Patterns in the distribution of social inequalities are not universal. Social inequalities in alcohol use differ by gender according to alcohol measure used and differ also across groups of countries. These variations should be taken into account when formulating international and cross-cultural alcohol policies.

It appeared that the social welfare system and gender equity of a country determines to a large extent how education, employment, and family roles are associated with heavy drinking.

Aims/hypothesis Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance. Methods The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice. Results Palmitate induced an impressive formation of extraand intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P 2 receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P 2 , was not able to inhibit insulin signalling. Conclusions/interpretation These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P 2 receptor to impair insulin signalling. In particular, S1P 2 inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.

Patients with proteinuric kidney diseases often experience symptoms of salt and water retention. It has been hypothesized that the dysregulated Na+ absorption is due to increased proteolytic cleavage of epithelial sodium channel (ENaC) and increased Na,K-ATPase expression. Microarray analysis identified a reduced corin mRNA expression in kidneys from rat models of puromycin aminonucleoside-induced nephrotic syndrome (PAN) and acute anti-Thy1 glomerulonephritis (GN). Corin has been shown to convert pro-atrial natriuretic peptide (ANP) to ANP. Because ANP resistance has been assumed to be a mechanism accounting for volume retention, experiments were undertaken to analyze the renal expression and function of corin. Immunohistochemistry revealed that corin co-localized with ANP. In PAN and GN, kidneys exhibited concomitant increased pro-ANP and decreased ANP protein expression levels consistent with low corin levels. Importantly, kidneys from corin −/− mice showed increased levels of renal β-ENaC, phosphodiesterase 5 (PDE5) and protein kinase G II (PKGII) when compared to wild-type mice. Similar expression profile was observed in cell culture experiments suggesting that the increase in PDE5 and PKGII could account for the increase in β-ENaC as observed in PAN and GN. To conclude, our data provide novel insights into the mechanisms of volume retention in renal disease with corin as an important new mediator that acts through PKGII induction and ENaC activation.

Lymphocyte depletion by FTY720 limits the progression of anti-thy 1-induced glomerulosclerosis toward chronic tubulointerstitial fibrosis and renal insufficiency. The data suggest that lymphocytes actively participate in the progression of chronic experimental kidney disease, and that FTY720 may be a novel approach to slow the progressive course of human chronic renal diseases.

Glomerular and tubulointerstitial soluble guanylate cyclase activity are discordantly altered in anti-thy1-induced chronic glomerulosclerosis. Stimulation of soluble guanylate cyclase signaling by Bay 41-2272 limits the progressive course of this model toward tubulointerstitial fibrosis and impaired renal function at least in part in a blood pressure-independent manner. The results suggest that soluble guanylate cyclase activation counteracts fibrosis and progression in chronic renal disease.

-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat. Am J Physiol Renal Physiol 294: F440-F449, 2008. First published December 19, 2007 doi:10.1152/ajprenal.00379.2007.-Treatment options in human mesangioproliferative glomerulonephritis/sclerosis, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low-dose mTOR inhibition by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high-dose anti-thy1 antibody injection into uninephrectomized rats. Rapamycin administration (2.5 mg ⅐ kg Ϫ1 ⅐ body wt Ϫ1 ) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. KruskalWallis and Mann-Whitney U-tests were used for statistical analysis. The course of chronic anti-thy1-induced glomerulosclerosis was significantly attenuated by low-dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (Ϫ38%), systolic blood pressure (Ϫ16 mmHg), tubulointerstitial and glomerular histological matrix accumulation (Ϫ61 and Ϫ24%), transforming growth factor-␤1 overexpression (Ϫ41 and Ϫ47%), collagen I deposition (Ϫ53 and Ϫ65%), cell proliferation (Ϫ90 and Ϫ76%), and leukocyte number (macrophages Ϫ52 and Ϫ53%; lymphocytes Ϫ58 and 51%), respectively. Rapamycin improved renal function as well (blood creatinine Ϫ0.68 mg/dl, urea Ϫ66.7 mg/day, and creatinine clearance ϩ0.13 ml ⅐ min Ϫ1

Glomerular nitric oxide signaling via cGMP is markedly impaired during injury of anti-thy1 glomerulonephritis, while it is highly up-regulated during subsequent repair. Further pharmacologic soluble guanylate cyclase stimulation limits glomerular TGF-beta overexpression and matrix expansion, suggesting that the soluble guanylate cyclase enzyme represents an important antifibrotic pathway in glomerular disease.