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1.  Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus 
Cardiovascular (CV) complications are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis being a common risk factor for prospective crisis of coronary artery diseases and/or cerebral infarction in DM subjects. From another point of view, asymmetric dimethylarginine (ADMA) has been established as an inhibitor of endogenous nitric oxide synthesis and the relationship between ADMA and arteriosclerosis has been reported. In our study with 87 type 2 DM (T2DM) patients, we have examined whether ADMA and other CV risk factors are the useful predictors of DMCV complications. After the measurement of the respective CV risk factors, we have followed the enrolled T2DM patients for 5 years. We have finally analyzed 77 patients. DMCV complications developed in 15 cases newly within 5 years, and 4 cases recurred. The concentrations of ADMA in plasma were markedly more elevated in 19 DM patients with CV complications than in 58 DM patients without CV complications. Urinary albumin (U-Alb), mean intimal-medial thickness (IMT) and ankle brachial index (ABI) were also higher in patients with CV complications. Multiple regression analyses showed that U-Alb had an influence on the high level of ADMA (standardized β = 6.59, P = 0.00014) independently of age, systolic BP, fibrinogen, mean IMT, plaque score, and ABI. The review indicates what is presently known regarding plasma ADMA that might be a new and meaningful biomarker of CV complications in DM subjects.
PMCID: PMC4436934  PMID: 25992325
Asymmetric dimethylarginine; Biomarker; Diabetes mellitus; Cardiovascular complications; Incretin
2.  Very Short-Term Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin on the Secretion of Insulin, Glucagon, and Incretin Hormones in Japanese Patients with Type 2 Diabetes Mellitus: Analysis of Meal Tolerance Test Data 
Drugs in R&D  2014;14(4):301-308.
Sitagliptin inhibits dipeptidyl peptidase-4, which inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. To assess its antidiabetic potency, we used meal tolerance tests (MTTs) to determine the very short-term effects of sitagliptin on plasma concentrations of insulin and glucagon.
On day 1, patients with newly diagnosed or uncontrolled type 2 diabetes mellitus started a calorie-restricted diet. On day 2, the first MTT was performed, before treatment with sitagliptin 50 mg/day started later the same day. On day 5, a second MTT was performed. Area under the concentration–time curves (AUCs) of relevant laboratory values were calculated [AUC from time zero to 2 h (AUC0–2h) and from time zero to 4 h (AUC0–4h)].
Fifteen patients were enrolled. AUCs for postprandial plasma glucose were decreased after 3 days of sitagliptin treatment [AUC0–2h 457 ± 115 mg/dL·h (25.4 ± 6.4 mmol/L·h) to 369 ± 108 mg/dL·h (20.5 ± 6.0 mmol/L·h); AUC0–4h 896 ± 248 mg/dL·h (49.7 ± 13.8 mmol/L·h) to 701 ± 246 mg/dL·h (38.9 ± 13.7 mmol/L·h); both p < 0.001]. AUC0–2h and AUC0–4h for postprandial plasma glucagon also decreased: 195 ± 57 to 180 ± 57 pg/mL·h (p < 0.05) and 376 ± 105 to 349 ± 105 pg/mL·h (p < 0.01), respectively. The AUC0–2h [median with quartile values (25 %, 75 %)] for active GLP-1 increased: 10.5 (8.5, 15.2) to 26.4 (16.7, 32.4) pmol/L·h (p = 0.03).
Very short-term (3-day) treatment with sitagliptin decreases postprandial plasma glucose significantly. This early reduction in glucose may result partly from suppression of excessive glucagon secretion, through a direct effect on active GLP-1. Improvement in postprandial plasma glucose, through suppression of glucagon secretion, is believed to be an advantage of sitagliptin for the treatment of patients with type 2 diabetes.
PMCID: PMC4311653  PMID: 25420579
3.  Profile of saxagliptin in the treatment of type 2 diabetes: focus on Japanese patients 
Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as α-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.
PMCID: PMC4103926  PMID: 25050065
dipeptidyl peptidase-4; incretin hormones; saxagliptin; type 2 diabetes mellitus; Japan; efficacy; safety; patient acceptability
4.  Effects of the naturally‐occurring disaccharides, palatinose and sucrose, on incretin secretion in healthy non‐obese subjects 
Incretins might play some pathophysiological role in glucose metabolism in diabetes and obesity; it is not clear whether or not the amount and the pattern of incretin secretion vary with different types of sugars. To evaluate the effect of two types of disaccharides on glucose metabolism and the kinetics of incretin secretion, plasma levels were measured after palatinose or sucrose ingestion in non‐obese healthy participants.
Materials and Methods
The study was carried out on healthy participants who were given a solution containing 50 g of palatinose or sucrose for ingestion. Blood samples were obtained before loading and after ingestion. Insulin, glucagon and incretins hormones were measured by the enzyme‐linked immunosorbent assay method.
When the data were compared between palatinose and sucrose ingestion, both plasma glucose values at 15, 30 and 60 min, and plasma insulin values at 15 and 30 min after palatinose loading were significantly lower than those after sucrose loading. Plasma levels of total glucose‐dependent insulinotropic polypeptide at 15–90 min after palatinose loading were significantly lower than those after sucrose loading. Plasma levels of total and active glucagon‐like peptide‐1 at 90 min and the area under the curve (60–120 min) of the total glucagon‐like peptide‐1 were significantly higher with palatinose‐loading than with sucrose loading.
Compared with sucrose, palatinose appears to have a more favorable effect on glucose metabolism and protection of pancreatic islets as a result of less hyperglycemic and hyperinsulinemic potency.
PMCID: PMC4015665  PMID: 24843667
Incretin; Palatinose; Type 2 diabetes mellitus
5.  Mid-term results of acetabular reconstruction using a Kerboull-type acetabular reinforcement device 
International Orthopaedics  2011;36(1):23-26.
The purpose of this study was to investigate the mid-term results of 32 acetabular reconstructions performed using a Kerboull-type acetabular reinforcement device and bone graft between June 1997 and January 2009.
The mean age of the patients at the time of surgery was 71.4 years (range 55–85). Patients were followed-up for a mean of 7.5 years (range 2.1–13.7). The acetabular bone defects according to the American Academy of Orthopaedic Surgeons system was type III for 29 hips and type IV for three hips. Bulk allografts were performed in 30 hips and morselised autografts (iliac bone) were performed in two hips. Clinical evaluations were made according to the criteria of Postel/Merle d’Aubigné.
The mean pre-operative Postel/Merle d’Aubigné hip score was 7.0±2.9, and the final follow-up hip score was 12.6±2.8. Six hips showed radiographic loosening, and two hips required further revision. A Kaplan-Meier analysis showed that the five-year and ten-year survival rates were 96.9% and 92.3%, respectively, using further revision of the acetabular device as an end point.
Acetabular reconstruction using a Kerboull-type acetabular reinforcement device and bone graft gives satisfactory mid-term results.
PMCID: PMC3251663  PMID: 21574052
6.  Correlation between p38 mitogen-activated protein kinase and human telomerase reverse transcriptase in sarcomas 
One of the major components of telomerase is the human telomerase reverse transcriptase (hTERT) as the catalytic protein. hTERT mRNA expression are reported to be associated with prognosis and tumor progression in several sarcomas. However, there is no clear understanding of the mechanisms of hTERT in human sarcomas. Recent studies have suggested that signals transmitted through p38 mitogen-activated protein kinase (MAPK) can increase or decrease hTERT transcription in human cells. The purpose of this study was to analyse the correlation between p38 MAPK and hTERT in sarcoma samples.
We investigated 36 soft tissue malignant fibrous histiocytomas (MFH), 24 liposarcomas (LS) and 9 bone MFH samples for hTERT and p38 MAPK expression. Quantitative detection of hTERT and p38 MAPK was performed by RT-PCR.
There was a significant positive correlation between the values of hTERT and p38 MAPK in all samples (r = 0.445, p = 0.0001), soft tissue MFH (r = 0.352, p = 0.0352), LS (r = 0.704, p = 0.0001) and bone MFH samples (r = 0.802, p = 0.0093). Patients who had a higher than average expression of p38 MAPK had a significantly worse prognosis than other patients (p = 0.0036).
p38 MAPK may play a role in up-regulation of hTERT, and therefore, p38 MAPK may be a useful marker in the assessment of hTERT and patients' prognosis in sarcomas.
PMCID: PMC3296589  PMID: 22243975
p38 mitogen-activated protein kinase; human telomerase reverse transcriptase; malignant fibrous histiocytoma; liposarcoma
7.  Liposarcoma Arising in the Foot: A Case Report 
Case Reports in Medicine  2009;2009:630203.
Liposarcoma is categorized as a soft tissue sarcoma and most commonly appears in the lower extremities and rarely in the foot during adulthood. We present a very rare case report of a primary well-differentiated liposarcoma arising in the foot on a 60-year-old female. Marginal resection of the tumor with metatarsal ray amputation was eventually performed. The patient's postoperative course was uneventful without recurrence 5 years after the original operation. The authors review the literature and also report on the low incidence of this tumor arising in the foot.
PMCID: PMC2774536  PMID: 19902014
8.  Immunohistochemical expression of promyelocytic leukemia body in soft tissue sarcomas 
The function of promyelocytic leukemia (PML) bodies is not well known but plays an important role in controlling cell proliferation, apoptosis and senescence. This study was undertaken to analyze the clinical significance of PML body expression in primary tumor samples from malignant fibrous histiocytoma (MFH) and liposarcoma patients.
We studied MFH and liposarcoma samples from 55 patients for PML bodies. Fluorescent immunostaining of PML bodies was performed in the paraffin-embedded tumor sections.
PML body immunostaining was identified in 63.9% of MFH and 63.2% of liposarcoma samples. PML body expression rates of all sarcoma cells were 1.5 ± 1.8% (range: 0–7.0) in MFH and 1.3 ± 1.4% (0–5.2) in liposarcoma samples. PML body expression (p = 0.0053) and a high rate of PML body expression (p = 0.0012) were significantly greater prognostic risk factors for death than the other clinical factors in MFH patients. All liposarcoma patients without expression of PML were disease free at the end of the study.
Our study suggests that the presence of PML bodies may indicate a poor prognosis for MFH and liposarcoma patients.
PMCID: PMC2611968  PMID: 19025608
9.  Nerve tolerance to high-dose-rate brachytherapy in patients with soft tissue sarcoma: a retrospective study 
BMC Cancer  2005;5:79.
Brachytherapy, interstitial tumor bed irradiation, following conservative surgery has been shown to provide excellent local control and limb preservation in patients with soft tissue sarcomas (STS), whereas little is known about the tolerance of peripheral nerves to brachytherapy. In particular, nerve tolerance to high-dose-rate (HDR) brachytherapy has never been properly evaluated. In this study, we examined the efficacy and radiation neurotoxicity of HDR brachytherapy in patients with STS in contact with neurovascular structures.
Between 1995 and 2000, seven patients with STS involving the neurovascular bundle were treated in our institute with limb-preserving surgery, followed by fractionated HDR brachytherapy. Pathological examination demonstrated that 6 patients had high-grade lesions with five cases of negative margins and one case with positive margins, and one patient had a low-grade lesion with a negative margin. Afterloading catheters placed within the tumor bed directly upon the preserved neurovascular structures were postoperatively loaded with Iridium-192 with a total dose of 50 Gy in 6 patients. One patient received 30 Gy of HDR brachytherapy combined with 20 Gy of adjuvant external beam radiation.
With a median follow-up of 4 years, the 5-year actuarial overall survival, disease-free survival, and local control rates were 83.3, 68.6, and 83.3%, respectively. None of the 7 patients developed HDR brachytherapy-induced peripheral neuropathy. Of 5 survivors, 3 evaluable patients had values of motor nerve conduction velocity of the preserved peripheral nerve in the normal range.
In this study, there were no practical and electrophysiological findings of neurotoxicity of HDR brachytherapy. Despite the small number of patients, our encouraging results are valuable for limb-preserving surgery of unmanageable STS involving critical neurovascular structures.
PMCID: PMC1181808  PMID: 16026629

Results 1-9 (9)