Publications by authors named "Paul Stromberg"

43 Publications

Histopathological comparisons of Staphylococcus aureus and Pseudomonas aeruginosa experimental infected porcine burn wounds.

Wound Repair Regen 2017 05 18;25(3):541-549. Epub 2017 May 18.

Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio.

Chronic skin wounds are a significant human health concern and are often complicated by infection with Pseudomonas aeruginosa and Staphylococcus aureus, particularly methicillin resistant S. aureus (MRSA). Translating the knowledge gained from extensive study of virulence mechanisms and pathogenesis of these bacterial species to new treatment modalities has been lacking in part due to a paucity of animal models able to recapitulate human disease. Our groups recently described a novel porcine chronic burn wound model for the study of bacterial infection; however, the histopathology of infection has yet to be described. The objective of this study is to define the histopathology of this model using important human chronic wound bacterial isolates. Porcine full-thickness burn wounds topically inoculated with P. aeruginosa strain PAO1, MRSA S. aureus strain USA300 or both bacteria were used to define and quantify histopathologic lesions. The development of a systemic, well-defined rubric for analysis allowed for evaluation of differences between infection groups. These differences, which included epithelial migration and proliferation, stromal necrosis, fluid accumulation and intensity and character of the innate and adaptive inflammatory cell responses, were identified temporally between infection groups. Mono-species infected wounds developed a hyper-proliferative wound edge. Coinfected wounds at day 35 had the largest wound sizes, increased amounts of neutrophilic inflammation, immaturity of the wound bed, and retention of necrotic tissue. Infection, regardless of species, inhibited wound contracture at all time points evaluated. Most importantly, this model recapitulated key features of chronic human wounds. Thus, this model will allow researchers to study novel treatment modalities in a biologically relevant animal model while monitoring both host and bacterial responses.
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http://dx.doi.org/10.1111/wrr.12527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245553PMC
May 2017

Variability of limb measurements performed by emergency medicine nurses in a simulated Crotalinae envenomation.

Am J Emerg Med 2016 Aug 4;34(8):1683-5. Epub 2016 May 4.

Department of Emergency Medicine, VCU Medical Center, Richmond, VA.

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http://dx.doi.org/10.1016/j.ajem.2016.04.051DOI Listing
August 2016

Airway compromise in children exposed to single-use laundry detergent pods: a poison center observational case series.

Am J Emerg Med 2015 Mar 3;33(3):349-51. Epub 2014 Dec 3.

Division of Clinical Toxicology, Department of Emergency Medicine, VCU Medical Center, Richmond, VA; Virginia Poison Center, Richmond, VA; Department of Emergency Medicine, VCU Medical Center, Richmond, VA. Electronic address:

Introduction: Single-use laundry detergent pods (LDPs) were introduced to the United States in 2010 but had been available in Europe as early as 2001. Case reports of unintentional exposures noted vomiting, ocular injuries, respiratory depression, and central nervous system depression. We summarize clinical effects from unintentional LDP exposures reported to a single poison center over 15 months.

Methods: Electronic poison center records were searched using verbatim field and both product and generic codes to identify laundry pod exposures from January 1, 2012, through April 9, 2013. Clinical effects were abstracted to a database and summarized using descriptive statistics.

Results: We identified 131 cases between March 2012 and April 2013. Median (interquartile range) age was 2.0 (1.5) years with 4 adult cases; all were coded as unintentional. The most common route was ingestion (120) followed by ocular (14) and dermal (6). Some patients had multiple routes of exposure. Of ingestion exposures, 79 (66%) were managed at home; and 41 (34%) were evaluated in a hospital, of which 9 patients were admitted. The median (interquartile range) age of admitted patients was 1.4 (1.1) years. Relevant findings in these admitted children included emesis (78%), central nervous system depression (22%), upper airway effects (56%), lower respiratory symptoms (33%), seizure (n = 1), and intubation (67%). One child with emesis initially managed at home was subsequently intubated for respiratory distress.

Discussion: Exposure to LDP can cause significant toxicity, particularly in infants and toddlers. Compared to traditional detergents, clinicians should be aware of the potential for airway compromise following exposure to LDP.
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http://dx.doi.org/10.1016/j.ajem.2014.11.044DOI Listing
March 2015

Gout exacerbation, weakness, hypotension--Dx?

J Fam Pract 2014 Aug;63(8):455-6

Department of Emergency Medicine, Carilion Clinic, Roanoke, VA, USA. Email:

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August 2014

Gastrointestinal perforation associated with endoscopy in cats and dogs.

