Chylomicronemia caused by lipoprotein lipase gene mutation related to a hyper-response of insulin secretion to glucose

A 39-year-old man with lipoprotein lipase (LPL) deficiency (height 177.7 cm, body weight 67 kg, and body mass index 21.2 kg/m2) showed severe hypertriglyceridemia (2,032 mg/dl). LPL activity and concentration were markedly low in postheparin plasma. LPL gene analysis revealed a homozygous mutation, Asp204 --> Glu in exon 5. Fasting plasma glucose (81 mg/dl) and insulin (2.7 microU/ml) levels were normal. Plasma glucose pattern during oral glucose (75 g) tolerance test was normal, however 30 minutes after glucose-loading the insulin secretion unexpectedly increased to 89.4 microU/ml. These data suggested that chylomicronemia might be related to a hyper-response of insulin secretion to glucose without obesity.     

Inherited deficiency of protein S in a Japanese family with recurrent venous thrombosis: a study of three generations

We found a new thrombophilic tendency in a family with protein S deficiency. The propositus, a 38-year-old Japanese man, is an offspring of consanguineous marriage and suffered from recurrent episodes of thromboembolism. Hemostatic studies, including platelet counts, platelet aggregation, assays of coagulation factors, and plasminogen activity were all within normal limits. The levels of antithrombin III, alpha 2-macroglobulin, protein C, and protein C inhibitor were also normal. However, functional protein S activity in plasma was markedly decreased (9%) in the propositus. The family study revealed that the reduced levels of functional protein S, less than 5% to 29% of normal (normal range: mean +/- 2 SD of 15 normal adults were 44 to 180%), were found in 11 members of this family over three generations. Six of 11 members had severe protein S deficiency (less than 5%), whereas five had partial deficiency. Four of eight adults with protein S deficiency had recurrent episodes of thrombosis. Immunologic levels of protein S antigen were variable in this family and did not correlate closely with the functional levels. These results suggest that the recurrent thrombotic disease in this family appears to be associated with an inherited deficiency of functional protein S.     

Systemic administration of recombinant human growth hormone induces expression of the c-fos gene in the hypothalamic arcuate and periventricular nuclei in hypophysectomized rats.

The neuronal expression of the protooncogene c-fos could serve as a marker of neural activity. To identify the brain sites responding to GH, rat brains after systemic administration of recombinant human GH (rhGH) were processed for hybridization histochemistry for c-fos mRNA. Adult male Wistar rats were hypophysectomized 10 days before rhGH administration. After hypophysectomy, rats received sc cortisone acetate (0.5 mg/kg BW) and L-T4 (20 microgram/kg BW) daily. Four international units (1.33 mg) of rhGH were given iv through an indwelling right atrial cannula. Vehicle was administered to control animals. The rhGH treatment was accompanied by expression of the c-fos gene in the arcuate nucleus (ARC) of the hypothalamus. The accumulation of the c-fos mRNA was transient, reaching maximum values at 60 min and decreasing thereafter to reach control levels within 120 min after rhGH injection. Among control animals, c-fos gene expression was not detected in the ARC. The c-fos mRNA was also detected in the paraventricular nucleus after rhGH administration; however, it was comparable to that in control animals. When rhGH was administered twice at 40-min intervals, c-fos gene expression was induced in the periventricular nucleus (PeV) as well as the ARC 40 min after the second rhGH injection. Throughout the studies, c-fos mRNA was not detected other than in the ARC, paraventricular nucleus, and PeV in the hypothalamus. In the ARC, distribution of the cells expressing the c-fos gene appears to overlap at least in part with somatostatin (SS) mRNA-containing cells. In the PeV, it appeared to correlate generally with the distribution of SS mRNA-containing cells. The data suggest that GH feeds back on neurons of hypothalamic PeV and ARC expressing SS mRNA, and that c-fos expression is involved in the feedback mechanism.     

IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner

BACKGROUND: In murine models of inflammatory bowel disease, colonic inflammation is considered to be caused by an aberrant Th1-type immune response. AIM: To investigate if systemic administration of interleukin (IL)-12 and IL-18 to wild-type BALB/c mice induces liver injury and intestinal inflammation, and if pathological changes are observed, what cytokines are involved. METHODS: Mice (BALB/c-wild-type (wt), MRL-lpr/lpr, BALB/c-interferon gamma knock out (IFN-gamma KO), C57BL/6-inducible nitric oxide synthase (iNOS) KO, and BALB/c tumour necrosis factor alpha (TNF-alpha) KO) were injected intraperitoneally each day with IL-12 (20 ng/g/mouse) and/or IL-18 (200 ng/g/mouse). RESULTS: Administration of IL-12 and IL-18 to BALB/c-wt mice induced prominent intestinal mucosal inflammation and fatty liver, leading to piloerection, bloody diarrhoea, and weight loss. IL-12 and IL-18 induced striking elevations in serum levels of IFN-gamma that caused NO production, although increased NO had no exacerbating effect on mice. Moreover, iNOS KO mice, or MRL lpr/lpr mice lacking functional Fas were equally susceptible to IL-12 and IL-18. Administration of IL-12 and IL-18 did not induce TNF-alpha production in wild-type mice, and the same treatment to TNF-alpha KO mice induced intestinal mucosal inflammation. Furthermore, they had diffuse and dense infiltration of small fat droplets in their hepatocytes associated with an increase in serum levels of liver enzymes. In contrast, the same treatment in IFN-gamma KO BALB/c mice and iNOS KO mice did not induce these changes. CONCLUSIONS: Our study strongly indicates that IL-18 together with IL-12 induces intestinal mucosal inflammation in an IFN-gamma dependent but TNF-alpha, NO, and Fas ligand independent manner, and fatty liver is dependent on IFN-gamma and NO.     

