Publications by authors named "Masafumi Morimoto"

66 Publications

Impaired neuronal activity and differential gene expression in STXBP1 encephalopathy patient iPSC-derived GABAergic neurons.

Hum Mol Genet 2021 May 7. Epub 2021 May 7.

Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan.

Syntaxin-binding protein 1 (STXBP1; also called MUNC18-1), encoded by STXBP1, is an essential component of the molecular machinery that controls synaptic vesicle docking and fusion. De novo pathogenic variants of STXBP1 cause a complex set of neurological disturbances, namely STXBP1 encephalopathy (STXBP1-E) that includes epilepsy, neurodevelopmental disorders, and neurodegeneration. Several animal studies have suggested the contribution of GABAergic dysfunction in STXBP1-E pathogenesis. However, the pathophysiological changes in GABAergic neurons of these patients are still poorly understood. Here, we exclusively generated GABAergic neurons from STXBP1-E patient-derived induced pluripotent stem cells (iPSCs) by transient expression of the transcription factors ASCL1 and DLX2. We also generated CRISPR/Cas9-edited isogenic iPSC-derived GABAergic (iPSC GABA) neurons as controls. We demonstrated that the reduction in STXBP1 protein levels in patient-derived iPSC GABA neurons was slight (approximately 20%) compared to the control neurons, despite a 50% reduction in STXBP1 mRNA levels. Using a microelectrode array-based assay, we found that patient-derived iPSC GABA neurons exhibited dysfunctional maturation with reduced numbers of spontaneous spikes and bursts. These findings reinforce the idea that GABAergic dysfunction is a crucial contributor to STXBP1-E pathogenesis. Moreover, gene expression analysis revealed specific dysregulation of genes previously implicated in epilepsy, neurodevelopment, and neurodegeneration in patient-derived iPSC GABA neurons, namely KCNH1, KCNH5, CNN3, RASGRF1, SEMA3A, SIAH3, and INPP5F. Thus, our study provides new insights for understanding the biological processes underlying the widespread neuropathological features of STXBP1-E.
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http://dx.doi.org/10.1093/hmg/ddab113DOI Listing
May 2021

Decline in subarachnoid haemorrhage volumes associated with the first wave of the COVID-19 pandemic.

Stroke Vasc Neurol 2021 Mar 26. Epub 2021 Mar 26.

Department of Radiology, Beaumont Hospital, Dublin, Ireland.

Background: During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study's objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines.

Methods: We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March-31 May 2020. The prior 1-year control period (1 March-31 May 2019) was obtained to account for seasonal variation.

Findings: There was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI -24.3% to -20.7%, p<0.0001). Embolisation of ruptured aneurysms declined with 1170-1035 procedures, respectively, representing an 11.5% (95%CI -13.5% to -9.8%, p=0.002) relative drop. Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations, a 24.9% relative decline (95% CI -28.0% to -22.1%, p<0.0001). A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1% (95% CI 32.3% to 50.6%, p=0.008) despite a decrease in SAH admissions in this tertile.

Interpretation: There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction.
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http://dx.doi.org/10.1136/svn-2020-000695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006491PMC
March 2021

Low-grade IVH in preterm infants causes cerebellar damage, motor, and cognitive impairment.

Pediatr Int 2021 Mar 11. Epub 2021 Mar 11.

Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Few studies have examined the effect of low-grade intraventricular hemorrhage (IVH) on the white matter in the cerebellum and its association with neurodevelopment. We evaluated cerebellar white matter at term-equivalent age (TEA) in preterm infants with low-grade IVH. Furthermore, we assessed neurodevelopmental outcomes at three years of age to examine the influence of low-grade IVH on neurodevelopment.

Methods: Thirteen infants with low-grade IVH and 26 without IVH, born at <30 weeks' postmenstrual age (PMA), were enrolled in this study. Diffusion tensor imaging (DTI) parameters, including fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the middle and superior cerebellar peduncles (SCP), were measured. Neurodevelopmental outcomes at three years of age were assessed and the correlation between DTI parameters and developmental quotient (DQ) was analyzed.

Results: Preterm infants with IVH showed lower FA values (p<0.01) and higher ADC values (p<0.05) in the SCP at TEA than the no-IVH group. Lower Postural-Motor and Cognitive-Adaptive DQ at three years of age were observed in the IVH compared to the no-IVH group. A significant correlation between the FA values in the SCP at TEA and the Posture-Motor DQ was observed at three years of age (p=0.043, r=0.50).

Conclusions: These data suggest that low-grade IVH in preterm infants affects the SCP at TEA, and that impaired cerebellar white matter correlates with poor motor development at three years of age.
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http://dx.doi.org/10.1111/ped.14691DOI Listing
March 2021

Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic Stroke: The SKIP Randomized Clinical Trial.

JAMA 2021 Jan;325(3):244-253

Department of Neurology, Nippon Medical School, Tokyo, Japan.

Importance: Whether intravenous thrombolysis is needed in combination with mechanical thrombectomy in patients with acute large vessel occlusion stroke is unclear.

Objective: To examine whether mechanical thrombectomy alone is noninferior to combined intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome.

Design, Setting, And Participants: Investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in Japan from January 1, 2017, to July 31, 2019, with final follow-up on October 31, 2019.

Interventions: Patients were randomly assigned to mechanical thrombectomy alone (n = 101) or combined intravenous thrombolysis (alteplase at a 0.6-mg/kg dose) plus mechanical thrombectomy (n = 103).

