Peripheral Blood BRCA1 Methylation Positively Correlates with Major Alzheimer's Disease Risk Factors.

BACKGROUND: Recent biomarker studies demonstrated that the central nervous system (CNS) environment can be observed from peripherally-derived samples. In a previous study, we demonstrated significant hypomethylation of the BRCA1 promoter region in neuronal cells from post-mortem brains of Alzheimer's disease patients through neuron-specific methylome analysis. Thus, we investigate the methylation changes in the BRCA1 promoter region in the blood samples. OBJECTIVES: To analyze the methylation level of the BRCA1 promoter in peripheral blood from AD patients and normal controls. DESIGN, SETTING, PARTICIPANTS: Genomic DNA samples from peripheral blood were obtained from the J-ADNI repository, and their biomarker data were obtained J-ADNI from the National Bioscience Database Center. Genomic DNA samples from an independent cohort for validation was obtained from Niigata University Hospital (Niigata, Japan). Amyloid positivity was defied by visual inspection of amyloid PET or a CSF Aß42 value ≤ 333 pg/mL at the baseline. MEASUREMENTS: Methylation level of the BRCA1 promoter was analyzed by pyrosequencing. RESULTS: Compared to normal controls, methylation of the BRCA1 promoter in AD patients was not significantly changed; however, in AD patients, it showed a positive correlation with AD risk factors. CONCLUSIONS: Our data confirmed the importance of cell-type specific methylome analysis and also suggested that environmental changes in the CNS can be detected by observing the peripheral blood, implying that the peripheral BRCA1 methylation level can be a surrogate for AD.

Cohort-Specific Optimization of Models Predicting Preclinical Alzheimer's Disease, to Enhance Screening Performance in the Middle of Preclinical Alzheimer's Disease Clinical Studies.

BACKGROUND: Models that can predict brain amyloid beta (Aß) status more accurately have been desired to identify participants for clinical trials of preclinical Alzheimer's disease (AD). However, potential heterogeneity between different cohorts and the limited cohort size have been the reasons preventing the development of reliable models applicable to the Asian population, including Japan. OBJECTIVES: We aim to propose a novel approach to predict preclinical AD while overcoming these constraints, by building models specifically optimized for ADNI or for J-ADNI, based on the larger samples from A4 study data. DESIGN AND PARTICIPANTS: This is a retrospective study including cognitive normal participants (CDR-global = 0) from A4 study, Alzheimer Disease Neuroimaging Initiative (ADNI), and Japanese-ADNI (J-ADNI) cohorts. MEASUREMENTS: The model is made up of age, sex, education years, history of AD, Clinical Dementia Rating-Sum of Boxes, Preclinical Alzheimer Cognitive Composite score, and APOE genotype, to predict the degree of amyloid accumulation in amyloid PET as Standardized Uptake Value ratio (SUVr). The model was at first built based on A4 data, and we can choose at which SUVr threshold configuration the A4-based model may achieve the best performance area under the curve (AUC) when applied to the random-split half ADNI or J-ADNI subset. We then evaluated whether the selected model may also achieve better performance in the remaining ADNI or J-ADNI subsets. RESULT: When compared to the results without optimization, this procedure showed efficacy of AUC improvement of up to approximately 0.10 when applied to the models "without APOE;" the degree of AUC improvement was larger in the ADNI cohort than in the J-ADNI cohort. CONCLUSIONS: The obtained AUC had improved mildly when compared to the AUC in case of literature-based predetermined SUVr threshold configuration. This means our procedure allowed us to predict preclinical AD among ADNI or J-ADNI second-half samples with slightly better predictive performance. Our optimizing method may be practically useful in the middle of the ongoing clinical study of preclinical AD, as a screening to further increase the prior probability of preclinical AD before amyloid testing.

Cardiac magnetic resonance in the assessment of pericardial abnormalities: a case series.

