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This cohort study examines the incidence of cancer diagnosis and risk factors among patients on a daily regimen of insulin.

Background: ANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP. Methods and Results: Immunohistochemical analysis of rat tissues revealed that NPR1 was abundantly expressed in endothelial cells and smooth muscle cells of small arteries and arterioles. Intravenous infusion of ANP significantly lowered systolic blood pressure in wild-type mice. ANP also significantly lowered systolic blood pressure in smooth muscle cell–specific Npr1 –knockout mice but not in endothelial cell–specific Npr1 –knockout mice. Moreover, ANP significantly lowered systolic blood pressure in Nos3 -knockout mice. In human umbilical vein endothelial cells, treatment with ANP did not influence nitric oxide production or intracellular Ca 2+ concentration, but it did hyperpolarize the cells. ANP-induced hyperpolarization of human umbilical vein endothelial cells was inhibited by several potassium channel blockers and was also abolished under knockdown of RGS2 (regulator of G-protein signaling 2), an GTPase activating protein in G-protein α-subunit. ANP increased Rgs2 mRNA expression in human umbilical vein endothelial cells but failed to lower systolic blood pressure in Rgs2 -knockout mice. Endothelial cell–specific Npr1 -overexpressing mice exhibited lower blood pressure than did wild-type mice independent of RGS2, and showed dilation of arterial vessels on synchrotron radiation microangiography. Conclusions: Together, these results indicate that vascular endothelial NPR1 plays a crucial role in ANP-mediated blood pressure regulation, presumably by a mechanism that is RGS2-dependent in the acute phase and RGS2-independent in the chronic phase.

College network education as the main development direction of modern education, although both for professional teachers and students provides a new platform, and provides sufficient conditions for the people to continue learning, but also show more quality problem, so the system understanding of college network education present situation, according to the practice of science of education evaluation system to judge the quality of education, To continuously improve the comprehensive management efficiency of network education in colleges and universities is the focus of attention of college education administrators at present. This paper studies the theoretical definition of ordinary differential equation model as the core, builds a quality evaluation system based on the innovation model of network education in colleges and universities, investigates and analyzes the implementation of network education in a university, and finally puts forward effective prospect prediction and improvement measures combined with the research results.

To conduct a systematic review and meta-analysis describing the association of thyroid function with posttraumatic stress disorder (PTSD) in adults.The authors conducted a comprehensive search from databases' inception to July 20, 2018. The meta-analysis included studies that reported mean values and standard deviation (SD) of thyroid hormone levels (thyroid-stimulating hormonelsqb;TSH], free thyroxinelsqb;FT4], free triiodothyroninelsqb;FT3], total T4lsqb;TT4], and total T3lsqb;TT3]) in patients with PTSD compared with controls. Five reviewers worked independently, in duplicate, to determine study inclusion, extract data, and assess risk of bias. The mean value and SD of the thyroid function tests were used to calculate the mean difference for each variable. Random-effects models for meta-analyses were applied.The meta-analysis included 10 observational studies at low-to-moderate risk of bias. Studies included 674 adults (373 PTSD, 301 controls). The meta-analytic estimates showed higher levels of FT3 (+0.28 pg/mL; P = .001) and TT3 (+18.90 ng/dL; P = .005) in patients with PTSD compared to controls. There were no differences in TSH, FT4, or TT4 levels between groups. In the subgroup analysis, patients with combat-related PTSD still had higher FT3 (+0.36 pg/mL; P = .0004) and higher TT3 (+31.62 ng/dL; P.00001) compared with controls. Conversely, patients with non-combat-related PTSD did not have differences in FT3 or TT3 levels compared with controls.There is scarce evidence regarding the association of thyroid disorders with PTSD. These findings add to the growing literature suggesting that thyroid function changes may be associated with PTSD.

There is no longitudinal study regarding the changes of insulin resistance (IR) status and the development of complications in type 1 diabetes (T1D). By analyzing data sets from DCCT/EDIC study, we investigated the associations of IR status changes and diabetic complications in T1D.Estimated glucose disposal rate (eGDR) was calculated at entry of DCCT and in EDIC year 12 (average 18.5 years later) to represent IR. The participants (n = 957) were divided into four groups based on IR changes from baseline: RR group (stayed resistant; n = 49), RS group (became sensitive; n = 42), SR group (became resistant; n = 197), and SS group (stayed sensitive; n = 669). The association of diabetic complications were analyzed by using multivariable logistic regression models.The improved IR decreased the risk of peripheral neuropathy, whereas the deteriorated IR increased the risk of diabetic complications including hypertension, peripheral artery disease, coronary artery calcification, retinopathy, albuminuria, peripheral neuropathy, and cardiac autonomic neuropathy (P 0.05). Moreover, RR group (HR = 3.59, 95% CI (2.05-6.32)), RS group (HR = 2.27, 95% CI (1.11-4.64)) and SR group (HR = 1.90, 95% CI (1.24-2.92)) had higher risk of cardiovascular events compared to SS group (P 0.05).This study highlights the importance of IR changes represented by eGDR in the development of diabetic complications. Patients with T1D and IR may require intensive therapy.

