Progressive pulmonary fibrosis (PPF): Estimation of incidence and treatment rates in Japan using a claims database.

BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders, a subset of which develop progressive pulmonary fibrosis (PPF). There is little information on the epidemiology and treatment of PPFs in Japan. This retrospective cohort study estimated the incidence probability of progression to PPFs in patients with fibrosing ILDs other than idiopathic pulmonary fibrosis in a real-world Japanese setting. Management procedures and treatment patterns were also quantified. METHODS: Data were extracted from the Medical Data Vision database from 01-Jan-2012 to 28-May-2020, comprising a 6.91-year patient identification period, 1-year pre-index period, and post-index period. The primary outcome was the cumulative incidence probability of progression to PPF up to 24 months. Subgroup analyses were performed by the presence/absence of connective tissue disease-ILD and by pre-specified ILD clinical diagnosis. RESULTS: Of the 34,960 eligible patients (mean age: 71.1 years, males: 52.5%), 14,580 (41.7%) progressed to PPF. The 24-month incidence probability of progression to PPF was 39.5%. A relatively comparable percentage of patients progressed across all ILD subtypes. Oral corticosteroids and tacrolimus were the most common therapies during the pre- and post-index periods. Treatment rates were very low in the post-index period. CONCLUSIONS: This is the first claims database study to estimate the incidence probability of progression to PPF in Japan. Progression appeared common in patients with chronic fibrosing ILDs, with comparable percentages of patients across all subtypes developing PPF at 2 years. Future studies should assess the impact of regular monitoring and early intervention on treating fibrotic ILDs and preventing progression.

Quality improvement of gluten-free rice flour bread through the addition of high-temperature water during processing.

Recently, there has been an increase in the demand for gluten-free bread due to health reasons. One of the flours used to produce gluten-free bread is rice flour; flour characteristics are very important for breadmaking. Although a study has shown that the addition of high-temperature water can improve the quality of rice flour bread, studies are yet to consider different rice properties. Therefore, the aim of this study was to investigate the effect of adding high-temperature water and rice flour characteristics on the quality of rice flour bread using six commercially available rice flours. The rice flours used in the sample had amylose content from 12.1% to 24.5%, damaged starch content from 2.4% to 5.5%, mode diameter from 16.3 to 63.3 µm, protein content from 5.4% to 6.1%, and moisture content in the range of 12.0%-15.0%. The results showed that regardless of the rice characteristics, breads prepared at the optimum watering temperature were puffier and softer than those prepared using cold water (5°C). For rice flours with similar particle size, the optimal water temperature and degree of gelatinization for breadmaking increased with rice flours with lower amylose content. Furthermore, the rheological properties of dough prepared at the optimum water addition temperature were stable, with loss modulus (G″) being dominant over the entire frequency range in the frequency sweep test. Since the water temperature added to the dough affects breadmaking properties more than the characteristics of the rice flour, adjusting the water temperature may enable the production of high-quality bread even with rice flour unsuitable for making. PRACTICAL APPLICATION: Presently, the addition of high-temperature water to rice flour has been shown to improve the bread quality. In this study, we investigated the effects of high-temperature water addition on the quality of rice flour bread using rice flour varieties with different flour characteristics. Even in rice flour with small particle size and low amylose content, which is not suitable for breadmaking, bread quality can be improved by adding hot water at around 70°C. This is a simple and practical method to improve the quality of gluten-free rice flour bread without adding thickeners.

Incidence Rate and Prevalence of Systemic Sclerosis and Systemic Sclerosis-Associated Interstitial Lung Disease in Japan: Analysis Using Japanese Claims Databases.