BACKGROUND: Cardiac magnetic resonance (CMR) has a unique role in evaluating pericardial disease, permitting non-invasive tissue analysis, and haemodynamic assessment. CASE SUMMARY: In Case 1 of recurrent pericarditis, CMR confirmed reactivation of inflammation with late gadolinium enhancement and native T1/T2 mapping techniques, prompting therapeutic changes. In constrictive pericarditis, CMR is the only modality capable of differentiating a subacute potentially reversible form (Case 2), from a chronic, burnt out irreversible phase characterized by constrictive physiology (Case 3). DISCUSSION: Cardiac magnetic resonance is an effective tool to tailor individual therapy, particularly in cases of recurrent and constrictive pericarditis. Late gadolinium enhancement provides diagnostic and prognostic information, and multiparametric mapping has emerged as a promising tool with incremental diagnostic value.

Observations of newborn blue sharks Prionace glauca in shallow inshore waters of the north-east Atlantic Ocean.

The anomalous presence of numerous blue shark Prionace glauca neonates and juveniles in shallow inshore waters of Galicia, north-west Spain, during the summers of 2014 and 2015 is reported. Changes in oceanographic conditions, high recruitment events or changes in the pupping area are discussed as possible causes of this unusual behaviour.

Nuclear magnetization in gallium arsenide quantum dots at zero magnetic field.

Optical and electrical control of the nuclear spin system allows enhancing the sensitivity of NMR applications and spin-based information storage and processing. Dynamic nuclear polarization in semiconductors is commonly achieved in the presence of a stabilizing external magnetic field. Here we report efficient optical pumping of nuclear spins at zero magnetic field in strain-free GaAs quantum dots. The strong interaction of a single, optically injected electron spin with the nuclear spins acts as a stabilizing, effective magnetic field (Knight field) on the nuclei. We optically tune the Knight field amplitude and direction. In combination with a small transverse magnetic field, we are able to control the longitudinal and transverse components of the nuclear spin polarization in the absence of lattice strain--that is, in dots with strongly reduced static nuclear quadrupole effects, as reproduced by our model calculations.

A new method for determining the optimal CT threshold for extracting the upper airway.

OBJECTIVES: The purpose of this study was to evaluate the optimal upper threshold levels of a number of individuals and determine the most suitable upper threshold. METHODS: A phantom model and ten patients were used in this study. The phantom was made of acrylic resin and urethane resin and had nine pillar-shaped air spaces. The subjects were ten female patients with jaw deformities who were not affected by respiratory disease. The optimal threshold levels were determined using the "calculation of CT value disparities" (CCTD) technique, which we devised. In other words, the mean CT values along two lines (air space and soft tissue) were calculated and the optimal threshold level was determined as the level that produced the maximum difference between the CT values measured inside and outside of the air-space border. RESULTS: The optimal upper threshold levels of the nine phantom holes calculated using the CCTD technique in the front-on standing position and side-on standing position were -434 HU and -456 HU, respectively. The optimal upper threshold level of the ten patients calculated using the CCTD technique was -472 HU. The true threshold level of each patient was defined as the optimal threshold level calculated using the CCTD technique. The mean threshold level was defined as -472 HU. The absolute differences between the volume measurements obtained with these two measures were considered. Therefore, the no error values were -460 HU and -470 HU. CONCLUSIONS: We consider that the most suitable upper threshold level for extracting the airway is from -460 HU to -470 HU.

Dark-bright mixing of interband transitions in symmetric semiconductor quantum dots.

In photoluminescence spectra of symmetric [111] grown GaAs/AlGaAs quantum dots in longitudinal magnetic fields applied along the growth axis, we observe in addition to the expected bright states also nominally dark transitions for both charged and neutral excitons. We uncover a strongly nonmonotonic, sign-changing field dependence of the bright neutral exciton splitting resulting from the interplay between exchange and Zeeman effects. Our theory shows quantitatively that these surprising experimental results are due to magnetic-field-induced ±3/2 heavy-hole mixing, an inherent property of systems with C(3v) point-group symmetry.

Lasing in ultra-narrow emission from GaAs quantum dots coupled with a two-dimensional layer.

We report electrically injected lasing in GaAs quantum dots (QDs) grown on GaAs(001) by droplet epitaxy. High-quality GaAs QDs with superior uniformity are formed using improved growth techniques involving the insertion of a two-dimensional layer, control of the As flux for GaAs crystallization, and thin AlGaAs layer capping with high-temperature annealing. The QDs show ultra-narrow luminescence with a linewidth of 20 meV. Ground-state lasing from a laser diode containing fivefold-stacked QD layers is observed at low temperature under pulsed operation.

