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Biomedical subjects

C K Lee

Publications and source records attributed to C K Lee.

At least 91 records · Page 5Linked to original sources
PubMed2000

The need for long-term surveillance for patients treated with curative radiotherapy for Hodgkin's disease: University of Minnesota experience.

PURPOSE: To examine the long-term outcome of Stage I, II, and III patients treated with curative radiotherapy for Hodgkin's disease at the University of Minnesota Hospital, with particular focus on long-term treatment-related complications and the need for long-term surveillance after treatment. METHODS AND MATERIALS: A total of 210 Stage I, II, and III patients (98 female, 112 male) treated at the University of Minnesota since 1970 were included in this study. All patients were laparotomy staged. Between 1970 and 1974, 35 high-risk patients (i.e., patients with large mediastinal mass, and/or hilar disease, and/or splenic involvement) and 40 low-risk patients were treated with standard field radiotherapy. From 1975 on, 67 high-risk patients received radical radiotherapy because of poor outcomes with standard radiotherapy, and 68 low-risk patients received standard radiotherapy. Salvage chemotherapy was given to 62 patients who recurred. Median follow-up for all patients was 15.6 years (range 0. 35-26.5 years). Long-term complications after treatment were assessed using standardized incidence ratios (SIR) and mortality ratios (SMR), with particular focus on cardiac complications and secondary malignancies. RESULTS: By study end, 70% of the patients are alive and 70% had never recurred. Complications included 33 second malignancies and 75 cardiovascular events. Patients treated for Hodgkin's disease had about 7 times the risk of dying from cardiac problems (SMR = 7.2) and 10 times the risk of dying from a second malignancy (SMR = 10.3) compared to the general population. In terms of absolute risk, Hodgkin's disease would cause seven additional deaths from secondary malignancies per year among 1000 patients and four additional deaths from cardiac problems. CONCLUSION: Hodgkin's disease patients treated successfully with radiotherapy are at an increased risk for developing long-term treatment-related cardiac disease and/or second malignancies. Careful monitoring of these patients is essential to manage morbidity and minimize mortality from these complications. Suggestions for the establishment of worldwide surveillance programs for these patients are proposed.

Adolescent↗
PubMed2000

A case-controlled study on the use of HBsAg-positive donors for allogeneic hematopoietic cell transplantation.

To compare the clinical and serological outcomes of patients receiving donors' marrow positive or negative for hepatitis B surface antigen (HBsAg), we studied 18 patients of allogeneic hematopoietic cell transplantation receiving HBsAg-positive marrow (group 1) and 18 receiving HBsAg-negative marrow (group 2). The recipients of the 2 groups were matched for hepatitis B virus (HBV) serology, sex, age, underlying hematological diseases, conditioning regimen, and prophylaxis against graft-versus-host diseases. Eight (44.4%) recipients in group 1 and 2 (11.1%) in group 2 suffered from HBV-related hepatitis posttransplant (P =.03). Furthermore, HBV-related hepatic failure was seen in 6 group 1 patients, but in none of the group 2 patients (P =.007). Five of the 9 (55.5%) HBsAg-negative recipients in group 1 became positive after receiving HBsAg-positive marrow. Serum HBV DNA was positive in all 5 donors of these patients, but in none of the donors of recipients who remained HBsAg negative (P =.008). Group 1 patients developing HBV-related hepatitis posttransplant were more likely to have a donor carrying a precore A(1896 )and/or core promoter T(1762)/A(1764) HBV variant (62. 5% versus 0%, P =.007). This study has demonstrated that a high incidence of HBV-related hepatitis was associated with the use of HBsAg-positive marrow for transplant, and a high viral load in the donor appeared to predispose recipients to the development of HBV-related hepatitis posttransplant. Further clinical trials will be necessary to determine the optimal management approach to this problem, including the use of the antiviral agents in the donors and the recipients. (Blood. 2000;96:452-458)

Adolescent↗
PubMed2000

The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection.

Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected hepatocytes by HBV-specific CD8 cells has been assumed to be the central mechanism causing both liver damage and virus control. To understand the role of cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays that require T cell expansion in vitro and human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients with persistent HBV infection were studied: one without liver inflammation and HBV replication, the other with liver inflammation and a high level of HBV replication. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the absence of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute number was similar because of the massive cellular infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a circulating reservoir of CD8(+) cells able to expand after specific virus recognition that was not detectable in highly viremic patients with liver inflammation. These results show that in the presence of an effective HBV-specific CD8 response, inhibition of virus replication can be independent of liver damage. When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology not only directly but by causing the recruitment of nonvirus-specific T cells.

