Btk is a positive regulator in the TREM-1/DAP12 signaling pathway

The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec kinases, becomes phosphorylated upon TREM-1 triggering. In U937-derived cell lines, in which expression of Btk was diminished by shRNA-mediated knockdown, phosphorylation of Erk1/2 and PLCγ1 and Ca2? mobilization were reduced after TREM-1 stimulation. Importantly, TREM-1-induced production of the pro-inflammatory cytokines, TNF-α and IL-8, and up-regulation of activation/differentiation cell surface markers were impaired in Btk knockdown cells. Similar results were obtained upon TREM-1 stimulation of BMDCs of Btk(-/-) mice. The analysis of cells containing Btk mutants revealed that intact membrane localization and a functional kinase domain were required for TREM-1-mediated signaling. Finally, after TREM-1 engagement, TNF-α production by PBMCs was reduced in the majority of patients suffering from X-linked agammaglobulinemia (XLA), a rare hereditary disease caused by mutations in the BTK gene. In conclusion, our data identify Btk as a positive regulator in the ITAM-mediated TREM-1/DAP12 pathway and suggest its implication in inflammatory processes.     

Human Leukocyte Antigen Sensitization in Solid Organ Transplantation: A Primer on Terminology,Testing, and Clinical Significance for the Apheresis Practitioner

The human leukocyte antigen (HLA) system is an important immunologic barrier that must be considered for successful solid organ transplantation. Formation of donor‐specific HLA antibodies in solid organ transplantation is an important cause of allograft injury and may contribute to recipient morbidity and mortality. Therapeutic plasma exchange is often requested to lower HLA antibody levels prior to or after transplantation and for management of HLA antibodies in the context of organ rejection. In this review, we summarize the current terminology, laboratory testing, and clinical significance of HLA sensitization in the solid organ transplant population. Furthermore, to illustrate applications of HLA testing in clinical practice, we summarize our own lung and kidney institutional protocols for managing HLA antibodies in the peri‐transplant setting.     

Molecular heterogeneity of G6PD deficiency in an Amazonian population and description of four new variants

To characterize the molecular variation in the glucose-6-phosphate dehydrogenase gene (G6PD), 196 asymptomatic and unrelated male G6PD-deficient blood donors from Belém, an Amazonian metropolis (Brazil), were analyzed. This deficiency was detected by horizontal agarose gel electrophoresis and quantitative spectrophotometric assay for enzyme activity. The mutations were searched by PCR/RFLP, SSCP, and direct DNA sequencing. The most frequent G6PD variant was the widespread and common G6PD A- (202G --> A, 376A --> G) observed in 161 subjects (82.1%). Besides this, we found another form of G6PD A- (968T --> C, 376A --> G) in 14 (7.1%) individuals, G6PD Seattle (844G --> C) in 4.6%, G6PD Santamaria (542A --> T, 376A --> G) in 2.5%, and G6PD Tokyo (1246G --> A) in one blood donor. Four novel variants were also identified: G6PD Belém (409C --> T; Pro137His), G6PD Ananindeua (376A --> G, 871G --> A; Asn126Asp, Val291Met), G6PD Crispim with four point mutations (375G --> T, 379G --> T, 383T --> C, and 384C --> T) leading to three amino acid substitutions (Met125Ile, Ala127Ser, and Leu128Pro), and G6PD Amazonia (185C --> A; Pro62His). The reported frequencies do not reflect the real values for blood donors from Belém, since an excess of individuals with "non A-" phenotype was included in this study to enhance the probability to find rare variants. Haplotype analyses were carried out for the less common G6PD variants identified in our study using PCR/RFLP for five polymorphic sites (FokI, PvuII, PstI, BclI, NlaIII). G6PD Crispim and G6PD Amazonia variants presented the most common haplotype found in G6PD B (- - + - -). G6PD Belém presented two haplotypes (- - + + +, - + + + +) and G6PD Ananindeua was found with the + - + - + haplotype. The reported heterogeneity probably is due to the great miscegenation, characteristic of the population of the Amazonian region, besides the apparently common occurrence of recurrent mutations in the G6PD gene.     

Novel α + β Zr Alloys with Enhanced Strength

Low-alloyed zirconium alloys are widely used in nuclear applications due to their low neutron absorption cross-section. These alloys, however, suffer from limited strength. Well-established guidelines for the development of Ti alloys were applied to design new two-phase ternary Zr alloys with improved mechanical properties. Zr-4Sn-4Nb and Zr-8Sn-4Nb alloys have been manufactured by vacuum arc melting, thermo-mechanically processed by annealing, forging, and aging to various microstructural conditions and thoroughly characterized. Detailed Scanning electron microscopy (SEM) analysis showed that the microstructural response of the alloys is rather similar to alpha + beta Ti alloys. Duplex microstructure containing primary alpha phase particles surrounded by lamellar alpha + beta microstructure can be achieved by thermal processing. Mechanical properties strongly depend on the previous treatment. Ultimate tensile strength exceeding 700 MPa was achieved exceeding the strength of commercial Zr alloys for nuclear applications by more than 50%. Such an improvement in strength more than compensates for the increased neutron absorption cross-section. This study aims to exploit the potential of alpha + beta Zr alloys for nuclear applications.     

Prognostic Impact of Hemoglobin Level Prior to Radiotherapy on Survival in Patients with Glioblastoma

PURPOSE: To evaluate prognostic factors in patients with glioblastoma treated with postoperative or primary radiotherapy. PATIENTS AND METHODS: From 1989 to 2000, a total of 100 patients underwent irradiation as part of their initial treatment for glioblastoma. All patients had undergone surgery or biopsy followed by conventional external-beam radiotherapy. 85 patients who received the planned dose of irradiation (60 Gy in 30 fractions) were analyzed for the influence of prognostic factors. 73/85 (86%) of patients were given postoperative irradiation, while 12/85 (14%) of patients were primarily treated with radiotherapy after biopsy. RESULTS: The median overall survival was 10.1 months (range, 3.7-49.8 months), the 1- and 2-year survival rates were 41% and 5%, respectively. Univariate analysis revealed age < or = 55 years (p < 0.001), pre-radiotherapy hemoglobin (Hb) level > 12 g/dl (p = 0.009), and pre-radiotherapy dose of dexamethasone < or = 2 mg/day (p = 0.005) to be associated with prolonged survival. At multivariate analysis, younger age (p < 0.001), higher Hb level (p = 0.002), lower dose of dexamethasone (p = 0.026), and a hemispheric tumor location (p = 0.019) were identified as independent prognostic factors for longer survival. The median survival for patients with an Hb level > 12 g/dl was 12.1 months compared to 7.9 months for those with a lower Hb level. Contingency-table statistics showed no significant differences for the two Hb groups in the distribution of other prognostic factors. CONCLUSION: The results indicate that lower Hb level prior to radiotherapy for glioblastoma can adversely influence prognosis. This finding deserves further evaluation.     

Musculoskeletal disorders in nursing workers: evidences associated to work conditions

This paper presents a review of national scientific articles that researched about musculoskeletal disorders in nursing workers. It was analyzed the articles published in MEDLINE, LILACS, BDENF-BIREME data basis, during the period of 1996 to 2005. The following selection criteria were adopted: musculoskeletal outcomes, nursing workers' population and publications in national journals indexed in the BIREME system. Fifteen articles met all the selection criteria. In most of them, the inappropriate work conditions were identified as risk factors for the development of musculoskeletal disorders. In these articles, the authors debate the necessity, not only, of a more in-depth research method about musculoskeletal disorders related to the nursing job, but also, the necessity to rethink the work organization.     

Lack of association between ENAM gene polymorphism and dental caries in primary and permanent teeth in Czech children

Clinical Oral Investigations - The enamelin gene (ENAM) polymorphism (rs12640848) was recently associated with dental caries in primary teeth in Polish children. The aims of the present study were...