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BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease caused by the expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of NOTCH2NLC. Although increasing evidence suggests that NIID affects various organs, its association with renal involvement remains unclear. We studied the genetic background of a family with NIID, in which four of five members presented with proteinuria as the initial manifestation. The renal pathology of three patients was diagnosed as focal segmental glomerulosclerosis (FSGS) at a previous hospital. These patients also presented with tremors, retinal degeneration, and episodic neurological events. Finally, one patient exhibited reversible bilateral thalamic high-intensity signal changes on diffusion-weighted imaging during episodic neurological events. METHODS: Exome sequencing (ES) and nanopore long-read whole-genome sequencing (LR-WGS) were performed on the index case, followed by nanopore target sequencing using Cas9-mediated PCR-free enrichment and methylation analysis. RESULTS: ES revealed no candidate variants; however, nanopore LR-WGS in the index case revealed expansion of short tandem repeats (STR) in NOTCH2NLC. Subsequent nanopore target sequencing using Cas9-mediated PCR-free enrichment showed STR expansion of NOTCH2NLC in an affected sibling and asymptomatic father. Methylation analysis using nanopore data revealed hypermethylation of the expanded allele in the asymptomatic father and partial hypermethylation in a mildly symptomatic sibling, whereas the expanded allele was hypomethylated in the index case. CONCLUSIONS: This investigation expands the clinical spectrum of NIID, suggesting that STR expansion of NOTCH2NLC is a cause of renal diseases, including FSGS.
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INTRODUCTION: Parkinson's disease (PD) presents with decreased heart rate variability (HRV) from its early stages. However, most of its evidence originates from HRV measurements in parasympathetic dominant states. In this study, we aimed to examine whether HRV in sympathetic dominant states during the head-up tilt table test (HUT) serves as a marker of autonomic dysfunction in PD and isolated REM sleep behavior disorder (iRBD). METHODS: We retrospectively assessed 102 patients with PD, 10 patients with iRBD, and 43 healthy controls. We then measured the coefficient of variation of RR intervals as an HRV parameter in sympathetic dominant states (CVRR-S) and parasympathetic dominant states (CVRR-P). Furthermore, we evaluated parameters of cardiac autonomic function, including HUT and the heart-to-mediastinum (H/M) ratio of cardiac metaiodobenzylguanidine scintigraphy. RESULTS: Patients with iRBD and PD at Hoehn and Yahr stage I exhibited a significantly decreased CVRR-S compared to healthy controls (controls vs. iRBD vs. PD; 1.82 ± 0.64 % vs. 1.13 ± 0.41 % vs. 1.15 ± 0.51 %, p < 0.001), although no further deterioration was observed in PD at more severe Hoehn and Yahr stages. CVRR-S showed a significant correlation with the H/M ratio in PD (r = 0.51, p < 0.001). Additionally, receiver operating characteristic (ROC) analysis revealed a larger area under the ROC curve in CVRR-S compared to that in CVRR-P for discriminating PD or iRBD from healthy controls. CONCLUSION: HRV in sympathetic dominant states shows the potential to be a marker of autonomic dysfunction in iRBD and early-stage PD, aiding in early diagnosis and patient stratification.
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Frequência Cardíaca , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/fisiopatologia , Masculino , Feminino , Idoso , Frequência Cardíaca/fisiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Sistema Nervoso Simpático/fisiopatologia , Teste da Mesa Inclinada , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/diagnósticoRESUMO
Giant pulmonary cyst in extremely low birth weight (ELBW) infants has been described as one of severe pulmonary diseases. Any definitive therapy for refractory cases, where conservative methods of treatments are not effective, has not been established as a standard. Herein, we report an ELBW infant with a giant pulmonary cyst cured by percutaneous drainage without any adverse events. A female infant was born with a birth weight of 327 g. Surfactant was administered on days 1 and 2 of life to treat respiratory distress syndrome. Tracheal intubation was performed and synchronized intermittent mandatory ventilation was promptly initiated following birth. On the course, right giant pulmonary cyst developed on day 9 after birth. Although we started conservative therapy, including right lateral decubitus positioning, high-frequency oscillatory ventilation, and systemic corticosteroid administration, the diameter of the cyst had reached 34 mm, and mediastinal displacement was observed on day 28 after birth when she weighed 393 g. She recovered by percutaneous drainage followed by suction with a pressure of -10 cm H 2 O under mild sedation for 3 days. We believe that percutaneous drainage can be one of the available options for unilateral pulmonary interstitial emphysema.
