Three enzymes carrying esterase domains have been identified in the rumen cellulolytic anaerobe Ruminococcus flavefaciens 17. The newly characterized CesA gene product (768 amino acids) includes an ...N-terminal acetylesterase domain and an unidentified C-terminal domain, while the previously characterized XynB enzyme (781 amino acids) includes an internal acetylesterase domain in addition to its N-terminal xylanase catalytic domain. A third gene, xynE, is predicted to encode a multidomain enzyme of 792 amino acids including a family 11 xylanase domain and a C-terminal esterase domain. The esterase domains from CesA and XynB share significant sequence identity (44%) and belong to carbohydrate esterase family 3; both domains are shown here to be capable of deacetylating acetylated xylans, but no evidence was found for ferulic acid esterase activity. The esterase domain of XynE, however, shares 42% amino acid identity with a family 1 phenolic acid esterase domain identified from Clostridum thermocellum XynZ. XynB, XynE and CesA all contain dockerin-like regions in addition to their catalytic domains, suggesting that these enzymes form part of a cellulosome-like multienzyme complex. The dockerin sequences of CesA and XynE differ significantly from those previously described in R. flavefaciens polysaccharidases, including XynB, suggesting that they might represent distinct dockerin specificities.
Conformationally altered proteins and protein fragments derived from the extracellular matrix and hemostatic system may function as naturally occurring angiogenesis inhibitors. One example of such a ...protein is cleaved high molecular weight kininogen (HKa). HKa inhibits angiogenesis by inducing apoptosis of proliferating endothelial cells, effects mediated largely by HKa domain 5. However, the mechanisms underlying the antiangiogenic activity of HKa have not been characterized, and its binding site on proliferating endothelial cells has not been defined. Here, we report that the induction of endothelial cell apoptosis by HKa, as well as the antiangiogenic activity of HKa in the chick chorioallantoic membrane, was inhibited completely by antitropomyosin monoclonal antibody TM-311. TM-311 also blocked the high-affinity Zn2+-dependent binding of HKa to both purified tropomyosin and proliferating endothelial cells. Confocal microscopic analysis of endothelial cells stained with monoclonal antibody TM-311, as well as biotin labeling of cell surface proteins on intact endothelial cells, revealed that tropomyosin exposure was enhanced on the surface of proliferating cells. These studies demonstrate that the antiangiogenic effects of HKa depend on high-affinity binding to endothelial cell tropomyosin.
Three different measures of the Big Five personality dimensions were developed from the battery of questionnaires used in the National Merit Twin Study: one from trait self-rating scales, one from ...personality inventory items, and one from an adjective check list. Behavior-genetic models were fit to what the three measures had in common, and to the variance distinctive to each. The results of the model fitting agreed with other recent studies in showing the Big Five dimensions to be substantially and about equally heritable, with little or no contribution of shared family environment. Heritabilities for males and females did not differ significantly. For Agreeableness and Conscientiousness, some effect of shared environment was found for measure-specific variance on the personality inventory, and for Extraversion and Neuroticism, models involving nonadditive genetic variance or twin contrast effects provided slightly better fits.
Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to ...determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo.
Multicentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up.
Nine English old-age psychiatry services.
A pragmatic trial. Eligibility: probable or possible Alzheimer's disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+.
clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer.
(1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily.
CSDD score. Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed.
Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine).
Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112).
Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group.
This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost-effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results.
Gastro-intestinal helminth infections trigger the release of interleukin-33 (IL-33), which induces type-2 helper T cells (Th2 cells) at the site of infection to produce IL-13, thereby contributing to ...host resistance in a T cell receptor (TCR)-independent manner. Here, we show that, as a prerequisite for IL-33-induced IL-13 secretion, Th2 cells required the expression of the epidermal growth factor receptor (EGFR) and of its ligand, amphiregulin, for the formation of a signaling complex between T1/ST2 (the IL-33R) and EGFR. This shared signaling complex allowed IL-33 to induce the EGFR-mediated activation of the MAP-kinase signaling pathway and consequently the expression of IL-13. Lack of EGFR expression on T cells abrogated IL-13 expression in infected tissues and impaired host resistance. EGFR expression on Th2 cells was TCR-signaling dependent, and therefore, our data reveal a mechanism by which antigen presentation controls the innate effector function of Th2 cells at the site of inflammation.
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•Mice lacking EGFR expression on T cells are more susceptible to worm infections•EGFR forms a complex with T1/ST2, allowing for IL-33 induced IL-13 expression•Amphiregulin-mediated EGFR activation is essential for complex formation with T1/ST2•EGFR expression is induced by TCR engagement and sustained by cytokines, such as TSLP
At the site of infection, Th2 cells secrete IL-13 upon exposure to IL-33. Minutti et al. now show that TCR-induced expression of the EGFR and its ligand amphiregulin was essential for IL-33-induced IL-13 secretion, revealing a mechanism whereby antigen-specific activation controls the innate effector function of Th2 cells.
Both cross-sectional and longitudinal studies in the United States have shown consistent changes between college age and middle adulthood. There appear to be declines in 3 of the 5 major factors of ...personality-Neuroticism, Extraversion, and Openness-and increases in Agreeableness and Conscientiousness. To examine cross-cultural generalizability of these findings, translations of the Revised NEO Personality Inventory were administered to samples in Germany, Italy, Portugal, Croatia, and South Korea (
N
= 7,363). Similar patterns of age differences were seen in each country, for both men and women. Common trends were also seen for the more specific traits that define the major factors. Because these nations differ substantially in culture and recent history, results suggest the hypothesis that these are universal maturational changes in adult personality.
We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia.
We randomly assigned hospitalized ...patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria).
In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001).
Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)
Discrepancy between self-report- and actigraphy-measured sleep, often considered an artifact of measurement error, has been well documented among insomnia patients. Sleep problems are common among ...older adults, and this discrepancy may represent meaningful sleep-related phenomenon, which could have clinical and research significance.
Sleep discrepancy was examined in 4 groups of older adults (N = 152, mean age = 71.93 years) based on sleep complaint versus no complaint and presence versus absence of insomnia symptoms. Participants completed the Beck Depression Inventory-second edition (BDI-II) and 14 nights of sleep diaries and actigraphy.
Controlling for covariates, group differences were found in the duration and frequency of discrepancy in sleep onset latency (SOLd) and wake after sleep onset (WASOd). Those with insomnia symptoms and complaints reported greater duration and frequency of WASOd than the other 3 groups. Quantities of SOLd and WASOd were related to BDI-II score and group status, indicating that sleep discrepancy has meaningful clinical correlates.
Discrepancy occurred across all groups but was pronounced among the group with both insomnia symptoms and complaints. This discrepancy may provide a means of quantifying and conceptualizing the transition from wake to sleep among older adults, particularly those with sleeping problems.
Background and Aim
The rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic‐associated fatty liver disease (MAFLD). This study aimed to ...prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population.
Method
Multicenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2‐year period.
Results
Three hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the “mixed” group), and non‐MAFLD (n = 179) were included in the study. Alcohol‐associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD‐HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self‐reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate.
Conclusion
Equal to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.
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