Exome Sequencing Reveals a Homozygous SYT14 Mutation in Adult-Onset, Autosomal-Recessive Spinocerebellar Ataxia with Psychomotor Retardation

Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a TaqMan assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an in vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders

Comparison of Visual Evoked Potential Components between Laser and Cathod-Ray Tubes Stimulation in Healthy Human Subjects

We studied the differences in latency and amplitude between the laser stimulated visual evoked potentials (VEPs) and the cathode-ray tubes (CRTs) stimulated VEPs to estimate the risk of inducing photosensitive epilepsy by laser displays. Twenty healthy subjects were recruited for the study. Red and blue light stimulations were flashed in 1, 7.5 and 15Hz. The latency of P1, N1, P2 and N2 in 1 Hz stimulation revealed no significant difference by a paired t test between laser and CRT stimulation. The peak-to-peak amplitude was significantly smaller with red or blue laser stimulation than with red or blue CRT stimulation, for PI-N1 and N1-P2 at 7.5Hz stimulation, and for N1-P2 and P2-N2 at 15Hz stimulation. We therefore postulate that laser does not produce more excitability to occipital cerebral cortex than CRT does. There was no evidence to say that laser stimulation is more dangerous as the risk of inducing photosensitive epilepsy than conventional CRT stimulation

筋萎縮性側索硬化症における筋核磁気共鳴画像(MRI)の検討

筋萎縮性側索硬化症(amyotrophic lateral sclerosis;ALS)の診断は,厚生労働省の診断基準に基づいて臨床症候,電気生理学的所見,病理学的所見などを基に総合的に判定して得られる.近年では,頭部核磁気共鳴画像(magnetic resonance imaging;MRI)上,内包後脚を中心として錐体路に一致して出現するT2高信号域が異常所見として報告されている.一方,筋MRIにおける筋内信号強度の上昇は,炎症および浮腫性変化を反映していると考えられている.非典型的なALSでは臨床症候と検査所見からだけでは他の疾患との鑑別が困難なこともあるため,今回我々は,ALS患者の下腿筋MRIについて検討した.対象は,ALS患者10例で男性7例,女性3例からなり,平均年齢は,68.6±11.2歳(49～87歳)である.発病初期より球症状が顕著な症例が1例,筋力低下が上肢に強い症例が3例,下肢に強い症例が6例あった.9例に下腿筋MRI,10例に針筋電図と末梢神経伝導検査を施行した.発病初期の筋力低下が下肢に強い6例の筋MRI・T2強調画像において筋内信号強度の上昇を認めた.それに対して筋力低下が上肢に強い症例や球症状の顕著な症例では,筋MRIの筋内信号強度は正常であった.また,筋内信号が上昇していた6例のうち5例における腓骨神経電気刺激で,複合筋活動電位の著明な振幅低下を認めた.ALS患者における筋MRI・T2強調画像の信号強度上昇は,脱神経後の浮腫性変化を反映していると考えられるため,ALS患者の病期判定や他疾患との鑑別が困難な場合の補助検査のひとつとして筋MRIは有用である.Various objective measurements can be used to diagnose amyotrophic lateral sclerosis (ALS). T2-weighted brain MRI images revealed high signal areas at the posterior limb of the internal capsules in ALS patients. Recently, muscle MRI proved useful to evaluate abnormalities of the muscle in myositis patients. Therefore, in the present study, we examined muscle MRI of leg muscles in ALS patients, and correlated MRI with functional measurements, such as muscle strength, and compound muscle action potential amplitude of the tibialis anterior (TA) after stimulation of the peroneal nerve. The subjects consisted of 10 ALS patients (7 males and 3 females), ranging in age from 49 to 87. Neurologic symptoms at the onset of ALS consisted of bulbar dysfunction in one patient, upper extremity involvement in three patients, and lower extremity involvement in six patients. Muscle MRI of the legs was performed in 9 (ALS patients. A peripheral nerve conduction study was performed on the peroneal nerve, with the recording electrode over the TA. The T2-weighted muscle MRI images revealed high signal aeras in the muscle in six ALS patients, whose muscle weakness existed predominantly in the lower extremities. Extracellular fluid accumulation has been proposed to be responsible for the signal increase of denervated muscles on T2-weighted muscle MRI images. We assume that muscle MRI is useful to demonstrate the distribution of muscle involvement in ALS patients and to assess the disease\u27s stage

