Publications by authors named "Caroline J Zeiss"

55 Publications

Animal Models of COVID-19 II. Comparative Immunology.

ILAR J 2021 Apr 29. Epub 2021 Apr 29.

Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

Developing strong animal models is essential for furthering our understanding of how the immune system functions in response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. The alarming speed at which SARS-CoV-2 has spread, and the high mortality rate of severe Coronavirus Disease 2019 (COVID-19), has required both basic science and clinical research to move at an unprecedented pace. Models previously developed to study the immune response against SARS-CoV have been rapidly deployed to now study SARS-CoV-2. To date, both small and large animal models are remarkably consistent when infected with SARS-CoV-2; however, certain models have proven more useful when answering specific immunological questions than others. Small animal models, such as Syrian hamsters, ferrets, and mice carrying the hACE2 transgene, appear to reliably recapitulate the initial cytokine surge seen in COVID-19 as well as show significant innate and adaptive cell infiltration in to the lung early in infection. Additionally, these models develop strong antibody responses to the virus, are protected from reinfection, and genetically modified versions exist that can be used to ask specific immunological questions. Large animal models such as rhesus and cynomologus macaques and African green monkeys are critical to understanding how the immune system responds to SARS-CoV-2 infection because they are considered to be the most similar to humans. These models are considered the gold standard for assessing vaccine efficacy and protection, and recapitulate the initial cytokine surge, immune cell infiltration into the lung, certain aspects of thrombosis, and the antibody and T-cell response to the virus. In this review, we discuss both small and large animal model studies previously used in SARS-CoV-2 research that may be useful in elucidating the immunological contributions to hallmark syndromes observed with COVID-19.
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http://dx.doi.org/10.1093/ilar/ilab010DOI Listing
April 2021

Animal Models of COVID-19. I. Comparative Virology and Disease Pathogenesis.

ILAR J 2021 Apr 9. Epub 2021 Apr 9.

Department of Comparative Medicine, John Hopkins School of Medicine, Baltimore, Maryland, USA.

The Coronavirus Disease 2019 (COVID-19) pandemic has fueled unprecedented development of animal models to understand disease pathogenesis, test therapeutics, and support vaccine development. Models previously developed to study severe acute respiratory syndrome coronavirus (SARS-CoV) have been rapidly deployed to study SARS-CoV-2. However, it has become clear that despite the common use of ACE2 as a receptor for both viruses, the host range of the 2 viruses does not entirely overlap. Distinct ACE2-interacting residues within the receptor binding domain of SARS-CoV and SARS-CoV-2, as well as species differences in additional proteases needed for activation and internalization of the virus, are likely sources of host differences between the 2 viruses. Spontaneous models include rhesus and cynomolgus macaques, African Green monkeys, hamsters, and ferrets. Viral shedding and transmission studies are more frequently reported in spontaneous models. Mice can be infected with SARS-CoV; however, mouse and rat ACE2 does not support SARS-CoV-2 infection. Murine models for COVID-19 are induced through genetic adaptation of SARS-CoV-2, creation of chimeric SARS-CoV and SARS-CoV-2 viruses, use of human ACE2 knock-in and transgenic mice, and viral transfection of wild-type mice with human ACE2. Core aspects of COVID-19 are faithfully reproduced across species and model. These include the acute nature and predominantly respiratory source of viral shedding, acute transient and nonfatal disease with a largely pulmonary phenotype, similar short-term immune responses, and age-enhanced disease. Severity of disease and tissue involvement (particularly brain) in transgenic mice varies by promoter. To date, these models have provided a remarkably consistent template on which to test therapeutics, understand immune responses, and test vaccine approaches. The role of comorbidity in disease severity and the range of severe organ-specific pathology in humans remains to be accurately modeled.
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http://dx.doi.org/10.1093/ilar/ilab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083356PMC
April 2021

Author Correction: AgRP neurons control compulsive exercise and survival in an activity-based anorexia model.

Nat Metab 2021 Feb;3(2):288

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1038/s42255-021-00351-5DOI Listing
February 2021

AgRP neurons control compulsive exercise and survival in an activity-based anorexia model.

Nat Metab 2020 11 26;2(11):1204-1211. Epub 2020 Oct 26.

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.

Hypothalamic agouti-related peptide (AgRP) and neuropeptide Y-expressing neurons have a critical role in driving food intake, but also in modulating complex, non-feeding behaviours. We interrogated whether AgRP neurons are relevant to the emergence of anorexia nervosa symptomatology in a mouse model. Here we show, using in vivo fibre photometry, a rapid inhibition of AgRP neuronal activity following voluntary cessation of running. All AgRP neuron-ablated, food-restricted mice die within 72 h of compulsive running, while daily activation of AgRP neurons using a chemogenetic tool increases voluntary running with no lethality of food-restricted animals. Animals with impaired AgRP neuronal circuits are unable to properly mobilize fuels during food-restriction-associated exercise; however, when provided with elevated fat content through diet, their death is completely prevented. Elevated fat content in the diet also prevents the long-term behavioural impact of food-restricted fit mice with elevated exercise volume. These observations elucidate a previously unsuspected organizational role of AgRP neurons, via the mediation of the periphery, in the regulation of compulsive exercise and its related lethality with possible implications for psychiatric conditions, such as anorexia nervosa.
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http://dx.doi.org/10.1038/s42255-020-00300-8DOI Listing
November 2020

Cutaneous and Pulmonary Mucormycosis in Rag1- and Il2rg-deficient Rats.