INTRODUCTION: Systemic sclerosis (SSc) is a complex autoimmune disease with increased mortality, and interstitial lung disease (ILD) is a major cause of death. There are no recent epidemiological data on SSc and SSc-associated ILD (SSc-ILD) in Japan and little is known about how patients with these diseases are treated. METHODS: The incidence rate and prevalence of SSc and SSc-ILD in Japan were estimated using the Japanese Medical Data Centre (JMDC) database. The demographic and clinical characteristics of patients and the immunomodulatory medications they received were also assessed using JMDC and the Medical Data Vision (MDV) databases. All analyses were descriptive. RESULTS: The overall incidence rates of SSc and SSc-ILD per 100,000 person-years were 6.6 (95% confidence interval [CI] 6.2-7.1) and 1.9 (95% CI 1.6-2.1), respectively, and the overall prevalence per 100,000 persons was 37.0 (95% CI 35.6-38.5) and 13.9 (95% CI 13.0-14.8), respectively. ILD was the most common comorbidity in patients with SSc present in approximately 30% of patients (JMDC, 29.3%; MDV, 30.1%). The immunomodulatory medications prescribed were similar in patients with SSc and SSc-ILD, and each of the medications in this analysis was prescribed in less than 15% of patients. CONCLUSION: We have demonstrated that estimates of prevalence and incidence rates of SSc and SSc-ILD in Japan are comparable to similar database studies conducted in the USA, using a medical claims database. Only a small proportion of patients were receiving immunomodulatory treatments, suggesting undertreatment in Japan. Incidence Rate and Prevalence of Systemic Sclerosis and Systemic Sclerosis-associated Interstitial Lung Disease in Japan: Analysis Using Japanese Claims Databases-A Video Abstract. (MP4 68892 KB).

Effect of the addition of high-temperature water on the properties of batter and bread made from gluten-free rice flour.

Increasing number of individuals worldwide are consuming gluten-free products, for example, bread, for health and other reasons. However, gluten-free products are currently expensive and/or their preparation involves the use of specialist machinery or food additives. In this study, we focused on the thickening effect of starch gelatinization and attempted to develop a novel method for gluten-free rice flour bread production without the use of additives. We aimed to determine the effect of adding high-temperature water to gluten-free rice flour on the properties of the resulting batter, primarily gelatinization. The water was tested at temperatures between 50 and 80°C, in 2°C increments. For comparison, control bread from gluten-free rice flour was made using cold (5°C) water. The addition of water at a temperature between 66 and 70°C significantly improved the specific volume and firmness of bread (p < 0.05, Dunnett's test; compared with control). Additionally, maintaining the gelatinization temperature of the bread batter for approximately 1-10 s and the degree of gelatinization of batter, approximately 5%-10%, were crucial for obtaining good-quality bread. Further, the addition of water at a temperature above 78°C adversely affected the bread-making properties. This simple method developed for making high-quality bread from gluten-free rice flour will make gluten-free bread products more widely available to and acceptable by the consumers. PRACTICAL APPLICATION: Currently, making high-quality bread from gluten-free rice flour involves the use of food additives or special rice flour. Here, we present a simple method for producing high-quality bread by manipulating the temperature of water added during the preparation of rice flour batter. We optimized the method by analyzing the gelatinization properties of the batter and determined the optimal water temperature suitable for bread making. This method yields high-quality gluten-free bread and is cost-effective and simple to implement.

Clinical characteristics and health-care resource utilization in patients with generalized pustular psoriasis using real-world evidence from the Japanese Medical Data Center database.

Little is known about the disease burden, health-care resource utilization (HCRU), or treatment of patients with generalized pustular psoriasis (GPP) in Japan. This retrospective cohort study used data from the Japanese Medical Data Center database to compare the demographics, comorbidities, and medication use of patients with GPP and plaque psoriasis and estimate their all-cause HCRU. The patient selection period was from January 1, 2015 to December 31, 2019, and patients must have had at least one confirmed inpatient claim or outpatient claim for GPP or plaque psoriasis. During the 12-month follow-up period, 110 patients with GPP and 20,254 patients with plaque psoriasis were identified. An age- and sex-matched (4:1) comparator control cohort, including members of the general population without a diagnosis of psoriasis (but allowing for a diagnosis of psoriatic arthritis), GPP, or palmoplantar pustulosis, was used. The most prevalent comorbidities in patients with GPP included allergic rhinoconjunctivitis, hypertension, and peptic ulcer disease. Patients with GPP were more likely to experience more comorbidities than those with plaque psoriasis, including asthma, chronic obstructive pulmonary disease, interstitial pneumonia, hyperuricemia and gout, tonsillitis, psoriatic arthritis, other psoriasis, and osteoporosis. Patients with GPP were more likely to be treated with a combination therapy than those with plaque psoriasis (65.5% vs 21.7%, respectively) and less likely to be treated with a topical medication alone (20.9% vs 50.8%). Patients with GPP had more outpatient visits than patients in the plaque psoriasis or matched control cohorts (mean [standard deviation], 14.8 [8.3] vs 11.0 [7.6] and 7.8 [7.2], respectively). They were also more likely to require inpatient hospitalization (24.5% vs 6.4% and 5.0%, respectively). Despite study limitations, patients with GPP in Japan were found to have a higher disease burden, including presence of comorbidities and medication use, than those with plaque psoriasis.

Safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in real-world patients with non-valvular atrial fibrillation: a retrospective analysis of contemporary Japanese administrative claims data.

Objective: To assess the safety (ie, risk of bleeding) and effectiveness (ie, risk of stroke/systemic embolism (SE)) separately for four non-vitamin K oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) versus warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF), including those at high risk of bleeding and treated with reduced doses of NOACs. Methods: We conducted a retrospective analysis of electronic health records and claims data from 372 acute care hospitals in Japan for patients with NVAF newly initiated on NOACs or warfarin. Baseline characteristics were balanced using inverse probability of treatment weighting with stabilised weights (s-IPTW). Bleeding risk and stroke/SE risk were expressed as HRs with 95% CIs. Two sensitivity analyses were conducted. Results: A total of 73 989 patients were eligible for analysis. Notably, 52.8%-81.9% of patients received reduced doses of NOACs. After applying s-IPTW, patient characteristics were well balanced across warfarin/NOAC cohorts. The mean within-cohort age, CHADS2 score and CHA2DS2-VASc score were 76 years, 2.2-2.3 and 3.8, respectively. In all age categories, the majority of the HRs for major bleeding, any bleeding and stroke/SE were equal to or below 1 for all NOACs versus warfarin. Apixaban was the only NOAC associated with a significantly lower risk of any bleeding. There was a trend towards increased risk reduction with NOACs versus warfarin in patients with body weight ≥60 kg. In patients with renal disease, the HRs for apixaban versus warfarin were below 1 for major bleeding, any bleeding and stroke/SE, with statistical significance observed for the risk reduction in stroke/SE versus warfarin. In the sensitivity analysis, there were no large differences in HRs between the two observational periods. Conclusions: In patients with NVAF primarily treated with reduced-dose NOACs, the risks of stroke/SE and major bleeding were significantly lower with NOACs versus warfarin.

Role of the α2 subunit of AMP-activated protein kinase and its nuclear localization in mitochondria and energy metabolism-related gene expressions in C2C12 cells.

