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In Argentina, during the decade of the 1990s major changes were introduced into the regulatory framework of the national obras sociales, or union-based health coverage plans. Using data from the Federal Administration of Public Income (AFIP) [Administración Federal de Ingresos Públicos], this study evaluates for the years 2004 and 2011: a) the importance of obras sociales within the healthcare system, b) the degree of concentration of this health social security subsystem, and c) the inequalities in the availability of funds among the obras sociales and their beneficiaries. The results show an increased importance of obras sociales within the Argentine health system. The concentration of funds distributed to the most important institutions within the subsystem showed no change, while the concentration of contributors to these institutions slightly increased and that of beneficiaries decreased. Finally, a reduction of the inequalities in funds per beneficiary received by different institutions was observed. This trend can be explained, among other factors, by the attenuation of wage differentials between branches of economic activity and the actions of the so-called Solidarity Redistribution Fund.

Progranulin (PGRN) is a recently identified adipokine that is supposed to have anti-inflammatory actions. The proinflammatory cytokine interleukin-1β (IL1β) stimulates several mediators of cartilage degradation. Toll like receptor-4 (TLR4) can bind to various damage-associated molecular patterns, leading to inflammatory condition. So far, no data exist of PGRN effects in inflammatory conditions induced by IL1β or lipopolysaccharide (LPS). Here, we investigated the anti-inflammatory potential of PGRN in IL1β- or LPS-induced inflammatory responses of chondrocytes. Human osteoarthritic chondrocytes and ATDC-5 cells were treated with PGRN in presence or not of IL1β or LPS. First, we showed that recombinant PGRN had no effects on cell viability. We present evidence that PGRN expression was increased during the differentiation of ATDC-5 cell line. Moreover, PGRN mRNA and protein expression is increased in cartilage, synovial and infrapatellar fat pad tissue samples from OA patients. PGRN mRNA levels are upregulated under TNFα and IL1β stimulation. Our data showed that PGRN is able to significantly counteract the IL1β-induced expression of NOS2, COX2, MMP13 and VCAM-1. LPS-induced expression of NOS2 is also decreased by PGRN. These effects are mediated, at least in part, through TNFR1. Taken together, our results suggest that PGRN has a clear anti-inflammatory function.

Aims: Disruptions in cardiac ion channels have shown to influence the impaired cardiac contraction in heart failure. We sought to determine the altered gene expression profile of this category in dilated cardiomyopathy (DCM) patients and relate the altered gene expression with the clinical signs present in our patients, such as ventricular dysfunction and sustained monomorphic ventricular tachycardia (SMVT)., Methods and Results: Left ventricular (LV) tissue samples were used in RNA-sequencing technique to elucidate the transcriptomic changes of 13 DCM patients compared to controls (n = 10). We analyzed the differential gene expression of cardiac ion channels, and we found a total of 34 altered genes. We found that the calcium channel CACNG8 mRNA and protein levels were down-regulated and highly and inversely related with LV ejection fraction (LVEF) (r = -0.78, P<0.01). Furthermore, the potassium channels KCNN3 and KCNJ2 mRNA and protein levels were up-regulated and showed also a significant and inverse correlation with LVEF (r = -0.61, P<0.05; r = -0.60, P<0.05) in patients with SMVT., Conclusion: A broad set of deregulated genes have been identified by RNA-sequencing technique. The relationship of CACNG8, KCNN3 and KCNJ2 with LVEF, and the up-regulation of KCNN3 and KCNJ2 in all patients with SMVT, irrespective of CACNG8 expression, suggest a significant role for these three ion flux related genes in the LV dysfunction present in this cardiomyopathy and an important relationship between KCNN3 and KCNJ2 up-regulation and the presence of SMVT.

Recent studies confer to IL-36α pro-inflammatory properties. However, little is known about the expression and function of IL-36α in cartilage. This study sought to analyze the expression of IL-36α in healthy and OA cartilage. Next, we determined the effects of recombinant IL-36α on catabolism and inflammation in chondrocytes. For completeness, part of the signaling pathway elicited by IL-36α was also explored. IL-36α expression was evaluated by immunohistochemistry and RT-qPCR. Expression of MMP-13, NOS2 and COX-2 was also determined in OA articular chondrocytes treated with recombinant IL-36α. IκB-α and P-p38 was explored by western blot. We observed a low constitutive expression of IL-36α in healthy human chondrocytes. However, OA chondrocytes likely expressed more IL-36α than healthy chondrocytes. In addition, immune cells infiltrated into the joint and PBMCs express higher levels of IL-36α in comparison to chondrocytes. OA chondrocytes, treated with IL-36α, showed significant increase in the expression of MMP-13, NOS2 and COX-2. Finally, IL-36α stimulated cells showed NFκB and p38 MAPK activated pathways. IL-36α acts as a pro-inflammatory cytokine at cartilage level, by increasing the expression of markers of inflammation and cartilage catabolism. Like other members of IL-1 family, IL-36α acts through the activation of NFκB and p38 MAPK pathway.

Nesfatin-1, which is derived from the NEFA/nucleobindin 2 (NUCB2) precursor, was recently identified as an anorexigenic peptide that is produced in several tissues including the hypothalamus. Currently, no data exist regarding the regulation of NUCB2/nesfatin-1 production in peripheral tissues, such as gastric mucosa and adipose tissue, through different periods of development. The aim of the present work was to study the variations on circulating levels, mRNA expression and tissue content in gastric mucosa and adipose tissue of NUCB2/nesfatin-1 with age and specially in two clue periods of maturation, weaning and puberty. The weaning period affected NUCB2/nesfatin-1 production in gastric tissue. The testosterone changes associated with the initiation of puberty regulated NUCB2/nesfatin-1 production via adipose tissue and gastric NUCB2/nesfatin-1 production. In conclusion, the production of NUCB2/nesfatin-1 by the stomach and adipose tissue fluctuates with age to regulate energy homeostasis during different states of development., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Extra-virgin olive oil (EVOO), a principal component of the Mediterranean diet (Med diet), is one of the most ancient known foods and has long been associated with health benefits. Many phenolic compounds extracted from Olea europea L. have attracted attention since their discovery. Among these phenolic constituents, oleocanthal has recently emerged as a potential therapeutic molecule for different diseases, showing relevant pharmacological properties in various pathogenic processes, including inflammation, cancers and neurodegenerative diseases. Here, we discuss and summarize the most recent pharmacological evidence for the medical relevance of oleocanthal, focusing our attention on its anti-inflammatory and chemotherapeutic roles., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Mitochondrial dysfunction plays a critical role in the development of ischaemic cardiomyopathy (ICM). In this study, the mitochondrial proteome in the cardiac tissue of ICM patients was analysed by quantitative differential electrophoresis (2D-DIGE) and mass spectrometry (MS) for the first time to provide new insights into cardiac dysfunction in this cardiomyopathy. We isolated mitochondria from LV samples of explanted hearts of ICM patients (n = 8) and control donors (n = 8) and used a proteomic approach to investigate the variations in mitochondrial protein expression. We found that most of the altered proteins were involved in cardiac energy metabolism (82%). We focused on ATPA, which is involved in energy production, and dihydrolipoyl dehydrogenase, implicated in substrate utilization, and observed that these molecules were overexpressed and that the changes detected in the processes mediated by these proteins were closely related. Notably, we found that ATPA overexpression was associated with reduction in LV mass (r = -0.74, P < 0.01). We also found a substantial increase in the expression of elongation factor Tu, a molecule implicated in protein synthesis, and PRDX3, involved in the stress response. All of these changes were validated using classical techniques and by using novel and precise selected reaction monitoring analysis and an RNA sequencing approach, with the total heart samples being increased to 24. This study provides key insights that enhance our understanding of the cellular mechanisms related to the pathophysiology of ICM and could lead to the development of aetiology-specific heart failure therapies. ATPA could serve as a molecular target suitable for new therapeutic interventions., (© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is a secreted glycoprotein that belongs to a group of transporters of small lipophilic molecules in circulation. LCN2 has been recently characterized as an adipose-derived cytokine. This adipokine is believed to bind small substances, such as steroids and lipopolysaccharides, and has been reported to have roles in the induction of apoptosis in hematopoietic cells, transport of fatty acids and iron, modulation of inflammation, and metabolic homeostasis. Recently, LCN2 has emerged as a useful biomarker and rheumatic diseases. This review provides an overview of LCN2 in inflammation, immunity, and metabolism.

Endocannabinoids has been described to be involved in articular degenerative disease by modulating nociception and immune system. However, the role of the endocannabinoid anandamide on chondrocyte cell viability is still unclear. Therefore, we decided to study anandamide's effects on chondrocytes viability and to evaluate its interactions with the catabolic factor TNF (tumor necrosis factor). Chondrocyte vitality was evaluated by MTT assay. We investigated LDH release, chromatin condensation, cleavage of focal adhesion kinase (FAK), and caspases-3, 8, and 9 activation. c-MYC mRNA levels were determined by RT-PCR. We studied by Western blot the activation patterns of AKT, AMPK, ERK, p38, and JNK kinases. Finally, we evaluate the effect of anandamide in TNF-induced caspase-3 cleavage. Anandamide decreased chondrocyte vitality independently of its receptors. It induced AMPK activation without LDH release. Anandamide induced chromatin condensation, activation of caspase-3, 8, and 9, and FAK cleavage. Surprisingly, despite anandamide inhibited cell proliferation, it increased c-MYC expression. Moreover anandamide inhibited AKT activation, whilst it induced a sustained activation of ERK, JNK, and p38. Finally, anandamide synergized with TNF-α in the cleavage of caspase-3. In conclusion, our findings suggest that anandamide, alone or in combination with TNF-α, may be a potential destructive agent in cartilage., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Introduction: Over the past 20 years, the idea that white adipose tissue (WAT) is simply an energy depot organ has been radically changed. Indeed, present understanding suggests WAT to be an endocrine organ capable of producing and secreting a wide variety of proteins termed adipokines. These adipokines appear to be relevant factors involved in a number of different functions, including metabolism, immune response, inflammation and bone metabolism., Areas Covered: In this review, the authors focus on the effects of several adipose tissue-derived factors in bone pathophysiology. They also consider how the modification of the adipokine network could potentially lead to promising treatment options for bone diseases., Expert Opinion: There are currently substantial developments being made in the understanding of the interplay between bone metabolism and the metabolic system. These insights could potentially lead to the development of new treatment strategies and interventions with the aim of successful outcomes in many people affected by bone disorders. Specifically, future research should look into the intimate mechanisms regulating peripheral and central activity of adipokines as it has potential for novel drug discovery.

Nesfatin-1 is a recently discovered satiety-inducing adipokine identified in hypothalamic regions that regulates energy balance. So far, no data exist on NUCB2/nesfatin-1 localization in human and murine chondrocytes. Here, we therefore investigated NUCB2/nesfatin-1 gene and protein expression in human and murine chondrocytes and the effect of nesfatin-1 on pro-inflammatory cytokines expression. Peptide localization was performed by laser confocal microscopy, NUCB2 mRNA expression was studied by RT-PCR and protein secretion was measured by XMap technology and Western blot analysis. First, we demonstrated cytoplasmic localization of NUCB2/nesfatin-1 peptide in both human and murine chondrocytes. We present evidence that both mRNA and protein expression of NUCB2 were increased during the differentiation of ATDC5 murine chondrocyte cell line. Furthermore, we demonstrated that nesfatin-1 induces IL-6 and MIP-1α mRNA expression and protein secretion in ATDC-5 cells challenged with IL-1, and also increases COX-2 mRNA expression in these cells. Finally, nesfatin-1 provoked a clear induction of pro-inflammatory agents, such as COX-2, IL-8, IL-6, and MIP-1α in human primary chondrocytes from OA patients., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

White adipose tissue is now recognized to be a multifactorial organ secreting several adipose-derived factors that have been collectively termed 'adipokines'. Adipokines are pleiotropic molecules that contribute to the so-called 'low-grade inflammatory state' of obese subjects creating a cluster of metabolic aberrations including autoimmune and inflammatory diseases that affect joints and bone. The aim of this review is to present knowledge about the role of adipokines in bone and cartilage function, as well as in inflammatory and degenerative joint disease. We discuss clinical implications and then survey attempts to exploit this role for therapeutic gain, which holds potential as a novel approach for drug development in bone and joint disease., (Copyright © 2013. Published by Elsevier Ltd.)

Inflammation is a complex mechanism of cell/tissue responses to injuries triggered by multiple causes, including trauma, pathogens or autoimmune abnormal responses. In the last years, a novel line of thought is emerging by giving a more holistic vision of chronic arthropathies through a recently identified group of molecules, called adipokines. Actually, most of these recently identified factors, produced prevalently by white adipose tissue but also by cells of the joints (chondrocytes and synovial fibroblasts) and immune cells, play a significant role in chronic inflammation. Adipokines dysregulation has emerged as a common characteristic of chronic inflammation in rheumatic diseases in particular when obesity or, more precisely, adipose tissue dysfunction is associated with common rheumatic diseases, such as osteoarthritis and rheumatoid arthritis. In this MiniReview, we discuss the role of adipokines in osteoarthritis and rheumatoid arthritis providing an updated overview of their pathophysiological role and potential use as therapeutic targets., (© 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.)

Lipocalin 2 (LCN2) has recently emerged as a novel adipokine involved in different processes including arthritis and chondrocyte inflammatory response. However, little is known about its activity on chondrocyte homeostasis and its regulation by nitric oxide (NO) Hence, we performed a set of experiments aimed to achieve a better understanding of this relationship. Cell vitality was tested in the ATDC5 cell line by the MTT colorimetric assay. Protein expression and gene expression was evaluated by Western blot and real time RT-PCR, respectively. NO production (determined as nitrite accumulation) was assayed by the Griess reaction. First, we demonstrated that LCN2 decreased murine chondrocytes vitality. Next, LCN2 co-stimulation with LPS enhanced NOS2 protein expression by murine chondrocytes. In addition, inhibition of LPS-induced nitric oxide production by aminoguanidine, a selective NOS2 inhibitor, significantly reduced LPS-mediated LCN2 expression. In contrast, treatment of murine chondrocytes with sodium nitroprussiate (SNP), a classic NO donor, scarcely induced LCN2 expression. Intriguingly, SNP addition to LPS-challenged chondrocytes, treated with aminoguanidine, provoked a strong induction of LCN2 expression. Finally, murine ATDC5 cells, co-cultured with LPS pre-challenged macrophages, had higher LCN2 expression in comparison with murine chondrocytes co-cultured with non pre-challenged macrophages. In this work we have described for the first time that NO is able to exert a control on LCN2 expression, suggesting the existence of a feedback loop regulating its expression., (Copyright © 2013 Orthopaedic Research Society.)

A large body of evidence from clinical and experimental studies is aiding to understand the close relationships between obesity and rheumatic diseases. For instance, it is generally accepted that obesity contributes to the development of osteoarthritis by increasing mechanical load of the joints, at least in weight bearing joints. However, besides mechanical effects, recent studies demonstrated that white adipose tissue is able to secrete a plethora of soluble factors, called adipokines, which have a critical role in the development and progression of some rheumatic diseases such as osteoarthritis and rheumatoid arthritis. In this article, we summarize the recent findings on the interaction of certain adipokines with the two most common rheumatic diseases: osteoarthritis and rheumatoid arthritis.

Aims: Given the relevance of degenerative joint diseases in our society, the development of a novel pharmacologic intervention is a critically important public health goal. Recently, oleocanthal, a polyphenolic natural compound from extra virgin olive oil, has emerged as a potential therapeutic weapon for the treatment of inflammatory degenerative diseases. The goal of this study was to further evaluate the anti-inflammatory activity of oleocanthal in murine macrophages J774 and murine chondrocytes ATDC5 with a particular focus on the inhibition of gene expression of pro-inflammatory factors such as MIP-1α and IL-6., Main Methods: ATDC5 murine chondrogenic cells and murine macrophages J774 were used. J774 macrophages were tested with different doses of oleocanthal and cell viability was evaluated using the MTT assay. Western blot analysis was carried on in J774 cells using anti NOS2 antibody. Nitrite accumulation was determined in culture supernatant using the Griess reaction. MIP-1α and IL-6 mRNA levels were determined using SYBR Green-based quantitative RT-PCR. MIP-1α and IL-6 protein levels were evaluated using specific ELISA assay. Several cytokines, involved in the inflammatory response, were also tested by BioPlex assay., Key Findings: First, oleocanthal inhibits LPS-induced NO production in J774 macrophages, without affecting cell viability. Moreover, it inhibits MIP-1α and IL-6 mRNA expression, as well as protein synthesis, in both ATDC5 chondrocytes and J774 macrophages. Oleocanthal also inhibits IL-1β, TNF-α and GM-CSF protein synthesis from LPS-stimulated macrophages., Significance: Our data confirm a clear potent role of oleocanthal as anti-inflammatory therapeutic agent for future treatment of arthritis or other inflammatory diseases., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To compare subthalamic nucleus (STN) to globus pallidus internus (GPi) deep brain stimulation (DBS) for control of motor fluctuations and for potential dyskinesia-suppressing qualities., Methods: We conducted a retrospective database review of all patients who underwent GPi or STN DBS for idiopathic Parkinson's disease. Direct dyskinesia suppression (dDS) was defined as improvement in dyskinesia subscore of the unified Parkinson's disease rating scale (UPDRS) part IV (items 32-34), despite lack of reduction in dopaminergic medication dosage. We analyzed the data using methods appropriate for a case-control study., Results: A total of 133 patients were evaluated. At the last evaluation Dyskinesia scores and motor fluctuations significantly improved in both the GPi (p < 0.0001) and STN groups (p < 0.0001). The GPi group was more likely than the STN group to experience dDS (odds ratio = 1.95, 95% CI = 0.556, 3.21). However, the association between DBS target and dDS was not statistically significant (Pearson chi-square = 2.286, p = 0.131)., Conclusions: The overall clinical outcome of STN and GPi DBS for control of dyskinesia and motor fluctuations was similar. STN and GPi DBS both had some direct dyskinesia suppression effects., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Apathy is a common neuropsychiatric feature of Parkinson's disease (PD), but little is known of relationships between apathy and specific medications in PD. Following a retrospective database and chart review of 181 Parkinson's patients, relationships between Apathy Scale scores and use of psychotropic and antiparkinsonian medications were examined with multiple regression. Controlling for age, sex, education, and depression, the use of selective serotonin reuptake inhibitors (SSRIs), but not other antidepressants, was associated with greater apathy. Use of monoamine oxidase B inhibitors was associated with less apathy. Longitudinal studies are needed to evaluate a potential SSRI-induced apathy syndrome in PD.

We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n=38) and DCM (n=27) patients, undergoing heart transplantation and control donors (n=6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p<0.05) and DCM (141%, p<0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p<0.05) and DCM (1.70-fold, p<0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p<0.0001), and it was increased in pathological hearts (p<0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p<0.05 and 131%, p<0.001) and DCM (56%, p<0.01 and 69%, p<0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p<0.001), perinucleolar chromatin (p<0.01) and dense fibrillar components (p<0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p<0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aims: The objectives of this study were to analyse the effect of heart failure (HF) on several proteins of nuclear pore complex (NPC) and their relationship with the human ventricular function., Methods and Results: A total of 88 human heart samples from ischemic (ICM, n = 52) and dilated (DCM, n = 36) patients undergoing heart transplant and control donors (CNT, n = 9) were analyzed by Western blot. Subcellular distribution of nucleoporins was analysed by fluorescence and immunocytochemistry. When we compared protein levels according to etiology, ICM showed significant higher levels of NDC1 (65%, p<0.0001), Nup160 (88%, p<0.0001) and Nup153 (137%, p = 0.004) than those of the CNT levels. Furthermore, DCM group showed significant differences for NDC1 (41%, p<0.0001), Nup160 (65%, p<0.0001), Nup153 (155%, p = 0.006) and Nup93 (88%, p<0.0001) compared with CNT. However, Nup155 and translocated promoter region (TPR) did not show significant differences in their levels in any etiology. Regarding the distribution of these proteins in cell nucleus, only NDC1 showed differences in HF. In addition, in the pathological group we obtained good relationship between the ventricular function parameters (LVEDD and LVESD) and Nup160 (r = -0382, p = 0.004; r = -0.290, p = 0.033; respectively)., Conclusions: This study shows alterations in specific proteins (NDC1, Nup160, Nup153 and Nup93) that compose NPC in ischaemic and dilated human heart. These changes, related to ventricular function, could be accompanied by alterations in the nucleocytoplasmic transport. Therefore, our findings may be the basis for a new approach to HF management.

Background and Objectives: The efficacy of posterior brachial plexus block for shoulder surgeries is demonstrated by different authors. However, there is no consensus on the ideal mass and volume of local anesthetic to be employed. The objetive of this study was to compare different volumes and masses of ropivacaine in posterior brachial plexus block in arthroscopic surgeries of the shoulder., Method: Sixty patients > 18 years, physical status ASA I and II, scheduled for unilateral arthroscopic surgeries of the shoulder were randomly placed in three groups: A (10 mL to 0.5%), B (20 mL to 0.5%), C (5 mL to 1%). The block was performed with a 22G needle of 100 mm connected to neurostimulator, in a point 3 cm lateral to the midpoint of C6 and C7 interspace, being injected the solution corresponding to each group. The postoperative pain was evaluated at the recovery room and within the first 24 hours of the postoperative period. The groups were compared on length of time until the first complaint of pain, visual numeric scale (VNS) score and morphine consumption within the first 24 hours., Results: There was no statistically significant difference between the three groups related to age, weight and height. There was no difference in length of time until the first complaint of pain, VNS scores over three and morphine consumption in the postoperative period between the groups., Conclusions: This study concluded that 5 mL of 1% ropivacaine promoted analgesic efficacy similar to 10 mL or 20 mL of 0.5% ropivacaine in the posterior brachial plexus block using neurostimulator., (Copyright © 2012 Elsevier Editora Ltda. All rights reserved.)

Patients with rheumatic diseases have an increased risk of mortality by cardiovascular events. In fact, several rheumatic diseases such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis are associated with a higher prevalence of cardiovascular diseases (CVDs). Although traditional cardiovascular risk factors have been involved in the pathogenesis of cardiovascular diseases in rheumatic patients, these alterations do not completely explain the enhanced cardiovascular risk in this population. Obesity and its pathologic alteration of fat mass and dysfunction, due to an altered pattern of secretion of proinflammatory adipokines, could be one of the links between cardiovascular and rheumatic diseases. Indeed, the incidence of CVDs is augmented in obese individuals with rheumatic disorders. Thus, in this paper we explore in detail the relationships among adipokines, rheumatic diseases, and cardiovascular complications by giving to the reader a holistic vision and several suggestions for future perspectives and potential clinical implications.

Background: Osteoarthritis (OA) and rheumatoid arthritis (RA), the most common rheumatic diseases, are characterized by irreversible degeneration of the joint tissues. There are several factors involved in the pathogenesis of these diseases including pro-inflammatory cytokines, adipokines and adhesion molecules., Objective: Up to now, the relationship between adipokines and adhesion molecules at cartilage level was not explored. Thus, the aim of this article was to study the effect of leptin and adiponectin on the expression of VCAM-1 in human and murine chondrocytes. For completeness, intracellular signal transduction pathway was also explored., Methods: VCAM-1 expression was assessed by quantitative RT-PCR and western blot analysis upon treatment with leptin, adiponectin and other pertinent reagents in cultured human primary chondrocytes. Signal transduction pathways have been explored by using specific pharmacological inhibitors in the adipokine-stimulated human primary chondrocytes and ATDC5 murine chondrocyte cell line., Results: Herein, we demonstrate, for the first time, that leptin and adiponectin increase VCAM-1 expression in human and murine chondrocytes. In addition, both adipokines have additive effect with IL-1β. Finally, we demonstrate that several kinases, including JAK2, PI3K and AMPK are at a play in the intracellular signalling of VCAM-1 induction., Conclusions: Taken together, our results suggest that leptin and adiponectin could perpetuate cartilage-degrading processes by inducing also factors responsible of leukocyte and monocyte infiltration at inflamed joints.

Until the identification of leptin, the first adipokine discovered in 1994, adipose tissue was considered only as an energy storage tissue. However, it is now clear that adipose tissue is an endocrine/paracrine/autocrine organ, which plays a relevant role in physiopathology of several inflammatory diseases. Actually, it is mainly involved not only in the low-grade inflammatory status in obesity but also in other relevant inflammatory conditions and autoimmune disorders. In this review article, we discuss the main biological activities of leptin, adiponectin, lipocalin-2, resistin, and visfatin, as well as their contributions to certain inflammatory conditions., (Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc.)

Deep brain stimulation (DBS) has become an important option for medication-refractory essential tremor (ET), but may contribute to worsened gait and falling. This study evaluates impaired gait in a cohort of patients treated with DBS with a retrospective review of ET patients before and after DBS implantation. Factors examined included: age, duration of symptoms, pre-morbid gait difficulties/falls, Fahn-Tolosa-Marin tremorrating scale (TRS) scores at baseline, 6 months post-unilateral DBS implantation, and 6 or 12 months post-bilateral implantation. All implantations targeted the nucleus ventralis intermediate (Vim). Thirty-eight patients (25 males, 13 females) were included. Twenty-five patients (65.8%) underwent unilateral DBS implantation and 13 (34.2%) bilateral. The mean age at surgery was 67.1 years ± 11.4 (range 34-81). The mean disease duration was 31 years ± 18.3 (range 6-67). Fifty-eight percent of patients had worsened gait post-operatively. Seventy percent of patients with unilateral Vim DBS experienced gait worsening while 55% of bilateral DBS patients experienced gait worsening. Patients with worsened gait post-DBS had higher baseline pre-operative TRS scores than those without worsened gait (43.1 points ± 8.4 vs. 33.1 points ± 10.1, p = 0.002) (odds ratio 2.5, p = 0.02). Gait/balance may worsen following DBS for medication refractory ET. Higher baseline TRS score may factor into these issues, although a larger prospective study will be required with a control population. The larger percentage of difficulties observed in unilateral versus bilateral cases likely reflected the bias not to proceed to second-sided surgery if gait/balance problems were encountered.

Purpose: We investigated whether the direct renin inhibitor aliskiren can affect metabolism in cardiomyocytes from rat, mouse and human sources., Methods and Results: At 10-50 μmol/L, aliskiren significantly increased medium-chain-fatty-acid uptake in primary-cultured neonatal-rat and HL-1 adult-mouse-derived cardiomyocytes (BODIPY-induced fluorescence intensity). The fatty-acid transporter CD-36 was correspondingly translocated to, but the glucose transporter Glut-4 away from, the sarcoplasmic reticulum/plasma membrane, in primary-cultured neonatal-rat (CD-36, Glut-4) and adult-human (CD-36) cardiomyocytes (confocal immunocytochemistry). Immunoblotting showed that aliskiren induced phosphorylation of ERK1/2 in cardiomyocytes from all three sources; responses were dose- and time-dependent, unaffected by renin treatment, and did not cause alterations in expression of (P)R or Igf2/M6P receptors. Microarray analysis of the complete genome of aliskiren-treated neonatal-rat cardiomyocytes, with RT-qPCR and immunoblot confirmation assays in rat and human primary cardiomyocytes, showed that aliskiren up-regulated mRNA and increased protein expression of several enzymes important in lipid and glucose metabolism and in cholesterol biosynthesis. Cardiomyocyte cell-cycle and viability were unaffected by aliskiren., Conclusions: Aliskiren can induce changes in fatty-acid and glucose uptake and expression of key enzymes of lipid and cholesterol metabolism, which are not associated with increased expression of (P)R or Igf2/M6P receptors, in cultured cardiomyocytes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Important advances in our understanding of the relationships between adipokines, inflammation and the immune response have been achieved in the past 10 years. White adipose tissue has emerged as a highly dynamic organ that releases a plethora of immune and inflammatory mediators that are involved in numerous diseases, including not only rheumatic diseases such as rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus, but also cardiovascular and metabolic complications that are frequently observed in rheumatic diseases. Our rapidly growing knowledge of adipokine biology is revealing the complexity of these amazing proteins, thereby redefining white adipose tissue as a key element of the inflammatory and immune response in rheumatic diseases. Adipokines exert potent modulatory actions on target tissues and cells involved in rheumatic disease, including cartilage, synovium, bone and various immune cells. In this Review, we describe the most recent advances in adipokine research in the context of rheumatic diseases, focusing primarily on leptin, adiponectin, visfatin and resistin, and also the potential role of newly identified adipokines such as chemerin, lipocalin 2 and serum amyloid A3.

Background: Obesity is a major risk factor for a plethora of diseases including joint disorders associated with cartilage destruction. Recently, it has been demonstrated that adipose tissue might contribute to degenerative joint diseases via the secretion of potent bioactive molecules termed adipokines., Objective: To study expression of the novel adipokines chemerin, lipocalin 2 (LCN2) and serum amyloid A3 (SAA3) in murine and human chondrocytes, under basal conditions, in response to a range of biological and pharmacological treatments, and during chondrocyte differentiation., Methods: Chemerin, LCN2 and SAA3 mRNA and protein expression were evaluated by quantitative real-time reverse transcription PCR and western blot analysis, respectively, in the ATDC-5 murine chondrocyte cell line, a human immortalised chondrocyte cell line (T/C-28a2) and primary cultured human chondrocytes., Results: Human and murine chondrocytes expressed chemerin, LCN2 and SAA3 mRNA; interleukin (IL)-1β was a potent inducer of these novel adipokines. Moreover, dexamethasone, lipopolysaccharides (LPS) and other relevant adipokines such as leptin and adiponectin were able to modulate chemerin, LCN2 and SAA3 mRNA expression alone and when coadministered. Intracellular signal transducers involved in the IL-1β-mediated upregulation of LCN2 and SAA3 included Janus kinase (JAK) 2, phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein (MAP) kinases. Finally, expression of chemerin, LCN2 and SAA3 mRNA expression were modulated throughout chondrocyte differentiation., Conclusion: Chemerin, LCN2 and SAA3 are implicated in chondrocyte pathophysiology, and regulated by other relevant factors that drive inflammatory process such as IL-1β, LPS and adipokines including leptin and adiponectin. It seems likely that JAK2, PI3K and MAP kinases are involved in mediating these responses.

The cloning of leptin in 1994 by Zhang et al. introduced a novel concept about white adipose tissue (WAT) as a very dynamic organ that releases a plethora of immune and inflammatory mediators, such as adipokines and cytokines, which are involved in multiple diseases. Actually, adipokines exert potent modulatory actions on target tissues involved in rheumatic diseases including cartilage, synovial, bone and immune cells. The goal of this paper is to elucidate the recent findings concerning the involvement of adipokines in rheumatic diseases, such as rheumatoid arthritis (RA), osteoarthritis (OA), and systemic lupus erythematosus (SLE).

White adipose tissue is currently considered to be an active endocrine organ that secretes a plethora of factors named adipokines, most of them proinflammatory in nature, which probably contribute to low-level systemic inflammation; a state that is often present in metabolic syndrome-associated chronic pathologies such as obesity and atherosclerosis. Leptin is historically and indisputably one of the most important adipokines secreted by fat cells, with a variety of physiological roles related to the control of metabolism, energy homeostasis and inflammatory response. One of these functions is the connection between nutritional status and immune competence. Indeed, leptin has been shown to modulate both the innate and adaptive immune responses in both normal and pathological conditions. It has been shown that conditions characterized by low leptin levels are associated with increased susceptibility to infection. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with increased secretion of leptin and the production of proinflammatory pathogenic cytokines. Thus, leptin can easily be considered a frank mediator of the inflammatory/immune response.

The current study aimed to compare the effects of the peptide hormone ghrelin and des-G, its unacylated isoform, on glucose and fatty acid uptake and to identify des-G-specific binding sites in cardiomyocytes. In the murine HL-1 adult cardiomyocyte line, ghrelin and des-G had opposing metabolic effects: des-G increased medium-chain fatty acid uptake (BODIPY fluorescence intensity), whereas neither ghrelin alone nor in combination with des-G did so. Ghrelin inhibited the increase in glucose uptake normally induced by insulin (rate of 2-[(3)H]deoxy-d-glucose incorporation), but des-G did not; des-G was also able to partially reverse the inhibitory effect of ghrelin. In HL-1 cells and primary cultures of neonatal rat cardiomyocytes, des-G but not ghrelin increased insulin-induced translocation of glucose transporter-4 from nuclear to cytoplasmic compartments (immunohistochemistry and quantitative confocal analysis). AKT was phosphorylated by insulin but not affected by ghrelin or des-G, whereas neither AMP-activated protein kinase nor phosphatase and tensin homolog deleted from chromosome 10 was phosphorylated by any treatments. HL-1 and primary-cultured mouse and rat cardiomyocytes each possessed two independent specific binding sites for des-G not recognized by ghrelin (radioreceptor assays). Neither ghrelin nor des-G affected viability (dimethylthiazol diphenyltetrazolium bromide assays), whereas both isoforms were equally protective against apoptosis. Therefore, in cardiomyocytes, des-G binds to specific receptors and has effects on glucose and medium-chain fatty acid uptake that are distinct from those of ghrelin. Real-time PCR indicated that expression levels of ghrelin O-acyltransferase RNA were comparable between HL-1 cells, human myocardial tissue, and human and murine stomach tissue, indicating the possibility of des-G conversion to ghrelin within our model.

In the mid-1990s, interest in adipose tissue - until then generally regarded as a mere energy reserve - was revived by the discovery of leptin. Since then numerous other cytokine-like hormones have been isolated from white adipose tissue. These adipokines have been investigated in relation to obesity, metabolic syndrome, insulin resistance and other pathological conditions and processes. In addition, it is now established that adipokines play a role in the maintenance of an inflammatory state in adipose tissue and in the development of obesity and comorbidities. The contributions of individual adipokines in the pathophysiological features of obesity have yet to be determined in full, but recent data highlight important roles for adipokines in lipid metabolism.

The discovery of leptin in 1994 marked the beginning of a new understanding about white adipose tissue (WAT) and modified a static vision of this tissue which was viewed up to the end of the 20th century as an inert tissue, devoted to body protection from heat loss and to passively storing energy. The identification of the product of the gene obese accentuated the role of adipose tissue in the physiopathology of obesity-linked diseases, and led to the discovery of various adipokines, many of a pro-inflammatory nature. It has become progressively manifest that WAT-derived adipokines can now be considered as the fulcrum between obesity-related environmental causes, such as nutrition and lifestyle, and the biochemical shifts that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. Herein, we review recent adipokine research, with particular emphasis to the role of leptin, adiponectin, resistin, and visfatin in chondrocyte function and skeleton, as well as in inflammatory and degenerative cartilage joint diseases.

Background/aims: The functional roles of endogenous Notch3 and Notch1 for protecting human hepatocellular carcinoma (HCC) lines against doxorubicin-induced death have been investigated. We previously reported aberrant Notch3 and Notch4 up-regulation in HCC and we have extended these observations to include Notch1., Methods: Notch1 expression was assessed by immunohistochemistry and immunoblotting. Notch3 and Notch1 expression were ablated in multiple HCC lines by stable retroviral transduction of short hairpin RNAs (shRNAs). Effects on doxorubicin sensitivity were evaluated with respect to cell growth, expression of specific cell cycle effectors and multiple apoptotic parameters., Results: Notch3 depletion increased p53 expression, doxorubicin uptake, DNA damage, the apoptosis inducing effects of doxorubicin and also impeded the cell cycle progression of HCC cells. Ablating p53 expression in Notch3 knockdown (KD) cells largely abolished their enhanced doxorubicin sensitivity; and Notch3 KD in p53(-/-) Hep3B cells failed to influence their response to doxorubicin. Although up-regulated in most HCC, Notch1 (unlike Notch3) did not contribute to the doxorubicin resistance of HCC lines., Conclusions: Our in vitro results represent the first evidence that Notch3 silencing in combination with chemotherapeutics could conceivably provide a novel strategy for HCC treatment that deserves further exploration.

Background: Obesity is the major cause of type 2 diabetes. In the mid 1990s interest in adipose tissue was revived by the discovery of leptin. The association of obesity and diabetes emphasizes their shared physiopathological features. At the end of the 1990s, ghrelin, a potent gastric orexigenic factor, was found to be involved in obesity. Leptin and ghrelin have opposite actions in several tissues including the regulation of feeding in the brain., Objective/methods: To survey the role of leptin and ghrelin in glucose metabolism. We summarize the current state of research and discuss the roles of ghrelin and leptin in glucose homeostases and the potential application of drugs targeting leptin and ghrelin signalling to prevent and treat diabetes., Results/conclusions: A pressing challenge is to determine how leptin, ghrelin and other adipokines or gastric factors are involved in metabolic disorders. Answering these questions will require the development of new pharmacological tools that target specific adipokine systems. Hopefully, new therapeutic targets will be identified.

Scientific interest in the biology of white adipose tissue (WAT) has increased since the discovery of leptin in 1994. The description of the effects of leptin, the product of the ob gene, has started to clarify the role of adipose tissue in the physiopathology of obesity related diseases and has helped in the identification of a great number of other molecules (named adipocytokines), some of them with a proinflammatory nature. In rheumatic diseases, adipocytokines derived from the WAT are among the most important factors related to obesity and promote inflammatory and/or autoimmune conditions. In this review we will present the most recent advances in adipocytokine research, with special attention to the role of leptin, adiponectin, resistin and visfatin and inflammatory, autoimmune and rheumatic diseases., (Copyright © 2008 Elsevier España, S.L. All rights reserved.)

Background and Objectives: Arthroscopic shoulder surgeries are associated with severe postoperative pain. Among the analgesic techniques available, brachial plexus block has the best results. The objective of this study was to determine which concentration of local analgesic used in the posterior brachial plexus block provides longer postoperative analgesia., Methods: Ninety patients undergoing posterior brachial plexus block were randomly divided into three groups of 30 patients each. Group 1: 20 mL of 0.5% ropivacaine; Group 2: 20 mL of 0.75% ropivacaine; and Group 3: 20 mL of 1% ropivacaine. The blockade was evaluated by assessing the thermal sensitivity using a cotton pad with alcohol and postoperative pain was evaluated according to a Verbal Numeric Scale (VNS) in the first 48 hours., Results: Postoperative analgesia was similar in all three groups according to the parameters evaluated: mean VNS, time until the first complaint of pain, and postoperative opioid consumption., Conclusions: This study demonstrated that posterior brachial plexus block provides effective analgesia for shoulder surgeries. Twenty milliliters of ropivacaine in the different concentrations used in this study promoted similar analgesia.

The acyltransferase that catalyzes ghrelin octanoylation has recently been identified as ghrelin O-acyltransferase (GOAT). GOAT belongs to a family of membrane-bound O-acyltransferases (MBOATs). GOAT covalently links a medium fatty-acid chain, typically octanoate, to the hydroxyl group of the third serine of ghrelin, a potent orexigenic peptide characterized by this unique post-translational modification. The discovery of GOAT raises important questions and reveals several therapeutical possibilities. Indeed, drugs that inhibit GOAT might be able to prevent diet-induced obesity and might be an effective therapy for type-2 diabetes, increasing insulin secretion and enhancing peripheral insulin sensitivity. Furthermore, research on GOAT is providing new insights into the pathophysiology of energy homeostasis and might lead to the identification of further therapeutic targets. Here, we review what is currently known about the regulatory role of GOAT and discuss the potential of this novel approach for treating obesity and type-2 diabetes.

Leptin, a 16 kDa non-glycosylated polypeptide produced primarily by adipocytes and released into the systemic circulation, exerts a multitude of regulatory functions including energy utilization and storage, regulation of various endocrine axes, bone metabolism, and thermoregulation. In addition to leptin's best known role as regulator of energy homeostasis, several studies indicate that leptin plays a pivotal role in immune and inflammatory response. Because of its dual nature as a hormone and cytokine, leptin can be nowadays considered the link between neuroendocrine and immune system. The increase in leptin production that occurs during infections and inflammatory processes strongly suggests that this adipokine is a part of the cytokines network which governs inflammatory/immune response and host defence mechanisms. Indeed, leptin plays a relevant role in inflammatory processes involving either innate or adaptive immune responses. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as encephalomyelitis, type I diabetes, bowel inflammation and also articular degenerative diseases such as rheumatoid arthritis and osteoarthritis. Although the mechanisms by which leptin exerts its action as modulator of inflammatory/immune response are likely to be more complex than predicted and far to be completely depicted, there is a general consensus about its pivotal role as pro-inflammatory and immune-modulating agent. Here, we review the most recent advances on leptin biology with a particular attention to its adipokine facet, even though its role as metabolic hormone will be also addressed.

The scientific interest in the biology of white adipose tissue (WAT) has increased since the discovery of leptin in 1994. The description of the product of the gene obese (ob) demonstrated the role of adipose tissue in the physiopathology of obesity-related diseases, and helped to increase the identification of numerous other adipokines, many of a pro-inflammatory nature. It has become increasingly evident that WAT-derived adipokines can be considered as a hub between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. In this Review, we will discuss the progress in adipokine research, focusing particular attention to the roles of leptin, adiponectin, resistin, visfatin, and other recently identified adipokines in inflammatory, autoimmune and rheumatic diseases.

Interest in the biology of white adipose tissue has increased dramatically since the discovery of leptin in 1994. The identification of the product of the gene obese (ob) threw light on the role of adipose tissue in the physiopathology of obesity-related diseases and spurred the identification of numerous other adipokines, many of a proinflammatory nature. It has become increasingly evident that white adipose tissue-derived cytokines mediate between obesity-related exogenous factors (nutrition and lifestyle) and the molecular events that lead to metabolic syndrome, inflammation, and cardiovascular diseases. Here we review recent adipokine research, with particular attention to the roles of adiponectin, leptin, resistin, visfatin, apelin, omentin, and chemerin in such conditions.

In a previous study, we established that leptin acts synergistically with interferon-gamma in inducing nitric oxide synthase type II in cultured chondrocytes via Janus kinase-2 activation. However, the exact molecular mechanism that accounts for this synergism is not completely understood. The aim of the present study was to further delineate the signalling pathway used by leptin/interferon-gamma in the nitric oxide synthase type II induction in chondrocytes. Consequently, the roles of PI-3 kinase, MEK1 and p38 kinase were investigated using specific pharmacological inhibitors (Wortmannin, LY 294002, PD 098,059 and SB 203580). For this purpose, the amount of stable nitrite, the end product of NO generation by activated chondrocytes, has been evaluated by Griess colorimetric reaction in culture medium of human primary chondrocytes and in the murine ATDC5 cell line stimulated with leptin (400 nM) and interferon-gamma (1 ng/ml), alone or in combination. Specific inhibitors for PI-3K, MEK1 and p38 were added 1 h before stimulation. Nitric oxide synthase type II mRNA was investigated by real-time RT-PCR and NOS type II protein expression has been evaluated by western blot analysis. Our results showed that, as expected, leptin synergizes with IFN-gamma in inducing NO accumulation in the supernatant of co-stimulated cells. Pre-treatment with Wortmannin, LY 294002, PD 098,059 and SB 203580 caused a significant decrease in nitrite production, NOS type II protein expression and NOS type II mRNA expression induced by leptin and interferon-gamma co-stimulation. These findings were confirmed in 15 and 21-day differentiated ATDC5 cells, and in normal human primary chondrocytes. This is the first report showing that NOS type II induction triggered by co-stimulation with leptin and interferon-gamma is mediated by a signaling pathway involving PI-3K, MEK1 and p38.

Background and Objectives: Arthroscopic surgeries of the shoulder are accompanied by severe postoperative pain. Among the analgesic techniques, brachial plexus block offers the best results. The objective of this study was to determine which volume of local anesthetic in the posterior brachial plexus block offers more adequate analgesia for those procedures., Methods: Ninety patients undergoing posterior brachial plexus block were randomly divided in three groups of 30 patients: Group 1 volume of 20 mL; Groups 2 volume of 30 mL; Group 3 volume of 40 mL. In all groups 0.375% ropivacaine was the anesthetic used. The blockade was evaluated by testing thermal sensitivity using a cotton ball embedded in alcohol, while postoperative pain was evaluated according to a verbal numeric scale (VNS) in the first 24 hours., Results: Postoperative analgesia was similar in all three groups according to the parameters evaluated: VNS of moderate pain, length of time until the first complaint of pain, and consumption of opioids. Consumption of non-opioid analgesics was greater in the 20 mL group after the 12th postoperative hour. In the 30 and 40 mL groups, the extension of the blockade was significantly greater., Conclusions: This study demonstrated that posterior brachial block promotes effective analgesia for surgeries of the shoulder. The three different volumes studied promoted similar analgesia. The greater extension of the blockade with larger doses did not translate into better analgesia.

Interest in the biology of white adipose tissue (WAT) has increased dramatically since the discovery of leptin in 1994. The identification of the product of the gene obese (ob) threw light on the role of adipose tissue in the physiopathology of obesity-related diseases, and spurred the identification of numerous other adipokines, many of a pro-inflammatory nature. It has become increasingly evident that WAT-derived cytokines mediate between obesity-related exogenous factors (nutrition and lifestyle) and the molecular events that lead to metabolic syndrome and inflammatory and/or autoimmune conditions. Here, we review recent adipokine research, with particular attention to the roles of leptin, adiponectin, resistin, visfatin, apelin, vaspin and hepcidin in such conditions.

Introduction and Objectives: The high level of metabolic activity present in visceral adipose tissue is associated with the development of atherothrombosis. Subcutaneous adipose tissue secretes larger quantities of the adipocytokines leptin and adiponectin than visceral adipose tissue. Epicardial adipose tissue secretes inflammatory mediators, and the resulting proinflammatory activity is greater than that associated with subcutaneous adipose tissue. The aim of this study was to compare adiponectin and leptin expression in human epicardial and subcutaneous adipose tissue., Methods: Samples of both epicardial and subcutaneous adipose tissue were taken from 46 patients who were undergoing heart surgery, coronary artery bypass surgery, or aortic or mitral valve replacement. Levels of protein and gene expression of leptin and adiponectin were assessed immunohistochemically and by RT-PCR, respectively. Levels of mRNA expression in the 2 adipose tissue types were compared by real-time quantitative PCR., Results: Significant differences were found between adiponectin and leptin mRNA expression in epicardial and subcutaneous adipose tissue, with epicardial adipose tissue exhibiting lower levels of adiponectin and leptin expression. Moreover, adiponectin and leptin mRNA expression in epicardial adipose tissue was higher in women than men., Conclusions: Adiponectin and leptin expression is lower in epicardial than in subcutaneous adipose tissue. Moreover, there are differences in adiponectin and leptin expression in epicardial adipose tissue between women and men.