Comp Med 2020 08 31;70(4):390-395. Epub 2020 Jul 31.

Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut.

Immunodeficient rats are valuable in transplantation studies, but are vulnerable to infection from opportunistic organisms such as fungi. Immunodeficient Rag1- and Il2rg-deficient (RRG) rats housed at our institution presented with dark, proliferative, keratinized dermal growths. Histologic and PCR results indicated that the predominant organism associated with these lesions was fungus from the family mostly of the genus The family of fungi are environmental saprophytes and are often found in rodent bedding. These fungi can cause invasive opportunistic infections in immunosuppressed humans and animals. We discuss husbandry practices for immunosuppressed rodents with a focus on controlling fungal contaminants.
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http://dx.doi.org/10.30802/AALAS-CM-20-000015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446636PMC
August 2020

Utility of spontaneous animal models of Alzheimer's disease in preclinical efficacy studies.

Authors:
Caroline J Zeiss

Cell Tissue Res 2020 May 27;380(2):273-286. Epub 2020 Apr 27.

Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, 06520, USA.

Spontaneous animal models of Alzheimer's disease (AD) offer the potential to bridge the translational gulf between promising rodent studies and failed human clinical trials. In this review, the relationship between cell biology, neuropathology, clinical phenotype and biomarker progression in human AD is summarized. Genetically altered animals have provided key insights into the cell biology of AD and, together with emerging stem cell systems, remain the most effective means to disentangle the entwined mechanisms that underlie AD. Translating therapeutic success from these models of familial AD to late onset human AD has been challenging. Spontaneous models of AD do not harbor AD-associated mutations and could potentially be used to demonstrate greater generalizability of new therapies to late onset AD. The value of such models has been advanced primarily on the basis of similar amyloid (and far less frequent, tangle) neuropathology. While these models are promising, this alone is insufficient for use of these models to assess efficacy of potential therapies. The correlation between progression of neuropathology and cognitive phenotype and the association of these with biomarker progression in these models is discussed, with an emphasis on the dog and non-human primates. Currently, interventional studies using these models are hampered by use of a variety of outcomes that are not easily comparable with those used in human trials and do not permit longitudinal assessment. Additional studies aimed at closing the gap between neuropathology and usable outcome measures would support more accurate subject selection, assessment of target engagement and evaluation of therapeutic efficacy.
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http://dx.doi.org/10.1007/s00441-020-03198-6DOI Listing
May 2020

Umbilical cord hypercoiling in two rhesus macaques (Macaca mulatta).

J Med Primatol 2020 04 26;49(2):113-115. Epub 2019 Dec 26.

Department of Comparative Medicine, Yale School of Medicine, New Haven, Connecticut.

Obstruction of umbilical blood flow is a common cause of death in fetal nonhuman primates, but cord accidents have not been reported in the macaque. We describe two cases of cord accident in rhesus macaques (Macaca mulatta) resulting in fetal death at approximately 110 and 50 days of gestation, respectively.
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http://dx.doi.org/10.1111/jmp.12457DOI Listing
April 2020

Menagerie: A text-mining tool to support animal-human translation in neurodegeneration research.

PLoS One 2019 17;14(12):e0226176. Epub 2019 Dec 17.

Lister Hill National Center for Biomedical Communications, National Library of Medicine, Bethesda, Maryland, United States of America.

Discovery studies in animals constitute a cornerstone of biomedical research, but suffer from lack of generalizability to human populations. We propose that large-scale interrogation of these data could reveal patterns of animal use that could narrow the translational divide. We describe a text-mining approach that extracts translationally useful data from PubMed abstracts. These comprise six modules: species, model, genes, interventions/disease modifiers, overall outcome and functional outcome measures. Existing National Library of Medicine natural language processing tools (SemRep, GNormPlus and the Chemical annotator) underpin the program and are further augmented by various rules, term lists, and machine learning models. Evaluation of the program using a 98-abstract test set achieved F1 scores ranging from 0.75-0.95 across all modules, and exceeded F1 scores obtained from comparable baseline programs. Next, the program was applied to a larger 14,481 abstract data set (2008-2017). Expected and previously identified patterns of species and model use for the field were obtained. As previously noted, the majority of studies reported promising outcomes. Longitudinal patterns of intervention type or gene mentions were demonstrated, and patterns of animal model use characteristic of the Parkinson's disease field were confirmed. The primary function of the program is to overcome low external validity of animal model systems by aggregating evidence across a diversity of models that capture different aspects of a multifaceted cellular process. Some aspects of the tool are generalizable, whereas others are field-specific. In the initial version presented here, we demonstrate proof of concept within a single disease area, Parkinson's disease. However, the program can be expanded in modular fashion to support a wider range of neurodegenerative diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226176PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917268PMC
March 2020

Transverse myelitis following measles vaccination in a rhesus macaque (Macaca mulatta).

J Med Primatol 2020 04 2;49(2):103-106. Epub 2019 Dec 2.

Department of Comparative Medicine, Yale School of Medicine, New Haven, CT.

