Center for Comparative Medicine

Davis, CA, United States

Center for Comparative Medicine

Davis, CA, United States
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Asmuth D.M.,University of California at Davis | Ma Z.-M.,University of California at Davis | Ma Z.-M.,Center for Comparative Medicine | Mann S.,University of California at Davis | And 10 more authors.
AIDS | Year: 2012

Objectives: To examine immune restoration in duodenal tissue and correlates of reduction of immune activation in chronic HIV-infected patients randomized to different treatment regimens. Design: Randomized clinical trial (RCT) comparing raltegravir to a non-nucleoside reverse transcriptase inhibitor-based regimen, both with fixed-dose tenofovir difumerate/emtricitabine. Methods: Antiretroviral therapy (ART)-naive volunteers underwent upper endoscopy for duodenal biopsies before and after 9 months of therapy. Tissue was paraffin-embedded for immunohistochemistry or digested into single-cell suspensions for flow cytometry of lymphocyte subsets and activation phenotype. Plasma-soluble CD14 levels were measured as a surrogate for bacterial translocation. Results: Sixteen HIV-positive and seven control individuals completed study procedures. Small increases in duodenal lamina propria CD4 T-cell numbers were observed, especially when viewed relative to populations in control volunteers, with no differences between treatment arms. The increase in CD4 T-cell percentage was due largely to declines in CD8 T-cell numbers, which were disproportionately increased compared to peripheral blood and controls. Patients randomized to the raltegravir arm had consistent declines in both sCD14 levels and CD8 T-cell numbers in the duodenal tissue lamina propria. Conclusions: This first RCT of lymphocyte population restoration in duodenal tissue demonstrates more modest increases in CD4 T-cell numbers during the first 9 months of therapy than when considering CD3/CD4 percentages only. Although reduced after 9 months of ART, disproportional increased CD8 populations persist in duodenal gastrointestinal-associated lymphoid tissue (GALT). Local rather than systemic antigenic stimulation appears to be driving expanded CD8 T lymphocytes in GALT. Factors other than viral-induced CD8 expansion may be contributing to this local immunologic response. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Asmuth D.M.,University of California at Davis | Asmuth D.M.,Veterans Administration Northern California Healthcare System | Ma Z.-M.,University of California at Davis | Ma Z.-M.,Center for Comparative Medicine | And 12 more authors.
AIDS | Year: 2013

Objectives: To examine the impact of serum-derived bovine immunoglobulin, an oral medical food known to neutralize bacterial antigen and reduce intestinal inflammation, on restoration of mucosal immunity and gastrointestinal function in individuals with HIV enteropathy. Design: Open-label trial with intensive 8-week phase of bovine serum immunoglobulin (SBI) 2.5 g twice daily with a 4-week washout period and an optional 9-month extension study. Methods: HIV enteropathy was defined as chronic gastrointestinal symptoms including frequent loose or watery stools despite no identifiable, reversible cause. Upper endoscopy for tissue immunofluorescent antibody assay and disaccharide gut permeability/absorption studies were performed before and after 8 weeks of SBI to test mucosal immunity and gastrointestinal function. Blood was collected for markers of microbial translocation, inflammation, and collagen kinetics. A validated gastrointestinal questionnaire assessed changes in symptoms. Results: All eight participants experienced profound improvement in symptoms with reduced bowel movements/day (P=0.008) and improvements in stool consistency (P=0.008). Gut permeability was normal before and after the intervention, but D-xylose absorption increased in seven of eight participants. Mucosal CD4+ lymphocyte densities increased by a median of 139.5 cells/mm2 from 213 to 322 cells/mm2 (P=0.016). Intestinal-fatty acid binding protein (I-FABP), a marker of enterocyte damage, initially rose in seven of eight participants after 8 weeks (P=0.039), and then fell below baseline in four of five who continued receiving SBI (P=0.12). Baseline serum I-FABP levels were negatively correlated with subsequent rise in mucosal CD4+ lymphocyte densities (r= -0.74, P=0.046). Conclusion: SBI significantly increases intestinal mucosal CD4+ lymphocyte counts, improves duodenal function, and showed evidence of promoting intestinal repair in the setting of HIV enteropathy. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Baumgarth N.,University of California at Davis | Waffarn E.E.,Center for Comparative Medicine | Nguyen T.T.,Center for Comparative Medicine
Annals of the New York Academy of Sciences | Year: 2015

