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Determination of Saccharin in foods by high performance liquid chromatography (HPLC) after extraction with dialysis was developed. Five to twenty grams of samples were cut into pieces and transferred into a cellophane tubing with 30 ml of 0.1 N HCl. The tubing was submerged in 0.1 N HCl in a messcylinder so that the total volume reached 200 ml. After 24 h of dialization with occasional mixing, the dialysate was analysed by HPLC on a column of NH2 using methanol -1% phosphoric acid (4 : 6) as mobile phase, and the elution was monitored by the absorbance at 230 nm. The minimum measurable amount was 0.005 g/kg, and the recoveries when added to soysauce and grape juice at concentrations of 0.1 to 0.5 g/kg were 96-101.7%.

The Tokyo metropolitan hospital society of chief medical technologist has carried out a staining survey once a year since 1992. This staining survey is performed to plan improvements of the staining technology at each hospital and reduction of differences among hospitals. This report describes the examination results for PAS stain, Papanicolaou stain, and PAM stain.

Oxidative stress is a critical mediator in liver injury of steatohepatitis. The transcription factor Nrf2 serves as a cellular stress sensor and is a key regulator for induction of hepatic detoxification and antioxidative stress systems. The involvement of Nrf2 in defense against the development of steatohepatitis remains unknown. We aimed to investigate the protective roles of Nrf2 in nutritional steatohepatitis using wild-type (WT) and Nrf2 gene-null ( Nrf2-null) mice. WT and Nrf2-null mice were fed a methionine- and choline-deficient (MCD) diet for 3 and 6 wk, and the liver tissues were analyzed for pathology and for expression levels of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. In WT mice fed an MCD diet, Nrf2 was potently activated in the livers, and steatohepatitis did not develop over the observation periods. However, in Nrf2-null mice fed an MCD diet, the pathological state of the steatohepatitis was aggravated in terms of fatty changes, inflammation, fibrosis, and iron accumulation. In the livers of the Nrf2-null mice, oxidative stress was significantly increased compared with that of WT mice based on the increased levels of 4-hydroxy-2-nonenal and malondialdehyde. This change was associated with the decreased levels of glutathione, detoxifying enzymes, catalase, and superoxide dismutase activity. Correlating well with the liver pathology, the mRNA levels of factors involved in fatty acid metabolism, inflammatory cytokines, and fibrogenesis-related genes were significantly increased in the livers of the Nrf2-null mice. These findings demonstrate that Nrf2 deletion in mice leads to rapid onset and progression of nutritional steatohepatitis induced by an MCD diet. Activation of Nrf2 could be a promising target toward developing new options for prevention and treatment of steatohepatitis.

Lymphoma is one of the causative factors of hypothalamus-pituitary dysfunction, and intravascular large B-cell lymphoma (IVLBCL) is a subtype of primary extranodal neoplasm. A 69-year-old woman visited our hospital because of general fatigue. We diagnosed her with presumable non-functional primary pituitary adenoma and subsequent dysfunction. Eight months after, the patient revisited our hospital because of dyspnea. Though we conducted systemic investigations including chest and abdomen enhanced computer tomography, transbronchial lung biopsy, and bone marrow biopsy, the diagnosis was not confirmed. Inadvertently, a breast cancer was found, and the surgical specimen proved that the patient had double cancer-adenocarcinoma and IVLBCL. Rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone regimen was initiated, and complete remission was achieved. Notably, the sellar mass returned to normal size with improved function. We reviewed 32 patients with primary parasellar lymphoma. In affected sites, both sellar and pituitary stalk (6.7%), both hypothalamus and pituitary stalk (6.7%), only sellar (63.3%), only pituitary stalk (6.7%), only hypothalamus (13.3%), and only clivus (3.3%) were observed. In hypothalamus-pituitary dysfunction, both anterior and posterior dysfunction (20.7%), only anterior dysfunction (58.6%), only posterior dysfunction (3.4%), and no dysfunction (17.2%) were observed. It seemed that hypothalamic lesion is related to both anterior and posterior dysfunction, while sellar lesion is related to mainly anterior dysfunction. In cranial nerve dysfunction, 2nd nerve dysfunction (45.2%) and 6th nerve dysfunction (35.5%) were frequently observed. It seemed that sellar lesion is related to both 2nd and 6th nerve dysfunction, while hypothalamic lesion is related to mainly 2nd nerve dysfunction.

Much of the cell injury caused by ultraviolet A (UVA) irradiation is associated with oxidative stress. Quercetin is a major natural polyphenol that is known to protect cells from UVA-induced damage. Here, we investigated the molecular mechanism of this protection. Quercetin pretreatment strongly suppressed UVA-induced apoptosis in human keratinocyte HaCaT cells, markedly increased protein levels of the transcription factor Nrf2, induced the expression of antioxidative genes, and dramatically reduced the production of reactive oxygen species following UVA irradiation. Importantly, these beneficial effects were greatly attenuated by downregulating Nrf2 expression. Thus, quercetin protects cells from UVA damage mainly by elevating intracellular antioxidative activity via the enhanced accumulation of a transcription factor for antioxidant genes, Nrf2.

