Experimental arthritis is dependent on mouse mast cell protease-5

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. The constitutive heparin+ (HP) mast cells (MCs) in mice express mouseMCprotease (mMCP)-5 and carboxypeptidaseA (mMC-CPA). The amino acid sequence ofmMCP-5is most similar to that of human chymase-1, as are the nucleotide sequences of their genes and transcripts. Using a homologous recombination approach, a C57BL/6 mouse line was created that possessed a disrupted mMCP-5 gene. The resulting mice were fertile and had no obvious developmental abnormality. Lack of mMCP-5 protein did not alter the granulation of the IL-3/IL-9-dependent mMCP-2+ MCs in the jejunal mucosa of Trichinella spiralisinfected mice. In contrast, the constitutive HP+ MCs in the tongues of mMCP-5-null mice were poorly granulated and lacked mMC-CPA protein. Bone marrow-derived MCs were readily developed from the transgenic mice using IL-3. Although these MCs contained high levels of mMC-CPA mRNA, they also lacked the latter exopeptidase. mMCP-5 protein is therefore needed to target translated mMC-CPA to the secretory granule along with HP-containing serglycin proteoglycans. Alternately, mMCP-5 is needed to protect mMC-CPA from autolysis in the cell's granules. Fibronectin was identified as a target of mMCP-5, and the exocytosis ofmMCP-5from theMCs in the mouse's peritoneal cavity resulted in the expression of metalloproteinase protease-9, which has been implicated in arthritis. In support of the latter finding, experimental arthritis was markedly reduced in mMCP-5-null mice relative to wildtype mice in two disease models

Pharmacists’ immunization experiences, beliefs, and attitudes in New Brunswick, Canada

Background: The expansion of pharmacist scope of practice to include provision of immunizations has occurred or is being considered in various countries. There are limited data evaluating the experiences of Canadian pharmacists in their role as immunizers. Objective: To describe the experiences of pharmacists in the Canadian province of New Brunswick as immunizers, including vaccines administered and perceived barriers and facilitators to providing immunizations. Methods: An anonymous, self-administered, web-based questionnaire was offered via email by the New Brunswick Pharmacists’ Association to all its members. The survey tool was adapted, with permission, from a tool previously used by the American Pharmacists Association and validated using content validity and test-retest reproducibility. Pharmacist reported immunization activities and perceived facilitators and barriers to providing immunization services were assessed. Results: Responses from 168 (response rate of 26%) were evaluable. Approximately 90% of respondents worked in community practice full time, 65% were female and 44% were practicing for 20 or more years. Greater than 75% reported administering: hepatitis A and B, influenza, and zoster vaccines. The majority of respondents felt fully accepted (agreed or strongly agreed) as immunization providers by patients, local physicians, and the provincial health department (97%, 70%, and 78%, respectively). Most commonly reported barriers were: lack of a universally funded influenza immunization program, insufficient staffing and space, and concerns around reimbursement for services. Conclusions: Pharmacists in New Brunswick, Canada are actively participating in the provision of a variety of immunizations and felt fully supported by patients and other healthcare providers. Barriers identified may provide insight to other jurisdictions considering expanding the role of pharmacists as immunizers

Impact of race pace on development of hyponatraemia in full- and half-marathoners

Objective. Prior studies of full-marathon participants have demonstrated a higher incidence of hyponatraemia in runners with completion times of 4 hours or more. Our primary aim was to determine if slower pace is associated with increased prevalence of hyponatraemia. Secondly, we evaluated the prevalence of hyponatraemia in full-marathoners v. halfmarathoners.Methods. This observational, cross-sectional study comprised consenting runners in the 26.2 With Donna, The National Marathon to Finish Breast Cancer, in Jacksonville Beach, Florida, February 2008. On race day, participants completed a questionnaire, provided finger-stick blood samples, and were weighed both pre- and post-race.Results. A significant negative association was found between pace and post-race sodium level (p<0.001). A negative correlation was found between finishing time and post-race sodium level (p<0.001). The prevalence of post-race hyponatraemia was 4% (4/106) among half-marathoners and 13% (12/89) among full-marathoners (P=0.02). An inverse correlation was found between sodium change and weight change, significant in fullmarathoners (r=-0.55, p<0.001) but not half-marathoners (r=- 0.23, p=0.042).Conclusions. Slower race pace and longer finishing times were associated with lower post-race sodium levels. Full-marathoners had a significantly higher prevalence of hyponatraemia. The development of hyponatraemia was associated with weight gain. Our data indicate that the relationship between post-race sodium concentration and pace differs according to the distance of the event. We can extrapolate from this data that longer racedistance with increased availability of fluid stations combined with a slower pace may increase the risk of developing exerciseinduced hyponatraemia

