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Background/Objectives The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. Design/Setting Eighteen-month, multi-centered, randomized controlled trial. Participants We plan to recruit 500 older adults aged 65–85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. Intervention The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. Measurements The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. Conclusions This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention. Electronic Supplementary Material Supplementary material is available for this article at 10.14283/jpad.2021.29 and is accessible for authorized users.

A retrospective, consecutive case series. The relationship between dysphagia and acute cervical spinal cord injury (CSCI) has been recently reported; however, the cause and mechanism of dysphagia are still not well understood. No definitive factors have yet been established according to multivariate analysis. The objective is to elucidate the incidence and risk factors of dysphagia in patients with acute CSCI. Spinal Injuries Center, Fukuoka, Japan. A total of 298 patients with acute CSCI, who were evaluated for neurological impairment within 3 days after injury, were reviewed. CSCI patients with tube dependence due to obvious aspiration after injury were defined as having dysphagia. The factors postulated to increase the risk for dysphagia, including the patient’s age, sex, American Spinal Injury Association (ASIA) impairment scale at 3 days after injury, level of injury, tracheostomy and operative treatment, were analyzed using a multiple logistic regression model. Of 298 patients, 21 were suffering from severe dysphagia after acute CSCI (7.0%). Of these 21 patients, 12 (57%) had CSCI at the C3–C4 level. Multivariable logistic regression analysis revealed that old age (>72 years), severe ASIA impairment scale (A or B) and presence of tracheostomy were significant risk factors of dysphagia. Level of injury ⩾C3–C4 was not a significant risk factor after adjustment for several potential confounders. The incidence of severe dysphagia associated with aspiration was 7%. Old age, severe paralysis and presence of tracheostomy may be the risk factors for dysphagia. The risk for dysphagia should be evaluated to prevent aspiration pneumonia.

Clinicians' evaluations of older adults sometimes reveal inconsistencies between objective and subjective dental status. This study investigated which factors contribute both to good objective masticatory function (OMF) and the poor subjective masticatory function (SMF) that often becomes a clinical issue. Study participants included 635 elderly community-dwelling Japanese adults who underwent a comprehensive geriatric health examination in 2012. SMF was assessed with a question from the Kihon Checklist on eating difficulties (poor or good). OMF was assessed by a colour-changing gum (poor or good). Also investigated were age, sex, depressive symptoms, instrumental activities of daily living (I-ADLs), number of people who joined the participant at dinner, grip strength, usual walking speed, number of remaining teeth, number of functional teeth and their occlusal force. The group with good OMF and good SMF, defined as group 1, and the group with good OMF but poor SMF, group 2, were compared. Logistic regression analyses confirmed that the number of remaining and functional teeth participants had was statistically unrelated to differences between OMF and SMF. Instead, differences were related to stronger depressive symptoms (OR = 1.67, CI = 1.14-2.44), less ability to conduct I-ADL activities (OR = 0.73, CI = 0.59-0.91), slower usual walking speeds (OR = 0.18, CI = 0.06-0.58) and less occlusal force (OR = 0.99, CI = 0.99-1.00). Depressive symptoms, I-ADLs, and physical function are shown to be significantly related to divergence between objective and subjective masticatory function in elderly Japanese. This suggests that dissociations between objective and subjective dental evaluations of elderly adults indicate need for assessment of their mental and physical function.

Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter 'D-shuttle' for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the terrestrial background radiation level of other regions/countries. © 2016 IOP Publishing Ltd.

Lysophosphatidic acid (LPA), a component of mildly-oxidized LDL and the lipid rich core of atherosclerotic plaques, elicits platelet activation. LPA is the ligand of G protein-coupled receptors (GPCR) of the EDG family (LPA(1-3)) and the newly identified LPA(4-7) subcluster. LPA(4), LPA(5) and LPA(7) increase cellular cAMP levels that would induce platelet inhibition rather than activation. In the present study we quantified the mRNA levels of the LPA(1-7) GPCR in human platelets and found a rank order LPA(4) = LPA(5) > LPA(7) > LPA(6) = LPA(2) >> LPA(1) > LPA(3). We examined platelet shape change using a panel of LPA receptor subtype-selective agonists and antagonists and compared them with their pharmacological profiles obtained in heterologous LPA(1-5) receptor expression systems. Responses to different natural acyl and alkyl species of LPA, and octyl phosphatidic acid analogs, alpha-substituted phosphonate analogs, N-palmitoyl-tyrosine phosphoric acid, N-palmitoyl-serine phosphoric acid were tested. All of these compounds elicited platelet activation and also inhibited LPA-induced platelet shape change after pre-incubation, suggesting that receptor desensitization is likely responsible for the inhibition of this response. Fatty acid free albumin (10 microM) lacking platelet activity completely inhibited platelet shape change induced by LPA with an IC(50) of 1.1 microM but had no effect on the activation of LPA(1,2,3,&5) expressed in endogenously non-LPA-responsive RH7777 cells. However, albumin reduced LPA(4) activation and shifted the dose-response curve to the right. LPA(5) transiently expressed in RH7777 cells showed preference to alkyl-LPA over acyl-LPA that is similar to that in platelets. LPA did not increase cAMP levels in platelets. In conclusion, our results with the pharmacological compounds and albumin demonstrate that LPA does not induce platelet shape change simply through activation of LPA(1-5), and the receptor(s) mediating LPA-induced platelet activation remains elusive.

A Bombyx EST cDNA database was searched using the Drosophila takeout gene and nine cDNAs were obtained. The homology search suggested that these genes are widespread in insects and organize a large gene family, and that they have hydrophobic ligands. A phylogenetic tree indicated that the genes are first divided into two large groups, juvenile hormone binding protein and other protein genes, and the latter group diversified within a short time at an early stage. The expression study of five Bombyx genes indicated that they are expressed in various tissues and are regulated by development and feeding conditions. The Bombyx genes might have roles related to the regulation of metabolism, growth or development related to nutritional conditions.

Hymenopteran insects (sawflies, ants, bees, and wasps) have an unusual genetic system called haplodiploidy, where parthenogenetically produced haploid eggs become males, and fertilized, diploid eggs become females. Several hypotheses have been proposed to explain the mechanism of such sex determination, including control at a single polymorphic locus. From experiments of mother-son mating and using a genetic marker, we show that a single multiallele locus controls sex determination in the turnip sawfly (Athalia rosae). We estimated the number of alleles at this single locus in a field population by analyzing the rate of diploid males in the field and the rate of diploid males by random crossing in the laboratory. Only one diploid male was discovered in 1306 diploid larvae collected in the field. However, the number of alleles calculated by random crossing in the laboratory was 45-50. We suggest that the effective population size may be much larger than that from the areas where we collected larvae, and that there are mechanisms for avoiding inbreeding, including protogyny, dispersion, and sperm displacement by second-mated males.

The purpose of this study was to investigate the relationship between cranio-cervical inclination and pharyngeal airway space (PAS) by measuring these parameters at different head postures in the same subjects and to obtain a regression equation to correct the values measured. Fifty lateral cephalometric radiographs taken at five different head postures per individual were obtained from ten adults (seven males and three females) aged from 25 to 30 years with nose breathers and Class I occlusion. The changes in cranio-cervical inclination produced by head extension were correlated with changes in the variables describing the PAS. The OPT/NSL (cranio-cervical inclination in the second vertebrae) and C3-Me (distance between the third vertebrae and the Menton) correlated strongly with PAS-TP (the most proximal distance measured between the posterior pharyngeal wall and the tongue base) in the pharyngeal airway space (r = 0.807 and 0.854 respectively). The regression equations were Y = - 27.177+0.39X (Y = PAS-TP, X = OPT/NSL), and Y = -21.105+0.402X (Y = PAS-TP, X = C3-Me), respectively. From these equations we could conclude that an increase of 10 degrees in OPT/NSL or 10 mm in C3-Me increased the pharyngeal airway space (PAS-TP) by about 4 mm.