Cytotoxic T lymphocyte antigen 4 gene polymorphism confers susceptibility to type 1 diabetes in Japanese children: analysis of association with HLA genotypes and autoantibodies

OBJECTIVE: Although the polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA4) gene have been shown to be associated with Type 1 diabetes in Caucasians, some conflicting results have been reported among subjects of different ethnic backgrounds. We examined a CTLA4 polymorphism and its relationship to human leucocyte antigen (HLA) genotypes and autoantibodies for glutamic acid decarboxylase 65 (GAD65) and IA-2 in Japanese children with Type 1 diabetes. SUBJECTS AND MEASUREMENTS: The study group consisted of 125 childhood-onset Japanese subjects (50 males, 75 females) with Type 1 diabetes. The CTLA4 A/G polymorphism at position 49 was analysed using a PCR-restriction fragment length polymorphism (PCR-RFLP) method. The HLA-DRB1 and DQB1 genotypes were defined by DNA analysis using PCR-sequence-specific oligonucleotide (PCR-SSO) probes. The GAD65 autoantibody (GAD65Ab) and IA-2 autoantibody (IA-2Ab) titres were measured using radioimmunoassay. RESULTS: The distribution of genotype frequencies differs between subjects with Type 1 diabetes (GG: 46%, AG: 50%, AA: 5%) and controls (GG: 39%, AG: 44%, AA: 17%) (P < 0.01). The frequency of the G allele is higher in the diabetes group than in the controls (P < 0.05). When the subjects were subdivided according to HLA genotype, the two major HLA high-risk groups, with DR9-DQ9 and DR4-DQ4, that are unique to Japanese populations showed no difference in their CTLA4 polymorphism frequencies. Although no association between the CTLA4 polymorphism and the prevalence of GAD65Ab was found, CTLA4 GG subjects that had been newly diagnosed (< 9 months) had significantly higher levels of autoantibodies than AG subjects (P < 0.01). The prevalence and titres of IA-2Ab were not associated with the CTLA4 polymorphism. CONCLUSIONS: The CTLA4 gene might confer a susceptibility to childhood-onset Type 1 diabetes in the Japanese population. The association between this CTLA4 polymorphism and the HLA genotype was similar for both major groups with HLA high-risk alleles. CTLA4 might contribute to the humoral immune response to GAD in newly diagnosed subjects.     

R-wave amplitude response to myocardial ischemia in hypertrophic cardiomyopathy

Background and Purpose

R-wave amplitude change during exercise has been reported to enhance diagnostic value for myocardial ischemia in coronary heart disease.

Methods

We summed up R-wave amplitude in all the 12 leads during exercise testing and correlated the results with regional myocardial ischemia or diffuse subendocardial ischemia as detected by scintigraphy in 49 patients with hypertrophic cardiomyopathy (HCM) and 16 controls.

Results

The sum of R-wave amplitude decreased during exercise in patients with HCM (mean, 12.4 mV to 11.7 mV, P < .01) as well as in controls (8.0 mV to 7.7 mV, P < .05). Percent changes in the sum of R-wave amplitude did not differ between 4 subgroups of patients with HCM: one having both regional and subendocardial ischemia, one only the former, one only the latter, and one neither of them (mean, 6.5%, 7.7%, 4.6%, and 5.1%; P = .79).

Conclusions

R-wave amplitude response to exercise failed to demonstrate myocardial ischemia in our patients with HCM.     

Interaction between gastric cancer stem cells and the tumor microenvironment

Gastric cancer (GC) remains a leading cause of cancer-related deaths worldwide. Cancer stem cells (CSCs) are selectively capable of tumor initiation and are implicated in tumor relapse and metastasis, thus, governing the prognosis of GC patients. Stromal cells and extracellular matrix adjacent to cancer cells are known to form a supportive environment for cancer progression. CSC properties are also regulated by their microenvironment through cell signaling and related factors. This review presents the current findings regarding the influence of the tumor microenvironment on GC stem cells, which will support the development of novel therapeutic strategies for patients with GC.     

Japan Gastroenterological Endoscopy Society guidelines for colorectal endoscopic submucosal dissection/endoscopic mucosal resection

Suitable lesions for endoscopic treatment include not only early colorectal carcinomas but also several types of precarcinomatous adenomas. It is important to establish practical guidelines wherein preoperative diagnosis of colorectal neoplasia and selection of endoscopic treatment procedures are appropriately outlined and to ensure that actual endoscopic treatment is useful and safe in general hospitals when carried out in accordance with guidelines. In cooperation with the Japanese Society for Cancer of the Colon and Rectum, the Japanese Society of Coloproctology, and the Japanese Society of Gastroenterology, the Japan Gastroenterological Endoscopy Society compiled colorectal endoscopic submucosal dissection/endoscopic mucosal resection guidelines by using evidence-based methods in 2014. The first edition of these guidelines was published 5 years ago. Accordingly, we have published the second edition of these guidelines based on recent new knowledge and evidence.