BACKGROUND: AMP-activated protein kinase (AMPK), a heterotrimer with α1 or α2 catalytic subunits, acts as an energy sensor and regulates cellular homeostasis. Whereas AMPKα1 is necessary for myogenesis in skeletal muscle, the role of AMPKα2 in myogenic differentiation and energy metabolism-related gene expressions has remained unclear. We here examined the specific roles of AMPKα1 and AMPKα2 in the myogenic differentiation and mitochondria and energy metabolism-related gene expressions in C2C12 cells. MATERIALS AND METHODS: Stable C2C12 cell lines expressing a scramble short hairpin RNA (shRNA) or shRNAs specific for AMPKα1 (shAMPKα1), AMPKα2 (shAMPKα2), or both AMPKα1 and AMPKα2 (shPanAMPK) were generated by lentivirus infection. Lentiviruses encoding wild-type AMPKα2 (WT-AMPKα2) or AMPKα2 with a mutated nuclear localization signal (ΔNLS-AMPKα2) were also constructed for introduction into myoblasts. Myogenesis was induced by culture of C2C12 myoblasts for 6 days in differentiation medium. RESULTS: The amount of AMPKα2 increased progressively, whereas that of AMPKα1 remained constant, during the differentiation of myoblasts into myotubes. Expression of shPanAMPK or shAMPKα1, but not that of shAMPKα2, attenuated the proliferation of myoblasts as well as the phosphorylation of both acetyl-CoA carboxylase and the autophagy-initiating kinase ULK1 in myotubes. Up-regulation of myogenin mRNA, a marker for the middle stage of myogenesis, was attenuated in differentiating myotubes expressing shPanAMPK or shAMPKα1. In contrast, up-regulation of gene expression for muscle creatine kinase (MCK), a late-stage differentiation marker, as well as for genes related to mitochondrial biogenesis including the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α1 and α4 (PGC-1α1 and PGC-1α4) and mitochondria-specific genes such as cytochrome c were attenuated in myotubes expressing shAMPKα2 or shPanAMPK. The diameter of myotubes expressing shPanAMPK or shAMPKα2 was reduced, whereas that of those expressing shAMPKα1 was increased, compared with myotubes expressing scramble shRNA. A portion of AMPKα2 became localized to the nucleus during myogenic differentiation. The AMPK activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) and 2-deoxyglucose (2DG) each induced the nuclear translocation of WT-AMPKα2, but not that of ΔNLS-AMPKα2. Finally, expression of WT-AMPKα2 increased the mRNA abundance of PGC-1α1 and MCK mRNAs as well as cell diameter and tended to increase that of PGC-1α4, whereas that of ΔNLS-AMPKα2 increased only the abundance of MCK mRNA, in myotubes depleted of endogenous AMPKα2. CONCLUSION: TAMPKα1 and AMPKα2 have distinct roles in myogenic differentiation of C2C12 cells, with AMPKα1 contributing to the middle stage of myogenesis and AMPKα2 to the late stage. AMPKα2 regulates gene expressions including MCK, PGC-1α1 and PGC-1α4 and mitochondria-specific genes such as cytochrome c during the late stage of differentiation. Furthermore, the nuclear translocation of AMPKα2 is necessary for maintenance of PGC-1α1 mRNA during myogenesis.

Safety and effectiveness of apixaban in comparison to warfarin in patients with nonvalvular atrial fibrillation: a propensity-matched analysis from Japanese administrative claims data.

OBJECTIVE: To investigate the risk of bleeding events and stroke/systemic embolism (SE) among Japanese patients with nonvalvular atrial fibrillation (NVAF), focusing on the initial dosage of apixaban and patient age. METHODS: This retrospective cohort study used de-identified electronic health records based claims data from 314 acute-care hospitals in Japan. NVAF patients newly initiated on warfarin or apixaban, with no prescription during the 180-day blanking period, were eligible. Patients were allocated to receive warfarin or 5 or 2.5 mg twice daily (BID) apixaban. One-to-one propensity-score matching was used to balance patient characteristics between apixaban and warfarin. RESULTS: Among 31,006 eligible patients, 11,972 matched pairs were identified for apixaban versus warfarin. Mean age ± standard deviation was 77.7 ± 10.0 and 77.6 ± 10.0 years and CHADS2 score was 2.2 ± 1.4 and 2.2 ± 1.4 for warfarin and apixaban, respectively. In the apixaban cohort, 39.4% of patients received the standard dose (5 mg BID) and 60.6% received the reduced dose (2.5 mg BID). Incidence rates (events per 100 person-years) of major bleeding, any bleeding and stroke/SE were 3.7, 23.1 and 3.1, and 2.5, 18.6 and 2.0 for warfarin and apixaban cohorts, respectively. Apixaban was associated with a significantly lower risk of any bleeding (hazard ratio [HR] 0.809, 95% confidence interval [CI] 0.731-0.895; p < .001), major bleeding (HR 0.655, 95% CI 0.505-0.849; p = .001) and stroke/SE (HR 0.637, 95% CI 0.478-0.850; p = .002). CONCLUSIONS: Our observational data from clinical practice broadly confirms the safety and efficacy results of pivotal randomized controlled trials of apixaban for stroke prevention among NVAF patients.

Activation of AMPK-Regulated CRH Neurons in the PVH is Sufficient and Necessary to Induce Dietary Preference for Carbohydrate over Fat.