A 16-year-old rhesus macaque presented with progressive, ascending quadriparesis following measles vaccination. He was diagnosed with transverse myelitis following MRI, gross necropsy, and histopathology. This is the first report of transverse myelitis in a rhesus macaque following measles vaccination.
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http://dx.doi.org/10.1111/jmp.12453DOI Listing
April 2020

Concentration-dependent Toxicity after Subcutaneous Administration of Meloxicam to C57BL/6N Mice ().

J Am Assoc Lab Anim Sci 2019 11 20;58(6):802-809. Epub 2019 Sep 20.

Department of Comparative Medicine, Yale School of Medicine, New Haven, Connecticut.

Studies using the Mouse Grimace Scale have shown that for many NSAID, including meloxicam, minimal doses of at least 20 mg/kg may be necessary to achieve adequate peri- and post-operative analgesia in mice. However, more data are needed to determine whether such NSAID doses exceed the threshold for gastrointestinal ulceration or induce other relevant pathology. We administered equal volumes of saline or injectable meloxicam (1 or 5 mg/mL) at a dose of 20 mg/kg SC to 20 young adult male and female C57BL/6N mice daily for 6 d and performed necropsies on all mice on the seventh day. Mice given 5 mg/mL meloxicam subcutaneously developed significantly more severe pathology at the injection site than saline controls. Pathology was characterized by full-thickness epidermal necrosis; cavitary lesions within subcutis, muscle, or fat; steatitis; and myositis. Mice that received 1 mg/mL meloxicam subcutaneously developed lesions that were qualitatively similar but far less severe than those after 5 mg/mL. However, no pathologic lesions typically associated with NSAID toxicity, such as gastric ulceration and liver and kidney lesions, were seen. These results demonstrate that although meloxicam injected subcutaneously causes concentration-dependent skin pathology at the injection site, a dose of 20 mg/kg can be safely administered subcutaneously at a concentration of 1 mg/mL for as long as 6 d.
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http://dx.doi.org/10.30802/AALAS-JAALAS-19-000037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926403PMC
November 2019

Doxorubicin-Induced Cardiotoxicity in Collaborative Cross (CC) Mice Recapitulates Individual Cardiotoxicity in Humans.

G3 (Bethesda) 2019 08 8;9(8):2637-2646. Epub 2019 Aug 8.

The Jackson Laboratory, Bar Harbor, ME 04609.

Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Genetic determinants contributing to this variation are difficult to study using current mouse models. Our objective was to determine whether a spectrum of anthracycline induced cardiac disease can be elicited across 10 Collaborative Cross mouse strains given the same dose of doxorubicin. Mice from ten distinct strains were given 5 mg/kg of doxorubicin intravenously once weekly for 5 weeks (total 25 mg/kg). Mice were killed at acute or chronic timepoints. Body weight was assessed weekly, followed by terminal complete blood count, pathology and a panel of biomarkers. Linear models were fit to assess effects of treatment, sex, and sex-by-treatment interactions for each timepoint. Impaired growth and cardiac pathology occurred across all strains. Severity of these varied by strain and sex, with greater severity in males. Cardiac troponin I and myosin light chain 3 demonstrated strain- and sex-specific elevations in the acute phase with subsequent decline despite ongoing progression of cardiac disease. Acute phase cardiac troponin I levels predicted the ultimate severity of cardiac pathology poorly, whereas myosin light chain 3 levels predicted the extent of chronic cardiac injury in males. Strain- and sex-dependent renal toxicity was evident. Regenerative anemia manifested during the acute period. We confirm that variable susceptibility to doxorubicin-induced cardiotoxicity observed in humans can be modeled in a panel of CC strains. In addition, we identified a potential predictive biomarker in males. CC strains provide reproducible models to explore mechanisms contributing to individual susceptibility in humans.
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http://dx.doi.org/10.1534/g3.119.400232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686936PMC
August 2019

An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease.

PLoS Genet 2019 03 19;15(3):e1007873. Epub 2019 Mar 19.

Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.

Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in both humans and dogs. Currently, no standard treatment is available, but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs*1395), was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium (RPE). The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.
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http://dx.doi.org/10.1371/journal.pgen.1007873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424408PMC
March 2019

Pathology Study Design, Conduct, and Reporting to Achieve Rigor and Reproducibility in Translational Research Using Animal Models.

ILAR J 2018 12;59(1):4-12

Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut.

In translational research, animal models are an important tool to aid in decision-making when taking potential therapies into human clinical trials. Recently, there have been a number of papers that have suggested limited concordance of preclinical animal experiments with subsequent human clinical experience. Assessments of preclinical animal studies have led to concerns about the reproducibility of data and have highlighted the need for an emphasis on rigor and quality in the planning, conduct, analysis, and reporting of such studies. The incorporation of a wider role for the comparative pathologist using pathology best practices in the planning and conduct of animal model-based research is one way to increase the quality and reproducibility of data. The use of optimal design and planning of tissue collection, incorporation of pathology methods into written protocols, conduct of pathology procedures using accepted best practices, and the use of optimal pathology analysis and reporting methods enhance the quality of the data acquired from many types of preclinical animal models and studies. Many of these pathology practices are well established in the discipline of toxicologic pathology and have a proven and useful track record in enhancing the data from animal-based studies used in safety assessment of human therapeutics. Some of this experience can be adopted by the wider community of preclinical investigators to increase the reproducibility of animal study data.
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http://dx.doi.org/10.1093/ilar/ily020DOI Listing
December 2018

Investigating the role of interleukin-1 beta and glutamate in inflammatory bowel disease and epilepsy using discovery browsing.

J Biomed Semantics 2018 12 27;9(1):25. Epub 2018 Dec 27.

Lister Hill National Center for Biomedical Communications, U.S. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD, USA.

Background: Structured electronic health records are a rich resource for identifying novel correlations, such as co-morbidities and adverse drug reactions. For drug development and better understanding of biomedical phenomena, such correlations need to be supported by viable hypotheses about the mechanisms involved, which can then form the basis of experimental investigations.

Methods: In this study, we demonstrate the use of discovery browsing, a literature-based discovery method, to generate plausible hypotheses elucidating correlations identified from structured clinical data. The method is supported by Semantic MEDLINE web application, which pinpoints interesting concepts and relevant MEDLINE citations, which are used to build a coherent hypothesis.

Results: Discovery browsing revealed a plausible explanation for the correlation between epilepsy and inflammatory bowel disease that was found in an earlier population study. The generated hypothesis involves interleukin-1 beta (IL-1 beta) and glutamate, and suggests that IL-1 beta influence on glutamate levels is involved in the etiology of both epilepsy and inflammatory bowel disease.

Conclusions: The approach presented in this paper can supplement population-based correlation studies by enabling the scientist to identify literature that may justify the novel patterns identified in such studies and can underpin basic biomedical research that can lead to improved treatments and better healthcare outcomes.
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http://dx.doi.org/10.1186/s13326-018-0192-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307110PMC
December 2018

Identification of a novel microRNA profile in pediatric patients with cancer treated with anthracycline chemotherapy.

Am J Physiol Heart Circ Physiol 2018 11 24;315(5):H1443-H1452. Epub 2018 Aug 24.

University of South Carolina School of Medicine , Columbia, South Carolina.

Anthracycline chemotherapy (AC) is associated with decline in left ventricular ejection fraction (LVEF), yet the mechanisms remain unclear. Although changes in microRNAs (miRs) have been identified in adult cardiovascular disease, miR profiles in pediatric patients with AC have not been well studied. The goal of this study was to examine miR profiles (unbiased array) in pediatric patients with AC compared with age-matched referent normal patients. We hypothesize that pediatric patients with AC will express a unique miR profile at the initiation and completion of therapy and will be related to LVEF. Serum was collected in pediatric patients (10-22 yr, n = 12) with newly diagnosed malignancy requiring AC within 24-48 h after the initiation of therapy (30-60 mg/m) and ~1 yr after completing therapy. A custom microarray of 84 miRs associated with cardiovascular disease was used (quantitative RT-PCR) and indexed to referent normal profiles (13-17 yr, n = 17). LVEF was computed by cardiac MRI. LVEF fell from AC initiation at ~1 yr after AC completion (64.28 ± 1.78% vs. 57.53 ± 0.95%, respectively, P = 0.004). Of the 84 miRs profiled, significant shifts in 17 miRs occurred relative to referent normal ( P ≤ 0.05). Moreover, the functional domain of miRs associated with myocardial differentiation and development fell over threefold at the completion of AC ( P ≤ 0.05). Moreover, eight miRs were significantly downregulated after AC completion in those patients with the greatest decline in LVEF (≥10%, P < 0.05). This study demonstrates, for the first time, that changes in miR expression occur in pediatric patients with AC. These findings suggest that miRs are a potential strategy for the early identification of patients with AC susceptible to left ventricular dysfunction. NEW & NOTEWORTHY Although anthracycline chemotherapy (AC) is effective for a number of pediatric cancers, an all too often consequence of AC is the development of left ventricular failure. The present study identified that specific shifts in the pattern of microRNAs, which regulate myocardial growth, function, and viability, occurred during and after AC in pediatric patients, whereby the magnitude of this shift was associated with the degree of left ventricular failure.
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http://dx.doi.org/10.1152/ajpheart.00252.2018DOI Listing
November 2018

Acute Abdominal Distension Due to Disseminated Peritoneal Neoplasia in a Rhesus Macaque ().

Comp Med 2018 10 23;68(5):403-410. Epub 2018 Aug 23.

Department of Comparative Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

This report describes the clinical, radiographic, and pathologic findings in a female rhesus macaque that presented with acute abdominal distension and tympany. The macaque was euthanized after evidence of severe colonic distension on radiography and observation of widespread peritoneal adhesions on exploratory laparotomy. Gross and histopathologic evaluation revealed extensive entrapment of gastrointestinal and reproductive tracts by serosal fibrovascular proliferative tissue containing foci of endometriosis. The diagnosis of endometrial stromal sarcoma was supported by expression of CD10, Wilm tumor 1, estrogen receptor, and progesterone receptor and failure to express immunohistochemical markers characteristic of a range of differential diagnoses. In humans, this relatively uncommon neoplasm can arise from sites of endometriosis and often presents clinically as intestinal obstruction, similar to the presentation in this macaque.
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http://dx.doi.org/10.30802/AALAS-CM-17-000112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200034PMC
October 2018

Use of integrated imaging and serum biomarker profiles to identify subclinical dysfunction in pediatric cancer patients treated with anthracyclines.

Cardiooncology 2018 1;4. Epub 2018 May 1.

University of South Carolina School of Medicine, Columbia, SC, USA.

