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Publications and source records attributed to A Takeda.
We measured the CSF tau protein levels in 26 patients with Guillain-Barré syndrome. The levels of the poor outcome group (Hughes grade at 6 months was between II and VI, n = 6) were higher than those of the good outcome group (0 or I, n = 20) (p < 0.0005). The higher levels of CSF tau may reflect axonal degeneration and could predict a poor clinical outcome in Guillain-Barré syndrome.
A search for the appearance of tau neutrinos from nu(mu) <--> nu(tau) oscillations in the atmospheric neutrinos has been performed using 1489.2 days of atmospheric neutrino data from the Super-Kamiokande-I experiment. A best fit tau neutrino appearance signal of 138+/-48(stat)-32(+15)(syst) events is obtained with an expectation of 78+/-26(syst). The hypothesis of no tau neutrino appearance is disfavored by 2.4 sigma.
BACKGROUND AND AIM: The production of prostaglandins is regulated by cyclo-oxygenases (COXs), which also have a role in tumour development and progression in various malignancies, including breast cancer. The mechanisms by which COX-2 contributes to unfavourable prognosis are still poorly understood. The association between expression of COX-2 and possible linked signalling pathways-namely, Akt, extracellular regulated kinases (ERK1/2), the stress-activated kinase p38 or Her-2/neu-is assessed in a series of 113 node-negative breast cancers. RESULTS: COX-2 was identified as an independent prognostic factor (p = 0.034) in node-negative breast cancer by survival analysis. The lack of a relationship between COX-2 expression and activated Akt, Erk1/2, p38 and Her-2/neu was indicated by statistical analysis. CONCLUSIONS: The prognostic effect of COX-2 expression on lymph node-negative breast cancer is confirmed-COX-2 is probably not regulated by HER-2, Akt, Erk1/2 or p38. Further studies are necessary for the elucidation of the signalling pathways responsible for the modification of COX-2 expression and the increased aggressiveness of breast cancers overexpressing COX-2.
The synthesis of a mg amount of pure argon containing fullerene allowed the synthesis of the first endohedral superconductors with critical temperatures lower than expected, an indication of the strong influence of the argon atom on the C60 cage.
BACKGROUND: The use of cholinesterase inhibitors for Alzheimer's disease (AD) is currently being appraised by the National Institute for Clinical Evidence (NICE). This article provides the latest evidence that NICE will be using as part of this appraisal process. OBJECTIVE: To provide a systematic review of the best quality evidence of the effects of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in people with mild to moderately-severe AD. DESIGN: Electronic databases were searched, references of all retrieved articles were checked, and experts were contacted for advice, peer review and to identify additional references. Randomised controlled trials (RCTs) were included if they fulfilled pre-specified criteria. Data were synthesised through a narrative review. RESULTS: Twenty-six RCTs that compared any one of the cholinesterase inhibitors with either a control group or with another cholinesterase inhibitor were included. The quality of reporting and methodology was varied. Treatment with donepezil, rivastigmine or galantamine resulted in significantly better cognitive performance using the ADAS-cog scale when compared with placebo. These findings were generally supported using the MMSE scale. Results from head to head comparisons were limited by the low number of studies and the study quality; generally showing no robust support for any one drug. Few studies evaluated quality of life. Adverse events were generally related to the gastrointestinal system, with a tendency for these to be more common in the treatment arms. CONCLUSIONS: The cholinesterase inhibitors donepezil, rivastigmine, and galantamine can delay cognitive impairment in patients with mild to moderately-severe AD for at least 6 months duration.
