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Biomedical subjects

J R Lee

Publications and source records attributed to J R Lee.

At least 55 records · Page 3Linked to original sources
PubMed1999

Time-dependent expression of ICAM-1 & VCAM-1 on coronaries of the heterotopically transplanted mouse heart.

To investigate the pathogenesis of accelerated graft atherosclerosis after cardiac transplantation, a genetically well-defined and reproducible animal model is required. We performed heterotopic intraabdominal heart transplantation between the two inbred strains of mice. Forty hearts from B10.A mice were transplanted into B10.BR mice. Recipients were sacrificed at 1, 3, 5, 7, 14, 28, and 42 days after implantation. The specimens from both donor and recipient were examined with fluorescent immunohistochemistry and the serial histopathologic changes were evaluated. In the donor hearts, ICAM-1 and VCAM-1 expressions were minimal at day 1 and they gradually increased, reaching their peaks on day 5 or 7 and remained unchanged by day 42. However, there were very little expressions in the recipients' hearts. Mean percent areas of intima in the donor coronaries revealed progressive increase by day 42. However, those in the recipients occupied consistently less than 5% of the lumen. In conclusion, we demonstrated that a heterotopic murine heart transplantation model was a useful tool to produce transplantation coronary artery disease and that adhesion molecules on the cardiac allografts were activated very early and remained elevated at all time-points, nonetheless the arterial lesion was detected after day 28 and its progression was accelerated thereafter.

Animals↗
PubMed1999

Effect of angiopeptin and aspirin on accelerated graft atherosclerosis in transplanted mouse heart.

In this study of the inhibitory effects of angiopeptin and aspirin on the development of accelerated graft atherosclerosis (AGAS), 22 B10.BR mice received intra-abdominal heterotopic heart transplants from B10.A mice, without immunosuppression. Group 1 (n = 5) received no pharmacological intervention, Group 2 (n = 6) was treated with angiopeptin, Group 3 (n = 5) with aspirin, and Group 4 (n = 6) with both. There was no significant difference in the incidence of AGAS among these groups. The magnitude of intimal lesion development showed less narrowing of large vessels (> 100 microns in diameter) in groups 2 and 4--i.e. the groups received angiopeptin (Group 1 = 46.9 +/- 9.3%, Group 2 = 28.5 +/- 9.2%, Group 3 = 44.1 +/- 10.9%, Group 4 = 24.2 +/- 5.9%; p < 0.01). Comparison of the fraction of tropomyosin-positive staining cells in the intima revealed a lesser degree of staining in Group 2 (p < 0.01). No intervention was effective in preventing smooth muscle cell proliferation in the media or inflammatory cell infiltration in the adventitia. In conclusion, our data suggest that angiopeptin is effective in the direct inhibition of intimal smooth muscle cell proliferation in relatively large vessels, whereas aspirin exhibits no inhibitory role in the progression of AGAS. Angiopeptin appears to be a potential therapeutic agent for inhibiting the progression of postoperative AGAS in clinical heart transplantation.

Animals↗
PubMed1999

Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma.

Metaplastic cell lineages arising in response to chronic injury are precursors for the evolution of dysplasia and adenocarcinoma. Although a subtype of intestinal metaplasia has been associated with gastric adenocarcinoma, the link between this lineage and the evolution of gastric adenocarcinoma has remained unclear. Wang et al (1998) have reported that an aberrant metaplastic cell lineage with morphological characteristics similar to Brunner's glands of the duodenum develops in the fundic mucosa of mice infected with Helicobacter felis. This metaplastic lineage expresses the trefoil peptide spasmolytic polypeptide (SP). Given the epidemiological association of Helicobacter species infection with gastric cancer, we hypothesized that this SP-expressing metaplastic (SPEM) lineage may represent a precursor to or appear commensurate with gastric adenocarcinoma. The SPEM lineage was present in 68% of fundic biopsies from patients with fundic Helicobacterpylori-associated gastritis, but was absent in biopsies of fundic mucosa from patients without H. pylori infection. In a review of archival samples from 22 resected gastric adenocarcinomas, we found the SPEM lineage in 91% of cases, typically located in mucosa adjacent to the carcinoma or areas of dysplasia. Importantly, 59% of resections showed SP immunoreactivity within dysplastic cells. These data indicate a strong association of the SPEM lineage with both chronic H. pylori infection and gastric adenocarcinoma.

Adenocarcinoma↗
PubMed1998

Extracellular signal-regulated kinase-2, but not c-Jun NH2-terminal kinase, activation correlates with surface IgM-mediated apoptosis in the WEHI 231 B cell line.

