Search

The phenomenon of ‘prion-like propagation’ in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein tau (MAPT) contains a microtubule-binding domain that consists of three or four repeats (3R/4R) due to alternative mRNA splicing of transcripts for the MAPT gene. Although a number of models for tau propagation have been reported, most use 4R human tau transgenic mice or adult wild-type mice expressing only endogenous 4R tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3R and 4R tau accumulate simultaneously, or that of Pick’s disease in which only 3R tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3R and 4R tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer’s disease (3R and 4R tauopathy), corticobasal degeneration (4R tauopathy) or Pick’s disease (3R tauopathy). At 8–9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3R and 4R tau in Alzheimer’s disease-injected brains, 4R tau only in corticobasal degeneration-injected brains and 3R tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick’s body-like inclusions were observed in Pick’s disease-injected mice, and accumulations characteristic of Pick’s disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick’s disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3R and 4R isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.

Introduction The patients with prostate cancer and low-volume osseous metastases who underwent local definitive therapies had lower risks of cancer-specific mortality. The usefulness of local definitive therapy for metastatic prostate cancer remains unclear. Case presentation A 76-year-old man visited a private hospital with a chief complaint of left lower limb pain. His serum prostate-specific antigen level was 365.156 ng/mL. Histological evaluation led to the initial diagnosis of adenocarcinoma of Gleason score 4 + 4 and clinical stage T3a N1 M1b. Although androgen deprivation therapy was performed, he developed metastatic castration-resistant prostate cancer 6 months after the initial treatment. Therefore, he received enzalutamide and attained a serum prostate-specific antigen level of 0.002 ng/mL 7 months after the second treatment. We performed robot-assisted radical prostatectomy 1 year after diagnosis. Histopathological examination revealed that prostate cancer cells disappeared into the prostate. Conclusion Robot-assisted radical prostatectomy in selected patients with metastatic castration-resistant prostate cancer may improve oncological outcomes.

Nanoscale γ precipitates in primary microscale γ′ precipitates of Ni-alloys have been recently observed in experiments. Nanoscale γ precipitates have been one of the potential factors changing the dislocation motion in primary γ′ precipitates and affecting mechanical properties of Ni-alloys. In this work, the dependency of the interaction between a superlattice screw dislocation and the spherical γ-Ni precipitates in γ′-Ni3Al intermetallics on the sizes of the γ precipitate is studied via molecular statics simulations. The calculated external stress, morphology of superlattice screw dislocation, and energy states show that the stress necessary to cut through the precipitate is significantly dependent on the interface between the γ precipitate and γ′-matrix as well as on the antiphase boundary (APB) energy; the interface between the γ precipitate and γ′-matrix inhibits the superlattice dislocation during cutting into the γ precipitate, whereas the APB expansion hinders the cut-out action. Among the examined cases, a precipitate of approximately 3 nm in diameter is found to require the largest stress to cut through. We show the origin of interaction between superlattice screw dislocation and γ precipitates in γ′ matrix from the atomic and energetic perspectives.

Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurones, but the relationship between impaired autophagy and Lewy bodies (LBs) remains unknown. α-Synuclein and p62, components of LBs, are the defining characteristic of Parkinson’s disease (PD). Until now, we have analyzed mice models and demonstrated p62 aggregates derived from an autophagic defect might serve as ‘seeds’ and can potentially be a cause of LB formation. P62 may be the key molecule for aggregate formation. To understand the mechanisms of LBs, we analyzed p62 homeostasis and inclusion formation using PD model mice. In PARK22-linked PD, intrinsically disordered mutant CHCHD2 initiates Lewy pathology. To determine the function of CHCHD2 for inclusions formation, we generated Chchd2-knockout (KO) mice and characterized the age-related pathological and motor phenotypes. Chchd2 KO mice exhibited p62 inclusion formation and dopaminergic neuronal loss in an age-dependent manner. These changes were associated with a reduction in mitochondria complex activity and abrogation of inner mitochondria structure. In particular, the OPA1 proteins, which regulate fusion of mitochondrial inner membranes, were immature in the mitochondria of CHCHD2-deficient mice. CHCHD2 regulates mitochondrial morphology and p62 homeostasis by controlling the level of OPA1. Our findings highlight the unexpected role of the homeostatic level of p62, which is regulated by a non-autophagic system, in controlling intracellular inclusion body formation, and indicate that the pathologic processes associated with the mitochondrial proteolytic system are crucial for loss of DA neurones.