Background: The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial natriuretic peptides and brain natriuretic peptides produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiologic and pathophysiologic roles of endogenous atrial natriuretic peptide/brain natriuretic peptide in the perinatal period are not fully understood. Methods: To clarify the physiologic and pathophysiologic roles of the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function. Results: In wild-type mice, lactation but not pregnancy induced reversible cardiac hypertrophy accompanied by increases in fetal cardiac gene mRNAs and ERK1/2 (extracellular signaling-regulated kinase) phosphorylation. Npr1-knockout mice exhibited significantly higher plasma aldosterone level than did wild-type mice, severe cardiac hypertrophy accompanied by fibrosis, and left ventricular dysfunction in the lactation period. Npr1-knockout mice showed a high mortality rate over consecutive pregnancy–lactation cycles. In the hearts of Npr1-knockout mice during or after the lactation period, an increase in interleukin-6 mRNA expression, phosphorylation of signal transducer and activator of transcription 3, and activation of the calcineurin–nuclear factor of the activated T cells pathway were observed. Pharmacologic inhibition of the mineralocorticoid receptor or neuron-specific deletion of the mineralocorticoid receptor gene significantly ameliorated cardiac hypertrophy in lactating Npr1-knockout mice. Anti–interleukin-6 receptor antibody administration tended to reduce cardiac hypertrophy in lactating Npr1-knockout mice. Conclusions: These results suggest that the characteristics of lactation-induced cardiac hypertrophy in wild-type mice are different from exercise-induced cardiac hypertrophy, and that the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system plays an important role in protecting the maternal heart from interleukin-6–induced inflammation and remodeling in the lactation period, a condition mimicking peripartum cardiomyopathy.

Thyroid disease is a very common condition that influences the entire human body, including cognitive function and mental health. As a result, thyroid disease has been associated with multiple neuropsychiatric conditions. However, the relationship between thyroid dysfunction and suicide is still controversial. We conducted a systematic review and meta-analysis to describe the association of thyroid function with suicidal behavior in adults. We searched four data bases (MEDLINE, EMBASE, PsycINFO, and Scopus) from their inception to 20 July 2018. Studies that reported mean values and standard deviation (SD) of thyroid hormone levels [Thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), and total triiodothyronine (TT3)] in patients with suicidal behavior compared with controls were included in this meta-analysis. The abstracts and papers retrieved with our search strategies were reviewed independently and in duplicate by four reviewers for assessment of inclusion criteria and data extraction, as well as for evaluation of risk of bias. Random-effects models were used in this meta-analysis to establish the mean difference on thyroid function tests between groups. Overall, 2278 articles were identified, and 13 studies met the inclusion criteria. These studies involved 2807 participants, including 826 participants identified with suicidal behavior. We found that patients with suicide behavior had lower levels of FT3 (−0.20 pg/mL; p = 0.02) and TT4 (−0.23 µg/dL; p = 0.045) compared to controls. We found no differences in either TSH, FT4, or TT3 levels among groups. With our search strategy, we did not identify studies with a comparison of overt/subclinical thyroid disease prevalence between patients with and without suicide behavior. The studies included in this meta-analysis had a low-to-moderate risk of bias. In the available literature, the evidence regarding the association of thyroid disorders and suicidal behavior is limited. We found that patients with suicidal behavior have significantly lower mean FT3 and TT4 levels when compared to patients without suicidal behavior. The clinical implications and pathophysiologic mechanisms of these differences remain unknown and further research is needed.

Background: There are few studies on the role of long-term glycemic variability in complications of type 1 diabetes (T1D). This study was aimed to investigate the associations of HbA1c variability represented by the coefficient of variation of HbA1c with incident microvascular complications in T1D by analyzing the data set from the DCCT/EDIC study. Methods: Patients (n = 1240) were divided into four groups by HbA1c variability quartiles. Incident microvascular complications were assessed for a duration of an average of 20.5 years. Multivariable models were performed to examine the associations between HbA1c variability and incident microvascular complications. Results: All incident microvascular complications were higher in the fourth quartile of the HbA1c variability group. After adjusting for clinical risk factors, HbA1c variability was positively associated with a higher risk of all diabetic microvascular complications ( P < .05). Specifically, it had 1.125 (1.082-1.170), 1.114 (1.074-1.154), 1.061 (1.024-1.099), or 1.088 (1.052-1.125) times higher odds (95% confidence interval [CI]) of having retinopathy, nephropathy, clinical neuropathy, or autonomic neuropathy, independent of mean HbA1c values ( P < .05). Furthermore, there were higher incident microvascular complications with higher HbA1c variability when HbA1c value was above the group median of 7.9%, while only higher incident autonomic neuropathy with higher HbA1c variability when HbA1c was below the group median. Conclusions: Our results showed a significant independent association between HbA1c variability and the risk of microvascular complications in T1D. HbA1c variability might be a supplemental risk stratification tool to mean HbA1c for microvascular complications in T1D.

