The glucagon-like peptide-1 receptor agonist, liraglutide, attenuates the progression of overt diabetic nephropathy in type 2 diabetic patients.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Glucagon-like peptide-1 (GLP-1) is one of the incretins, gut hormones released from the intestine in response to food intake. GLP-1 receptor (GLP-1R) agonists have been used to treat type 2 diabetes. Here, we studied the effect of the administration of a GLP-1R agonist, liraglutide, on proteinuria and the progression of overt DN in type 2 diabetic patients. Twenty-three type 2 diabetic patients with overt DN, who had already been treated with blockade of renin-angiotensin system under dietary sodium restriction, were given liraglutide for a period of 12 months. Treatment with liraglutide caused a significant decrease in HbA1c from 7.4 ± 0.2% to 6.9 ± 0.3% (p = 0.04), and in body mass index (BMI) from 27.6 ± 0.9 kg/m² to 26.5 ± 0.8 kg/m² after 12 months (p < 0.001), while systolic blood pressure did not change. The progression of DN was determined as the rate of decline in estimated glomerular filtration rate (eGFR). The 12-month administration of liraglutide caused a significant decrease in proteinuria from 2.53 ± 0.48 g/g creatinine to 1.47 ± 0.28 g/g creatinine (p = 0.002). The administration of liraglutide also substantially diminished the rate of decline in eGFR from 6.6 ± 1.5 mL/min/1.73 m²/year to 0.3 ± 1.9 mL/min/1.73 m²/year (p = 0.003). Liraglutide can be used not only for reducing HbA1c and BMI, but also for attenuating the progression of nephropathy in type 2 diabetic patients.

Association of depression and suicidal ideation with unreasonable patient demands and complaints among Japanese physicians: a national cross-sectional survey.

BACKGROUND: Physicians' mental health can be affected by unreasonable demands and complaints made by patients. PURPOSE: The purpose of this study is to determine the association between depressive symptoms and suicidal ideation among physicians working in hospitals in Japan and unreasonable patient demands and complaints. METHODS: We sent an anonymous questionnaire to 10,000 randomly selected physicians working at hospitals who were members of the Japan Medical Association. The anonymous self-report questionnaire sought to determine the number of unreasonable demands and complaints made by patients or their family members reported by physicians in the previous 6 months. Depressive symptoms and suicidal ideation were measured using the Japanese version of the Quick Inventory of Depressive Symptomatology (QIDS). Logistic regression analysis was used to explore the associations of depressive symptoms and suicidal ideation with reported unreasonable demands and complaints. RESULTS: Among the 3,864 respondents, men (46.3%) reported experiencing unreasonable patient demands and complaints more frequently than women (40.4%). Depressive symptoms were indicated in 8.3% of men and 10.5% of women, and 5.7% of men and 5.8% women were determined to exhibit suicidal ideation. The number of unreasonable demands and complaints in the previous 6 months was significantly associated with depressive symptoms and suicidal ideation for both men and women (P for trend <0.01). CONCLUSIONS: Physicians should recognize the health risks of unreasonable demands and complaints, and hospitals should provide support for physicians dealing with these stressors.

National survey of the association of depressive symptoms with the number of off duty and on-call, and sleep hours among physicians working in Japanese hospitals: a cross sectional study.

BACKGROUND: Physicians' mental health may be adversely affected by the number of days of work and time spent on-call, and improved by sleep and days-off. The aim of this study was to determine the associations of depressive symptoms with taking days of off duty, hours of sleep, and the number of days of on-call and overnight work among physicians working in Japanese hospitals. METHODS: A cross-sectional study as a national survey was conducted by mail. The study population was 10,000 randomly selected physicians working in hospitals who were also members of the Japan Medical Association (response rate 40.5%). Self-reported anonymous questionnaire was sent to assess the number of days off-duty, overnight work, and on-calls, and the average number of sleep hours on days not working overnight in the previous one month. Depressive state was determined by the Japanese version of the Quick Inventory of Depressive Symptomatology. Logistic regression analysis was used to explore the associations between depressive symptoms and the studied variables. RESULTS: Among the respondents, 8.3% of men and 10.5% of women were determined to be depressed. For both men and women, depressive state was associated with having no off-duty days and averaging less than 5 hours of sleep on days not doing overnight work. Depressive state was positively associated with being on-call more than 5 days per month for men, and more than 8 days per month for women, and was negatively associated with being off-duty more than 8 days per month for men. CONCLUSION: Some physicians need some support to maintain their mental health. Physicians who do not take enough days-off, who reduced sleep hours, and who have certain number of days on-calls may develop depressive symptoms.

