Hypoadiponectinemia in type 2 diabetes mellitus in men is associated with sympathetic overactivity as evaluated by cardiac 123I-metaiodobenzylguanidine scintigraphy

Hypoadiponectinemia is associated with insulin resistance. However, there is very limited information about the relationship between plasma adiponectin and cardiac autonomic nervous function. We tested the hypothesis that hypoadiponectinemia is associated with cardiac sympathetic overactivity in patients with type 2 diabetes mellitus. Thirty-three male type 2 diabetic patients not on insulin treatment were classified into a hypoadiponectinemia group (plasma adiponectin concentration, <4.0 microg/mL; age, 58.6 +/- 8.6 years [mean +/- SD]; n = 14) and an age-matched normoadiponectinemia group (serum adiponectin concentration, >/=4.0 microg/mL; age, 58.2 +/- 8.1 years; n = 19). In each patient, baroreflex sensitivity, heart rate variability, plasma norepinephrine concentration, and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphic findings were assessed. Compared with the normoadiponectinemia group, the hypoadiponectinemia group had a higher body mass index (P < .01), higher plasma concentrations of glucose and insulin (P < .05 and P < .01, respectively), higher homeostasis model assessment of insulin resistance (HOMA-IR) values (P < .005), higher plasma triglyceride levels (P < .05), and lower plasma high-density lipoprotein cholesterol levels (P < .05). In the hypoadiponectinemia group, the autonomic function measurements included a lower baroreflex sensitivity (P< .05) and a lower delayed myocardial uptake of (123)I-MIBG (P < .01) with a higher washout rate (P < .05). Multiple regression analysis revealed that the plasma adiponectin level was independently associated with HOMA-IR (F = 9.916) and the percent washout rate of (123)I-MIBG (F = 5.985). Our results suggest that in middle-aged men with type 2 diabetes mellitus, hypoadiponectinemia is associated with cardiac sympathetic overactivity as determined by (123)I-MIBG scintigraphy.     

Correlations of high-sensitivity C-reactive protein and atherosclerosis in Japanese type 2 diabetic patients

BACKGROUND: The elevated level of high-sensitivity C-reactive protein (HSCRP) and aortic stiffness are associated with high mortality in type 2 diabetic patients. We tested the hypothesis that the HSCRP correlates with aortic stiffness and insulin resistance in type 2 diabetic patients. MATERIAL AND METHODS: The study consisted of 46 Japanese patients with type 2 diabetes and high HSCRP group (0.3-1.0 mg/dl, age: 57+/-5 years, mean+/-s.d.) and a control group of 55 age-matched patients with low HSCRP group (<0.3 mg/dl, 57+/-6 years). Brachial-ankle pulse wave velocity (BaPWV) was measured by automatic oscillometric method and was used as an index of atherosclerosis. RESULTS: The body mass index (BMI) values (P<0.05) and waist circumferences (P<0.0005) and the waist-to-hip ratios (P<0.05) were higher in the high HSCRP group than in the low HSCRP group. The BaPWV was higher in the high HSCRP group than in the low HSCRP group (P<0.0001). Fasting plasma glucose (FPG; P<0.005) and insulin concentrations (P<0.0001), and the homeostasis model assessment (HOMA) index (P<0.0001), were higher in the high HSCRP group than in the low HSCRP group. Multiple regression analysis showed that HSCRP levels were independently predicted by BaPWV and HOMA index. CONCLUSIONS: Our results indicate that the elevated level of HSCRP in Japanese patients with type 2 diabetes is characterized by increased aortic stiffness and insulin resistance, and that the BaPWV and HOMA index are independent predictors of HSCRP.     

Diabetic retinopathy is associated with visceral fat accumulation in Japanese type 2 diabetes mellitus patients

The presence of diabetic retinopathy (DR) and increased of visceral fat accumulation (VFA) are associated with high mortality in type 2 diabetes mellitus patients. This preliminary study was therefore designed to test the hypothesis that DR is associated with insulin resistance and VFA in type 2 diabetes mellitus patients without insulin treatment. A total of 102 type 2 diabetes mellitus patients were divided into 2 groups: DR group (age, 60 ± 6 years [mean ± SD]; n = 31) and no diabetic retinopathy (NDR) group (59 ± 5 years, n = 71). The level of blood glucose was assessed by fasting plasma glucose, fasting immunoreactive insulin, homeostasis model assessment index, and hemoglobin A_1c. The fat distribution was evaluated by measuring the VFA by abdominal computed tomography at the umbilical level. The body mass index and waist circumference were higher in the DR group than in the NDR group (P < .001 and P < .0005, respectively). Plasma levels of triglyceride were higher, whereas high-density lipoprotein cholesterol was lower, in the DR group than in the NDR group (P < .005 and P < .0001, respectively). Fasting plasma glucose (P < .0005), insulin concentrations (P < .0001), homeostasis model assessment index (P < .0001), and VFA (P < .0001) levels were higher in the DR group than in the NDR group. Multivariate logistic analysis revealed that DR was independently predicted by high VFA and insulin resistance. The results of this preliminary study indicate that the presence of DR was associated with high VFA and insulin resistance in Japanese patients with type 2 diabetes mellitus.     