J Am Anim Hosp Assoc 2014 Sep-Oct;50(5):322-9

Great Lakes Veterinary Specialists, Cleveland, OH (S.I.); and Department of Veterinary Clinical Sciences (R.S., S.J.) and Department of Veterinary Biosciences (P.S.), The Ohio State University, Columbus, OH.

Gastrointestinal endoscopy is a minimally invasive diagnostic tool for cats and dogs with signs of gastrointestinal disease. This retrospective study examined the case records of six cats and one dog diagnosed with perforation secondary to gastrointestinal endoscopy. Gastrointestinal perforation occurred in 1.6% of cats and 0.1% of dogs that underwent endoscopy during the 17 yr study period (from 1993 to 2010). It can be difficult to predict what animals are at risk for gastrointestinal perforation but possible risk factors suggested by this study include small intestinal infiltrative disease in cats and preexisting gastrointestinal ulceration in both cats and dogs. Overall, gastrointestinal endoscopy is associated with a low rate of gastrointestinal perforation.
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http://dx.doi.org/10.5326/JAAHA-MS-5727DOI Listing
July 2016

Activated Charcoal Does Not Reduce Duration of Phenytoin Toxicity in Hospitalized Patients.

Am J Ther 2016 May-Jun;23(3):e773-7

Division of Clinical Toxicology, Department of Emergency Medicine, Virginia Commonwealth University, Richmond, VA.

Phenytoin toxicity frequently results in a prolonged inpatient admission. Several publications avow multidose activated charcoal (MDAC) will enhance the elimination of phenytoin. However, these claims are not consistent, and the mechanism of enhanced eliminaiton is unproven. The aim of this investigation is to compare the time to reach a clinical composite end point in phenytoin overdose patients treated with no activated charcoal (NoAC), single-dose activated charcoal (SDAC), and MDAC. This was a retrospective study using electronic poison center data. Patients treated in a health care facility with phenytoin concentrations >20 mg/L were included. Patients were grouped by use of SDAC, MDAC, and NoAC. The primary end points were either time to resolution of symptoms, hospital discharge, or the case was closed by a toxicologist. After applying inclusion and exclusion criteria, 132 cases were included for analysis. There were 88 NoAC, 13 SDAC, and 31 MDAC cases. The groups were similar in symptomatology, age, and chronicity of expsoure. Mean peak phenytoin concentrations (SD) were 42 mg/L (12), 41 mg/L (11), and 42 mg/L (11) for NoAC, SDAC, and MDAC, respectively. Mean time to reach the study end point was 39 hours [95% confidence interval (CI), 31-48], 52 hours (95% CI, 36-68), and 60 hours (95% CI, 45-75) for NoAC, SDAC, and MDAC, respectively. The groups appeared similar with respect to peak phenytoin concentrations and prevalence of signs and symptoms. In this observational series, the use of activated charcoal was associated with increased time to reach the composite end point of clinical improvement.
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http://dx.doi.org/10.1097/MJT.0000000000000058DOI Listing
February 2017

Clinical outcomes in newer anticonvulsant overdose: a poison center observational study.

J Med Toxicol 2014 Sep;10(3):254-60

Division of Clinical Toxicology, VCU Medical Center, Richmond, VA, USA,

Clinicians have limited experience with assessment and treatment of overdose from newer anticonvulsant medications. The aim of this investigation was to evaluate clinical effects of newer anticonvulsant overdose, determine if a relationship exists between dose and clinical effect, and if a particular agent appears more toxic in overdose. This was a retrospective study using electronic poison center data, evaluating clinical outcomes from newer anticonvulsant overdose. The Toxicall™ database from January 1, 2002 to December 31, 2011 was queried using key words: "gabapentin," "lamotrigine," "levetiracetam," "tiagabine," "topiramate," "zonisamide," "pregabalin," and "oxcarbazine." Polypharmacy overdose and children less than 15 years of age were excluded. Charts were reviewed by two abstractors for pharmaceutical, self-reported dose, clinical effect score, and clinical signs, symptoms, and vital signs recorded in the chart. Ordinal logistic regression was used to evaluate the relationship between drug type, dose, age, and sex to clinical effect score. Out of 501 cases identified, 347 met the final inclusion criteria. There were 116 gabapentin, 67 lamotrigine, 15 levetiracetam, 15 tiagabine, 56 topiramate, 23 pregabalin, and 55 oxcarbazepine cases. Overdose of newer anticonvulsants frequently results in altered mental status. Seizures may be more common with tiagabine, lamotrigine, and oxcarbazepine. There was one death reported from intentional overdose of topiramate. An information index was created to rank drug toxicity based on reported signs and symptoms for each overdose. There was no significant effect of dose on severity of outcome (β = 0.12, p = 0.23). However, the risk of a more severe outcome score was significantly increased with tiagabine relative to other drugs (β = 2.8, p = 0.001). Lamotrigine ranked highest in terms of toxicity (HT = 1.66) and number of interventions performed (HI = 1.17), and levetiracetam the lowest (HT = 0.98; HI = 0.88). We could not identify a dose-effect in these data which likely reflects the limitations of self-reported doses. Despite limitations of these data, the risk of more severe outcome scores appear to be higher with tiagabine overdose while lamotrigine overdose appears to result in more reported signs, symptoms, and interventions.
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http://dx.doi.org/10.1007/s13181-014-0384-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141920PMC
September 2014

Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer.

