Kinetics of versican-expressing macrophages in bone marrow after cord blood stem cell transplantation for treatment of acute myelogenous leukaemia.

AIMS: To determine versican-producing cells in normocellular bone marrow and to evaluate chronological alteration in the number of versican-producing macrophages in bone marrow of patients with acute myelogenous leukaemia (AML) after cord blood stem cell transplantation (CBSCT) to gain insight in the significance of versican in recovery of haematopoiesis. METHODS: We enrolled seven age-matched unrelated patients with normocellular bone marrow for determining versican-producing cells in bone marrow, CBSCT-treated patients with AML, 18 with fine and other four with poor engraftment, for determining chronological alteration of versican-expressing and CD68-expressing cells in transplanted bone marrow in reference to the total cells. Clot samples of patients with AML were collected from the +16 to +55 day after transplantation and separated into four groups. We included an AML case whose specimen was obtained on the +9 day. Cells positive in immunohistochemistry using antibodies to versican and CD68 were counted to obtain the mean±SD in a unit area of the bone marrow, plotted chronologically and compared with the numbers from the age-matched normocellular group. RESULTS: We determined by a double immunohistochemistry that the versican-expressing cells in bone marrow are macrophages. The time-course curve demonstrated an inverse relationship between the versican-positive macrophages and the total cells in the transplanted bone marrow for over 55 days. In bone marrow of poor engraftment cases, versican-positive macrophages appeared to be decreased in comparison with age-matched and sampling day-matched patients. CONCLUSIONS: These results suggest that versican and/or versican-expressing macrophages positively contribute to bone marrow regeneration of patients with AML after CBSCT.

The strong relation between post-hemodialysis blood methylglyoxal levels and post-hemodialysis blood glucose concentration rise.

BACKGROUND: Hemodialysis is known to decrease blood glucose concentration (BGC), insulin, and methylglyoxal levels. However, the effects of decreases in these factors on the increase in post-hemodialysis BGC remain unknown. This study identifies the effects of hemodialysis-induced changes in concentrations of these elements on post-hemodialysis BGC. METHODS: Study subjects included seventeen insulin-treated diabetes patients receiving hemodialysis. The fluctuations in BGC on hemodialysis-treatment days and non-hemodialysis-treatment days were evaluated using a continuous glucose monitoring system. BGC was evaluated before breakfast, before starting hemodialysis, at the end of hemodialysis, 1 h post-hemodialysis (lunch), and 6 h post-hemodialysis (dinner). BGC, insulin, and methylglyoxal levels were measured at the start and end of hemodialysis. This study also evaluated the changes in the concentrations of glucose and insulin in the arterial line and the venous line during hemodialysis. RESULTS: Hemodialysis decreases BGC, insulin, and methylglyoxal levels. Concentrations of glucose and insulin in the arterial line gradually decreased during dialysis, while concentrations in the venous line approached their original concentrations in the dialysis solution. BGC rose sharply after eating lunch 1 h post-hemodialysis. The blood glucose, insulin, and methylglyoxal concentrations at the end of hemodialysis were associated with the M values and the mean amplitude of glycemic excursion values between before lunch and dinner. In particular, methylglyoxal concentration at the end of hemodialysis was strongly related to the post-hemodialysis increase in BGC. CONCLUSION: Hemodialysis-induced decreases in methylglyoxal concentrations and methylglyoxal concentration at the end of hemodialysis influence post-hemodialysis fluctuations in BGC.

[On the correlation between histological and cytological diagnosis, and the intrinsic 5 subtypes].

