Vitamin D seems to protect against cardiovascular disease, but the reported effects of vitamin D on patient outcomes in CKD are controversial. We conducted a prospective, double blind, randomized, placebocontrolled trial to determine whether oral activated vitamin D reduces left ventricular (LV) mass in patients with stages 3-5 CKD with LV hypertrophy. Subjects with echocardiographic criteria of LV hypertrophy were randomly assigned to receive either oral paricalcitol (1 mg) one time daily (n=30) or matching placebo (n=30) for 52 weeks. The primary end point was change in LV mass index over 52 weeks, which was measured by cardiac magnetic resonance imaging. early diastolic and systolic mitral annular velocities, and ratio of early mitral inflow velocity to early diastolic mitral annular velocity did not differ between the groups. However, paricalcitol treatment significantly reduced intact parathyroid hormone (P,0.001) and alkaline phosphatase (P=0.001) levels as well as the number of cardiovascular-related hospitalizations compared with placebo. In conclusion, 52 weeks of treatment with oral paricalcitol (1 mg one time daily) significantly improved secondary hyperparathyroidism but did not alter measures of LV structure and function in patients with severe CKD.

Cerebral palsy (CP), a neurodevelopmental disorder characterized by irreversible, nonprogressive central motor dysfunction, is commonly associated with prematurity or perinatal brain injury. However, accumulating evidence suggests deleterious genomic variants may contribute to CP in addition to environmental insults. To identify genes contributing to risk for CP, we performed whole-exome sequencing on 250 parent-offspring CP trios. We identified a significant contribution of damaging de novo mutations (DNMs), especially in genes that are intolerant to loss of function mutations. Eight genes had multiple, independently-arising damaging DNMs, including two novel CP-associated genes, FBXO31 and RHOB, and four genes previously implicated in cerebral palsy phenotypes, TUBA1A, CTNNB1, SPAST, and ATL1. Functional experiments, including molecular and biochemical assays and patient fibroblast studies indicate that the recurrent RHOB mutation identified in patients enhances Rho effector binding in the active state and that the FBXO31 mutation leads to elevated levels of cyclin D. Analysis of candidate CP risk genes highlighted genetic overlap with hereditary spastic paraplegia as well as intellectual disability, autism, and epilepsy, converging with epidemiologic findings. Computational network analysis of risk genes identified significant enrichment of Rho GTPase, extracellular matrix, focal adhesions, cytoskeleton, and cell projection pathways. CP risk genes in Rho GTPase, cytoskeleton and cell projection pathways were found to play an important role in neuromotor development via a Drosophila reverse genetics screen. Based on enrichment analysis, we estimate that an excess of damaging de novo and inherited recessive variants collectively account for ~14% of the cases in our cohort, whereas perinatal asphyxia is currently estimated to occur in 8-10% of CP cases. Together, these findings provide evidence for the role of genetically-mediated dysregulation of early brain connectivity in CP.

Mice with a targeted mutation of 3b-hydroxysterol D 7

Objective. To examine the prevalence of subclinical atherosclerosis in patients with psoriatic arthritis (PsA) compared with healthy controls, and to identify clinical and biologic markers for atherosclerotic disease in this patient population. Methods. Subclinical atherosclerosis was defined as the average of intima-media thickness (IMT) measures in the common carotid artery, bifurcation, and internal carotid artery on both sides above the 95th percentile of healthy controls. IMT was measured using carotid ultrasonography in 82 consecutive PsA patients and 82 healthy controls matched on age, sex, and ethnicity. We also ascertained traditional and novel cardiovascular (CV) risk factors, Framingham risk score (FRS), disease severity, treatment, and inflammatory markers in all PsA patients. Results. No PsA patients had clinically overt CV diseases. After adjusting for traditional CV risk factors, PsA patients had a higher prevalence of subclinical atherosclerosis. PsA patients with subclinical atherosclerosis had significantly increased sugar, total triglyceride levels, total cholesterol/high-density cholesterol, white cell count, and patients' global assessment score compared with those without subclinical atherosclerosis. Using logistic regression analysis, independent explanatory variables associated with subclinical atherosclerosis in PsA included increased sugar and total triglyceride levels. The FRS was similar in PsA patients with or without subclinical atherosclerosis. Twenty-six (35%) of 74 patients had subclinical atherosclerosis despite having a low CV risk. Conclusion. PsA is associated with subclinical atherosclerosis after adjusting for traditional CV risk factors. Independent explanatory variables associated with subclinical atherosclerosis in PsA included increased sugar and total triglyceride levels. Carotid IMT can identify PsA patients with subclinical atherosclerosis who may benefit from early intervention.