Aim Sequestosome 1 (SQSTM1)/A170/p62 plays an important role in membrane-receptor mediated signal transduction and autophagic protein degradation. Although the mechanism involved is not clear, sqstm1 gene knockout (KO) mice develop mature-onset obesity and insulin resistance, leading to type II diabetes. KO mice show accumulation of fat in white adipose tissue and the liver when fed a standard diet. Acarbose is an alpha-glucosidase inhibitor that improves insulin sensitivity and decreases postprandial hyperglycemia, and it is used to treat type 2 diabetes. We examined whether or not dietary acarbose prevented obesity and simple steatosis in KO mice. Methods Wild-type (WT) and KO mice were fed a standard diet with or without acarbose (0.8% w/w) from 15-25 weeks of age. The body weight and the fat content of adipose tissue and the liver were measured, and changes of lipid metabolism in these tissues were assessed from gene expression. Results Acarbose treatment suppressed weight gain and the development of hepatic steatosis in KO mice. Acarbose treatment up-regulated hepatic expression of the pparalpha, ucp-2, and abca1 genes, as well as srebp1c, pparalpha, and ppargamma in adipose tissue. In WT mice, however, acarbose treatment had little influence on weight gain and gene expression. Conclusions The results of this study suggest that long-term administration of acarbose is effective for prevention of obesity and simple steatosis in SQSTM1-KO mice.

Annual surveys conducted by the Japanese Society of Anesthesiologists repeatedly show that hemorrhage is the leading cause of life-threatening events in the operating room.We performed a questionnaire survey regarding the present status of critical hemorrhage/ blood transfusion occurring in the operating room on an institutional scale and individual blood transfusion management in cases of massive hemorrhage (or = 5,000 ml) in hospitals withor = 500 beds and those with an accredited Department of Anesthesiology regarded as regional hospitals.Of 384 institutions, 247 responded to the questionnaire (response rate: 64%), and 692,241 cases managed by anesthesiologists in 2006 were registered. There were 2,657 cases of massive hemorrhage above the circulating blood volume in the operating room, and 404 of them were critical. Thus, the number of cases of massive hemorrhage was 6.6 times that of cases of critical events due to hemorrhage. In the survey of individual cases of massive hemorrhage (or = 5,000 ml), 1,257 cases were registered in 2006, of whom 196 cases (15.6%) died within 30 post-operative days and 160 cases (12.7%) had some sequelae. The amount of transfused red blood cell concentrate was 25.2 +/- 24.2 units. The amount of red blood cell concentrates stocked for emergency was 12.7 +/- 10.1 units for blood group A, 9.7 +/- 7.3 units for group B, 11.9 +/- 9.6 group AB, and 11.3 +/- 11.0 for group O. Therefore, for those other than group O cases, 21-46 units of red blood cell concentrates seemed to be available in the hospital. The survey of individual cases showed uncross-matched, same blood group transfusion and compatible, different blood group transfusion were performed in only 8.2% and 4.3%, respectively. The lowest hemoglobin concentration was below 5 g x dl(-1) in 16.7% of the cases, but uncross-matched, same blood group transfusion was performed only in 19.0% and compatible, different blood group red cell concentrate transfusion in 5.2%. Even in cases who required cardiac massage, uncross-matched, same blood group transfusion was performed only in 17.1% and compatible, different blood group red cell concentrate transfusion in 8.5%. Intraoperative blood salvage was performed in only 5.7% in cases who underwent non-cardiac surgery. The "Guidelines for the Management of Critical Hemorrhage" proposed in 2007 or the manuals for in-hospital emergency blood transfusion were insufficiently recognized, even by anesthesiologists, and rarely known by surgeons. There were no such manuals in more than 60% of the institutions.Undertransfusion may occur in 16.7-28.3% of cases of massive hemorrhage in the operating room, and the rate of emergency blood transfusion was much lower than this percentage. To avoid operation-associated deaths from hemorrhage, the improvement of hospital systems for emergency blood transfusion, including the active use of intraoperative blood salvage, should be promoted.

Aim: Our objective was to determine the relationship between defective swallowing mechanics and the location of brain lesions in stroke patients. Methods: We evaluated swallowing mechanics in 37 stroke patients and 10 age-matched control subjects by videofluoroscopy. Subjects were asked to swallow 10 successive 1.0-mL and three successive 2.5-mL boluses of barium suspension at intervals of approximately 15–30 s. We measured oral transit time, pharyngeal delay time and pharyngeal transit time. Results: Patients could be divided into two groups based on the pharyngeal delay time for a 1.0-mL bolus swallow. One group showed little variation during successive swallowing tests, similar to the control group. In the other group pharyngeal delay times varied during successive trials often tending to increase with successive swallows. Magnetic resonance imaging studies of the brain revealed infarcts or hemorrhages in swallow-related areas in the latter group, while in the former group lesions were localized to areas unrelated to swallowing. Conclusion: Damage to swallow-related areas may reduce their sensitivity to incoming signals from the oral cavity thereby impairing preparations to generate motor command signals and compromising their ability to send sufficient voluntary descending command signals to activate the swallowing central pattern generator located in the medulla. This deficiency becomes more evident with successive swallows and manifests as impaired swallowing mechanics.