Allelic diversity of the MHC class II DRB genes in brown bears (Ursus arctos) and a comparison of DRB sequences within the family Ursidae.

The allelic diversity of the DRB locus in major histocompatibility complex (MHC) genes was analyzed in the brown bear (Ursus arctos) from the Hokkaido Island of Japan, Siberia, and Kodiak of Alaska. Nineteen alleles of the DRB exon 2 were identified from a total of 38 individuals of U. arctos and were highly polymorphic. Comparisons of non-synonymous and synonymous substitutions in the antigen-binding sites of deduced amino acid sequences indicated evidence for balancing selection on the bear DRB locus. The phylogenetic analysis of the DRB alleles among three genera (Ursus, Tremarctos, and Ailuropoda) in the family Ursidae revealed that DRB allelic lineages were not separated according to species. This strongly shows trans-species persistence of DRB alleles within the Ursidae.

Prospective randomized comparison of DisCoVisc and Healon5 in phacoemulsification and intraocular lens implantation.

PURPOSE: To compare two ophthalmic viscosurgical devices (OVDs), DisCoVisc (viscous dispersive) and Healon5 (viscoadaptive), in terms of their overall clinical performance during phacoemulsification and intraocular lens (IOL) implantation. METHODS: In 323 patients (DisCoVisc; 157, Healon5; 166), the surgeons evaluated on a three-point scale, the maintenance of anterior chamber (AC) during continuous curvilinear capsulorhexis (CCC), maintenance of AC during IOL implantation, retention during phacoemulsification, ease of injection, facilitation of CCC, transparency during surgery, and ease of removal from the eye. The time needed to completely remove OVDs after IOL implantation was measured. Masked examiners measured intraocular pressure (IOP), corneal thickness, and corneal endothelial cell count up to 90 days postoperatively. RESULTS: DisCoVisc was assessed to be significantly better than Healon5 in maintenance of AC during CCC (P=0.0008, Cochran-Mantel-Haenszel test) and IOL implantation (P=0.0055), retention during phacoemulsification (P=0.0009), ease of injection (P<0.0001), facilitation of CCC (P<0.0001), transparency (P<0.0001), and ease of removal (P<0.0001). The washout time was 29.6+/-13.4 and 36.2+/-17.5 s in the DisCoVisc and Healon5 groups, respectively (P=0.0002, unpaired t-test). The mean endothelial cell loss was 1.8+/-8.7% in the DisCoVisc group and 3.8+/-8.3% in the Healon5 group (P=0.0358). There were no statistically significant between-group differences in IOP and corneal thickness. CONCLUSION: DisCoVisc was better retained in the eye during phacoemulsification and was easier to remove after IOL implantation. The corneal endothelial cell loss was significantly less with DisCoVisc than with Healon5. It was indicated that the whole surgical process can be efficiently covered by DisCoVisc alone.

Ultra-narrow emission from single GaAs self-assembled quantum dots grown by droplet epitaxy.

We realized ultra-narrow excitonic emission from single GaAs/AlGaAs quantum dots (QDs) grown by a refined droplet epitaxy technique. We found that uncapped quantum dots can be annealed at 400 degrees C without major changes in their morphology, thus enabling an AlGaAs capping layer to be grown at that temperature. Consequently, we demonstrate a fourfold reduction of the linewidth of the emission together with an increased recombination lifetime, compared to the conventional droplet epitaxial QDs. The averaged linewidth of neutral excitons measured by micro-photoluminescence on single quantum dots was around 35 microeV.

Edaravone (MCI-186) is effective as a free radical scavenger following arteriovenous sheathotomy for treatment of macular oedema associated with branch retinal vein occlusion.

