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BACKGROUND: Surveys using questionnaires to collect epidemiologic data may be subject to misclassification. Here, we analyzed a headache questionnaire to evaluate which questions led to a classification other than migraine. METHODS: Anonymized surveys coupled with medical claims data from individuals 19-74 years old were obtained from DeSC Healthcare Inc. to examine proportions of patients with primary headache disorders (i.e.; migraine, tension-type headache, cluster headache, and "other headache disorders"). Six criteria that determined migraine were used to explore how people with other headache disorders responded to these questions. RESULTS: Among the 21480 respondents, 7331 (34.0%) reported having headaches. 691 (3.2%) respondents reported migraine, 1441 (6.7%) had tension-type headache, 21 (0.1%) had cluster headache, and 5208 (24.2%) reported other headache disorders. Responses of participants with other headache disorders were analyzed, and the top 3 criteria combined with "Symptoms associated with headache" were "Site of pain" (7.3%), "Headache changes in severity during daily activities" (6.4%), and the 3 criteria combined (8.8%). The symptoms associated with headache were "Stiff shoulders" (13.6%), "Stiff neck" (9.4%), or "Nausea or vomiting" (8.7%), Photophobia" (3.3%) and "Phonophobia" (2.5%). CONCLUSIONS: Prevalence of migraine as diagnosed by questionnaire was much lower than expected while the prevalence of "other headache" was higher than expected. We believe the reason for this observation was due to misclassification, and resulted from the failure of the questionnaire to identify some features of migraine that would have been revealed by clinical history taking. Questionnaires should, therefore, be carefully designed, and doctors should be educated, on how to ask questions and record information when conducting semi-structured interviews with patients, to obtain more precise information about their symptoms, including photophobia and phonophobia.
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Trastornos Migrañosos , Humanos , Persona de Mediana Edad , Adulto , Masculino , Femenino , Prevalencia , Trastornos Migrañosos/epidemiología , Trastornos Migrañosos/diagnóstico , Anciano , Encuestas y Cuestionarios , Adulto Joven , Trastornos de Cefalalgia/epidemiología , Trastornos de Cefalalgia/diagnóstico , Internet , Encuestas EpidemiológicasRESUMEN
Physiological functioning and homeostasis of the brain rely on finely tuned synaptic transmission, which involves nanoscale alignment between presynaptic neurotransmitter-release machinery and postsynaptic receptors. However, the molecular identity and physiological significance of transsynaptic nanoalignment remain incompletely understood. Here, we report that epilepsy gene products, a secreted protein LGI1 and its receptor ADAM22, govern transsynaptic nanoalignment to prevent epilepsy. We found that LGI1-ADAM22 instructs PSD-95 family membrane-associated guanylate kinases (MAGUKs) to organize transsynaptic protein networks, including NMDA/AMPA receptors, Kv1 channels, and LRRTM4-Neurexin adhesion molecules. Adam22ΔC5/ΔC5 knock-in mice devoid of the ADAM22-MAGUK interaction display lethal epilepsy of hippocampal origin, representing the mouse model for ADAM22-related epileptic encephalopathy. This model shows less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission in the hippocampus. Strikingly, without ADAM22 binding, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Furthermore, forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in nonneuronal cells. Collectively, this study reveals LGI1-ADAM22-MAGUK as an essential component of transsynaptic nanoarchitecture for precise synaptic transmission and epilepsy prevention.
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Proteínas ADAM/genética , Epilepsia/genética , Guanilato-Quinasas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas del Tejido Nervioso/genética , Transmisión Sináptica/genética , Animales , Encéfalo/metabolismo , Encéfalo/patología , Proteínas de Unión al Calcio/genética , Modelos Animales de Enfermedad , Epilepsia/patología , Epilepsia/prevención & control , Técnicas de Sustitución del Gen , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Proteínas de la Membrana/genética , Ratones , Moléculas de Adhesión de Célula Nerviosa/genética , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/genética , Canales de Potasio de la Superfamilia Shaker/genéticaRESUMEN
Schematic illustration of cortically induced dynamic activity changes of the output nuclei of the basal ganglia (the internal segment of the globus pallidus, GPi and the substantia nigra pars reticulata, SNr) in the healthy and diseased states. The height of the dam along the time course controls the expression of voluntary movements. Its alterations could cause a variety of movement disorders, such as Parkinson's disease and hyperkinetic disorders. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Trastornos del Movimiento , Enfermedad de Parkinson , Humanos , Ganglios Basales , Globo Pálido , Sustancia NegraRESUMEN
BACKGROUND: Limited epidemiological data are available for headache disorders in Japan, and no recent studies have reported the impact of several primary headache disorders in Japan. This study aimed to report the up-to-date epidemiological data and impact of primary headaches on daily activities as well as the use of medical care, clinical features, and pain severity/activity impairment using nationwide data in Japan. METHODS: We used anonymized online survey data coupled with medical claims data, from individuals aged 19-74 years old, that were provided by DeSC Healthcare Inc. The outcomes included the prevalence of migraine, tension-type headache, cluster headache, and other headache types stratified by age and sex, use of medical care, clinical features, medication use, and severity of pain/activity impairment. All outcomes were examined separately for each headache type. This is the second paper reported concurrently with this research. RESULTS: The study population comprised 691/1,441/21/5,208 individuals with migraine/tension-type headache/cluster headache/other headache types, respectively. The prevalence of migraine and tension-type headache was higher in women than in men but was similar for cluster headache (male vs. female, 1.7% vs. 7.4%, 5.3% vs. 10.8%, and 0.1% vs. 0.1%, respectively). The percentage of individuals with migraine, tension-type headache, cluster headache who had not seen a doctor was 81.0%, 92.0%, 57.1%, respectively. The common headache triggers were fatigue in migraine and tension-type headache, and weather-related phenomena and turning of the seasons in migraine. Common activities refrained from or reduced by headaches were "operating a computer or smartphone", "drinking alcohol", and "going to crowded places" in all three headache types and housework-related activities in women. Among individuals taking medicines, 16.8%, 15.8%, 47.6% with migraine, tension-type headache, and cluster headache reported moderate to severe pain, respectively, and 12.6%, 7.7%, 19.0% reported moderate to severe disability, respectively. CONCLUSIONS: This study found various triggers of headache attacks, and daily activities refrained from or reduced by headaches. Additionally, this study suggested that the disease burden in people possibly experiencing tension-type headaches, many of whom had not seen a doctor. The study findings are of clinical value for the diagnosis and treatment of primary headaches.
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Cefalalgia Histamínica , Trastornos Migrañosos , Cefalea de Tipo Tensional , Humanos , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Japón , Cefalea/epidemiología , Trastornos Migrañosos/tratamiento farmacológicoRESUMEN
l-3,4-dihydroxyphenylalanine (l-DOPA) is an effective treatment for Parkinson's disease (PD); however, long-term treatment induces l-DOPA-induced dyskinesia (LID). To elucidate its pathophysiology, we developed a mouse model of LID by daily administration of l-DOPA to PD male ICR mice treated with 6-hydroxydopamine (6-OHDA), and recorded the spontaneous and cortically evoked neuronal activity in the external segment of the globus pallidus (GPe) and substantia nigra pars reticulata (SNr), the connecting and output nuclei of the basal ganglia, respectively, in awake conditions. Spontaneous firing rates of GPe neurons were decreased in the dyskinesia-off state (≥24 h after l-DOPA injection) and increased in the dyskinesia-on state (20-100 min after l-DOPA injection while showing dyskinesia), while those of SNr neurons showed no significant changes. GPe and SNr neurons showed bursting activity and low-frequency oscillation in the PD, dyskinesia-off, and dyskinesia-on states. In the GPe, cortically evoked late excitation was increased in the PD and dyskinesia-off states but decreased in the dyskinesia-on state. In the SNr, cortically evoked inhibition was largely suppressed, and monophasic excitation became dominant in the PD state. Chronic l-DOPA treatment partially recovered inhibition and suppressed late excitation in the dyskinesia-off state. In the dyskinesia-on state, inhibition was further enhanced, and late excitation was largely suppressed. Cortically evoked inhibition and late excitation in the SNr are mediated by the cortico-striato-SNr direct and cortico-striato-GPe-subthalamo-SNr indirect pathways, respectively. Thus, in the dyskinesia-on state, signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed, underlying LID.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is caused by progressive loss of midbrain dopaminergic neurons, characterized by tremor, rigidity, and akinesia, and estimated to affect around six million people world-wide. Dopamine replacement therapy is the gold standard for PD treatment; however, control of symptoms using l-3,4-dihydroxyphenylalanine (l-DOPA) becomes difficult over time because of abnormal involuntary movements (AIMs) known as l-DOPA-induced dyskinesia (LID), one of the major issues for advanced PD. Our electrophysiological data suggest that dynamic changes in the basal ganglia circuitry underlie LID; signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed. These results will provide the rationale for the development of more effective treatments for LID.
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Ganglios Basales/fisiopatología , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa/toxicidad , Transmisión Sináptica/fisiología , Animales , Ganglios Basales/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Transmisión Sináptica/efectos de los fármacosRESUMEN
BACKGROUND: Migraine is a chronic disease characterized by episodic headache attacks. No recent studies have, however been conducted on the epidemiology of migraine or the treatment landscape in Japan. This study was conducted as a fact-finding survey using medical claims data and an online survey on migraine and headaches, conducted among members of health insurance associations with the objective of gaining an understanding of migraine prevalence and the treatment status in Japan. METHODS: The study methodology utilized a unique approach of combined data sources. The data sources used in this study are medical claims data and linked online survey data provided by DeSC Healthcare Inc (DeSC). The primary outcomes (from survey responses) were: the overall number and proportion of migraine patients; and the overall prevalence of migraine, stratified by age and sex. The secondary outcomes (from survey responses) were use of medical care; and clinical features/headache symptoms. The analysis population included all individuals who had response data for surveys conducted by DeSC. The online survey data and medical claims data were summarized. RESULTS: The data population comprised 21,480 individuals. On the basis of the survey results, including probable cases, the overall prevalence of migraine was 3.2%. The highest prevalence of migraine was observed in patients aged 30-39 years. The prevalence of migraine in women was 4.4 times higher than in men. The percentage of migraine patients who had not been seen by a doctor was 81.0%. More than 80% of patients were taking over-the-counter drugs and 4.8% took prescription medicines only. Approximately 52.9% of patients considered that the intensity of pain symptoms was severe. Moreover, the majority of patients (72.9%) considered that the impairment of daily life activities was of moderate or severe degree. CONCLUSIONS: In Japan, the percentage of people with migraine who did not receive medical attention is as high as 80%. Additionally, the majority of patients tend to endure symptoms and continue with everyday activities. With innovative treatment approaches becoming available it is necessary to disseminate information that migraine is not a simple headache but an illness that requires medical treatment and consultation.
