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Biomedical subjects

K A Kelly

Publications and source records attributed to K A Kelly.

At least 37 records · Page 2Linked to original sources
PubMed1999

New insights into porcine-human synteny conservation.

Eleven genes were mapped to the porcine genome with the aim of improving the human-porcine comparative gene map. Five of these genes were from regions of the human genome painted by porcine chromosomal probes; of these, two mapped to chromosomes not expected from the painting results. Among the six genes from human regions not painted by porcine chromosomal probes, three genes did not map where expected by the principle of parsimony. Several of the gene assignments indicate the existence of small regions of conserved synteny not detected by heterologous chromosome painting, especially in telomeric regions. We have also detected new rearrangements in gene order within the regions of correspondence between human Chromosome (HSA) 15 and porcine Chromosome (SSC) 1 as well as between HSA4 and SSC8.

Animals↗
PubMed1999

Long-term survival among patients operated upon for peptic ulcer disease.

BACKGROUND: Although surgery has been used widely for treating peptic ulcer disease, there is conflicting evidence with respect to subsequent life expectancy and the determinants of mortality. Our aim was to compare long-term survival in a large, population-based cohort of operated patients with that expected in the general population. METHODS: We followed 471 Rochester, Minnesota residents who had surgery for peptic ulcer at the Mayo Clinic during 1956-85 for a total of 6174 person-years. Patients were followed through their complete (inpatient and outpatient) medical records in the community until death or last clinical contact and death certificates were obtained for all who succumbed. We compared observed survival and cause-specific death rates in this cohort with expected values and identified the determinants of short (30 day) and long-term mortality. RESULTS AND CONCLUSIONS: Survival was worse than expected, but excess deaths were confined to those with perforated ulcers (42 deaths observed; 18.8 expected). Independent predictors of death included age, male gender, emergency operation, gastric ulcer and cigarette smoking. Most deaths were due to heart disease and cancer, but only those due to digestive diseases (standardized mortality ratio (SMR) 3.8, 95% CI 2.4-5.7) and respiratory diseases (SMR 1.9, 95% CI 1.3-2.7) were increased compared to expected figures. Overall survival was reduced in this cohort but was normal among those whose ulcers were not perforated. However, the data suggest an adverse role for alcohol and smoking in these patients.

Adult↗
PubMed1999

Mapping of two tumor suppressor genes in the pig.

Mutations in the breast cancer 1, early onset (BRCA1) gene confer an increased risk of breast and ovarian cancer in humans. The human MAD (mothers against decapentaplegic, Drosophila) homolog 4 (MADH4) locus is a target for deletion in pancreatic and other cancers. Given the role of the pig in biomedical studies, pig orthologs of BRCA1 and MADH4 were identified and localized in the porcine genome.

Animals↗
PubMed1998

Internalization of Chlamydia by dendritic cells and stimulation of Chlamydia-specific T cells.

Chlamydia species are the causative agents of trachoma, various forms of pneumonia, and the most common sexually transmitted diseases. Although the infection cycle has been extensively characterized in epithelial cells, where the Chlamydia entry-vacuoles avoid fusion with host-cell lysosomes, the cellular immune response has received less attention. Moreover, despite the abundant presence of dendritic cells (DC) in the sites of infection, the interaction between Chlamydia and DC has never been studied. We observe that DC kill Chlamydia trachomatis and Chlamydia psittaci. The chlamydiae are internalized by the DC in a nonspecific manner through macropinocytosis, and the macropinosomes fuse subsequently with DC lysosomes expressing MHC class II molecules. The interaction induces maturation of the DC, since presentation of an exogenous Ag is severely inhibited after a 1-day incubation, although chlamydial Ags are still presented and recognized by Chlamydia-specific CD4+ T cells. Thus, DC most likely play a role in initiating the T cell response in vivo and could potentially be used in adoptive transfer therapies to vaccinate against Chlamydia.

Animals↗
PubMed1998

Preoperative perfusion of bypassed ileum does not improve postoperative function.

