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Takeshi Ishihara

Publications and source records attributed to Takeshi Ishihara.

At least 19 recordsLinked to original sources
PubMed2007

Phase I study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer.

PURPOSE: The primary objective of this study was to determine the maximum-tolerated dose (MTD) of S-1, an oral fluoropyrimidine derivative, with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day from Day 1 to 14 and 22 to 35 at escalating doses from 60 to 80 mg/m(2)/day. RESULTS: Sixteen patients were enrolled in this study. Three patients received S-1 at 60 mg/m(2)/day, 3 at 70 mg/m(2)/day, and 10 at 80 mg/m(2)/day. Though 1 patient at the final dose level (80 mg/m(2)/day) experienced a dose limiting toxicity (biliary infection with Grade 3 neutropenia), the MTD was not reached in this study. The most common toxicities were anorexia and leukocytopenia, with Grade 3 toxicity occurring in 31% and 6.3% of the patients, respectively. CONCLUSIONS: The recommended dose of S-1 with concurrent radiotherapy was determined to be 80 mg/m(2)/day from Day 1 to 14 and 22 to 35 in patients with locally advanced pancreatic cancer. Oral S-1 and radiotherapy is well tolerated and feasible and should be further investigated.

Aged↗
PubMed2006

Amyotrophic lateral sclerosis with dementia: an autopsy case showing many Bunina bodies, tau-positive neuronal and astrocytic plaque-like pathologies, and pallido-nigral degeneration.

We report the case of a 54-year-old woman with mental retardation who developed frontotemporal dementia and amyotrophic lateral sclerosis (ALS) in the presenium. She presented with dementia at age 48, and motor neuron signs developed at age 53. She had no family history of dementia or ALS. Postmortem examination disclosed histopathological features of ALS, including pyramidal tract degeneration, mild loss of motor neurons, and many Bunina bodies immunoreactive for cystatin C, but not ubiquitin-positive inclusions. Unusual features of this case included severe neuronal loss in the substantia nigra and medial globus pallidus. The subthalamic nucleus, limbic system, and cerebral cortex were well preserved. In addition, neurofibrillary tangles (NFTs) were found in the frontal, temporal, insular, and cingulate cortices, nucleus basalis of Meynert, and locus coeruleus, and to a lesser degree, in the dentate nucleus, cerebellum, hippocampus, and amygdala. No ballooned neurons, tufted astrocytes, or astrocytic plaques were found. Tau immunostaining demonstrated many pretangles rather than NFTs and glial lesions resembling astrocytic plaques in the frontal and temporal cortices. This glial tau pathology predominantly developed in the middle to deep layers in the primary motor cortex, and was frequently associated with the walls of blood vessels. NFTs were immunolabeled with 3-repeat and 4-repeat specific antibodies against tau, respectively. Although the pathophysiological relationship between tau pathology and the selective involvement of motor neurons, substantia nigra, and globus pallidus was unclear, we considered that it might be more than coincidental.

Amyotrophic Lateral Sclerosis↗
PubMed2006

G(olf) protein levels in rat striatum are increased by chronic antidepressant administration and decreased by olfactory bulbectomy.

There are many studies of the mechanisms of antidepressants; however, most of these studies were conducted on the hippocampus or frontal cortex. In the present study, we hypothesized that the nucleus accumbens and caudate/putamen might be major targets for antidepressant effects. Thus, we focused on G(olf) protein, a stimulant alpha-subunit of G protein that is coupled with the dopamine D1 receptor and specifically expressed in the striatum (nucleus accumbens, caudate/putamen and olfactory tubercle) in the rat brain. We examined the effects of chronic administration of imipramine, fluvoxamine, maprotiline and, as a negative control, cocaine on the level of G(olf) protein in the rat striatum. We also examined the effect of olfactory bulbectomy. Chronic imipramine treatment (10 mg/kg for 2 or 4 weeks) significantly increased the level of G(olf) in the striatum (by 17% or 18%, respectively), although this increase was not apparent after only 1 week of treatment. The time course of these changes corresponded well to that of the clinical efficacy of imipramine. Chronic fluvoxamine and maprotiline treatment (20 mg/kg for 2 weeks) also significantly increased the level of G(olf) (by 9% and 25%, respectively), but cocaine did not alter it significantly. Bulbectomy decreased the G(olf) protein level by 9%. The increases in G(olf) protein after chronic administration of these three different classes of antidepressants and the decrease after bulbectomy suggest that G(olf) protein may play an important role in the antidepressant effect.