In this study, we developed a classification method for gender and age ranges using convolutional neural networks (CNNs). We trained an architecture using a time series of smartphone application-connecting durations and demographics of datasets containing gender and age ranges. The inputs were in the form of big data for all application categories of the time series, automatically collected from a single source panel of individuals with smartphones. The demographics of gender and age ranges were used for prediction. To identify the demographics of individuals, this study extracted effective features of mobile website access activities. We proposed a feature learning model from the raw inputs to solve the problem of classifying gender and age ranges using a deep convolutional neural network, which is an important but challenging task in digital marketing. For companies that can obtain only web application logs but not the demographics of gender and age ranges, this research may provide a possible solution that can be applied in digital marketing.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

[This corrects the article DOI: 10.1371/journal.pone.0216823.].

Granulin (Grn) mutations were identified in familial frontotemporal lobar degeneration (FTLD) patients with TAR DNA-binding protein of 43 kd (TDP-43) pathology. Grn transcript haploinsufficiency is proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. Thus, these mutations are strongly involved in FTLD pathogenesis. Moreover, recent findings indicate that Grn mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease. To investigate the influence of PGRN on amyloid beta (Aβ) accumulation, amyloid precursor protein (APP) transgenic mice were interbred with Grn-deficient mice, producing APP transgenic mice harboring the Grn hemizygote (APP/Grn+/−). Brains were collected from 16–18-month-old APP and APP/Grn+/− mice and sequential extraction of proteins, immunoblotting and immunohistochemical analysis were performed. Immunohistochemical analysis showed that the number and area of Aβ plaque was significantly decreased in APP/Grn+/− mice as compared to APP mice. Immunoblotting analysis revealed that Aβ was reduced in the sarkosyl-insoluble fraction of 16–18-month-old APP/Grn+/− mice as compared with that of APP transgenic mice. Our data suggest that PGRN haploinsufficiency may decrease accumulation of Aβ.

There have been few comprehensive studies on Haemophilus influenza-positive urethritis.In this retrospective study, we enrolled 68 men with H. influenzae-positive urethritis, including coinfections with Neisseria gonorrhoeae, Chlamydia trachomatis, and/or genital mycoplasmas: 2, 3, 20, and 43 treated with ceftriaxone, levofloxacin, sitafloxacin, and extended-release azithromycin (azithromycin-SR), respectively. We assessed microbiological outcomes in 54 men and clinical outcomes in 46 with H. influenzae-positive monomicrobial nongonococcal urethritis. We determined minimum inhibitory concentrations (MICs) of 6 antimicrobial agents for 59 pretreatment isolates.H. influenzae was eradicated from the men treated with ceftriaxone, levofloxacin, or sitafloxacin. The eradication rate with azithromycin-SR was 85.3%. The disappearance or alleviation of urethritis symptoms and the decreases in leukocyte counts in first-voided urine were significantly associated with the eradication of H. influenzae after treatment. For the isolates, ceftriaxone, levofloxacin, sitafloxacin, azithromycin, tetracycline, and doxycycline MICs were ≤0.008-0.25, 0.008-0.5, 0.001-0.008, 0.12-1, 0.25-16, and 0.25-2 μg/mL, respectively. The azithromycin MICs for 3 of 4 strains persisting after azithromycin-SR administration were 1 μg/mL. H. influenzae with an azithromycin MIC of 1 μg/mL increased chronologically.H. influenzae showed good responses to the chemotherapies for urethritis. The significant associations of the clinical outcomes of the chemotherapies with their microbiological outcomes suggested that H. influenzae could play pathogenic roles in urethritis. All isolates, except for one with decreased susceptibility to tetracyclines, were susceptible to the examined agents. However, the increase in H. influenzae with an azithromycin MIC of 1 μg/mL might threaten efficacies of azithromycin regimens on H. influenzae-positive urethritis.

The purpose of this study was to evaluate the retinal function by electroretinograms (ERGs) recorded with the RETeval system using skin electrodes after pars plana vitrectomy (PPV) with gas tamponade in eyes with a rhegmatogeneous retinal detachment (RRD). Flicker ERGs were recorded from 17 eyes with an RRD before (baseline), within 2 weeks after the PPV when the size of the tamponade gas was approximately one-half of the vitreous cavity (P1), and when the gas had been completely absorbed (P2). The amplitudes of the flicker ERGs at each phase were compared to that at the baseline. The median (25th, 75th percentile) of the amplitude was 10.0 µV (5.5, 13.0 µV) at the baseline, 11.7 µV at P1 (7.8, 14.8 µV; P = 0.003), and 17.1 µV at P2 (11.7 23.3 μV; P (P = 0.723, P = 0.001; Spearman’s rank correlation coefficient). We conclude that recordings the flicker ERGs with skin electrodes can be used to assess the physiology of eyes even with the vitreous cavity half-filled with the gas used to tamponade the retina.

