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Current Opinion in Endocrinology, Diabetes and Obesity - Current Table Of Contents

Editorial introductions.
Page: viiDOI: 10.1097/MED.0b013e32831c7004
Pharmacogenetics of osteoporosis and the prospect of individualized prognosis and individualized therapy.
Page: 481DOI: 10.1097/MED.0b013e32831a46beAuthors: Nguyen, Tuan V; Center, Jacqueline R; Eisman, John A
Assessment of vitamin D status and definition of a normal circulating range of 25-hydroxyvitamin D.
Page: 489DOI: 10.1097/MED.0b013e328317ca6cAuthors: Hollis, Bruce W

PubMed: 0013-7227

Impact of Small Molecule Glucokinase Activator on Glucose Metabolism and Beta Cell Mass.
Nakamura A, Terauchi Y, Ohyama S, Kubota J, Shimazaki H, Nambu T, Takamoto I, Kubota N, Eiki J, Yoshioka N, Kadowaki T, Koike T Related Articles Impact of Small Molecule Glucokinase Activator on Glucose Metabolism and Beta Cell Mass. Endocrinology. 2008 Nov 13; Authors: Nakamura A, Terauchi Y, Ohyama S, Kubota J, Shimazaki H, Nambu T, Takamoto I, Kubota N, Eiki J, Yoshioka N, Kadowaki T, Koike T We investigated the effect of glucokinase activator (GKA) on glucose metabolism and beta cell mass. We analyzed four mouse groups: wild-type mice and beta cell-specific haploinsufficiency of glucokinase gene (Gck(+/-)) mice on a high-fat (HF) diet; each genotype was also treated with GKA mixed in the HF diet. Rodent insulinoma cells and isolated islets were used to evaluate beta cell proliferation by GKA. After 20 weeks on the above diets, there were no differences in body weight, lipid profiles and liver triglyceride content among the four groups. Glucose tolerance was improved shortly after the GKA treatment in both genotypes of mice. Beta cell mass increased in wild-type mice compared with Gck(+/-) mice, but a further increase was not observed after the administration of GKA in both genotypes. Interestingly, GKA was able to upregulate insulin receptor substrate-2 (Irs-2) expression in insulinoma cells and isolated islets. The administration of GKA increased 5-bromo-2-deoxyuridine (BrdU) incorporation in insulinoma cells, and 3 days' administration of GKA markedly increased BrdU incorporation in mice treated with GKA in both genotypes, compared with those without GKA. In conclusion, GKA was able to chronically improve glucose metabolism for mice on the HF diet. While chronic GKA administration failed to cause a further increase in beta cell mass in vivo, GKA was able to increase beta cell proliferation in vitro and with a 3-day-administration in vivo. This apparent discrepancy can be explained by a chronic reduction in ambient blood glucose levels by GKA treatment. PMID: 19008318 [PubMed - as supplied by publisher]
Importance of PCSK9 in the hormonal and dietary regulation of rat liver LDL receptors.
Persson L, Gälman C, Angelin B, Rudling M Related Articles Importance of PCSK9 in the hormonal and dietary regulation of rat liver LDL receptors. Endocrinology. 2008 Nov 13; Authors: Persson L, Gälman C, Angelin B, Rudling M Hormonal or dietary challenge can stimulate hepatic LDL-receptor (LDLR) expression through posttranscriptional mechanisms. We here tested whether such observations may be due to regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). Treatment with glucagon resulted in a 2-fold increase in hepatic LDLR protein expression while its mRNA levels were reduced, this occurred simultaneously with a 70% reduction in PCSK9 expression. Insulin treatment resulted in responses opposite to those seen by treatment with glucagon. Furthermore, high-dose ethinylestradiol treatment reduced PCSK9 expression by half. Finally, feeding of rats with dietary cholesterol reduced PCSK9 expression, resulting in an increased number of hepatic LDLRs despite a reduction of LDLR mRNA levels. Regulation of PCSK9 occurred in part through sterol regulatory element binding protein-2 (SREBP-2), but changes in this cholesterol-controlled transcription factor could not explain all hormonal effects seen. We conclude that the hormonal and dietary regulation of hepatic LDLRs also involves posttranscriptional regulation by PCSK9. The identification of PCSK9 regulation by these various treatments is important in understanding of the physiological function of this protein, and points to new targets for therapeutic treatments to increase hepatic LDLR numbers. PMID: 19008317 [PubMed - as supplied by publisher]
Cells expressing RFRP-1/3, the mammalian GnIH orthologs, are not hypophysiotropic neuroendocrine neurons in the rat.
