Developmental Programming by Maternal Insulin Resistance: Hyperinsulinemia,Glucose Intolerance,and Dysregulated Lipid Metabolism in Male Offspring of Insulin-Resistant Mice

Maternal obesity and gestational diabetes mellitus (GDM) are associated with obesity and diabetes risk in offspring. We tested whether maternal insulin resistance, which frequently coexists with GDM and obesity, could independently contribute to dysregulation of offspring metabolism. Female mice haploinsufficient for insulin receptor substrate-1 (IRS1-het) are hyperinsulinemic and insulin resistant during pregnancy, despite normal plasma glucose and body weight, and thus serve as a model of isolated maternal insulin resistance. Wild-type (WT) offspring of IRS1-het dams insulin resistance-exposed [IR-exposed] were compared with WT offspring of WT dams. Despite no differences in adiposity, male IR-exposed pups were glucose intolerant (P = 0.04) and hyperinsulinemic (1.3-fold increase, P = 0.02) by 1 month of age and developed progressive fasting hyperglycemia. Moreover, male IR-exposed pups challenged with high-fat diet exhibited insulin resistance. Liver lipidomic analysis of 3-week-old IR-exposed males revealed increases in the 16:1n7 fraction of several lipid classes, suggesting increased Scd1 activity. By 6 months of age, IR-exposed males had increased lipid accumulation in liver as well as increased plasma refed fatty acids, consistent with disrupted lipid metabolism. Our results indicate that isolated maternal insulin resistance, even in the absence of hyperglycemia or obesity, can promote metabolic perturbations in male offspring.     

Evaluation of characteristics and surgical outcomes in cervical spondylotic amyotrophy

Background:

Cervical spondylotic amyotrophy (CSA) is a rare clinical syndrome resulting from cervical spondylosis. Surgical treatment includes anterior cervical decompression and fusion (ACDF), and laminoplasty with or without foraminotomy. Some studies indicate that ACDF is an effective method for treating CSA because anterior decompression with or without medial foraminotomy can completely eliminate anterior and/or anterolateral lesions. We retrospectively evaluated outcome of surgical outcome by anterior cervical decompression and fusion (ACDF).

Materials and Methods:

28 CSA patients, among whom 12 had proximal type CSA and 16 had distal type CSA, treated by ACDF, were evaluated clinicoradiologically. The improvement in atrophic muscle power was assessed by manual muscle testing (MMT) and the recovery rate of the patients was determined on the basis of the Japanese Orthopedic Association (JOA) scores. Patient satisfaction was also examined.

Results:

The percentage of patients, who gained 1 or more grades of muscle power improvement, as determined by MMT, was 91.7% for those with proximal type CSA and 37.5% for those with distal type CSA (P < 0.01). The JOA score-based recovery rates of patients with proximal type and distal type CSA were 60.8% and 41.8%, respectively (P < 0.05). Patient satisfaction was 8.2 for those with proximal type CSA and 6.9 for those with distal type CSA (P < 0.01). A correlation was observed among the levels of improvement in muscle power, JOA score based recovery rate, patient satisfaction and course of disease (P < 0.05).

Conclusion:

ACDF can effectively improve the clinical function of patients with CSA and result in good patient satisfaction despite the surgical outcomes for distal type CSA being inferior to those for proximal type CSA. Course of disease is the fundamental factor that affects the surgical outcomes for CSA. We recommend that patients with CSA undergo surgical intervention as early as possible.     

Interleukin-6 Concentration in the Transgenic Pig's Liver Preserved for 24 Hours in Biolasol Solution

Introduction

Increasing the human lifespan contributes to a higher number of patients with end-stage organ failure, which in turn stimulates the search for alternative sources. Xenotransplantation seems to be a promising approach in this respect.

Objective

Analysis of changes in interleukin (IL)-6 concentration during 24-hour preservation of transgenic swine livers, depending on the kind of transgenesis and preservation solution used.

Materials and methods

The experiment was carried out in swine livers with transferred human genes that were divided into 5 groups. The following human genes were transferred: α1,2-fucosyltransferase (group I and II), α-galactosidase (III), combined α1,2-fucosyltransferase/α-galactosidase transgene (IV), and livers without modification (V). The livers were perfused and subsequently stored for 24 hours in Ringer's (group I) or Biolasol solutions (II–V). Reflush was then performed. IL-6 concentration was analyzed in the solution samples collected at the beginning and end of perfusion, and after 24 hours of preservation. ELISA was used to evaluate IL-6 concentration.

Results

In liver homogenates from group I, IL-6 concentration after 24 hours of preservation increased by 8.24% compared to the levels observed after perfusion, whereas in the other groups IL-6 concentration decreased. The most significant decrease, 49.51%, was observed in group II; the least significant in group IV, 10.72%. In case of supernatants, a statistically significant increase of AUC_0–30min level in relation to perfusion was observed in every group after 24-hour preservation and reperfusion. The highest values of AUC_0–30min were observed in group I (α1,2-fucosyltransferase, Ringer's solution).

