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A systematic review and meta-analysis were conducted, according to the PRISMA methodology, to summarize current evidence on the prevalence and predictors of long-term glucocorticoid (GC) treatment and disease relapses in the real-life management of polymyalgia rheumatica (PMR). Out of 5442 retrieved studies, 21 were eligible for meta-analysis and 24 for qualitative analysis. The pooled proportions of patients still taking GCs at 1, 2, and 5 years were respectively 77% (95%CI 71–83%), 51% (95%CI 41–61%), and 25% (95CI% 15–36%). No significant difference was recorded by distinguishing study cohorts recruited before and after the issue of the international recommendations in 2010. The pooled proportion of patients experiencing at least one relapse at 1 year from treatment initiation was 43% (95%CI 29–56%). Female gender, acute-phase reactants levels, peripheral arthritis, starting GCs dosage, and tapering speed were the most frequently investigated potential predictors of prolonged GC treatment and relapse, but with inconsistent results. Only a few studies and with conflicting results evaluated the potential role of early treatment with methotrexate in reducing the GC exposure and the risk of relapse in PMR. This study showed that a high rate of prolonged GC treatment is still recorded in the management of PMR. The relapse rate, even remarkable, can only partially explain the long-term GC treatment, suggesting that other and not yet identified factors may be involved. Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies. Key Points: • High rate of long-term glucocorticoid (GC) treatment is recorded in polymyalgia rheumatica (PMR), being 77%, 51%, and 25% of patients still on GCs after respectively 1, 2, and 5 years. • A pooled relapse rate of 43% at 1 year, even remarkable, can only partially explain the long-term GC treatment in PMR. • Several studies have attempted to identify potential predictors of prolonged treatment with GCs and relapse, but with inconsistent results. • Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to update the understanding of the development of paradoxical immune-mediated glomerular disorders (IGDs) in patients with rheumatic diseases treated with biologics and targeted synthetic drugs (ts-drugs). Methods: A systematic literature review was performed by searching PubMed for articles published between 1 January 2014 and 1 January 2020 reporting on the development of IGD in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or systemic lupus erythematosus (SLE) who were receiving biologics or ts-drugs. IGDs were classified on the basis of clinical, laboratory and histopathological data as (1) glomerulonephritis associated with systemic vasculitis (GNSV), (2) isolated autoimmune renal disorder (IARD) or (3) glomerulonephritis in SLE and in lupus-like syndrome (GNLS). The World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment was applied to evaluate the causal relationship between IGD and specific drugs. The classification was based on a six-category scale, where the "certain" and "probable" categories were deemed clinically relevant relationships. Results: The literature search retrieved 875 articles. Of these, 16 articles reported IGD data, for a total of 25 cases. According to the WHO-UMC assessment, the strength of the causal relationship between IGDs and investigated drugs was higher for anti-tumor necrosis factor-α agents (a clinically relevant relationship was found in four of six cases), abatacept (one of two cases), tocilizumab (two cases), ustekinumab (one case) and tofacitinib (one case) than for rituximab (nine cases), belimumab (three cases) or secukinumab (one case), which showed a weak causal relationship with these paradoxical events. No cases associated with apremilast or baricitinib were found. The retrieved cases were classified as 11 GNLS, seven IARD and seven GNSV. Conclusions: Biologics and ts-drugs can cause IGDs. These events are rare, and the causative effect of a specific drug is hard to establish. When a patient is suspected of having an IGD, the drug should be discontinued, and treatment for the new-onset renal disorder should be promptly started. [ABSTRACT FROM AUTHOR]

Nowadays, autonomous service robots are becoming an important topic in robotic research. Differently from typical industrial scenarios, with highly controlled environments, service robots must show an additional robustness to task perturbations and changes in the characteristics of their sensory feedback. In this paper, a robot is taught to perform two different cleaning tasks over a table, using a learning from demonstration paradigm. However, differently from other approaches, a convolutional neural network is used to generalize the demonstrations to different, not yet seen dirt or stain patterns on the same table using only visual feedback, and to perform cleaning movements accordingly. Robustness to robot posture and illumination changes is achieved using data augmentation techniques and camera images transformation. This robustness allows the transfer of knowledge regarding execution of cleaning tasks between heterogeneous robots operating in different environmental settings. To demonstrate the viability of the proposed approach, a network trained in Lisbon to perform cleaning tasks, using the iCub robot, is successfully employed by the DoRo robot in Peccioli, Italy. [ABSTRACT FROM AUTHOR]

