Bi-weekly Glycated Albumin Measurement was Useful to Encourage Behavioral Changes in People with Type 2 Diabetes Mellitus.

INTRODUCTION: Hemoglobin A1c (HbA1c), representing the average blood glucose over 1-2 months, is the most commonly used glycemic marker in people with diabetes. Glycated albumin (GA) reflects the average blood glucose over the most recent 1-2 weeks. We considered whether the faster response of GA compared with HbA1c could make people with diabetes realize their glycemic control intuitively and effectively. METHODS: We randomized 61 people with diabetes into the control and intervention groups. Blood samples were collected from both every fortnight over an 8-week period (five times; visit 1-5). Only the intervention group was notified of the GA levels on the same day. At the beginning and end of the study, International Physical Activity Questionnaire and Eating Behavior Questionnaire assessments, and body composition measurements were conducted. RESULTS: The body weight change was significantly lower in the intervention group at visit 2 and visit 5. The percent body fat change was lower, while the percent skeletal muscle mass change at visit 5 was higher in the intervention group. Increasing GA trend was observed in the control group, but not in the intervention group. The fasting plasma glucose and HbA1c changes at visit 5 were similar in the two groups. Physical activity level change tended to be higher in the intervention group. The YN Eating Behavior Questionnaire score changes were similar in the two groups. CONCLUSION: Bi-weekly GA measurement over an 8-week period in people with type 2 diabetes induced behavioral changes. Development of this method is expected to improve diabetes management. TRIAL REGISTRATION: UMIN000037795.

Associations of sleep quality with the skeletal muscle strength in patients with type 2 diabetes with poor glycemic control.

AIMS/INTRODUCTION: Patients with type 2 diabetes mellitus are reported to be at a high risk for sarcopenia, and are known to have a poorer sleep quality. However, the association between sleep quality and skeletal muscle in patients with type 2 diabetes mellitus is not yet precisely understood. MATERIALS AND METHODS: A total of 110 inpatients with type 2 diabetes mellitus aged 40-90 years were enrolled. The sleep quality was assessed using the Pittsburgh sleep quality index (PSQI). Skeletal muscle mass was measured using bioelectrical impedance analysis. Muscle strength was evaluated by measuring the grip strength. We also performed dietary surveys and measurements of the plasma amino acid levels. RESULTS: A high total score on the PSQI was significantly associated with reduced muscle strength, and the association persisted even after adjustments for confounders. On the other hand, adjusted analysis did not reveal any significant associations between the PSQI total score and the skeletal muscle mass. In regard to the associations with subscores of the PSQI, the scores for sleep latency, sleep efficiency, and daytime dysfunction were significantly negatively associated with the muscle strength. Although poor sleep quality was associated with a high confectionery intake and low plasma arginine, citrulline, and ornithine levels, neither confectionery intake levels nor the plasma levels of these amino acids was associated with the muscle strength. CONCLUSIONS: Our study revealed a significant association between the sleep quality and muscle strength in patients with type 2 diabetes mellitus. These results suggest that poor sleep quality is an important risk factor for sarcopenia in patients with type 2 diabetes mellitus.

Evaluation of glycated albumin levels in tears and saliva as a marker in patients with diabetes mellitus.

AIMS: Glycated albumin (GA) is a biomarker, whose level reflects glycemic control status over the previous 2 weeks. To develop a non-invasive method for evaluating glycemic control in people with diabetes mellitus, we investigated the measurement of GA levels in tears and saliva, which could be collected noninvasively. METHODS: Tear and saliva samples were collected from 48 participants with diabetes mellitus. The GA levels in the tear and saliva specimens were measured by Liquid Chromatography-Mass Spectrometry (LC-MS/MS). RESULTS: GA levels in both tear and saliva samples were significantly correlated with the GA levels in the blood (P < 0.001). Multiple regression analysis revealed that these correlations were maintained even after adjustments for the BMI, age, and nephropathy stage (P < 0.001). CONCLUSION: GA levels in tear and saliva specimens, as diabetes-related biomarkers, can be measured non-invasively. Since this measurement can be performed noninvasively and not as frequently as compared with the more invasive finger prick method, it is expected to reduce the burden on people with diabetes in terms of both the invasiveness and cost-effectiveness. In the future, we would like to verify the effect of regular GA measurement on the glycemic control while considering the clinical cost-effectiveness.