AIMS: To determine whether edaravone (MCI-186), a free radical scavenger, can reduce macular oedema and improve the visual acuity after arteriovenous sheathotomy in eyes with a branch retinal vein occlusion (BRVO). METHODS: Forty-seven eyes of 47 consecutive patients with a BRVO who were treated with arteriovenous sheathotomy were studied. The patients were assigned prospectively to either Group R who received 30 mg of edaravone (Radicut) systemically during the vitrectomy or Group N who did not receive any drugs. The postoperative visual acuity was measured before and 12 months after the operation. RESULTS: At 12 months postoperatively, the best-corrected visual acuity (BCVA) in logarithm of the minimum angle of resolution (logMAR) units improved significantly from 0.22 to 0.56 logMAR units in Group R and from 0.20 to 0.27 units in Group N (p = 0.016). Twenty-three of 27 cases (85%) in Group R and four of 15 cases (27%) in Group N showed an improvement in BCVA of >0.2 logMAR units (p = 0.0025). CONCLUSION: The better visual acuity in patients given edaravone than those without endaravone during the arteriovenous sheathotomy suggests that edaravone improved the physiology of the retinal cells after the arteriovenous sheathotomy.

Neuronal intranuclear hyaline inclusion disease with rapidly progressive neurological symptoms.

This report describes a male patient who presented with symptoms suggestive of spinocerebellar degeneration and who died of respiratory failure at the age of 7 years but was diagnosed, at autopsy, as having neuronal intranuclear hyaline inclusion disease. Neuronal intranuclear hyaline inclusion disease is a progressive and degenerative disease; diagnosis is possible only by neuropathological analysis. This is a rare disorder; few cases with early childhood onset and rapidly progressive neurologic symptoms have been documented. According to previous reports, most neurons in the central nervous system exhibited intranuclear eosinophilic inclusion bodies; neuronal depletion appeared to be restricted to the cerebellar cortex and the medullary inferior olivary nuclei, consistent with the fact that clinical deficit appears to correspond to the site of neuronal depletion and not to where eosinophilic bodies are detected. Immunohistochemical analysis revealed that these inclusions were positive for ubiquitin. The case presented herein clearly indicates that neuronal intranuclear hyaline inclusion disease should be considered as a differential diagnosis of cases involving spinocerebellar degeneration with childhood onset.

Immunohistopathological study of the oral lichenoid lesions of chronic GVHD.

BACKGROUND: Chronic graft-vs.-host disease (cGVHD) is a common and serious complication after bone marrow transplantation (BMT). However, the detailed process of oral lichenoid lesions of cGVHD is still unknown. Therefore, we investigated the immunohistopathological features of cGVHD compared with oral lichen planus (OLP) and healthy controls. METHODS: Nineteen allogenic BMT recipients with a histopathological diagnosis of cGVHD were investigated. We investigated the immunohistopathological features of cGVHD compared with OLP and healthy controls. RESULTS: Immunohistopathological features showed that the infiltrations of CD4-positive T cells of cGVHD and OLP were significantly larger than those of the normal oral mucosa (P < 0.005). A larger number of CD8-positive T cells was infiltrated in cGVHD and OLP compared with the normal oral mucosa (P < 0.001). The difference in the number of CD4- and CD8-positive T cells between cGVHD and OLP was not significant. The infiltrations of Langerhans cells (CD1a) in cGVHD and OLP were significantly larger than those in the normal oral mucosa (P < 0.005). The difference in the number of Langerhans cells between cGVHD and OLP was not significant. CD68-positive macrophages were more frequently seen in cGVHD and OLP than in the normal oral mucosa (P < 0.0001). The difference in the number of CD68-positive macrophages between cGVHD and OLP was not significant. CONCLUSIONS: It is suggested that Langerhans cells and CD8-positive T cell may play a major role in the pathogenesis of the oral lichenoid lesions of cGVHD, and the immune response was inducted in OLP as well as the oral lichenoid lesion of cGVHD in this study.

Autonomic neural functions in space.