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Trastornos Migrañosos , Femenino , Cefalea/epidemiología , Humanos , Seguro de Salud , Japón/epidemiología , Masculino , Trastornos Migrañosos/diagnóstico , PrevalenciaRESUMEN
AIM: Prognosis of liver cirrhosis patients is poor when ascites is present and liver function is impaired, but such up-to-date information from a large-scale, real-world setting is limited in Japan. We aimed to investigate the hospital mortality of Japanese liver cirrhosis inpatients. METHODS: This retrospective cohort study included data on liver cirrhosis inpatients between January 2011 and September 2018 extracted from an administrative claims database. The outcome was in-hospital mortality. The 1- and 3-year cumulative survival rates were examined for liver cirrhosis etiology, Child-Pugh classification, or ascites presence/absence using Kaplan-Meier analysis. The survival up to 1 year for tolvaptan prescription/nonprescription was examined. RESULTS: We analyzed the data of 57 769 inpatients. Survival rates did not substantially differ among etiologies, with a better prognosis for alcohol etiology and poorer prognosis for hepatitis C virus. According to the Child-Pugh classification, the 1- and 3-year survival rates were 90.2% and 75.3% for grade A, 73.5% and 53.9% for grade B, and 41.9% and 28.9% for grade C, respectively. Patients without ascites had a higher survival rate (83.2% and 67.0% at 1 and 3 years, respectively) than those with ascites (51.9% and 36.3%, respectively). Based on examining matched patients with ascites using a propensity score, prognosis was poor in general but was better at 6 months (58.1%) or similar at 1 year (47.1%) in patients prescribed tolvaptan compared to those not prescribed tolvaptan (54.8% and 47.5%, respectively). CONCLUSIONS: Poorer prognosis was suggested in inpatients with cirrhosis who had a worse Child-Pugh grade and ascites.
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Dystonin (Dst) is a causative gene for Dystonia musculorum (dt) mice, which is an inherited disorder exhibiting dystonia-like movement and ataxia with sensory degeneration. Dst is expressed in a variety of tissues, including the central nervous system and the peripheral nervous system (PNS), muscles, and skin. However, the Dst-expressing cell type(s) for dt phenotypes have not been well characterized. To address the questions whether the disruption of Dst in Schwann cells induces movement disorders and how much impact does it have on dt phenotypes, we generated Dst conditional knockout (cKO) mice using P0-Cre transgenic mice and Dst gene trap mice. First, we assessed the P0-Cre transgene-dependent Cre recombination using tdTomato reporter mice and then confirmed the preferential tdTomato expression in Schwann cells. In the Dst cKO mice, Dst mRNA expression was significantly decreased in Schwann cells, but it was intact in most of the sensory neurons in the dorsal root ganglion. Next, we analyzed the phenotype of Dst cKO mice. They exhibited a normal motor phenotype during juvenile periods, and thereafter, started exhibiting an ataxia. Behavioral tests and electrophysiological analyses demonstrated impaired motor abilities and slowed motor nerve conduction velocity in Dst cKO mice, but these mice did not manifest dystonic movements. Electron microscopic observation of the PNS of Dst cKO mice revealed significant numbers of hypomyelinated axons and numerous infiltrating macrophages engulfing myelin debris. These results indicate that Dst is important for normal PNS myelin organization and Dst disruption in Schwann cells induces late-onset neuropathy and sensory ataxia. MAIN POINTS: Dystonin (Dst) disruption in Schwann cells results in late-onset neuropathy and sensory ataxia. Dst in Schwann cells is important for normal myelin organization in the peripheral nervous system.
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Ataxia , Distonía , Animales , Ataxia/genética , Trastornos Distónicos , Distonina , Ratones , Ratones Transgénicos , Células de SchwannRESUMEN
In order to understand the pathobiology of neurotrophic keratopathy, we established a mouse model by coagulating the first branch of the trigeminal nerve (V1 nerve). In our model, the sensory nerve in the central cornea disappeared and remaining fibers were sparse in the peripheral limbal region. Impaired corneal epithelial healing in the mouse model was associated with suppression of both cell proliferation and expression of stem cell markers in peripheral/limbal epithelium as well as a reduction of transient receptor potential vanilloid 4 (TRPV4) expression in tissue. TRPV4 gene knockout also suppressed epithelial repair in mouse cornea, although it did not seem to directly modulate migration of epithelium. In a co-culture experiment, TRPV4-introduced KO trigeminal ganglion upregulated nerve growth factor (NGF) in cultured corneal epithelial cells, but ganglion with a control vector did not. TRPV4 gene introduction into a damaged V1 nerve rescues the impairment of epithelial healing in association with partial recovery of the stem/progenitor cell markers and upregulation of cell proliferation and of NGF expression in the peripheral/limbal epithelium. Gene transfer of TRPV4 did not accelerate the regeneration of nerve fibers. Sensory nerve TRPV4 is critical to maintain stemness of peripheral/limbal basal cells, and is one of the major mechanisms of homeostasis maintenance of corneal epithelium.
