Acute haemorrhagic leucoencephalitis in a Californian sea lion (Zalophus californianus).
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Animals↗
Biomedical subjects
A Takeda
Publications and source records attributed to A Takeda.
ZD6126 inhibits orthotopic growth and peritoneal carcinomatosis in a mouse model of human gastric cancer.
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.
Adenocarcinoma↗
Cyclosporine nephrotoxicity: how does it affect renal allograft function and transplant morphology?
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.
Arterioles↗
Clinical success of Neoral absorption profile.
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.
Adult↗
Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells.
The epidermal growth factor receptor (EGF-R) pathway plays a pivotal role in the progression of human gastric cancer. The angiogenic factor vascular endothelial growth factor (VEGF) has been shown to be induced by EGF in various cancer cell lines. Neuropilin-1 (NRP-1) acts as a coreceptor for VEGF-165 and increases its affinity for VEGF receptor 2 (VEGFR-2) in endothelial cells. Furthermore, NRP-1 has been found to be expressed by tumour cells and has been shown to enhance tumour angiogenesis and growth in preclinical models. We examined the expression of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines. NRP-1 expression was expressed in five of seven cell lines, and EGF-R expression closely mirrored NRP-1 expression. Moreover, in EGF-R-positive NCI-N87 and ST-2 cells, EGF induced both NRP-1 and VEGF mRNA expression. C225, a monoclonal antibody to EGF-R, blocked EGF-induced NRP-1 and VEGF expression in NCI-N87 cells in a dose-dependent manner. The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line prevented EGF induction of NRP-1 and VEGF. These results suggest that regulation of NRP-1 expression in human gastric cancer is intimately associated with the EGF/EGF-R system. Activation of EGF-R might contribute to gastric cancer angiogenesis by a mechanism that involves upregulation of VEGF and NRP-1 expression via multiple signalling pathways.
Base Sequence↗
Influence of manganese on the release of neurotransmitters in rat striatum.
On the basis of the evidence that manganese may be released along with glutamate into the extracellular space in the hippocampus and amygdala, the release of manganese and its influence in the striatum was examined by using the in vivo microdialysis method in the present study. The release of 54Mn previously taken up by the striatum into the extracellular space was enhanced during stimulation with 100 mM KCl. This enhancement of 54Mn release into the striatal extracellular space was inhibited by addition of 1 micro M tetrodotoxin. When the rat striatum was perfused with artificial CSF containing 200 nM MnCl(2), the levels of GABA in the perfusate were remarkably decreased, while the levels of glutamate, aspartate, and glycine in the perfusate were not appreciably decreased. These results suggest that manganese released into the synaptic cleft in a calcium- and impulse-dependent manner may influence GABA release in the striatum.
Animals↗
Oxidative stress and predominant Abeta42(43) deposition in myopathies with rimmed vacuoles.
This study was undertaken to determine the C terminus of amyloid beta protein (Abeta), accumulated in vacuolated muscle fibers, and compare these findings to the level of oxidative stress. Eight patients with myopathies characterized by rimmed vacuoles (RVs) were analyzed. Monoclonal antibodies specific to Abeta40 or Abeta42(43) revealed that the Abeta42(43) immunoreactivity was solely distributed in the vacuolated muscle fibers, and that only a part was also immunopositive for anti-Abeta40. Quantitative analyses in four specimens, in which eight or more vacuolated muscle fibers were observed, revealed that the mean incidence of Abeta42(43)-positive muscle fibers was 79.5+/-6.2% in total vacuolated muscle fibers, whereas that of the Abeta40-positive fibers was 42.9+/-12.6%. The predominance of Abeta42(43) deposition was statistically significant ( P<0.05). Abeta deposition was then compared with the distribution of oxidative nucleic acid damage in muscle fibers using a monoclonal antibody against 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine (8OHdG&G). The cytoplasmic staining for anti-8OHdG&G was found not only in vacuolated muscle fibers, but also in other muscle fibers including morphologically normal ones. Positive staining was completely abolished by RNase pretreatment and, thus, was suggested to reflect an increase of cellular RNA oxidation. The distribution of 8OHdG&G was much broader than the Abeta deposition. These data suggest that Abeta42(43) is predominantly involved in the pathogenesis of muscle fiber degeneration with RVs, and that oxidative damage may precede Abeta deposition in muscle fibers and play a key role in the pathomechanism of myopathies with RVs.