Food selection is essential for metabolic homeostasis and is influenced by nutritional state, food palatability, and social factors such as stress. However, the mechanism responsible for selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) remains unknown. Here, we show that activation of a subset of corticotropin-releasing hormone (CRH)-positive neurons in the rostral region of the paraventricular hypothalamus (PVH) induces selection of an HCD over an HFD in mice during refeeding after fasting, resulting in a rapid recovery from the change in ketone metabolism. These neurons manifest activation of AMP-activated protein kinase (AMPK) during food deprivation, and this activation is necessary and sufficient for selection of an HCD over an HFD. Furthermore, this effect is mediated by carnitine palmitoyltransferase 1c (CPT1c). Thus, our results identify the specific neurons and intracellular signaling pathway responsible for regulation of the complex behavior of selection between an HCD and an HFD. VIDEO ABSTRACT.

Induction of glucose uptake in skeletal muscle by central leptin is mediated by muscle ß2-adrenergic receptor but not by AMPK.

Leptin increases glucose uptake and fatty acid oxidation (FAO) in red-type skeletal muscle. However, the mechanism remains unknown. We have investigated the role of ß2-adrenergic receptor (AR), the major ß-AR isoform in skeletal muscle, and AMPK in leptin-induced muscle glucose uptake of mice. Leptin injection into the ventromedial hypothalamus (VMH) increased 2-deoxy-D-glucose (2DG) uptake in red-type skeletal muscle in wild-type (WT) mice accompanied with increased phosphorylation of the insulin receptor (IR) and Akt as well as of norepinephrine (NE) turnover in the muscle. Leptin-induced 2DG uptake was not observed in ß-AR-deficient (ß-less) mice despite that AMPK phosphorylation was increased in the muscle. Forced expression of ß2-AR in the unilateral hind limb of ß-less mice restored leptin-induced glucose uptake and enhancement of insulin signalling in red-type skeletal muscle. Leptin increased 2DG uptake and enhanced insulin signalling in red-type skeletal muscle of mice expressing a dominant negative form of AMPK (DN-AMPK) in skeletal muscle. Thus, leptin increases glucose uptake and enhances insulin signalling in red-type skeletal muscle via activation of sympathetic nerves and ß2-AR in muscle and in a manner independent of muscle AMPK.

Activation of SF1 Neurons in the Ventromedial Hypothalamus by DREADD Technology Increases Insulin Sensitivity in Peripheral Tissues.

The ventromedial hypothalamus (VMH) regulates glucose and energy metabolism in mammals. Optogenetic stimulation of VMH neurons that express steroidogenic factor 1 (SF1) induces hyperglycemia. However, leptin acting via the VMH stimulates whole-body glucose utilization and insulin sensitivity in some peripheral tissues, and this effect of leptin appears to be mediated by SF1 neurons. We examined the effects of activation of SF1 neurons with DREADD (designer receptors exclusively activated by designer drugs) technology. Activation of SF1 neurons by an intraperitoneal injection of clozapine-N-oxide (CNO), a specific hM3Dq ligand, reduced food intake and increased energy expenditure in mice expressing hM3Dq in SF1 neurons. It also increased whole-body glucose utilization and glucose uptake in red-type skeletal muscle, heart, and interscapular brown adipose tissue, as well as glucose production and glycogen phosphorylase a activity in the liver, thereby maintaining blood glucose levels. During hyperinsulinemic-euglycemic clamp, such activation of SF1 neurons increased insulin-induced glucose uptake in the same peripheral tissues and tended to enhance insulin-induced suppression of glucose production by suppressing gluconeogenic gene expression and glycogen phosphorylase a activity in the liver. DREADD technology is thus an important tool for studies of the role of the brain in the regulation of insulin sensitivity in peripheral tissues.

Leptin receptor signaling is required for high-fat diet-induced atrophic gastritis in mice.

