Soluble form of the APP fragment, sAPPß, positively regulates tau secretion.

Extracellular tau has been highlighted in the pathogenesis of Alzheimer disease (AD), which is the most common neurodegenerative disease. Pathological analyses as well as model animal studies suggest that amyloid-ß peptide (Aß) deposition facilitates the spreading of tau aggregation pathology via extracellular tau. However, the precise mechanism of tau secretion remains unknown. Here, we show that the overexpression of amyloid precursor protein (APP) enhances the secretion of tau phosphorylated at threonine 181 in mouse neuroblastoma Neuro2a cells. Moreover, we found that soluble amyloid precursor protein ß (sAPPß), which is generated by ß-site APP cleaving enzyme 1 (BACE1), mediates tau secretion. Our results demonstrate that BACE1-mediated cleavage of APP plays pathological roles in AD pathogenesis by not only Aß production, but by the spreading of tau aggregation pathology via sAPPß in AD patients.

Parcellation of the murine cortical hindlimb area is demonstrated by its subcortical connectivity and cytoarchitecture.

Although corticospinal neurons are known to be distributed in both the primary motor and somatosensory cortices (S1), details of the projection pattern of their fibers to the lumbar cord gray matter remain largely uncharacterized, especially in rodents. We previously investigated the cortical area projecting to the gray matter of the fourth lumbar cord segment (L4) (L4 Cx) in mice. In the present study, we injected an anterograde tracer into multiple sites to cover the entire L4 Cx. We found that (1) the rostromedial part of the L4 Cx projects to the intermediate and ventral zones of the lumbar cord gray matter, (2) the lateral part projects to the medial dorsal horn, and (3) the caudal part projects to the lateral dorsal horn. We also found that the border between the rostromedial and caudolateral parts corresponds to the border between the agranular and granular cortex. Analysis of the somatotopic patterns formed by the cortical projection cells and the primary sensory neurons innervating the skin of the hindlimb and its related area suggests that the lateral part corresponds to the S1 hindlimb area and the caudal part to the S1 trunk area. Examination of thalamic innervation by the L4 Cx revealed that the caudolateral L4 Cx focally projects to the ventrobasal complex (VB) and the posterior complex (PO), while the medial L4 Cx widely projects to the PO but little to the VB. These findings suggest that the L4 Cx is parceled into subregions defined by the cytoarchitecture and subcortical projection.

[Multicenter Evaluation of Cine Angiography and Digital Subtraction Angiography Dose Rate for Various Angiography Programs: Comparison with Fluoroscopic Dose Rate].

We conducted a nationwide multicenter survey of various interventional radiology (IVR) procedures. Data were collected from 385 X-ray systems in 126 institutions, including 432 cine programs and 380 digital subtraction angiography (DSA) programs for diagnostic catheterization, percutaneous coronary intervention (PCI), ablation, transcatheter aortic valve implantation (TAVI), neurologic IVR, thorax IVR, abdominal IVR, and endovascular therapy (EVT). Fluoroscopic and cine dose rates were 10.1 mGy/min and 110.7 mGy/min, respectively, whereas for DSA programs, the median fluoroscopic and DSA dose rates were 8.0 mGy/min and 224.8 mGy/min, respectively. The DSA dose rate was more than twice the cine dose rate. The largest difference between dose rates was for diagnostic catheterization, which had a cine dose rate of 142.6 mGy/min and a fluoroscopic dose rate of 12.6 mGy/min (by a factor of 12.5), followed by EVT, which had a DSA dose rate of 216.0 mGy/min and a fluoroscopic dose rate of 7.7 mGy/min (by a factor of 29.6). The smallest difference between dose rates was for TAVI, which had a cine dose rate of 96.8 mGy/min and a fluoroscopic dose rate of 12.0 mGy/min (by a factor of 8.9), followed by neurologic IVR, which had a DSA dose rate of 227.9 mGy/min and a fluoroscopic dose rate of 9.6 mGy/min (by a factor of 22.6). Compared with the fluoroscopic dose rates, the cine dose rates were 9-13 times higher and the DSA dose rates were 22-30 times higher; the DSA dose rates were more than double the cine dose rates.

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.

[Multicenter Survey on Radiation Dose of Cardiac Intervention].

We conducted a nationwide survey of multiple institutions and collected data of various interventional procedures in the field of cardiology. Included in the analysis were 126 institutions, 381 X-ray systems, and 805 protocols. The dose values were compared with the Japanese diagnostic reference levels (DRLs) 2015. Fluoroscopy time, air kerma at the patient entrance reference point (Ka, r), and air kerma-area product (PKA ) were analyzed for various interventional procedures in 5,734 cardiology patients. The fluoroscopic dose rate (FDR) for pulmonary vein isolation (PVI) was less than half that of the 75th percentile of the Japanese DRLs 2015. The 75th percentiles of fluoroscopy time, Ka, r, and PKA for the respective interventional procedures were as follows: 11.0 min, 735 mGy, and 64 Gyï½¥cm2 for diagnostic coronary angiography (CA); 13.2 min, 839 mGy, and 75 Gyï½¥cm2 for CA + left ventriculography; 34.4 min, 1,810 mGy, and 148 Gyï½¥cm2 for percutaneous coronary intervention (PCI) excluding chronic total occlusion; 80.1 min, 4,338 mGy, and 312 Gyï½¥cm2 for PCI for chronic total occlusion; 74.4 min, 833 mGy, and 90 Gyï½¥cm2 for PVI; and 34.0 min, 795 mGy, and 94 Gyï½¥cm2 for transcatheter aortic valve implantation, respectively. In assessing dose values in interventional radiology, the difficulty of the technique needs to be considered, and the DRL values for FDR, fluoroscopic time, Ka, r, and PKA for each interventional procedure are considered necessary when reassessing or updating DRLs.