This study evaluated whether twice daily isotonic perfusion of the bypassed ileum for six weeks would enhance its motor activity and its absorption of fluids, electrolytes, and vitamin B12. The study also determined if patients undergoing perfusion had improved bowel function and decreased hospital stay after ileostomy closure. Following proctocolectomy, ileal pouch-anal canal anastomosis, and diverting loop ileostomy, six patients self-infused an isotonic solution (sucrose and sodium chloride) into the bypassed ileum twice daily, while seven patients did not (controls). Two months following proctocolectomy, and just prior to ileostomy closure, a manometric catheter assembly was placed into the unused distal ileum via the stoma and the distal ileum perfused with an isotonic sodium chloride solution for 3 hr during fasting and 3 hr after a meal. Absorption was measured, single and clustered pressure waves were identified, and a motility index was calculated. Water absorption, motility index, and cluster parameters did not improve in perfused patients compared to controls during fasting or after a meal, nor did perfused patients have improved vitamin B12 absorption. The perfused patients also did no better clinically following ileostomy takedown; the onset of bowel movements, their frequency, time to tolerate a diet, and hospital stay were similar to controls. We conclude that six weeks of twice daily isotonic perfusion did not improve motor activity or water, electrolyte, and vitamin B12 absorption in the bypassed distal ileum after proctocolectomy, ileal pouch-anal canal anastomosis, and loop ileostomy. The perfusion also did not improve bowel function after ileostomy takedown.

Chronic Disease↗
PubMed1998

J ileal pouch-anal anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 patients.

AIM: The purpose of the study was to determine the risk of postoperative complications and the functional outcome after a hand-sewn ileal pouch-anal anastomosis (IPAA) for ulcerative colitis using a single J-shaped pouch design. METHODS: Preoperative function, operative morbidity and long-term functional outcome were assessed prospectively in 1310 patients who underwent IPAA between 1981 and 1994 for ulcerative colitis. RESULTS: Three patients died after operation. Postoperative pelvic sepsis rates decreased from 7 per cent in 1981-1985 to 3 per cent in 1991-1994 (P = 0.02). After mean follow-up of 6.5 (range 2-15) years, the mean number of stools was 5 per day and 1 per night. Frequent daytime and nighttime incontinence occurred in 7 and 12 per cent of patients respectively, and did not change over a 10-year period. The cumulative probability of suffering at least one episode of 'clinical' pouchitis was 18 and 48 per cent at 1 and 10 years and the cumulative probability of pouch failure at 1 and 10 years was 2 and 9 per cent respectively. CONCLUSION: These results indicate that increased experience decreases the risk of pouch-related complications and that with time the functional results remain stable, but the failure rate increases.

Adolescent↗
PubMed1998

Murine bone marrow stromally derived BMS2 adipocytes support differentiation and function of osteoclast-like cells in vitro.

Stromal cells are required for in vitro osteoclast differentiation and maturation. The murine bone marrow stromally derived BMS2 cell line exhibits adipocytic and osteoblastic features as well as the ability to support lymphopoiesis and myelopoiesis. This work examined the ability of the BMS2 cell in either the preadipocyte or adipocyte state to support the formation of osteoclast-like cells. BMS2 cells can be induced to undergo adipogenic differentiation in response to treatment with glucocorticoids or thiazolidinedione compounds. Primary bone marrow cells, enriched for hematopoietic progenitors and depleted of their adherent stromal and macrophage populations, were stimulated with vitamin D3 (vitamin D; 10(-8) M) to undergo osteoclast differentiation and maturation when cocultured with BMS2 cells. In both preadipocyte and adipocyte-enriched BMS2 stromal layers, comparable numbers of tartrate-resistant acid phosphatase-positive osteoclast-like cells, characterized by their response to salmon calcitonin with an increase in cAMP and formation of resorption pits on bovine bone slices, were formed. The gene expression and protein levels of macrophage colony-stimulating factor produced by preadipocyte and adipocyte-rich BMS2 layers were comparable. However, adipocyte-rich stromal layers supported osteoclast-like cell formation longer in culture than preadipocytes, independent of the agent used to induce adipocyte differentiation. These studies demonstrate for the first time that fully differentiated adipocyte stromal cells can support osteoclast-like cell formation and function in vitro.

