BASIC AND TRANSLATIONAL LIVER the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1-/mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1. CONCLUSIONS: Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with dietinduced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.

The pontine noradrenergic cell groups, A5, A6 (locus coeruleus), and A7, provide the only noradrenergic innervation of the spinal cord, but the individual contribution of each of these populations to the regional innervation of the spinal cord remains controversial. We have used an adeno-associated viral (AAV) vector encoding green fluorescent protein under an artificial dopamine beta-hydroxylase (PRSx8) promoter, to trace the spinal projections from the A5, A6, and A7 groups. Projections from all three groups travel through the spinal cord in both the lateral and ventral funiculi and in the dorsal surface of the dorsal horn, but A6 axons take predominantly the dorsal and ventral routes whereas A5 and A7 axons take a predominantly lateral route. The A6 group provides the densest innervation at all levels, and includes all parts of the spinal gray matter, but it is particularly dense in the dorsal horn. The A7 group provides the next most dense innervation, again including all parts of the spinal cord, but is it denser in the ventral horn. The A5 group supplies only sparse innervation to the dorsal and ventral horns and to the cervical and lumbosacral levels, but provides the densest innervation to the thoracic intermediolateral cell column, and in particular to the sympathetic preganglionic neurons. Thus, the pontine noradrenergic cell groups project in a roughly topographic and complementary fashion onto the spinal cord. The pattern of spinal projections observed suggests that the locus coeruleus might have the greatest effect on somatosensory transmission, the A7 group on motor function, and the A5 group on sympathetic function.

Background-Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs. Summary-THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-L-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver. Conclusions-TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/

The hypothalamic control of hepatic glucose production is an evident aspect of energy homeostasis. In addition to the control of glucose metabolism by the circadian timing system, the hypothalamus also serves as a key relay center for (humoral) feedback information from the periphery, with the important role for hypothalamic leptin receptors as a striking example. The hypothalamic biological clock uses its projections to the preautonomic hypothalamic neurons to control the daily rhythms in plasma glucose concentration, glucose uptake, and insulin sensitivity. Euglycemic, hyperinsulinemic clamp experiments combined with either sympathetic-, parasympathetic-, or sham-denervations of the autonomic input to the liver have further delineated the hypothalamic pathways that mediate the control of the circadian timing system over glucose metabolism. In addition, these experiments clearly showed both that next to the biological clock peripheral hormones may "use" the preautonomic neurons in the hypothalamus to affect hepatic glucose metabolism, and that similar pathways may be involved in the control of lipid metabolism in liver and white adipose tissue.

Excessive secretion of triglyceride-rich very low-density lipoproteins (VLDL-TG) contributes to diabetic dyslipidemia. Earlier studies have indicated a possible role for the hypothalamus and autonomic nervous system in the regulation of VLDL-TG. In the current study, we investigated whether the autonomic nervous system and hypothalamic neuropeptide Y (NPY) release during fasting regulates hepatic VLDL-TG secretion. We report that, in fasted rats, an intact hypothalamic arcuate nucleus and hepatic sympathetic innervation are necessary to maintain VLDL-TG secretion. Furthermore, the hepatic sympathetic innervation is necessary to mediate the stimulatory effect of intracerebroventricular administration of NPY on VLDL-TG secretion. Since the intracerebroventricular administration of NPY increases VLDL-TG secretion by the liver without affecting lipolysis, its effect on lipid metabolism appears to be selective to the liver. Together, our findings indicate that the increased release of NPY during fasting stimulates the sympathetic nervous system to maintain VLDL-TG secretion at a postprandial level.

This study demonstrated the efficacy and safety of low-dose TH therapy for NAFLD in men. TH or TH analogs may be beneficial for this condition.

To cite this article: Bruinstroop E, Klok FA, van de Ree MA, Oosterwijk FL, Huisman MV. Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis. J Thromb Haemost 2009; 7: 611-8. Summary. Background:The evidence on the optimal duration of treatment in patients with an idiopathic venous thromboembolic event (VTE) is inconclusive. D-dimer testing to predict recurrent VTE has been evaluated in several studies. Objectives: We performed a meta-analysis of studies of patients with idiopathic VTE treated with oral anticoagulation therapy (OAT) to assess the prognostic value of elevated D-dimer levels 1 month after discontinuation of OAT for VTE recurrence. Patients/Methods: The MEDLINE, EMBASE and Cochrane databases were searched to identify relevant studies. Studies were eligible for inclusion if they included patients with idiopathic VTE and in addition reported results for this group separately, had measured D-dimer approximately 1 month after discontinuation of OAT and had reported on recurrence of VTE. A random-effects model was used to pool study results. Results: Data from four studies (1539 patients) were included in the current analysis. All studies reported on the number of recurrent events in the normal and elevated D-dimer groups. Overall, 125 of 751 patients (16.6%) with elevated D-dimer levels experienced recurrent VTE during the period of follow-up compared with 57 of 788 patients (7.2%) with normal D-dimer levels. Elevated D-dimer levels were significantly associated with recurrent VTE (odds ratio , 2.36; 95% CI, 1.65 to 3.36). Conclusions: Elevated D-dimer levels measured 1 month after discontinuation of OAT identify patients with idiopathic VTE at higher risk of recurrence.

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