PLoS One 2013 16;8(8):e71533. Epub 2013 Aug 16.

Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.

Tumor fibroblasts are active partners in tumor progression, but the genes and pathways that mediate this collaboration are ill-defined. Previous work demonstrates that Ets2 function in stromal cells significantly contributes to breast tumor progression. Conditional mouse models were used to study the function of Ets2 in both mammary stromal fibroblasts and epithelial cells. Conditional inactivation of Ets2 in stromal fibroblasts in PyMT and ErbB2 driven tumors significantly reduced tumor growth, however deletion of Ets2 in epithelial cells in the PyMT model had no significant effect. Analysis of gene expression in fibroblasts revealed a tumor- and Ets2-dependent gene signature that was enriched in genes important for ECM remodeling, cell migration, and angiogenesis in both PyMT and ErbB2 driven-tumors. Consistent with these results, PyMT and ErbB2 tumors lacking Ets2 in fibroblasts had fewer functional blood vessels, and Ets2 in fibroblasts elicited changes in gene expression in tumor endothelial cells consistent with this phenotype. An in vivo angiogenesis assay revealed the ability of Ets2 in fibroblasts to promote blood vessel formation in the absence of tumor cells. Importantly, the Ets2-dependent gene expression signatures from both mouse models were able to distinguish human breast tumor stroma from normal stroma, and correlated with patient outcomes in two whole tumor breast cancer data sets. The data reveals a key function for Ets2 in tumor fibroblasts in signaling to endothelial cells to promote tumor angiogenesis. The results highlight the collaborative networks that orchestrate communication between stromal cells and tumor cells, and suggest that targeting tumor fibroblasts may be an effective strategy for developing novel anti-angiogenic therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071533PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745457PMC
April 2014

Pathology in practice. Congenital porphyria in a kitten.

J Am Vet Med Assoc 2013 Jul;243(2):217-9

Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.

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http://dx.doi.org/10.2460/javma.243.2.217DOI Listing
July 2013

Cases from NACCT acute and intensive care symposium: altered mental status, seizures, and rash in a fumigation company employee.

Clin Toxicol (Phila) 2013 Mar;51(3):182-5

Division of Clinical Toxicology, Department of Emergency Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0522, USA.

Context: Methyl bromide is a halogenated aliphatic hydrocarbon that exists as a colorless gas or a volatile liquid. Methyl bromide historically had been used in fire extinguishers but is more commonly used as a gas fumigant for soil-borne diseases and pests. Methyl bromide is being phased out due to concerns for ozone depletion but can still be found. It is readily absorbed through the lungs while dermal absorption can also occur. Signs and symptoms of severe exposures include headache, respiratory distress, pulmonary hemorrhage, and seizures. In large pulmonary exposures, death can occur as rapidly as 1 h usually from respiratory failure. Methyl bromide can penetrate clothing and protective equipment presenting challenges to first responders. There is a debate over the mechanism of toxicity of methyl bromide and the role of hemodialysis and chelation in treatment.

Case Details: A 22-year-old female employee of a fumigation company contacted emergency medical services (EMS) after opening a tank of compressed methyl bromide in her car. She was initially combative and confused. She underwent two water dermal decontaminations and was transported to the nearest tertiary center. She rapidly progressed to obtundation with seizure-like activity and dysrhythmias. Despite the supportive care and resuscitative efforts, she died approximately 1 h after her call to EMS.

Discussion: Methyl bromide exposures can be fatal, and this case highlights the difficulty in managing these acutely poisoned patients. Questions for consideration after this case include time spent on decontamination, use of adjunctive anti-epileptic drugs, role of chelation therapy, and the role of hemodialysis in the treatment of methyl bromide poisoning.
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http://dx.doi.org/10.3109/15563650.2013.772624DOI Listing
March 2013

IL-10 inhibits mature fibrotic granuloma formation during Mycobacterium tuberculosis infection.

J Immunol 2013 Mar 8;190(6):2778-90. Epub 2013 Feb 8.

Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA.