We retrieved clinical data of 13 men having herpes simplex virus (HSV)-induced non-gonococcal urethritis (NGU) without visible herpetic lesions. They visited a clinic in Sendai, Japan, between April 2013 and December 2015. All the men complained of dysuria. Meatitis was observed in 9 of the 13 men. Mononuclear cells were observed in the urethral smears from 9 men. The 13 men were treated with azithromycin or sitafloxacin regimen. First-voided urine (FVU) specimens became negative for HSV in 8 of the 10 men who returned to the clinic after antibacterial treatment, and urethritis symptoms were alleviated. However, herpetic lesions were observed at the follow-up visits in 3 men, and 2 of them were still positive for HSV in their FVU. HSV could be a cause of acute urethritis without causing visible herpetic lesions. The shedding of HSV from the urethra would spontaneously cease with alleviation of urethritis symptoms in most cases of HSV-induced NGU without antiviral therapy. However, new herpetic lesions could be developed in some cases. Early antiviral therapy is beneficial for patients with HSV infections. The development of meatitis and the mononuclear cell response in the urethral smear could be helpful to diagnose HSV-induced NGU. Therefore, we should presumptively initiate anti-HSV therapy for patients with signs and symptoms suggestive of HSV-induced NGU at their first presentation.

Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo process of formation remains unknown. Synuclein, a component of LBs, is the defining characteristic of Parkinson’s disease (PD). Here, we characterize dopamine (DA) neuron–specific autophagy-deficient mice and provide in vivo evidence for LB formation. Synuclein deposition is preceded by p62 and resulted in the formation of inclusions containing synuclein and p62. The number and size of these inclusions were gradually increased in neurites rather than soma with aging. These inclusions may facilitate peripheral failures. As a result, DA neuron loss and motor dysfunction including the hindlimb defect were observed in 120-week-old mice. P62 aggregates derived from an autophagic defect might serve as “seeds” and can potentially be cause of LB formation.

We analyzed the 23S rRNA, gyrA and parC genes of Chlamydia trachomatis DNAs from men with urethritis and determined microbiological outcomes of an extended-release azithromycin (azithromycin-SR) regimen (2 g once daily for 1 day) and a sitafloxacin regimen (100 mg twice daily for 7 days) for chlamydial urethritis to clarify the macrolide and fluoroquinolone resistance status of clinical strains of C. trachomatis. We amplified the portions of 2 alleles of the 23S rRNA gene and the gyrA and parC genes from C. trachomatis DNAs in 284 first-voided urine specimens from men with chlamydial urethritis by PCR and sequenced their PCR products. We enrolled 369 men with chlamydial urethritis, comprising 314 and 55 treated with the azithromycin-SR regimen and the sitafloxacin regimen, respectively. Alleles 1 and/or 2 of the 23S rRNA gene were analyzed in 162 specimens. No mutations were found in the sequenced regions, including the central portion of domain V. The gyrA and parC genes were analyzed in 118 and 113 specimens, respectively. No amino acid changes were found within the quinolone resistance-determining region of the gyrA gene and in the sequenced region of the parC gene. The microbiological outcomes of the azithromycin-SR and sitafloxacin regimens were assessed in 176 and 30 men, respectively. The eradication rates were 96.0% (95% CI 93.1%–98.9%) for the azithromycin-SR regimen and 100% for the sitafloxacin regimen. Clinical strains of C. trachomatis with macrolide and/or fluoroquinolone resistance would be uncommon, and azithromycin or fluoroquinolone regimens could be recommended as treatments for chlamydial infections.

Granulin (GRN) mutations have been identified in familial frontotemporal lobar degeneration patients with ubiquitin pathology. GRN transcript haploinsufficiency is proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. Thus, these mutations are strongly involved in frontotemporal lobar degeneration pathogenesis. Moreover, recent findings indicate that GRN mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer disease and corticobasal degeneration. To investigate the potential influence of a decline in PGRN protein on tau accumulation, P301L tau transgenic mice were interbred with GRN-deficient mice, producing P301L tau transgenic mice harboring the GRN hemizygote. Brains were collected from 13- and 19-month-old mice, and sequential extraction of proteins, immunoblotting, and immunohistochemical analyses were performed. Immunoblotting analysis revealed that tau phosphorylation was accelerated in the Tris-saline soluble fraction of 13-month-old and in the sarkosyl-insoluble fraction of 19-month-old P301L tau/GRN hemizygotes compared with those in fractions from P301L tau transgenic mice. Activity of cyclin-dependent kinases was also upregulated in the brains of P301L tau/GRN hemizygote mice. Although the mechanisms involved in these findings remain unknown, our data suggest that a reduction in PGRN protein might contribute to phosphorylation and intraneuronal accumulation of tau.

Of 73 clinical strains of Haemophilus influenzae isolated from the urethra of men with urogenital infections, we enrolled 6 strains (8.2%) with levofloxacin (LVFX) minimum inhibitory concentrations (MICs) of ≥0.03 μg/ml in this study. All the strains were isolated from non-gonococcal urethritis (NGU). We amplified the quinolone resistance-determining region of the gyrA gene and the analogous region of the parC gene from bacterial DNAs by PCR and sequenced the PCR products. Two strains with a LVFX MIC of 0.03 μg/ml had an amino acid change of Asp88 to Gly in GyrA. One with a LVFX MIC of 0.06 μg/ml had a change of Asp88 to Tyr in GyrA. Two with respective LVFX MICs of 0.12 and 0.25 μg/ml had a change of Ser84 to Leu in GyrA. One with a LVFX MIC of 1 μg/ml had changes of Ser84 to Leu in GyrA and of Ser84 to Ile in ParC. Multilocus sequence typing showed two strains with a change of Asp88 to Gly in GyrA had the same sequence type, but the others had sequence types different from each other. Single amino acid changes in GyrA alone or single changes in both GyrA and ParC could contribute to decreased susceptibility to fluoroquinolones in H. influenzae isolates from NGU. Most of the isolates with GyrA and/or ParC alterations would be multiclonal. The prevalence of such isolates would be relatively low, and they would still be susceptible to fluoroquinolones commonly prescribed for treatment of NGU.

In 2006, mutations in the granulin gene were identified in patients with familial Frontotemporal Lobar Degeneration. Granulin transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin protein. Granulin mutations were initially found in tau-negative patients, though recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease and corticobasal degeneration. Moreover, a reduction in progranulin in tau transgenic mice is associated with increasing tau accumulation. To investigate the influence of a decline in progranulin protein on other forms of neurodegenerative-related protein accumulation, human granulin mutation cases were investigated by histochemical and biochemical analyses. Results showed a neuronal and glial tau accumulation in granulin mutation cases. Tau staining revealed neuronal pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated α-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau was present in the sarkosyl-insoluble fraction, and composed of three- and four-repeat tau isoforms, resembling Alzheimer’s disease. Our data suggest that progranulin reduction might be the cause of multiple proteinopathies due to the accelerating accumulation of abnormal proteins including TDP-43 proteinopathy, tauopathy and α-synucleinopathy.

We observed fluoroquinolone treatment failures in 2 men with Mycoplasma genitalium-positive non-gonococcal urethritis in Japan. A fluoroquinolone regimen of sitafloxacin 100 mg twice daily for 7 days failed to eradicate M. genitalium. In both cases, M. genitalium had fluoroquinolone resistance-associated amino acid changes both in GyrA and ParC and a macrolide resistance-associated mutation in the 23S rRNA gene. The emergence of such multi-drug resistant strains can threaten antimicrobial chemotherapy for M. genitalium infections in Japan, because we will lose the first- (azithromycin) and second-line (sitafloxacin) antimicrobial agents to treat M. genitalium infections. We prescribed an extended minocycline regimen of minocycline 100 mg twice daily for 14 days for our patients, and the regimen was successful in eradicating the M. genitalium. The extended minocycline regimen might be an option that we can try when treating multi-drug resistant M. genitalium infections in clinical practice.

Concomitant deposition of amyloid -beta protein (Aβ) and neuronal tau as neurofibrillary tangles in the human brain is a hallmark of Alzheimer disease (AD). Because these deposits increase during normal aging, it has been proposed that aging brains may also undergo AD-like changes. To investigate the neuropathological changes that occur in the aging primate brain, we examined 21 brains of cynomolgus monkeys (7–36 years old) for Aβ- and tau-positive lesions. We found, 1) extensive deposition of Aβ in brains of cynomolgus monkeys over 25 years of age, 2) selective deposition of 4-repeat tau as pretangles in neurons, and as coiled body-like structures in oligodendroglia-like cells and astrocytes, 3) preferential distribution of tau in the basal ganglia and neocortex rather than the hippocampus, and 4) age-associated increases in 30–34 kDa AT8- and RD4-positive tau fragments in sarkosyl-insoluble fractions. We further labeled tau-positive structures using diaminobezidine enhanced with nickel, and visualized nickel-labeled structures by energy-dispersive X-ray (EDX) analysis of ultrathin sections. This allowed us to distinguish between nickel-labeled tau and background electron-dense structures, and we found that tau localized to 20–25 nm straight filaments in oligodendroglia-like cells and neurons. Our results indicate that the cytopathology and distribution of tau deposits in aged cynomolgus brains resemble those of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) rather than AD. Thus, even in the presence of Aβ, age-associated deposition of tau in non-human primates likely does not occur through AD-associated mechanisms. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0385-5) contains supplementary material, which is available to authorized users.

