Interferon beta treatment: Bioavailability and antiviral activity in multiple sclerosis patients

Viral infections have been appointed as the main component of environmental susceptibility to multiple sclerosis (MS). Interferon beta is an immunomudulatory treatment that is able to modify the natural course of the disease; nonetheless, its mechanism of action in not well established yet. The objectives of the present study were (1) to evaluate the bioavailability of interferon beta through the measurement of the expression of myxovirus resistance protein (MxA), metalloproteinase 9 (MMP-9), and its inhibitor (TIMP-1); (2) to analyze its antiviral efficiency through the measurement of human herpesvirus-6 (HHV-6) prevalence; and (3) to correlate both parameters (bioavailability and antiviral efficiency) with the relapse rate in multiple sclerosis (MS) patients treated with interferon beta. Pairs of blood and serum samples were collected from 54 MS patients during five visits in 1 year: one before the start of the treatment and four during interferon beta treatment. Expression of MxA, MMP-9, and TIMP-1 was analyzed by quatitative real-time polymerase chain reaction (qRT-PCR) and HHV-6 genomes were detected by qPCR. The results showed a correlation between MxA and relapse rate (P = .014). MMP-9/TIMP-1 ratio was increased among the patients with relapses, and decreased among the relapse-free patients, although differences were not statistically significant. Furthermore, our results suggest a possible role for HHV-6 in MS, because 42.8% of patients with viral reactivations experienced at least one relapse versus 22.5% of patients without viral reactivations. Lastly, regarding the antiviral effectiveness of the interferon beta, the HHV-6 prevalence decreased from 58% to 36% in PBMCs and from 18.5% to 12.2% in sera; furthermore, a good correlation with the bioavailability of interferon beta was found, because patients with a decrease in HHV-6 prevalence had higher levels of MxA (P = .046, at the third month).     

Prolonged travel and venous thromboembolism findings from the RIETE registry

There is a lack of information on clinical risk factors for venous thromboembolism (VTE) development following prolonged traveling. Clinical characteristics and additional risk factors for VTE in travelers were analyzed in RIETE, an ongoing registry of patients with symptomatic, confirmed acute VTE. Of 26,172 patients enrolled in RIETE as of May 2009, 2% developed VTE in association with recent traveling. Travelers were ten years younger, had significantly more previous VTE events (20% vs. 16%; OR: 1.4; 95%CI: 1.1-1.7) and their body mass index (BMI) was 28.4 ± 5.1 vs. 27.7 ± 5.2 in other patients from the registry (P = 0.004). 115 (20%) of recent travelers had previous VTE compared to 16% among others patients (OR: 1.4; 95%CI: 1.1-1.7). Recent travelers used hormones significantly more frequently (8.7% vs. 3.7%; OR: 2.5; 95% CI: 1.8-3.3) and more often had a positive thrombophilia test (16% vs. 8.7%; OR: 2; 95%CI: 1.6-2.6). Travelers used LMWH prophylaxis significantly less frequently than other patients in the registry (2.4% vs. 13%; OR 0.2; 95%CI: 0.1-0.3). There were differences in VTE risk in professional drivers compared to passengers. The current study demonstrates four risk factors for VTE development after long traveling: high BMI, previous VTE, hormone use and thrombophilia. Studies of prophylactic antithrombotic therapy in high risk travelers are warranted.     

Stepwise functional connectivity reveals altered sensory‐multimodal integration in medication‐naïve adults with attention deficit hyperactivity disorder

Neuroimaging studies indicate that children with attention‐deficit/hyperactivity disorder (ADHD) present alterations in several functional networks of the sensation‐to‐cognition spectrum. These alterations include functional overconnectivity within sensory regions and underconnectivity between sensory regions and neural hubs supporting higher order cognitive functions. Today, it is unknown whether this same pattern of alterations persists in adult patients with ADHD who had never been medicated for their condition. The aim of the present study was to assess whether medication‐naïve adults with ADHD presented alterations in functional networks of the sensation‐to‐cognition spectrum. Thirty‐one medication‐naïve adults with ADHD and twenty‐two healthy adults underwent resting‐state functional magnetic resonance imaging (rs‐fMRI). Stepwise functional connectivity (SFC) was used to characterize the pattern of functional connectivity between sensory seed regions and the rest of the brain at direct, short, intermediate, and long functional connectivity distances, thus covering the continuum from the sensory input to the neural hubs supporting higher order cognitive functions. As compared to controls, adults with ADHD presented increased SFC degree within primary sensory regions and decreased SFC degree between sensory seeds and higher order integration nodes. In addition, they exhibited decreased connectivity degree between sensory seeds and regions of the default‐mode network. Consistently, the higher the score in clinical severity scales the lower connectivity degree between seed regions and the default mode network.     

Progression of brain volume changes in adolescent-onset psychosis

Little is known about the changes that take place in the adolescent brain over the first few years following the onset of psychosis. The present longitudinal study builds on an earlier cross-sectional report demonstrating brain abnormalities in adolescent-onset psychosis patients with a recent-onset first episode of psychosis. Magnetic resonance imaging studies were obtained at baseline and 2 years later from 21 adolescents with psychosis and 34 healthy controls matched for age, gender, and years of education. Whole-brain volumes and gray matter (GM) and cerebrospinal fluid (CSF) volumes of the frontal, parietal, temporal, and occipital lobes were measured at baseline and at 2-year follow-up. In the frontal lobe, the rate of GM volume loss was significantly higher in male patients (2.9% and 2.0%, respectively, for left and right) than in controls (1.2% and 0.7%, respectively, for left and right). In the left frontal lobe, male patients showed a significantly higher rate of CSF volume increase than controls (8.6% vs 6.4%). These differences in rates of volume change were observed in male and female patients, although only males showed significant time x diagnosis interactions. This negative finding in females should be interpreted with caution as the study was underpowered to detect change in women due to limited sample size. An exploratory analysis revealed that schizophrenia and nonschizophrenia psychotic disorders showed similar volume change patterns relative to controls. Change in clinical status was not correlated with longitudinal brain changes. Our results support progression of frontal lobe changes in males with adolescent-onset psychosis.     

Cellular composition and organization of the spinal cord central canal during metamorphosis of the frog Xenopus laevis

Studying the cellular composition and morphological changes of cells lining the central canal during Xenopus laevis metamorphosis could contribute to understand postnatal development and spinal cord regeneration. Here we report the analysis of central canal cells at different stages during metamorphosis using immunofluorescence for protein markers expression, transmission and scanning electron microscopy and cell proliferation assays. The central canal was regionalized according to expression of glial markers, ultrastructure, and proliferation in dorsal, lateral, and ventral domains with differences between larvae and froglets. In regenerative larvae, all cell types were uniciliated, have a radial morphology, and elongated nuclei with lax chromatin, resembling radial glial cells. Important differences in cells of nonregenerative froglets were observed, although uniciliated cells were found, the most abundant cells had multicilia and revealed extensive changes in the maturation and differentiation state. The majority of dividing cells in larvae corresponded to uniciliated cells at dorsal and lateral domains in a cervical‐lumbar gradient, correlating with undifferentiated features. Neurons contacting the lumen of the central canal were detected in both stages and revealed extensive changes in the maturation and differentiation state. However, in froglets a very low proportion of cells incorporate 5‐ethynyl‐2′‐deoxyuridine (EdU), associated with the differentiated profile and with the increase of multiciliated cells. Our work showed progressive changes in the cell types lining the central canal of Xenopus laevis spinal cord which are correlated with the regenerative capacities.     

Predictive force programming in the grip-lift task: the role of memory links between arbitrary cues and object weight

We tested the ability of healthy participants to learn an association between arbitrary sensory cues and the weight of an object to be lifted using a precision grip between the index finger and thumb. Right-handed participants performed a series of grip-lift tasks with each hand. In a first experiment, participants lifted two objects of equal visual appearance which unexpectedly and randomly changed their weight. In two subsequent experiments, the change in object weight was indicated by cues, which were presented (i) visually or (ii) auditorily. When no cue about the weight of the object to be lifted was presented, participants programmed grip force according to the most recent lift, regardless of the hand used. In contrast, participants were able to rapidly establish an association between a particular sensory cue with a given weight and scaled grip force precisely to the actual weight thereafter, regardless of the hand used or the sensory modality of the cue. We discuss our data within the theoretical concept of internal models.     

Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients

Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury. It is a response to various diseases of variable etiology, including SARS-CoV infection. To date, a comprehensive study of the genomic physiopathology of ARDS (and SARS) is lacking, primarily due to the difficulty of finding suitable materials to study the disease process at a tissue level (instead of blood, sputa or swaps). Hereby we attempt to provide such study by analyzing autopsy lung samples from patient who died of SARS and showed different degrees of severity of the pulmonary involvement. We performed real-time quantitative PCR analysis of 107 genes with functional roles in inflammation, coagulation, fibrosis and apoptosis; some key genes were confirmed at a protein expression level by immunohistochemistry and correlated to the degree of morphological severity present in the individual samples analyzed. Significant expression levels were identified for ANPEP (a receptor for CoV), as well as inhibition of the STAT1 pathway, IFNs production and CXCL10 (a T-cell recruiter). Other genes unassociated to date with ARDS/SARS include C1Qb, C5R1, CASP3, CASP9, CD14, CD68, FGF7, HLA-DRA, IGF1, IRF3, MALAT-1, MSR1, NFIL3, SLPI, USP33, CLC, GBP1 and TAC1. As a result, we proposed to therapeutically target some of these genes with compounds such as ANPEP inhibitors, SLPI and dexamethasone. Ultimately, this study may serve as a model for future, tissue-based analyses of fibroinflammatory conditions affecting the lung.