Stimulation of the dorsal part of the fastigial nucleus in macaques is known to evoke ipsilateral saccades, while those of the ventral part produce contralateral saccades. It was found that stimulation of the transitional zone moved the visual axis (eyes) to converge at an area (focus) in the oculomotor range, regardless of the initial eye position. These saccades were designated as ‘converging saccades’. Converging saccades were directed to the focus, but the eyes did not attain the focus in one motion. Only the repetition of stimuli brought the eyes near the focus. When stimulation is applied to the transitional zone at progressively more ventral sites, the focus gradually shifted, starting from the ipsilateral hemifield to the contralateral hemifield by taking various routes.

In order to confirm efficacy, safety and utility of mizoribine (MZR) for treatment of rheumatoid arthritis, we conducted a 24 weeks double-blind controlled study using lobenzarit disodium (CCA) as a control drug and obtained the following results.(1) The study involved 72 cases for MZR group and 77 cases for CCA group. There were no significant differences in patients' backgrounds between the two groups.(2) Final global improvement rate was evaluated as “improvement” or more in 26.8% (15/56) for MZR group vs. 12.3% (8/65) for CCA group, “slight improvement” or more in 55.4% (31/56) for MZR group VS. 36.9% (24/65) for CCA group. There was no significance for any of these differences.(3) The incidence of side effects of MZR group was 31.9% and that of CCA group was 48.7%. No serious side effect was observed in both groups.(4) Radiographic films of 41 patients participating in this study were evaluated in a random order by two readers. Only in the CCA group (21 patients) was a statistically significant increase in the mean value of erosion score as well as damage score. These results show that MZR do retarded radiographic progression of joint destruction in the treatment of rheumatoid arthritis.(5) The utility of MZR group was superior to CCA group. These results indicate that mizoribine is a useful drug for treatment of rheumatoid arthritis.

Five new macrolides, spirastrellolides C (3) to G (7), have been isolated from extracts of the marine sponge Spirastrella coccinea collected in Dominica. Their structures have been elucidated by a combination of spectroscopic analysis and chemical transformations.

In multiple system atrophy (MSA), it has been accepted that the motor-related cortical area may degenerate. However, there have been few investigations of the postcentral cortex of the somatosensory area. For this reason, we investigated the effects of MSA on both the precentral and the postcentral cortex and were able to demonstrate degenerative changes in each. Furthermore, our study showed that degeneration of the postcentral cortex preceded that of the precentral cortex. In addition, we showed that the Betz cells were not selectively lost, but merely depleted like other neurons of the deep cortical layers. Therefore, the effects of MSA are apparently related to selective loss of the small-sized myelinated fibers in the corticospinal tract.

The severity of the disorder of voluntary movement in 89 chronic hemiparetic patients was correlated with the degenerative reduction of descending fibres evaluated by the magnitude of the shrinkage of the cerebral peduncles (CP) in computed tomographic (CT) images. The severity of hemiplegic posture and motor disturbance in the proximal and distal muscles was related to the total amount of residual descending fibres in the CP. In all patients whose CPs were less than 60% of the normal size, recovery from disturbance in reaching and grasping movements and impairment of relative independent finger movements was incomplete. Recovery of these movements occurred when more than 60% of the CP was spared and the degree of recovery from motor weakness was positively correlated with the quantity of intact fibres spared (residual CP ratio). The ability to perform fine and discrete movements with the fingers, known to be an essential function of the pyramidal system, was consistently impaired in patients with severe shrinkage involving the medial division of the CP. There was no particular correlation between the CP shrinkage and neurological signs such as spasticity, hyperreflexia, and pathological reflexes.

Atrial fibrillation (AF) is a frequent complication after coronary artery bypass surgery. Postoperative AF can lead to thromboembolic events, prolonged hospital stay, and increased costs. Recent reports have shown that an elevated plasma brain natriuretic peptide (BNP) level is associated with AF. The purpose of this prospective study was to test the hypothesis that preoperative BNP level is a predictor of postoperative AF following off-pump coronary artery bypass surgery (OPCAB). One hundred and fifty patients without a history of AF undergoing elective isolated OPCAB were enrolled. Plasma BNP level was measured preoperatively. Heart rate and rhythm were continuously monitored during the first 72 h after surgery. Twenty-six patients (17.3%) exhibited postoperative AF. This proportion is similar to those reported in earlier studies. Univariate analysis demonstrated that age (odds ratio [OR], 1.060; 95% confidence interval [CI], 1.008 to 1.114; P = 0.023), previous myocardial infarction (MI; OR, 2.628; 95% CI, 1.031 to 6.697; P = 0.043), and BNP level (OR, 7.336; 95% CI, 2.401 to 22.409 / log BNP level; P < 0.001) were accurate predictors of postoperative AF. Stepwise multivariate regression analysis indicated age (OR, 1.059; 95% CI, 1.002 to 1.120; P = 0.043) and BNP level (OR, 6.272; 95% CI, 1.980 to 19.861/log BNP level; P = 0.002) as the only independent predictors of postoperative AF. Preoperative BNP level is an independent predictor of postoperative AF following OPCAB. Our findings permit us to stratify the risk of AF and to plan prophylactic strategies in high-risk patients.

Background and Aim: Helicobacter pylori (H. pylori) infection enhances the production of reactive oxygen species and peroxynitrite, thereby resulting in oxidative tissue damage. In this study, we examined the role of peroxiredoxin I (Prx I), a stress-induced antioxidant enzyme, in protecting gastric mucosa from H. pylori-induced gastric mucosal injury. Methods: Wild type (Prx I+/+) and Prx I-deficient type (Prx I–/–) mice were maintained for 2 to 12 months with or without infection of H. pylori, Sydney strain-1. Gastric mucosal expression of Prx I was assessed by immunoblot analysis and immunohistochemistry. The degree of gastritis was evaluated by the updated Sydney system and by mucosal levels of inflammatory cytokines (MIP-2, IL-1β, and TNF-α). Oxidative DNA injury and apoptosis were analyzed by mucosal level of 8-hydroxy-2′-deoxyguanosine, and the number of apoptotic cells stained with a single-stranded DNA antibody, respectively. Results: H. pylori infection upregulated gastric mucosal Prx I expression in the Prx I+/+ but not the Prx I–/– mice. H. pylori infection also induced more severe gastritis and a more prominent increase in MIP level, more marked oxidative DNA injury, and apoptosis in the Prx I–/– than the Prx I+/+ mice. In the absence of H. pylori infection, no changes were demonstrated in gastric mucosa in either the Prx I+/+ or the Prx I−/− mice. Conclusion: These data suggest that H. pylori infection upregulates gastric mucosal Prx I expression, and further, that Prx I plays an important role in gastric mucosal protection against oxidative injury induced by H. pylori infection.

Five new macrolides, spirastrellolides C (3) to G (7), have been isolated from extracts of the marine sponge Spirastrella coccinea collected in Dominica. Their structures have been elucidated by a combination of spectroscopic analysis and chemical transformations.

Background Operative resection is the treatment of choice for colorectal liver metastasis. In the present study, we investigated the prognostic factors after hepatic resection, focusing on the concomitant resection of extrahepatic metastases. Method A retrospective cohort study was performed in 187 consecutive patients who had undergone initial hepatic resections for colorectal metastases using the Cox proportional hazards model. Results The overall survival rates at 3, 5, and 10 years were 49%, 30%, and 22%, respectively. Hilar lymph node involvement (HLN), localized peritoneal seeding (P), and distant organ metastasis (M) were resected in addition to the liver metastases in 9, 13, and 21 patients, respectively. The P and M factors were related univariately to an unfavorable patient prognosis, but the HLN factor was not. In a multivariate regression analysis, the hazard ratios of these three factors of interest were 1.58 (HLN; 95% confidence interval 0.64–2.52, median survival 48 months), 2.12 (P; 1.38–2.85, 18 months), and 3.07 (M; 2.45–3.68, 19 months), respectively. Conclusion Aggressive operative resection for colorectal liver metastases yielded an acceptable long-term outcome. The presence of distant organ metastasis seems to be a contraindication for operative intervention and/or resection; although the number of patients enrolled in the present study was small, resection of localized peritoneal seeding or hilar lymph node involvement, in addition to the resection of the liver metastases, may benefit patient survival.

The new macrolide spirastrellolide B (5) has been isolated from extracts of the marine sponge Spirastrella coccinea collected in Dominica. Chemical transformations of spirastrellolide B have converted it to a bromine-containing crystalline derivative 8 that has a truncated side chain. Single-crystal X-ray diffraction analysis of the derivative 8 has revealed the absolute configuration of the macrolide core of spirstrellolide B to be 3R,7S,9S,11S,13R,14S,17S,20S,21R, 22S,23S,24S,27R,29S,31R,34S,35R,37S,38S.