Background: Thyroid disorders are very prevalent and could affect virtually the entire human body, including cognitive and psychiatric domains. However, the relationship between thyroid dysfunction and suicide is still controversial. Material and Methods: A systematic review and meta-analysis was conducted to describe the association of thyroid function with suicide ideation/attempt in adults. A comprehensive search from databases’ inception (MEDLINE, EMBASE, Cochrane, PsycINFO, PsycArticles, PSYNDEX and Scopus) to July 20, 2018 was conducted with no language restrictions. We included studies that reported mean values and standard deviation (SD) of thyroid hormone levels [Thyroid-stimulant hormone (TSH), free T4 (FT4), free T3 (FT3), total T4 (TT4), and total T3 (TT3)] in patients with suicide ideation/attempt compared with controls. Four reviewers worked independently and in duplicate for assessment of inclusion criteria, data extraction, and assessment of risk of bias. The mean value and SD of the thyroid function tests were used to calculate the mean difference for each subgroup. Random-effects models for meta-analyses were applied. Results: Overall, 2278 articles were identified, and 13 observational studies met the inclusion criteria. These studies involved 2651 participants, including 817 participants diagnosed with suicidal ideation/attempt. Group sizes of patients with suicide ideation/attempt ranged from 7 to 122 participants with mean age ranging from 23 to 49 years. Control group sizes ranged from 8 to 464 participants with mean age ranging from 24 to 50 years. Two studies included only women, two studies included only men, and 9 studies included both (% female range: 29 to 78%). Patients with suicide ideation/attempt had lower levels of FT3 (-0.19 pg/mL; P=0.04) and TT4 (-0.23 µg/dL; P=0.05) compared to controls. There were no differences in TSH, TT3 or FT4 levels between groups. In a subgroup analysis comparing current suicidal ideation vs current suicidal attempt vs history of suicidal ideation/attempt with the control group, there were no differences in any of the thyroid function tests. None of the included studies compared rates of overt/subclinical thyroid disease among groups. The overall risk of bias of the included studies was low-to-moderate. Conclusions: There is scarce evidence regarding the association of thyroid disorders and suicide. We found statistically significant lower thyroid hormone levels in patients with suicidal ideation/attempt. The clinical implications of this finding remain unknown and further research is needed to evaluate the association of thyroid disorders with suicide.

Introduction Pseudohypoparathyroidism (PHP) is characterized by renal resistance to the effects of parathyroid hormone (PTH) resulting in hypocalcemia, hyperphosphatemia and elevated parathyroid hormone (PTH). Hypercalcemia in PHP has previously been reported to occur due to the development of tertiary hyperparathyroidism or due to over-replacement of calcitriol. This is the first reported case of parathyroid carcinoma in a patient with PHP. The presenting features were hypercalcemia and marked elevation of PTH over the course of 3 years. Clinical case A 47 year old woman with PHP type 1B presented for evaluation of hypercalcemia for the past 3 years. She was diagnosed with PHP at the age of 5 after a hypocalcemia seizure. At that time, she had hypocalcemia (5.5-6 mg/dl), hyperphosphatemia (9.3-9.7 mg/dl) and elevated PTH (2442 pg/ml, normal 160-360 pg/ml). Renal function was normal. Tubular reabsorption of phosphate was unchanged at 98% after an injection of PTH leading to the diagnosis of PHP. She had a long history of non-adherence to medication and multiple hypocalcemic seizures. She developed hypercalcemia (10.9 mg/dl), elevated PTH (1064.7 pg/ml, normal 12-88 pg/ml) and normalization of serum phosphate (2.8 mg/dl) at the age of 44 while on calcitriol 0.25 mcg daily. She remained hypercalcemic when calcitriol was stopped. Neck ultrasound revealed a 2.2 x 1.6 x 1.3 cm exophytic, hypoechoic nodule at the inferior pole of the left thyroid lobe with increased vascularity. It was irregularly marginated along the thyroid and had no clear border anteriorly along the strap muscles. Parathyroid exploration and total thyroidectomy was performed. Pathology revealed parathyroid carcinoma with multiple foci of vascular invasion and one focus of soft tissue extension. Post-operative PTH declined to 2.6 pg/ml and patient had recurrence of hypocalcemia (total calcium 6.5 mg/dl) due to which calcitriol was restarted. She developed hungry bone syndrome necessitating IV calcium for 2 days. Conclusion The initial presentation with spontaneous hypercalcemia and history of non-adherence with medication prompted concern for tertiary hyperparathyroidism but the PTH elevation was higher than in prior cases of tertiary hyperparathyroidism and had doubled over 3 years despite medical therapy with calcitriol raising concern for a neoplastic process. Rapid development of hypercalcemia in a patient with PHP should raise the suspicion for parathyroid carcinoma. PHP type 1B is associated with defects in the regulatory elements of GNAS1 whereas PHP type 1A is due to loss of function mutations in GNAS1. All cases of hypercalcemic hyperparathyroidism in PHP have been noted in PHP type 1B which indicates that the resistance to PTH in PHP type 1B is only relative and can be overcome when the PTH becomes markedly elevated. The PTH elevation was sufficient to excrete urinary phosphate and normalize the serum phosphate level.