In patients with type 2 diabetes, fibrinolysis is considered impaired by increased plasma concentrations of plasminogen activator inhibitor (PAI)-1. However, several investigators found both coagulation and fibrinolysis to be activated in these patients. We further characterized the balance between coagulation and fibrinolysis in lean and obese patients with type 2 diabetes. We studied 112 type 2 diabetic patients (66 lean, 46 obese) and 69 age-matched healthy subjects (46 lean, 23 obese). We measured plasma concentrations of fibrinogen and prothrombin F1+2 (F1+2) as indicating coagulation activity and plasmin-antiplasmin complex (PAP) and D dimer as indicating fibrinolytic activity. Plasma PAI-1 concentrations also were determined. Plasma concentrations of F1+2, PAP, D dimer, and PAI-1 were higher in diabetic patients than in control subjects. Plasma fibrinogen and F1+2 were similar between lean and obese diabetic patients, but plasma PAP and D dimer were significantly lower in obese than lean diabetic patients (P

Aims The present study examines the relationship between markers of endothelial dysfunction and diabetic neuropathy or consequent neuropathic foot ulceration in patients with Type 2 diabetes mellitus. Methods We studied 65 Type 2 diabetic patients including 25 diabetic patients without neuropathy, 27 with neuropathy but no history of foot ulceration, and 13 with neuropathic ulceration. Plasma concentrations of von Willebrand factor (vWF) and soluble thrombomodulin (TM), measures of endothelial dysfunction, were determined by enzyme immunoassays. We performed various tests quantifying aspects of diabetic neuropathy including vibration perception threshold (VPT; for sensory neuropathy), coefficient of variation of R–R intervals (CVR–R; for cardiac autonomic neuropathy), and cold-induced vasodilation in the great toe for peripheral sympathetic neuropathy. Results CVR–R and cold-induced vasodilation were significantly diminished in patients with neuropathic foot ulceration compared with patients with neuropathy but no history of foot ulceration. Plasma vWF concentrations were positively correlated with VPT and cold-induced vasodilation test, and were inversely correlated with CVR–R. Multivariate analysis disclosed that VPT and percentage vasodilation were independent factors for plasma vWF. Plasma vWF was significantly elevated in patients with foot ulceration compared with patients without neuropathy or those with neuropathy but not foot ulceration. However, plasma TM concentrations did not differ between the three groups. Conclusions Diabetic patients with neuropathic foot ulceration had severe impairment of cardiac autonomic and peripheral sympathetic nerves. Elevation of vWF in plasma was associated with neuropathic foot ulceration, linking endothelial dysfunction to foot ulceration.

Endothelial dysfunction plays a pivotal role in the initial stage of atherosclerosis. Insulin resistance is associated with accelerated atherosclerosis, especially coronary heart disease. To elucidate the relationship between endothelial dysfunction and insulin resistance or insulin resistance syndrome in patients with type 2 diabetes, we investigated the correlation between plasma soluble thrombomodulin (TM) and von Willebrand factor (vWF), measures of endothelial dysfunction, and the degree of insulin resistance evaluated by homeostasis assessment models of insulin resistance (HOMA-IR), or variables of insulin resistance syndrome. We studied 53 patients with type 2 diabetes, 23 treated with diet alone and 30 treated with sulfonylureas, who had normal renal function. The plasma soluble TM concentrations were highly correlated with HOMA-IR (r = 0.64, p < 0.0001), the plasma insulin (r = 0.72, p < 0.0001), the systolic blood pressure (r = 0.45, p = 0.0005), and the plasma fibrinogen (r = 0.43, p = 0.0018), while they were inversely correlated with the serum HDL cholesterol concentrations (r=- 0.27, p = 0.0344). The plasma vWF concentrations were positively correlated with HOMA-IR (r = 0.35, p= 0.0151) and the plasma fibrinogen (r = 0.32, p = 0.0203), but not with the plasma insulin, the systolic blood pressure or the HDL cholesterol concentrations. Furthermore, plasma TM, but not vWF, was positively correlated with total number of variables of insulin resistance syndrome (r = 0.45, p = 0.0005). These results indicate that endothelial dysfunction may be associated with the pathogenesis of insulin resistance syndrome as well as insulin resistance, and that the plasma TM might reflect endothelial damage better than the plasma vWF in the state of insulin resistance in patients with type 2 diabetes.

The purpose of this study was to compare the ability of Lipiodol-computed tomography (CT), power Doppler (PD) sonography, and dynamic magnetic resonance imaging (MRI) in evaluating the therapeutic effect of transcatheter arterial chemoembolization (TACE) on hepatocellular carcinoma (HCC).TACE was performed by injecting an emulsion consisting of Lipiodol and a chemotherapeutic drug, followed by gelatin sponge particles, into 54 patients with 84 HCC lesions. Five to 7 days later, Lipiodol-CT, PD sonography, and dynamic MRI were performed. Findings from the three modalities were correlated with relapse within 1 year after TACE.All lesions with blood flow on PD sonography or intratumoral enhancement on dynamic MRI relapsed regardless of the findings with Lipiodol-CT. None of the negatively enhanced lesions on dynamic MRI relapsed regardless of the Lipiodol-CT findings. However, the readers could not evaluate the contrast uptake in 14 lesions that were already hyperintense on the precontrast images. These cases were considered unsuitable for qualitative assessment and reduced the applicability of MRI to 83% of the examined lesions (70 of 84). Although PD sonography perfectly predicted relapse in superficial (0-5 cm from abdominal surface) lesions of the right hepatic lobe, blood flow in deep (5 cm) or left lobe lesions was undetectable regardless of the occurrence of relapse. As a result, Lipiodol-CT displayed 76.0% sensitivity, 67.6% specificity, and 72.6% accuracy. The sensitivity, specificity, and accuracy of PD sonography were 34.0%, 100%, and 60.7%, respectively. In the 70 lesions in which evaluation was possible, dynamic MRI achieved 100% sensitivity, 100% specificity, and 100% accuracy.Of the three modalities, dynamic MRI was the best for evaluating the efficacy of TACE in the treatment of HCC. We also found that superficial lesions of the right lobe are good candidates for PD sonography. However, high signals on precontrast MR images, motion artifacts, and ultrasonic attenuation remain key limitations.

To elucidate the relationship between the recovery of skin temperature in an extremity after exposure to cold water and various factors associated with diabetes, we measured skin temperature in type2 diabetic patients (N=61) and control subjects (N=16). A thermo-tracer was used in thermographic measurements. The right third toe of each subject was immersed in cold water at 0 degrees C for 10 sec. Rt represents the recovery rate of skin temperature at t min after exposure. Rt was significantly reduced in the diabetic patients every 5 min in the 20 min period following exposure compared with control subjects. The diabetic patients group exhibited a significantly positive correlation between R20 and the ankle-brachial index. R20 in the diabetic patients showed a significantly positive correlation with the reduction in systolic blood pressure at the arm observed in Schellong's test. In addition, R20 showed a significantly negative correlation with plasma levels of fibrinogen and plasminogen activator inhibitor-1. However, the severity of diabetic retinopathy and nephropathy was not significantly related to R20 in the diabetic patients. The present data indicate that the recovery of skin temperature after immersion in cold water was markedly reduced in patients with type 2 diabetes mellitus as compared with healthy control subjects. Peripheral arteriosclerosis, impaired sympathetic nerve function and the activation of the blood coagulation system may all contribute to this reduced recovery of skin temperature.

