Ectopic Expression Induces Abnormal Somatodendritic Distribution of Tau in the Mouse Brain.

Tau is a microtubule (MT)-associated protein that is localized to the axon. In Alzheimer's disease, the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. To investigate how this mislocalization occurs, we recently developed immunohistochemical tools that can separately detect endogenous mouse and exogenous human tau with high sensitivity, which allows us to visualize not only the pathological but also the pre-aggregated tau in mouse brain tissues of both sexes. Using these antibodies, we found that in tau-transgenic mouse brains, exogenous human tau was abundant in dendrites and somata even in the presymptomatic period, whereas the axonal localization of endogenous mouse tau was unaffected. In stark contrast, exogenous tau was properly localized to the axon in human tau knock-in mice. We tracked this difference to the temporal expression patterns of tau. Endogenous mouse tau and exogenous human tau in human tau knock-in mice exhibited high expression levels during the neonatal period and strong suppression into the adulthood. However, human tau in transgenic mice was expressed continuously and at high levels in adult animals. These results indicated the uncontrolled expression of exogenous tau beyond the developmental period as a cause of mislocalization in the transgenic mice. Superresolution microscopic and biochemical analyses also indicated that the interaction between MTs and exogenous tau was impaired only in the tau-transgenic mice, but not in knock-in mice. Thus, the ectopic expression of tau may be critical for its somatodendritic mislocalization, a key step of the tauopathy.SIGNIFICANCE STATEMENT Somatodendritic localization of tau may be an early step leading to the neuronal degeneration in tauopathies. However, the mechanisms of the normal axonal distribution of tau and the mislocalization of pathological tau remain obscure. Our immunohistochemical and biochemical analyses demonstrated that the endogenous mouse tau is transiently expressed in neonatal brains, that exogenous human tau expressed corresponding to such tau expression profile can distribute into the axon, and that the constitutive expression of tau into adulthood (e.g., human tau in transgenic mice) results in abnormal somatodendritic localization. Thus, the expression profile of tau is tightly associated with the localization of tau, and the ectopic expression of tau in matured neurons may be involved in the pathogenesis of tauopathy.

Trafficking of Kv2.1 Channels to the Axon Initial Segment by a Novel Nonconventional Secretory Pathway.

Kv2.1 is a major delayed-rectifier voltage-gated potassium channel widely expressed in neurons of the CNS. Kv2.1 localizes in high-density cell-surface clusters in the soma and proximal dendrites as well as in the axon initial segment (AIS). Given the crucial roles of both of these compartments in integrating signal input and then generating output, this localization of Kv2.1 is ideal for regulating the overall excitability of neurons. Here we used fluorescence recovery after photobleaching imaging, mutagenesis, and pharmacological interventions to investigate the molecular mechanisms that control the localization of Kv2.1 in these two different membrane compartments in cultured rat hippocampal neurons of mixed sex. Our data uncover a unique ability of Kv2.1 channels to use two molecularly distinct trafficking pathways to accomplish this. Somatodendritic Kv2.1 channels are targeted by the conventional secretory pathway, whereas axonal Kv2.1 channels are targeted by a nonconventional trafficking pathway independent of the Golgi apparatus. We further identified a new AIS trafficking motif in the C-terminus of Kv2.1, and show that putative phosphorylation sites in this region are critical for the restricted and clustered localization in the AIS. These results indicate that neurons can regulate the expression and clustering of Kv2.1 in different membrane domains independently by using two distinct localization mechanisms, which would allow neurons to precisely control local membrane excitability.SIGNIFICANCE STATEMENT Our study uncovered a novel mechanism that targets the Kv2.1 voltage-gated potassium channel to two distinct trafficking pathways and two distinct subcellular destinations: the somatodendritic plasma membrane and that of the axon initial segment. We also identified a distinct motif, including putative phosphorylation sites, that is important for the AIS localization. This raises the possibility that the destination of a channel protein can be dynamically regulated via changes in post-translational modification, which would impact the excitability of specific membrane compartments.

Effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans: a crossover double-blind study.

PURPOSE: Recently, attention has been paid to dexmedetomidine, a selective α-2 adrenoceptor agonist, as a possible additive for local anesthesia. However, the effect of locally injected dexmedetomidine on the anesthetic action in humans has not fully been clarified. Thus, the purpose of the present study was to evaluate the effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans. MATERIALS AND METHODS: Twenty healthy volunteers were included in the present crossover double-blinded study. Lidocaine solution or lidocaine plus dexmedetomidine solution was submucosally injected into the alveolar mucosa in a crossover and double-blinded manner. The local anesthetic effect of the solutions was evaluated by measuring the current perception threshold (CPT) in the oral mucosa for 120 minutes after injection. Furthermore, the sedation level, blood pressure, and heart rate of the volunteers were evaluated. For statistical analysis, the Wilcoxon signed rank test and 2-way repeated measures analysis of variation were used. RESULTS: The CPT was increased with the 2 solutions and peaked 10 minutes after injection. CPT values 10 and 20 minutes after injection of lidocaine plus dexmedetomidine solution were considerably higher than those with lidocaine solution. The duration of an important increase in the CPT after injection with lidocaine plus dexmedetomidine solution was longer than that with lidocaine. Furthermore, the area under the time curve of CPT was considerably higher with lidocaine plus dexmedetomidine solution than with lidocaine solution. No volunteer showed a change in sedation level, blood pressure, or heart rate after injection with either test solution throughout the experiment. CONCLUSION: The present study showed that a combination of dexmedetomidine plus lidocaine considerably enhances the local anesthetic potency of lidocaine without any major influences on the cardiovascular system when locally injected into the oral mucosa.

Chronic orofacial pain in dental patients: retrospective investigation over 12 years.

Orofacial pain is often difficult to diagnose and treat. However, there have been few reports on the clinical observation of dental patients with orofacial pain. We retrospectively investigated the characteristics of 221 dental patients who had suffered from persistent orofacial pain. Data were collected from the outpatient medical records in our clinic over the past 12 years. More than half of the patients (53.8%) had suffered with pain for more than 6 months from pain onset until the first visit to our clinic. The main diagnoses were neuropathic pain (30.3%), myofascial pain (23.5%), psychogenic pain (20.4%), odontogenic toothache (17.2%), and others (7.7%) such as temporomandibular disorders and glossitis. The treatments included pharmacotherapy, splint therapy, and others such as nerve block, dental treatment, physiotherapy, and/or psychotherapy. Excluding the patients (52 of 221 initially enrolled patients) with unknown responses to treatment, 65.7% showed remission or a significant improvement in pain in response to treatment. Although only a small group of patients had odontogenic toothache, the rate of improvement was highest for this disorder. In conclusion, early consultation with a dentist is useful to prevent chronicity of odontogenic pain and to make a differential diagnosis in patients with orofacial pain.

Regulatory mechanisms for the axonal localization of tau protein in neurons.

Tau is a microtubule (MT)-associated protein that is thought to be localized to the axon. However, its precise localization in developing neurons and mechanisms for the axonal localization have not been fully addressed. In this study, we found that the axonal localization of tau in cultured rat hippocampal neurons mainly occur during early neuronal development. Interestingly, transient expression of human tau in very immature neurons, but not in mature neurons, mimicked the developmental localization of endogenous tau to the axon. We therefore were able to establish an experimental model, in which exogenously expressed tau can be properly localized to the axon. Using this model, we obtained a surprising finding that the axonal localization of tau did not require stable MT binding. Tau lacking the MT-binding domain (MTBD) exhibited high diffusivity but localized properly to the axon. In contrast, a dephosphorylation-mimetic mutant of the proline-rich region 2 showed reinforced MT binding and mislocalization. Our results suggest that tight binding to MTs prevents tau from entering the axon and results in mislocalization in the soma and dendrites when expressed in mature neurons. This study therefore provides a novel mechanism independent of MTBD for the axonal localization of tau.

Independent factors affecting recovery time after sedation in patients with intellectual disabilities.

Purpose : The purpose of this study was to identify independent factors associated with prolonged recovery time after intravenous sedation for dental treatment in patients with intellectual disabilities. Methods : This study was designed as a prospective cohort study. Participants were patients with intellectual disabilities, for whom sedation for dental treatment was planned in Okayama University Hospital. The outcome variable was recovery time. The predictor variables were patient background, antiepileptic and psychotropic drugs, and anesthesia-related variables. Factors affecting the outcome were examined with multiple regression analysis. Results : We enrolled 260 cases in this study. Oral midazolam was a strong independent determinant in prolonged recovery time. Teeth extraction, short treatment time and lower body mass index were significant independent predictors of prolonged recovery time. Conclusion : Oral midazolam is a clear independent determinant of prolonged recovery time after sedation, while psychotropic drugs and antiepileptic drugs were not independent determinants in this study.

Incidence of tuberculous meningitis in the State of Santa Catarina, Brazil.

INTRODUCTION: The aim of this study was to estimate the incidence of tuberculous meningitis in the State of Santa Catarina (SC), Brazil, during the period from 2001 to 2010. METHODS: Ecological, temporal, and descriptive methods were employed using data obtained from the Information System on Disease Notification (Sistema de Informação de Agravos de Notificação). RESULTS: One hundred sixteen reported cases of tuberculous meningitis occurred from 2001 to 2010, corresponding to 1.2% (0.2 cases/100,000 inhabitants) of all meningitis cases reported in SC. There was a predominance of new cases in males, corresponding to 56.9% of new cases (0.2 cases/100,000 inhabitants; males vs. females; p=0.374), in patients aged 20-39 years, corresponding to 52.6% of new cases (0.5 cases/100,000 inhabitants; 20-39 years versus others; p<0.001), and in urban areas, corresponding to 91.4% of new cases (0.2 cases/100,000 inhabitants; urban vs. rural; p=0.003). In 48.3% of cases, the outcome was death. CONCLUSIONS: The incidence rate of tuberculous meningitis in SC has increased within the last decade, with the most affected population comprising young adult white males with an average education. Thus, tuberculous meningitis remains a serious disease, emphasizing the need for disease prevention with vaccination campaigns against tuberculosis, the development of faster and more accurate diagnostic methods, and the use of current epidemiological knowledge regarding the disease to facilitate the establishment of early treatment.

Incidence of tuberculous meningitis in the State of Santa Catarina, Brazil

Introduction The aim of this study was to estimate the incidence of tuberculous meningitis in the State of Santa Catarina (SC), Brazil, during the period from 2001 to 2010. Methods Ecological, temporal, and descriptive methods were employed using data obtained from the Information System on Disease Notification (Sistema de Informação de Agravos de Notificação). Results One hundred sixteen reported cases of tuberculous meningitis occurred from 2001 to 2010, corresponding to 1.2% (0.2 cases/100,000 inhabitants) of all meningitis cases reported in SC. There was a predominance of new cases in males, corresponding to 56.9% of new cases (0.2 cases/100,000 inhabitants; males vs. females; p=0.374), in patients aged 20-39 years, corresponding to 52.6% of new cases (0.5 cases/100,000 inhabitants; 20-39 years versus others; p<0.001), and in urban areas, corresponding to 91.4% of new cases (0.2 cases/100,000 inhabitants; urban vs. rural; p=0.003). In 48.3% of cases, the outcome was death. Conclusions The incidence rate of tuberculous meningitis in SC has increased within the last decade, with the most affected population comprising young adult white males with an average education. Thus, tuberculous meningitis remains a serious disease, emphasizing the need for disease prevention with vaccination campaigns against tuberculosis, the development of faster and more accurate diagnostic methods, and the use of current epidemiological knowledge regarding the disease to facilitate the establishment of early treatment. .

Análise dos dados epidemiológicos dos laudos de carcinoma espinocelular / Analysis of epidemiological data from the reports of squamous cell carcinoma

JUSTIFICATIVA E OBJETIVOS: O carcinoma espinocelular (CEC) é um tumor maligno das células queratinizantes da epiderme e seus anexos, sendo resultante da radiação solar cumulativa durante toda a vida. Mais comum em pacientes idosos, acima dos 70 anos. O objetivo deste estudo foi estudar o perfil epidemiológico dos pacientes diagnosticados com CEC. MÉTODO: Estudo transversal e descritivo no município de Criciúma, SC, no período de junho de 2009 a junho de 2010. A população foi composta por 74 pacientes com diagnóstico de CEC comprovados em três laboratórios de patologia que são enviados a grande totalidade dos laudos do sistema público de saúde e privado. Para verificar se as diferenças encontradas entre grupos quanto a dados paramétricos foi significativa (p < 0,05) utilizou-se o teste t de Student e para os dados não paramétricos foi utilizado o teste do Qui-quadrado. Os valores obtidos foram comparados e a análise estatística realizada através dos softwares SPSS e Microsoft Excel. RESULTADOS: A média de idade foi de 69,46 anos. O sexo mais acometido foi o feminino 55,4%. Todos os pacientes apresentavam ceratose actínica sendo a face o local mais acometido (72,9%). A maioria dos pacientes com efélides, também apresentavam queimadura solar na infância 73%. Em relação a cor dos cabelos, 54% possuíam cabelos claros e 50% olhos claros. 43,2% dos pacientes relataram exposição solar continua. CONCLUSÃO: O perfil epidemiológico associado ao câncer de pele epidermoide foi compatível com a literatura atual.

BACKGROUND AND OBJECTIVES: Squamous cell carcinoma (SCC) is a malignant tumor of keratinizing cells of the epidermis and its annexes, and is the result of cumulative solar radiation over lifetime. It is more common in elderly patients over 70 years. The objective of this study was to analyze the epidemiological profile of patients diagnosed with SCC. METHOD: Cross-sectional descriptive study in the city of Criciúma, state of Santa Catarina, from June 2009 to July 2010. The population consisted of 74 patients with diagnosis of squamous cell carcinoma diagnosed in three pathology laboratories to where most reports from the public and private health system are sent. In order to check whether the differences between groups regarding parametric data were significant (p < 0.05), we used the Student t test, and for the nonparametric data Chi-square test was used. The values were compared and statistical analysis was performed with the use of SPSS and Microsoft Excel software.RESULTS: The mean age was 69.46 years. The most affected gender was the female, with 55.4%. All patients had actinic keratosis, with the face being the most commonly affected (72.9%).Most patients with ephelides also had sunburns in childhood (73%). Regarding color of hair, 54% had light hair, and 50%had light-colored eyes. 43.2% of patients reported continuous exposure to sunlight.CONCLUSION: The epidemiological profile associated with squamous cell skin cancer is consistent with current literature.