Background: The multiple endocrine neoplasia type 1 (MEN1) syndrome is a rare autosomal dominant inherited tumor syndrome. Mutations in the MEN1 gene are detectable in approximately 70-90% of kindreds with classic MEN1 syndrome (1). We present the case of a patient with a novel MEN1 gene mutation. Clinical Case: A 41 year old Caucasian male with a diagnosis of MEN1 syndrome has been followed up in our clinic for 20 years. At the age of 21, he had two parathyroid glands resection for hypercalcemia which revealed an adenoma of the right superior parathyroid gland. He had one more parathyroid gland resected 6 months later for persistent hypercalcemia. Around that time, he also had appendectomy for suspected appendicitis and the pathology results showed a carcinoid tumor of the appendix. At the age of 33, he underwent total parathyroidectomy, thymectomy, and auto transplantation of half parathyroid gland in the left forearm for recurrent hypercalcemia. At the age of 39, he developed frequent hypoglycemic episodes with symptoms including confusion. Serum glucose levels of 20-30 mg/dL were documented during the episodes. A 72 hours fasting test showed a plasma glucose level of 53 mg/dL, with insulin level of 25.6 mU/L, proinsulin level of 5.2 pmol/L, C-peptide level of 5 ng/mL and low beta- hydroxybutyrate level. In response to 1 mg glucagon intravenous injection, plasma glucose level improved by 83 mg/dL in 30 minutes. He then had selective arterial calcium stimulation test and the results showed the insulin peak rising after stimulation in the splenic artery suggested that the lesion was in the body and tail of the pancreas. He had partial pancreatectomy for insulinoma, however, the pathology results were consistent with vasoactive intestinal polypeptide- producing tumor (VIPoma) rather than insulinoma. The serum tests also supported a diagnosis of VIPoma: the VIP levels were 96.3 pg/mL preoperatively and 65 pg/mL postoperatively. Notably, he had intermittent abdominal pain after food intake and chronic watery diarrhea 5-7 times a day before pancreatectomy, which resolved after the surgery. The patient underwent genetic screening for MEN1 mutations which revealed the presence of a novel germline deletion mutation in exon 8 (1078delC), resulting in frame shifting of its coded menin protein (Arg360fsX13). Conclusion: We describe a novel MEN1 gene mutation (1078delC) in a patient with typical clinical manifestations of MEN1 syndrome including parathyroid adenomas, appendix carcinoid tumor, VIPoma, and insulinoma. The concurrence of pancreatic VIPoma and insulinoma or the existence of a pancreatic neuroendocrine tumor co-producing insulin and VIP in MEN1 patients has not been reported previously. Reference: (1) Agarwal SK. The future: genetics advances in MEN1 therapeutic approaches and management strategies. Endocr Relat Cancer. 2017;24:T119-T134.

Obesity has been recognized as a worldwide pandemic, and the first-line treatment is weight loss via a calorie restricted diet (1). Obstructive sleep apnea (OSA) is recognized as one of the key obesity-related comorbidities and has complex interactions with obesity and weight loss treatments. Treating OSA with continuous positive airway pressure (CPAP) is recommended widely in clinical practice as an adjunct therapy with weight loss despite a lack of evidence to support the strategy. Therefore, we conducted a retrospective study with the patients seen in UAMS weight loss clinic from 1/1/2014 to 8/31/2017. Patients were eligible if they were 18-65 years old, body mass index >= 30 and < 50, and underwent a 16-week intensive calorie restriction weight loss program obtained by strict calorie restriction (800 Kcal per day), exercise programs, weekly individual counseling and cognitive behavioral therapy. Patients who suffered from thyroid dysfunction, uncontrolled diabetes, active infection, active malignancy, or end-organ damage were excluded. Participants underwent a standardized medical examination before and every week in the program. Of the 300 patients included in the analysis, the average ages was 55 ± 10 years old, and 236 (78.7%) were female. They were divided into three groups based on self- reported OSA symptoms and CPAP treatment status: asymptomatic OSA group (OSA-A, n = 89), symptomatic group (OSA-S, n = 164), and OSA on CPAP treatment group (OSA-T, n = 47). In 16 weeks, the absolute weight loss of the OSA-T group was significantly higher than that of the OSA-S and OSA-A groups (-12.1 ± 5.9 vs. -9.5 ± 5.5 vs. -8.7 ± 5.3 kg, P < 0.01), whereas, the percentage weight loss of the OSA-T group was not significantly higher than that of the OSA-A and OSA-S groups (-10.46 ± 5.63% vs. -9.14 ± 4.89% vs. -8.47 ± 4.97%, P = 0.065). There had no difference of the absolute weight loss between OSA-A group and OSA-S group. Further analysis established a correlation of CPAP treatment to the absolute weight loss (Spearman’s correlation coefficient -0.181, P = 0.013) after adjustment of baseline body mass index, age and gender. Our results showed that the patients who had CPAP treatment achieved a larger weight reduction than non-CPAP treatment patients in a 16-week intensive calorie restriction weight loss program. Sleep quality may impact success in weight loss programs and several mechanisms may underpin this. Reference: (1) Varady KA. Intermittent versus daily calorie restriction: Which diet regimen is more effective for weight loss? Obes Rev. 2011;12:e593-e601.