Conclusion

The study indicates the hepatoprotective action of Biolasol solution.     

Dopamine and Noradrenaline Are Unrelated to Renalase,Heart Rate,and Blood Pressure in Heart Transplant Recipients

Introduction

Renalase may degrade catecholamines and regulate sympathetic tone and blood pressure. The aim of this study was to assess dopamine, norepinephrine, and renalase in 80 heart transplant recipients and 22 healthy volunteers and their correlations with heart rate, blood pressure control, type of hypotensive therapy, and renal function.

Patients and Methods

Renalase, dopamine, and norepinephrine were studied by using commercially available assays.

Results

Renalase levels were higher in heart transplant recipients compared with healthy volunteers, and noradrenaline levels were lower in the studied cohort patients than in the healthy volunteers. Noradrenaline was correlated with white blood cell count (r = −0.21, P < .05), copeptin (r = 0.41, P < .01), and left ventricular diameter (r = −0.29, P < .05), whereas dopamine was correlated in univariate analysis with white blood cell count (r = −0.22, P < .05), posterior wall of left ventricular diameter (r = 0.58, P < .01), and left atrium diameter (r = −0.31, P < .05). Neither noradrenaline nor dopamine was correlated with heart rate, blood pressure, kidney function, or New York Heart Association class. Noradrenaline was significantly higher in patients with elevated diastolic blood pressure (>90 mm Hg) compared with those with normal diastolic blood pressure (P < .05). Renalase was related to kidney function but was unrelated to catecholamines.

Conclusions

Elevated renalase levels in heart transplant patients were related to kidney function but not linked to the sympathetic nervous system activity in this study population. In heart transplant recipients, these findings might suggest that sympathetic denervation and the modulation of β-receptors persist.     

Growth Differentiation Factor 15 Is Related to Anemia and Iron Metabolism in Heart Allograft Recipients and Patients With Chronic Heart Failure

Background

Growth differentiation factor (GDF) 15 was recently identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia, or inflammation. The aim of this study was to assess GDF15 levels and its correlation with iron parameters in 134 stable heart transplant recipients compared with 157 patients with chronic heart failure (CHF).

Methods

Complete blood count, urea, creatinine, lipids, fasting glucose, and iron status were studied with the use of standard laboratory methods. We assessed GDF15, hepcidin, and soluble transferrin receptor (sTfR) with commercially available assays.

Results

Mean levels of GDF15 and hepcidin were significantly higher in heart allograft recipients compared with patients with chronic heart failure (P < .001). GDF15 was significantly higher in patients with anemia compared with nonanemic counterparts in both groups. In univariate analysis in heart transplant recipients, GDF15 was related to kidney function, age, time after transplantation, hepcidin, sTfR, hemoglobin, transferrin saturation, ejection fraction (EF), and New York Heart Association functional class. GDF15 was not related to serum iron or ferritin in both groups. In multivariate analysis, sTfR, creatinine, and age were found to be predictors of GDF15. In univariate analysis in CHF patients, GDF15 was related to creatinine, erythrocyte count, hemoglobin, hepcidin, and total iron binding capacity and tended to correlate with EF. In multivariate analysis, hepcidin, creatinine, and EF were found to be predictors of GDF15 in CHF.

Conclusions

GDF15, by affecting iron status, might be involved in the pathogenesis of anemia in patients with cardiovascular pathology.     

Targeted thrombolysis strategies for neuroprotective effect

Stroke is usually treated by systemic thrombolytic therapy if the patient presents within an appropriate time window. There is also widespread interest in the development of thrombolytic agents that can be used in cases of delayed presentation. Current agents that can be used in cases of delayed presentation of nerve damage by thrombus. Current systemic thrombolytic therapy is associated with adverse effects such as fibrinogenolysis and bleeding. In an attempt to increase the efficacy, safety, and specificity of thrombolytic therapy, a number of targeted thrombolytic agents have been studied in recent years. This review focuses on the concepts underlying targeted thrombolytic therapy and describes recent drug developments in this field.     

Genes in the serotonin pathway are associated with bipolar affective disorder in a Han Chinese population

Serotonin plays an important role in mood regulation, but the involvement of serotonin pathway genes in the development of bipolar I disorder (BP-I), a mood disorder, is not clear. We selected 21 singlenucleotide polymorphisms (SNPs) within the HTR2A gene, 8 within the SLC6A4 gene and 23 within the TPH2 gene for genotyping using the GoldenGate genotyping assay. A total of 375 patients with BP-I and 475 normal controls were recruited. Two out of 21 SNPs (rs1475196 and rs9567747) in the HTR2A gene and 1/23 SNPs (rs17110566) in the TPH2 gene were significantly associated with BP-I, both genotype-wise and allele-wise. Furthermore, a specific haplotype in the HTR2A gene showed a significant association with BP-I. Our results indicate that the HTR2A and TPH2 genes in the serotonin pathway play important roles in susceptibility to BP-I.