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BACKGROUND: Pulmonary alveolar proteinosis (PAP) is characterized by an abnormal accumulation of surfactants in the alveoli. Most cases are classified as autoimmune PAP (APAP) because they are associated with autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). However, GM-CSF autoantibody levels are unlikely to correlate with the disease severity or prognosis of APAP. METHODS: We collected clinical records and measured 38 serum cytokine concentrations for consecutive patients with APAP. After exclusion of 21 cytokines because of undetectable levels, 17 cytokine levels were compared between low and high disease severity scores (DSSs). We also compared whole lung lavage (WLL)-free survival with cut-off values defined by receiver operating characteristic (ROC) curves of cytokine levels and WLL administration at 11 months. RESULTS: Nineteen patients with APAP were enrolled in the study. Five were classified as DSS 1 or 2, while the others were classified as DSS 4 or 5. Comparison between DSS 1-2 and 4-5 revealed that the concentrations of IP-10 and GRO increased in the latter groups (p < 0.05). Fifteen patients underwent WLL. Comparison between those who underwent WLL within 11 months and the others showed that IP-10 and TNF-α were tended to be elevated in the former group (p = 0.082 and 0.057, respectively). The cut-off values of IP-10, 308.8 pg/mL and TNF-α, 19.1 pg/mL, defined by the ROC curves, significantly separated WLL-free survivals with log-rank analyses (p = 0.005). CONCLUSIONS: The concentrations of IP-10 and GRO may reflect the DSSs of APAP. A combination of IP-10 and TNF-α levels could be a biomarker to predict WLL-free survival.
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Doenças Autoimunes , Citocinas , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Proteinose Alveolar Pulmonar , Índice de Gravidade de Doença , Humanos , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/diagnóstico , Proteinose Alveolar Pulmonar/sangue , Proteinose Alveolar Pulmonar/terapia , Prognóstico , Citocinas/sangue , Masculino , Feminino , Doenças Autoimunes/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Pessoa de Meia-Idade , Adulto , Autoanticorpos/sangue , Quimiocina CXCL10/sangue , Idoso , Fator de Necrose Tumoral alfa/sangue , Biomarcadores/sangue , Lavagem Broncoalveolar , Adulto JovemRESUMO
A 50-year-old man diagnosed with anti-contactin 1 (CNTN1) antibody-associated chronic inflammatory demyelinating polyneuropathy (CIDP) was referred to our department for the evaluation of proteinuria. A kidney biopsy revealed membranous nephropathy (MN). Immunohistochemistry for CNTN1 revealed positive granular staining along the glomerular basement membrane, confirming anti-CNTN1 antibody-associated MN. Immunofluorescence showed a full-house pattern, and several autoantibodies, such as anti-nuclear antibody, anti-double-strand DNA antibody, and anti-cardiolipin antibody, were detected in the patient's serum. Although limited autoantibodies have been investigated in some of the reported cases, a variety of autoantibodies might be produced in anti-CNTN1 antibody-associated CIDP, accompanied by MN.
