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PubMed | Dartmouth College, Childrens Hospital of UPMC and University of Pittsburgh
Type: | Journal: Journal of applied physiology (Bethesda, Md. : 1985) | Year: 2017

Breath is hypothesized to contain clinically relevant information, useful for the diagnosis and monitoring of disease, as well as understanding underlying pathogenesis. Non-human primates, such as the cynomolgus macaque, serve as an important model for the study of human disease, including over 70 different human infections. In this feasibility study, exhaled breath was successfully collected in less than five minutes under Biosafety Level 3 conditions from five anesthetized, intubated cynomolgus and rhesus macaques, before and after lung infection with M. tuberculosis. The breath was subsequently analyzed using comprehensive two-dimensional gas chromatography coupled to mass spectrometry . A total of 384 macaque breath features were detected, with hydrocarbons being the most abundant. We provide putative identification for 19 breath molecules and report on overlap between the identified macaque breath compounds and those identified in previous human studies.


Mu X.,Childrens Hospital of UPMC | Mu X.,University of Pittsburgh | Li Y.,Childrens Hospital of UPMC | Li Y.,University of Pittsburgh
Journal of Cellular and Molecular Medicine | Year: 2011

The limitation in successfully acquiring large populations of stem cell has impeded their application. A new method based on the dedifferentiation of adult somatic cells to generate induced multipotent stem cells would allow us to obtain a large amount of autologous stem cells for regenerative medicine. The current work was proposed to induce a sub-population of cells with characteristics of muscle stem cells from myoblasts through conditional treatment of transforming growth factor (TGF)-β1. Our results show that a lower concentration of TGF-β1 is able to promote C2C12 myoblasts to express stem cell markers as well as to repress myogenic proteins, which involves a mechanism of dedifferentiation. Moreover, TGF-β1 treatment promoted the proliferation-arrested C2C12 myoblasts to re-enter the S-phase. We also investigated the multi-differentiation potentials of the dedifferentiated cells. TGF-β1 pre-treated C2C12 myoblasts were implanted into mice to repair dystrophic skeletal muscle or injured bone. In addition to the C2C12 myoblasts, similar effects of TGF-β1 were also observed in the primary myoblasts of mice. Our results suggest that TGF-β1 is effective as a molecular trigger for the dedifferentiation of skeletal muscle myoblasts and could be used to generate a large pool of progenitor cells that collectively behave as multipotent stem cell-like cells for regenerative medicine applications. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.


Castro E.C.C.,Childrens Hospital of UPMC | Devine W.,Childrens Hospital of UPMC | Galambos C.,Childrens Hospital of UPMC
Pediatric and Developmental Pathology | Year: 2010

Anomalies of the cardinal vein system (CVS) are uncommon but if unidentified can lead to life-threatening complications. We report a case with a novel malformation of the CVS. Autopsy with in situ dissection of heart and large vessels in a 25-day-old infant was performed. The infant was diagnosed with congenital heart disease, and systemic venous malformations were suspected by imaging. Correlation between premortem imaging and postmortem anatomy was performed. The superior and inferior left venous systems developed abnormally. A persistent left superior vena cava (PLSVC) drained into the right atrium via the coronary sinus. A persistent left inferior vena cava (PLIVC) continued with the hemiazygos vein (HV), which drained into the PLSVC. The innominate vein was absent. The left renal vein was connected to the HV. Two common iliac veins were identified. The left drained into the PLIVC and the right into the right inferior vena cava (IVC). Perinatal echocardiography identified only the dilated HV draining to an LSVC and a small IVC. Congenital heart disease included hypoplastic left ventricle with hypoplastic aortic arch and subaortic stenosis, which were diagnosed by fetal ultrasound. Remodeling of components of CVS takes place during development, and unknown mechanisms guide this process. Defects of this process can lead to variable malformations, as demonstrated by this case. To our knowledge, the combination of complex malformations of both superior and IVC systems that extends to the common iliac veins has not been reported. We recommend identifying vascular anomalies in situ during autopsy before anatomic relationships are altered. © 2010 Society for Pediatric Pathology.


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.


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.


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.