Protective immunity and latent Mycobacterium tuberculosis infection in humans are associated with the formation of mature protective granulomas within the lung. Unfortunately, understanding the importance of such structures has been hindered by the lack of small-animal models that can develop mature granulomas. In this article, we describe for the first time, to our knowledge, the formation of mature, fibrotic M. tuberculosis-containing pulmonary granulomas in a mouse model of IL-10 deficiency (CBA/J IL-10(-/-)). Long-term control of M. tuberculosis infection in the absence of IL-10 was also associated with an early and enhanced capacity for Ag presentation and a significant increase in the generation of multifunctional T cells. Although IL-10 deficiency is known to enhance Th1 immune responses in general, we demonstrate in this study using transient anti-IL-10R treatment that it is the presence of IL-10 in vivo during the first month of M. tuberculosis infection that plays a definitive role in the inhibition of optimum protective immunity that can establish the environment for mature granuloma formation. Although the importance of IL-10 during M. tuberculosis infection has been debated, our data demonstrate that in CBA/J mice, IL-10 plays a significant early inhibitory role in preventing the development of protective immunity associated with containment of M. tuberculosis infection.
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http://dx.doi.org/10.4049/jimmunol.1202722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594073PMC
March 2013

Killer cell lectin-like receptor G1 deficiency significantly enhances survival after Mycobacterium tuberculosis infection.

Infect Immun 2013 Apr 22;81(4):1090-9. Epub 2013 Jan 22.

Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.

The expression of T cell differentiation markers is known to increase during Mycobacterium tuberculosis infection, and yet the biological role of such markers remains unclear. We examined the requirement of the T cell differentiation marker killer cell lectin-like receptor G1 (KLRG1) during M. tuberculosis infection using mice deficient in KLRG1. KLRG1(-/-) mice had a significant survival extension after M. tuberculosis infection compared to wild-type controls, and maintained a significantly lower level of pulmonary M. tuberculosis throughout chronic infection. Improved control of M. tuberculosis infection was associated with an increased number of activated pulmonary CD4(+) T cells capable of secreting gamma interferon (IFN-γ). Our report is the first to show an in vivo impact of KLRG1 on disease control.
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http://dx.doi.org/10.1128/IAI.01199-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639586PMC
April 2013

Influence of submission form characteristics on clinical information received in biopsy accession.

J Vet Diagn Invest 2012 Nov 13;24(6):1073-82. Epub 2012 Sep 13.

Department of Animal and Food Sciences, University of Delaware, Newark, DE, USA.

Clinical information supplied to diagnostic laboratories through biopsy submission forms is crucial to accurate, timely diagnosis and to clinicopathologic correlation between microscopic findings and the clinical condition of the patient. The current study attempts to quantify the prevalence of deficient and inadequate submissions in veterinary biopsy service and to determine whether form characteristics, such as the open or closed nature of the form and the presence of specific prompts, influence reporting of essential case information. The hypotheses of this study are, first, that deficient and inadequate biopsy submissions do occur in veterinary medicine and, second, that open-type biopsy submission forms elicit quantitatively and qualitatively more complete case information overall, and in specific content areas, compared to closed-type biopsy submission forms. Three percent of submissions reviewed were information deficient, devoid of information beyond patient signalment, and more than 88% of forms supplied inadequate clinical information in at least 1 key content area. Both form type and specific prompts significantly influenced reporting of important clinical information. This study demonstrates the need and lays the foundation for informational completeness research in veterinary medicine.
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http://dx.doi.org/10.1177/1040638712458783DOI Listing
November 2012

CBA/J mice generate protective immunity to soluble Ag85 but fail to respond efficiently to Ag85 during natural Mycobacterium tuberculosis infection.

Eur J Immunol 2012 Apr;42(4):870-9

Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, USA.

In CBA/J mice, susceptibility to Mycobacterium tuberculosis (M.tb) is associated with low interferon-gamma (IFN-γ) responses to antigens (Antigen 85 (Ag85) and early secreted antigenic target-6 (ESAT-6)) that have been defined as immunodominant. Here, we asked whether the failure of CBA/J mice to recognize Ag85 is a consequence of M.tb infection or whether CBA/J mice have a general defect in generating specific T-cell responses to this protein antigen. We compared CBA/J mice during primary M.tb infection, Ag85 vaccination followed by M.tb challenge, or M.tb memory immune mice for their capacity to generate Ag85-specific IFN-γ responses and to control M.tb infection. CBA/J mice did not respond efficiently to Ag85 in the context of natural infection or re-infection. In contrast, CBA/J mice could generate Ag85-specific IFN-γ responses and protective immunity when this antigen was delivered as a soluble protein. Our data indicate that although M.tb infection of CBA/J mice does not drive an Ag85 response, these mice can fully and protectively respond to Ag85 if it is delivered as a vaccine. The data from this experimental model suggest that the Ag85-containing vaccines in clinical trials should protect M.tb susceptible humans.
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http://dx.doi.org/10.1002/eji.201142054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641789PMC
April 2012

Woman with a hand ulcer.