Hypoglossal Nerve Palsy as a Cause of Severe Dysphagia along with the Oropharyngeal Stenosis due to Occipitocervical Kyphosis.

Hypoglossal nerve palsy (HNP) is a potential cause of dysphagia. A 66-year-old man presented to our hospital with dysphagia and neck pain. One year prior to his first visit, he had been diagnosed with upper cervical tuberculosis and had undergone posterior C1-2 fixation. The physical examination led to the diagnosis of dysphagia with HNP, and he had severe weight loss. Radiographic examination revealed that the O-C kyphosis had been exacerbated and that the deformity was likely the primary cause of HNP. To restore the swallowing function, O-C fusion surgery was performed. Postoperatively, the patient showed immediate improvement of dysphagia with gradual recovery of hypoglossal nerve function. In the last follow-up evaluation, swallowing function was confirmed with no signs of HNP. Our results indicate that HNP could be more prevalent in cases with severe cervical kyphosis, being underdiagnosed due to the more apparent signs of the oropharyngeal narrowing.

[FAMILIAL OCCURRENCE OF SUMMER-TYPE HYPERSENSITIVITY PNEUMONITIS IN DEFECTIVE HOME].

A 53-year-old-woman presented our hospital with 1 month history of exertional dyspnea and mild fever. When examined, temperature was 37.2℃ and her respiratory rate of 22/min with an O2 saturation of 95% (02 4L/min), the rest of her vital signs were normal. The Chest X-ray was significant for ground-grass attenuation, and computed tomography showed diffuse nodular lesions bilaterally. She reported that the floorboard in the living room had been rotten last two months, and her husband was admitted to another hospital with similar symptoms the day before. We suspected that she and her husband have familial hypersensitivity pneumonitis although their children who live in the same house don't have any symptoms. After the admission, her respiratory status improved without treatment. The trans-bronchial lung biopsy specimens showed lymphocytic infiltration in alveolar area, and epithelioid cell granuloma consisted of CD68-positive macrophages. These findings corresponded to subacute hypersensitivity pneumonitis. The bronchoalveolar lavage revealed predominant lymphocytes of 92%, with a low CD4/8 ratio of 0.39. Serum anti-Trichosporon asahii antibodies were positive. With the result of positive environmental challenge test in her house, which showed elicited dyspnea and temperature increase up to 38℃ a few hours after she came back home, the patient was diagnosed as having summer-type hypersensitivity pneumonitis. Her husband was also diagnosed as the same disease, and symptoms improved with antigen avoidance and prednisolone. The patient was discharged to her relative's place for the moment of house repair. The patient's symptoms did not recur after her house was repaired.

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Recurrent cerebral aneurysm formation and rupture within a short period due to invasive aspergillosis of the nasal sinus; pathological analysis of the catastrophic clinical course.

Destructive infiltration of invasive fungal sinusitis can easily occur into the central nervous system (CNS). Cerebral aneurysms associated with fungal infection are highly vulnerable to rupture, and can frequently and rapidly take a serious clinical course. We experienced a patient who twice developed cerebral aneurysm followed by rupture due to invasive fugal sinusitis. This 77-year-old man was admitted for progressive bilateral visual disturbance, which was initially treated as idiopathic hypertrophic pachymeningitis. The patient subsequently suffered subarachnoid hemorrhage (SAH) twice in only 12 days. Both SAH originated from different newly formed cerebral aneurysms. Trapping was performed for both ruptured aneurysms. Pathological examination of the resected aneurysms indicated the presence of fungi determined to be Aspergillus. This Aspergillus infection was also discovered inside the frontal sinus by endoscopic biopsy, so a regimen of antifungal agents was instituted. Prolonged antifungal therapy caused renal impairment, which ultimately led to the patient's death. Autopsy detected no mycotic infiltration of the major cerebral arteries, except for the 2 ruptured cerebral aneurysms. However, prolonged mycosis of the CNS, such as in the deep part in the falx cerebri and in the small veins proximal to the tentorium cerebelli, was observed, indicating that mycosis invading the cranium is refractory even to long-term administration of antifungal agents. The present case strongly suggests that urgent and proactive definitive diagnosis is essential to successfully treat invasive paranasal sinus aspergillosis. If infiltration of the CNS is suspected, early surgical resection and antifungal therapy must be initiated immediately.

Clinical features and haplotype analysis of newly identified Japanese patients with gelsolin-related familial amyloidosis of Finnish type.

Familial amyloidosis of the Finnish type (FAF) is an autosomal dominant form of systematic amyloidosis characterized by lattice corneal dystrophy, cranial neuropathy, and cutis laxa. Although FAF has been frequently found in the Finnish population, FAF is a considerably rare disorder in other regions. In this study, we examined the clinical characteristics as well as the haplotypes of six Japanese patients with FAF from five families. They showed the typical clinical presentations of FAF, but we found a broad range of ages at onset of neurological symptoms. All members had the c.654G>A mutation in GSN. To evaluate the disease haplotypes, high-density single-nucleotide polymorphism (SNP) arrays were used and disease-relevant haplotypes were reconstructed. Haplotype analysis in the four apparently unrelated families suggested a common founder haplotype. In a sporadic FAF patient, however, the haplotype was dissimilar to the founder haplotype. The present study demonstrated that a founder mutation in most of the Japanese families with FAF, except for a sporadic patient in whom a de novo mutation event was suggested as the origin of the mutation.