Headaches in the emergency department -a survey of patients' characteristics, facts and needs.

BACKGROUND AND AIM: Headache is very often the cause for seeking an emergency department (ED). However, less is known about the different diagnosis of headache disorders in the ED, their management and treatment. The aim of this survey is to analyse the management of headache patients in two different ED in Europe. METHODS: This retrospective survey was performed from September 2018 until January 2019. Patients were collected from the San Luca Hospital, Milan, Italy and the Ordensklinikum Barmherzige Schwestern, Linz, Austria. Only patients with a non-traumatic headache, as the primary reason for medical clarification, were included. Patients were analysed for their complexity and range of examination, their diagnoses, acute treatment and overall efficacy rate. RESULTS: The survey consists of 415 patients, with a mean age of 43.32 (SD ±17.72); 65% were female. Technical investigation was performed in 57.8% of patients. For acute treatment non-steroidal-anti-inflammatory drugs (NSAIDs) were the most used, whereas triptans were not given. A primary headache disorder was diagnosed in 45.3% of patients, being migraine the most common, but in 32% of cases the diagnosis was not further specified. Life-threatening secondary headaches accounted for less than 2% of cases. CONCLUSIONS: The vast majority of patients attending an ED because of headache are suffering from a primary headache disorder. Life-threatening secondary headaches are rare but seek attention. NSAIDs are by far the most common drugs for treating headaches in the ED, but not triptans.

Ablation of Perk in Schwann Cells Improves Myelination in the S63del Charcot-Marie-Tooth 1B Mouse.

In factory cells, the accumulation of misfolded protein provokes the unfolded protein response (UPR). For example, deletion of serine 63 (S63del) in myelin protein zero (P0) induces P0 accumulation in the endoplasmic reticulum (ER) of Schwann cells and a persistent UPR associated with Charcot-Marie-Tooth 1B (CMT1B) demyelinating peripheral neuropathy in human and mouse. PERK (protein kinase RNA-like ER kinase) is the ER stress sensor that attenuates global translation by phosphorylating eIF2α. Inhibition of the eIF2α holophosphatase GADD34:PP1, increases the phosphorylation of eIF2α in Schwann cells and largely rescues S63del neuropathy. Nonetheless, reducing phosphorylation of eIF2α, by Perk haploinsufficiency, also ameliorates the myelin defects of S63del nerves. This contradictory finding prompted us to investigate whether the beneficial effect of Perk deficiency on myelination could derive from neurons. To test this hypothesis, we generated and compared Schwann cell- and neuron-specific ablation of Perk in S63del nerves. Our data suggest that the detrimental effect of Perk in CMT1B derives primarily from Schwann cells. Furthermore, we show that Perk loss of function in Schwann cells restores myelination without diminishing accumulation of P0 or markers of ER stress, suggesting that Perk may modulate myelination through a pathway independent of the UPR. SIGNIFICANCE STATEMENT: In many endoplasmic reticulum (ER) stress-related disorders, activation of the unfolded protein sensor protein kinase RNA-like ER kinase (PERK) kinase is beneficial. Nonetheless, in Charcot-Marie-Tooth 1B neuropathy mice, we show that activation of PERK in Schwann cells, but not in neurons, is detrimental for myelination. PERK may interfere with myelination, independent of its role in ER stress.

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model.

Type I mucopolysaccharidosis (MPS I) is a lysosomal storage disorder caused by the deficiency of α-L-iduronidase, which results in glycosaminoglycan accumulation in tissues. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation (the last being present exclusively in the severe Hurler variant). The available treatments, enzyme-replacement therapy and hematopoietic stem cell (HSC) transplantation, can ameliorate most disease manifestations, but their outcome on skeletal and brain disease could be further improved. We demonstrate here that HSC gene therapy, based on lentiviral vectors, completely corrects disease manifestations in the mouse model. Of note, the therapeutic benefit provided by gene therapy on critical MPS I manifestations, such as neurologic and skeletal disease, greatly exceeds that exerted by HSC transplantation, the standard of care treatment for Hurler patients. Interestingly, therapeutic efficacy of HSC gene therapy is strictly dependent on the achievement of supranormal enzyme activity in the hematopoietic system of transplanted mice, which allows enzyme delivery to the brain and skeleton for disease correction. Overall, our data provide evidence of an efficacious treatment for MPS I Hurler patients, warranting future development toward clinical testing.

Monitoring disease evolution and treatment response in lysosomal disorders by the peripheral benzodiazepine receptor ligand PK11195.

Microglia activation and neuroinflammation play a pivotal role in the pathogenesis of lysosomal storage disorders (LSD) affecting the central nervous system (CNS), which are amenable to treatment by hematopoietic stem cell transplantation (HSCT). HSCT efficacy relies on replacing the intra- and extra-vascular hematopoietic cell compartments, including CNS microglia, with a cell population expressing the functional enzyme. Non-invasive and quantitative assessment of microglia activation and of its reduction upon HSCT might allow for evaluation of disease evolution and response to treatment in LSD. We here demonstrate that microglia activation can be quantified ex vivo and in vivo by PET using the peripheral benzodiazepine receptor ligand PK11195 in two models of LSD. Furthermore, we show a differential PBR binding following microglia replacement by donor cells in mice undergoing HSCT. Our data indicates that PBR ligands constitute valuable tools for monitoring the evolution and the response to treatment of LSD with CNS involvement, and enable us to evaluate whether the turnover between endogenous and donor microglia following HSCT could be adequate enough to delay disease progression.

Nonsurgical endodontic management of dens invaginatus: a report of two cases.

Dens invaginatus is a malformation affecting mainly the superior lateral incisors. It is defined as an infolding of the crown hard tissues, including the enamel and dentin, and can extend up to the root apex. Root canal treatment of this abnormality is considered difficult due to the complex anatomy presented by these teeth. This case series presents nonsurgical endodontic treatment in two cases of dens invaginatus (type II and III) in maxillary lateral incisors. This nonsurgical or conventional endodontic treatment results in healing of the periapical lesions associated with both cases, with no need for extra intervention e.g. surgical or invasive management. The manual instrumentation associated with sodium hypochlorite and calcium hydroxide were able to completely heal the lesions.  Radiographic exams were carried out to control and asses the healing. Nonsurgical treatment was successful in both cases with adequate repair after a 6-year follow-up with radiographic and tomographic assessments.

Perk Ablation Ameliorates Myelination in S63del-Charcot-Marie-Tooth 1B Neuropathy.

In peripheral nerves, P0 glycoprotein accounts for more than 20% of myelin protein content. P0 is synthesized by Schwann cells, processed in the endoplasmic reticulum (ER) and enters the secretory pathway. However, the mutant P0 with S63 deleted (P0S63del) accumulates in the ER lumen and induces a demyelinating neuropathy in Charcot-Marie-Tooth disease type 1B (CMT1B)-S63del mice. Accumulation of P0S63del in the ER triggers a persistent unfolded protein response. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER stress sensor that phosphorylates eukaryotic initiation factor 2 alpha (eIF2alpha) in order to attenuate protein synthesis. We have shown that increasing phosphophorylated-eIF2alpha (P-eIF2alpha) is a potent therapeutic strategy, improving myelination and motor function in S63del mice. Here, we explore the converse experiment:Perkhaploinsufficiency reduces P-eIF2alpha in S63del nerves as expected, but surprisingly, ameliorates, rather than worsens S63del neuropathy. Motor performance and myelin abnormalities improved in S63del//Perk+/- compared with S63del mice. These data suggest that mechanisms other than protein translation might be involved in CMT1B/S63del neuropathy. In addition,Perkdeficiency in other cells may contribute to demyelination in a non-Schwann-cell autonomous manner.

Defining peripheral nervous system dysfunction in the SOD-1G93A transgenic rat model of amyotrophic lateral sclerosis.

Growing evidence indicates that alterations within the peripheral nervous system (PNS) are involved at an early stage in the amyotrophic lateral sclerosis (ALS) pathogenetic cascade. In this study, magnetic resonance imaging (MRI), neurophysiologic analyses, and histologic analyses were used to monitor the extent of PNS damage in the hSOD-1 ALS rat model. The imaging signature of the disease was defined using in vivo MRI of the sciatic nerve. Initial abnormalities were detected in the nerves by an increase in T2 relaxation time before the onset of clinical disease; diffusion MRI showed a progressive increase in mean and radial diffusivity and reduction of fractional anisotropy at advanced stages of disease. Histologic analysis demonstrated early impairment of the blood-nerve barrier followed by acute axonal degeneration associated with endoneurial edema and macrophage response in motor nerve compartments. Progressive axonal degeneration and motor nerve fiber loss correlated with MRI and neurophysiologic changes. These functional and morphologic investigations of the PNS might be applied in following disease progression in preclinical therapeutic studies. This study establishes the PNS signature in this rat ALS model (shedding new light into pathogenesis) and provides a rationale for translating into future systematic MRI studies of PNS involvement in patients with ALS.

Jab1 regulates Schwann cell proliferation and axonal sorting through p27.

Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211- and, possibly, neuregulin 1 (Nrg1)-derived signals. However, how these signals are integrated in Schwann cells is largely unknown. We now report that the nuclear Jun activation domain-binding protein 1 (Jab1) may transduce laminin211 signals to regulate Schwann cell number and differentiation during axonal sorting. Mice with inactivation of Jab1 in Schwann cells develop a dysmyelinating neuropathy with axonal sorting defects. Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation. Genetic down-regulation of p27 levels in Jab1-null mice restores Schwann cell number, differentiation, and axonal sorting and rescues the dysmyelinating neuropathy. Thus, Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation. Finally, Jab1 may constitute a key molecule in the pathogenesis of dysmyelinating neuropathies.