Patients with a neurodevelopmental disorder such as Rett syndrome (RS), as well as their families, have complex needs that affect their quality of life (QoL). Therefore, both families and patients with RS must be provided with multidisciplinary health care that can identify the clinical features that most affect their QoL and mental health risks. The main objective of this paper is to provide a comprehensive overview of the QoL subdimensions of families affected by RS, including both the parents and children. We conducted a systematic review, following PRISMA criteria, of the data in the PubMed, PsycINFO, Cuiden, and LILACS databases. The results indicated that when considering the family as a whole, RS equally affects the physical and psychological QoL dimensions; the next most affected was the social dimension. According to parents’ reports, seizures are one of the main factors that decreases their QoL. Thus, from a clinical point of view, controlling seizure activity of children with RS is the main way of improving the QoL of their parents. Interventions in patients affected by RS should be based on the improvement of visual contact and concentration, reducing somnolence, and increasing mobility. The subdimensions of QoL that were most affected in parents of girls with RS were those related to mental health and feelings of well-being. [ABSTRACT FROM AUTHOR]

Spinal cord compression is a complex and challenging condition that greatly affects the quality of life. Non-pharmacological techniques have only been studied to a very lesser extent; although they are evidence to be beneficial. We performed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) analysis of the scientific literature in several databases (Medline, Cochrane, Scopus, Cuiden, Pubmed, Lilacs and Embase); using the following keywords: spinal cord compression, spine compression, mobilization, positioning, brace and bracing. Eleven studies met the inclusion criteria and were finally included in the systematic review. 3 of them were related to metastatic spinal cord compression, 5 to spinal cord compression due to other causes and the last 3 of them regarded the health professional´s knowledge in oncology patients. In all cases, it seems possible to manage spinal cord compression by using external mobilization and braces and that this treatment is beneficial to patients. Positioning plays a massive role in the disease and can improve or worsen the condition when used improperly; the supine position is overused and can have a negative impact both physically and psychologically. Non-pharmacological interventions could be useful for pain management, cardiovascular alterations and patients’ well-being. One randomized clinical trial demonstrated that massage therapy, using either broad compression massage or light contact touch massage improved pain control. There is an urgent need of randomized clinical trials with these interventions in order to achieve an improved care of these patients. [ABSTRACT FROM AUTHOR]

The results of an experimental trial, carried out using a specifically prepared microbial starter, in an automated pilot plant, are presented. The microbial starter was composed by Lb. pentosus strains. The automatized process was compared with natural fermentation in plastic vats, as control. Relevant process parameters, chemico-physical determinations, instrumental texture, and microbiological analyses were carried out to monitor the fermentation process. Driving the process in controlled conditions resulted in a more rapid acidification, pH reaching lower values than the control. In controlled conditions, inoculated lactobacilli carried out a fast colonization supplanting more rapidly spoilage microflora. In started samples, yeasts number increased until reaching 5 log at 60 days, keeping this value constant until the end of the trials, while, in control batches, their growth was more rapid, reaching 5 log from 15 to 30 days, but their number decreased to 3 log at 90 days. The two processes produced olives with comparable texture profile. However, olives coming from the controlled process resulted debittered in 3 months (descriptive sensory analyses and oleuropein quantification in HPLC), while naturally fermented olives resulted not yet debittered at the end of the trial (180 days). Slight differences were found in few other sensory descriptors. Our results showed that, along with the use of effective autochthonous microbial starters, the innovation of processing plants is the next step towards the shortening of the processing time and the safety assurance of the product, while retaining the sensory quality of naturally fermented olives, using an environmentally friendly technology. [ABSTRACT FROM AUTHOR]