Bellayr I.H.,Childrens Hospital of UPMC | Bellayr I.H.,University of Pittsburgh | Gharaibeh B.,University of Pittsburgh | Huard J.,University of Pittsburgh | And 2 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2010

The liver is unique for its ability to regenerate after injury, however, critical injuries or disease cause it to lose this quality. Stem cells have been explored as a possibility to restore the function of seriously damaged livers, based on their self-renewability and multiple differentiation capacity. These experiments examine the ability of muscle derived stem cells (MDSCs) to differentiate into hepatocyte-like cells in vitro and acquire functional liver attributes for repairing damaged livers. In vitro experiments were performed using MDSCs from postnatal mice and mouse hepatocyte cell lines. Our data revealed that MDSCs differentiated into hepatocyte-like cells and expressed liver cell markers, albumin, hepatocyte nuclear factor 4α, and alpha feto-protein, both at the RNA and protein level. Additionally, in vivo studies showed successful engraftment of MDSCs into hepatectomized mouse livers of mice. These results provide evidence suggesting that MDSCs have the capacity to differentiate into liver cell-like cells and may serve as potential candidates to aid in liver regeneration.


Mu X.,Childrens Hospital of UPMC | Mu X.,University of Pittsburgh | Peng H.,University of Pittsburgh | Pan H.,Childrens Hospital of UPMC | And 4 more authors.
PLoS ONE | Year: 2011

Background: Dedifferentiation of muscle cells in the tissue of mammals has yet to be observed. One of the challenges facing the study of skeletal muscle cell dedifferentiation is the availability of a reliable model that can confidentially distinguish differentiated cell populations of myotubes and non-fused mononuclear cells, including stem cells that can coexist within the population of cells being studied. Methodology/Principal Findings: In the current study, we created a Cre/Lox-β-galactosidase system, which can specifically tag differentiated multinuclear myotubes and myotube-generated mononuclear cells based on the activation of the marker gene, β-galactosidase. By using this system in an adult mouse model, we found that β-galactosidase positive mononuclear cells were generated from β-galactosidase positive multinuclear myofibers upon muscle injury. We also demonstrated that these mononuclear cells can develop into a variety of different muscle cell lineages, i.e., myoblasts, satellite cells, and muscle derived stem cells. Conclusions/Significance: These novel findings demonstrated, for the first time, that cellular dedifferentiation of skeletal muscle cells actually occurs in mammalian skeletal muscle following traumatic injury in vivo. © 2011 Mu et al.


PubMed | Hospital Sirio Libanes, Federal University of Rio Grande do Sul, Franklin And Marshall College, Clinic for Special Children and 3 more.
Type: Journal Article | Journal: Molecular genetics and metabolism | Year: 2016

Maple syrup urine disease (MSUD) is an inherited disorder of branched chain ketoacid (BCKA) oxidation associated with episodic and chronic brain disease. Transplantation of liver from an unrelated deceased donor restores 9-13% whole-body BCKA oxidation capacity and stabilizes MSUD. Recent reports document encouraging short-term outcomes for MSUD patients who received a liver segment from mutation heterozygous living related donors (LRDT). To investigate effects of living related versus deceased unrelated grafts, we studied four Brazilian MSUD patients treated with LRDT who were followed for a mean 19 12 postoperative months, and compared metabolic and clinical outcomes to 37 classical MSUD patients treated with deceased donor transplant. Patient and graft survival for LRDT were 100%. Three of 4 MSUD livers were successfully domino transplanted into non-MSUD subjects. Following LRDT, all subjects resumed a protein-unrestricted diet as mean plasma leucine decreased from 224 306 M to 143 44 M and allo-isoleucine decreased 91%. We observed no episodes of hyperleucinemia during 80 aggregate postoperative patient-months. Mean plasma leucine:isoleucine:valine concentration ratios were ~2:1:4 after deceased donor transplant compared to ~1:1:1.5 following LRDT, resulting in differences of predicted cerebral amino acid uptake. Mutant heterozygous liver segments effectively maintain steady-state BCAA and BCKA homeostasis on an unrestricted diet and during most catabolic states, but might have different metabolic effects than grafts from unrelated deceased donors. Neither living related nor deceased donor transplant affords complete protection from metabolic intoxication, but both strategies represent viable alternatives to nutritional management.


PubMed | University of Maryland Baltimore County, University of Toledo, University of California at Los Angeles, Childrens Hospital of UPMC and 4 more.
Type: Journal Article | Journal: Cell host & microbe | Year: 2016

Signaling through the IL-17 receptor (IL-17R) is required to prevent oropharyngeal candidiasis (OPC) in mice and humans. However, the IL-17-responsive cell type(s) that mediate protection are unknown. Using radiation chimeras, we were able to rule out a requirement for IL-17RA in the hematopoietic compartment. We saw remarkable concordance of IL-17-controlled gene expression in C.albicans-infected human oral epithelial cells (OECs) and in tongue tissue from mice with OPC. To interrogate the role of the IL-17R in OECs, wegenerated mice with conditional deletion of IL-17RA in superficial oral and esophageal epithelial cells (Il17ra

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