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Objective To explore whether anxiety and depression are associated with clinical measures of disease for adolescent patients with juvenile idiopathic arthritis (JIA) and whether anxiety and depression are associated with increased peripheral proinflammatory cytokine levels in adolescent patients with JIA and in healthy adolescent controls. Methods A total of 136 patients with JIA and 88 healthy controls ages 13-18 years completed questionnaires on anxiety and depressive symptoms. For patients with JIA, pain, disability, physician global assessment (using a visual analog scale [VAS]), and number of joints with active inflammation (active joint count) were recorded. In a subsample, we assessed lipopolysaccharide-stimulated interleukin 6 (IL-6) production from peripheral blood mononuclear cells, serum IL-6, cortisol, and C-reactive protein levels. Data were analyzed by linear regression analysis. Results Levels of anxiety and depressive symptoms in patients with JIA were not significantly different than those in healthy controls. For patients with JIA, anxiety was significantly associated with disability (β = 0.009, P = 0.002), pain (β = 0.029, P = 0.011), and physician global assessment VAS (β = 0.019, P = 0.012), but not with active joint count (β = 0.014, P = 0.120). Anxiety was not associated with any laboratory measures of inflammation for JIA patients. These relationships were also true for depressive symptoms. For healthy controls, there was a trend toward an association of anxiety (but not depressive symptoms) with stimulated IL-6 (β = 0.004, P = 0.052). Conclusion Adolescent patients with JIA experience equivalent levels of anxiety and depressive symptoms as healthy adolescents. For adolescent patients with JIA, anxiety and depressive symptoms are associated with pain, disability, and physician global assessment VAS, but not with inflammation.

Photoreceptor cell transplantation into the mouse retina has been shown to result in the transfer of cytoplasmic material between donor and host photoreceptors. Recently it has been found that this inter-photoreceptor material transfer process is likely to be mediated by nanotube-like structures connecting donor and host photoreceptors. By leveraging cone-specific reporter mice and super-resolution microscopy we provide evidence for the transfer of cytoplasmic material also from endogenous cones to endogenous rod photoreceptors and the existence of nanotube-like cell-cell connections possibly mediating this process in the adult mouse retina, together with preliminary data indicating that horizontal material transfer may also occur in the human retina.

Cone Dystrophy with Supernormal Rod Response (CDSRR) is a rare autosomal recessive disorder leading to severe visual impairment in humans, but little is known about its unique pathophysiology. We have previously shown that CDSRR is caused by mutations in the KCNV2 (Potassium Voltage-Gated Channel Modifier Subfamily V Member 2) gene encoding the Kv8.2 subunit, a modulatory subunit of voltage-gated potassium (Kv) channels. In a recent study, we validated a novel mouse model of Kv8.2 deficiency at a late stage of the disease and showed that it replicates the human electroretinogram (ERG) phenotype. In this current study, we focused our investigation on young adult retinas to look for early markers of disease and evaluate their effect on retinal morphology, electrophysiology and immune response in both the Kv8.2 knockout (KO) mouse and in the Kv2.1 KO mouse, the obligate partner of Kv8.2 in functional retinal Kv channels. By evaluating the severity of retinal dystrophy in these KO models, we demonstrated that retinas of Kv KO mice have significantly higher apoptotic cells, a thinner outer nuclear cell layer and increased activated microglia cells in the subretinal space. Our results indicate that in the murine retina, the loss of Kv8.2 subunits contributes to early cellular and physiological changes leading to retinal dysfunction. These results could have potential implications in the early management of CDSRR despite its relatively nonprogressive nature in humans.

While comorbidity between coronary heart disease (CHD) and depression is evident, it is unclear whether the two diseases have shared underlying mechanisms. We performed a range of analyses in 367,703 unrelated middle-aged participants of European ancestry from UK Biobank, a population-based cohort study, to assess whether comorbidity is primarily due to genetic or environmental factors, and to test whether cardiovascular risk factors and CHD are likely to be causally related to depression using Mendelian randomization. We showed family history of heart disease was associated with a 20% increase in depression risk (95% confidence interval [CI] 16–24%, p

Usher syndrome is a genetic disorder causing neurosensory hearing loss and blindness from retinitis pigmentosa (RP). Adaptive techniques such as braille, digital and optical magnifiers, mobility training, cochlear implants, or other assistive listening devices are indispensable for reducing disability. However, there is currently no treatment to reduce or arrest sensory cell degeneration. There are several classes of treatments for Usher syndrome being investigated. The present article reviews the progress this research has made towards delivering commercial options for patients with Usher syndrome.

Resumo O pseudoaneurisma da artéria esplênica é uma entidade rara, com pouco mais de 150 casos descritos na literatura. A pancreatite é a etiologia mais comum, seguida do trauma. Em contraposição ao aneurisma verdadeiro, esse pseudoaneurisma é frequentemente sintomático, com risco de ruptura de 47% e mortalidade de 90%, quando não tratado. Descrevemos o caso de uma paciente de 48 anos que apresentou hemorragia gastrointestinal associada a pancreatite crônica agudizada. Durante investigação, a endoscopia evidenciou sinais de sangramento recente, e a angiorressonância de abdome observou volumoso pseudoaneurisma da artéria esplênica. Foi submetida a tratamento endovascular com embolização com micromolas, não apresentando novos episódios de sangramento. Atualmente, o tratamento endovascular é efetivo com baixa morbimortalidade e taxas de sucesso de 79-100%, sendo uma técnica viável para pacientes com processo inflamatório abdominal em franca atividade. Realizamos uma revisão das técnicas endovasculares e agentes embolizantes usados para o tratamento dessa patologia.

Integrated production systems have been used with various crops, and their use in floriculture is innovative. The effects of green fertilization in floriculture and the appropriate fertilization levels are still unknown. The aim was to identify the best dose of chemical fertilizer, with or without green fertilization, for integrated production of ‘Carola’ roses. The treatments consisted of 4 doses of the chemical fertilization recommended for rose bushes, (25%, 50%, 75%, and 100%), with or without green fertilization (calopo). Plants that were not treated with 100% (or complete) of chemical fertilization were supplemented monthly with Bokashi (16 g/plant, via the soil) and biofertilizer (5% via the leaves). The assessments were conducted 3 times per week for a year. The use of less chemical fertilizer did not affect rose production or quality, whereas the use of green fertilization did not provide a satisfactory outcome. The analyses, biometric, accumulation and nutrient content, and chemical characteristics of the soil, indicated that green fertilization with calopo was not beneficial. Moreover, with the exception of nitrogen and magnesium, there is the possibility of using 75% of the recommended chemical fertilization in rose bushes. Resumo O sistema de produção integrada vem sendo utilizado em várias culturas, sendo inovador o seu uso em floricultura. Nessa atividade ainda são desconhecidos os efeitos de adubação verde ainda como os níveis de adubação fornecidos não são precisos. O objetivo foi identificar a melhor dose de adubo químico associado ou não à adubação verde, em produção integrada de rosas ‘Carola’. Os tratamentos consistiram de quatro porcentagens de adubação química, segundo a recomendação para Minas Gerais, (25%, 50%, 75% e 100%) associado ou não à adubação verde (calopogônio). Plantas que não receberam 100% da adubação química receberam a complementação de Bokashi (16 g/planta, via solo) e biofertilizante (5% foliar), em aplicações mensais. As avaliações foram realizadas três vezes por semana em um ano. A redução da adubação química não prejudicou a produção e qualidade das rosas, mas o adubo verde não foi benéfico. Os resultados das análises biométricas, de acúmulo, teor de nutrientes e características químicas do solo indicam que a adubação verde com calopogônio não é eficiente e, exceto para nitrogênio e magnésio, há possibilidade de utilização de até 75% da adubação química recomendada.

Mutations in theKCNV2gene, which encodes the voltage-gated K+channel protein Kv8.2, cause a distinctive form of cone dystrophy with a supernormal rod response (CDSRR). Kv8.2 channel subunits only form functional channels when combined in a heterotetramer with Kv2.1 subunits encoded by theKCNB1gene. The CDSRR disease phenotype indicates that photoreceptor adaptation is disrupted. The electroretinogram (ERG) response of affected individuals shows depressed rod and cone activity, but what distinguishes this disease is the supernormal rod response to a bright flash of light. Here, we have utilized knock-out mutations of both genes in the mouse to study the pathophysiology of CDSRR. The Kv8.2 knock-out (KO) mice show many similarities to the human disorder, including a depressed a-wave and an elevated b-wave response with bright light stimulation. Optical coherence tomography (OCT) imaging and immunohistochemistry indicate that the changes in six-month-old Kv8.2 KO retinae are largely limited to the outer nuclear layer (ONL), while outer segments appear intact. In addition, there is a significant increase in TUNEL-positive cells throughout the retina. The Kv2.1 KO and double KO mice also show a severely depressed a-wave, but the elevated b-wave response is absent. Interestingly, in all three KO genotypes, the c-wave is totally absent. The differential response shown here of these KO lines, that either possess homomeric channels or lack channels completely, has provided further insights into the role of K+channels in the generation of the a-, b-, and c-wave components of the ERG.

Background: This study evaluates whether the initial amount of dietary protein intake could influence the combined effect of high-intensity interval training (HIIT) and citrulline (CIT), or HIIT alone, on body composition, muscle strength, and functional capacities in obese older adults. Methods: Seventy-three sedentary obese older men and women who completed a 12-week elliptical HIIT program with double-blinded randomized supplementation of CIT or placebo (PLA) were divided into four groups according to their initial protein intake (CIT&ndash, PROT+: n = 21, CIT&ndash, PROT&minus, n = 19, PLA&ndash, PROT+: n = 19, n = 14). Body composition (fat and fat-free masses), handgrip (HSr) strength, knee extensor (KESr) strength, muscle power, and functional capacities were measured pre-intervention and post-intervention. Results: Following the intervention, the four groups improved significantly regarding all the parameters measured. For the same initial amount of protein intake, the CIT&ndash, group decreased more gynoid fat mass (p = 0.04) than the PLA&ndash, group. The CIT&ndash, PROT+ group increased more KESr (p = 0.04) than the PLA&ndash, PROT+ group. In addition, the CIT&ndash, group decreased more gynoid FM (p = 0.02) and improved more leg FFM (p = 0.02) and HSr (p = 0.02) than the CIT&ndash, PROT+ group. Conclusion: HIIT combined with CIT induced greater positive changes than in the PLA groups. The combination seems more beneficial in participants consuming less than 1 g/kg/d of protein, since greater improvements on body composition and muscle strength were observed.

[Background]: Tryptophan breakdown is an important mechanism in several diseases e.g. inflammation and stress-induced inflammation have been associated with the development of depression via enhanced tryptophan breakdown. Depression is a major public health problem which commonly starts during adolescence, thus identifying underlying mechanisms during early life is crucial in prevention. The aim of this work was to verify whether independent and interacting associations of psychosocial stress and inflammation on tryptophan breakdown already exist in children and adolescents as a vulnerable age group., [Methods]: Two cross-sectional population-based samples of children/adolescents (8–18 y) were available: 315 from the European HELENA study and 164 from the Belgian ChiBS study. In fasting serum samples, tryptophan, kynurenine, kynurenic acid, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-ɣ, soluble vascular adhesion molecule 1 (sVCAM1) and soluble intercellular adhesion molecule 1 (sICAM1) were measured. Psychological stress was measured by stress reports (subjective) and cortisol (objective – awakening salivary cortisol or hair cortisol). Linear regressions with stress or inflammation as predictor were adjusted for age, sex, body mass index, puberty, socio-economic status and country., [Results]: In both cohorts, inflammation as measured by higher levels of CRP, sVCAM1 and sICAM1 was associated with kynurenine/tryptophan ratio and thus enhanced tryptophan breakdown (beta: 0.145–0.429). Psychological stress was only associated with tryptophan breakdown in the presence of higher inflammatory levels (TNF-α in both populations)., [Conclusions]: Inflammatory levels were replicable key in enhancing tryptophan breakdown along the kynurenine pathway, even at young age and in a non-clinical sample. The stress-inflammation interaction indicated that only the stress exposures inducing higher inflammatory levels (or in an already existing inflammatory status) were associated with more tryptophan breakdown. This data further contributes to our understanding of pathways to disease development, and may help identifying those more likely to develop stress or inflammation-related illnesses., This work was supported by the Research Foundation – Flanders (grant number FWO.3E0.2015.0043.01 and FWO.KAN.2015.0017.01). The HELENA Study was carried out with the financial support of the European Community Sixth RTD Framework Programme (Contract FOODCT-2005-007034). The writing group takes sole responsibility for the content of this article. The European Community is not liable for any use that may be made of the information contained therein. The hair cortisol analyses were sponsored by the Institute for the Promotion of Innovation through Science and Technology in Flanders (grant number SBO-120054). Livia A. Carvalho is funded by the MRC Immunopsychiatry Consortium (RG71546)

Background: To compare the effects of high-intensity interval training (HIIT) alone vs. HIIT combined with L-citrulline (CIT) supplementation on functional capacity and muscle function in dynapenic-obese elderly. Methods: A total of 56 obese (fat mass: men &gt, 25%, women &gt, 35%) and dynapenic (grip strength/body weight: women &lt, 0.44, men &lt, 0.61) subjects were recruited and divided in two groups: HIIT+CIT (n = 26, age: 6 5 &plusmn, four years) vs. HIIT+Placebo (PLA, n = 30, age: 68 &plusmn, four years). Participants followed a 12-week HIIT using an elliptical trainer. Participants took a single and isocaloric 10 g-dose of CIT or PLA every day. Body composition, functional and aerobic capacities, absolute or relative upper and lower limbs muscle strength, muscle power, and energy balance were measured pre and post intervention. Results: Both groups significantly improved functional capacity and muscle function. However, HIIT+CIT demonstrated greater improvements in fast-paced Timed Up &amp, Go (p = 0.04) and upper limbs muscle strength (absolute and relative) (p = 0.05) than HIIT+Placebo. Conclusion: CIT supplementation when combined with HIIT seems to induce greater improvements in upper limbs muscle strength and walking speed in dynapenic-obese elderly. Further studies are needed to confirm our results, to elucidate the mechanisms underlying the beneficial effects of CIT and to define the long-term impact of CIT/HIIT.

Widespread gene transfer to the retina is challenging as it requires vector systems to overcome physical and biochemical barriers to enter and diffuse throughout retinal tissue. We investigated whether exosome-associated adeno-associated virus, (exo-AAV) enabled broad retinal targeting following intravitreal (IVT) injection, as exosomes have been shown to traverse biological barriers and mediate widespread distribution upon systemic injection. We packaged an AAV genome encoding green fluorescent protein (GFP) into conventional AAV2 and exo-AAV2 vectors. Vectors were IVT injected into the eyes of adult mice. GFP expression was noninvasively monitored by fundus imaging and retinal expression was analyzed 4 weeks post-injection by qRT-PCR and histology. Exo-AAV2 outperformed conventional AAV2 in GFP expression based on fundus image analysis and qRT-PCR. Exo-AAV2 demonstrated deeper penetration in the retina, efficiently reaching the inner nuclear and outer plexiform, and to a lesser extent the outer nuclear layer. Cell targets were ganglion cells, bipolar cells, Müller cells, and photoreceptors. Exo-AAV2 serves as a robust gene delivery tool for murine retina, and the simplicity of production and isolation should make it widely applicable to basic research of the eye.

Growing numbers of mental health organizations are developing community music-making interventions for service users; however, to date there has been little research into their efficacy or mechanisms of effect. This study was an exploratory examination of whether 10 weeks of group drumming could improve depression, anxiety and social resilience among service users compared with a non-music control group (with participants allocated to group by geographical location.) Significant improvements were found in the drumming group but not the control group: by week 6 there were decreases in depression (-2.14 SE 0.50 CI -3.16 to -1.11) and increases in social resilience (7.69 SE 2.00 CI 3.60 to 11.78), and by week 10 these had further improved (depression: -3.41 SE 0.62 CI -4.68 to -2.15; social resilience: 10.59 SE 1.78 CI 6.94 to 14.24) alongside significant improvements in anxiety (-2.21 SE 0.50 CI -3.24 to -1.19) and mental wellbeing (6.14 SE 0.92 CI 4.25 to 8.04). All significant changes were maintained at 3 months follow-up. Furthermore, it is now recognised that many mental health conditions are characterised by underlying inflammatory immune responses. Consequently, participants in the drumming group also provided saliva samples to test for cortisol and the cytokines interleukin (IL) 4, IL6, IL17, tumour necrosis factor alpha (TNFα), and monocyte chemoattractant protein (MCP) 1. Across the 10 weeks there was a shift away from a pro-inflammatory towards an anti-inflammatory immune profile. Consequently, this study demonstrates the psychological benefits of group drumming and also suggests underlying biological effects, supporting its therapeutic potential for mental health.\ud \ud A video relating to this article is viewable via Google Chrome at: https://www.youtube.com/watch?v=VnferrIKPOg

Obsessional states show an average point prevalence of 1%-3% and a lifetime prevalence of 2%-2.5%. Most treatment-seeking patients with obsessions continue to experience significant symptoms after 2 years of prospective follow-up. A significant burden of impairment, distress, and comorbidity characterize the course of the illness, leading to an increased need for a better understanding of the nature and management of this condition. This review aims to give a representation of the current pharmacological and psychotherapeutic strategies used in the treatment of obsessive-compulsive disorder. Antidepressants (clomipramine and selective serotonin reuptake inhibitors) are generally the first-line choice used to handle obsessional states, showing good response rates and long-term positive outcomes. About 40% of patients fail to respond to selective serotonin reuptake inhibitors. So far, additional pharmacological treatment strategies have been shown to be effective, ie, administration of high doses of selective serotonin reuptake inhibitors, as well as combinations of different drugs, such as dopamine antagonists, are considered efficacious and well tolerated strategies in terms of symptom remission and side effects. Psychotherapy also plays an important role in the management of obsessive-compulsive disorder, being effective for a wide range of symptoms, and many studies have assessed its long-term efficacy, especially when added to appropriate pharmacotherapy. In this paper, we also give a description of the clinical and psychological features likely to characterize patients refractory to treatment for this illness, with the aim of highlighting the need for greater attention to more patient-oriented management of the disease.

Introduction: Immune activation is a characteristic of schizophrenia (SCZ), bipolar disorder (BD) and unipolar major depressive disorder (MDD). The triggering receptor expressed on myeloid cells 1 (TREM-1), its' adaptor molecule DAP12 and their transcription factor (TF) PU.1 are important key genes in inflammation and expressed in activated monocytes and microglia. Aim: To test: (1) if the expressions of TREM-1, DAP12 and PU.1 are increased in monocytes of patients with severe psychiatric disorders and (2) if PU.1 and the TFs ATF3 and EGR3 (which have been found as prominent increased monocyte genes in previous studies) are involved in the regulation of TREM-1 and DAP12 expression. Methods: Using Q-PCR, we studied the gene expression of TREM-1, DAP12, PU.1, ATF3 and EGR3 in the monocytes of 73 patients with severe psychiatric disorders (27 recent onset SCZ patients, 22 BD patients and 24 MDD patients) and of 79 healthy controls (HC). Using in silico TF binding site prediction and in vivo chromatin immunoprecipitation (ChIP), we studied the actual binding of EGR3, ATF3 and PU.1 to the promoter regions of TREM-1 and DAP12. Results: 1. TREM-1 gene expression was increased in the monocytes of SCZ and BD patients and tended to be increased in the monocytes of MDD patients. 2. DAP12 gene levels were neither increased in the monocytes of SCZ, BD, nor MDD patients. 3. PU.1 expression levels were increased in the monocytes of MDD patients, but not in those of SCZ and BD patients. 4. TREM-1 expression levels correlated in particular to ATF3 and EGR3 expression levels, DAP12 expression levels correlated in particular to PU.1 expression levels. 5. We found using binding site prediction and ChIP assays that the TFs EGR3 and ATF3 indeed bound to the TREM-1 promoter, PU.1 bound to both the TREM-1 and DAP12 promoter. Conclusion: In this study, we provide evidence that TREM-1 gene expression is significantly increased in monocytes of SCZ and BD patients and that the TREM-1 gene is a target gene of the TFs ATF3 and EGR3. In MDD patients, PU.1 gene expression was increased with a tendency for TREM-1 gene over expression. Our observations support the concept that monocytes are in a pro-inflammatory state in severe psychiatric conditions and suggest differences in monocyte inflammatory set points between SCZ. BD and MDD. (C) 2011 Elsevier Inc. All rights reserved.

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3-10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5'-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27(Kip1) and p57(Kip2). In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.

The purpose of this study was to analyze glutathione antioxidant defense system in elderly patients treated for hypertension. Studies were carried out in the blood collected from 18 hypertensive and 15 age- and sex-matched controls, all subjects age over 60. Hypertensives were on their usual antihypertensive treatment at the time of blood collection. The concentration of glutathione (GSH) in whole blood and activities of glutathione peroxidase (GPx-1), glutathione transferase (GST), and glutathione reductase (GR) in erythrocytes were measured. The data from patients and controls were compared using independent-samples t test. P value of 0.05 and less was considered statistically significant. We observed increased glutathione-related antioxidant defense in treated hypertensive elderly patients (HT) when compared with healthy controls (C). Mean GSH concentration was significantly higher in HT when compared with C: 3.1 ± 0.29 and 2.6 ± 0.25 mmol/L, respectively, P < 0.001. Mean activity of GR was significantly higher in HT group if compared with C: 83.4 ± 15.25 U/g Hb versus 64.2 ± 8.26 U/g Hb, respectively, P < 0.001. Mean activity of GST was significantly higher in HT group compared with C: 3.0 ± 0.60 mmol CDNB-GSH/mgHb/min and 2.6 ± 0.36 mmol CDNB-GSH/mgHb/min, respectively, P < 0.05. No difference in GPx activity was observed between two groups. These results show that glutathione-related antioxidant defense system was enhanced in elderly hypertensive patients treated for their conditions. This suggests important role of glutathione system in blood pressure regulation. Alterations in concentration and activity of antioxidants observed during antihypertensive medication are likely to be related to the effect of the treatment on NO bioavailability.

Objective Inflammatory processes may play an important role in the development of acute coronary syndromes in people with type 2 diabetes; thus, strategies to control inflammation are of clinical importance. We examined the cross-sectional association between objectively assessed physical activity and inflammatory markers in a sample of people with type 2 diabetes. Methods Participants were 71 men and 41 women (mean age=63.9±7 years), without a history of cardiovascular disease, drawn from primary care clinics. Physical activity was objectively measured using waist-worn accelerometers (Actigraph GT3X) during waking hours for seven consecutive days. Results We observed inverse associations between moderate-to-vigorous physical activity (per 10 min) with plasma interleukin-6 (B=−0.035, 95% CI −0.056 to −0.015), interleukin-1ra (B=−0.033, 95% CI −0.051 to −0.015), and monocyte chemotactic protein-1 (B=−0.011, 95% CI −0.021 to 0.000). These associations largely persisted in multivariable adjusted models, although body mass index considerably attenuated the effect estimate. Conclusions These data demonstrate an inverse association between physical activity and inflammatory markers in people with type 2 diabetes.

Background Shorter telomere length and poor sleep are more prevalent at older ages, but their relationship is uncertain. This study explored associations between sleep duration and telomere length in a sample of healthy middle and early old age people. Methods Participants were 434 men and women aged 63.3 years on average drawn from the Whitehall II cohort study. Sleep duration was measured by self-report. Results There was a linear association between sleep duration and leukocyte telomere length in men but not in women (P = 0.035). Men reporting shorter sleep duration had shorter telomeres, independently of age, body mass index, smoking, educational attainment, current employment, cynical hostility scores and depressive symptoms. Telomeres were on average 6% shorter in men sleeping 5 hours or fewer compared with those sleeping more than 7 hours per night. Conclusion This study adds to the growing literature relating sleep duration with biomarkers of aging, and suggests that shortening of telomeres might reflect mechanisms through which short sleep contributes to pathological conditions in older men.

Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/-)/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling.

Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 muM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.

The maturity in our understanding of the genetics and the pathogenesis of disease in degenerative retinal disorders has intersected in past years with a novel treatment paradigm in which a genetic intervention may lead to sustained therapeutic benefit, and in some cases even restoration of vision. Here, we review this prospect of retinal gene therapy, discuss the enabling technologies that have led to first-in-human demonstrations of efficacy and safety, and the road that led to this exciting point in time.

Neurotrophic factors regulate the survival and growth of neurons, and influence synaptic efficiency and plasticity. Several studies suggest the existence of a relationship between changes in neurotrophic levels and bipolar disorder (BD). The glial cell-line derived neurotrophic factor (GDNF) influences monoaminergic neurons and glial cells, but its role in BD patients is controversial. In order to elucidate it we evaluated plasma levels of GDNF in a sample of 70 BD patients (35 in mania and 35 in euthymia) and compared with 50 healthy controls matched for age, gender and educational levels. GDNF plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were assessed by a Mini-International Neuropsychiatric Interview (MINI-plus), Young Mania and Hamilton Depression Rating Scales. Plasma GDNF levels were significantly increased in BD patients in euthymia compared with BD patients in mania and healthy controls (p

The ancestral complement of cone visual pigments in vertebrates comprises four classes whose protein components are encoded by opsin genes and whose spectral sensitivities range from ultraviolet to red. This complement has been retained throughout the radiations of teleosts, amphibians, reptiles and birds. However, eutherian mammals have lost the shortwave-sensitive-2 (SWS2) and middlewave-sensitive (Rh2) classes [1] and retain only the longwave-sensitive (LWS) and shortwave-sensitive-1 (SWS1) classes.