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Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3 mutations.

In the present study, CSF concentrations of NFL, t-tau, p-tau, GFAP, S-100B, YKL-40, MCP-1, α-sAPP, β-sAPP, and Aβ38, Aβ40, Aβ42 were measured in 324 MS patients to test whether a correlation among the biomarkers exists and whether the profile of CSF biomarkers varies among the different types of MS. The CSF concentrations of NFL were significantly higher in RRMS while CSF concentrations of GFAP were higher in PPMS. CSF concentrations of NFL correlated with YKL-40 in CIS patients while CSF concentrations of GFAP correlated with YKL-40 in RRMS patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Cell-adhesion molecules (CAMs) dynamics in Multiple Sclerosis (MS) patients have been widely studied after Natalizumab (NTZ) introduction. However, their temporal dynamics after NTZ withdrawal (NTZ-W) has not been described. We prospectively evaluate changes in the expression levels of CAMs (CD49d, CD29, L-Selectin and CD11a) involved in T cell migration of 22 MS patients after NTZ-W. CD49d, CD29 and CD11a expression experienced a continuous increase expression two months after NTZ-W and Cd49d expression at month six after NTZ-W correlated to NTZ treatment duration, both in CD45 + CD4 + and CD45 + CD8 + . CD49d expression up to month three after NTZ-W was related to MS activity in CD45 + CD8 + at the end of the study. Results from this study suggest that patients with a longer NTZ treatment are more susceptible to present a "molecular rebound" after NTZ-W. CD49d determination may be a useful tool to closely monitor MS activity in patients who interrupt NTZ., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The view that the functional maturation of the brain is the result of an environmentally driven adaptation of genetically preprogrammed neuronal networks is an important current concept in developmental neuroscience and psychology. This hypothesis proposes that early traumatic experiences or early life stress (ELS) as a negative environmental experience provide a major risk factor for the development of dysfunctional brain circuits and as a consequence for the emergence of behavioral dysfunctions and mental disorders in later life periods. This view is supported by an increasing number of clinical as well as experimental animal studies revealing that early life traumas can induce functional 'scars' in the brain, especially in brain circuits, which are essential for emotional control, learning, and memory functions. Such gene × environment interactions are modulated by specific epigenetic mechanisms, which are suggested to be the key factors of transgenerational epigenetic inheritance. Indeed, there is increasing evidence for inter- and transgenerational cycles of environmentally driven neuronal and behavioral adaptations mediated by epigenetic mechanisms. Finally, recent concepts postulate that, dependent on type, time point, and duration of ELS exposure, also positive functional adaptations may occur in the relevant brain pathways, leading to better stress coping and resilience against adversities later in life.

The aim of this study is to investigate whether induction of myxovirus resistance protein A (MxA) mRNA after 3 months of interferon-β administration is related to the treatment response in multiple sclerosis (MS) patients. In this prospective study, MS patients were enrolled before starting treatment. Demographic, clinical and radiological variables were recorded. Blood samples were obtained before, and at 3 and 12 months after interferon-β treatment. Real-time PCR was used to analyze MxA mRNA expression. Patients were classified as MxA-low or -high depending on MxA levels at baseline, and as MxA-induced or -non-induced according to whether an increase in MxA expression was detected at month 3. Time to the next relapse was investigated using Cox proportional hazards regression analysis. One hundred and four patients were selected and followed for a median of 2.2 years (IQR 1.6-3.5). On Cox regression analysis, a higher EDSS score before treatment (HR 1.57; 95 % CI 1.02-2.40; p = 0.039), MxA-high status at baseline (HR 2.71; 95 % CI 1.26-5.81; p = 0.010), and MxA-non-induced at month 3 (HR 2.49; 95 % CI 1.08-5.68; p = 0.031), were predictors of poor response to interferon-β in naïve MS patients. Patients showing a lower capacity for MxA induction following 3 months of interferon-β treatment are more likely to be non-responders to this therapy.

