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1. Elimination or Prolongation of ACE Inhibitors and ARB in Coronavirus Disease 2019 (REPLACECOVID)

Author: Jordana B. Cohen, MD, MSCE, Thomas C. Hanff, MD, MPH, University of Arizona, Department of Medicine, Hospital Nacional Carlos Alberto Seguín Escobedo, Arequipa, Peru, Department of Nephrology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru, Hypertension Unit, Department of Pathology, Hospital Español de Mendoza, National University of Cuyo, IMBECU-CONICET, Mendoza, Argentina, Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA, Division of Infectious Diseases, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada, Unidad de VIH, Hospital Civil de Guadalajara and Universidad de Guadalajara, Guadalajara, Mexico, Universidad Católica de Buenos Aires, Buenos Aires, Argentina, Departamento de Medicina Interna, Hospital Obrero number 3 Caja Nacional de Salud, Santa Cruz de la Sierra, Bolivia, Departamento de Medicina, Hospital Alberto Barton Thompson, Callao, Peru, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden, Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA, Departamento de Emergencia, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru, Division of Cardiology, Department of Medicine, Hospital Español, Buenos Aires, Argentina, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA, Jesse Chittams, MS, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA, Charles R Vasquez, MD, and Julio A. Chirinos, Associate Professor of Medicine at the Hospital of the University of Pennsylvania
Published: 2021

2. Wnt Signaling Promotes Neuronal Differentiation from Mesenchymal Stem Cells Through Activation of Tlx3

Author: Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Pediatrics University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Pediatrics University of Michigan Medical School, Ann Arbor, Michigan, USA ; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA, Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA ; Telephone: 317-278-9621; Fax: 317-278-9620 ; Stark Neurosciences Research Institute, Indiana University School of Medicine, 950 West Walnut Street, R2-419, Indianapolis, Indiana 46202, USA, Kondo, Takako, Matsuoka, Akihiro J., Shimomura, Atsushi, Koehler, Karl R., Chan, Rebecca J., Miller, Josef M., Srour, Edward F., Hashino, Eri, Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Pediatrics University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Pediatrics University of Michigan Medical School, Ann Arbor, Michigan, USA ; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA, Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA ; Telephone: 317-278-9621; Fax: 317-278-9620 ; Stark Neurosciences Research Institute, Indiana University School of Medicine, 950 West Walnut Street, R2-419, Indianapolis, Indiana 46202, USA, Kondo, Takako, Matsuoka, Akihiro J., Shimomura, Atsushi, Koehler, Karl R., Chan, Rebecca J., Miller, Josef M., Srour, Edward F., and Hashino, Eri
Abstract: Wnt/??-catenin signaling promotes neural differentiation by activation of the neuron-specific transcription factors, Neurogenin1 ( Ngn1 ), NeuroD , and Brn3a , in the nervous system. As neurons in cranial sensory ganglia and dorsal root ganglia transiently express Ngn1, NeuroD , and Brn3a during embryonic development, we hypothesized that Wnt proteins could instructively promote a sensory neuronal fate from mesenchymal stem cells (MSCs) directed to differentiate into neurons. Consistent with our hypothesis, Wnt1 induced expression of sensory neuron markers including Ngn1, NeuroD , and Brn3a , as well as glutamatergic markers in neurally induced MSCs in vitro and promoted engraftment of transplanted MSCs in the inner ear bearing selective loss of sensory neurons in vivo. Given the consensus function of T-cell leukemia 3 ( Tlx3 ), as a glutamatergic selector gene, we postulated that the effects of canonical Wnt signaling on sensory neuron and glutamatergic marker gene expression in MSCs may be mediated by Tlx3 . We first confirmed that Wnt1 indeed upregulates Tlx3 expression, which can be suppressed by canonical Wnt inhibitors. Next, our chromatin immunoprecipitation assays revealed that T-cell factor 3/4, Wnt-activated DNA binding proteins, interact with a regulatory region of Tlx3 in MSCs after neural induction. Furthermore, we demonstrated that forced expression of Tlx3 in MSCs induced sensory and glutamatergic neuron markers after neural induction. Together, these results identify Tlx3 as a novel target for canonical Wnt signaling that confers somatic stem cells with a sensory neuron phenotype upon neural induction. S TEM C ELLS 2011;29:836???846
Published: 2011

3. A complex 6p25 rearrangement in a child with multiple epiphyseal dysplasia

Author: Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan ; Division of Pediatric Genetics, University of Michigan Medical Center, D5240 MPB, 1500 East Medical Center Drive, SPC 5718, Ann Arbor, MI 48109-5718., Department of Otolaryngology-Head and Neck Surgery, The University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan ; Department of Human Genetics, The University of Michigan Medical School, Ann Arbor, Michigan, Bedoyan, Jirair K., Lesperance, Marci M., Ackley, Todd, Iyer, Ramaswamy K., Innis, Jeffrey W., Misra, Vinod K., Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan ; Division of Pediatric Genetics, University of Michigan Medical Center, D5240 MPB, 1500 East Medical Center Drive, SPC 5718, Ann Arbor, MI 48109-5718., Department of Otolaryngology-Head and Neck Surgery, The University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan ; Department of Human Genetics, The University of Michigan Medical School, Ann Arbor, Michigan, Bedoyan, Jirair K., Lesperance, Marci M., Ackley, Todd, Iyer, Ramaswamy K., Innis, Jeffrey W., and Misra, Vinod K.
Abstract: Genomic rearrangements are increasingly recognized as important contributors to human disease. Here we report on an 11½-year-old child with myopia, Duane retraction syndrome, bilateral mixed hearing loss, skeletal anomalies including multiple epiphyseal dysplasia, and global developmental delay, and a complex 6p25 genomic rearrangement. We have employed oligonucleotide-based comparative genomic hybridization arrays (aCGH) of different resolutions (44 and 244K) as well as a 1 M single nucleotide polymorphism (SNP) array to analyze this complex rearrangement. Our analyses reveal a complex rearrangement involving a ∼2.21 Mb interstitial deletion, a ∼240 kb terminal deletion, and a 70–80 kb region in between these two deletions that shows maintenance of genomic copy number. The interstitial deletion contains eight known genes, including three Forkhead box containing (FOX) transcription factors ( FOXQ1 , FOXF2 , and FOXC1 ). The region maintaining genomic copy number partly overlaps the dual specificity protein phosphatase 22 ( DUSP22 ) gene. Array analyses suggest a homozygous loss of genomic material at the 5′ end of DUSP22 , which was corroborated using TaqMan® copy number analysis. It is possible that this homozygous genomic loss may render both copies of DUSP22 or its products non-functional. Our analysis suggests a rearrangement mechanism distinct from a previously reported replication-based error-prone mechanism without template switching for a specific 6p25 rearrangement with a 1.22 Mb interstitial deletion. Our study demonstrates the utility and limitations of using oligonucleotide-based aCGH and SNP array technologies of increasing resolutions in order to identify complex DNA rearrangements and gene disruptions. © 2010 Wiley-Liss, Inc.
Published: 2011

4. First Symposium on ???Anatomie im Nationalsozialismus??? (???Anatomy in National Socialism???), W??rzburg, Germany, September 29, 2010

Author: Division of Anatomical Sciences, Office of Medical Education, University of Michigan Medical School, Ann Arbor, Michigan, USA ; Department of Anatomical Sciences, Office of Medical Education, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Anatomical Sciences Office of Medical Education University of Michigan Medical School Ann Arbor, Michigan, USA, Hildebrandt, Sabine, Division of Anatomical Sciences, Office of Medical Education, University of Michigan Medical School, Ann Arbor, Michigan, USA ; Department of Anatomical Sciences, Office of Medical Education, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Anatomical Sciences Office of Medical Education University of Michigan Medical School Ann Arbor, Michigan, USA, and Hildebrandt, Sabine
Abstract: No abstract.
Published: 2011

5. RESPONSE LETTER TO DRS. MARTIN AND ALESSI

Author: Sleep Disorders Center, Department of Neurology, University of Michigan Health System, Ann Arbor, MI, Department of Health Management and Policy, School of Public Health, Institute of Gerontology, University of Michigan Medical School, Ann Arbor, MI, Institute of Gerontology, University of Michigan Medical School, Ann Arbor, MI, Avidan, Alon Y., Fries, Brant E., Szafara, Kristina L., Chervin, Ronald D., Sleep Disorders Center, Department of Neurology, University of Michigan Health System, Ann Arbor, MI, Department of Health Management and Policy, School of Public Health, Institute of Gerontology, University of Michigan Medical School, Ann Arbor, MI, Institute of Gerontology, University of Michigan Medical School, Ann Arbor, MI, Avidan, Alon Y., Fries, Brant E., Szafara, Kristina L., and Chervin, Ronald D.
Published: 2010

6. African ancestry and higher prevalence of triple-negative breast cancer

Author: Department of Pathology, University of Michigan, Ann Arbor, Michigan, University of Michigan Medical School, Ann Arbor, Michigan, University of Michigan Medical School, Ann Arbor, Michigan ; Breast Care Center, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan ; Department of Surgery, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, University of Michigan Medical School, Ann Arbor, Michigan ; Breast Care Center, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan ; Department of Surgery, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan ; Fax: (734) 647-9647 ; Director, Breast Care Center, Professor, Department of Surgery, University of Michigan, 1500 E. Medical Center Drive, 3308 Cancer Center, Ann Arbor, MI 48109-0932, Department of Pathology, Ford Health System, Detroit, Michigan ; Center for Clinical Epidemiology and Biostatistics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, School of Public Health, University of Illinois, Chicago, Illinois, Komfo Anokye Teaching Hospital, Kumasi, Ghana, Department of Pathology, Ford Health System, Detroit, Michigan, Stark, Azadeh, Kleer, Celina G., Martin, Iman, Awuah, Baffour, Nsiah-Asare, Anthony, Takyi, Valerie, Braman, Maria, E. Quayson, Solomon, Zarbo, Richard, Wicha, Max, Newman, Lisa, Department of Pathology, University of Michigan, Ann Arbor, Michigan, University of Michigan Medical School, Ann Arbor, Michigan, University of Michigan Medical School, Ann Arbor, Michigan ; Breast Care Center, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan ; Department of Surgery, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, University of Michigan Medical School, Ann Arbor, Michigan ; Breast Care Center, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan ; Department of Surgery, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan ; Fax: (734) 647-9647 ; Director, Breast Care Center, Professor, Department of Surgery, University of Michigan, 1500 E. Medical Center Drive, 3308 Cancer Center, Ann Arbor, MI 48109-0932, Department of Pathology, Ford Health System, Detroit, Michigan ; Center for Clinical Epidemiology and Biostatistics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, School of Public Health, University of Illinois, Chicago, Illinois, Komfo Anokye Teaching Hospital, Kumasi, Ghana, Department of Pathology, Ford Health System, Detroit, Michigan, Stark, Azadeh, Kleer, Celina G., Martin, Iman, Awuah, Baffour, Nsiah-Asare, Anthony, Takyi, Valerie, Braman, Maria, E. Quayson, Solomon, Zarbo, Richard, Wicha, Max, and Newman, Lisa
Abstract: BACKGROUND: The study of breast cancer in women with African ancestry offers the promise of identifying markers for risk assessment and treatment of triple-negative disease. METHODS: African American and white American women with invasive cancer diagnosed at the Henry Ford Health System comprised the primary study population, and Ghanaian patients diagnosed and/or treated at the Komfo Anokye Teaching Hospital in Kumasi, Ghana constituted the comparison group. Formalin-fixed, paraffin-embedded specimens were transported to the University of Michigan for histopathology confirmation, and assessment of estrogen and progesterone receptors and HER-2/ neu expression. RESULTS: The study population included 1008 white Americans, 581 African Americans, and 75 Ghanaians. Mean age at diagnosis was 48.0 years for Ghanaian, 60.8 years for African American, and 62.4 for white American cases ( P = .002). Proportions of Ghanaian, African American, and white American cases with estrogen receptor-negative tumors were 76%, 36%, and 22%, respectively ( P < .001), and proportions with triple-negative disease were 82%, 26%, and 16%, respectively ( P < .001). All Ghanaian cases were palpable, locally advanced cancers; 57 (76%) were grade 3. A total of 147 American women were diagnosed as stage III or IV; of these, 67.5% (n = 46) of African Americans and 44.6% (n = 29) of white Americans were grade 3. Among palpable, grade 3 cancers, Ghanaians had the highest prevalence of triple-negative tumors (82.2%), followed by African Americans (32.8%) and white Americans (10.2%). CONCLUSIONS: Our study demonstrates progressively increasing frequency of estrogen receptor-negative and triple-negative tumors among breast cancer patients with white American, African American, and Ghanaian/African backgrounds. This pattern indicates a need for additional investigations correlating the extent of African ancestry and high-risk breast cancer subtypes. Cancer 2010. ?? 2010 American Cancer Society.
Published: 2010

