Development of a large plano-elliptical neutron-focusing supermirror with metallic substrates.

Results of this study demonstrated that electroless nickel-phosphorus (NiP) plated metal substrate is an excellent material for producing large aspherical neutron-focusing supermirrors. A large plano-elliptical neutron-focusing supermirror comprising two metallic segments was fabricated using single-point diamond cutting, precision polishing and supermirror coating. The average surface roughness of the metallic substrates was approximately 0.3 nm rms. For evaluation, the focusing supermirror was installed at the SOFIA neutron reflectometer, showing high neutron reflectivity and giving minimal beam width of 0.34 mm in FWHM. Because of the large beam divergence accepted by the mirror, the count rate with the focusing mirror was 3.3 times higher than that obtained using conventional two-slit collimation.

New fabrication method for an ellipsoidal neutron focusing mirror with a metal substrate.

We propose an ellipsoidal neutron focusing mirror using a metal substrate made with electroless nickel-phosphorus (NiP) plated material for the first time. Electroless NiP has great advantages for realizing an ellipsoidal neutron mirror because of its amorphous structure, good machinability and relatively large critical angle of total reflection for neutrons. We manufactured the mirror by combining ultrahigh precision cutting and fine polishing to generate high form accuracy and low surface roughness. The form accuracy of the mirror was estimated to be 5.3 µm P-V and 0.8 µm P-V for the minor-axis and major-axis direction respectively, while the surface roughness was reduced to 0.2 nm rms. The effect of form error on focusing spot size was evaluated by using a laser beam and the focusing performance of the mirror was verified by neutron experiments.

Impact of the COVID-19 pandemic on patients with mental health problems and the differences among diagnostic categories.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a total upending of our daily lives. While anxiety and depression were frequently reported among the general population, the pandemic's impact on patients with mental health problems remains unknown. METHODS: A cross-sectional questionnaire survey involving 1,166 patients was conducted at one psychiatric hospital and one mental health clinic. RESULTS: Symptom deterioration was reported in 23% to 34% of the patients and 9% to 20% reported increase in drug dosage. No significant differences were reported in these items among diagnostic categories. Patients with F3 (mood disorders) reported more psychological stress during the pandemic's beginning and during the emergency. Patients with F2 (schizophrenia, schizotypal, and delusional disorders) did online shopping and meetings less frequently, and reported poorer adherence of 3C's, while mask management was stricter in patients with F4 (neurotic, stress-related, and somatoform disorders). Symptom deterioration was significantly associated with increase in drug dosage, new physical symptoms, anxiety unrelated to COVID-19, stress at the beginning of pandemic, stress during the 'state of emergency', poor adaptability to environmental change, daily life changes, decrease in sleeping time, and decrease in time spent outside. CONCLUSION: One third of patients reported symptom deterioration during the pandemic, which was associated with stress and daily life changes. Patients with good adaptability to environmental changes might resilient against symptom deterioration. Providing continuous support to help patients manage their daily life in this COVID-19 era may minimize the risk of symptom deterioration.

Argyrophilic grain disease with delusions and hallucinations: a pathological study.

No clear clinical syndrome for argyrophilic grain disease (AGD) has yet been identified. Previous studies have documented its clinical features, namely, personality changes characterized by emotional disorder involving aggression or ill temper and relatively well-preserved cognitive function, but the clinical manifestations of delusions and hallucinations as they appear in AGD have not been thoroughly described. Here, we report on a 72-year-old Japanese AGD patient who showed psychiatric symptoms, memory impairment and emotional change. He perceived and described a person who was not present and tried to grasp things on the floor though nothing was there. He also insisted that somebody was watching him and consequently always kept his curtains closed. These psychiatric symptoms were observed at an early stage in the patient's disease course. Serial neuroradiological examination showed progressive atrophy of the bilateral temporal lobes. The patient died at 79 years-of-age. Microscopic neuropathological examination showed transactivation responsive region (TAR)-DNA-binding protein of 43 kDa (TDP-43) positive structures in addition to widespread argyrophilic grains and coiled bodies. According to recent recommendations for pathological diagnosis, this case corresponds to AGD with limbic TDP-43 pathology. This case shows that patients with AGD that is eventually confirmed through autopsy can present with delusions and hallucinations early in the course of their disease. The clinical significance of TDP-43 pathology in the brains of patients with AGD remains uncertain.

MONOPOL - A traveling-wave magnetic neutron spin resonator for tailoring polarized neutron beams.