Adrenergic Uptake Inhibitors↗
PubMed2006

Long-term outcome of endoscopic metallic stenting for benign biliary stenosis associated with chronic pancreatitis.

AIM: Endoscopic metal stenting (EMS) offers good results in short to medium term follow-up for bile duct stenosis associated with chronic pancreatitis (CP); however, longer follow-up is needed to determine if EMS has the potential to become the treatment of first choice. METHODS: EMS was performed in eight patients with severe common bile duct stenosis due to CP. After the resolution of cholestasis by endoscopic naso-biliary drainage three patients were subjected to EMS while, the other five underwent EMS following plastic tube stenting. The patients were followed up for more than 5 years through periodical laboratory tests and imaging techniques. RESULTS: EMS was successfully performed in all the patients. Two patients died due to causes unrelated to the procedure: one with an acute myocardial infarction and the other with maxillary carcinoma at 2.8 and 5.5 years after EMS, respectively. One patient died with cholangitis because of EMS clogging 3.6 years after EMS. None of these three patients had showed symptoms of cholestasis during the follow-up period. Two patients developed choledocholithiasis and two suffered from duodenal ulcers due to dislodgement of the stent between 4.8 and 7.3 years after stenting; however, they were successfully treated endoscopically. Thus, five of eight patients are alive at present after a mean follow-up period of 7.4 years. CONCLUSION: EMS is evidently one of the very promising treatment options for bile duct stenosis associated with CP, provided the patients are closely followed up; thus setting a system for their prompt management on emergency is desirable.

Adult↗
PubMed2006

Efficacy of s-type stents for the treatment of the main pancreatic duct stricture in patients with chronic pancreatitis.

OBJECTIVE: Stents have been used to relieve pancreatic duct stricture and upstream dilatation. However, many of these stents are straight-type stents originally manufactured for biliary use. A plastic stent that was developed for use in the pancreatic duct was used in this study and its usefulness investigated. MATERIAL AND METHODS: The stent (s-type stent: 10 Fr in diameter) has two alternate flexions and the shape resembles the tilde mark " approximately " in appearance. After obtaining informed consent, stents were placed in 20 patients with abdominal pain caused by chronic pancreatitis and stricture of the distal main pancreatic duct. The stents were removed according to the clinical manifestations and replaced with new ones if the stricture persisted. RESULTS: In total, 33 stents were placed in 20 patients. Pain relief was attained in 19 patients (95%). The stricture improved after one stenting in 8 patients (40%). Owing to persistent stricture, the stenting was repeated in 11 patients. The 50% stent indwelling period was 369.0 days. No proximal or distal migration of the stent occurred and there were no serious complications. CONCLUSIONS: In view of its long durability as a stent and no migration, the s-stent is safe and useful for the management of pancreatic ductal strictures in patients with chronic pancreatitis.

Adult↗
PubMed2006

[Combination chemotherapy with gemcitabine and S-1 for advanced pancreatic cancer].