BACKGROUND: Obesity increases the risk for malignancies in various tissues including the stomach. Atrophic gastritis with precancerous lesions is an obesity-associated disease; however, the mechanisms that underlie the development of obesity-associated atrophic gastritis are unknown. Leptin is a hormone derived from stomach as well as adipose tissue and gastric leptin is involved in the development of gastric cancer. The aim of the current study is to investigate the involvement of leptin receptor signaling in the development of atrophic gastritis during diet-induced obesity. METHODS: Male C57BL/6, ob/ob and db/db mice were fed a high-fat diet (HFD) or a control diet (CD) from 1 week to 5 months. Pathological changes of the gastric mucosa and the expression of molecules associated with atrophic gastritis were evaluated in these mice. RESULTS: HFD feeding induced gastric mucosal hyperplasia with increased gastric leptin expression. Mucosal hyperplasia was accompanied by a higher frequency of Ki67-positive proliferating cells and atrophy of the gastric glands in the presence of inflammation, which increased following HFD feeding. Activation of ObR signaling-associated molecules such as ObR, STAT3, Akt, and ERK was detected in the gastric mucosa of mice fed the HFD for 1 week. The morphological alterations associated with gastric mucosal atrophy and the expression of Muc2 and Cdx2 resemble those associated with human intestinal metaplasia. In contrast to wild-type mice, leptin-deficient ob/ob mice and leptin receptor-mutated db/db mice did not show increased Cdx2 expression in response to HFD feeding. CONCLUSION: Together, these results suggest that activation of the leptin signaling pathway in the stomach is required to develop obesity-associated atrophic gastritis.

Sympathetic Nerve Activity Maintains an Anti-Inflammatory State in Adipose Tissue in Male Mice by Inhibiting TNF-α Gene Expression in Macrophages.

Adipose tissue macrophages (ATMs) play an important role in the inflammatory response in obese animals. How ATMs are regulated in lean animals has remained elusive, however. We now show that the sympathetic nervous system (SNS) is necessary to maintain the abundance of the mRNA for the proinflammatory cytokine TNF-α at a low level in ATMs of lean mice. Intracerebroventricular injection of agouti-related neuropeptide increased the amount of TNF-α mRNA in epididymal (epi) white adipose tissue (WAT), but not in interscapular brown adipose tissue (BAT), through inhibition of sympathetic nerve activity in epiWAT. The surgical denervation and ß-adrenergic antagonist propranolol up-regulated TNF-α mRNA in both epiWAT and BAT in vivo. Signaling by the ß2-adrenergic receptor (AR) and protein kinase A down-regulated TNF-α mRNA in epiWAT explants and suppressed lipopolysaccharide-induced up-regulation of TNF-α mRNA in the stromal vascular fraction of this tissue. ß-AR-deficient (ß-less) mice manifested an increased plasma TNF-α concentration and increased TNF-α mRNA abundance in epiWAT and BAT. TNF-α mRNA abundance was greater in ATMs (CD11b(+) cells of the stromal vascular fraction) from epiWAT or BAT of wild-type mice than in corresponding CD11b(-) cells, and ß2-AR mRNA abundance was greater in ATMs than in CD11b(-) cells of epiWAT. Our results show that the SNS and ß2-AR-protein kinase A pathway maintain an anti-inflammatory state in ATMs of lean mice in vivo, and that the brain melanocortin pathway plays a role in maintaining this state in WAT of lean mice via the SNS.

The relationship between repolarization parameters and serum electrolyte levels in patients with J wave syndromes.