We report on first experimental tests of a neutron magnetic spin resonator at a very cold neutron beam port of the high flux reactor at the ILL Grenoble. When placed between two supermirror neutron polarizers and operated in a pulsed traveling-wave mode it allows to decouple its time- and wavelength-resolution and can therefore be used simultaneously as electronically tunable monochromator and fast beam chopper. As a first 'real' scientific application we intend its implementation in the PERC (p roton and e lectron r adiation c hannel) project related to high-precision experiments in neutron beta decay.

Focusing and imaging of cold neutrons with a permanent magnetic lens.

This paper reports imaging of objects with slow neutrons, specifically very cold neutrons and cold neutrons, at Institut Laue Langevin, using novel, permanent magnet (Nd2Fe14B) compound refractive lenses (MCRL) with a large 2.5 cm bore diameter. The MCRL focuses and images spin-up neutrons and defocuses spin-down neutrons via a large, radial magnetic field gradient. A single lens neutron microscope, composed of an MCRL objective lens with 2-fold magnification, was tested using very cold (slow) neutrons at 45 Å wavelength. One-to-one imaging was obtained using 16.7 Å polarized neutrons. The magnetic field gradient of the MCRL was measured by raster-scanned pencil beams on D33. Finally, a compound neutron microscope was realized using an MCRL condenser lens, which provided increased illumination of objects, and an MCRL as objective lens to produce 3.5-fold magnification.

Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

OBJECTIVE: TAR DNA-binding protein of 43kDa (TDP-43) is deposited as cytoplasmic and intranuclear inclusions in brains of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Previous studies reported that abnormal phosphorylation takes place in deposited TDP-43. The aim of this study was to identify the phosphorylation sites and responsible kinases, and to clarify the pathological significance of phosphorylation of TDP-43. METHODS: We generated multiple antibodies specific to phosphorylated TDP-43 by immunizing phosphopeptides of TDP-43, and analyzed FTLD-U and ALS brains by immunohistochemistry, immunoelectron microscopy, and immunoblots. In addition, we performed investigations aimed at identifying the responsible kinases, and we assessed the effects of phosphorylation on TDP-43 oligomerization and fibrillization. RESULTS: We identified multiple phosphorylation sites in carboxyl-terminal regions of deposited TDP-43. Phosphorylation-specific antibodies stained more inclusions than antibodies to ubiquitin and, unlike existing commercially available anti-TDP-43 antibodies, did not stain normal nuclei. Ultrastructurally, these antibodies labeled abnormal fibers of 15nm diameter and on immunoblots recognized hyperphosphorylated TDP-43 at 45kDa, with additional 18 to 26kDa fragments in sarkosyl-insoluble fractions from FTLD-U and ALS brains. The phosphorylated epitopes were generated by casein kinase-1 and -2, and phosphorylation led to increased oligomerization and fibrillization of TDP-43. INTERPRETATION: These results suggest that phosphorylated TDP-43 is a major component of the inclusions, and that abnormal phosphorylation of TDP-43 is a critical step in the pathogenesis of FTLD-U and ALS. Phosphorylation-specific antibodies will be powerful tools for the investigation of these disorders.

Three cases of schizophrenia for which olanzapine was effective after early acute phase.

AIMS: It clarifies a difference between early acute phase and late acute phase in medication. METHODS: The present report describes three patients with schizophrenia who presented with restlessness and excitement requiring hospitalization. RESULTS: Treatment with risperidone solution orally or parenteral haloperidol until the day after admission, followed by olanzapine, successfully improved the clinical condition of the patients. In the early stage of hospitalization, selection of fast-acting drugs that can be administered to uncooperative patients is considered preferable, focusing on rapid control of symptoms and behavioral disorders, whereas after this early stage, olanzapine is preferable for improving patient compliance in addition to stabilizing symptoms. CONCLUSIONS: Because the target symptoms differ between the early and late acute phases, the term 'acute phase' used in the broad sense should be divided into two units, each requiring a different therapeutic strategy, and independent clinical approaches should be considered in order to provide more suitable treatment.

[Frontotemporal dementia (FTD) and genetic mutations including progranulin gene].