Rizwan MZ, Porteous R, Herbison AE, Anderson GM Related Articles Cells expressing RFRP-1/3, the mammalian GnIH orthologs, are not hypophysiotropic neuroendocrine neurons in the rat. Endocrinology. 2008 Nov 13; Authors: Rizwan MZ, Porteous R, Herbison AE, Anderson GM An RFamide peptide named gonadotropin-inhibitory hormone (GnIH), that directly inhibits gonadotropin synthesis and secretion from the anterior pituitary gland, has recently been discovered in the avian hypothalamus. It is not known if the mammalian orthologs of GnIH, RFamide-related peptide (RFRP)-1 and -3, act in the same way. We used a newly-generated antibody against the rat RFRP precursor combined with retrograde tract tracing to characterize the cell body distribution and fiber projections of RFRP-1 and -3 (RFRP-1/3) neurons in rats. RFRP-1/3-immunoreactive cell bodies were found exclusively within the dorsomedial hypothalamus. Immunoreactive fibers were observed in the septal-preoptic area, hypothalamus, mid-brain, brainstem and hippocampus, but not in the external zone of the median eminence. Intraperitoneal injection of the retrograde tracer Fluoro-Gold in rats resulted in the labeling of the majority of gonadotropin-releasing hormone (GnRH) neurons but essentially no RFRP-1/3 neurons. In contrast, intracerebral injections of Fluoro-Gold into the rostral preoptic area and CA2/CA3 hippocampus resulted in the labeling of 75+/-5% and 21+/-8% of RFRP-1/3 cell bodies, respectively. To assess actions at the pituitary in vivo, RFRP-3 was administered as an intravenous bolus to ovariectomized rats and plasma luteinizing hormone (LH) concentration measured at 0, 2.5, 5, 10 and 30 minutes. RFRP-3 had no effects on basal secretion, but GnRH-stimulated LH release was reduced by approximately 25% at 5 minutes. Together, these observations suggest that RFRP-3 is not a hypophysiotropic neuroendocrine hormone in rats. PMID: 19008316 [PubMed - as supplied by publisher]
Blockade of Estrogen Receptor Signaling Inhibits Growth and Migration of Medulloblastoma.
Belcher SM, Ma X, Le HH Related Articles Blockade of Estrogen Receptor Signaling Inhibits Growth and Migration of Medulloblastoma. Endocrinology. 2008 Nov 13; Authors: Belcher SM, Ma X, Le HH Medulloblastoma is the most common malignant brain tumors in children. These invasive neuroectodermal tumors arise from cerebellar granule cell-like precursors. In the developing cerebellum, estrogen influences growth and viability of granule cell precursors that transiently express elevated levels estrogen receptor beta (ERbeta) during differentiation. Immunoanalysis revealed that ERbeta was expressed in the maturing human cerebellum, in all 22 primary medulloblastoma tumors analyzed, and in two medulloblastoma-derived cell lines (D283Med and Daoy). Very low levels of ERalpha-like proteins were detected in each cell line and 41% of tumor samples. Physiologic concentrations of the 17beta-estradiol, or the ERbeta-selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile diarylpropionitrile dose dependently increased medulloblastoma growth and cellular migration. In contrast the ERalpha selective agonist (4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol did not influence MD growth. Similar to previous studies in normal cerebellar granule cell precursors, these studies demonstrate that the physiology actions estrogens in MD are mediated by ERbeta. Preclinical studies assessing the therapeutic efficacy of anti-estrogen chemotherapeutics for treating human MD were performed. It was found that pharmacological inhibition of ER-mediated signaling with the ER antagonist drug Faslodex (ICI182,780) blocked all estrogen-mediated effects in both cell culture and xenograft models of human MD. These studies have revealed that functional ERbeta expression is a fundamental aspect of medulloblastoma biology and has defined anti-estrogen therapy as a potentially efficacious clinical approach to improve the long-term outcomes for MD patients. PMID: 19008315 [PubMed - as supplied by publisher]
TRAIL inhibits experimental autoimmune thyroiditis by the expansion of CD4+CD25+ regulatory T cells.