7. Expression and function of CXCL16 in a novel model of gout

Author: University of Michigan Medical School, Ann Arbor ; University of Michigan Medical School, Division of Rheumatology, 109 Zina Pitcher Place, 4023 BSRB Box 2200, Ann Arbor, MI 48109-2200, University of Michigan Medical School, Ann Arbor, University of Michigan Medical School and Ann Arbor VA Medical Center, Ann Arbor, Ruth, Jeffrey H., Arendt, Monica D., Amin, M. Asif, Ahmed, Salahuddin, Marotte, Hubert, Rabquer, Bradley J., Lesch, Charles, Lee, Solhee, Koch, Alisa E., University of Michigan Medical School, Ann Arbor ; University of Michigan Medical School, Division of Rheumatology, 109 Zina Pitcher Place, 4023 BSRB Box 2200, Ann Arbor, MI 48109-2200, University of Michigan Medical School, Ann Arbor, University of Michigan Medical School and Ann Arbor VA Medical Center, Ann Arbor, Ruth, Jeffrey H., Arendt, Monica D., Amin, M. Asif, Ahmed, Salahuddin, Marotte, Hubert, Rabquer, Bradley J., Lesch, Charles, Lee, Solhee, and Koch, Alisa E.
Abstract: Objective To better define the activity of soluble CXCL16 in the recruitment of polymorphonuclear neutrophils (PMNs) in vivo, utilizing a novel animal model of gout involving engraftment of SCID mice with normal human synovial tissue (ST) injected intragraft with gouty human synovial fluid (SF). Methods For in vitro studies, a modified Boyden chemotaxis system was used to identify CXCL16 as an active recruitment factor for PMNs in gouty SF. Migration of PMNs could be reduced by neutralization of CXCL16 activity in gouty SF. For in vivo analyses, fluorescent dye???tagged PMNs were injected intravenously into SCID mice while, simultaneously, diluted gouty SF containing CXCL16, or depleted of CXCL16 by antibody blocking, was administered intragraft. In addition, the receptor for CXCL16, CXCR6, was inhibited by incubating PMNs with a neutralizing anti-CXCR6 antibody prior to injection into the mouse chimeras. Recruitment of PMNs to the gouty SF???injected normal human ST was then examined in this SCID mouse chimera system. Results CXCL16 concentrations were highly elevated in gouty SF, and PMNs were observed to migrate in response to CXCL16 in vitro. Normal human ST???SCID mouse chimeras injected intragraft with gouty SF that had been depleted of CXCL16 during PMN transfer showed a significant reduction of 50% in PMN recruitment to engrafted tissue as compared with that after administration of sham-depleted gouty SF. Similar findings were achieved when PMNs were incubated with a neutralizing anti-CXCR6 antibody before injection into chimeras. Conclusion Overall, the results of this study outline the effectiveness of the human???SCID mouse chimera system as a viable animal model of gout, serving to identify the primary function of CXCL16 as a significant mediator of in vivo recruitment of PMNs to gouty SF.
Published: 2010

8. Chemotherapy alone for organ preservation in advanced laryngeal cancer

Author: Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI ; Vasu Divi and Francis P. Worden contributed equally to this work., Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI ; Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan Medical School, Ann Arbor, MI ; Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, Department of Biostatistics, University of Michigan Medical School, Ann Arbor, MI, Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan Medical School, Ann Arbor, MI, Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI ; Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan Medical School, Ann Arbor, MI, Divi, Vasu, Worden, Francis P., Prince, Mark E., Eisbruch, Avraham, Lee, Julia S., Bradford, Carol R., Chepeha, Douglas B., Teknos, Theodoros N., Hogikyan, Norman D., Moyer, Jeffrey S., Tsien, Christina I., Urba, Susan G., Wolf, Gregory T., Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI ; Vasu Divi and Francis P. Worden contributed equally to this work., Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI ; Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan Medical School, Ann Arbor, MI ; Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, Department of Biostatistics, University of Michigan Medical School, Ann Arbor, MI, Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan Medical School, Ann Arbor, MI, Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI ; Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan Medical School, Ann Arbor, MI, Divi, Vasu, Worden, Francis P., Prince, Mark E., Eisbruch, Avraham, Lee, Julia S., Bradford, Carol R., Chepeha, Douglas B., Teknos, Theodoros N., Hogikyan, Norman D., Moyer, Jeffrey S., Tsien, Christina I., Urba, Susan G., and Wolf, Gregory T.
Abstract: Background. For patients with advanced laryngeal cancer, a trial was designed to determine if chemotherapy alone, in patients achieving a complete histologic complete response after a single neoadjuvant cycle, was an effective treatment with less morbidity than concurrent chemoradiotherapy. Methods. Thirty-two patients with advanced laryngeal or hypopharyngeal cancer received 1 cycle of induction chemotherapy, and subsequent treatment was decided based on response. Results. A histologic complete response was achieved in 4 patients and were treated with chemotherapy alone. All 4 patients' cancer relapsed in the neck and required surgery and postoperative radiotherapy (RT). Twenty-five patients were treated with concomitant chemoradiation. Three patients were treated with surgery. Overall survival and disease-specific survival at 3 years were 68% and 78%, respectively. Conclusion. Chemotherapy alone is not feasible for long-term control of regional disease in patients with advanced laryngeal cancer even when they achieve a histologic complete response at the primary site. ?? 2009 Wiley Periodicals, Inc. Head Neck, 2010
Published: 2010

9. Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: Evidence for phenotype determination by modifying genes Conflict of interest: Nothing to declare.

Author: Departments of Obstetrics and Gynecology and Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts ; Department of Pediatrics, University of Massachusetts Medical School, Lake Avenue North, Worcester, MA 01655., Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, Department of Medicine, University of Washington Medical School, Seattle, Washington, Newburger, Peter E., Pindyck, Talia N., Zhu, Zhiqing, Bolyard, Audrey Anna, Aprikyan, Andrew A. G., Dale, David C., Smith, Gary D., Boxer, Laurence A., Departments of Obstetrics and Gynecology and Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts ; Department of Pediatrics, University of Massachusetts Medical School, Lake Avenue North, Worcester, MA 01655., Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, Department of Medicine, University of Washington Medical School, Seattle, Washington, Newburger, Peter E., Pindyck, Talia N., Zhu, Zhiqing, Bolyard, Audrey Anna, Aprikyan, Andrew A. G., Dale, David C., Smith, Gary D., and Boxer, Laurence A.
Abstract: Background Cyclic neutropenia (CN) and severe congenital neutropenia (SCN) are disorders of neutrophil production that differ markedly in disease severity. Mutations of the ELANE gene (the symbol recently replacing ELA2 ) are considered largely responsible for most cases of CN and SCN, but specific mutations are typically associated with one or the other. Procedure We performed ELANE genotyping on all individuals and paternal sperm in an SCN kindred with eight SCN progeny of a sperm donor and six different mothers. Results One patient with CN had the same S97L ELANE mutation as seven patients with the SCN phenotype. The mutant allele was detected in the donor's spermatozoa, representing 18% of the ELANE gene pool, but not in DNA from his lymphocytes, neutrophils, or buccal mucosa, indicating gonadal mosaicism. Conclusions The coexistence of CN and SCN phenotypes in this kindred with a shared paternal haplotype strongly suggests both a role for modifying genes in determination of congenital neutropenia disease phenotypes, and the classification of CN and SCN within a spectrum of phenotypes expressing varying degrees of the same disease process. Pediatr Blood Cancer. 2010;55:314???317. ?? 2010 Wiley???Liss, Inc.
Published: 2010

10. Experimental cerebral malaria progresses independently of the Nlrp3 inflammasome

Author: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA, Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA ; Paul H. Dekruif Professor of Pathology, University of Michigan Medical School, 1500 E. Medical Center Dr, 4215 CCGC, Ann Arbor, MI 48109, USA Fax: +1-734-647-9654, Laboratory of Host Defense, Immunology Frontier Research Center, World Premier Immunology Institute, Osaka University, Osaka, Japan, Laboratory of Host Defense, Immunology Frontier Research Center, World Premier Immunology Institute, Osaka University, Osaka, Japan ; Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan, Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan, Department of Medical Parasitology, New York University School of Medicine, New York, NY, USA, Reimer, Thornik, Shaw, Michael H., Franchi, Luigi, Coban, Cevayir, Ishii, Ken J., Akira, Shizuo, Horii, Toshihiro, Rodriguez, Ana, N????ez, Gabriel, Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA, Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA ; Paul H. Dekruif Professor of Pathology, University of Michigan Medical School, 1500 E. Medical Center Dr, 4215 CCGC, Ann Arbor, MI 48109, USA Fax: +1-734-647-9654, Laboratory of Host Defense, Immunology Frontier Research Center, World Premier Immunology Institute, Osaka University, Osaka, Japan, Laboratory of Host Defense, Immunology Frontier Research Center, World Premier Immunology Institute, Osaka University, Osaka, Japan ; Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan, Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan, Department of Medical Parasitology, New York University School of Medicine, New York, NY, USA, Reimer, Thornik, Shaw, Michael H., Franchi, Luigi, Coban, Cevayir, Ishii, Ken J., Akira, Shizuo, Horii, Toshihiro, Rodriguez, Ana, and N????ez, Gabriel
Abstract: Cerebral malaria is the most severe complication of Plasmodium falciparum infection in humans and the pathogenesis is still unclear. Using the P. berghei ANKA infection model of mice, we investigated a potential involvement of Nlrp3 and the inflammasome in the pathogenesis of cerebral malaria. Nlrp3 mRNA expression was upregulated in brain endothelial cells after exposure to P. berghei ANKA. Although ??-hematin, a synthetic compound of the parasites heme polymer hemozoin, induced the release of IL-1?? in macrophages through Nlrp3, we did not obtain evidence for a role of IL-1?? in vivo . Nlrp3 knock-out mice displayed a delayed onset of cerebral malaria; however, mice deficient in caspase-1, the adaptor protein ASC or the IL-1 receptor succumbed as WT mice. These results indicate that the role of Nlrp3 in experimental cerebral malaria is independent of the inflammasome and the IL-1 receptor pathway.
Published: 2010

11. Fast food and neighborhood stroke risk

Author: Stroke Program, University of Michigan Medical School, Ann Arbor, MI ; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI ; University of Michigan Cardiovascular Center, Room 3194, 1500 East Medical Center Dr. SPC #5855, Ann Arbor, MI 48109-5855, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, Stroke Program, University of Michigan Medical School, Ann Arbor, MI, Stroke Program, University of Michigan Medical School, Ann Arbor, MI ; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, Morgenstern, Lewis B., Escobar, James D., S??nchez, Brisa N., Hughes, Rebecca, Zuniga, Belinda G., Garcia, Nelda, Lisabeth, Lynda D., Stroke Program, University of Michigan Medical School, Ann Arbor, MI ; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI ; University of Michigan Cardiovascular Center, Room 3194, 1500 East Medical Center Dr. SPC #5855, Ann Arbor, MI 48109-5855, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, Stroke Program, University of Michigan Medical School, Ann Arbor, MI, Stroke Program, University of Michigan Medical School, Ann Arbor, MI ; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, Morgenstern, Lewis B., Escobar, James D., S??nchez, Brisa N., Hughes, Rebecca, Zuniga, Belinda G., Garcia, Nelda, and Lisabeth, Lynda D.
Abstract: Objective To investigate the association between the number of fast food restaurants and ischemic stroke in neighborhoods. Methods This work was a prespecified part of the Brain Attack in Corpus Christi (BASIC) project. Ischemic stroke cases were prospectively ascertained in Nueces County, Texas. Home addresses were geocoded and used to establish the census tract for each stroke case. Census tracts were used as proxies for neighborhoods (n = 64). Using a standard definition, fast food restaurants were identified from a commercial list. Poisson regression was used to study the association between the number of fast food restaurants in the neighborhood, using a 1-mile buffer around each census tract, and the risk of stroke in the neighborhood. Models were adjusted for demographics and neighborhood socioeconomic status (SES). Results There were 1,247 completed ischemic strokes from January 2000 through June 2003 and 262 fast food restaurants. The median number of fast food restaurants per census tract including buffer was 22 (interquartile range, 12???33). Adjusting for neighborhood demographics and SES, the association of fast food restaurants with stroke was significant ( p = 0.02). The association suggested that the risk of stroke in a neighborhood increased by 1% for every fast food restaurant (relative risk, 1.01; 95% confidence interval [CI], 1.00???1.01). The relative risk of stroke comparing neighborhoods in the 75th to the 25th percentile of the distribution of fast food restaurants was 1.13 (95% CI, 1.02???1.25). Interpretation Controlling for demographic and SES factors, there was a significant association between fast food restaurants and stroke risk in neighborhoods in this community-based study. Ann Neurol 2009;66:165???170
Published: 2009