Research on familial frontotemporal lobar degeneration (FTLD) has led to the discovery of disease-causing genes: microtubule-associated protein tau (MAPT), progranulin (PGRN) and valosin-containing protein (VCP). TAR DNA-binding protein of 43 kDa (TDP-43) has been identified as a major component of tau-negative ubiquitin-positive inclusions in familial and sporadic FTLD and amyotrophic lateral sclerosis (ALS), which are now referred to as TDP-43 proteinopathy. Recent findings of mutations in TDP-43 gene in familial and sporadic ALS cases confirm the pathogenetic role for TDP-43 in neurodegeneration. TDP-43 proteinopathies have been classified into 4 pathological subtypes. Type 1 is characterized by numerous dystrophic neurites (DNs), Type 2 has numerous neuronal cytoplasmic inclusions (NCIs), Type 3 has NCIs and DNs and Type 4 has neuronal intranuclear inclusions (NIIs) and DNs. There is a close relationship between such pathological subtypes of TDP-43 proteinopathy and the immunoblot pattern of C-terminal fragments of accumulated TDP-43. These results parallel our earlier findings of differing C-terminal tau fragments in progressive supranuclear palsy and corticobasal degeneration, despite identical composition of tau isoforms. Taken together, these results suggest that elucidating the mechanism of C-terminal fragment origination may shed light on the pathogenesis of several neurodegenerative disorders involving TDP-43 proteinopathy and tauopathy.

[Significance of the TDP-43 deposition in FTLD-U and ALS].

Tau-negative and ubiquitin-positive inclusions (UPI) are the pathological hallmarks of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, TDP-43, a heterogeneous nuclear ribonucleoprotein was identified as a component of these UPI. However, it remains to be determined whether TDP-43 is the major component of UPI, because only antibodies recognizing both normal and abnormal TDP-43 have been available. We raised antibodies to phosphopeptides representing 36 out of 64 candidate phosphorylation sites of human TDP-43. Of the generated antibodies, pS379, pS403/404, pS409, pS410 and pS409/410 clearly labeled UPI and glial cytoplasmic inclusions but not the nuclei. Immunoblot analyses of sarkosyl insoluble fractions demonstrated that the phosphorylation-specific antibodies recognized TDP-43 at -45 kDa, smearing substances and the -25 kDa fragment, all of which were present in the brains of FTLD-U and ALS but not controls. These antibodies did not recognize normal TDP-43 at 43 kDa. These results clearly indicate that abnormally phosphorylated full-length TDP-43 and the C-terminal fragments are the major component of UPI in FTLD-U and ALS. These findings together with recent discovery of mutations in the TDP-43 gene in ALS strongly suggest that TDP-43 is the

Ubiquitin-positive frontotemporal lobar degeneration presenting with progressive Gogi (word-meaning) aphasia. A neuropsychological, radiological and pathological evaluation of a Japanese semantic dementia patient.

A patient with progressive anomia and alexia with agraphia for kanji (Japanese morphograms) is described. The patient showed a deficit in single-word comprehension and on-reading (a type of reading that conveys phonetic value) dominance in kanji reading, i.e. on-preceding (pronouncing first with on-reading, irrespective of its preferred reading) and kun-deletion (inability to recall and recognize kun-reading [another type of reading that conveys meaning]) when reading a single-character kanji. These features were due to loss of lexico-semantic information and thus the patient was regarded as having progressive Gogi (word-meaning) aphasia by Imura, a Japanese manifestation of semantic dementia. Macroscopically, neuropathological examination disclosed atrophy of the left frontotemporal lobe with accentuation in the anterior portion of the temporal lobe. Histologically, there was neuronal loss in the cerebral cortex, hippocampus, parahippocampal gyrus, amygdala, caudate nucleus, and putamen. Ubiquitin-immunoreactive neuronal inclusions were present in the hippocampal dentate granular cells. This case demonstrates that progressive Gogi aphasia is semiologically identical to semantic dementia, and our patient clinicopathologically resembled those of Rossor et al. [Rossor, M.N., Revesz, T., Lantos, P.L., Warrington, E.K. Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain 2000; 123: 267-76.] and Hodges et al. [Hodges, J.R., Davies, R.R., Xuereb, J.H., Casey, B., Broe, M., Bak, T.H., et al. Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004; 56: 399-406.].

Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases.

We investigated the occurrence of T cells in the brain parenchyma of Alzheimer's disease (AD), non-AD degenerative dementias and controls by semi-quantitative analysis of immunohistochemically stained tissue sections. In all cases, we found at least some T cells. The number of T cells was increased in the majority of AD cases compared with other cases. The phenotype of T cells in the AD brain indicates that they are activated but are not fully differentiated. Antigen-triggered clonal expansion is not likely to take place. Local inflammatory conditions might cause accumulation and activation of T cells in the AD brain.

Neuronal and glial inclusions in frontotemporal dementia with or without motor neuron disease are immunopositive for p62.