Japanese General Rules presented by the Japanese Breast Cancer Society have been long time applied in Japan. This classification uniquely adds subtypes into the group of invasive ductal carcinomas (IDC) and reported to be correlated to patients' clinical course. The latest St. Gallen consensus meeting reported the use of 5 molecules, and introduced alternative definition in the breast cancer classification. The purpose of this study is to relate the Japanese subgrouping of IDC with the 5 subtypes and to investigate whether these classifications could predict early and late recurrence and whether cytological diagnosis is influenced by the tumor phenotypes. Analyzing 127 cases, we observed that the Ki-67 labeling index (LI) of the 5 subtypes, luminal A, luminal B-Her2--/- Her2+, Her2-subtype and basal-like, is increased in this order. Though the Japanese histological groups, papillotubular, solid-tubular and scirrhous, included more or less those subtypes, the luminal types were more represented in papillotubular and scirrhous subtypes, and the solid-tubular type in non luminal subtypes. The Ki-67 LI 14% served as a cutoff for differentiating invasive from non-invasive ductal carcinomas. Breast cancers recur within 5 years after the clinical onset when the Ki-67 LI exceeded 14%. These data suggest that, (1) the intrinsic subtyping is an accurate modality in diagnosing breast cancers, (2) it can predict the recurrence duration, (3) the solid-tubular type of the Japanese classification is likely an aggressive form among breast cancers, and (4) the cytological diagnosis is presently a powerful tool in determining malignancy.

Eicosapentaenoic acid improves glycemic control in elderly bedridden patients with type 2 diabetes.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are ω3-polyunsaturated fatty acids mainly contained in the blue-backed fish oil, and are effective in decreasing the lipids disorder and the cardiovascular incidence among diabetic patients. Moreover, it has been suggested that EPA and DHA may improve the insulin resistance and glucose metabolism. However, the clinical effects of EPA and DHA on glucose metabolism remain unclear. We aimed to clarify the effects of EPA/DHA treatment on glycemic control in type 2 diabetes mellitus. This study was a multicenter prospective randomized controlled trial involving 30 elderly type 2 diabetic patients on a liquid diet. Their exercises were almost zero and the content of their meals was strictly managed and understood well. Therefore, the difference by the individual's life was a minimum. The subjects were divided into two groups: those receiving EPA/DHA-rich liquid diet [EPA/DHA (+)] or liquid diet lacking EPA/DHA [EPA/DHA (-)]. Changes in factors related to glucose and lipid metabolism were assessed after the three-month study. Serum concentrations of EPA rose in EPA/DHA (+), although the levels of DHA and fasting C-peptide remained unchanged in EPA/DHA (+). In addition, there was a significant decline in the fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), fasting remnant-like particles and apolipoprotein (apo) B in EPA/DHA (+), compared with the values in EPA/DHA (-). EPA/DHA-rich diet might improve glucose metabolism in elderly type 2 diabetic patients on a liquid diet. This phenomenon may be due to the improved insulin resistance mediated by the rise in serum EPA concentrations.

A decline in glomerular filtration rate rather than renal arterial stenotic lesions, per se, predicts cardiovascular-renal events in type 2 diabetic patients.

BACKGROUND: In diabetic patients with renal artery arteriosclerosis (RAAS), the factors associated with a greater risk for cardiovascular-renal events (CVREs) remain unclear: the decline in estimated glomerular filtration rate (eGFR) caused by RAAS or the advance of arteriosclerosis that causes RAAS. Hence, the features to determine which best predicts the onset of CVREs in such patients were compared. METHODS AND RESULTS: The renal arteries of 162 type 2 diabetes patients were assessed by using magnetic resonance angiography (RAAS diagnosed as arteriosclerotic stenosis ≥50%) and they were studied longitudinally over 7 years. The influence of the presence/absence of RAAS, a decline in eGFR, clinical factors, surrogate arteriosclerotic markers and ischemic markers on patient's CVREs were assessed. A Cox regression analysis showed the detection of RAAS to be an independent risk factor for CVREs (bilateral RAAS was an extremely strong risk factor for the development of CVREs within 1,000 days), as was the decline in eGFR in a logistic regression analysis; the latter being a more powerful risk factor for CVREs. A multiple regression analysis revealed angiopoietin-2, a marker of ischemia, to be a risk factor for the decline in eGFR. CONCLUSIONS: A decline in renal function but not the renal arterial stenotic lesion itself appears to be associated with an increased incidence of CVREs in type 2 diabetic patients with RAAS.