Effect of Evolocumab on Vulnerable Coronary Plaques: A Serial Coronary Computed Tomography Angiography Study.

This study investigated the effects of evolocumab on vulnerable coronary plaques and factors associated with the change in stability and size of plaques in patients taking statins. Vulnerable coronary plaques were defined using coronary computed tomography (CT) angiography as having a density of <50 HU within the region of interest and a remodeling index ≥1.1. The changes in minimum CT density, remodeling index, and percent stenosis of vulnerable coronary plaques after six months of evolocumab administration were retrospectively analyzed in 136 vulnerable coronary plaques from 98 patients (68 men and 30 women; mean age: 72.9 ± 8.7 years) treated with a statin. The administration of evolocumab significantly increased the minimum CT density (39.1 ± 8.1 HU to 84.9 ± 31.4 HU, p < 0.001), reduced the remodeling index (1.29 ± 0.11 to 1.19 ± 0.10, p < 0.001), and decreased the percent stenosis (27.0 ± 10.4% to 21.2 ± 9.8%, p < 0.001). Multiple linear regression analysis revealed that baseline percent stenosis (standard coefficient (ß) = -0.391, p = 0.002) independently correlated with the change in minimum CT density, whereas the baseline remodeling index (ß = -0.368, p < 0.001) independently correlated with a change in the remodeling index. Evolocumab stabilized vulnerable coronary plaques and reduced their size. These results suggest that evolocumab protects against coronary artery disease progression in patients taking statins.

Effects of Evolocumab on Carotid Intima-Media Thickness and Clinical Parameters in Patients Taking a Statin.

We determined the effects of evolocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, on carotid intima-media thickness (IMT) and the factors associated with the change in carotid IMT in patients taking a statin. The change in carotid mean and maximum IMT before and after the initiation of evolocumab treatment was retrospectively analyzed in 229 statin-treated patients. The changes in clinical parameters, including serum lipid concentrations, were also evaluated. Evolocumab significantly reduced the increase in carotid mean and maximum IMT (0.09 ± 0.13 mm/year to -0.04 ± 0.16 mm/year, p < 0.001 and 0.17 ± 0.38 mm/year to 0.08 ± 0.47 mm/year, p = 0.02). Evolocumab reduced serum total cholesterol, low-density lipoprotein-cholesterol, triglyceride, and lipoprotein (a) concentrations (each p < 0.001), and increased serum high-density lipoprotein (HDL)-cholesterol concentrations (p = 0.01). Multiple linear regression analysis revealed that the change in HDL-cholesterol (standard coefficient (ß) = -0.120, p = 0.04) and carotid mean IMT (ß = -0.467, p < 0.001) were independently correlated with the change in carotid mean IMT during the administration of evolocumab, whereas the change in HDL-cholesterol (ß = -0.208, p = 0.002) and log-triglyceride (ß = -0.167, p = 0.01) independently correlated with the change in carotid maximum IMT. Evolocumab reduced the increase in carotid IMT in patients taking a statin. These results suggest that evolocumab is protective against carotid atherosclerosis in patients undergoing statin therapy.

Pharmacogenetics of hormone replacement therapy for climacteric symptoms.

