Basal Status Research Articles

Hydrogen peroxide induces vasorelaxation by enhancing 4-aminopyridine-sensitive Kv currents through S-glutathionylation

Hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor. Since opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, this study was performed to assess whether H2O2 acts as a vasodilator in the rat mesenteric artery and, if so, to determine the underlying mechanisms. H2O2 elicited concentration-dependent relaxation in mesenteric arteries precontracted with norepinephrine. The vasodilatory effect of H2O2 was reversed by treatment with dithiothreitol. H2O2-elicited vasodilation was significantly reduced by blocking 4-aminopyridine (4-AP)-sensitive Kv channels, but it was resistant to blockers of big-conductance Ca2+-activated K+ channels and inward rectifier K+ channels. A patch-clamp study in mesenteric arterial smooth muscle cells (MASMCs) showed that H2O2 increased Kv currents in a concentration-dependent manner. H2O2 speeded up Kv channel activation and shifted steady state activation to hyperpolarizing potentials. Similar channel activation was seen with oxidized glutathione (GSSG). The H2O2-mediated channel activation was prevented by glutathione reductase. Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester showed incorporation of glutathione (GSH) in the Kv channel proteins in the presence of H2O2. Interestingly, conditions of increased oxidative stress within MASMCs impaired the capacity of H2O2 to stimulate Kv channels. Not only was the H2O2 stimulatory effect much weaker, but the inhibitory effect of H2O2 was unmasked. These data suggest that H2O2 activates 4-AP-sensitive Kv channels, possibly through S-glutathionylation, which elicits smooth muscle relaxation in rat mesenteric arteries. Furthermore, our results support the idea that the basal redox status of MASMCs determines the response of Kv currents to H2O2.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-014-1513-3) contains supplementary material, which is available to authorized users.

Basal functional status predicts three-month mortality after a heart failure hospitalization in elderly patients — The prospective RICA study

BackgroundMany elderly heart failure (HF) patients show some degree of functional impairment. The study aim was to evaluate the functional status of oldest-old cohort of patients hospitalized with a diagnosis of decompensated (HF), and to analyze whether preadmission functional status predicts risk of 3-month mortality. MethodsWe analyzed 1431 elderly (≥75years) patients prospectively included in the Spanish National Registry on HF (RICA). We added Barthel Index (BI) to the usual HF patient assessment to measure patients' functional status, and we evaluated the relationship between preadmission BI values and 3-month mortality. ResultsThe mean age of patients was 82.3 (4.6) years. Patients' mean preadmission BI score was 81.3 (21.5); 802 patients (55.9%) had BI scores <61. Multivariate analysis confirmed an independent association between poor preadmission BI and older age, female sex, higher comorbidity, cognitive impairment, previous institutionalization, worse New York Heart Association (NYHA) functional class and lack of beta-blocker use. A total of 210 patients died (14.7%) after 3months of follow-up. Cox multivariate analyses found that higher preadmission BI is correlated with reduced all-cause, 3-month postdischarge mortality [hazard ratio (HR) 0.981; CI95% 0.975–0.986, p<0.001]. Other variables independently associated with 3-month mortality were male sex, lower body mass index, lower systolic blood pressure, a diagnosis of diabetes and chronic kidney disease, worse NYHA class and not receiving treatment with beta-blockers. ConclusionsSevere functional disability is present among more than half of older patients admitted because of a HF decompensation. For this population, preadmission BI is a strong predictor of short-term mortality.

Relationship between genotoxic effects of breast cancer treatments and patient basal DNA integrity.