Chronic Intestinal Pseudo-obstruction with Mitochondrial Diseases.

Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder of intestinal dysmotility characterized by chronic symptoms, including vomiting and abdominal pain, associated with bowel obstruction without any mechanical obstructive causes. We herein report a case of mitochondrial diseases with recurrent duodenal obstruction that was initially diagnosed as superior mesenteric artery syndrome (SMAS) for a few years but was later diagnosed as CIPO. Since CIPO is known to be associated with mitochondrial diseases, it should be considered in the differential diagnosis of patients with mitochondrial diseases presenting with recurrent intestinal obstruction.

TP0463518, a novel inhibitor for hypoxia-inducible factor prolyl hydroxylases, increases erythropoietin in rodents and monkeys with a good pharmacokinetics-pharmacodynamics correlation.

Hypoxia-inducible factor prolyl hydroxylases (PHDs) inhibitor stabilizes hypoxia inducible factor alpha, which increases erythropoietin (EPO) expression via the hypoxia response element. Therefore, PHDs inhibitors have been developed as novel therapeutic agents for anemia. Here, we characterize the in vitro and in vivo pharmacological profiles of TP0463518, 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid, a novel potent PHDs inhibitor. TP0463518 competitively inhibited human PHD2 with a Ki value of 5.3 nM. TP0463518 also inhibited human PHD1/3 with IC50 values of 18 and 63 nM as well as monkey PHD2 with an IC50 value of 22 nM. In normal mice and rats, TP0463518 significantly increased the serum EPO levels at doses of 5 and 20 mg/kg, respectively. The correlation factors for serum EPO and the serum TP0463518 levels were 0.95 in mice and 0.92 in rats. TP0463518 also increased the serum EPO level in 5/6 nephrectomized chronic kidney disease model rats at a dose of 10 mg/kg, with a correlation factor for serum EPO and the serum TP0463518 levels of 0.82. Finally, the effect of TP0463518 in monkeys was investigated. TP0463518 was promptly removed with a half-life of 5.2 h and increased the area under the curve (AUC) of EPO at a dose of 5 mg/kg. The EPO and TP0463518 levels were also correlated. These results suggest that TP0463518 induces endogenous EPO with a strong pharmacokinetic-pharmacodynamic correlation and may contribute to desirable hemoglobin control in patients with renal anemia.

In-Hospital Mortality for Hepatic Portal Venous Gas: Analysis of 1590 Patients Using a Japanese National Inpatient Database.

BACKGROUND: Hepatic portal venous gas (HPVG) is rare but potentially serious condition. Main cause of HPVG is bowel ischemia, while detection of HPVG without bowel ischemia may have been increasing possibly due to widespread use of computed tomography. However, little is known about variation in etiologies of HPVG and mortality of HPVG with each etiology. We examined patient backgrounds, underlying diseases, and in-hospital mortality of HPVG patients using a national inpatient database. METHODS: Using the Diagnosis Procedure Combination database in Japan, we identified inpatients diagnosed with HPVG from July 1, 2010 to March 31, 2015. Patients' data included age, sex, comorbidities at admission, complications after admission, body mass index, surgical procedures, medications, and discharge status. In-hospital mortality was compared between the subgroups divided by the patient backgrounds and underlying diseases. RESULTS: A total of 1590 patients were identified during the study period. The mean age was 79.3 years old and the proportion of bowel ischemia was 53%. The overall in-hospital mortality was 27.3%. In-hospital mortality of HPVG with bowel ischemia, gastrointestinal tract (GIT) obstruction or dilation, GIT perforation, GIT infection, or sepsis was 26.8, 31.1, 33.3, 13.6, or 56.4%, respectively. Among patients with bowel ischemia, 32.2% patients received operation and their in-hospital mortality was 16.5%. CONCLUSIONS: HPVG patients in the present study were relatively older but less likely to die than those in previous studies. Attention should be paid to the fact that mortality of HPVG without bowel ischemia was not always lower compared to that with bowel ischemia.