Wang SH, Chen GH, Fan Y, Van Antwerp M, Baker JR Related Articles TRAIL inhibits experimental autoimmune thyroiditis by the expansion of CD4+CD25+ regulatory T cells. Endocrinology. 2008 Nov 13; Authors: Wang SH, Chen GH, Fan Y, Van Antwerp M, Baker JR There have been several reports that TRAIL (TNF-related apoptosis-inducing ligand) has the ability to suppress the development of experimental autoimmune diseases, including a mouse model of experimental autoimmune encephalomyelitis (EAE), a rabbit model of rheumatoid arthritis, type 1 diabetes mellitus (T1DM) in mice and experimental autoimmune thyroiditis (EAT) in mice. However, the mechanism underlying TRAIL effect is not well defined. In the present study, we specifically examine TRAIL effects on CD4(+)CD25(+) regulatory T cells. CD4(+)CD25(+) T cells prepared from mouse thyroglobulin (mTg)-immunized CBA/J mice proliferate in the presence of TRAIL and dendritic cells in vitro. These CD4(+)CD25(+) T cells included both CD4(+)CD25(+)CD45RB(Low) (regulatory) and CD4(+)CD25(+)CD45RB(High) (effector) T cells. Our results demonstrated that mTg-immunized mice treated with TRAIL showed significant increases in the number of CD4(+)CD25(+)CD45RB(Low) T cells compared to mice immunized with mTg alone. CD4(+)CD25(+)CD45RB(Low) T cells expressed much higher levels of Foxp3, IL-10 and TGFbeta1 than CD4(+)CD25(+)CD45RB(High) T cells, and these cells can completely suppress the proliferation of the mTg-primed splenocytes in lower concentrations than the un-fractionated CD4(+)CD25(+) T cells. Furthermore, transfer of these cells into CBA/J mice prior to mTg-primed splenocyte injection could markedly reduce the frequency and severity of EAT development. CD4(+)CD25(+)CD45RB(Low) T cells were more effective at suppressing histological thyroiditis than un-fractionated cells. These results indicated that TRAIL can increase the number of mTg-specific CD4(+)CD25(+)CD45RB(Low) T cells, inhibiting autoimmune responses and preventing the progression of EAT. These findings reveal a novel mechanism by which TRAIL could inhibit autoimmune disease. PMID: 19008314 [PubMed - as supplied by publisher]
Orexin-A hyperphagia: Hindbrain participation in consummatory feeding responses.
Baird JP, Choe A, Loveland JL, Beck J, Mahoney CE, Lord JS, Grigg LA Related Articles Orexin-A hyperphagia: Hindbrain participation in consummatory feeding responses. Endocrinology. 2008 Nov 13; Authors: Baird JP, Choe A, Loveland JL, Beck J, Mahoney CE, Lord JS, Grigg LA Orexin-A (ORXA) is an orexigenic neuropeptide produced the lateral hypothalamus that increases food intake when injected into the brain ventricles or forebrain nuclei. We used a licking microstructure analysis to evaluate hindbrain and forebrain ORXA effects in intact and hindbrain-lesioned rats, to identify the motivational and anatomical bases of ORXA hyperphagia. Intact rats with cannulas in the fourth brain ventricle (4V) received vehicle (aCSF) or ORXA (0.1, 0.4, 1 or 10 nM) injections prior to 90 min access to 0.1M sucrose. Meal size and frequency were increased in a double dissociated manner by the 1nM and 10nM doses, respectively. In Experiment 2, 4V 1nM ORXA was applied to rats offered solutions varied in caloric and gustatory intensity (water, 0.1M and 1M sucrose). ORXA increased meal frequency for all tastants. ORXA increased meal size only for 0.1M sucrose, by prolonging the meal without affecting early ingestion rate or burst size, suggesting that 4V ORXA influenced inhibitory post-ingestive feedback rather than taste evaluation. In Experiment 3, rats with cannulas in the third ventricle (3V) received dorsal medullary lesions centered on the area postrema (APX) or sham procedures (SHAM), and licking for water, 0.1M and 1M sucrose was evaluated after 1nM 3V ORXA/aCSF injections. 3V ORXA increased 0.1M sucrose meal size and meal frequency for all tastants in the SHAM group, as observed after 4V ORXA in Experiment 2. In the APX group, 3V ORXA injections influenced meal frequency, but they no longer increased meal size. However, the APX rats increased meal size for 0.1M sucrose after food and water deprivation and after 3V Angiotensin II injection. They also showed meal size suppression after 3V injection of the melanocortin 3/4 receptor agonist, melanotan II (1nM). These findings suggest that the area postrema and subjacent nucleus of the solitary tract are necessary for increases in consummatory (meal size) but not appetitive (meal frequency) responses to 3V ORXA. The meal size increases may be due to reduced postingestive feedback inhibition induced by ORXA delivered to either the hindbrain or forebrain ventricles. PMID: 19008313 [PubMed - as supplied by publisher]
A Positive Feedback between Activated ERK and COX/LOX Maintains Proliferation and Migration of Breast Cancer Cells.