Main Outcomes And Measures: The primary efficacy end point was a favorable outcome defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 2 at 90 days, with a noninferiority margin odds ratio of 0.74, assessed using a 1-sided significance threshold of .025 (97.5% CI). There were 7 prespecified secondary efficacy end points, including mortality by day 90. There were 4 prespecified safety end points, including any intracerebral hemorrhage and symptomatic intracerebral hemorrhage within 36 hours.

Results: Among 204 patients (median age, 74 years; 62.7% men; median National Institutes of Health Stroke Scale score, 18), all patients completed the trial. Favorable outcome occurred in 60 patients (59.4%) in the mechanical thrombectomy alone group and 59 patients (57.3%) in the combined intravenous thrombolysis plus mechanical thrombectomy group, with no significant between-group difference (difference, 2.1% [1-sided 97.5% CI, -11.4% to ∞]; odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ∞]; P = .18 for noninferiority). Among the 7 secondary efficacy end points and 4 safety end points, 10 were not significantly different, including mortality at 90 days (8 [7.9%] vs 9 [8.7%]; difference, -0.8% [95% CI, -9.5% to 7.8%]; odds ratio, 0.90 [95% CI, 0.33 to 2.43]; P > .99). Any intracerebral hemorrhage was observed less frequently in the mechanical thrombectomy alone group than in the combined group (34 [33.7%] vs 52 [50.5%]; difference, -16.8% [95% CI, -32.1% to -1.6%]; odds ratio, 0.50 [95% CI, 0.28 to 0.88]; P = .02). Symptomatic intracerebral hemorrhage was not significantly different between groups (6 [5.9%] vs 8 [7.7%]; difference, -1.8% [95% CI, -9.7% to 6.1%]; odds ratio, 0.75 [95% CI, 0.25 to 2.24]; P = .78).

Conclusions And Relevance: Among patients with acute large vessel occlusion stroke, mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, failed to demonstrate noninferiority regarding favorable functional outcome. However, the wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority.

Trial Registration: umin.ac.jp/ctr Identifier: UMIN000021488.
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http://dx.doi.org/10.1001/jama.2020.23522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816103PMC
January 2021

Paroxysmal Atrial Fibrillation in Cryptogenic Stroke Patients With Major-Vessel Occlusion.

Front Neurol 2020 12;11:580572. Epub 2020 Nov 12.

Department of Neurology, Osaka University, Suita, Japan.

To determine whether acute major-vessel occlusion (MVO) predicts atrial fibrillation (AF) in cryptogenic stroke (CS) patients, we analyzed the association between acute MVO and AF detected by insertable cardiac monitoring (ICM). We conducted a retrospective, multicenter, observational study of patients with CS who underwent ICM implantation between October 2016 and March 2018. In this analysis, we included follow-up data until June 2018. We analyzed the association of MVO with AF detected by ICM. We included 84 consecutive patients with CS who underwent ICM implantation. The proportion of patients with newly detected AF by ICM was higher in patients with MVO than in those without (41% [12/29] vs. 13% [7/55], < 0.01) within 90 days of ICM implantation. The MVO was associated with AF after adjustment for each clinically relevant factor. MVO was independently associated with AF detection in patients with CS, which suggests that MVO may be a useful predictor of latent AF. It is therefore essential to actively assess latent AF in patients with CS presenting with MVO.
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http://dx.doi.org/10.3389/fneur.2020.580572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689035PMC
November 2020

Dysbiosis of Oral Microbiota Associated with Palmoplantar Pustulosis.

Dermatology 2021 4;237(3):347-356. Epub 2020 Dec 4.

Laboratory of Molecular and Genetic Information, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan,

Background: Dysbiosis of oral microbiota is implicated not only in oral inflammatory lesions, but also in a variety of extraoral diseases. The etiology of palmoplantar pustulosis (PPP) remains unclear; however, it has been suggested that chronic inflammation caused by periodontopathic bacterial infection may play a role.

Objectives/methods: To determine whether patients with PPP have altered diversity and composition of oral microbiota, we conducted the 16S rDNA analysis using saliva samples collected from 21 outpatients with PPP and 10 healthy individuals.

Results: We found that the proportion of bacteria in the phylum Proteobacteria was significantly lower in PPP patients (p = 0.025). At the genus level, patients with PPP had a significantly lower abundance of Neisseria (p = 0.014), which best accounted for the observed decrease in Proteobacteria. We also identified multiple minor genera and species that were represented at a significantly higher level in the PPP group, several of which have been associated with periodontal diseases.

Conclusion: Our results suggest a possible link between PPP and dysbiosis of oral microbiota, particularly the lower abundance of Neisseria, the most predominant genus of Proteobacteria in healthy oral microbiota. Probiotics that improves oral dysbiosis may be beneficial for patients with PPP as an adjunctive therapy.
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http://dx.doi.org/10.1159/000511622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117382PMC
December 2020

A novel Drosophila model for neurodevelopmental disorders associated with Shwachman-Diamond syndrome.

Neurosci Lett 2020 11 25;739:135449. Epub 2020 Oct 25.

Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan.

Genetic defects in ribosome biogenesis result in a group of diseases called ribosomopathies. Patients with ribosomopathies manifest multiorgan phenotypes, including neurological impairments. A well-characterized ribosomopathy, Shwachman-Diamond syndrome (SDS), is mainly associated with loss-of-function mutations in the causal gene SBDS. Children with SDS have neurodevelopmental disorders; however, the neurological consequences of SBDS dysfunction remain poorly defined. In the present study, we investigated the phenotype of Drosophila melanogaster following knockdown of CG8549, the Drosophila ortholog of human SBDS, to provide evidence for the neurological consequences of reduction in physiological SBDS functions. The pan-neuron-specific knockdown of CG8549 was associated with locomotive disabilities, mechanically induced seizures, hyperactivity, learning impairments, and anatomical defects in presynaptic terminals. These results provide the first evidence of a direct link between a reduction in physiological SBDS function and neurological impairments.
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http://dx.doi.org/10.1016/j.neulet.2020.135449DOI Listing
November 2020

Safety of Early Administration of Apixaban on Clinical Outcomes in Patients with Acute Large Vessel Occlusion.

Transl Stroke Res 2021 Apr 7;12(2):266-274. Epub 2020 Aug 7.

Department of Clinical Epidemiology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.

Early administration of direct oral anticoagulants in patients with acute large vessel occlusion (LVO) and nonvalvular atrial fibrillation (NVAF) is a concern, as endovascular therapy (EVT) became highly utilized. We conducted a historical and prospective multicenter registry at 38 centers in Japan from July 2016 to February 2018. Patients aged ≥ 20 years with NVAF and acute LVO or stenosis who received apixaban within 14 days from onset were included. We compared patients who received apixaban < 48 h (Early group) and ≥ 48 h (Late group) after onset in terms of the primary outcome (a composite of ischemic events, major bleeding events, and all-cause deaths). The secondary outcomes were each component of the primary outcome. Among the 686 patients, the median time from onset to administration was 2.5 days (range, 0-14; Early 263, Late 423). The Alberta Stroke Program Early CT Score (ASPECTS) and diffusion-weighted imaging (DWI)-ASPECTS) were significantly higher in the Early group than in the Late group. Recombinant tissue plasminogen activator (rt-PA) and EVT were more utilized in the Early group (rt-PA 46% vs. 35%, p = 0.003; EVT 62% vs. 46%, p < 0.0001). The cumulative incidence of primary outcome was similar between groups (ischemic events: Early 1.9% vs. Late 0.5% at 30 days; 3.5% vs. 0.7% at 90 days, major bleeding 3.4% vs. 2.9% at 30 days; 5.0% vs. 3.4% at 90 days). Early administration of apixaban (< 48 h), after onset of acute LVO in patients with NVAF, was generally safe compared with those who received it Late (≥ 48 h). http://www.clinicaltrials.gov . Unique identifier: NCT02818868 (June 30, 2016).
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http://dx.doi.org/10.1007/s12975-020-00839-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925454PMC
April 2021

Prenatal clinical manifestations in individuals with variants.

J Med Genet 2020 Jul 30. Epub 2020 Jul 30.

Department of Pediatric Neurology, Bobath Memorial Hospital, Osaka, Osaka, Japan.

Background: Variants in the type IV collagen gene () cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with variants remain unclear.

Methods: We examined in 218 individuals with suspected /2-related brain defects. Among those arising from variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.

Results: Pathogenic variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.

Conclusions: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and gene testing should be considered when pathogenic variants are strongly suspected.
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http://dx.doi.org/10.1136/jmedgenet-2020-106896DOI Listing
July 2020

[A Case of Thrombectomy beyond One Day after Stroke Onset Resistant to Medical Treatment].

No Shinkei Geka 2020 Jul;48(7):627-632

Department of Neurosurgery, Yokohamashintoshi Neurosurgical Hospital.

We report a case of thrombectomy beyond one day of onset of right middle cerebral artery occlusion. An 82-year-old woman who presented with difficulty in body movements was transferred to our hospital. After admission, left-sided weakness and dysarthria worsened with an National Institutes of Health Stroke Scale of 9. The initial MRI DWI on admission revealed multiple hyper intense signals in the right cerebral hemisphere and MR angiography revealed occlusion of the right internal carotid artery. We performed medical treatment because FLAIR also revealed hyper intense signals in the same lesion as the DWI image, and more than one day had passed since the onset. However, her symptoms worsened and we performed angiography on the next day, and found contrast defects like crab claw at the top of the right internal carotid artery. Even though more than one day had passed since the onset, we assumed that thrombectomy could prevent the worsening of symptoms. The procedure was a success and it resulted in complete reperfusion to the right middle cerebral artery. She showed improvement after the procedure. According to this case, thrombectomy one day from onset could be considered as a treatment option for large vessel occlusion with good collateral flow in the cases resistant to medical treatment.
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http://dx.doi.org/10.11477/mf.1436204242DOI Listing
July 2020

Two Cases of Posterior Cerebral Artery P2 Segment Occlusion with Motor Weakness Improved by Acute Mechanical Thrombectomy.

World Neurosurg 2020 10 17;142:13-16. Epub 2020 Jun 17.

Department of Neurology and Neuroendovascular Treatment, Yokohama Shintoshi Neurosurgical Hospital, Yokohama, Japan.

Background: Clinical evidence to support the use of mechanical thrombectomy (MT) for posterior cerebral artery P2 segment occlusion (P2O) has not been established, and hemiplegia due to P2O improved by MT to our knowledge has not yet been reported. We report 2 cases of P2O with hemiplegia improved by MT.

Case Description: In case 1, a 68-year-old man was admitted with right hemiplegia and dysesthesia (National Institutes of Health Stroke Scale score 14). Head magnetic resonance imaging showed acute ischemia in the left inferolateral thalamus and posterior limb of the internal capsule. Angiography showed left P2O, which was recanalized after MT. Hemiplegia improved immediately following recanalization, and modified Rankin Scale score at discharge was 0. In case 2, a 69-year-old man was admitted with left hemiplegia and dysesthesia (National Institutes of Health Stroke Scale score 8). Head magnetic resonance imaging showed acute ischemia in the right inferolateral thalamus and posterior limb of the internal capsule. Angiography showed right P2O, which was recanalized after MT, as in case 1. His symptoms resolved completely.