12. Comorbid anxiety as a suicide risk factor among depressed veterans

Author: Department of Veterans Affairs, Health Services Research and Development (HSR&D) Center of Excellence, Serious Mental Illness Treatment Research and Evaluation Center (SMITREC), Ann Arbor, Michigan ; Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Psychiatry, University of Michigan Medical School, Rachel Upjohn Building, 4250 Plymouth Road, Ann Arbor, MI 48109, Department of Veterans Affairs, Health Services Research and Development (HSR&D) Center of Excellence, Serious Mental Illness Treatment Research and Evaluation Center (SMITREC), Ann Arbor, Michigan ; Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan, Department of Veterans Affairs, Health Services Research and Development (HSR&D) Center of Excellence, Serious Mental Illness Treatment Research and Evaluation Center (SMITREC), Ann Arbor, Michigan, Pfeiffer, Paul N., Ganoczy, Dara, Ilgen, Mark, Zivin, Kara, Valenstein, Marcia, Department of Veterans Affairs, Health Services Research and Development (HSR&D) Center of Excellence, Serious Mental Illness Treatment Research and Evaluation Center (SMITREC), Ann Arbor, Michigan ; Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Psychiatry, University of Michigan Medical School, Rachel Upjohn Building, 4250 Plymouth Road, Ann Arbor, MI 48109, Department of Veterans Affairs, Health Services Research and Development (HSR&D) Center of Excellence, Serious Mental Illness Treatment Research and Evaluation Center (SMITREC), Ann Arbor, Michigan ; Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan, Department of Veterans Affairs, Health Services Research and Development (HSR&D) Center of Excellence, Serious Mental Illness Treatment Research and Evaluation Center (SMITREC), Ann Arbor, Michigan, Pfeiffer, Paul N., Ganoczy, Dara, Ilgen, Mark, Zivin, Kara, and Valenstein, Marcia
Abstract: Background: Depressive disorders greatly increase suicide risk; however, little is known about the contribution of comorbid anxiety disorders or anxiety symptoms to the risk of suicide death among depressed patients. We examined whether depressed veterans with comorbid anxiety had higher risks of suicide death. Methods: Using VA administrative databases we identified 887,859 patients with depression. We then used univariate and multivariate logistic regression, controlling for demographics and substance use disorders, to determine the odds ratios of completed suicide associated with individual comorbid anxiety disorders, the presence of any comorbid anxiety disorder, the prescription of an antianxiety medication, or the prescription of a high dose of an antianxiety medication. Results: In multivariate analyses, the odds of completed suicide were significantly increased for patients with panic disorder (OR 1.26, 95% CI: 1.04???1.53), generalized anxiety disorder (OR 1.27, 95% CI: 1.09???1.47), and anxiety disorder, not otherwise specified (OR 1.25, 95% CI: 1.12???1.38). The odds of completed suicide were also greater among patients who received any antianxiety medication (OR 1.71, 95% CI: 1.55???1.88), and were further increased among those who received high dose treatment (OR 2.26, 95% CI: 1.98???2.57). Odds of completed suicide were decreased among patients with comorbid posttraumatic stress disorder (OR 0.87, 95% CI: 0.77???0.97), and there was no statistically significant relationship between social phobia, obsessive???compulsive disorder, and all other anxiety disorders and suicide. Conclusions: These findings emphasize the importance of comorbid anxiety disorders and symptoms in increasing suicide risk among depressed patients and may inform suicide prevention efforts among these patients. Depression and Anxiety, 2009. ?? 2009 Wiley-Liss, Inc.
Published: 2009

13. A need for logical and consistent anatomical nomenclature for cutaneous nerves of the limbs

Author: Division of Anatomical Sciences, University of Michigan Medical School, Ann Arbor, Michigan ; Division of Anatomical Sciences, University of Michigan Medical School, Ann Arbor, MI 48109-0608, USA, Division of Anatomical Sciences, University of Michigan Medical School, Ann Arbor, Michigan, Gest, Thomas R., Burkel, William E., Cortright, Gerald W., Division of Anatomical Sciences, University of Michigan Medical School, Ann Arbor, Michigan ; Division of Anatomical Sciences, University of Michigan Medical School, Ann Arbor, MI 48109-0608, USA, Division of Anatomical Sciences, University of Michigan Medical School, Ann Arbor, Michigan, Gest, Thomas R., Burkel, William E., and Cortright, Gerald W.
Abstract: The system of anatomical nomenclature needs to be logical and consistent. However, variations in translation to English of the Latin and Greek terminology used in Nomina Anatomica and Terminologia Anatomica have led to some inconsistency in the nomenclature of cutaneous nerves in the limbs. An historical review of cutaneous nerve nomenclature reveals that there are two general naming conventions: one primarily American and one primarily British. The American convention presents cutaneous nerves of the limbs in the format ???medial brachial cutaneous nerve,??? while the British convention presents the same nerve as ???medial cutaneous nerve of the arm,??? thereby translating ???brachii??? to ???of the arm.??? If logically and consistently applied throughout the body, the British convention would rename the sural nerve to the ???nerve of the calf,??? the brachial artery would become the ???artery of the arm,??? the femoral nerve would be ???nerve of the thigh,??? and femur would be ???bone of the thigh??? or ???thigh bone.??? The British convention leads to many other nomenclatural inconsistencies, which would seem to make learning anatomy more difficult for the beginning student. In this era of contracting anatomy curricula, every effort should be made to keep anatomical nomenclature simple, logical, and consistent. Anat Sci Ed 2:126???134, 2009. ?? 2009 American Association of Anatomists.
Published: 2009

14. Genome-wide linkage scan for prostate cancer susceptibility from the university of michigan prostate cancer genetics project: Suggestive evidence for linkage at 16q23

Author: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, Michigan ; Professor of Internal Medicine And Urology, University of Michigan Health System, 7216 Cancer Center, SPC 5948, 1500 East Medical Center Drive Ann Arbor, MI 48109., Department of Genetics, University of North Carolina, Chapel Hill, North Carolina ; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina ; The Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, Karmanos Cancer Institute, Detroit, Michigan ; Department of Internal Medicine, Wayne State University, Detroit, Michigan, The Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, Lange, Ethan M., Beebe-Dimmer, Jennifer L., Ray, Anna M., Zuhlke, Kimberly A., Ellis, Jaclyn, Wang, Yunfei, Walters, Sarah, Cooney, Kathleen A., Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, Michigan ; Professor of Internal Medicine And Urology, University of Michigan Health System, 7216 Cancer Center, SPC 5948, 1500 East Medical Center Drive Ann Arbor, MI 48109., Department of Genetics, University of North Carolina, Chapel Hill, North Carolina ; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina ; The Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, Karmanos Cancer Institute, Detroit, Michigan ; Department of Internal Medicine, Wayne State University, Detroit, Michigan, The Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, Lange, Ethan M., Beebe-Dimmer, Jennifer L., Ray, Anna M., Zuhlke, Kimberly A., Ellis, Jaclyn, Wang, Yunfei, Walters, Sarah, and Cooney, Kathleen A.
Abstract: BACKGROUND Prostate cancer linkage studies have been used to localize rare and presumably highly penetrant cancer susceptibility genes. Underlying genetic heterogeneity, as well as the high sporadic background of the disease, has resulted in many signals that are often not reproducible between research studies. METHODS We conducted a SNP-based genome wide linkage scan on 131 Caucasian prostate cancer families participating in the University of Michigan Prostate Cancer Genetics Project (PCGP). RESULTS The strongest evidence for linkage was detected at 16q23 (LOD???=???2.70 at rs1079635). Prostate cancer linkage to the same region of 16q23 has been observed by others and the region contains several strong candidate genes including the known prostate cancer tumor suppressor genes ATBF1 and WWOX . This linkage signal was not detected in our prior linkage study on 175 PCGP families, illustrating the genetic heterogeneity underlying prostate cancer susceptibility. CONCLUSIONS Further linkage studies in combination with tumor analyses from linked families are in progress to identify the putative hereditary prostate cancer gene at 16q23. Prostate 69:385???391, 2009. ?? 2008 Wiley-Liss, Inc.
Published: 2009

15. Influence of hormones and hormone metabolites on the growth of schwann cells derived from embryonic stem cells and on tumor cell lines expressing variable levels of neurofibromin This article was accepted for inclusion in the Special Focus on Stem Cells??? Developmental Dynamics 236 #12 .

Author: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Internal Medicine-Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan ; Department of Cell and Developmental Biology, University of Michigan Medical School, 3053 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, Department of Pediatrics, Neurology Division, University of Florida College of Medicine, Gainesville, Florida, Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, Roth, Therese M., Ramamurthy, Poornapriya, Muir, David, Wallace, Margaret R., Zhu, Yuan, Chang, Lou, Barald, Kate F., Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Internal Medicine-Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan ; Department of Cell and Developmental Biology, University of Michigan Medical School, 3053 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, Department of Pediatrics, Neurology Division, University of Florida College of Medicine, Gainesville, Florida, Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, Roth, Therese M., Ramamurthy, Poornapriya, Muir, David, Wallace, Margaret R., Zhu, Yuan, Chang, Lou, and Barald, Kate F.
Abstract: Loss of neurofibromin, the protein product of the tumor suppressor gene neurofibromatosis type 1 (NF1), is associated with neurofibromas, composed largely of Schwann cells. The number and size of neurofibromas in NF1 patients have been shown to increase during pregnancy. A mouse embryonic stem cell (mESC) model was used, in which mESCs with varying levels of neurofibromin were differentiated into Schwann-like cells. NF1 cell lines derived from a malignant and a benign human tumor were used to study proliferation in response to hormones. Estrogen and androgen receptors were not expressed or expressed at very low levels in the NF1+/+ cells, at low levels in NF1+/???cells, and robust levels in NF1???/???cells. A 17??-estradiol (E2) metabolite, 2-methoxy estradiol (2ME2) is cytotoxic to the NF1???/??? malignant tumor cell line, and inhibits proliferation in the other cell lines. 2ME2 or its derivatives could provide new treatment avenues for NF1 hormone-sensitive tumors at times of greatet hormonal influence. Developmental Dynamics 237:513???524, 2008.?? 2008 Wiley-Liss, Inc.
Published: 2008

16. Generation and expression of a Hoxa11eGFP targeted allele in mice

Author: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; University of Michigan Medical Center, 109 Zina Pitcher Place, 2053 BSRB, Ann Arbor, MI 48109-2200, Nelson, Lisa T., Rakshit, Sabita, Sun, Hanshi, Wellik, Deneen M., Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; University of Michigan Medical Center, 109 Zina Pitcher Place, 2053 BSRB, Ann Arbor, MI 48109-2200, Nelson, Lisa T., Rakshit, Sabita, Sun, Hanshi, and Wellik, Deneen M.
Abstract: Hox genes are crucial for body axis specification during embryonic development. Hoxa11 plays a role in anteroposterior patterning of the axial skeleton, development of the urogenital tract of both sexes, and proximodistal patterning of the limbs. Hoxa11 expression is also observed in the neural tube. Herein, we report the generation of a Hoxa11eGFP targeted knock-in allele in mice in which eGFP replaces the first coding exon of Hoxa11 as an in-frame fusion. This allele closely recapitulates the reported mRNA expression patterns for Hoxa11 . Hoxa11eGFP can be visualized in the tail, neural tube, limbs, kidneys, and reproductive tract of both sexes. Additionally, homozygous mutants recapitulate reported phenotypes for Hoxa11 loss of function mice, exhibiting loss of fertility in both males and females. This targeted mouse line will prove useful as a vital marker for Hoxa11 protein localization during control (heterozygous) or mutant organogenesis. Developmental Dynamics 237:3410???3416, 2008. ?? 2008 Wiley-Liss, Inc.
Published: 2008

17. Work hour rules and contributors to patient care mistakes: A focus group study with internal medicine residents Part of this data was presented at the national Society of Hospital Medicine meeting, April 2005, at the national Society of General Internal Medicine meeting, May 2005, and at the regional Society of General Internal Medicine meeting, September 2005.

Author: University of Michigan Medical School, Ann Arbor, Michigan, Ann Arbor VA Medical Center, Ann Arbor, Michigan ; University of Michigan Medical School, Ann Arbor, Michigan, Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin ; Medical College of Wisconsin, Milwaukee, Wisconsin ; Fax: (414) 382-5017 ; Primary Care Division, Clement J. Zablocki VAMC, 5000 W. National Avenue, Milwaukee, WI 53295, St. Joseph Mercy Medical Center, Ann Arbor, Michigan, Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin ; Medical College of Wisconsin, Milwaukee, Wisconsin, Fletcher, Kathlyn E., Parekh, Vikas, Halasyamani, Lakshmi, Kaufman, Samuel R., Schapira, Marilyn, Ertl, Kristyn, Saint, Sanjay, University of Michigan Medical School, Ann Arbor, Michigan, Ann Arbor VA Medical Center, Ann Arbor, Michigan ; University of Michigan Medical School, Ann Arbor, Michigan, Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin ; Medical College of Wisconsin, Milwaukee, Wisconsin ; Fax: (414) 382-5017 ; Primary Care Division, Clement J. Zablocki VAMC, 5000 W. National Avenue, Milwaukee, WI 53295, St. Joseph Mercy Medical Center, Ann Arbor, Michigan, Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin ; Medical College of Wisconsin, Milwaukee, Wisconsin, Fletcher, Kathlyn E., Parekh, Vikas, Halasyamani, Lakshmi, Kaufman, Samuel R., Schapira, Marilyn, Ertl, Kristyn, and Saint, Sanjay
Abstract: BACKGROUND: The ???Swiss cheese model??? of systems accidents is commonly applied to patient safety, implying that many ???holes??? must align before an adverse event occurs. The Accreditation Council for Graduate Medical Education (ACGME) instituted work hour limitations to fill one such hole by reducing resident fatigue. OBJECTIVE: The objective of this study was to determine how residents perceive the impact of the ACGME rules and other factors on patient safety. DESIGN: The study was designed as a focus group study. PARTICIPANTS: Participating in the study were 28 internal medicine residents, of whom 13 were from a university-based program that includes both an academic medical center and a Veterans Affair (VA) hospital, 9 were from a community-based program, and 6 were from a freestanding medical college that includes a large private teaching hospital and a VA hospital. MEASUREMENT: Grounded theory analysis was used to examine transcripts of the focus group discussions. RESULTS: A model of contributors to patient care errors emerged including fatigue, inexperience, sign-outs, not knowing patients, ???entropy??? (which we defined as ???overall chaos in the system???), and workload. Participants described the impact of both intended and unintended consequences of the work hour rules on patient care. Residents reported improved well-being and less fatigue, but had concern about the effect of reduced continuity on patient care. CONCLUSION: Our focus group participants perceived that the ACGME work hour limitations had minimized the impact of resident fatigue on patient care errors. Other contributors to errors remained and were often exacerbated by methods to maintain compliance with the rules. Journal of Hospital Medicine 2008;3:228???237.
Published: 2008

18. Developmental expression and differential cellular localization of obscurin and obscurin-associated kinase in cardiac muscle cells

Author: Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109-0204 ; Room 8303, MSRB III, Division of Pediatric Cardiology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109., Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109-0204, Borisov, Andrei B., Raeker, Maide Ö., Russell, Mark W., Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109-0204 ; Room 8303, MSRB III, Division of Pediatric Cardiology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109., Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109-0204, Borisov, Andrei B., Raeker, Maide Ö., and Russell, Mark W.
Abstract: The article to which this erratum refers, J Cell Biochem 2007: 10.1002/jcb.21551 , was originally published online in Wiley InterScience 27 Nov 2007. © 2008 Wiley-Liss, Inc.
Published: 2008

19. Genetic polymorphisms in CYP17 , CYP3A4 , CYP19A1 , SRD5A2 , IGF-1 , and IGFBP-3 and prostate cancer risk in African-American men: The Flint Men's Health Study

Author: Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan ; Assistant Research Professor, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0759., Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, Department of Genetics, University of North Carolina, Chapel Hill, North Carolina ; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, Sarma, Aruna V., Dunn, Rodney L., Lange, Leslie A., Ray, Anna, Wang, Yunfei, Lange, Ethan M., Cooney, Kathleen A., Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan ; Assistant Research Professor, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0759., Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, Department of Genetics, University of North Carolina, Chapel Hill, North Carolina ; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, Sarma, Aruna V., Dunn, Rodney L., Lange, Leslie A., Ray, Anna, Wang, Yunfei, Lange, Ethan M., and Cooney, Kathleen A.
Abstract: BACKGROUND Association studies have examined the significance of several candidate genes based on biological pathways relevant to prostate carcinogenesis, including both the androgen and insulin-like growth factor pathways. Clinical and epidemiologic evidence suggest that androgens, specifically testosterone and dihydrotestosterone (DHT) are important not only in normal prostate growth but in the pathogenesis of prostate cancer. Similarly, the insulin-like growth factor-1 (IGF-1) signaling pathway regulates both cellular proliferation and apoptosis. Therefore, genes involved in the biosynthesis, activation, metabolism and degradation of androgens and the stimulation of mitogenic and antiapoptotic activities of prostate epithelial cells represent important candidates for affecting the development and progression of prostate cancer. METHODS Using resources from the Flint Men's Health Study, a population-based case control study of African-American men aged 40???79, we evaluated the associations between selected single-nucleotide polymorphisms (SNPs) in the CYP17 , CYP3A4 , CYP19A1 , SDR5A2 , IGF1 , and IGFBP3 genes and prostate cancer diagnosis in 473 men (131 prostate cancer cases and 342 disease-free controls). RESULTS We found a significant association between prostate cancer and selected CYP17 SNP genotypes, with the heterozygous genotype conferring decreased risk. Suggestive evidence for association between IGF1 SNPs and prostate cancer were also found. No significant associations were observed between SNPs in the other genes and prostate cancer. CONCLUSIONS These findings suggest that variation in or around CYP17 and/or IGF1 may be associated with prostate cancer development in the African-American population. Additional studies are needed to determine whether these polymorphisms are indeed associated with prostate cancer risk in African Americans. Prostate 68: 296???305, 2008. ?? 2007 Wiley-Liss, Inc.
Published: 2008

20. Direct monitoring pressure overload predicts cardiac hypertrophy in mice

Author: Department of Molecular and Integrative Physiology, University of Michigan Medical School, 7744 Med. Sci. II, 1150 W. Med. Ctr. Dr., Ann Arbor, MI 48109-0622, USA, Department of Molecular and Integrative Physiology, University of Michigan Medical School, 7744 Med. Sci. II, 1150 W. Med. Ctr. Dr., Ann Arbor, MI 48109-0622, USA; Department of Surgery (Vascular), University of Michigan Medical School, Ann Arbor, MI, USA; Department of Surgery, William Beaumont Hospital, Royal Oak, MI, USA, Department of Molecular and Integrative Physiology, University of Michigan Medical School, 7744 Med. Sci. II, 1150 W. Med. Ctr. Dr., Ann Arbor, MI 48109-0622, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, Metabolism Endocrinology and Diabetes Division, University of Michigan Medical School, Ann Arbor, MI, USA, Ann Arbor, Duan, Sheng Zhong, Ivashchenko, Christine Y., Whitesall, Steven E., D'Alecy, Louis G., Mortensen, Richard M., Department of Molecular and Integrative Physiology, University of Michigan Medical School, 7744 Med. Sci. II, 1150 W. Med. Ctr. Dr., Ann Arbor, MI 48109-0622, USA, Department of Molecular and Integrative Physiology, University of Michigan Medical School, 7744 Med. Sci. II, 1150 W. Med. Ctr. Dr., Ann Arbor, MI 48109-0622, USA; Department of Surgery (Vascular), University of Michigan Medical School, Ann Arbor, MI, USA; Department of Surgery, William Beaumont Hospital, Royal Oak, MI, USA, Department of Molecular and Integrative Physiology, University of Michigan Medical School, 7744 Med. Sci. II, 1150 W. Med. Ctr. Dr., Ann Arbor, MI 48109-0622, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, Metabolism Endocrinology and Diabetes Division, University of Michigan Medical School, Ann Arbor, MI, USA, Ann Arbor, Duan, Sheng Zhong, Ivashchenko, Christine Y., Whitesall, Steven E., D'Alecy, Louis G., and Mortensen, Richard M.
Abstract: Pressure overload (POL) is a classical model for studying cardiac hypertrophy, but there has been no direct measure of hemodynamics in a conscious ambulatory mouse model of POL. We used abdominal aortic constriction to produce POL and radiotelemetry to measure the blood pressure and heart rate for three weeks. The cardiac size correlated with the systolic pressure in the last week is better than other hemodynamic parameters. Cardiac fibrosis was more correlated to the cardiac size than to the systolic pressure. The expression of the cardiac genes that are typically associated with cardiac hypertrophy was correlated with both cardiac size and systolic pressure. In conclusion, the systolic pressure is the major determinant of cardiac hypertrophy in the murine POL model. In contrast, cardiac fibrosis shows the influence of other factors besides systolic pressure. The combination of the POL model with continuous direct measurements of hemodynamics represents a significant technological advance and will lead to an extended usefulness of POL methodologically.
Published: 2008

21. Utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma, and malignant mesothelioma in effusions

Author: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pathology, The University of Michigan Medical School, 1500 E. Medical Center Drive, Room 2G332, Ann Arbor, MI 48109, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, Pu, Robert T., Pang, Yijun, Michael, Claire W., Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pathology, The University of Michigan Medical School, 1500 E. Medical Center Drive, Room 2G332, Ann Arbor, MI 48109, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, Pu, Robert T., Pang, Yijun, and Michael, Claire W.
Abstract: To distinguish carcinoma, either adenocarcinoma (ADC) or squamous cell carcinoma (SCC), and malignant mesothelioma (MM) in effusion can be a diagnostic challenge based on morphology alone. This study evaluates the utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in effusions when ADC and SCC of the lung are in the differential diagnosis with MM. A cohort of 43 effusions consisting of lung ADC ( N = 10), SCC ( N = 15), and MM ( N = 18, mostly (16) pleural based), was subjected to immunostains using the above mentioned antibodies. WT-1 was positive in 100% MM, 0% ADC, and 0% SCC cases while p63 was positive in 0% MM, 30% ADC, and 80% SCC cases. Stain for MOC31 was positive in 100% ADC, 67% SCC, and 35% MM cases. Similarly, mesothelin antibody stained 100% ADC, 60% SCC, and 47% MM cases. Antibodies for K903 and CK5/6 stained 100% SCC cases but fewer ADC cases (40 and 10%, respectively). In conclusion, in this cohort of mostly pleural malignant effusion, MM can be identified with positive staining for WT-1 and negative staining for p63. Conversely, negative staining with WT-1 and positive staining for p63 exclude MM. Used as part of an immunostain panel, cytokeratin markers (CK5/6 and K903) are useful in differentiating SCC from ADC when MM is already excluded, and MOC31 might have limited value in differentiating ADC from MM. A negative stain with MOC31 can exclude lung ADC. Mesothelin, on the other hand, is not useful in the differential diagnosis of ADC, SCC, and MM. Diagn. Cytopathol. 2008;36:20–25. © 2007 Wiley-Liss, Inc.
Published: 2008

22. Health behaviors of head and neck cancer patients the first year after diagnosis

Author: VA HSR&D Center for Practice Management and Outcomes Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan ; Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan ; School of Nursing, University of Michigan, Ann Arbor, Michigan ; VA HSR&D Center for Practice Management and Outcomes Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, VA HSR&D Center for Practice Management and Outcomes Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan ; School of Nursing, University of Michigan, Ann Arbor, Michigan, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan ; Department of Epidemiology, University of Michigan, Ann Arbor, Michigan ; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Otolaryngology, Henry Ford Health System, Detroit, Michigan, VA HSR&D Center for Practice Management and Outcomes Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, Duffy, Sonia A., Khan, Mumtaz J., Ronis, David L., Fowler, Karen E., Gruber, Stephen B., Wolf, Gregory T., Terrell, Jeffrey E., VA HSR&D Center for Practice Management and Outcomes Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan ; Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan ; School of Nursing, University of Michigan, Ann Arbor, Michigan ; VA HSR&D Center for Practice Management and Outcomes Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, VA HSR&D Center for Practice Management and Outcomes Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan ; School of Nursing, University of Michigan, Ann Arbor, Michigan, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan ; Department of Epidemiology, University of Michigan, Ann Arbor, Michigan ; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Otolaryngology, Henry Ford Health System, Detroit, Michigan, VA HSR&D Center for Practice Management and Outcomes Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, Duffy, Sonia A., Khan, Mumtaz J., Ronis, David L., Fowler, Karen E., Gruber, Stephen B., Wolf, Gregory T., and Terrell, Jeffrey E.
Abstract: Background. This prospective, cohort study is the first to describe 5 health behaviors of head and neck cancer patients the first year after diagnosis. Methods. Patients ( N = 283) were recruited in otolaryngology clinic waiting rooms and asked to complete written surveys. A medical record audit was also conducted. Descriptive statistics and multivariate analyses were conducted to determine which variables were associated with the 5 health behaviors. Results. Half of the patients smoked and 25% were problem drinkers. Over half of the smokers and drinkers quit 1 year post-diagnosis. Smoking and problem drinking were highly associated and both were associated with lower body mass index (BMI) ( p < .01). Moreover, physical activity and sleep were associated with each other ( p < .01). Low SLEEP (Medical Outcomes Study Sleep Scale) scores were common and highly associated with depression ( p < .01). Conclusion. The health behaviors of head and neck cancer patients are interrelated, and assessing and treating these behaviors together may be beneficial. © 2007 Wiley Periodicals, Inc. Head Neck, 2008
Published: 2008

