Challenges in the Development of Biological Approaches for the Treatment of Degenerative Disc Disease.

There are numerous innovative and promising approaches aimed at slowing, reversing, or healing degenerative disc disease. However, multiple treatment-specific impediments slow progress toward realizing the benefits of these therapies. First, the exact pathophysiology underlying degenerative disc disease remains complicated and challenging to study. In addition, the study of the spine and intervertebral disc in animal models is difficult to translate to humans, hindering the utility of preclinical research. Biological treatments are subject to the complex biomechanical environment in which native discs degenerate. The regulatory approval environment for these therapeutics will likely involve a high degree of scrutiny. Finally, patient selection and assessment of outcomes are a particular challenge in this clinical setting.

La influencia de las condiciones meteorológicas ambientales en la mortalidad por suicidio en la provincia de Córdoba / Influence of meteorological conditions on suicide rate in the province of Córdoba

INTRODUCCIÓN: La mortalidad por suicidio se ha incrementado en las últimas décadas. Existen múltiples factores que influyen en el riesgo de la conducta suicida (biológicos, cognitivos y relacionados con la personalidad) que pueden interactuar con los cambios meteorológicos ambientales. El objetivo del estudio fue conocer cómo influyen ciertas variables meteorológicas (temperatura, racha de viento y precipitaciones) en las muertes por suicidio en la provincia de Córdoba durante un período temporal concreto. MATERIAL Y MÉTODOS: Mediante un estudio observacional, analítico y retrospectivo se recogieron un total de 100 suicidios registrados en el Instituto de Medicina Legal y Ciencias Forenses de Córdoba, recopilando variables sociodemográficas, antecedentes patológicos, factores relacionados con el suicidio y variables meteorológicas obtenidas de la web de la Agencia Estatal de Meteorología. RESULTADOS: Se obtuvo significación estadística en cuanto al sexo y su relación con la racha de viento; demostrando asociación con rachas mayores de viento en suicidios de mujeres con respecto al de hombres (p = 0,043). Se observó también una asociación entre el sexo y las estaciones del año (p = 0,042) concluyendo que las mujeres cometen suicidios con más frecuencia durante la primavera (45,8%), mientras que los hombres llevan a cabo el acto suicida preferentemente durante el otoño (28,9%). CONCLUSIONES: Nuestro estudio indica que los suicidios se ven influenciados por las variables meteorológicas; en concreto aporta ciertas novedades en cuanto a la influencia de la velocidad de la racha de viento y el patrón estacional con el sexo

INTRODUCTION: Suicide mortality has increased in recent decades. There are multiple factors influencing the risk of suicidal behaviour (biological, cognitive and personality-related factors) that could interact with seasonal changes. The aim was to determine how certain meteorological factors (temperature, wind and rainfall) influenced suicides in the province of Córdoba committed over a specific time period. MATERIAL AND METHODS: A total of 100 suicides registered in the Institute of Legal Medicine of Forensic Sciences of the province of Córdoba were collected through an observational, analytical and retrospective study. We recorded sociodemographic variables, pathological background, factors related to suicide and meteorological variables according to the website of the State Meteorological Agency. RESULTS: Statistical significance was obtained regarding sex and its relationship with wind; showing an association of women's suicides with higher wind speed in comparison to men (P=.043). An association was also observed between sex and the seasons of the year (P=.042) concluding that women commit suicide more frequently during the spring (45.8%), while men commit suicide more often the autumn (28.9%). CONCLUSIONS: Our study suggests that suicides are influenced by meteorological variables; in particular it offers some new insights in relation to the influence of wind speed and seasonality according to sex

Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease.

Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-ß, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.

Healthy active older adults have enhanced K+ channel-dependent endothelial vasodilatory mechanisms.

Microvascular endothelial dysfunction, a precursor to atherosclerotic cardiovascular disease, increases with aging. Endothelium-derived hyperpolarizing factors (EDHFs), which act through K+ channels, regulate blood flow and are important to vascular health. It is unclear how EDHFs change with healthy aging. To evaluate microvascular endothelial reliance on K+ channel-mediated dilation as a function of age in healthy humans. Microvascular function was assessed using intradermal microdialysis in healthy younger (Y; n = 7; 3 M/4 W; 26 ± 1 yr) and older adults (O; n = 12; 5 M/7 W; 64 ± 2 yr) matched for V̇o2peak (Y: 39.0 ± 3.8, O: 37.6 ± 3.1 mL·kg-1·min-1). Participants underwent graded local infusions of: the K+ channel activator Na2S (10-6 to 10-1 M), acetylcholine (ACh, 10-10 to 10-1 M), ACh + the K+ channel inhibitor tetraethylammonium (TEA; 25 or 50 mM), and ACh + the nitric oxide synthase-inhibitor l-NAME (15 mM). Red blood cell flux was measured with laser-Doppler flowmetry and used to calculate cutaneous vascular conductance (CVC; flux/mean arterial pressure) as a percentage of each site-specific maximum (%CVCmax, 43°C+28 mM sodium nitroprusside). The %CVCmax response to Na2S was higher in older adults (mean, O: 51.7 ± 3.9% vs. Y: 36.1 ± 5.3%; P = 0.03). %CVCmax was lower in the ACh+TEA vs. the ACh site starting at 10-5 M (ACh: 34.0 ± 5.7% vs. ACh+TEA: 19.4 ± 4.5%; P = 0.002) in older and at 10-4 M (ACh: 54.5 ± 9.4% vs. ACh+TEA: 31.2 ± 6.7%; P = 0.0002) in younger adults. %CVCmax was lower in the ACh+l-NAME vs. the ACh site in both groups starting at 10-4 M ACh (Y: P < 0.001; O: P = 0.02). Healthy active older adults have enhanced K+ channel-dependent endothelial vasodilatory mechanisms, suggesting increased responsiveness to EDHFs with age.

DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation.

Recognizing the importance of leukocyte trafficking in inflammation led to some therapeutic breakthroughs. However, many inflammatory pathologies remain without specific therapy. This review discusses leukocytes in the context of sterile inflammation, a process caused by sterile (non-microbial) molecules, comprising damage-associated molecular patterns (DAMPs). DAMPs bind specific receptors to activate inflammation and start a highly optimized sequence of immune cell recruitment of neutrophils and monocytes to initiate effective tissue repair. When DAMPs are cleared, the recruited leukocytes change from a proinflammatory to a reparative program, a switch that is locally supervised by invariant natural killer T cells. In addition, neutrophils exit the inflammatory site and reverse transmigrate back to the bloodstream. Inflammation persists when the program switch or reverse transmigration fails, or when the coordinated leukocyte effort cannot clear the immunostimulatory molecules. The latter causes inappropriate leukocyte activation, a driver of many pathologies associated with poor lifestyle choices. We discuss lifestyle-associated inflammatory diseases and their corresponding immunostimulatory lifestyle-associated molecular patterns (LAMPs) and distinguish them from DAMPs.

Chronic ethanol consumption enhances inducible endothelium-dependent hyperpolarizing factor-mediated relaxation in the rat artery.

The inducible endothelium-dependent hyperpolarizing factor (iEDHF) pathway is activated as a compensatory response to adverse changes in the body. It causes vasorelaxation and maintains circulatory homeostasis in the organs. Small to moderate quantities of ethanol enhance vascular relaxation. However, its mechanism and the involvement of the iEDHF pathway in this process are unknown. Therefore, we studied iEDHF-mediated, acetylcholine-induced, endothelium-dependent relaxation in the superior mesenteric arteries (SMAs) of rats chronically fed ethanol. Rats were administered a standard diet (S-Control group), Lieber's control diet (L-Control group), or Lieber's ethanol diet (EtOH group). SMA relaxation was assessed by isometric tension measurements. Arachidonate 15-lipoxygenase (ALOX15) and soluble epoxide hydrolase (sEH) were determined by immunoblot. Acetylcholine-induced, endothelium-dependent relaxation was significantly greater in the EtOH than the control groups. These differences persisted after PGI2 and NO blockade. Thus, the increase in acetylcholine-induced relaxation was EDHF-mediated. In the EtOH group, however, it was prevented by iEDHF inhibitors. ALOX15 and sEH protein expression levels were higher in the EtOH than the L-Control group. The increase in acetylcholine-induced relaxation by chronic ethanol consumption was mediated by the iEDHF pathway. This mechanism may compensate for the blood pressure elevation induced by ethanol. This study suggests that iEDHF is induced during proper drinking and may help prevent the onset of cardiovascular conditions.

Direct Impairment of the Endothelial Function by Acute Indoxyl Sulfate through Declined Nitric Oxide and Not Endothelium-Derived Hyperpolarizing Factor or Vasodilator Prostaglandins in the Rat Superior Mesenteric Artery.

Upon stimulation, endothelial cells release various factors to regulate the vascular tone. In particular, vasorelaxing factors, called endothelium-derived relaxing factors (EDRFs), are altered in the production and/or release, as well as their signaling every vessel and under pathophysiological states, including cardiovascular, kidney, and metabolic diseases. Although indoxyl sulfate is known as a protein-bound uremic toxin and circulating levels are elevated in the impaired kidney functions, direct impact on the vascular function, especially EDRF's signaling, remains unclear. In this study, we hypothesize that acute exposure to indoxyl sulfate could alter vascular relaxation in the rat superior mesenteric artery. Accordingly, we measured acetylcholine (ACh)-induced endothelium-dependent relaxation in the absence and presence of several inhibitors to divide into each EDRF, including nitric oxide (NO), vasodilator prostaglandins (PGs), and endothelium-derived hyperpolarizing factor (EDHF). Indoxyl sulfate reduced the sensitivity to ACh but not sodium nitroprusside. Under cyclooxygenase (COX) inhibition or inhibitions of COX plus source of EDHF, such as small (SKCa)- and intermediate (IKCa)-conductance calcium-activated K+ channels, the decreased sensitivity to ACh in indoxyl sulfate exposed vessel was still preserved. However, under inhibition of NO synthase (NOS) or inhibitions of NOS and COX, the difference of sensitivity to ACh between vehicle and indoxyl sulfate was eliminated. These findings indicated that acute exposure of indoxyl sulfate in the rat superior mesenteric artery specifically explicitly impaired NO signaling but not EDHF or vasodilator PGs.

Using biological factors to individualize interventions for youth with conduct problems: Current state and ethical issues.

A growing body of evidence suggests that biological factors such as genes, hormone levels, brain structure, and brain functioning influence the development and trajectory of conduct problems in youth. In addition, biological factors affect how individuals respond to the environment, including how individuals respond to programs designed to prevent or treat conduct problems. Programs designed to reduce behavior problems in youth would have the greatest impact if they were targeted toward youth who need it the most (e.g., who are mostly likely to demonstrate persistent behavior problems) as well as youth who may benefit the most from the program. Biological information may improve our ability to make decisions about which type or level of intervention is best for a particular child, thus maximizing overall effectiveness, but it also raises a number of ethical concerns. These include the idea that we may be providing fewer services to some youth based on biological factors, and that information about biological risk could potentially lead to discrimination or labeling. In this article, I discuss the risks and benefits of using biological information to individualize interventions for youth with conduct problems.

Paraoxonase 1 in endothelial cells impairs vasodilation induced by arachidonic acid lactone metabolite.

INTRODUCTION: Paraoxonase 1 (PON1) is a high density lipoprotein (HDL)-associated lactonase, which is known for its antiatherogenic properties. Previous studies in PON1 knockout (PON1KO) mice revealed that PON1KO mice have low blood pressure, which is inversely correlated with the renal levels of the cytochrome P450 -derived arachidonic acid metabolite 5,6-epoxyeicosatrienoic acid (5,6-EET). Our previous studies revealed that 5,6-EET is unstable, transforming to the δ-lactone isomer 5,6-δ-DHTL, an endothelium-derived hyperpolarizing factor (EDHF) that mediates vasodilation, and it is a potential substrate for PON1. AIM: To elucidate the role of PON1 in the modulation of vascular resistance via the regulation of the lactone-containing metabolite 5,6-δ-DHTL. RESULTS: In mouse resistance arteries, PON1 was found to be present and active in the endothelial layer. Vascular reactivity experiments revealed that 5,6-δ-DHTL dose-dependently dilates PON1KO mouse mesenteric arteries significantly more than wild type (w.t.) resistance arteries. Pre-incubation with HDL or rePON1 reduced 5,6-δ-DHTL-dependent vasodilation. FACS analyses and confocal microscopy experiments revealed that fluorescence-tagged rePON1 penetrates into human endothelial cells' (ECs') in both dose- and time- dependent manner, accumulate in the perinuclear compartment, and retains its lactonase activity in the cells. The presence of rePON1, but not the presence of PON1 loss-of-lactonase-activity mutant, reduced the Ca2+ influx in the ECs mediated by 5,6-δ-DHTL. CONCLUSION: PON1 lactonase activity in the endothelium affects vascular dilation by regulating Ca2+ influx mediated by the lactone-containing EDHF 5,6-δ-DHTL.

Endothelial dysfunction in renal arcuate arteries of obese Zucker rats: The roles of nitric oxide, endothelium-derived hyperpolarizing factors, and calcium-activated K+ channels.

The roles of nitric oxide (NO), endothelium-derived hyperpolarizing factors (EDHF), and calcium-activated K+ (KCa) channels in diabetes-associated endothelial dysfunction of small renal arteries are not clear. The present study investigated acetylcholine (ACh)-induced vasorelaxation of renal arcuate arteries from obese Zucker (OZ) rats at different diabetes durations, and the relative contribution of NO, EDHF, and KCa channels to the endothelial dysfunction. OZ rats of 7 weeks (prediabetic stage), 12 weeks (early diabetic stage), and 20 weeks (late diabetic stage), and time-matched lean control rats, were studied. Segments of arcuate arteries (130 to 180 µm) were isolated, cannulated and pressurized. Vascular endothelial functions were tested using ACh-induced vasodilation. Our experiments demonstrated: (1) ACh-elicited vasodilation was impaired in OZ rats of 20 weeks, but not in rats of 7 and 12 weeks; (2) inhibition of NO or EDHF (contributed by epoxyeicosatrienoic acids [EETs]) production significantly decreased ACh-induced vasodilation in both lean and OZ rats of 20 weeks. The reduction of ACh-induced vasodilation by inhibition of NO or EDHF formation was less in OZ rats, as compared to lean rats; and (3) inhibition of KCa channels markedly reduced ACh-induced vasodilation in lean control rats, but not in OZ rats of 20 weeks. Our observations indicated that endothelium-dependent vasodilation in renal arcuate arteries is impaired in diabetes mellitus; NO and EDHF, mainly EETs, dominate the ACh-induced vasodilation in renal arcuate arteries; the contribution of NO and EETs is impaired in diabetic rats; KCa channels are involved in ACh-induced vasodilation; and the activity of KCa channels is downregulated in diabetes mellitus.

Hyperandrogenemia reduces endothelium-derived hyperpolarizing factor-mediated relaxation in mesenteric artery of female rats.

Women with polycystic ovary syndrome (PCOS) are often presented with hyperandrogenemia along with vascular dysfunction and elevated blood pressure. In animal models of PCOS, anti-androgen treatment decreased blood pressure, indicating a key role for androgens in the development of hypertension. However, the underlying androgen-mediated mechanism that contributes to increased blood pressure is not known. This study determined whether elevated androgens affect endothelium-derived hyperpolarizing factor (EDHF)-mediated vascular relaxation responses through alteration in function of gap junctional proteins. Female rats were implanted with placebo or dihydrotestosterone (DHT) pellets (7.5 mg, 90-day release). After 12 weeks of DHT exposure, blood pressure was assessed through carotid arterial catheter and endothelium-dependent mesenteric arterial EDHF relaxation using wire myograph. Connexin expression in mesenteric arteries was also examined. Elevated DHT significantly increased mean arterial pressure and decreased endothelium-dependent EDHF-mediated acetylcholine relaxation. Inhibition of Cx40 did not have any effect, while inhibition of Cx37 decreased EDHF relaxation to a similar magnitude in both controls and DHT females. On the other hand, inhibition of Cx43 significantly attenuated EDHF relaxation in mesenteric arteries of controls but not DHT females. Elevated DHT did not alter Cx37 or Cx40, but decreased Cx43 mRNA and protein levels in mesenteric arteries. In vitro exposure of DHT to cultured mesenteric artery smooth muscle cells dose-dependently downregulated Cx43 expression. In conclusion, increased blood pressure in hyperandrogenic females is due, at least in part, to decreased EDHF-mediated vascular relaxation responses. Decreased Cx43 expression and activity may play a role in contributing to androgen-induced decrease in EDHF function.

Glycolytic activity in breast cancer using 18F-FDG PET/CT as prognostic predictor: A molecular phenotype approach / Actividad glicolítica en el cancer de mama mediante 18F-FDG PET/TC como predictor pronóstico: aproximación del fenotipo molecular

Aim. To explore the relationship between basal 18F-FDG uptake in breast tumors and survival in patients with breast cancer (BC) using a molecular phenotype approach. Material and Methods. This prospective and multicentre study included 193 women diagnosed with BC. All patients underwent an 18F-FDG PET/CT prior to treatment. Maximum standardized uptake value (SUVmax) in tumor (T), lymph nodes (N), and the N/T index was obtained in all the cases. Metabolic stage was established. As regards biological prognostic parameters, tumors were classified into molecular sub-types and risk categories. Overall survival (OS) and disease free survival (DFS) were obtained. An analysis was performed on the relationship between semi-quantitative metabolic parameters with molecular phenotypes and risk categories. The effect of molecular sub-type and risk categories in prognosis was analyzed using Kaplan-Meier and univariate and multivariate tests. Results. Statistical differences were found in both SUVT and SUVN, according to the molecular sub-types and risk classifications, with higher semi-quantitative values in more biologically aggressive tumors. No statistical differences were observed with respect to the N/T index. Kaplan–Meier analysis revealed that risk categories were significantly related to DFS and OS. In the multivariate analysis, metabolic stage and risk phenotype showed a significant association with DFS. Conclusion. High-risk phenotype category showed a worst prognosis with respect to the other categories with higher SUVmax in primary tumor and lymph nodes (AU)

Objetivo. Analizar la relación entre la captación basal de 18F-FDG en tumores mamarios y la supervivencia en pacientes con cancer de mama (CM) bajo la aproximación del fenotipo molecular. Material y métodos. Este estudio prospectivo y multicentrico incluyó 193 mujeres diagnosticadas de CM. Todas las pacientes fueron sometidas a una 18F-FDG PET/TC previa al tratamiento. Se obtuvo el SUVmax en el tumor (T), ganglios linfáticos (N) así como el índice N/T en todos los casos. Además se determinó el estadio metabólico. Atendiendo a los factores biológicos pronósticos, los tumores fueron clasificados en subtipos moleculares y categorias de riesgo. Se obtuvo tanto la supervivencia global (SG) como la supervivencia libre de enfermedad (SLE). Se estudió la relación entre los parámetros metabólicos semicuantitativos con los fenotipos moleculares y las categorías de riesgo. Se analizó el efecto del subtipo molecular y las categorías de riesgo en el pronóstico mediante análisis de Kaplan–Meier y test uni y multivariantes. Resultados. Se encontraron diferencias estadísticamente significativas en tanto el SUVT como el SUVN, deacuerdo a los fenotipos moleculares y las categorías de riesgo, con valores mayores en los tumores biológicamente más agresivos. No se observaron diferencias con respecto al índice N/T. El análisis de Kaplan–Meier reveló que las categorías de riesgo se relacionaron de forma significativa con la SG y SLE. En el análisis multivariante, el estadio metabólico y la categoría de riesgo mostraron asociación significativa con la SLE. Conclusion. La categoría de alto riesgo manifestó un peor pronóstico con respecto a las otras categorías, con mayores valores de SUVmax tanto en el tumor primario como en ganglios linfáticos (AU)

Preconditioning at a distance: Involvement of endothelial vasoactive substances in cardioprotection against ischemia-reperfusion injury.

There is growing preclinical as well as clinical evidence supporting remote ischemic preconditioning (RIPC), in which short cycles of non-fatal ischemia followed by reperfusion to an organ or tissue distant from the heart elicits cardioprotection. It is the most practical, non-invasive, cost-free, and clinically compatible, secure procedure for reducing ischemia-reperfusion induced injury. The use of a conventional blood pressure cuff on the upper or lower limb in eliciting cardioprotection has expedited its clinical applicability. Endothelium has been documented to respond very quickly to blood flow and hypoxia by releasing different humoral factors such as endothelium derived releasing factor, endothelium derived contracting factor, endothelium derived hyperpolarizing factor. In recent years, there have been studies suggesting the key role of endothelial derived factors in RIPC induced cardioprotection. The signaling cascade involves nitric oxide, gap junctions, epoxyeicosatrienoic (EETs) acids, Ca-activated K(+) channels, angiotensin II, thromboxane A2, superoxide anions and prostacyclin. The present review describes the role of these endothelial derived factors in RIPC induced cardioprotection with possible mechanisms.

NO synthase inhibition attenuates EDHF-mediated relaxation induced by TRPV4 channel agonist GSK1016790A in the rat pulmonary artery: Role of TxA2.

BACKGROUND: The aim of the present study was to observe the concomitant activation of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) pathways by TRPV4 channel agonist GSK1016790A in the rat pulmonary artery and explore the mechanism by which NO synthase inhibition attenuates EDHF-mediated relaxation in endothelium-intact rat pulmonary artery. METHODS: Tension experiments were conducted on the pulmonary artery from male Wistar rats. RESULTS: TRPV4 channel agonist GSK1016790A (GSK) caused concentration-dependent relaxation (Emax 86.9±4.6%; pD2 8.7±0.24) of the endothelium-intact rat pulmonary artery. Combined presence of apamin and TRAM-34 significantly attenuated the relaxation (Emax 61.1±6.0%) to GSK. l-NAME (100µM) significantly attenuated (8.2±2.9%) the relaxation response to GSK that was resistant to apamin plus TRAM-34. However, presence of ICI192605 or furegrelate alongwith l-NAME revealed the GSK-mediated EDHF-response (Emax of 28.5±5.2%; Emax 24.5±4.3%) in this vessel, respectively. Further, these two TxA2 modulators (ICI/furegrelate) alongwith l-NAME had no effect on SNP-induced endothelium-independent relaxation in comparison to l-NAME alone. This EDHF-mediated relaxation was sensitive to inhibition by K(+) channel blockers apamin and TRAM-34 or 60mMK(+) depolarizing solution. Further, combined presence of apamin and TRAM-34 in U46619 pre-contracted pulmonary arterial rings significantly reduced the maximal relaxation (Emax 71.6±6.9%) elicited by GSK, but had no effect on the pD2 (8.1±0.03) of the TRPV4 channel agonist in comparison to controls (Emax, 92.4±4.3% and pD2, 8.3±0.06). CONCLUSION: The present study suggests that NO and EDHF are released concomitantly and NO synthase inhibition attenuates GSK-induced EDHF response through thromboxane pathway in the rat pulmonary artery.

Hydrogen Sulfide and Urogenital Tract.

In this chapter the role played by H2S in the physiopathology of urogenital tract revising animal and human data available in the current relevant literature is discussed. H2S pathway has been demonstrated to be involved in the mechanism underlying penile erection in human and experimental animal. Both cystathionine-ß synthase (CBS) and cystathionine-γ lyase (CSE) are expressed in the human corpus cavernosum and exogenous H2S relaxes isolated human corpus cavernosum strips in an endothelium-independent manner. Hydrogen sulfide pathway also accounts for the direct vasodilatory effect operated by testosterone on isolated vessels. Convincing evidence suggests that H2S can influence the cGMP pathway by inhibiting the phosphodiesterase 5 (PDE-5) activity. All these findings taken together suggest an important role for the H2S pathway in human corpus cavernosum homeostasis. However, H2S effect is not confined to human corpus cavernosum but also plays an important role in human bladder. Human bladder expresses mainly CBS and generates in vitro detectable amount of H2S. In addition the bladder relaxant effect of the PDE-5 inhibitor sildenafil involves H2S as mediator. In conclusion the H2S pathway is not only involved in penile erection but also plays a role in bladder homeostasis. In addition the finding that it involved in the mechanism of action of PDE-5 inhibitors strongly suggests that modulation of this pathway can represent a therapeutic target for the treatment of erectile dysfunction and bladder diseases.

Cells and secretome--towards endogenous cell re-activation for cartilage repair.

Regenerative medicine approaches to cartilage tissue repair have mainly been concerned with the implantation of a scaffold material containing monolayer expanded cells into the defect, with the aim to differentiate the cells into chondrocytes. While this may be a valid approach, the secretome of the implanted cells and its effects on the endogenous resident cells, is gaining in interest. This review aims to summarize the knowledge on the secretome of mesenchymal stem cells, including knowledge from other tissues, in order to indicate how these mechanisms may be of value in repairing articular cartilage defects. Potential therapies and their effects on the repair of articular cartilage defects will be discussed, with a focus on the transition from classical cell therapy to the implantation of cell free matrices releasing specific cytokines.

[Signal molecules of endometrium: gerontological and general pathhological aspects].

The review describes neuro-immuno-endocrine signal molecules expression in human endometrial cells in the normal conditions, in the pathology and during aging. Human endometrial cells synthesizes estrogen, progesterone, estradiol, progestin, cell adhesion molecules (integrines α1ß1, α4ß1, αVß3, L-selectin, Е-catgerin, MUC1), grow factors (TGF, EGF, HB-EGF, IGF), cytokines (IL-1, IL-2, INF-α, IL-12, СХСL10, CXCL11, CXCR3), various immune cells markers (CD68, CD105, CD163, CD16, CD56, CD4, CD8), heat shock proteins (HSP60, HSP70, HSP90, VEGF, MMP). Changes of this molecules expression level are the base of the social significant diseases as endometriosis, endometrial cancer and infertility. Thus, the investigation of neuro-immuno-endocrine interactions in endometrial cells can be used for new drugs creating, in differential diagnostics of endometrial cancer and increasing of extracorporal fertilization success.

Characterizing occupational risk perception: the case of biological, ergonomic and organizational hazards in Spanish healthcare workers

Understanding how risk is perceived by workers is necessary for effective risk communication and risk management. This study adapts key elements of the psychometric perspective to characterize occupational risk perception at a worker level. A total of 313 Spanish healthcare workers evaluated relevant hazards in their workplaces related to biological, ergonomic and organizational factors. A questionnaire elicited workers' ratings of 3 occupational hazards on 9 risk attributes along with perceived risk. Factor and regression analyses reveal regularities in how different risks are perceived, while, at the same time, the procedure helps to summarize specificities in the perception of each hazard. The main regularity is the weight of feeling of dread/severity in order to characterize the risk perceived (β ranges from .22 to .41; p < .001). Data also suggest an underestimation of expert knowledge in relation to the personal knowledge of risk. Thus, participants consider their knowledge of the risk related to biological, ergonomic, and organizational hazards to be higher than the knowledge attributed to the occupational experts (mean differences 95% CIs [.10, .30], [.54, .94], and [0.52, 1.05]). We demonstrate the application of a feasible and systematic procedure to capture how workers perceive hazards in their immediate work environment (AU)

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Tranilast increases vasodilator response to acetylcholine in rat mesenteric resistance arteries through increased EDHF participation.

BACKGROUND AND PURPOSE: Tranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA). EXPERIMENTAL APPROACH: Acetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats. To assess the possible participation of endothelial nitric oxide or prostanoids, acetylcholine-induced relaxation was analyzed in the presence of L-NAME or indomethacin. The participation of endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced response was analyzed by preincubation with TRAM-34 plus apamin or by precontraction with a high K+ solution. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619. KEY RESULTS: Acetylcholine-induced relaxation was greater in tranilast-incubated MRA. Acetylcholine-induced vasodilation was decreased by L-NAME in a similar manner in both experimental groups. Indomethacin did not modify vasodilation. Preincubation with a high K+ solution or TRAM-34 plus apamin reduced the vasodilation to ACh more markedly in tranilast-incubated segments. NO and superoxide anion production, and vasodilator responses to DEA-NO or NS1619 remained unmodified in the presence of tranilast. CONCLUSIONS AND IMPLICATIONS: Tranilast increased the endothelium-dependent relaxation to acetylcholine in rat MRA. This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channels.