Conclusions: P2O may cause severe motor deficit. In such cases, MT may contribute to safely improving patients' deficits.
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http://dx.doi.org/10.1016/j.wneu.2020.06.085DOI Listing
October 2020

Higher Prevalence of Nickel and Palladium Hypersensitivity in Patients with Ulcerative Colitis.

Int Arch Allergy Immunol 2020 21;181(6):456-461. Epub 2020 Apr 21.

Takanawa Clinic, Tokyo, Japan,

Background: The etiology of ulcerative colitis (UC) remains elusive even though many genetic and environmental pathogenic factors have been reported. Aberrant inflammatory responses mediated by specific subsets of T cells have been observed in ulcerative lesions of UC patients.

Objectives: To elucidate the involvement of a delayed-type hypersensitivity reaction in UC, we focused on dental metal hypersensitivity, a T cell-mediated, delayed-type allergic reaction that causes oral contact mucositis and systemic cutaneous inflammation.

Method: We recruited 65 Japanese UC patients and 22 healthy controls (HC) and used the in vitro lymphocyte stimulation test to quantify their sensitivity to zinc, gold, nickel, and palladium - the metals that have been widely used in dentistry. All subjects were users of metallic dental implants and/or prostheses containing zinc, gold, nickel, and/or palladium as major constituents.

Results: Sixty percent of the UC patients were hypersensitive to at least one metal species, whereas 32% of the HC were hypersensitive to only a single metal species. The overall incidence of metal hypersensitivity was significantly higher for UC patients than for HC. Furthermore, a significantly greater proportion of UC patients were hypersensitive to nickel or palladium. The severity of the sensitivity to nickel and palladium was also significantly greater for UC patients than for HC.

Conclusions: This pilot study demonstrates that UC patients have a significantly higher incidence of hypersensitivity to nickel and palladium, suggesting the possible involvement of dental metal hypersensitivity in UC pathogenesis.
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http://dx.doi.org/10.1159/000506633DOI Listing
November 2020

Frequent Premature Atrial Contractions in Cryptogenic Stroke Predict Atrial Fibrillation Detection with Insertable Cardiac Monitoring.

Cerebrovasc Dis 2020 5;49(2):144-150. Epub 2020 Feb 5.

Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.

Objective: To determine whether frequent premature atrial contractions (PAC) predict atrial fibrillation (AF) in cryptogenic stroke patients, we analyzed the association between frequent PACs in 24-h Holter electrocardiogram recording and AF detected by insertable cardiac monitoring (ICM).

Methods: We retrospectively analyzed a database of 66 consecutive patients with cryptogenic stroke who received ICM implantation between October 2016 and March 2018 at 5 stroke centers. We included the follow-up data until June 2018 in this analysis. We defined frequent PACs as the upper quartile of the 66 patients. We analyzed the association of frequent PACs with AF detected by ICM.

Results: Frequent PACs were defined as >222 PACs per a 24-h period. The proportion of patients with newly detected AF by ICM was higher in patients with frequent PACs than those without (50% [8/16] vs. 22% [11/50], p < 0.05). Frequent PACs were associated with AF detection and time to the first AF after adjustment for CHADS2 score after index stroke, high plasma -B-type natriuretic peptide (BNP; >100 pg/mL) or serum -N-terminal pro-BNP levels (>300 pg/mL), and large left atrial diameter (≥45 mm).

Conclusion: High frequency of PACs in cryptogenic stroke may be a strong predictor of AF detected by ICM.
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http://dx.doi.org/10.1159/000505958DOI Listing
September 2020

Higher incidence of zinc and nickel hypersensitivity in patients with irritable bowel syndrome.

Immun Inflamm Dis 2019 12 24;7(4):304-307. Epub 2019 Oct 24.

Takanawa Clinic, Tokyo, Japan.

Introduction: The etiology of irritable bowel syndrome (IBS) remains elusive even though several genetic and environmental pathogenic factors have been reported. IBS is considered to be a functional disorder without any detectable lesions in the patient's bowel. However, many studies have demonstrated that a subset of IBS patients have low-grade inflammation and aberrant T-cell activation in their intestinal mucosa. To elucidate the immune mechanism underlying the mucosal inflammation in IBS, we focused on dental metal hypersensitivity, a T cell-mediated, delayed-type allergic reaction that causes oral contact mucositis and systemic cutaneous inflammation.

Methods: We recruited 147 Japanese IBS patients and 22 healthy controls (HCs). The subjects underwent the in vitro lymphocyte stimulation test to quantify their sensitivity to zinc, gold, nickel, and palladium, the metals that have been commonly used in dentistry.

Results: A total of 56.5% of the IBS patients were hypersensitive to at least one metal species, whereas 31.8% of HC were hypersensitive to only a single metal species. The overall incidence of metal hypersensitivity was significantly higher for IBS patients than for HC. Furthermore, a significantly higher proportion of IBS patients were hypersensitive to zinc and/or nickel. The severity of the sensitivity to zinc and nickel was also significantly greater for IBS patients than for HC. There was no significant difference in the sensitization rates and the sensitivity among the IBS subtypes.

Conclusions: This pilot study demonstrates that IBS patients have a significantly higher prevalence of hypersensitivity to zinc and nickel, suggesting the possible involvement of dental metal hypersensitivity in IBS pathogenesis in a subset of patients.
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http://dx.doi.org/10.1002/iid3.274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842818PMC
December 2019

UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes.

J Hum Genet 2019 Nov 12;64(11):1055-1065. Epub 2019 Sep 12.

Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.

We aimed to find a new causative gene and elucidate the molecular mechanisms underlying a new type of hereditary spastic paraplegia (HSP). Patients with HSP were recruited from the Japan Spastic Paraplegia Research Consortium (JASPAC). Exome sequencing of genomic DNA from patients in four families was carried out, followed by Sanger sequencing of the UBAP1 gene. A mouse homolog of one UBAP1 frameshift mutation carried by one of the patients was created as a disease model. Functional properties of the UBAP1 wild type and UBAP1-mutant in mouse hippocampus neurons were examined. We identified three novel heterozygous loss of function mutations (c.425_426delAG, c.312delC, and c.535G>T) in the UBAP1 gene as the genetic cause of a new type of HSP (SPG80). All the patients presented identical clinical features of a pure type of juvenile-onset HSP. Functional studies on mouse hippocampal neurons revealed that the C-terminal deletion UBAP1-mutant of our disease model had lost its ability to bind ubiquitin in vitro. Overexpression of the UBAP1 wild type interacts directly with ubiquitin on enlarged endosomes, while the UBAP1-mutant cannot be recruited to endosome membranes. Our study demonstrated that mutations in the UBAP1 gene cause a new type of HSP and elucidated its pathogenesis. The full-length UBAP1 protein is involved in endosomal dynamics in neurons, while loss of UBAP1 function may perturb endosomal fusion and sorting of ubiquitinated cargos. These effects could be more prominent in neurons, thereby giving rise to the phenotype of a neurodegenerative disease such as HSP.
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http://dx.doi.org/10.1038/s10038-019-0670-9DOI Listing
November 2019

High Detection Rate of Atrial Fibrillation With Insertable Cardiac Monitor Implantation in Patients With Cryptogenic Stroke Diagnosed by Magnetic Resonance Imaging.

J Stroke Cerebrovasc Dis 2019 Sep 21;28(9):2569-2573. Epub 2019 Jun 21.

Basic Clinical Science and Public Health, Tokai University School of Medicine, Isehara, Japan.

Background: Detection and treatment of atrial fibrillation (AF) is a major goal in preventing secondary stroke. Insertable cardiac monitors (ICMs) are available for diagnosis of arrhythmia monitoring in patients with cryptogenic stroke. Magnetic resonance imaging (MRI)-based diagnostic evaluation for acute ischemic stroke subtype classification is common in Japan and can be useful for specific diagnosis of cryptogenic stroke.

Purpose: We aimed to investigate the detection rate of AF with an ICM in patients with cryptogenic stroke who were diagnosed by MRI.

Methods: We performed a retrospective, multicenter, observational study. AF monitoring data of an ICM (Reveal LINQ) in patients with cryptogenic stroke were registered from 5 stroke centers in Japan between October 2016 and March 2018. ICM candidates in cryptogenic stroke were diagnosed by MRI-based evaluation and selected according to the criteria proposed by the Japan Stroke Society. Detection of AF was defined as AF for longer than 120 seconds.

Results: Eighty-four consecutive patients (64 men; aged 38-90 years) underwent ICM implantation after diagnosis of cryptogenic stroke. AF was detected in 22 of 84 (26.2%) patients with an ICM during a median follow-up of 221.5 days (range: 93-365 days). The detection rate of AF within 3 months after ICM implantation was 21.4%.

Conclusions: The AF detection rate with an ICM is approximately one fifth within 3 months in patients with cryptogenic stroke as diagnosed by MRI. Our data suggest that the Japanese criteria based on MRI may be useful for selecting adequate candidates for ICM implantation.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.05.023DOI Listing
September 2019

Gender differences in occurrence of behavioral and emotional problems at the lower grades of elementary school: Association with developmental and behavioral characteristics at 5 years.

Brain Dev 2019 Oct 18;41(9):760-768. Epub 2019 Jun 18.

Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.

Aim: We examined whether developmental status and behavioral problems at age five were related to the occurrence of behavioral and emotional problems in the lower grades of elementary school among non-clinical children who did not receive specialized support for developmental problems in early childhood.

Methods: The participants were 367 (non-clinical: 325) second- and third-grade elementary school children. The mean age at follow-up was 7.63 (SD = 0.62). Parents completed a questionnaire about their children's developmental status and behavioral problems during a community health check-up for 5-year-olds. Behavioral and emotional problems at school age were assessed using the Strengths and Difficulties Questionnaire (SDQ). The association between developmental and behavioral characteristics at age five and each of the SDQ subscales at school age was analyzed with logistic regression.

Results: Hyperactivity/inattention, conduct problems, and emotional problems at school age were associated with developmental and behavioral factors in 5-year-olds. The problem of hyperactivity/inattention at school age was associated with hyperactivity/inattention in both genders, and significant gender differences were identified. The relationship with hyperactivity at the age of five was significant for boys, whereas the relationship with inattention was only significant for girls. Emotional problems were significantly associated with social behaviors and developmental status at five years of age only in girls.

Conclusions: It is necessary for clinicians and teachers to consider the relation of developmental and behavioral characteristics to the background of behavioral and emotional problems at school age and to be aware of gender differences.
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http://dx.doi.org/10.1016/j.braindev.2019.06.001DOI Listing
October 2019

Plasma neurofilament light chain: A potential prognostic biomarker of dementia in adult Down syndrome patients.

PLoS One 2019 5;14(4):e0211575. Epub 2019 Apr 5.

Department of Neurology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.