PurposeTo assess the physiology of the retina by electroretinography (ERG) with skin electrodes in eyes that had undergone vitrectomy with silicone oil (SO) tamponade.DesignRetrospective case series.MethodERGs were recorded from eleven eyes with complex vitreoretinal disorders and from the normal fellow eyes. The affected eyes underwent pars plana vitrectomy (PPV) with SO tamponade. ERGs were recorded before and after the SO was removed. The amplitudes and implicit times of the a- and b-waves of the affected eyes were compared to those of the normal fellow eyes. In addition, the ratios of the amplitudes of the b-waves of the affected eyes to those of the fellow eyes were compared before and after the SO was removed.ResultsERGs were recordable from 7 eyes (63.6%) before the SO was removed and 11 eyes (100%) after the SO was removed. The a- and b-wave amplitudes were significantly smaller in the affected eyes than those of the fellow eyes at the baseline. The b-wave amplitude before the removal of the SO was significantly and positively correlated with that after the SO removal. The ratios of the b-waves of the affected/normal fellow eye significantly increased after the SO was removed.ConclusionThe results indicate that ERGs picked up by skin electrode can be used to assess the physiology of the retina in eyes with a SO tamponade. The amplitude of the b-waves of the ERGs in silicone-filled eyes can be used to predict the amplitude after the silicone is removed.

We investigated the pathological features of frontotemporal lobar degeneration (FTLD) with fused in sarcoma protein (FUS) accumulation (FTLD-FUS) in the Japanese population. Only one out of nine FTLD-FUS cases showed pathology that corresponds to atypical FTLD with ubiquitin-positive inclusions (aFTLD-U). Five were basophilic inclusion body disease (BIBD) and two were neuronal intermediate filament inclusion disease. The last case was unclassifiable and was associated with dystrophic neurites (DNs) as the predominant FUS pathology. The results of this study indicate an ethnic difference from western countries. In Japan, BIBD is the most common subtype of FTLD-FUS and aFTLD-U is rare, a finding which contrasts with aFTLD-U being the most common form in western countries. Immunohistochemical analyses of these FTLD-FUS cases reveal that FUS abnormally accumulated in neuronal cytoplasmic inclusions (NCIs) and DNs has an immunohistochemical profile distinct from that of normal, nuclear FUS. NCIs and DNs are more readily stained than the nuclei by antibodies to the middle portion of FUS. Antibodies to the carboxyl terminal portion, on the other hand, stain the nuclei more readily than NCIs and DNs. Such an immunohistochemical profile of NCIs and DNs was similar to that of cytoplasmic granular FUS staining which we previously reported to be associated with dendrites and synapses. Redistribution of FUS from the nucleus to the cytoplasm could be associated with the formation of abnormal FUS aggregates in FTLD-FUS.

Whether or not the oral intake of metals such as aluminium (Al) and zinc (Zn) is a risk for Alzheimer's disease (AD) has been a matter of controversy. Lack of AD pathology in patients with Al encephalopathy indicates Al does not cause AD. On the other hand, some epidemiological studies have suggested high Al increases the occurrence of AD. Our purpose is to test if high Al in drinking water is a risk factor for AD. We administered Al and Zn in drinking water to Tg2576, a transgenic mouse model for amyloid β-protein (Aβ) deposition with the Aβ precursor protein (AβPP) mutations (K670N/M671L), and Tg2576/tau(P301L), a model for Aβ and tau deposition. Deionized water was given to the control Tg2576 and Tg2576/tau. After administration for 4-10 months of approximately 100 mg/kg body weight Al or Zn per day, we were not able to find by quantitative immunohistochemical analyses differences in the deposition of Aβ and tau between the treated and untreated groups. Nor did the Al or Zn treatment affect the amount of soluble Aβ and Aβ*56, an Aβ oligomer, measured by ELISA or immunoblot. The oral intake of excess Al or Zn does not accelerate AD pathology in the transgenic mouse models for Aβ and tau accumulation. Such results do not seem to support the notion that excessive oral intake of Al or Zn is a risk factor for AD.

Progressive nonfluent aphasia (PNFA) is a clinical subtype of frontotemporal lobar degeneration (FTLD). FTLD with tau accumulation (FTLD-tau) and FTLD with TDP-43 accumulation (FTLD-TDP) both cause PNFA. We reviewed clinical records of 29 FTLD-TDP cases in the brain archive of our institute and found only one case of PNFA. The patient was an 81-year-old male at death. There was no family history of dementia or aphasia. He presented with slow, labored and nonfluent speech at age 75. Behavioral abnormality and movement disorders were absent. MRI at age 76 demonstrated atrophy of the perisylvian regions, including the inferior frontal gyrus, insular gyrus and superior temporal gyrus. The atrophy was more severe in the left hemisphere than the right. On post mortem examinations, neuronal loss was evident in these regions as well as in the substantia nigra. There were abundant TDP-43-immunoreactive neuronal cytoplasmic inclusions and round or irregular-shaped structures in the affected cerebral cortices. A few dystrophic neurites and neuronal intranuclear inclusions were also seen. FTLD-TDP showing PNFA seems to be rare but does exist in Japan, similar to that in other countries.

Clinical information on familial amyotrophic lateral sclerosis (FALS) with Gly72Ser mutation in the Cu/Zn superoxide dismutase-1 (SOD1) gene has been limited and autopsy findings remain to be clarified. We describe one Japanese family with ALS carrying Gly72Ser mutation in the SOD1 gene, in which autopsy was performed on one affected member. The autopsied female patient developed muscle weakness of the left thigh at age 66 and showed transient upper motor neuron signs. She died of respiratory failure 13 months after onset without artificial respiratory support. There were no symptoms suggesting bladder or rectal dysfunction throughout the clinical course. Her brother with ALS was shown to have Gly72Ser mutation in the SOD1 gene. Histopathologically, motor neurons were markedly decreased throughout the whole spinal cord, whereas corticospinal tract involvement was very mild and was demonstrated only by CD68 immunohistochemistry. Degeneration was evident in the posterior funiculus, Clarke's nucleus, posterior cerebellar tract, and Onuf's nucleus. Neuronal hyaline inclusions were rarely observed in the neurons of the spinal cord anterior horn including Onuf's nucleus, and were immunoreactive for SOD1. To date, neuron loss in Onuf's nucleus has hardly been seen in ALS, except in the patients showing prolonged disease duration with artificial respiratory support. Involvement of Onuf's nucleus may be a characteristic pathological feature in FALS with Gly72Ser mutation in the SOD1 gene.

This paper describes the gaze guidance with emotional expression of a head robot, called Kamin-FA1. We propose to use not only the gaze control of the robot, but also the facial expression to guide a human being's gaze to the target. We provide the information of the target of gaze intuitively to the human based on joint attention with Kamin-FA1. The robot has a facial expression function using a curved surface display. We examined the effect of emotional expression on the gaze guidance in terms of the accuracy and reaction speed. We conducted experiments of human gaze measurement during the gaze guidance with emotional expression to evaluate the role of emotional expression. The results of the gaze guidance experiments showed that gaze guidance with emotional expression caused a more accurate and quicker response than that without emotional expression. In particular, the expression of surprise has better performance in the gaze guidance compared with the normal expression. Furthermore, emotional expressions of angry and surprise impressed the subjects in dangerous situations, while normal and happy situations gave the impression of a safe situation at the target of gaze., Advanced robotics. 23(14):1831-1848 (2009)

A Japanese male developed gradual loss of spontaneous speech at age 60. Three years later meaningful speech had deteriorated to the point that it had become restricted to monotonous utterances. Neuropsychological examination at age 62 showed that he had severe non-fluent aphasia. A brain MRI demonstrated mild cortical atrophy with ischemic lesions in the cerebral white matter. He was diagnosed as having primary progressive aphasia. At age 63, he was admitted to the hospital to reevaluate the neurological condition. Neurologic examination showed severe non-fluent aphasia, hyperreflexia, snout and sucking reflexes. No alien hand was observed. He was able to walk, dress, wash himself and use chopsticks as well as name real objects. At age 65, 99Tc-hexamethylpropyleneamine oxime single photon emission computed tomography (HMPAO-SPECT) revealed diffuse cerebral hypoperfusion that was particularly prominent in the left frontal lobe. An MRI showed progressive cortical atrophy with the definite atrophy of the left paracentral gyrus. The hippocampal formation and putamen were also atrophic. He died of pneumonia at age 67. The brain weighed 810 g with atrophy of the frontal lobe, globus pallidus, enlargement of the lateral ventricles and depigmentation of the substantia nigra. Microscopic examination showed severe neuronal loss and gliosis in the cerebral cortex, globus pallidus interna and substantia nigra. Ballooned neurons were observed in the cerebral cortex. Gallyas-Braak method revealed numerous astrocytic plaques and argentophilic threads in the cerebrum. Clinical diagnosis of corticobasal degeneration sometimes is difficult in individuals with atypical clinical presentations. More exact clinical and radiological criteria may warrant a diagnosis of corticobasal degeneration.