Serum concentration of soluble thrombomodulin (TM) is thought to be a marker for endothelial damage. Although several studies have reported that serum TM concentrations are increased in patients with diabetes mellitus, there is little information on the physiological function of soluble TM in human plasma. To evaluate the relationship of soluble TM in plasma between coagulation and/or fibrinolysis system in patients with diabetes, we measured plasma soluble TM, protein C activity (a natural anticoagulant induced by thrombin–TM complex), prothrombin F1+2 (a direct marker of thrombin generation), and plasmin–α2-antiplasmin complex (PAP) and D dimer (measures of fibrinolytic activity) in 55 patients with type 2 diabetes mellitus. The plasma concentrations of soluble TM (P

To determine whether a difference exists in the relative ability of power Doppler sonography and conventional color Doppler sonography to detect the intratumoral vasculature of hepatocellular carcinoma based on lesion size and location.Sixty patients with 88 hepatocellular carcinoma lesions that showed tumor staining on angiography and were enhanced on dynamic computed tomography were evaluated. Power Doppler sonography and color Doppler sonography were used to detect the intratumoral vasculature, and their sensitivity to blood flow was evaluated.Power Doppler sonography showed a superior detection rate for lesions smaller than 2 cm and located 4-8 cm from the abdominal surface in the right hepatic lobe as compared with color Doppler sonography (p0.01). Neither power Doppler sonography nor color Doppler sonography depicted the intratumoral vasculature of lesions located more than 8 cm from the abdominal surface (n = 14). Both color Doppler imagings exhibited a low detection rate for lesions in the left hepatic lobe (n = 31, p0.01).Power Doppler sonography should be applied in the evaluation of small or intermediate depth lesions because it is more sensitive to these lesions than color Doppler sonography, but it is not useful for left lobe and deep lesions.

We investigated whether rats with obstructive jaundice produced with bile duct ligation for 2 weeks are more susceptible to the additional stress of lipopolysaccharide (LPS) administration than sham-operated rats and also examined the effects of N-acetylcysteine (NAC) on LPS stimulation in rats with bile duct ligation. The effects of LPS on the mitochondrial glutathione pool and on oxidative stress of polymorphonuclear leukocytes were investigated in cholestatic rats. Serum concentrations of α-glutathione S-transferase showed that lipopolysaccharide stimulation caused more severe hepatocellular injury in cholestatic rats than in sham-operated rats. In addition, concentrations of mitochondrial reduced and oxidized glutathione and hepatic adenosine triphosphate showed that LPS stimulation decreased mitochondrial function more in cholestatic rats than in sham-operated rats. Intraperitoneal administration of NAC for 2 weeks significantly improved mitochondrial function and decreased hepatocellular injury. However, the oxidative stress of polymorphonuclear leukocytes that had infiltrated hepatic tissue was increased by NAC. The present results indicate that the cholestatic liver is susceptible to the additional stress of LPS, that NAC suppresses the adverse effects of LPS in cholestatic livers, and that the oxidative stress of polymorphonuclear leukocytes is not significantly involved in mitochondrial dysfunction or hepatocellular injury in this model.

Power spectral analysis (PSA) of the variation in heart rate is useful in determining the relative activity of the sympathetic and parasympathetic nerves. In this study, PSA was used to investigate the relationship between abnormalities in autonomic nerve function and the presence of thyroid disorders in patients with autoimmune thyroid diseases. The low frequency (LF) or high frequency (HF) components of R-R variations were determined by PSA. The coefficient of variation of the R-R time intervals (CV(R-R)) was positively correlated with HF in healthy subjects. In untreated hyperthyroid patients with Graves' disease, the CV(R-R) and HF values were significantly lower than in healthy controls. Moreover, the LF/HF ratio in patients with untreated Graves' disease was significantly higher, and the LF/HF ratio in hypothyroid patients with Hashimoto's thyroiditis was significantly lower than in healthy controls. A negative correlation was observed between serum levels of free thyroid hormones (FT4 and FT3) and HF in Graves' disease patients. In some hyperthyroid patients, antithyroid drug therapy or beta-blocker administration gradually restored reduced HF values. Present results suggest that relative vagal nerve activity is reduced in hyperthyroid patients and that this reduction is reversible according to the decrease in serum levels of thyroid hormones.

OBJECTIVE To evaluate the relationship between diabetic autonomic neuropathy and diabetic neuropathic foot ulceration, we used power spectral analysis (PSA) of heart rate variation, which provides the accurate simultaneous quantification of parasympathetic and sympathetic activities, to assess autonomic function in diabetic patients. RESEARCH DESIGN AND METHODS We studied 55 NIDDM patients including 10 diabetic patients without neuropathy, 23 diabetic patients with neuropathy and no history of foot ulceration, and 22 diabetic patients with neuropathic foot ulceration. We performed PSA of 100 R-R intervals at rest and analyzed the results by fast Fourier transformation. RESULTS The low frequency (LF) power, which reflects sympathetic activity, and the high frequency (HF) power, which reflects parasympathetic (vagal) activity, were inversely correlated with the duration of diabetes and the fasting plasma glucose (FPG) levels. By multiple regression analysis, the FPG remained with significant influence on both LF and HF powers. The LF and HF powers were positively correlated with motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) in the upper and lower limbs and the coefficient of variation of R-R intervals. The LF and HF powers were significantly reduced in patients with neuropathy and patients with foot ulceration compared with patients without neuropathy. Although the median MCV and SCV were similar between diabetic patients with neuropathy and patients with foot ulceration, both the LF and HF powers were significantly decreased in patients with foot ulceration compared with patients with neuropathy. There was no difference in the value of the LF:HF ratio, an index of sympathovagal balance, among three subgroups. We observed a positive correlation between LF and HF power in all subjects; however, the LF and HF powers were not correlated in the subgroups of patients with foot ulceration. CONCLUSIONS These results showed that diabetic patients with neuropathic foot ulceration have a greater impairment in spectral indexes of autonomic activity obtained by PSA than patients with neuropathy and no history of foot ulceration, whereas no difference was present in nerve conduction velocities.

PURPOSE Irinotecan (CPT-11) is effective against small-cell lung cancer (SCLC) as monotherapy. Cisplatin is also a key drug against SCLC. We conducted a phase II study of CPT-11 combined with cisplatin to evaluate the efficacy and toxicity of this regimen in patients with previously untreated SCLC. PATIENTS AND METHODS Seventy-five patients with previously untreated SCLC were enrolled onto the study. CPT-11 60 mg/m2 was administered intravenously on days 1, 8, and 15 in combination with cisplatin 60 mg/m2 on day 1 every 28 days. Four courses of chemotherapy followed by thoracic irradiation were given to patients with limited disease (LD) and six courses to patients with extensive disease (ED). RESULTS The overall response rate was 84%, with a complete response (CR) rate of 29%. Forty patients with LD achieved an overall response rate of 83% and a CR rate of 30% and 35 patients with ED achieved an overall response rate of 86% and a CR rate of 29%. The median response duration was 8.0 months for LD patients and 6.6 months for ED patients. The median survival was 14.3 months for LD patients and 13.0 months for ED patients. The major grade 3 or 4 toxicities were neutropenia (77%), leukopenia (45%), diarrhea (19%), and anemia (39%). Two patients died with concomitant neutropenia and diarrhea. CONCLUSION This is a new active regimen for SCLC, especially ED-SCLC, with acceptable toxicity. A phase III study that compares CPT-11/cisplatin with etoposide/cisplatin for ED-SCLC is now being conducted.