CD8-Positive T-Lymphocytes↗
PubMed2000

Type I IFN modulates innate and specific antiviral immunity.

IFNs protect from virus infection by inducing an antiviral state and by modulating the immune response. Using mice deficient in multiple aspects of IFN signaling, we found that type I and type II IFN play distinct although complementing roles in the resolution of influenza viral disease. Both types of IFN influenced the profile of cytokines produced by T lymphocytes, with a significant bias toward Th2 differentiation occurring in the absence of responsiveness to either IFN. However, although a Th1 bias produced through inhibition of Th2 differentiation by IFN-gamma was not required to resolve infection, loss of type I IFN responsiveness led to exacerbated disease pathology characterized by granulocytic pulmonary inflammatory infiltrates. Responsiveness to type I IFN did not influence the generation of virus-specific cytotoxic lymphocytes or the rate of viral clearance, but induction of IL-10 and IL-15 in infected lungs through a type I IFN-dependent pathway correlated with a protective response to virus. Combined loss of both IFN pathways led to a severely polarized proinflammatory immune response and exacerbated disease. These results reveal an unexpected role for type I IFN in coordinating the host response to viral infection and controlling inflammation in the absence of a direct effect on virus replication.

Adjuvants, Immunologic↗
PubMed2000

STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma.

Lymphocytes derived from mice deficient in STAT1 showed reduced apoptosis and enhanced proliferation in vitro. To understand the involvement of STAT1 in the observed reduction in apoptosis, we examined the levels of caspase and bcl-2 family genes that are involved in cell survival and/or apoptosis. The levels of caspase 1 and 11, two enzymes involved in both cytokine protein processing and induction of apoptosis, were reduced in STAT1-/- cells compared with wild-type. However, the levels of bcl-2 genes were comparable in both mice. STAT1-/- cells also displayed an enhanced proliferation following TCR stimulation. This hyperproliferation could not be ascribed completely to the loss of IFN-gamma-mediated antiproliferation. First, similar phenotypes were also observed in fibroblasts and pre-B cells derived from STAT1-/- mice, which do not produce IFN-gamma. Second, comparisons with cells lacking the gene for IFN-gamma or with cells treated with neutralizing Abs to IFN-gamma only partially mimicked the STAT1-/- phenotype. Interestingly, the kinetics of degradation of p27kip1, a CDK inhibitor, following TCR ligation were faster, and, concomitantly, the up-regulation of CDK2 kinase activity and protein levels were increased in stimulated T cells of STAT1-/- mice relative to those of wild-type mice. Furthermore, STAT1-/- animals were more susceptible to carcinogen-induced thymic tumors, a possible consequence of altered T cell growth and/or survival. These results demonstrate an essential role for STAT1 for lymphocyte survival and proliferation that is only partially dependent on IFN-gamma signaling.

Animals↗
PubMed2000

Polysaccharide vaccines for preventing serogroup A meningococcal meningitis.

BACKGROUND: Controlled trials over two decades ago showed that the polysaccharide vaccine prevented meningococcal meningitis. Subsequent observational studies suggested variations in the level and duration of protection, particularly among young children. OBJECTIVES: To determine the effect of polysaccharide serogroup A vaccine for preventing serogroup A meningococcal meningitis. SEARCH STRATEGY: MEDLINE and the Cochrane Controlled Trials Register. SELECTION CRITERIA: Randomised and other prospective controlled trials. DATA COLLECTION AND ANALYSIS: One reviewer collected data and assessed the methodologic quality of the trials. Data were pooled using the Exact method to assess vaccine efficacy at one, two and three years post-vaccination. MAIN RESULTS: The protective effect within the first year was consistent across all eight trials, including one with participants exclusively under six years of age (in Finland); overall vaccine efficacy was 95% (Exact 95% CI 87%, 99%). The Finnish trial lacked statistical power to assess the effect of a booster dose given to children less than 18 months old. In the three other trials that included children less than six years old (one in Sudan and two in Nigeria), none of the vaccinated children developed meningitis, but the statistical significance of this finding was undetermined. Protection extended into the second (in two studies) and third (in one study) years after vaccination, but these results were also not statistically significant. REVIEWER'S CONCLUSIONS: When compared with current recommendations, the methodological quality and relative incompleteness of the published reports could arguably render the trials invalid for this review. However, it was unlikely that the results of the trials in such diverse settings would have been biased towards a strong and consistent protective effect. Immunogenicity trials were not included in this review. Stage two of the review will assess the vaccine effect from observational studies.

Humans↗
PubMed2000

Synthesis and antiviral activity of novel methylene cyclopropyl nucleosides.

Novel exomethylene cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate 5 was synthesized in 4 steps, from Feists acid 1 and was condensed with purine derivatives by the SN2 type reaction to give some cyclopropyl nucleosides. The synthesized nucleosides did not showed any significant antiviral activity against HSV-1, HSV-2, HCMV, HIV-1, HIV-2, and HBV up to 100 microM.

Antiviral Agents↗
PubMed2000

Designs and syntheses of oxathiin carboxanilide analogues and their antiviral activities.

Syntheses of new analogues of oxathiin carboxanilide (UC84) and their antiviral activities were described. The heterocyclic carboxylic acids including oxathiins (4), thiazines (9) and dithiins (13) in which the methyl was replaced either by lipophilic trifluoromethyl- or bulky phenyl-group were synthesized starting from beta-keto esters (5). Reaction of 4, 9 and 13 with thionyl chloride followed by treatment of the substituted aniline 22 gave the corresponding carboxanilides (24a-24f). The carboxanilides were subjected to Laweson's reagent the corresponding thiocarboxanilides (24g-24k). The antiviral activities of the synthesized compounds against human immunodeficiency virus type 1 (HIV-1), poliovirus type 1 (PV-1), coxsackie B virus type 3 (CoxB-3), vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) were presented. The antiviral activity against HIV-1 of dithiin carboxanilide (24e) was similar with that of UC84 (24a). The corresponding thiocarboxanilides (24g-24k) showed higher inhibitory activity against HIV-1 than the carboxanilides (24a, 24b, 24d, 24e). The compounds in which ether the lipophilic trifluoromethyl substituents (24d, 24f, 24i, 24k) or bulky phenyl substituent is present in the heterocyclic compounds showed lower inhibitory activity than that of the methyl substituents is present in the compounds against the HIV-1. But the trifluoromethylated dithiin (24f) showed higher inhibitory activity against PV-1 and CoxB-3 virus than commercial antiviral agents, ribavirin (RV).

Antiviral Agents↗
PubMed2000

A mouse thymic stromal cell line producing macrophage-colony stimulating factor and interleukin-6.

A thymic stromal cell line, TFGD, was established from a thymic tumor mass developed spontaneously in p53 knock out mouse, and was found to produce cytokines that could induce bone marrow hematopoietic stem cells (HSCs) to differentiate into macrophages. The cytokines produced by the TFGD line were assessed by immunoassays. High level of macrophage-colony stimulating factor (M-CSF) and interleukin (IL)-6 was detected in the TFGD-culture supernatant, whereas granulocyte/macrophage-colony stimulating factor (GM-CSF), IL-3, IL-4, IL-5, IL-13, or interferon (IFN)-gamma was undetectable. Blocking experiments showed that anti-M-CSF monoclonal antibody could neutralize the differentiation-inducing activity shown by the TFGD-culture supernatant. Dot blot analysis of the total RNA isolated from the cultured fetal thymic stromal cells showed that M-CSF transcripts were expressed in the normal thymus. These observations, together with the earlier finding that M-CSF plus IL-6 is the optimal combination of cytokines for the induction of macrophage differentiation from HSCs in vitro, may indicate that thymic macrophages could be generated within the thymus by cytokines involving M-CSF.

Animals↗
PubMed2000

Osteoconduction at porous hydroxyapatite with various pore configurations.

To assess the histological response and the reinforcing effects of bone ingrowth within porous hydroxyapatite (HA) implants depending on pore geometry, four kinds of cylindrical-type with parallel linear pores phi50, 100, 300, 500 microm), one kind of sponge-type with irregular interconnecting pores (phi250 microm) and one cross-type with crossing linear pores (phi100 x 120 microm) of porous HA were prepared. Eighty-four rabbits were divided into six groups, and a 5 x 5 x 7 mm sized porous HA block was inserted through the medial cortical window of the proximal tibia. Histomorphological changes were examined using light and scanning electron microscopy. A biomechanical compression test was performed using material test machines. After implantation, the implants showed different histological changes depending on pore geometry. Active osteoconduction was also found in the phi50 microm sized cylindrical-type porous HA. Evidence of remodeling of new bone and bone marrow formation within porous HA was found in the larger cylindrical-types (phi300, 500 microm), and the sponge- and cross-types. The biomechanical test showed that the ultimate compressive strength increased significantly in the phi300 microm sized cylindrical-type, and in the sponge- and cross-types eight weeks after implantation. Porous HA with cylindrical pores could be a useful graft material due to its strength, osteoconductivity and the ease with which its pore geometry can be controlled.

Animals↗
PubMed2000

Endothelium-dependent vasorelaxant and antiproliferative effects of apigenin.

This study was designed to determine whether the relaxant effect of apigenin was endothelium dependent and to examine the possible antiproliferative effect of apigenin. Apigenin relaxed the phenylephrine-precontracted endothelium-intact aortic rings with IC(50) value of 3.7+/-0.5 microM and removal of a functional endothelium significantly attenuated this relaxation (IC(50)=8.2+/-0.9 microM). However, apigenin did not affect the 0.1 microM phorbol 12,13-dibutyrate-induced contraction (IC(50)=34.6+/-1.2 microM) within the concentration range that relaxed the phenylephrine-contracted arteries, suggesting that apigenin did not influence protein kinase C-mediated contractile mechanisms in rat aorta. Pretreatment of apigenin significantly potentiated the relaxant effect of acetylcholine on phenylephrine-induced contraction. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) or methylene blue reduced the relaxant effect of apigenin. Apigenin (10 microM) increased the guanosine 3',5'-cyclic monophosphate (cGMP) content of endothelium-intact tissues. Pretreatment with L-NAME (100 microM) or removal of endothelium significantly suppressed the effect of apigenin on cGMP production. In addition, apigenin significantly inhibited [3H]thymidine incorporation into DNA of primary cultured rat aortic smooth muscle cell in a dose-dependent manner. These findings suggest that besides influx and release of Ca(2+), nitric oxide (NO) and cGMP may account for the apigenin-induced endothelium-dependent relaxation and hypotensive activity. Both vasorelaxant and antiproliferative activities may contribute to a benefit of apigenin in the vascular system.

Animals↗
PubMed2000

Antiherpetic activities of acidic protein bound polysacchride isolated from Ganoderma lucidum alone and in combinations with acyclovir and vidarabine.

To investigate antiherpetic activity, an acidic protein bound polysaccharide (APBP) was isolated from carpophores of Ganoderma lucidum. This brownish APBP was isolated from water soluble substances of the carpophores by activity-guided isolation method. APBP was tested for its antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) by plaque reduction assay in tissue culture. APBP showed potent antiviral activity against HSV-1 and HSV-2 in Vero cells at its 50% effective concentration (EC(50)) of 300 and 440 microg/ml, respectively. APBP had no cytotoxicity on Vero cells at a concentration of 1 x 10(4) microg/ml. APBP exhibited a potent antiviral activity with selectivity index (SI) of more than 22.73. The combined antiherpetic effects of APBP with nucleoside antiherpetic agents, acyclovir (ACV) and vidarabine (ara-A), were examined on the multiplication of these two strains of herpesviruses in Vero cells by the combination assay. The results of combination assay were evaluated by the combination index (CI) that was calculated by the multiple drug effect analysis. CI values were in the range 0.47-0.51 for a combination of APBP with ACV, and in the range of 1.02-1.18 for a combination of APBP with ara-A. The combinations of APBP with ACV on HSV-1 and HSV-2 showed potent synergistic effects, and these results suggest that the possibility of developing APBP as a new antiherpetic agent.

Acyclovir↗
PubMed2000

Possible mode of antiviral activity of acidic protein bound polysaccharide isolated from Ganoderma lucidum on herpes simplex viruses.

Two protein bound polysaccharides, a neutral protein bound polysaccharide (NPBP) and an acidic protein bound polysaccharide (APBP), were isolated from water soluble substances of Ganoderma lucidum by EtOH precipitation and DEAE-cellulose column chromatography. Their antiviral activities against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) were then investigated by plaque reduction assay. APBP exhibited more potent HSV-1 and HSV-2 antiviral activity than NPBP with 50% effective concentration (EC(50)) of 300-520 microg/ml. In order to examine the possible mode of the antiviral activity of APBP its virucidal effect, antiviral activity in preincubation, attachment and penetration assay were tested with HSV-1 and HSV-2. APBP was found to have a direct virucidal effect on HSV-1 and HSV-2. APBP did not induce IFN or IFN-like materials in vitro and is not expected to induce a change from a normal state to an antiviral state. APBP in concentrations of 100 and 90 microg/ml inhibited up to 50% of the attachment of HSV-1 and HSV-2 to Vero cells and was also found to prevent penetration of both types of HSV into Vero cells. These results show that the antiherpetic activity of APBP seems to be related to its binding with HSV-specific glycoproteins responsible for the attachment and penetration, and APBP impedes the complex interactions of viruses with cell plasma membranes.

