Possibility of valence-fluctuation mediated superconductivity in Cd-doped CeIrIn5_5 probed by In-NQR

We report on a pressure-induced evolution of exotic superconductivity and spin correlations in CeIr(In$_{1-x}$Cd$_{x}$)$_5$ by means of In-Nuclear-Quadrupole-Resonance (NQR) studies. Measurements of an NQR spectrum and nuclear-spin-lattice-relaxation rate $1/T_1$ have revealed that antiferromagnetism induced by the Cd-doping emerges locally around Cd dopants, but superconductivity is suddenly induced at $T_c$ = 0.7 and 0.9 K at 2.34 and 2.75 GPa, respectively. The unique superconducting characteristics with a large fraction of the residual density of state at the Fermi level that increases with $T_c$ differ from those for anisotropic superconductivity mediated by antiferromagnetic correlations. By incorporating the pressure dependence of the NQR frequency pointing to the valence change of Ce, we suggest that unconventional superconductivity in the CeIr(In$_{1-x}$Cd$_{x}$)$_5$ system may be mediated by valence fluctuations.Comment: Accepted for publication in Physical Review Letter

A Complete Expression Profile of Matrix-Degrading Metalloproteinases in Dupuytren’s Disease

Dupuytren’s disease (DD) is a common fibrotic condition of the palmar fascia, leading to deposition of collagen-rich cords and finger contractions. The metzincin superfamily contains key enzymes in the turnover of collagen and other extracellular matrix macromolecules. A number of broad-spectrum matrix metalloproteinase inhibitors, used in cancer clinical trials, caused side effects of DD-like contractures. We tested the hypothesis that changes in the expression of specific metalloproteinases underlie or contribute to the fibrosis and contracture seen in DD. We collected tissue from patients with DD and used normal palmar fascia as a control. We profiled the expression of the entire matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases (TIMP), and a disintegrin and metalloproteinase domain with thrombospondin motif (ADAMTS) gene families in these tissues using real-time reverse-transcription polymerase chain reaction. A number of metalloproteinases and inhibitors are regulated in DD. The expression of 3 key collagenases, MMP1, MMP13, and MMP14 is increased significantly in the DD nodule, as is the expression of the collagen biosynthetic enzyme ADAMTS14. The expression of MMP7, an enzyme with broad substrate specificity, is increased in the DD nodule and remains equally expressed in the DD cord. TIMP1 expression is increased significantly in DD nodule compared with normal palmar fascia. This study measured the expression of all MMP, ADAMTS, and TIMP genes in DD. Contraction and fibrosis may result from: (1) increased collagen biosynthesis mediated by increased ADAMTS-14; (2) an increased level of TIMP-1 blocking MMP-1– and MMP-13–mediated collagenolysis; and (3) contraction enabled by MMP-14–mediated pericellular collagenolysis (and potentially MMP-7), which may escape inhibition by TIMP-1. The complete expression profile will provide a knowledge-based approach to novel therapeutics targeting these genes

New Universality Class of Quantum Criticality in Ce- and Yb-based Heavy Fermions

A new universality class of quantum criticality emerging in itinerant electron systems with strong local electron correlations is discussed. The quantum criticality of a Ce- or Yb-valence transition gives us a unified explanation for unconventional criticality commonly observed in heavy fermion metals such as YbRh2Si2 and \beta-YbAlB4, YbCu5-xAlx, and CeIrIn5. The key origin is due to the locality of the critical valence fluctuation mode emerging near the quantum critical end point of the first-order valence transition, which is caused by strong electron correlations for f electrons. Wider relevance of this new criticality and important future measurements to uncover its origin are also discussed.Comment: 20 pages, 4 figure

Relaxin, a pleiotropic vasodilator for the treatment of heart failure

Relaxin is a naturally occurring peptide hormone that plays a central role in the hemodynamic and renovascular adaptive changes that occur during pregnancy. Triggering similar changes could potentially be beneficial in the treatment of patients with heart failure. The effects of relaxin include the production of nitric oxide, inhibition of endothelin, inhibition of angiotensin II, production of VEGF, and production of matrix metalloproteinases. These effects lead to systemic and renal vasodilation, increased arterial compliance, and other vascular changes. The recognition of this has led to the study of relaxin for the treatment of heart failure. An initial pilot study has shown favorable hemodynamic effects in patients with heart failure, including reduction in ventricular filling pressures and increased cardiac output. The ongoing RELAX-AHF clinical program is designed to evaluate the effects of relaxin on the symptoms and outcomes in a large group of patients admitted to hospital for acute heart failure. This review will summarize both the biology of relaxin and the data supporting its potential efficacy in human heart failure

Relaxin: Review of Biology and Potential Role in Treating Heart Failure

Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone. More recently, relaxin has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. An understanding of these physiologic effects has led to the evaluation of relaxin as a pharmacologic agent for the treatment of patients with acute heart failure. Preliminary results have been encouraging. In addition, the other known biologic properties of relaxin, including anti-inflammatory effects, extracellular matrix remodeling effects, and angiogenic and anti-ischemic effects, all may play a role in potential benefits of relaxin therapy. Ongoing, large-scale clinical testing will provide additional insights into the potential role of relaxin in the treatment of heart failure

