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Biomedical subjects

A Ko

Publications and source records attributed to A Ko.

At least 19 recordsLinked to original sources
PubMed2004

Effects of ibuprofen on molecular markers of cartilage and synovium turnover in patients with knee osteoarthritis.

OBJECTIVE: The aim of this study was to evaluate the effect of ibuprofen on the urinary excretion of C-terminal crosslinking telopeptide of type II collagen (CTX-II) and urinary glucosyl galactosyl pyridinoline (Glc-Gal-PYD), two new molecular markers of cartilage and synovial tissue metabolism, respectively, in patients with knee osteoarthritis (OA). METHODS: We studied 201 patients with knee pain and radiographic evidence of knee OA who were on treatment with non-steroidal anti-inflammatory drugs (NSAIDs) prior to study initiation. After an initial screening visit, patients were withdrawn from their pre-study NSAID and, following a flare of their OA symptoms, were randomised to ibuprofen (2400 mg/day) or placebo. Urinary CTX-II and Glc-Gal-PYD levels were measured at time of randomisation (baseline) and after 4-6 weeks of treatment. RESULTS: After 4 to 6 weeks, urinary CTX-II (+17%, p = 0.023) and Glc-Gal-PYD (+10%, p = 0.020) increased significantly from baseline in the placebo group whereas marginal or no increase was observed in the ibuprofen group (CTX-II +2%, NS and Glc-Gal-PYD +4%, p = 0.045). For urinary CTX-II, the difference in the change from baseline between placebo and ibuprofen treated groups was significant (13%, p = 0.017). At baseline, urinary levels of CTX-II and Glc-Gal-PYD were higher in patients with knee swelling (n = 127) than in those without (n = 74) (p<0.02 for both markers). When patients were stratified according to presence or absence of knee swelling at baseline, the increases over 4-6 weeks of urinary CTX-II and Glc-Gal-PYD in the placebo group were restricted to patients with knee swelling (+22% from baseline, p = 0.001 and +12%, p = 0.011, for urinary CTX-II and Glc-Gal-PYD respectively). In patients with knee swelling who were treated with ibuprofen this increase was not observed and the difference from placebo was significant for urinary CTX-II (p = 0.014). CONCLUSION: In patients with a flare of knee OA, specifically in patients with evidence of joint inflammation documented by knee swelling, there was a significant increase in markers reflecting cartilage and synovium metabolism that could partly be prevented by high doses of ibuprofen. These data suggest that patients with a flare of knee OA are characterised by increased cartilage and synovial tissue degradation, which may be partly prevented by high doses of NSAIDs.

Acute Disease↗
PubMed2002

Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis.

OBJECTIVES: To evaluate the clinical efficacy and tolerability of etoricoxib in the treatment of osteoarthritis (OA) of the knee and define the clinically active dose range for further clinical trials. METHODS: This two-part, randomized, double-blind, placebo- and active comparator-controlled trial was conducted in 617 adults with knee OA. In Part 1 (6 weeks), patients received placebo, etoricoxib 5, 10, 30, 60 or 90 mg q.d. In Part 2 (8 weeks), patients received etoricoxib 30, 60 or 90 mg q.d. or diclofenac 50 mg t.i.d., predetermined at Part 1 allocation. Efficacy and safety were evaluated. Primary efficacy end-points were the Western Ontario and McMaster's University Osteoarthritis Index (WOMAC) Pain subscale, Patient Global Assessment of Response to Therapy, and Investigator Global Assessment of Disease Status. RESULTS: At 6 weeks, etoricoxib 5, 10, 30, 60 and 90 mg each demonstrated clinical efficacy superior to placebo. Maximal efficacy was seen with 60 mg. In Part 2, etoricoxib 30, 60 and 90 mg were generally similar to diclofenac. Patients receiving etoricoxib 30, 60 or 90 mg in Parts I and II had sustained effects over 14 weeks. All treatments were well tolerated. CONCLUSIONS: Etoricoxib 60 mg once daily showed maximal efficacy in treating OA in this study. Etoricoxib 5-90 mg once daily was generally well tolerated in OA patients for up to 14 weeks.

Adult↗
PubMed2001

A canine model of gastroesophageal reflux disease (GERD).

