Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly

Most of acromegaly is caused by a sporadic somatotropinoma and a couple of novel gene mutations responsible for somatotropinoma have recently been reported. To determine the cause of sporadic somatotropinoma in Japanese patients, we analyzed 61 consecutive Japanese patients with somatotropinoma without apparent family history. Comprehensive genetic analysis revealed that 31 patients harbored guanine nucleotide-binding protein, alpha stimulating (GNAS) mutations (50.8%) and three patients harbored aryl hydrocarbon receptor interacting protein (AIP) mutations (4.9%). No patients had G protein-coupled receptor 101 (GPR101) mutations. The patients in this cohort study were categorized into three groups of AIP, GNAS, and others and compared the clinical characteristics. The AIP group exhibited significantly younger age at diagnosis, larger tumor, and higher nadir GH during oral glucose tolerance test. In all patients with AIP mutation, macro- and invasive tumor was detected and repetitive surgery or postoperative medical therapy was needed. One case showed a refractory response to postoperative somatostatin analogue (SSA) but after the addition of cabergoline as combined therapy, serum IGF-I levels were controlled. The other case showed a modest response to SSA and the switching to cabergoline monotherapy was also effective. These data suggest that although resistance to SSA has been reported in patients with AIP mutations, the response to dopamine agonist (DA) may be retained. In conclusion, the cause of sporadic somatotropinoma in Japanese patients was comparable with the previous reports in Caucasians, patients with AIP mutations showed unique clinical characteristics, and DA may be a therapeutic option for patients with AIP mutations

PERFORMA AKUSTIK PADA RUANG MUSIK DI SEKOLAH LUAR BIASA NEGERI MARAWOLA KABUPATEN SIGI

Ruang musik dengan menggunakan bahan isolasi bunyi dari glasswool yang dipadukan dengan beberapa bahan bangunan, seperti tripleks, hardboard dan dinding bata, serta desain tata letak ruang dan bukaan yang spesifik sesuai dengan aturan performa akustik pada umumnya, dimana akan dibahas eksplorasi desain akustik dengan pendekatan analisa pengaruh level/tingkatan suara.Hasil penelitian menunjukkan bahwa kajian performa level suara dan performa akuistik menunjukkan hasil yang signifikan yaitu mampu menghilangkan dengung dalam ruang sehingga menghasilkan suara musik yang baik dalam ruang dan mampu menahan rambatan bunyi poda lingkungan sekitarnya sehingga keberadaan ruang musik di Sekolah Luar Biasa Marawola tersebut tidak menggangu aktifitas belajar-mengajar pada ruang sekitarny

Unacylated ghrelin promotes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R1a activity: evidence for target cell-induced acylation

Despite being unable to activate the cognate ghrelin receptor (GHS-R), unacylated ghrelin (UAG) possesses a unique activity spectrum that includes promoting bone marrow adipogenesis. Since a receptor mediating this action has not been identified, we re-appraised the potential interaction of UAG with GHS-R in the regulation of bone marrow adiposity. Surprisingly, the adipogenic effects of intra-bone marrow (ibm)-infused acylated ghrelin (AG) and UAG were abolished in male GHS-R-null mice. Gas chromatography showed that isolated tibial marrow adipocytes contain the medium-chain fatty acids utilised in the acylation of UAG, including octanoic acid. Additionally, immunohistochemistry and immunogold electron microscopy revealed that tibial marrow adipocytes show prominent expression of the UAG-activating enzyme ghrelin O-acyl transferase (GOAT), which is located in the membranes of lipid trafficking vesicles and in the plasma membrane. Finally, the adipogenic effect of ibm-infused UAG was completely abolished in GOAT-KO mice. Thus, the adipogenic action of exogenous UAG in tibial marrow is dependent upon acylation by GOAT and activation of GHS-R. This suggests that UAG is subject to target cell-mediated activation – a novel mechanism for manipulating hormone activity

A cross-sectional investigation of regional patterns of diet and cardio-metabolic risk in India

<p>Abstract</p> <p>Background</p> <p>The role of diet in India's rapidly progressing chronic disease epidemic is unclear; moreover, diet may vary considerably across North-South regions.</p> <p>Methods</p> <p>The India Health Study was a multicenter study of men and women aged 35-69, who provided diet, lifestyle, and medical histories, as well as blood pressure, fasting blood, urine, and anthropometric measurements. In each region (Delhi, n = 824; Mumbai, n = 743; Trivandrum, n = 2,247), we identified two dietary patterns with factor analysis. In multiple logistic regression models adjusted for age, gender, education, income, marital status, religion, physical activity, tobacco, alcohol, and total energy intake, we investigated associations between regional dietary patterns and abdominal adiposity, hypertension, diabetes, and dyslipidemia.</p> <p>Results</p> <p>Across the regions, more than 80% of the participants met the criteria for abdominal adiposity and 10 to 28% of participants were considered diabetic. In Delhi, the "fruit and dairy" dietary pattern was positively associated with abdominal adiposity [highest versus lowest tertile, multivariate-adjusted OR and 95% CI: 2.32 (1.03-5.23); P_trend= 0.008] and hypertension [2.20 (1.47-3.31); P_trend< 0.0001]. In Trivandrum, the "pulses and rice" pattern was inversely related to diabetes [0.70 (0.51-0.95); P_trend= 0.03] and the "snacks and sweets" pattern was positively associated with abdominal adiposity [2.05 (1.34-3.14); P_trend= 0.03]. In Mumbai, the "fruit and vegetable" pattern was inversely associated with hypertension [0.63 (0.40-0.99); P_trend= 0.05] and the "snack and meat" pattern appeared to be positively associated with abdominal adiposity.</p> <p>Conclusions</p> <p>Cardio-metabolic risk factors were highly prevalent in this population. Across all regions, we found little evidence of a Westernized diet; however, dietary patterns characterized by animal products, fried snacks, or sweets appeared to be positively associated with abdominal adiposity. Conversely, more traditional diets in the Southern regions were inversely related to diabetes and hypertension. Continued investigation of diet, as well as other environmental and biological factors, will be needed to better understand the risk profile in this population and potential means of prevention.</p

Foregut mesenchyme contributes cells to pancreatic acini during embryonic development in a chick-quail chimera model.

To understand causes of developmental abnormalities of the pancreas, it is essential to understand its normal embryonic development. Current understanding of the development of pancreatic exocrine tissue is that it develops solely from embryonic epithelium, while the role of the surrounding mesenchyme is to signal to this epithelium and form connective tissue. Recent work in our laboratory has shown that pancreatic bud mesenchyme can contribute cells to islets during embryonic development. However, no published studies have investigated in detail whether mesenchyme contributes cells to the exocrine structures of the pancreas. The aim of this study was to investigate whether cells from foregut mesenchyme can contribute to pancreatic acini during embryonic development. Chick-quail chimera recombinant organs were constructed using pancreatic epithelium and mesenchyme from either the pancreas (n=12) or stomach (n=25). These were cultured for 7 days in 3-D collagen gels. The resulting specimens were analysed using morphological criteria and fluorescent immunocytochemistry against pancreatic amylase, insulin, and the quail-specific nucleolar antigen QCPN. Two independent observers determined the origins of acini as either solely epithelial, solely mesenchymal, or of mixed origin. Results are expressed as percentages of total acini identified in each group. Statistical analysis was performed using chi(2) tests (P<0.01 was considered statistically significant). Recombinations of pancreatic epithelium and pancreatic mesenchyme yielded 11 acini, of which 45% were derived from epithelium only, 45% from mesenchyme only, and 10% of mixed origin. Recombinations of pancreatic epithelium and stomach mesenchyme yielded 78 acini, of which 40% were derived from epithelium only, 32% from mesenchyme only, and 28% of mixed origin. When acini with any mesenchymal cellular contribution were considered as a group, there was no significant difference between stomach and pancreatic mesenchymal contribution (P=0.72). This is the first study to demonstrate the cellular contribution of mesenchyme to pancreatic exocrine structures. Our data show that mesenchyme contributes cells to pancreatic acini during development in this model and that mesenchyme derived from stomach and pancreatic sources are both able to form acini

Foregut mesenchyme contributes cells to islets during pancreatic development in a 3-dimensional avian model

Current interest in the potential use of pancreatic stem-cells in the treatment of insulin dependent diabetes mellitus has led to increased research into normal pancreatic development. Pancreatic organogenesis involves branching morphogenesis of undifferentiated epithelium within surrounding mesenchyme. Current understanding is that the pancreatic islets develop exclusively from the epithelium of the embryonic buds. However, a cellular contribution to islets by mesenchyme has not been conclusively excluded. We present evidence that the mesenchyme of both the dorsal pancreatic bud and stomach rudiment make a substantial contribution of cells to islets during development in a three-dimensional avian model. These data suggest that mesenchyme can be a source not only of signals but also of cells for the definitive epithelia, making pancreatic organogenesis more akin to that of the kidney than to other endodermal organs. This raises the possibility for the use of mesenchymal cells as stem- or progenitor- cells for islet transplantation

Metabolic alterations derived from absence of Two-Pore Channel 1 at cardiac level.

Two-pore channels (TPCs or TPCNs) are novel voltage-gated ion channels that have been postulated to act as Ca2+ and/or Na+ channels expressed exclusively in acidic organelles such as endosomes and lysosomes. TPCNs participate in the regulation of diverse biological processes and recently have been proposed to be involved in the pathophysiology of metabolic disorders such as obesity, fatty liver disease and type 2 diabetes mellitus. Due to the importance of these pathologies in the development of cardiovascular diseases, we aimed to study the possible role of two-pore channel 1 (TPCN1) in the regulation of cardiac metabolism. To explore the cardiac function of TPCN1, we developed proteomic approaches as 2-DE-MALDI-MS and LC-MALDI-MS in the cardiac left ventricle of TPCN1 KO and WT mice, and found alterations in several proteins implicated in glucose and fatty acid metabolism in TPCN1 KO vs. WT mice. The results confirmed the altered expression of HFABP, a key fatty acid transport protein, and of enolase and PGK1, the key enzymes in the glycolytic process. Finally, in vitro experiments performed in neonatal rat cardiomyocytes, in which TPCN1 was silenced using siRNAs, confirmed that the downregulation of TPCN1 gene expression increased 2-deoxy-D-[3H]-glucose uptake and GLUT4 mobilization into cell peripherals in cardiac cells. Our results are the first to suggest a potential role for TPCNs in cardiac metabolism regulation