People with Down syndrome (DS) are at high risk of developing Alzheimer disease (AD) with aging. The diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. Plasma neurofilament light chain (NfL) is one of the established biomarkers of AD, suggesting that it may be useful as an indicator of dementia in DS patients. The aims of this study were: 1) to examine whether plasma levels of NfL in DS patients are correlated with decreased adaptive behavior scores one year after sample collection, and 2) to compare plasma levels of NfL in adults with DS and an age-matched healthy control population. In this study, plasma levels of NfL in 24 patients with DS and 24 control participants were measured by the single-molecule immunoarray (Simoa) method. We observed significantly increased plasma NfL levels in the DS compared with the control group. There was a significant correlation between age and levels of plasma NfL in both groups. This age-dependent elevation was steeper in the DS compared with the control group. Moreover, elevated plasma NfL was associated with decreased adaptive behavior scores one year later, after age-adjustment. Previously reported blood-based biomarkers available in Simoa for DS, plasma total tau and phosphorylated tau, were not significantly correlated with the annual decrement of adaptive behavior scores after age-adjustment. These results suggest that plasma NfL has the potential to serve as an objective biomarker to predict dementia in adult DS patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211575PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450630PMC
December 2019

The randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ICA and M1 occlusion (SKIP study).

Int J Stroke 2019 10 29;14(7):752-755. Epub 2019 Mar 29.

Division of Stroke Prevention and Treatment, Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Rationale: Bridging therapy with endovascular therapy (EVT) and intravenous thrombolysis (IVT) has been reported to improve outcomes for acute stroke patients with large-vessel occlusion in the anterior circulation. While the IVT may increase the reperfusion rate, the risk of hemorrhagic complications increases. Whether EVT without IVT (direct EVT) is equally effective as bridging therapy in acute stroke remains unclear.

Aim: This randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator for acute stroke with ICA and M1 occlusion aims to clarify the efficacy and safety of direct EVT compared with bridging therapy.

Methods And Design: This is an investigator-initiated, multicenter, prospective, randomized, open-treatment, blinded-endpoint clinical trial. The target patient number is 200, comprising 100 patients receiving direct EVT and 100 receiving bridging therapy.

Study Outcome: The primary efficacy endpoint is a modified Rankin Scale score of 0-2 at 90 days. Safety outcome measures are any intracranial hemorrhage at 24 h.

Discussion: This trial may help determine whether direct EVT should be recommended as a routine clinical strategy for ischemic stroke patients within 4.5 h from onset. Direct EVT would then become the choice of therapy in stroke centers with endovascular facilities.

Trial Registration: UMIN000021488.
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http://dx.doi.org/10.1177/1747493019840932DOI Listing
October 2019

High-fat diet accelerates extreme obesity with hyperphagia in female heterozygous Mecp2-null mice.

PLoS One 2019 4;14(1):e0210184. Epub 2019 Jan 4.

Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutation of the methyl-CpG-binding protein 2 (MECP2) gene. Although RTT has been associated with obesity, the underlying mechanism has not yet been elucidated. In this study, female heterozygous Mecp2-null mice (Mecp2+/- mice), a model of RTT, were fed a normal chow diet or high-fat diet (HFD), and the changes in molecular signaling pathways were investigated. Specifically, we examined the expression of genes related to the hypothalamus and dopamine reward circuitry, which represent a central network of feeding behavior control. In particular, dopamine reward circuitry has been shown to regulate hedonic feeding behavior, and its disruption is associated with HFD-related changes in palatability. The Mecp2+/- mice that were fed the normal chow showed normal body weight and food consumption, whereas those fed the HFD showed extreme obesity with hyperphagia, an increase of body fat mass, glucose intolerance, and insulin resistance compared with wild-type mice fed the HFD (WT-HFD mice). The main cause of obesity in Mecp2+/--HFD mice was a remarkable increase in calorie intake, with no difference in oxygen consumption or locomotor activity. Agouti-related peptide mRNA and protein levels were increased, whereas proopiomelanocortin mRNA and protein levels were reduced in Mecp2+/--HFD mice with hyperleptinemia, which play an essential role in appetite and satiety in the hypothalamus. The conditioned place preference test revealed that Mecp2+/- mice preferred the HFD. Tyrosine hydroxylase and dopamine transporter mRNA levels in the ventral tegmental area, and dopamine receptor and dopamine- and cAMP-regulated phosphoprotein mRNA levels in the nucleus accumbens were significantly lower in Mecp2+/--HFD mice than those of WT-HFD mice. Thus, HFD feeding induced dysregulation of food intake in the hypothalamus and dopamine reward circuitry, and accelerated the development of extreme obesity associated with addiction-like eating behavior in Mecp2+/- mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210184PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319720PMC
September 2019

Cerebellar peduncle injury predicts motor impairments in preterm infants: A quantitative tractography study at term-equivalent age.

Brain Dev 2018 Oct;40(9):743-752

Department of Medical Science, School of Nursing, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Purpose: Cerebellar injury is well established as an important finding in preterm infants with cerebral palsy (CP). In this study, we investigated associations between injury to the cerebellar peduncles and motor impairments in preterm infants using quantitative tractography at term-equivalent age, which represents an early phase before the onset of motor impairments.

Methods: We studied 64 preterm infants who were born at <33 weeks gestational age. These infants were divided into three groups: CP, Non-CP (defined as infants with periventricular leukomalacia but having normal motor function), and a Normal group. Diffusion tensor imaging was performed at term-equivalent age and motor function was assessed no earlier than a corrected age of 2 years. Using tractography, we measured fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the superior cerebellar peduncles (SCP) and middle cerebellar peduncles (MCP), as well as the motor/sensory tracts.

Results: The infants in the CP group had significantly lower FA of the SCP and sensory tract than those in the other groups. There was no significant difference in FA and ADC of the motor tract among the three groups. Severity of CP had a significant correlation with FA of the MCP, but not with the FA of other white matter tracts.

Conclusion: Our results suggested that the infants with CP had injuries of the ascending tracts (e.g. the SCP and sensory tract), and that additional MCP injury might increase the severity of CP. Quantitative tractography assessment at term-equivalent age may be useful for screening preterm infants for prediction of future motor impairments.
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http://dx.doi.org/10.1016/j.braindev.2018.04.013DOI Listing
October 2018

Frequency and risk factors for subsyndromal delirium in an intensive care unit.

Intensive Crit Care Nurs 2018 Aug 30;47:15-22. Epub 2018 Mar 30.

Graduate School of Nursing for Health Care Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address:

Objective: Delirium and subsyndromal delirium in critically ill patients are important determinants of long-term functional disability and cognitive impairment. However, few outcome studies on sub-syndromal delirium have been reported. Thus, this study aimed to evaluate the incidence of delirium and sub-syndromal delirium as well as the risk factors and progression to delirium.

Design: A prospective cohort study.

Setting: Six bed medical and surgical intensive care unit in Otsu Municipal Hospital in Japan.

Methods: Delirium and sub syndromal delirium were evaluated using the Intensive Care Delirium Screening Checklist scores and the demographic data of the patients recorded. Statistical analyses were conducted using the Mann-Whitney U test and chi-square test for comparison. We also compared groups using multivariate analyses.

Results: Of the 380 patients who were screened, 15.8% and 33.9% had delirium or sub syndromal delirium, respectively and 9.5% of patients progressed from a state of sub syndromal delirium to delirium. Older age, predisposing cognitive impairment, blood transfusion, higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, low red blood cell count and high C-reactive protein levels were the risk factors highly associated with subsyndromal delirium symptoms. Older age, acute admission, steroid use, the utilisation of restraints and lower PaO were the determinants of progression to delirium.

Conclusions: A high incidence of sub syndromal delirium was observed in critically ill patients. Patient with sub syndromal delirium must be promptly identified and treated due to the risk of progression to delirium.
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http://dx.doi.org/10.1016/j.iccn.2018.02.010DOI Listing
August 2018

A 5-Year Follow-Up of Triple-Seronegative Myasthenia Gravis Successfully Treated with Tacrolimus Therapy.

Neuropediatrics 2018 06 4;49(3):200-203. Epub 2018 Jan 4.

Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.

Seronegative myasthenia gravis (MG) is a generalized form of MG that is diagnosed on the basis of clinical symptoms, electrophysiological testing, and pharmacological responses, in the absence of a seropositive status for anti-acetylcholine receptor (AChR) antibodies. Generalized MG that is seronegative for anti-AChR, anti-muscle-specific kinase (MuSK), and anti-low density lipoprotein receptor related protein 4 (Lrp4) antibodies is known as triple-seronegative MG. We here describe a case of triple-seronegative MG in an 8-year-old boy. His first symptom was dysphagia, at 3 years of age, and he subsequently developed ptosis, rhinolalia, and a waddling gait. A genetic analysis was conducted to exclude the possibility of congenital myasthenia syndrome due to the patient's resistance to steroid therapy. His condition was successfully managed with tacrolimus therapy over a 5-year follow-up period. Recently, several studies have reported the therapeutic utility of tacrolimus in juvenile seropositive MG; in contrast, a few reports have described tacrolimus treatment in cases of seronegative MG. Our findings suggest that tacrolimus therapy is a safe and effective option for the treatment of juvenile seronegative MG.
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http://dx.doi.org/10.1055/s-0037-1618591DOI Listing
June 2018

Identification of the Basic Sites on Nitrogen-Substituted Microporous and Mesoporous Silicate Frameworks Using CO as a Probe Molecule.

Langmuir 2018 01 17;34(4):1376-1385. Epub 2018 Jan 17.

Quantachrome Corporation , Boynton Beach, Florida 33426, United States.

Carbon dioxide was shown to identify surface basic properties of nitrogen-substituted microporous and mesoporous silicas, in addition to conventional basic oxides, by a detailed study using isotherm and heat of adsorption measurements as well as by infrared spectroscopy. A hydrogen-bonded weak interaction was primarily observed between CO and silanol (Si-OH) and silamine (Si-NH-Si) groups. The heat of adsorption of CO demonstrated that the latter adspecies were formed preferentially over the former, although a much higher amount of linear CO adspecies were found on SBA-15 mesoporous silica because of the presence of a large quantity of silanol groups on its surface. Carbamate-type chemisorbed adspecies were not detected on silamino sites, whereas carbonate-type adspecies were formed on alkali ion-exchanged zeolites and also residual sodium ions on the surface of silicalite-1. CO was shown to be a successful probe molecule for identifying weakly interactive hydrogen-bonding sites, and it has potential as a surface probe for strongly interactive nucleophilic sites derived from alkaline ions or a methylated silamino group, Si-N(CH)-Si.
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http://dx.doi.org/10.1021/acs.langmuir.7b03769DOI Listing
January 2018

DHA Mitigates Autistic Behaviors Accompanied by Dopaminergic Change in a Gene/Prenatal Stress Mouse Model.

Neuroscience 2018 02 27;371:407-419. Epub 2017 Dec 27.

Department of Radiology, University of Missouri, Columbia, MO, USA; Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, USA; Department of Psychological Sciences, University of Missouri, Columbia, MO, USA; Departments of Radiology and Neurology, William and Nancy Thompson Chair in Radiology, University of Missouri, Columbia, MO, USA. Electronic address:

Autism Spectrum Disorder (ASD) is characterized by impairments in social interaction, social communication, and repetitive and stereotyped behaviors. Recent work has begun to explore gene × environmental interactions in the etiology of ASD. We previously reported that prenatal stress exposure in stress-susceptible heterozygous serotonin transporter (SERT) KO pregnant dams in a mouse model resulted in autism-like behavior in the offspring (SERT/S mice). The association between prenatal stress and ASD appears to be affected by maternal SERT genotype in clinical populations as well. Using the mouse model, we examined autistic-like behaviors in greater detail, and additionally explored whether diet supplementation with docosahexaenoic acid (DHA) may mitigate the behavioral changes. Only male SERT/S mice showed social impairment and stereotyped behavior, and DHA supplementation ameliorated some of these behaviors. We also measured monoamine levels in the SERT/S mice after three treatment paradigms: DHA-rich diet continuously from breeding (DHA diet), DHA-rich diet only after weaning (CTL/DHA diet) and control diet only (CTL diet). The dopamine (DA) content in the striatum was significantly increased in the SERT/S mice compared with wild-type (WT) mice, whereas no difference was observed with noradrenaline and serotonin content. Moreover, DA content in the striatum was significantly reduced in the SERT/S mice with the DHA-rich diet provided continuously from breeding. The results indicate that autism-associated behaviors and changes in the dopaminergic system in this setting can be mitigated with DHA supplementation.
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http://dx.doi.org/10.1016/j.neuroscience.2017.12.029DOI Listing
February 2018

Increased levels of plasma total tau in adult Down syndrome.

PLoS One 2017 30;12(11):e0188802. Epub 2017 Nov 30.

Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Down syndrome (DS) is the most prevalent chromosomal abnormality. Early-onset dementia with the pathology of Alzheimer's disease (AD) frequently develops in DS. Reliable blood biomarkers are needed to support the diagnosis for dementia in DS, since positron emission tomography or cerebrospinal fluid sampling is burdensome, particularly for patients with DS. Plasma t-tau is one of the established biomarkers for the diagnosis of AD, suggesting the potential value of t-tau as a biomarker for dementia in DS. The aim of this study was to assess and compare plasma levels of t-tau in adults with DS and in an age-matched control population. In this study, plasma levels of t-tau in 21 patients with DS and 22 control participants were measured by an ultrasensitive immunoassay technology, the single-molecule immunoarray (Simoa) method. We observed significantly increased plasma t-tau levels in the DS group (mean ± standard deviation (SD) = 0.643±0.493) compared to those in the control group (mean ± SD = 0.470±0.232): P = 0.0050. Moreover, age dependent correlation of plasma t-tau was only found in the DS group, and not in the control group. These findings suggest that elevated plasma t-tau levels reflect AD pathology and therefore have potential as an objective biomarker to detect dementia in adult DS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188802PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708632PMC
December 2017

Nanoporosity Change on Elastic Relaxation of Partially Folded Graphene Monoliths.

Langmuir 2017 12 11;33(51):14565-14570. Epub 2017 Dec 11.

Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey , Rutgers, New Jersey 08854-8058, United States.

Fabrication of nanographene shows a promising route for production of designed porous carbons, which is indispensable for highly efficient molecular separation and energy storage applications. This process requires a better understanding of the mechanical properties of nanographene in their aggregated structure. We studied the structural and mechanical properties of nanographene monoliths compressed at 43 MPa over different times from 3 to 25 h. While in monoliths compressed over shorter time adsorption isotherms of Ar at 87 K or N at 77 K exhibited a prominent hysteresis due to presence of predominant mesopores, compression for long time induces a low pressure hysteresis. On the other hand, compression for 25 h increases the microporosity evaluated by Ar adsorption, not by N adsorption, indicating that 25 h compression rearranges the nanographene stacking structure to produce ultramicropores that can be accessible only for Ar. TEM, X-ray diffraction, and Raman spectroscopic studies indicated that the compression for 25 h unfolds double-bent-like structures, relaxing the unstable nanographene stacked structure formed on the initial compression without nanographene sheets collapse. This behavior stems from the highly elastic nature of the nanographenes.
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http://dx.doi.org/10.1021/acs.langmuir.7b03328DOI Listing
December 2017

Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: do mutations contribute to vulnerability to parkinsonism?

NPJ Parkinsons Dis 2017 31;3:13. Epub 2017 Mar 31.

Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566 Japan.

Phosphoglycerate kinase 1 (PGK-1) is a glycolytic enzyme encoded by , which maps to the X chromosome. PGK-1 deficiency causes X-linked recessive hereditary chronic hemolytic anemia, myopathy, and neurological disorders due to insufficient ATP regeneration. Early-onset parkinsonism has occasionally been reported as a neurological complication of this condition. However, heterozygous carriers of PGK-1 deficiency were thought to be neurologically asymptomatic. Here, we report a boy with PGK-1 deficiency and his mother, a carrier of a heterozygous mutation in , both of whom presented with early-onset parkinsonism. The boy developed parkinsonism at 9 years of age. His parkinsonism partially responded to levodopa treatment. l-metaiodobenzylguanidine (MIBG) uptake was normal. His mother, who exhibited normal PGK-1 activity in erythrocytes, developed parkinsonism at 36 years of age. Her symptoms were undistinguishable from those of Parkinson's disease (PD), despite her normal uptake of MIBG. Neither a point mutation in nor multiplication of was found. Additionally, hotspots of and were not mutated. To our knowledge, this report provides the first description of parkinsonism in a carrier of PGK-1 deficiency. Interestingly, is located within the confirmed susceptibility locus for PD known as . These observations suggest that mutations confer susceptibility to PD.
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http://dx.doi.org/10.1038/s41531-017-0014-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459803PMC
March 2017