Acid Phosphatase↗
PubMed1998

1,25-Dihydroxy vitamin D3 inhibits adipocyte differentiation and gene expression in murine bone marrow stromal cell clones and primary cultures.

Bone marrow stromal stem cells differentiate into adipocytes and osteoblasts. These two lineages are thought to be reciprocally related, in part due to the observation that the osteoblast-inducing factor, 1,25 dihydroxy vitamin D3 [1,25(OH)2D3], inhibited adipogenesis of rat femoral-derived stromal cell cultures. However, the literature is divided concerning the adipogenic effects of this steroid hormone. This work examined the effect of 1,25(OH)2D3 (10(-12)-10(-8) M) on murine femoral-derived bone marrow stromal cell differentiation in response to adipogenic agonists employing two different classes of nuclear hormone receptors: the glucocorticoid receptor (hydrocortisone) or peroxisome proliferator-activated receptors (thiazolidinediones). Experiments used the multipotent murine bone marrow stromal cell line, BMS2, and its subclones, as well as primary-derived murine bone marrow stromal cell cultures. In all systems examined, 1,25(OH)2D3 blocked adipogenesis induced by hydrocortisone, methylisobutylxanthine, and indomethacin based on flow cytometric analysis of lipid accumulation. This correlated with reduced messenger RNA levels of the late adipocyte gene markers, aP2 and adipsin. In the BMS2 subclone no. 24, the 1,25(OH)2D3 actions were concentration dependent. Whereas 1,25(OH)2D3 partially inhibited thiazolidinedione-induced adipogenesis in the parental BMS2 cell line, it had minimal effect on the thiazolidinedione-induced differentiation of the BMS2 subclone and primary cultures. These findings indicate that 1,25(OH)2D3, at nanomolar concentrations, completely inhibits murine bone marrow stromal cell differentiation in response to glucocorticoid-based adipogenic agonists but is a less effective adipogenic antagonist following induction with thiazolidinediones. This work supports the conclusion that 1,25(OH)2D3 inhibits murine femoral-derived bone marrow stromal cell adipogenesis.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Oxidative stress in toxicology: established mammalian and emerging piscine model systems.

Interest in the toxicological aspects of oxidative stress has grown in recent years, and research has become increasingly focused on the mechanistic aspects of oxidative damage and cellular responses in biological systems. Toxic consequences of oxidative stress at the subcellular level include lipid peroxidation and oxidative damage to DNA and proteins. These effects are often used as end points in the study of oxidative stress. Typically, mammalian species have been used as models to study oxidative stress and to elucidate the mechanisms underlying cellular damage and response, largely because of the interest in human health issues surrounding oxidative stress. However, it is becoming apparent that oxidative stress also affects aquatic organisms exposed to environmental pollutants. Research in fish has demonstrated that mammalian and piscine systems exhibit similar toxicological and adaptive responses to oxidative stress. This suggests that piscine models, in addition to traditional mammalian models, may be useful for further understanding the mechanisms underlying the oxidative stress response.

Animals↗
PubMed1998

The derivation and characterization of stromal cell lines from the bone marrow of p53-/- mice: new insights into osteoblast and adipocyte differentiation.

We have derived a series of clonal cell lines from the bone marrow of p53-/- mice that represent different stages of osteoblast and adipocyte differentiation. All cell lines show indefinite growth potential (>300 population doublings) and have generation times of 12-20 h. These cell lines have been grouped into three categories. The least mature clones are heterogeneous and appear to contain a subpopulation of stem cells, which can spontaneously generate foci that contain either adipocytes or mineralizing osteoblasts. The second category of clones are homogeneous and clearly correspond to mature osteoblasts because they express high levels of the anticipated osteoblastic markers in a stable fashion and cannot differentiate into adipocytes even in the presence of inducers. The clones in the third category are the most unique. Initially they appeared to correspond to mature osteoblasts because they express alkaline phosphatase in a homogeneous manner, secrete type I collagen, show a significant cyclic adenosine monophosphate response to parathyroid hormone, secrete osteocalcin, and mineralize extensively after only 4-7 days. However, in contrast to the mature osteoblasts, these clones can be induced to undergo massive adipocyte differentiation, and this differentiation is accompanied by the complete loss of expression of all osteoblastic markers except alkaline phosphatase. These observations indicate that some cells that have acquired all of the characteristics of mature osteoblasts can be diverted to the adipocyte pathway. Further characterization of these clones may be particularly relevant to osteoporotic conditions where increased adipocyte formation appears to occur at the expense of osteoblast formation.