TiO 2 /g-C 3 N 4 nanofibers with diameter of 100–200 nm were prepared by electrospinning method after calcination at high temperature, using polyvinylpyrrolidone (PVP), Melamine (C 3 H 6 N 6 ), Ti(OC 4 H 9 ) 4 as raw materials. The composite nanofibers were characterized by XRD, FT-IR, SEM, UV–vis and PL respectively. The effects of different g-C 3 N 4 contents on structure and photocatalytic degradation of the composite nanofibers were investigated. The results indicated that with increasing g-C 3 N 4 content, the diameter of the composite fibers increased and the morphology changed from uniform structure to a nonuniform one, containing beads. The composite nanofibers displayed the best photocatalytic degradation on RhB, when the g-C 3 N 4 content was 0.8 wt%. The degree of degradation was up to 99% at the optimal conditions of 40 min. The degradation activity of the composite nanofibers on RhB, MB and MO was found to be higher than that of the TiO 2 nanofibers.

A series of novel Eu3+ doped tungstate Li2Mg2 (WO4)3 red phosphors were successfully synthesized by a solid-state reaction method. The phase structure, photoluminescence properties and thermal stability of the phosphor were investigated in detail. The Li2Mg2 (WO4)3:Eu3+ phosphors show dominant emission peak at 620 nm (5D0→7F2 transition) upon the strongest excitation at 398 nm (7F0→5L6 transition). The optimal doping concentration of Eu3+ is determined to be 0.06 mol in order to obtain the maximum emission intensity. The dependence of the emission intensity on temperature denominates that Li2Mg2 (WO4)3:Eu3+ phosphor has a relatively good thermal quenching effect. The Commission Internationale del’Eclairage coordinates was measured as (0.678, 0.322) with high color purity, being close to the National Television Standard Committee system standard for red chromaticity (0.670, 0.330). The above studies indicate that Li2Mg2 (WO4)3:Eu3+ is a promising candidate as the red phosphor for near ultraviolet-based white LEDs application.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since vendredi 4 novembre 2016

The common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF), is now considered as one of the main public health burdens that is associated with grave implications. Neurohormonal systems play a critical role in cardiovascular homeostasis, pathophysiology, and cardiovascular diseases. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for CHF, in addition to the conventional medications encompassing beta receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Clinical trials also indicate that in CHF patients with low insulin-like growth factor-1 or low thyroid hormone levels, supplemental treatment with growth hormone or thyroid hormone seems to be cardioprotective; and in CHF patients with volume overload the vasopressin antagonists can relieve the symptoms superior to loop diuretics. Furthermore, a combination of selective glucocorticoid receptor agonist and mineralocorticoid receptor antagonist may be used in patients with diuretic resistance. Finally, the potential cardiovascular efficacy and safety of incretin-based therapies, testosterone or estrogen supplementation needs to be prudently evaluated in large-scale clinical studies. In this review, we briefly discuss the therapeutic effects of several key hormones in CHF.

Morphology-controlled magnesium oxide nanowhiskers have been fabricated on quartz glass fiber substrates using Mg particles as the raw material at relatively low temperatures of 550 °C and 600 °C. The as-prepared nanowhisker and nanocrosses samples were characterized using Field Emission Scanning Electron Microscopy (FE-SEM), Transmission Electron Microscopy (TEM), Selected Area Electron Diffraction (SAED) and Energy Dispersive X-ray Spectrum (EDS). The MgO nanowhiskers were found to have crystallized structures with growth along the [100] direction. The surfaces of the crossing whisker are considered to be in the (200) lattice plane. The partial pressure of the Mg vapor and the annealing time have played significant roles in determining the diameter and morphology of the nanowhisker. Their adsorption capacity can reduce the concentration of methylene blue solution, which may drive potential applications in biological or environmental areas.

The activation of Gq-protein-coupled receptors induces proliferation of vascular smooth muscle cells (VSMCs) proliferation and is involved in vascular remodeling. The regulator of G protein signaling 2 (RGS2), which accelerates the termination of Gq protein signaling, may play a role in vascular remodeling. However, this role remains unclear.Aortic balloon injury or sham operation was produced in male Wistar rats. Histological examination and gene expression analysis were performed after surgery. In cultured VSMCs after modulation of RGS2 expression, cell proliferation was also evaluated.At day 3 after injury, RGS2 transcription was reduced by 52.8% (P 0.05 vs. sham group) with vascular remodeling. In cultured VSMCs stimulated by endothelin-1, phenylephrine or angiotensin II, the proliferation of RGS2 overexpressed cells was significantly inhibited; the proliferation of RGS2 downregulated cells was significantly promoted, compared with that of RGS2 normal cells. Moreover, after incubation with angiotensin II of high concentration (10 μmol/l) or long term (8 h), the RGS2 expression was clearly downregulated in cultured VSMCs. Administration of an angiotensin receptor blocker, valsartan (20 mg/kg per day) starting from 1 week preballoon injury to 3 days after injury, restored aortic RGS2 transcription and improved vascular remodeling.These results suggested that the inhibiting effect of RGS2 on VSMC proliferation is downregulated in vascular remodeling of injured rat aorta, and this effect is likely to be mediated by angiotensin II signaling.