Clin Toxicol (Phila) 2012 Mar;50(3):221-2

Division of Clinical Toxicology, Department of Emergency Medicine, VCU Medical Center, Richmond, VA 23298-0522, USA.

A 20-year-old woman presented to the emergency department for evaluation of a wound to left hand (Fig. 1). She admitted having a history of chronic severe headaches requiring daily use of analgesics. She first noted the ulcer approximately 10 months prior to presentation. Her examination was remarkable for a 10-cm by 8-cm ulceration to the dorsum of her left hand with exposed and necrotic metacarpals. Fibrous exudate was present in the wound-bed, and the ulcer was associated with a foul odor. She was afebrile on presentation with a peripheral white blood cell count of 6.4 x109/L, CRP 1.9 mg/dL, and ESR 15 mm/h.
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http://dx.doi.org/10.3109/15563650.2012.660571DOI Listing
March 2012

Pathology in practice. Reactive renal polyps and prostatic carcinoma.

J Am Vet Med Assoc 2011 Aug;239(4):447-9

Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.

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http://dx.doi.org/10.2460/javma.239.4.447DOI Listing
August 2011

Mast cell tumors in a llama (Lama glama).

J Vet Diagn Invest 2010 Sep;22(5):808-11

Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.

A 9-year-old female llama (Lama glama) that served as a blood donor at The Ohio State University Veterinary Teaching Hospital developed multiple small, raised, firm, non-haired cutaneous masses on the right hip, left cheek, and right and left shoulders. Cytological evaluation of fine-needle aspirates from the cutaneous mass from the left shoulder and right hip comprised many well-differentiated, highly granulated mast cells with moderate numbers of eosinophils. Occasional mast cells exhibited erythrophagocytosis and contained a small amount of hemosiderin or several variably sized vacuoles. A cytologic diagnosis of mast cell tumor with evidence of prior hemorrhage was made, and the masses were surgically removed. Microscopically, each mass consisted of sheets of neoplastic round cells that formed nonencapsulated nodules in the dermis and infiltrated into the adjacent dermal collagen. Eosinophils were scattered among the mast cells at the periphery of the nodules. Neoplastic mast cells, but not eosinophils, exhibited positive membrane KIT expression and cytoplasmic vimentin staining. A final diagnosis of mast cell tumor was made based on cytology, histology, and immunohistochemistry.
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http://dx.doi.org/10.1177/104063871002200531DOI Listing
September 2010

CCL5 participates in early protection against Mycobacterium tuberculosis.

J Leukoc Biol 2010 Jun 6;87(6):1153-65. Epub 2010 Apr 6.

Center for Microbial Interface Biology and Department of Veterinary Biosciences, The Ohio State University, 1046 Biomedical Research Tower, 460 West 12th Ave., Columbus, OH 43210, USA.

Control of M.tb, the causative agent of TB, requires immune cell recruitment to form lung granulomas. The chemokines and chemokine receptors that promote cell migration for granuloma formation, however, are not defined completely. As immunity to M.tb manifests slowly in the lungs, a better understanding of specific roles for chemokines, in particular those that promote M.tb-protective T(H)1 responses, may identify targets that could accelerate granuloma formation. The chemokine CCL5 has been detected in patients with TB and implicated in control of M.tb infection. To define a role for CCL5 in vivo during M.tb infection, CCL5 KO mice were infected with a low dose of aerosolized M.tb. During early M.tb infection, CCL5 KO mice localized fewer APCs and chemokine receptor-positive T cells to the lungs and had microscopic evidence of altered cell trafficking to M.tb granulomas. Early acquired immunity and granuloma function were transiently impaired when CCL5 was absent, evident by delayed IFN-gamma responses and poor control of M.tb growth. Lung cells from M.tb-infected CCL5 KO mice eventually reached or exceeded the levels of WT mice, likely as a result of partial compensation by the CCL5-related ligand, CCL4, and not because of CCL3. Finally, our results suggest that most T cells use CCR5 but not CCR1 to interact with these ligands. Overall, these results contribute to a model of M.tb granuloma formation dependent on temporal regulation of chemokines rather than on redundant or promiscuous interactions.
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http://dx.doi.org/10.1189/jlb.1109742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872537PMC
June 2010

Allele-specific tumor spectrum in pten knockin mice.

