Tapered fibertrodes for optoelectrical neural interfacing in small brain volumes with reduced artefacts.

Deciphering the neural patterns underlying brain functions is essential to understanding how neurons are organized into networks. This deciphering has been greatly facilitated by optogenetics and its combination with optoelectronic devices to control neural activity with millisecond temporal resolution and cell type specificity. However, targeting small brain volumes causes photoelectric artefacts, in particular when light emission and recording sites are close to each other. We take advantage of the photonic properties of tapered fibres to develop integrated 'fibertrodes' able to optically activate small brain volumes with abated photoelectric noise. Electrodes are positioned very close to light emitting points by non-planar microfabrication, with angled light emission allowing the simultaneous optogenetic manipulation and electrical read-out of one to three neurons, with no photoelectric artefacts, in vivo. The unconventional implementation of two-photon polymerization on the curved taper edge enables the fabrication of recoding sites all around the implant, making fibertrodes a promising complement to planar microimplants.

Gut-lung Microbiota Interactions in Chronic Obstructive Pulmonary Disease (COPD): Potential Mechanisms Driving Progression to COPD and Epidemiological Data.

This paper focuses on the gut-lung axis in the context of Inflammatory Bowel Disease (IBD) and Chronic Obstructive Pulmonary Disease (COPD), highlighting the key role played by microbial dysbiosis and the impact of environmental and genetic factors on the innate and acquired immune system and on chronic inflammation in the intestinal and pulmonary tracts. Recent evidence indicates that Antigen-Presenting Cells (APCs) perform regulatory activity influencing the composition of the microbiota. APCs (macrophages, dendritic cells, B cells) possess membrane receptors known as Pattern Recognition Receptors (PRRs), a category of toll-like receptors (TLRs). PRRs recognise distinct microbial structures and microbial metabolites called Signals, which modulate the saprophytic microbial equilibrium of the healthy microbiota by recognising molecular profiles associated with commensal microbes (Microbe-Associated Molecular Patterns, MAMPs). During dysbiosis, pathogenic bacteria can prompt an inflammatory response, producing PAMPs (Pathogen-Associated Molecular Patterns) thereby activating the proliferation of inflammatory response cells, both local and systemic. This series of regulatory and immune-response events is responsible (together with chronic infection, incorrect diet, obesity, etc.) for the systemic chronic inflammation (SCI) known as "low-grade inflammation" typical of COPD and IBD. This review looks at immunological research and explores the role of the microbiota, looking at two recent clinical studies, SPIROMICS and AERIS. There is a need for further clinical studies to characterize the pulmonary microbiota and to obtain new information about the pathogenesis of lung disease to improve our knowledge and treatment strategies and identify new therapeutic targets.

Obstructive sleep apnea syndrome: coagulation anomalies and treatment with continuous positive airway pressure.

INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a highly prevalent sleep disorder associated with severe cardiovascular events, morbidity and mortality. Recent evidence has highlighted OSAS as an independent risk factor for an excessive platelet activation and arterial thrombosis, but the underlying mechanisms have not yet been determined. Studies in cell culture and animal models have significantly increased our understanding of the mechanisms of inflammation in OSAS. Hypoxia is a critical pathophysiological element that leads to an intense sympathetic activity, in association with systemic inflammation, oxidative stress and procoagulant activity. While platelet dysfunction and/or hypercoagulability play an important role in the pathogenesis of vascular disease, there are limited studies on the potential role of blood viscosity in the development of vascular disease in OSAS. CONCLUSION: Further studies are required to determine the precise role of hypercoagulability in the cardiovascular pathogenesis of OSAS, particularly its interaction with oxidative stress, thrombotic tendency and endothelial dysfunction. Nasal continuous positive airway pressure (nCPAP), the gold standard treatment for OSAS, not only significantly reduced apnea-hypopnoea indices but also markers of hypercoagulability, thus representing a potential mechanisms by which CPAP reduces the rate of cardiovascular morbidity and mortality in OSAS patients.

Selective cyclooxygenase-1 inhibition by p6 and gastrotoxicity: preliminary investigation.

BACKGROUND/AIMS: Gastrointestinal damage (GD) is commonly associated with the inhibition of cyclooxygenase (COX)-1, one of the two known COXs, by traditional non-steroidal anti-inflammatory drugs. More recent evidences have proven that GD is caused by the simultaneous inhibition of the two COXs. This study was designed to evaluate the effect of the selective COX-1 inhibition on gastric integrity. METHODS: GD was evaluated in male CD1 mice. Drugs were administered by gastric gavage at a dose of 50 mg/kg (injection volume of 100 µl). Control mice received an equal volume of the vehicle (10% ethanol). Each mouse, in groups of at least 6 mice, received one dose/day for 5 days. RESULTS: In Western blot analysis, COX-1 expression levels were found to be significantly reduced in mice treated with 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) in comparison to mice pretreated with aspirin (ASA), which exhibited higher levels of COX-1, thus confirming the high selectivity of P6 towards COX-1 enzyme inhibition. Mucosal sections obtained from ASA-treated mice showed breaks in the epithelial barrier and a marked alteration of foveolae and gastric glands, whereas stomachs isolated from mice sacrificed after 5 days of chronic administration of P6 (at a dose of up to 50 mg/kg/day) showed sporadic transient mucosal hyperemia and did not seem to display any significant gastric damage. CONCLUSIONS: The selective COX-1 inhibition by P6 does not cause gastric damage in mice but preserves mucosal integrity.

Ser9p-GSK3ß Modulation Contributes to the Protective Effects of Vitamin C in Neuroinflammation.

BACKGROUND: The prolonged activation of microglia and excessive production of pro-inflammatory cytokines can lead to chronic neuroinflammation, which is an important pathological feature of Parkinson's disease (PD). We have previously reported the protective effect of Vitamin C (Vit C) on a mouse model of PD. However, its effect on microglial functions in neuroinflammation remains to be clarified. Glycogen synthase kinase 3ß (GSK3ß) is a serine/threonine kinase having a role in driving inflammatory responses, making GSK3ß inhibitors a promising target for anti-inflammatory research. METHODS: In this study, we investigated the possible involvement of GSK3ß in Vit C neuroprotective effects by using a well-known 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD and a cellular model of neuroinflammation, represented by Lipopolysaccharide (LPS)-activated BV-2 microglial cells. RESULTS: We demonstrated the ability of Vit C to decrease the expression of different mediators involved in the inflammatory responses, such as TLR4, p-IKBα, and the phosphorylated forms of p38 and AKT. In addition, we demonstrated for the first time that Vit C promotes the GSK3ß inhibition by stimulating its phosphorylation at Ser9. CONCLUSION: This study evidenced that Vit C exerts an anti-inflammatory function in microglia, promoting the upregulation of the M2 phenotype through the activation of the Wnt/ß-catenin signaling pathway.

Obstructive sleep apnea syndrome: blood viscosity, blood coagulation abnormalities, and early atherosclerosis.

Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for atherosclerosis and arterial thrombosis, which are associated with high cardiovascular (CV) morbidity and mortality. In studies performed in clinical populations with elevated CV event risk profiles, the occurrence of moderate to severe OSAS was very often accompanied by a worsened vascular function and increased prevalence of structural abnormalities. Recent investigations of atherosclerosis in OSAS have focused on thrombotic tendency and blood viscosity, providing new insight into mechanisms of the disease. Despite that knowledge about the mechanisms of development of CV disease in patients with OSAS is still incomplete, observations confirm a relationship between sleep-disordered breathing and the rheological properties (flow properties) of blood. While platelet dysfunction and hypercoagulability (PDMPs, PaI-1, and SF) play important roles in the pathogenesis of vascular disease, there are limited studies on the potential role of blood viscosity in the development of vascular disease in OSAS.

Oligodendrocytes Prune Axons Containing α-Synuclein Aggregates In Vivo: Lewy Neurites as Precursors of Glial Cytoplasmic Inclusions in Multiple System Atrophy?

α-Synucleinopathies are spreading neurodegenerative disorders characterized by the intracellular accumulation of insoluble aggregates populated by α-Synuclein (α-Syn) fibrils. In Parkinson's disease (PD) and dementia with Lewy bodies, intraneuronal α-Syn aggregates are referred to as Lewy bodies in the somata and as Lewy neurites in the neuronal processes. In multiple system atrophy (MSA) α-Syn aggregates are also found within mature oligodendrocytes (OLs) where they form Glial Cytoplasmic Inclusions (GCIs). However, the origin of GCIs remains enigmatic: (i) mature OLs do not express α-Syn, precluding the seeding and the buildup of inclusions and (ii) the artificial overexpression of α-Syn in OLs of transgenic mice results in a burden of soluble phosphorylated α-Syn but fails to form α-Syn fibrils. In contrast, mass spectrometry of α-Syn fibrillar aggregates from MSA patients points to the neuronal origin of the proteins intimately associated with the fibrils within the GCIs. This suggests that GCIs are preassembled in neurons and only secondarily incorporated into OLs. Interestingly, we recently isolated a synthetic human α-Syn fibril strain (1B fibrils) capable of seeding a type of neuronal inclusion observed early and specifically during MSA. Our goal was thus to investigate whether the neuronal α-Syn pathology seeded by 1B fibrils could eventually be transmitted to OLs to form GCIs in vivo. After confirming that mature OLs did not express α-Syn to detectable levels in the adult mouse brain, a series of mice received unilateral intra-striatal injections of 1B fibrils. The resulting α-Syn pathology was visualized using phospho-S129 α-Syn immunoreactivity (pSyn). We found that even though 1B fibrils were injected unilaterally, many pSyn-positive neuronal somas were present in layer V of the contralateral perirhinal cortex after 6 weeks. This suggested a fast retrograde spread of the pathology along the axons of crossing cortico-striatal neurons. We thus scrutinized the posterior limb of the anterior commissure, i.e., the myelinated interhemispheric tract containing the axons of these neurons: we indeed observed numerous pSyn-positive linear Lewy Neurites oriented parallel to the commissural axis, corresponding to axonal segments filled with aggregated α-Syn, with no obvious signs of OL α-Syn pathology at this stage. After 6 months however, the commissural Lewy neurites were no longer parallel but fragmented, curled up, sometimes squeezed in-between two consecutive OLs in interfascicular strands, or even engulfed inside OL perikarya, thus forming GCIs. We conclude that the 1B fibril strain can rapidly induce an α-Syn pathology typical of MSA in mice, in which the appearance of GCIs results from the pruning of diseased axonal segments containing aggregated α-Syn.

Increased hexosamine biosynthetic pathway flux alters cell-cell adhesion in INS-1E cells and murine islets.

PURPOSE: In type 2 Diabetes, ß-cell failure is caused by loss of cell mass, mostly by apoptosis, but also by simple dysfunction (dedifferentiation, decline of glucose-stimulated insulin secretion). Apoptosis and dysfunction are caused, at least in part, by glucotoxicity, in which increased flux of glucose in the hexosamine biosynthetic pathway plays a role. In this study, we sought to clarify whether increased hexosamine biosynthetic pathway flux affects another important aspect of ß-cell physiology, that is ß-cell-ß-cell homotypic interactions. METHODS: We used INS-1E cells and murine islets. The expression and cellular distribution of E-cadherin and ß-catenin was evaluated by immunofluorescence, immunohistochemistry and western blot. Cell-cell adhesion was examined by the hanging-drop aggregation assay, islet architecture by isolation and microscopic observation. RESULTS: E-cadherin expression was not changed by increased hexosamine biosynthetic pathway flux, however, there was a decrease of cell surface, and an increase in intracellular E-cadherin. Moreover, intracellular E-cadherin delocalized, at least in part, from the Golgi complex to the endoplasmic reticulum. Beta-catenin was found to parallel the E-cadherin redistribution, showing a dislocation from the plasmamembrane to the cytosol. These changes had as a phenotypic consequence a decreased ability of INS-1E to aggregate. Finally, in ex vivo experiments, glucosamine was able to alter islet structure and to decrease surface abundandance of E-cadherin and ß-catenin. CONCLUSION: Increased hexosamine biosynthetic pathway flux alters E-cadherin cellular localization both in INS-1E cells and murine islets and affects cell-cell adhesion and islet morphology. These changes are likely caused by alterations of E-cadherin function, highlighting a new potential target to counteract the consequences of glucotoxicity on ß-cells.

Neurons with Cat's Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions.

The distinct neuropathological features of the different α-Synucleinopathies, as well as the diversity of the α-Synuclein (α-Syn) intracellular inclusion bodies observed in post mortem brain sections, are thought to reflect the strain diversity characterizing invasive α-Syn amyloids. However, this "one strain, one disease" view is still hypothetical, and to date, a possible disease-specific contribution of non-amyloid factors has not been ruled out. In Multiple System Atrophy (MSA), the buildup of α-Syn inclusions in oligodendrocytes seems to result from the terminal storage of α-Syn amyloid aggregates first pre-assembled in neurons. This assembly occurs at the level of neuronal cytoplasmic inclusions, and even earlier, within neuronal intranuclear inclusions (NIIs). Intriguingly, α-Syn NIIs are never observed in α-Synucleinopathies other than MSA, suggesting that these inclusions originate (i) from the unique molecular properties of the α-Syn fibril strains encountered in this disease, or alternatively, (ii) from other factors specifically dysregulated in MSA and driving the intranuclear fibrillization of α-Syn. We report the isolation and structural characterization of a synthetic human α-Syn fibril strain uniquely capable of seeding α-Syn fibrillization inside the nuclear compartment. In primary mouse cortical neurons, this strain provokes the buildup of NIIs with a remarkable morphology reminiscent of cat's eye marbles (see video abstract). These α-Syn inclusions form giant patterns made of one, two, or three lentiform beams that span the whole intranuclear volume, pushing apart the chromatin. The input fibrils are no longer detectable inside the NIIs, where they become dominated by the aggregation of endogenous α-Syn. In addition to its phosphorylation at S129, α-Syn forming the NIIs acquires an epitope antibody reactivity profile that indicates its organization into fibrils, and is associated with the classical markers of α-Syn pathology p62 and ubiquitin. NIIs are also observed in vivo after intracerebral injection of the fibril strain in mice. Our data thus show that the ability to seed NIIs is a strain property that is integrally encoded in the fibril supramolecular architecture. Upstream alterations of cellular mechanisms are not required. In contrast to the lentiform TDP-43 NIIs, which are observed in certain frontotemporal dementias and which are conditional upon GRN or VCP mutations, our data support the hypothesis that the presence of α-Syn NIIs in MSA is instead purely amyloid-strain-dependent.

MPTP-induced neuroinflammation increases the expression of pro-inflammatory cytokines and their receptors in mouse brain.

Parkinson's disease (PD) is a common neurodegenerative disease characterised by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Despite intensive research, the cause of neuronal loss in PD is poorly understood. Inflammatory mechanisms have been implicated in the pathophysiology of PD. In this study, conducted on an experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, we investigated the expression of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6 and their receptors (IL-1RI, TNF-αRI, IL-6Rα) at the SN and caudate-putamen (CP) levels. In MPTP-treated animals we observed a significant increase in IL-1ß, TNF-α and IL-6 mRNA expression levels both in the SN and CP in comparison with untreated mice. In addition, both mRNA and protein levels of IL-1RI, TNF-αRI and IL-6Rα were significantly enhanced in the SN of MPTP-treated mice in comparison to controls, whereas no significant differences were observed in the CP between treated and untreated mice. Overall, these results indicate a role of both pro-inflammatory cytokines and their receptors in the pathogenesis of PD.

Formyl Peptide Receptor (FPR)1 Modulation by Resveratrol in an LPS-Induced Neuroinflammatory Animal Model.

Among therapeutic approaches that have been investigated, targeting of receptors implicated in managing neuroinflammation has been described. One such family of receptors comprises the formyl peptide receptors (FPRs) whose ligands could play a role in host defense. The murine FPR gene family includes at least six members while in humans there are only three. The two most important members are the Fpr1 and Fpr2. Fpr1encodes murine FPR1, which is considered the murine orthologue of human FPR. Resveratrol, a non-flavonoid polyphenol rich in red wine and grapes, apart from its beneficial health effects and anti-inflammatory properties, has been reported to reduce neuroinflammation in different neurodegenerative disease models. Resveratrol anti-inflammatory responses involve the activation of the protein deacetylase sirtuin 1 (SIRT1) gene. In this work we have investigated in an LPS-based murine model of neuroinflammation the role of FPR1, examining not only if this receptor undergoes a reduction of its expression during neuroinflammation, but also whether treatment with resveratrol was able to modulate its expression leading to an amelioration of neuroinflammatory picture in a murine model of neuroinflammation. Results of this work showed that FPR1 together with SIRT1 resulted upregulated by resveratrol treatment and that this increase is associated with an amelioration of the neuroinflammatory picture, as demonstrated by the induction of IL-10 and IL1-RA expression and the downregulation of proinflammatory mediators, such as TNF-α and IL-1ß. The expression and the modulation of FPR1 by resveratrol may be evaluated in order to propose a novel anti-inflammatory and pro-resolving therapeutic approach for the reduction of the detrimental effects associated with neuro-inflammation based neurodegenerative diseases and also as a promising strategy to promote human health by a diet rich in antioxidative bioactive compounds.

Inflammatory Response Modulation by Vitamin C in an MPTP Mouse Model of Parkinson's Disease.

Vitamin C (Vit C) is anutrient present in many foods, particularly citrus fruits, green vegetables, tomatoes, and potatoes. Vit C is studied for its applications in the prevention and management of different pathologies, including neurodegenerative diseases. Neuroinflammation is a defense mechanism activated by a stimulus or an insult that is aimed at the preservation of the brain by promoting tissue repair and removing cellular debris; however, persistent inflammatory responses are detrimental and may lead to the pathogenesis and progression of neurodegenerative diseases like Parkinson's disease (PD) and Alzheimer's disease. PD is one of the most common chronic progressive neurodegenerative disorders, and oxidative stress is one of the most important factors involved in its pathogenesis and progression.Due to this, research on antioxidant and anti-inflammatory compounds is an important target for counteracting neurodegenerative diseases, including PD. In the central nervous system, the presence of Vit C in the brain is higher than in other body districts, but why and how this occurs is still unknown. In this research, Vit C, with its anti-inflammatory and anti-oxidative properties, is studied to better understand its contribution to brain protection; in particular, we have investigated the neuroprotective effects of Vit C in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD and its role in the modulation of neuroinflammation. First, we observed that Vit C significantly decreased the MPTP-induced loss of tyrosine hydroxylase (TH)-positive dopaminergic neuronal cells in the substantia nigra, as well as microglial cell activation and astrogliosis. Furthermore, gait and spontaneous locomotor activity, evaluated by an automated treadmill and the Open Field test, respectively, were partially ameliorated by Vit C treatment in MPTP-intoxicated animals. In relation to neuroinflammation, results show that Vit C reduced the protein and mRNA expression of inflammatory cytokines such as IL-6, TLR4, TNF-α, iNOS, and CD40, while anti-inflammatory proteins such as IL-10, CD163, TGF-ß, and IL-4 increased. Interestingly, we show for the first time that Vit C reduces neuroinflammation by modulating microglial polarization and astrocyte activation. Moreover, Vit C was able to reduce NLRP3 activation, which is linked to the pathogenesis of many inflammatory diseases, including neuroinflammatory disorders. In conclusion, our study provides evidence that Vit C may represent a new promising dietary supplement for the prevention and alleviation of the inflammatory cascade of PD, thus contributing to neuroprotection.

Influence of the anatomical features of different brain regions on the spatial localization of fiber photometry signals.

Fiber photometry is widely used in neuroscience labs for in vivo detection of functional fluorescence from optical indicators of neuronal activity with a simple optical fiber. The fiber is commonly placed next to the region of interest to both excite and collect the fluorescence signal. However, the path of both excitation and fluorescence photons is altered by the uneven optical properties of the brain, due to local variation of the refractive index, different cellular types, densities and shapes. Nonetheless, the effect of the local anatomy on the actual shape and extent of the volume of tissue that interfaces with the fiber has received little attention so far. To fill this gap, we measured the size and shape of fiber photometry efficiency field in the primary motor and somatosensory cortex, in the hippocampus and in the striatum of the mouse brain, highlighting how their substructures determine the detected signal and the depth at which photons can be mined. Importantly, we show that the information on the spatial expression of the fluorescent probes alone is not sufficient to account for the contribution of local subregions to the overall collected signal, and it must be combined with the optical properties of the tissue adjacent to the fiber tip.

Fixed-pressure nCPAP in patients with obstructive sleep apnea (OSA) syndrome and chronic obstructive pulmonary disease (COPD): a 24-month follow-up study.

PURPOSE: The aim of this study was to investigate the time course of body weight, daytime sleepiness, and functional cardiorespiratory parameters in patients with both chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSA), after institution of domiciliary nasal continuous positive airway pressure (nCPAP). METHODS: Twelve consecutive obese outpatients (mean age = 61 +/- 11 years; four women) were evaluated before (baseline) and after 3, 12, and 24 months of nocturnal nCPAP (4 h per night). RESULTS: At baseline, all patients were hypercapnic and hypoxemic, suffering from night desaturation (T (90) is the percentage of total recording time (TRT) spent with SaO(2)

A specific lipid metabolic profile is associated with the epithelial mesenchymal transition program.

Several studies have identified a specific metabolic program that is associated with the process of epithelial-mesenchymal transition (EMT). Whereas much is known about the association between glucose metabolism and EMT, the contribution of lipid metabolism is not still completely understood. Here, we studied epithelial and mesenchymal breast cancer cells by proteomic and lipidomic approaches and identified significant differences that characterised these models concerning specific metabolic enzymes and metabolites including fatty acids and phospholipids. Higher levels of monounsaturated fatty acids together with increased expression of enzymes of de novo fatty acid synthesis is the distinct signature of epithelial with respect to mesenchymal cells that, on the contrary, show reduced lipogenesis, higher polyunsaturated fatty acids level and increased expression of genes involved in the triacylglycerol (TAG) synthesis and lipid droplets formation. In the mesenchymal model, the diacylglycerol acyltransferase (DGAT)-1 appears to be the major enzyme involved in TAG synthesis and inhibition of DGAT1, but not DGAT2, drastically reduces the incorporation of labeled palmitate into TAG. Moreover, knockdown of ß-catenin demonstrated that this metabolic phenotype in under the control of a network of transcriptional factors and that ß-catenin has a specific role in the regulation of lipid metabolism in mesenchymal cells.

Molecular and functional expression of high conductance Ca 2+ activated K+ channels in the eel intestinal epithelium.

Several types of K(+) channels have been identified in epithelial cells. Among them high conductance Ca(2+)-activated K(+) channels (BK channels) are of relevant importance for their involvement in regulatory volume decrease (RVD) response following hypotonic stress. The aim of the present work was to investigate the functional and molecular expression of BK in the eel intestine, which is a useful experimental model for cell volume regulation research. In the present paper using rat BK channel-specific primer, a RT-PCR signal of 696 pb cDNA was detected in eel intestine, whole nucleotide sequence showed high similarity (83%) to the alpha subunit of BK channel family. BK channel protein expression was verified by immunoblotting and confocal microscopy, while the functional role of BK channels in epithelial ion transport mechanisms and cell volume regulation was examined by electrophysiological and morphometric analysis on the intact tissue. BK(Ca) channels appeared to be localized along all the plasma membrane of the enterocytes; the apical part of the villi showed the most intense immunostaining. These channels were silent in basal condition, but were activated on both membranes (apical and basolateral) by increasing intracellular Ca(2+) concentration with the Ca(2+) ionophore ionomycin (1 microM). BK(Ca) channels were also activated on both membranes by hypotonic swelling of the epithelium and their inhibition by 100 nM iberiotoxin (specific BK(Ca) inhibitor) abolished the Regulatory Volume Decrease (RVD) of the intestinal cells after hypotonic swelling. In conclusion, our results demonstrated the molecular and functional expression of high conductance Ca(2+) -activated K(+) channels in eel intestine; the physiological role of these channels is mainly related to the RVD response of the epithelial cells following hypotonic swelling.

Expression of TLR4 and CD14 in the central nervous system (CNS) in a MPTP mouse model of Parkinson's-like disease.

Systemic infections are often associated with neurodegenerative processes in many diseases of the central nervous system (CNS), including Parkinson's disease. Toll-like receptor (TLR)4 and CD14 act as receptors for lipopolysaccharide (LPS) released by gram-negative bacteria. In this contest, CD14 functions as the main LPS ligand and TLR4 transmits the LPS signal into the cell. In this paper, we investigated the expression of TLR4 and CD14, in different anatomical areas of the CNS, in an experimental model of Parkinson's-like disease, represented by MPTP-treated mouse. In particular, we analyzed the gene transcripts and proteins expression of CD14 and TLR4, in the substantia nigra and caudate-putamen nuclei of these animals. Results demonstrated an augmented expression of both CD14 and TLR4 in the substantia nigra of mice treated with MPTP in comparison to untreated animals, suggesting that the endotoxin receptors are over expressed in different manner in specific areas of the CNS during Parkinson's-like disease.

Radio Electric Asymmetric Conveyer Technology Modulates Neuroinflammation in a Mouse Model of Neurodegeneration.

In this study, the effects of Radio Electric Asymmetric Conveyer (REAC), a non-invasive physical treatment, on neuroinflammatory responses in a mouse model of parkinsonism induced by intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), were investigated in vivo. We found that the REAC tissue optimization treatment specific for neuro-regenerative purposes (REAC TO-RGN-N) attenuated the inflammatory picture evoked by MPTP-induced nigro-striatal damage in mice, decreasing the levels of pro-inflammatory molecules and increasing anti-inflammatory mediators. Besides, there was a significant reduction of both astrocyte and microglial activation in MPTP-treated mice exposed to REAC TO-RGN-N. These results indicated that REAC TO-RGN-N treatment modulates the pro-inflammatory responses and reduces neuronal damage in MPTP-induced parkinsonism.

Statins May Prevent Atherosclerotic Disease in OSA Patients without Co-Morbidities?

Obstructive sleep apnoea (OSA) is characterized by repetitive interruptions of breathing, causing Chronic Intermittent Hypoxia (CIH) that can be involved in the development and progression of cardiovascular diseases. There is evidence showing a close relationship between OSA and atherosclerosis, even in patients who do not show co-morbidities such as hypertension, diabetes, high levels of lowdensity lipoprotein cholesterol (LDL-C), cigarette smoking and obesity, which can activate the endothelium. This endothelium activation due to CIH and specific to OSA seems to be dependent on a different pathway. The current first line therapy for OSA is the application of the continuous positive airway pressure (CPAP), but it alone is not enough to reduce cardiometabolic risk in patients with OSA. In contrast, statins, via their pleiotropic property, might be able to change inflammation and early atherosclerosis, lipid profile and cardiovascular outcomes in OSA. The role of statins in OSA patients with or without any co-morbidities could potentially prevent coronary vascular risk and stroke and in the future, represent an additional treatment option along with CPAP therapy. Strengthening the prevention strategies against atherosclerosis in OSA should be one of the focal aims for healthcare programs of the future.

A Qualitative and Quantitative Study of the Innervation of the Human Non Pregnant Uterus.

Human female reproductive system is closely dependent by hormonal stimulation. Anyway it is now commonly stated that autonomic innervation system regulates, along with hormonal stimulation, the uterine physiology. Cholinergic and adrenergic innervations have a critical role in mediating input to the uterus, but other neurotransmitters and neuropeptides exist that influence uterine physiology, as well. In the present investigation, we analyzed the uterine distribution of a large set of neurotransmitters, focusing on adrenergic, noradredenergic, acetylcholine (AChE) positive, dopaminergic, serotoninergic and peptidergic neurofibers; among these latter, we focused on those releasing prolattine, enkephalines (ENKs), Vasoactive Intestinal Polypeptide (VIP), substance P (SP) and oxytocine. Authors demonstrate the differential localization of these neurofibers in non pregnant uterine fundus, corpus and cervix, sampling myometrial assays of 31 patients submitted to hysterectomy. In fundus uteri, we observed a prevalence of prolactinergic (32.1 ± 1.4 Conventional Unit, C.U.) and adrenergic (36.4 ± 4.5 C.U.) neurofibers; in uterine body VIP positive neurofibers (32.6 ± 4.8 C.U.) and prolactinergic neurofibers (30.3 ± 1.2 C.U.) were the most represented. In uterine cervix, we detected the highest concentration of all the neurofibers analysed, with enkephalinergic neurofibers (94 ± 1.7 C.U.), oxitocinergic neurofibers (72.1 ± 5.1 C.U.), SP positive neurofibers (66.1 ± 4.4 C.U.), acetylcholine positive neurofibers (64.5± 3.6 C.U.), serotoninergic neurofibers (56.4 ± 3.9 C.U.) and VIP positive neurofibers (58.3 ± 5.2 C.U.) being the most expressed. This study demonstrates that uterine cervix harbors a higher concentration of almost all neurotransmitters, compared to the other two uterine anatomic sites. The uterine cervix is largely involved during pregnancy and labor, and the rich neurotransmitters density could contribute to confer to the cervix a proper potential plasticity, necessary for pregnancy and labour.