BACKGROUND: Although a variety of antireflux procedures and medications are used to treat gastroesophageal reflux disease (GERD), reliable large-animal models of GERD that can be used to objectively compare the efficacy of these treatments are lacking. METHODS: Esophageal manometry and 24-h gastroesophageal pH monitoring with event data were performed in 18 mongrel dogs with a cervical esophagopexy. We then calculated a modified DeMeester score: The Duke Canine reflux score (DCR). Thereafter, the animals underwent a 4-cm anterior distal esophageal myotomy, incision of the left diaphragmatic crus, and intrathoracic gastric cardiopexy. Postoperative 24-h pH and manometry were obtained 2 weeks later. RESULTS: The postoperative 24-h pH results showed a significant increase in the mean DCR score (5.9 +/- 4.5 vs 84.9 +/- 56.1, p < 0.0002), and manometry indicated a significant decrease in mean lower esophageal sphincter (LES) pressure (7.1 +/- 2.9 vs 3.2 +/- 2.5 mmHg, p < 0.0001). CONCLUSION: This technique reliably creates a canine model of GERD.

Animals↗
PubMed2001

Histologic evaluation of fetal brains following maternal pneumoperitoneum.

BACKGROUND: The purpose of this study was to determine if maternal pneumoperitoneum with carbon dioxide (CO2) produces evidence of central nervous system (CNS) injury in preterm fetal guinea pigs. METHODS: Thirty pregnant guinea pigs at gestational day (GD) 45 were assigned at random to one of three treatment groups: anesthesia only, CO2 pneumoperitoneum (5 mmHg), or laparotomy. Dams were killed 3 or 5 days postprocedure and fetal brains (83 total) harvested and fixed for subsequent histopathologic evaluation. For comparative purposes, histologic features of fetal guinea pig brain injury were defined from examination of fetal brains harvested from an additional dam that underwent laparotomy with 20 min of uterine arterial occlusion. RESULTS: Carbon dioxide pneumoperitoneum did not increase maternal/fetal morbidity. No evidence of brain injury was found in fetuses from any of the treatment groups. CONCLUSION: Carbon dioxide pneumoperitoneum at 5 mmHg for 40 min in the pregnant guinea pig does not produce evidence of fetal brain injury.

Animals↗
PubMed2001

CTLA-4 blockade enhances the CTL responses to the p53 self-tumor antigen.

p53 is an attractive target for cancer immunotherapy because it is overexpressed in a high proportion of many different types of tumors. However, it is also expressed in normal tissues and acts as a toleragen in vivo. Previously, detailed examination of the repertoire specific for the murine p53(261-269) epitope in conventional and p53-deficient mice demonstrated that because of expression of p53, the CD8(+) T cells that respond to this epitope express low-affinity TCRs. It has been reported that tolerance to tumor Ags can be broken by in vivo administration of anti-CTLA-4 mAb. With the goal of overriding tolerance and achieving optimal activation of p53-specific CTL, the current study has assessed the effect of anti-CTLA-4 mAb on the p53-specific repertoire. It was found that blockade of CTLA-4 engagement at the time of antigenic stimulation induced a vigorous amplification of the CTL responses to p53 as well as proportionate expansion of the memory T cell pool. This effect was dependent on the presence of CD4(+) T cell help and correlated with an enhancement of helper function. However, anti-CTLA-4 treatment did not enhance the avidity of the resultant p53-specific CTL populations and, therefore, could not reverse this important consequence of tolerance.

Abatacept↗
PubMed2001

Radiation after mastectomy in high-risk patients: is it necessary?

A retrospective review of cases from 1988 through 1992 was performed examining high-risk breast cancer patients treated with modified radical mastectomy without postoperative radiation at a single institution. Locoregional recurrence, distant metastases, overall survival, and number of lymph nodes removed were examined. This was compared with recent Danish and Canadian studies. Thirty-three premenopausal node-positive breast cancer patients had a 9 per cent locoregional recurrence rate. In the Danish and Canadian studies the locoregional recurrence rates were 32 and 21 per cent. These were reduced to 9 per cent and 10 per cent respectively in the radiated arms. Our locoregional recurrence in nonradiated patients was similar to that in the radiated arms of the studies and improved when compared with recurrence in their non-radiated controls. The adequacy of the axillary lymph node dissection was examined. In the current study a median of 18 lymph nodes were recovered with only 3 per cent containing less than 12 nodes. In the Danish study a median of seven lymph nodes were removed. Similarly in the Canadian trial a median of 11 nodes were removed. With complete axillary dissection results equivalent to those of postoperative adjuvant radiation is achieved. Further randomized controlled studies with standard axillary dissections are needed before the recommendation of routine postoperative radiotherapy.

Adult↗
PubMed2000

Characterization of CD8+ T lymphocytes that persist after peripheral tolerance to a self antigen expressed in the pancreas.