Both hexarelin and its natural analog ghrelin exert comparable cardioprotective activities. A single dose of ghrelin administered at the very acute phase after experimental myocardial infarction positively affects cardiac function in chronic heart failure. Therefore, this study aimed to determine whether a single dose of oral hexarelin has the same effect in the chronic disease phase. Myocardial infarction or sham operation was generated by left coronary artery ligation in male C57BL/6J mice, which subsequently received one dose of hexarelin or vehicle treatment by oral gavage 30 min after operation. Although the mortality within 14 days after myocardial infarction did not differ between the groups, hexarelin treatment protected cardiac function in the chronic phase as evidenced by higher ejection fraction and fractional shortening, as well as lower lung weight/body weight and lung weight/tibial length ratios, compared with vehicle treatment. Hexarelin treatment concurrently lowered plasma epinephrine and dopamine levels, and shifted the balance of autonomic nervous activity toward parasympathetic nervous activity as evidenced by a smaller low/high-frequency power ratio and larger normalized high-frequency power on heart rate variability analysis. The results first demonstrate that one dose of oral hexarelin treatment potentially protects chronic cardiac function after acute myocardial infarction, and implicate that activating growth hormone secretagogue receptor 1a might be beneficial for cardioprotection, although other mechanism may also be involved.

The regulator of G-protein signaling 2 (RGS2) has been shown to be crucial in the regulation of vascular tone and blood pressure. The vascular activities of adrenomedullin (ADM) and adrenotension (ADT), two natural peptides, are dependent upon the modulation of RGS2 expression. However, the effects and pathways involved in their modulation remain unknown. This study aimed to observe the changes of RGS2 expression in response to ADM and ADT in cultured vascular smooth muscle cells and to clarify the potential signaling pathways in vitro. In the present study, vascular smooth muscle cells (VSMCs) were cultured with ADM and ADT of various concentrations for different time periods, and the gene expression of RGS2 was analyzed by PCR. ADM significantly increased the gene expression at 0.5 h to ~35-fold of that at baseline, whereas ADT marginally increased the expression after 1-2 h. SQ22,536 and chelerythrine were used to block the protein kinase A (PKA) and PKC pathways activated by incubation with ADM. The gene expression of RGS2 was reduced by SQ22,536 only. Furthermore, when SQ22,536 and chelerythrine were added to the cells incubated with ADT, the gene expression was markedly reduced by both SQ22,536 and chelerythrine. In conclusion, ADM immediately showed a marked increase in the gene expression of RGS2 in cultured VSMCs via a cAMP-dependent pathway and ADT gradu- ally showed a marginal increase in the gene expression via a cAMP-dependent pathway and a PKC pathway.

Both ghrelin and the synthetic analog hexarelin are reported to possess cardioprotective actions that are mainly exerted through different receptors. However, their effects on acute myocardial infarction have not been compared in vivo. This study aimed to clarify whether hexarelin treatment can compensate for ghrelin deficiency in ghrelin-knockout mice and to compare the effects of hexarelin (400 nmol/kg/d, sc) and equimolar ghrelin treatment after myocardial infarction. Myocardial infarction was produced by left coronary artery ligation in male ghrelin-knockout mice, which then received ghrelin, hexarelin, or vehicle treatment for 2 weeks. The mortality within 2 weeks was significantly lower in the hexarelin group (6.7%) and ghrelin group (14.3%) than in the vehicle group (50%) (P < .05). A comparison of cardiac function 2 weeks after infarction showed that in the ghrelin and hexarelin treatment groups, cardiac output was greater, whereas systolic function, represented by ejection fraction, and diastolic function, represented by dP/dt min (peak rate of pressure decline), were significantly superior compared with the vehicle group (P < .05). Hexarelin treatment was more effective than ghrelin treatment, as indicated by the ejection fraction, dP/dt max (peak rate of pressure rise), and dP/dt min. Telemetry recording and heart rate variability analysis demonstrated that sympathetic nervous activity was clearly suppressed in the hexarelin and ghrelin groups relative to the vehicle group. Our data demonstrated that hexarelin treatment can result in better heart function than ghrelin treatment 2 weeks after myocardial infarction in ghrelin-knockout mice, although both hormones have similar effects on heart rate variability and mortality.