Proc Natl Acad Sci U S A 2010 Mar 1;107(11):5142-7. Epub 2010 Mar 1.

Department of Molecular Genetics, College of Biological Sciences, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.

Germline mutations in the tumor suppressor gene PTEN (phosphatase and tensin homology deleted on chromosome 10) cause Cowden and Bannayan-Riley-Ruvalcaba (BRR) syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas, and variable cancer risk. Here, we modeled three sentinel mutant alleles of PTEN identified in patients with Cowden syndrome and show that the nonsense Pten(4-5) and missense Pten(C124R) and Pten(G129E) alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectra with varying severity and age of onset. Allele-specific differences may be accounted for by loss of function for Pten(4-5), hypomorphic function for Pten(C124R), and gain of function for Pten(G129E). These data demonstrate that the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specific mutations in PTEN that alter protein function through distinct mechanisms.
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http://dx.doi.org/10.1073/pnas.0912524107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841921PMC
March 2010

Pten in stromal fibroblasts suppresses mammary epithelial tumours.

Nature 2009 Oct;461(7267):1084-91

Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA.

The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.
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http://dx.doi.org/10.1038/nature08486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2767301PMC
October 2009

Effects of aging on the immunopathologic response to sepsis.

Crit Care Med 2009 Mar;37(3):1018-23

Department of Surgery, Washington University School of Medicine, St Louis, MO, USA.

Objective: Aging is associated with increased inflammation following sepsis. The purpose of this study was to determine whether this represents a fundamental age-based difference in the host response or is secondary to the increased mortality seen in aged hosts.

Design: Prospective, randomized controlled study.

Setting: Animal laboratory in a university medical center.

Subjects: Young (6-12 weeks) and aged (20-24 months) FVB/N mice.

Interventions: Mice were subjected to 2 x 25 or 1 x 30 cecal ligation and puncture (CLP).

Measurements And Main Results: Survival was similar in young mice subjected to 2 x 25 CLP and aged mice subjected to 1 x 30 CLP (p = 0.15). Young mice subjected to 1 x 30 CLP had improved survival compared with the other groups (p < 0.05). When injury was held constant but mortality was greater, both systemic and peritoneal levels of tumor necrosis factor-alpha, interleukin (IL)-6, IL-10, and monocyte chemotactic protein-1 were elevated 24 hours after CLP in aged animals compared with young animals (p < 0.05). When mortality was similar but injury severity was different, there were no significant differences in systemic cytokines between aged mice and young mice. In contrast, peritoneal levels of tumor necrosis factor-alpha, IL-6, and IL-10 were higher in aged mice subjected to 1 x 30 CLP than young mice subjected to 2 x 25 CLP despite their similar mortalities (p < 0.05). There were no significant differences in either bacteremia or peritoneal cultures when animals of different ages sustained similar injuries or had different injuries with similar mortalities.

Conclusions: Aged mice are more likely to die of sepsis than young mice when subjected to an equivalent insult, and this is associated with increases in both systemic and local inflammation. There is an exaggerated local but not systemic inflammatory response in aged mice compared with young mice when mortality is similar. This suggests that systemic processes that culminate in death may be age independent, but the local inflammatory response may be greater with aging.
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http://dx.doi.org/10.1097/CCM.0b013e3181968f3aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760736PMC
March 2009

CD4+ lymphocytes control gut epithelial apoptosis and mediate survival in sepsis.

FASEB J 2009 Jun 21;23(6):1817-25. Epub 2009 Jan 21.

Department of Surgery, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110, USA.

Lymphocytes help determine whether gut epithelial cells proliferate or differentiate but are not known to affect whether they live or die. Here, we report that lymphocytes play a controlling role in mediating gut epithelial apoptosis in sepsis but not under basal conditions. Gut epithelial apoptosis is similar in unmanipulated Rag-1(-/-) and wild-type (WT) mice. However, Rag-1(-/-) animals have a 5-fold augmentation in gut epithelial apoptosis following cecal ligation and puncture (CLP) compared to septic WT mice. Reconstitution of lymphocytes in Rag-1(-/-) mice via adoptive transfer decreases intestinal apoptosis to levels seen in WT animals. Subset analysis indicates that CD4(+) but not CD8(+), gammadelta, or B cells are responsible for the antiapoptotic effect of lymphocytes on the gut epithelium. Gut-specific overexpression of Bcl-2 in transgenic mice decreases mortality following CLP. This survival benefit is lymphocyte dependent since gut-specific overexpression of Bcl-2 fails to alter survival when the transgene is overexpressed in Rag-1(-/-) mice. Further, adoptively transferring lymphocytes to Rag-1(-/-) mice that simultaneously overexpress gut-specific Bcl-2 results in improved mortality following sepsis. Thus, sepsis unmasks CD4(+) lymphocyte control of gut apoptosis that is not present under homeostatic conditions, which acts as a key determinant of both cellular survival and host mortality.
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http://dx.doi.org/10.1096/fj.08-119024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698654PMC
June 2009

Adjuvant CCNU (lomustine) and prednisone chemotherapy for dogs with incompletely excised grade 2 mast cell tumors.