Mutations in the genes for sarcomeric proteins in Japanese patients with onset sporadic hypertrophic cardiomyopathy after age 40 years

This study was conducted to assess the hypothesis that mutations in the genes for sarcomeric proteins are the molecular cause for older-onset sporadic hypertrophic cardiomyopathy (HC) in Japanese patients. Molecular genetic approaches have demonstrated that familial HC is caused by mutations in genes encoding sarcomeric proteins. Recent studies have shown that sarcomeric gene mutations can also be a molecular cause of older-onset and/or sporadic HC. However, genetic studies to date have examined only a limited number of older Caucasian patients with HC. Clinical evaluations were performed in patients with HC onset after 40 years of age, and the sequence encoding the beta-cardiac myosin heavy chain, cardiac troponin T, cardiac troponin I, cardiac myosin binding protein-C, myosin ventricular regulatory light chain, and myosin ventricular essential light chain genes was analyzed. When a putative mutation was identified, clinical evaluations and genetic studies were subsequently performed on all first-degree relatives. Forty-one patients with sporadic HC onset after 40 years of age (31 men, 10 women; mean age 63+/-10 years at the time of study) were studied. Four novel missense mutations in the cardiac myosin binding protein-C gene (arginine to tryptophan at codon 160, glutamic acid to lysine at codon 334, glycine to arginine at codon 507, and threonine to methionine at codon 1,046) and a previously reported missense mutation in the beta-cardiac myosin heavy chain gene (arginine to histidine at codon 663) were identified in 5 of the 41 patients. No family members carried these mutations or had clinical evidence of HC. In conclusion, mutations in the cardiac myosin binding protein-C are the most common cause of older-onset sporadic HC in Japan.     

House dust mite (HDM) antigen in naturally occurring lesions of atopic dermatitis (AD): the relationship between HDM antigen in the skin and HDM antigen-specific IgE antibody.

To elucidate the etiological role of house dust mite (HDM) antigen in the pathogenesis of atopic dermatitis (AD), we conducted immunohistochemical studies on the localization of HDM antigen in naturally occurring lesions of AD. HDM antigens were found in the epidermis and dermis in 19 of 38 cases. All of the 19 patients had HDM antigen-specific IgE antibody, but HDM antigen was not detected in the lesions of patients without HDM antigen-specific IgE or in control skin specimens. Most HDM antigens were located on Langerhans cells (LCs) or near helper T cells. Our findings suggest that HDM antigen is the causative factor in the development of eczematous lesions of AD, and thus we hypothesized that IgE-mediated allergic contact sensitivity to HDM antigen plays an important role in the pathogenesis of AD.     

Prevalence and Clinical Features of Chronic Daily Headache in a Headache Clinic

Although chronic daily headache is regarded as a syndrome encountered in headache clinics, clinical characteristics have only rarely been studied and the condition has not been documented in Thailand. To investigate the prevalence as well as clinical features of chronic daily headache in Thai patients, 220 patients visiting Chulalongkorn Headache Clinic were examined. Sixty cases (27.3%) were diagnosed as suffering from chronic daily headache (male to female ratio, 1:5.7).
The average age of these patients was 32.7 ± 9.6 years. Based on the International Headache Society (IHS) criteria, 30% of patients with chronic daily headache could be diagnosed as suffering from migraine end 36.7% from chronic tension-type headache, whereas the remainder had combined features of both headache types and were not classifiable. Diffuse steady pain was the most common headache type reported (65%), however, associated features characteristic of migraine were often noted. These included photophobia (70%), phonophobia (56.7%) and nausea (43%). Thirty-four cases (56.7%) reported that their headache could be aggravated by stress. Daily use of analgesics was reported in 58.3% of cases. We concluded that chronic daily headache is a common problem. Although the mechanism has not been fully clarified, the prevalence of associated psychological factors and analgesic overuse imply their involvement in the pathogenesis of this condition. The criteria of the IHS are not entirely suitable for diagnosis and classification of this disorder, and modification of this classification system is needed.     

