Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity

Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10⁻⁵) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10⁻⁴). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10⁻⁶) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r² = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10⁻³). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.     

Targeted Disruption of G0/G1 Switch Gene 2 Enhances Adipose Lipolysis,Alters Hepatic Energy Balance,and Alleviates High-Fat Diet–Induced Liver Steatosis

Recent biochemical and cell-based studies identified G₀/G₁ switch gene 2 (G0S2) as an inhibitor of adipose triglyceride lipase (ATGL), a key mediator of intracellular triacylglycerol (TG) mobilization. Here, we show that upon fasting, G0S2 protein expression exhibits an increase in liver and a decrease in adipose tissue. Global knockout of G0S2 in mice enhanced adipose lipolysis and attenuated gain of body weight and adiposity. More strikingly, G0S2 knockout mice displayed a drastic decrease in hepatic TG content and were resistant to high-fat diet (HFD)-induced liver steatosis, both of which were reproduced by liver-specific G0S2 knockdown. Mice with hepatic G0S2 knockdown also showed increased ketogenesis, accelerated gluconeogenesis, and decelerated glycogenolysis. Conversely, overexpression of G0S2 inhibited fatty acid oxidation in mouse primary hepatocytes and caused sustained steatosis in liver accompanied by deficient TG clearance during the fasting-refeeding transition. In response to HFD, there was a profound increase in hepatic G0S2 expression in the fed state. Global and hepatic ablation of G0S2 both led to improved insulin sensitivity in HFD-fed mice. Our findings implicate a physiological role for G0S2 in the control of adaptive energy response to fasting and as a contributor to obesity-associated liver steatosis.     

Meta-analysis of randomized controlled trials comparing Lichtenstein and totally extraperitoneal laparoscopic hernioplasty in treatment of inguinal hernias

Background

Finding the optimal approach to repair an inguinal hernia is controversial. Therefore, for the scientific evaluation of the total extraperitoneal (TEP) and Lichtenstein mesh techniques for the repair of inguinal hernia, meta-analyses of randomized controlled trials are necessary.

Methods

A complete literature search was conducted in the Cochrane Controlled Trials Register Databases, Pubmed, Embase, International Scientific Institute databases, and Chinese Biomedical Literature Database in various languages.

Results

Randomized controlled trials (13), including 3279 patients, were retrieved from the electronic databases. The Lichtenstein group was associated with a shorter operating time; however, results show that TEP repair enabled patients a shorter time to return to work, less chronic pain compared with Lichtenstein operation. There was no significant difference in seromas, wound infections, or neuralgia. There are no statistically significant difference in terms of hernia recurrence when the follow-up time is ≤3 y. When follow-up time is >3 y, TEP repair shows a higher recurrence rate compared with Lichtenstein repairs.

Conclusions

There was insufficient evidence to determine the greater effectiveness between TEP and Lichtenstein mesh techniques. In future research, it is necessary for subgroup analyses of unilateral primary hernias, recurrent hernias, and simultaneous bilateral repair to be conducted to define the indications for the TEP approach.     

Isolation and characterization of microsatellite loci in the Chinese water snake Enhydris chinensis (Colubridae)

The Chinese water snake Enhydris chinensis is an ovoviviparous colubrid snake distributed in China and Vietnam. It is commonly used in the production of Chinese snake oil, which is known for treating ailments such as fever, joint pain, and headache. It is listed as a vulnerable species according to the China red data book of endangered animals. Specific molecular markers such as mitochondrial DNA and microsatellite loci are helpful for us to get a better understanding of population structure and evolutionary history of the snake and take effective conservation action for this species. Here, we characterize eight polymorphic microsatellite loci isolated from E. chinensis genomic libraries. Forty-seven individuals were collected from Ji’an population in Jiangxi, China. These markers revealed a high degree of genetic diversity (3–10 alleles per locus) and heterozygosity (H _O ranged from 0.532 to 0.957, and H _E ranged from 0.565 to 0.806). No locus exhibited significant deviations from Hardy–Weinberg equilibrium. There was no evidence of linkage disequilibrium among pairs of loci. The results of this paper will be useful for future study of population structure and genetic diversity of E. chinensis.     