Both extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) have been implicated in mediating the signaling events that precede apoptosis. We studied the activation of these kinases during apoptosis of WEHI 231 B cells. Surface IgM ligation induces apoptosis of WEHI 231 cells. This effect is augmented by simultaneous engagement of CD95 and is inhibited by costimulation with either CD40 or IL-4R. We determined that surface IgM ligation activates ERK2 to a much greater level than JNK, and that IgM-mediated ERK2 activation is enhanced by costimulation with anti-CD95. Costimulation with either IL-4 or anti-CD40 interferes with anti-IgM-stimulated ERK2 activation. Transient expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) inhibits both ERK2 activation and cell death following stimulation with anti-IgM and the combination of anti-IgM plus anti-CD95. CD40 engagement alone activates JNK, but IL-4 stimulation does not. N-acetyl-L-cysteine pretreatment, which blocks CD40-mediated JNK activation, does not affect the ability of CD40 to inhibit anti-IgM-mediated ERK2 activation and apoptosis. Together, these data suggest that JNK activation is not required for CD40 inhibition of surface IgM-induced cell death and that ERK2 plays an active role in mediating anti-IgM-induced apoptosis of WEHI 231 B cells.

Acetylcysteine↗
PubMed1998

Molecular characterization of a common fragile site (FRA7H) on human chromosome 7 by the cloning of a simian virus 40 integration site.

Common fragile sites are chromosomal loci prone to breakage and rearrangement, hypothesized to provide targets for foreign DNA integration. We cloned a simian virus 40 integration site and showed by fluorescent in situ hybridization analysis that the integration event had occurred within a common aphidicolin-induced fragile site on human chromosome 7, FRA7H. A region of 161 kb spanning FRA7H was defined and sequenced. Several regions with a potential unusual DNA structure, including high-flexibility, low-stability, and non-B-DNA-forming sequences were identified in this region. We performed a similar analysis on the published FRA3B sequence and the putative partial FRA7G, which also revealed an impressive cluster of regions with high flexibility and low stability. Thus, these unusual DNA characteristics are possibly intrinsic properties of common fragile sites that may affect their replication and condensation as well as organization, and may lead to fragility.

Base Sequence↗
PubMed1998

Genomic structure of the human congenital chloride diarrhea (CLD) gene.

Congenital chloride diarrhea (CLD) is caused by mutations in a gene which encodes an intestinal anion transporter. We report here the complete genomic organization of the human CLD gene which spans approximately 39kb, and comprises 21 exons. All exon/intron boundaries conform to the GT/AG rule. An analysis of the putative promoter region sequence shows a putative TATA box and predicts multiple transcription factor binding sites. The genomic structure was determined using DNA from several sources including multiple large-insert libaries and genomic DNA from Finnish CLD patients and controls. Exon-specific primers developed in this study will facilitate mutation screening studies of patients with the disease. Genomic sequencing of a BAC clone H_RG364P16 revealed the presence of another, highly homologous gene 3' of the CLD gene, with a similar genomic structure, recently identified as the Pendred syndrome gene (PDS).

Base Sequence↗
PubMed1998

Risk of recurrent seizures after two unprovoked seizures.

BACKGROUND: Patients with a single unprovoked seizure have about a 35 percent risk of recurrence in the subsequent five years. We studied the risk of recurrence after two unprovoked seizures. METHODS: We prospectively followed 204 patients with a first unprovoked seizure from the day of the initial seizure. Information was obtained from patients (and verified by a review of their medical records) about the dates and circumstances of any subsequent seizures. The risk of a second, third, and fourth seizure was estimated by the Kaplan-Meier method. RESULTS: Of the 204 patients, 63 had a second seizure, 41 a third seizure, and 26 a fourth seizure. The mean age of the patients was 36 years, 10 percent were less than 16 years of age, 70 percent were male, 71 percent had epilepsy of unknown cause, and 66 percent had generalized seizures. The risk of a second unprovoked seizure was 33 percent. Among those with a second seizure, the risk of a third unprovoked seizure was 73 percent; among those with a third unprovoked seizure, the risk of a fourth was 76 percent. Most recurrences occurred within one year of the second or third seizure. The risk of a third seizure was higher in those with a presumed cause of epilepsy (relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.4). CONCLUSIONS: Although only about one third of patients with a first unprovoked seizure will have further seizures within five years, about three quarters of those with two or three unprovoked seizures have further seizures within four years.

Adolescent↗
PubMed1998

Production of reactive oxygen intermediates following CD40 ligation correlates with c-Jun N-terminal kinase activation and IL-6 secretion in murine B lymphocytes.

Recent studies indicate that reactive oxygen intermediates (ROI) serve as second messengers in cell signaling. ROI have been implicated in the activation of NF-kappaB as well as c-Jun N-terminal kinase (JNK) in response to IL-1 and TNF-alpha stimulation. In this report we examine whether intracellular ROI are involved in CD40 receptor signaling. We show that CD40 engagement on resting splenic B lymphocytes and murine B lymphoma WEHI 231 cells generates ROI. Blocking ROI production by preincubation with the antioxidant N-acetyl-L-cysteine inhibits JNK activation, NF-kappaB-driven luciferase activity, and IL-6 secretion following CD40 ligation, suggesting a role for ROI in CD40-mediated signaling events. Furthermore, transfection of WEHI 231 cells with a plasmid encoding Mn-superoxide dismutase interferes with CD40-induced NF-kappaB activation, providing further support for ROI involvement in this pathway. Collectively, these data demonstrate that ROI may serve as second messengers linking CD40 engagement on B cells to important downstream activation events.

Animals↗
PubMed1998

Malignant rhabdoid tumor of the duodenum.

