Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 117
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-33176129

RESUMO

PURPOSE: Upper airway obstruction (UAO) and oxygen desaturation are risk factors for major complications of intravenous sedation (IVS) in pediatric dental patients. This study aimed to investigate the use of a nasal high-flow (NHF) system for the prevention of UAO and oxygen desaturation in pediatric dental patients under IVS. METHODS: The authors implemented a prospective randomized design. Thirty pediatric patients (aged 3 to 12), scheduled for dental treatment under IVS, were enrolled in this study. The subjects were randomly assigned to 1 of 2 groups: patients who received oxygen at 5 L/minute through a nasal cannula (NC group) and patients who received oxygen at 2 kg/L/minute, up to a maximum of 30 L/minute, through the NHF system (NHF group). The predictor variable was flow rate. The primary outcome variable was the need for intervention during treatment, and the secondary outcome variable was the lowest peripheral capillary oxygen saturation values during the procedure. Additional study variables measured included patient age, gender, weight, height, and surgical duration. The Mann-Whitney U test and Fisher exact test were used for statistical analysis, with P < .05 considered as significant. RESULTS: Both the NC (n = 15; mean age, 6.2 ± 2.3) and NHF (n = 15; mean age, 5.9 ± 2.5) groups had a male:female ratio of 2:1. The use of the NHF system significantly improved the lowest peripheral capillary oxygen saturation values during treatment (P < .05). Jaw lifting, to relieve UAO and facilitate spontaneous breathing, was required in both the NC (n = 10) and NHF (n = 3) groups (P < .05). The need for interventions during treatment was significantly lower in the NHF group (P < .05). CONCLUSIONS: The results of this study suggest that the use of the NHF system can prevent UAO and improve the respiratory condition of pediatric dental patients under IVS.

2.
Cell Death Dis ; 11(10): 909, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097688

RESUMO

Cytoplasmic inclusion of TAR DNA-binding protein 43 (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and a subtype of frontotemporal lobar degeneration (FTLD). Recent studies have suggested that the formation of cytoplasmic TDP-43 aggregates is dependent on a liquid-liquid phase separation (LLPS) mechanism. However, it is unclear whether TDP-43 pathology is induced through a single intracellular mechanism such as LLPS. To identify intracellular mechanisms responsible for TDP-43 aggregation, we established a TDP-43 aggregation screening system using a cultured neuronal cell line stably expressing EGFP-fused TDP-43 and a mammalian expression library of the inherited ALS/FTLD causative genes, and performed a screening. We found that microtubule-related proteins (MRPs) and RNA-binding proteins (RBPs) co-aggregated with TDP-43. MRPs and RBPs sequestered TDP-43 into the cytoplasmic aggregates through distinct mechanisms, such as microtubules and LLPS, respectively. The MRPs-induced TDP-43 aggregates were co-localized with aggresomal markers and dependent on histone deacetylase 6 (HDAC6), suggesting that aggresome formation induced the co-aggregation. However, the MRPs-induced aggregates were not affected by 1,6-hexanediol, an LLPS inhibitor. On the other hand, the RBPs-induced TDP-43 aggregates were sensitive to 1,6-hexanediol, but not dependent on microtubules or HDAC6. In sporadic ALS patients, approximately half of skein-like TDP-43 inclusions were co-localized with HDAC6, but round and granular type inclusion were not. Moreover, HDAC6-positive and HDAC6-negative inclusions were found in the same ALS patient, suggesting that the two distinct pathways are both involved in TDP-43 pathology. Our findings suggest that at least two distinct pathways (i.e., aggresome formation and LLPS) are involved in inducing the TDP-43 pathologies.