23. Generation of mice with a conditional allele of the p120 Ras GTPase-activating protein

Author: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109, Transgenic Animal Model Core, University of Michigan Medical School, Ann Arbor, Michigan 48109, Transgenic Animal Model Core, University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Microbiology and Immunology, University of Michigan Medical School, 6606 Med. Sci. II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0620, Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, Lapinski, Philip E., Bauler, Timothy J., Brown, Eric J., Hughes, Elizabeth D., Saunders, Thomas L., King, Philip D., Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109, Transgenic Animal Model Core, University of Michigan Medical School, Ann Arbor, Michigan 48109, Transgenic Animal Model Core, University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Microbiology and Immunology, University of Michigan Medical School, 6606 Med. Sci. II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0620, Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, Lapinski, Philip E., Bauler, Timothy J., Brown, Eric J., Hughes, Elizabeth D., Saunders, Thomas L., and King, Philip D.
Abstract: p120 Ras GTPase-activating protein (RasGAP) encoded by the rasa1 gene in mice is a prototypical member of the RasGAP family of proteins involved in negative-regulation of the p21 Ras proto-oncogene. RasGAP has been implicated in signal transduction through a number of cell surface receptors. In humans, inactivating mutations in the coding region of the RASA1 gene cause capillary malformation arteriovenous malformation. In mice, generalized disruption of the rasa1 gene results in early embryonic lethality associated with defective vasculogenesis and increased apoptosis of neuronal cells. The early lethality in this mouse model precludes its use to further study the importance of RasGAP as a regulator of cell function. Therefore, to circumvent this problem, we have generated a conditional rasa1 knockout mouse. In this mouse, an exon that encodes a part of the RasGAP protein essential for catalytic activity has been flanked by loxP recognition sites. With the use of different constitutive and inducible Cre transgenic mouse lines, we show that deletion of this exon from the rasa1 locus results in effective loss of expression of catalytically-active RasGAP from a variety of adult tissues. The conditional rasa1 mouse will be useful for the analysis of the role of RasGAP in mature cell types. genesis 45:762–767, 2007. © 2007 Wiley-Liss, Inc.
Published: 2008

24. Regulation of fibronectin and laminin binding activity in cultured human lymphoblastic cell lines

Author: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48 109-0602 ; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48 109-0602, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48 109-0602, Stoolman, Lloyd M., Wang, Tai-Ling, Situ, Rui, Varani, James, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48 109-0602 ; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48 109-0602, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48 109-0602, Stoolman, Lloyd M., Wang, Tai-Ling, Situ, Rui, and Varani, James
Published: 2007

25. CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway

Author: University of Michigan Medical School, Ann Arbor, and Northwestern University Feinberg School of Medicine, Chicago, Illinois, University of Michigan Medical School, Ann Arbor, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Veterans Administration Chicago Health Care Medical Center, Chicago, Illinois, and Ann Arbor Veterans Administration, Ann Arbor, Michigan ; University of Michigan Medical School, Department of Medicine, Rheumatology Division, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0680, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Ruth, Jeffrey H., Haas, Christian S., Park, Christy C., Amin, M. Asif, Martinez, Rita J., Haines, G. Kenneth, Shahrara, Shiva, Campbell, Phillip L., Koch, Alisa E., University of Michigan Medical School, Ann Arbor, and Northwestern University Feinberg School of Medicine, Chicago, Illinois, University of Michigan Medical School, Ann Arbor, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Veterans Administration Chicago Health Care Medical Center, Chicago, Illinois, and Ann Arbor Veterans Administration, Ann Arbor, Michigan ; University of Michigan Medical School, Department of Medicine, Rheumatology Division, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0680, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Ruth, Jeffrey H., Haas, Christian S., Park, Christy C., Amin, M. Asif, Martinez, Rita J., Haines, G. Kenneth, Shahrara, Shiva, Campbell, Phillip L., and Koch, Alisa E.
Published: 2007

26. Antiapoptotic effect of found in inflammatory zone (FIZZ)1 on mouse lung fibroblasts No conflicts of interest were declared.

Author: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA ; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA., Chung, M. J., Liu, T., Ullenbruch, M. R., Phan, S. H., Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA ; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA., Chung, M. J., Liu, T., Ullenbruch, M. R., and Phan, S. H.
Abstract: Myofibroblasts play an essential role in the abnormal deposition of extracellular matrix in pulmonary fibrosis. The presence or prolonged survival of these cells may be a key factor in the pathogenesis of progressive pulmonary fibrosis. Found in inflammatory zone (FIZZ)1 can induce myofibroblast differentiation and has an antiapoptotic effect on embryonic lung explant cultures. In this study, we investigated whether FIZZ1 also has an antiapoptotic effect on mouse lung fibroblasts (MLFs). Cells were treated with FIZZ1 for 24 h and then apoptosis was induced by TNF?? in the presence of cycloheximide (CHX). FIZZ1 exhibited an antiapoptotic effect in MLFs, as assessed by flow cytometric analysis and TUNEL staining. Moreover, the cell number was higher in the FIZZ1-treated group relative to the non-treated control group after treatment with TNF?? and CHX. FIZZ1 treatment also inhibited the apoptotic agent-induced activities of caspase-3 and caspase-8. Examination of potential signalling pathways revealed that FIZZ1 induced rapid phosphorylation of ERK-1/2, while PD98059, a MEK/ERK inhibitor, markedly induced activation of caspase-3. This anti-apoptotic effect of FIZZ1 was associated with induction of myofibroblast differentiation in response to FIZZ1 stimulation. Taken together, these findings suggest that FIZZ1 is involved in pulmonary fibrosis through both induction of myofibroblast differentiation and increased or prolonged survival of myofibroblasts. This effect of FIZZ1 was mediated by inhibition of caspase-3 and -8, with involvement of the ERK pathway. Copyright ?? 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Published: 2007

27. ICOS and B7 costimulatory molecule expression identifies activated cellular subsets in rheumatoid arthritis

Author: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 ; Research Assistant Professor of Internal Medicine, University of Michigan Medical School, Division of Rheumatology, 109 Zina Pitcher Place. 4380 BSRB, Box 2200, Ann Arbor, MI 48109-2200, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 ; Veteran's Administration, Ann Arbor, Michigan 48109, Inflammation, Experimental Medicine Divisions, Millenium Pharmaceuticals Inc., Cambridge, Massachusetts 02142, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, Ruth, Jeffrey H., Rottman, James B., Kingsbury, Gillian A., Coyle, Anthony J., Haines, G. Kenneth, Pope, Richard M., Koch, Alisa E., Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 ; Research Assistant Professor of Internal Medicine, University of Michigan Medical School, Division of Rheumatology, 109 Zina Pitcher Place. 4380 BSRB, Box 2200, Ann Arbor, MI 48109-2200, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 ; Veteran's Administration, Ann Arbor, Michigan 48109, Inflammation, Experimental Medicine Divisions, Millenium Pharmaceuticals Inc., Cambridge, Massachusetts 02142, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, Ruth, Jeffrey H., Rottman, James B., Kingsbury, Gillian A., Coyle, Anthony J., Haines, G. Kenneth, Pope, Richard M., and Koch, Alisa E.
Abstract: To better define important cell subsets expressing activation markers in rheumatoid arthritis (RA), we compared selective lymphocyte and monocyte B7H1, B7H2, B7RP.1, B7RP.2, and inducible costimulatory molecule (ICOS) expression from normal peripheral blood (NL PB), RA PB, and RA synovial fluid (SF) by multicolor flow cytometry and immunohistochemistry. RA SF memory lymphocytes expressed B7RP.1 and B7RP.2, suggesting that T-cells may function as antigen presenting cells (APCs) in RA joints. We found similar results for ICOS expression. RA SF CD14+ monocytes also expressed B7RP.1 (an ICOS ligand) and the homologous ligand B7RP.2, identifying monocytes as potential mediators of antigen processing and lymphocyte activation in RA. Furthermore, we found an increased population of RA SF CD14+ monocytes expressing B7H1 and B7H2. [The FACS analysis was supported by immunohistochemistry, showing intense lymphocyte and APC (macrophages with dendritic morphology) ICOS staining in RA synovial tissue (ST). Overall, these results define elevated populations of memoryT-lymphocytes expressing proinflammatory B7 molecules in RA SF that either stimulate T cells through ICOS (via ICOS ligands B7RP.1 and B7RP.2), or down-regulate RA ST T-lymphocytes through B7H1 and B7H2.] Therefore, in the same joint, there may exist positive and negative influences on the inflammatory response, and perhaps, the negative signals dominate as joint inflammation resolves. © 2007 International Society for Analytical Cytology
Published: 2007

28. In vivo inhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheumatoid arthritis

Author: University of Michigan Medical School, Ann Arbor ; Drs. Haas, Amin, and Ruth contributed equally to this work., University of Michigan Medical School, Ann Arbor, University of Michigan Medical School, Ann Arbor, and Department of Veterans Affairs Medical Center, Ann Arbor, Michigan ; Frederick G. L. Huetwell and William D. Robinson, MD, Professor of Rheumatology, University of Michigan Medical School, 4045 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, Midwestern University, Downers Grove, Illinois, Northwestern University Feinberg Medical School, Chicago, Illinois, Haas, Christian S., Amin, M. Asif, Ruth, Jeffrey H., Allen, Brittany L., Ahmed, Salahuddin, Pakozdi, Angela, Woods, James M., Shahrara, Shiva, Koch, Alisa E., University of Michigan Medical School, Ann Arbor ; Drs. Haas, Amin, and Ruth contributed equally to this work., University of Michigan Medical School, Ann Arbor, University of Michigan Medical School, Ann Arbor, and Department of Veterans Affairs Medical Center, Ann Arbor, Michigan ; Frederick G. L. Huetwell and William D. Robinson, MD, Professor of Rheumatology, University of Michigan Medical School, 4045 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, Midwestern University, Downers Grove, Illinois, Northwestern University Feinberg Medical School, Chicago, Illinois, Haas, Christian S., Amin, M. Asif, Ruth, Jeffrey H., Allen, Brittany L., Ahmed, Salahuddin, Pakozdi, Angela, Woods, James M., Shahrara, Shiva, and Koch, Alisa E.
Abstract: Objective Interleukin-13 (IL-13) is a pleiotropic cytokine that can affect vessel formation, an important component of the rheumatoid arthritis (RA) synovial tissue pannus. The purpose of this study was to use a gene therapy approach to investigate the role of IL-13 in angiogenesis in vivo, using a rat adjuvant-induced arthritis model of RA. Methods Ankle joints of female rats were injected preventatively with an adenovirus vector containing human IL-13 (AxCAIL-13), a control vector with no insert (AxCANI), or phosphate buffered saline (PBS). Joints were harvested at the peak of arthritis, and histologic and biochemical features were evaluated. Results AxCAIL-13–treated joint homogenates had lower hemoglobin levels, suggesting reduced joint vascularity, and both endothelial cell migration and tube formation were significantly inhibited ( P < 0.05). Similarly, AxCAIL-13 inhibited capillary sprouting in the rat aortic ring assay and vessel growth in the Matrigel plug in vivo assay. IL-13 gene delivery resulted in up-regulation and association of phosphorylated ERK-1/2 and protein kinase CΑ/ΒII, suggesting a novel pathway in IL-13–mediated angiostasis. The angiostatic effect of AxCAIL-13 was associated with down-regulation of proangiogenic cytokines (IL-18, cytokine-induced neutrophil chemoattractant 1/CXCL1, lipopolysaccharide-induced CXC chemokine/CXCL5) and up-regulation of the angiogenesis inhibitor endostatin. The expression and activity of matrix metalloproteinases 2 and 9, which participate in angiogenesis, was impaired in response to IL-13 as compared with AxCANI and PBS treatment. Conclusion Our findings support a role for IL-13 as an in vivo antiangiogenic factor and provide a rationale for its use in RA to control pathologic neovascularization.
Published: 2007

29. Presentation of arthritogenic peptide to antigen-specific T cells by fibroblast-like synoviocytes

Author: University of Michigan Rheumatic Disease Core Center, Ann Arbor ; University of Michigan Medical School, Ann Arbor, University of Michigan Rheumatic Disease Core Center, Ann Arbor ; University of Michigan Medical School, Ann Arbor ; University of Michigan, Room 3918 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0358, Beckman Research Institute, Duarte, California, Tran, Chinh N., Davis, Michael J., Tesmer, Laura A., Endres, Judith L., Motyl, Christopher D., Smuda, Craig, Somers, Emily C., Chung, Kevin C., Urquhart, Andrew G., Lundy, Steven K., Kovats, Susan, Fox, David A., University of Michigan Rheumatic Disease Core Center, Ann Arbor ; University of Michigan Medical School, Ann Arbor, University of Michigan Rheumatic Disease Core Center, Ann Arbor ; University of Michigan Medical School, Ann Arbor ; University of Michigan, Room 3918 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0358, Beckman Research Institute, Duarte, California, Tran, Chinh N., Davis, Michael J., Tesmer, Laura A., Endres, Judith L., Motyl, Christopher D., Smuda, Craig, Somers, Emily C., Chung, Kevin C., Urquhart, Andrew G., Lundy, Steven K., Kovats, Susan, and Fox, David A.
Abstract: Objective To assess the ability of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) to function as antigen-presenting cells (APCs) for arthritogenic autoantigens found within inflamed joint tissues. Methods Human class II major histocompatibility complex (MHC)–typed FLS were used as APCs for murine class II MHC–restricted CD4 T cell hybridomas. Interferon-Γ (IFNΓ)–treated, antigen-loaded FLS were cocultured with T cell hybridomas specific for immunodominant portions of human cartilage gp-39 (HC gp-39) or human type II collagen (CII). T cell hybridoma activation was measured by enzyme-linked immunosorbent assay of culture supernatants for interleukin-2. Both synthetic peptide and synovial fluid (SF) were used as sources of antigen. APC function in cocultures was inhibited by using blocking antibodies to human class II MHC, CD54, or CD58, or to murine CD4, CD11a, or CD2. Results Human FLS could present peptides from the autoantigens HC gp-39 and human CII to antigen-specific MHC-restricted T cell hybridomas. This response required pretreatment of FLS with IFNΓ, showed MHC restriction, and was dependent on human class II MHC and murine CD4 for effective antigen presentation. Furthermore, FLS were able to extract and present antigens found within human SF to both the HC gp-39 and human CII T cell hybridomas in an IFNΓ-dependent and MHC-restricted manner. Conclusion RA FLS can function as APCs and are able to present peptides derived from autoantigens found within joint tissues to activated T cells in vitro. In the context of inflamed synovial tissues, FLS may be an important and hitherto overlooked subset of APCs that could contribute to autoreactive immune responses.
Published: 2007