Hormone replacement therapy (HRT) is highly effective for women suffering from climacteric symptoms, with occasionally severe side effects. To determine which women needs HRT for climacteric symptoms indeed, pharmacogenetical approach for HRT was performed. Under the condition of minimal HRT, 33 patients required HRT for more than 1 year and the remaining 156 did not. Three single nucleotide polymorphisms (SNPs) in estrogen receptor alpha (ERalpha) gene and 3 SNPs and a microsatellite polymorphism in estrogen receptor beta (ERbeta) gene were analyzed using LightTyper and PCR. Homozygous for 18 CA repeats of D14S1026 (OR 8.00, 95% CI 2.56-25.02, P<0.001) and rs1256049 (OR 6.35, 95% CI 2.38-16.92, P=0.004) in ERbeta associated with minimal HRT. In contrast, rs1271572 in 789bp upstream region of ERbeta (OR 0.30, 95% CI 0.14-0.65, P=0.002) gene decreased HRT. rs2228480 in ERalpha gene also increased HRT. Tailored decisions can be expected on the future use of HRT referring genetic polymorphisms of individuals.

Risk factors and utility of maximum carotid intima-media thickness as a surrogate marker for coronary artery stenosis.

BACKGROUND: This study investigated the factors associated with coronary artery stenosis in outpatients. Furthermore, the usefulness of maximum carotid intima-media thickness (maximum-IMT) as a surrogate marker of coronary artery stenosis was evaluated. METHODS: We conducted a single-center retrospective study. A total of 601 outpatients (338 males; 263 females; mean age, 69.8±10.0 years) who underwent coronary computed tomography angiography between April 2006 and March 2012 were analyzed. The associations between coronary artery stenosis (≥75%) as determined by coronary computed tomography angiography and clinical and laboratory parameters were evaluated by multivariate logistic regression. Validation of maximum-IMT as measured by ultrasonography as a surrogate marker of coronary artery stenosis was analyzed by receiver operating characteristic (ROC) curve analysis. RESULTS: The estimated glomerular filtration rate (eGFR: mL/min/1.73 m2) (odds ratio [OR] 0.985, p<0.01), diabetes mellitus (OR 1.98, p<0.05), and maximum-IMT (mm) (OR 1.76, p<0.01) were significantly associated with coronary artery stenosis (≥75%). In analysis of each group categorized by identified factors, such as renal impairment (eGFR <60 mL/min/1.73 m2) and diabetes mellitus, the ROC curve of maximum-IMT was significant in the group of patients with diabetes mellitus without renal impairment (p<0.01) (cutoff value of maximum-IMT, 2.0 mm; sensitivity, 0.74; and specificity, 0.54) but not in other groups. CONCLUSION: Renal impairment, diabetes mellitus, and increased maximum-IMT may be significant risk factors of coronary artery stenosis. Maximum-IMT as measured by ultrasonography may be a useful surrogate marker for coronary artery stenosis in patients with diabetes mellitus without renal impairment but not in other patients.

Association of cytosine-adenine repeat polymorphism of the estrogen receptor-beta gene with menopausal symptoms.