3.
Am J Physiol Renal Physiol ; 319(4): F603-F611, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830538

RESUMO

The acyl-CoA synthetase medium-chain family member 2 (Acsm2) gene was first identified and cloned by our group as a kidney-specific "KS" gene. However, its expression pattern and function remain to be clarified. In the present study, we found that the Acsm2 gene was expressed specifically and at a high level in normal adult kidneys. Expression of Acsm2 in kidneys followed a maturational pattern: it was low in newborn mice and increased with kidney development and maturation. In situ hybridization and immunohistochemistry revealed that Acsm2 was expressed specifically in proximal tubular cells of adult kidneys. Data from the Encyclopedia of DNA Elements database revealed that the Acsm2 gene locus in the mouse has specific histone modifications related to the active transcription of the gene exclusively in kidney cells. Following acute kidney injury, partial unilateral ureteral obstruction, and chronic kidney diseases, expression of Acsm2 in the proximal tubules was significantly decreased. In human samples, the expression pattern of ACSM2A, a homolog of mouse Acsm2, was similar to that in mice, and its expression decreased with several types of renal injuries. These results indicate that the expression of Acsm2 parallels the structural and functional maturation of proximal tubular cells. Downregulation of its expression in several models of kidney disease suggests that Acms2 may serve as a novel marker of proximal tubular injury and/or dysfunction.


Assuntos
Coenzima A Ligases/metabolismo , Células Epiteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Animais , Coenzima A Ligases/genética , Modelos Animais de Doenças , Células Epiteliais/patologia , Fibrose , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Renina/genética , Renina/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
4.
EBioMedicine ; 59: 102980, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32862101

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits. METHODS: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model. FINDING: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds. INTERPRETATION: Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19). FUNDING: Project funding was supported by the ALS Association grant (WA1128) and Fostering Joint International Research (19KK0214) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Compostos Organosselênicos/uso terapêutico , Superóxido Dismutase-1/metabolismo , Esclerose Amiotrófica Lateral/mortalidade , Esclerose Amiotrófica Lateral/patologia , Animais , Azóis/química , Azóis/metabolismo , Azóis/uso terapêutico , Betacoronavirus/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Dimerização , Modelos Animais de Doenças , Estabilidade Enzimática , Camundongos , Camundongos Transgênicos , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Compostos Organosselênicos/química , Compostos Organosselênicos/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Superóxido Dismutase-1/genética , Taxa de Sobrevida , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/metabolismo
5.
Anesth Prog ; 67(2): 79-85, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32633772

RESUMO

This study investigated the effectiveness of subglottic irrigation (SI) with 100 mL of saline on reducing bacterial contamination in the subglottic space during oral surgery procedures without the use of throat packs. Subglottic lavage and irrigation were performed through the suction lumen located on specialized endotracheal tubes (ETTs) with capabilities of permitting evacuation from the subglottic space. Fifty-three patients who were scheduled for oral surgery procedures under general anesthesia while intubated with specialized ETTs at Kyushu Dental University Hospital were enrolled in this study. Subglottic irrigation was performed, and the sample fluid was collected through the ETT suction lumen for smear and culture bacterial examinations after 3 points in time: immediately after intubation, after completing the surgical procedure, and again after SI. Oral surgery without a throat pack significantly increased bacterial contamination in the subglottic lavage (p < .001), and SI decreased bacterial contamination (p < .001) similarly to levels found after tracheal intubation. Subglottic irrigation with 100 mL of saline was effective in reducing bacterial load in the subglottic space to levels similarly noted immediately after intubation for patients undergoing intraoral surgical procedures without the use of a throat pack.

6.
Artigo em Japonês | MEDLINE | ID: mdl-32641595

RESUMO

OBJECTIVES: In Japan, the population is aging and there is a declining birth rate. It is an important occupational health issue to support the balance between illness treatment (including nursing care, childcare, etc.) and work. Many patients require mental and financial support to help them with their work-treatment balance. In 2016, the Ministry of Health, Labor and Welfare provided guidelines for supporting employee's work-treatment balance, and in 2018, "Consulting Fee" was approved as an insured medical treatment when clinic doctors supported their patients for continuing to work. The request for the consulting fee requires that the clinician and the occupational physician exchange information on the support necessary for the patient to continue working. Generally, occupational physicians obtain medical information from clinicians to give advice on a worker's employment considerations. However, we do not know what kind of workplace information clinicians hope to know when treating their patients. Therefore, we conducted this survey to clarify how occupational physicians could provide useful information to clinicians. METHODS: We asked approximately 1,500 occupational physicians from the Occupational Health Subcommittee of the Japan Society for Occupational Health to provide us with a letter sent to their clinician to assist workers. From the collected letters, the structural parts of the letters (titles, greetings, acknowledgments, etc.) were removed. We defined a section as a contextual unit that does not impair the meaning. The prepared sections underwent qualitative inductive analysis using the content analysis method of "Berelson, B." RESULTS: A total of 103 cases and 178 documents from 42 people were included in the analysis. Extracting descriptions that could be interpreted as providing information, including descriptions related to treatment, employment, and living environment, and opinions and suggestions from occupational physicians resulted in 596 sections. As a result of the qualitative and inductive classification, the information was classified into three large categories that consisted of information provision, opinions of occupational physicians, and information handling, five middle and eighteen small classifications. In addition, some good practices that were considered significant to clinicians were illustrated. CONCLUSIONS: We analyzed and categorized the information present in the letters sent by occupational physicians to clinicians. The letter does not need to contain all the information in the category table. However, it is important that it should have the necessary and sufficient information considering the case in question. We believe that this category table will aid occupational physicians in writing letters to clinicians.

7.
Hum Reprod ; 35(5): 1019-1028, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32383453

RESUMO

STUDY QUESTION: What technique can be used to successfully cryopreserve three or fewer ejaculated spermatozoa from cryptozoospermic men and is the physical and cognitive development of children born after this technique normal? SUMMARY ANSWER: The modified cryopreservation method for three or fewer human spermatozoa from cryptozoospermic men showed a recovery rate above 95% and a survival rate just under 90%, and the physical and cognitive abilities of the children born after ICSI were comparable to those born after natural conception. WHAT IS KNOWN ALREADY: Clinical outcomes of ICSI using cryptozoospermic men's ejaculated spermatozoa are considered to be inferior to that using testicular spermatozoa from microsurgical testicular sperm extraction (Micro-TESE), possibly because the DNA fragmentation rate is higher in ejaculated spermatozoa than in testicular spermatozoa from Micro-TESE. STUDY DESIGN, SIZE, DURATION: Evaluation of the efficiency of cryopreservation of three or fewer spermatozoa was conducted retrospectively at St. Mother Clinic. The physical and cognitive development of children born after this method was studied between 2011 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included 28 cryptozoospermic men who had three or fewer morphologically normal and motile spermatozoa in their ejaculate after centrifugation and who preferred using cryopreserved spermatozoa to Micro-TESE. Control subjects were 31 cryptozoospermic patients using fresh spermatozoa from their ejaculates and 20 non-obstructive azoospermic patients with fewer than 10 spermatozoa obtained by TESE and vitrified. Clinical outcomes among three groups, vitrified spermatozoa from the ejaculate, fresh spermatozoa from the ejaculate and vitrified spermatozoa from the testis, were statistically analysed. For the 7-year follow up study of the 14 children born after ICSI using the ejaculated vitrified spermatozoa, the Japanese government-issued Boshi Kenko Techo (Mother-Child Handbook) and Kinder Infant Development Scale (KIDS scale) were used to determine whether their physical and cognitive development was comparable to that of naturally conceived children. MAIN RESULTS AND THE ROLE OF CHANCE: Recovery and survival rates were 97.8% (510/521) and 87.1% (444/510) for vitrified spermatozoa from the ejaculate and 92.7% (152/164) and 60.5% (92/152) for vitrified spermatozoa from the testis. Clinical pregnancies (%), miscarriages (%) and live birth rates (%), respectively, among the three groups were as follows: vitrified spermatozoa from the ejaculate: 15(25.0), 2(13.3), 13(21.7); fresh spermatozoa from the ejaculate: 26(24.3), 5(19.2), 20(18.7); and vitrified spermatozoa from the testis: 3(16.7), 0(0.0), 3(16.7). Among the groups, there were no statistically significant differences except for the sperm survival rate and the oocyte fertilisation rate, which were lower for vitrified spermatozoa from the testis compared with vitrified spermatozoa from the ejaculate. The 7-year follow-up study showed that the physical and cognitive development of 14 children born after ICSI using vitrified ejaculated spermatozoa from the ejaculate was comparable to that of naturally conceived children. LIMITATIONS, REASONS FOR CAUTIONS: The maximum number of spermatozoa to which this method can be applied successfully is about 10. When the number of aspirated spermatozoa is over 10, some of them change direction after colliding with each other inside the aspiration pipette and reach the mineral oil, and once this happens, they cannot be expelled out of the pipette. Even though we did not find evidence of DNA fragmentation, further studies with larger participant numbers and longer time periods are necessary. WIDER IMPLICATIONS OF THE FINDINGS: This technique is very useful for the cryopreservation of very small numbers of testicular spermatozoa (fewer than 10) in order to avoid or reduce Micro-TESE interventions. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received to undertake this study. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

8.
Anat Sci Int ; 95(3): 425-428, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32077000

RESUMO

Although the thoracic duct (TD) requires special attention during thoracic surgery, to our knowledge, its detailed course in the situs inversus totalis (SIT) case has not been reported. We encountered an 86-year-old Japanese female cadaver with SIT during a student anatomical practice and examine the TD. The TD originated from the cisterna chyli at the level of the 2nd lumbar vertebra, ascended along with the left side of aorta and then passed behind the aortic arch on the right side of the esophagus. The TD turned right at the first thoracic vertebra and finally emptied into the basal portion of the right external jugular vein without branching. The present running pathway of the TD was approximately in the inverted position of the normal, but its connection site to the vein and manner was very rare and has not been reported to date. Therefore, this junctional anomaly may occur during the developmental period in SIT. Further anatomical and embryological studies are required, but this report provides useful morphogenetic information of the TD and lymphovenous junction in SIT.


Assuntos
Cadáver , Situs Inversus/patologia , Ducto Torácico/anormalidades , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos
9.
Heliyon ; 6(1): e03301, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32051870

RESUMO

N-Acetyl-p-aminophenol (APAP/acetaminophen) is a widely used analgesic/antipyretic with weaker inhibitory effects on cyclooxygenase compared to those of non-steroidal anti-inflammatory drugs. The effect of APAP is mediated by its metabolites, N-arachidonoyl-phenolamine and N-acetyl-p-benzoquinone imine, which activate transient receptor potential (TRP) channels, including TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) or cannabinoid receptor type 1. However, the exact molecular mechanism underlying the cellular actions of APAP remains unclear. Recently, we observed that APAP promotes cell migration through TRPV4; in this study, we examined the effect of APAP on Ca2+-channel activity of TRPV4. In the rat cell line PC12 expressing TRPV4, GSK1016790A (GSK), a TRPV4 agonist, stimulated an increase in [Ca2+]i; these effects were abrogated by HC-067047 treatment. This GSK-induced Ca2+ entry through TRPV4 was inhibited by APAP in a dose-dependent manner, whereas APAP alone did not affect [Ca2+]i. The specificity of the effect of APAP on TRPV4 was further confirmed using HeLa cells, which lack endogenous TRPV4 but stably express exogenous TRPV4 (HeLa-mTRPV4). GSK-induced [Ca2+]i elevation was only observed in HeLa-mTRPV4 cells compared to that in the control HeLa cells, indicating the specific action of GSK on TRPV4. APAP dose-dependently suppressed this GSK-induced Ca2+ entry in HeLa-mTRPV4. However, it is unlikely that the metabolites of APAP were involved in these effects as the reaction in this study was rapid. The results suggest that APAP suppresses the newly identified target TRPV4 without being metabolized and exerts antipyretic/analgesic and/or other effects on TRPV4-related phenomena in the body. The effect of APAP on TRPV4 was opposite to that on TRPV1 or TRPA1, as the latter is activated by APAP.

10.
Mol Genet Genomic Med ; 8(3): e1145, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953910

RESUMO

BACKGROUND: TOP2B encodes type II topoisomerase beta, which controls topological changes during DNA transcription. TOP2B is expressed in the developing nervous system and is involved in brain development and neural differentiation. Recently, a de novo missense TOP2B variant (c.187C>T) has been identified in an individual with neurodevelopmental disorder (NDD). However, the association between TOP2B variants and NDDs remains uncertain. METHODS: Trio-based whole-exome sequencing was performed on a 7-year-old girl, presenting muscle hypotonia, stereotypic hand movements, epilepsy, global developmental delay, and autism spectrum disorder. Brain magnetic resonance images were normal. She was unable to walk independently and spoke no meaningful words. RESULTS: We found a de novo variant in TOP2B (NM_001330700.1:c.187C>T, p.(His63Tyr)), which is identical to the previous case. The clinical features of the two individuals with the c.187C>T variant overlapped. CONCLUSION: Our study supports the finding that TOP2B variants may cause NDDs.

11.
Brain Dev ; 42(4): 363-368, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31932101

RESUMO

BACKGROUND: Biallelic variants in POLR3A encoding the largest subunit of RNA polymerase III cause POLR3-related (or 4H) leukodystrophy characterized by neurologic dysfunction, abnormal dentition, endocrine abnormalities and ocular abnormality. Recently, whole-exome sequencing enabled the discovery of POLR3A variants in cases lacking diffuse hypomyelination, the principal MRI phenotype of POLR3-related leukodystrophy. Homozygous c.1771-6C > G variants in POLR3A were recently suggested to cause striatal and red nucleus involvement without white matter involvement. CASE REPORT: Here, we report three cases in two families with biallelic POLR3A variants. We identified two sets of compound heterozygous variants in POLR3A, c.1771-6C > G and c.791C > T, p.(Pro264Leu) for family 1 and c.1771-6C > G and c.2671C > T, p.(Arg891*) for family 2. Both families had the c.1771-6C > G variant, which led to aberrant mRNA splicing. Neuropsychiatric regression and severe intellectual disability were identified in three patients. Two cases showed dystonia and oligodontia. Notably, characteristic bilateral symmetric atrophy and abnormal signal of the striatum without diffuse white matter signal change were observed in brain MRI of all three individuals. CONCLUSIONS: Striatum abnormalities may be another distinctive MRI finding associated with POLR3A variants, especially in cases including c.1771-6C > G variants and our cases can expand the phenotypic spectrum of POLR3A-related disorders.


Assuntos
Corpo Estriado/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , RNA Polimerase III/genética , Criança , Corpo Estriado/diagnóstico por imagem , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Humanos , Masculino , Linhagem
12.
Mol Brain ; 13(1): 8, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959210

RESUMO

Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43), a DNA/RNA binding protein, is a pathological signature of amyotrophic lateral sclerosis (ALS). Missense mutations in the TARDBP gene are also found in inherited and sporadic ALS, indicating that dysfunction in TDP-43 is causative for ALS. To model TDP-43-linked ALS in rodents, we generated TDP-43 knock-in mice with inherited ALS patient-derived TDP-43M337V mutation. Homozygous TDP-43M337V mice developed normally without exhibiting detectable motor dysfunction and neurodegeneration. However, splicing of mRNAs regulated by TDP-43 was deregulated in the spinal cords of TDP-43M337V mice. Together with the recently reported TDP-43 knock-in mice with ALS-linked mutations, our finding indicates that ALS patient-derived mutations in the TARDBP gene at a carboxyl-terminal domain of TDP-43 may cause a gain of splicing function by TDP-43, however, were insufficient to induce robust neurodegeneration in mice.

13.
Arthrosc Tech ; 8(7): e755-e762, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31485403

RESUMO

Anterior cruciate ligament reconstruction using an all-inside method to reduce bone damage caused by drill hole preparation and enhance the stability of the reconstructed ligament in the drill hole has been reported in recent years. We made a custom-designed drill guide pin and reamer, which are assembled in the joint, to create drill holes in the femur and tibia. For the transtibial method, our femoral drill hole-positioning technique, which uses a laser, is extremely convenient for accurate positioning of the drill holes. Therefore, a combination of these methods facilitates implementation of the all-inside double-bundle anterior cruciate ligament reconstruction technique.

14.
Acta Neuropathol Commun ; 7(1): 118, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345270

RESUMO

Intracellular mislocalization of TAR DNA-binding protein 43 (TDP-43), a nuclear DNA/RNA-binding protein involved in RNA metabolism, is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Although the aggregation-prone, TDP-43 C-terminal domain is widely considered as a key component of TDP-43 pathology in ALS, recent studies including ours suggest that TDP-43 N-terminal fragments (TDP-∆C) may also contribute to the motor dysfunction in ALS. However, the specific pathological functions of TDP-43 N-terminal fragments in mice have not been elucidated. Here, we established TDP-∆C knock-in mice missing a part of exon 6 of murine Tardbp gene, which encodes the C-terminal region of TDP-43. Homozygous TDP-∆C mice showed embryonic lethality, indicating that the N-terminal domain of TDP-43 alone is not sufficient for normal development. In contrast, heterozygous TDP-∆C mice developed normally but exhibited age-dependent mild motor dysfunction with a loss of C-boutons, large cholinergic synaptic terminals on spinal α-motor neurons. TDP-∆C protein broadly perturbed gene expression in the spinal cords of aged heterozygous TDP-∆C mice, including downregulation of Notch1 mRNA. Moreover, the level of Notch1 mRNA was suppressed both by TDP-43 depletion and TDP-∆C expression in Neuro2a cells. Decreased Notch1 mRNA expression in aged TDP-∆C mice was associated with the age-dependent motor dysfunction and loss of Akt surviving signal. Our findings indicate that the N-terminal region of TDP-43 derived from TDP-∆C induces the age-dependent motor dysfunction associated with impaired Notch1-Akt axis in mice.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas Proto-Oncogênicas c-akt/biossíntese , Receptor Notch1/biossíntese , Transdução de Sinais/fisiologia , Fatores Etários , Esclerose Amiotrófica Lateral/genética , Animais , Linhagem Celular Tumoral , Células Cultivadas , Proteínas de Ligação a DNA/genética , Técnicas de Introdução de Genes , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/genética , Receptor Notch1/genética
15.
Acta Odontol Scand ; 77(7): 525-533, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31190586

RESUMO

Objectives: The aim of cross-sectional study was to investigate the association between sensory processing patterns and dental fear among female undergraduates. Material and methods: Three hundred and ten female university students were included in the present study. Dental fear and sensory processing patterns were measured using the Dental Fear Survey and Adolescent/Adult Sensory Profile with other possible confounders, respectively. Sensory processing patterns were categorized into sensory sensitivity, sensory avoidance, low registration and sensation seeking. We conducted structural equation modelling based on the hypothesis that sensory processing directly affects dental fear, including the confounding role of negative experiences with dentistry, autistic traits and the mediating role of trait anxiety. Results: Based on our proposed model, sensory processing patterns, excluding sensation seeking and negative experiences significantly contributed to dental fear (ß = 0.33, p < .001 and ß = 0.32, p < .001, respectively) and autistic traits and trait anxiety did not significantly contribute to dental fear. Conclusions: Extreme sensory processing patterns seem to be associated with a high level of dental fear; thus, the difference in sensory processing might play an important role in the aetiology of dental fear.


Assuntos
Ansiedade ao Tratamento Odontológico/psicologia , Assistência Odontológica/psicologia , Medo , Sensação , Estudantes/psicologia , Adolescente , Adulto , Estudos Transversais , Ansiedade ao Tratamento Odontológico/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Inquéritos e Questionários , Universidades , Adulto Jovem
16.
Reprod Med Biol ; 18(2): 128-139, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30996676

RESUMO

Background: The pregnancy and delivery rates following assisted reproductive technology (ART) start to decrease and that the miscarriage rate increases rapidly from 35 years old. The miscarriage rate exceeds 50% at 43 years old. The number of aneuploid fetuses in miscarriages increases according to female age, reaching more than 90% when women are over 40 years old. Methods: Different cytoplasmic donation technologies used to rescue aged oocytes with high percentage of aneuploidy were analyzed, and their efficacy compared. Main findings Results: Germinal vesicle transfer (GVT) might be superior to spindle chromosome transfer (ST) theoretically from the point of higher capability of rescuing the disjunction at meiosis I which cannot be helped by ST. However, actually, in vitro maturation (IVM) of oocyte after GVT has not yet been totally completed. ST among other nuclear donations showed the higher possibility to rescue them, due to the fact it does not require in vitro maturation and it has an ethical advantage over pronuclear transfer (PNT) which requires the destruction of an embryo. Conclusion: Spindle chromosome transfer has the potential to rescue aged oocytes to some extent, but we have to continue the basic study further to establish the clinical application of cytoplasmic donation to rescue aged oocytes.

17.
Oncotarget ; 10(3): 404-414, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30719233

RESUMO

Melanoma, one of the most aggressive neoplasms, is characterized by rapid cell proliferation. Transducin-like Enhancer of Split (TLE) is an important regulator of cell proliferation via Histone deacetylase (HDAC) recruitment. Given that HDAC activity is associated with melanoma progression, we examined the relationship between TLE3, a TLE family member, and melanoma. TLE3 expression was increased during the progression of human patient melanoma (p < 0.05). Overexpression of Tle3 in B16 murine melanoma cells led to an increase in cell proliferation (p < 0.01) as well as the number of cyclinD1-positive cells. in vivo injection of mice with B16 cells overexpressing Tle3 resulted in larger tumor formation than in mice injected with control cells (p < 0.05). In contrast, siRNA-mediated knockdown of Tle3 in B16 cells or TLE3 in HMV-II human melanoma cells decreased proliferation (p < 0.01). Treatment of B16 cells with trichostatin A (2.5 µM), a class I and II HDAC inhibitor, prevented the effect s of Tle3 on proliferation. In conclusion, these data indicate that Tle3 is required, at least in part, for proliferation in the B16 mouse melanoma model.

18.
Brain Dev ; 41(5): 474-479, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30723005

RESUMO

Whole-exome sequencing (WES) can comprehensively detect both pathogenic single nucleotide variants and copy number variants, enabling identification of a coexistence of two or more genetic etiologies. Here we report a family consisting of individuals with Becker muscular dystrophy and rippling muscle disease. The proband, a 12-year-old boy, was diagnosed with Becker muscular dystrophy with exon 45-55 DMD deletions at age 4. He had myalgia and muscle stiffness. Interestingly, percussion-induced muscle mounding (PIMM), which is a characteristic of rippling muscle disease, was also observed. The father also showed muscle stiffness, myalgia, fatigability, muscle rippling and PIMM. WES revealed a missense CAV3 mutation (NM_033337.2:c.80G>A) in the proband, the father, the oldest sister and the grandmother, who had an elevated serum creatine kinase (CK) level. The c.80G>A mutation was considered pathogenic according to ACMG guidelines. The second older sister, the mother and the paternal grandfather did not have the CAV3 mutation and had normal CK. Using two programs for copy number analysis with WES data, we successfully identified the DMD deletion in the proband, the older sister and the mother. We revealed the coexistence of the CAV3 mutation and the DMD deletion in a family with complex muscular diseases and confirmed the usefulness of WES for elucidating such etiology.


Assuntos
Caveolina 3/genética , Distrofina/genética , Doenças Musculares/genética , Distrofia Muscular de Duchenne/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologia , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Linhagem
19.
Fertil Steril ; 110(3): 443-451, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30098696

RESUMO

OBJECTIVE: To compare physical and cognitive development of babies born after round spermatid injection (ROSI) with those born after natural conception. DESIGN: Comparison of efficiencies of ROSI and ICSI using testicular spermatozoa, performed in the St. Mother Clinic. Physical and cognitive development of ROSI babies recorded by parents in the government-issued Mother-Child Handbook was checked and verified by attending pediatricians. Data included baby's weight gain and response to parents' voice/gesture. SETTING: Assisted reproduction technology practice. PATIENT(S): A total of 721 men participated in ROSI; 90 ROSI babies were followed for 2 years for their physical and cognitive development. Control subjects were 1,818 naturally born babies. INTERVENTION(S): Surgical retrieval of spermatogenic cells from testes; selection and injection of round spermatids into oocytes; oocyte activation, in vitro culture of fertilized eggs, and embryo transfer to mothers. MAIN OUTCOME MEASURE(S): Physical and cognitive development of ROSI babies (e.g., body weight increase, response to parents, and understanding and speaking simple language) compared with naturally born babies. RESULT(S): Of 90 ROSI babies, three had congenital aberrations at birth, which corrected spontaneously (ventricular septa) or after surgery (cleft lip and omphalocele). Physical and cognitive development of ROSI babies was similar to those of naturally born babies. CONCLUSION(S): There were no significant differences between ROSI and naturally conceived babies in either physical or cognitive development during the first 2 years after birth. CLINICAL TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry UMIN000006117.


Assuntos
Desenvolvimento Infantil/fisiologia , Fertilização In Vitro/tendências , Oócitos/crescimento & desenvolvimento , Injeções de Esperma Intracitoplásmicas/tendências , Espermátides/crescimento & desenvolvimento , Adulto , Coeficiente de Natalidade/tendências , Pré-Escolar , Feminino , Fertilização In Vitro/métodos , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Oócitos/fisiologia , Gravidez , Injeções de Esperma Intracitoplásmicas/métodos , Espermátides/fisiologia , Inquéritos e Questionários , Adulto Jovem
20.
Nihon Eiseigaku Zasshi ; 73(2): 235-240, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29848876

RESUMO

OBJECTIVES: The stress check program has been part of annual employees' health screening since 2015. Employees are recommended, but not obliged, to undergo the stress check offered. This study was designed to examine the factors associated with stress check attendance. METHODS: A total of 31,156 Japanese employees who underwent an annual health examination and a stress check service at an Occupational Health Service Center in 2016 participated in this study. Data from the annual health examination and stress check service included stress check attendance, date of attendance (if implemented), gender, age, workplace industry, number of employees at the workplace, and tobacco and alcohol consumption. Data were analyzed using multiple logistic regression. RESULTS: The mean rate of stress check attendance was 90.8%. A higher rate of stress check attendance was associated with a lower duration from the annual health examination, age ≥30 years, construction and transport industry, and 50-999 employees at the workplace. A lower rate of stress check attendance was associated with medical and welfare industry and ≥1,000 employees at the workplace. CONCLUSIONS: These findings provide insights into developing strategies for improving the rate of stress check attendance. In particular, stress check attendance may improve if the stress check service and annual health examination are conducted simultaneously.


Assuntos
Saúde Mental , Saúde do Trabalhador , Exame Físico , Testes Psicológicos , Estresse Psicológico/diagnóstico , Adolescente , Adulto , Fatores Etários , Consumo de Bebidas Alcoólicas , Feminino , Humanos , Japão , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Exame Físico/métodos , Testes Psicológicos/estatística & dados numéricos , Fumar , Estresse Psicológico/prevenção & controle , Fatores de Tempo , Local de Trabalho , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA