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BACKGROUND: Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including synaptic regeneration. OBJECTIVES: In a parkinsonian rat model, we test the hypotheses that exercise: (a) increases synaptic density and reduces neuroinflammation and (b) lowers the nociceptive threshold by increasing µ-opioid receptor expression. METHODS: Brain autoradiography was performed on rats unilaterally injected with either 6-hydroxydopamine (6-OHDA) or saline and subjected to treadmill exercise over 5 weeks. [3H]UCB-J was used to measure synaptic vesicle glycoprotein 2A (SV2A) density. Dopamine D2/3 receptor and µ-opioid receptor availability were assessed with [3H]Raclopride and [3H]DAMGO, respectively, while neuroinflammation was detected with the 18kDA translocator protein (TSPO) marker [3H]PK11195. The nociceptive threshold was determined prior to and throughout the exercise protocol. RESULTS: We confirmed a dopaminegic deficit with increased striatal [3H]Raclopride D2/3 receptor availability and reduced nigral tyrosine hydroxylase immunoreactivity in the ipsilateral hemisphere of all 6-OHDA-injected rats. Sedentary rats lesioned with 6-OHDA showed significant reduction of ipsilateral striatal and substantia nigra [3H]UCB-J binding while [3H]PK11195 showed increased ipsilateral striatal neuroinflammation. Lesioned rats who exercised had higher levels of ipsilateral striatal [3H]UCB-J binding and lower levels of neuroinflammation compared to sedentary lesioned rats. Striatal 6-OHDA injections reduced thalamic µ-opioid receptor availability but subsequent exercise restored binding. Exercise also raised thalamic and hippocampal SV2A synaptic density in 6-OHDA lesioned rats, accompanied by a rise in nociceptive threshold. CONCLUSION: These data suggest that treadmill exercise protects nigral and striatal synaptic integrity in a rat lesion model of PD - possibly by promoting compensatory mechanisms. Exercise was also associated with reduced neuroinflammation post lesioning and altered opioid transmission resulting in an increased nociceptive threshold.

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COVID-19 is an infectious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). Vesicular skin rashes have been reported as associated with COVID-19, but there is little information about this cutaneous manifestation. We designed a prospective observational study of patients diagnosed with COVID-19 who had vesicular lesions. Clinical characterization of skin findings was conducted by dermatologists. When possible, histological analysis and detection of SARS-CoV-2 in the content of the vesicles was performed. In total, 24 patients were included. A disseminated pattern was found in 18 patients (75%), and a localized pattern was found in 6 (25%). Median duration of the skin rash was 10 days. Of the 24 patients, 19 (79.2%) developed the skin rash after the onset of COVID-19 symptoms. Histological examination in two patients was consistent with viral infection, SARS-CoV-2 was not detected in four patients. This single-centre study shows the clinical characteristics of vesicular skin rashes in patients with COVID-19.

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In addition to motor symptoms, Parkinson's disease (PD) presents high prevalence of painful symptoms responsible for worsening quality of life of PD patients. Physical exercise can improve such painful symptoms. This study evaluated the effects of exercise on nociceptive threshold using an unilateral rat model of PD, as well as the role played by cannabinoid and opioid receptors in areas responsible for pain pathways. For PD induction, Wistar rats were injected with 6-OHDA. 15 days after, rats either remained sedentary or were forced to exercise three times a week for 40 min. Motor and nociceptive behaviors were evaluated through cylinder and mechanical hyperalgesia tests, respectively. The animals were euthanized for analysis of cannabinoid receptor type 1 (CB1) and type 2 (CB2), and µ-opioid receptor (MOR) in the anterior cingulate cortex (ACC), periaqueductal gray matter (PAG), and thalamus areas by immunohistochemistry (IHC) and Western blotting. Our data revealed a decrease in the nociceptive threshold in both forepaws after surgery; in contrast, there was improvement in painful symptoms after the exercise protocol. For cannabinoid system there were an increase in CB2 expression in the ACC and PAG, and in CB1 levels in the PAG. And for opioid system there was an increase of MOR expression in the thalamus. Thus, modulation of those receptors by physical exercise can be an important non-pharmacological intervention to reduce painful symptoms in a rat model of PD, contributing to knowledge and promotion of better treatment aimed at improving the quality of life of PD patients.