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Epitelio Corneal , Células Madre , Canales Catiónicos TRPV/metabolismo , Nervio Trigémino/metabolismo , Cicatrización de Heridas/fisiología , Animales , Células Cultivadas , Epitelio Corneal/citología , Epitelio Corneal/lesiones , Epitelio Corneal/metabolismo , Técnicas de Inactivación de Genes , Ratones , Células Madre/citología , Células Madre/metabolismo , Canales Catiónicos TRPV/genética , Nervio Trigémino/químicaRESUMEN
Recently, palliative care units are required to provide home-care support. In our palliative care unit, we support withh ospital discharge according to patient's wishes. In 2 years since April 2016, 104 of 536 hospitalized patients were discharged home (home discharge rate 19.4%). Among these patients, 30 died at home. Using the cases of the 30 patients, we investigated proper discharge and home-care support. As a background factor, the existence of"care by a woman"and"opioid unused" was likely to facilitate death at home. The patient was widely introduced to 18 clinics in the local area, not a specific medical institution. As reasons for home discharge,"Advanced understanding of medical condition" and"Recognition of the goodness of home"was cited. The median time from discharge to death at home is as short as 14 days, and so cooperation between the hospital and the home medical team is indispensable. To that end, the hospital guarantees emergency hospitalization, and the home medical team needs to accept discharge of the patient who is approaching death.
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Líquidos Corporales , Servicios de Atención de Salud a Domicilio , Cuidados Paliativos , Alta del Paciente , Femenino , Hospitalización , HumanosRESUMEN
BACKGROUND: Endoscopic submucosal dissection (ESD) is the preferred treatment for esophageal squamous cell carcinoma (ESCC). However, ESD can be difficult when patients move due to insufficient sedation. We conducted a prospective confirmatory single arm study to evaluate the efficacy of using dexmedetomidine (DEX) in combination with midazolam as a novel sedation for ESD. METHODS: Endoscopic submucosal dissection was performed without intubation in 65 patients. The primary outcome was the proportion of patients who did not move or require restraint during ESD, compared to historical control of ESD performed under midazolam sedation. Secondary outcomes included the frequency of complications and self-report questionnaires from patients and endoscopists. RESULTS: Restraint was not required in 97% of patients sedated using the combination of DEX and midazolam. Depressed respiration, low blood pressure, and bradycardia occurred in 23, 37, and 26% of patients, respectively. All patients recovered without severe complication. Occurrence of low blood pressure and bradycardia were higher, while respiratory depression was lower for the combination group than for the historical control group. The amount of midazolam used was significantly lower than in the control. Of note, 94% of patients had no painful sensations, with 3 reporting chest pain and 3 having a recollection of the procedure. Endoscopists were satisfied with the sedation in 94% of cases. All lesions were resected in en bloc fashion, without perforation. CONCLUSIONS: The combination of DEX and midazolam provided effective sedation for ESD for ESCC.
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Dexmedetomidina/efectos adversos , Resección Endoscópica de la Mucosa/métodos , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/cirugía , Hipnóticos y Sedantes/efectos adversos , Midazolam/efectos adversos , Anciano , Anciano de 80 o más Años , Anestesia/efectos adversos , Anestesia/métodos , Estudios de Casos y Controles , Dexmedetomidina/administración & dosificación , Quimioterapia Combinada/métodos , Resección Endoscópica de la Mucosa/tendencias , Endoscopía/psicología , Endoscopía/estadística & datos numéricos , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Femenino , Humanos , Hipnóticos y Sedantes/administración & dosificación , Japón/epidemiología , Masculino , Midazolam/administración & dosificación , Persona de Mediana Edad , Satisfacción Personal , Estudios Prospectivos , Estudios Retrospectivos , Autoinforme/estadística & datos numéricos , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
To understand how information from different cortical areas is integrated and processed through the cortico-basal ganglia pathways, we used optogenetics to systematically stimulate the sensorimotor cortex and examined basal ganglia activity. We utilized Thy1-ChR2-YFP transgenic mice, in which channelrhodopsin 2 is robustly expressed in layer V pyramidal neurons. We applied light spots to the sensorimotor cortex in a grid pattern and examined neuronal responses in the globus pallidus (GP) and entopeduncular nucleus (EPN), which are the relay and output nuclei of the basal ganglia, respectively. Light stimulation typically induced a triphasic response composed of early excitation, inhibition, and late excitation in GP/EPN neurons. Other response patterns lacking 1 or 2 of the components were also observed. The distribution of the cortical sites whose stimulation induced a triphasic response was confined, whereas stimulation of the large surrounding areas induced early and late excitation without inhibition. Our results suggest that cortical inputs to the GP/EPN are organized in a "local inhibitory and global excitatory" manner. Such organization seems to be the neuronal basis for information processing through the cortico-basal ganglia pathways, that is, releasing and terminating necessary information at an appropriate timing, while simultaneously suppressing other unnecessary information.
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Ganglios Basales/fisiología , Células Piramidales/fisiología , Corteza Sensoriomotora/fisiología , Potenciales de Acción , Animales , Ganglios Basales/citología , Mapeo Encefálico , Estimulación Eléctrica , Femenino , Masculino , Ratones Transgénicos , Inhibición Neural/fisiología , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Optogenética , Estimulación Luminosa , Células Piramidales/citología , Corteza Sensoriomotora/citología , Procesamiento de Señales Asistido por ComputadorRESUMEN
Our palliative care unit(PCU)supports the home care patient through emergencyacceptance for 24 hours, and 26.6%of inpatients died within 1 week after hospitalization in 2015. We examined the background of patients who became hospitalized in the imminent condition of life. Symptoms of dyspnea and generalized weakness were causes of hospitalization even with experienced home medical intervention, and there was a tendencyof the rate of death within 1 week after hospitalization to be high. Qualityof palliative care for short-term death cases after PCU hospitalization is a major concern.
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Servicios de Atención de Salud a Domicilio , Hospitalización , Cuidado Terminal , Humanos , Pacientes Internos , Mortalidad/tendencias , Cuidados PaliativosRESUMEN
The sense of taste is achieved by cooperation of many signaling molecules expressed in taste cells, which code and transmit information on quality and intensity of taste to the nervous system. Viral vector-mediated gene transfer techniques have been proven to be useful to study and control function of a gene product in vivo However, there is no transduction method for taste cells in live animals. Here, we have established a method for inducing foreign gene expression in mouse taste cells in vivo by recombinant adeno-associated virus (AAV) vector. First, using enhanced green fluorescent protein (EGFP) as a reporter, we screened 6 AAV serotypes along with a recombinant lentivirus vector for their ability to transduce taste cells. One week after viral injection into the submucosa of the tongue, EGFP expression in fungiform taste cells was observed only in animals injected with AAV-DJ, a synthetic serotype. Next, time course of AAV-DJ-mediated EGFP expression in fungiform taste cells was evaluated. Intragemmal EGFP signals appeared after a delay, rapidly increased until 7 days postinjection, and gradually decreased over the next few weeks probably because of the cell turnover. Finally, the taste cell types susceptible to AAV-DJ transduction were characterized. EGFP expression was observed in PLCß2-immunoreactive type II and aromatic l-amino acid decarboxylase (AADC)-immunoreactive type III taste cells as well as in cells immunonegative for both PLCß2 and AADC, demonstrating that AAV-DJ does not discriminate functional taste cell types. In conclusion, the method established in this study will be a promising tool to study the mechanism of taste.