Neuroscientific studies show that humans tend to stabilize their head orientation, while accomplishing a locomotor task. This is beneficial to image stabilization and in general to keep a reference frame for the body. In robotics, too, head stabilization during robot walking provides advantages in robot vision and gaze-guided locomotion. In order to obtain the head movement behaviors found in human walk, it is necessary and sufficient to be able to control the orientation (roll, pitch and yaw) of the head in space. Based on these principles, three controllers have been designed. We developed two classic robotic controllers, an inverse kinematics based controller, an inverse kinematics differential controller and a bio-inspired adaptive controller based on feedback error learning. The controllers use the inertial feedback from a IMU sensor and control neck joints in order to align the head orientation with the global orientation reference. We present the results for the head stabilization controllers, on two sets of experiments, validating the robustness of the proposed control methods. In particular, we focus our analysis on the effectiveness of the bio-inspired adaptive controller against the classic robotic controllers. The first set of experiments, tested on a simulated robot, focused on the controllers response to a set of disturbance frequencies and a step function. The other set of experiments were carried out on the SABIAN robot, where these controllers were implemented in conjunction with a model of the vestibulo-ocular reflex (VOR) and opto-kinetic reflex (OKR). Such a setup permits to compare the performances of the considered head stabilization controllers in conditions which mimic the human stabilization mechanisms composed of the joint effect of VOR, OKR and stabilization of the head. The results show that the bio-inspired adaptive controller is more beneficial for the stabilization of the head in tasks involving a sinusoidal torso disturbance, and it shows comparable performances to the inverse kinematics controller in case of the step response and the locomotion experiments conducted on the real robot. [ABSTRACT FROM AUTHOR]

Bio-inspired robots still rely on classic robot control although advances in neurophysiology allow adaptation to control as well. However, the connection of a robot to spiking neuronal networks needs adjustments for each purpose and requires frequent adaptation during an iterative development. Existing approaches cannot bridge the gap between robotics and neuroscience or do not account for frequent adaptations. The contribution of this paper is an architecture and domain-specific language (DSL) for connecting robots to spiking neuronal networks for iterative testing in simulations, allowing neuroscientists to abstract from implementation details. The framework is implemented in a web-based platform. We validate the applicability of our approach with a case study based on image processing for controlling a four-wheeled robot in an experiment setting inspired by Braitenberg vehicles. [ABSTRACT FROM AUTHOR]

Serotonergic neurons of the raphe nuclei exhibit anatomical, neurochemical and elecrophysiological heterogeneity that likely underpins their specific role in multiple behaviors. However, the precise organization of serotonin (5-HT) neurons to orchestrate 5-HT release patterns throughout the brain is not well understood. We compared the electrophysiological and neurochemical properties of dorsal and median raphe 5-HT neurons projecting to the medial prefrontal cortex (mPFC), amygdala (BLA) and dorsal hippocampus (dHP), combining retrograde tract tracing with brain slice electrophysiology and single-cell RT-PCR in Pet1-EGFP mice. Our results show that 5-HT neurons projecting to the dHP and the mPFC and the BLA form largely non-overlapping populations and that BLA-projecting neurons have characteristic excitability and membrane properties. In addition, using an unbiased clustering method that correlates anatomical, molecular and electrophysiological phenotypes, we find that 5-HT neurons with projections to the mPFC and the dHP segregate from those projecting to the BLA. Single-cell gene profiling showed a restricted expression of the peptide galanin in the population of 5-HT neurons projecting to the mPFC. Finally, cluster analysis allowed identifying an atypical subtype of 5-HT neuron with low excitability, long firing delays and preferential expression of the vesicular glutamate transporter type 3. Overall, these findings allow to define correlated anatomical and physiological identities of serotonin raphe neurons that help understanding how discrete raphe cells subpopulations account for the heterogeneous activities of the midbrain serotonergic system. [ABSTRACT FROM AUTHOR]