You J, Mi D, Zhou X, Qiao L, Zhang H, Zhang X, Ye L Related Articles A Positive Feedback between Activated ERK and COX/LOX Maintains Proliferation and Migration of Breast Cancer Cells. Endocrinology. 2008 Nov 13; Authors: You J, Mi D, Zhou X, Qiao L, Zhang H, Zhang X, Ye L Metastasis of breast cancer cells is the leading cause of death of breast cancer patients. Why do breast cancer cells with high metastatic potential always keep in high proliferation and migration? The endogenous signaling pathways associated with tumor metastasis remain unclear. In the present study, we address whether a link between ERK and the enzymes associated with arachidonic acid metabolism contributes to the proliferation and migration of breast cancer cells. In order to identify endogenous signaling pathways involved in sustaining proliferation and migration of breast cancer cells, we carried out parallel studies of human breast cancer cell lines that differ in their metastatic potential. Our data showed that cell lines with high metastatic potential, including LM-MCF-7 and MDA-MB-231, exhibited significantly high, sustained levels of phosphorylated ERK (pERK1/2) relative to MCF-7 cells. Our findings showed that beta-catenin, cyclin D1 and survivin serve downstream effectors of pERK1/2, whereas Gi/o proteins, PLC and PKC serve upstream activators of pERK1/2. In addition, arachidonic acid metabolites were able to activate Gi/o proteins, PLC, PKC and pERK1/2 cascades through COX and LOX. In contrast, activated ERK1/2 promoted arachidonic acid metabolism through a positive feedback loop, which conduces to a high proliferative potential and the migration of the breast cancer cells. Taken together, our data provide new mechanistic insights into possible endogenous signaling metastatic signaling pathways involved in maintaining proliferation and migration of breast cancer cells. PMID: 19008312 [PubMed - as supplied by publisher]
Differential Neuroendocrine Expression of Multiple Brain-Derived Neurotrophic Factor Transcripts.
Kidane AH, Heinrich G, Dirks RP, de Ruyck BA, Lubsen NH, Roubos EW, Jenks BG Related Articles Differential Neuroendocrine Expression of Multiple Brain-Derived Neurotrophic Factor Transcripts. Endocrinology. 2008 Nov 13; Authors: Kidane AH, Heinrich G, Dirks RP, de Ruyck BA, Lubsen NH, Roubos EW, Jenks BG Brain-derived neurotrophic factor (BDNF) is a neurotrophin with important growth-promoting properties. We report here the first characterization of a BDNF gene in an amphibian, Xenopus laevis, and demonstrate that environmental factors can activate this gene in a promoter-specific fashion. The Xenopus BDNF gene contains six promoter-specific 5'-exons and one 3'-protein-encoding exon. We examined the expression of promoter-specific transcripts in Xenopus neuroendocrine melanotrope cells. These cells make a good model to study how environmental factors control gene expression. In animals placed on a black background melanotrope cells more actively produce and release alpha-melanophore-stimulating hormone (alphaMSH) than in animals on a white background. BDNF is co-sequestered and co-released with alphaMSH, and stimulates biosynthesis of proopiomelanocortin (POMC), the precursor protein for alphaMSH. Our analysis of the expression of the BDNF transcripts revealed that there is differential utilization of some BDNF promoters in melanotrope cells depending on the adaptation state of the frog. During black-background adaptation, stimulation of expression of BDNF transcript IV preceded that of the POMC transcript, suggesting the BDNF gene is an effector gene for POMC expression. The possible mechanisms regulating expression of the various transcripts are discussed on the basis of the potential calcium- and cAMP-responsive elements in the promoter region of exon IV. Finally, we show that the upstream open reading frames of BDNF transcripts I and IV markedly decrease BDNF translation efficiency, giving the first indication for a functional role of untranslated BDNF exons. PMID: 19008311 [PubMed - as supplied by publisher]
Adrenomedullin Improves Cardiac Expression of Heat-Shock Protein 72 and Tolerance against Ischemia/Reperfusion Injury in Insulin-Resistant Rats.
