IL-21 induces apoptosis of antigen-specific CD8+ T lymphocytes

IL-21, a member of the common gamma-chain family of cytokines, has pleiotropic effects on T, B, and NK cells. We found that IL-21 and the prototype common gamma-chain cytokine IL-2 can stimulate proliferation and cytokine secretion by Ag-specific rhesus monkey CD8+ T cells. However, unique among the members of this family of cytokines, we found that IL-21 drives these cells to apoptosis by down-regulation of Bcl-2. These findings suggest that IL-21 may play an important role in the contraction of CD8+ T cell responses.     

Ribavirin enhances osteoclast formation through osteoblasts via up-regulation of TRANCE/RANKL

Hepatitis C combination therapy comprising ribavirin and interferon-α causes dramatic improvement with the sustained virological response; however, this treatment may result in the loss of bone mineral density. To investigate the effects of ribavirin on bone cells, we examined osteoblast differentiation as well as the formation of osteoclasts from their precursors. Ribavirin enhances osteoclast formation through osteoblasts by up-regulation of TRANCE/RANKL gene expression, whereas it has no significant effect on either osteoblast differentiation or on bone formation. Understanding ribavirin’s underlying mechanism of action on bone cells will enable the improved management of bone loss in chronic hepatitis C patients.     

Identification of a novel, orally bioavailable histamine H(3) receptor antagonist based on the 4-benzyl-(1H-imidazol-4-yl) template

A novel series of histamine H(3) receptor antagonists, based on the 4-benzyl-(1H-imidazole-4-yl) template, incorporating urea and carbamate linkers has been prepared. Compound 3j is a selective H(3) antagonist and demonstrates excellent oral plasma levels in the rat and monkey.     

DEF6, a Novel Substrate for the Tec Kinase ITK, Contains a Glutamine-rich Aggregation-prone Region and Forms Cytoplasmic Granules that Co-localize with P-bodies

Localization of DEF6 (SLAT/IBP), a Rho-family guanine nucleotide exchange factor, to the center of the immune synapse is dependent upon ITK, a Tec-family kinase that regulates the spatiotemporal organization of components of T cell signaling pathways and Cdc42-dependent actin polymerization. Here we demonstrate that ITK both interacts with DEF6 and phosphorylates DEF6 at tyrosine residues Tyr(210) and Tyr(222). Expression of a GFP-tagged Y210E-Y222E phosphomimic resulted in the formation of DEF6 cytoplasmic granules that co-localized with decapping enzyme 1 (DCP1), a marker of P-bodies; sites of mRNA degradation. Similarly treatment of cells with puromycin or sodium arsenite, reagents that arrest translation, also resulted in the accumulation of DEF6 in cytoplasmic granules. Bioinformatics analysis identified a glutamine-rich, heptad-repeat region; a feature of aggregating proteins, within the C-terminal region of DEF6 with the potential to promote granule formation through a phosphorylation-dependent unmasking of this region. These data suggest that in addition to its role as a GEF, DEF6 may also function in regulating mRNA translation.     

Murine spleen contains a diversity of myeloid and dendritic cells distinct in antigen presenting function

The spleen contains multiple subsets of myeloid and dendritic cells (DC). DC are important antigen presenting cells (APC) which induce and control the adaptive immune response. They are cells specialized for antigen capture, processing and presentation to naïve T cells. However, DC are a heterogeneous population and each subset differs subtly in phenotype, function and location. Similarly, myeloid cell subsets can be distinguished which can also play an important role in the regulation of immunity. This review aims to characterize splenic subsets of DC and myeloid cells to better understand their individual roles in the immune response.     

Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease

Most individuals with Down Syndrome (DS) show an early-onset of Alzheimer's disease (AD), which potentially results from the presence of an extra copy of a segment of chromosome 21. Located on chromosome 21 are the genes that encode β-amyloid (Aβ) precursor protein ( APP ), a key protein involved in the pathogenesis of AD, and dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A ( DYRK1A ), a proline-directed protein kinase that plays a critical role in neurodevelopment. Here, we describe a potential mechanism for the regulation of AD pathology in DS brains by DYRK1A-mediated phosphorylation of APP. We show that APP is phosphorylated at Thr668 by DYRK1A in vitro and in mammalian cells. The amounts of phospho-APP and Aβ are increased in the brains of transgenic mice that over-express the human DYRK1A protein. Furthermore, we show that the amounts of phospho-APP as well as those of APP and DYRK1A are elevated in human DS brains. Taken together, these results reveal a potential regulatory link between APP and DYRK1A in DS brains, and suggest that the over-expression of DYRK1A in DS may play a role in accelerating AD pathogenesis through phosphorylation of APP.     