Adult↗
Are there inequities in the assessment of dementia under Japan's LTC insurance system?
BACKGROUND: Just two years after its inception, Japan's Long-term Care (LTC) insurance system is facing considerable criticism about whether or not it has developed a fair and appropriate way of allocating resources to the nation's disabled elderly population, especially those people with dementia. OBJECTIVE: The present study has investigated: (i) the relation of the Government-Certified Disability Index (GCDI) of the LTC insurance system to characteristics of people with dementia and their family caregivers; and (ii) whether the GCDI scores adequately reflect needs of people with DAT (dementia of Alzheimer's type) and VD (vascular-type dementia). METHODS: Subjects were assessed on their visits to outpatient clinics for their Activities of Daily Living (ADL), behavioural disturbances, MMSE, GCDI, service utilization and caregiver burden. Correlation analyses were conducted to examine the relationships among these variables, which were subsequently compared between the DAT and VD patients. RESULTS AND CONCLUSIONS: The GCDI was found to be associated with patients' ADLs and MMSE scores, and not with behavioural disturbances or caregiver burden. Compared to VD patients, people with DAT tended to have more behavioural disturbances but better ADL functioning. As a result, DAT patients were classified as 'less disabled' on their GCDI than VD patients, even though their caregivers felt as much burden as the caregivers of VD patients. These results show that the GCDI probably underestimates the impact of behaviour problems. Suggestions are made for a more balanced assessment of demented patients that is more consistent with their needs.
Activities of Daily Living↗
Immature dendritic cell/tumor cell fusions induce potent antitumour immunity.
BACKGROUND: Maturation of dendritic cells (DCs) is important to induce antigen-specific antitumour immunity in cancer immunotherapy with antigen-loaded DCs. However, DCs from tumour-bearing hosts are immature and functionally defective for antigen presentation. We examined whether DCs from tumour-bearing mice could be an effective part of a DC/tumour cell fusion vaccine. MATERIALS AND METHODS: Dendritic cells from healthy (DC-Hs) or MC38 tumour-bearing mice (DC-TBs) were examined for endocytotic capacity of FITC-labelled dextran, antigen-presenting capacity in allogeneic mixed leucocyte reaction (allo-MLR) and expression of I-Ab, CD80, and CD86. Fusion cells (FCs) of DC-Hs or DC-TBs and MC38 cells (FC-Hs or FC-TBs) were generated by treatment with polyethylene glycol (PEG). Mice vaccinated with FC-Hs or FC-TBs were studied for cytolytic activity of splenocytes and suppressive activity against established MC38 pulmonary metastases. RESULTS: Dendritic cell-TBs showed higher endocytotic capacity and lower antigen-presenting capacity than did DC-Hs, results indicating that DC-TBs are more immature and functionally defective for antigen presentation than are DC-Hs. Expression of surface molecules, however, was almost same between DC-Hs and DC-TBs. Splenocytes from mice immunized with FC-Hs or FC-TBs induced the same high cytolytic activity against MC38 cells. Vaccination of mice with FC-Hs or FC-TBs resulted in the same significant suppressive effect against established pulmonary metastases of MC38. CONCLUSION: Dendritic cells from tumour-bearing mice, despite being functionally defective, are effective vehicles for immunotherapy using DC/tumour cell fusion vaccines.
Animals↗
Increased vascular endothelial growth factor in acute eosinophilic pneumonia.
Acute eosinophilic pneumonia (AEP) is associated with the presence of diffuse pulmonary infiltrates on the chest radiograph and an increased number of eosinophils and an elevation of interleukin (IL)-5 levels in bronchoalveolar lavage (BAL) fluid. Vascular endothelial growth factor (VEGF) is a constitutively expressed protein encoded by messenger ribonucleic acid in human eosinophils and is released following stimulation with IL-5. However, the roles of IL-5 and VEGF in the pathogenesis or activity of this disease have not been clarified. The authors investigated the cells and the levels of these two factors in BAL fluid in five AEP patients and five normal controls before and after corticosteroid treatment. The absolute number of eosinophils-mL(-1), IL-5 and VEGF levels in patients before treatment were higher than in controls (53.8 versus 0.3 x 10(4) x mL(-1), 490.1 versus 5.2 pg x mL(-1) and 643.0 versus 133.9 pg x mL(-1), respectively). IL-5 and VEGF rapidly decreased to the control level in parallel with clinical improvement. The relationship between eosinophilia and IL-5 and VEGF levels was strongly significant. Elevated interleukin-5 in the lung may initiate the recruitment of eosinophils and enhance the release of mediators, such as vascular endothelial growth factor from eosinophils, which, in turn, increases the permeability of blood vessels.