BACKGROUND: Intravenous administration of magnesium (Mg(2+)) is effective for polymorphic ventricular tachycardia via homogenization of transmural ventricular repolarization. Mg(2+) likely plays some role in the heterogeneity of repolarization in J wave syndromes. OBJECTIVE: To investigate the relationship between the repolarization parameters and serum Mg(2+), potassium (K(+)), and calcium (Ca(2+)) levels in J wave syndromes. METHODS: Thirteen J-wave syndrome patients (Brugada and early repolarization [ER] syndromes), with documented episodes of ventricular fibrillation (VF), and 13 ER pattern (ERP) or Brugada type ECG patients were enrolled (25 males, mean age 48 ± 15 years). The 12-lead ECG-derived parameters including the QT, QT dispersion (QTd), Tpeak-Tend (Tp-e) interval, Tp-e dispersion (Tp-ed), Tp-e/QT ratio, and activation recovery interval (ARI) dispersion were calculated; the correlations between these parameters and electrolytes including Mg(2+), K(+), and Ca(2+) were analyzed. RESULTS: Although there was no association between serum K(+) or Ca(2+) and QTd, there was a strong negative correlation between serum Mg(2+) and QTd in J wave syndrome patients with a history of VF (r = -0.715, p = 0.006). Also, there was a tendency for a negative correlation between Mg(2+) and Tp-ed or ARI dispersion in J wave syndrome patients with a history of VF (r = -0.513, p = 0.072 and r = -0.53, p = 0.063, respectively). On the other hand, in 13 patients with a Brugada type ECG or ERP, no correlation was observed between serum Mg(2+) and the QTd, Tp-ed or ARI dispersion. CONCLUSION: Serum Mg(2+) may play an important role in the cardiac repolarization process in J wave syndromes.

Extracellular signal-regulated kinase in the ventromedial hypothalamus mediates leptin-induced glucose uptake in red-type skeletal muscle.

Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal-regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocortin receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of the MEK-ERK pathway in the VMH by leptin may play a role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus and leading to an increase in insulin sensitivity in red-type muscle.

Involvement of the sigma1 receptor in the antidepressant-like effects of fluvoxamine in the forced swimming test in comparison with the effects elicited by paroxetine.

We studied the involvement of the sigma(1) receptor in the antidepressant-like effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in DBA/2 mice using the forced swimming test. The effects of the selective sigma(1) receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD1047) at 1mg/kg significantly antagonized the anti-immobility elicited by fluvoxamine (10mg/kg). However, the anti-immobility effects elicited by another SSRI, paroxetine (5m/kg), were not altered by BD1047. The selective sigma(1) receptor agonist 2S-(2α,6α,11R(*))-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol ((+)SKF-10047) elicited dose-dependent anti-immobility effects in DBA/2 mice. BD1047 significantly blocked the anti-immobility effects induced by (+)SKF-10047 at 10mg/kg. These results suggested that the sigma(1) receptor was associated with fluvoxamine-induced antidepressant-like effects but not with paroxetine-induced antidepressant-like effects.

Mid-term results of everolimus-eluting stent in a Japanese population compared with a US randomized cohort: SPIRIT III Japan Registry with harmonization by doing.

UNLABELLED: To address safety concerns with first-generation drug-eluting stents (DESs), the everolimus-eluting stent (EES) has been developed as a second-generation DES. The study aim was to: (1) demonstrate that use of the EES in Japanese patients is non-inferior to use of the paclitaxel-eluting stent (PES) in US patients; and (2) compare vessel response to the EES in Japanese vs US patients. METHODS: The SPIRIT III Japan Registry, a prospective single-arm multicenter study was a part of the SPIRIT III global clinical program using harmonization by doing. The primary endpoint was in-segment late loss at 8 months, compared to US PES. RESULTS: A total of 88 subjects were enrolled in the Japan EES group. Angiographic in-segment late loss was significantly less in Japan EES vs US PES (0.15 ± 0.34 mm vs 0.28 ± 0.48 mm, respectively; P=.0185; Pnon-inferio r<.0001), while target vessel failure (TVF; 8.0% vs 9.9%) and major adverse cardiac events (MACE) at 9 months (5.7% vs 8.8%) were not significantly different between the 2 groups. No differences were observed between Japan and US EES populations in terms of late loss, TVF, or MACE. Neointimal volume and postprocedural incomplete stent apposition rate were lower in Japan EES vs US EES/PES. CONCLUSION: The SPIRIT III Japan Registry met the primary endpoint of lower late loss in the Japan EES group vs the US PES group, with comparable results for EES between the Japanese and US patients.

Risk factors for mortality in patients with Mallory-Weiss syndrome.