Stress and the major stress hormone corticosterone induce profound influences in the brain. Altered histone modification and transcriptional dysfunction have been implicated in stress-related mental disorders. We previously found that repeated stress caused an impairment of prefrontal cortex (PFC)-mediated cognitive functions by increasing the ubiquitination and degradation of AMPA-type glutamate receptors via a mechanism depending on the E3 ubiquitin ligase Nedd4. Here, we demonstrated that in PFC of repeatedly stressed rats, active glucocorticoid receptor had the increased binding to the glucocorticoid response element of histone deacetylase 2 (HDAC2) promoter, resulting in the upregulation of HDAC2. Inhibition or knock-down of HDAC2 blocked the stress-induced impairment of synaptic transmission, AMPAR expression, and recognition memory. Furthermore, we found that, in stressed animals, the HDAC2-dependent downregulation of histone methyltransferase Ehmt2 (G9a) led to the loss of repressive histone methylation at the Nedd4-1 promoter and the transcriptional activation of Nedd4. These results have provided an epigenetic mechanism and a potential treatment strategy for the detrimental effects of chronic stress., Significance Statement: Prolonged stress exposure can induce altered histone modification and transcriptional dysfunction, which may underlie the profound influence of stress in regulating brain functions. We report an important finding about the epigenetic mechanism controlling the detrimental effects of repeated stress on synaptic transmission and cognitive function. First, it has revealed the stress-induced alteration of key epigenetic regulators HDAC2 and Ehmt2, which determines the synaptic and behavioral effects of repeated stress. Second, it has uncovered the stress-induced histone modification of the target gene Nedd4, an E3 ligase that is critically involved in the ubiquitination and degradation of AMPA receptors and cognition. Third, it has provided the epigenetic approach, HDAC2 inhibition or knock-down, to rescue synaptic and cognitive functions in stressed animals., (Copyright © 2016 the authors 0270-6474/16/362119-12$15.00/0.)

Myxovirus resistance protein A (MxA) is a molecule induced after interferon-β injection. The aim of this study was to investigate whether MxA determination one year after starting interferon-β can predict treatment response in multiple sclerosis patients. MxA mRNA expression was evaluated in blood samples obtained at baseline and at month 12. Clinical variables were prospectively recorded. A threshold of 5 was defined to establish MxA induction. On survival analysis, time to the next relapse and to EDSS progression were significantly longer in patients showing MxA induction, suggesting that MxA induction after one year may be useful to identify interferon-β responders., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The development of the brain depends on an individual's nature (genes) and nurture (environments). This interaction between genetic predispositions and environmental events during brain development drives the maturation of functional brain circuits such as sensory, motor, emotional, and complex cognitive pathways. Adverse environmental conditions such as early life stress can interfere with the functional development of emotional and cognitive brain systems and thereby increase the risk of developing psychiatric disorders later in life. In order to develop more efficient and individualized protective and therapeutic interventions, it is essential to understand how environmental stressors during infancy affect cellular and molecular mechanisms involved in brain maturation. Animal models of early life stress have been able to reveal brain structural and metabolic changes in prefrontolimbic circuits, which are time, brain region, neuron, and sex specific. By focusing on animal models of separation stress during infancy, this review highlights epigenetic and cytoarchitectural modifications which are assumed to mediate lasting changes of brain function and behavior., (© 2016 S. Karger AG, Basel.)

Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging, and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDA receptor (NMDAR) synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism-like phenotypes. Thus, targeting actin regulators provides a strategy for autism treatment., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate glial and neuronal biomarkers in cerebrospinal fluid (CSF) samples from patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), and to evaluate their ability to predict conversion from CIS to clinically definite MS (CDMS) and also disability progression in MS., Methods: CSF levels of neurofilament light protein (NFL), t-tau, p-tau, glial fibrillary acidic protein (GFAP), S-100B, human chitinase 3-like 1 protein (YKL-40), monocyte chemoattractant protein-1 (MCP-1), α-sAPP and β-sAPP; and Aβ38, Aβ40 and Aβ42, were analyzed in 109 CIS patients and 192 RRMS patients. The mean follow-up time of these 301 patients was 11.7 ± 6.4 years., Results: High levels of NFL were associated with early conversion from CIS to CDMS (hazard ratio (HR) with 95% confidence interval (CI): 2.69 (1.75 - 4.15); p < 0.0001). High levels of YKL-40 and GFAP were associated with earlier progression in the Expanded Disability Status Scale (EDSS), score 3: YKL-40 (HR (95% CI): 2.78 (1.48 - 5.23); p = 0.001) and GFAP (HR (95% CI): 1.83 (1.01 - 3.35); p = 0.04). High levels of YKL-40 were associated with earlier progression to EDSS 6 (HR (95% CI): 4.57 (1.01 - 20.83); p = 0.05)., Conclusions: CSF levels of NFL in CIS patients are an independent prognostic marker for conversion to CDMS. Whereas, CSF levels of YKL-40 and GFAP are independent prognostic markers for disability progression in MS., (© The Author(s), 2015.)

Introduction: We evaluated the effectiveness of natalizumab in patients with highly active, relapsing-remitting multiple sclerosis (HA-RRMS) to identify baseline predictors associated with freedom from disease activity., Methods: We analyzed 70 patients treated with natalizumab and followed for at least 1 year with progression of disability of ≥1 point on the EDSS before starting therapy. We recorded freedom from clinical activity, radiological activity, and disease activity (clinical and radiological)., Results: The median (IQR) follow-up was 2.3 (2.0-3.8) years. Of the 52 patients who completed 2 years of treatment, 25 were free of disease activity (48.1%). The ARR decreased from a mean ± SD of 2.49 ± 0.86 at baseline to 0.47 ± 0.83 at the end of the first year (p < 0.001) and 0.34 ± 0.69 at the end of the second year (p < 0.001). The percentage of patients with gadolinium-enhanced lesions decreased from 21 at baseline to 5.7 at the end of the first year (p < 0.001) and to 5.8 during the second year (p < 0.005). Baseline EDSS ≤3.0 was significantly associated with freedom from disease activity (OR, 2.49; 95% CI, 1.24-4.99; p = 0.010)., Conclusions: Natalizumab is effective in patients with HA-RRMS. Baseline EDSS ≤3.0 increases the probability of remaining disease-free in HA-RRMS treated with natalizumab., (© 2015 S. Karger AG, Basel.)

Background: Myxovirus resistance protein A (MxA) is a molecule induced after interferon-beta injection, mostly used to evaluate its bioactivity. There is little available data on clinical utility of baseline MxA mRNA status. The objective of the study is to investigate whether baseline MxA mRNA expression can predict relapse and disease progression in multiple sclerosis patients treated with interferon-beta., Methods: Baseline blood samples were obtained before the first interferon-beta dose was administered to evaluate MxA mRNA expression using real-time polymerase chain reaction (PCR). Demographic and clinical variables were prospectively recorded to define treatment responder and non responder groups., Results: 104 patients were included in the study. Baseline MxA mRNA expression was significantly lower in the group of patients who met the definition of responders (1.07 vs 1.95, Student t test, p<0.0001). A threshold of 1.096 was established using Receiver Operating Characteristic analysis to differentiate between responders and non-responders (sensitivity 73.9%, specificity 69.0%). Survival analysis using this threshold showed that time to next relapse (p<0.0001) and to EDSS progression (p = 0.01) were significantly higher in patients with lower MxA titers., Conclusion: The results suggest that baseline MxA mRNA levels may be useful for predicting whether multiple sclerosis patients will respond or not to interferon-beta treatment.

Background: Patients with a first episode of longitudinal extensive transverse myelopathy (LETM) were reviewed with two objectives: to evaluate the clinical spectrum of LETM and to analyze the related clinical and laboratory variables that can be used as functional prognostic markers., Methods: A retrospective review was conducted of clinical, radiologic and biochemical data of patients admitted for LETM between 1993 and 2011., Results: Our cohort included 72 patients [median age 41 years, interquartile range (IQR) 29-61.5]. Median follow-up was 34 months (IQR 17.2-63). The modified Rankin Scale (mRS) score was ≥2 at the end of follow-up in 72.2%. The final diagnosis was idiopathic LETM in 22 patients, multiple sclerosis in 18, parainfectious disease in 11, systemic disease in 9, spinal cord infarction and neuromyelitis optica spectrum disorders in 3 patients each, and acute demyelinating encephalomyelitis, dural fistula, and tumor-related LETM in 2 patients each. Unfavorable outcome was associated with mRS ≥2 at admission [odds ratio (OR) 1.39, 95% confidence interval (CI) 1.16-1.66] and older age (OR 1.06, 95% CI 1.01-1.11)., Conclusion: Idiopathic LETM was the most frequent diagnosis at the end of follow-up. Older age and clinically severe disease at onset were independent prognostic factors of poorer functional recovery., (© 2014 S. Karger AG, Basel.)

Vaccines are powerful public health tools that have been of tremendous benefit in protecting vulnerable populations worldwide from many pathogens. However, vaccine- preventable diseases still remain a considerable burden and this is particularly true among aging and aged populations in industrialized countries. The predicted demographic shift in the population landscape towards an ever-increasing aging population and the evidence suggesting that older individuals mount less-than optimal immune response to vaccination have raised the question of improving vaccine responses in older individuals. This review presents recent progress in the understanding at the cellular and molecular levels of age related immune decline and strategies to translate current knowledge into the development of immunization strategies to promote healthy aging, keeping older members of our society autonomous and independent.

Age-associated atrophy of the thymus with coincident reduction in thymopoeisis, decline in thymic output, and subsequent immune dysfunction has been reversed by the use of interleukin-7 (IL-7). In the earlier studies and in clinical trials, delivery of IL-7 has been by multiple injections over several days to maintain effective activity levels in the tissues. This is unlikely to meet with high compliance rates in future clinical use, and so we tested alternate routes of delivery using a technique involving tagging IL-7 with fluorescent dye that emits in the near-infrared region and whose fluorescence can be visualized within the tissues of live animals. We have shown that intratracheal instillation, enabling transfer through the lungs, provides an effective route for delivering IL-7 into the bloodstream and from there into the tissues in older animals. Delivery is rapid and widespread tissue distribution is seen. Comparison of administration either subcutaneously or by instillation reveals that IL-7 delivery by the pulmonary route provides significantly greater transmission to lymphoid tissues when compared with injection. In functional assessment studies, pulmonary administration led to significantly improved intrathymic T cell development in older animals when compared with IL-7 delivered by injection. Furthermore, in these older animals, delivery of IL-7 by intratracheal instillation was not accompanied by any apparent adverse events when compared with controls receiving saline vehicle by instillation or animals receiving IL-7 by subcutaneous injection.

Background and Objective: Multiple sclerosis (MS) has been consistently associated with the HLA-DR2 haplotype and particularly with the HLA-DRB1*15 allele. Epistatic interactions between both parental alleles in the DRB1 loci have been shown to modify the MS susceptibility risk. This study investigated the frequencies of various HLA-DRB1 genotypes, their impact on MS susceptibility and their correlation with the clinical severity in a Spanish population., Methods: A genotype was considered as the combination of the two parental DRB1 alleles. We compared the frequencies of the genotypes in a sporadic MS population (n=380) with those of an unrelated healthy control cohort (n=1088). We correlated the different genotypes with the age at onset, gender distribution, symptoms at onset, course of the disease and progression severity by means of the time to reach the progressive phase and EDSS scores of 3 and 6., Results: We found 81 different genotypes. There were four different MS-predisposing genotypes. Three of them contained the DRB1*15 allele (DRB1*03/15, DRB1*04/15, and DRB1*08/15) and the fourth was homozygote for the DRB1*03 allele. The highest odds ratio was found with the genotype DRB1*08/15 (OR=3.88, 95% CI=1.83-8.26, p<0.01), followed by DRB1*03/03 (OR=3.15, 95% CI=1.93-5.14, p<0.01), DRB1*03/15 (OR=2.72, 95% CI=1.88-3.94, p<0.01) and DRB1*04/15 (OR=2.54, 95% CI=1.64-3.98, p<0.01). The DRB1*01/04 and the DRB1*15/15 genotypes were associated with a shorter time to reach an EDSS score of 6., Conclusions: Our results show the importance of epistatic interactions among the HLA-DRB1 alleles, modifying the risk for MS as well as its clinical severity., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The usefulness of antibiotic prophylaxis in biliary surgery is well established. When antibiotic prophylaxis is not used, wound infection rates after biliary surgery range from 10% to 25%. With antibiotic prophylaxis, the rates can be reduced to less than 5%. Three questions are still controversial: Do all patients undergoing biliary surgery require antibiotic prophylaxis? What is the ideal antibiotic for use in biliary surgery? What should be the duration of antibiotic prophylaxis? In this study we prospectively evaluated the efficacy of a single dose of antibiotic prophylaxis in biliary surgery, administered to patients at high risk for infection, in a trial comparing cefonicid (a cephalosporin with a long half-life) with mezlocillin (a broad-spectrum ureidopenicillin).