BACKGROUND: The nature and severity of menopausal symptoms are highly variable among women. Polymorphisms of the estrogen receptor-beta (ERbeta) gene, such as cytosine-adenine (CA) dinucleotide repeats in intron 5, have been implicated in various diseases. OBJECTIVE: We investigated the possible role of a CA dinucleotide repeat polymorphism in intron 5 of the ERbeta gene in the occurrence of menopausal and premenstrual symptoms. METHODS: Fifty-one postmenopausal Japanese women were interviewed about premenstrual symptoms, menopausal symptoms, and use of hormone replacement therapy. Menopausal symptoms were divided into vasomotor, psychological, and musculoskeletal symptoms, and summary scores were created on the basis of severity. CA repeat polymorphism of the ERbeta gene was examined using denaturing high-performance liquid chromatography with the WAVE DNA Fragment Analysis System (Transgenomic Inc., Omaha, Nebraska). RESULTS: The number of CA repeats of the ERP gene ranged from 14 to 25, and subjects could be divided into 3 groups: those with < or =17 repeats, or extremely short (E); 18 to 21 repeats, or short (S); and > or =22 repeats, or long (L). Four genotypes of CA repeats (EL, SS, SL, and LL) were found among the subjects, with SL being the most common. Relative to subjects with the SL genotype, women with SS had a 7.0-fold increased risk of vasomotor symptoms (odds ratio [OR] = 7.0; 95% CI, 1.25-39.15; P < 0.05), a 13.0-fold higher risk of psychological symptoms (OR = 13.0; 95% CI, 1.44-117.2; P < 0.01), and a 7.6-fold increased risk of premenstrual symptoms (OR = 7.6; 95% CI, 1.61-35.9; P = 0.01). The EL genotype was associated with an increased risk of vasomotor symptoms (P < 0.05), depression (P < 0.01), and premenstrual symptoms (P < 0.01). CONCLUSIONS: CA repeat polymorphism of the ERbeta gene may be associated with menopausal and premenstrual symptoms. Premenstrual symptom scores were significantly related to menopausal symptom scores.

Azelnidipine and amlodipine: a comparison of their pharmacokinetics and effects on ambulatory blood pressure.

We objected: 1) To compare the effects of azelnidipine and amlodipine on 24-h blood pressure; 2) To monitor the plasma concentration vs. the time profile in order to assess the association between pharmacokinetics and hypotensive activity after administration of either drug for 6 weeks. Blood pressure and pulse rate were measured by 24-h monitoring with a portable automatic monitor in a randomized double-blind study of 46 patients with essential hypertension. Azelnidipine 16 mg (23 patients) or amlodipine 5 mg (23 patients) was administered once daily for 6 weeks. Pharmacokinetics were analyzed after the last dose was taken. Both drugs showed similar effects on the office blood pressure and pulse rate. During 24-h monitoring, both drugs caused a decrease in systolic blood pressure of 13 mmHg and had a similar hypotensive profile during the daytime period (07:00-21:30). The pulse rate decreased by 2 beats/min in the azelnidipine group, whereas it significantly increased by 4 beats/min in the amlodipine group. Similar trends in the blood pressure and pulse rate were observed during the nighttime (22:00-6:30) and over 24 h. Excessive blood pressure reduction during the nighttime was not seen in either group. The pharmacokinetic results indicated that the plasma half-life (t1/2) of amlodipine was 38.5 +/- 19.8 h and that of azelnidipine was 8.68 +/- 1.33 h. Despite this difference in pharmacokinetics, the hypotensive effects of amlodipine and azelnidipine were similar throughout the 24-h administration period.

[Electronic links between hospitals or clinics and pharmacies: structure and operation of WAKASHIO pharmacotherapeusis network].

We developed the WAKASHIO Pharmacotherapeusis Network system. This system electronically links physicians' offices with pharmacies to share clinical records and offers the means for real time bi-directional information input. The system is equipped with individual signature (handwriting) recognition protocols to ensure strict enforcement of security and privacy. The network enables front-line pharmacists to access to pertinent clinical records. We performed a series of tests (a "shakedown cruise") of the system and examined the role of the pharmacist as a counselor for patient compliance with prescribed therapeutic regimens. The results indicated the following: 1) This system provides an unequivocal means of communication between physicians and pharmacists. 2) This system is useful for judicious resolution of potential problems arising from separation of the domains of prescriber and dispenser. 3) A noteworthy finding was that community pharmacists devote substantial time/effort to counseling patients concerning their pharmacotherapeutic regimens. 4) Over 80% of patients responded with statements such as "Now I understand my medicines better," and "I am free of anxiety over my medication now." Thus the system provides a powerful tool to promote patient compliance based on pharmacological knowledge. Our future plans for the system include: 1) implementation of an inquiry/response protocol to enhance risk management; 2) online prescription issuance; and 3) expansion of the database used for patient counseling and improvement of the counseling method. Finally, physician-pharmacist collaboration through the system will contribute to a clear redefinition of their respective roles in community medical care services.