While retinal image motion is the primary input for smooth-pursuit, its efficiency depends on cognitive processes including prediction. Reports are conflicting on impaired prediction during pursuit in Parkinson's disease. By separating two major components of prediction (image motion direction memory and movement preparation) using a memory-based pursuit task, and by comparing tracking eye movements with those during a simple ramp-pursuit task that did not require visual memory, we examined smooth-pursuit in 25 patients with Parkinson's disease and compared the results with 14 age-matched controls. In the memory-based pursuit task, cue 1 indicated visual motion direction, whereas cue 2 instructed the subjects to prepare to pursue or not to pursue. Based on the cue-information memory, subjects were asked to pursue the correct spot from two oppositely moving spots or not to pursue. In 24/25 patients, the cue-information memory was normal, but movement preparation and execution were impaired. Specifically, unlike controls, most of the patients (18/24 = 75%) lacked initial pursuit during the memory task and started tracking the correct spot by saccades. Conversely, during simple ramp-pursuit, most patients (83%) exhibited initial pursuit. Popping-out of the correct spot motion during memory-based pursuit was ineffective for enhancing initial pursuit. The results were similar irrespective of levodopa/dopamine agonist medication. Our results indicate that the extra-retinal mechanisms of most patients are dysfunctional in initiating memory-based (not simple ramp) pursuit. A dysfunctional pursuit loop between frontal eye fields (FEF) and basal ganglia may contribute to the impairment of extra-retinal mechanisms, resulting in deficient pursuit commands from the FEF to brainstem.

We report a case of transcortical sensory aphasia occurred after extensive infarction of left cerebral hemisphere. A 68-year-old, right-handed man with atrial fibrillation suddenly developed cerebral embolism of left middle cerebral artery. He was treated conservatively, and the right hemiplegia, aphasia, apraxia in a slight degree and right hemispatial neglect in a slight degree consequently existed. MRI showed a large cortical and subcortical infarct lesion including the left Broca's area, central region, perisylvian area with Wernicke's area and temporal lobe. In contrast, neuropsychological evaluation using the Western Aphasia Battery (WAB) demonstrated transcortical sensory aphasia, e.g., fluency 8, auditory comprehension 1. repetition 10 and object naming 2.4. In addition to preserved repetition, both linguistic prosody and affective prosody were well preserved. Most cases with transcortical sensory aphasia are known to occur with the lesion including temporo-parieto-occipital junction of dominant hemisphere. Our patient and a few other reported cases of transcortical sensory aphasia had a lesion in perisylvian area including Wernicke's area. Therefore, it is possible that their minor hemisphere worked selectively for repetition. Furthermore, we suggest that this patient presented dissociative aphasia that all the process of repetition and the function of linguistic and emotional prosody were represented in the right hemisphere and the other functions including comprehension of word meanings were existed in the left hemisphere. We believe that our case of transcortical sensory aphasia with dissociative aphasia gives a suggestion about the mechanism and localization of repetition and prosody in the whole system of language.

To evaluate the effect of interferon beta-1b (IFNB-1b) on multiple sclerosis (MS) with severe optic nerve and spinal cord demyelination, we examined the relationship between IFNB-1b treatment outcome and the clinical and genetic characteristics of three types of demyelinating diseases of the central nervous system, i.e., neuromyelitis optica (NMO), MS and MS with severe optic-spinal demyelination. Japanese MS frequently carried HLA DPB1*0501, which is associated with NMO. MS with DPB1*0501 showed severe optic-spinal demyelination represented by longitudinally extensive spinal cord lesion, blindness and CSF pleocytosis. IFNB-1b treatment did not succeed in these patients because of the increase of optic nerve and spinal cord relapse and other severe side effects. IFNB-1b should not be administered to demyelinating patients with genetic and clinical characteristics mimicking NMO such as HLA DPB1*0501 allele, longitudinally extensive spinal cord lesion, blindness and CSF pleocytosis even if they have symptomatic cerebral lesions as typically seen in MS. The present study strongly suggests that these patients should be diagnosed as having NMO.

An 80-year-old diabetic man undergoing emergent off-pump coronary artery bypass grafting for acute myocardial infarction developed anaphylactic shock immediately following administering a small dose of protamine sulfate. Preoperative examination revealed atrial fibrillation, severe three-vessel coronary artery disease and impaired left ventricular function with ejection fraction of 40% and severe septal as well as apical hypokinesis and akinesis. After successful completion of coronary bypass grafting, a total of 40 mg of protamine sulfate was given through the central venous line. Three minutes after protamine administration, profound hypotension occurred. Pulmonary artery pressure was low and the left ventricle was almost empty by transesophageal echocardiography. Hypotension was refractory to rapid administration of 2 l of crystalloid and albumin, and repeated administrations of phenylephrine. Blood pressure finally returned towards baseline after infusion of norepinephrine 0.2 microg x kg(-1) x min(-1) and epinephrine 0.1 microg x kg(-1) x min(-1). Hemoconcentration and impaired oxygenation were also noted. The situation suggested anaphylactic shock due to protamine. He had diabetes mellitus for 20 years and been treated by protamine containing insulin. Postoperative interview revealed that the patient had experienced urticaria over the abdominal area with neutral protamine hagedorn (NPH) insulin administration. This history suggested that the patient had been sensitized by protamine before surgery. Although it is rare to experience anaphylactic shock due to protamine, it is important to elicit the detailed allergic history to insulin in diabetic patients. Because anaphylactic shock still carries high mortality even in a patient without cardiac disease, we were lucky to save this elderly patient with acute myocardial infarction and compromised left ventricular function.

[structure: see text] Laboratory cultures of an undescribed streptomycete obtained from the surface of a British Columbia lichen produce uncialamycin (1), a new enediyne antibiotic. The structure of uncialamycin (1) has been elucidated by analysis of spectroscopic data. Uncialamycin (1) exhibits potent in vitro antibacterial activity against gram-positive and gram-negative human pathogens, including Burkholderia cepacia, a major cause of morbidity and mortality in patients with cystic fibrosis.

To characterize T cell immunity in Japanese neuromyelitis optica (NMO), we examined the T cell receptor (TCR) repertoire in NMO patients with complementarity-determining region 3 (CDR3) spectratyping and compared the results with those from multiple sclerosis (MS) patients and healthy subjects. Both NMO and MS patients had a larger number of clonally expanded Vbeta genes than healthy subjects. Moreover, NMO patients had a significantly larger number of expanded Vbetas than MS patients. The detailed analysis revealed that Vbeta1 and Vbeta13 were significantly activated in NMO than MS. These results reflected unique pathophysiology of Japanese NMO, which is distinguishable from that of MS. Furthermore, longitudinal examinations of the TCR repertoire demonstrated that the number of clonally expanded Vbetas in NMO correlates with the Kurtzke Expanded disability status scale (EDSS). Although the activation pattern of the TCR repertoire in relapsing-remitting MS (RRMS) was similar to that in NMO, secondary progressive MS (SPMS) patients with longer disease durations and higher EDSS scores consistently had a smaller number of clonally expanded Vbetas than RRMS patients. Detailed TCR investigations will provide useful information to evaluate the clinical and immunological status of NMO and MS and to develop effective immunotherapies.

Peroxiredoxin I (Prx I) is a key cytoplasmic peroxidase that reduces intracellular hydroperoxides in concert with thioredoxin. To study the role of tissue Prx I in protection from oxidative stress, we generated Prx I−/− mice by gene trapping. We then evaluated the acute-phase tissue damage caused by ferric-nitrilotriacetate (Fe-NTA). Increases in serum aspartate aminotransferase and alanine aminotransferase levels were significantly greater in Prx I−/− than wild-type mice, 4 and 12 h after the injection of Fe-NTA. Using real-time EPR imaging, we examined the reduction of the stable paramagnetic nitroxyl radical 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl in vivo, and found that the half-life of this spin probe in the liver and kidney was significantly prolonged in the Prx I−/− mice. These results demonstrate that Prx I−/− mice have less reducing activity and are more susceptible to the damage mediated by reactive oxygen species in vivo than wild-type mice.

The patient was a 61-year-old man who was referred to our hospital with a complaint of epigastric pain. Upper gastrointestinal endoscopy and X-ray examination of the stomach revealed type 3 cancer in the gastric antrum, extending to the middle body. It was about 9 cm in diameter, and the biopsy specimen revealed moderately differentiated tubular adenocarcinoma. Abdominal CT scan showed marked enlargement of No. 3 lymph nodes along the lesser curvature of the stomach. Examination of the blood showed a hemoglobin of 10.2 g/dl, CEA 5.8 ng/ml, CA19-9 330.5 U/ml. For this gastric cancer, clinical Stage IIIA (cT3N1HOPOMO), neoadjuvant chemotherapy with TS-1/CDDP was planned. TS-1 (120 mg/day) was orally administered for 3 weeks followed by a drug-free-2-week period as the first course, and 93 mg (60 mg/m2) of CDDP administered by intravenous drip on day 8. There were grade 2 nausea and grade 3 appetite loss by intravenous administration of CDDP in the second course. An upper GI series revealed 33% reduction of gastric cancer, and laboratory studies CEA and CA 19-9 showed normal values. One month after the second course of chemotherapy, total gastrectomy, splenectomy and lymph node dissection D2 were performed. The pathological specimens showed no cancer cells in the surgically obtained stomach and lymph nodes, so the histological effect was Grade 3. The postoperative course was satisfactory, and he now attends outpatient department without any findings of recurrence 12 months after the operation. TS-1/CDDP chemotherapy produced a high response in this case, and it may be useful as neoadjuvant chemotherapy for advanced gastric cancer.

Axinelloside A was isolated from the lipophilic extract of the Japanese marine sponge Axinella infundibula as a strong human telomerase inhibitor (IC(50) 2.0 microg/mL). It has the molecular weight of 4780.4 as the monoisotopic mass of the 19 sodium salt. The chemical structure was elucidated mainly by spectroscopic methods (2D NMR and MS). Axinelloside A consists of twelve sugars, e.g., a scyllo-inositol, a D-arabinose, 5 D-galactoses, and 5 L-fucoses, together with an (R)-3-hydroxy-octadecanoic acid, 3 (E)-2-hexadecenoic acids, and 19 sulfates.

Lemierre syndrome is characterized by anaerobic bacterial infection in the head and neck, causing thrombophlebitis of the jugular vein and septic metastasis to various distant organs, most often the lungs. Here we describe previously unreported clinical features of cerebral infarctions and brain abscess due to metastatic septic embolism of this uncommon but lethal syndrome, and the successful course of treatment with ampicillin, cefotaxime and metronidazole.

The Nrf2-Keap1 system coordinately regulates cytoprotective gene expression via the antioxidant responsive element (ARE). The expression of several ARE-regulated genes was found to be up-regulated in endothelial cells by laminar shear stress, suggesting that Nrf2 contributes to the anti-atherosclerosis response via the ARE. To gain further insight into the roles that Nrf2 plays in the development of atherosclerosis, we examined how Nrf2 regulates gene expression in response to anti-atherogenic laminar flow (L-flow) or pro-atherogenic oscillatory flow (O-flow). Exposure of human aortic endothelial cells (HAECs) to L-flow, but not to O-flow, induced the expression of cytoprotective genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1) by 5-fold and heme oxygenase-1 by 8-fold. The critical contribution of Nrf2 to the expression induced by L-flow was ascertained in siRNA-mediated knock-down experiments. Two cyclooxygenase-2 (COX-2) specific inhibitors attenuated Nrf2 nuclear accumulation in the acute phase of L-flow exposure. A downstream product of COX-2, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), activated the Nrf2 regulatory pathway in HAECs through binding to the cysteines of Keap1. These results demonstrate that 15d-PGJ2 is essential for L-flow to activate Nrf2 and induce anti-atherosclerotic gene expression. Whereas both L-flow and O-flow induced the nuclear accumulation of Nrf2 to comparable levels, chromatin immunoprecipitation analysis revealed that Nrf2 binding to the NQO1 ARE was significantly diminished in the case of O-flow compared with that of L-flow. These results suggest that O-flow inhibits Nrf2 activity at the DNA binding step, thereby suppressing athero-protective gene expression and hence predisposing the blood vessels to the formation of atherosclerosis.

Strongylophorine-26, a new meroditerpenoid, was recently identified as an inhibitor of cancer cell invasion. This study was undertaken to characterize its mechanism of action. We find that strongylophorine-26 inhibits the motility of MDA-MB-231 breast carcinoma cells on a plastic surface. Upon addition of strongylophorine-26, rapid cell contraction and depolarization occurred, followed by spreading and flattening of the entire cell. Treated cells exhibited increased membrane ruffling throughout and extended lamellipodia in all directions. Strongylophorine-26 induced a decrease in actin stress fibers, a dramatic increase in the size and number of focal adhesions, and the appearance of a dense meshwork of actin filaments around the cell periphery. Strongylophorine-26 caused a transient activation of the small GTPase Rho and treatment with the Rho inhibitor C3 exoenzyme abrogated the anti-invasive activity of strongylophorine-26. These effects are distinct from those of many motility and angiogenesis inhibitors that seem to act by a common mechanism involving the induction of actin stress fibers. This difference in mechanism of action sets strongylophorine-26 apart as an experimental anticancer agent and indicates that pharmacologic inhibition of cell migration may be achieved by mechanisms not involving the stabilization of actin stress fibers.

In order to clarify differences of treadmill from overground locomotion, experiments were carried out on 10 volunteers (five males and five females). Sole-floor reaction force was recorded from five anatomically discrete points with strain gauge transducers of 14 mm diameter attached firmly to the sole of bare-foot. At first the subject was asked to walk on the laboratory floor at his/her preferred velocity. After the average velocity was obtained, the subject was asked to walk on the treadmill at the same velocity of average overground walking. Stance period at treadmill walking shortened to 93.3% (P < 0.01) of the value at overground walking. Coefficient of variation of stance period was significantly smaller at the treadmill walking than at overground walking. Strain gauge-floor contact times were shorter in the treadmill walking; heel 81.2%, first metatarsal 93.5%, third metatarsal 93.6%, fifth metatarsal 90.6% and at great toe 93.2% of overground locomotion. Cadence during treadmill locomotion was significantly larger than overground walking (106.6%, P < 0.05). These results show that when subjects walk on the treadmill and on laboratory floor at the identical speed, stance period shortened by 6.7% while cadence increased by 6.6% on the treadmill.

Central venous catheterization is commonly performed by puncturing the internal jugular vein. However, placement of central venous catheters is not without risk. We compared the Argyle and the Insyte in terms of usefulness and incidence of complications during central venous catheterization.Twenty adult patients for cardiac operation were randomly allocated into two groups; 10 patients in the Argyle group (Group A) and 10 patients in the Insyte group (Group B).In both groups, no kinking or stucking of the guide wire occurred during insertion. No accidental puncture of the carotid artery occurred in Group B, while it occurred in one case in Group A. The time required for insertion of the guide wire was not significantly different between the two groups, though it tended to be shorter in Group B than in Group A (19.3 +/- 14.6 sec vs 34.6 +/- 34.0 sec). On ultrasonography, the Argyle was observed to compress the internal jugular vein and to be prone to penetrate both anterior and posterior walls.Using the Argyle makes it a little more difficult to place the needle in the appropriate venous lumen. We conclude that central venous catheterization with the Insyte was quicker and safer than with the Argyle.

