levels of p38 phosphorylation were decreased in OA chondrocytes compared with normal chondrocytes. These findings together indicate the importance of this pathway in the regulation of cartilage physiology and its relevance to OA pathogenesis. At in vivo level, systematic administration of a specific p38 MAPK inhibitor, SB203580, continuously for over a month led to a significant loss of proteoglycan; aggrecan and cartilage thickness. On the other hand, SB203580 treated normal rats showed a significant increase in TUNEL positive cells, cartilage hypertrophy markers such as Type 10 collagen, Runt-related transcription factor and Matrix metalloproteinase-13 and substantially induced OA like phenotypic changes in the normal rats. In addition, menisectomy induced OA rat models that were treated with p38 inhibitor showed aggravation of cartilage damage. Conclusions In summary, this study has provided evidence that the component of the p38 MAPK pathway is important to maintain the cartilage health and its inhibition can lead to severe cartilage degenerative changes. The observations in this study highlight the possibility of using activators of the p38 pathway as an alternative approach in the treatment of OA.

Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.