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Dependovirus/genética , Técnicas de Transferencia de Gen , Vectores Genéticos/genética , Papilas Gustativas/citología , Papilas Gustativas/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
We identified a novel spontaneous mutant mouse showing motor symptoms that are similar to those of the dystonia musculorum (dt) mouse. The observations suggested that the mutant mice inherited the mild dt phenotype as an autosomal recessive trait. Linkage analysis showed that the causative gene was located near D1Mit373 and D1Mit410 microsatellite markers on chromosome 1, which are close to the dystonin (Dst) gene locus. To investigate whether Dst is the causative gene of the novel mutant phenotype, we crossed the mutant with Dst gene trap (DstGt) mice. Compound heterozygotes showed a typical dt phenotype with sensory degeneration and progressive motor symptoms. DNA sequencing analysis identified a nonsense mutation within the spectrin repeats of the plakin domain. The novel mutant allele was named dt23Rbrc. Motor abnormalities in homozygous dt23Rbrc/dt23Rbrc mice are not as severe as homozygous DstGt/DstGt mice. Histological analyses showed abnormal neurofilament (NF) accumulation in the nervous system of homozygous dt23Rbrc/dt23Rbrc mice, which is characteristic of the dt phenotype. We mapped the distribution of abnormal NF-accumulated neurons in the brain and found that they were located specifically in the brainstem, spinal cord, and in regions such as the vestibular nucleus, reticular nucleus, and red nucleus, which are implicated in posture and motor coordination pathways. The quantification of abnormal NF accumulation in the cytoplasm and spheroids (axons) of neurons showed that abnormal NF immunoreactivity was lower in homozygous dt23Rbrc/dt23Rbrc mice than in homozygous DstGt/DstGt mice. Therefore, we have identified a novel hypomorphic allele of dt, which causes histological abnormalities in the central nervous system that may account for the abnormal motor phenotype. This novel spontaneously occurring mutant may become a good model of hereditary sensory and autonomic neuropathy type 6, which is caused by mutations in the human DST gene.
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Trastornos Distónicos/complicaciones , Trastornos Distónicos/genética , Distonina/genética , Regulación del Desarrollo de la Expresión Génica/genética , Trastornos Heredodegenerativos del Sistema Nervioso/etiología , Repeticiones de Microsatélite/genética , Factores de Edad , Animales , Animales Recién Nacidos , Cromosomas Humanos Par 1/genética , Trastornos Distónicos/patología , Distonina/metabolismo , Potenciales Evocados Motores/genética , Conducta Exploratoria/fisiología , Genotipo , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Trastornos Heredodegenerativos del Sistema Nervioso/patología , Humanos , Filamentos Intermedios/genética , Filamentos Intermedios/metabolismo , Filamentos Intermedios/ultraestructura , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Actividad Motora/genética , Neuronas/fisiología , Neuronas/ultraestructura , Reflejo de Enderezamiento/genética , Percepción Espacial/fisiologíaRESUMEN
Nausea and vomiting are among the most common and distressing symptoms in patients with advanced cancer. Olanzapine, an antipsychotic agent, is known to have an affinity for multiple neurotransmitter receptors. Previous studies have reported olanzapine to be efficacious in the treatment of nausea and vomiting. Although it has been administered at a number of facilities, its applicability to treat nausea and vomiting in patients with advanced cancer is poorly understood. We investigated the use of olanzapine for nausea and vomiting in patients with advanced cancer at multiple centers. This retrospective study was carried out at seven palliative care units and three facilities with palliative care teams in Japan from 2013 to 2015. The dosage of olanzapine, treatment duration, and duration from initial use until death were collected from the medical records. One hundred and eight patients met our inclusion criteria. The average dose of olanzapine was 3.6 mg (2.5 mg, n = 61; 5 mg, n = 46; 10 mg, n = 1) and average treatment duration was 18.7 days. The average duration from initial use until death was 39.0 days. There were no differences in the duration of administration until death between olanzapine doses (2.5 and 5 mg). Our results suggest that olanzapine have been used in patients with poor prognoses for nausea and vomiting in patients with advanced cancer. Conducting a prospective trial would further yield promising results.