Mouse B-1 cells are not only major producers of steady-state natural antibodies but also rapid responders to infections and inflammation. These discrete functions may be the outcomes of distinct environmental or developmental triggers that drive B-1 cells toward IgM production or an effector cell fate. Alternatively, distinct B-1 cell subsets may exist, which differ in their functional plasticity. In this paper, we summarize existing data suggesting that B-1 cells form a heterogeneous group of cells with distinct developmental requirements and nonoverlapping functions. Most spleen B-1 cells differ in development from that of bone marrow and peritoneal cavity B-1 cells, in that they develop in the absence of natural IgM. Functional heterogeneity is revealed by findings that B-1 cells in the bone marrow and spleen, but not the peritoneal cavity, generate natural serum IgM, while the latter are rapid responders to inflammatory and infectious insults, resulting in their relocation to secondary lymphoid tissues. A clearer understanding of the developmental and functional differences within the B-1 cell pool may reveal how they might be harnessed for prophylaxis or therapy. © 2015 New York Academy of Sciences.

Weiss E.E.,Center for Laboratory Animal Science | Evans K.D.,Center for Comparative Medicine | Griffey S.M.,University of California at Davis
Journal of the American Association for Laboratory Animal Science | Year: 2012

Fur mites were diagnosed in a colony of mice at our research institution. In the current study, we compared the effectiveness of PCR and tape test in a small population of mice at the onset of diagnosis and throughout treatment. Samples were collected 1 d prior to treatment with permethrin impregnated cotton balls and 6 and 12 wk after treatment. PCR confirmed the presence of Myocoptes musculinus and Radfordia affinis or Myobia musculi, but tape test confirmed only the presence of Myocoptes spp. The results of the PCR and tape test agreed 97.2% of the time during active infection on day 1, but only 59.5% and 48.4% of results coincided at 6 and 12 wk after treatment, respectively. At 6 wk, 11 of the 37 samples were PCR-negative but tape-test-positive, compared with 9 of the 31 samples at 12 wk. Our results show that PCR is a reliable diagnostic method during active fur mite infection but that false-negative results are possible after treatment. Negative PCR results after treatment should be interpreted carefully, and a secondary diagnostic method should be considered. Copyright © 2012 by the American Association for Laboratory Animal Science.

Darlington Y.,Baylor College of Medicine | Nguyen T.-A.,Baylor College of Medicine | Moon S.-H.,Baylor College of Medicine | Herron A.,Center for Comparative Medicine | And 4 more authors.
Oncogene | Year: 2012

Wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that dephosphorylates proteins in the ataxia telangiectasia mutated (ATM)-initiated DNA damage response pathway. WIP1 may have a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair. To better understand the effects of WIP1 on ATM signaling, we crossed Atm-deficient mice to Wip1-deficient mice and characterized phenotypes of the double knockout progeny. We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes. Atm null mice, like ATM-deficient humans with the inherited syndrome ataxia telangiectasia, exhibit radiation sensitivity, fertility defects, and are T-cell lymphoma prone. Most double knockout mice were largely protected from lymphoma development and had a greatly extended lifespan compared with Atm null mice. Double knockout mice had increased p53 and H2AX phosphorylation and p21 expression compared with their Atm null counterparts, indicating enhanced p53 and DNA damage responses. Additionally, double knockout splenocytes displayed reduced chromosomal instability compared with Atm null mice. Finally, doubly null mice were partially rescued from gametogenesis defects observed in Atm null mice. These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular. © 2012 Macmillan Publishers Limited All rights reserved.

Gupta S.,University of California at Irvine | Pegu P.,Animal Models and Retroviral Vaccine Section | Venzon D.J.,U.S. National Institutes of Health | Gach J.S.,University of California at Irvine | And 6 more authors.
Journal of Infectious Diseases | Year: 2015

Background. The time to acquisition of simian immunodeficiency virus (SIV) infection following low-dose repeated rectal challenge correlated inversely with the number of transmitted/founder strains among macaques vaccinated with ALVAC-SIV/gp120 or gp120 alone. We determined if the ability of postvaccination, prechallenge sera to enhance SIVmac251 transcytosis across epithelial cells was associated with transmitted/founder strain number. Methods.Transcytosis was carried out by exposing sera and SIVmac251 to the apical surface of human endometrial carcinoma (HEC-1A) cells at pH 6.0 and 12 hours later quantifying virus in fluid bathing the basolateral cell surface (maintained at pH 7.4). These conditions allow Fc neonatal receptor (FcRn)-dependent shuttling of virus across cells. Results.There was a strong correlation between the amount of virus transcytosed and number of transmitted variants (R = 0.86, P <. 0001). We also found that 4 animals who remained uninfected after repeated rectal challenges had lower serum transcytosis activity than did 19 animals who subsequently became infected (P =. 003). Using immunohistochemistry, we demonstrated FcRn on columnar epithelial cells facing the lumen of the macaque rectum. Conclusions.Vaccine-induced antibody capable of enhancing transcytosis in vitro via FcRn may play a role in determining transmitted/founder strain number and infection outcomes following in vivo challenge. © 2014 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