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Glomerulonefrite Membranosa , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Masculino , Humanos , Pessoa de Meia-Idade , Glomerulonefrite Membranosa/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Autoanticorpos , Membrana Basal Glomerular , ProteinúriaRESUMO
BACKGROUND: In infants born weighing ≤500 g, little has been studied about the association between neurodevelopmental prognosis and growth. This study aimed to evaluate the association between neurodevelopmental impairment (NDI) and z-scores of physical measurements in infants born weighing ≤500 g. METHODS: A single-center, retrospective cohort study in a level IV neonatal intensive care unit in Japan. Infants born weighing ≤500 g between 2010 and 2019 were eligible. Z-scores in weight, length/height, and head circumference at birth, due date (or discharge), 6 and 18 months of corrected age, and 3 years of age were compared between infants with and without NDI at 3 years of age. Three infants with severe intraventricular hemorrhage or periventricular leukomalacia were excluded from the comparison analyses. NDI was defined as having a developmental quotient of ≤70, cerebral palsy, visual impairment, or hearing impairment. RESULTS: Of 22 eligible infants, the incidence of NDI at 3 years of age was 54.5%. The z-score was significantly smaller in the NDI group (n = 10) than that in the non-NDI group (n = 9) in head circumference at birth (median, -1.94 vs. -0.75; Z = 0.54; p = 0.020), and in height at 18 months of corrected age (median, -2.84 vs. -1.79; Z = 0.58; p = 0.013) and 3 years of age (median, -2.02 vs. -1.21; Z = 0.47; p = 0.046). CONCLUSIONS: NDI at 3 years of age was associated with a small head circumference z-score at birth, height at 18 months of corrected age, and height at 3 years of age in infants born weighing ≤500 g.
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Paralisia Cerebral , Doenças do Prematuro , Recém-Nascido , Lactente , Humanos , Pré-Escolar , Peso ao Nascer , Estudos Retrospectivos , PrognósticoRESUMO
Ubiquitin-like 3 (UBL3) is a membrane-anchored protein that plays a crucial role in sorting proteins into small extracellular vesicles. Aggregations of alpha-synuclein (α-syn) are associated with the pathology of neurodegenerative diseases such as Parkinson's disease. Recently, the interaction between UBL3 and α-syn was discovered, with potential implications in clearing excess α-syn from neurons and its role in disease spread. However, the regulator that can mediate the interaction between UBL3 and α-syn remains unclear. In this study, using the split gaussian luciferase complementation assay and RNA interference technology, we identified that QSOX2, HTATIP2, UBE3C, MGST3, NSF, HECTD1, SAE1, and ATG3 were involved in downregulating the interaction between UBL3 and α-syn. Notably, silencing MGST3 had the most significant impact. Immunocytochemistry staining confirmed the impact of MGST3 silencing on the co-localization of UBL3 and α-syn in cells. MGST3 is a part of the antioxidant system, and silencing MGST3 is believed to contribute to oxidative stress. We induced oxidative stress with hydrogen peroxide, observing its effect on the UBL3-α-syn interaction, and showing that 800 µM of H2O2 downregulated this interaction. In conclusion, silencing MGST3 downregulates the interaction between UBL3 and α-syn.
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Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn) has been widely studied for its involvement in α-synucleinopathies. However, it is still unknown whether UBL3 interacts with α-syn, and is influenced by drugs or compounds. In this study, we investigated the interaction between UBL3 and α-syn, and any ensuing possible functional and pathological implications. We found that UBL3 can interact with α-syn by the Gaussia princeps based split luciferase complementation assay in cells and immunoprecipitation, while cysteine residues at its C-terminal, which are considered important as PTM factors for UBL3, were not essential for the interaction. The interaction was upregulated by 1-methyl-4-phenylpyridinium exposure. In drug screen results, the interaction was significantly downregulated by the treatment of osimertinib. These results suggest that UBL3 interacts with α-syn in cells and is significantly downregulated by epidermal growth factor receptor (EGFR) pathway inhibitor osimertinib. Therefore, the UBL3 pathway may be a new therapeutic target for α-synucleinopathies in the future.