We report the first case of inclusion body myositis (IBM) which occurred after interferon-alpha treatment for chronic hepatitis C. A 63-year-old man contracted hepatitis C virus (HCV) and human T cell leukemia virus type 1 (HTLV-1) from a blood transfusion at age of 18. At age 57, he was treated with interferon-alpha (IFN alpha) for chronic hepatitis C. A month later, he developed muscle weakness in the proximal part of his lower extremities. IBM was diagnosed after a muscle biopsy at age 62. Steroid therapy improved his muscle power. One year later, worsening of his hepatic condition required re-administration of IFN alpha after gradual decrease and discontinuation of prednisolone. However, several days later, he rapidly became weaker and required a cane to walk. Elevated serum creatine kinase (2,199IU/L) and abnormal intensity in his MRI of thigh were demonstrated. The second muscle biopsy, performed after obtaining the informed consent from our patient, confirmed relapse of IBM. His symptoms improved again after discontinuation of IFN alpha and re-induction of prednisolone. Although a few cases each of IBM associated with HCV or HTLV-1 have been reported, the pathogenesis of virus-associated inflammatory myositis has not been clearly understood. Moreover, there has been no description on IBM associated with IFN alpha treatment, though several cases of polymyositis have been reported. Our case suggests that infection of HCV and HTLV-1 may be immunologically involved in the development of IBM and that IFN alpha can be directly related to onset and relapse of IBM.

Strongylophorine-26 (1), a new meroditerpenoid that shows activity in an anti-invasion assay, has been isolated from the marine sponge Petrosia (Strongylophora) corticata collected in Papua New Guinea. The structure of 1 was elucidated by analysis of spectroscopic data.

Role of a central fixation target on the latencies of visually guided manual movement was analyzed on young healthy subjects, age-matched control subjects and patients with Parkinson's disease (Hoehn and Yahr stages II, III, and IV). Two paradigms were used: overlap paradigm where a central fixation target was lighted throughout the test, and gap paradigm where a central fixation target was turned off 200 ms before a peripheral target was lighted. The subject was first asked to fixate the central target then instructed to locate a peripheral target with a laser beam spot, operated with wrist flexion or extension as quickly as possible. Latencies of gap paradigm are always shorter than those of overlap task in all the groups. Latencies of both overlap and gap tasks prolonged from young to elder, from elder to PD II, from PD II to PD III and from PD III to PD IV. Also latencies were extremely prolonged in the overlap tasks and correlated with disease severity. Latencies in the gap tasks were less prolonged as compared with those in the overlap tasks. The visual fixation target prolonged the visuo-motor latency in association with severity of Parkinson's disease.

Crude extracts of the North Sea marine sponge Pachymatisma johnstonia showed promising activity in a new assay for inhibitors of bacterial type III secretion. Bioassay-guided fractionation resulted in the isolation of the pachymosides, a new family of sponge glycolipids. A major part of the structural diversity in this family of glycolipids involves increasing degrees of acetylation and differing positions of acetylation on a common pachymoside glycolipid template. All of the metabolites with these variations in acetylation pattern were converted into the same peracetylpachymoside methyl ester (2) for purification and spectroscopic analysis. Pachymoside A (1) is the component of the mixture that has natural acetylation at the eight galactose hydroxyls and at the C-6 hydroxyls of glucose-B and glucose-D. Chemical degradation and transformation in conjunction with extensive analysis of 800 MHz NMR data was used to elucidate the structure of pachymoside A (1). Key words: Pachymatisma johnstonia, marine sponge, pachymoside, glycolipid.

Sole-floor reaction forces were recorded from five anatomically discrete points to analyze characteristics of human locomotion. Strain gauge of 14 mm diameter were firmly attached to the sole of bare-foot for recording force changes from the following five points: (1) medial process of calcaneus, (2) head of 1st metatarsal, (3) head of 3rd metatarsal, (4) head of 5th metatarsal and (5) great toe. Fifteen healthy adults were asked to walk at 2, 4, 6 and 8 km/h and to run at 8 km/h on the treadmill. Sole-floor reaction forces from 1st to 5th metatarsals show reciprocal changes during stance phase, while force from 1st metatarsal is strong 5th metatarsal shows weak reaction and vice versa. This phenomenon may be an expression of locomotor program to maintain vertical stability of the body during stance phase. There was a linear relation between walking speeds and sum of force from the five points, although sum of forces from three metatarsals did not change significantly during the walking speeds, indicating mainly calcaneus and great toe contribute to increasing walking speed. During running the sum of force from the three metatarsals increased sharply, joining the other two points to increase thrust.