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice.

P0 glycoprotein is an abundant product of terminal differentiation in myelinating Schwann cells. The mutant P0S63del causes Charcot-Marie-Tooth 1B neuropathy in humans, and a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum of Schwann cells, where it promotes unfolded protein stress and elicits an unfolded protein response (UPR) associated with translational attenuation. Ablation of Chop, a UPR mediator, from S63del mice completely rescues their motor deficit and reduces active demyelination by half. Here, we show that Gadd34 is a detrimental effector of CHOP that reactivates translation too aggressively in myelinating Schwann cells. Genetic or pharmacological limitation of Gadd34 function moderates translational reactivation, improves myelination in S63del nerves, and reduces accumulation of P0S63del in the ER. Resetting translational homeostasis may provide a therapeutic strategy in tissues impaired by misfolded proteins that are synthesized during terminal differentiation.

Knowledge, Behaviour and Practices regarding Oral Health among Public School Students / Conhecimento, comportamento e práticas em saúde bucal apresentados por escolares da Rede Pública de Ensino

Objective: The aim of this study was to assess the knowledge, behaviour and practices regarding caries lesions, periodontal disease, preventive measures, diet and oral hygiene among public school students by using specific questionnaire and then guide them on the main educational and preventive methods for oral health. Material and Methods: A total of 376 students aged between 11 and 15 years old were evaluated. The students answered a questionnaire and watched a 10-minute educational video on tooth-brushing techniques, use of dental floss and diet. All the participants were given toothbrushes, dentifrice and dental floss. The resulting data were submitted to descriptive statistical analysis. Results: It was found that 54.26% of the school students were female, 95.21% had knowledge on caries lesions and only 15.96% know about periodontal disease. The surgeon-dentist was pointed out by 66.34% of the students as the responsible for guiding them on oral hygiene, with lack of hygiene being accounted for caries lesions and periodontal disease (64.09% and 38.30%, respectively). Toothbrush, dentifrice and dental floss were the most used resources for oral hygiene by 72.34% of the participants. Dental floss was used by 42.29% of the students, whereas 38.64% fail in doing so claiming they do not know how to use it. Conclusion: The school students showed knowledge on educational and preventive methods for oral health, but with some deficiencies; the majority of them were given guidelines on how to avoid oral problems by a surgeondentist; it is necessary to emphasise the importance of using dental floss in educational programs aimed at modifying the students' behaviour and practices regarding oral health. (AU)

Objetivo: O objetivo deste estudo foi avaliar o conhecimento, comportamento e práticas de escolares da Rede Pública de Ensino sobre cárie, doença periodontal, medidas preventivas, dieta e higiene bucal por meio de um questionário específico e, posteriormente orientá-los sobre os principais métodos educativos e preventivos em saúde bucal. Material e Métodos: Foram avaliados 376 estudantes com idade entre 11 e 15 anos. Os escolares responderam um questionário e assistiram um vídeo educativo com duração de 10 minutos sobre técnicas de escovação, utilização do fio dental e dieta. Todos os alunos participantes receberam uma escova, creme dental e fio dental. Os dados obtidos foram submetidos à análise estatística descritiva. Resultados: Os resultados mostraram que 54,26% dos escolares eram do gênero feminino, 95,21% apresentaram conhecimento sobre cárie e apenas 15,96% sobre doença periodontal. O Cirurgião Dentista foi apontado como responsável pela orientação sobre higienização bucal por 66,34% dos escolares, sendo a falta de higiene responsabilizada tanto pela etiologia da cárie como da doença periodontal (64,09% e 38,30%, respectivamente). Escova, creme dental e fio dental são os recursos mais utilizados para higienização bucal por 72,34% dos entrevistados. O fio dental é utilizado por 42,29% dos alunos, e 38,64% não o utilizam alegando que não sabem utilizar. Conclusão: Os escolares avaliados apresentam conhecimento sobre métodos educativos e preventivos em saúde bucal, com algumas deficiências; a maioria dos escolares teve acesso a orientações sobre como evitar problemas bucais por meio do Cirurgião Dentista; é necessário enfatizar a importância do uso do fio dental nos programas educativos para modificar o comportamento e as práticas dos escolares em relação à saúde bucal.(AU)

Urokinase plasminogen receptor and the fibrinolytic complex play a role in nerve repair after nerve crush in mice, and in human neuropathies.

Remodeling of extracellular matrix (ECM) is a critical step in peripheral nerve regeneration. In fact, in human neuropathies, endoneurial ECM enriched in fibrin and vitronectin associates with poor regeneration and worse clinical prognosis. Accordingly in animal models, modification of the fibrinolytic complex activity has profound effects on nerve regeneration: high fibrinolytic activity and low levels of fibrin correlate with better nerve regeneration. The urokinase plasminogen receptor (uPAR) is a major component of the fibrinolytic complex, and binding to urokinase plasminogen activator (uPA) promotes fibrinolysis and cell movement. uPAR is expressed in peripheral nerves, however, little is known on its potential function on nerve development and regeneration. Thus, we investigated uPAR null mice and observed that uPAR is dispensable for nerve development, whereas, loss of uPAR affects nerve regeneration. uPAR null mice showed reduced nerve repair after sciatic nerve crush. This was a consequence of reduced fibrinolytic activity and increased deposition of endoneurial fibrin and vitronectin. Exogenous fibrinolysis in uPAR null mice rescued nerve repair after sciatic nerve crush. Finally, we measured the fibrinolytic activity in sural nerve biopsies from patients with peripheral neuropathies. We showed that neuropathies with defective regeneration had reduced fibrinolytic activity. On the contrary, neuropathies with signs of active regeneration displayed higher fibrinolytic activity. Overall, our results suggest that enforced fibrinolysis may facilitate regeneration and outcome of peripheral neuropathies.

Impact of fatigue on the efficacy of rehabilitation in multiple sclerosis.

Fatigue is considered to be one of the most common and disabling symptoms among individuals with multiple sclerosis (MS). The aim of this study is to investigate if an intensive, short-term inpatient rehabilitation program is able to improve fatigue in MS, and if fatigue is able to negatively influence the clinical and functional outcome of rehabilitation in MS. One-hundred eighty six consecutively recruited MS patients underwent an intensive, short-term inpatient rehabilitation program. Sixty-four of them were selected for this study according to our inclusion criteria and compared to a control group of 22 MS patients who did not follow a rehabilitation program. We measured fatigue symptoms with the Fatigue Severity Scale (FSS) before and after rehabilitation, and classified patients into fatigued (FMS) in the case of an FSS score ≥36 and into non-fatigued MS (NFMS) in the case of an FSS <36. Expanded Disability Status Scale (EDSS) and Functional Independence Measure (FIM) were used as clinical outcome measures of the efficacy of the rehabilitation program. In our sample, an intensive, short-term rehabilitation treatment is able to determine a significant reduction of fatigue symptoms compared to untreated MS patients (p < 0.0001); however, the presence of fatigue at the beginning of the rehab program seems not to have any impact on the clinical and functional outcome of rehabilitation. An intensive inpatient rehabilitation trial decreases symptom of fatigue in MS patients; furthermore fatigue seems not to modify the amelioration of disability and impairment determined by a rehabilitation program.

Concentração Inibitória Mínima (CIM) de dentifrícios infantis sobre cepas de Streptococcus mutans / Minimum inhibitory concentration (MIC) of children´s toothpastes on Streptococcus mutans isolates

O declínio da prevalência da doença cárie observado nos países industrializados nas últimas décadas tem sido atribuído, principalmente, ao uso abrangente de dentifrícios fluoretados. Associado ao flúor, outros antimicrobianos são incluídos nos dentifrícios com a finalidade de controlar biofilme dentário e agir sobre estreptococcus do grupo mutans. O objetivo deste estudo foi avaliar in vitro a efetividade antimicrobiana de dez dentifrícios (oito infantis, um de uso adulto e um manipulado sem fluoretos). Os dentifrícios foram diluídos (0,93 a 120 mg/mL) e o efeito foi verificado sobre 25 cepas de Streptococcus mutans, utilizando-se método de diluição em ágar. Com base nos resultados obtidos, pode-se interferir que três dentifrícios infantis contendo lauril sulfato de sódio e 1100 ppm F foram efetivos frente a cepas de S. mutans apresentando CIM de 15 mg/mL de produto; dois dentifrícios infantis contendo lauril sulfato de sódio e 500 e 1127 ppm F respectivamente, apresentaram CIM de 30 mg/mL para S. mutans; um dentifrício contendo lauril sulfato de sódio e não apresentando fluoretos, apresentou CIM de 120 mg/mL para S. mutans; dois dentifrícios infantis que não apresentaram inibição das cepas de S. mutans não continham lauril sulfato de sódio e fluoretos em sua composição; o dentifríco com indicação para adultos inibiu as cepas de S. mutans na concentração de 15 mg/mL. Este produto não aprsentava lauril sulfato de sódio em sua composição, mas apresentava maior quantidade de fluoretos (1470 ppm F). Estes resultados sugerem que na presença de fluoretos nos dentifrícios, independente de sua concentração, apresentaram ação mais efetiva do que o lauril sulfato de sódio sobre as cepas de S. mutans testadas.