Autonomic neural functions are important to regulate vital functions in the living body. There are different methods to evaluate indirectly and directly autonomic, sympathetic and parasympathetic, neural functions of human body. Among various methods, microneurography is a technique to evaluate directly sympathetic neural functions in humans. Using this technique sympathetic neural traffic leading to skeletal muscles (muscle sympathetic nerve activity; MSNA) can be recorded from human peripheral nerves in situ. MSNA plays essentially important roles to maintain blood pressure homeostasis against gravity. Orthostatic intolerance is an important problem as an autonomic dysfunction encountered after exposure of human beings to microgravity. There exist at least two different types of sympathetic neural responses, low and high responders to orthostatic stress in orthostatic hypotension seen in neurological disorders. To answer the question if post-spaceflight orthostatic intolerance is induced by low or high MSNA responses to orthostatic stress, MSNA was microneurographically recorded for the first time before, during and after spaceflight in 1998 under Neurolab international research project. The same activity has been recorded during and/or after ground-based short- and long-term simulations of microgravity. MSNA was rather enhanced on the 12(th) and 13(th) day of spaceflight and just after landing day. Postflight MSNA response to head-up tilt was well preserved in astronauts who were orthostatically well tolerant. MSNA was suppressed during short-term simulation of microgravity less than 2 hours but was enhanced after long-term simulation of microgravity more than 3 days. Orthostatic intolerance after exposure to long-term simulation of microgravity was associated with reduced MSNA response to orthostatic stress with impaired baroreflex functions. These findings obtained from MSNA recordings in subjects exposed to space as well as short- and long-term simulations of microgravity indicate that sympathetic neural control is lowered when exposed to short-term microgravity but becomes enhanced after exposure to long-term microgravity. A lack of enhanced sympathetic neural response to orthostatic stress may induce orthostatic intolerance. Based on these findings effective countermeasures should be developed to prevent autonomic dysfunctions induced by exposure to microgravity. These include development of prescription and devices of physical exercise, electrical and magnetic nerve stimulations, body vibration, elastic bandage and stocking, lower body negative pressure, artificial gravity, medical drugs, and combinations of them. These countermeasures will be beneficial to prevent autonomic dysfunctions related to gravitational stress such encountered in bedridden subjects as orthostatic hypotension, atrophy of antigravity muscles and so on. This is particularly important in the present aged-society with many bedridden elderly people. The knowledge accumulated from studies on autonomic neural functions in space should be very useful to establish effective countermeasures and preventive methods for gravity-dependent autonomic dysfunctions.

Microneurographically recorded Ia discharge from the tibial nerve mainly transmits the angular velocity of the ankle joint in humans.

Investigations of the Ia afferent discharge in clarifying problems in disused and malused skeletal muscles have been carried out mainly in muscles of the upper extremities. However, such problems actually occur more frequently in the antigravity muscles of the lower extremities, such as the triceps surae muscle. An analysis of microneurographically recorded Ia discharges from the tibial nerve innervating the triceps surae muscle during dynamic movement of the ankle joint indicated that they mainly transmitted information on the angular velocity of the joint. However, the information on the position sense of the joint was not as well transmitted through Ia discharges. There was no correlation between the joint angle and the static response. However, the dynamic response of a Ia afferent was well correlated to the angular velocity. It is concluded that the human proprioception of the triceps surae muscle was not dependent on the position of the ankle joint, but largely on its movement by the stretching of the muscle.

Sympathetic nerve activity in hypotension and orthostatic intolerance.

AIM: The present paper reviews how changes in sympathetic nerve activity are related to hypotensive episodes and orthostatic intolerance in humans. RESULTS: It has been well documented that sympathetic neural traffic to skeletal muscles (muscle sympathetic nerve activity; MSNA) plays an essential role in maintaining blood pressure homeostasis mainly through baroreflex. The MSNA responded to gravitational loading from the head to the leg (+Gz) during passive head-up tilt (HUT). Patients who suffered from orthostatic hypotension with or without syncope were classified into at least two groups; low and high responders of MSNA to orthostatic loading. The typical examples belonging to the former group were patients of multiple system atrophy who had very low basal sympathetic outflow to muscle which responded extremely poorly to HUT. Patients of multiple system atrophy presented also postprandial hypotension in which muscle sympathetic response to oral glucose administration was absent. The latter group was represented by subjects who manifested vasovagal syncope with normal or even higher muscle sympathetic response to HUT, which was suddenly withdrawn concomitantly with bradycardia and hypotension. Similar withdrawal of sympathetic nerve traffic to muscle was encountered in a rare case of idiopathic non-orthostatic episodic hypotension which accompanied bradycardia. The MSNA was suppressed by short-term exposure to microgravity but was enhanced after long-term exposure to microgravity. Orthostatic intolerance after long-term exposure to microgravity was related to progressive reduction of muscle sympathetic response to orthostatic loading with impaired arterial baroreflex. CONCLUSION: It is concluded that hypotensive episodes are closely related to poor or lack of muscle sympathetic outflow, but may depend on various neural mechanisms to induce it.