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AIM: Cytomegalovirus (CMV) is a virus that can cause congenital and postnatal infections. Postnatal CMV is mainly transmitted via breast milk and blood transfusions. Frozen-thawed breast milk is used to prevent postnatal CMV infection. A prospective cohort study was conducted to determine the infection rate, risk, and clinical findings of postnatal CMV infection. METHODS: This prospective cohort study included infants born at 32 weeks or earlier than the gestational age (GA). Participants were prospectively screened for infection in the urine by performing urine CMV DNA tests twice, that is, once within the first 3 weeks of life and again after 35 weeks postmenstrual age (PMA). Postnatal CMV infection was defined as a case of CMV negative tests within 3 weeks of birth and CMV positive tests after 35 weeks PMA. CMV-negative blood products were used for transfusions in all cases. RESULTS: A total of 139 patients were subjected to two urine CMV DNA tests. The prevalence of postnatal CMV infection was 5.0%. One patient died of sepsis-like syndrome. The risk factors of postnatal CMV infection were younger GA and older age of the mother. The characteristic clinical findings of postnatal CMV infection were pneumonia. CONCLUSIONS: Frozen-thawed breast milk feeding is not fully effective in preventing postnatal CMV infection. The prevention of postnatal CMV infection is important to further improve the survival rate of preterm infants. Development of guidelines on breast milk feeding for the prevention of postnatal CMV infection is necessary in Japan.
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Infecções por Citomegalovirus , Recém-Nascido Prematuro , Lactente , Feminino , Recém-Nascido , Humanos , Citomegalovirus , Estudos Prospectivos , Infecções por Citomegalovirus/epidemiologia , Aleitamento Materno , Leite Humano , Transmissão Vertical de Doenças Infecciosas/prevenção & controleRESUMO
BACKGROUND: The neurofilament light chain (NfL) is receiving increased attention as a biomarker of neurological diseases, as NfL concentration elevated in the blood and cerebrospinal fluid after neuronal damage. However, few studies have addressed NfL in epilepsy. We aimed to investigate the alteration of serum NfL in adult patients with epilepsy, and the association between this biomarker and cognitive impairment. METHODS: A total of 38 consecutive patients with epilepsy and 24 controls underwent cross-sectional measurement of serum NfL levels and cognitive testing using the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), the Frontal Assessment Battery (FAB), the Trail-Making Test, and the Stroop Color-Word Test. Statistical analysis was performed with Student's t-test to compare serum NfL levels between the epilepsy group and the control group, and with Spearman's correlation and age-corrected partial correlation analyses to evaluate the association between serum NfL level and cognitive impairment in epilepst patients. RESULTS: There was no difference in serum NfL levels between the epilepsy and control groups (epilepsy [mean ± SD]: 17.3 ± 13.9 pg/mL; control: 17.7 ± 11.5 pg/mL; p = .92); however, the MoCA-J scores were lower in the epilepsy group (26.6 ± 3.1 vs. 28.1 ± 1.6; p = .03). The age-corrected partial correlation analysis showed a correlation between serum NfL level and cognitive test scores in the epilepsy group (MMSE: rs = -.63, p < .01; MoCA-J: rs = -.54, p < .01; FAB: rs = -.68, p < .01), whereas serum NfL levels were correlated exclusively with MMSE scores in the control group (rs = .44, p = .04). SIGNIFICANCE: In adult epilepsy patients, the serum NfL level was not significantly elevated, but was correlated with cognitive test scores. Our findings suggest that serum NfL concentration could be an indicator of cognitive function in epilepsy patients.
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Disfunção Cognitiva , Epilepsia , Adulto , Humanos , Filamentos Intermediários , Estudos Transversais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Epilepsia/complicações , BiomarcadoresRESUMO
Although the outcomes of active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) are generally excellent, some patients undergo conversion surgery for various reasons, including disease progression. We studied the outcomes of PTMC patients who underwent AS, who underwent conversion surgery after AS, and who underwent immediate surgery. Between 2005 and 2019, 4,635 patients were diagnosed with low-risk cT1aN0M0 PTMC at Kuma Hospital: 2,896 opted for AS (AS group) and 1,739 underwent immediate surgery (Surgery group). In the AS group, 242 patients underwent conversion surgery (Conversion group): 72 owing to disease progression (Conversion-prog group) and 170 for other reasons (Conversion-non-prog group). Of the 1,739 patients in the Surgery group, 1,625 had no high-risk features (Surgery-low-risk group). Locoregional recurrence (LRR) occurred in 9, 1, 1, and 0 patient in the Surgery-low-risk group, the Conversion-prog group, the AS group, and the Conversion-non-prog group, respectively. The LRR rate of the AS group was significantly lower than that of the Surgery-low-risk group (0.1% vs. 0.7% at 10 years, p = 0.006). Additionally, the LRR rate of the Conversion group (0.6% at 10 years, p = 0.741) and that of the Conversion-prog group (3.3% at 10 years, p = 0.103) did not significantly differ from the LRR of the Surgery-low-risk group. As the postoperative prognosis of patients with progressive PTMC who underwent conversion surgery did not significantly differ from that of patients who underwent immediate surgery, we think that AS may have resulted in efficient identification of the small proportion of patients with progressive PTMC that require surgical treatment.