Background: Anthracycline induced cardiomyopathy is a major cause of mortality and morbidity among pediatric cancer survivors. It has been postulated that oxidative stress induction and inflammation may play a role in the pathogenesis of this process. Accordingly, the present study performed an assessment of biomarker profiles and functional imaging parameters focused upon potential early determinants of anthracycline induced cardiomyopathy.

Methods: Patients (10-22 years) were prospectively enrolled between January 2013 and November 2014. Thirteen subjects completed the study and underwent serial cardiac magnetic resonance imaging and plasma biomarker profiling performed 24-48 h after the first anthracycline dose and at set dose intervals. In addition, we collected plasma samples from 62 healthy controls to examine normal plasma biomarker profiles.

Results: Left ventricular ejection fraction (LVEF) decreased from 64.3 ± 6.2 at the first visit to 57.5 ± 3.3 ( = 0.004) 1 year after chemotherapy. A decline in longitudinal strain magnitude occurred at lower cumulative doses. A differential inflammatory/matrix signature emerged in anthracycline induced cardiomyopathy patients compared to normal including increased interleukin-8 and MMP levels. With longer periods of anthracycline dosing, MMP-7, a marker of macrophage proteolytic activation, increased by 165 ± 54% whereas interleukin-10 an anti-inflammatory marker decreased by 75 ± 13% (both < 0.05). MMP7 correlated with time dependent changes in EF.

Conclusions: Asymptomatic pediatric patients exposed to anthracycline therapy develop abnormal strain parameters at lower cumulative doses when compared to changes in EF. A differential biomarker signature containing both inflammatory and matrix domains occur early in anthracycline treatment. Dynamic changes in these domains occur with increased anthracycline doses and progression to anthracycline induced cardiomyopathy. These findings provide potential prognostic and mechanistic insights into the natural history of anthracycline induced cardiomyopathy.

Trial Registration Number: NCT03211520 Date of Registration February 13, 2017, retrospectively registered.
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http://dx.doi.org/10.1186/s40959-018-0030-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995570PMC
May 2018

Cutaneous Toxicity in a Laboratory Beagle () after Chronic Administration of Doxorubicin Hydrochloride.

Comp Med 2018 02;68(1):56-62

Department of Comparative Medicine, Department of Medicine, Yale Translational Research Imaging Center, Yale University, New Haven, Connecticut.

An adult female beagle (Canis lupus familiaris) used in a model of doxorubicin-induced cardiomyopathy presented with epithelial desquamation on the shoulders and ventrum after receiving the 8th weekly intravenous dose of the free form of doxorubicin (20 mg/m2; total accumulation, 160 mg/m2). The lesions were empirically treated with topical disinfectants and topical and systemic antibiotics. Despite treatment, the lesions progressed and ulcerated. Bacterial culture revealed Staphylococcus aureus, but trichogram, skin scraping, and fungal culture were negative for microorganisms. Skin biopsies revealed epidermal and apocrine gland hyperplasia, apocrine gland dilation, abnormal maturation of epithelial keratinocytes, and perivascular lymphocytic infiltration. These histopathologic findings resemble those in humans and canines after chronic administration of doxorubicin-containing pegylated liposomes. Here we report a clinical presentation after chronic administration of the free form of doxorubicin. In dogs, cutaneous toxicity after administration of pegylated liposomal doxorubicin is most often localized to the footpads, limbs, and axillary and urogenital regions. In the current case, lesions affected the ventrum and trunk but did not involve the footpads or axillary or urogenital regions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824140PMC
February 2018

Surfactant protein C dampens inflammation by decreasing JAK/STAT activation during lung repair.

Am J Physiol Lung Cell Mol Physiol 2018 05 18;314(5):L882-L892. Epub 2018 Jan 18.

Department of Cell Biology, Yale School of Medicine , New Haven, Connecticut.

Surfactant protein C (SPC), a key component of pulmonary surfactant, also plays a role in regulating inflammation. SPC deficiency in patients and mouse models is associated with increased inflammation and delayed repair, but the key drivers of SPC-regulated inflammation in response to injury are largely unknown. This study focuses on a new mechanism of SPC as an anti-inflammatory molecule using SPC-TK/SPC-KO (surfactant protein C-thymidine kinase/surfactant protein C knockout) mice, which represent a novel sterile injury model that mimics clinical acute respiratory distress syndrome (ARDS). SPC-TK mice express the inducible suicide gene thymidine kinase from by the SPC promoter, which targets alveolar type 2 (AT2) cells for depletion in response to ganciclovir (GCV). We compared GCV-induced injury and repair in SPC-TK mice that have normal endogenous SPC expression with SPC-TK/SPC-KO mice lacking SPC expression. In contrast to SPC-TK mice, SPC-TK/SPC-KO mice treated with GCV exhibited more severe inflammation, resulting in over 90% mortality; there was only 8% mortality of SPC-TK animals. SPC-TK/SPC-KO mice had highly elevated inflammatory cytokines and granulocyte infiltration in the bronchoalveolar lavage (BAL) fluid. Consistent with a proinflammatory phenotype, immunofluorescence revealed increased phosphorylated signal transduction and activation of transcription 3 (pSTAT3), suggesting enhanced Janus kinase (JAK)/STAT activation in inflammatory and AT2 cells of SPC-TK/SPC-KO mice. The level of suppressor of cytokine signaling 3, an anti-inflammatory mediator that decreases pSTAT3 signaling, was significantly decreased in the BAL fluid of SPC-TK/SPC-KO mice. Hyperactivation of pSTAT3 and inflammation were rescued by AZD1480, a JAK1/2 inhibitor. Our findings showing a novel role for SPC in regulating inflammation via JAK/STAT may have clinical applications.
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http://dx.doi.org/10.1152/ajplung.00418.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008135PMC
May 2018

Immune responses to the real world.