As a result of expression of the influenza hemagglutinin (HA) in the pancreatic islets, the repertoire of HA-specific CD8+ T lymphocytes in InsHA transgenic mice (D2 mice expressing the HA transgene under control of the rat insulin promoter) is comprised of cells that are less responsive to cognate Ag than are HA-specific CD8+ T lymphocytes from conventional mice. Previous studies of tolerance induction involving TCR transgenic T lymphocytes suggested that a variety of different mechanisms can reduce avidity for Ag, including altered cell surface expression of molecules involved in Ag recognition and a deficiency in signaling through the TCR complex. To determine which, if any, of these mechanisms pertain to CD8+ T lymphocytes within a conventional repertoire, HA-specific CD8+ T lymphocytes from B10.D2 mice and B10.D2 InsHA transgenic mice were compared with respect to expression of cell surface molecules, TCR gene utilization, binding of tetrameric KdHA complexes, lytic mechanisms, and diabetogenic potential. No evidence was found for reduced expression of TCR or CD8 by InsHA-derived CTL, nor was there evidence for a defect in triggering lytic activity. However, avidity differences between CD8+ clones correlated with their ability to bind KdHA tetramers. These results argue that most of the KdHA-specific T lymphocytes in InsHA mice are not intrinsically different from KdHA-specific T lymphocytes isolated from conventional animals. They simply express TCRs that are less avid in their binding to KdHA.

Animals↗
PubMed2000

The treatment with alendronate in hemifacial spasm associated with Paget's disease of bone.

The association of Paget's disease of bone and hemifacial spasm has rarely been reported. Hemifacial spasm is often associated with compression of the facial nerve by a vascular loop at the point where the nerve leaves the brainstem before traversing the cerebellopontine angle. It is believed that narrowing of the cerebellopontine angle cistern caused by Paget's disease increases the chance of vascular compression of the facial nerve. Whilst specific antipagetic therapy such as calcitonin has been used with good response in hemifacial spasm associated with Paget's disease, the usefulness of the newer bisphosphonates is not clear. A 65-year-old woman with hemifacial spasm associated with Paget's disease was treated with alendronate, and the hemifacial spasm became very infrequent 4 months after commencement of the therapy.

Aged↗
PubMed2000

Treatment of pseudotumors with nonsteroidal antiinflammatory drugs.

Large inflammatory pseudotumors (IPT) traditionally are managed with extensive surgical resection. This approach, which often is associated with significant morbidity, has been deemed necessary because of the uncertainty of diagnosis, symptomatology, and involvement of vital structures. Also, there is a lack of other reliable therapy for this clinically aggressive yet histologically benign disease characterized by an overreactive inflammatory response. The authors treated 2 cases of abdominal IPT with nonsteroidal antiinflammatory drug (NSAID) with successful results. After a diagnosis of IPT on tumor biopsy, an NSAID trial can confirm the diagnosis and treat the disease by causing tumor shrinkage and eventual resolution. Excision remains indicated in easily resectable tumors and in nonresponders to NSAID therapy.

Adolescent↗
PubMed2000

The effect of rofecoxib on the pharmacodynamics and pharmcokinetics of warfarin.

OBJECTIVE: The objective of this study was to examine the effect of 3 doses of rofecoxib (12.5, 25, and 50 mg) on the pharmacodynamics and pharmacokinetics of warfarin. METHODS: Two single-dose (12.5 or 50 mg of rofecoxib with 25 mg or 30 mg of oral warfarin, respectively, on day 7 of each period) trials (N = 12 men) and 1 steady-state warfarin trial (25 mg rofecoxib; N = 15, 13 men and 2 women) were completed as two-period, randomized, balanced, crossover, double-blind designs. The prothrombin time international normalized ratio (INR) and S(-) and R(+) warfarin enantiomers were assessed during 144 hours after the single warfarin doses. In the steady-state warfarin trial, after the attainment of a stable INR (1.4-1.7), the stable warfarin dose was co-administered with rofecoxib (25 mg) and placebo over two 21-day periods. After the dose of warfarin on day 21, INR and S(-) and R(+) warfarin were assessed during 24 hours. RESULTS: Compared with placebo, rofecoxib slightly increased the INR by approximately 5% (90% confidence interval on the geometric ratio, 1.03, 1.08) and 11% (1.04, 1.19) for the two single-dose warfarin trials with 12.5 and 50 mg of rofecoxib, respectively. In the steady-state warfarin study with 25 mg of rofecoxib, the INR was increased by 8% (1.02, 1.15). Rofecoxib had no significant effect (versus placebo) on the pharmacokinetics of S(-) warfarin. However, in the 3 studies, treatment with 12.5, 25, and 50 mg of rofecoxib was associated with a 27%, 38%, and 40% increase in the area under the plasma concentration-time curve of the biologically less active R(+) warfarin. CONCLUSIONS: Rofecoxib increased plasma concentrations of the biologically less active R(+) warfarin, which accounted for a small increase in INR. The approximately 8% increase in INR at steady state with warfarin co-administered with 25 mg of rofecoxib is not likely to be clinically important in most patients taking warfarin. However, standard monitoring of INR values should be conducted when therapy with rofecoxib is initiated or changed, particularly in the first few days, for patients receiving warfarin.

Adult↗
PubMed2000

Self-tolerance and the composition of T cell repertoire.

T cell recognition of self-major histocompatibility complex-peptide complexes dictates the composition of the T cell receptor repertoire. Research projects in our laboratory deal with the mechanisms that regulate the composition of the repertoire specific for self-antigens and the defects that can result in autoimmunity. Two different types of disease models are under investigation: juvenile (type I) diabetes and cancer. Both of these diseases are impacted by the presence of anti-self CD8 cells, yet in opposite ways. By understanding the mechanisms of peripheral tolerance and the reasons they fail in autoimmunity, we may learn how to prevent undesirable autoimmunity and how to encourage an autoimmune response when it is needed to eliminate tumor cells.

Autoimmunity↗
PubMed1999

Comparing the relative role of perforin/granzyme versus Fas/Fas ligand cytotoxic pathways in CD8+ T cell-mediated insulin-dependent diabetes mellitus.

CD8+ cytotoxic T cells play a critical role in initiating insulin-dependent diabetes mellitus. The relative contribution of each of the major cytotoxic pathways, perforin/granzyme and Fas/Fas ligand (FasL), in the induction of autoimmune diabetes remains controversial. To evaluate the role of each lytic pathway in beta cell lysis and induction of diabetes, we have used a transgenic mouse model in which beta cells expressing the influenza virus hemagglutinin (HA) are destroyed by HA-specific CD8+ T cells from clone-4 TCR-transgenic mice. Upon adoptive transfer of CD8+ T cells from perforin-deficient clone-4 TCR mice, there was a 30-fold increase in the number of T cells required to induce diabetes. In contrast, elimination of the Fas/FasL pathway of cytotoxicity had little consequence. When both pathways of cytolysis were eliminated, mice did not become diabetic. Using a model of spontaneous diabetes, which occurs in double transgenic neonates that express both clone-4 TCR and Ins-HA transgenes, mice deficient in either the perforin or FasL/Fas lytic pathway become diabetic soon after birth. This indicates that, in the neonate, large numbers of autoreactive CD8+ T cells can lead to destruction of islet beta cells by either pathway.

Adoptive Transfer↗
PubMed1999

Multiformic modulation of endotoxin effects by linomide.

Linomide is a potent immunomodulator that either enhances or suppresses certain immunological processes. Of particular interest is this compound's capacity to inhibit a variety of organ-specific autoimmune diseases. Here, we report on the effects of linomide on several immunological reactions elicited by endotoxin (LPS), both in vivo and in vitro. In rats and mice linomide inhibited the elicitation of endotoxin-induced uveitis (EIU), an acute inflammatory eye disease that develops within 24 h following footpad injection of LPS. Linomide also inhibited the production of TNF-alpha and IL-6 by LPS-stimulated rat and mouse macrophage monolayers. On the other hand, treatment with linomide significantly increased the levels of IL-1beta (mice and less in rats), IL-6 (rats), and TNF-alpha (mice) in serum samples collected 2 h following injection with LPS. The increased production of proinflammatory cytokines in linomide-treated mice was also indicated by the enhanced lethal effect of LPS in these mice. The finding of elevated levels of these cytokines in animals with suppressed EIU is also in line with previous observations of an inverse relationship between EIU severity and levels of TNF-alpha. Data recorded here underscore the unique capacity of linomide to both enhance and suppress the immune system.

Adjuvants, Immunologic↗
PubMed1999

Efficacy of finasteride is maintained in patients with benign prostatic hyperplasia treated for 5 years. The North American Finasteride Study Group.