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Neoplasias da Glândula Tireoide , Tireoidectomia , Humanos , Conduta Expectante , Recidiva Local de Neoplasia/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Fatores de Risco , Progressão da Doença , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVES: To assess the clinical and electrophysiologic features of female carriers and early-stage male patients with spinal and bulbar muscular atrophy (SBMA) to elucidate the early pathophysiologic changes of the disease. METHODS: Female carriers, early-stage male patients with SBMA, and age-matched male and female healthy controls were recruited. The results of motor functional scales, motor unit number estimation, dual-energy X-ray absorptiometry, and peripheral blood tests were compared between female carriers and healthy female controls and between patients with SBMA and healthy male controls. EMG was also investigated in female carriers. RESULTS: We enrolled 21 female carriers and 11 early-stage male patients. Seventeen female and 14 male age-matched healthy controls were also enrolled. Female carriers experienced early-stage symptoms such as muscle cramps more frequently than healthy female controls. Decreased motor unit number estimation and EMG abnormalities including high amplitude or polyphasic potentials were observed in female carriers together with mild muscle weakness in neck flexion and a slow walking speed. Changes of muscle-related markers, including serum creatine kinase and dual-energy X-ray absorptiometry, were clearly detected in early-stage male patients with SBMA, but not in female carriers. DISCUSSION: The present study revealed that female carriers of SBMA manifest mild muscular weakness associated with changes in neurogenic biomarkers. Conversely, male patients showed neurogenic and myopathic changes even at the early stage. These results suggest a testosterone-independent neurodegenerative pathophysiology in female SBMA carriers.
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Atrofia Bulboespinal Ligada ao X , Atrofia Muscular Espinal , Humanos , Masculino , Feminino , Atrofia Muscular Espinal/diagnóstico por imagem , HeterozigotoRESUMO
BACKGROUND: Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and is gradually spreading worldwide. We assessed the effect of thyroid-stimulating hormone (TSH) levels on PTMC enlargement in patients on AS. METHODS: We enrolled 2705 patients with cytologically diagnosed PTMC who had undergone AS between January 2005 and July 2019. Patients with Graves disease were excluded. The median AS period was 5.5 years (range 1.0-15.7 years). Tumor enlargement was defined as a size increase ≥3 mm. Chi-square test, Kaplan-Meier method, log-rank test, Cox proportional hazard, and logistic regression were used to compare variables. RESULTS: Ninety-two patients (3.4%) experienced tumor enlargement; the 5-, 10-, and 15-year enlargement rates were 3.0%, 5.5%, and 6.2%, respectively. Young age (<40 years, p < 0.001), large tumor size (≥9 mm, p = 0.017), and high detailed TSH score (≥3, higher than the lower normal limit, p = 0.011) were significant factors relating to tumor enlargement in the multivariate analysis. In a subset of patients aged <40 years, a low detailed TSH score (<3) was an independent factor against tumor enlargement (p = 0.039). Only 22 patients (0.8%) experienced novel lymph node metastasis; the 5-, 10-, and 15-year node metastasis rates were very low, at 0.9%, 1.1%, and 1.1%, respectively. CONCLUSIONS: Young patients with PTMC are more likely to experience tumor growth. Mild TSH suppression to achieve a low normal range may prevent carcinoma enlargement; however, prospective studies are needed to draw more reliable conclusions.