Lab Anim (NY) 2017 12;47(1):13-14

Johns Hopkins School of Medicine, Department of Comparative Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1038/laban.1384DOI Listing
December 2017

Informatics Support for Basic Research in Biomedicine.

ILAR J 2017 07;58(1):80-89

Lister Hill National Center for Biomedical Communications, National Library of Medicine, Bethesda, Maryland. School of Information Sciences, University of Illinois, Urbana-Champaign; Center for Informatics in Science and Scholarship. Lister Hill National Center for Biomedical Communications, National Library of Medicine, Bethesda, Maryland. Lister Hill National Center for Biomedical Communications, National Library of Medicine, Bethesda, Maryland. Lister Hill National Center for Biomedical Communications, National Library of Medicine, Bethesda, Maryland. School of Information Sciences, University of Illinois Urbana-Champaign, Champaign, Illinois. Yale University School of Medicine, New Haven, Connecticut.

Informatics methodologies exploit computer-assisted techniques to help biomedical researchers manage large amounts of information. In this paper, we focus on the biomedical research literature (MEDLINE). We first provide an overview of some text mining techniques that offer assistance in research by identifying biomedical entities (e.g., genes, substances, and diseases) and relations between them in text.We then discuss Semantic MEDLINE, an application that integrates PubMed document retrieval, concept and relation identification, and visualization, thus enabling a user to explore concepts and relations from within a set of retrieved citations. Semantic MEDLINE provides a roadmap through content and helps users discern patterns in large numbers of retrieved citations. We illustrate its use with an informatics method we call "discovery browsing," which provides a principled way of navigating through selected aspects of some biomedical research area. The method supports an iterative process that accommodates learning and hypothesis formation in which a user is provided with high level connections before delving into details.As a use case, we examine current developments in basic research on mechanisms of Alzheimer's disease. Out of the nearly 90 000 citations returned by the PubMed query "Alzheimer's disease," discovery browsing led us to 73 citations on sortilin and that disorder. We provide a synopsis of the basic research reported in 15 of these. There is wide-spread consensus among researchers working with a range of animal models and human cells that increased sortilin expression and decreased receptor expression are associated with amyloid beta and/or amyloid precursor protein.
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http://dx.doi.org/10.1093/ilar/ilx004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886329PMC
July 2017

Bridging the Gap between Reproducibility and Translation: Data Resources and Approaches.

ILAR J 2017 07;58(1):1-3

Yale University School of Medicine, New Haven, Connecticut. University of Colorado, Anschutz Medical Campus in Aurora, Colorado.

Animal research has constituted a fundamental means to achieve groundbreaking therapies for human disease. However, for complex diseases, promising preclinical results have failed to translate to the clinic. Reasons for this disparity are multifactorial. These include the challenges inherent in modeling complex disease in animals, as well issues of study design, reproducibility and operational norms within the biomedical research enterprise. In this issue, we explore the range of information resources available for the comparative study of disease, as well as challenges to the ultimate translation of preclinical findings. Genomics resources in support of translational research are described for zebrafish, mice, rats and non-human primates. The utility of transcriptomics to explore the temporal basis of lesion development in toxicologic pathology is reviewed. Integration of the ever-increasing volume of text-based and bioinformatics data is a significant challenge, and in this issue, informatics resources and general text mining methodologies to explore and aggregate text data are described. Finally, factors contributing to both reproducibility and translatability are examined. Guidelines designed to address reproducibility are essential to improving individual studies. To this end, a viewpoint from the National Institutes of Health on measures needed to enhance rigor and reproducibility is given, as well as an overview of the role of the Institutional Animal Care and Use Committee in this regard. The challenge of improving generalizability of animal experiments so that their findings can be more frequently extended to the intended human population remains. Reasons why models that replicate key aspects of human disease fail to be predictive in humans are explored in two fields in which translation has been a challenge: sepsis and neurodegeneration.
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http://dx.doi.org/10.1093/ilar/ilx017DOI Listing
July 2017

From Reproducibility to Translation in Neurodegenerative Disease.

Authors:
Caroline J Zeiss

ILAR J 2017 07;58(1):106-114

Yale University School of Medicine, New Haven, Connecticut.

Despite tremendous investment and preclinical success in neurodegenerative disease, effective disease-altering treatments for patients have remained elusive. One highly cited reason for this discrepancy is flawed animal study design and reporting. If this can be broadly remedied, reproducibility of preclinical studies will improve. However, without concurrent efforts to improve generalizability, these improvements may not translate effectively from animal experiments to more complex human neurodegenerative diseases. Mechanistic and phenotypic variability of neurodegenerative disease is such that most models are only able to interrogate individual aspects of complex phenomena. One approach is to consider animals as models of individual targets rather than as models of individual diseases and to migrate the concept of predictive validity from the individual model to the body of experiments that demonstrate translatability of a target. Both exploratory and therapeutic preclinical studies are dependent upon study design methods that promote rigor and reproducibility. However, the body of evidence that is needed to demonstrate efficacy in therapeutic studies is substantially broader than that needed for exploratory studies. In addition to requiring rigor within individual experiments, convincing evidence for therapeutic potential must assess the relationships between model choice, intended goal of the intervention, pharmacologic criteria, and integration of biomarker data with outcome measures that are clinically relevant to humans. It is conceivable that proof-of-concept studies will migrate to cell-based systems and that animal systems will be increasingly reserved for more distal translational purposes. If this occurs, it is likely to prompt reexamination of what the term "translational" truly means.
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http://dx.doi.org/10.1093/ilar/ilx006DOI Listing
July 2017

β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares.

Cell Rep 2017 02;18(9):2077-2087

Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Yale Center for Research on Aging, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:

Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.
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http://dx.doi.org/10.1016/j.celrep.2017.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527297PMC
February 2017

Established patterns of animal study design undermine translation of disease-modifying therapies for Parkinson's disease.

PLoS One 2017 9;12(2):e0171790. Epub 2017 Feb 9.

Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

Translation of disease-modifying therapies in neurodegenerative disease has been disappointing. Parkinson's disease (PD) was used to compare patterns of preclinical study design for symptomatic and potentially disease-modifying interventions. We examined the relationship of model, intervention type and timing, outcomes and outcome measures in 543 animal and human studies (1973-2015) across a contemporary cohort of animal and human interventional studies (n = 445), animal studies for approved interventions (n = 28), animal and human studies for those that failed to translate (n = 70). Detailed study design data were collected for 216 studies in non-human primate (NHP) and rodent toxin-induced models. Species-specific patterns of study design prevailed regardless of whether interventions were symptomatic or potentially disease-modifying. In humans and NHPs, interventions were typically given to both sexes well after the PD phenotype was established, and clinical outcome measures were collected at single (symptomatic) or multiple (disease-modifying) time-points. In rodents, interventions often preceded induction of the model, acute toxic protocols were common, usually given to young males, clinical outcome measures were used less commonly, and outcomes were less commonly assessed at multiple time points. These patterns were more prevalent in mice than rats. In contrast, study design factors such as randomization and blinding did not differ appreciably across symptomatic and disease-modifying intervention categories. The translational gap for potentially disease-modifying interventions in PD in part results from study designs, particularly in mice, that fail to model the progressive nature and relatively late intervention characteristic of PD, or that anchor mechanistic and neuropathologic data to longitudinal clinical outcomes. Even if measures to improve reproducibility are broadly adopted, perpetuation of these norms will continue to impede effective translation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300282PMC
September 2017

Long-Term Clinical Outcomes in Diabetic Rhesus Macaques (Macaca mulatta) Treated with Medroxyprogesterone Acetate for Endometriosis.

Comp Med 2016 ;66(4):343-8

Section of Comparative Medicine, Yale University, New Haven, Connecticut, USA.

Depot medroxyprogesterone acetate (DMPA) is a common medical treatment for endometriosis in NHP. Because DMPA reportedly impairs glucoregulatory function in humans and rhesus macaques, as well as predisposes humans to diabetes mellitus (DM), we performed a retrospective study to further investigate its potential long-term clinical effects in animals with and without DM. Using a cohort of 29 rhesus macaques, we explored the hypotheses that DMPA treatment accelerates the onset of DM and that its use in rhesus macaques with endometriosis worsens clinical outcome measures (lifespan, body weight and body condition score). For both body weight and body condition score, a declining and statistically significant trend in mean values was evident as macaques developed either DM, or endometriosis or both. The addition of DMPA did not significantly alter this pattern. The presence of DM, endometriosis, or DMPA treatment statistically but not clinically significantly increased risk of death. Similarly, the presence of the 2 highly correlated variables endometriosis and DMPA treatment statistically but not clinically significantly increased the risk of incident DM. These results indicate that DMPA treatment was associated with worsening trends in lifespan and incident DM, however these trends did not achieve clinical significance in this cohort.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983176PMC
October 2017

Demodex musculi Infestation in Genetically Immunomodulated Mice.

Comp Med 2016 ;66(4):278-85

Department of Comparative Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Demodex musculi, a prostigmatid mite that has been reported infrequently in laboratory mice, has been identified with increasing frequency in contemporary colonies of immunodeficient mice. Here we describe 2 episodes of D. musculi infestation with associated clinical signs in various genetically engineered mouse strains, as well as treatment strategies and an investigation into transmissibility and host susceptibility. The first case involved D. musculi associated with clinical signs and pathologic lesions in BALB/c-Tg(DO11.10)Il13(tm) mice, which have a defect in type 2 helper T cell (Th2) immunity. Subsequent investigation revealed mite transmission to both parental strains (BALB/c-Tg[DO11.10] and BALB/c-Il13(tm)), BALB/c-Il13/Il4(tm), and wild-type BALB/c. All Tg(DO11.10)Il13(tm) mice remained infested throughout the investigation, and D. musculi were recovered from all strains when they were cohoused with BALB/c-Tg(DO11.10)Il13(tm) index mice. However, only Il13(tm) and Il13/Il4(tm) mice demonstrated persistent infestation after index mice were removed. Only BALB/c-Tg(DO11.10)Il13(tm) showed clinical signs, suggesting that the phenotypic dysfunction of Th2 immunity is sufficient for persistent infestation, whereas clinical disease associated with D. musculi appears to be genotype-specific. This pattern was further exemplified in the second case, which involved NOD.Cg-Prkdc(scid)Il2r(tm1Wjl)/SzJ (NSG) and C;129S4 Rag2(tm1.1Flv) Il2rg(tm1.1Flv)/J mice with varying degrees of blepharitis, conjunctivitis, and facial pruritis. Topical amitraz decreased mite burden but did not eliminate infestation or markedly ameliorate clinical signs. Furthermore, mite burden began to increase by 1 mo posttreatment, suggesting that topical amitraz is an ineffective treatment for D. musculi. These experiences illustrate the need for vigilance regarding opportunistic and uncommon pathogens in rodent colonies, especially among mice with immunologic deficits.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983169PMC
October 2017