Radiotherapy and chemotherapy cause genotoxic side effects that are highly variable among patients. In this study, we evaluated DNA integrity using the comet assay in peripheral blood lymphocytes from breast cancer patients before ("pre-treatment patients"; n=47) and after ("post-treatment patients"; n=24) radiotherapy and/or chemotherapy treatment and from healthy donors (n=15). Comet evaluation was made by visual (types 0-4) and digital (percentage of DNA remaining in the comet head=% head DNA) analysis. The association between the level of DNA damage and cancer prognostic factors was assessed. The treatments caused a significant increase in DNA damage registered by both visual (p<0.001) and digital (p<0.001) analyses. No significant associations between the level of DNA damage in pre-treatment patients and cancer prognostic factors were found. A significant correlation between the comet results from each patient before and after treatment (r=0.64, p=0.001) was observed. The % head DNA in post-treatment samples from patients with a high level of DNA damage before treatment (30.3±3.1%, p<0.01) was lower than in post-treatment samples from patients with a low-to-medium level of DNA damage before therapy (49.2±4.4%). These results support the usefulness of the comet assay as a sensitive technique to evaluate basal DNA status and DNA damage caused by cancer treatments. The comet assay could contribute to treatment decisions, especially by taking into account the patient's basal DNA damage before therapy.

Evidence for multiple MHC class II β loci in New Zealand’s critically endangered kakapo, Strigops habroptilus

Immunologically important genes of the major histocompatibility complex (MHC) have been characterized in a number of avian species with the general finding of considerable variation in size and structural organization among organisms. A range of nonpasserines which represent early-diverging Neoave lineages have been described as having only one MHC class II β locus potentially leading to the conclusion that this is the ancestral condition. Here, we examine the monotypic, early-diverging, critically endangered kakapo, Strigops habroptilus, for allelic variation at MHC class II β exon 2, as part of species' recovery efforts. We found two to four confirmed sequence variants per individual indicating the presence of more than one MHC class II β locus. Given the kakapo's basal evolutionary status, evidence for multiple MHC class II β loci seems to counter the proposed mono-locus history of modern birds. However, MHC gene duplication, maintenance, and loss among and within bird species may confound avian relationships making it difficult to elucidate the ancestral state. This study adds essential data for disentangling the course of MHC structural evolution in birds.

Effect of a poly(ADP‐ribose) polymerase‐1 inhibitor against esophageal squamous cell carcinoma cell lines

Effective molecular target drugs that improve therapeutic efficacy with fewer adverse effects for esophageal cancer are highly anticipated. Poly(ADP-ribose) polymerase (PARP) inhibitors have been proposed as low-toxicity agents to treat double strand break (DSB)-repair defective tumors. Several findings imply the potential relevance of DSB repair defects in the tumorigenesis of esophageal squamous cell carcinoma (ESCC). We evaluated the effect of a PARP Inhibitor (AZD2281) on the TE-series ESCC cell lines. Of these eight cell lines, the clonogenic survival of one (TE-6) was reduced by AZD2281 to the level of DSB repair-defective Capan-1 and HCC1937 cells. AZD2281-induced DNA damage was implied by increases in γ-H2AX and cell cycle arrest at G2/M phase. The impairment of DSB repair in TE-6 cells was suggested by a sustained increase in γ-H2AX levels and the tail moment calculated from a neutral comet assay after X-ray irradiation. Because the formation of nuclear DSB repair protein foci was impaired in TE-6 cells, whole-exome sequencing of these cells was performed to explore the gene mutations that might be responsible. A novel mutation in RNF8, an E3 ligase targeting γ-H2AX was identified. Consistent with this, polyubiquitination of γ-H2AX after irradiation was impaired in TE-6 cells. Thus, AZD2281 induced growth retardation of the DSB repair-impaired TE-6 cells. Interestingly, a strong correlation between basal expression levels of γ-H2AX and sensitivity to AZD2281was observed in the TE-series cells (R2 = 0.5345). Because the assessment of basal DSB status could serve as a biomarker for selecting PARP inhibitor-tractable tumors, further investigation is warranted.

RETRACTED: Bone mineral density of lumbar spine and femur in patients with gynecologic cancer.