The incidence and mortality of pancreatic cancer has increased very rapidly in Japan. The five-year survival rate is still poor at less than 10%, because it is commonly considered to be linked to a high incidence of distant metastasis even at the initial diagnosis as well as to the tumor's resistance to anticancer agents. Although gemcitabine has been the most widely used chemotherapeutic agent in patients with advanced pancreatic cancer (APC), gemcitabine monotherapy has obvious limitations. Therefore, various combinations with other agents have been investigated to improving the survival of patients with APC. Under these circumstances, we conducted a phase I /II trial of gemcitabine with S-1, an oral fluorouracil derivative, to determine the maximum tolerated dose and to evaluate the activity and toxicity of such a combination in patients with APC. S-1 was administered orally twice daily each day for 14 days and gemcitabine on days 8 and 15 of each cycle, and this cycle was repeated every 21 days. As a result, S-1 30 mg/m2 orally twice daily and gemcitabine 1,000 mg/m2 were selected as the recommended dose. The toxicities observed were mainly hematological ones with mild non-hematological toxicities. An encouragingly high response rate was observed. This result is very promising, but the survival benefit in comparison with gemcitabine monotherapy needs to be confirmed in a future randomized clinical trial.

Adenocarcinoma↗
PubMed2005

Pancreatic juice cytology in the diagnosis of intraductal papillary mucinous neoplasm of the pancreas: significance of sampling by peroral pancreatoscopy.

BACKGROUND: The examination of pancreatic juice cytology could hypothetically contribute to the establishment of a definite diagnosis of malignant intraductal papillary mucinous neoplasm of the pancreas (IPMN), but to the authors' knowledge, its significance has not been confirmed to date. The current study was conducted to assess the diagnostic value of pancreatic juice cytology in IPMN and to examine the usefulness of peroral pancreatoscopy (POPS) in sampling pancreatic juice. METHODS: The study subjects were comprised of 103 patients with IPMN who underwent surgical resection of pancreatic tumors (adenoma in 29 patients, borderline in 17 patients, carcinoma in situ in 25 patients, and invasive carcinoma in 32 patients). Pancreatic juice was collected with a catheter in 71 patients and by POPS in 32 patients. Patients with pancreatic carcinoma (n = 81) and chronic pancreatitis (n = 76) also were investigated. RESULTS: The cytologic diagnosis was found to be of nondiagnostic value in only one patient with an IPMN, whereas it was of no diagnostic value in 14 of the patients with pancreatic carcinoma (17.3%), a difference that was statically significant (P < 0.001). The location of the IPMN (either in the pancreas or the pancreatic ducts) was not found to significantly affect the diagnostic value of the test. The sensitivity for IPMN was 62.2% when pancreatic juice was collected by POPS, and was 38.2% when it was collected using a catheter. In the case of pancreatic carcinoma, the sensitivity of pancreatic juice cytology was found to be 25.4%, which was significantly lower than that for IPMN when the pancreatic juice was collected by POPS (P < 0.001). CONCLUSIONS: Pancreatic juice cytology was found to have better diagnostic value in the patients with IPMNs compared with those with pancreatic carcinoma. POPS was found to be useful for the collection of pancreatic juice.

Adenocarcinoma, Mucinous↗
PubMed2005

Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies.

Lithium, a widely used drug for treating affective disorders, is known to inhibit glycogen synthase kinase-3 (GSK-3), which is one of the major tau kinases. Thus, lithium could have therapeutic benefit in neurodegenerative tauopathies by reducing tau hyperphosphorylation. We tested this hypothesis and showed that long-term administration of lithium at relatively low therapeutic concentrations to transgenic mice that recapitulate Alzheimer's disease (AD)-like tau pathologies reduces tau lesions, primarily by promoting their ubiquitination rather than by inhibiting tau phosphorylation. These findings suggest novel mechanisms whereby lithium treatment could ameliorate tauopathies including AD. Because lithium also has been shown to reduce the burden of amyloid-beta pathologies, it is plausible that lithium could reduce the formation of both amyloid plaques and tau tangles, the two pathological hallmarks of AD, and thereby ameliorate the behavioral deficits in AD.

Animals↗
PubMed2005

Hydrogenated 1,4-insertion of butadiene in the copolymerization with propylene using an isospecific zirconocene catalyst.