Clostridium perfringens enterotoxin C-terminal domain labeled to fluorescent dyes for in vivo visualization of micrometastatic chemotherapy-resistant ovarian cancer.

Int J Cancer 2015 Dec 18;137(11):2618-29. Epub 2015 Aug 18.

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT.

Identification of micrometastatic disease at the time of surgery remains extremely challenging in ovarian cancer patients. We used fluorescence microscopy, an in vivo imaging system and a fluorescence stereo microscope to evaluate fluorescence distribution in Claudin-3- and -4-overexpressing ovarian tumors, floating tumor clumps isolated from ascites and healthy organs. To do so, mice harboring chemotherapy-naïve and chemotherapy-resistant human ovarian cancer xenografts or patient-derived xenografts (PDXs) were treated with the carboxyl-terminal binding domain of the Clostridium perfringens enterotoxin (c-CPE) conjugated to FITC (FITC-c-CPE) or the near-infrared (NIR) fluorescent tag IRDye CW800 (CW800-c-CPE) either intraperitoneally (IP) or intravenously (IV). We found tumor fluorescence to plateau at 30 min after IP injection of both the FITC-c-CPE and the CW800-c-CPE peptides and to be significantly higher than in healthy organs (p < 0.01). After IV injection of CW800-c-CPE, tumor fluorescence plateaued at 6 hr while the most favorable tumor-to-background fluorescence ratio (TBR) was found at 48 hr in both mouse models. Importantly, fluorescent c-CPE was highly sensitive for the in vivo visualization of peritoneal micrometastatic tumor implants and the identification of ovarian tumor spheroids floating in malignant ascites that were otherwise not detectable by conventional visual observation. The use of the fluorescent c-CPE peptide may represent a novel and effective optical approach at the time of primary debulking surgery for the real-time detection of micrometastatic ovarian disease overexpressing the Claudin-3 and -4 receptors or the identification of residual disease at the time of interval debulking surgery after neoadjuvant chemotherapy treatment.
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http://dx.doi.org/10.1002/ijc.29632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573336PMC
December 2015

Improving the predictive value of interventional animal models data.

Authors:
Caroline J Zeiss

Drug Discov Today 2015 Apr 4;20(4):475-82. Epub 2014 Nov 4.

Section of Comparative Medicine, Yale University School of Medicine, 375 Congress Ave, New Haven, CT 06520, USA. Electronic address:

For many chronic diseases, translational success using the animal model paradigm has reached an impasse. Using Alzheimer's disease as an example, this review employs a networks-based method to assess repeatability of outcomes across species, by intervention and mechanism. Over 75% of animal studies reported an improved outcome. Strain background was a significant potential confounder. Five percent of interventions had been tested across animals and humans, or examined across three or more animal models. Positive outcomes across species emerged for donepezil, memantine and exercise. Repeatable positive outcomes in animals were identified for the amyloid hypothesis and three additional mechanisms. This approach supports in silico reduction of positive outcomes bias in animal studies.
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http://dx.doi.org/10.1016/j.drudis.2014.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417064PMC
April 2015

Invasive ductular carcinoma in 2 rhesus macaques (Macaca mulatta).

Comp Med 2014 Aug;64(4):314-22

Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

In the United States, breast cancer is the most common malignancy among women, with an estimated lifetime incidence of approximately 12% in American women. Invasive ductal carcinoma is the most common form of breast cancer in women, accounting for approximately 60% of all breast carcinomas. Prognostic markers are used to assess aggressiveness, invasiveness, and extent of spread of a neoplasm and thus may be correlated with patient survival. Immunohistochemistry is currently widely used for this purpose, with a variety of prognostication markers available. Classic markers for breast cancer in women include estrogen and progesterone receptor steroid hormone proteins and human epidermal growth factor receptor 2. Many additional markers have been used in diagnosis and prognostication, including p53, p63, and E-cadherin and cell proliferation markers such as Ki67. Despite an estimated lifetime incidence of approximately 6.1%, naturally occurring mammary neoplasms in nonhuman primates are uncommonly reported, with only sporadic references over the past 75 y. The majority of reported tumors occur in rhesus macaques, although this prevalence has been suggested to be a consequence of their high frequency of usage in biomedical research. Here we present 2 cases of mammary carcinoma in adult female intact rhesus macaques, with cytology, histopathology, and extensive immunohistochemical analysis. According to current classifications for human breast tumors, both tumors were classified as invasive ductal carcinoma. The prognostic value of immunohistochemical markers in human breast cancer and in reported cases in nonhuman primates is discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170097PMC
August 2014