Clinical and Translational Research Center

Buffalo, NY, United States

Clinical and Translational Research Center

Buffalo, NY, United States
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Murphy T.F.,Clinical and Translational Research Center | Brauer A.L.,Clinical and Translational Research Center | Kirkham C.,Clinical and Translational Research Center | Johnson A.,Clinical and Translational Research Center | And 2 more authors.
Infection and Immunity | Year: 2013

Moraxella catarrhalis is a human respiratory tract pathogen that causes otitis media in children and lower respiratory tract infections in adults with chronic obstructive pulmonary disease. We have identified and characterized a zinc uptake ABC transporter that is present in all strains of M. catarrhalis tested. A mutant in which the znu gene cluster is knocked out shows markedly impaired growth compared to the wild type in medium that contains trace zinc; growth is restored to wild-type levels by supplementing medium with zinc but not with other divalent cations. Thermal-shift assays showed that the purified recombinant substrate binding protein ZnuA binds zinc but does not bind other divalent cations. Invasion assays with human respiratory epithelial cells demonstrated that the zinc ABC transporter of M. catarrhalis is critical for invasion of respiratory epithelial cells, an observation that is especially relevant because an intracellular reservoir of M. catarrhalis is present in the human respiratory tract and this reservoir is important for persistence. The znu knockout mutant showed marked impairment in its capacity to persist in the respiratory tract compared to the wild type in a mouse pulmonary clearance model. We conclude that the zinc uptake ABC transporter mediates uptake of zinc in environments with very low zinc concentrations and is critical for full virulence of M. catarrhalis in the respiratory tract in facilitating intracellular invasion of epithelial cells and persistence in the respiratory tract. © 2013, American Society for Microbiology.


Garces S.,Instituto Gulbenkian Of Ciencia | Garces S.,Hospital Garcia Of Orta | Antunes M.,University of Lisbon | Benito-Garcia E.,Clinical and Translational Research Center | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Introduction Clinical remission is today the treatment goal for rheumatoid arthritis (RA), which requires fast and assertive therapeutic decisions for a tight control of disease activity. Few objective parameters are available to guide clinical decisions, particularly in switcher patients. We designed a preliminary algorithm introducing immunogenicity assessment in the current approach to patients with RA receiving tumour necrosis factor inhibitors (TNFi). Objective To evaluate the concordance between the new algorithm and current clinical practice, comparing the effectiveness of 'immunogenicity-based' versus 'empirical-based' switches in a cohort of patients with established RA receiving biologics. Methods: EULAR therapeutic response was evaluated in 105 patients with RA (naive or switchers) over one year, through generalised estimation equation (GEE) analyses. Serum drug trough levels were assessed by ELISA and antidrug antibodies (ADAb) by Bridging ELISA. Results: During follow-up, 48.6% of patients had therapeutic decisions concordant with the proposed algorithm (Group A), and 51.4% had discordant decisions (Group B). One year after the therapeutic decision, patients from Group A had a higher probability of achieving response (OR=7.91, p<0.001, 95% CI 3.27 to 19.13) and low disease activity (OR=9.77, p<0.001, 95% CI 4.69 to 20.37) than patients in Group B. Conclusions: Immunogenicity assessment might help to optimise therapeutic decisions, leading to a better control of disease activity with significantly better clinical outcomes in patients with RA receiving TNFi.


Adams J.S.,Orthopaedic Hospital Research Center | Rafison B.,Orthopaedic Hospital Research Center | Witzel S.,Clinical and Translational Research Center | Chun R.,Orthopaedic Hospital Research Center | And 3 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2014

Provided here is a collective review of research on the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinology and paracrinology, as opposed to the traditional endocrinology, of vitamin D to regulate the innate and adaptive immune responses, particularly in human granuloma-forming diseases like tuberculosis. Special emphasis is placed on soluble factors (i.e., cytokines) in the local microenvironment of these human diseases that coordinate amplification and feedback inhibition of the macrophage CYP27B1-hydroxylase. Principal among these factors are Type I and Type II interferons (IFNs); the Type II IFN, IFN-γ, stimulates the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D (25OHD) by the granuloma-forming disease-activated macrophage, while the Type I IFNs, IFN-α and IFN-β, block the hydroxylation reaction. The Type I IFN response is associated with more aggressive disease, while the Type II IFN response, the one that promotes 1,25(OH)2D production by the macrophage, is associated with more confined disease. Tilting the balance in the human immune response toward a confined disease phenotype is enabled by the presence of sufficient extracellular 25OHD to modulate IFN-γ-promoted and substrate 25OH-driven intracellular synthesis of 1,25(OH)2D. This article is part of a Special Issue entitled 'Vitamin D Workshop'. © 2014 Elsevier Ltd.