We examined whether warm ischemia-reperfusion (I/R) damage of the rat steatotic liver can be reduced by administration of S-adenosyl-L-methionine (SAMe). We examined the effect of SAMe on the mitochondrial reduced-glutathione (GSH) pool. Sixty minutes of partial left lobar vascular clamping followed by 2 h of reperfusion were employed for a model of hepatic warm ischemia. Either 5% dextrose or SAMe was injected intraperitoneally 2 h before I/R in steatotic rats (S-D5% or S-SAMe group). Serum liver enzyme concentrations 2 h after reperfusion were significantly lower in the S-SAMe group than in the S-D5% group. The cytosolic and mitochondrial GSH concentrations after I/R were significantly higher in the S-SAMe group than in the S-D5% group (p < 0.05). The cytosolic and mitochondrial oxidized-glutathione/GSH ratios after I/R were significantly greater in the S-D5% group than in the S-SAMe group (p < 0.01). The adenosine triphosphate concentration was higher in the S-SAMe group than in the S-D5% group (p = 0.0515). These results show that hepatocellular and mitochondrial oxidative stress after I/R in the steatotic liver can be reduced by administration of SAMe. The results also show that mitochondrial function and hepatocellular integrity can be restored by administration of SAMe in steatotic rats.

Serum levels of markers for bone remodeling and diabetic metabolic markers were measured in subjects with non-insulin-dependent diabetes mellitus (NIDDM) to investigate the relationship between early diabetic nephropathy and calcium/bone metabolism. 1 α ,25(OH) 2 D 3 (Vit D), osteocalcin (OC), intact parathyroid hormone (PTH) and urine albumin excretion (UAE) were measured in all subjects. Serum levels of Vit D and OC were significantly decreased in diabetic subjects compared to age-matched, non-diabetic controls. In diabetic patients, a significant positive correlation was observed between intact PTH and OC. No significant correlation was found between levels of Vit D and OC. In early diabetic nephropathy without increased serum creatinine, Vit D decreased and OC increased with increasing UAE. Levels of hemoglobin A 1c (HbA 1c ) and fructosamine (FRA) were not correlated with levels of Vit D or OC. Levels of Vit D were decreased and levels of OC were increased in diabetic subjects with proliferative retinopathy or with micro- or macro-albuminuria. Conclusions : Results of the present study indicate that changes in bone remodeling markers such as Vit D and OC levels are present in the early stages of diabetic nephropathy, and that circulating intact PTH is important in restoring the reduced OC levels in diabetic patients, probably as a reflection of bone remodeling.

Protein-energy malnutrition is a common disorder in the elderly. Although serum albumin is commonly used as a nutritional marker, data is lacking on serum albumin levels in the elderly. The purpose of this study was to determine whether serum albumin levels decrease with advancing age and to establish reference value and interval of laboratory data for elderly people (75 years and over). Blood samples from 13821 healthy people, 42064 outpatients, and 15959 inpatients were collected during 2008. Blood from 127 of our nutrition support team (NST) patients was also collected during August 2006 and May 2009, and analyzed. Serum albumin, hemoglobin, total cholesterol levels and lymphocyte count were determined. We analyzed the change in each parameter in accordance with age, compared the data for elderly people with younger people, and established new reference values. Clinical outcomes were examined depending on the improved reference values. Albumin was lower in older persons than in younger persons. The estimated reference value and interval were 42 (48–36) g/l in older persons and was much lower in NST patients. Hemoglobin was decreased while cholesterol and lymphocyte count were not changed in older persons: all were markedly decreased in NST patients. Terms of hospital stay were significantly longer and mortality rates were significantly higher in older persons, comparing from above to below using a new reference value of albumin (36 g/l). The serum albumin level decreases with advancing age, but it was maintained to some extent in healthy older people. Serum albumin levels related to the clinical outcome. Hemoglobin and cholesterol levels and lymphocyte count were all lower in NST patients. These measurements may be valuable markers of nutritional status and can help in guiding the need for nutritional support.

myo-Inositol, a major compatible osmolyte in renal medulla, is accumulated in kidney-derived epithelial cells cultured in hypertonic media via Na/myoinositol cotransporter (SMIT). The altered medium osmolality of Madin-Darby canine kidney cells leads to changes in the transcription of the SMIT gene and mRNA abundance. To investigate whether SMIT is regulated by tonicity in vivo, renal medullary myoinositol and SMIT mRNA was measured in rats in hydrated and dehydrated states. Rats were divided into two groups: (1) hydrated rats, free access to 3% sucrose water; (2) dehydrated rats, 3 days of water deprivation. Urine sodium, potassium, urea, and osmolality in dehydrated rats were significantly higher than in hydrated rats. Renal medullary sodium, urea, and myo-inositol in dehydrated rats were significantly higher than in hydrated rats. Northern analysis revealed that there was a message hybridized to SMIT cDNA in the cortex and outer and inner medulla of the kidney. Compared with hydrated rats, SMIT mRNA in dehydrated rats was 2.6-fold higher in the outer medulla and 2.5-fold higher in the inner medulla. These results indicate that there is osmoregulatory SMIT in the outer and inner medulla of the kidney and that myo-inositol accumulation in this region is probably due to the increased expression of the SMIT gene.

The purpose of the current study was to evaluate the incidence and course of upper-extremity deep vein thrombosis (UEDVT) related to an implanted central venous port (CV-port) system in cancer patients. From July 2007 to July 2008, 92 consecutive patients who underwent implantation of a CV-port for chemotherapy for colorectal cancer were prospectively enrolled in the study. All patients were examined at prescribed intervals by ultrasonography (US) to estimate the incidence of catheter-related venous thrombosis. We categorised ultrasound diagnosis into three types: Type 0, no thrombus; Type I, thrombi around catheter without obstruction of venous flow; Type II: thrombi with obstruction of venous flow. Upon initial ultrasound examination, 25 cases (27%) were categorised as Type 0, 64 (70%) as Type I and III (3%) as Type II. Of the 64 Type-I cases, 4 cases worsened to Type II within a month, and 3 others (including 1 patient who developed pulmonary embolism) became Type II after 1 month. Of the other Type-I cases, 12 cases improved to Type 0 and 45 cases remained Type I. All 10 patients categorised as Type II underwent anticoagulant therapy and resumed their chemotherapy without exacerbations of thrombosis. In cancer patients undergoing long-term chemotherapy, there is an unexpectedly high prevalence of catheter-related UEDVT, which can be detected by ultrasound at an early stage after implantation of a CV-port. Given that cancer patients with UEDVT may have worse outcomes than those without, clinicians should consider careful monitoring for UEDVT and introducing anticoagulant therapy.