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Antieméticos/administración & dosificación , Benzodiazepinas/administración & dosificación , Náusea/tratamiento farmacológico , Vómitos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antipsicóticos/administración & dosificación , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Olanzapina , Cuidados Paliativos/métodos , Comodidad del Paciente , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and consequent motor dysfunction. Zonisamide (1,2-benzisoxazole-3-methanesulfonamide), which was originally developed as an antiepileptic drug, has been found to have therapeutic benefits for PD. However, the pharmacological mechanisms behind the beneficial actions of zonisamide in PD are not fully understood. Here, we investigated the neuroprotective effects of zonisamide on nigrostriatal dopaminergic neurons of the Engrailed mutant mouse, a genetic model of PD. Chronic administration of zonisamide in Engrailed mutant mice was shown to improve the survival of nigrostriatal dopaminergic neurons compared with that under saline treatment. In addition, dopaminergic terminals in the striatum and the motor function were improved in zonisamide-treated Engrailed mutant mice to the levels of those in control mice. To clarify the mechanism behind the neuroprotective effects of zonisamide, the contents of neurotrophic factors were determined after chronic administration of zonisamide. Brain-derived neurotrophic factor content was increased in the striatum and ventral midbrain of the zonisamide-treated mice compared to saline-treated mice. These findings imply that zonisamide reduces nigrostriatal dopaminergic cell death through brain-derived neurotrophic factor signaling and may have similar beneficial effects in human parkinsonian patients as well.
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Encéfalo/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Isoxazoles/farmacología , Degeneración Nerviosa/patología , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/patología , Animales , Antioxidantes/farmacología , Antiparkinsonianos/farmacología , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Neuronas Dopaminérgicas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Degeneración Nerviosa/metabolismo , ZonisamidaRESUMEN
The striatum and subthalamic nucleus (STN) are the input stations of the basal ganglia and receive excitatory afferents from the cerebral cortex. The basal ganglia control voluntary movements through three parallel pathways mediated by the input stations: the hyperdirect pathway, which conveys direct cortical inputs to the substantia nigra pars reticulata (SNr), the output nucleus, through the STN; the direct pathway, which arises from striatal neurons expressing dopamine D1 receptors and projects to the SNr; and the indirect pathway, which arises from striatal neurons expressing dopamine D2 receptors (D2Rs) and projects indirectly to the SNr by way of the globus pallidus (GP) and STN. Our previous study showed that immunotoxin-mediated cell targeted ablation of D2R-expressing striatal neurons in mice induced motor hyperactivity. To elucidate the mechanism underlying the hyperactivity, here we examined neuronal activity in the GP and SNr. The ablation of D2R-expressing striatal neurons had little effect on spontaneous activity in the GP and SNr, but induced dramatic changes in the cortically evoked triphasic response composed of early excitation, inhibition, and late excitation in the GP and SNr (i.e., reduced inhibition in the GP, and reduced late excitation in the GP and SNr). In contrast, the ablation of striatal cholinergic interneurons, which also express D2Rs, did not show such effects. Therefore, the reduction of the cortically evoked late excitation in the SNr seems to be responsible for hyperactivity. These observations suggest that phasic late excitation in the SNr through the striatopallidal indirect pathway plays a key role in stopping movements.
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Cuerpo Estriado/fisiología , Globo Pálido/fisiología , Hipercinesia/fisiopatología , Transducción de Señal/fisiología , Sustancia Negra/fisiología , Animales , Femenino , Humanos , Hipercinesia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Vías Nerviosas/fisiologíaRESUMEN
The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst-a isoforms, which contain actin-binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well-recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (Dst(Gt) ) encodes a mutant Dystonin-LacZ fusion protein, which is detectable by X-gal (5-bromo-4-chloro-3-indolyl-ß-D-galactoside) staining. We observed wide expression of the actin-binding domain-containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell-autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar-thalamo-striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel Dst(Gt) mice showed that a loss-of-function mutation in the actin-binding domain-containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose Dst(Gt) allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.