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The aim of the present study was to optimize the protocol for sampling marine macroalgae to be used to biomonitor heavy metal contamination in marine ecosystems. For this purpose, we collected 50 subsamples of the brown seaweed Fucus vesiculosus at random in each of three sampling sites (SS) and determined the concentrations of Al, As, Cd, Co, Cr, Cu, Fe, Hg, N, Ni, Pb, Zn and δ15N. We used semivariograms to explore the possible existence of spatial structure in the concentrations of the elements. Spatial structure was observed in 88% of the semivariograms studied, with element concentrations varying longitudinally and transversally along the SS. Using randomization techniques, we estimated that in each SS, a minimum of 30 evenly distributed subsamples should be collected within three bands parallel to the coastline (and also at different heights on the rocks if necessary), and analyzed in a single composite sample representative of the intra-SS variability.

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The ignition time (tig) of the mechanically induced self-sustaining reaction (MSR) process involving the formation of TiB2 from Ti/2B elemental mixtures was used to study the influence of the ratio (k = -ω v /ω d ) between the rotational speed of the supporting disc (ω d ) and vials (ω v ) on the milling efficiency of a Pulverisette 4 planetary mill. The variation of the inverse of the ignition time (1/tig), which is directly related to the milling power provided by the planetary mill, with the process conditions has shown that it is not possible to find a single k value as optimal independently of the experimental conditions used (ω d and the ball-to-powder ratio, BPR). Moreover, it was observed that the lowest milling efficiency (longer tig values) was found for k = 1, which is the usual value employed in routine laboratory works. The best efficiencies were found for the larger k values (2.5 or 3). At lower ω d, the shortest tig was obtained for k = 2.5 and at higher ω d for k = 3, independently of BPR.

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This clinical report illustrates a conservative technique to mask enamel discolorations in maxillary anterior teeth caused by hypomineralization associated with enamel fluorosis and subsequent direct resin composite to improve the anterior esthetics. The treatment consisted of at-home whitening with 10% carbamide peroxide gel with potassium nitrate and sodium fluoride in a custom-fitted tray to mask the brown-stained areas, followed by resin infiltration to mask the white spot areas. An existing resin composite restoration in the maxillary right central incisor was subsequently replaced after completion of the whitening and resin infiltration procedures, whereas the two misaligned and rotated maxillary lateral incisors were built up with direct resin composite restorations to provide the illusion of adequate arch alignment, as the patient was unable to use orthodontic therapy.

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Carvacrol is a monoterpene that has been linked to neuroprotection in several animal models of neurodegeneration, including ischemia, epilepsy and traumatic neuronal injury. In this study, we investigated the effects of carvacrol (i.p.) upon the neurodegeneration induced by 6-hydroxy-dopamine unilateral intrastriatal injections in mice. We have also used the cylinder test to assess the behavioral effects of carvacrol in that model of Parkinson's disease, and immunoblots to evaluate the levels of caspase-3 and TRPM7, one of major targets of carvacrol. Behavioral testing revealed that carvacrol largely reduced the asymmetrical use of the forelimbs induced by unilateral 6-hydroxy-dopamine. Carvacrol dramatically reduced the loss of tyrosine hydroxylase immunostaining both in the substantia nigra and in the striatum that are typical of the model. Immunoblots for tyrosine hydroxylase confirmed this effect. Caspase-3 levels were very high after toxin injections, but carvacrol appeared to reduce them to control levels. Finally, TRPM7, observed by immunoblots, increased after 6-hydroxy-dopamine, suggesting the involvement of this cation channel in the ensuing neurodegenerative process. The present data suggest that carvacrol promotes a marked neuroprotection in the 6-hydroxy-dopamine model of Parkinson's disease, possibly by its non-specific blocking effect upon TRPM7 channels.

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The loss of nigral dopaminergic neurons typical in Parkinson's disease (PD) is responsible for hyperexcitability of medium spiny neurons resulting in abnormal corticostriatal glutamatergic synaptic drive. Considering the neuroprotective effect of exercise, the changes promoted by exercise on AMPA-type glutamate receptors (AMPARs), and the role of activity-regulated cytoskeleton-associated protein (Arc) in the AMPARs trafficking, we studied the impact of short and long-term treadmill exercise during evolution of the unilateral 6-hydroxy-dopamine (6-OHDA) animal model of PD. Wistar rats were divided into sedentary and exercised groups, with and without lesion by 6-OHDA and followed up to 4 months. The exercised groups were subjected to a moderate treadmill exercise 3×/week. We measured the proteins tyrosine hydroxylase (TH), Arc, GluA1, and GluA2/3 in the striatum, substantia nigra, and motor cortex. Our results showed a higher reduction of TH expression in all sedentary groups when compared to all exercised groups in striatum and substantia nigra. In general, larger changes occurred in the striatum in the first and third months after training. After 1 month of exercise, there was significant increase of GluA2/3 with concomitant reduction of GluA1 and Arc. As a balanced system, these changes were reversed in the third month, showing an increase of Arc and GluA1 and decrease of GluA2/3. Similar results for GluAs and Arc were observed in the motor cortex of the exercised animals. These modifications may be relevant for corticostriatal circuits in PD, since the exercise-dependent plasticity can modulate GluAs expression and maybe neuronal excitability.

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BACKGROUND: Many attempts have been undertaken to better predict outcome after liver transplantation. The aim of this study was to identify the pre- and intraoperative variables that may influence the survival after liver transplantation, at a single institution. METHODS: Anesthetic records from 543 consecutive patients who underwent liver transplantation from June 2006 to June 2014 were reviewed in this retrospective study. Patients undergoing retransplantation were excluded from the analysis, as were patients with familial amyloid polyneuropathy. Preoperative variables studied were age, sex, Model for End-Stage Liver Disease score, primary diagnosis, cold ischemia time, preoperative international normalized ratio, serum albumin, and and hemoglobin levels. Intraoperative variables included were norepinephrine consumption, blood loss, red blood cell transfusion, and surgical time. Variables significant in the univariate analysis with a P value of <.2 were included in a multivariate Cox regression model. RESULTS: Only red blood cell transfusion (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.04-1.29) and female sex (HR, 1.71; 95% CI, 1.10-2.65) were identified as significant independent predictors for survival after liver transplantation. Because of proportionality assumption violation, the multivariate Cox regression model was subsequently upgraded by adding a time-varying interaction between red blood cell transfusion and time since liver transplantation. As a result, we found that at 3 months after liver transplantation, the rate of dying increased 14% (95% CI, 2%-26%) for each unit transfused, and at 6 months it increased 12% (95% CI, 0.3%-24%). CONCLUSIONS: Red blood cell transfusion ceased to influence survival from 1 year onward.

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To develop an internationally standardized protocol for the moss bag technique application, the research team participating in the FP7 European project "MOSSclone" focused on the optimization of the moss bags exposure in terms of bag characteristics (shape of the bags, mesh size, weight/surface ratio), duration and height of exposure by comparing traditional moss bags to a new concept bag, "Mossphere". In particular, the effects of each variable on the metal uptake from the air were evaluated by a systematic experimental design carried out in urban, industrial, agricultural and background areas of three European countries with oceanic, Mediterranean and continental climate. The results evidenced that the shape, the mesh size of the bags and the exposure height (in the tested ranges), did not significantly influence the uptake capacity of the transplanted moss. The aspects more affecting the element uptake were represented by the density of the moss inside the bags and the relative ratio between its weight and the surface area of the bag. We found that, the lower the density, the higher the uptake recorded. Moreover, three weeks of exposure were not enough to have a consistent uptake signal in all the environments tested, thus we suggest an exposure period not shorter than 6 weeks, which is appropriate in most situations. The above results were confirmed in all the countries and scenarios tested. The adoption of a shared exposure protocol by the research community is strongly recommended since it is a key aspect to make biomonitoring surveys directly comparable, also in view of its recognition as a monitoring method by the EU legislation.

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The interferon-stimulated gene 15 (ISG15) plays an important role in the pathogenesis of hepatitis C virus (HCV) infection. ISG15-regulated proteins have previously been identified that putatively affect this proviral interaction. The present observational study aimed to elucidate the relation between ISG15 and these host factors during HCV infection. Transcriptomic and proteomic analyses were performed using liver samples of HCV-infected (n = 54) and uninfected (n = 10) or HBV-infected controls (n = 23). Primary human hepatocytes (PHH) were treated with Toll-like receptor ligands, interferons and kinase inhibitors. Expression of ISG15 and proteasome subunit alpha type-6 (PSMA6) was suppressed in subgenomic HCV replicon cell lines using specific siRNAs. Comparison of hepatic expression patterns revealed significantly increased signals for ISG15, IFIT1, HNRNPK and PSMA6 on the protein level as well as ISG15, IFIT1 and PSMA6 on the mRNA level in HCV-infected patients. In contrast to interferon-stimulated genes, PSMA6 expression occurred independent of HCV load and genotype. In PHH, the expression of ISG15 and PSMA6 was distinctly induced by poly(I:C), depending on IRF3 activation or PI3K/AKT signalling, respectively. Suppression of PSMA6 in HCV replicon cells led to significant induction of ISG15 expression, thus combined knock-down of both genes abrogated the antiviral effect induced by the separate suppression of ISG15. These data indicate that hepatic expression of PSMA6, which is upregulated during viral hepatitis, likely depends on TLR3 activation. PSMA6 affects the expression of immunoregulatory ISG15, a proviral factor in the pathogenesis of HCV infection. Therefore, the proteasome might be involved in the enigmatic interaction between ISG15 and HCV.

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