We examined the immunoreactivity of p62 in five cases of frontotemporal dementia (FTD) with ubiquitin-positive, tau-negative inclusions. Only one case had clinical features suggestive of motor neuron disease (MND). In all cases, ubiquitin-positive neuronal inclusions and neurites in the hippocampal region and cerebral neocortex were immunohistochemically positive for p62. Moreover, in the temporal region of a case of FTD with MND, many oligodendrocytes and some astrocytes were positive for p62. These results suggest that the degenerative process involves p62 in FTD and that the process takes place not only in neurons but also in glial cells.

Number of striatal D-neurons is reduced in autopsy brains of schizophrenics.

The human striatum, especially its ventral part, the nucleus accumbens, contains numerous neurons immunoreactive for aromatic L-amino acid decarboxylase (AADC, the second-step monoamine synthesizing enzyme, =DDC: dopa decarboxylase), but not for tyrosine hydroxylase (TH, the first-step catecholamine synthesizing enzyme) or tryptophan hydroxylase (TPH, the first-step serotonin synthesizing enzyme) (Neurosci Lett 232 (1997) 111-114). These AADC (+)/TH (-)/TPH (-) neurons are named as D-neurons (Jaeger CB, Ruggiero DA, Albert VR, Joh TH, Reis DJ. Immunocytochemical localization of aromatic-L-amino acid decarboxylase. In: Bjorklund A, Hokfelt T, editors. Classical transmission in the CNS, Part I, Handbook of chemical neuroanatomy, vol. 2. Amsterdam: Elsevier, 1984. pp. 387-418). The nucleus accumbens is one of the brain regions that is involved in the pathogenesis of schizophrenia. We examined the distribution of striatal D-neurons using AADC immunohistochemistry and postmortem brains obtained by legal and pathological autopsies (nine controls (27-75 years old) and nine schizophrenics (32-78 years old), postmortem interval to fixation (PMI): 2-30 h). Because the number of AADC-positive neurons per section had a tendency to reduce in the case with longer PMI, we analyzed specimens of five controls (27-64 years old) and six schizophrenics (51-78 years old) in which the PMI was less than 8 h. The number of AADC-positive neurons was reduced in the striatum of schizophrenics compared to that of controls. The reduction was significant in the nucleus accumbens (P<0.05, t-test). D-Neurons might be involved in the pathogenesis of schizophrenia. Further studies using sex-, age- and PMI-matched controls are essential.

Perioperative features of coronary artery bypass grafting in patients aged 75 years or older.

OBJECTIVES: Coronary artery bypass grafting (CABG) is well established as an effective operation to overcome ischemic heart disease; however, the number of aged patients with a high operative risk undergoing this procedure has increased in recent years. This retrospective study evaluates our experience of performing CABG in a consecutive series of patients aged 75 years or older. METHODS: To assess the hospital mortality and morbidity associated with this procedure, we retrospectively analyzed 49 patients aged 75 years or older (Elderly Group) who underwent CABG and compared the results with those of 88 patients aged 65-74 years (Control Group) who underwent CABG during the same period. Patients were examined for cerebrovascular diseases, and those with significant stenosis underwent pulsatile cardiopulmonary bypass. To avoid pulmonary complications, patients were extubated early. RESULTS: The Control Group had a significantly higher incidence of arterial grafts than the Elderly Group (0.8 +/- 0.5 versus 0.3 +/- 0.5; p < 0.0001). The Elderly Group had a significantly higher incidence of postoperative complications than the Control Group, with supraventricular arrhythmia in 57.1% versus 28.4%, (p = 0.0009), delirium in 36.7% versus 11.4%, (p = 0.0004), pneumonia in 6.1% versus 0%, (p = 0.0439), and intubation duration of 88.3 +/- 212.5 hours versus 37.2 +/- 92 hours (p = 0.0296), respectively. However, there was no significant difference in hospital mortality between the two groups, being 8.2% versus, 2.3%, in the Elderly group and Control Group, respectively (p = 0.1867). CONCLUSION: These findings indicated that when elderly patients were appropriately managed, CABG could be performed with an acceptably low risk to mortality.

[Argyrophilic grain disease clinically mimicking Parkinson's disease with dementia: report of an autopsy case].