[Contributions of certified diabetes educator (CDE) on the improvement of medical services for diabetes in the Sanbu area].

The age-adjusted mortality rate by diabetes mellitus in Chiba prefecture is significantly higher than that of the national average. In the Sanbu medical service area where our hospital is located, there are many patients who are suffering from diabetic complications due to low recognition of diabetes. On the other hand, the number of doctors in the Sanbu area is lower than a half of the national average. In this report, we introduce the activity of medical services provided by a member of the lifestyle-related disease control team, which mainly consist with CDEs. The lifestyle-related disease control team was established in June 2003 for providing improved medical services for lifestyle related diseases and for the primary and secondary prevention of diabetes. The member of the medical team is required to accumulate experience in teaching patients and to continuously improve the quality of medical treatment.

Lamotrigine in binge-eating disorder associated with bipolar II depression and treatment-resistant type 2 diabetes mellitus: a case report.

BACKGROUND: Lamotrigine (LMG) is an anticonvulsant currently registered for the treatment of bipolar disorder (BP) depression. We report the case of a 61-year-old woman with comorbid binge-eating disorder (BED), BP depression, and treatment-resistant type 2 diabetes mellitus (T2DM), in which LMG showed significant efficacy against BED and BP depression and resulted in a drastic decrease in plasma glucose levels. CASE REPORT: The patient had had untreated BP depression, BED, and T2DM for more than 30 years. We prescribed LMG at 25 mg/d for BP depression and titrated it up to 50 mg/d over 4 weeks, then maintained this dose for the next 16 weeks. At follow-up after the first 4-week period, she reported a significant decrease in compulsive eating impulses and depressive mood, and her positive reports were consistent in the following months. Hemoglobin A1c levels at National Glycohemoglobin Standardization Program decreased drastically from 9.6% to 7.1% over the 20 weeks after initiating treatment. CONCLUSION: This case suggests that LMG might be beneficial for BED with concomitant BP depression, and potentially for treatment-resistant T2DM, if this refractoriness is identified to result from comorbidity of BED and BP.

One-step detection of the 2009 pandemic influenza A(H1N1) virus by the RT-SmartAmp assay and its clinical validation.

BACKGROUND: In 2009, a pandemic (pdm) influenza A(H1N1) virus infection quickly circulated globally resulting in about 18,000 deaths around the world. In Japan, infected patients accounted for 16% of the total population. The possibility of human-to-human transmission of highly pathogenic novel influenza viruses is becoming a fear for human health and society. METHODOLOGY: To address the clinical need for rapid diagnosis, we have developed a new method, the "RT-SmartAmp assay", to rapidly detect the 2009 pandemic influenza A(H1N1) virus from patient swab samples. The RT-SmartAmp assay comprises both reverse transcriptase (RT) and isothermal DNA amplification reactions in one step, where RNA extraction and PCR reaction are not required. We used an exciton-controlled hybridization-sensitive fluorescent primer to specifically detect the HA segment of the 2009 pdm influenza A(H1N1) virus within 40 minutes without cross-reacting with the seasonal A(H1N1), A(H3N2), or B-type (Victoria) viruses. RESULTS AND CONCLUSIONS: We evaluated the RT-SmartAmp method in clinical research carried out in Japan during a pandemic period of October 2009 to January 2010. A total of 255 swab samples were collected from outpatients with influenza-like illness at three hospitals and eleven clinics located in the Tokyo and Chiba areas in Japan. The 2009 pdm influenza A(H1N1) virus was detected by the RT-SmartAmp assay, and the detection results were subsequently compared with data of current influenza diagnostic tests (lateral flow immuno-chromatographic tests) and viral genome sequence analysis. In conclusion, by the RT-SmartAmp assay we could detect the 2009 pdm influenza A(H1N1) virus in patients' swab samples even in early stages after the initial onset of influenza symptoms. Thus, the RT-SmartAmp assay is considered to provide a simple and practical tool to rapidly detect the 2009 pdm influenza A(H1N1) virus.

Integrated care through disease-oriented clinical care pathways: experience from Japan's regional health planning initiatives.

INTRODUCTION: In April 2008, Japan launched a radical reform in regional health planning that emphasized the development of disease-oriented clinical care pathways. These 'inter-provider critical paths' have sought to ensure effective integration of various providers ranging among primary care practitioners, acute care hospitals, rehabilitation hospitals, long-term care facilities and home care. DESCRIPTION OF POLICY PRACTICE: All 47 prefectures in Japan developed their Regional Health Plans pursuant to the guideline requiring that these should include at least four diseases: diabetes, acute myocardial infarction, cerebrovascular accident and cancer. To illustrate the care pathways developed, this paper describes the guideline referring to strokes and provides examples of the new Regional Health Plans as well as examples of disease-oriented inter-provider clinical paths. In particular, the paper examines the development of information sharing through electronic health records (EHR) to enhance effective integration among providers is discussed. DISCUSSION AND CONCLUSION: Japan's reform in 2008 is unique in that the concept of 'disease-oriented regional inter-provider critical paths' was adopted as a national policy and all 47 prefectures developed their Regional Health Plans simultaneously. How much the new regional health planning policy has improved the quality and outcome of care remains to be seen and will be evaluated in 2013 after the five-year planned period of implementation has concluded. Whilst electronic health records appear to be a useful tool in supporting care integration they do not guarantee success in the application of an inter-provider critical path.

Mutation analysis of 2009 pandemic influenza A(H1N1) viruses collected in Japan during the peak phase of the pandemic.

BACKGROUND: Pandemic influenza A(H1N1) virus infection quickly circulated worldwide in 2009. In Japan, the first case was reported in May 2009, one month after its outbreak in Mexico. Thereafter, A(H1N1) infection spread widely throughout the country. It is of great importance to profile and understand the situation regarding viral mutations and their circulation in Japan to accumulate a knowledge base and to prepare clinical response platforms before a second pandemic (pdm) wave emerges. METHODOLOGY: A total of 253 swab samples were collected from patients with influenza-like illness in the Osaka, Tokyo, and Chiba areas both in May 2009 and between October 2009 and January 2010. We analyzed partial sequences of the hemagglutinin (HA) and neuraminidase (NA) genes of the 2009 pdm influenza virus in the collected clinical samples. By phylogenetic analysis, we identified major variants of the 2009 pdm influenza virus and critical mutations associated with severe cases, including drug-resistance mutations. RESULTS AND CONCLUSIONS: Our sequence analysis has revealed that both HA-S220T and NA-N248D are major non-synonymous mutations that clearly discriminate the 2009 pdm influenza viruses identified in the very early phase (May 2009) from those found in the peak phase (October 2009 to January 2010) in Japan. By phylogenetic analysis, we found 14 micro-clades within the viruses collected during the peak phase. Among them, 12 were new micro-clades, while two were previously reported. Oseltamivir resistance-related mutations, i.e., NA-H275Y and NA-N295S, were also detected in sporadic cases in Osaka and Tokyo.

Vasospastic angina in a 13-year-old female patient whose only symptom was toothache.

Vasospastic angina was confirmed in a 13-year-old female patient at autopsy. The patient's only symptom was recurrent toothache, which began when she was 10 years old. In November 2000, she was evaluated at our medical center; however, all examinations were judged normal. Six months later, she suffered a severe toothache. She went to school the next morning after the symptoms improved. She lost consciousness at school and was given cardiopulmonary resuscitation but could not be revived. At autopsy, her three coronary vessels showed marked intimal hyperplasia, and multiple focal myocardial infarctions were observed in the lateral wall of the left ventricle. The patient's only clinical symptom was toothache and none of the physicians realized that this was caused by angina. Vasospastic angina begins at a young age and is one of the causes of sudden death in adolescents.