Intense research aimed to find solutions for the cure of diabetes mellitus, based on stem cell therapy to replace hypoglycemic drug or insulin administration, has been conducted over the past decades. A variety of stem cells, including induced pluripotent stem cells, embryonic stem cells, or adult stem cells such as bone marrow-, adipose tissue-, and Wharton jelly-derived stem cells, have demonstrated their ability to differentiate into insulin-producing cells and secret insulin in response to high-glucose stimulation. However, achievement of the final goal for routinely clinical application of stem cell therapy is still out of reach. In this chapter, new advances in stem cell therapy for diabetes mellitus were reviewed and discussed in attempt to clarify where we are and how we may go to reach the final goal of the cure of diabetes mellitus.

Ghrelin is a growth hormone-releasing polypeptide that was first isolated from the rat stomach in 1999. High expression of growth hormone secretagogue receptor, the ghrelin receptor, in the heart, kidney, and blood vessels provides evidence of ghrelin activity in blood pressure regulation. Circulating ghrelin concentrations are reported to be inversely correlated with blood pressure, and the acute and chronic effects of ghrelin in decreasing blood pressure have been reported in animals with normal blood pressure, healthy individuals, animals and patients with heart failure, and animals with hypertension. The mechanism by which ghrelin regulates blood pressure appears to be related to modulation of the autonomic nervous system, direct vasodilatory activities, and kidney diuresis. Thus, modulation of the signaling pathway through ghrelin may provide a novel concept for treating hypertension. In this review, we discuss the current evidence and potential mechanisms of ghrelin activity in blood pressure regulation.

Background: Serum CA19-9 level is a sensitive marker for pancreatic tissue damage; however, its correlation factors are still unclear in diabetic patients. This study was aimed to investigate the correlation factors of serum CA 19-9 levels in these patients. Methods and Results: Based on their serum CA19-9 levels, 412 diabetic patients (57 type 1 and 355 type 2) were divided into the negative group (432 cases, CA19-9 < 37 U /ml) and the positive group (31 cases, CA19-9 ≥ 37 U /ml). The two groups were compared with age, sex, duration of diabetic history, hemoglobin A1c, blood lipid, fasting C-peptide level, and area under the curve C-peptide. The difference was significant between 2 groups in age, hemoglobin A1c, total cholesterol, highdensity lipoprotein cholesterol, fasting C-peptide level, and area under the curve C-peptide (P < 0.05). A multivariate linear regression model found that the type of diabetes, hemoglobin A1c, area under the curve C-peptide, and high-density lipoprotein cholesterol are the independent contributors to CA19-9 levels. Conclusion: The results indicated that CA19-9 levels in patients with diabetes mellitus were related to not only age and sex but also diabetic type, hemoglobin A1c, lipid metabolism, and pancreatic beta cell function.

Cardiac hypertrophy, which is commonly caused by hypertension, is a major risk factor for heart failure and sudden death. Endogenous ghrelin has been shown to exert a beneficial effect on cardiac dysfunction and postinfarction remodeling via modulation of the autonomic nervous system. However, ghrelin’s ability to attenuate cardiac hypertrophy and its potential mechanism of action are unknown. In this study, cardiac hypertrophy was induced by transverse aortic constriction in ghrelin knockout mice and their wild-type littermates. After 12 weeks, the ghrelin knockout mice showed significantly increased cardiac hypertrophy compared with wild-type mice, as evidenced by their significantly greater heart weight/tibial length ratios (9.2±1.9 versus 7.9±0.8 mg/mm), left ventricular anterior wall thickness (1.3±0.2 versus 1.0±0.2 mm), and posterior wall thickness (1.1±0.3 versus 0.9±0.1 mm). Furthermore, compared with wild-type mice, ghrelin knockout mice showed suppression of the cholinergic anti-inflammatory pathway, as indicated by reduced parasympathetic nerve activity and higher plasma interleukin-1β and interleukin-6 levels. The administration of either nicotine or ghrelin activated the cholinergic anti-inflammatory pathway and attenuated cardiac hypertrophy in ghrelin knockout mice. In conclusion, our results show that endogenous ghrelin plays a crucial role in the progression of pressure overload–induced cardiac hypertrophy via a mechanism that involves the activation of the cholinergic anti-inflammatory pathway.

Ghrelin, a growth hormone–releasing peptide that was first discovered in the stomach of rats in 1999, is an endogenous ligand of growth hormone secretagogue receptors (GHSRs).1 Through binding to its receptors in the brain, ghrelin was initially shown to strongly stimulate the release of growth hormone and promote food intake.2 Subsequent studies revealed that GHSRs are expressed ubiquitously in many organs and tissues, and ghrelin functionally participates in the regulation of diverse processes including appetite control, energy balance, body weight maintenance, glucose and fat metabolism, cell proliferation, and apoptosis, as well as the modulation of gastrointestinal, cardiovascular, pulmonary, and immune functions.3,4 The primary receptor of ghrelin is currently thought to be GHSR1a; however, other unidentified receptors might exist.5,6 The high expression of GHSR1a in the heart and large vessels provides evidence of its cardiac activity,7 indicating ghrelin is a promising new therapeutic agent for cardiovascular diseases. In this review, we discuss some of the characteristic features of ghrelin treatment and its possible therapeutic roles in animals and patients afflicted with common cardiovascular diseases. Ghrelin is produced predominantly in the stomach and is secreted from the submucosal layer into the bloodstream but not into the gastrointestinal tract. In situ analyses revealed that ghrelin and its mRNA are mainly localized in X/A-like cells, a major endocrine population in the gastric oxyntic mucosa that are morphologically similar to pancreatic α cells.1 Cells that produce low levels of ghrelin are also found in the lung, bowel, pancreas, kidney, placenta, testis, hypothalamus, pituitary gland, and the immune system.8–18 Ghrelin is reportedly produced in neoplastic tissues such as gastric and intestinal carcinoids and medullary thyroid carcinomas.19–21 In addition to endogenous ghrelin, growth hormone secretagogues, a heterogeneous group of synthetically produced …