Regional difference in cancer detection rate in prostate cancer screening by a local municipality in Japan.

PURPOSE: We conducted the present retrospective study to elucidate regional differences in the quality of secondary screening in the prostate cancer (PCA) screening program by a local municipality in Japan. METHODS: Of 115,881 men who attended the PCA screening in 36 municipalities between 2001 and 2011, a total of 6,099 men consulted hospitals for secondary screening. The cancer detection rate (CDR) at the secondary screening was calculated, and municipalities were classified into three CDR groups according to the age-adjusted observed-to-expected ratios of CDR. Of the secondary screening facilities, hospitals in Ibaraki Prefecture screening less than 100 patients were classified as group I facilities and the others as group II facilities. RESULTS: Overall, 2,320 of 6,099 secondary screening patients underwent prostate biopsy, and 1,073 men were diagnosed with PCA. The overall CDR at the secondary screening was 17.6%, but it varied from 5.6% to 34.4% among municipalities. Although there were no significant differences in age and prostate-specific antigen (PSA) distribution among the three CDR groups, a significantly higher rate of patients in low CDR municipalities visited group I facilities. Both biopsy rates and CDRs of secondary screening at group II facilities were significantly higher than those of group I facilities (P=0.0001). Multivariate analysis showed that the secondary screening at group II facilities as well as age and PSA levels were independent contributing factors for PCA detection. CONCLUSIONS: CDRs at secondary screening varied widely among municipalities in Ibaraki Prefecture. Variation in CDRs was associated with biopsy rates.

Serum S100B is a useful surrogate marker for long-term outcomes in photochemically-induced thrombotic stroke rat models.

In recent years, serum S100B has been used as a secondary endpoint in some clinical trials, in which serum S100B has successfully indicated the benefits or harm done by the tested agents. Compared to clinical stroke studies, few experimental stroke studies report using serum S100B as a surrogate marker for estimating the long-term effects of neuroprotectants. This study sought to observe serum S100B kinetics in PIT stroke models and to clarify the association between serum S100B and both final infarct volumes and long-term neurological outcomes. Furthermore, to demonstrate that early elevations in serum S100B reflect successful neuroprotective treatment, a pharmacological study was performed with a non-competitive NMDA glutamate receptor antagonist, MK-801. Serum S100B levels were significantly elevated after PIT stroke, reaching peak values 48 h after the onset and declining thereafter. Single measurements of serum S100B as early as 48 h after PIT stroke correlated significantly with final infarct volumes and long-term neurological outcomes. Elevated serum S100B was significantly attenuated by MK-801, correlating significantly with long-term beneficial effects of MK-801 on infarct volumes and neurological outcomes. Our results showed that single measurements of serum S100B 48 h after PIT stroke would serve as an early and simple surrogate marker for long-term evaluation of histological and neurological outcomes in PIT stroke rat models.

Serum S100B indicates brain edema formation and predicts long-term neurological outcomes in rat transient middle cerebral artery occlusion model.