Objective To compare the bone mineral density (BMD) of the lumbar spine and femur in postmenopausal women with cervical and endometrial cancer without bone metastasis with that in normal control postmenopausal women Methods We retrospectively analyzed the BMD of the lumbar spine and femur using dual-energy X-ray absorptiometry in 130 patients with cervical cancer, 68 patients with endometrial cancer, and 225 healthy controls. Results The serum levels of calcium, phosphorus, osteocalcin, total alkaline phosphatase and urine deoxypyridinoline were measured in all participants. Age, body mass index, parity and time since menopause were not significantly different between the three groups. The T-scores of basal BMD at the fourth lumbar vertebra (L4) were significantly lower in patients with cervical cancer (- 0.68 ± 0.10) compared to those in the other two groups. Additionally, the incidence of osteoporosis at L4 according to the basal status of bone mass was significantly higher in patients with cervical cancer (10.0%) compared to that in controls (0.4%). Urine deoxypyridinoline levels were significantly higher in patients with cervical cancer compared to those in controls. No differences in basal BMD of the lumbar spine and femur were observed between patients with endometrial cancer and controls, and no significant differences in biochemical markers were detected between patients with endometrial cancer and controls. Conclusion Our results suggest that postmenopausal women with cervical cancer have a lower BMD and are at increased risk of osteoporosis in the lumbar spine before receiving anticancer treatment compared with postmenopausal women with endometrial cancer.

Donor and Recipient STR Analysis Before Allogeneic Haematopoietic Stem Cell Transplantation: Possible Correlation With Post-Transplant Outcome

Background The chimerism analysis after allogeneic haematopoietic stem cell transplantation (HSCT) is a useful tool to monitor the engraftment of donor cells and to early predict graft failure or disease relapse. Among several available methods to perform chimerism study, multiplex fluorescent short tandem repeat (STR) analysis represent a sensitive, accurate and reproducible technique. It provide a high rate of discrimination between donor and recipient cells since that fluorescent signal is proportional to the cells number, obtaining a quantitative assessment of chimerism. Aims Evaluation of a possible correlation between basal donor/recipient allelic discrepancies and post-transplant outcome in terms of graft versus host disease (GvHD) development, neutrophil engraftment, relapse, DFS and OS. Methods We enrolled 111 patients (pts) affected by onco-haematological diseases, consecutively submitted to HSCT at our division between February 2005 and December 2012. Pts were 67 males and 44 females with a median age of 51 years (range 14-70). Underlying diseases were: 58 AML, 10 MDS, 16 ALL, 8 CLL, 6 MM, 2 HL, 9 NHL, 1 IMF, 1 MPD. Myeloablative conditioning regimen was used in 26 pts while a reduced conditioning regimen was used for the other 85 pts. Graft was obtained from sibling donor and unrelated donor in 65 and 46 pts, respectively. GvHD prophylaxis was performed with cyclosporine (CSA) and methotrexate in 61 pts, CSA and mycophenolate mofetil in 43 pts and CSA in 7 pts. Donor and recipient allelic status was performed using a multiplex PCR amplification of ten STR loci: Amelogenin alleles X/Y, D3S1358, FGA, D8S1179, D18S51, D13S317, vWA, D21S11, D5S818, D7S820. We evaluated the donor/recipient (D/R) match or mismatch for each locus and the following variables: GvHD development and onset time, time to neutrophil engraftment, relapse, DFS and OS. Statistical analysis was performed by Kaplan Meier analysis using IBM SPSS Statistics 20 Core System. Results Pts with D/R mismatch for D8S1179 locus achieved neutrophil engraftment (ANC&gt;1* 109/L) at a median time of 18 days (CI 95% 17.202-18.798) compared with 21 days (CI 95% 17.328-24.672) of pts with D/R match for the same locus (p=0.007) (Figure 1A). Pts with D/R mismatch for D3S1358 locus developed acute GvHD at a median time of 20 days (CI 95% 15.781-24.219) compared with 29 days (CI 95% 15.421-42.579) of pts with D/R match for the same locus (p=0.031) (Figure 1B). Pts with D/R mismatch for D3S1358 locus showed an OS of 16 months (CI 95% 11.016-20.984) compared with 41 months (CI 95% 25.420-56.580) of pts with D/R match for the same locus (p=0.025) (Figure 1C). Pts with D/R mismatch for D8S1179 locus showed an OS of 16 months (CI 95% 8.528-23.472) compared with 56 months (CI 95% 11.254-78.057) of pts with D/R match for the same locus (p=0.012) (Figure 1D). No relationships were found with relapse, DFS neither for the other loci. Summary Our results highlight that pts who presented a D/R mismatch for D8S1179 locus showed an earlier neutrophil engraftment but a worse OS compared with the others. Moreover, for D3S1358 locus, D/R mismatch was associated with an earlier onset of acute GvHD after HSCT and with a shorter OS than the D/R match ones. Conclusion STRs are highly polymorphic di-, tri- and tetra-nucleotide repeat non-coding sequences, which are interspersed throughout the genome. Whether or not discrepancies between donor and recipient basal allelic status could be considered useful in predicting post-transplant outcome will require validation in a large sample of pts. Disclosures: No relevant conflicts of interest to declare.

