Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

The statistical neuroanatomy of frontal networks in the macaque

We were interested in gaining insight into the functional properties of frontal networks based upon their anatomical inputs. We took a neuroinformatics approach, carrying out maximum likelihood hierarchical cluster analysis on 25 frontal cortical areas based upon their anatomical connections, with 68 input areas representing exterosensory, chemosensory, motor, limbic, and other frontal inputs. The analysis revealed a set of statistically robust clusters. We used these clusters to divide the frontal areas into 5 groups, including ventral-lateral, ventral-medial, dorsal-medial, dorsal-lateral, and caudal-orbital groups. Each of these groups was defined by a unique set of inputs. This organization provides insight into the differential roles of each group of areas and suggests a gradient by which orbital and ventral-medial areas may be responsible for decision-making processes based on emotion and primary reinforcers, and lateral frontal areas are more involved in integrating affective and rational information into a common framework

Patient-reported treatment burden of chronic immune thrombocytopenia therapies

<p>Abstract</p> <p>Background</p> <p>Chronic immune thrombocytopenia (ITP) is a debilitating autoimmune disorder that causes a reduction in blood platelets and increased risk of bleeding. ITP is currently managed with various pharmacologic therapies and splenectomy.</p> <p>This study was conducted to assess patient perceived and reported treatment side effects, as well as the perceived burden or bother, and need to reduce or stop treatment, associated with these side effects among adult patients with chronic ITP.</p> <p>Methods</p> <p>A Web-enabled survey was administered to members of a US-based ITP patient support group. Patients reported demographic and clinical characteristics, ITP treatments' side effects for treatments received since diagnosed, level of bother (or distress), and need to reduce or stop treatment, associated with side effects. Current and past exposure was assessed for five specific treatment types: corticosteroids (CS), intravenous immunoglobulin (IVIg), anti-D immunoglobulin (anti-D), rituximab (RT), and splenectomy (SPL), as well as for other patient-referenced therapies (captured as "other").</p> <p>Results</p> <p>The survey was completed by 589 patients; 78% female, 89% white, mean age 48 years (SD = 14.71), and 68% reported a typical low platelet count of < 50,000/μL. Current or past treatment with CS was reported by 92% (n = 542) of patients, 56% (n = 322) for IVIg, 36% (n = 209) for anti-D, 36% (n = 213) for RT, and 39% (n = 227) for SPL. A substantial proportion of CS-treated patients reported side effects (98%, <it>P </it>< 0.05), were highly bothered by their side effects (53.1%, <it>P </it>< 0.05), and reported the need to stop or reduce treatment due to side effects (37.8%, <it>P </it>< 0.05). Among patients reporting side effects of treatment, significant associations were noted for the number of side effects, aggregate bother of reported side effects, and the need to stop or reduce treatment (all <it>P </it>< 0.05).</p> <p>Conclusions</p> <p>Current ITP treatments, particularly corticosteroids, are associated with multiple bothersome side effects that may lead to patients stopping or reducing therapy. Open, informed and complete communication between clinician and patient regarding both the benefits and the side effects of ITP treatment may better prepare patients for their prescribed regimens.</p

MEG resting state functional connectivity in Parkinson's disease related dementia

Parkinson's disease (PD) related dementia (PDD) develops in up to 60% of patients, but the pathophysiology is far from being elucidated. Abnormalities of resting state functional connectivity have been reported in Alzheimer's disease (AD). The present study was performed to determine whether PDD is likewise characterized by changes in resting state functional connectivity. MEG recordings were obtained in 13 demented and 13 non-demented PD patients. The synchronization likelihood (SL) was calculated within and between cortical areas in six frequency bands. Compared to non-demented PD, PDD was characterized by lower fronto-temporal SL in the alpha range, lower intertemporal SL in delta, theta and alpha1 bands as well as decreased centro-parietal gamma band synchronization. In addition, higher parieto-occipital synchronization in the alpha2 and beta bands was found in PDD. The observed changes in functional connectivity are reminiscent of changes in AD, and may reflect reduced cholinergic activity and/or loss of cortico-cortical anatomical connections in PDD. © 2008 The Author(s)

Dynamic Effective Connectivity of Inter-Areal Brain Circuits

Anatomic connections between brain areas affect information flow between neuronal circuits and the synchronization of neuronal activity. However, such structural connectivity does not coincide with effective connectivity (or, more precisely, causal connectivity), related to the elusive question “Which areas cause the present activity of which others?”. Effective connectivity is directed and depends flexibly on contexts and tasks. Here we show that dynamic effective connectivity can emerge from transitions in the collective organization of coherent neural activity. Integrating simulation and semi-analytic approaches, we study mesoscale network motifs of interacting cortical areas, modeled as large random networks of spiking neurons or as simple rate units. Through a causal analysis of time-series of model neural activity, we show that different dynamical states generated by a same structural connectivity motif correspond to distinct effective connectivity motifs. Such effective motifs can display a dominant directionality, due to spontaneous symmetry breaking and effective entrainment between local brain rhythms, although all connections in the considered structural motifs are reciprocal. We show then that transitions between effective connectivity configurations (like, for instance, reversal in the direction of inter-areal interactions) can be triggered reliably by brief perturbation inputs, properly timed with respect to an ongoing local oscillation, without the need for plastic synaptic changes. Finally, we analyze how the information encoded in spiking patterns of a local neuronal population is propagated across a fixed structural connectivity motif, demonstrating that changes in the active effective connectivity regulate both the efficiency and the directionality of information transfer. Previous studies stressed the role played by coherent oscillations in establishing efficient communication between distant areas. Going beyond these early proposals, we advance here that dynamic interactions between brain rhythms provide as well the basis for the self-organized control of this “communication-through-coherence”, making thus possible a fast “on-demand” reconfiguration of global information routing modalities

The connecting health and technology study: A 6-month randomized controlled trial to improve nutrition behaviours using a mobile food record and text messaging support in young adults

© 2016 Kerr et al. Background: Early adulthood represents the transition to independent living which is a period when changes in diet and body weight are likely to occur. This presents an ideal time for health interventions to reduce the effect of health problems and risk factors for chronic disease in later life. As young adults are high users of mobile devices, interventions that use this technology may improve engagement. The Connecting Health and Technology study aimed to evaluate the effectiveness of tailored dietary feedback and weekly text messaging to improve dietary intake of fruit, vegetables and junk food over 6 months among a population-based sample of men and women (aged 18-30 years). Methods: A three-arm, parallel, randomized control trial was conducted. After baseline assessments, participants were randomized to one of three groups: A) dietary feedback and weekly text messages, B) dietary feedback only or C) control group. Dietary intake was assessed using a mobile food record App (mFR) where participants captured images of foods and beverages consumed over 4-days at baseline and post-intervention. The primary outcomes were changes in serves of fruits, vegetables, energy-dense nutrient-poor (EDNP) foods and sugar-sweetened beverages (SSB). The intervention effects were assessed using linear mixed effect models for change in food group serves. Results: Young adults (n = 247) were randomized to group A (n = 82), group B (n = 83), or group C (n = 82). Overall, no changes in food group serves for either intervention groups were observed. An unanticipated outcome was a mean weight reduction of 1.7 kg (P = .02) among the dietary feedback only. Men who received dietary feedback only, significantly reduced their serves of EDNP foods by a mean of 1.4 serves/day (P = .02). Women who received dietary feedback only significantly reduced their intake of SSB (P = .04) by an average of 0.2 serves/day compared with controls. Conclusions: Tailored dietary feedback only resulted in a decrease in EDNP foods in men and SSB in women, together with a reduction in body weight. Using a mobile food record for dietary assessment and tailored feedback has great potential for future health promotion interventions targeting diet and weight in young adults. Trial Registration: Australian Clinical Trials Registry Registration number: ACTRN12612000250831

A prospective, randomised, controlled, double-blind phase I-II clinical trial on the safety of A-Part® Gel as adhesion prophylaxis after major abdominal surgery versus non-treated group

<p>Abstract</p> <p>Background</p> <p>Postoperative adhesions occur when fibrous strands of internal scar tissue bind anatomical structures to one another. The most common cause of intra-abdominal adhesions is previous intra-abdominal surgical intervention. Up to 74% of intestinal obstructions are caused by post surgical adhesions. Although a variety of methods and agents have been investigated to prevent post surgical adhesions, the problem of peritoneal adhesions remains largely unsolved. Materials serving as an adhesion barrier are much needed.</p> <p>Methods/Design</p> <p>This is a prospective, randomised, controlled, patient blinded and observer blinded, single centre phase I-II trial, which evaluates the safety of A-Part^®Gel as an adhesion prophylaxis after major abdominal wall surgery, in comparison to an untreated control group. 60 patients undergoing an elective median laparotomy without prior abdominal surgery are randomly allocated into two groups of a 1:1- ratio. Safety parameter and primary endpoint of the study is the occurrence of wound healing impairment or peritonitis within 28 (+10) days after surgery. The frequency of anastomotic leakage within 28 days after operation, occurrence of adverse and serious adverse events during hospital stay up to 3 months and the rate of adhesions along the scar within 3 months are defined as secondary endpoints. After hospital discharge the investigator will examine the enrolled patients at 28 (+10) days and 3 months (±14 days) after surgery.</p> <p>Discussion</p> <p>This trial aims to assess, whether the intra-peritoneal application of A-Part^®Gel is safe and efficacious in the prevention of post-surgical adhesions after median laparotomy, in comparison to untreated controls.</p> <p>Trial registration</p> <p>NCT00646412</p

Acute effects of intracranial hypertension and ARDS on pulmonary and neuronal damage: a randomized experimental study in pigs

Abstract PURPOSE: To determine reciprocal and synergistic effects of acute intracranial hypertension and ARDS on neuronal and pulmonary damage and to define possible mechanisms. METHODS: Twenty-eight mechanically ventilated pigs were randomized to four groups of seven each: control; acute intracranial hypertension (AICH); acute respiratory distress syndrome (ARDS); acute respiratory distress syndrome in combination with acute intracranial hypertension (ARDS + AICH). AICH was induced with an intracranial balloon catheter and the inflation volume was adjusted to keep intracranial pressure (ICP) at 30-40 cmH2O. ARDS was induced by oleic acid infusion. Respiratory function, hemodynamics, extravascular lung water index (ELWI), lung and brain computed tomography (CT) scans, as well as inflammatory mediators, S100B, and neuronal serum enolase (NSE) were measured over a 4-h period. Lung and brain tissue were collected and examined at the end of the experiment. RESULTS: In both healthy and injured lungs, AICH caused increases in NSE and TNF-alpha plasma concentrations, extravascular lung water, and lung density in CT, the extent of poorly aerated (dystelectatic) and atelectatic lung regions, and an increase in the brain tissue water content. ARDS and AICH in combination induced damage in the hippocampus and decreased density in brain CT. CONCLUSIONS: AICH induces lung injury and also exacerbates pre-existing damage. Increased extravascular lung water is an early marker. ARDS has a detrimental effect on the brain and acts synergistically with intracranial hypertension to cause histological hippocampal damage

Masking of Figure-Ground Texture and Single Targets by Surround Inhibition: A Computational Spiking Model

A visual stimulus can be made invisible, i.e. masked, by the presentation of a second stimulus. In the sensory cortex, neural responses to a masked stimulus are suppressed, yet how this suppression comes about is still debated. Inhibitory models explain masking by asserting that the mask exerts an inhibitory influence on the responses of a neuron evoked by the target. However, other models argue that the masking interferes with recurrent or reentrant processing. Using computer modeling, we show that surround inhibition evoked by ON and OFF responses to the mask suppresses the responses to a briefly presented stimulus in forward and backward masking paradigms. Our model results resemble several previously described psychophysical and neurophysiological findings in perceptual masking experiments and are in line with earlier theoretical descriptions of masking. We suggest that precise spatiotemporal influence of surround inhibition is relevant for visual detection