A humanized TCR retaining authentic specificity and affinity conferred potent anti‐tumour cytotoxicity

The affinity of T‐cell receptor (TCR) determines the efficacy of TCR‐based immunotherapy. By using human leucocyte antigen (HLA)‐A*02 transgenic mice, a TCR was generated previously specific for human tumour testis antigen peptide MAGE‐A3_112–120 (KVAELVHFL) HLA‐A*02 complex. We developed an approach to humanize the murine TCR by replacing the mouse framework with sequences of folding optimized human TCR variable domains for retaining binding affinity. The resultant humanized TCR exhibited higher affinity and conferred better anti‐tumour activity than its parent murine MAGE‐A3 TCR (SRm1). In addition, the affinity of humanized TCR was enhanced further to achieve improved T‐cell activation. Our studies demonstrated that the human TCR variable domain frameworks could provide support for complementarity‐determining regions from a murine TCR, and retain the original binding activity. It could be used as a generic approach of TCR humanization.     

Filling defects of the left atrial appendage on multidetector computed tomography: their disappearance following catheter ablation of atrial fibrillation and the detection of LAA thrombi by MDCT

Filling defects of the left atrial appendage (LAA) on multidetector computed tomography (MDCT) are known to occur, not only due to LAA thrombi formation, but also due to the disturbance of blood flow in the LAA of patients with atrial fibrillation (AF). The purpose of this study was to evaluate the impact of the maintenance of sinus rhythm via ablation on the incidence of LAA filling defects on MDCT in patients with AF. A total of 459 consecutive patients were included in the present study. Prior to ablation, MDCT and transesophageal echocardiography (TEE) were performed. AF ablation was performed in patients without LAA thrombi confirmed on TEE. The LAA filling defects were evaluated on MDCT at 3 months after ablation. LAA filling defects were detected on MDCT in 51 patients (11.1 %), among whom the absence of LAA thrombi was confirmed in 42 patients using TEE. The LAA Doppler velocity in patients with LAA filling defects was lower than that of patients without filling defects (0.61 ± 0.19 vs. 0.47 ± 0.21 m/s; P < 0.0001). The sensitivity, specificity and negative predictive value of MDCT in the detection of thrombi were 100, 91 and 100 %, respectively. No LAA filling defects were observed on MDCT at 3 months after ablation in any of the patients, including the patients in whom filling defects were noted prior to the procedure. MDCT is useful for evaluating the presence of LAA thrombi and the blood flow of the LAA. The catheter ablation of AF not only suppresses AF, but also eliminates LAA filling defect on MDCT suggesting the improvement of LAA blood flow.     

Transient elastography identifies liver recipients with nonviral graft disease after transplantation: a guide for liver biopsy

Transient elastography (TE) reliably predicts the severity of recurrent hepatitis C virus after orthotopic liver transplantation (OLT); however, its accuracy in evaluating nonviral liver graft damage is unknown. Between 2006 and 2009, 69 OLT recipients [37 for hepatitis B virus/hepatitis D virus (recurrence-free), 20 for autoimmune/cholestatic liver disease, 6 for alcoholic liver disease, and 6 for mixed etiologies] underwent protocol/on-demand liver biopsy (LB) and concomitant TE. A histological diagnosis of graft disease was made according to criteria defined by the Banff working group. Sixty-five patients (94%) had reliable TE examinations during a median post-OLT follow-up of 18 months (range = 7-251 months). LB samples (median length = 35 mm) showed graft damage in 28 patients (43%): idiopathic chronic hepatitis (11), steatohepatitis (3), rejection (3), cholangitis (2), and autoimmune/cholestatic recurrence (9). Patients with graft damage had significantly higher serum liver enzyme levels and TE results (median = 7.8 kPa, range = 5.4-27.4 kPa) than the 37 patients without graft damage (median = 5.3 kPa, range = 3.1-7.4 kPa, P < 0.001). By a receiver operating characteristic curve analysis, 2 TE cutoffs for the diagnosis of graft damage were identified: 5.3 kPa with 100% sensitivity and 7.4 kPa with 100% specificity. The pretest probability of graft damage was 43%; in patients with TE values ≤5.3 kPa, the posttest probability of graft damage fell to 0%, but in patients with TE results >7.4 kPa, the posttest probability increased to 100%. In conclusion, the dual TE cutoff allows accurate discrimination between the absence and presence of nonviral liver graft damage and improves the clinical management of OLT recipients in terms of the selection of patients most in need of LB.