Adipocytes↗
PubMed1997

Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system.

Mutations of CD95 and CD95L, lpr and gld, respectively, are associated with spontaneous autoimmune disease and alteration of immune privilege. In lpr or gld animals these processes would be expected to exacerbate experimental allergic encephalomyelitis (EAE), an animal model of the autoimmune demyelinating disease multiple sclerosis. However, here we show that the lpr and gld mutations did not overcome the MHC-defined limits of disease and, surprisingly, did not exacerbate the pathology of EAE on a sensitive haplotype. In fact, the mutations dramatically ameliorated clinical signs of EAE without affecting the development of a Th1 response or inflammatory cell infiltration into the central nervous system. Fewer apoptotic cells were detected in inflammatory lesions of lpr mice than in wild-type lesions of similar severity. Our results indicate that CD95L is not an instrumental component of immune privilege in the central nervous system, and that functional CD95 and CD95L are important for the progression of clinical disease.

Animals↗
PubMed1997

Crystal structure and resonance Raman studies of protocatechuate 3,4-dioxygenase complexed with 3,4-dihydroxyphenylacetate.

The crystal structure of the anaerobic complex of Pseudomonas putida protocatechuate 3,4-dioxygenase (3,4-PCD) bound with the alternative substrate, 3,4-dihydroxyphenylacetate (HPCA), is reported at 2.4 A resolution and refined to an R factor of 0.17. Formation of the active site Fe(III).HPCA chelated complex causes the endogenous axial tyrosinate, Tyr447 (147beta), to dissociate from the iron and rotate into an alternative orientation analogous to that previously observed in the anaerobic 3,4-PCD.3,4-dihydroxybenzoate complex (3, 4-PCD.PCA) [Orville, A. M., Lipscomb, J. D., & Ohlendorf, D. H. (1997) Biochemistry 36, 10052-10066]. Two orientations of the aromatic ring of HPCA related by an approximate 180 degrees rotation within the active site are consistent with the electron density. Resonance Raman (rR) spectroscopic data from Brevibacteriumfuscum 3,4-PCD.HPCA complex in solution reveals low frequency rR vibrational bands between 500 and 650 cm-1 as well as a band at approximately 1320 cm-1 which are diagnostic of a HPCA. Fe(III) chelate complex. 18O labeling of HPCA at either the C4 or C3 hydroxyl group unambiguously establishes the vibrational coupling modes associated with the five-membered chelate ring system. Analysis of these data suggests that the Fe(III)-HPCAO4 bond is shorter than the Fe(III)-HPCAO3 bond. This consequently favors the model for the crystal structure in which the C3 phenolic function occupies the Fe3+ ligand site opposite the endogenous ligand Tyr408(Oeta) (108beta). This is essentially the same binding orientation as proposed for PCA in the crystal structure of the anaerobic 3,4-PCD.PCA complex based solely on direct modeling of the 2Fo - Fc electron density and suggests that this is the conformation required for catalysis.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Reconstitution of SCID mice with haemopoietic precursors: a detailed analysis of gamma delta T-cell reconstitution.