A polypoid malignant rhabdoid tumor of the duodenum is presented. The pattern of metastatic spread in this 58-year-old man included multiple duodenal and small intestinal transmural tumor implants and a large peribronchial lymph node causing superior vena cava syndrome. Microscopically, the tumor was composed of a diffuse population of rhabdoid cells characterized by homogeneous globular cytoplasmic inclusions that tended to indent or displace eccentric, vesicular nuclei with nucleoli. No glandular features were noted. Immunohistochemical and ultrastructural evaluation revealed that these inclusions contained vimentin, an intermediate filament of the mesenchymal cytoskeleton. Phenotypic features of a rhabdoid tumor have been reported in 10 poorly differentiated malignancies of the gastrointestinal tract. This is the first case report of a malignant rhabdoid tumor of the small intestine. Regardless of the site of the lesion, tumors showing these features are generally associated with a poor prognosis.

Duodenal Neoplasms↗
PubMed1998

Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.

Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms. With few exceptions, patients follow a homogeneous clinical course despite the existence of genetic heterogeneity. Biopsy of various tissues, including brain, revealed characteristic polyglucosan inclusions called Lafora bodies, which suggested LD might be a generalized storage disease. Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain. Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD. These mutations are predicted to cause deleterious effects in the putative protein product, named laforin, resulting in LD.

Alternative Splicing↗
PubMed1998

Use of leukocyte depletion to decrease injury after lung preservation and rewarming ischemia: an experimental model.

BACKGROUND: Hypothermia is critical for proper lung preservation. Ideally, the lungs should be maintained at the optimal preservation temperature during the entire ischemic interval. Lung rewarming during implantation is commonly observed. This study was undertaken to investigate the severity of rewarming ischemia on preservation injury and the possibility of minimizing this by use of leukocyte depletion during initial reperfusion. METHODS: Four experimental groups were tested as follows: neonatal piglet heart-lung blocks were either (1) placed on an isolated, blood-perfused, working heart-lung circuit without intervening ischemia (control, n = 6), (2) reperfused on the circuit with whole blood (WB, n = 6) after 13 hours of preservation, (3) reperfused with WB after 12 hours of preservation and 1 hour of rewarming (RWB, n = 5), or (4) reperfused with leukocyte-depleted blood for an initial 10 minutes followed by WB, after 12 hours of preservation and 1 hour of rewarming (n = 6). All groups were studied for 4 hours. RESULTS: The partial pressure of arterial oxygen and lung compliance were significantly lower in the RWB group than in controls (113.8+/-33.1 vs 417.3+/-6.2 mm Hg, p < 0.01; and 0.8+/-0.2 vs 2.9+/-0.4 ml/cm H2O, p < 0.05, respectively). Pulmonary vascular resistance and lung wet/dry weight ratios were significantly higher in the RWB group than in controls (15884.1+/-11354.8 vs 6108.3+/-1309.9 dyne x sec x cm[-5], p < 0.05; and 7.13+/-0.24 vs 5.82+/-0.35, p < 0.05, respectively). The WB and leukocyte-depleted groups did not differ significantly from controls for any measured parameter. CONCLUSIONS: This model confirms that rewarming ischemia during lung implantation exacerbates reperfusion injury. Leukocyte-depleted reperfusion as tested for a short period of time (10 minutes) ameliorates this injury and therefore should be considered for clinical lung transplantation.

Animals↗
PubMed1997

Carcinoid tumors of the lung and family history of cancer.

Family history of cancer has been described among patients with lung neoplasms. Carcinoid tumors, originally thought to be slow growing and nonmetastatic, have not historically been included in these studies. In some instances these tumors have demonstrated aggressive metastatic potential. A medical record review of 86 patients with histopathologically confirmed carcinoid tumors of the lung, treated at the University of Texas M.D. Anderson Cancer Center between 1959 and 1994, was conducted to describe family history of cancer. Family history of cancer was recorded in 74 (86%) of the medical records and 32 (43%) reported first-degree relatives with cancer. Five-year survival for patients with affected relatives was 45% and 73% for patients without affected relatives (p = .23). Among 67 patients without metastatic disease at diagnosis, the risk of distant metastasis by 5 years was 40% among patients with a positive family history of cancer compared to 6% of the patients without affected relatives (p = .03), (rate ratio 5.01). These results suggest that genetic susceptibility may affect the metastatic potential of some carcinoid tumors.

Carcinoid Tumor↗
PubMed1997

Resources for human genetics on the World Wide Web.

A little over a century ago, the HMS Beagle sailed the Pacific Ocean bringing Charles Darwin to the perfect environment in which to piece together his observations forming the theory of evolution. Now, geneticists and laypeople alike surf the equally formidable waters of the internet in search of enlightenment. Here, we attempt to help you navigate towards resources for human genetics by providing maps to three destinations: The Human Genome Project (Box 1), education (Box 2), and human genetic diseases (Box 3). For each, we highlight a few sites that we consider are the most informative and original. A more extensive list containing other useful sites has been compiled and posted on a 'jump site' at: http:/(/)www.cgdn.generes.ca/.

Computer Communication Networks↗