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OBJECTIVES: To provide an update review of the best quality evidence for the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine for mild to moderately severe Alzheimer's disease (AD) and of memantine for moderately severe to severe AD. DATA SOURCES: Electronic databases, experts in the field and manufacturer submissions to the National Institute for Health and Clinical Excellence (NICE). REVIEW METHODS: A systematic review of the literature and an economic evaluation were undertaken. The quality of included randomised controlled trials (RCTs) was assessed using criteria developed by the NHS Centre for Reviews and Dissemination. An outline assessment of economic evaluations was undertaken using a standard checklist. The clinical and cost-effectiveness data were synthesised through a narrative review with full tabulation of the results of included studies. Where appropriate, meta-analysis of data was undertaken. RESULTS: For mild to moderately severe AD, the results of the study suggested that all three treatments were beneficial when assessed using cognitive outcome measures. Global outcome measures were positive for donepezil and rivastigmine, but mixed for galantamine. Results for measures of function were mixed for donepezil and rivastigmine, but positive for galantamine. Behaviour and mood measures were mixed for donepezil and galantamine, but showed no benefit for rivastigmine. For memantine, two published RCTs were included; in one of these trials the participants were already being treated with donepezil. The results suggest that memantine is beneficial when assessed using functional and global measurements. The effect of memantine on cognitive and behaviour and mood outcomes is, however, less clear. Literature on the cost-effectiveness of donepezil, rivastigmine and galantamine was dominated by industry-sponsored studies, and studies varied in methods and results. Of the three UK studies, two report donepezil as not cost-effective, whereas a third study reports an additional cost (1996 pounds sterling) of between 1200 pounds sterling and 7000 pounds sterling per year in a non-severe AD health state (concerns over these estimates are raised, suggesting that they may underestimate the true cost-effectiveness of donepezil). Cost-effectiveness analysis undertaken in this review suggests that donepezil treatment has a cost per quality-adjusted life-year (QALY) in excess of 80,000 pounds sterling, with donepezil treatment reducing the mean time spent in full-time care (delays progression of AD) by 1.42-1.59 months (over a 5-year period). From four published cost-effectiveness studies, two UK studies report additional costs associated with rivastigmine treatment. Cost-effectiveness analysis undertaken in the current review suggests that rivastigmine treatment has a cost per QALY in excess of 57,000 pounds sterling, with rivastigmine treatment reducing the mean time spent in full-time care (delays progression) by 1.43-1.63 months (over a 5-year period). From five published cost-effectiveness studies, one UK study reports a cost per QALY of 8693 pounds sterling for 16-mg galantamine treatment and 10,051 pounds sterling for 24-mg galantamine treatment (concerns raised suggest that this may underestimate the true cost-effectiveness of galantamine). Cost-effectiveness analysis undertaken in the present review suggests that galantamine treatment has a cost per QALY in excess of 68,000 pounds sterling, with galantamine reducing the time spent in full-time care (delays progression) by 1.42-1.73 months (over a 5-year period). From two published cost-effectiveness studies, one reports analysis for the UK, finding that memantine treatment results in cost savings and benefits in terms of delaying disease progression (concerns raised suggest that this may underestimate the true cost-effectiveness of memantine). In the current review, the cost-effectiveness of memantine has not been modelled separately, but where alternative parameter inputs on the cost structure and utility values have been used in a reanalysis using the industry model, the cost-effectiveness is reported at between 37,000 pounds sterling and 52,000 pounds sterling per QALY, with this alternative analysis still based on what is regarded as an optimistic or favourable effectiveness profile for memantine. CONCLUSIONS: Although results from the clinical effectiveness review suggest that these treatments may be beneficial, a number of issues need to be considered when assessing the results of the present review, such as the characteristics of the participants included in the individual trials, the outcome measures used, the length of study duration, the effects of attrition and the relationship between statistical significance and clinical significance. Many included trials were sponsored by industry. For donepezil, rivastigmine and galantamine, the cost savings associated with reducing the mean time spent in full-time care do not offset the cost of treatment sufficiently to bring estimated cost-effectiveness to levels generally considered acceptable by NHS policy makers. It is difficult to draw conclusions on the cost-effectiveness of memantine; it is suggested that further amendments to the potentially optimistic industry model (measure of effect) would offer higher cost per QALY estimates. Future research should include: information on the quality of the outcome measures used; development of quality of life instruments for patients and carers; studies assessing the effects of these interventions of durations longer than 12 months; comparisons of benefits between interventions; and research on the prediction of disease progression.
OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of adefovirdipivoxil (ADV) and pegylated interferon alfa-2a (PEG) for the treatment of adults with chronic hepatitis B infection (CHB). DATA SOURCES: Electronic databases for the period from 1995-6 to April 2005. Websites of the relevant organisations. REVIEW METHODS: Searches were made for studies of clinical effectiveness, cost-effectiveness, quality of life, resource use/costs and epidemiology/natural history. Randomised controlled trials (RCTs) were included that compared PEG and ADV with currently licensed treatments for CHB, including non-pegylated ('standard') interferon alfa (IFN), lamivudine (LAM), and best supportive care. The trials were reviewed in a narrative synthesis but meta-analysis was not undertaken owing to heterogeneity in the interventions and comparators evaluated. A model was developed to estimate the cost-effectiveness (cost-utility) of PEG and of ADV compared with IFN, LAM and best supportive care in a UK cohort of adults with CHB. The perspective of the cost-effectiveness analysis was that of the NHS and personal social services. A Markov state transition model was constructed, informed by a systematic search of the literature to identify source material on the natural history, epidemiology and treatment of CHB. Interventions were evaluated against their closest comparator (for PEG this is IFN, and for ADV this is LAM). In addition, the cost-effectiveness of sequential treatment scenarios was modelled. RESULTS: A total of 1086 references to clinical effectiveness studies were identified, of which seven fully published RCTs and one systematic review met the inclusion criteria. Four of the RCTs evaluated the effectiveness of ADV and three reported results for PEG. In addition, a conference abstract was included reporting interim results from an on-going Phase II RCT of ADV in combination with LAM. The published trials were of good quality, although details of randomisation and allocation of concealment were poorly reported. ADV was significantly more effective than placebo. Response rates were in the range 21-51% compared with 0%, respectively. For patients resistant to LAM, response rates were significantly higher for those treated with ADV in addition to on-going LAM (35-85%) than those who continued on LAM with placebo (0-11%). Significant alanine aminotransferase (ALT) reductions to normal levels were observed in all studies. For treatment-naive patients, seroconversion rates were 12-14% for ADV compared with 6% for placebo (statistically significant), rates were higher for LAM-resistant patients who received ADV in addition to on-going LAM (8%) than those who continued on LAM with placebo (2%) (no significance value was reported), and rates were higher for LAM-resistant patients who switched to ADV than those who continued on LAM with placebo (11 versus 0%, respectively; not statistically significant). HBsAg loss or seroconversion was observed in less than 5% of patients taking ADV. Two ADV studies reported changes in liver histology. In general, histological improvement and necroinflammatory activity/fibrosis scores were significantly better in ADV groups than in placebo groups. Dose discontinuations for safety reasons were low for patients receiving ADV. With the exception of headache, the most commonly reported adverse events were often seen in the placebo groups in similar proportions to the ADV groups, with different trials reporting conflicting results. PEG/LAM dual therapy and PEG monotherapy were similar in effect on HBV DNA and ALT levels, and both were significantly superior to LAM monotherapy. Response rates were higher for HBeAg-negative patients than for HBeAg-positive patients. HBeAg seroconversion rates at follow-up were significantly higher for PEG monotherapy patients than for those receiving either a combination of PEG and LAM or LAM monotherapy (32, 27 and 19%, respectively). For the comparison between PEG and IFN-2a, there was a significant difference in the combined outcome of ALT normalisation, HBV DNA response and HBeAg seroconversion at follow-up (24 versus 12%, respectively). Changes in liver histology were reported by two studies. There was no statistically significant difference in histological improvement between the PEG monotherapy groups, the LAM monotherapy groups and the dual therapy groups. Two PEG trials reported small percentages (up to 5%) of HBsAg loss or seroconversion among patients receiving PEG either as monotherapy or in combination with LAM, but no HBsAg loss or seroconversion was reported in those receiving LAM monotherapy. Health-related quality of life (HRQoL) scores, as measured by the Short Form with 36 Items, decreased during treatment, but returned to at least baseline levels at follow-up (based on unpublished data). For HBeAg-positive patients, there were no significant differences in scores between treatment groups. Dose discontinuations for safety reasons were significantly higher for patients receiving PEG than for patients receiving LAM monotherapy. The most commonly reported adverse events in the PEG studies were headache, pyrexia, fatigue, myalgia and alopecia. Only one fully published economic evaluation was identified, reporting a US cost-effectiveness study of ADV as salvage therapy for chronic hepatitis B with LAM resistance. A Markov model was used to estimate cost-effectiveness of interferon alfa (6-12 months), LAM and LAM followed by ADV when resistance occurs. ADV generated the most (undiscounted) life-years, but at highest costs, with an incremental cost-effectiveness ratio (ICER) of US$14,204 per life-year gained. Using our model, incremental cost per QALY estimates (baseline cohort of all patients) were: 5994 pounds for IFN compared with best supportive care, 6119 pounds for PEG compared with IFN, 3685 pounds for LAM compared with best supportive care, and 16,569 pounds for ADV compared with LAM. Incremental cost per QALY estimates (HBeAg-positive patients only) were: 7936 pounds for IFN (24 weeks) compared with best supportive care, 16,166 pounds for PEG (48 weeks) compared with IFN (24 weeks), 3489 pounds for LAM compared with best supportive care, and 15,289 pounds for ADV compared with LAM. Incremental cost per QALY estimates (HBeAg-negative patients only) were: 3922 pounds for IFN (48 weeks) compared with best supportive care, 2162 pounds for PEG (48 weeks) compared with IFN (24 weeks), 4131 pounds for LAM compared with best supportive care, and 18,620 pounds for ADV compared with LAM. For the sequential treatment strategies, incremental cost per QALY estimates ranged from 3604 pounds (IFN followed by LAM versus IFN alone) to 11,402 pounds (IFN followed by LAM with adefovir salvage versus IFN followed by LAM). In all of these cases, the ICERs are well within the range that would conventionally be regarded as being cost-effective. The probabilistic sensitivity analysis found that LAM is a cost-effective option at lower willingness-to-pay thresholds for health outcomes, but as the threshold is increased adefovir is increasingly likely to be the optimal intervention. Where a willingness-to-pay threshold of above 10,000 pounds per QALY is employed, PEG is highly likely to be the optimal intervention compared with IFN (based on a cohort of HBeAg-positive and -negative patients). Interferon alfa (non-pegylated or pegylated) followed by LAM would be the optimal strategy at lower willingness-to-pay thresholds. As the threshold increases, the sequential treatment strategy of PEG followed by LAM with adefovir added as salvage therapy is increasingly likely to be the optimal intervention. CONCLUSIONS: ADV and PEG are associated with significant improvements in a number of biochemical, virological and histological outcomes in both HBeAg-positive and -negative patients. For a small proportion of patients this is associated with resolution of infection. For another proportion it leads to remission and a reduced risk of progressing to cirrhosis, hepatocellular carcinoma, liver transplant and death. For others who do not respond or who relapse, retreatment with another agent is necessary. The results of our cost-effectiveness analysis demonstrate that incremental costs per QALY for a range of comparisons were between 5994 pounds and 16,569 pounds and within the range considered by NHS decision-makers to represent good value for money. When subjected to sensitivity analysis, most costs per QALY estimates remained under 30,000 pounds. Further RCT evidence of the effectiveness of anti-viral treatment is required, particularly for subgroups of patients with different genotypes, patients with cirrhosis, patients from different ethnic groups, patients with co-infections (e.g. HIV, HCV) and co-morbidities, liver transplant patients and children and adolescents.
A 5-year-old boy was referred to our institute for cardiac evaluation having been previously seen at another center. He had been diagnosed a pulmonary atresia with intact ventricular septum just after birth, and undergone Blalock-Taussig shunts. Although his central pulmonary artery pressure was high (mean pressure 26 mmHg) after bilateral Blalock-Taussig shunts, multiple peripheral pulmonary artery stenosis protected his pulmonary vascular bed from pressure load. We released the multiple pulmonary artery stenosis partly by catheter intervention and partly by surgical operation, and staged Fontan operation was completed. The surgery in combination with catheter therapies would expand the indication of Fontan-type operation, and it would contribute to the patients' postoperative prognosis.
OBJECTIVES: To assess the clinical and cost-effectiveness of drotrecogin alfa (activated) for the treatment of adults with severe sepsis in a UK context. DATA SOURCES: Electronic databases. Data from the commercial use of the drug up to April 2002. Data from the manufacturer submission to the National Institute for Clinical Excellence (NICE). REVIEW METHODS: A systematic review of the literature and an economic evaluation were undertaken. Data were synthesised through a narrative review with full tabulation of results from included studies. RESULTS: The evidence on the effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis came primarily from one large pivotal randomised controlled trial, the PROWESS study. This study demonstrated a statistically significant absolute reduction in 28-day mortality of 6.5%. Longer term survival benefit was maintained to 90 days. By 9 months, the trend towards increased median survival was non-significant, although the survival curves did not cross. Results presented by the number of organ dysfunctions were not statistically significant, but when mortality rates for those with two or more organ failures were combined, the relative risk of death was significantly lower in those treated with drotrecogin alfa (activated) compared with placebo. However, this report highlights a number of considerations relevant to the subgroup analyses reported for the PROWESS study. Published cost-effectiveness studies of treatment with drotrecogin alfa (activated) have applied a range of methods to the estimation of benefits, estimating an incremental gain per treated patient of between 0.38 and 0.68 life-years (for patients with severe sepsis). For patients with severe sepsis and multiple organ dysfunction, the manufacturer (Eli Lilly) estimated an incremental gain of 1.115 life-years per treated patient, compared to 1.351 life-years per treated patient estimated by the Southampton Health Technology Assessments Centre (SHTAC). These latter UK analyses are based on a patient group that is more severely affected by disease, where effectiveness is greater and the baseline risk of all-cause mortality is much higher (SHTAC analysis), these factors are associated with the noted difference in effect. The three published cost-effectiveness studies report cost for US and Canadian patient groups; for those patients with severe sepsis they report the additional cost per patient treated in a range around 10,000-16,000 dollars. The manufacturer's submission reports analysis for the UK, based on 28-day survival data in patients with severe sepsis and multiple organ dysfunction (the European licence indication), with the additional mean cost per treated patient estimated to be 5106 pounds. The analysis undertaken by SHTAC, for a UK group of patients with severe sepsis and multiple organ dysfunction, estimates an additional mean cost per patient treated of 6661 pounds. The manufacturer's submission to NICE presents cost-effectiveness estimates for drotrecogin alfa (activated) in the UK, in patients with severe sepsis and multiple organ dysfunction, at 6637 pounds per quality-adjusted life-year (QALY) based on 28-day effectiveness data, and 10,937 pounds per QALY based on longer term follow-up data. SHTAC developed an independent cost-effectiveness model and estimated a base-case cost per QALY of 8228 pounds in patients with severe sepsis and multiple organ failure (based on 28-day survival data). Simulation results indicate that where the NHS is willing to pay 20,000 pounds per QALY, drotrecogin alfa (activated) is a cost-effective use of resources in 98.7% of cases. Published economic evaluations report various sensitivity analyses, with results sensitive to changes in the measure of treatment effect, but otherwise studies reported that results were robust to variations in most assumptions used in the cost-effectiveness analysis. CONCLUSIONS: Drotrecogin alfa (activated) plus best supportive care appears clinically and cost-effective compared with best supportive care alone, in a UK cohort of severe sepsis patients, and in the subgroup of more severely affected patients with severe sepsis and multiple organ failure. The introduction of drotrecogin alfa (activated) will involve a substantial additional cost to the NHS. The treatment-eligible population in England and Wales may comprise up to 16,570 patients, with an estimated annual drug acquisition cost of over 80 million pounds, excluding VAT. Further research is required on the longer term impact of drotrecogin alfa (activated) on both mortality and morbidity in UK patients with severe sepsis, on the clinical and cost-effectiveness of drotrecogin alfa (activated) in children (under 18 years) with severe sepsis, and on the effect of the timing of dosage and duration of treatment on outcomes in severe sepsis.
SETTING: Retrospective review of patients with pulmonary Mycobacterium avium complex (MAC) disease treated with clarithromycin. OBJECTIVES: To investigate whether the short-term response to treatment predicts long-term outcomes, and to analyse what explanatory variables are associated with the efficacy and outcome of treatment. DESIGN: Sputum conversion rates in short- and long-term outcomes were evaluated for 111 patients. Respectively 9 and 10 explanatory variables were analysed for their association with both response and outcomes. RESULTS: Eighty-four patients (75.7%) showed good short-term response and 94 (82.0%) showed good long-term outcomes. Women and patients with satisfactory nutrition status showed good short-term response. Patients with small lesions and those treated for >12 months after sputum conversion showed good long-term outcomes. Patients who showed good short-term response, in the group with large lesions, showed significantly good long-term outcomes (P = 0.0382). CONCLUSION: There were differences between prognostic factors reflecting short-term response and long-term outcomes. The short-term response predicts long-term outcomes in certain groups divided by prognostic factor. To establish standard treatment for pulmonary MAC disease, it is important to determine a standardised method of evaluation of treatment taking such factors into consideration.
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The purpose of this study was to examine the effects of ZD6126, a novel vascular-targeting agent, on tumour growth and angiogenesis in an orthotopic model of gastric cancer. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. After the tumours were established (day 14), therapy was initiated. Mice (n=11-12/group) received (a). vehicle, (b). ZD6126 at 100 mg x kg day(-1) i.p. one time per week or (c) ZD6126 at 100 mg x kg day(-1) i.p. five times per week. Tumour mass, volume and the presence or absence of peritoneal carcinomatosis were determined at sacrifice on day 38. Tumours from each group were stained for markers of blood vessels, proliferation and apoptosis. To further define the time frame of the vascular-targeting effects of chronic therapy with ZD6126, TMK-1 cells were again injected into the gastric wall of mice in a second experiment. On day 14, a single i.p. injection of ZD6126 100 mg x kg(-1) mouse(-1) or vehicle was delivered. Groups of three mice each were killed and the tumours harvested at days 1, 3 and 5 post-ZD6126 injection. Tumours were processed and stained for endothelial and tumour cell apoptosis and proliferation. No overt toxicity was observed with ZD6126 therapy. ZD6126 led to a marked inhibition of tumour growth (82% decrease vs control (P<0.001)). ZD6126 also led to a significant decrease in the incidence of peritoneal carcinomatosis (10 out of 12 controls, vs one out of 12 ZD6126) (P<0.01). Histological analysis of tumours revealed large regions of central necrosis in the treated group, as well as a dramatic increase in tumour cell apoptosis (7.4-fold increase (P<0.001)), consistent with the vascular-targeting activity of ZD6126. Mice treated with ZD6126 demonstrated a 59% decrease in PCNA-positive cells (P< 0.02), indicating reduced tumour cell proliferation. In addition, tumours treated with ZD6126 exhibited a 40% decrease in microvessel density (P<0.05). Results from mice treated with a single injection of ZD6126 demonstrated the acute effects this agent has on the tumour vasculature. The ratio of endothelial cell apoptosis to endothelial cell proliferation was increased within 24 h of a single injection. In conclusion, ZD6126 significantly inhibited tumour growth and metastasis in an orthotopic model of human gastric adenocarcinoma, without detectable problematic adverse effects. These data suggest that ZD6126 may be worthy of investigation in the treatment of primary gastric adenocarcinoma.
Chronic CSA nephrotoxicity is the second most important diagnosis responsible for the late graft failure. CSA associated arteriolopathy (CAA) is a well-known lesion of chronic CSA nephrotoxicity. The clinicopathological characteristics and the significance of CSA nephrotoxicity have changed following reduction in CSA doses and implementation of monitoring of blood levels. Seventy-four CAA patients on CSA therapy were classified as functioning (n=30) or loss groups (n=44). There was no significant difference in severity of CAA. The concomitant lesion of chronic rejection, but not the severity of CAA, was the most important risk factor for graft loss. Among 54 recipients with focal segmental glomerulosclerosis lesions (FGS), 32 (59%) were diagnosed as CAA associated glomerulopathy (CAG). Eighteen of the 32 CAG patients lost their grafts upon follow-up. Decreasing the CSA dosage to maintain lower blood levels than the usually optimal concentrations, but not discontinuation of CSA, has been useful to retard the progression of graft dysfunction in half of 15 isolated pure CAG patients. Patients with increasing daily proteinuria exceeding 2 grams lost their graft function despite CSA reductions. CAA is not a specific lesion of chronic CSA nephrotoxicity; the FGS lesion is also a nonspecific lesion often seen in renal allografts. Isolated chronic CSA arteriolopathy of severe degree has a fairly good prognosis under controlled CSA therapy. The FGS lesion accompanying CAA is considered to be CSA-associated glomerulopathy. These data contribute to therapeutic plans for renal transplant patients during long-term CSA treatment.