Identification of the stages of diabetic nephropathy at which angiotensin II receptor blockers most effectively suppress albuminuria.

BACKGROUND: It is unclear when angiotensin II receptor blockers (ARBs) produce their strongest antialbuminuric effect (AAE) in patients with diabetic nephropathy. ARBs produce stronger AAEs when urinary excretion of reactive oxygen species (ROS) and/or of angiotensinogen (AGT) is higher before treatment, although the relationship between ROS, AGT, and the urinary albumin-to-creatinine ratio (ACR) is unclear. We sought to define the relationship between ROS and ACR and establish the stage at which ARBs exert maximal AAEs. METHODS: Urinary ROS and AGT and the ACR were measured in 277 hypertensive type 2 diabetic patients before ARB treatment, and changes in the ACR were analyzed over 16 weeks. RESULTS: Urinary AGT and ROS showed similar changes as the disease progressed, and the increase in ACR often observed in patients with lower ROS and AGT reflects the mild AAE produced by ARBs. ROS and AGT levels and the AAE were all highest in albuminuric patients (ACR = 30-1,000 mg/g creatinine), whereas normoalbuminuric patients (ACR < 30mg/g creatinine) displayed variable ROS values and AAEs. Glycemic control exerted a stronger AAE than ARBs in normoalbuminuric patients, whereas it had a weak AAE in most nephrotic (ACR ≥ 1,000 mg/g creatinine) patients, who had low basal ROS and AGT values. Lowering blood pressure was effective at all stages and appeared to promote an AAE, even in nephrotic patients. CONCLUSIONS: ARBs produce a maximal AAE in albuminuric patients, and lowering blood pressure enhances the AAE in patients at all stages, including the nephrotic stage.

The glucagon-like peptide-1 analog liraglutide suppresses ghrelin and controls diabetes in a patient with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic disease characterized by severe morbid obesity in association with hyperphagia and type 2 diabetes mellitus. Liraglutide is a glucagon-like peptide (GLP)-1 analog that controls appetite, decreases body weight and improves glycemic control. However, it is unclear if PWS patients with diabetes experience similar benefits of liraglutide therapy. In a 25 year-old female hyperglycemic PWS patient, liraglutide monotherapy improved her Hemoglobin A1c remarkably (12.6% to 6.1%) while steadily decreasing her body mass index (BMI: 39.1 kg/m(2) to 35.7 kg/m(2)). We offered this patient continued liraglutide therapy for one year to determine the effect on various metabolic parameters. Her hyperphagia was controlled soon after liraglutide treatment commenced and remained so throughout the treatment. The metabolic parameters changed as follows: visceral fat area fell from 150.1 to 113.2 (cm(2)); plasma insulin rose from 108.1 to 277.0 (pmol/L); plasma active GLP-1 dropped from 2.1 to 1.2 (fmol/L); plasma active ghrelin diminished from 137.0 to 27.7 (pmol/L). While plasma active ghrelin before treatment was abnormally high, even though her GLP-1 was normal, both decreased following liraglutide therapy. These results suggest that in addition to its insulinotropic effects, other potential mechanisms activated by liraglutide therapy may reduce the plasma ghrelin levels elevated in PWS, leading to an improvement in overeating, BMI and visceral fat, as well as glycemic control.

Effects of the Great East Japan Earthquake and huge tsunami on glycaemic control and blood pressure in patients with diabetes mellitus.