Poly(propylene-ran-1,3-butadiene) that contained pendant vinyl groups derived from 1,2-inserted butadiene units was selectively synthesized by rac-dimethylsilylbis(2-methyl-4-phenylindenyl)zirconium dichloride (Ph-Ind) activated with modified methylaluminoxane (MMAO) in the presence of hydrogen. The copolymers obtained without hydrogen had 1,2-inserted and 1,4-inserted butadiene units. The addition of hydrogen to the copolymerization improved the activity by approximately 1000-fold and gave the copolymer only with 1,2-inserted butadiene units, of which the content was equal to the copolymer obtained without hydrogen. The 13C NMR analysis of the copolymers clarified that butadiene also inserted into the copolymer as a tetramethylene unit, of which the content was almost the same as that of 1,4-inserted butadiene units observed in the absence of hydrogen. No signal that could be assigned to cyclic structures or long branched side chains was observed. These results indicate that pi-allyl species of zirconocenes formed by 1,4-butadiene insertion at the growing polymer chain ends transformed to the tetramethylene chain end by hydrogenation and continued successive propylene insertion.

Journal Article↗
PubMed2005

Proteome analysis of human metaphase chromosomes.

DNA is packaged as chromatin in the interphase nucleus. During mitosis, chromatin fibers are highly condensed to form metaphase chromosomes, which ensure equal segregation of replicated chromosomal DNA into the daughter cells. Despite >1 century of research on metaphase chromosomes, information regarding the higher order structure of metaphase chromosomes is limited, and it is still not clear which proteins are involved in further folding of the chromatin fiber into metaphase chromosomes. To obtain a global view of the chromosomal proteins, we performed proteome analyses on three types of isolated human metaphase chromosomes. We first show the results from comparative proteome analyses of two types of isolated human metaphase chromosomes that have been frequently used in biochemical and morphological analyses. 209 proteins were quantitatively identified and classified into six groups on the basis of their known interphase localization. Furthermore, a list of 107 proteins was obtained from the proteome analyses of highly purified metaphase chromosomes, the majority of which are essential for chromosome structure and function. Based on the information obtained on these proteins and on their localizations during mitosis as assessed by immunostaining, we present a four-layer model of metaphase chromosomes. According to this model, the chromosomal proteins have been newly classified into each of four groups: chromosome coating proteins, chromosome peripheral proteins, chromosome structural proteins, and chromosome fibrous proteins. This analysis represents the first compositional view of human metaphase chromosomes and provides a protein framework for future research on this topic.

Chromatin↗
PubMed2005

FLR-4, a novel serine/threonine protein kinase, regulates defecation rhythm in Caenorhabditis elegans.

The defecation behavior of the nematode Caenorhabditis elegans is controlled by a 45-s ultradian rhythm. An essential component of the clock that regulates the rhythm is the inositol trisphosphate receptor in the intestine, but other components remain to be discovered. Here, we show that the flr-4 gene, whose mutants exhibit very short defecation cycle periods, encodes a novel serine/threonine protein kinase with a carboxyl terminal hydrophobic region. The expression of functional flr-4::GFP was detected in the intestine, part of pharyngeal muscles and a pair of neurons, but expression of flr-4 in the intestine was sufficient for the wild-type phenotype. Furthermore, laser killing of the flr-4-expressing neurons did not change the defecation phenotypes of wild-type and flr-4 mutant animals. Temperature-shift experiments with a temperature-sensitive flr-4 mutant suggested that FLR-4 acts in a cell-functional rather than developmental aspect in the regulation of defecation rhythms. The function of FLR-4 was impaired by missense mutations in the kinase domain and near the hydrophobic region, where the latter allele seemed to be a weak antimorph. Thus, a novel protein kinase with a unique structural feature acts in the intestine to increase the length of defecation cycle periods.

Alleles↗
PubMed2005

Long-term results of extracorporeal shockwave lithotripsy and endoscopic therapy for pancreatic stones.