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Neoplasias da Glândula Tireoide , Tireotropina , Humanos , Adulto , Conduta Expectante , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Fatores de Risco , Estudos RetrospectivosRESUMO
Background: Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and has gradually spread worldwide. We previously demonstrated that AS is associated with a much lower incidence of unfavorable events than immediate surgery (IS). However, conversion surgery (CS) raises concerns about increased surgical complications due to advanced disease. In this study, we conducted a comparative analysis of unfavorable events after IS and CS. Methods: Between 2005 and 2019, 4635 patients clinically diagnosed with low-risk PTMC at Kuma Hospital were enrolled. Of these, 2896 underwent AS (AS group), and the remaining 1739 underwent IS (IS group). To date, 242 patients (0.8%) in the AS group have undergone CS for various reasons (CS group). Results: The incidence of unfavorable events, such as levothyroxine administration after surgery, postoperative hematoma, transient/persistent hypoparathyroidism, and transient/persistent vocal cord paralysis, did not differ between the CS and IS groups. None of the patients in the CS group had permanent vocal cord paralysis; however, this occurred in 15 patients (0.9%) in the IS group and was caused by accidental injury in 4 patients and carcinoma invasion in 11 patients. The incidence of surgery, levothyroxine administration, postoperative hematoma, transient/permanent hypoparathyroidism, and vocal cord paralysis was significantly higher (p < 0.001) in the IS group than in the AS group. There were no differences in the incidence of lymph node recurrence and overall mortality between the AS and IS groups. None of the patients in the AS and IS groups showed distant metastasis or died from thyroid carcinoma. Conclusions: There were no differences in the incidence of unfavorable events between the CS group and the IS group. Although none of the CS and AS groups had permanent vocal cord paralysis, accidental injury of the recurrent laryngeal nerve occurred in four patients (0.2%) in the IS group. The IS group had a significantly higher incidence of unfavorable events than the AS group. The prognoses of patients in both the AS and IS groups were excellent. Therefore, we recommend AS as the first-line management for low-risk PTMC.
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Lesões Acidentais , Hipoparatireoidismo , Neoplasias da Glândula Tireoide , Paralisia das Pregas Vocais , Humanos , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/complicações , Paralisia das Pregas Vocais/etiologia , Conduta Expectante , Lesões Acidentais/complicações , Lesões Acidentais/cirurgia , Tiroxina , Neoplasias da Glândula Tireoide/patologia , Progressão da Doença , Hematoma , Tireoidectomia/efeitos adversos , Estudos RetrospectivosRESUMO
Epithelioid hemangioendothelioma (EHE) affects many organs, particularly lung and liver, and typically presents as multiple lesions. Treatment for EHE is not yet standardized, but surgery is appropriate when lesions are resectable. In our patient, radiography revealed multiple bilateral pulmonary nodules, and CT showed several liver tumors. The liver masses and those in the right lung were removed during the initial surgery; pathology of hepatic specimens confirmed the diagnosis of EHE. During the second operation, the left lung nodules were excised, and all were EHEs. Surgical removal of multiorgan multinodular EHE is a viable treatment option, especially for young patients.
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Background and Objectives: We investigated the genetic basis and brain metabolism and blood flow of a Japanese family with spinocerebellar degeneration (SCD), with multiple affected members for 3 generations. Methods: After excluding DNA repeat expansion (RE) of common SCD genes by fragment analysis, we performed whole-exome sequencing (WES) and whole-genome sequencing (WGS). Homozygosity mapping was performed using these data. REs were investigated with WGS data using ExpansionHunter Denovo and Expansion Hunter. Results: WES and WGS were unable to identify likely pathogenic variants, and homozygosity mapping failed to narrow down the locus. However, ExpansionHunter Denovo detected REs in intron 2 of the RFC1 gene and led us to the diagnosis of RFC1-related disorders. Subsequent repeat-primed PCR and Southern blot hybridization analyses revealed that 3 of 6 patients and 1 suspected individual had expansions of AAGGG ((AAGGG)exp) and (ACAGG)exp repeats in a compound heterozygous state and 3 had a homozygous (ACAGG)exp. The patients showed a variety of clinical features, including adult-onset ataxia, sensorimotor neuropathy, head tremor, parkinsonism, dystonia, and cognitive impairment. A comparison of previous reports with those of the family in study suggested that motor neuropathy could be a feature of compound heterozygous patients and biallelic (ACAGG)exp patients. Cognitive function tests showed cognitive impairment with a predominance of frontal lobe dysfunction. Examination of MRI, SPECT, and 18F-fluorodeoxyglucose-PET showed clear cortical damage with frontal lobe predominance in 1 case, but no cerebral damage was evident in the other 2 cases. Discussion: Our report shows the usefulness of WGS and RE detection tools for SCD of unknown cause. The studied family with RFC1-related disorders included patients with (ACAGG)exp and (AAGGG)exp in a compound heterozygous state and was characterized by motor neuropathy. Based on the results of cognitive function tests and imaging studies, 1 patient presented with cognitive impairment due to frontal lobe metabolic changes, but there were also patients who presented with cognitive impairment without apparent cerebral metabolic or blood flow, suggesting that other factors are also associated with cognitive impairment.