BACKGROUND/AIMS: Although the majority of patients with Mallory-Weiss syndrome (MWS) have a benign course, in some patients MWS results in a fatal outcome. Therefore, this study was carried out to analyze the risk factors for mortality in patients with MWS. METHODOLOGY: The medical records of patients with MWS seen between March 1994 and July 2007 were reviewed retrospectively. The demographic characteristics, clinical and laboratory parameters, and endoscopic findings of the patients were analyzed and the risk factors for mortality were evaluated. RESULTS: A total of ninety-three patients (13 female and 80 male patients; median age, 53 years) were treated. The mortality rate was 9.7% (9/93). The patients with a fatal outcome were of advanced age and had a higher frequency of shock on arrival, lower hemoglobin level, more prolonged prothrombin time, higher AST and ALT levels, higher frequency of detection of exposed vessels on endoscopy, higher frequency of rebleeding, longer hospital stay, and required a larger volume of blood transfusion than those who did not have a fatal outcome. According to the results of a multivariate analysis, the significant risk factors for mortality in the MWS patients were advanced age (OR 1.222, 95% CI 1.015-1.028), very low hemoglobin level (OR 2.137, 95% CI 1.063-4.295), elevated AST level (OR 1.007, 95% CI 1.001-1.013), and presence of the clinical symptom of tarry stool (OR 45.45, 95% CI 1.080-1000). CONCLUSIONS: Intensive care with close monitoring is required for patients of advanced age with a low hemoglobin level, an elevated AST level, and the clinical symptom of tarry stool, since these are of prognostic importance in terms of the mortality in MWS patients.

Solitary Peutz-Jeghers type hamartomatous polyps in the duodenum are not always associated with a low risk of cancer: two case reports.

INTRODUCTION: A hamartomatous polyp without associated mucocutaneous pigmentation or a family history of Peutz-Jeghers Syndrome is diagnosed as a solitary Peutz-Jeghers type hamartomatous polyp. As compared with Peutz-Jeghers Syndrome, Peutz-Jeghers type hamartomatous polyps are diagnosed with a lower risk of cancer and are regarded as a different disorder. CASE PRESENTATION: In case one, we describe an 84-year-old Japanese man with a 14 mm duodenal polyp. Endoscopic mucosal resection was performed and histological examination showed findings suggestive of a hamartomatous polyp with a focus of well-differentiated adenocarcinoma. In case two, we describe a 76-year-old Japanese man who had been treated for prostate, rectal and lung cancer. Upper gastrointestinal endoscopy revealed a duodenal polyp measuring 15 mm in diameter. Endoscopic mucosal resection was performed, and histological examination showed findings suggestive of a hamartomatous polyp. Liver and thyroid cancers were found after the endoscopic treatment. CONCLUSION: Although duodenal solitary hamartomatous polyps are associated with a lower risk of cancer, four patients, including our cases, have been diagnosed with cancerous polyps. Patients with duodenal solitary hamartomatous polyps should be treated by endoscopic or surgical resection and need whole-body screening.

An enzymatic photometric assay for 2-deoxyglucose uptake in insulin-responsive tissues and 3T3-L1 adipocytes.

An enzymatic assay adapted to photometric analysis with 96-well microplates was evaluated for the measurement of 2-deoxyglucose (2DG) uptake in insulin-responsive tissues and differentiated 3T3-L1 adipocytes. For in vivo measurements, a small amount of nonradiolabeled 2DG was injected into mice without affecting glucose metabolism. For photometric quantification of the small amount of 2-deoxyglucose 6-phosphate (2DG6P) that accumulates in cells, we introduced glucose-6-phosphate dehydrogenase, glutathione reductase, and 5,5'-dithiobis(2-nitrobenzoic acid) to the recycling amplification reaction of NADPH. We optimized the enzyme reaction for complete oxidation of endogenous glucose 6-phosphate (G6P) and glucose in mouse tissues in vivo and serum as well as in 3T3-L1 adipocytes in vitro. All reactions are performed in one 96-well microplate by consecutive addition of reagents, and the assay is able to quantify 2DG and 2DG6P in the range of 5-80 pmol. The results obtained with the assay for 2DG uptake in vitro and in vivo in the absence or presence of insulin stimulation was similar to those obtained with the standard radioisotopic method. Thus, the enzymatic assay should prove to be useful for measurement of 2DG uptake in insulin-responsive tissues in vivo as well as in cultured cells.