J Am Anim Hosp Assoc 2009 Jan-Feb;45(1):14-8

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, 601 Vernon L. Tharp Street, Columbus, Ohio 43210, USA.

The use of adjuvant 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; lomustine) to treat incompletely excised canine mast cell tumors (MCTs) has not been evaluated. Medical records of 12 dogs with grade 2 MCT treated with incomplete surgical excision and adjuvant CCNU and prednisone chemotherapy were reviewed. Local recurrence rate, metastasis rate, and survival time were evaluated. None of the dogs developed local recurrence or regional/ distant metastases. Two dogs developed fatal liver failure. The 1- and 2-year progression-free rates of surviving dogs were 100% and 77%, respectively. Postoperative adjuvant CCNU appears to be a useful alternative to radiation therapy for incompletely excised canine cutaneous MCTs.
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http://dx.doi.org/10.5326/0450014DOI Listing
March 2009

Cervical thymoma originating in ectopic thymic tissue in a cat.

Vet Clin Pathol 2008 Dec;37(4):397-402

Department of Veterinary Clinical Sciences and Veterinary Teaching Hospital, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.

An 11-year-old female spayed domestic shorthair cat was referred to The Ohio State University Veterinary Teaching Hospital (OSU-VTH) for evaluation of a 6 x 4 x 3.5 cm mass in the left midcervical region causing increased respiratory sounds and lateral deviation of the trachea. A fine needle aspirate of the mass was obtained before referral and the cytology results were compatible with a reactive lymph node. Immunocytochemistry showed increased numbers of CD3+ T lymphocytes and small numbers of CD20+ and CD79a+ medium to large lymphocytes. Differential diagnoses from the referral pathologist were T-cell-rich B-cell lymphoma and feline Hodgkin's-like lymphoma. A subsequent fine needle aspirate performed at the OSU-VTH showed similar results. On flow cytometry the majority of cells were CD3+ T lymphocytes that were double positive for CD4 and CD8 (73%), compatible with either a double-positive (CD4+CD8+) T-cell lymphoma or lymphocytes from ectopic thymic tissue. The mass was surgically removed. Histopathology and immunohistochemistry of the mass revealed a predominant population of CD3+ small lymphocytes and small numbers of medium to large lymphocytes with moderate anisocytosis and anysokaryosis. A population of cytokeratin-positive epithelial cells surrounded small microcystic structures filled with eosinophilic material and structures interpreted as Hassall's corpuscles. These findings were consistent with thymic tissue and a diagnosis of ectopic thymoma was made. PCR results for lymphocyte antigen receptor rearrangement (PARR) were negative. The cat had no evidence of disease 16 months after removal of the mass. To our knowledge this is the first report of an ectopic cervical thymoma in a cat. The clinical and diagnostic features of this unusual case will be useful in helping veterinarians and pathologists obtain a presurgical diagnosis and establish a prognosis for similar lesions.
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http://dx.doi.org/10.1111/j.1939-165X.2008.00061.xDOI Listing
December 2008

Interleukin-10 promotes Mycobacterium tuberculosis disease progression in CBA/J mice.

J Immunol 2008 Oct;181(8):5545-50

Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA.

IL-10 is a potent immunomodulatory cytokine that affects innate and acquired immune responses. The immunological consequences of IL-10 production during pulmonary tuberculosis (TB) are currently unknown, although IL-10 has been implicated in reactivation TB in humans and with TB disease in mice. Using Mycobacterium tuberculosis-susceptible CBA/J mice, we show that blocking the action of IL-10 in vivo during chronic infection stabilized the pulmonary bacterial load and improved survival. Furthermore, this beneficial outcome was highly associated with the recruitment of T cells to the lungs and enhanced T cell IFN-gamma production. Our results indicate that IL-10 promotes TB disease progression. These findings have important diagnostic and/or therapeutic implications for the prevention of reactivation TB in humans.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728584PMC
http://dx.doi.org/10.4049/jimmunol.181.8.5545DOI Listing
October 2008

Myocardial transcriptional profiles in a murine model of sepsis: evidence for the importance of age.

Pediatr Crit Care Med 2008 Sep;9(5):530-5

Center for Critical Illness and Health Engineering and the Departments of Pediatrics and Surgery, Washington University School of Medicine, St. Louis, MO, USA.