Torigoe Y, Takahashi N, Hara M, Yoshimatsu H, Saikawa T Related Articles Adrenomedullin Improves Cardiac Expression of Heat-Shock Protein 72 and Tolerance against Ischemia/Reperfusion Injury in Insulin-Resistant Rats. Endocrinology. 2008 Nov 13; Authors: Torigoe Y, Takahashi N, Hara M, Yoshimatsu H, Saikawa T We recently reported that long-term treatment with pioglitazone restored cardiac Akt phosphorylation in response to hyperthermia (HT) and subsequent cardiac heat-shock protein-72 (HSP72) expression, in heredity insulin-resistance rats, via improvement of insulin sensitivity. Because adrenomedullin (AM) promotes Akt phosphorylation and attenuate myocardial ischemia/reperfusion injury, we tested the hypothesis that pretreatment with AM before HT could restore depressed Akt activation and cardiac HSP72 expression, thereby enhancing protection against ischemia/reperfusion injury in this model. At 16 weeks of age, male insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats were treated with AM (0.05 microg/kg/min i.v.) or vehicle for 60 min. Thereafter, HT (43 degrees C for 20 min) or normothermia (NT; 37 degrees C for 20 min) was applied. The heart was isolated 1 h and 24 h after HT. 1) Either AM or HT induced myocardial Akt phosphorylation in a PI3K-dependent manner, which was augmented by their combination. 2) Akt phosphorylation induced by HT, or combination of HT and AM, was attenuated in insulin-resistant OLETF rat hearts. 3) The levels of Akt phosphorylation in response to AM and/or HT correlated with reperfusion-induced LV functional recovery and amount of released CK during reperfusion. 4) AM protected the hearts of OLETF rats and LETO rats. Our results suggest that AM pretreatment could enhance HT-induced myocardial Akt phosphorylation and subsequent HSP72 expression in a PI3K-dependent manner, in association with tolerance against ischemia/reperfusion injury. This intervention was effective even in insulin-resistant hearts. PMID: 19008310 [PubMed - as supplied by publisher]

PubMed: 0804-4643

Normal overall mortality in Addison's disease, but young patients are at risk of premature death.
Erichsen M, Løvås K, Fougner K, Svartberg J, Hauge E, Bollerslev J, Berg J, Mella B, Husebye E Related Articles Normal overall mortality in Addison's disease, but young patients are at risk of premature death. Eur J Endocrinol. 2008 Nov 14; Authors: Erichsen M, Løvås K, Fougner K, Svartberg J, Hauge E, Bollerslev J, Berg J, Mella B, Husebye E Abstract Context: Primary adrenal insufficiency (Addison's disease) is a rare autoimmune disease. Until recently, life expectancy in Addison's disease was considered normal. Objective: To determine the mortality in Addison's disease. Design and methods: (i) Patients registered with Addison's disease in Norway 1943-2005 were identified through search in hospital diagnosis registries. Scrutiny of the medical records provided diagnostic accuracy and age at diagnosis. (ii) The patients who had died were identified from the National Directory of Residents. (iii) Background mortality data was obtained from Statistics Norway, and standard mortality rate (SMR) calculated. (iv) Death diagnoses were obtained from the Norwegian Death Cause Registry. Results: Eight hundred and eleven patients with Addison's disease were identified, of whom 147 were deceased. Overall SMR was 1.15 [95% CI 0.96-1.35], similar in females (1.18 [0.92-1.44]) and males (1.10 [0.80-1.39]). Patients diagnosed before the age of 40 had significantly elevated SMR at 1.50 [95% CI 1.09-2.01], most pronounced in males (2.03 [1.19-2.86]). Acute adrenal failure was a major cause of death; infection and sudden death were more common than in the general population. The mean ages at death for females (75.7 years) and males (64.8 years) were 3.2 and 11.2 years less than estimated life expectancy. Conclusion: Addison's disease is still a potentially lethal condition, with excess mortality in acute adrenal failure, infection and sudden death in patients diagnosed at young age. Otherwise, the prognosis is excellent for patients with Addison's disease. PMID: 19011006 [PubMed - as supplied by publisher]

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