Vacuum-assisted closure (VAC) therapy is a unique system that helps promote wound healing. We report a case of severe ischemic foot in which VAC therapy markedly improved wound healing. A 73-year-old man underwent left axillopopliteal bypass and left 3rd, 4th , and 5th digital amputations for gangrene. Although his amputation stumps were complicated with methicillin-resistant Staphylococcus aureus (MRSA) infection, the stumps were successfully healed by VAC. He also had gangrene in his right 1st toe, which could not healed by VAC alone, and we performed right femoropopliteal bypass and right 1st digital amputation. The stump with MRSA infection was also successfully healed by VAC. Histopathologic examination revealed a lot of microvessels in the increased granulation tissue.

Alpha(1)-adrenoceptor antagonists are extensively used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia. Among the side effects, ejaculatory dysfunction occurs more frequently with drugs that are relatively selective for alpha(1A)-adrenoceptors compared with other drugs of this class. This suggests that alpha(1A)-adrenoceptors may contribute to ejaculation. However, this has not been studied at the molecular level.The physiological contribution of each alpha(1)-adrenoceptor subtype was characterized using alpha(1)-adrenoceptor subtype-selective knockout (KO) mice (alpha(1A)-, alpha(1B)- and alpha(1D)-AR KO mice) since the subtype-specific drugs available are only moderately selective. We analysed the role of alpha(1)-adrenoceptors in the blood pressure and vascular response as well as ejaculation by determining these variables in alpha(1)-adrenoceptor subtype-selective KO mice and in mice with all their alpha(1)-adrenoceptor subtypes deleted (alpha(1)-AR triple-KO mice).The pregnancy rate was reduced by 50% in alpha(1A)-adrenoceptor KO mice, and this reduction was dramatically enhanced in alpha(1)-adrenoceptor triple-KO mice. Contractile tension of the vas deferens in response to noradrenaline was markedly decreased in alpha(1A)-adrenoceptor KO mice, and this contraction was completely abolished in alpha(1)-adrenoceptor triple-KO mice. This attenuation of contractility was also observed in the electrically stimulated vas deferens.These results demonstrate that alpha(1)-adrenoceptors, particularly alpha(1A)-adrenoceptors, are required for normal contractility of the vas deferens and consequent sperm ejaculation as well as having a function in fertility.

Few studies have compared the efficacy of proton pump inhibitors in resolving the symptoms of non-erosive reflux disease (NERD) and of erosive gastro-oesophageal reflux disease (GERD) in Japan.To investigate and compare the efficacy of 4-week course of rabeprazole 10 mg/day on symptom resolution in NERD and erosive GERD in Japan.The modified Los Angeles classification was used to grade endoscopically GERD in patients with heartburn (Grades N and M: NERD, Grades A and B: mild reflux oesophagitis (RO), and Grades C and D: severe RO). Rabeprazole 10 mg/day was administered for 4 weeks to 180 patients who kept symptom diaries.Complete relief of the symptoms was achieved in 35.8% of the NERD group and 55.4% of the erosive GERD group (mild RO: 51.1% and severe RO: 77.8%). Rabeprazole was significantly more effective in erosive GERD than in NERD patients. Among the NERD subgroups (Grades N and M), no difference in symptom improvement was observed.Four-week, rabeprazole 10 mg/day acid suppression therapy was effective in resolving symptoms in Japanese GERD patients. This therapy was more effective in erosive GERD than in NERD patients, and in those with severe RO than in those with mild RO.

Ranitidine has been found to have anti-inflammatory action as well as antisecretory action in experimental models. However, there are no reports in human gastric ulcer. The aim of this study was to investigate the effects of ranitidine compared with those of famotidine on the quality of gastric ulcer healing. We randomly assigned 69 consecutive patients with gastric ulcers to ranitidine (n = 34) or famotidine (n = 35) for 12 weeks, with endoscopic assessment of the quality of gastric ulcer healing and histological assessment of gastric mucosa 12 weeks after treatment started. Ulcer healing rates of over 95% were very similar in the two groups. The rates of ulcer scars with a flat pattern (good-quality healing) were significantly higher in the ranitidine group than in the famotidine group (per protocol, 63.0% and 34.5%, p = 0.033). The neutrophil infiltration score in the body mucosa treated with famotidine, but not ranitidine, significantly increased after treatment. In contrast, the mononuclear cell infiltration score in the antral mucosa treated with ranitidine, but not in that treated with famotidine, had significantly decreased. In conclusion, initial therapy with ranitidine significantly improved the quality of gastric ulcer healing and the histological scores of gastric mucosa compared with famotidine.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H. pylori) are major factors in gastritis and peptic ulcer However, the role of NSAIDs and H. pylori infection in dyspepsia remains unclear. Gastric adaptive relaxation may be related to the pathogenesis of functional dyspepsia because the response is often disturbed in dyspeptic patients. In this study, we investigated the effects of indomethacin or H. pylori water extracts on gastric adaptive relaxation. This experiment was performed using the modified method of Desai et al. Isolated guinea-pig stomach in an organ bath was monitored for intragastric pressure and volume. Adaptive relaxation was induced by gastric luminal distention. The effects of indomethacin and H. pylori on gastric relaxation were tested in this system. Indomethacin (1 x 10(-5) M) significantly inhibited adaptive relaxation. Indomethacin (3 x 10(-6) M) induced gastric relaxation in a dose-dependent fashion. However, aspirin at a concentration sufficient for cyclooxygenase (COX)-1 inhibition did not induce gastric relaxation. Preincubation with N-nitro-L-arginine methyl ester, a nitric oxide (NO)-synthase inhibitor, inhibited indomethacin-induced gastric relaxation. Adaptive relaxation was not affected by H. pylori water extracts. In conclusion, indomethacin inhibited adaptive relaxation via prior gastric relaxation. NO production, but not COX-1 inhibition, may be involved in this effect of indomethacin. H. pylori water extracts may not have direct effects on adaptive relaxation. Inhibition of adaptive relaxation may be one of the major mechanisms underlying NSAID-induced dyspepsia.

The association between cure of Helicobacter pylori infection and the development of gastro-oesophageal reflux disease is controversial.To examine the prevalence of symptomatic GERD (sGERD) in Japanese patients with peptic ulcer disease after successful eradication and identify associated factors affecting sGERD development.We retrospectively examined 72 patients (40 gastric ulcer and 32 duodenal ulcer) with successful eradication. Associated factors such as age, gender, drinking and smoking habits, body mass index, presence of gastric atrophy and hiatal hernia were analysed.Seven (9.7%) of 72 peptic ulcer patients newly developed sGERD. There were no differences in mean age, gender, smoking habit, drinking habit, body mass index, or presence of gastric atrophy and hiatal hernia between the sGERD and non-sGERD groups, while the proportion of subjects aged over 70 was significantly higher in the sGERD than the non-sGERD group. Six of 40 patients with gastric ulcer newly developed sGERD while only one of 32 patients with duodenal ulcer developed it.Approximately 10% of Japanese patients with peptic ulcer disease newly developed sGERD after cure of H. pylori infection. Age70 years was associated with development of sGERD. Eradication in patients in this age group should be carefully determined.