Clinical guidelines for treating caries in adults following a minimal intervention policy?Evidence and consensus based report

Objectives: In 2002, FDI (World Dental Federation) published a policy advocating that caries be treated by minimal intervention (MI). This MI policy has been accepted worldwide and is taught in universities. But acceptance in general dental practice has been slower, especially in Japan where healthcare payment and practice favour drilling and filling. To help disseminate this MI policy into general practice, the Japanese Society of Conservative Dentistry developed an evidence-based clinical guideline for restoring carious permanent teeth in adult patients. Methods: The guideline was developed by a committee of nine university clinicians and a librarian. The committee selected the most frequent clinical questions in treating caries and used electronic databases to search and assess the best scientific evidence for each. Members then added their clinical experience and discussed to reach consensus on each question on treating caries with MI policy. Graded recommendations and guidance were made for each clinical question. The provisional guideline was strengthened after review and discussion with university researchers and general practitioners. Results: The guideline addresses the 16 most frequent clinical questions in treating adult caries, including restorative methods and how to tackle root caries. Recommendations for treatment using MI policy were developed using the best scientific evidence and consensus of experienced clinicians. Clinical significance: The guideline offers a practical expert view of treating caries with the MI policy that incorporates the best scientific evidence, the latest techniques, the most preferable materials and the general consensus of expert clinicians

Anti-angiogenic action of hyperthermia by suppressing gene expression and production of tumour-derived vascular endothelial growth factor in vivo and in vitro

Vascular endothelial growth factor is an important angiogenic factor for tumour progression because it increases endothelial-cell proliferation and remodels extracellular matrix in blood vessels. We demonstrated that hyperthermia at 42°C, termed heat shock, suppressed the gene expression and production of vascular endothelial growth factor in human fibrosarcoma HT-1080 cells and inhibited its in vitro angiogenic action on human umbilical vein endothelial cells. The gene expression of alternative splicing variants for vascular endothelial growth factor, VEGF121, VEGF165 and VEGF189, was constitutively detected in HT-1080 cells, but the VEGF189 transcript was less abundant than VEGF121 and VEGF165. When HT-1080 cells were treated with heat shock at 42°C for 4 h and then maintained at 37°C for another 24 h, the gene expression of all vascular endothelial growth factor variants was suppressed. In addition, HT-1080 cells were found to produce abundant VEGF165, but much less VEGF121, both of which were inhibited by heat shock. Furthermore, the level of vascular endothelial growth factor in sera from six cancer patients was significantly diminished 2–3 weeks after completion of whole-body hyperthermia at 42°C (49.9±36.5 pg ml−1, P<0.01) as compared with that prior to the treatment (177.0±77.5 pg ml−1). On the other hand, HT-1080 cell-conditioned medium showed vascular endothelial growth factor-dependent cell proliferative activity and the augmentation of pro-matrix metalloproteinase-1 production in human umbilical vein endothelial cells. The augmentation of endothelial-cell proliferation and pro-matrix metalloproteinase-1 production was poor when human umbilical vein endothelial cells were treated with conditioned medium from heat-shocked HT-1080 cells. These results suggest that hyperthermia acts as an anti-angiogenic strategy by suppressing the expression of tumour-derived vascular endothelial growth factor production and thereby inhibiting endothelial-cell proliferation and extracellular matrix remodelling in blood vessels

Control of Cell Migration and Inflammatory Mediators Production by CORM-2 in Osteoarthritic Synoviocytes

BackgroundOsteoarthritis (OA) is the most widespread degenerative joint disease. Inflamed synovial cells contribute to the release of inflammatory and catabolic mediators during OA leading to destruction of articular tissues. We have shown previously that CO-releasing molecules exert anti-inflammatory effects in animal models and OA chondrocytes. We have studied the ability of CORM-2 to modify the migration of human OA synoviocytes and the production of chemokines and other mediators sustaining inflammatory and catabolic processes in the OA joint.Methodology/Principal FindingsOA synoviocytes were stimulated with interleukin(IL)-1β in the absence or presence of CORM-2. Migration assay was performed using transwell chambers. Gene expression was analyzed by quantitative PCR and protein expression by Western Blot and ELISA. CORM-2 reduced the proliferation and migration of OA synoviocytes, the expression of IL-8, CCL2, CCL20, matrix metalloproteinase(MMP)-1 and MMP-3, and the production of oxidative stress. We found that CORM-2 reduced the phosphorylation of extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase1/2 and to a lesser extent p38. Our results also showed that CORM-2 significantly decreased the activation of nuclear factor-κB and activator protein-1 regulating the transcription of chemokines and MMPs in OA synoviocytes.Conclusion/SignificanceA number of synoviocyte functions relevant in OA synovitis and articular degradation can be down-regulated by CORM-2. These results support the interest of this class of agents for the development of novel therapeutic strategies in inflammatory and degenerative conditions

Vasodilators in the treatment of acute heart failure: what we know, what we don’t

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients’ outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1–2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice