Electrically Tunable Reactivity of Substrate-Supported Cobalt Oxide Nanocrystals.

First-row transition metal oxides are promising materials for catalyzing the oxygen evolution reaction. Surface sensitive techniques provide a unique perspective allowing the study of the structure, adsorption sites, and reactivity of catalysts at the atomic scale, which furnishes rationalization and improves the design of highly efficient catalytic materials. Here, a scanning probe microscopy study complemented by density functional theory on the structural and electronic properties of CoO nanoislands grown on Au(111) is reported. Two distinct phases are observed: The most extended displays a Moiré pattern (α-region), while the less abundant is 1Co:1Au coincidental (ß-region). As a result of the surface registry, in the ß-region the oxide adlayer is compressed by 9%, increasing the unoccupied local density of states and enhancing the selective water adsorption at low temperature through a cobalt inversion mechanism. Tip-induced voltage pulses irreversibly transform α- into ß-regions, thus opening avenues to modify the structure and reactivity of transition metal oxides by external stimuli like electric fields.

Tracking the Light-Induced Excited-State Dynamics and Structural Configurations of an Extraordinarily Long-Lived Metastable State at Room Temperature.

Time-resolved X-ray (Tr-XAS) and optical transient absorption (OTA) spectroscopy on the pico-microsecond timescale coupled with density functional theory calculations are applied to study the light-induced spin crossover processes of a Fe-based macrocyclic complex in solution. Tr-XAS analysis after light illumination shows the formation of a seven-coordinated high-spin quintet metastable state, which relaxes to a six-coordinated high-spin configuration before decaying to the ground state. Kinetic analysis of the macrocyclic complex reveals an unprecedented long-lived decay lifetime of approximately 42.6 µs. Comparative studies with a non-macrocyclic counterpart illustrate a significantly shortened approximately 568-fold decay lifetime of about 75 ns, and highlight the importance of the ligand arrangement in stabilizing the reactivity of the excited state. Lastly, OTA analysis shows the seven-coordinated high-spin state to be formed within approximately 6.2 ps. These findings provide a complete understanding of the spin crossover reaction and relaxation pathways of the macrocyclic complex, and reveal the importance of a flexible coordination environment for their rational design.

Protective Effects of Human and Mouse Soluble Scavenger-Like CD6 Lymphocyte Receptor in a Lethal Model of Polymicrobial Sepsis.

Sepsis still constitutes an unmet clinical need, which could benefit from novel adjunctive strategies to conventional antibiotic therapy. The soluble form of the scavenger-like human CD6 lymphocyte receptor (shCD6) binds to key pathogenic components from Gram-positive and -negative bacteria and shows time- and dose-dependent efficacy in mouse models of monobacterial sepsis. The objective of the present work was to demonstrate the effectiveness of infusing mouse and human sCD6 by different systemic routes, either alone or as adjunctive therapy to gold standard antibiotics, in a lethal model of polymicrobial sepsis. To this end, C57BL/6 mice undergoing high-grade septic shock induced by cecal ligation and puncture (CLP; ≥90% lethality) were infused via the intraperitoneal (i.p.) or intravenous (i.v.) route with shCD6 at different doses and time points, either alone or in combination with imipenem/cilastatin (I/C) at a dose of 33 mg/kg of body weight every 8 h. Significantly reduced mortality and proinflammatory cytokine levels were observed by i.p. infusion of a single shCD6 dose (1.25 mg/kg) 1 h pre- or post-CLP. When using the i.v. route, mice survival was significantly extended by starting shCD6 infusion at later time points post-CLP (up to 6 h after CLP). Significant adjunctive effects on mouse survival were observed by i.p. or i.v. infusion of shCD6 in combination with i.p. I/C post-CLP. Similar results were obtained in mice expressing high sustained levels (5 to 10 µg/ml) of mouse sCD6 in serum by means of transduction with hepatotropic adeno-associated virus (AAV). Taken together, the data support the conserved antibacterial effects of human and mouse sCD6 and their use as adjunctive therapy in experimental models of complex and severe polymicrobial sepsis.

First enantiospecific syntheses of marine merosesquiterpenes neopetrosiquinones a and B: evaluation of biological activity.

The first enantiospecific syntheses of neopetrosiquinones A (6) and B (7), two merosesquiterpenes isolated from the deep-water sponge Neopetrosia cf. proxima, from the labdane diterpene trans-communic acid (10) have been achieved. A key step of the synthetic sequence is the simultaneous aromatization of the C ring and the benzylic oxidation on C-7 of an advanced intermediate, mediated by the oxygen-DDQ system. The in vitro antiproliferative activities of neopetrosiquinone B (7) and of the synthetic intermediates 8 and 9 against human breast (MCF-7), lung (A-549), and colon (T-84) tumor cell lines have been assayed. The most potent was compound 9 (IC50 = 4.1 µM), which was twice as active as natural compound 7 (IC50 = 8.3 µM) against A-549 cells. In addition, the treatment with these compounds resulted in an induction of apoptosis. These findings indicate that the terpene benzoquinones reported here might be potentially useful as anticancer agents.

O2 adsorption dependent photoluminescence emission from metal oxide nanoparticles.

Optical properties of metal oxide nanoparticles are subject to synthesis related defects and impurities. Using photoluminescence spectroscopy and UV diffuse reflectance in conjunction with Auger electron spectroscopic surface analysis we investigated the effect of surface composition and oxygen adsorption on the photoluminescence properties of vapor phase grown ZnO and MgO nanoparticles. On hydroxylated MgO nanoparticles as a reference system, intense photoluminescence features exclusively originate from surface excitons, the radiative deactivation of which results in collisional quenching in an O2 atmosphere. Conversely, on as-prepared ZnO nanoparticles a broad yellow emission feature centered at hνEm = 2.1 eV exhibits an O2 induced intensity increase. Attributed to oxygen interstitials as recombination centers this enhancement effect originates from adsorbate-induced band bending, which is pertinent to the photoluminescence active region of the nanoparticles. Annealing induced trends in the optical properties of the two prototypical metal oxide nanoparticle systems, ZnO and MgO, are explained by changes in the surface composition and underline that particle surface and interface changes that result from handling and processing of nanoparticles critically affect luminescence.

Proton transfer chains in cold plasmas of H2 with small amounts of N2. The prevalence of NH4(+).

The ion-molecule chemistry of the astronomically relevant H(3)(+), N(2)H(+), and NH(4)(+) ions has been investigated in the weakly ionized cold plasmas formed in glow discharges of H(2) with small amounts of nitrogen. The concentrations of neutrals and ions were determined by means of mass spectrometry, and electron temperatures and densities were measured using Langmuir probes. A kinetic model was used for the interpretation of the results. The selection of experimental conditions allowed the generation of ion distributions with different relative weights of the mentioned protonated species and the model calculations showed that the observed ion distributions can be explained by the occurrence of a very efficient H(3)(+) → N(2)H(+) → NH(4)(+) proton transfer chain. The NH(4)(+) ion, which is dominant in most of the cases studied, is ultimately derived from the small amount of NH(3) produced at the reactor walls. NH(4)(+) tends to be preponderant in the ion distributions even for NH(3) density ratios as low as 1%. Due to the high proton affinity of ammonia, this molecule is readily transformed into NH(4)(+) upon collision with H(3)(+) or N(2)H(+). It is conjectured that these results can be extrapolated to most of the small molecules predominant in the interstellar medium, which also have proton affinities lower than that of NH(3). The results support the predictions of astrochemical models indicating that NH(4)(+) could be a preponderant ion in some warm environments like hot cores, where NH(3) molecules have desorbed from the grains.

Cadmium modifies the cell cycle and apoptotic profiles of human breast cancer cells treated with 5-fluorouracil.

Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd.

Structure-Activity Studies of Novel Di-substituted [1,2,5]oxadiazolo [3,4-b]pyrazine Analogs Targeting the A-loop Regulatory Site of p38 MAP Kinase.