BACKGROUND & AIMS: The aim of this study was to evaluate the short- and long-term results of extracorporeal shockwave lithotripsy (ESWL) and endoscopic therapy for pancreatic stones. METHODS: A total of 117 patients with pancreatic stones underwent ESWL and endoscopic treatment in our institute. Seventy patients who were followed-up for over 3 years after treatment were evaluated retrospectively. RESULTS: Immediate pain relief was achieved in 97% and complete removal of stones was achieved in 56%. During the long-term follow-up evaluation, 49 of 70 patients continued to be asymptomatic. Pain recurred more frequently in patients with incomplete removal than in those with complete removal (P < .05). Twenty-one patients who became symptomatic during the follow-up period underwent additional therapy, and pain relief was attained without surgery in all of them. Both endocrine and exocrine function deteriorated after the long-term follow-up period (P < .05). CONCLUSIONS: ESWL and endoscopic treatment of pancreatic stones proved to be effective for long-term pain relief, especially in patients in whom stones were removed completely at initial therapy.

Adolescent↗
PubMed2005

Long-term follow-up of intraductal papillary mucinous neoplasm of the pancreas with ultrasonography.

BACKGROUND & AIMS: Most intraductal papillary mucinous neoplasms of the pancreas (IPMNs) have a favorable prognosis. This study was undertaken to clarify the clinical course of IPMNs and to set the criteria for surgical treatment on the basis of long-term follow-up by periodic transabdominal ultrasonography (US). METHODS: Eighty-one patients with IPMN were periodically subjected to US (>3 years); 27 were reviewed retrospectively (12 with benign neoplasms [adenoma, borderline] and 15 with malignant tumors [carcinoma in situ, invasive cancer]) and 54 prospectively. US examination was focused on the main pancreatic duct (MPD) diameter, cyst diameter, and presence or absence and height of the protruding lesion. Differences between the benign and malignant groups were examined to set the criteria for surgical treatment. Follow-up results of prospective patients were investigated. RESULTS: The increase of the MPD or the cyst diameter was significantly greater in the malignant group (P < .01). Maximum increases of the MPD diameter by 2.2 mm/year, the cyst diameter by 11.3 mm/year, and emergence or increase of the height of the protruding lesion by 3.3 mm/year were predominantly observed in the malignant group (accuracy, 90.9%, 81.3%, and 81.5%, respectively). The majority of the prospective patients showed no significant changes of these parameters; however, 2 patients (3.7%) were operated on, with the post-surgery histopathologic diagnosis of cancer. CONCLUSIONS: Periodic imaging follow-up is useful to detect a malignant IPMN. Changes in MPD diameter, cyst diameter, and/or size of the protruding lesion are the practical criteria for selecting surgery.

Aged↗
PubMed2005

Usefulness of plasma vascular endothelial growth factor in the diagnosis of pancreatic carcinoma: differential diagnosis, tumor progression, and patient survival.

OBJECTIVES: This study aimed to examine the usefulness of plasma vascular endothelial growth factor (p-VEGF) in patients with pancreatic carcinoma (PC) as a tumor marker for PC in comparison with chronic pancreatitis (CP) and to clarify the relationship between p-VEGF and the clinicopathological features of PC. METHODS: The subjects were 69 patients with PC, 35 with CP, and 26 healthy volunteers (control group). The p-VEGF levels were measured by enzyme-linked immunoassay. RESULTS: p-VEGF levels were significantly higher in the PC group compared with the CP and control groups (P < 0.0001). A cut-off level of 149.5 pg/mL, discriminating between PC and CP, was determined based on a receiver operating characteristic curve. Using this cut-off level, the sensitivity was 60%, specificity was 96%, and accuracy was 73%. Patients with PC with distant metastases exhibited a significantly higher level of p-VEGF compared with those without metastasis (P = 0.0113). Multivariate analysis indicated that a high level of p-VEGF was an independent prognostic factor, and a significant association was observed between p-VEGF and median survival time (P = 0.0092). CONCLUSIONS: p-VEGF proved useful in differentiating between PC and CP, and in patients with PC, a high level of p-VEGF may be a predictor of distant metastases and poor prognosis.

Adult↗
PubMed2005

Delusion of theft and phantom intruder delusion in demented elderly patients in Japan.

Delusion of theft and phantom intruder delusion are among the most frequent delusions in dementia. The purpose of this study was to clarify the clinical characteristics of patients with these symptoms. The authors conducted a questionnaire survey; items included age, gender, dementia diagnosis, cognitive function, and activities of daily living. Other clinical characteristics were evaluated using the quality of life questionnaire for dementia. A total of 217 patients with dementia were rated. Frequencies of delusion of theft were as follows: frequent, 7%; sometimes, 11%; rare, 16%; and none, 66%. Frequencies of phantom intruder delusion were as follows: frequent, 4%; sometimes, 10%; rare, 9%; and none, 77%. Comparison between positive and negative groups with these symptoms revealed that positive groups had higher scores in 2 of 6 domains of the quality of life questionnaire for dementia, namely, negative affect and actions, and restlessness. The positive group with delusion of theft had higher scores in cognitive function and activities of daily living than did the negative group. These results suggest that negative affect and action and restlessness might be related to delusion of theft or phantom intruder delusion and that delusion of theft frequently occurs in the early stage of dementia.

Activities of Daily Living↗
PubMed2005

Multidrug resistance-associated protein MRP-1 regulates dauer diapause by its export activity in Caenorhabditis elegans.

Multidrug resistance-associated proteins (MRPs), when overexpressed, confer drug resistance to cancer cells by exporting anti-cancer agents through the cell membrane, but their role in animal development has not been elucidated. Here we show that an MRP homolog regulates larval development in the nematode Caenorhabditis elegans. C. elegans forms a special third-stage larva called a dauer larva under conditions inappropriate for growth. By contrast, we found that mutants in mrp-1, an MRP homolog gene, form dauer larvae even under conditions appropriate for growth, in the background of certain mutations that partially block the insulin signaling pathway. A functional mrp-1::GFP gene was shown to be expressed in many tissues, and the wild-type mrp-1 gene must be expressed in multiple tissues for a wild-type phenotype. Human MRP1 could substitute for C. elegans MRP-1 in dauer larva regulation, and an inhibitor of the human MRP1 transport activity impaired this function, showing that export activity is required for normal dauer larva regulation. Epistasis studies revealed that MRP-1 acts in neither the TGF-beta nor the cGMP signaling pathway. mrp-1 mutations enhanced the dauer-constitutive phenotype of mutants in the insulin signaling pathway more strongly than that in other pathways. Thus, MRP-1, through its export activity, supports the induction of the normal (non-dauer) life cycle by the insulin signaling pathway.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Assessment of portal vein invasion in pancreatic cancer by fusion 3-dimensional ultrasonography.

OBJECTIVE: The purpose of this study was to assess the usefulness of a newly developed imaging technique, fusion 3-dimensional ultrasonography (3DUS) in the diagnosis of portal vein (PV) invasion in patients with pancreatic cancer (PC). METHODS: Fourteen patients with proven PC were examined by fusion 3DUS presented as shaded volume-rendering and multiplanar reconstruction images. The surgical findings were obtained in all patients (12 with resection and 2 without). The findings were compared with those of 2-dimensional ultrasonography (2DUS), contrast-enhanced computed tomography (CT), dynamic CT (DCT), angiography, and surgical findings. Portal vein invasion was assessed by 3 independent radiologists for each modality, and objectivity of the assessment was examined by interobserver variability analysis (kappa value). RESULTS: On the basis of surgical findings, the accuracy rates of 2DUS, fusion 3DUS, DCT, and angiography were 78.6%, 92.9%, 85.3%, and 66.7%, respectively. The kappa values of 2DUS, fusion 3DUS, DCT, and angiography for PV invasion were 0.57, 0.90, 0.63, and 0.49, respectively, being most objective in fusion 3DUS. CONCLUSIONS: Fusion 3DUS is useful for diagnosis of PV invasion of PC.

Adult↗