OBJECTIVE: To examine the effects of a huge tsunami resulting from the Great East Japan Earthquake on blood pressure (BP) control and glycaemic control in diabetic patients. DESIGN: A retrospective study. SETTING: Tohoku University, Japan. PARTICIPANTS: 63 patients were visiting Rikuzentakata Hospital for diabetic treatment before the earthquake and returned to the clinic in July after the earthquake, and they were analysed in the present study. The subjects were divided into two groups: those who were hit by the tsunami, the Tsunami (+) group (n=28), and those who were not, the Tsunami (-) group (n=35), and the groups' parameters and their changes were compared. PRIMARY OUTCOME MEASURE: Changes of HbA1c. SECONDARY OUTCOME MEASURES: Changes of BP, body mass index. RESULTS: HbA1c and both BP increased, while the numbers of most drugs taken decreased in both groups. Parameter changes were significantly greater in the Tsunami (+) group. All medical data stored at the hospital was lost in the tsunami. The Tsunami (+) patients also had their own records of treatment washed away, so it was difficult to replicate their pre-earthquake drug prescriptions afterwards. In comparison, the Tsunami (-) patients kept their treatment information, making it possible to resume the treatment they had been receiving before the earthquake. The BP rose only slightly in men, whereas it rose sharply in women, even though they had not been directly affected by the tsunami. BP rose markedly in both genders affected by the tsunami. CONCLUSIONS: All medical information was lost in the tsunami, and glycaemic and BP controls of the tsunami-affected patients worsened more than those of patients who had been affected by the earthquake alone. Women may be more sensitive to changes in the living environment that result from a major earthquake than are men.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, decreases systolic blood pressure in Japanese hypertensive patients with type 2 diabetes.

Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a newly developed oral hypoglycemic agent. Sitagliptin increases the level of glucagon-like polypeptide (GLP)-1 that increases insulin secretion. In addition, GLP-1 decreases salt intake and increases urinary salt excretion. Therefore, the sitagliptin treatment might lower blood pressure in hypertensive patients with type 2 diabetes. It also remains to be examined whether the reduction in blood pressure with sitagliptin treatment is related to the blood glucose improvement and the body weight decrease. To identify beneficial effects of sitagliptin treatment, we administered sitagliptin (50 mg) on alternate days to seventeen type 2 diabetes outpatients with insufficient blood glucose control (8 males and 9 females; mean age of 67.1 years). The patients were also treated with oral hypoglycemic agents and antihypertensive drugs for six months before and during the sitagliptin administration. We measured the level of hemoglobin (Hb) A1c, systolic blood pressure (SBP), and body mass index (BMI) for up to six months thereafter. Their BMIs remained unchanged. The levels of HbA1c were dropped from 6.5 ± 0.3% to 5.8 ± 0.3%, while SBP was also dropped from 130.0 ± 37.2 mmHg to 119.7 ± 9.4 mmHg. However, the degree of the decrease in HbA1c levels was not significantly correlated with that of SBP (r = 0.24). In conclusion, the present findings suggest that sitagliptin lowers SBP without reducing BMI, independent of the blood glucose reduction. The hypotensive effect is apparent with the alternate-day regimen of sitagliptin at a lower dose compared to the everyday medication.

Methylglyoxal is a predictor in type 2 diabetic patients of intima-media thickening and elevation of blood pressure.

We test whether plasma level of methylglyoxal (MG) is an independent risk factor predicting the progression of diabetic macroangiopathy or microangiopathy in type 2 diabetic patients. We measured in 50 type 2 diabetic patients plasma levels of MG and 3-deoxyglucosone (DG) using an electrospray ionization-liquid chromatography-mass spectrometry. We assessed the correlations between baseline levels of MG or DG and the percentage changes after 5 years of clinical parameters linked to diabetic macroangiopathy or microangiopathy, that is, intima-media thickness (IMT), systolic blood pressure (SBP), the amount of urinary albumin excretion (ACR), pulse wave velocity (PWV), and estimated glomerular filtration rate (eGFR). Multiple regression analysis was performed using the percentage changes in IMT, SBP, ACR, PWV, and eGFR over the 5-year period as the independent or objective variables and the values of MG, DG, glycohemoglobin A1c, body mass index, triglyceride, and diabetic duration at the baseline as the dependent variables. The values of IMT, PWV, SBP, and ACR all increase, but eGFR reduces with time during the 5-year period. Baseline level of MG correlates significantly with the percentage changes of IMT, SBP, ACR, PWV, and eGFR, whereas that of DG does only with ACR. A multiple regression analysis reveals that MG is an independent risk factor for the percentage changes of IMT, PWV, and SBP but not for those of ACR and eGFR. DG is an independent risk factor for the percentage change of ACR. MG is a predictor in type 2 diabetic patients of intima-media thickening, of increase of PWV, and of elevation of SBP.