INTRODUCTION: In the quest for novel allosteric inhibitors of the p38 MAP kinase, we recently described the A-loop regulatory site, identified by means of molecular modeling studies together with the disclosure of a small molecule hit with a moderate inhibitory profile. Starting from this structure, we subsequently identified two additional hits with simpler molecular structures from an in silico screening study, using a substructure search in the SciFinder database. After corroboration of their inhibitory profile, analysis of their structures permitted to conclude about the suitability of the [1,2,5]oxadiazolo[3,4-b]pyrazine (furazano[ 3,4-b]pyrazine) scaffold for the development of potent A-loop regulatory site p38 MAP kinase inhibitors. Accordingly, we report the synthesis and pharmacological evaluation of a series of di-substituted analogs with a potent inhibitory profile of p38 MAP kinase, as shown by in vitro assays of their capability to inhibit IL-1ß secretion in human monocyte-derived macrophages. OBJECTIVE: To find small molecule potent inhibitors of the p38 MAP kinase A-loop regulatory site. METHODS: Starting from this structure, we subsequently identified two additional hits with simpler molecular structures from an in silico screening study, using a substructure search in the SciFinder database. After corroboration of their inhibitory profile, we carried out a hit-tolead optimization process guided by molecular modeling using a [1,2,5]oxadiazolo[3,4- b]pyrazine (furazano[3,4-b]pyrazine) scaffold. RESULTS: We report the synthesis and pharmacological evaluation of a series of di-substituted analogs with a potent inhibitory profile of p38 MAP kinase, as shown by in vitro assays of their capability to inhibit IL-1ß secretion in human monocyte-derived macrophages. CONCLUSION: We describe in the present work a series of [1,2,5]oxadiazolo[3,4-b]pyrazine (furazano[3,4-b]pyrazine), which are potent inhibitors of IL-1ß secretion in human monocytederived macrophages allosteric modulators of the p38 MAP kinase A-loop regulatory site.

Isotopic exchange processes in cold plasmas of H2/D2 mixtures.

Isotope exchange in low pressure cold plasmas of H(2)/D(2) mixtures has been investigated by means of mass spectrometric measurements of neutrals and ions, and kinetic model calculations. The measurements, which include also electron temperatures and densities, were performed in a stainless steel hollow cathode reactor for three discharge pressures: 1, 2 and 8 Pa, and for mixture compositions ranging from 100% H(2) to 100% D(2). The data are analyzed in the light of the model calculations, which are in good global agreement with the experiments. Isotope selective effects are found both in the surface recombination and in the gas-phase ionic chemistry. The dissociation of the fuel gas molecules is followed by wall recycling, which regenerates H(2) and D(2) and produces HD. Atomic recombination at the wall is found to proceed through an Eley-Rideal mechanism, with a preference for reaction of the adsorbed atoms with gas phase D atoms. The best fit probabilities for Eley-Rideal abstraction with H and D are: γ(ER H) = 1.5 × 10(-3), γ(ER D) = 2.0 × 10(-3). Concerning ions, at 1 Pa the diatomic species H(2)(+), D(2)(+) and HD(+), formed directly by electron impact, prevail in the distributions, and at 8 Pa, the triatomic ions H(3)(+), H(2)D(+), HD(2)(+) and D(3)(+), produced primarily in reactions of diatomic ions with molecules, dominate the plasma composition. In this higher pressure regime, the formation of the mixed ions H(2)D(+) and HD(2)(+) is favoured in comparison with that of H(3)(+) and D(3)(+), as expected on statistical grounds. The model results predict a very small preference, undetectable within the precision of the measurements, for the generation of triatomic ions with a higher degree of deuteration, which is probably a residual influence at room temperature of the marked zero point energy effects (ZPE), relevant for deuterium fractionation in interstellar space. In contrast, ZPE effects are found to be decisive for the observed distribution of monoatomic ions H(+) and D(+), even at room temperature. The final H(+)/D(+) ratio is determined to a great extent by proton (and deuteron) exchange, which favours the enhancement of H(+) and the concomitant decrease of D(+).

Neutral and ion chemistry in low pressure dc plasmas of H2/N2 mixtures: routes for the efficient production of NH3 and NH4(+).

The chemistry in low pressure (0.8-8 Pa) plasmas of H(2) + 10% N(2) mixtures has been experimentally investigated in a hollow cathode dc reactor using electrical probes for the estimation of electron temperatures and densities, and mass spectrometry to determine the concentration of ions and stable neutral species. The analysis of the measurements by means of a kinetic model has allowed the identification of the main physicochemical mechanisms responsible for the observed distributions of neutrals and ions and for their evolution with discharge pressure. The chemistry of neutral species is dominated by the formation of appreciable amounts of NH(3) at the metallic walls of the reactor through the successive hydrogenation of atomic nitrogen and nitrogen containing radicals. Both Eley-Rideal and Langmuir-Hinshelwood mechanisms are needed in the chain of hydrogenation steps in order to account satisfactorily for the observed ammonia concentrations, which, in the steady state, are found to reach values ~30-70% of those of N(2). The ionic composition of the plasma, which is entirely due to gas-phase processes, is the result of a competition between direct electron impact dissociation, more relevant for high electron temperatures (lower pressures), and ion-molecule chemistry that prevails for the lower electron temperatures (higher pressures). At the lowest pressure, products from the protonation of the precursor molecules (H(3)(+), N(2)H(+) and NH(4)(+)) and others from direct ionization (H(2)(+) and NH(3)(+)) are found in comparable amounts. At the higher pressures, the ionic distribution is largely dominated by ammonium. It is found that collisions of H(3)(+), NH(3)(+) and N(2)H(+) with the minor neutral component NH(3) are to a great extent responsible for the final prevalence of NH(4)(+).

Discovery of novel 2,3,5-trisubstituted pyridine analogs as potent inhibitors of IL-1ß via modulation of the p38 MAPK signaling pathway.

Interleukin-1ß is a central mediator of innate immune responses and inflammation. It plays a key role in a wide variety of pathologies, ranging from autoinflammatory diseases to metabolic syndrome and malignant tumors. It is well established that its inhibition results in a rapid and sustained reduction in disease severity, underlining the importance of having a repertoire of drugs of this class. At present, there are only three interleukin-1ß blockers approved in the clinic. All of them are biologics, requiring parenteral administration and resulting in expensive treatments. In an exercise to identify small molecule allosteric inhibitors of MAP kinases, we discovered a series of compounds that block IL-1ß release produced as a consequence of a stimulus involved in triggering an inflammatory response. The present study reports the hit-to-lead optimization process that permitted the identification of the compound 13b (AIK3-305) an orally available, potent and selective inhibitor of IL-1ß. Furthermore, the study also reports the results of an in vivo efficacy study of 13b in a LPS endotoxic shock model in male BALB/c mice, where IL-1ß inhibition is monitored in different tissues.

Enhanced stability of gold clusters supported on hydroxylated MgO(001) surfaces.

The influence of surface hydroxylation on nucleation and sintering of gold nanoparticles was studied by comparison of Au deposition and thermal sintering on ideally terminated MgO(001) and hydroxylated MgO thin films, respectively. A combination of different spectroscopic techniques (TDS, XPS, IRAS) allows to establish a correlation between the degree of surface hydroxylation and the stability of gold atoms and clusters. Hydroxyl groups destabilize gold atoms on the MgO surface at 90 K; however, they enhance the stability of small gold clusters toward sintering at higher temperature.

[Immunological Status against Hepatitis B among Healthcare Workers in Two Public Health Departments of the Valencian Community (Spain)]. / Estado inmunológico frente a la Hepatitis B del personal sanitario en dos departamentos de salud de la Comunidad Valenciana (España).

OBJECTIVE: To estimate the prevalence of immunity against Hepatitis B virus among all healthcare workers linked to the Departments of Public Health in Torrevieja and Elx-Crevillent,two municipalities in the Valencian Community, Spain. METHODS: Cross-sectional descriptive study of healthcare workers in two different public health departments. Once the sample was obtained, the anti-hepatitis B surface antibody (anti-HBsAb) levels were abstracted based on serological test results recorded in the workers' medical records. Titers of anti-HBsAB ≥10mlU / ml were considered as evience of immunity. The variables analyzed were classified by department, gender, age (18-34; 35-49;≥50 years); professional category (physicians / nursing / other health personnel / nonhealth personnel); service at risk of contagion (Yes / No); immunity (≥10mlU/ml, 〈10mlU/ml,missing) and systematic anti-HBs vaccination by date of birth (Yes / No). RESULTS: The study population consisted of 2674 workers. The highest proportions of workers were female(68.8%), between 35 and 49 years of age (52.8%), and employed in nursing,(32.2%). Overall, 74.9% of employees had evidence of hepatitis B immunity, 11.3% had no inmunity, and 13.8% was missing information on serology. Among those employees with serological information (n=2306), lack of immunity was highest among males (17.8%).Protective titers were inversely proportional to age, with the lowest titers being found in the oldest age groups. Non-healthcare personnel and physicians also had lower levels of protection (36.9% and 11.1%, respectively). CONCLUSIONS: Despite identifying high levels of immunity among healthcare workers, the percentages of non-immunized employees and those lacking immunological information underscores the need to implement new communication strategies aimed at these at-risk groups.

OBJETIVO: Estimar la prevalencia de inmunización frente al virus de la Hepatitis B del personal sanitario, vinculado a los Departamentos de Salud de Torrevieja y Elche-Crevillente, de la Comunidad Valenciana. MÉTODOS: Estudio descriptivo transversal en todos los trabajadores sanitarios de dos departamentos de Salud. Obtenida la muestra se identificó los niveles de anticuerpos de superficie del virus de la Hepatitis B a través de los resultados serológicos ubicados en las historias clínicas. Se consideró inmunizado a títulos de anti-HBs ≥10mlU/ml. Las variablesanalizadas fueron categorizadas según: Departamento; Género; Edad (18-34; 35-49; >50años); categoría profesional (facultativos/Enfermería/Otro personal sanitario/Personal no sanitario); Servicio riesgo contagio (Si/No); Inmunidad (≥10mlU/ml / 〈10mlU/ml / No Dato) y Vacunacion sistemática anti-HBs según fecha nacimiento (Si/No). RESULTADOS: El personal estudiado ascendió a 2674. Predominó el género femenino 68,8%, el grupo de edad 35-49 años, 52,8%, y la categoría profesional de Enfermería, 32,2%. Un 74,9% de los resultados serológicos identificaron niveles de protección anti-HBs, frente al 11,3% no inmune, y un 13,8% que no disponían de información. Del personal con información serológica (2306), obtuvieron porcentajes de no protección más elevadas la categoría masculina, 17,8%. Los niveles de protección fueron inversamente proporcionales según la variable edad, menor inmunidad a mayor edad. El personal no sanitario y los facultativosarrojaron niveles de protección más bajos, 36,9% y 11,1% respectivamente. CONCLUSIONES: A pesar de identificarse una inmunidad elevada, el porcentaje de no inmunizadosy de ausencia de información inmunológica plantea la necesidad de implementar nuevas estrategias de comunicación dirigidas a este colectivo.

Lowered cortistatin expression is an early event in the human diabetic retina and is associated with apoptosis and glial activation.

PURPOSE: Cortistatin (CST), a neuropeptide with strong structural and functional similarities to somatostatin, is abundant in the vitreous fluid, and it is decreased in patients with proliferative diabetic retinopathy. The aims of the present study were to explore whether the retina produces CST, and to compare its expression between diabetic and nondiabetic donors. Retinal neurodegeneration was assessed by measuring glial fibrilar acidic protein (GFAP) by confocal laser microscopy and counting the apoptotic TUNEL positive cells in which nuclear fragmentation as well as condensation were present. METHODS: Human postmortem eyes (10) from five diabetic donors were compared with 10 eyes from five nondiabetic donors, matched by age. CST mRNA (RT-PCR) and CST (confocal laser microscopy) were measured separately in both the neuroretina and retinal pigment epithelium (RPE). Retinal neurodegeneration was assessed by measuring glial fibrillar acidic protein (GFAP) by confocal laser microscopy and counting the apoptotic cells by TUNEL. RESULTS: CST was found to be produced by the human retina, and higher levels of CST mRNA were found in RPE than in the neuroretina. CST mRNA levels in diabetic donors were significantly lower in both the RPE (p=0.001) and the neuroretina (p=0.03) in comparison with nondiabetic donors. CST immunofluorescence was in agreement with mRNA expression, but the differences were only significant when comparing neuroretinas (p=0.03). Increased GFAP and a higher degree of apoptosis were observed in diabetic retinas in comparison with nondiabetic retinas. These changes were inversely related with CST levels. CONCLUSIONS: CST is expressed in the human retina. There is more CST in the RPE than in the neuroretina. A lower expression of CST exists in diabetic retinas and it is associated with retinal neurodegeneration.

BRCA1: a new genomic marker for non-small-cell lung cancer.

We are all aware of the recent rapid changes in cancer management mostly achieved with emerging new data regarding tumor biology. Currently, research in oncology is mainly focused on identifying the unique molecular characteristics of neoplasms and developing new targeted drugs to treat them. Although some tumors have specific genetic alterations that set off a cause-and-effect process after targeted treatment, those who work in the lung cancer field recognize that this is a more complex disease in which various genetic disorders carry its distinctive aggressiveness. At this time, the efforts of the scientific community are directed toward the identification of predictive markers to customize treatment based on specific genomic or protein expression profiles of individual tumors. This report provides a review on the breast cancer susceptibility gene 1, a promising gene determinant of response to different types of chemotherapy and its potential applications as a new molecular marker in lung cancer.

Mesenchymal stem cell's secretome promotes selective enrichment of cancer stem-like cells with specific cytogenetic profile.

Cancer stem cells (CSCs) are responsible for tumor initiation, metastasis and cancer recurrence, however the involvement of microenvironment is crucial. Here, we have analyzed how human mesenchymal stem cells (MSCs)-derived conditioned medium (CM) affect colon and melanoma CSCs enrichment and maintenance. Our results strongly suggest that the secretome of CM-MSCs selects and maintains subpopulations with high expression of CSCs markers and ALDH1 activity, low proliferation rates with G1 phase arrest, and notably retain in vivo these properties. Cytogenetic analyses indicated that CM-cultured cells contain alterations in chromosome 17 (17q25). Subsequent SKY-FISH analyses suggested that genes located in 17q25 might be involved in stem-cell maintenance. The characterization of secreted proteins present in CM-MSCs revealed that four cytokines and seven growth factors are directly linked to the CSCs enrichment reported in this study. Further analyses revealed that the combination of just IL6 and HGF is enough to provide cancer cells with better stemness properties. In conclusion, this study demonstrates how specific chromosomal alterations present in CSCs subpopulations might represent an advantage for their in vitro maintenance and in vivo stemness properties.

Human CD6 Down-Modulation following T-Cell Activation Compromises Lymphocyte Survival and Proliferative Responses.

Available evidence indicates that the CD6 lymphocyte surface receptor is involved in T-cell developmental and activation processes, by facilitating cell-to-cell adhesive contacts with antigen-presenting cells and likely modulating T-cell receptor (TCR) signaling. Here, we show that in vitro activation of human T cells under different TCR-ligation conditions leads to surface downregulation of CD6 expression. This phenomenon was (i) concomitant to increased levels of soluble CD6 (sCD6) in culture supernatants, (ii) partially reverted by protease inhibitors, (iii) not associated to CD6 mRNA down-regulation, and (iv) reversible by stimulus removal. CD6 down-modulation inversely correlated with the upregulation of CD25 in both FoxP3- (Tact) and FoxP3+ (Treg) T-cell subsets. Furthermore, ex vivo analysis of peripheral CD4+ and CD8+ T cells with activated (CD25+) or effector memory (effector memory T cell, CD45RA-CCR7-) phenotype present lower CD6 levels than their naïve or central memory (central memory T cell, CD45RA-CCR7+) counterparts. CD6lo/- T cells resulting from in vitro T-cell activation show higher apoptosis and lower proliferation levels than CD6hi T cells, supporting the relevance of CD6 in the induction of proper T-cell proliferative responses and resistance to apoptosis. Accordingly, CD6 transfectants also showed higher viability when exposed to TCR-independent apoptosis-inducing conditions in comparison with untransfected cells. Taken together, these results provide insight into the origin of sCD6 and the previously reported circulating CD6-negative T-cell subset in humans, as well as into the functional consequences of CD6 down-modulation on ongoing T-cell responses, which includes sensitization to apoptotic events and attenuation of T-cell proliferative responses.

Intravitreous hepatocyte growth factor in patients with proliferative diabetic retinopathy: a case-control study.

The aim of the present study was to evaluate the vitreous levels of hepatocyte growth factor (HGF) in patients with proliferative diabetic retinopathy (PDR) and to investigate its relationship with vascular endothelial growth factor (VEGF) and retinopathy activity. In addition, the relationship between intravitreous HGF levels and the presence of epiretinal membranes (ERM), as well as the expression of c-Met in ERM were also investigated. In this case-control study, serum and vitreous samples as well as ERM specimens were obtained during vitrectomy from 28 diabetic patients with PDR and 30 non-diabetic control subjects. HGF and VEGF were determined by ELISA and c-Met expression by immunohistochemistry. Vitreal levels of both VEGF and HGF were higher in patients with PDR in comparison with the control group (p<0.0001). However, after correcting for total vitreous protein concentration, HGF (ng/mg of proteins) was lower in diabetic patients than in non-diabetic control subjects (p=0.02). No correlation was detected between the vitreal levels of HGF and VEGF. In addition, intravitreous VEGF but not HGF was found to be related to PDR activity. Both diabetic patients and non-diabetic patients in whom ERM had been excised presented higher HGF intravitreous levels. Finally, a significant expression of c-Met in ERM membranes were observed in both diabetic patients with PDR and in non-diabetic subjects. In conclusion, both HGF and VEGF increased, but were not related, in the vitreous fluid of diabetic patients with PDR. Our findings suggest that HGF is related to pathological conditions in which fibroproliferative processes or wound healing are involved rather than with angiogenesis itself.

Somatostatin molecular variants in the vitreous fluid: a comparative study between diabetic patients with proliferative diabetic retinopathy and nondiabetic control subjects.

OBJECTIVE: There is growing evidence to indicate that somatostatin could be added to the list of natural antiangiogenic factors that exist in the vitreous fluid. In addition, a deficit of intravitreous somatostatin-like immunoreactivity (SLI) has been found in diabetic patients with proliferative diabetic retinopathy (PDR). In the present study, we have determined the main molecular variants of somatostatin (somatostatin-14 and somatostatin-28) in the vitreous fluid and plasma of nondiabetic control subjects and diabetic patients with PDR. In addition, the contribution of cortistatin, a neuropeptide with strong structural similarities to somatostatin, to SLI and its levels in vitreous and plasma in both nondiabetic and diabetic patients has also been measured. RESERCH DESIGN AND METHODS: Plasma and vitreous fluid from 22 diabetic patients with PDR and 22 nondiabetic control subjects were analyzed. Somatostatin-14, somatostatin-28 and cortistatin were measured by radioimmunoassay but separation by high-performance liquid chromatography was required to measure somatostatin-14. RESULTS: The predominant molecular form of somatostatin within the vitreous fluid was somatostatin-28 (fivefold higher than somatostatin-14 in control subjects and threefold higher in patients with PDR). Cortistatin significantly contributed to SLI and its intravitreous levels were higher than those detected in plasma (nondiabetic control subjects: 147 [102-837] vs. 78 [24-32] pg/ml; patients with PDR: 187 [87-998] vs. 62 [24-472] pg/ml; P = 0.01 for both). Intravitreous somatostatin-14 was similar in both subjects with PDR and the control group (P = 0.87). By contrast, somatostatin-28 concentration was lower in patients with PDR than in nondiabetic control subjects (350 +/- 32 vs. 595 +/- 66 pg/ml; P = 0.004). CONCLUSIONS: Somatostatin-28 is the main molecular variant in the vitreous fluid. The intravitreous SLI deficit detected in patients with PDR is mainly due to somatostatin-28. Cortistatin is abundant in the vitreous fluid and significantly contributes to SLI. These findings could open up new strategies for PDR treatment.