The effects of rebamipide on chronic gastritis associated with Helicobacter pylori have not been well-defined. We compared these effects of rebamipide with those of cimetidine in Mongolian gerbils infected with H. pylori.Mongolian gerbils with or without H. pylori were divided into 10 groups 6 weeks after inoculation and fed diets containing a drug (rebamipide or cimetidine) or control diet. All animals were sacrificed 4 weeks after grouping. Their stomachs were examined for histology, colonization by H. pylori, myeloperoxidase activity (myeloperoxidase), production of neutrophil chemokine (CINC/KC) and tumour necrosis factor-alpha (TNF-alpha), and serum gastrin levels.H. pylori colonized all of the inoculated animals. Neither rebamipide nor cimetidine decreased myeloperoxidase activity, but each reduced wet stomach weight in H. pylori-infected animals. The amount of increase in CINC/KC and TNF-alpha in gastric tissue caused by H. pylori infection was decreased by treatment with rebamipide or cimetidine. H. pylori infection increased serum gastrin levels, and this increase was significantly enhanced by cimetidine but not rebamipide.Rebamipide may improve H. pylori-infected chronic gastritis by preventing the production of inflammatory cytokines and chemokines, as does cimetidine, but may be preferable to cimetidine for long-term administration for treatment of H. pylori-infected chronic gastritis due to its effect on serum gastrin levels.

This year's American Society of Clinical Oncology International Symposium devoted 2 hours to a lively discussion of various aspects of anticancer drug discovery and development throughout the world. The scientific program started with an overview of efforts directed toward promoting international collaboration in natural product-derived anticancer drug discovery. This was followed by a discussion on the importance of interethnic differences and pharmacogenetics in anticancer drug development. Thereafter, this part of the program was completed by a description of the activities of the newly created Singapore-Hong Kong-Australia Drug Development Consortium and an overview of the contribution of Japan to anticancer drug development. The logistics and regulatory aspects of clinical trials with new anticancer agents in different parts of the world were then presented, with an emphasis on Europe, North America, and Japan. The program was completed with a panel discussion of the efforts to harmonize the exchange of clinical data originating from one region of the globe with other territories, with input from official representatives of the United States Food and Drug Administration and the Medical Devices Evaluation Center of Japan.

Disturbances in the reservoir function of the stomach may cause epigastric fullness or early satiety, which are the main symptoms in patients with dysmotility-like functional dyspepsia. Gastric adaptive relaxation is involved in the reservoir function of the proximal stomach. Ecabet sodium, synthesized from abietic acid, is widely used in Japan as an antiulcer drug. The purpose of this study was to evaluate the effects of ecabet on gastric adaptive relaxation in isolated guinea-pig stomachs. Changes in intragastric volume and pressure were recorded in the presence of atropine and guanethidine. Gastric adaptive relaxation was triggered by luminal distention. Ecabet at the dose of 20 mmol/l in solutions at two pHs (pH 3.0 and 7.4) significantly lowered the threshold pressure needed for such relaxation and increased intragastric volume, but lower doses had little or no effect. The results suggested that this antiulcer drug might improve symptoms in patients with dysmotility-like functional dyspepsia.

Epidermal growth factor (EGF), which binds to EGF receptors (EGF-R), stimulates oesophageal epithelial cell proliferation, enabling rapid repair after mucosal injury. In the normal human oesophageal epithelium, EGF-R expression is present and confined to the basal layer.To examine histological changes in and dynamics of EGF-R expression during healing after acid reflux oesophagitis in a rat model.Gastric acid reflux oesophagitis was induced in Wistar rats by ligation of the pylorus and the transitional region between the forestomach and the grandular portion for 5 h, followed by release of both ligations. Rats were killed 7 and 14 days after production of oesophagitis to examine macroscopic and histological changes as well as dynamics of EGF-R expression. Epithelial cell proliferation was assessed by bromodeoxyuridine (BrdU) uptake, and expression of EGF-R mRNA and protein by RT-PCR and Western blotting or immunohistochemistry.Gastric acid reflux induced erosive and ulcerative mucosal lesions in the lower and middle part of the oesophagus. These lesions were healed by 14 days and histologically showed thickening of the oesophageal epithelium from 41.11 +/- 3.09 microm in controls to 142.73 +/- 11.59 microm (P0.001) in ligated rats, as well as elongation of papillae and basal cell hyperplasia. The number of BrdU-positive cells among basal cells on day 14 was significantly increased from 7.1 +/- 0.8/field in controls to 30.9 +/- 3.0/field in ligated rats. Expression of EGF-R mRNA and protein was significantly increased on day 14 and most basal cells were immunohistochemically positive in both BrdU and EGF-R staining.Acid reflux-induced oesophageal injury caused basal cell hyperplasia with an increase in cell proliferation and EGF-R expression. Activation of EGF-R gene and protein in response to acid reflux-induced injury may facilitate mucosal healing. These results suggest that epidermal growth factor receptors play a crucial role in healing after acid reflux oesophagitis in rats.

The usefulness of intraesophageal monitoring of bilirubin, in diagnosing gastroesophageal reflux, was studied.Bilirubin concentration and pH at 5 cm oral and anal to the esophagogastric junction were monitored for 24 hours in 19 patients with reflux esophagitis. The duration of bilirubin presented and pH less than 4.0 were obtained as the holding time (HT) of bilirubin and acid, respectively.There was no difference between HT of bilirubin and acid in the stomach and esophagus. In the stomach, HT of bilirubin did not correlate with acid. Whereas, in both of bilirubin and acid, HT in the esophagus correlated significantly with that in the stomach. The correlation was more definite for bilirubin than acid.Bilirubin and acid presented in the upper stomach for sufficient period independently. Bilirubin monitoring was useful to evaluate the etiology of damaging the esophageal mucosa and causes of symptoms by estimating duodenogastro-esophageal reflux, which has synergistic effect with acid.

The efficacy of thoracoscopic radical esophagectomy for cancer has yet to be established, mainly because previous reports have not included a sufficient number of cases.Seventy-five treatment-naive patients with esophageal cancer without contiguous spread underwent esophageal mobilization and extensive mediastinal lymphadenectomy through a 5-cm mini-thoracotomy and four trocar ports.Video-assisted thoracoscopic surgery was performed without major intraoperative complications or emergency conversion to open surgery. We retrieved 34.1+/-13.0 mediastinal nodes, including 11.5+/-3.8 tracheobronchial nodes and 6.2+/-3.0 recurrent laryngeal nodes. Mean time of operation and blood loss were less in the last 39 patients than the first 36 (186.7+/-25.3 min and 165.4+/-101.8 g vs 270. 2+/-96.0 min and 421.5+/-31.2 g, respectively: p0.0001 and p0.001). Pulmonary morbidity was 5% in the later 39 patients. Survival was 90%, 80%, and 57% at 1, 2, and 5 years after surgery.Thoracoscopic radical esophagectomy has less morbidity and comparable survival to conventional surgery, after a moderate amount of experience. Mini-thoracotomy is essential to perform the procedure safely and effectively.

Water-immersion and restraint stress is associated with an increase in neutrophil infiltration into the gastric mucosa, but the mechanism responsible for this infiltration is unclear. We investigated the involvement of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF-alpha) in neutrophil infiltration in stress-induced gastric injury in rats. Rats were administered neutralizing antibody against ICAM-1 or TNF-alpha and were subjected to induction of gastric injury by 6-hr water-immersion and restraint stress. To evaluate the relationship between gastric acid and neutrophil infiltration, some rats were given cimetidine before administration of stress. Neutralizing antibodies inhibited both the lesion formation and the increase in myeloperoxidase activity induced by stress. Expression of ICAM-1 on endothelial cells was increased by stress, accompanied by an increase of TNF-alpha-positive cells. Antibody against TNF-alpha inhibited this increase in ICAM-1 expression. Cimetidine almost completely inhibited gastric lesions, but did not affect myeloperoxidase activity. In conclusion, neutrophil infiltration in stress-induced gastric injury may be mediated by ICAM-1 and TNF-alpha, but not gastric acid, and may play crucial roles in the progression of gastric injury.