G protein-coupled receptor signaling plays a crucial role in platelet function. Regulators of G protein signaling (RGSs), which accelerate the deactivation of G protein signaling, are expressed in platelets. However, RGS expression has not been studied in the context of aspirin resistance. We compared RGS mRNA levels in platelets from 39 aspirin-resistant patients and 50 aspirin-sensitive patients with metabolic syndrome. Although there were no clinical differences between the two groups, transcripts of RGS2, RGS10, and RGS18 were significantly higher in aspirin-resistant patients than in aspirin-sensitive patients. This study is the first to demonstrate that RGS transcripts are elevated in aspirin-resistant platelets from patients with metabolic syndrome.

Hexarelin, a synthetic growth hormone-releasing peptide, can bind to and activate the growth hormone secretagogue receptor (GHSR) in the brain similar to its natural analog ghrelin. However, the peripheral distribution of GHSR in the heart and blood vessels suggests that hexarelin might have direct cardiovascular actions beyond growth hormone release and neuroendocrine effects. Furthermore, the non-GHSR CD36 had been demonstrated to be a specific cardiac receptor for hexarelin and to mediate its cardioprotective effects. When compared with ghrelin, hexarelin is chemically more stable and functionally more potent. Therefore, it may be a promising therapeutic agent for some cardiovascular conditions. In this concise review, we discuss the current evidence for the cardiovascular action of hexarelin.

T lymphocytes have been demonstrated to play a role in the development of diabetic proteinuria. However, the alteration of circulating T lymphocytes has not been investigated in a type 2 diabetic cohort. A cross-sectional study was conducted in Peking University Aerospace Center Hospital. 510 participants were type 2 diabetes mellitus, 30-70 years of age. Patients with immune disease, medical conditions that affect immune function, infection, or end-organ damage were excluded. The percentage of circulating CD8+ T lymphocytes was significantly associated with albuminuria in the cohort. The impact of albuminuria to CD8+ T lymphocytes in a multivariate linear regression model was indicated by the B- coefficient (95% confidence interval) 1.812 (0.204-3.421, P=0.03). Our data first showed that the percentage of circulating CD8+ T cells is associated with albuminuria in type 2 diabetes mellitus, which may support the rationality of systemic inhibition of T lymphocytes in treating albuminuria in these patients.

Volume overload during pregnancy results in transient and reversible cardiac hypertrophy in pregnant females. Endogenous atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) acts through the common receptor, guanylyl cyclase-A (GC-A) to lower blood pressure, induce diuresis/natriuresis, and dilate blood vessels. Although the roles of endogenous natriuretic peptides/GC-A system on the cardiovascular system have been well investigated, those on the puerperal period have not been elucidated. The aim of this study was to investigate the physiological role of endogenous natriuretic peptides/GC-A system in the puerperal period by comparing pregnant wild-type (WT) and GC-A knockout (GC-A-KO) mice. Although blood pressure in GC-A-KO mice was not changed during pregnancy or after delivery, there was a dramatic postpartum increase in cardiac weight. Interestingly, the cardiac hypertrophy and interstitial fibrosis in GC-A-KO were dramatically accelerated by repeated pregnancy/lactation cycles (Figure ​(Figure1).1). Moreover, a significant decline in cardiac function, as well as up-regulation of fetal cardiac genes, was observed in the multiparous GC-A-KO heart. Importantly, the hypertrophic change in GC-A-KO heart was observed not during gestation, but during lactation. Furthermore, the lactation-induced cardiac hypertrophy in GC-A-KO was significantly suppressed by avoiding the breast feeding. Our results suggest that the defect in endogenous cardiac natriuretic peptide/GC-A system promotes cardiomyopathy during puerperal period, especially during lactation. Figure 1 Significant cardiac hypertrophy was observed in GC-A-knockout mice during the puerperal period.

Background Atrial natriuretic peptide (ANP) has been used clinically for the treatment of heart failure patients in Japan, and also exhibits a variety of physiological effects through binding guanylyl cyclase-A (GC-A) receptor. We and other groups has been reported that GC-A is abundantly expressed in endothelial cells. In the present study, we explored the therapeutic potential of endothelial ANP/ GC-A system for the treatment of metabolic syndrome.