30. A mouse embryonic stem cell model of Schwann cell differentiation for studies of the role of neurofibromatosis type 1 in Schwann cell development and tumor formation

Author: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; The Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; Program in Neuroscience, University of Michigan, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; The Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan ; Program in Neuroscience, University of Michigan, Ann Arbor, Michigan ; Department of Cell and Developmental Biology, University of Michigan Medical School, 3053 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA, Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, Roth, Therese M., Ramamurthy, Poornapriya, Ebisu, Fumi, Lisak, Robert P., Bealmear, Beverly M., Barald, Kate F., Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; The Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; Program in Neuroscience, University of Michigan, Ann Arbor, Michigan, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan ; The Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan ; Program in Neuroscience, University of Michigan, Ann Arbor, Michigan ; Department of Cell and Developmental Biology, University of Michigan Medical School, 3053 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA, Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, Roth, Therese M., Ramamurthy, Poornapriya, Ebisu, Fumi, Lisak, Robert P., Bealmear, Beverly M., and Barald, Kate F.
Abstract: The neurofibromatosis Type 1 (NF1) gene functions as a tumor suppressor gene. One known function of neurofibromin, the NF1 protein product, is to accelerate the slow intrinsic GTPase activity of Ras to increase the production of inactive rasGDP, with wide-ranging effects on p21ras pathways. Loss of neurofibromin in the autosomal dominant disorder NF1 is associated with tumors of the peripheral nervous system, particularly neurofibromas, benign lesions in which the major affected cell type is the Schwann cell (SC). NF1 is the most common cancer predisposition syndrome affecting the nervous system. We have developed an in vitro system for differentiating mouse embryonic stem cells (mESC) that are NF1 wild type (+/+), heterozygous (+/−), or null (−/−) into SC-like cells to study the role of NF1 in SC development and tumor formation. These mES-generated SC-like cells, regardless of their NF1 status, express SC markers correlated with their stage of maturation, including myelin proteins. They also support and preferentially direct neurite outgrowth from primary neurons. NF1 null and heterozygous SC-like cells proliferate at an accelerated rate compared to NF1 wild type; this growth advantage can be reverted to wild type levels using an inhibitor of MAP kinase kinase (Mek). The mESC of all NF1 types can also be differentiated into neuron-like cells. This novel model system provides an ideal paradigm for studies of the role of NF1 in cell growth and differentiation of the different cell types affected by NF1 in cells with differing levels of neurofibromin that are neither transformed nor malignant. © 2007 Wiley-Liss, Inc.
Published: 2007

31. Regulation of E-cadherin and ??-catenin by Ca 2+ in colon carcinoma is dependent on calcium-sensing receptor expression and function

Author: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI ; Fax: +734-763-6476. ; Department of Pathology, The University of Michigan, 1301 Catherine Road/Box 0602, Ann Arbor, MI 48109, USA, Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University Cancer Institute, Springfield, IL, Bhagavathula, Narasimharao, Hanosh, Andrew W., Nerusu, Kamalakar C., Appelman, Henry, Chakrabarty, Subhas, Varani, James, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI ; Fax: +734-763-6476. ; Department of Pathology, The University of Michigan, 1301 Catherine Road/Box 0602, Ann Arbor, MI 48109, USA, Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University Cancer Institute, Springfield, IL, Bhagavathula, Narasimharao, Hanosh, Andrew W., Nerusu, Kamalakar C., Appelman, Henry, Chakrabarty, Subhas, and Varani, James
Abstract: An siRNA directed against the extracellular calcium-sensing receptor (CaSR) was used to down-regulate this protein in CBS colon carcinoma cells. In additional studies, we utilized a variant of the parental CBS line that demonstrates CaSR expression but does not upregulate this protein in response to extracellular Ca 2+ . In neither the siRNA-transfected cells nor the Ca 2+ -nonresponsive variant cells did inclusion of Ca 2+ in the culture medium inhibit proliferation or induce morphological alterations. Extracellular Ca 2+ also failed to induce E-cadherin production or a shift in ??-catenin from the cytoplasm to the cell membrane. In mock-transfected cells and in a Ca 2+ -responsive variant line derived from the same parental CBS cells, Ca 2+ treatment resulted in growth-reduction. This was accompanied by increased E-cadherin production and a shift in ??-catenin distribution from the cytoplasm to the cell membrane. Additionally, down-regulation of c-myc and cyclin D1 expression was observed in mock-transfected cells and in the Ca 2+ -responsive variant line (along with reduced T cell factor transcriptional activation). Neither c-myc nor cyclin D1 was significantly down-regulated in the siRNA-transfected cells or in the Ca 2+ -nonresponsive variant cells upon Ca 2+ stimulation. In histological sections of human colon carcinoma CaSR was significantly reduced as compared to the level in normal colonic crypt epithelial cells. Where CaSR expression was high, strong surface staining for E-cadherin and ??-catenin was observed. Where CaSR expression was reduced, ??-catenin surface expression was likewise reduced. ?? 2007 Wiley-Liss, Inc.
Published: 2007

32. An essential role for CCAAT/enhancer binding protein ?? in bleomycin-induced pulmonary fibrosis No conflicts of interest were declared.

Author: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA ; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA., Hu, B., Ullenbruch, M. R., Jin, H., Gharaee-Kermani, M., Phan, S. H., Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA ; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA., Hu, B., Ullenbruch, M. R., Jin, H., Gharaee-Kermani, M., and Phan, S. H.
Abstract: Pulmonary fibrosis is characterized by inflammation, genesis of myofibroblasts, and abnormal tissue repair. Despite extensive research, its pathogenesis remains incompletely understood. Previously, the transcription factor CCAAT/enhancer binding protein ?? (C/EBP??) was found to be a key regulator of myofibroblast differentiation in vitro , and to be involved in the acute phase and inflammatory responses. In an attempt to test the role of C/EBP?? in the development of pulmonary fibrosis, experiments using C/EBP ?? null mice and their wild-type littermates were conducted. Our findings indicated that, compared to wild-type mice, animals deficient in C/EBP?? showed significantly reduced fibrotic lesions and collagen deposition in the lung upon endotracheal injection of bleomycin. Further studies on the mechanisms by which C/EBP?? regulates fibrosis indicated that knockout of C/EBP ?? attenuates inflammatory cytokine expression in bleomycin-treated mice. The reduced ??-smooth muscle actin gene expression in either isolated lung fibroblasts or lung tissue from bleomycin or saline-treated C/EBP?? deficient mice suggests that C/EBP?? regulates myofibroblast differentiation during fibrosis. Consistent with this finding, cells from C/EBP?? deficient mice exhibited higher proliferative rates than those from wild-type mice. These data suggest that C/EBP?? plays an essential role in pulmonary fibrosis and that this role appears to be multifactorial with respect to cytokine expression, cell differentiation, and proliferation. Copyright ?? 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Published: 2007

33. Features of the metabolic syndrome and prostate cancer in African-American men

Author: Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan ; Fax: (734) 764–3192. ; Department of Epidemiology, University of Michigan School of Public Health, 109 South Observatory Street, Ann Arbor, MI 48109, Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan ; Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Beebe-Dimmer, Jennifer L., Dunn, Rodney L., Sarma, Aruna V., Montie, James E., Cooney, Kathleen A., Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan ; Fax: (734) 764–3192. ; Department of Epidemiology, University of Michigan School of Public Health, 109 South Observatory Street, Ann Arbor, MI 48109, Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan ; Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, Beebe-Dimmer, Jennifer L., Dunn, Rodney L., Sarma, Aruna V., Montie, James E., and Cooney, Kathleen A.
Abstract: BACKGROUND. Metabolic syndrome refers to a cluster of conditions that includes hypertension, dyslipidemia, central adiposity, and high blood glucose levels. Over the past decade, a growing body of literature suggests that metabolic syndrome may be associated with several different forms of cancer. Because prostate cancer risk is highest among African Americans, and these men, similarly, are more prone to developing specific features of the metabolic syndrome, including hypertension and type-2 diabetes, any relationships would have a significant impact on developing strategies for the primary prevention of prostate cancer. METHODS. The Flint Men's Health Study is a community-based, case-control study of prostate cancer conducted exclusively among African Americans. Prostate cancer cases and controls completed an interviewer-administered questionnaire that asked about the respondent's history of high blood pressure and diabetes. All men also participated in a physical examination in which several measures of body composition, including waist circumference, were collected. RESULTS. Hypertension was reported more commonly among men with prostate cancer (cases) compared with men in the control group (odds ratio [OR]. 2.4; 95% confidence interval [95% CI], 1.5–3.7), and cases were more likely to have a waist circumference >102 cm (OR, 1.8; 95% CI, 1.2–2.9). However, self-reported diabetes was not associated with prostate cancer risk. The men with prostate cancer also were more likely than controls to exhibit multiple syndrome characteristics (OR, 1.9; 95% CI, 1.2–3.0). CONCLUSIONS. The current results indicated that features of the metabolic syndrome, specifically abdominal obesity and hypertension, are associated with prostate cancer in African-American men. This relationship, if it is proved causal, suggests that prevention or control of these conditions eventually may lead to a reduction in the incidence of prostate cancer in this high-risk minority group. Cancer 2007
Published: 2007

34. Ethnic differences in stroke recurrence

Author: Department of Epidemiology, University of Michigan School of Public Health ; Stroke Program, University of Michigan Medical School, Ann Arbor, MI ; Department of Epidemiology, University of Michigan School of Public Health, 109 South Observatory, Ann Arbor, MI 48109-2029, Stroke Program, University of Michigan Medical School, Ann Arbor, MI, Department of Epidemiology, University of Michigan School of Public Health ; Stroke Program, University of Michigan Medical School, Ann Arbor, MI, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, Lisabeth, Lynda D., Smith, Melinda A., Brown, Devin L., Moyé, Lemuel A., Risser, Jan M. H., Morgenstern, Lewis B., Department of Epidemiology, University of Michigan School of Public Health ; Stroke Program, University of Michigan Medical School, Ann Arbor, MI ; Department of Epidemiology, University of Michigan School of Public Health, 109 South Observatory, Ann Arbor, MI 48109-2029, Stroke Program, University of Michigan Medical School, Ann Arbor, MI, Department of Epidemiology, University of Michigan School of Public Health ; Stroke Program, University of Michigan Medical School, Ann Arbor, MI, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, Lisabeth, Lynda D., Smith, Melinda A., Brown, Devin L., Moyé, Lemuel A., Risser, Jan M. H., and Morgenstern, Lewis B.
Abstract: Objective To determine whether stroke recurrence and the effect of recurrence on mortality differ by ethnicity. Methods Using methods from the Brain Attack Surveillance in Corpus Christi project, we prospectively identified first-ever ischemic strokes from emergency department logs and hospital admissions (January 2000 to December 2004). Recurrent strokes and deaths were identified for the same period. Cumulative probability of stroke recurrence was estimated. Cox proportional hazards models were used to examine ethnic differences in recurrence and to examine the relation among ethnicity, recurrence, and mortality. Results During the time interval, 1,345 first-ever ischemic strokes were validated. Median age of patients was 72 years; 53% were Mexican American (MA). There were 126 recurrent strokes. Cumulative risk for recurrence at 30 days and 1 year was 2.6 and 7.5%, respectively. MAs had higher risk for stroke recurrence (risk ratio, 1.57; 95% confidence interval, 1.05–2.34) compared with non-Hispanic white patients, adjusted for demographics, stroke risk factors, and stroke severity. Stroke recurrence was related to mortality to a similar extent across ethnic groups (non-Hispanic white patients: risk ratio, 3.32; 95% confidence interval, 2.07–5.32; MAs: risk ratio, 2.35; 95% confidence interval, 1.42–3.88). Interpretation MAs had higher stroke recurrence risk compared with non-Hispanic white patients. Stroke recurrence had an important impact on mortality. Efforts to reduce stroke recurrence in MAs are needed. Ann Neurol 2006
Published: 2007

35. Fine-needle aspiration of spinal osteoblastoma in a patient with lymphangiomatosis

Author: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pathology, University of Michigan Hospitals, 1500 E. Medical Center Drive, Room 2G332, Ann Arbor, MI 48109, Rhode, Michael G., Lucas, David R., Krueger, Cynthia H., Pu, Robert T., Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pathology, University of Michigan Hospitals, 1500 E. Medical Center Drive, Room 2G332, Ann Arbor, MI 48109, Rhode, Michael G., Lucas, David R., Krueger, Cynthia H., and Pu, Robert T.
Abstract: Diagnosis of osteoblastoma by fine-needle aspiration (FNA) is rare, as in most patients, excisional biopsy is performed. We report a case of FNA diagnosis of a spinal osteoblastoma in a lymphangiomatosis patient. The patient had a history of lymphangiomatosis since birth with lymphangiomas removed from various locations, and had radiograph evidence of multifocal vertebral involvement. He presented with an enlarging C3 posterior element vertebral lesion. Clinically and radiologically, it was suspicious for lymphangiomatosis involvement. A computed tomography (CT)-guided FNA yielded a moderately cellular specimen. Lesional cells exhibited plasmacytoid features, fine chromatin, smooth nuclear membranes, and binucleation, in a background of occasional osteoclastic cells, spindle cells, and osteoid matrix. A cytological diagnosis of osteoblastoma was favored and confirmed with follow-up surgical biopsy. We believe that this is the first case reporting an osteoblastoma diagnosed by FNA in a lymphangiomatosis patient. We describe the clinical and cytological findings of osteoblastoma and its differential diagnosis. Diagn. Cytopathol. 2006;34:295–297. © 2006 Wiley-Liss, Inc.
Published: 2007

36. Does Hurthle cell lesion/neoplasm predict malignancy more than follicular lesion/neoplasm on thyroid fine-needle aspiration?