We investigated the clinical benefits of cyclosporine microemulsion preconcentrate (CyA-MEPC; Neoral) in 16 de novo renal transplant recipients. The dose of CyA-MEPC was managed from AUC(0-4h), with serial target values of AUC(0-4h) at 5000-->4000-->3000-->2000 ng. hr/mL. The frequency of acute rejection episodes was 25%. The decreased renal function reached a low value of 12.5%, and creatinine was stable. Therefore, setting the target AUC(0-4h) value in the early phase at 5000 ng.hr/mL is an effective strategy to prevent acute rejection episodes. The single dose of Neoral given immediately after the renal transplant was 6 mg/kg (making a daily dose of 12 mg/kg). Thereafter, the dose-normalized AUC(0-4h) was set at a constant value to 4 weeks posttransplant. At week 4, the single dose was decreased to 4 mg/kg twice daily (a daily dose of 8 mg/kg). From these studies a daily dose of 12 mg/kg is suggested to be the appropriate amount for the first dose immediately after transplant. The renal biopsy performed at 6 months posttransplant showed neither cyclosporine-induced renal impairments, nor findings of chronic rejection, suggesting that 2000 ng.hr/mL is an appropriate target AUC(0-4h) value in the maintenance phase. These results suggest that it is possible to set the target value of C2 monitoring in the maintenance phase to a value slightly lower than that proposed from other studies.
BACKGROUND: Human runt-related transcription factor gene 3 (RUNX3) is considered as a possible candidate of tumour suppressor gene in human gastric carcinoma. MATERIALS AND METHODS: To investigate the RUNX3 protein expression in human gastric mucosa and carcinoma, we generated a polyclonal antibody, AS251, which recognized amino acid sequences from 251 to 266 of human RUNX3. The AS251 antibody was immunoreactive with only RUNX3 protein, but not with RUNX1 and RUNX2. The AS251-antibody was available for Western blotting and immunohistochemistry using paraffin-embedded specimens. RESULTS: Western-blot analysis revealed that three (MKN-1, -7 and -45) of six human gastric carcinoma cell lines variably expressed RUNX3 protein, consistent with the expression pattern of RUNX3 mRNA reported previously by Li et al. (Cell 2002;109:113-24). Immunohistochemistry disclosed RUNX3 protein in most chief cells and a few gastrin-containing G cells in normal mucosa, but not in intestinal metaplasia and carcinoma cells. CONCLUSIONS: These data suggest that RUNX3 may play a physiologic role in chief cells and G cells in gastric mucosa, and that suppression of RUNX3 expression in intestinal metaplasia and carcinoma of human stomach may be implicated in gastric carcinogenesis.
It is well known that cyclooxygenase (COX) -2 is expressed in a variety of human malignant solid tumors, associated with tumor angiogenesis, cell proliferation and inhibition of apoptosis. Here, we examined the effect of NS398, a selective COX-2 inhibitor, on two human esophageal squamous cell carcinoma (SCC) cell lines, TE-1 and TE-12. Western blot analysis confirmed the expression of COX-2 in TE-12, but not in TE-1. Treatment with 100microM NS398 suppressed the cell viability in TE-12 (48.6% of control) after 48 hours, in contrast to showing no effects in TE-1. The apoptotic index was extremely low in both cell lines after the treatment. NS398 clearly increased the number of cells in the G2/M phase and decreased the cells in the G1 and S phases in TE-12, but not TE-1. A pre-G1 fraction was not noted in either cell line. Moreover, TE-12 cells showed a decrease in the expression levels of cyclin B1 and an increase in p27Kip1. These findings suggest that NS398 inhibits cell growth and induces G2/M arrest in human SCC cells expressing COX-2.
The in vitro generation of dendritic cells (DCs) enables us to practice antitumor immune therapy. Peripheral monocytes can differentiate to DCs in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) in vitro. To generate a large number of DCs, we compared the number of DCs generated from leukapheresis products to those from conventional blood samplings in healthy volunteers. The induction rates of the DCs were equal for these two blood samplings, and 10(7) DCs were obtainable from one leukapheresis product. In contrast, the number of DCs varied significantly depending on the individual (30-50% in good responders vs. less than 10% in poor responders). DCs appeared as aggregates of indented cells during culture in good responders, while large cells were floating sparsely in poor responders. Repeated administration of GM-CSF and IL-4 improved the yields of DCs and induced proliferation of autologous lymphocytes in poor responders. As a prototype of cell therapy, the generation of DCs will require a titration of differentiation processes, depending on each individual's responsiveness to cytokines.