Acute Disease↗
Disseminated Mycobacterium avium complex (DMAC) in an immunocompetent adult.
A female patient with multiple osteomyelitis and pulmonary Mycobacterium avium disease visited an orthopaedic clinic with back pain. Systemic bone scan showed multiple sites of increased radioactivity in the vertebral bodies, right scapula, femurs and ribs. M. avium was isolated from sputum and a sample aspirated from the right scapula. The route of infection was unknown as there was no history of trauma or surgery. HIV testing was negative. As there was no underlying immunological disease she was diagnosed as disseminated M. avium complex (DMAC) disease in an immunocompetent adult. Cytokine production on several stimuli from peripheral blood mononuclear cells was similar to that in pulmonary M. avium patients. Sequence analysis of IFN-gamma receptor revealed no nucleotide substitution. We detected serotypes 1, 2 and 4 from mycobacteria cultured from the right scapula, and conclude that this case could be the result of undetected immune deficiency and/or unrecognised virulence of the infecting isolate.
Female↗
Impaired interleukin-1beta converting enzyme (ICE) activity in patients with pulmonary tuberculosis.
We measured the activity of IL-1beta converting enzyme (ICE) of monocytes from pulmonary tuberculosis (PTB) patients. Peripheral blood mononuclear cells (PBMCs) and serum were collected from PTB patients (n = 16) and healthy subjects (n = 6). Serum IL-18 levels were significantly higher in PTB patients (515.9 +/- 326.5 pg/ml) than in controls (108.7 +/- 65.2 pg/ml) (P < 0.01), but gradually decreased with tuberculosis therapy. ICE activity was significantly lower in TB patients (65.3 +/- 34.4 vs. 142.2 +/- 75.6 U/mg) (P < 0.05). Serum IL-18 levels inversely correlated with ICE activity (P < 0.05). Altered ICE activity may explain why there is reduced IFN-gamma production from PBMCs; however, serum IL-18 is probably not regulated by ICE in monocytes in TB patients.
Caspase 1↗
Expression of angiogenic factors predicts response to chemoradiotherapy and prognosis of oesophageal squamous cell carcinoma.
The ability to predict patients' responses to chemoradiotherapy by analyzing pre-treatment biopsy specimens would be valuable for managing oesophageal squamous-cell cancer. To this end, the expression of p53, thymidine phosphorylase and vascular endothelial cell growth factor was analyzed by immunohistochemistry in 52 patients with oesophageal squamous-cell cancer prior to chemoradiotherapy. Treatment consisted of radiotherapy (40 Gy) and 5 day-infusion of 5-Fluorouracil (500 mg m(-2) per day) combined with cisplatin (10 mg m(-2) per day). Following treatment, imaging and endoscopic reassessment was performed to establish treatment response. Thirty-one patients underwent radical surgery and 21 patients were treated with an additional 20 Gy of radiotherapy. Of the tumours studied, 58% were p53-positive, 40% thymidine phosphorylase-positive and 44% vascular endothelial cell growth factor-positive. A clinical response was observed in 36 patients (69%) and was negatively associated with thymidine phosphorylase expression (P=0.02) and vascular endothelial cell growth factor expression (P<0.001). However, the 5-year survival rate was significantly lower only in patients with vascular endothelial cell growth factor-positive tumours (P=0.037). Multivariate analysis identified vascular endothelial cell growth factor as a significant independent prognostic factor (P=0.0147). These results suggest that expression of angiogenic factors has predictive value for the treatment response and outcome of patients with oesophageal cancer.
Angiogenesis Inducing Agents↗
Usefulness of monitoring of AUC(0-4h) during the induction period of immunosuppressive therapy with tacrolimus after renal transplantation.
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Area Under Curve↗
Beneficial effect of antibody removal and enhanced immuno suppression in flow cytometry cross match-positive and ABO-incompatible renal transplantation.
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ABO Blood-Group System↗
Manganese influences the levels of neurotransmitters in synapses in rat brain.
54Mn previously taken up by the amygdala is released along with known neurotransmitters into the extracellular space during stimulation with 100 mM KCl. The possibility of manganese release from neuron terminals in a calcium- and impulse-dependent manner was examined by using the in vivo microdialysis method in the present study. The increase of (54)Mn release into the amygdalar extracellular space during stimulation with high K(+) was inhibited by addition of 1 microM tetrodotoxin. This increase of (54)Mn release into the extracellular space by stimulation with high K(+) was also observed in the hippocampus, but not in the substantia nigra. The increment of glutamate in the extracellular space during stimulation with high K(+) was highly correlated with that of (54)Mn, suggesting that manganese is concurrently released with glutamate from neuron terminals. The level of (54)Mn in the extracellular space in the hippocampus was increased with that of glutamate, but not with those of GABA and glycine, during stimulation with 100 mM KCl in the presence of 30 microM kainate. This increase was more marked than during stimulation with 30 microM kainate alone. It is likely that manganese is released from glutamatergic neuron terminals. When the rat hippocampus was perfused with artificial cerebrospinal fluid containing 20 or 200 nM MnCl(2), the levels of glutamate, aspartate and GABA in the perfusate were dose-dependently decreased during perfusion with manganese. The present findings demonstrate that manganese released into the synaptic cleft may influence synaptic neurotransmission.
Animals↗
Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model.
We hypothesised that the combination of anti-angiogenic and anti-epidermal growth factor (EFG)-receptor (R) therapies would more effectively inhibit gastric cancer growth than single-agent therapy. TMK-1 gastric cancer cells were injected into the gastric wall of nude mice to generate tumours. After 4 days, mice were randomly assigned to the following groups: control, DC101 ([vascular endothelial growth factor (VEGF)-receptor (R)-2 antibody], C225 (EGF-R antibody), or a combination of DC101 and C225. The combination therapy significantly inhibited gastric tumour growth compared with the control group, whereas the decrease in tumour growth in mice treated with DC101 or C225 alone did not reach statistical significance. All mice administered DC101 demonstrated decreased tumour vascularity and increased endothelial cell apoptosis. C225 alone did not affect angiogenesis, but inhibited tumour cell proliferation. The combination therapy led to a further decrease in tumour cell proliferation. The combination of anti-VEGF-R and anti-EGF-R therapies was effective in inhibiting gastric cancer growth. These findings support the hypothesis that inhibiting multiple biological pathways that mediate tumour growth may be an effective therapeutic strategy.
Animals↗
[Effect of acupuncture on the expression of NT3 in the process of spinal plasticity].
OBJECTIVE: To explore the change in the expression of NT3 in the process of promoting the plasticity of spinal cord by acupuncture. METHODS: Five adult cats were subjected to unilateral spared root rhizotomy; their L1-L5, L7-S2 dorsal root ganglia (DRG) were sectioned, but L4 was spared. And two groups of acupoints [Zusani (St.36) and Xuanzhong (G. B.39); Futu (St.32) and Sanyingjiao (Sp.6)] located in hind limb were electro-stimulated for thirty minutes q.d. x 7. At seven days, after acupuncture, the L5 segment of spinal cord and spared dorsal root ganglion (L6) were taken and made into frozen section 20 microns in thickness. Immunohistochemistry (NT3 antibody 1:1500) and in situ hybridization (NT3 cRNA probe 1:100) techniques were used. The numbers of positive neuron for NT3 and it's mRNA in large, medium, small neuron of L6 DRG and the numbers of positive neurons and glia cells for NT3 in lamina II were counted respectively. RESULTS: The numbers of positive large, small neurons for NT3 and its mRNA in DRG and the number of positive neurons and glia cells for NT3 in lamina II on the acupuncture side increased apparently than those on the non-acupuncture side (P < 0.05). However, the positive signal of NT3 mRNA in lamina II was not seen in our study. CONCLUSION: The results indicate that acupuncture promoting the plasticity of spinal cord involves both the increase in expression of NT3 in large and small neurons of spared DRG and the increase in number of NT3 positive neurons and glia cells in spinal lamina II. Moreover, NT3 may play a role in the process of promoting the plasticity of spinal cord by acupuncture.
Animals↗