The impact of visceral fat in nonalcoholic fatty liver disease: cross-sectional and longitudinal studies.

BACKGROUND: Nonalcoholic fatty liver disease is increasing worldwide, and attention is being paid to its association with obesity and metabolic syndrome. The aim of this study was to elucidate the role of visceral fat accumulation in hepatic steatosis by cross-sectional and longitudinal studies. METHODS: We enrolled 125 patients in a cross-sectional study and 28 patients in a longitudinal study and examined visceral and subcutaneous fat thickness, hepatic steatosis score, and biochemical parameters. In the longitudinal study, the influence of weight change on fat distribution and hepatic steatosis was investigated. RESULTS: In the cross-sectional study, the severity of hepatic steatosis showed a significant positive correlation with body mass index, visceral fat thickness, serum albumin, alanine aminotransferase (ALT), cholinesterase, fasting insulin, and the homeostasis model assessment of insulin resistance. ALT, visceral fat thickness, and serum albumin were independent factors for hepatic steatosis. In the longitudinal study, visceral fat thickness fluctuated closely with changes in body weight, and had the strongest relationship with the change of hepatic steatosis by multivariate analysis. CONCLUSIONS: Visceral fat was the most important factor for the development of hepatic steatosis. Visceral fat thickness can be measured by sonography easily, noninvasively, and repeatedly for assessment of central obesity and monitoring of the efficacy of treatment of nonalcoholic fatty liver disease.

Sonographic subcutaneous and visceral fat indices represent the distribution of body fat volume.

BACKGROUND: A reliable method for direct measurement of both subcutaneous and visceral fat volume is the measurement of fat tissue area from tomographic pictures by CT or by MR imaging. However, these are not widely usable because of high cost and/or exposure to radiation. METHODS: We compared sonographic subcutaneous and visceral fat indices with fat distribution by serial-slice MR imaging in 17 subjects. Sonographic subcutaneous or visceral fat index is standardized thickness of subcutaneous fat tissue or the intra-abdominal depth at the level of umbilicus by height. RESULTS: Sonographic visceral fat index and intra-abdominal depth were significantly correlated with visceral fat volume by serial-slice MR imaging (r = 0.746, r = 0.726, respectively). Similarly, sonographic subcutaneous fat index and subcutaneous fat thickness were significantly correlated with subcutaneous fat volume by serial-slice MR imaging (r = 0.825, r = 0.816, respectively). The ratio of sonographic visceral fat index and sonographic subcutaneous fat index was closely correlated with the ratio of the visceral fat volume and the subcutaneous fat volume by single-slice MR imaging, which proves to be related to cardiovascular disease risk (r = 0.722). CONCLUSION: Sonographic subcutaneous or visceral fat index could be an easily measured and inexpensive indicator for the assessment of fat distribution instead of CT or MR imaging.

[Case of straight sinus venous thrombosis presenting as depression and disorientation due to bilateral thalamic lesions].

A 45-year-old man was admitted to our hospital because of progressive inactivity and mild disturbance of consciousness which appeared two weeks ago. Brain CT revealed symmetric hypointensity of bilateral thalamus, and the lesion appeared hyperintensity on T2 weighted MRI image. He was first considered as immune-mediated cerebritis, and steroid pulse therapy was applied, but the clinical features were not improved. The diagnosis of cerebral venous thrombosis was established, when MR venography (MRV) showed severe stenosis in straight sinus. Consciousness was improved after the start of anticoagulation therapy, but mild dementia was remained as a sequela. MRV was useful to distinguish straight sinus thrombosis from cerebritis in this case.