Author: Department of Pathology, Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pathology, University of Michigan Medical School, 1500 E. Medical Center Drive, Room 2G332/BOX 0054, Ann Arbor, MI, Biostatistic Unit, Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pathology, Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, Long island Jewish Medical Center, New Hyde Park, New York, Pu, Robert T., Yang, Jack, Wasserman, Patricia G., Bhuiya, Tawfiqul, Griffith, Kent A., Michael, Claire W., Department of Pathology, Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pathology, University of Michigan Medical School, 1500 E. Medical Center Drive, Room 2G332/BOX 0054, Ann Arbor, MI, Biostatistic Unit, Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, Department of Pathology, Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, Long island Jewish Medical Center, New Hyde Park, New York, Pu, Robert T., Yang, Jack, Wasserman, Patricia G., Bhuiya, Tawfiqul, Griffith, Kent A., and Michael, Claire W.
Abstract: Thyroid fine-needle aspiration (FNA) is a standard procedure for the clinical triage of thyroid nodules. The diagnosis of an adequately sampled thyroid FNA is generally grouped into three categories: benign, malignant, and indeterminate. The latter group usually includes follicular neoplasm, follicular lesion, and sometimes a more specific diagnosis such as Hurthle cell neoplasm or follicular lesion/neoplasm with Hurthle cell change. Whether a FNA diagnosis of Hurthle cell lesion/neoplasm (HLN) denotes a worse clinical outcome than follicular lesion/neoplasm (FLN) remains controversial. A cohort of 303 thyroid FNA cases with follow-up thyroidectomy in our institutes was identified, with the follow-up excision diagnosis compared to the FNA diagnosis in order to address this issue. Of this cohort, 87 cases had an FNA diagnosis of HLN while 216 cases had a diagnosis of FLN. Upon excision, the FNA diagnosis of HLN group had 14 cases of goiter/nodular hyperplasia (16%), 46 cases of adenoma (12 follicular adenoma (14%) and 34 cases of Hurthle cell adenoma (39%)), and 27 cases of carcinoma (31%, 12 papillary carcinoma and 15 Hurthle cell carcinoma). The FLN group had 74 cases of goiter/nodular hyperplasia (34.3%), 8 cases of Hashimoto thyroiditis (3.7%), 73 cases of follicular adenoma (33.8%), one case of granular cell tumor, and 60 cases of carcinoma (27.8%, 46 papillary carcinoma, 12 follicular carcinoma, and 1 Hurthle cell carcinoma and 1 parathyroid carcinoma) upon excision. There is no significant difference in predicting cancer between the two cytology diagnosis groups (HLN versus FLN, 31% versus 27.8%, P = 0.5771). When sorting all the cases by the surgical diagnosis, while comparable for age at diagnosis, the cancer group having the higher proportion of male patients than the non-cancer group (28.7% versus 16.7%, P = 0.0259). Hurthle cell carcinoma patients are typically older than patients with other cancer diagnoses (59 versus 44, P = 0.0077). Our results suggest
Published: 2007

37. Northern analyses using single-stranded probes do not support a role for GATA/GACA repeats in sex determination in mice and men

Author: Departments of Human Genetics and Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, Departments of Human Genetics and Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, Durbin, Edward J., Stalvey, John R. D., Erickson, Robert P., Departments of Human Genetics and Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, Departments of Human Genetics and Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan ; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, Durbin, Edward J., Stalvey, John R. D., and Erickson, Robert P.
Abstract: The possible role of GATA/GACA repeated sequences in mammalian sex determination was investigated using Northern analyses of mouse and human RNA. Brain, liver, and gonadal RNA from three developmental stages of mice of both sexes and also human fetal RNA from various tissues were hybridized to both sense and antisense Bkm riboprobes as well as to the synthetic oligonucleotide (GATA) 5 . At low levels of stringency, putative transcripts of various sizes were observed in all tissue samples with all probes. At high stringency, only a putative transcript of approximately 12 kb was observed, but this was later shown to consist of contaminating DNA. No sex-specific differences were observed in any tissue or developmental stage. Thus, we find no evidence that the GATA/GACA repeated sequences are specifically expressed in quantities detectable by Northern analyses in a manner important to mammalian sex determination.
Published: 2007

38. Calmodulin is associated with microtubules forming in PTK 1 cells upon release from nocodazole treatment

Author: Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor ; 4728 Medical Science II, Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, MI 48109-0616, Sweet, Stuart C., Rogers, Charles M., Welsh, Michael J., Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor ; 4728 Medical Science II, Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, MI 48109-0616, Sweet, Stuart C., Rogers, Charles M., and Welsh, Michael J.
Abstract: To investigate the association of calmodulin (CaM) with microtubules (MTs) in the mitotic apparatus (MA), the distributions of CaM and tubulin were examined in cells in which the normal spindle organization had been altered. A fluorescent CaM conjugate with tetramethylrhodamine isothiocyanate (CaM-TRITC) and a dichlorotriazinyl aminofluorescein conjugate with tubulin (tubulin-DTAF) were injected into cells that had been treated with the MT inhibitor nocodazole. With moderate nocodazole concentration (0.3 ??g/ml, 37??C, 4 h) in live cells, CaM-TRITC and tubulin-DTAF concentrated identically on or near the centrosomes and kinetochores. In serial sections of these cells, small MT segments were observed by transmission electron microscopy (TEM) in the regions where fluorescent protein had concentrated. When a higher drug concentration was used (3.0 ??g/ml, 37??C, 4 h), no regions of CaM-TRITC or tubulin-DTAF localization were observed, and no MTs were observed when serial sections were examined by TEM. However, following release from the high-concentration nocodazole block, CaM-TRITC colocalized with newly formed MTs at the kinetochores and centrosomes. Later in the recovery period, when chromosome-to-pole fibers had formed, CaM association with kinetochores diminished, ultimately attaining its normal pole-proximal association with kinetochore MTs in cells that progressed through mitosis. We interpret these observations as supporting the hypothesis that in the MA, CaM attains a physical association with kinetochore MTs and suggest that CaM-associated MTs may be inherently more stable.
Published: 2007

39. Development of a tomographic myelin scan

Author: Department of Biology Chemistry, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, Division of Nuclear Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Aarbor, MI 48109, Department of Biology Chemistry, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 ; University of Michigan, Neuroscience Laboratory Bldg, 1103 E Huron, Ann Arbor, MI 48109, Frey, Kirk A., Wieland, Donald M., Brown, Lawrence E., Rogers, W. Leslie, Agranoff, Bernard W., Department of Biology Chemistry, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, Division of Nuclear Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Aarbor, MI 48109, Department of Biology Chemistry, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 ; University of Michigan, Neuroscience Laboratory Bldg, 1103 E Huron, Ann Arbor, MI 48109, Frey, Kirk A., Wieland, Donald M., Brown, Lawrence E., Rogers, W. Leslie, and Agranoff, Bernard W.
Abstract: The principle that myelin can be imaged nonivnvasiely using the emission tomographic distribution of a lipophilic radioactive tracer was investigated. Properties of agents suitable for noninvasive myelin scanning are discussed with specific reference to blood-brain barrier permeability, metabolism, and tracer lipophilicity. The brain distributions of inert tracers are correlated with their partitioning between octanol and saline. A test probe, iodobenzene, was labeled with iodine 125 for preliminary invasive studies in the rabbit. The equilibrium brain distribution, determined either autoradiographically of by regional dissection, corresponded closely to that of myelin. 123 I-labeled iodobenzene, a gamma-emitting analog, was then administered to a monkey, and tomographic reconstruction revealed a pattern of brain uptake corresponding to white matter.
Published: 2007

40. Mitogenic activity of neu differentiation factor/heregulin mimics that of epidermal growth factor and insulin-like growth factor-I in human mammary epithelial cells

Author: Department of Radiation Oncology, Division of Radiation and Cancer Biology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0582, Department of Radiation Oncology, Division of Radiation and Cancer Biology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0582 ; Department of Radiation Oncology, University of Michigan Medical School, 1331 East Ann Street, Ann Arbor, MI 48109-0582, Ram, Tracy G., Kokeny, Kristine E., Dilts, Cheryl A., Ethier, Stephen P., Department of Radiation Oncology, Division of Radiation and Cancer Biology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0582, Department of Radiation Oncology, Division of Radiation and Cancer Biology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0582 ; Department of Radiation Oncology, University of Michigan Medical School, 1331 East Ann Street, Ann Arbor, MI 48109-0582, Ram, Tracy G., Kokeny, Kristine E., Dilts, Cheryl A., and Ethier, Stephen P.
Abstract: Recently, a family of growth factors has been described that activates erbB-2 receptors. These factors, known as the neu differentiation factors (NDF) or heregulins (HRG), induce tyrosine phosphorylation of erbB-2 receptors as a result of their direct interaction with either erbB-3 or erbB-4 receptors. Although it is known that expression of erbB-2 receptors has relevance in human breast cancer progression, how erbB-2, -3 and -4 receptors regulate mammary epithelial cell proliferation is not known. Therefore, experiments were carried out to study the mitogenic activity of NDF/HRG on the human mammary epithelial cell line MCF-10A which can be cultured continuously under serum-free conditions. MCF-10A cells, like primary cultures of normal human mammary epithelial cells, express an absolute requirement for exogenous epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) for growth. The results of these experiments indicate that NDF/HRG can induce tyrosine phosphorylation of p185erbB-2 in MCF-10A cells and is mitogenic for these cells. This is consistent with the coexpression of erbB-2 and erbB-3 mRNA that we have observed in MCF-10A cells. In addition, we found that NDF/HRG can substitute for either EGF or IGF-I to stimulate proliferation of these cells. The ability to substitute for both EGF and IGF-I is a unique property of NDF/HRG and is not shared by other members of the EGF or IGF family of growth factors, nor by other factors that we have studied. A striking isoform specificity was also observed which indicated that the Β-isoforms of NDF/HRG were greater than ten times more mitogenic than the Α-isoforms. We also examined the mitogenic activity of NDF/HRG on MCF-10A cells that overexpress the erbB-2 receptor as a result of infection with a retroviral vector containing the human c-erbB-2 gene (MCF-10AerbB-2 cells). These studies indicated that MCF-10AerbB-2 cells have increased sensitivity to the mitogenic effects of NDF/HRG and that these cells ar
Published: 2007

41. Developmental patterning of rod and cone photoreceptors in embryonic zebrafish

Author: Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0616 ; Dept. of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, MI 48109-0616, Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0616, Raymond, Pamela A., Barthel, Linda K., Curran, Gary A., Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0616 ; Dept. of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, MI 48109-0616, Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0616, Raymond, Pamela A., Barthel, Linda K., and Curran, Gary A.
Abstract: Cone photoreceptors in the zebrafish retina are arranged in a crystalline lattice, with each spectral subtype at a specific position in the array: rod photoreceptors are inserted around the cones. Patterning events and developmental mechanisms that lead to the formation of the cone mosaic are not known. To begin investigating this issue, we examined the initial stages of opsin expression in zebrafish embryos by in situ hybridization with goldfish opsin cRNA probes to determine how and when the cone mosaic pattern arises. We found both differences and similarities in the spatiotemporal patterns of rod and cone development, which suggest the following: (1) Expression of opsin message (including rod opsin, blue and red cone opsins) was initiated at 50–52 hours postfertilization by a few photoreceptors which were consistently found in a ventral patch of retina located nasal to the choroid fissure. (2) The cone mosaic pattern was generated by a crystallization-like process initiated in the precocial ventral patch and secondarily in nasal retina, which then swept like a wave into dorsotemporal retina. (3) The pattern of differentiation of rods in the ventronasal patch differed substantially from that in the remainder of the retina, suggesting that these precocial rods might differ from typical rods. (4) Developmental maturation of rods in zebrafish, as reflected by expression of opsin, may be accelerated compared to cones, which are thought to become postmitotic before rods. These data are consistent with a model in which lateral inductive interactions among differentiating photoreceptors lead to patterning of the array. © 1995 Wiley-Liss, Inc.
Published: 2007