Argyrophilic grain disease (AGD) is a neurodegenerative dementia, which is neuropathologically characterized by the spindle-or comma-shaped argyrophilic grains scattered in the neuropil of hippocampal area. Several research reports have disclosed the pathological, biochemical and genetic characteristics of AGD, whereas the clinical aspects have not been fully investigated. Here we report an autopsy case of AGD. She developed tremor at age 63, and then developed dyskinesia, rigidity and gait disturbance. Thereafter, she had cognitive impairment and emotional disturbance at age 71, and died of pneumonia at age 76. She was clinically diagnosed as Parkinson's disease with dementia due to the presence of parkinsonism and dementia. Macroscopically, the brain demonstrated mild atrophy, and the weight was 1,240 g. Many argyrophilic grains were found in the hippocampus and amygdala. Coiled bodies and ballooned neurons were also present, while Alzheimer-type neurofibrillary changes were mild, consistent with stage 2 of Braak's classification. This case was neuropathologically diagnosed as AGD. In contrast, no remarkable pathological changes, including neuronal loss and Lewy bodies, were found in the nigra, locus ceruleus and basal nuclei. On the basis of the above-mentioned clinicopathological findings, parkinsonism with dementia is considered to be one of the clinical manifestations of AGD.

[Preliminary reports on psychiatric practice in correctional facilities].

In October 2001, Nanashakon, a council composed of seven psychiatry-related organizations in Japan, decided to launch an investigation into forensic psychiatry in Japan, and established a working team (WT) for this purpose. From its establishment to March 2004, the WT performed surveys and analyses of the current situation of preliminary reports by psychiatric experts (preliminary reports) and of psychiatric practice in correctional facilities. Based on the results, the WT has presented proposals including guidelines for preliminary reports. In January 2002, the WT conducted an awareness survey on the status quo of testimony by psychiatric experts and forensic psychiatry, targeting the members of the Japanese Society of Psychiatry and Neurology, and obtained 666 replies. The survey revealed various critical opinions such as skepticism over the current punishment imposed on criminal patients with mental disorders. In February 2002, the WT obtained data on preliminary reports (2,042 cases) compiled prior to prosecution in FY2000 from the Japanese Ministry of Justice. Reviewing the details and differences between the evaluation by psychiatrists and the decision by public prosecutors, the WT pointed out the ambiguity of criteria used for the evaluation of competency of weak-minded persons and the criteria for criminal punishment. Around the same time, the WT was also asked by a news agency to analyze the preliminary reports of 50 district public prosecutor offices. The results revealed marked regional differences in the operation of the preliminary evaluation system for competency. In January 2003, the WT collected 146 preliminary reports from around the country for comparison and review, and again found conspicuous individual and regional discrepancies in the format and content. Based on these results, the WT conducted a hearing of 41 expert opinions on preliminary reports, and in January 2004, proposed guidelines outlining a format model of preliminary reports, and a training and authorizing system for forensic psychiatrists, to standardize preliminary reports and enhance their reliability. In February 2004, the WT conducted a questionnaire survey on the current situation of psychiatry in correctional facilities, targeting doctors with experience working under these circumstances. Fifty-one replies were obtained. Most of the respondents approved of the current system. However, to incite arguments in this area, attempts were made to draw critical responses and discussion by presenting data on the current situation of psychiatric practice in correctional facilities.

Dopamine neurons in the ventral tegmental area: an autopsy case of disorganized type of schizophrenia.

The mesolimbic dopamine (DA) system has been associated with the pathogenesis of schizophrenia. Here, we examined DA-containing neuronal structures of the ventral tegmental area (VTA) of an autopsy case of disorganized type of schizophrenia (75-year-old female), using tyrosine hydroxylase (TH) immunohistochemistry. A free floating method using 50-µm cryostat sections and three-dimensional imaging analyzer AxioVision were applied to observe the wide range structures of TH-immunoreactive (-ir) neurons. TH-ir neuronal cell bodies in the VTA of the present case had irregular shape and various size, and TH-ir neuronal processes had irregular thickness and straightened shape or curved shape having many corners, when compared to a control autopsy case with no detectable neurological and psychiatric diseases (64-year-old male). The mechanisms underlying the morphological characteristics of DA neurons of the brains with schizophrenia should be elucidated epigenetically as well as genetically.

Methamphetamine psychosis in which tardive dystonia was successfully treated with clonazepam.

Reported herein is a case of methamphetamine psychosis in which tardive dystonia was treated successfully with clonazepam. The patient was a 69-year-old man who had taken methamphetamine habitually for approximately 40 years. Auditory hallucinations had developed 25 years previously, for which haloperidol had been prescribed. Tardive dystonia had developed in December 2005. Haloperidol was withdrawn and risperidone or olanzapine alone had been administered, but neither had improved the dystonic posture. However, when clonazepam was added, a gradual improvement in the dystonic posture became evident. Tardive dystonia is currently treated on a trial-and-error basis. Accumulation of further cases similar to the present one is very important for establishing an effective treatment.