富士川流域におけるCreutzfeldt-Jakob病の疫学的検討

1970年代以降,静岡,山梨両県の富士川流域にCreutzfeldt-Jakob病(CJD)が多いことは知られていたが,筆者らは同地域に位置する共立蒲原総合病院で1999年の1年間に3例のCJD患者を経験したことから,静岡,山梨両県の36施設に対し,1990年から1999年の10年間にわたるCJD患者についてのアンケート調査を行なった.36施設中26施設から文献例を含む合計34例のCJD患者が確認された.症例は男性16例,女性18例で,平均発症年齢は62.5±10.7歳であった.遺伝子変異が10/34例(29.4%)にみられ,全例がcodon 200の変異(CJD^)であり,そのうち2家系に家族内発症を認めた.臨床所見では高率にミオクローヌス(95.7%)と脳波上の周期性同期性放電(periodic synchronous discharge,PSD)(95.7%)を認め,従来の孤発例やCJD^の特徴と一致していた.過去10年間では富士川中流地区に,1999年の1年間では下流地区に,それぞれCJD患者の有為な集積が確認された(ボアソン分析でpの10例のうち8例が富士川流域(7例が中流～下流地区)の出身であったことから,同地区がCJD^の主たる集積地区と考えられた.また周辺の静岡市から三島市にかけても症例(CJD^2例を含む)が散見され,同地区まで含めた範囲をCJD関連地域として注目すべきと考えた.An epidemiological study of Creutzfeldt-Jakob disease (CJD) was carried out during the period between 1990 and 1999. A total of 34 cases with CJD was collected from the information provided by neurologists, psychiatrists, and neurosurgeons in Shizuoka and Yamanashi Prefecture. There was no significant difference between males and females. The average age of onset was 62.5 years, with high occurrence seen in patients in their fifties, sixties, and seventies. The mean duration of CJD was 7.3 months. There were no cases with a cadaveric dural graft. There were two families with CJD patients having codon 200 mutations. Myoclonus occurred in 95.7% of cases and there were electroencephalographic (EEG) tracings with periodic synchronous discharges (PSD) in 95.7% of the cases. Ten patients had a mutation at codon 200 of prion protein gene (CJD^) . In the middle reaches of the Fuji River basin (Yamanashi Prefecture), the retrospective incidence of CJD between 1990 and 1999 was 5.77 cases/million/annum; highly significant clustering (p = 0.01) was confirmed in this area. The point prevalence rate in 1999 at the lower reaches of the Fuji River (eastern part of Shizuoka Prefecture) was 9.78 cases/million/annum. These results demonstrated significant clusters of CJD patients at the middle and lower reaches of the Fuji River. The incidence of CJD^ appeared to be much higher in these areas than other areas in Japan

ミトコンドリア脳筋症における少量ジクロロ酢酸療法の臨床的評価 : ジクロロ酢酸少量内服療法が卒中様発作抑制に有効であった5症例について

筋生検・ミトコンドリアDNA遺伝子診断などによりMELASと診断され,脳卒中様発作を繰り返し,頭部MRIで病変が確認された成人MELAS5症例に,少量のジクロロ酢酸を含むLiverall^を投与し,脳卒中様発作を抑制できるか臨床経過を検討した.内服開始後は,全例で頭部MRI画像上病変を認める脳卒中様発作は生じなかった.従来小児科領域で報告されていた必要量よりも少量で発作を抑制できる可能性があると考えられた.しかし,血清中の乳酸・ピルビン酸は異常値を示す場合もあり,痙攣発作やイレウスなどの合併症状を呈する症例も2例あり,今後の検討が必要と考えられた.本論文の要旨は,第44回日本神経学会総会(横浜,2003年5月)において発表した.In five adult patients with MELAS, we evaluated clinical symptoms, FLAIR and DWI brain MRI, and serum level of lactate and pyruvic acid, to assess whether stroke-like episodes in MELAS are suppressed by small dose of dichloroacetate. After beginning oral therapy of Liverall^ for MELAS, none of the five cases showed any occurrence of the stroke-like episodes associated with brain MRI lesions. We noticed that the stroke-like episodes were suppressed by using a smaller dose of dichloroacetate, compared with the dose required for therapy of pediatric patients with MELAS. In spite of favorable effect of Liverall^ for MELAS in symptomatic and MRI evaluations, the serum level of lactate and pyruvic acid continued to show abnormal values and convulsive seizures or ileus occurred in a few cases. Further investigations are required to know whether Liverall^ is a useful therapeutic drug

Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks

无线传感器网络，作为全球未来十大技术之一，集成了传感器技术、嵌入式计算技术、分布式信息处理和自组织网技术，可实时感知、采集、处理、传输网络分布区域内的各种信息数据，在军事国防、生物医疗、环境监测、抢险救灾、防恐反恐、危险区域远程控制等领域具有十分广阔的应用前景。 本文研究分析了无线传感器网络的已有路由协议，并针对大规模的无线传感器网络设计了一种树状路由协议，它根据节点地址信息来形成路由，从而简化了复杂繁冗的路由表查找和维护，节省了不必要的开销，提高了路由效率，实现了快速有效的数据传输。 为支持此路由协议本文提出了一种自适应动态地址分配算——ADAR（AdaptiveDynamicAddre...As one of the ten high technologies in the future, wireless sensor network, which is the integration of micro-sensors, embedded computing, modern network and Ad Hoc technologies, can apperceive, collect, process and transmit various information data within the region. It can be used in military defense, biomedical, environmental monitoring, disaster relief, counter-terrorism, remote control of haz...学位：工学硕士院系专业：信息科学与技术学院通信工程系_通信与信息系统学号：2332007115216

Outbreak of a new coronavirus (SARS-CoV-2) infection and pollen exposure

The inference that this paper points out is that the stimulating environmental factor behind why the SARS-CoV-2 epidemic occurred in Wuhan is probably pollen from the plant kingdom. We started in 2003 to point out the epidemiological fact that Kawasaki disease is probably a Pollen-Induced Disease (PID) triggered by pollen exposure. Subsequently, we also examined the correlation analysis between the cyclical changes in pollen count and the changes in the number of new patients with respect to the incidence of 40 designated intractable diseases and 24 cancers and malignancies over a 40-year period, and were able to show a significant association. Since the 1990s, it has been reported that the number of pollen scattered in Wuhan, China is far higher than the number of pollen scattered in other parts of Japan, and is by far the highest in China. Before the COVID-19 epidemic began, it is conceivable that some of the allergic prone (allergic constitution) residents of Wuhan City, who have been exposed to large amounts of pollen in the spring and small amounts of precursor pollen in the fall each year, fell into a compromised immune state in November. Through a mechanism similar to the initial process of carcinogenesis triggered by pollen exposure, patients infected with the old coronavirus, which is a foreign substance, are thought to have developed a mechanism whereby the old coronavirus mutates (becomes highly toxic) in the host body in the course of their biological response to the virus. This supposed host response process (trick) allows the virus to expand its mutation at the genetic level, which is beyond the control of the host human, during the replication process. As a result, the virus will cause a situation (condition) that will lead to an infectious disease pandemic that can be transmitted from person to person who have not yet developed resistance. It is implied that within the host, a suicidal pathological process, costly to humanity, may be occurring in a process similar to that of individual carcinogenesis.</p

The Relationship between Annual Airborne Pollen Levels and Occurrence of All Cancers, and Lung, Stomach, Colorectal, Pancreatic and Breast Cancers: A Retrospective Study from the National Registry Database of Cancer Incidence in Japan, 1975–2015

Suppression of risk factors including smoking, overdrinking and infections by human papilloma and hepatitis B and C viruses has been recommended for cancer prevention; however, identification of other environmental risk factors has not been enough. Besides the 2003 report that Kawasaki disease may be triggered by pollen exposure, 40 Japanese specific intractable diseases have recently been reported as &ldquo;pollen diseases&rdquo;, also potentially triggered by pollen exposure. Various human organs are affected by pollen exposure, leading to systemic vasculitis; autoimmune connective tissue diseases, inflammatory bowel diseases and intractable neuromuscular and bone diseases, suggesting the common effects of pollen exposure on fundamental functions of vital metabolism. In this context, cancer and malignant tumors may be another group of intractable diseases triggered by epigenetic pollen exposure. Thus, this study compared the number of newly registered patients with 24 types of cancer and airborne pollen levels measured from 1975 to 2015. We searched for statistical correlations with Bonferroni correction between the annual number of newly registered patients for all cancers or for each of lung, stomach, colorectal, pancreatic and breast cancers in the patient-registry year &ldquo;x&rdquo;, and annual airborne pollen levels measured in the same year as &ldquo;x&rdquo;, or 1&ndash;7 years prior to the year &ldquo;x&rdquo;. The number of newly registered patients for lung, and pancreatic cancers in the patient-registry year &ldquo;x&rdquo; was highly correlated with airborne pollen levels measured 2 years prior to &ldquo;x&rdquo;. That for breast cancer was correlated with pollen levels measured 2 and 5 years prior to &ldquo;x&rdquo;. To our knowledge, this is the first rapid communication of the association between pollen levels and cancer incidence