No abstract

To investigate how colesevelam (CL) HCl improves hyperglycemia, studies were conducted in diet-induced obesity (F-DIO) rats, which develop insulin resistance when fed a high-energy (high fat/high sucrose) diet (HE). The rats were fed HE; HE ϩ 2% CL; HE ϩ 0.02% SC-435 (SC), an apical sodium-dependent bile acid transporter inhibitor; and regular chow (controls). After 4 wk of treatment, both in the HE group and the SC ϩ HE group, plasma glucose and insulin levels remained elevated compared with baseline values throughout an oral glucose tolerance test (OGTT). In contrast, in the CL ϩ HE group, plasma glucose levels returned to baseline by the end of the test, and insulin peaked in 15-30 min and then returned to baseline. CL induced release of glucagon-like peptide-1 (GLP-1) because the area under the curve of plasma total GLP-1 in the CL ϩ HE group was significantly greater than in the HE group during the OGTT. Bile acid concentrations in the portal blood did not decrease in the HE group but declined significantly both in the CL ϩ HE and SC ϩ HE groups with reduced farnesoid X receptor activation compared with controls. We concluded that CL reduces plasma glucose levels by improving insulin resistance in this rat model. It is unlikely that the improvement is attributable to decreased bile acid flux to the liver but is likely secondary to induced GLP-1 secretion, which improves insulin release. fatty acid; intestinal absorption; cholesterol 7␣-hydroxylase; glucagon-like peptide-1 EXCESSIVE GLUCONEOGENESIS in the liver contributes greatly to fasting and postprandial hyperglycemia. Recently, it has been shown that both bile acids and the bile acid sensor farnesoid X receptor (FXR), in addition to their well-known roles in bile acid metabolism and enterohepatic homeostasis, are involved in glucose homeostasis. Treatment with bile acids inhibits the expression of genes involved in gluconeogenesis in HepG2 cells as well as in mice (4,22). The suppressive effects of bile acids and FXR on gluconeogenesis was confirmed by the observation by Ma et al. (17) that activation of FXR by cholic acid (CA) suppressed the expression of genes involved in gluconeogenesis in wild-type but not FXRϪ/Ϫ mice, in which gluconeogenesis in the liver was dysregulated. More importantly, it has been noted that FXR also plays an important role in the regulation of insulin sensitivity because glucose intolerance and insulin resistance were observed in FXR-null mice (3,17,24), whereas treatment with the FXR agonist GW4064 (3, 24) or overexpression of constitutively active FXR (24) improved insulin sensitivity in diabetic mouse models. However, many studies indicate that bile acid sequestrants that block bile acid absorption and decreased activation of FXR also improve hyperglycemia in diabetic animals as well as in patients (1,20). Although various hypotheses have been proposed, the specific mechanism(s) by which bile acid sequestrants improve glycemic control remain unclear. Colesevelam (CL) HCl (Welchol) is such a bile acid sequestrant, and rece...

PsA patients without established CVD disease and in the absence of traditional CV risk factors have a high prevalence of subclinical LV dysfunction.

The regulation of the rabbit apical sodium-dependent bile acid transporter (ASBT) was studied both in vivo and in vitro. New Zealand White rabbits were fed 0.5% deoxycholic acid (DCA) or SC-435, a competitive ASBT inhibitor, for 1 wk. In DCA-fed rabbits, ASBT expression was repressed, associated with activated FXR, and evidenced by increased ileal short heterodimer partner (SHP) mRNA. Feeding SC-435 to the rabbits blocked bile acid absorption, decreased SHP mRNA, and increased ASBT expression. A 1.9-kb rabbit ASBT 5Ј-flanking region (promoter) was cloned, and a cis-acting element for ␣-fetoprotein transcription factor (FTF) was identified (Ϫ1166/ Ϫ1158). The effects of transcriptional factors and different bile acids on the rabbit ASBT promoter were studied in Caco-2 cells. FTF stimulated the rabbit ASBT promoter activity fourfold but not after the FTF binding site was deleted from the promoter. Increasing the SHP protein notably inhibited FTF-dependent trans-activation of rabbit ASBT. Adding hydrophobic bile acids deoxycholic acid, chenodeoxycholic acid, and cholic acid, activating ligands for FXR, inhibited rabbit ASBT promoter activity in Caco-2 cells, but this inhibitory effect was abolished after the FTF binding site was deleted. Ursodeoxycholic acid and ursocholic acid, nonactivating ligands for FXR, did not repress ASBT promoter activity. Thus the rabbit ASBT promoter is negative-feedback regulated by bile acids via a functional FTF binding site. Only FXR-activating ligands can downregulate rabbit ASBT expression through the regulatory cascade FXR-SHP-FTF.THE APICAL SODIUM-DEPENDANT bile acid cotransporter (ASBT/ SLC10A2) is the primary bile salt uptake protein in the intestine. It is mainly located on the apical surface of the terminal ileal enterocytes and is also expressed on renal proximal tubular cells and large cholangiocytes (12,19). ASBT is an efficient transporter for conjugated and unconjugated bile salts. Bile salt reabsorption by ASBT in the ileum is sodium dependent and can be saturated (7). ASBT has been cloned from the human (26), rabbit (11), rat (19), mouse (17), and hamster (25).Regulation of ASBT expression by intestinal bile acid flux has been studied in guinea pigs (13), rats (2,8,10,18,20), and mice (21). However, whether ASBT expression is positively or negatively regulated by increasing bile acid flux remains controversial. Observations in guinea pigs (13) and mice (21) showed that ASBT was negatively regulated by the intestinal bile acid flux, whereas in rats, ASBT was positively regulated by bile acids (8,10,18,20). Nevertheless, the results reported by Arrese et al. (2) showed that in rats, no regulatory response to changes in the intestinal bile acid flux occurred. Recently, Chen et al. (5) identified a physiologically functional liver receptor homolog-1 (LRH-1; also called FTF, ␣-fetoprotein transcription factor in other species) transcriptional binding site in the mouse ASBT promoter that was not present in the rat. As a result, chenodeoxycholic acid (CDCA), an activating lig...