Evidence for A1 and A3 receptors mediating adenosine-induced intracellular calcium release in the dorsal root ganglion neurons by using confocal microscopy imaging

Adenosine exerts a key role in analgesia. In the present study, adenosine-induced Ca²⁺ responses were revealed by using confocal microscopy imaging in the rat dorsal root ganglia (DRG) neurons in vitro. Our results showed that adenosine could evoke increases in the intracellular Ca²⁺ concentration in the DRG neurons. In addition, by application of selective receptor antagonists, two types of receptors, A₁R and A₃R, were identified to be involved in the adenosine-induced Ca²⁺ release from intracellular stores in neurons. Altogether, these results suggest that confocal microscopy imaging combined with fluorescent dyes could help to detect the analgesic-induced ion signaling in single cell.     

Comparative outcomes of the tubularized incised plate and transverse island flap onlay techniques for the repair of proximal hypospadias

Purpose

The optimal management of proximal hypospadias remains uncertain. In this study, the surgical outcomes of tubularized incised plate repair (TIP) and transverse island flap (TVIF) onlay urethroplasty in boys with hypospadias were compared.

Methods

A total of 176 patients with proximal hypospadias underwent TIP (n = 83) or TVIF onlay repairs (n = 93) by a single surgeon and were evaluated retrospectively. No patient received a testosterone injection prior to surgery. A retrospective review of their medical records collected data regarding age at surgery, chordee, dorsal plication, hypospadias site, penoscrotal transposition, bifid scrotum, congenital hernia, undescended testis and any postoperative complications, including fistula, recurrent curvature, dehiscence, diverticulum, meatal stenosis and urethral stricture. The pediatric penile perception score (PPPS) was completed by parents to evaluate their perception of cosmetic outcomes.

Results

There was no statistical difference in age or any of the anatomical and clinical features of hypospadias. The median follow-up duration was 22 months (range 12–48 months) and 25 months (14–51 months) for the TIP and TVIF onlay groups, respectively. The overall complication rate in the TVIF onlay group was 21.5 % (20/93), which was higher than 18.1 % (15/83) in the TIP group, but the difference was not statistically significant (P = 0.569). The most common complication was urethrocutaneous fistula, occurring in 9.6 % (8/83) of the TIP group and 10.8 % (10/93) of the TVIF onlay group. There were no significant differences in the rate of any complication and the overall PPPS between the two groups.

Conclusion

TIP and TVIF onlay are clinically equivalent for the repair of proximal hypospadias.     

A retrospective study of laparoscopic unilateral adrenalectomy for primary hyperaldosteronism caused by unilateral adrenal hyperplasia

Objective

To evaluated the long-term outcomes of laparoscopic unilateral adrenalectomy for primary aldosteronism (PA) caused by unilateral adrenal hyperplasia (UAH).

Methods

One hundred and sixty-four patients who underwent laparoscopic unilateral adrenalectomy for UAH from January 2004 to December 2011 were entered in this retrospective analysis. Patients demographics, perioperative parameters, and follow-up results were recorded and analyzed statistically.

Results

All 164 cases suffered hypertension with biochemical evidence of hyperaldosteronism prior to operation. Hypokalemia was observed in 52/164 (37.14 %) patients. UAH was proved by multi-slice computed tomography (MSCT). All operations were completed successfully without any conversions or complications. Postoperative pathology confirmed that 164 cases were cortical nodular hyperplasia, of which 4 cases coexist with medullary hyperplasia and 7 with micro-adenoma. At the median follow-up of 48 months, hypertension was cured in 88 (53.7 %) patients, improved in 71 (43.3 %) patients, and refractory in 5 (3.05 %) patients. Hypokalemia and hyperaldosteronism were cured in all patients except re-elevation of blood pressure and plasma aldosterone in two patients 1 month after adrenalectomy.

Conclusions

As an underestimated subtype of PA, UAH is accepted gradually. Laparoscopic unilateral adrenalectomy is nowadays the preferred approach to treat patients with PA caused by UAH. When adrenal venous sampling is not allowed, high-resolution MSCT is a reliable test for lateralization of aldosterone hypersecretion in carefully selected patients and 97 % had either cure or improvement in blood pressure control.