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Cowper-Smith C.D.,Dalhousie University | Dingle R.N.,Dalhousie University | Guo Y.,Childrens Hospital of UPMC | Burkard R.,State University of New York at Buffalo | Phillips D.P.,Dalhousie University
Journal of the Acoustical Society of America | Year: 2010

Two hallmark features of auditory neuropathy (AN) are normal outer hair cell function in the presence of an absent/abnormal auditory brainstem response (ABR). Studies of human AN patients are unable to determine whether disruption of the ABR is the result of a reduction of neural input, a loss of auditory nerve fiber (ANF) synchrony, or both. Neurophysiological data from the carboplatin model of AN reveal intact neural synchrony in the auditory nerve and inferior colliculus, despite significant reductions in neural input. These data suggest that (1), intact neural synchrony is available to support an ABR following carboplatin treatment and, (2), impaired spike timing intrinsic to neurons is required for the disruption of the ABR observed in human AN. © 2010 Acoustical Society of America. Source

Huppler A.R.,Childrens Hospital of UPMC | Bishu S.,University of Pittsburgh | Gaffen S.L.,University of Pittsburgh
Arthritis Research and Therapy | Year: 2012

IL-17 and related cytokines are direct and indirect targets of selective immunosuppressive agents for the treatment of autoimmune diseases and other diseases of pathologic inflammation. Insights into the potential adverse effects of IL-17 blockade can be drawn from the experience of patients with deficiencies in the IL-17 pathway. A unifying theme of susceptibility to mucocutaneous candidiasis is seen in both mice and humans with a variety of genetic defects that converge on this pathway. Mucocutaneous candidiasis is a superficial infection of mucosal, nail or skin surfaces usually caused by the fungal pathogen Candida albicans. The morbidity of the disease includes significant pain, weight loss and secondary complications, including carcinoma and aneurysms. This review describes the known human diseases associated with chronic mucocutaneous candidiasis (CMC) as well as the known and proposed connections to IL-17 signaling. The human diseases include defects in IL-17 signaling due to autoantibodies (AIRE deficiency), receptor mutations (IL-17 receptor mutations) or mutations in the cytokine genes (IL17F and IL17A). Hyper-IgE syndrome is characterized by elevated serum IgE, dermatitis and recurrent infections, including CMC due to impaired generation of IL-17-producing Th17 cells. Mutations in STAT1, IL12B and IL12RB1 result in CMC secondary to decreased IL-17 production through different mechanisms. Dectin-1 defects and CARD9 defects result in susceptibility to C. albicans because of impaired host recognition of the pathogen and subsequent impaired generation of IL-17-producing T cells. Thus, recent discoveries of genetic predisposition to CMC have driven the recognition of the role of IL-17 in protection from mucosal fungal infection and should guide counseling and management of patients treated with pharmacologic IL-17 blockade. © 2012 BioMed Central Ltd. Source

Wolfe L.A.,Childrens Hospital of UPMC | Wolfe L.A.,National Human Genome Research Institute | He M.,Emory University | Vockley J.,Childrens Hospital of UPMC | And 9 more authors.
Journal of Inherited Metabolic Disease | Year: 2010

We describe a 22-year-old male who developed severe hypoglycemia and lethargy during an acute illness at 4 months of age and subsequently grew and developed normally. At age 4 years he developed recurrent vomiting with mild hyperammonemia and dehydration requiring frequent hospitalizations. Glutaric aciduria Type II was suspected based upon biochemical findings and managed with cornstarch, carnitine and riboflavin supplements. He did not experience metabolic crises between ages 4-12 years. He experienced recurrent vomiting, mild hyperammonemia, and generalized weakness associated with acute illnesses and growth spurts. At age 18 years, he developed exercise intolerance and proximal muscle weakness leading to the identification of multiple acyl-CoAdehydrogenase and complex II/III deficiencies in both skeletal muscle and liver. Subsequent molecular characterization of the ETFDH gene revealed novel heterozygous mutations, p.G274X:c.820 G>T (exon 7) and p.P534L: c.1601 C>T (exon 12), the latter within the iron sulfurcluster and predicted to affect ubiquinone reductase activity of ETFDH and the docking of ETF to ETFDH. Our case supports the concept of a structural interaction between ETFDH and other enzyme partners, and suggests that the conformational change upon ETF binding to ETFDH may play a key role in linking ETFDH to II/III super-complex formation. © SSIEM and Springer 2010. Source

Zaoutis T.E.,Childrens Hospital of Philadelphia | Webber S.,Childrens Hospital of UPMC | Naftel D.C.,University of Alabama at Birmingham | Chrisant M.A.,Childrens Hospital of UPMC | And 4 more authors.
Pediatric Transplantation | Year: 2011

There are limited data on the incidence or risk factors for IFI in pediatric heart transplant recipients. The purpose of this study was to describe the incidence and types of IFI, to determine risk factors for outcomes of IFI, and to assist in decision-making concerning the need for prophylactic strategies in pediatric heart transplant recipients. Data from a multi-institutional registry of 1854 patients transplanted between 01/93 and 12/04 were analyzed to determine risk factors and outcomes of children with IFI post-heart transplantation. One hundred and thirty-nine episodes of IFI occurred in 123 patients and made up 6.8% of the total number of post-transplant infections. IFI was most commonly attributed to yeast (66.2%), followed by mold (15.8%) and Pneumocystis jiroveci (13%). Ninety percent of the yeast infections were caused by Candida spp., and Aspergillus spp. was causative in 82% of the mold infections. There was a significantly increased risk of fungal infection associated with pretransplant invasive procedures (e.g., ECMO, prior surgery, VAD, mechanical ventilation) with an incremental risk with increasing numbers of invasive procedures (early phase 0 vs. 1, RR 1.3; 0 vs. 3, RR 2.3; p < 0.001). In multivariate analysis, previous surgery (p = 0.05) and mechanical support at transplantation (p = 0.01) remained significant. Forty-nine percent of recipients with IFI died, all within six months post-transplant. Invasive fungal infections are uncommon in pediatric heart transplant recipients. Risk and mortality are highest in the first six months post-transplant especially in patients with previous surgery and those requiring mechanical support. Prophylactic strategies for high-risk patients should be considered and warrants further study. © 2010 John Wiley & Sons A/S. Source

Srinath A.,Childrens Hospital of UPMC | Young E.,University of Pittsburgh | Szigethy E.,University of Pittsburgh
Inflammatory Bowel Diseases | Year: 2014

Abdominal pain is a common symptom in patients with inflammatory bowel disease (IBD) that negatively affects quality of life and can lead to increased health-seeking behavior. Although abdominal pain has been traditionally attributed to inflammation, there is growing literature demonstrating the existence of functional abdominal pain in patients with IBD, of which there are a variety of potential causes. Thus, when approaching a patient with IBD who has abdominal pain, in addition to IBD-related complications (e.g., inflammation/stricture), it is important to screen for related contributors, including peripheral factors (visceral hypersensitivity, bacterial overgrowth, and bowel dysmotility) and centrally mediated neurobiological and psychosocial underpinnings. These central factors include psychological symptoms/diagnoses, sleep disturbance, and stress. Opioid-induced hyperalgesia (e.g., narcotic bowel syndrome) is also growing in recognition as a potential central source of abdominal pain. This review draws from clinical studies and animal models of colitis and abdominal pain to consider how knowledge of these potential etiologies can be used to individualize treatment of abdominal pain in patients with IBD, including consideration of potential novel treatment modalities for the future. Accurate assessment of the source(s) of pain in patients with IBD can help guide appropriate diagnostic workup and use of disease-modifying therapy. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc. Source

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