PubMed | Clinical and Translational Research Center
Type: | Journal: The Journal of steroid biochemistry and molecular biology | Year: 2014

Provided here is a collective review of research on the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinology and paracrinology, as opposed to the traditional endocrinology, of vitamin D to regulate the innate and adaptive immune responses, particularly in human granuloma-forming diseases like tuberculosis. Special emphasis is placed on soluble factors (i.e., cytokines) in the local microenvironment of these human diseases that coordinate amplification and feedback inhibition of the macrophage CYP27B1-hydroxylase. Principal among these factors are Type I and Type II interferons (IFNs); the Type II IFN, IFN-, stimulates the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D (25OHD) by the granuloma-forming disease-activated macrophage, while the Type I IFNs, IFN- and IFN-, block the hydroxylation reaction. The Type I IFN response is associated with more aggressive disease, while the Type II IFN response, the one that promotes 1,25(OH)2D production by the macrophage, is associated with more confined disease. Tilting the balance in the human immune response toward a confined disease phenotype is enabled by the presence of sufficient extracellular 25OHD to modulate IFN--promoted and substrate 25OH-driven intracellular synthesis of 1,25(OH)2D. This article is part of a Special Issue entitled Vitamin D Workshop.


Grimberg A.,Children's Hospital of Philadelphia | Grimberg A.,University of Pennsylvania | Cousounis P.,Children's Hospital of Philadelphia | Cucchiara A.J.,Clinical and Translational Research Center | And 4 more authors.
Hormone Research in Paediatrics | Year: 2015

To examine parental concerns about child growth and factors that drive parents' decisions whether to intervene medically with their child's height. Methods: Parents of 9-to 14-year-old pediatric primary care patients of various heights, oversampled for those with short stature, participated in exploratory focus groups and nominal group technique sessions. Growth concerns expressed by the groups were incorporated into a survey, completed by 1,820 parents, and rated for their degree of impact on medical decision-making. Ordinal logistic regression modeled concern scores against parent traits. Explanatory focus groups clarified the survey results. Results: Research team consensus and factor analysis organized the 22 distinct concerns expressed by the parent groups into 7 categories. Categories rated as having the greatest influence on parental decisionmaking involved: treatment efficacy and side effects, child health and psychosocial function. Level of concern was highly associated with parental education and parenting style. Conclusion: Psychosocial issues are influential, but parental decision-making is most impacted by concerns about treatment and child health. By discussing the real risks and benefits of hormone treatment and addressing parents' perceptions of what is needed for physical and psychosocial health, clinicians can be highly effective educators to assure that treatment is used only as medically indicated. © 2015 S. Karger AG, Basel.


Maloney A.E.,University of Massachusetts Medical School | Stempel A.,Clinical and Translational Research Center | Wood M.E.,University of Massachusetts Medical School | Patraitis C.,Clinical and Translational Research Center | Beaudoin C.,Grand Valley State University
Games for Health Journal | Year: 2012

Background: Children need opportunities to have physical activity (PA). Using exergames could be a feasible and acceptable way to boost PA in middle schools. Our goal was to increase PA by 40 minutes per week and to determine how much time, if any, was spent in moderate-to-vigorous PA (MVPA). Subjects and Methods: Eighty-four middle school youth were in a pilot study for 20 weeks: half in the Generation Fit (GenFit) intervention group and half in the control group. The GenFit group played the exergame for the first 10 weeks (Session 1), and the control group joined from 10 to 20 weeks (Session 2). The main outcome was exergaming time per student per week. Results: Fifty-eight students completed the pilot after 26 youth at School C were excluded for administrative reasons. Of those remaining, 40 students at School A and 18 students at School B, the average age of the sample was 13.7 years (SD=0.6), and average body mass index percentile was close to 70. During Session 1, the average dance time per child was 49 minutes per week, versus 54 minutes per week in Session 2. Mean body mass index percentile decreased by 5.6 for children who participated in GenFit, compared with 0.2 for children in the control group. At end point, accelerometers showed over half of the dance time was spent in MVPA. Qualitative data showed that most children found the exergame acceptable. Conclusions: A dance exergame in middle schools offered opportunities for PA. About half of the exergame time was spent in MVPA. Exergames may be feasible and acceptable in middle schools to boost PA, and access could provide a way for schools to support the health of students. © Copyright 2012, Mary Ann Liebert, Inc.


Tremblay M.,University of Montréal | Tremblay M.,Clinical and Translational Research Center | Brisson D.,University of Montréal | Brisson D.,Clinical and Translational Research Center | And 2 more authors.
Hypertension Research | Year: 2016

Despite the numerous common pathways connecting blood pressure regulation to somatostatin (SST) metabolism, the SST gene has never been seen as a significant blood pressure modulator. The aim of this study was to evaluate the association between a poly-T repeat sequence (rs34872250) in the promoter of the SST gene and blood pressure, according to the obesity status. We genotyped 1918 French-Canadian subjects from a founder population. Analyses were performed according to the length of the poly-T repeat sequence on both alleles and divided into two groups, the 13/13-13/14 group and the 13/15-13/16 group. The effect of age, gender, body mass index, antihypertensive drugs and diabetic status were considered. Systolic, diastolic and mean blood pressures are significantly higher among the 13/15-13/16 group in the whole sample (P<0.05). Whereas the differences remain significant in women, they turn to be non-significant when men are considered alone. The risk of hypertension is increased in the 13/15-13/16 group, particularly among overweight/obese subjects. Systolic blood pressure is significantly higher among overweight/obese carriers of the 13/15-13/16 alleles in the whole sample (P<0.001), in men (P=0.006) and in women (P=0.002), even after correction for age and antihypertensive drugs. These results suggest that the poly-T repeat sequence polymorphism in the promoter of the SST gene is associated with significant variations of blood pressure and could modulate the risk of hypertension, particularly among women. © 2016 The Japanese Society of Hypertension All rights reserved.

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