42. Effect of ovariectomy on the hypothalamic content of immunoreactive gonadotropin-releasing hormone in the female mouse as revealed by quantitative immunocytochemistry and radioimmunoassay

Author: Department of Anatomy and Cell Biology and the Reproductive Endocrinology Program, The University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Anatomy and Cell Biology, Medical Science II Building, The University of Michigan Medical School, Ann Arbor, MI 48109, Department of Anatomy and Cell Biology and the Reproductive Endocrinology Program, The University of Michigan Medical School, Ann Arbor, Michigan 48109, Briski, Karen P., Baker, Burton L., Christensen, A. Kent, Department of Anatomy and Cell Biology and the Reproductive Endocrinology Program, The University of Michigan Medical School, Ann Arbor, Michigan 48109 ; Department of Anatomy and Cell Biology, Medical Science II Building, The University of Michigan Medical School, Ann Arbor, MI 48109, Department of Anatomy and Cell Biology and the Reproductive Endocrinology Program, The University of Michigan Medical School, Ann Arbor, Michigan 48109, Briski, Karen P., Baker, Burton L., and Christensen, A. Kent
Abstract: Our radioimmunoassay data reveal that ovariectomy for either one or two months resulted in a significant decrease in the GnRH content of the mouse basal hypothalamus, while in mice ovariectomized for two weeks the GnRH levels did not differ significantly from controls. Parallel immunocytochemical analyses gave similar results. Tissue sections from specific regions of the median eminence in intact and ovariectomized mice were immunolabeled for GnRH with the peroxidase-antiperoxidase procedure of Sternberger. Differences in area and average unit density of the reaction product were measured with a Quantiment 720 image analyzer. At two weeks after ovariectomy, a majority of matched sections from intact and ovariectomized animals, taken in each sampled region of the median eminence, showed no visually apparent difference in GnRH immunoreactivity. Quantitative image analysis of these preparations revealed no statistically significant difference in either the area of neural tissue covered by deposit or the average unit density of this material in any given region. In contrast, in mice ovariectomized for either one or two months, immunolabeled GnRH was decreased throughout the cephalo-caudal extent of the median eminence. In each region, a reduction in reaction deposit was observed over most of the area in which GnRH is localized, especially in the medial aspects of this distribution. Image analysis of these preparations revealed a significant reduction of both specimen area immunolabeled for GnRH and the average unit density of reaction product in each region of the median eminence. While the decrease in density was uniform throughout the median eminence, the greatest reduction in area covered by deposit occurred in the infundibular region. The demonstration of a decrease in basal hypothalamic GnRH in the chronically ovariectomized mouse suggests that GnRH neurosecretion is increased in response to the absence of the ovaries and supports the premise that tonic secretion o
Published: 2007

43. Revisiting reliability of quantified perineal ultrasound: Bland and Altman analysis of a new protocol for the rectangular coordinate method

Author: University of Michigan School of Nursing, Ann Arbor, Michigan, University of Michigan School of Nursing, Ann Arbor, Michigan ; Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan ; Research Assistant Professor, 400 N. Ingalls, Room 3247, University of Michigan School of Nursing/Division II, Ann Arbor, MI 48109-0482., Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan, University of Michigan School of Nursing, Ann Arbor, Michigan ; Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan, Armstrong, S. M., Miller, Josef M., Benson, K., Jain, S., Panagopoulos, K., DeLancey, John O. L., Sampselle, Carolyn M., University of Michigan School of Nursing, Ann Arbor, Michigan, University of Michigan School of Nursing, Ann Arbor, Michigan ; Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan ; Research Assistant Professor, 400 N. Ingalls, Room 3247, University of Michigan School of Nursing/Division II, Ann Arbor, MI 48109-0482., Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan, University of Michigan School of Nursing, Ann Arbor, Michigan ; Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan, Armstrong, S. M., Miller, Josef M., Benson, K., Jain, S., Panagopoulos, K., DeLancey, John O. L., and Sampselle, Carolyn M.
Abstract: Aims This study tested the reliability of a new protocol for the rectangular coordinate method of quantifying perineal ultrasound. Methods Representative scans of healthy primiparous females were quantified by positioning a pubic bone template, drawn onto an acetate sheet containing x–y axes, over scans, by aligning the x-axis with the pubic bone central axis. Values for x (D x ) and y (D y ) located the urethrovesical junction (UVJ) at Rest, and at maximal Valsalva and Kegel. Range of motion (V–K) was calculated. Bland and Altman analysis, correlations, and t -tests determined intra- and inter-rater reliability, and variance due to designation of the pubic bone central axis (template control). Results Correlations averaged 0.72, 0.70, and 0.92 for intra-rater, inter-rater, and template control experiments. D x Rest, D x Kegel, and V–K were reliable in all experiments. First and second measures for inter-rater D y Rest and D y Kegel, and template control D y Valsalva were significantly different. Bland and Altman analysis showed D y Rest, D y Kegel, and D x and D y Valsalva for both reliability experiments to have limits of agreement (LOA's) large enough to explain ≥50% of the actual value ranges. Template control LOA's explained ≤30% of the actual value ranges. Conclusions The reliability of this protocol varied according to the conditions analyzed; accurate reliability assessment of all conditions required Bland and Altman analysis; and the designation of the pubic bone central axis remained a source of variance between investigators. Our results suggest Bland and Altman analysis be used with each study that quantifies perineal ultrasound. Neurourol. Urodynam. 25:731–738, 2006. © 2006 Wiley-Liss, Inc.
Published: 2007

44. Saccharomyces cerevisiae mutants altered in vacuole function are defective in copper detoxification and iron-responsive gene transcription

Author: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606, U.S.A., Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606, U.S.A. ; Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606, U.S.A. Phone: (313)763-5717; fax: (313)763-4581, Szczypka, Mark S., Zhu, Zhiwu, Silar, Philippe, Thiele, Dennis J., Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606, U.S.A., Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606, U.S.A. ; Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606, U.S.A. Phone: (313)763-5717; fax: (313)763-4581, Szczypka, Mark S., Zhu, Zhiwu, Silar, Philippe, and Thiele, Dennis J.
Abstract: The metal ions, Cu 2+/+ and Fe 3+/2+, are essential co-factors for a wide variety of enzymatic reactions. However, both metal ions are toxic when hyper-accumulated or maldistributed within cells due to their ability to generate damaging free radicals or through the displacement of other physiological metal ions from metalloproteins. Although copper transport into yeast cells is apparently independent of iron, the known dependence on Cu 2+ for high affinity transport of Fe 2+ into yeast cells has established a physiological link between these two trace metal ions. In this study we demonstrate that proteins encoded by genes previously demonstrated to play critical roles in vacuole assembly or acidification, PEP3, PEP5 and VMA3, are also required for normal copper and iron metal ion homeostasis. Yeast cells lacking a functional PEP3 or PEP5 gene are hypersensitive to copper and render the normally iron-repressible FET3 gene, encoding a multi-copper Fe(II) oxidase involved in Fe 2+ transport, also repressible by exogenous copper ions. The inability of these same vacuolar mutant strains to repress FET3 mRNA levels in the presence of an iron-unresponsive allele of the AFT1 regulatory gene are consistent with alterations in the intracellular distribution or redox states of Fe 3+/2+ in the presence of elevated extracellular concentrations of copper ions. Therefore, the yeast vacuole is an important organelle for maintaining the homeostatic convergence of the essential yet toxic copper and iron ions.?? 1997 John Wiley & Sons, Ltd.
Published: 2006

45. Syndrome X: Is it for real?

Author: Department of Human Genetics, University of Michigan Medical School, Ann Arbor ; Department of Human Genetics, Box 0618, M4780 Medical Science I, University of Michigan, Ann Arbor, MI 48109-0618, Department of Medicine, University of Michigan Medical School, Ann Arbor, Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan, Neel, James V., Julius, Stevo, Weder, Alan B., Yamada, Michiko, Kardia, Sharon L.R., Haviland, Martha B., Department of Human Genetics, University of Michigan Medical School, Ann Arbor ; Department of Human Genetics, Box 0618, M4780 Medical Science I, University of Michigan, Ann Arbor, MI 48109-0618, Department of Medicine, University of Michigan Medical School, Ann Arbor, Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan, Neel, James V., Julius, Stevo, Weder, Alan B., Yamada, Michiko, Kardia, Sharon L.R., and Haviland, Martha B.
Published: 2006

46. Responsiveness of human T lymphocytes to bacterial superantigens presented by cultured rheumatoid arthritis synoviocytes

Author: University of Michigan Medical School, Ann Arbor, University of Michigan Medical School, Ann Arbor ; Division of Rheumatology, University of Michigan Medical Center, R4669 Kresge I, Box 0531, 200 Zina Pitcher Place, Ann Arbor, MI 48109-0531, Tsai, Carlene, Diaz, Luis A., Singer, Nora G., Li, Lan Lan, Kirsch, Anita H., Mitra, Raj, Nickoloff, Brian J., Crofford, Leslie J., Fox, David A., University of Michigan Medical School, Ann Arbor, University of Michigan Medical School, Ann Arbor ; Division of Rheumatology, University of Michigan Medical Center, R4669 Kresge I, Box 0531, 200 Zina Pitcher Place, Ann Arbor, MI 48109-0531, Tsai, Carlene, Diaz, Luis A., Singer, Nora G., Li, Lan Lan, Kirsch, Anita H., Mitra, Raj, Nickoloff, Brian J., Crofford, Leslie J., and Fox, David A.
Published: 2006

47. Connective tissue activation. xxxvi. the origin, variety, distribution, and biologic fate of connective tissue activating peptide-iii isoforms: characteristics in patients with rheumatic, renal, and arterial disease

Author: Rackham Arthritis Research Unit and the Rheumatology, Cardiology, and Nephrology Divisions, Department of Internal Medicine, and the Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor. ; Department of Internal Medicine, The University of Michigan Medical Center, Room 4570 Kresge I, Box 0531, Ann Arbor, MI 48109-0531, Rackham Arthritis Research Unit and the Rheumatology, Cardiology, and Nephrology Divisions, Department of Internal Medicine, and the Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor., Castor, C. William, Andrews, Philip C., Swartz, Richard D., Ellis, S.G., Hossler, Paul A., Clark, M.R., Matteson, Eric L., Sachter, E.F., Rackham Arthritis Research Unit and the Rheumatology, Cardiology, and Nephrology Divisions, Department of Internal Medicine, and the Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor. ; Department of Internal Medicine, The University of Michigan Medical Center, Room 4570 Kresge I, Box 0531, Ann Arbor, MI 48109-0531, Rackham Arthritis Research Unit and the Rheumatology, Cardiology, and Nephrology Divisions, Department of Internal Medicine, and the Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor., Castor, C. William, Andrews, Philip C., Swartz, Richard D., Ellis, S.G., Hossler, Paul A., Clark, M.R., Matteson, Eric L., and Sachter, E.F.
Published: 2006

48. Connective tissue activation. xxxv. detection of connective tissue activating peptide-iii isoforms in synovium from osteoarthritis and rheumatoid arthritis patients: patterns of interaction with other synovial cytokines in cell culture

Author: Rackham Arthritis Research Unit, Rheumatology Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. ; Department of Internal Medicine, University of Michigan Medical Center, Room 4570 Kresge I, Box 0531, Ann Arbor, MI 48109-0531, Rackham Arthritis Research Unit, Rheumatology Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan., Castor, C. William, Smith, E.M., Hossler, Paul A., Bignall, M. Charlene, Aaron, B.P., Rackham Arthritis Research Unit, Rheumatology Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. ; Department of Internal Medicine, University of Michigan Medical Center, Room 4570 Kresge I, Box 0531, Ann Arbor, MI 48109-0531, Rackham Arthritis Research Unit, Rheumatology Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan., Castor, C. William, Smith, E.M., Hossler, Paul A., Bignall, M. Charlene, and Aaron, B.P.
Published: 2006

49. Connective tissue activating peptide III induction of synthesis and secretion of plasminogen activator by synovial fibroblasts

Author: Department of Pediatrics and Communicable Diseases and the Rackham Arthritis Research Unit, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor. ; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, Department of Pediatrics and Communicable Diseases and the Rackham Arthritis Research Unit, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor., Ragsdale, Carol Godoshian, Castor, C. William, Roberts, Dedra J., Swartz, Kenneth H., Department of Pediatrics and Communicable Diseases and the Rackham Arthritis Research Unit, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor. ; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, Department of Pediatrics and Communicable Diseases and the Rackham Arthritis Research Unit, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor., Ragsdale, Carol Godoshian, Castor, C. William, Roberts, Dedra J., and Swartz, Kenneth H.
Published: 2006

50. Amphetamine increases the phosphorylation of neuromodulin and synapsin I in rat striatal synaptosomes

Author: Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0632 ; 2220E MSRB III, Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, Iwata, Shin-Ichi, Keikilani Hewlett, G.H., Gnegy, Margaret E., Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0632 ; 2220E MSRB III, Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, Iwata, Shin-Ichi, Keikilani Hewlett, G.H., and Gnegy, Margaret E.
Published: 2006

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