Glutamine in the intensive care unit

To analyze the recent literature (2011-2013) on glutamine supplementation of parenteral and enteral nutrition in critically ill patients. Potential confounding factors that may explain conflicting results are suggested. Some recent, prospective, multicenter trials and two small trials yielded conflicting results that weigh heavily in the conclusions of a recent meta-analysis. Heterogeneity of the patients enrolled (especially in terms of injury severity, age, and basal nutritional status) and difficulties in identifying patients truly in need of glutamine supplementation may explain the discrepancies. Glutamine supplementation has been recognized as beneficial in acutely injured patients. However, recent conflicting results in either 'real-life conditions' or very severe situations suggest that its indications need to be more precisely determined.

MitoPark mice, an animal model of Parkinson’s disease, show enhanced prepulse inhibition of acoustic startle and no loss of gating in response to the adenosine A2A antagonist SCH 412348

Psychoses are debilitating side effects associated with current dopaminergic treatments for Parkinson's disease (PD). Prepulse inhibition (PPI), in which a non-startling stimulus reduces startle response to a subsequent startle-eliciting stimulus, is important in filtering out extraneous sensory stimuli. PPI deficits induced by dopamine agonists can model symptoms of psychosis. Adenosine A(2A) receptor antagonists, being developed as novel PD treatments, indirectly modulate dopamine signaling in the basal ganglia and may have an improved psychosis profile which could be detected using the PPI model. The aims of this study is to characterize PPI in MitoPark mice, which exhibit progressive loss of dopamine signaling and develop a Parkinson-like motor phenotype, and assess standard and novel PD treatment effects on PPI in MitoPark mice, which more closely mimic the basal ganglia dopamine status of PD patients. MitoPark mice displayed enhanced PPI as dopamine tone decreased with age, consistent with studies in intact mice that show enhanced PPI in response to dopamine antagonists. Paradoxically, older MitoParks were more sensitive to PPI disruption when challenged with dopamine agonists such as apomorphine or pramipexole. Alternatively, SCH 412348, an adenosine A(2A) antagonist, did not disrupt PPI in MitoPark mice at doses that normalized hypoactivity. Use of MitoPark mice in the PPI assay to assess the potential for PD treatment to produce psychoses likely represents a more disease-relevant model. SCH 412348 does not differentially disrupt PPI as do dopamine agonists, perhaps indicative of an improved psychosis profile of adenosine A(2A) antagonists, even in PD patients with decreased dopamine tone in the basal ganglia.

Epistasis in iron metabolism: complex interactions between Cp, Mon1a, and Slc40a1 loci and tissue iron in mice

Disorders of iron metabolism are among the most common acquired and constitutive diseases. Hemochromatosis has a solid genetic basis and in Northern European populations it is usually associated with homozygosity for the C282Y mutation in the HFE protein. However, the penetrance of this mutation is incomplete and the clinical presentation is highly variable. The rare and common variants identified so far as genetic modifiers of HFE-related hemochromatosis are unable to account for the phenotypic heterogeneity of this disorder. There are wide variations in the basal iron status of common inbred mouse strains, and this diversity may reflect the genetic background of the phenotypic diversity under pathological conditions. We therefore examined the genetic basis of iron homeostasis using quantitative trait loci mapping applied to the HcB-15 recombinant congenic strains for tissue and serum iron indices. Two highly significant QTL containing either the N374S Mon1a mutation or the Ferroportin locus were found to be major determinants in spleen and liver iron loading. Interestingly, when considering possible epistatic interactions, the effects of Mon1a on macrophage iron export are conditioned by the genotype at the Slc40a1 locus. Only mice that are C57BL/10ScSnA homozygous at both loci display a lower spleen iron burden. Furthermore, the liver-iron lowering effect of the N374S Mon1a mutation is observed only in mice that display a nonsense mutation in the Ceruloplasmin (Cp) gene. This study highlights the existence of genetic interactions between Cp, Mon1a, and the Slc40a1 locus in iron metabolism, suggesting that epistasis may be a crucial determinant of the variable biological and clinical presentations in iron disorders.

Fibromyalgia: anti-inflammatory and stress responses after acute moderate exercise.

Fibromyalgia (FM) is characterized in part by an elevated inflammatory status, and “modified exercise” is currently proposed as being a good therapeutic help for these patients. However, the mechanisms involved in the exercise-induced benefits are still poorly understood. The objective was to evaluate the effect of a single bout of moderate cycling (45 min at 55% VO2 max) on the inflammatory (serum IL-8; chemotaxis and O2 − production by neutrophils; and IL-1β, TNF-α, IL-6, IL-10, and IL-18 release by monocytes) and stress (cortisol; NA; and eHsp72) responses in women diagnosed with FM compared with an aged-matched control group of healthy women (HW). IL-8, NA, and eHsp72 were determined by ELISA. Cytokines released by monocytes were determined by Bio-Plex® system (LUMINEX). Cortisol was determined by electrochemoluminiscence, chemotaxis was evaluated in Boyden chambers and O2 − production by NBT reduction. In the FM patients, the exercise induced a decrease in the systemic concentration of IL-8, cortisol, NA, and eHsp72; as well as in the neutrophil’s chemotaxis and O2 − production and in the inflammatory cytokine release by monocytes. This was contrary to the completely expected exercise-induced increase in all those biomarkers in HW. In conclusion, single sessions of moderate cycling can improve the inflammatory status in FM patients, reaching values close to the situation of aged-matched HW at their basal status. The neuroendocrine mechanism seems to be an exercise-induced decrease in the stress response of these patients.

Reduction of rectal doses by removal of gas in the rectum during vaginal cuff brachytherapy

The goal of this work was to evaluate whether the volume reduction related to removal of gas in the rectum could be translated in lower doses to organs at risk (OAR) during vaginal cuff brachytherapy (VBT). Fourteen pairs of brachytherapy planning CT scans derived from 11patients were re-segmented and re-planned using the same parameters. The only difference between pairs of CTs was the presence or lack of gas in the rectum. The first CT showed the basal status and the second was carried out after gas removal with a tube. A set of values derived from bladder and rectum dose-volume histograms (DVH) and dose-surface histograms (DSH) were extracted. Moreover the cylinder position related to the patient craniocaudal axis was recorded. Rectum volume decreased significantly from 77.8 ± 45 to 55.43 ± 17.6ml (p = 0.0052) after gas removal. Such volume diminution represented a significant reduction on all rectal DVH parameters analyzed except D25 % and D50 %. DSH parameter results were similar to previous ones. A nonsignificant increase of the bladder volume was observed and was associated with an increase of the DVH metrics analyzed. Removal of gas pockets is a simple and inexpensive maneuver that decreases rectal dose parameters on VBT, which can be translated as a better therapeutic ratio. It also suggests that other actions directed to empty the rectum could have a similar effect.

Role of DNA methyltransferase 1 on the altered eNOS expression in human umbilical endothelium from intrauterine growth restricted fetuses

Reduced fetal growth associates with endothelial dysfunction and cardiovascular risk in both young and adult offspring and the nitric oxide (NO) system has been implicated in these effects. Epigenetic processes are likely to underlie such effects, but there is to date no evidence that endothelial dysfunction in early life results from epigenetic processes on key genes in the NO system, such as NOS3 (eNOS) and ARG2 (arginase-2). We determined basal DNA methylation status in NOS3 and ARG2 promoters, and DNA methyltransferase 1 (DNMT1) effect on eNOS and arginase-2 expression using human endothelial cells isolated from umbilical arteries (HUAEC) and veins (HUVEC) from control and intrauterine growth restricted (IUGR) fetuses. Compared with cells from control pregnancies, eNOS protein and mRNA levels were increased in HUAEC, but decreased in HUVEC, from IUGR, while arginase-2 levels were increased in IUGR-HUVEC. The NOS3 promoter showed a decrease in DNA methylation at CpG -352 in IUGR-HUAEC, and an increase in IUGR-HUVEC, when compared with control cells. Methylation in the hypoxia response element of the NOS3 promoter was increased in IUGR-HUAEC and decreased in HUVEC. Methylation in the AGR2 promoter in IUGR-HUVEC was decreased in a putative HRE, and without changes in IUGR-HUAEC. Silencing of DNMT1 expression normalized eNOS expression in IUGR endothelial cells, and restored the normal response to hypoxia in HUVEC, without effects on arginase-2. This data suggest that eNOS expression in IUGR-derived endothelial cells is programmed by altered DNA methylation, and can be reversed by transient silencing of the DNA methylation machinery.

Obesity and Thyroid Cancer: Is Leptin the (Only) Link?

Obesity and Thyroid Cancer: Is Leptin the (Only) Link?

Metabolic and Regulatory Responses in Citrus Rootstocks in Response to Adverse Environmental Conditions

In response to adverse environmental conditions, plants modify their metabolism to adapt to the new conditions. To differentiate common responses to abiotic stress from specific adaptation to a certain stress condition, two citrus rootstocks (Carrizo citrange and Cleopatra mandarin) with a different ability to tolerate stress were subjected to soil flooding and drought, two water stress conditions. In response to these conditions, both genotypes showed altered root proline and phenylpropanoid levels, especially cinnamic acid, which was a common feature to Carrizo and Cleopatra. This was correlated with alterations in the levels of phenylpropanoid derivatives likely involved in lignin biosynthesis. In the regulatory part, levels of both stress hormones abscisic acid (ABA) and jasmonic acid (JA) decreased in response to soil flooding irrespective of the genotype’s relative flooding tolerance, but, on the other hand, the concentration of both metabolites increased in response to drought, showing a transient accumulation of JA after a few days and a progressive pattern of ABA increase. These responses are probably associated with different regulatory processes under soil flooding and drought. In addition, alterations in indole acetic acid (IAA) levels in citrus roots seemed to be associated with particular stress tolerance. Moreover, both genotypes exhibited a low degree of overlap in the metabolites induced under similar stress conditions, indicating a specific mechanism to cope with stress in plant species. Results also indicated a different metabolic basal status in both genotypes that could contribute to stress tolerance.

Plasma oxylipin profiling identifies polyunsaturated vicinal diols as responsive to arachidonic acid and docosahexaenoic acid intake in growing piglets

The dose-responsiveness of plasma oxylipins to incremental dietary intake of arachidonic acid (20:4n-6; ARA) and docosahexaenoic acid (22:6n-3; DHA) was determined in piglets. Piglets randomly received one of six formulas (n = 8 per group) from days 3 to 27 postnatally. Diets contained incremental ARA or incremental DHA levels as follows (% fatty acid, ARA/DHA): (A1) 0.1/1.0; (A2) 0.53/1.0; (A3-D3) 0.69/1.0; (A4) 1.1/1.0; (D1) 0.66/0.33; and (D2) 0.67/0.62, resulting in incremental intake (g/kg BW/day) of ARA: 0.07 ± 0.01, 0.43 ± 0.03, 0.55 ± 0.03, and 0.82 ± 0.05 at constant DHA intake (0.82 ± 0.05), or incremental intake of DHA: 0.27 ± 0.02, 0.49 ± 0.03, and 0.81 ± 0.05 at constant ARA intake (0.54 ± 0.04). Plasma oxylipin concentrations and free plasma PUFA levels were determined at day 28 using LC-MS/MS. Incremental dietary ARA intake dose-dependently increased plasma ARA levels. In parallel, ARA intake dose-dependently increased ARA-derived diols 5,6- and 14,15-dihydroxyeicosatrienoic acid (DiHETrE) and linoleic acid-derived 12,13-dihydroxyoctadecenoic acid (DiHOME), downstream metabolites of cytochrome P450 expoxygenase (CYP). The ARA epoxide products from CYP are important in vascular homeostatic maintenance. Incremental DHA intake increased plasma DHA and most markedly raised the eicosapentaenoic acid (EPA) metabolite 17,18-dihydroxyeicosatetraenoic acid (DiHETE) and the DHA metabolite 19,20-dihydroxydocosapentaenoic acid (DiHDPE). In conclusion, increasing ARA and DHA intake dose-dependently influenced endogenous n-6 and n-3 oxylipin plasma concentrations in growing piglets, although the biological relevance of these findings remains to be determined.

Late-life depressive symptoms: Prediction models of change

BackgroundDepression is a well-recognised problem in the elderly. The aim of this study was to determine the factors associated with predictors of change in depressive symptoms, both in subjects with and without baseline significant depressive symptoms. MethodsLongitudinal study of community-dwelling elderly people (>60 years or older), baseline evaluations, and two additional evaluations were reported. Depressive symptoms were measured using a 30-item geriatric depression scale, and a score of 11 was used as cut-off point for significant depressive symptoms in order to stratify the analyses in two groups: with significant depressive symptoms and without significant depressive symptoms. Sociodemographic data, social support, anxiety, cognition, positive affect, control locus, activities of daily living, recent traumatic life events, physical activity, comorbidities, and quality of life were evaluated. Multi-level generalised estimating equation model was used to assess the impact on the trajectory of depressive symptoms. ResultsA number of 7882 subjects were assessed, with 29.42% attrition. At baseline assessment, mean age was 70.96 years, 61.15% were women. Trajectories of depressive symptoms had a decreasing trend. Stronger associations in those with significant depressive symptoms, were social support (OR.971, p<.001), chronic pain (OR 2.277, p<.001) and higher locus of control (OR.581, p<.001). In contrast for those without baseline significant depressive symptoms anxiety and a higher locus of control were the strongest associations. ConclusionsNew insights into late-life depression are provided, with special emphasis in differentiated factors influencing the trajectory when stratifying regarding basal status of significant depressive symptoms. LimitationsThe study has not included clinical evaluations and nutritional assessments.

Metabolic syndrome, circulating RBP4, testosterone, and SHBG predict weight regain at 6 months after weight loss in men

Weight loss helps reduce the symptoms of the metabolic syndrome (MetS) in the obese, but weight regain after active weight loss is common. The changes and predictive role of circulating adipokines and sex hormones for weight regain in men during dietary intervention, and also the effect of basal MetS status on weight regain, were investigated. Twenty-four men who continued to lose weight (WL) and 24 men who regained weight (WR) during the 6-month follow-up period after weight loss were selected from the Diogenes Study. Their circulating concentrations of leptin, adiponectin, retinol-binding protein 4 (RBP4), luteinizing hormone, prolactin, progesterone, total and free testosterone, and sex hormone-binding globulin (SHBG) were measured at baseline, after 8-week low-calorie diet-induced active weight loss, and after a subsequent 26-week ad libitum weight maintenance diet, and analyzed together with anthropometrical and physiological parameters. Overweight and obese men with MetS at baseline had higher risk to regain weight (odds ratio = 2.8, P = 0.015). High baseline RBP4, low total testosterone, and low SHBG are predictors of weight loss regain (different between WR and WL with P = 0.001, 0.038, and 0.044, respectively). These variables may play roles in the link between MetS and weight loss regain.

Activity of eribulin on skin metastases in breast cancer patients.

e12021 Background: Skin metastases (SM) occur in 20% of metastatic breast cancer (mBC). Clinical trials rarely describe them, even if they affect quality of life and self-perception of the disease. Eribulin (E) is a new drug, approved in mBC, after at least 2 lines of chemotherapy. The aim of this survey is to evaluate the activity of E treatment on SM compared to other metastatic sites, and on cutaneous symptoms (pain, infiltration, bleeding, smell, ulceration). Methods: This multicenter survey was conducted from November 2012 to January 2013 in 14 Italian Cancer Centers. Oncologists completed a database with patient (pts), tumor and treatment characteristics. Descriptive summary statistics were applied. Progression-free survival (PFS) was calculated according to Kaplan-Meier method. Results: 109 pts with mBC on E treatment were considered. 23/109 (21%) pts with SM were identified and analyzed. E was started between January 2012 and October 2012. Median age 63 (31-81). Prior chemotherapy lines: 4 (1-10). Prior hormonal lines: 1 (0-4). Basal Karnofski performance status 90 (50-100). 21/23 pts had other metastases, the remaining 2 had exclusively skin disease. SM were predominantly in the thorax (91%) and presented infiltration in 78%, ulceration in 70%, pain in 43%, bleeding in 43% and smell in 17% of cases. According to RECIST criteria, after E 43% of patients obtained a partial response (PR), 35% stable disease (SD), 22% progressive disease (PD). We evaluated skin response independently and found that 26% obtained a complete response (CR); 22% PR, 39% SD, 13% PD. Skin responses were in complete accordance with overall response in 16/23 (70%) pts, in partial accordance in 4 pts (skin CR, with an overall PR) and were discordant in 3 pts (1 skin SD despite overall PR, and 2 cutaneous CR despite overall PD). We found an improvement in SM symptoms: pain control was gained in 50% (5/10) of pts, as well as improvement in smell (50%, 2/4) and bleeding (50%, 5/10). Infiltration disappeared in 3/18 pts (17%). With a median follow up of 6 months, 21 (91%) pts had PD, median PFS was 4.3 months (95%CI 2.9–6). Conclusions: During E an improvement in skin metastases symptoms was observed; in the majority of cases, the response rate of SM was coherent with systemic responses.

The meninges: A staging site for immune cell interactions in early experimental autoimmune encephalomyelitis (P4166)

Abstract Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system in which immune mediate damage to white matter myelin is well characterized. However, improved imaging has revealed that inflammation in the meninges, tissues that are proximal to the CNS, also occurs and corresponds to cortical grey matter lesion formation in early disease. Together with evidence of activated T cells and tertiary lymphoid follicle formation within these tissues, these data suggest that the meninges are critical sites of immune cell activity. Yet little is known about the basal and disease-associated immune status of these tissues. Using a murine model of MS, we evaluated the immune cell makeup of the meninges in naïve mice and asked how this changes during the course of disease. CD4+ and CD8+ T cells, macrophages, dendritic cells, mast cells and neutrophils are detected in naïve mice and increased numbers of neutrophils and macrophages are observed in preclinical disease. A population of innate lymphoid cells (ILCs: CD3-, CD4+/-, RORγt+, IL-7Rα+) also normally resides in the meninges and this population is reduced in mast cell deficient mice. These data confirm that the meninges are an active site of immune response in early disease. We speculate that meningeal ILCs may provide a mechanism for the development of tertiary lymphoid follicle formation as well as contribute to Th17 cell activation and thereby amplify meningeal inflammation.