This longitudinal study examined numbers of homebound and bed bound individuals over time, and risk factors in a rural community elderly populations. A total of 731 older persons who needed no assistance of another person in traveling from their homes participated in the baseline survey in 1992 and were assessed annually for their ability to travel for subsequent six-years. We defined operationally a homebound status as the necessity for assistance of another person to be able to leave home, but without being bedbound. During the follow-up period, 86 homebound (23.7 per 1,000 person-years) and 32 bedbound cases (8.4 per 1,000 person-years) were noted, the former being 2.8 times more likely to occur. Of the newly bound cases 26% returned to a state capable of leaving home by themselves one year later, and maintained this independent living level even two years later. Of the other cases who remained as homebound or bedbound one year later, only one (1/31) had returned to independent living after two years; most of them became bedbound at home, hospital admitted or deceased. Stepwise multiple logistic regression analysis showed that independent risk factors for the homebound include older age, male gender, slower walking speed, history of hospital admission in the previous year, lower masticatory ability, and higher level of serum beta 2-microglobin. These results indicate that health promotion programs for prevention of becoming homebound among community elderly people should target more intensively assistance to maintaining walking and masticatory ability. In addition, public health professionals should pay more attention to elderly people shortly after hospital discharge.

It is not known how Shiga toxins (Stxs), which are major virulence factors of enterohemorrhagic Escherichia coli, can affect the host immune system. We investigated the effect of Stx2 on murine thymic cells in vivo and in vitro. After intraperitoneal administration of Stx2, the body weight of mice (BW) and the organ index of thymocytes (OIT) gradually decreased from day 1 to day 4. Apoptosis of thymocytes, assessed by TUNEL staining, and DNA fragmentation assay, was marked on day 3 and day 4. Decrease in BW and OIT due to Stx2 was antagonized by the simultaneous administration of murine anti-Stx2 IgG antibody with Stx2. In vitro administration of Stx2 also induced apoptosis of cultured thymocytes on day 3 and day 4 in a dose-dependent fashion. These results showed that Stx2 directly caused apoptosis of thymocytes in vivo and in vitro. Our findings imply that StA2 may be intimately related to pathogenesis of E. coli O157:H7 infection, by causing apoptosis of thymus.

To examine the cannabinoid hypothesis for pathogenesis of schizophrenia, we examined two kinds of polymorphisms of the CNR1 gene, which encodes human CB1 receptor, a subclass of central cannabinoid receptors, in schizophrenics and age-matched controls in the Japanese population. Allelic and genotypic distributions of polymorphism 1359G/A at codon 453 in the coding region and AAT triplet repeats in the 3' flanking region in the Japanese population were quite different from those in Caucasians. Although the polymorphism 1359G/A was not associated with schizophrenia, the triplet repeat polymorphism of the CNR1 gene was significantly associated with schizophrenia, especially the hebephrenic subtype (P = 0.0028). Hebephrenic schizophrenia showed significantly increased rate of the 9 repeat allele (P = 0.032, OR = 2.30, 95% CI (1.91-2.69)), and decreased rate of the 17 repeat allele (P = 0.011, OR = 0.208, 95% CI (0.098-0.439)). The present findings indicated that certain alleles or genotypes of the CNR1 gene may confer a susceptibility of schizophrenia, especially of the hebephrenic type.

To provide a detailed assessment of micrometastases of colorectal cancer by anatomical mapping of regional lymph nodes (LNs), we analyzed 237 LNs from 11 patients with colorectal cancer by reverse transcription-PCR (RT-PCR) using carcinoembryonic antigen and cytokeratin 20 as genetic markers. All dissected LNs were mapped anatomically and subjected to detection assays for micrometastases. Immunohistochemical analysis was also performed using anti-pancytokeratin antibody AE1/AE3 to confirm the existence of occult cancer cells. By histological analysis, 20 of 237 LNs contained metastatic cells, and they were all positive by both immunohistochemistry and RT-PCR. Of the 217 histologically negative LNs, 14 (6.5%) harbored micrometastases by immunohistochemistry, and 57 (26.2%) were positive for at least one of the two genetic markers. Lymphatic mappings of all patients showed that micrometastases were distributed not only at the pericolic LNs but often at distant LNS: Clinical follow-up study showed that two patients developed recurrence within 1 year after surgery, and both of them had RT-PCR-positive micrometastases in not less than 70% of LNs examined. Moreover, both patients had frequent micrometastases at distant LNs, i.e., those around the root or along the inferior mesenteric artery, when compared with patients with no recurrence. Our findings suggest that genetic diagnosis using the RT-PCR method may be clinically useful along with conventional pathological diagnosis, especially when micrometastases spread to distant LNS

The incidence and severity of coronary artery disease were studied in patients with acute aortic dissection (AAD), and compared with coronary artery disease in patients with abdominal aortic aneurysm (AAA) or arteriosclerosis obliterans (ASO).A total of 71 patients(42 males, 29 females, mean age 61.4 +/- 10.0 years) with AAD, undergoing coronary angiography between 1988 and 1999, were studied including 38 patients with open communication type and 33 patients with thrombosed type. According to the Stanford classification, 18 patients were type A and 53 patients were type B. Patients with AAD following Marfan syndrome or chest trauma were excluded from the study. Selective coronary angiography was performed in age- and sex-matched patients with AAA(n = 57; 42 males, 15 females, mean age 63.9 +/- 4.6 years) or ASO (n = 95; 66 males, 29 females, mean age 62.4 +/- 9.4 years). Coronary artery disease was defined asor = 75% stenosis (left main trunk lesion ofor = 50% stenosis) by multidirectional imaging.Significant coronary artery disease was demonstrated in 14 patients with AAD (19.7%), 25 patients with AAA (43.9%), and 49 patients with ASO (51.5%). The incidence of coronary artery disease was significantly lower in the AAD group than in the other two groups (p0.05). One-vessel disease was present in approximately 70% of the patients with AAD and coronary artery disease. In contrast, multivessel disease was observed in approximately 50% of patients with AAA and ASO. Classification of the patients with AAD according to the blood flow in the false lumen showed coronary artery disease was more highly associated with the thrombosed type [10 (30.3%) of 33 patients] than the open communication type [4 (10.5%) of 38 patients]. Multivariate logistic regression analysis of the patients with AAD showed coronary artery disease was associated with a high serum total cholesterol level (p = 0.025) and the thrombosed type (p = 0.043).The incidence of coronary artery disease was significantly lower among patients with AAD than among age- and sex-matched patients with AAA or ASO. Coronary artery disease developed in 30% of the patients with the thrombosed type of AAD, although the prognosis seemed to be good.

Fibronectin (FN) is important for wound healing via cell proliferation, adhesion, differentiation, and matrix formation. Fetal types of FN mRNA, which include the region of EIIIA or EIIIB, are well expressed during embryonic development and wound healing. This study was done to investigate the mRNA expression of full-length FN, EIIIA- and EIIIB-FN, and the localization of FN in the gastric tissues during ulcer healing with northern blot analysis and immunohistochemical technique. Gastric ulcers in rats were produced by acetic acid. EIIIA- and EIIIB-FN mRNA were not detected in normal gastric tissues, but were expressed in the ulcerated tissues throughout the healing phase. However, on day 60 (in the scarred phase), the EIIIA- and EIIIB-FN mRNA had disappeared. The levels of full-length FN mRNA were increased from day 3 to 32 compared with the control levels, and decreased to the control levels on day 60. Full-length FN was predominantly localized at the mesenchyme around the infiltrating inflammatory cells in the granulation tissues and the basement membranes of the nonproliferating epithelial cells, which were regenerated at the ulcer margin. Thus, fetal gene transcripts of FN suggest the important role of fetal FN in gastric ulcer healing, mainly via the migration of mesenchymal and epithelial cells.