OBJECTIVES: The purpose of this open-label study extension was to assess the long-term safety and efficacy of finasteride in the treatment of men with benign prostatic hyperplasia (BPH). METHODS: A Phase III North American BPH trial originally enrolled 895 men, 297 of whom were randomized to receive finasteride 5 mg. An enlarged prostate gland by digital rectal examination, symptoms of urinary obstruction, and a maximal urinary flow rate of less than 15 mL/s were required for entry. Patients who completed the initial 12-month, double-blind, placebo-controlled study were invited to participate in an open-label extension for 4 additional years. RESULTS: Of the 297 patients initially randomized to receive finasteride 5 mg, 259 completed 12 months in the double-blind period and 186 completed 48 months of open-label therapy. Prostate volume reached a nadir of -24.6% at month 24, and the effect was maintained through month 60. Compared with baseline values, month 60 prostate volume was decreased by 22.7% (P<0.001), the quasi-American Urological Association symptom score was decreased by 4.3 points, and maximal urinary flow was increased by 2.3 mL/s (P<0.001) on average. Finasteride was well tolerated, with no significant increase in the prevalence of sexual adverse events over time. CONCLUSIONS: Patients treated with finasteride 5 mg maintained an initial decrease in prostate volume and improvement in symptom score and maximal urinary flow rate over 5 years.

Double-Blind Method↗
PubMed1999

Laparoscopy and mesothelioma.

Malignant mesothelioma is a well-recognized long-term sequela of chronic asbestos exposure. Asbestos use in the United States began in the 1950s and was widespread until the mid-1970s. Although currently only 2.2 cases per million population per year are diagnosed, disease incidence is increasing because of the long latency of this neoplasm. A latency of 15-50 years means that a higher incidence of this neoplasm can be anticipated in the future. The authors report a patient with peritoneal mesothelioma and no known prior exposure to asbestos. The diagnosis was confirmed by exploratory laparoscopy, which entailed biopsies of the diaphragm and of the peritoneal and abdominal walls, and by cytologic evaluation of 700 ml ascitis fluid. At present, exploratory laparoscopy offers the quickest, safest, and least invasive way to confirm the clinical diagnosis of peritoneal malignant mesothelioma.

Aged↗
PubMed1998

Effects of cardiotrophin-1 on haemodynamics and cardiac function in conscious rats.

Cardiotrophin-1 (CT-1), a newly discovered cytokine, has been shown to induce cardiac hypertrophy in vitro and in vivo. The present study examined the effects of CT-1 on haemodynamics and cardiac function. The measurements of haemodynamic parameters were made using in-dwelling catheters and flow probes in conscious, unrestrained rats. Intravenous administration of CT-1 caused a dose-dependent decrease in mean arterial pressure (MAP), and an increase in heart rate (HR). CT-1 (100 micrograms/kg) significantly elevated cardiac output and HR, and decreased MAP and systemic vascular resistance. Stroke volume was unaltered, suggesting that the CT-1 induced increase in cardiac output was secondary to increased HR. There was no significant difference in left ventricular maximal dP/dt between the CT-1-treated and vehicle-treated groups, suggesting that CT-1 might not induce a meaningful change in ventricular contractility. Pretreatment with intravenous N omega-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, significantly attenuated the depressor and tachycardic responses to CT-1. These results indicate that nitric oxide plays an important role in mediating the haemodynamic effects of CT-1.

Animals↗
PubMed1998

Methylation of CpG island is not a ubiquitous mechanism for the loss of oestrogen receptor in breast cancer cells.

Methylation has been shown to play an important role in the down-regulation of oestrogen receptors (ER) in breast cancer cells. One critical question that remains unclear is whether methylation can account for the loss of ER expression in cells derived from an ER-positive cell line. This laboratory has established an in vitro cell system using long-term growth of human ER-positive breast cancer cell line T47D in oestrogen-free medium. A clonal cell line, T47D:C4:2 (C4:2), has been characterized. Unlike T47D:A18 (A18), which is a T47D line maintained in oestrogen medium, C4:2 has lost the expression of ER and hormone responsiveness. DNA fingerprinting and restriction fragment length polymorphism (RFLP) analysis results confirmed that C4:2 was of the same lineage as A18. These cell lines provide an invaluable system to study the mechanism of ER expression and regulatory pathways leading to hormone-independent growth. The results here clearly demonstrate that the ER CpG island in C4:2 cells remains unmethylated. The loss of ER in the cell line must be due to mechanisms other than methylation. We also evaluated the ER CpG island in the MDA-MB-231:10A (10A) cell line, which is a clone from the MDA-MB-231 line obtained from ATCC and the DNA from the MDA-MB-231 cell line used in the original report. Unlike the cell line from the report, which showed a full methylation pattern in the island, the 10A line only showed a partial methylation pattern in the CpG island. Possible mechanisms pertaining to the heterogeneous methylation pattern of the ER CpG island in the breast cancer cells are discussed.

Breast Neoplasms↗