Cardiac MIBG WR, but not SAECG, HRV, or QT dispersion, is a powerful predictor of SCD in patients with mild-to-moderate CHF, independently of LVEF.

IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxiainduced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.pulmonary arterial hypertension | interleukin-21 | interleukin-6 | Th17 cells | M2 macrophage

Gene expression is controlled by epigenetic mechanisms such as histone acetylation and methylation, and recent studies have revealed that key developmental steps are regulated by the trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3). Using ChIP sequencing technology combined with real-time PCR, we here demonstrate that the H3K27me3 observed in the Nfatc1 gene in bone marrow-derived macrophages (BMMs) was markedly reduced in mature osteoclasts. Jumonji domain-containing 3 (Jmjd3), a H3K27 demethylase, was induced in bone marrow-derived macrophages and in the vicinity of the transcription start site (TSS) of nuclear factor-activated T cells (NFAT) c1 in response to receptor activator of nuclear factor-kB ligand (RANKL) stimulation. Gene silencing of the Jmjd3 gene by short hairpin RNA reduced demethylation of H3K27me3 at the TSS of Nfatc1 and suppressed RANKL-induced osteoclastogenesis. These results suggest that the demethylation of H3K27me3 in the Nfatc1 gene locus by Jmjd3 plays a critical role in RANKL-induced osteoclast differentiation. ß

Previous studies have shown that transforming growth factor b (TGF-b) promotes receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis. However, the underlying molecular mechanisms have not been elucidated. When TGF-b signals were blocked either by a specific inhibitor of TGF-b type 1 receptor kinase activity, SB431542, or by introducing a dominant-negative mutant of TGF-b type 2 receptor, RANKL-induced osteoclastogenesis was almost completely suppressed. Blockade of Smad signaling by overexpression of Smad7 or c-Ski markedly suppressed RANKL-induced osteoclastogenesis, and retroviral induction of an activated mutant of Smad2 or Smad3 reversed the inhibitory effect of SB431542. Immunoprecipitation analysis revealed that Smad2/3 directly associates with the TRAF6-TAB1-TAK1 molecular complex, which is generated in response to RANKL stimulation and plays an essential role in osteoclast differentiation. TRAF6-TAB1-TAK1 complex formation was not observed when TGF-b signaling was blocked. Analysis using deletion mutants revealed that the MH2 domain of Smad3 is necessary for TRAF6-TAB1-TAK1 complex formation, downstream signal transduction, and osteoclast formation. In addition, gene silencing of Smad3 in osteoclast precursors markedly suppressed RANKLinduced osteoclast differentiation. In summary, TGF-b is indispensable in RANKL-induced osteoclastogenesis, and the binding of Smad3 to the TRAF6-TAB1-TAK1 complex is crucial for RANKL-induced osteoclastogenic signaling. ß

The incidences of arterial dissection of the vertebral artery (VA) of aortic origin and VA of subclavian artery origin were determined. The origins of the left and right VAs were confirmed by angiography in 860 and 717 patients, respectively. Left VA of aortic origin was found in 21 patients (6 females and 15 males) but no right VA of aortic origin was found. Left VA of left subclavian artery origin was found in 837 patients and right VA of right subclavian artery origin in 717 patients. Arterial dissection of the VA occurred in 17 patients (6 females and 11 males), four patients with left VA of aortic origin, seven with left VA of left subclavian artery origin, four with right VA of right subclavian artery origin, and two with bilateral VAs of subclavian artery origin. Left VA of aortic origin (4 of 21 patients) was associated with a significantly higher incidence of VA dissection than left VA of left subclavian artery origin and right VA of right subclavian artery origin (p º 0.001). Left VA of aortic origin is associated with a predilection for VA dissection in comparison to VA of subclavian artery origin.

The origin and developmental mechanisms underlying coronary vessels are not fully elucidated. Here we show that myocardium-derived angiopoietin-1 (Ang1) is essential for coronary vein formation in the developing heart. Cardiomyocyte-specific Ang1 deletion results in defective formation of the subepicardial coronary veins, but had no significant effect on the formation of intramyocardial coronary arteries. The endothelial cells (ECs) of the sinus venosus (SV) are heterogeneous population, composed of APJ-positive and APJ-negative ECs. Among these, the APJ-negative ECs migrate from the SV into the atrial and ventricular myocardium in Ang1-dependent manner. In addition, Ang1 may positively regulate venous differentiation of the subepicardial APJ-negative ECs in the heart. Consistently, in vitro experiments show that Ang1 indeed promotes venous differentiation of the immature ECs. Collectively, our results indicate that myocardial Ang1 positively regulates coronary vein formation presumably by promoting the proliferation, migration and differentiation of immature ECs derived from the SV.

In order to treat syringomyelia associated with adult type Chiari malformation, the authors developed a method of expansive suboccipital cranioplasty (ESC) that involves enlarging the small posterior fossa to obtain a sufficient flow of cerebrospinal fluid (CSF). The relative effectiveness of ESC with the obex plugged and not plugged was also examined, as well as other factors influencing the operative results. Twenty patients without arachnoid adhesion at the major cistern underwent ESC without opening the arachnoid membrane at the major cistern. After surgery, all improved with no recurrence and CSF flow study using magnetic resonance (MR) imaging showed significant improvement of the flow at the major cistern. Another 20 patients without arachnoid adhesion also underwent ESC but with obex plugging. Sixteen improved and one displayed only temporary improvement with recurrent syringomyelia due to postoperative arachnoid adhesions. The remaining three showed no change in spite of shrinkage of the syrinx on postoperative MR imaging. These three patients had displayed pre-operative symptoms over an approximately 10-year period involving almost the entire axial plain of the spinal cord, and presented a large syrinx before surgery. In 4 patients with arachnoid adhesions, all required intra-arachnoid procedures in addition to ESC. Intra-arachnoid procedures are not necessary to facilitate restoration of CSF flow in patients without arachnoid adhesions, because ESC can release the CSF flow blockage in the major cistern even without plugging of the obex. An associated arachnoid adhesion at the major cistern or a long-standing syringomyelia with irreversible damage of the spinal cord results in a poor operative prognosis. When posterior fossa surgery fails, insufficient decompression or postoperative arachnoid adhesions at the major cistern as the cause of treatment's failure should be evaluated by CSF flow studies using phase contrast MR imaging.

There is no evidence that pregnancy increases the risk of cerebrovascular accident or that bypass surgery decreases its risk. Poor prognosis of the patient or the newborn is mostly caused by cerebral hemorrhage and not by cerebral ischemia. It is important to control blood pressure and especially to avoid toxemia during pregnancy. Either cesarean section or vaginal delivery can be accomplished safely. Any anesthetic method can be used, provided special attention is given to avoiding hypocapnia, hypotension, and hypertension. Oral contraceptives should be avoided.