A well-known characteristic of gamma delta T cells is that they are produced in waves during ontogeny, with cells expressing T-cell receptor V gamma 5 appearing early in fetal thymic ontogeny, followed by V gamma 6, then by other gamma delta T-cell types. In addition, evidence exists to suggest that the potential of haemopoietic precursors to generate different types of gamma delta T cells changes in ontogeny. We have used these observations as the basis for an extensive study of the potential for haemopoietic precursors isolated from fetal liver, neonatal spleen and adult bone marrow to reconstitute severe combined immunodeficient (SCID) mice. Mice that were reconstituted as newborns with fetal liver cells most closely resembled normal C.B-17 mice with respect to both lymphocyte numbers and subsets, while mice reconstituted with adult bone marrow had fewer cells than normal mice. This deficit spanned both T and B cells in all organs examined. Among the gamma delta T-cell subsets examined, the ability to reconstitute V gamma 4+ cells was particularly dependent on the ontogenic age of the reconstituting presursors, with fetal liver cells having the greatest capacity to generate V gamma 4+ cells, and adult bone marrow cells the least. The vast majority of the T cells produced in the reconstituted mice were of donor origin, and the level of reconstitution was found to be dependent upon some factor other than the presursor frequency.

Aging↗
PubMed1997

Ileal pouch-anal canal anastomosis for familial adenomatous polyposis: early and late results.

OBJECTIVE: The objective was to review the early and late results of ileal pouch-anal anastomosis (IPAA) done for patients with familial adenomatous polyposis (FAP). SUMMARY BACKGROUND DATA: Patients with FAP will have colorectal adenomas develop and die of colorectal cancer if left untreated. Ileal pouch-anal anastomosis removes all disease-bearing mucosa while preserving transanal passage of stools. METHODS: Between 1981 and 1994, 187 patients with FAP, 11 to 59 years of age with a mean follow-up of 60 months (range, 5-170 months) had proctocolectomy and IPAA at Mayo Medical Center in Rochester, Minnesota. All patients had a proximal anal canal mucosal excision and a hand-sewn anastomosis of the pouch to the anal canal at the dentate line. A temporary ileostomy was used in 85% of the patients. RESULTS: No early postoperative deaths occurred, although two patients died later of metastatic colorectal carcinoma present at their initial operation. More important, no patient had a new cancer develop after IPAA. The overall morbidity after operation was 24%, with small bowel obstruction being the most common complication (13%). Patients had four bowel movements/24 hours and good fecal control, which continued during follow-up. CONCLUSIONS: The IPAA eradicates the risk of colorectal cancer in patients with FAP. It can be performed with low mortality, acceptable morbidity, and good functional results over the long term.

Adenomatous Polyposis Coli↗
PubMed1997

Identification of homing receptors that mediate the recruitment of CD4 T cells to the genital tract following intravaginal infection with Chlamydia trachomatis.

Murine genital infection induced with the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn) elicits a short-lived protective immunity mediated primarily by Th1 CD4 cells. To understand the development of local cell-mediated immunity against C. trachomatis infection, we investigated the mechanism(s) which mediates CD4 lymphocyte migration to the genital mucosa by identifying molecules that could support this process. We found that primarily CD4 cells were recruited to the genital tract (GT) during primary and challenge MoPn infection. Peak levels were found 21 days after primary inoculation (15.4% +/- 2.7%) and 7 days (31.3% +/- 8.5%) after challenge but diminished after resolution of infection. The CD4 cells appeared to be recruited to the GT in response to infection since these cells expressed the profile of activated, or memory, cells. We also observed up-regulation of homing receptors containing LFA-1 (CD11a) and alpha4 (CD49d) on GT CD4 cells over the course of infection. Furthermore, the mucosal homing receptor chain, beta7, but not the peripheral homing receptor chain beta1 (CD29), was detected on GT CD4 cells. MoPn-infected GT tissue expressed the endothelial cell ligands vascular cell adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), and mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which correspond to the homing receptors on GT CD4 cells. Interestingly, VCAM-1 and MAdCAM-1 were not expressed in the GTs of uninfected mice but were temporarily induced following infection, indicating that expression of endothelial ligands in the GT are regulated by chlamydial infection. These data suggest that recruitment of CD4 cells to the GT is mediated through LFA-1:ICAM-1 and alpha4beta7:MAdCAM-1-VCAM-1 interactions.

Animals↗