Macrophage activation syndrome: a frequent but under-diagnosed complication associated with rheumatic diseases.

Macrophage activation syndrome (MAS) or hemophagocytic syndrome is a severe complication of chronic rheumatic diseases especially in systemic-onset juvenile rheumatoid arthritis (JRA). Although the cause of MAS is unknown, dysregulation of macrophage-lymphocyte interactions with subsequent increases in the levels of both T cell-derived and macrophage-derived cytokines could be involved in this syndrome, leading to an intense systemic inflammatory reaction, which accounts for the main clinical picture. Patients usually present with an acute febrile illness, hepatosplenomegaly, lymphadenopathy, cutaneous and mucosal bleeding, pancytopenia, and central nervous system, cardiac, and renal involvement. Treatment of MAS in patients with rheumatic diseases has not been standardized yet, but it commonly includes a variety of agents such as high-dose corticosteroids, cyclosporine, cyclophosphamide, etoposide, and intravenous immunoglobulin (IVIG). This article reviews the current literature about the pathogenesis, clinical manifestation, diagnosis, and treatment of this severe complication associated with rheumatic diseases.     

Additive thrombin inhibition by fast moving heparin and dermatan sulfate explains the anticoagulant effect of sulodexide,a natural mixture of glycosaminoglycans

Introduction: The aim of the study was to evaluate the mechanism of the anticoagulant action of sulodexide, a mixture of glycosaminoglycans (GAGs) composed of dermatan sulfate (DS) and fast moving heparin (FMH), in vitro. Materials and methods: Thrombin clotting time (TCT) was measured in human platelet poor plasma (PPP). A chromogenic substrate assay was used to determine the pseudo-first order constant kinetic of thrombin inhibition (k′=k_obs/min) either in defibrinated PPP or antithrombin (AT) or heparin cofactor II (HCII) depleted defibrinated PPP in the absence and presence of sulodexide or its components, alone and in combination. The interaction between DS and FMH was analysed by both the algebraic fractional and isobole graphical methods. Results: Sulodexide, DS and FMH produced a dose-dependent prolongation of TCT with unclottable TCT at sulodexide above 4 μg/ml and at DS or FMH above 5 μg/ml. Sulodexide and its components alone and in combination produced a dose-dependent linear increase in the rate of thrombin inhibition in defibrinated PPP. The algebraic fractional and the isobole graphical methods indicated an additive effect between DS and FMH. In AT depleted PPP, the dose-dependent increase in k′ produced by sulodexide was significantly lower than in PPP, while the dose-dependent increase in k′ produced by DS was similar to the increase produced in PPP. In HCII depleted PPP, the dose-dependent increase in k′ produced by sulodexide was significantly lower than in PPP, while the dose-dependent increase in k′ produced by FMH was similar to the increase produced in PPP. Conclusions: Thrombin inhibition produced by sulodexide is due to the additive effect of its components, namely, HCII catalysis by DS and AT catalysis by FMH.     

Culture conditions determine the prevalence of bipolar and monopolar neurons in cultures of dissociated spiral ganglion

To gain insight into the mechanisms that control the generation or maintenance of the characteristic bipolar morphology of cochlear spiral ganglion neurons, we have taken advantage of our recently developed procedure for culture of dissociated newborn mouse spiral ganglion. In these cultures, inclusion of the cytokine leukemia inhibitory factor (LIF) in the medium increases neuronal survival and the number of bipolar neurons. Here we tested effects of two other LIF-type cytokines (ciliary neurotrophic factor, CNTF; and human recombinant oncostatin M, hOSM) and of bone morphogenetic protein 4 (BMP4) on survival, morphology and neurite lengths of neurons in cultures of dissociated spiral ganglion. Like LIF, CNTF and hOSM increased neuronal survival and the number of surviving bipolar neurons. BMP4 also increased neuronal survival, but unlike LIF, CNTF and hOSM, increased the number of monopolar neurons and neurons with no neurites. In addition, population histograms demonstrate that the population lengths of the longer and shorter neurites of bipolar neurons were shorter in BMP4 containing cultures than in control or LIF cultures. When LIF and BMP4 were simultaneously added to the cultures, the BMP4 effects predominated. These experiments demonstrate that exposure to different environmental conditions can result in different morphologies in the surviving population of spiral ganglion neurons in culture.     

Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

Mutations that lead to Huntington’s disease (HD) result in increased transmission at glutamatergic corticostriatal synapses at early presymptomatic stages that have been postulated to set the stage for pathological changes and symptoms that are observed at later ages. Based on this, pharmacological interventions that reverse excessive corticostriatal transmission may provide a novel approach for reducing early physiological changes and motor symptoms observed in HD. We report that activation of the M₄ subtype of muscarinic acetylcholine receptor reduces transmission at corticostriatal synapses and that this effect is dramatically enhanced in presymptomatic YAC128 HD and BACHD relative to wild-type mice. Furthermore, chronic administration of a novel highly selective M₄ positive allosteric modulator (PAM) beginning at presymptomatic ages improves motor and synaptic deficits in 5-mo-old YAC128 mice. These data raise the exciting possibility that selective M₄ PAMs could provide a therapeutic strategy for the treatment of HD.Huntington’s disease (HD) is a rare and fatal neurodegenerative disease caused by an expansion of a CAG triplet repeat in Htt, the gene that encodes for the protein huntingtin (1, 2). HD is characterized by a prediagnostic phase that includes subtle changes in personality, cognition, and motor function, followed by a more severe symptomatic stage initially characterized by hyperkinesia (chorea), motor incoordination, deterioration of cognitive abilities, and psychiatric symptoms. At later stages of disease progression, patients experience dystonia, rigidity, and bradykinesia, and ultimately death (3–7). The cortex and striatum are the most severely affected brain regions in HD and, interestingly, an increasing number of reports suggest that alterations in cortical and striatal physiology are present in prediagnostic individuals and in young HD mice (6–16).Striatal spiny projection neurons (SPNs) receive large glutamatergic inputs from the cortex and thalamus, as well as dopaminergic innervation from the substantia nigra. In the healthy striatum, the interplay of these neurotransmitters coordinates the activity of SPNs and striatal interneurons, regulating motor planning and execution as well as cognition and motivation (17, 18). Htt mutations lead to an early increase in striatal glutamatergic transmission, which begins during the asymptomatic phase of HD (12–14) and could contribute to synaptic changes observed in later stages of HD (19, 20). Based on this, pharmacological agents that reduce excitatory transmission in the striatum could reduce or prevent the progression of alterations in striatal synaptic function and behavior observed in symptomatic stages of HD.Muscarinic acetylcholine receptors (mAChRs), particularly M₄, can inhibit transmission at corticostriatal synapses (21–25). Therefore, it is possible that selective activation of specific mAChR subtypes could normalize excessive corticostriatal transmission in HD. Interestingly, previous studies also suggest that HD is associated with alterations of striatal cholinergic markers, including mAChRs (26–29). We now provide exciting new evidence that M₄-mediated control of corticostriatal transmission is increased in young asymptomatic HD mice and that M₄ positive allosteric modulators (PAMs) may represent a new treatment strategy for normalizing early changes in corticostriatal transmission and reducing the progression of HD.     

Neuroprotective Effects of Propofol in Models of Cerebral Ischemia: Inhibition of Mitochondrial Swelling as a Possible Mechanism

Background: Propofol (2,6-diisopropylphenol) has been shown to attenuate neuronal injury in a number of experimental conditions, but studies in models of cerebral ischemia have yielded conflicting results. Moreover, the mechanisms involved in its neuroprotective effects are yet unclear.

Methods: The authors evaluated the neuroprotective effects of propofol in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation, an in vitro model of cerebral ischemia. To investigate its possible mechanism of action, the authors then examined whether propofol could reduce Ca2+-induced rat brain mitochondrial swelling, an index of mitochondrial membrane permeability, as well as the mitochondrial swelling evoked by oxygen-glucose deprivation in CA1 pyramidal cells by transmission electron microscopy. Finally, they evaluated whether propofol could attenuate the infarct size and improve the neurobehavioral outcome in rats subjected to permanent middle cerebral artery occlusion in vivo.

Results: When present in the incubation medium during oxygen-glucose deprivation and the subsequent 24 h recovery period, propofol (10-100 [mu]m) attenuated CA1 injury in hippocampal slices in vitro. Ca2+-induced brain mitochondrial swelling was prevented by 30-100 [mu]m propofol, and so were the ultrastructural mitochondrial changes in CA1 pyramidal cells exposed to oxygen-glucose deprivation. Twenty-four hours after permanent middle cerebral artery occlusion, propofol (100 mg/kg, intraperitoneal) reduced the infarct size by approximately 30% when administered immediately after and up to 30 min after the occlusion. Finally, propofol administered within 30 min after middle cerebral artery occlusion was unable to affect the global neurobehavioral score but significantly preserved spontaneous activity in ischemic rats.     

Targeting Selective Activation of M1 for the Treatment of Alzheimer’s Disease: Further Chemical Optimization and Pharmacological Characterization of the M1 Positive Allosteric Modulator ML169

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The impact of rheumatic diseases on sexual function

Sexuality is a complex aspect of the human being’s life and is more than of only the sexual act. Normal sexual functioning consists of sexual activity with transition through the phases from arousal to relaxation with no problems, and with a feeling of pleasure, fulfillment and satisfaction. Rheumatic diseases may affect all aspects of life including sexual functioning. The reasons for disturbing sexual functioning are multifactorial and comprise disease-related factors as well as therapy. In rheumatoid arthritis and ankylosing spondylitis patients, pain and depression could be the principal factors contributing to sexual dysfunction. On the other hand, in women with Sjögren’s syndrome, systemic lupus erythematosus and systemic sclerosis sexual dysfunction is apparently most associated to vaginal discomfort or pain during intercourse. Finally, sexual dysfunction in patients with fibromyalgia could be principally associated with depression, but the characteristic symptoms of fibromyalgia (generalized pain, stiffness, fatigue and poor sleep) may contribute to the occurrence of sexual dysfunction. The treatment of sexual dysfunction will depend on the specific patient’s symptoms, however, there are some general recommendations including: exploring different positions, using analgesics drug, heat and muscle relaxants before sexual activity and exploring alternative methods of sexual expression. This is a systemic review about the impact of several rheumatic diseases on sexual functioning. There are no previous overviews about this topic so far.     

Axillary vein thrombosis as a manifestation of rapidly progressive neuropathic arthropathy of the shoulder associated with syringomyelia

Neuropathic arthropathy is a destructive joint disease associated frequently with loss of proprioception. Syringomyelia (with or without Arnold-Chiari malformation) is characterized by slow progression over many years; the joints involved most frequently are the shoulders and elbows. Neuropathic arthropathy of the hand is rare, and clinical features are vasomotor problems, digital ulcers, thickening of the fingers, and painless subluxation of the finger joints. We report an unusual case of neuropathic arthropathy of the shoulder and hands, associated with syringomyelia without Arnold-Chiari malformation. Neuropathic arthropathy of the shoulder was rapidly progressive, and axillary vein thrombosis was the first manifestation; however, neuropathic arthropathy of the hands was unrecognized for 7 years, and painless ulceration of the fingers with spontaneous amputation of the terminal phalanx and Raynaud phenomenon were the initial manifestations. To our knowledge, this is the first report of a patient with this constellation of findings.     

Differential role of mGlu1 and mGlu5 receptors in rat hippocampal slice models of ischemic tolerance

Activation of glutamate receptors has been proposed as a key factor in the induction of ischemic tolerance. We used organotypic rat hippocampal slices exposed to 30 min oxygen-glucose deprivation (OGD) to evaluate postischemic pyramidal cell death in the CA1 subregion. In this model, 10 min exposure to OGD 24 h before the exposure to toxic OGD was not lethal and reduced the subsequent OGD neurotoxicity by approximately 53% (ischemic preconditioning). Similarly, a 30 min exposure to the group I mGlu receptor agonist DHPG (10 microM) significantly reduced OGD neurotoxicity 24 h later (pharmacological preconditioning). Ischemic tolerance did not develop when either the selective mGlu1 antagonists LY367385 and 3-MATIDA or the AMPA/KA antagonist CNQX were present in the incubation medium during exposure to sublethal OGD. Neither the NMDA antagonist MK801 nor the mGlu5 antagonist MPEP affected the preconditioning process. On the other hand, pharmacological preconditioning was prevented not only by LY367385 or CNQX, but also by MPEP. In preconditioned slices, the toxic responses to AMPA or NMDA were reduced. The neurotoxicty of 100 microM DHPG in slices simultaneously exposed to a mild (20 min) OGD was differentially altered in the two preconditioning paradigms. After ischemic preconditioning, DHPG neurotoxicity was reduced in a manner that was sensitive to LY367385 but not to MPEP, whereas after pharmacological preconditioning it was enhanced in a manner that was sensitive to MPEP but not to LY367385. Our results show that mGlu1 and mGlu5 receptors are differentially involved in the induction and expression of ischemic tolerance following two diverse preconditioning stimuli.