Animals↗
PubMed2000

Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2.

STAT5 is activated in a broad spectrum of human hematologic malignancies. We addressed whether STAT5 activation is necessary for the myelo- and lymphoproliferative disease induced by TEL/JAK2 using a genetic approach. Whereas mice transplanted with bone marrow transduced with retrovirus expressing TEL/JAK2 develop a rapidly fatal myelo- and lymphoproliferative syndrome, reconstitution with bone marrow derived from Stat5ab-deficient mice expressing TEL/JAK2 did not induce disease. Disease induction in the Stat5a/b-deficient background was rescued with a bicistronic retrovirus encoding TEL/JAK2 and Stat5a. Furthermore, myeloproliferative disease was induced by reconstitution with bone marrow cells expressing a constitutively active mutant, Stat5a, or a single Stat5a target, murine oncostatin M (mOSM). These data define a critical role for Stat5a/b and mOSM in the pathogenesis of TEL/JAK2 disease.

Animals↗
PubMed2000

A null mutant of the Streptomyces virginiae barA gene encoding a butyrolactone autoregulator receptor and its phenotypic and transcriptional analysis.

The Streptomyces virginiae barA gene encodes a specific receptor protein for virginiae butanolide (VB), one of the gamma-butyrolactone autoregulators of Streptomyces species. By homologous recombination, a barA null strain was constructed to clarify the in vivo function of BarA protein in S. virginiae. The deltabarA mutant showed no difference in terms of growth, but lost VB production and produced virginiamycin 7 h earlier than the wild-type strain. These results indicated that, phenotypically, BarA protein acts negatively in virginiamycin biosynthesis and positively in VB biosynthesis. Furthermore, Northern (RNA) blot analysis of the DeltabarA mutant revealed that transcription of the BarA target gene (barB) was derepressed, confirming that BarA acts as a transcriptional repressor in S. virginiae.

Journal Article↗
PubMed2000

Isolation of bacteria other than Helicobacter pylori from stomachs of squirrel monkeys (Saimiri spp.) with gastritis.

Gastric biopsy specimens obtained from 12 squirrel monkeys (Saimiri spp.) were investigated by culture for the presence of bacteria. The stomachs of two monkeys with gastritis were colonized with gram-negative, urease-positive bacteria, identified as Ochrobactrum anthropi by the Vitek and API NFT methods (BioMérieux). A third monkey with gastritis was positive for Aeromonas salmonicida and Pseudomonas vesicularis (both urease-negative). No Helicobacter pylori was isolated from squirrel monkeys. Light microscopic and transmission electron microscopic examination revealed that the O. anthropi isolates were covered by extracellular material, indicating a capsule. Characterization of the O. anthropi urease revealed Michaelis-Menten constants (Km values) of 6.2 and 4.0 mM urea for the ureases of O. anthropi isolates S664 and S1835, respectively, and 3.7 for type strain 49188. Western blot analysis using H. pylori- and H. felis-specific antibodies detected shared antigenic epitopes between the ureases of H. pylori, H. felis, and O. anthropi. The apparent molecular mass of the urease enzymes of the O. anthropi isolates was determined on 6% nondenaturing gels to be approximately 82 kDa. Antimicrobial susceptibility tests, using the MicroScan method (Dade International), revealed multidrug resistance for the O. anthropi isolates with susceptibilities for the antibiotics amikacin, ciprofloxacin, gentamicin, cefoperazone, tobramycin, imipenem, and trimethoprim/sulfamethoxazole.

Aeromonas↗
PubMed2000

Gene-expression profile of the ageing brain in mice.

Ageing of the brain leads to impairments in cognitive and motor skills, and is the major risk factor for several common neurological disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Recent studies suggest that normal brain ageing is associated with subtle morphological and functional alterations in specific neuronal circuits, as opposed to large-scale neuronal loss. In fact, ageing of the central nervous system in diverse mammalian species shares many features, such as atrophy of pyramidal neurons, synaptic atrophy, decrease of striatal dopamine receptors, accumulation of fluorescent pigments, cytoskeletal abnormalities, and reactive astrocytes and microglia. To provide the first global analysis of brain ageing at the molecular level, we used oligonucleotide arrays representing 6,347 genes to determine the gene-expression profile of the ageing neocortex and cerebellum in mice. Ageing resulted in a gene-expression profile indicative of an inflammatory response, oxidative stress and reduced neurotrophic support in both brain regions. At the transcriptional level, brain ageing in mice displays parallels with human neurodegenerative disorders. Caloric restriction, which retards the ageing process in mammals, selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses.

Aging↗