Investigation of attentional bias in obsessive compulsive disorder with and without depression in visual search

Copyright: © 2013 Morein-Zamir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedWhether Obsessive Compulsive Disorder (OCD) is associated with an increased attentional bias to emotive stimuli remains controversial. Additionally, it is unclear whether comorbid depression modulates abnormal emotional processing in OCD. This study examined attentional bias to OC-relevant scenes using a visual search task. Controls, non-depressed and depressed OCD patients searched for their personally selected positive images amongst their negative distractors, and vice versa. Whilst the OCD groups were slower than healthy individuals in rating the images, there were no group differences in the magnitude of negative bias to concern-related scenes. A second experiment employing a common set of images replicated the results on an additional sample of OCD patients. Although there was a larger bias to negative OC-related images without pre-exposure overall, no group differences in attentional bias were observed. However, OCD patients subsequently rated the images more slowly and more negatively, again suggesting post-attentional processing abnormalities. The results argue against a robust attentional bias in OCD patients, regardless of their depression status and speak to generalized difficulties disengaging from negative valence stimuli. Rather, post-attentional processing abnormalities may account for differences in emotional processing in OCD.Peer reviewedFinal Published versio

The Role of Cytokines which Signal through the Common γ Chain Cytokine Receptor in the Reversal of HIV Specific CD4(+) and CD8(+) T Cell Anergy

BACKGROUND: HIV specific T cells are putatively anergic in vivo. IL-2, a member of a class of cytokines that binds to receptors containing the common gamma chain (γc) has been shown to reverse anergy. We examined the role of γc cytokines in reversing HIV specific T cell anergy. METHODS: PBMC from untreated HIV-infected individuals were briefly exposed to a panel of γc cytokines, and frequencies of gag specific T cells were enumerated by intracellular IFN-γ flow cytometry. RESULTS: Of the γc cytokines, brief exposure to IL-2, IL-15, or combined IL-15/IL-7 significantly enhanced (range 2–7 fold) the CD4(+) and CD8(+) T cell IFN-γ responses to HIV gag, with IL-15 giving the greatest enhancement. The effects of cytokines were not due to enhanced proliferation of pre-existing antigen specific cells, but were due to a combination of enhanced cytokine production from antigen specific T cells plus activation of non-epitope specific T cells. CONCLUSIONS: These observations support the notion that a significant number of HIV specific T cells are circulating in an anergic state. IL-2, IL-7 and particularly IL-15 as an immune modulator to reverse HIV-1 specific T cell anergy should be investigated, with the caveat that non-specific activation of T cells may also be induced

Characterization of a Large Group of Individuals with Huntington Disease and Their Relatives Enrolled in the COHORT Study

Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition.We conducted a cohort study in the United States, Canada, and Australia of members of families affected by HD. We collected demographic and clinical data, conducted the Unified Huntington's Disease Rating Scale and Mini-Mental State Examination, and determined Huntingtin trinucleotide CAG repeat length. We report primarily on cross-sectional baseline data from this recently completed prospective, longitudinal, observational study.As of December 31, 2009, 2,318 individuals enrolled; of these, 1,985 (85.6%) were classified into six analysis groups. Three groups had expanded CAG alleles (36 repeats or more): individuals with clinically diagnosed HD [n = 930], and clinically unaffected first-degree relatives who had previously pursued [n = 248] or not pursued [n = 112] predictive DNA testing. Three groups lacked expanded alleles: first-degree relatives who had previously pursued [n = 41] or not pursued [n = 224] genetic testing, and spouses and caregivers [n = 430]. Baseline mean performance differed across groups in all motor, behavioral, cognitive, and functional measures (p<0.001). Clinically unaffected individuals with expanded alleles weighed less (76.0 vs. 79.6 kg; p = 0.01) and had lower cognitive scores (28.5 vs. 29.1 on the Mini Mental State Examination; p = 0.008) than individuals without expanded alleles. The frequency of "high normal" repeat lengths (27 to 35) was 2.5% and repeat lengths associated with reduced penetrance (36 to 39) was 2.7%.Baseline analysis of COHORT study participants revealed differences that emerge prior to clinical diagnosis. Longitudinal investigation of this cohort will further characterize the natural history of HD and genetic and biological modifiers.Clinicaltrials.gov NCT00313495

Differences between Belgian and Brazilian Group A Streptococcus Epidemiologic Landscape

BACKGROUND: Group A Streptococcus (GAS) clinical and molecular epidemiology varies with location and time. These differences are not or are poorly understood. METHODS AND FINDINGS: We prospectively studied the epidemiology of GAS infections among children in outpatient hospital clinics in Brussels (Belgium) and Brasília (Brazil). Clinical questionnaires were filled out and microbiological sampling was performed. GAS isolates were emm-typed according to the Center for Disease Control protocol. emm pattern was predicted for each isolate. 334 GAS isolates were recovered from 706 children. Skin infections were frequent in Brasília (48% of the GAS infections), whereas pharyngitis were predominant (88%) in Brussels. The mean age of children with GAS pharyngitis in Brussels was lower than in Brasília (65/92 months, p<0.001). emm-typing revealed striking differences between Brazilian and Belgian GAS isolates. While 20 distinct emm-types were identified among 200 Belgian isolates, 48 were found among 128 Brazilian isolates. Belgian isolates belong mainly to emm pattern A–C (55%) and E (42.5%) while emm pattern E (51.5%) and D (36%) were predominant in Brasília. In Brasília, emm pattern D isolates were recovered from 18.5% of the pharyngitis, although this emm pattern is supposed to have a skin tropism. By contrast, A–C pattern isolates were unfrequently recovered in a region where rheumatic fever is still highly prevalent. CONCLUSIONS: Epidemiologic features of GAS from a pediatric population were very different in an industrialised country and a low incomes region, not only in term of clinical presentation, but also in terms of genetic diversity and distribution of emm patterns. These differences should be taken into account for designing treatment guidelines and vaccine strategies

Export of a Toxoplasma gondii Rhoptry Neck Protein Complex at the Host Cell Membrane to Form the Moving Junction during Invasion

One of the most conserved features of the invasion process in Apicomplexa parasites is the formation of a moving junction (MJ) between the apex of the parasite and the host cell membrane that moves along the parasite and serves as support to propel it inside the host cell. The MJ was, up to a recent period, completely unknown at the molecular level. Recently, proteins originated from two distinct post-Golgi specialised secretory organelles, the micronemes (for AMA1) and the neck of the rhoptries (for RON2/RON4/RON5 proteins), have been shown to form a complex. AMA1 and RON4 in particular, have been localised to the MJ during invasion. Using biochemical approaches, we have identified RON8 as an additional member of the complex. We also demonstrated that all RON proteins are present at the MJ during invasion. Using metabolic labelling and immunoprecipitation, we showed that RON2 and AMA1 were able to interact in the absence of the other members. We also discovered that all MJ proteins are subjected to proteolytic maturation during trafficking to their respective organelles and that they could associate as non-mature forms in vitro. Finally, whereas AMA1 has previously been shown to be inserted into the parasite membrane upon secretion, we demonstrated, using differential permeabilization and loading of RON-specific antibodies into the host cell, that the RON complex is targeted to the host cell membrane, where RON4/5/8 remain associated with the cytoplasmic face. Globally, these results point toward a model of MJ organization where the parasite would be secreting and inserting interacting components on either side of the MJ, both at the host and at its own plasma membranes

THE VAXED PROJECT: An Assessment of Immunization Education in Canadian Health Professional Programs

<p>Abstract</p> <p>Background</p> <p>Knowledge & attitudes of healthcare providers (HCP) have significant impact on frequency with which vaccines are offered & accepted but many HCP are ill equipped to make informed recommendations about vaccine merits & risks. We performed an assessment of the educational needs of trainees regarding immunization and used the information thus ascertained to develop multi-faceted, evaluable, educational tools which can be integrated into formal education curricula.</p> <p>Methods</p> <p>(i) A questionnaire was sent to all Canadian nursing, medical & pharmacy schools to assess immunization-related curriculum content (ii) A 77-item web-based, validated questionnaire was emailed to final-year students in medicine, nursing, & pharmacy at two universities in Nova Scotia, Canada to assess knowledge, attitudes, & behaviors reflecting current immunization curriculum.</p> <p>Results</p> <p>The curriculum review yielded responses from 18%, 48%, & 56% of medical, nursing, & pharmacy schools, respectively. Time spent on immunization content varied substantially between & within disciplines from <1 to >50 hrs. Most schools reported some content regarding vaccine preventable diseases, immunization practice & clinical skills but there was considerable variability and fewer schools had learning objectives or formal evaluation in these areas. 74% of respondents didn't feel comfortable discussing vaccine side effects with parents/patients & only 21% felt they received adequate teaching regarding immunization during training.</p> <p>Conclusions</p> <p>Important gaps were identified in the knowledge of graduating nursing, medical, & pharmacy trainees regarding vaccine indications/contraindications, adverse events & safety. The national curriculum review revealed wide variability in immunization curriculum content & evaluation. There is clearly a need for educators to assess current curricula and adapt existing educational resources such as the Immunization Competencies for Health Professionals in Canada.</p

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined