DUSP1/MKP-1 represents another piece in the P2X7R intracellular signaling puzzle in cerebellar cells: our last journey with Mª Teresa along the purinergic pathways of Eden.

The P2X7 receptor (P2X7R) stands out within the purinergic family as it has exclusive pharmacological and regulatory features, and it fulfills distinct roles depending on the type of stimulation and cellular environment. Tonic activation of P2X7R promotes cell proliferation, whereas sustained activation is associated with cell death. Yet strikingly, prolonged P2X7R activation in rat cerebellar granule neurons and astrocytes does not affect cell survival. The intracellular pathways activated by P2X7Rs involve proteins like MAPKs, ERK1/2 and p38, and interactions with growth factor receptors could explain their behavior in populations of rat cerebellar cells. In this study, we set out to characterize the intracellular mechanisms through which P2X7Rs and Trk receptors, EGFR (epidermal growth factor receptor) and BDNFR (brain-derived neurotrophic factor receptor), regulate the dual-specificity phosphatase DUSP1. In cerebellar astrocytes, the regulation of DUSP1 expression by P2X7R depends on ERK and p38 activation. EGFR stimulation can also induce DUSP1 expression, albeit less strongly than P2X7R. Conversely, EGF was virtually ineffective in regulating DUSP1 in granule neurons, a cell type in which BDNF is the main regulator of DUSP1 expression and P2X7R only induces a mild response. Indeed, the regulation of DUSP1 elicited by BDNF reflects the balance between both transcriptional and post-transcriptional mechanisms. Importantly, when the regulation of DUSP1 expression is compromised, the viability of both astrocytes and neurons is impaired, suggesting this phosphatase is essential to maintain proper cell cytoarchitecture and functioning.

Efficacy of antimalarials in oral lichen planus: A systematic review.

OBJECTIVE: To evaluate whether hydroxychloroquine (HCQ) or chloroquine (CQ) are effective for the treatment of oral lichen planus (OLP). MATERIALS AND METHODS: A literature search was conducted in four databases. Clinical studies investigating the effect of HCQ/CQ in patients with OLP were included. RESULTS: Eleven studies were included. Four were RCTs and seven quasi-experimental studies. The studies included 390 patients diagnosed with OLP, of which 326 and 7 received HCQ and CQ, respectively. 46 patients received topical dexamethasone, 5 placebo and 6 griseofulvin as controls. Five studies assessed pain, and all of them obtained pain reduction with the use of HCQ. Six studies reported objective clinical improvement of OLP with the use of HCQ. Five studies that used a subjective scale obtained that 24%-100% of the patients achieved a complete/almost complete improvement of OLP lesions and its symptomatology. The most frequent side effects were vision problems, gastric discomfort, rash, nauseas, headaches, skin pigmentation, and elevated kidney function. 17 patients had to withdraw from the studies. CONCLUSIONS: Current evidence is scarce to confirm HCQ as a therapeutic option for OLP. More RCTs are needed to compare its efficacy with topical corticosteroids and to evaluate whether HCQ reduces relapses of OLP.

Efficacy and safety of a bioadhesive gel containing propolis extract, nanovitamin C and nanovitamin E on desquamative gingivitis: a double-blind, randomized, clinical trial.

OBJECTIVES: To evaluate the efficacy of a gel-containing propolis extract, nanovitamin C, and nanovitamin E as adjuvants to professional plaque removal on desquamative gingivitis (DG). MATERIALS AND METHODS: A randomized clinical trial was conducted on patients suffering DG due to mucocutaneous diseases. Patients received professional supragingival prophylaxis with oral hygiene instructions and were randomly assigned to use test or control gels as toothpaste and to apply it on DG lesions 3 times/day for 4 weeks. DG clinical score (DGCS), clinical periodontal variables, and visual analog scale (VAS) for pain and oral health impact profile (OHIP-14) were collected at baseline, 2 and 4 weeks. RESULTS: Twenty-two patients were randomly assigned to test (n = 11) or control group (n = 11). Eighteen had diagnosis of oral lichen planus and four of mucous membrane pemphigoid. DGCS statistically decreased in both groups after treatment with no significant differences between groups. Clinical periodontal outcomes decreased in both groups, but no significant differences were observed. Periodontal variables statistically improved only in test group after treatment. VAS and OHIP-14 scores decreased in test and control groups without significant differences. However, only one test group showed a statistically significant decrease in VAS and OHIP-14 scores after treatment. No adverse effects were reported. CONCLUSIONS: Test gel may alleviate DG and improve quality of life without side effects. CLINICAL RELEVANCE: A gel-containing propolis extract, nanovitamin C, and nanovitamin E as adjuvants to mechanical debridement may improve both clinical and patient related outcomes in DG patients without side effects. CLINICAL TRIAL REGISTRATION: The study protocol was registered at clinicaltrials.gov with the following number: NCT05124366 on October 16, 2021.

Usefulness of implementing the OHIP-14 questionnaire to assess the impact of xerostomia and hyposalivation on quality of life in patients with primary Sjögren's syndrome.

BACKGROUND: The aim of this study is to analyze if the results of the Oral Health Impact Profile-14 questionnaire (OHIP-14) in patients with primary Sjögren's syndrome (pSS) are correlated with salivary flow and level of xerostomia. METHODS: This observational cross-sectional study was conducted in 61 patients (60 women, one man, mean age 57.64 [13.52]) diagnosed of pSS according to the American-European Criteria (2002). After recording demographic, medical and dental data (decayed-missing-filled teeth index [DMFT]), unstimulated (UWS) and stimulated (SWS) salivary flows were collected. Subsequently, UWS flow was categorized into two groups (<0.1 ml/min and ≥0.1 ml/min) and SWS into three groups (<0.1 ml/min, 0.1-0.7 ml/min and >0.7 ml/min). Patients also filled out a visual analog scale (VAS) for xerostomia and OHIP-14 for self-reported quality of life (QoL). RESULTS: Data showed positive and significant correlation between OHIP-14 and xerostomia, based on VAS results (r = 0.52; p = 0.001). Furthermore, there was a negative correlation between UWS and OHIP-14 scores (r = -0.34; p = 0.006) and VAS for xerostomia (r = -0.22; p = 0.09). No significant correlation was found between SWS and OHIP-14 or VAS neither between DMFT and OHIP-14. When assessing the level of QoL by the UWS and SWS flow categories a significant association was found for UWS (p = 0.001) but not for SWS (p = 0.11). The OHIP-14 values were higher in the groups with lower salivary flow. The multiple linear regression to predict OHIP-14 only selected VAS for xerostomia as a statistically significant predictor. CONCLUSIONS: Increased level of xerostomia and reduced UWS flow decrease oral health-related QoL in patients with pSS.

Short-term efficacy of a gel containing propolis extract, nanovitamin C and nanovitamin E on peri-implant mucositis: A double-blind, randomized, clinical trial.

OBJECTIVE: To determine the efficacy of a gel containing propolis extract, nanovitamin C and nanovitamin E as adjuvant to mechanical debridement in the treatment of peri-implant mucositis (PM). BACKGROUND: Propolis has anti-inflammatory and antibacterial effect that may improve peri-implant health. METHODS: A randomized, double-blind study was performed on patients with at least one implant with PM. Participants received a professional prophylaxis and were instructed to use either test or a control gel as toothpaste three times/day for 1 month. Clinical and microbiological parameters were evaluated. PM resolution was considered in absence of bleeding on probing (BOP). Data were analysed with Mann-Whitney U, Wilcoxon signed-rank and chi-square tests. RESULTS: Forty-six patients participated (23 in each group). After treatment, 26.1% of test patients showed complete PM resolution versus 0% in control group (p = .02). Significant reductions were observed in plaque index (p = .03), BOP (p = .04) and probing depths (p = .027) in test compared with control group. The reduction in Tannerella forsythia was statistically greater in test than in control group at 1-month follow-up (p = .02). Porphyromonas gingivalis was statistically reduced in test group from baseline to 1-month follow-up (p = .05). CONCLUSION: Test gel clinically improved PM and showed certain antimicrobial effect after 1 month in comparison with control group. Further long-term clinical trials are required to confirm these results.

Association of salivary inflammatory biomarkers with primary Sjögren's syndrome.

BACKGROUND: Primary Sjogren's syndrome (pSS) is an autoimmune disease that leads to salivary and lacrimal gland dysfunction. The adaptive immune response associated with T helper-2 lymphocytes appears to be altered in these patients. Therefore, the objective of this study was to determine the salivary levels of interleukin (IL)-6, IL-5, and IL-4 in patients with pSS when compared to a healthy control (HC) group. The secondary objectives were to study whether ILs levels in pSS patients were associated with salivary flow, patient-reported outcomes (PROMs) for xerostomia and oral health quality of life (Oral Health Impact Profile-14 [OHIP-14]), pSS classification criteria and presence of extraglandular manifestations. METHODS: A case-control study was conducted in 36 patients with pSS and 35 HCs. Cytokine levels were measured using high-sensitivity multiplex map human immunoassays. Unstimulated and stimulated whole saliva were collected and patients filled out questionnaires. The Mann-Whitney U test, chi-squared test, and Spearman correlation test were used. RESULTS: Interleukin-6 was significantly higher in pSS patients than in HCs (P = .0001). IL-6 was significantly higher in pSS patients with a positive salivary gland biopsy (P = .04), whole stimulated saliva hyposalivation (P = .02), and presence of musculoskeletal disorders (P = .03). There was a non-significant positive correlation between IL-6 levels and PROMs for xerostomia (r = .31; P = .06) and OHIP-14 (r = .07; P = .68) in pSS patients. Levels of IL-4 and IL-5 were not detected in both pSS and HCs patients. CONCLUSIONS: Salivary IL-6 levels are significantly associated with pSS patients, and therefore, it is hypothesized that this biomarker may be useful in the diagnosis and follow-up of this disease.

Effects of Xerostom® products on xerostomia in primary Sjögren's syndrome: A randomized clinical trial.

OBJECTIVES: To assess the effects of Xerostom® toothpaste and mouthwash in primary Sjögren's syndrome (pSS) patients with xerostomia. SUBJECTS AND METHODS: A double-blinded, randomized study where patients were assigned at baseline test or control products. Patients used the products 3 times/day/28 days. We used a visual analogue scale (VAS) for xerostomia and an Oral Health Impact Profile-14 (OHIP-14), baseline and after treatment, to assess possible improvement. RESULTS: A total of 28 patients with pSS were included in this study, but only 24 finished it (all women, mean age 55.21 ± 11.87), and 13 patients received the test and 11 the control. VAS and OHIP-14 scores decreased in both groups after treatment but significant differences between groups were not found. We do not detect VAS intragroup significant differences before and after treatment in test and control groups. A significant improvement in OHIP-14 was identified in the treatment group, while no significant differences were observed in the control group. No adverse effects were present. CONCLUSIONS: Xerostom® toothpaste and mouthrinse may alleviate and improve quality of life without associated side effects, but further research with a larger number of participants and follow-up are necessary to establish the positive efficacy of these topical products in pSS patients.

Neuron-astrocyte signaling is preserved in the aging brain.

Astrocytes play crucial roles in brain homeostasis and are emerging as regulatory elements of neuronal and synaptic physiology by responding to neurotransmitters with Ca2+ elevations and releasing gliotransmitters that activate neuronal receptors. Aging involves neuronal and astrocytic alterations, being considered risk factor for neurodegenerative diseases. Most evidence of the astrocyte-neuron signaling is derived from studies with young animals; however, the features of astrocyte-neuron signaling in adult and aging brain remain largely unknown. We have investigated the existence and properties of astrocyte-neuron signaling in physiologically and pathologically aging mouse hippocampal and cortical slices at different lifetime points (0.5 to 20 month-old animals). We found that astrocytes preserved their ability to express spontaneous and neurotransmitter-dependent intracellular Ca2+ signals from juvenile to aging brains. Likewise, resting levels of gliotransmission, assessed by neuronal NMDAR activation by glutamate released from astrocytes, were largely preserved with similar properties in all tested age groups, but DHPG-induced gliotransmission was reduced in aged mice. In contrast, gliotransmission was enhanced in the APP/PS1 mouse model of Alzheimer's disease, indicating a dysregulation of astrocyte-neuron signaling in pathological conditions. Disruption of the astrocytic IP3 R2 mediated-signaling, which is required for neurotransmitter-induced astrocyte Ca2+ signals and gliotransmission, boosted the progression of amyloid plaque deposits and synaptic plasticity impairments in APP/PS1 mice at early stages of the disease. Therefore, astrocyte-neuron interaction is a fundamental signaling, largely conserved in the adult and aging brain of healthy animals, but it is altered in Alzheimer's disease, suggesting that dysfunctions of astrocyte Ca2+ physiology may contribute to this neurodegenerative disease. GLIA 2017 GLIA 2017;65:569-580.

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease.

BACKGROUND: The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both cholinergic and monoamine oxidase dysfunctions are involved in the pathological process. Thus, we hypothesized that the development of therapies focused on these targets might be effective. We have developed and assessed a new product, coded ASS234, a multipotent acetyl and butyrylcholinesterase/monoamine oxidase A-B inhibitor with a potent inhibitory effect on amyloid-ß aggregation as well as antioxidant and antiapoptotic properties. But there is a need to reliably correlate in vitro and in vivo drug release data. METHODS: We examined the effect of ASS234 on cognition in healthy adult C57BL/6J mice in a model of scopolamine-induced cognitive impairment that often accompanies normal and pathological aging. Also, in a characterized transgenic APPswe/PS1ΔE9 mouse model of Alzheimer disease, we examined the effects of short-term ASS234 treatment on plaque deposition and gliosis using immunohistochemistry. Toxicology of ASS234 was assessed using a quantitative high-throughput in vitro cytotoxicity screening assay following the MTT assay method in HepG2 liver cells. RESULTS: In vivo, ASS234 significantly decreased scopolamine-induced learning deficits in C57BL/6J mice. Also, reduction of amyloid plaque burden and gliosis in the cortex and hippocampus was assessed. In vitro, ASS234 exhibited lesser toxicity than donepezil and tacrine. LIMITATIONS: The study was conducted in male mice only. Although the Alzheimer disease model does not recapitulate all features of the human disease, it exhibits progressive monoaminergic neurodegeneration. CONCLUSION: ASS234 is a promising alternative drug of choice to treat the cognitive decline and neurodegeneration underlying Alzheimer disease.

Neuroprotective and antioxidant properties of new quinolylnitrones in in vitro and in vivo cerebral ischemia models.

Cerebral ischemia is a condition affecting an increasing number of people worldwide, and the main cause of disability. Current research focuses on the search for neuroprotective drugs for its treatment, based on the molecular targets involved in the ischemic cascade. Nitrones are potent antioxidant molecules that can reduce oxidative stress. Here we report the neuroprotective properties and the antioxidant power of the six new quinolylnitrones (QNs) 1-6 for their potential application in stroke therapy. QNs 1-4 are 2-chloro-8-hydroxy-substituted QNs bearing N-t-butyl or N-benzyl substituents at the nitrone motif located at C3, whereas QN5 and QN6 are 8-hydroxy QNs bearing N-t-butyl or N-benzyl substituents at the nitrone motif located at C2, respectively. In vitro neuroprotection studies using QNs 1-6 in an oxygen-glucose-deprivation model of cerebral ischemia, in human neuroblastoma cell cultures, indicate that all QNs have promising neuroprotective, anti-necrotic, anti-apoptotic, and anti-oxidant properties against experimental ischemia-reperfusion in neuronal cultures. QN6 stands out as the most balanced nitrone out of all tested QNs, as it strongly prevents decreased neuronal metabolic activity (EC50 = 3.97 ± 0.78 µM), as well as necrotic (EC50 = 3.79 ± 0.83 µM) and apoptotic cell death (EC50 = 3.99 ± 0.21 µM). QN6 showed high capacity to decrease superoxide production (EC50 = 3.94 ± 0.76 µM), similar to its parent molecule α-phenyl-tert-butyl nitrone (PBN) and the well-known anti-oxidant molecule N-acetyl-L-cysteine (NAC). Thus, QN6 demonstrated the highest antioxidant power out of the other tested QNs. Finally, in vivo treatment with QN6 in an experimental permanent stroke model elicited a significant reduction (75.21 ± 5.31%) of the volume size of brain lesion. Overall, QN6 is a potential agent for the therapy of cerebral ischemia that should be further investigated.

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.

We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 µmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.

Hypothermia prevents nitric oxide system changes in retina induced by severe perinatal asphyxia.

One-third of asphyctic neonates develop long-term neurological injuries, including several degrees of ischemic proliferative retinopathy (IPR) such as retinopathy of prematurity (ROP). Given that the retina is altered by perinatal asphyxia, our aim was to study the effects of nitric oxide (NO) in the retina in order to analyze its impact on the retinal injury. Application of hypothermia was evaluated as preventive treatment. Sprague-Dawley rats were subjected to perinatal asphyxia [either at 37°C (PA group) or at 15°C (HYP group)]. Full-term rats were used as controls (CTL). A significantly increased activity of both constitutive NO synthase (nNOS, Ca(2+)-dependent) and inducible NO synthase (iNOS, Ca(2+)-independent) was observed in PA retinas from 21 days old up to 60 days old with respect to age-matched CTL, with a significant increase along the time course in the PA. nNOS was immunolocalized at amacrine, horizontal, and ganglion cells of the PA group, with a significant increase in relative optical density (R.O.D.), cellular area, and number of cells. iNOS immunoreactivity was observed in the inner nuclear layer and in the internal Müller cell processes of PA, with a significant increase in R.O.D. and colocalizing with GFAP in the 60-day-old PA group. Six nitrated protein species were increased in retinas from PA rats. Nitrotyrosine immunoreactivity showed a localization similar to that of iNOS, with increased R.O.D. in the PA group and colocalization with GFAP in 60-day-old animals. HYP prevented all the changes observed in PA rats. Although the NO system displays changes induced by hypoxia-ischemia, hypothermia application shows a strong protective effect.

Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions.

The adrenomedullin (AM) gene, adm, is widely expressed in the central nervous system (CNS) and several functions have been suggested for brain AM. Until now, a formal confirmation of these actions using genetic models has been elusive since the systemic adm knockout results in embryo lethality. We have built a conditional knockout mouse model using the Cre/loxP approach. When crossed with transgenic mice expressing the Cre recombinase under the tubulin Talpha-1 promoter, we obtained animals with no AM expression in the CNS but normal levels in other organs. These animals lead normal lives and do not present any gross morphological defect. Specific areas of the brain of animals lacking CNS AM contain hyperpolymerized tubulin, a consequence of AM downregulation. Behavioral analysis shows that mice with no AM in their brain have impaired motor coordination and are hyperactive and overanxious when compared to their wild-type littermates. Treatment with methylphenidate, haloperidol, and diazepam did not show differences between genotypes. Circulating levels of adrenocorticotropic hormone and corticosterone were similar in knockout and wild-type mice. Animals with no brain AM were less resistant to hypobaric hypoxia than wild-type mice, demonstrating the neuroprotective function of AM in the CNS. In conclusion, AM exerts a beneficial action in the brain by maintaining homeostasis both under normal and stress conditions.

Protocolised odontological assessment of patients with primary Sjögren's syndrome. / Evaluación protocolizada odontológica en el paciente con síndrome de Sjögren primario. Proyecto EPOX-SSp: metodología y objetivos.

OBJECTIVE: The aim of this study is to describe the findings of a protocolised odontological evaluation of patients with primary Sjögren's syndrome (pSS) treated in rheumatology units in the Community of Madrid. METHODS: Multicentric descriptive study in which pSS patients classified according to the American-European consensus of 2002 criteria were included. We collected the demographic, clinical and serological data of each patient. A complete oral examination was performed and salivary flow and the CAOD caries index were collected. The patients completed the visual analogue scale for xerostomia, the Oral Health Impact Profile-14 questionnaire and an oral health questionnaire. RESULTS: Sixty-one patients were recruited. Ninety-eight percent were women and the mean age of the patients was 57 years. Pathological oral signs (unstimulated salivary flow/salivary glands sialography/scintigraphy) were present in 52.5% of the patients, anti-Ro/anti-La were positive in 90.2%. Ninety-two percent of the patients reported xerostomia and 61% of the patients suffered from hyposialia. Thirty-five patients presented oral mucosa lesions. CAOD index was 16.97±7.93 and visual analogue scale for xerostomia was 46.69±14.43. The results of the OHIP-14 questionnaire were 23.13±14.16. Patients with pathological oral signs obtained a significantly higher Oral Health Impact Profile-14 score (P=.03). We also found that patients with peripheral nervous system involvement obtained a significantly higher Oral Health Impact Profile-14 score (P=.001) CONCLUSIONS: The presence of xerostomia in this cohort of pSS patients was high and hyposialia was present in 61% of the patients. Oral lesions appeared in more than half of the subjects. Oral health had a negative impact on the quality of life of patients with pSS, being higher in those with pathological objective oral signs and in those with peripheral nervous system involvement.

Xerostomia and Aalivary Flow in Patients Taking Antihypertensive Drugs.

The aims of this systematic review are (1) to compare the prevalence of xerostomia and hyposalivation between patients taking antihypertensive drugs with a control group (CG), (2) to compare salivary flow rate between patients treated with a CG, and (3) to identify which antihypertensives produce xerostomia. This systematic review was carried out according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. To evaluate methodological quality of the eligible studies Cochrane Collaboration tool for assessing the risk of bias for clinical trials and the modified Newcastle-Ottawa scale case-control studies were used. The databases were searched for studies up to November 19th 2019. The search strategy yielded 6201 results and 13 publications were finally included (five clinical trials and eight case-control studies). The results of the included studies did not provide evidence to state that patients taking antihypertensives suffer more xerostomia or hyposalivation than patients not taking them. With regard to salivary flow, only two clinical studies showed a significant decrease in salivary flow and even one showed a significant increase after treatment. The case-control studies showed great variability in salivary flow, but in this case most studies showed how salivary flow is lower in patients medicated with antihypertensive drugs. The great variability of antihypertensive drugs included, the types of studies and the outcomes collected made it impossible to study which antihypertensive drug produces more salivary alterations. The quality assessment showed how each of the studies was of low methodological quality. Therefore, future studies about this topic are necessary to confirm whether antihypertensive drugs produce salivary alterations.

[Christmas work dinners. A pattern of recreational use of alcohol and other drugs?]. / Las cenas navideñas de empresa. Un modelo de consumo recreativo de alcohol y otras drogas?

The aim of this study was to develop an exploratory approach to characterizing the pattern of recreational abuse of alcohol and other drugs abuse at Christmas work dinners. An adaptation of the rapid assessment methodology RARE was carried out through the combination of quantitative (rapid assessment surveys, n=444) and qualitative (observations and semistructured interviews, n=8) techniques. The fieldwork was carried out at 13 restaurants in Valencia and Alicante (Spain) in December 2007. In general we observed a marked increase in the use of alcohol and other substances compared to the rest of the year, though restaurant staff perceived a decrease in alcohol abuse attributable to new road traffic legislation. Cocaine is perceived as the illicit substance most widely used at such events. Younger coworkers initiate older ones in the use of illicit drugs, and the the latter may use this behaviour as a means of feeling younger and more uninhibited. Christmas work dinners propitiate a recreational substance-use pattern that requires adapted preventive and restrictive interventions, such as the introduction of suitable transport initiatives and the restriction of alcohol serving hours.

Giant dumbbell C2C3 neurofibroma invading prebulbar cistern: Case report and literature review.

BACKGROUND: Neurofibromatosis 1 (NF1) has a broad spectrum of clinical manifestations, most typically involving café-au-lait spots and skin neurofibromas. Only 2% of patients with NF1 have symptomatic spinal tumors. CASE DESCRIPTION: A patient with a previous diagnosis of NF1 presented with cervicalgia, dysphagia/mild dysphonia, gait alteration, and progressive hypoesthesia involving all four limbs. The magnetic resonance documented a giant dumbbell neurofibroma arising between the C2 and C3 levels which extended toward the foramen magnum, causing medullary and bulbar compression. The major challenge of surgical management was the enormous size and location this C2-C3 (5 cm × 4 cm × 5.1 cm) lesion. CONCLUSIONS: Compression of the foramen magnum attributed to a dumbbell giant spinal neurofibroma at the C2C3 level resulting in prebulbar cisterns should be among the differential diagnostic considerations for patients presenting with tetraparesis and underlying NF1.

Adrenomedullin expression is up-regulated by acute hypobaric hypoxia in the cerebral cortex of the adult rat.

Hypobaric hypoxia can produce neuropsychological disorders such as insomnia, dizziness, memory deficiencies, headache and nausea. Here we report the changes in adrenomedullin (AM) expression observed in rats exposed to hypobaric hypoxia and different times of reoxygenation. AM immunoreactivity was transiently elevated in the cerebral cortex after 7 h of exposure to a simulated altitude of 8325 m (27 000 ft). This higher expression was seen in all pyramidal cells and in a subset of small interneurons. AM-positive nonpyramidal neurons contained also calbindin and calretinin, but no parvalbumin immunoreactivity, thus identifying them as bipolar and double bouquet cells. Small blood vessels and related astroglia also became immunoreactive following the hypobaric insult. AM up-regulation decreased progressively with the time of reoxygenation, reaching almost control levels after 5 days. Real-time PCR quantification of AM mRNA and Western blotting confirmed the up-regulation of AM expression following hypobaria. In addition, hypobaria modulates alternative splicing of the AM gene resulting in a higher production of AM. Our data show that AM expression regulation constitutes a cortical response to hypobaria, suggesting that AM modulation may provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaria.

Changes in the expression pattern of the nitrergic system of ovine cerebellum affected by scrapie.

The constitutive and inducible isoforms of nitric oxide synthase (NOS) and the end-product of nitration, nitrotyrosine, were analyzed by immunohistochemistry, Western blotting, and enzymatic activity in sheep at different stages of the prion disease, scrapie. Four groups were studied: 1) nonaffected (control), 2) preclinical, 3) clinical, and 4) terminal. Constitutive neuronal NOS (nNOS) was the most abundant isoform present in cerebellar neurons of the sheep. Expression of nNOS increased in preclinical animals but diminished in the late stages of the disease. The Purkinje cells that usually are not immunoreactive for this protein became immunopositive in the clinical phase. In unaffected sheep, the inducible isoform (iNOS) was slightly positive in the Purkinje cells. As the disease progressed, the immunoreactivity of Purkinje neurons for iNOS increased. At the final stages, numerous iNOS-positive microglial cells were found in the molecular layer. There was a basal level of protein nitration in the cerebellum of unaffected sheep, especially in the molecular layer. As the disease progressed, the distal prolongations of the Purkinje cells and the astroglia became immunoreactive for nitrotyrosine. Our results suggest that the nitrergic system reacts to the progression of spongiform diseases and may be part of their pathogenesis mechanism.

The nitric oxide donor LA 419 decreases brain damage in a focal ischemia model.

Stroke affects a large number of people, especially in developed countries, but treatment options are limited. Over the years, it has become clear that nitric oxide (NO) plays a major role in this pathology and that treatments that either reduce or increase NO presence may provide an alternative route for reducing the sequelae of brain ischemia. The NO donor LA 419 previously has been shown to protect the brain tissue from ischemic damage in an experimental model of global brain ischemia. Here we study whether this holds true for focal ischemia, a condition closer to the more common form of human stroke. Ischemia was induced in rats by a stereotaxic injection of endothelin-1, a potent vasoconstrictor, in the striatum. Seven days after the injection, magnetic resonance imaging (MRI) found a significant elevation in apparent diffusion coefficient (ADC) in the injected striatum of untreated rats, due to ischemia-induced vascular edema. Animals that received LA 419 prior to injection with endothelin-1 showed an ADC undistinguishable from the contralateral striatum or from the striatum of rats not treated with LA 419. In addition, immunohistochemistry with antibodies against neuronal nitric oxide synthase (nNOS), inducible NOS (iNOS), and nitrotyrosine showed a marked increase in the expression of these markers of NO production following ischemic treatment that was dampened by treatment with LA 419. In summary, our results clearly show that the NO donor LA 419 may be a useful compound for the prevention and/or treatment of focal brain ischemia.