This report concerns an autopsy case of sporadic amyotrophic lateral sclerosis (ALS) clinically diagnosed as having spinal progressive muscular atrophy (SPMA). The patient was a Japanese woman without hereditary burden. She developed muscle weakness in the distal part of the right upper extremity at age 52, followed by muscle weakness in the left upper extremity and lower extremities at age 54 and 64, respectively. At age 66 she could not walk, even with assistance. Fasciculation and atrophy of the tongue appeared at age 68, followed by dysphagia and dysarthria at age 70. She died of respiratory disturbance at age 71. During the clinical course, neurological examination revealed neither Babinski sign nor hyperreflexia. No respirator administration was performed throughout the clinical course. Neuropathological examination disclosed not only neuronal loss with gliosis in the hypoglossal nucleus and anterior horns of the spinal cord, but also loss of Betz cells and degeneration of the pyramidal tract. Based on these clinicopathological findings and a literature review of sporadic autopsy cases of ALS with long clinical course (10 years or more), including four cases without pyramidal signs, we believe that sporadic ALS of long clinical course mimicking SPMA exists.

We investigated postmortem human brain tissues to determine whether systemic inflammation causes activation of vascular endothelial cells and perivascular cells. In some cases, we used serum concentrations of an acute-phase reactant, C-reactive protein (CRP), as an index of systemic inflammation. Since the serum concentration of CRP at the agonal stage was available only in a limited number of patients, we estimated the degree of systemic inflammation by the intensity of immunohistochemical staining of the residual blood in brain tissue for CRP. Expressions of intercellular adhesion molecule (ICAM)-1, CD40 and cyclooxygenase (COX)-2 were used as markers for activation of vascular endothelial cells. Activation of perivascular cells was estimated by the occurrence of HLA-DR- and CD68-positive perivascular cells. In cases without brain lesions, activation of vascular endothelial cells and perivascular cells was related to the degree of systemic inflammation. In cases with brain lesions, these cells are often activated even in the absence of systemic inflammation. We suggest that inflammatory stimuli derived from the peripheral blood and the brain parenchyma adjunctly activate vascular cells. Under such circumstances, low-grade inflammation in the pre-existing brain lesions might enhance inflammatory signaling to the brain parenchyma from the periphery. The results of this study could explain the vulnerability of neurological patients to delirium caused by systemic inflammatory conditions.

Accumulation of abnormally phosphorylated tau results in the formation of neurofibrillary tangles (NFTs) in the neuronal cell soma and neuropil threads (NTs) in the cell processes. In the present study, we used immunohistochemistry to investigate serially cut thick tissue sections from the brains of patients with Alzheimer's disease (AD) and non-demented elderly subjects. In the early stages of neurofibrillary pathology, clusters of NTs occurred occasionally in the cerebral cortex. Each NTs cluster, the entire extent of which was observed in the serial sections, corresponded to a dendritic tree that was arborized from a tau-positive neuron. Adult human brain contains six tau isoforms with three having three carboxyl-terminal tandem repeat sequences that are encoded by exon 10 (3R-tau) and the other three having four repeat sequences (4R-tau). Three isoform patterns, 3R-tau(+)/4R-tau(-), 3R-tau(-)/4R-tau(+) and 3R-tau(+)/4R-tau(+), were seen in NFTs in early stage AD lesions. In an individual neuron, the isoform pattern was consistent between the NFTs in the cell soma and the NTs in the cell processes. The results of this study indicate that, in early stages of AD and age-associated neurofibrillary changes, tau accumulates simultaneously in the cell soma and cell processes of affected neurons. The process of AD and age-associated tau pathology is not tau-isoform-specific, but the ratio of 3R-tau and 4R-tau isoforms involved in the neurofibrillary changes varies and is specific to individual neurons.

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.

On September 1997, the Conference of Parties to the International Convention for the Prevention of Pollution from Ships adopted the Technical Code on Control of Emission of Nitrogen Oxides from Marine Diesel Engines. The purpose of this Code is to specify the requirements for the testing, survey and certification of marine diesel engines to ensure they comply with NOx limits. This paper describes the proposal for amend-ments to NOx Code on test condition fa submitted by Japan, the research conducted by the authors on“Follow-up Survey on NOx Concentration from Cogeneration Engines”, and the countermeasures of 4 stroke medium speed diesel engine for IMO regulation on NOx.