To assess the usefulness of serum S100B as a biomarker, the present study proceeded by observing serum S100B kinetics in a rat transient middle cerebral artery occlusion (MCAO) model, then assessed the correlation between serum S100B and both brain edema formation and neurological outcomes. Study results showed increases in serum S100B concentrations, peaking 48 h after MCAO. Brain water content in the ipsilateral hemisphere significantly increased from 24 h after MCAO, and reached peak value 72 h after MCAO. A single measurement of serum S100B 48 h after MCAO showed significant correlations with maximal extent of brain edema 72 h after MCAO. Furthermore, S100B concentrations 48 h after MCAO significantly correlated with infarct volumes. Neurological outcomes were estimated in a long-term study, where a gradual recovery was observed up to 168 h after MCAO. Serum S100B 48 h after MCAO was found to show higher correlation with neurological score 168 h after MCAO than those 48 h after MCAO. These findings suggest that serum S100B is an effective biomarker in predicting both extent of brain edema and long-term neurological outcomes in a rat transient MCAO model.

Effects of TS-022, a newly developed prostanoid DP1 receptor agonist, on experimental pruritus, cutaneous barrier disruptions and atopic dermatitis in mice.

TS-022, {4-[(1R, 2S, 3R, 5R)-5-Chloro-2-((S)-3-cyclohexyl-3-hydroxyprop-1-ynyl)-3-hydroxycyclopentyl] butylthio} acetic acid monohydrate, inhibits ADP-induced platelet aggregation, an effect significantly antagonized, as in the case of prostaglandin D(2) by the prostanoid DP(1) receptor antagonist (BW A868C). TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for patients with atopic dermatitis. We examined the effects of TS-022 on experimental pruritus, cutaneous barrier disruption, and atopic dermatitis and in in vitro immune function tests. Topically applied TS-022 significantly suppressed scratching in skin-lesioned NC/Nga mice from a concentration of 2.5 nM, and this scratch-suppressive activity was significantly antagonized by BW A868C. Tacrolimus (FK-506) and dexamethasone, used as reference drugs for atopic dermatitis, also exhibited suppressive effects against scratching, but only at concentrations of 125 and 25,000 microM. TS-022 applied topically, once a day for 2 days, significantly accelerated repair of the cutaneous barrier disruption caused by mechanical scratching, from concentrations of 2.5 nM. This acceleration of repair of the disrupted cutaneous barrier by this drug was also significantly antagonized by BW A868C. FK-506 and dexamethasone showed no beneficial effects on the repair of the disrupted cutaneous barrier. Repeated topical application of 2.5 microM of TS-022 and 12.5 microM of FK-506 once a day for 6 weeks significantly improved the skin inflammation scores in the NC/Nga mice. In regard to the effects of TS-022 in vitro, the inhibitory activity of TS-022 against concanavalin A-induced cytokine production by splenocytes was marginal as compared with that of FK-506 or dexamethasone. These results suggest that the beneficial therapeutic effects of TS-022 in NC/Nga mice with atopic dermatitis are mediated by its suppressive effect on scratching and its effect of accelerating repair of the disrupted cutaneous barrier, both effects being attributable to its prostanoid DP(1) receptor agonistic activity.

Effect of a new inhibitor of the synthesis of 20-HETE on cerebral ischemia reperfusion injury.

BACKGROUND AND PURPOSE: Arachidonic acid that is released following cerebral ischemia can be metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a potent vasoconstrictor that may contribute to ischemic injury. This study examined the effects of blockading the synthesis of 20-HETE with TS-011 on infarct size after transient occlusion of the middle cerebral artery (MCAO) of rats and after thromboembolic stroke in monkeys. METHODS: Rats were treated with TS-011 or vehicle at various times after MCAO. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and plasma levels of 20-HETE were determined by liquid chromatography mass spectrometry (LC/MS). The effect of TS-011 on infarct size was also studied in monkeys after introduction of a clot into the internal carotid artery. RESULTS: Plasma levels of 20-HETE increased after MCAO in rats. TS-011 (0.01 to 1.0 mg/kg per hour) reduced infarct volume by 40%. Chronic administration of TS-011 for 7 days reduced neurological deficits after MCAO in rats. TS-011 given in combination with tissue plasminogen activator also improved neurological outcome in the stroke model in monkeys. CONCLUSIONS: These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.