PubMed | Center for Comparative Medicine, Comparative Pathology Laboratory and and University of California at Davis
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

RNA-binding motif protein 38 (Rbm38), also called RNPC1 [RNA-binding region (RNP1, RRM) containing 1], is a target of the p53 family and modulates p53 expression via mRNA translation. To investigate the biological function of Rbm38 in vivo, we generated an Rbm38-null mouse model. We showed that mice deficient in Rbm38 exhibit signs of accelerated aging and are prone to hematopoietic defects and spontaneous tumors. To determine the biological significance of the p53-Rbm38 loop, we showed that Rbm38 deficiency enhances accumulation of p53 induced by ionizing radiation (IR) and sensitizes mice to IR-induced lethality in a p53-dependent manner. Most importantly, Rbm38 deficiency markedly decreases the tumor penetrance in mice heterozygous for p53 via enhanced p53 expression. Interestingly, we found that Rbm38 deficiency shortens the life span of, and promotes lymphomagenesis in, mice deficient in p53. These results provide genetic evidence that Rbm38 is necessary for normal hematopoiesis and for suppressing accelerated aging and tumorigenesis. Thus, the p53-Rbm38 axis might be explored for extending longevity and for tumor suppression.

Moore M.E.,Center for Comparative Medicine | Boren T.,Umeå University | Solnick J.V.,Center for Comparative Medicine
Gut Microbes | Year: 2011

Helicobacter pylori is the primary cause of peptic ulcer disease and is estimated to account for about 60% of all cases of gastric cancer, the second most common cause of cancer death worldwide. Among the H. pylori virulence factors associated with disease, in addition to the well-known cag pathogenicity island, is the BabA adhesin, an outer membrane protein that binds with high affinity to fucosylated glycans on the gastric epithelium, such as Lewis B (Leb) and related terminal fucose residues found on the blood group O (H antigen), A and B antigens. BabA-mediated attachment to the gastric mucosa promotes chronic inflammation and gastric pathology, which from the bacterial perspective carries both risks and benefits. We recently described modulation in expression of BabA and related outer membrane proteins that occurs during colonization of experimental animals.1,2 Here we put these findings into a broader context, and speculate on their implications for the host-pathogen relationship. © 2011 Landes Bioscience.

Cardiff R.D.,Center for Comparative Medicine | Borowsky A.D.,Center for Comparative Medicine
Journal of Clinical Investigation | Year: 2014

Current breast cancer classification systems are based on molecular evaluation of tumor receptor status and do not account for distinct morphological phenotypes. In other types of cancer, taxonomy based on normal cell phenotypes has been extremely useful for diagnosis and treatment strategies. In this issue of the JCI, Santagata and colleagues developed a breast cancer classification scheme based on characterization of healthy mammary cells. Reclassification of breast cancer cells and breast cancer tissue microarrays with this system correlated with prognosis better than the standard receptor status designation. This scheme provides a major advance toward our understanding of the origin of the cells in the breast and breast cancers. © Copyright 2014 American Society for Clinical Investigation.

PubMed | Center for Comparative Medicine
Type: Journal Article | Journal: American journal of physiology. Lung cellular and molecular physiology | Year: 2011

Infection with Mycobacterium tuberculosis primarily produces a multifocal distribution of pulmonary granulomas in which the pathogen resides. Accordingly, quantitative assessment of the bacterial load and pathology is a substantial challenge in tuberculosis. Such assessments are critical for studies of the pathogenesis and for the development of vaccines and drugs in animal models of experimental M. tuberculosis infection. Stereology enables unbiased quantitation of three-dimensional objects from two-dimensional sections and thus is suited to quantify histological lesions. We have developed a protocol for stereological analysis of the lung in rhesus macaques inoculated with a pathogenic clinical strain of M. tuberculosis (Erdman strain). These animals exhibit a pattern of infection and tuberculosis similar to that of naturally infected humans. Conditions were optimized for collecting lung samples in a nonbiased, random manner. Bacterial load in these samples was assessed by a standard plating assay, and granulomas were graded and enumerated microscopically. Stereological analysis provided quantitative data that supported a significant correlation between bacterial load and lung granulomas. Thus this stereological approach enables a quantitative, statistically valid analysis of the impact of M. tuberculosis infection in the lung and will serve as an essential tool for objectively comparing the efficacy of drugs and vaccines.

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