Background. Few studies have focused on sudden death among apparently healthy workers, and the risk factors have not been fully discussed. Methods. A nested case-control study was conducted among 164,017 male employees receiving annual medical checkups in Japan. Most recent medical checkup data of 242 sudden death victims (mean age, 48.0 years) were compared with corresponding data of 505 age-, workplace-, and job-type-matched male controls. Odds ratios (ORs) and their 95% confidence intervals (CIs) for each variable were calculated by logistic regression. Results. OR (95% CI) significantly increased with advancing blood pressure, reaching 6.6 (3.4–13.1) for systolic blood pressure ≥ 160 mm Hg relative to that

Lesions of Alzheimer disease are associated with low-grade but sustained inflammatory responses. Activated microglia agglomerate in the center of senile plaques. Reactive astrocytes marginate the amyloid beta-protein (A beta) deposits and extend their processes toward the center of plaques. Both microglia and astrocytes are known to secrete a wide variety of molecules involved in inflammation and are potential sources of proinflammatory elements in the brain. Dystrophic neurites occur in senile plaques with such glial reactions, suggesting the relevance of inflammatory responses to the neuronal degeneration in Alzheimer disease. Activated glial cells are, therefore, targets of anti-inflammatory therapy of Alzheimer disease. However, evidence also indicates that these cells eliminate A beta from the brain. A beta is produced continuously in both the normal and the AD brain. Under normal conditions, A beta is removed successfully before it accumulates as extracellular amyloid fibrils. Even in Alzheimer disease, a large portion of A beta may be cleared from the brain with a small portion being left and deposited as neurotoxic senile plaques. Both in vivo and in vitro studies showed the effective uptake of A beta by microglia. Before clinical application, it must be determined whether the treatment that suppresses glial activation and inflammatory responses inhibits A beta removal by glial cells.

The effect of LiOH pretreatment on the H 2 absorption by LaNi 5 was examined using a high pressure volumetric apparatus. In the course of H 2 absorption and desorption cycles, air was introduced into the reaction bed and oxidized for 5–25 min after each evacuation. Absorption kinetics after oxidation were measured. The absorption reaction was significantly disturbed in case when no pretreatment had been applied, however, the LiOH pretreated sample reacted with H 2 drastically even after the significant oxidations. A similar effect was also observed after a H 2 O pretreatment.

We investigated immunohistochemically the localization of amyloid beta-protein (Abeta) with amino-terminal aspartate (N1[D]) in brains of patients with Alzheimer's disease, diffuse Lewy body disease and Down's syndrome. A monoclonal antibody, 4G8, which recognizes the middle portion of Abeta, was used as a reference antibody to label the total Abeta deposits. Double staining with anti-Abeta(N1[D]) and 4G8 revealed that Abeta deposits in the subiculum and the neocortical deep layers often lacked N1[D] immunoreactivity, indicating N-terminal truncation of Abeta in these deposits. Abeta deposits in the neocortical superficial layers and the presubicular parvopyramidal layer always contained Abeta with N1[D]. Such regional as well as laminar differences in the distribution of Abeta beginning at N1[D] suggest that some local factors influence N-terminal processing of Abeta deposited in the brain.

Diffuse amyloid β-protein (Aβ) deposits with numerous glial cells containing C-terminal Aβ fragments occur in the cerebral cortex of patients with Alzheimer's disease. By using a panel of antibodies specific for various epitopes in the Aβ peptide, we have investigated the immunohistochemical nature of the diffuse Aβ deposits. The extracellular material contains Aβ with a C-terminus at residue valine40 (Aβ40) as well as residues alanine42/threonine43 (Aβ42). The N-termini include aspartate1, pyroglutamate3, and pyroglutamate11, with pyroglutamate3 being dominant. Microglia and astrocytes in and around these deposits contain intensely staining granules. Most of these granules are negative for antibodies to the N-terminally located sequences of Aβ. These include 6E10 (Aβ1–17), 6F/3D (Aβ8–17), and the N-terminal antibodies specific to aspartate1, pyroglutamate3, and pyroglutamate11. The C-termini of intraglial Aβ are comparable with those of the extracellular deposits. The microglia and astrocytes have quiescent morphology compared with those associated with senile plaques and other lesions such as ischemia. Complement activation in these deposits is not prominent and often below the sensitivity of immunohistochemical detection. Although factors which may cause this type of deposit remain unclear, lack of strong tissue responses suggests that these deposits are a very early stage of Aβ deposition. They were found only inconsistently and were absent in a number of cases examined in this study. Further analysis of these deposits might provide important clues regarding the accumulation and clearance of Aβ in Alzheimer's disease brain. GLIA 25:324–331, 1999. © 1999 Wiley-Liss, Inc.