Background: Age influences outcome of sepsis and septic shock. The mechanism of this age-dependent vulnerability to sepsis remains largely unknown. Because much of the mortality and morbidity associated with sepsis and septic shock is the result of severe derangements in the cardiovascular system, it is possible that the myocardium responds to injury in a developmentally influenced manner. We hypothesized that analysis of cardiac RNA expression profiles may differentiate between the myocardial response to sepsis in young and old mice.

Methods And Results: Sixteen FVB/N male mice were stratified based on age. Young animals were 6 wks old, correlating to 4 to 6 human years, and aged animals were 20 months old correlating to 70 to 80 human years. Animals underwent either cecal ligation and puncture to produce polymicrobial sepsis or a sham operation. Both ventricles were excised after kill at 24 hrs. There were 53 genes that differed in RNA abundance between the four groups (false discovery rate of 0.005, p < 0.00001). Additionally, four genes were associated with an age-dependent response to sepsis: CYP2B2 (cytochrome P450, family 2, subfamily B, polypeptide 6), VGLL2 (vestigial like 2), and PAH (phenylalanine hydroxylase). The fourth gene is an expressed sequence tag, the function of which is related to the cytochrome P450 family. These genes play roles in phenylalanine, tyrosine, tryptophan, and fatty acid metabolism.

Conclusions: This report describes the transcriptional response of the heart to sepsis. In addition, our findings suggest that these differences are in part age-dependent and serve as hypothesis generation.
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http://dx.doi.org/10.1097/PCC.0b013e3181849a2fDOI Listing
September 2008

Mouse development with a single E2F activator.

Nature 2008 Aug 25;454(7208):1137-41. Epub 2008 Jun 25.

Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA.

The E2F family is conserved from Caenorhabditis elegans to mammals, with some family members having transcription activation functions and others having repressor functions. Whereas C. elegans and Drosophila melanogaster have a single E2F activator protein and repressor protein, mammals have at least three activator and five repressor proteins. Why such genetic complexity evolved in mammals is not known. To begin to evaluate this genetic complexity, we targeted the inactivation of the entire subset of activators, E2f1, E2f2, E2f3a and E2f3b, singly or in combination in mice. We demonstrate that E2f3a is sufficient to support mouse embryonic and postnatal development. Remarkably, expression of E2f3b or E2f1 from the E2f3a locus (E2f3a(3bki) or E2f3a(1ki), respectively) suppressed all the postnatal phenotypes associated with the inactivation of E2f3a. We conclude that there is significant functional redundancy among activators and that the specific requirement for E2f3a during postnatal development is dictated by regulatory sequences governing its selective spatiotemporal expression and not by its intrinsic protein functions. These findings provide a molecular basis for the observed specificity among E2F activators during development.
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http://dx.doi.org/10.1038/nature07066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288824PMC
August 2008

Developing and fostering a dynamic program for training in veterinary pathology and clinical pathology: veterinary students to post-graduate education.

J Vet Med Educ 2007 ;34(4):464-72

Department of Veterinary Bioscience, The Ohio State University, Columbus, OH 43210-1093, USA.

Recent reports project a deficiency of veterinary pathologists, indicating a need to train highly qualified veterinary pathologists, particularly in academic veterinary medicine. The need to provide high-quality research training for veterinary pathologists has been recognized by the veterinary pathology training program of the Ohio State University (OSU) since its inception. The OSU program incorporates elements of both residency training and graduate education into a unified program. This review illustrates the components and structure of the training program and reflects on future challenges in training veterinary pathologists. Key elements of the OSU program include an experienced faculty, dedicated staff, and high-quality students who have a sense of common mission. The program is supported through cultural and infrastructure support. Financial compensation, limited research funding, and attractive work environments, including work-life balance, will undoubtedly continue to be forces in the marketplace for veterinary pathologists. To remain competitive and to expand the ability to train veterinary pathologists with research skills, programs must support strong faculty members, provide appropriate infrastructure support, and seek active partnerships with private industry to expand program opportunities. Shortages of trained faculty may be partially resolved by regional cooperation to share faculty expertise or through the use of communications technology to bridge distances between programs. To foster continued interest in academic careers, training programs will need to continue to evolve and respond to trainees' needs while maintaining strong allegiances to high-quality pathology training. Work-life balance, collegial environments that foster a culture of respect for veterinary pathology, and continued efforts to reach out to veterinary students to provide opportunities to learn about the diverse careers offered in veterinary pathology will pay long-term dividends for the future of the profession.
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http://dx.doi.org/10.3138/jvme.34.4.464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057672PMC
March 2008