Although the extracellular serine protease tissue plasminogen activator (tPA) is involved in pathophysiological processes such as learning and memory, anxiety, epilepsy, stroke, and Alzheimer's disease, information about its regional, cellular, and subcellular distribution in vivo is lacking. In the present study, we observed, in healthy mice and rats, the presence of tPA in endothelial cells, oligodendrocytes, mastocytes, and ependymocytes, but not in pericytes, microglial cells, and astrocytes. Moreover, blockage of the axo-dendritic transport unmasked tPA expression in neurons of cortical and hippocampal areas. Interestingly, combined electrophysiological recordings, single-cell reverse transcription polymerase chain reaction (RT-PCR), and immunohistological analyses revealed that the presence of tPA is restricted to subsets of excitatory pyramidal glutamatergic neurons. We further evidenced that tPA is stored in synaptobrevin-2-positive glutamatergic synaptic vesicles. Based on all these data, we propose the existence of tPA-ergic neurons in the mature brain. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate systemic sclerosis (SSc) hospitalizations through a retrospective population-based study analyzing administrative data during 2001-2012 in Sardinia, an Italian region with universal Health System coverage. Data on hospital discharge records with ICD-9-CM code for SSc (710.1) were obtained from the Department of Health and Hygiene. Two-tailed Cochran-Armitage test for trend was applied to analyze the annual trend for primary and non-primary discharge diagnoses. SSc prevalence was also estimated. This study included 4981 hospitalizations in 736 patients (84.8 % women). Hospitalizations with SSc as primary diagnosis were 3631 (72.9 %). Their annual number significantly increased during study period, from 143 in 2001 to 390 in 2012. Annual trend analysis revealed statistically significant increase in number and percentage of interstitial lung disease ( p < 0.0001), pulmonary arterial hypertension ( p < 0.0024), osteoporotic fragility fractures ( p < 0.0001), ulcers, and gangrene ( p = 0.0037) as non-primary diagnoses associated with SSc. Although the number of admissions with SSc as non-primary diagnosis showed a slight reduction during the study period, the annual number and percentage of admissions with respiratory failure ( p = 0.0016) and congestive heart failure ( p < 0.0001) as primary diagnosis showed a significant upward trend. Admissions for intravenous infusion, mainly day-hospital, accounted for 19.1 % of all hospitalizations for SSc and showed a significant ( p = 0.0002) upward trend in 2001-2012. The 2012 SSc prevalence in Sardinia was estimated to be 34.8 per 100,000 inhabitants. Hospital care utilization for SSc is changing over time, showing increased hospitalizations aimed at the early recognition and treatment for the major manifestations and complications of SSc. [ABSTRACT FROM AUTHOR]

The interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in interaction between immune and nervous system. Although IL-6 has neurotrophic properties and beneficial effects in the CNS, its overexpression is generally detrimental, adding to the pathophysiology associated with CNS disorders. The source of the increase in peripheral IL-6 remains to be established and varies among different pathologies, but has been found to be associated with cognitive dysfunction in several pathologies. This comprehensive review provides an update summary of the studies performed in humans concerning the role of central and peripheral IL-6 in cognitive dysfunction in dementias and in other systemic diseases accompained by cognitive dysfuction such as cardiovascular, liver disease, Behçet's disease and systemic lupus erythematosus. Further research is needed to correlate specific deficits in IL-6 and its receptors in pathologies characterized by cognitive dysfunction and to understand how systemic IL-6 affects high cerebral function in order to open new directions in pharmacological treatments that modulate IL-6 signalling. [ABSTRACT FROM AUTHOR]

Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by a combination of reciprocal social deficits, communication impairment, and rigid ritualistic interest and stereotypies. The etiology is generally multifactorial, including genetic, immunological and/or environmental factors. A group of ASD has been linked to mitochondrial dysfunction with subsequent deficiency in energy production. Patients with ASD and mitochondrial disease often show signs and symptoms uncommon to idiopathic ASD such as cardiac, pancreatic or liver dysfunction, cardiac, growth retardation, fatigability, but in some cases semiology is different. We show two clinical cases of ASD associated to a deficiency of the mitochondrial respiratory chain (complex I+III and IV) with different clinical presentations. In one case, signs and symptoms of mitochondrial disorder were mild and the second diagnosis was attained many years after that of ASD. These findings support the recent growing body of evidence that ASD can be associated with mitochondrial disorder. Children with ASD and abnormal neurologic or systemic findings should be evaluated for mitochondrial disorder. [ABSTRACT FROM AUTHOR]

This mini-review focus on our studies on alterations in glutamatergic neurotransmission and their role in neurological alterations in rat models of chronic hyperammonemia and hepatic encephalopathy (HE). Hyperammonemia impairs the glutamate-nitric oxide (NO)-cGMP pathway in cerebellum, which is responsible for reduced learning ability. We studied the underlying mechanisms and designed treatments to restore the pathway and learning. This was achieved by treatment with: phosphodiesterase 5 inhibitors, cGMP, anti-inflammatories (ibuprofen), p38 inhibitors or GABA receptor antagonists (bicuculline). Hyperammonemia alters signal transduction associated to metabotropic glutamate receptors (mGluRs). Hypokinesia in hyperammonemia and HE is due to increased extracellular glutamate and mGluR1 activation in substantia nigra; blocking this receptor restores motor activity. The motor responses to mGluRs activation in nucleus accumbens (NAcc) are altered in hyperammonemia and HE, with reduced dopamine and increased glutamate release. This leads to activation of different neuronal circuits and enhanced motor responses. These studies show that altered responses to activation of NMDA receptors and mGluRs play essential roles in cognitive and motor alterations in hyperammonemia and HE and provide new treatments restoring cognitive and motor function. [ABSTRACT FROM AUTHOR]

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a neurological disease associated with hepatic dysfunction. Current knowledge suggests that hyperammonemia, related to liver failure, is a main factor contributing to the cerebral alterations in HE and that hyperammonemia might impair signal transduction associated with post-translational modification of proteins such as tyrosine-nitration and phosphorylation. However, the molecular bases of the HE remain unclear and very little is known about the occurrence of post-translational modification on in vivo proteins. In this exploratory study we look for evidence of post-translation modifications of proteins in the cerebellum of experimental HE rat models using a proteomic approach. For the first time we showed that hyperammonemia without liver failure (HA rats) and experimental HE with liver failure due to portacaval shunt (PCS rats) lead to a reduced protein nitration in rat cerebellum, where the undernitrated proteins were involved in energy metabolism and cytoskeleton remodelling. Moreover we showed that tyrosine nitration loss of these proteins was not necessarily associated to a change in their phosphorylation state as result of the disease. Interestingly the rat cerebellum phosphoproteome was mainly perturbed in PCS rats, whereas HA rats did not shown appreciable changes in their phosphoprotein profile. Since the protein nitration level decreased similarly in the cerebellum of both HA and PCS rats, this implies that the two disease models share common effects but also present some differential signalling effects in the cerebellum of the same animals. This study highlights the interest for studying the concerted action of multiple signalling pathways in HE development. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Between 30 and 50% of the cirrhotic patients who do not show symptoms of clinical hepatic encephalopathy (HE) present minimal hepatic encephalopathy (MHE), with mild cognitive impairment. MHE impairs the quality of life, increases the risk of suffering accidents, predicts the appearance of clinical HE, and is associated with shortened lifespan. Early detection of MHE would be very useful. The 'gold standard' for MHE diagnosis is the psychometric hepatic encephalopathy score (PHES). However, it is time consuming and needs adjusting for age and educational level. It would be very useful to have some blood biomarker reflecting the presence of MHE in cirrhotic patients. The aim of this work was to identify serum molecules useful as biomarkers for MHE.METHODS:We measured in 63 controls, 43 cirrhotic patients without MHE, and 44 patients with MHE, from Hospital Clinico de Valencia, serum levels of different amino acids, cyclic guanosine monophosphate (cGMP), nitrites+nitrates, and 3-nitrotyrosine. We analyzed for each parameter its diagnostic accuracy as an indicator of MHE, as assessed using the PHES.RESULTS:These studies supported that 3-nitro-tyrosine is a good marker for MHE. To validate its utility as a biomarker for MHE, we analyzed in a second cohort of 44 cirrhotic patients without MHE and 18 patients with MHE, from Hospital Arnau de Vilanova, serum levels of 3-nitro-tyrosine, methionine, and citrulline. Citrulline (173±17%), methionine (173±16%), and 3-nitro-tyrosine (857±92%) were increased in sera from patients with MHE when compared with those without MHE. The receiver operating characteristic (ROC) curve analysis of 3-nitro-tyrosine for the diagnosis of MHE in the first cohort showed an area under the curve (AUC) value of 0.96 (95% confidence interval 0.93-0.99). At the cutoff of 14 nM, the specificity was 93%, sensitivity 89%, and positive and negative predictive values were both 91%. When the same cutoff was applied to the second cohort, the specificity was 83% and sensitivity was 94%. The positive and negative predictive values were 70 and 97%, respectively.CONCLUSIONS:This pilot study, to be validated in a larger cohort, shows that determination of 3-nitro-tyrosine in serum, which is easy and not time consuming, is useful to identify patients with MHE, with good sensitivity, specificity, and positive and negative predictive values. [ABSTRACT FROM AUTHOR]

Cyclic GMP (cGMP) modulates important cerebral processes including some forms of learning and memory. cGMP pathways are strongly altered in hyperammonemia and hepatic encephalopathy (HE). Patients with liver cirrhosis show reduced intracellular cGMP in lymphocytes, increased cGMP in plasma and increased activation of soluble guanylate cyclase by nitric oxide (NO) in lymphocytes, which correlates with minimal HE assessed by psychometric tests. Activation of soluble guanylate cyclase by NO is also increased in cerebral cortex, but reduced in cerebellum, from patients who died with HE. This opposite alteration is reproduced in vivo in rats with chronic hyperammonemia or HE. A main pathway modulating cGMP levels in brain is the glutamate-NO-cGMP pathway. The function of this pathway is impaired both in cerebellum and cortex of rats with hyperammonemia or HE. Impairment of this pathway is responsible for reduced ability to learn some types of tasks. Restoring the pathway and cGMP levels in brain restores learning ability. This may be achieved by administering phosphodiesterase inhibitors (zaprinast, sildenafil), cGMP, anti-inflammatories (ibuprofen) or antagonists of GABAA receptors (bicuculline). These data support that increasing cGMP by safe pharmacological means may be a new therapeutic approach to improve cognitive function in patients with minimal or clinical HE. [ABSTRACT FROM AUTHOR]

Abstract  Patients with hepatic encephalopathy (HE) may present different neurological alterations including impaired cognitive function and altered motor activity and coordination. HE may lead to coma and death. Many of these neurological alterations are the consequence of altered neurotransmission. Hyperammonemia is a main contributor to the alterations in neurotransmission and in neurological functions in HE. Both glutamatergic and GABAergic neurotransmission are altered in animal models of HE. We review some of these alterations, especially those alterations in glutamatergic neurotransmission responsible for some specific neurological alterations in hyperammonemia and HE: the role 1) of excessive NMDA receptors activation in death induced by acute hyperammonemia; 2) of impaired function of the glutamate-nitric oxide-cGMP pathway, associated to NMDA receptors, in cognitive impairment in chronic HE; 3) of increased extracellular glutamate and activation of metabotropic glutamate receptors in substantia nigra in hypokinesia in chronic HE. The therapeutic implications are discussed. We also review the alterations in the function of the neuronal circuits between basal ganglia-thalamus-cortex modulating motor activity and the role of sequential alterations in glutamatergic and GABAergic neurotransmission in these alterations. HE would be a consequence of altered neuronal communication due to alterations in general neurotransmission involving different neurotransmitter systems in different neurons. [ABSTRACT FROM AUTHOR]

The association of HLA-B27 with ankylosing spondylitis (AS) is the strongest among all inflammatory diseases. However, the exact role of these molecules in disease pathogenesis is still unknown. The existence of HLA-B27 variants rarely found in patients introduces a further level of complexity. It is now accepted that other genes of minor impact contribute to modify disease susceptibility and these genes might be diverse in different populations depending on the genetic background. We report here a study performed in Sardinia, an outlier population in which two major HLA-B27 subtypes are present, B *2705 strongly associated with AS and B *2709 which is not, and show the co-occurrence of the B *2705 allele with a single nucleotide polymorphism (SNP) mapping at 3′-UTR of the receptor 1 (VIPR1) for the vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties. This same SNP is associated with a different kinetics of down-modulation of the VIPR1 mRNA in monocytes after exposure to lipopolysaccharide (P=0.004). This particular setting, HLA-B *2705 and a functional polymorphism in VIPR1 gene, might be due to a founder effect or might be the result of a selective pressure. Irrespectively, the consequent downregulation of this receptor in the presence of a ‘danger’ signal might influence susceptibility to AS.Genes and Immunity (2008) 9, 659–667; doi:10.1038/gene.2008.60; published online 31 July 2008 [ABSTRACT FROM AUTHOR]

Hemorrhagic events due to production of antibodies directed against coagulation factors are rarely observed in systemic lupus erythematosus (SLE). We report the case of a patient with clinically quiescent SLE who developed factor VIII inhibitor in acquired hemophilia presenting as hemarthrosis. Initial treatment with FVII, FVIII and FIX plasma concentrate, metilprednisolone and immunoglobulins i.v. were started but new hemorrhagic manifestation occurred. Plasma exchange was also administered, but it was discontinued early due to partial efficacy. In addition, pulse cyclophosphamide 0.5 g/m2 was started. Eight weeks later, FVIII and FIX activity returned within normal ranges, FVIII and FIX inhibitors decreased significantly and hemorrhagic manifestations disappeared. The rare occurrence of acquired hemophilia due to the presence of anti-factor VIII antibodies associated to SLE, which was reviewed, might explain the lack of therapeutic guide-lines; indeed therapeutic options are available but the outcome in each single patient is not predictable. [ABSTRACT FROM AUTHOR]

Neuroscience produces a vast amount of data from an enormous diversity of neurons. A neuronal classification system is essential to organize such data and the knowledge that is derived from them. Classification depends on the unequivocal identification of the features that distinguish one type of neuron from another. The problems inherent in this are particularly acute when studying cortical interneurons. To tackle this, we convened a representative group of researchers to agree on a set of terms to describe the anatomical, physiological and molecular features of GABAergic interneurons of the cerebral cortex. The resulting terminology might provide a stepping stone towards a future classification of these complex and heterogeneous cells. Consistent adoption will be important for the success of such an initiative, and we also encourage the active involvement of the broader scientific community in the dynamic evolution of this project. [ABSTRACT FROM AUTHOR]

Abstract  The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy. [ABSTRACT FROM AUTHOR]

One of the neurological complications in hepatic encephalopathy is the impairment of motor coordination and function. Clinical signs of basal ganglia, cortico-spinal and cerebellar dysfunction have been commonly detected in these patients. We are studying the molecular bases of the alterations in motor coordination and function in hepatic encephalopathy. Hyperammonemia is considered the main factor responsible for the neurological alterations in patients with hepatic encephalopathy. Activation of metabotropic glutamate receptors (mGluRs) in the nucleus accumbens (NAcc) induces locomotion in rats. Asa first step in our studies on the alterations in motor coordinationand function in hyperammonemia and hepatic encephalopathy we studiedwhether the control of motor function by mGluRs in the NAcc is altered in hyperammonemic rats. The locomotor activity induced by injection into the nucleus accumbens (NAcc) of DHPG, an agonist of group I mGluRs was significantly increased in hyperammonemic rats. Injectionof DHPG increased extracellular dopamine but not glutamate in the NAcc of control rats. In hyperammonemic rats DHPG-induced increase in dopamine was significantly reduced, and extracellular glutamate increased 6-fold. The content of mGluR 1 but not mGluR 5, is increased in the NAcc of hyperammonemic rats. Blockade of mGluR 1 completely prevented motor and neurochemical effects induced by DHPG. These results show that modulation of both motor function and extracellular concentration of neurotransmitters by mGluRs in the NAcc is altered in hyperammonemia. This may contribute to the alterations in motor function in hepatic encephalopathy. [ABSTRACT FROM AUTHOR]

NMDA receptors in cerebellum have specific characteristics that make their function and modulation different from those of NMDA receptors in other brain areas. The properties of the NMDA receptor that modulate its function: Subunit composition, post‐translational modifications and synaptic localization are summarized in an accompanying article. In this review we summarize how different signaling molecules modulate the function of NMDA receptors. The function of the receptors is modulated by the co‐agonists glycine and serine and this modulation is different in cerebellum than in other areas. The NMDA receptor also has binding sites for polyamines that regulate its function. Other signaling molecules that modulate NMDA receptors function are: cAMP, neurotrophic factors such as BDNF, FGF‐2 or neuregulins. These and other molecules allow an interplay between NMDA receptors and other receptors for neurotransmitters that may in this way modulate NMDA receptor function. This has been reported, for example, for metabotropic glutamate receptors. The expression and function of NMDA receptor is also modulated by synaptic activity, allowing an adaptation of the receptors function to the external inputs. NMDA receptors modulate important cerebral processes. NMDA receptors in different brain areas seem to modulate different processes. Cerebellar NMDA receptors play a special role in the modulation of motor learning and coordination. This is also briefly reviewed. [ABSTRACT FROM AUTHOR]

NMDA receptors modulate important cerebral processes such as synaptic plasticity, long‐term potentiation, learning and memory, etc. NMDA receptors in cerebellum have specific characteristics that make their function and modulation different from those of NMDA receptors in other brain areas. In this and the accompanying review we summarize the information available on the modulation of NMDA receptors in cerebellum. We review the properties of the NMDA receptor that modulate its function: subunit composition, post‐translational modifications and synaptic localization. NMDA receptors are heteromeric ligand‐gated ion channels assembled from two families of subunits, NR1 and NR2. There are at least eight splicing variant isoforms of the NR1 subunit and four types of NR2 subunits: NR2A, NR2B, NR2C and NR2D. NMDA receptors with different subunit composition or different splice variants of NR1 subunit have different properties. The expression of the different subunits and splicing variants varies during development. Two special characteristics of NMDA receptors in cerebellum that do not occur in other brain areas are the enrichment in the NR2C subunit and in the splice variant NR1b. As a consequence of these and other factors the pharmacology of NMDA receptors is also different in cerebellum than in other brain areas. The function and localization of NMDA receptors is also modulated by postranslational modifications including phosphorylation, glycosylation and nytrosylation. NMDA receptors are phosphorylated in serines of both NR1 and NR2 subunits and in tyrosines of NR2 subunits. Another factor modulating NMDA receptors function is the synaptic localization. The trafficking and clustering of NMDA receptors is modulated by phosphorylation and by interaction with other proteins. The signaling pathways and physiological modulators regulating NMDA receptor function as well as the role of these receptors in motor learning and coordination are reviewed in an accompanying article. [ABSTRACT FROM AUTHOR]

We have recently shown that repeated exposure to caffeine sensitizes rats to the motor activating effects of dopamine D1 and D2 receptor agonists. In order to study the role of dopamine in this effect, sensitization to caffeine and cross-sensitization between caffeine and amphetamine was evaluated by studying turning behavior and in vivo striatal dopamine release in unilaterally 6-hydroxydopamine-lesioned rats. Administration of caffeine (15 mg/kg) for 2 weeks, on alternate days, induced a significant increase in ipsilateral turning behavior during the course of treatment, indicating that sensitization to caffeine took place in the intact striatum. Caffeine modestly increased dopamine release in the intact dorsa-lateral striatum and no significant difference between the first (+38%) and the last (+51%) injection was observed. Amphetamine (2 mg/kg) induced a significantly higher ipsilateral turning behavior in caffeine-sensitized rats than in vehicle-pretreated rats, however, a similar increase in dopamine release (+900 and +800%) was observed in the two groups. The results are the first demonstration that caffeine pre-exposure sensitizes the motor-stimulant effects of caffeine itself and of amphetamine. Sensitized ipsilateral turning after caffeine and amphetamine are not correlated to modification in striatal dopamine release, rather, postsynaptic modifications in dopamine and adenosine receptor interaction might be involved in the sensitization phenomena observed. [ABSTRACT FROM AUTHOR]

Presents a study to examine the acute motor response to the dopamine D-sub-1 receptor agonist SKF 77434 and the D-sub-2/D-sub-3 receptor agonist quinpirole in rats treated subchronically with caffeine or vehicle, either in a test cage (paired group) or in a home cage (home group). Methods; Results; Conclusion that the results provide support for the presence of long-term functional interactions between drugs acting at the adenosine and dopamine receptor levels.

Forty randomly selected patients with systemic lupus erythematosus (SLE) were studied by clinical and serologic parameters and magnetic resonance imaging (MRI). Abnormal MRI was found in 15/40 patients (37,5%): all 15 cases showed multiple widespread small-sized areas of increased signal in T2 in the white matter; in one of these patients MRI also displayed a large area with a reduced signal in T1 and an increased signal in T2 involving both the white and the gray matter. Among the 15 patients with abnormal MRI, only 7 had neuropsychiatric symptoms. The presence of MRI changes was highest in patients with organic type symptoms and was associated to the highest disease severity scores. A long-term follow up of asymptomatic patients would be useful to establish whether the application of MRI is appropriate for the assessment of CNS involvement in SLE. [ABSTRACT FROM AUTHOR]

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We report a case of bleomycin-induced scleroderma in a 35-year-old woman treated with chemotherapy for Hodgkin’s disease. Approximately 6 months after the first chemotherapy cycle, the patient developed skin sclerosis in both arms. The lesion showed no signs of spontaneous clinical amelioration and treatment with steroids was unsuccessful. A partial remission of the skin sclerosis was instead obtained by the administration of d-penicillamine. A family history revealed other cases of autoimmune diseases and HLA typing showed the presence of antigens associated with scleroderma. The association between bleomycin therapy and scleroderma is discussed. [ABSTRACT FROM AUTHOR]

Investigates the neuromodulation of sleep promoting neurons from the ventrolateral preoptic nucleus (VLPO) by neurotransmitters and neuropeptides crucial to sleep regulation. Indication that two different sleep-promoting neurons might co-exist in the VLPO; Suggestion that modafinil, a wake-promoting drug used in the treatment of narcolepsy, blocks the reuptake of norepinephrine by the noradrenergic terminals on sleep-promoting neurons from the VLPO.