Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week,open-label,controlled trial (STOP-OB)

Metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i) is the most common therapy for Japanese patients with type 2 diabetes. This 24-week, multicentre, open-label, parallel-group trial randomized patients on dual therapy to add-on tofogliflozin (20 mg/day, n = 33) or glimepiride (0.5 mg/day, n = 31). The primary outcome was change in body fat percentage. The secondary outcomes included changes in HbA1c, fat mass, fat-free mass, liver function variables and uric acid. Tofogliflozin and glimepiride reduced HbA1c to a similar extent. Body fat percentage did not change from baseline in either group. Fat mass was reduced by tofogliflozin but was increased by glimepiride (by −2.0 ± 1.7 kg and +1.6 ± 1.6 kg, P = .002). Fat-free mass was also reduced by tofogliflozin and increased by glimepiride (by −1.3 ± 1.3 kg and +0.9 ± 2.0 kg, P < .001). Alanine aminotransferase and uric acid levels were reduced by tofogliflozin (P = .006 and P < .001, respectively). These data provide novel information useful for selecting the third oral agent for patients whose diabetes is inadequately controlled with metformin plus DPP-4i dual therapy.     

IL-1 Receptor Antagonist Blocks the Lipopolysaccharide-Induced Inhibition of Gastric Motility in Freely Moving Conscious Rats

Background and Aims

Endotoxin/lipopolysaccharide (LPS) alters gastrointestinal functions. However, little is known as to whether LPS could change gastric antral contractility in freely moving conscious animals. We tried to clarify this problem and the associated mechanisms.

Methods

In this study, we recorded intraluminal gastric pressure waves in freely moving conscious rats by manometric catheter located in the antrum. Area under the manometric trace was evaluated as motor index (MI).

Results

Intraperitoneal injection of LPS at doses of 0.2?mg/kg or more significantly inhibited MI. The inhibition started immediately after the administration of LPS and lasted over 1?h. Intraperitoneal injection of IL-1β potently decreased MI while neither IL-6 nor TNF-α inhibited gastric motility, suggesting IL-1β specifically reduced gastric motility. Next, we examined the hypothesis that endogenous IL-1 mediates the LPS-induced inhibition of gastric motility. To address the speculation, an IL-1 receptor antagonist (IL-1Ra) was used to block IL-1 signaling. Pretreatment with IL-1Ra at a dose of 20?mg/kg significantly blocked the inhibition of gastric contractility by LPS at a dose of 0.2?mg/kg.

Conclusions

These results suggest for the first time that LPS or IL-1β is capable of inhibiting gastric motility in conscious rats and that endogenously released IL-1 may mediate the LPS-evoked inhibition of gastric antral motility. This evidence also led us to speculate that IL-1Ra may be a therapeutic tool for patients with disturbed gastrointestinal functions under septic conditions.     

Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia

Fifty percent of Diamond-Blackfan anemia (DBA) patients possess mutations in genes coding for ribosomal proteins (RPs). To identify new mutations, we investigated large deletions in the RP genes RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26. We developed an easy method based on quantitative-PCR in which the threshold cycle correlates to gene copy number. Using this approach, we were able to diagnose 7 of 27 Japanese patients (25.9%) possessing mutations that were not detected by sequencing. Among these large deletions, similar results were obtained with 6 of 7 patients screened with a single nucleotide polymorphism array. We found an extensive intragenic deletion in RPS19, including exons 1-3. We also found 1 proband with an RPL5 deletion, 1 patient with an RPL35A deletion, 3 with RPS17 deletions, and 1 with an RPS19 deletion. In particular, the large deletions in the RPL5 and RPS17 alleles are novel. All patients with a large deletion had a growth retardation phenotype. Our data suggest that large deletions in RP genes comprise a sizable fraction of DBA patients in Japan. In addition, our novel approach may become a useful tool for screening gene copy numbers of known DBA genes.     

Causes of thrombocytopenia in chronic hepatitis C viral infection

We retrospectively studied 89 patients with chronic hepatitis C virus (HCV) infection, including 50 chronic hepatitis (CH) cases, 18 liver cirrhosis (LC) cases, and 21 LC with hepatocellular carcinoma (LC + HCC) cases, with regard to various factors related with thrombocytopenia. The platelet count decreased with the stage advancement of liver diseases. Multiple regression analysis revealed that splenomegaly and von Willebrand factor (vWF) were explanatory variables that correlated with thrombocytopenia. Splenomegaly appears to be the most responsible factor, although there are a considerable number of thrombocytopenic cases without splenomegaly, suggesting other factors may also be responsible. The vWF level is inversely correlated with the platelet count. Soluble thrombomodulin, a marker of endothelial dysfunction, increases with the advancement of liver fibrosis. It is positively correlated with vWF and inversely with the platelet count. Our present results imply that vascular endothelial dysfunction is also involved in thrombocytopenia during chronic HCV infection.     

A case of left ventricular aneurysm caused by localized myocardial infarction

A 73-year-old man was hospitalized for unstable angina pectoris with no history of myocardial infarction. After undergoing percutaneous coronary intervention, left ventriculography incidentally revealed a cavity in the anterior wall, and echocardiography found the cavity wall to be dyskinetic. Myocardial contrast echocardiography revealed that the wall of the cavity was surrounded by myocardial tissue with low perfusion. Furthermore, radial strain in the wall of the cavity was low. Myocardial scintigraphy showed a localized defect on the anterior wall. The patient was finally diagnosed as true aneurysm after asymptomatic and localized myocardial infarction, and has since been followed up by echocardiography in the outpatient clinic.     

Construction of revised versions of the self-perception profile for children, adolescents and college students in Japan

This study developed revised Japanese versions of the self-perception profile for Children, for Adolescents and for College Students. The original versions have an idiosyncratic and time-consuming item format, which was revised by using only one statement for each item. Subjects were fifth to sixth grade students (Boys=129, Girls= 152), tenth to twelfth grade students (Boys=112, Girls=100), and college students (Boys=96, Girls=153) in Japan. The reliability and validity measures showed that the revised versions were similar to the original versions. The present study provides some evidence for the use of these scales with Japanese students.     

Circadian rhythm of serum concentration of small dense low-density lipoprotein cholesterol

BACKGROUND: The atherogenicity of small dense low-density lipoprotein (sdLDL) has been reported and recently a new easy-handling method for measuring serum concentration of sdLDL cholesterol (sdLDLC) has been developed. Using this method, we observed the circadian rhythm of sdLDLC to determine the adequacy of fasting measurement of it and to seek the modulator of the atherogenic lipoprotein. METHODS: Study population was consisted of 20 healthy volunteers (10 women and 10 men, mean age 28 y). They had 3 meals per day and blood samples were taken before and 2 h after every meal and next morning. Serum concentrations of sdLDLC and other valuables including triglyceride (TG) and remnant-like particles cholesterol (RLPC) were determined. RESULTS: Serum concentration of sdLDLC had a unique circadian rhythm that was highest before breakfast (fasting status), decreased after each meal, hit the bottom after dinner and then increased during at night. Fasting sdLDLC was highly correlated with TG levels. The sum of the 6 TG values during a day (i.e., average TG level) had higher correlation coefficient with sdLDLC than fasting TG or fasting RLPC. CONCLUSIONS: From the observation of the unique circadian rhythm, measuring sdLDLC at fasting status is exactly reasonable because it never underestimate the risk of atherosclerotic diseases. Measuring sdLDLC can also be used as a marker for average TG levels regardless of the existence of postprandial hyperlipidemia.