This study investigated the cause for needing airway maneuvers to maintain a patent airway during the use of cuffed oropharyngeal airway (COPA). Twenty adult patients (29.4+/-6.8 years-old, ASA 1-2) scheduled for minor gynecological surgery who required brief manipulations of the airway despite COPA use following the manufacture's guidelines, were enrolled in this study. To obtain airway patency, 15 patients required only the head-tilt maneuver. In eight of the 15 patients, the laryngeal inlet was opened partially (n=4) or completely (n=4). Despite lifting the epiglottis, the laryngeal inlet was incomplete at the level of pharyngeal view. The patency of the laryngeal inlet was decided by the extent of the distance between the posterior pharyngeal wall and the lateral glossoepiglottic fold, which was made by hyoid bone. In the other seven patients, the head-tilt maneuver elevated the epiglottis and completely opened the laryngeal inlet. Five patients required both the jaw-thrust and head-tilt maneuver. Of these patients lifting the epiglottis was incomplete in three and the laryngeal inlet was partially collapsed in one even after the airway manipulations. The airways in these three patients, however, became patent after manipulations despite the persisting partial obstruction.

To determine the limits of the duration of in vivo transferred foreign gene expression, we conducted electroporation (EP), a powerful non-viral means of gene transfer for living animals, into skeletal muscle of rats and mice with a luciferase, GFP or erythropoietin (EPO)-encoding reporter plasmid. The luciferase reporter plasmid was used for optimization of EP conditions, while GFP and EPO plasmids were used for monitoring the duration of gene expression. In the rat, increased hematocrit levels were maintained for at least 9 weeks with approximately a 3-fold increase in plasma EPO protein concentration at 4 weeks post-transfection. In the mouse, the GFP plasmid transfer confirmed that the reporter gene expression lasted as long as 3 months post-transfection. By introducing the EPO gene in vivo in the mouse, increased hematocrit levels revealed that duration of reporter gene expression was at least 14.5 months after in vivo gene EP into skeletal muscle. These results implicate an excellent potential of in vivo gene EP, applicable to both experimental and therapeutic purposes.

Objective to investigate and compare the predictive values of four physical performance measures for the onset of functional dependence in older Japanese people living at home. Design a population-based prospective cohort study. Setting Nangai village, Akita Prefecture, Japan. Methods out of the population aged 65 years and older living in Nangai (n = 940) in 1992, we measured hand grip-strength, one-leg standing, and usual and maximum walking speeds in 736 subjects who were independent in the five basic activities of daily living. Their functional status was assessed each year for the subsequent 6 years. The outcome event was the onset of functional dependence, defined as a new disability in one or more of the five basic activities of daily living, or death of a subject who had shown no disability at the previous follow-up. Results even after controlling for age, sex and a number of chronic conditions, lower scores on each baseline performance measure showed increased risk for the onset of functional dependence. Maximum walking speed was most sensitive in predicting future dependence for those aged 65-74 years, while usual walking speed was most sensitive for people aged > or = 75 years. Conclusion walking speed was the best physical performance measure for predicting the onset of functional dependence in a Japanese rural older population.

The cytoprotective effect of rabeprazole, a new proton pump inhibitor, against ethanol-induced gastric mucosal damage was investigated in rats. Rats received intraperitoneal injections of rabeprazole once only or once daily for 3 days. Subsequently, the rats were given 1 ml of absolute ethanol by oral intubation. Some rats given rabeprazole were treated with N-omega-nitro-L-arginine methyl ester (L-NAME) or indomethacin. Repeated administration of rabeprazole significantly inhibited ethanol-induced gastric mucosal damage, although single administration of this drug did not. Pretreatment with L-NAME abolished the cytoprotective effect of rabeprazole. This inhibitory effect of L-NAME was reversed by L-arginine but not by D-arginine. Pretreatment with indomethacin did not influence the cytoprotective effect of rabeprazole. These results suggest that repeated intraperitoneal administration of rabeprazole has a cytoprotective effect against ethanol-induced gastric mucosal damage and that this effect may be mediated via nitric oxide but not via prostaglandins.

The presence of regional lymph node metastasis is one of the most significant poor-prognosis factors in patients with biliary tract carcinoma. To establish a sensitive reverse transcription (RT)-PCR assay to detect micrometastases in lymph nodes of biliary tract carcinoma, we first investigated the optimal markers in biliary tract carcinoma. The expressions of the six candidates for a suitable RT-PCR marker [mammaglobin B, carcinoembryonic antigen (CEA), cytokeratin (CK) 20, prostate-specific antigen, and melanoma antigens (MAGE-1 and MAGE-3)] were evaluated in two bile duct cancer cell lines and human biliary tract carcinoma tissues. Of 32 carcinoma tissues, mammaglobin B, CEA, prostate-specific antigen, MAGE-1, MAGE-3, and CK 20 were expressed in 28 (88%), 26 (81%), 4 (13%), 5 (16%), 7 (22%), and 9 (28%), respectively. Mammaglobin B and CEA were considered to be good markers of the six candidates. We then examined 209 lymph nodes obtained from 15 patients with biliary tract carcinoma by RT-PCR assay using both mammaglobin B and CEA and compared the results with those of histological examination. All of 20 histologically positive lymph nodes for metastasis displayed the PCR product(s) of marker genes. Of 189 histologically negative nodes, 24 (13%) nodes expressed mammaglobin B and/or CEA mRNA, suggesting the presence of micrometastasis. Our findings suggest that mammaglobin B and CEA could be useful RT-PCR markers for the detection of lymph node micrometastases in biliary tract carcinomas. Our RT-PCR assay allows accurate clinical staging necessary for patient stratification with respect to adjuvant therapy after surgery.

Submucosal injection of endothelin (ET)-1 induces gastric ulcer. We investigated the roles of neutrophils and adhesion molecules (intercellular adhesion molecule (ICAM)-1 and CD18) in the development of ET-1-induced ulcers in rats. Ulcers were induced by submucosal injection of ET-1. Rats were injected with anti-neutrophil serum or F(ab')2 fragments of irrelevant mouse IgG2a (control), anti-ICAM-1 antibody, or anti-CD18 antibody. Ulcer tissues were subjected to measurement of myeloperoxidase (MPO) activity, ulcer size, and immunohistochemical study. Within 3 hr, arterial vasoconstriction and vascular congestion were observed at sites of ET-1 injection. By 6 hr, vascular congestion had disappeared, and ICAM-1 expression had markedly increased in venules in deep portions of the mucosa and submucosa, accompanied by an increase in the number of CD18-positive neutrophils. By 48 hr, ulcers that extended into the submucosa had developed. In controls, MPO activity gradually increased and was maximal by 6 hr. Neutrophil depletion, and immunoneutralizing of ICAM-1 and CD18 inhibited the increase in MPO activity, and decreased ulcer sizes measured at 48 hr. In conclusion, ET-1 causes ischemia-reperfusion injury, and neutrophil accumulation after reperfusion mediated by the ICAM-1-CD18 pathway may be important in the development of ET-1-induced gastric ulcer.