Ultrasound enhanced prehospital thrombolysis using microbubbles infusion in patients with acute ST elevation myocardial infarction: Rationale and design of the Sonolysis study

Background

The CONSORT Statement provides recommendations for reporting randomized controlled trials. We assessed the extent to which leading medical journals that publish reports of randomized trials incorporate the CONSORT recommendations into their journal and editorial processes.

Methods

This article reports on two observational studies. Study 1: We examined the online version of 'Instructions to Authors' for 165 high impact factor medical journals and extracted all text mentioning the CONSORT Statement or CONSORT extension papers. Any mention of the International Committee of Medical Journal Editors (ICMJE) or clinical trial registration were also sought and extracted. Study 2: We surveyed the editor-in-chief, or editorial office, for each of the 165 journals about their journal's endorsement of CONSORT recommendations and its incorporation into their editorial and peer-review processes.

Results

Study 1: Thirty-eight percent (62/165) of journals mentioned the CONSORT Statement in their online 'Instructions to Authors'; of these 37% (23/62) stated this was a requirement, 63% (39/62) were less clear in their recommendations. Very few journals mentioned the CONSORT extension papers. Journals that referred to CONSORT were more likely to refer to ICMJE guidelines (RR 2.16; 95% CI 1.51 to 3.08) and clinical trial registration (RR 3.67; 95% CI 2.36 to 5.71) than those journals which did not. Study 2: Thirty-nine percent (64/165) of journals responded to the on-line survey, the majority were journal editors. Eighty-eight percent (50/57) of journals recommended authors comply with the CONSORT Statement; 62% (35/56) said they would require this. Forty-one percent (22/53) reported incorporating CONSORT into their peer-review process and 47% (25/53) into their editorial process. Eighty-one percent (47/58) reported including CONSORT in their 'Instructions to Authors' although there was some inconsistency when cross checking information on the journal's website. Sixty-nine percent (31/45) of journals recommended authors comply with the CONSORT extension for cluster trials, 60% (27/45) for harms and 42% (19/45) for non-inferiority and equivalence trials. Few journals mentioned these extensions in their 'Instructions to Authors'.

Conclusion

Journals should be more explicit in their recommendations and expectations of authors regarding the CONSORT Statement and related CONSORT extensions papers.     

The Dynamics, Prevalence and Impact of Nematode Infections in Organically Raised Sheep in Sweden

A three-year survey (1997–99) was carried out on organically reared sheep flocks throughout Sweden. The aim was to determine the prevalence and intensity of nematode infections and to establish relationships between sheep management practices and parasite infections. Faecal samples from ewes and lambs were collected from 152 organic flocks around lambing-time and during the grazing-period for analysis. Results were compared with the different management practices that farmers use to prevent parasitism in their flocks. A high proportion of the flocks was infected with nematodes. The most prevalent species were Haemonchus contortus, Teladorsagia circumeincta, Trichostrongylus axei, T. colubriformis and Chabertia ovina and infections progressively increased during summer in lambs grazing on permanent pastures. Severity of parasitic infection in lambs was highly dependent on egg output from the ewes. H. contortus was found in 37% of the flocks, even at latitudes approximating the Polar Circle. Nematodirus battus was recorded for the first time in Sweden during the course of this study. Lambs turned out onto permanent pasture showed higher nematode faecal egg counts (epg) than lambs that had grazed on pastures, which had not carried sheep the previous year. This beneficial effect of lambs grazing non-infected pastures persisted if the ewes were treated with an anthelmintic before turn-out and if the lambs were kept on pastures of low infectivity after weaning. In lambs, the prevalence and the magnitude of their egg counts were higher during autumn in flocks where lambs were slaughtered after 8 months of age, compared with flocks where all lambs were slaughtered before this age. These results will be used in providing advice to farmers of ways to modify their flock management in order to minimise the use of anthelmintics, but at the same time efficiently produce prime lambs.