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OBJECTIVE: Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. METHODS: In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS). RESULTS: In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p <0.001); the change in the distal latencies between room temperature and cold exposure conditions correlated with the change in grip power. In the MEXPRESS trial, 20 participants took mexiletine or lactose, three times a day for 4 weeks with a crossover design. There was no difference in distal latencies at room temperature and under cold exposure between mexiletine and placebo groups as the primary endpoint. However, tongue pressure and 10-sec grip and release test under cold exposure were improved in the mexiletine group. There were no serious adverse events throughout the study period. INTERPRETATION: Cold paresis is common and associated with prolongation of distal latency in SBMA. The results of the phase II clinical trial revealed that mexiletine showed short-term safety, but it did not restore cold exposure-induced prolongation of distal latency.
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Atrofia Bulboespinal Ligada ao X , Mexiletina , Humanos , Mexiletina/farmacologia , Mexiletina/uso terapêutico , Atrofia Bulboespinal Ligada ao X/tratamento farmacológico , Atrofia Bulboespinal Ligada ao X/complicações , Pressão , Língua , Debilidade Muscular , Paresia/complicaçõesRESUMO
INTRODUCTION: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy. METHODS: This cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients' demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG. RESULTS: Ninety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score. CONCLUSION: Both DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores.
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Doença de Parkinson , Transtorno do Comportamento do Sono REM , Sinucleinopatias , Humanos , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/complicações , Proteínas da Membrana Plasmática de Transporte de Dopamina , 3-Iodobenzilguanidina , Japão , alfa-Sinucleína , Estudos Transversais , Estudos Prospectivos , Doença de Parkinson/complicações , BiomarcadoresRESUMO
Several previous reports have shown interstitial lung disease (ILD) to be a predictor of poor prognosis in patients with chronic pulmonary aspergillosis (CPA). However, there is a lack of clarity regarding patient background and the prognostic factors in CPA associated with ILD (CPA-ILD). Therefore, we assessed these points to obtain valuable information for clinical practice. We retrospectively surveyed and collected data from 459 patients who had serum examination for anti-Aspergillus antibody. Of these patients, we extracted and investigated CPA-ILD patients. We ultimately analyzed 32 CPA-ILD patients. Patient background factors more frequently showed the patients to be older (mean: 74.9 years), male (75.0%), and to have a smoking history (71.9%). Median survival time from the diagnosis of ILD was 76.0 months, whereas that from the diagnosis of CPA-ILD was 25.5 months. No significant differences in survival were found in regard to each ILD pattern and the presence of idiopathic pulmonary fibrosis. A higher level of C-reactive protein was a significant predictor of mortality by Cox regression analysis. CPA complicating ILD is associated with poor prognosis. ILD patients with older age, male sex, and smoking history should be aware of the potential for the development of CPA in ILD. If such patients have elevated markers of inflammation, prompt induction of antifungal treatment may improve their prognosis. Clinicians should be aware of which complications of CPA may lead to a poor prognosis for any ILD not just those limited to idiopathic pulmonary fibrosis or usual interstitial pneumonia pattern.