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SLC5A6 encodes the sodium-dependent multivitamin transporter, a transmembrane protein that uptakes biotin, pantothenic acid, and lipoic acid. Biallelic SLC5A6 variants cause sodium-dependent multivitamin transporter deficiency (SMVTD) and childhood-onset biotin-responsive peripheral motor neuropathy (COMNB), which both respond well to replacement therapy with the above three nutrients. SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy. Without nutrient replacement therapy, SMVTD can be lethal in early childhood. COMNB is clinically milder and has a later onset than SMVTD, at approximately 10 years of age. COMNB symptoms are mostly limited to peripheral motor neuropathy. Here we report three patients from one Japanese family harboring novel compound heterozygous missense variants in SLC5A6, namely NM_021095.4:c.[221C>T];[642G>C] p.[(Ser74Phe)];[(Gln214His)]. Both variants were predicted to be deleterious through multiple lines of evidence, including amino acid conservation, in silico predictions of pathogenicity, and protein structure considerations. Drosophila analysis also showed c.221C>T to be pathogenic. All three patients had congenital brain cysts on neonatal cranial imaging, but no other morphological abnormalities. They also had a mild motor developmental delay that almost completely resolved despite no treatment. In terms of severity, their phenotypes were intermediate between SMVTD and COMNB. From these findings we propose a new SLC5A6-related disorder, spontaneously remitting developmental delay with brain cysts (SRDDBC) whose phenotypic severity is between that of SMVTD and COMNB. Further clinical and genetic evidence is needed to support our suggestion.
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Cistos , Simportadores , Pré-Escolar , Humanos , Recém-Nascido , Biotina/genética , Biotina/metabolismo , Fenótipo , Sódio/metabolismo , Simportadores/genética , Simportadores/metabolismoRESUMO
Urinary cotinine concentration (UCC) reflects smoking status. However, in pregnant women, its association with adverse birth outcomes related to fetal growth is not widely known. Thus, we aimed to explore this relationship by focusing on dose-response relationships. We investigated 86,638 pregnant women enrolled between 2011 and 2014 in a prospective cohort study in Japan and observed three birth outcomes (preterm birth, low birth weight, and small-for-gestational age). We measured UCC in the second or third trimester, and categorized the participants using cut-off values (negative cotinine concentration, passive cotinine concentration, and active cotinine concentration corresponding to non-smokers, passive smokers, and active smokers, respectively). Logistic regression analyses were conducted to evaluate the risks, and dose-response relationships were visualized using restricted cubic spline curves. Analyses based on self-reported smoking status were also performed. We found that in low active and highly active cotinine concentrations, the adjusted odds ratios (aORs) of birth outcomes were significantly increased (preterm birth, 1.24 [95% CI 1.06-1.46], 1.39 [95% CI 1.19-1.62]; low birth weight, 1.40 [95% CI 1.24-1.58], 2.27 [95% CI 2.05-2.53]; small-for-gestational age, 1.35 [95% CI 1.19-1.52], 2.39 [95% CI 2.16-2.65]). Restricted cubic spline curves demonstrated risk elevations in the active cotinine concentration range. Our research revealed dose-response relationships between UCC during pregnancy and the risks of preterm birth, low birth weight, and small-for-gestational age. Measurement of UCC to ascertain smoking status during pregnancy may be a useful approach for predicting the risks of these birth outcomes.
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Cotinina , Nascimento Prematuro , Criança , Cotinina/análise , Feminino , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/epidemiologia , Estudos Prospectivos , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
BACKGROUND: The extremes of maternal pre-pregnancy body mass index (BMI) are known to be risk factors associated with obstetric and adverse perinatal outcomes. Among Japanese women aged 20 years or older, the prevalence of underweight (BMI < 18.5 kg/m2) was 11.5% in 2019. Maternal thinness is a health problem caused by the desire to become slim. This study aimed to investigate the association between the severity of maternal low pre-pregnancy BMI and adverse perinatal outcomes, including preterm birth (PTB), low birth weight (LBW), and small-for-gestational age (SGA). METHODS: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant individuals between 2011 and 2014. Pre-pregnancy BMI was categorized as severe-moderate underweight (BMI < 16.9 kg/m2), mild underweight (BMI, 17.0-18.4 kg/m2), low-normal weight (BMI, 18.5-19.9 kg/m2), high-normal weight (BMI, 20.0-22.9 kg/m2), overweight (BMI, 23.0-24.9 kg/m2), and obese (BMI ≥ 25.0 kg/m2). The high-normal weight group was used as the reference for statistical analyses. Adjusted logistic regression was performed to evaluate the association between pre-pregnancy BMI and PTB, LBW, and SGA. RESULTS: Of 92,260 singleton pregnant individuals, the prevalence was 2.7% for severe-moderate underweight, 12.9% for mild underweight, and 24.5% for low-normal weight. The prevalence of adverse outcomes was 4.6% for PTB, 8.1% for LBW, and 7.6% for SGA. The adjusted odds ratios (aORs) for PTB were 1.72 (95% confidence interval [CI], 1.46-2.03) for severe-moderate underweight and 1.26 (95% CI, 1.14-1.39) for mild underweight. The aORs of LBW were 2.55 (95% CI, 2.27-2.86) for severe-moderate underweight, 1.64 (95% CI, 1.53-1.76) for mild underweight, and 1.23 (95% CI, 1.16-1.31) for low-normal weight. The aORs of SGA were 2.53 (95% CI, 2.25-2.84) for severe-moderate underweight, 1.66 (95% CI, 1.55-1.79) for mild underweight, and 1.29 (95% CI, 1.21-1.38) for low-normal weight. CONCLUSIONS: A dose-response relationship was found between the severity of low pre-pregnancy BMI and PTB, LBW, and SGA. Even low-normal BMI (18.5-19.9 kg/m2) increased the risk of LBW and SGA. This study provides useful information for pre-conception counseling in lean individuals.
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Índice de Massa Corporal , Recém-Nascido de Baixo Peso , Recém-Nascido Pequeno para a Idade Gestacional , Resultado da Gravidez/epidemiologia , Nascimento Prematuro , Magreza/epidemiologia , Adulto , Povo Asiático/etnologia , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Japão/epidemiologia , Gravidez , Prevalência , Estudos ProspectivosRESUMO
AIM: We aimed to grasp the actual working hours of Japanese obstetricians and gynecologists (OB/GYN doctors) as accurately as possible, using the same method of the Ministry of Health, Labour, and Welfare (MHLW). METHODS: The time study targeted OB/GYN doctors working at 10 universities nationwide including Niigata University and 21 institutions which take a role of perinatal care in Niigata prefecture. Working hours per week were calculated based on the following categories: regular and overtime work inside the hospital, work outside the hospital, self-improvement, education, research, and others. Data on weekly working hours were converted to yearly data for analyses. RESULTS: A time study of 10 universities nationwide revealed that 30% of doctors work overtime for more than 1860 h even if they do not include on-call shifts in their working hours. In 21 institutions in Niigata, physicians in Niigata University worked more overtime than other hospitals. It became clear that community health care was supported by dispatching physicians working at university. Furthermore, the results of simulations predicted the pessimistic situation of perinatal medical care in Niigata. CONCLUSIONS: Our study showed the possibility to exist much more OB/GYN doctors who work more than 1860 h of overtime work per year than the data presented by the MHLW based on nation-wide survey in 2019. The fact that the working hours at the side jobs had a great influence on the increase in overtime work of physicians in University was the same result as the report of MHLW published in 2021.
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Ginecologia , Médicos , Humanos , Japão , Inquéritos e Questionários , Estudos de Tempo e MovimentoRESUMO
Although children with orofacial clefts have an increased risk for sleep-disordered breathing, no studies have examined the association of sleep duration. Thus, this study aimed to examine associations between orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age in Japan.A cohort study from the Japan Environment and Children's Study.This study consisted of 91â 497 children, including ones with isolated cleft lip and palate (n = 69), isolated cleft lip only (n = 48), and isolated cleft palate only (n = 37), for which recruitment was undertaken during 2011 to 2014.Seep durations (hours per day) at 1 month, 6 months, 1 year, and 3 years of age, as reported by their mothers.In the control group, mean sleep durations and standard deviations at 1 month, 6 months, 1 year, and 3 years of age were 15.2 (2.5), 13.6 (1.9), 12.9 (1.6), and 11.6 (1.2) h, respectively. Compared to the control group, linear regression models reported effect sizes and 95% confidence intervals shorter than 1â h for sleep duration of each type of isolated orofacial cleft at each time point.This study suggested null associations between isolated orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age. Children with isolated orofacial clefts had sufficient mean sleep duration.
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Although cytology-based screening programs have significantly reduced mortality and morbidity from cervical cancer, the global consensus is that primary human papillomavirus (HPV) testing for cervical screening increases detection of high-grade cervical intraepithelial neoplasia (CIN) and invasive cancer. However, the optimal triage strategy for HPV-positive women to avoid over-referral to colposcopy may be setting specific. As Japan requires data that have been generated domestically to modify screening guidelines, we conducted a 3-year prospective study, COMparison of HPV genotyping And Cytology Triage (COMPACT), to evaluate the potential role of HPV16/18 partial genotyping and cytology for primary HPV screening. In total, 14 642 women aged 20 to 69 years undergoing routine screening at 3 centers in Hokkaido were enrolled. Conventional cytology and HPV testing were carried out. Women with abnormal cytology or HPV16/18 positivity underwent colposcopy. Those with 12 other high-risk (hr) HPV types underwent repeat cytology after 6 months. Primary study endpoints were detection of high-grade cervical disease defined as CIN2/CIN3 or greater as determined by consensus pathology. Prevalence of cytological abnormalities was 2.4%. hrHPV, HPV 16, and HPV 18 were detected in 4.6%, 0.9%, and 0.3% of women, respectively. HPV16/18 were detected in all (8/8) invasive cervical cancers and in all (2/2) adenocarcinomas in situ. Both cytological abnormalities and hrHPV positivity declined with increasing age. This is the first Japanese study to investigate the role of partial genotyping and cytology in an HPV-based screening program. Results should help policy-makers develop guidelines for future cervical screening programs and management of cervical abnormalities based on HPV genotype.
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Citodiagnóstico/métodos , Detecção Precoce de Câncer/métodos , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , Colposcopia , Feminino , Genótipo , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/fisiologia , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/fisiologia , Humanos , Pessoa de Meia-Idade , Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Estudos Prospectivos , Triagem/métodos , Neoplasias do Colo do Útero/virologia , Adulto Jovem , Displasia do Colo do Útero/virologiaRESUMO
Socioeconomic status and smoking are reportedly associated with underweight and obesity; however, their associations among pregnant women are unknown. This study aimed to investigate whether socioeconomic factors, namely educational attainment, household income, marital status, and employment status, were associated with pre-pregnancy body mass index (BMI) categories, including severe-moderate underweight (BMI ≤ 16.9 kg/m2), mild underweight (BMI, 17.0-18.4 kg/m2), overweight (BMI, 25.0-29.9 kg/m2), and obese (BMI ≥ 30.0 kg/m2) among Japanese pregnant women using data from the Japan Environment and Children's Study (JECS). In total, pregnant women were included 96,751. Age- and parity-adjusted multivariable multinomial logistic regression analyses assessed socioeconomic factors and smoking associations with falling within abnormal BMI categories (normal BMI as the reference group). Lower education and lower household were associated with overweight and obesity, and, especially, lowest education and household income had relatively higher point estimate relative ratios (RRs) of 3.97 and 2.84, respectively. Regarding the risks for underweight, however, only junior high school education had a significantly higher RR for severely to moderately underweight. Regarding occupational status, homemakers or the unemployed had a higher RR for severe-moderate underweight, overweight, and obesity. Unmarried, divorced, or bereaved women had significantly higher RRs for mildly underweight status. Quitting smoking early in pregnancy/still smoking had higher RRs for all four not having normal BMI outcomes; however, quitting smoking before pregnancy had a higher RR only for obese individuals. Lower educational attainment and smoking are essential intervention targets for obesity and severe-moderate underweight prevention in younger women. Lower household income is also a necessary target for obesity.
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Índice de Massa Corporal , Magreza , Humanos , Feminino , Gravidez , Japão/epidemiologia , Adulto , Estudos Transversais , Magreza/epidemiologia , Fatores Socioeconômicos , Obesidade/epidemiologia , Fumar/epidemiologia , Sobrepeso/epidemiologia , Adulto Jovem , Fatores de RiscoRESUMO
OBJECTIVES: To investigate the association between multimorbidity during pregnancy and neurodevelopmental delay in offspring using data from a Japanese nationwide birth cohort study. DESIGN: This study was a prospective birth cohort study. SETTING: This study population included 104 059 fetal records who participated in The Japan Environment and Children's Study from 2011 to 2014. PARTICIPANTS: Pregnant women whose children had undergone developmental testing were included in this analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Neurodevelopment of offspring was assessed using the Japanese version of the Ages and Stages Questionnaire, third edition, comprising five developmental domains. The number of comorbidities among the pregnant women was categorised as zero, single disease or multimorbidity (two or more diseases). Maternal chronic conditions included in multimorbidity were defined as conditions with high prevalence among women of reproductive age. A multivariate logistic regression analysis was conducted to examine the association between multimorbidity in pregnant women and offspring development. RESULTS: Pregnant women with multimorbidity, single disease and no disease accounted for 3.6%, 30.6% and 65.8%, respectively. The ORs for neurodevelopmental impairment during the follow-up period were similar for infants of mothers with no disease comorbidity and those with a single disease comorbidity. However, the ORs for neurodevelopmental impairment were significantly higher for children born to mothers with multimorbidity compared with those born to healthy mothers. CONCLUSION: An association was observed between the number of comorbidities in pregnant women and developmental delay in offspring. Multimorbidity in pregnant women may be associated with neurodevelopmental delay in their offspring. Further research is required in this regard in many other regions of the world.
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Coorte de Nascimento , Multimorbidade , Transtornos do Neurodesenvolvimento , Complicações na Gravidez , Humanos , Feminino , Gravidez , Japão/epidemiologia , Estudos Prospectivos , Adulto , Transtornos do Neurodesenvolvimento/epidemiologia , Complicações na Gravidez/epidemiologia , Lactente , Masculino , Pré-Escolar , Desenvolvimento Infantil , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Modelos Logísticos , Recém-Nascido , Doença Crônica/epidemiologia , CriançaRESUMO
OBJECTIVE: To identify epidemiologic risk factors and investigate whether the characteristics of removed ovarian tissue during surgery influence the recurrence of endometriomas. DESIGN: Retrospective cohort study. SETTING: Medical university hospital. POPULATION: 248 women with endometriomas. METHODS: All women who had a minimum of 2 years of follow-up after the laparoscopic excision of endometriomas were analysed retrospectively. Specimens were analysed histologically. MAIN OUTCOME MEASURES: Sixteen epidemiologic variables were analysed as possible risk factors for recurrence. The association between the characteristics of removed ovarian tissue (the thickness of the cyst wall, the thickness of ovarian tissue, and the morphological features) and endometrioma recurrence was investigated. RESULTS: The cumulative incidence of endometriomas reached 42% at 60 months after surgery. We identified only a younger age at surgery as a risk factor, and postoperative pregnancy as a preventive factor. There were no differences in the mean thickness of the cyst wall and the removed ovarian tissue between patients with and without recurrence. No statistically significant associations were found between the morphologic characteristics of removed cyst wall, ovarian tissue, graded on a semi-quantitative basis, and recurrence. CONCLUSIONS: These results suggest that the rate of endometrioma recurrence had a significant relation to patient age and postoperative pregnancy; however, there was no association between the histological characteristics of the excised tissue and recurrence.
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Endometriose/patologia , Doenças Ovarianas/patologia , Adolescente , Adulto , Fatores Etários , Endometriose/cirurgia , Feminino , Seguimentos , Humanos , Laparoscopia , Pessoa de Meia-Idade , Análise Multivariada , Doenças Ovarianas/cirurgia , Gravidez , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Fatores de Risco , Estatísticas não Paramétricas , Adulto JovemRESUMO
Introduction: Remote antenatal checkups were conducted on the northernmost island of Japan to reduce the burden of hospital visits among pregnant women. This study aims to investigate the effectiveness and safety of remote antenatal checkups for pregnant women living on a remote island. Methods: This observational study included singleton pregnancies on Rebun Island between October 2020 and September 2022. General surgeons conducted medical interviews and performed fetal sonography using an obstetrician videoconference system at the main central hospital. The primary outcomes were the degrees of physical, mental, and economic burdens of hospital visits and the levels of anxiety and satisfaction with remote antenatal checkups as assessed using a questionnaire survey. Moreover, we investigated the incidence of adverse perinatal events, including maternal death, fetal death, neonatal death, severe neonatal neurological disorders, and other obstetric complications. Results: This study included 16 out of 22 pregnant women from Rebun Island who visited the central hospital. No adverse perinatal events occurred as a result of the remote antenatal checkups. One pregnant woman had gestational diabetes, whereas the others had no obstetric complications. The participants underwent a median of two remote antenatal checkups. According to a questionnaire survey, 90.0%, 80.0%, and 70.0% of the pregnant women perceived improvements in their physical, mental, and economic burdens, respectively. Although 70.0% of the participants experienced anxiety regarding remote antenatal checkups before the introduction, all were satisfied after delivery. Conclusions: Remote antenatal checkups effectively reduced the burden of hospital visits for pregnant women, who reported high levels of satisfaction. Furthermore, antenatal checkups were safely conducted on remote islands.
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This study aimed to document the complication status of infants with orofacial clefts born between 2011 and 2014 in Japan. This was a descriptive study using data from the Japan Environment and Children's Study. Among 103 060 pregnancies, 248 infants with orofacial clefts were included (livebirth, 239; stillbirth, 4; miscarriage, 5). The items of interest were complication status of orofacial clefts: isolated (typical orofacial clefts only); multi-malformed (orofacial clefts with unrelated major defects); syndromic (orofacial clefts with a syndrome or a chromosomal defect). Regarding the cleft subtypes, of 248 infants with orofacial clefts, 104 had cleft lip with cleft palate (CLP) (41.9%), 68 had cleft lip without cleft palate (CL) (27.4%), 58 had cleft palate without cleft lip (CP) (23.4%), and 18 were nonclassified (7.3%). In infants with CLP, the proportions of isolated, multi-malformed, and syndromic phenotypes were 73.1%, 15.4%, and 11.5%, respectively. In infants with CL, the proportions were 79.4%, 16.2%, and 4.4%, respectively. In infants with CP, the proportions were 69.0%, 13.8%, and 17.2%, respectively. The most frequently associated congenital anomaly was congenital heart disease. In infants with syndromic CLP, 41.7% had trisomy 13. In infants with syndromic CP, 80.0% had the Pierre Robin sequence. Congenital heart disease could be the most frequently associated congenital anomaly. The most frequently associated syndrome could be trisomy 13 in those with CLP and Pierre Robin sequence in those with CP.
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Fenda Labial , Fissura Palatina , Cardiopatias Congênitas , Síndrome de Pierre Robin , Humanos , Gravidez , Feminino , Fenda Labial/diagnóstico , Fenda Labial/epidemiologia , Fenda Labial/genética , Fissura Palatina/diagnóstico , Fissura Palatina/epidemiologia , Fissura Palatina/genética , Síndrome da Trissomia do Cromossomo 13 , Japão/epidemiologia , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologiaRESUMO
OBJECTIVES: Multimorbidity is defined as the coexistence of two or more chronic physical or psychological conditions within an individual. The association between maternal multimorbidity and adverse perinatal outcomes such as preterm delivery and low birth weight has not been well studied. Therefore, this study aimed to investigate this association. METHODS: We conducted a prospective cohort study using data from the Japan Environment and Children's Study of pregnant women between 2011 and 2014. Those with data on chronic maternal conditions were included in the study and categorised as having no chronic condition, one chronic condition or multimorbidities. The primary outcomes were the incidence of preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA). Adjusted logistic regression was performed to estimate ORs (aORs) and 95% CIs. RESULTS: Of the 104 062 fetal records, 86 885 singleton pregnant women were analysed. The median maternal age and body mass index were 31 years and 20.5 kg/m2, respectively. The prevalence of pregnant women with one or more chronic conditions was 40.2%. The prevalence of maternal multimorbidity was 6.3%, and that of PTB, LBW, and SGA were 4.6%, 8.1%, and 7.5%, respectively. Pre-pregnancy underweight women were the most common, observed in 15.6% of multimorbidity cases, followed by domestic violence from intimate partner in 13.0%. Maternal multimorbidity was significantly associated with PTB (aOR 1.50; 95% CI 1.33-1.69), LBW (aOR 1.49; 95% CI 1.35-1.63) and SGA (aOR 1.33; 95% CI 1.20-1.46). CONCLUSION: Maternal multimorbidity was associated with adverse perinatal outcomes, including PTB, LBW and SGA. The risk of adverse perinatal outcomes tends to increase with a rise in the number of chronic maternal conditions. Multimorbidity becomes more prevalent among pregnant women, making our findings important for preconception counselling.
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Nascimento Prematuro , Feminino , Recém-Nascido , Gravidez , Criança , Humanos , Nascimento Prematuro/epidemiologia , Estudos Prospectivos , Estudos de Coortes , Idade Gestacional , Japão/epidemiologia , Multimorbidade , Fatores de Risco , Recém-Nascido de Baixo Peso , Recém-Nascido Pequeno para a Idade Gestacional , Retardo do Crescimento Fetal/epidemiologia , Peso ao NascerRESUMO
The change in physiological parameters and subjective feelings according to the speed of drinking alcohol has not been reported to date. The aim of this randomized crossover pilot study was to investigate the objective and subjective effects of different speeds of alcohol ingestion in healthy volunteers. Accordingly, 11 male and 7 female healthy Japanese adults were asked to consume 480 mL of beer at three different drinking speeds (80, 40, and 20 mL/5 min). According to the objective measurement, the transient increase in blood alcohol and serum uric acid concentrations was most inhibited at a drinking speed of 20 mL/5 min. Acetate, lactate, pyruvate, and lactate/pyruvate ratios did not differ between the three drinking speeds. Stimulant feelings measured by the subjective scores of the Brief Biphasic Alcohol Effects Scale did not differ between the three speeds. However, the sedative feeling score obtained at a drinking speed of 20 mL/5 min (the slowest speed of alcohol consumption) was significantly weakened in comparison with those obtained at drinking speeds of 40 and 80 mL/5 min. Therefore, a slower consumption of alcohol mitigated the subjective sedative feeling. The effects of slower alcohol consumption may be caused by the slower slope of the increasing trend of blood alcohol concentration.
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Cerveja , Hipnóticos e Sedativos , Adulto , Masculino , Humanos , Feminino , Hipnóticos e Sedativos/farmacologia , Projetos Piloto , Consumo de Bebidas Alcoólicas , Concentração Alcoólica no Sangue , Ácido Úrico , Etanol/farmacologia , Lactatos , PiruvatosRESUMO
The effects of alcohol consumption on health are suggested to depend on the amount of alcohol consumed. We investigated the objective and subjective health effects of the daily consumption of a small amount of alcohol in healthy individuals using a randomized, double-blind, placebo-controlled crossover study. Accordingly, 15 male and 27 female Japanese adults with average or lower general well-being schedule (GWBS) scores were asked to consume a beverage with 0.5% (v/v) alcohol (~4 g of alcohol a day; test beverage) and a placebo beverage two times daily for 4 weeks each. Regular low-level alcohol consumption significantly decreased the serum liver function indexes (aspartic aminotransferase, alanine aminotransferase, and lactate dehydrogenase) before and after consumption (p = 0.034, 0.033, and 0.013, respectively). The small amount of alcohol did not affect the participants' GWBS scores; however, a stratified analysis with poor subjective well-being revealed that these changes differed significantly between low-level alcohol consumption and placebo-treated subjects (16.0 vs. 11.5, p = 0.041). In addition, changes in serum testosterone levels demonstrated a higher trend in the group that received the test beverage compared with the group that received the placebo beverage (p = 0.051). Daily low-level alcohol consumption may have positive effects on liver function and subjective well-being.
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The cervical cytology of our patient transformed from squamous cell carcinoma to negative for intraepithelial lesion or malignancy, possibly due to the graft-versus-tumor effect following allogeneic stem cell transplantation.
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Thyroid hormone (T3) is critical for growth, differentiation, and maintenance of metabolic homeostasis. Mice with a knock-in mutation in the thyroid hormone receptor alpha gene (TRalpha1PV) were created previously to explore the roles of mutated TRalpha1 in vivo. TRalpha1PV is a dominant negative mutant with a frameshift mutation in the carboxyl-terminal 14 amino acids that results in the loss of T3 binding and transcription capacity. Homozygous knock-in TRalpha1(PV/PV) mice are embryonic lethal, and heterozygous TRalpha1(PV/+) mice display the striking phenotype of dwarfism. These mutant mice provide a valuable tool for identifying the defects that contribute to dwarfism. Here we show that white adipose tissue (WAT) mass was markedly reduced in TRalpha1(PV/+) mice. The expression of peroxisome proliferator-activated receptor gamma (PPARgamma), the key regulator of adipogenesis, was repressed at both mRNA and protein levels in WAT of TRalpha1(PV/+) mice. Moreover, TRalpha1PV acted to inhibit the transcription activity of PPARgamma by competition with PPARgamma for binding to PPARgamma response elements and for heterodimerization with the retinoid X receptors. The expression of TRalpha1PV blocked the T3-dependent adipogenesis of 3T3-L1 cells and repressed the expression of PPARgamma. Thus, mutations of TRalpha1 severely affect adipogenesis via cross talk with PPARgamma signaling. The present study suggests that defects in adipogenesis could contribute to the phenotypic manifestation of reduced body weight in TRalpha1(PV/+) mice.
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Adipogenia , Receptores alfa dos Hormônios Tireóideos/genética , Receptores alfa dos Hormônios Tireóideos/metabolismo , Adipócitos Brancos/citologia , Adipócitos Brancos/metabolismo , Adipogenia/genética , Sequência de Aminoácidos , Animais , Linhagem Celular , Feminino , Humanos , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Mutação/genética , PPAR gama/genética , PPAR gama/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores alfa dos Hormônios Tireóideos/química , Ativação Transcricional/genéticaRESUMO
OBJECTIVE: Diagnosis of lymph node metastasis is a critical issue in the treatment of cervical cancer. Many studies describing sentinel node navigation surgery (SNNS) for examination of node status have been reported in the past decade. In this study, the feasibility of node status diagnosis by SNNS, including intraoperative frozen section diagnosis, in patients with early and advanced cervical cancer was evaluated. PATIENTS AND METHODS: Fifty-eight cervical cancer patients with early and advanced stage disease were enrolled. All patients were treated with backup pelvic lymphadenectomy after SNNS. To detect sentinel lymph nodes (SLNs), radioactive material and/or blue dye were used as tracers. Lymph nodes confirmed as SLNs were immediately sent to pathologists and diagnosed by frozen section intraoperatively. RESULTS: A total of 118 and 16 SLNs were pathologically investigated in early and advanced stage cervical cancer, respectively. The detection rate of SLNs in the early and advanced stages was 94.7% and 66.7%, respectively, whereas the detection rate using 1 or 2 tracers was 62.5% and 90%, respectively. The false-negative rate and negative predictive value was 0% and 100% for all stages. Pathological diagnosis by frozen section was completed within 30 minutes in all cases. CONCLUSIONS: Our data demonstrate that SNNS in cervical cancer is a promising procedure for patients with early stage (up to Ib1) disease, especially patients with small tumor diameter (<2.0 cm). However, SNNS raises several points for discussion before it can be established as a practical clinical procedure or as part of a subsequent radical hysterectomy.
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Adenocarcinoma/cirurgia , Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Pelve , Neoplasias do Colo do Útero/cirurgia , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adulto , Idoso , Reações Falso-Positivas , Feminino , Humanos , Histerectomia , Período Intraoperatório , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Modelos Biológicos , Estadiamento de Neoplasias/métodos , Pelve/cirurgia , Valor Preditivo dos Testes , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologiaRESUMO
Follicular thyroid cancer (FTC) is known to metastasize to distant sites via hematogenous spread; however, the underlying pathways that contribute to metastasis remain unknown. Recent creation of a knockin mutant mouse that expresses a mutant thyroid hormone receptor-beta (TRbeta(PV/PV) mouse) that spontaneously develops thyroid cancer with metastasis similar to humans has provided new opportunities to study contributors to FTC metastasis. This study evaluates the role of gelsolin, an actin-regulatory protein, in modulating the metastatic potential of FTC. Gelsolin was previously found by cDNA microarray analysis to be down-regulated in TRbeta(PV/PV) mice as compared with wild-type mice. This study found an age-dependent reduction of gelsolin protein abundance in TRbeta(PV/PV) mice as tumorigenesis progressed. Knockdown of gelsolin by small interfering RNA resulted in increased tumor cell motility and increased gelsolin expression by histone deacetylase inhibitor (trichostatin A) led to decreased cell motility. Additional biochemical analyses demonstrated that gelsolin physically interacted with TRbeta1 or PV in vivo and in vitro. The interaction regions were mapped to the C terminus of gelsolin and the DNA binding domain of TR. The physical interaction of gelsolin with PV reduced its binding to actin, leading to disarrayed cytoskeletal architectures. These results suggest that PV-induced alteration of the actin/gelsolin cytoskeleton contributes to increased cell motility. Thus, the present study uncovered a novel PV-mediated oncogenic pathway that could contribute to the local tumor progression and metastatic potential of thyroid carcinogenesis.
Assuntos
Carcinoma Papilar, Variante Folicular/patologia , Gelsolina/metabolismo , Gelsolina/fisiologia , Receptores beta dos Hormônios Tireóideos/metabolismo , Neoplasias da Glândula Tireoide/patologia , Actinas/metabolismo , Animais , Movimento Celular/genética , Células Cultivadas , Chlorocebus aethiops , Modelos Animais de Doenças , Progressão da Doença , Camundongos , Camundongos Transgênicos , Proteínas Mutantes/metabolismo , Ligação Proteica , Glândula Tireoide/metabolismo , Receptores beta dos Hormônios Tireóideos/genéticaRESUMO
HOX genes encode transcription factors that function to establish basic body pattern during embryogenesis and maintain the function of specific organs in the adult. Recent studies have demonstrated that HOX genes are also involved in oncogenesis in a range of malignancies. To elucidate whether HOX genes contribute to ovarian carcinogenesis, we created an expression profile of HOX genes using ovarian derived materials from surgical samples and epithelial ovarian cancer cells derived from five different cell lines. Real-time quantitative RT-PCR assay indicated overexpression of 14 HOX genes in clusters A and B but only 2 genes in clusters C and D. Of the 16 HOX genes, overexpression of paralogs of HOX3, HOX4 and HOX7 is seen in cluster A and B, and of HOX13 in all paralogs. In addition, HOXB7, HOXA13 and HOXB13 showed high levels of overexpression in cancer cells and tissues whereas no or little expression was observed in normal controls. To examine whether overexpressed HOX genes regulate invasion of ovarian cancer cells directly, we introduced an antisense DNA fragment of overexpressed HOXB7 and HOXB13, and HOXC5 that did not show overexpression into SKOV3 cells by electroporation. Antisense introduction followed by chemoinvasion assay using matrigel chamber demonstrated that SKOV3 cells introduced an antisense of each HOXB7 and HOXB13 showed 85% and 50% reduction of invasion ability compared to the parental SKOV3 cells, respectively. In contrast, antisense of HOXC5 introduced cells showed no significant difference of the invasion ability. These results suggest an important role of overexpressed HOX genes, especially for invasive characteristics of ovarian cancer cells.
Assuntos
Movimento Celular/genética , Proteínas de Homeodomínio/genética , Oligonucleotídeos Antissenso/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/fisiopatologia , Isoformas de Proteínas/genética , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
The phosphatidylinositol 3-kinase/AKT pathway is crucial to many cell functions, and its dysregulation in tumors is a common finding. The molecular basis of follicular thyroid cancer metastasis is not well understood but may also be influenced by AKT activation. We previously created a knockin mutant mouse that expresses a mutant thyroid hormone receptor-beta gene (TRbetaPV mouse) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. In this study, we investigated whether our mouse model exhibits similar AKT activation as human follicular thyroid cancer. Western blot analysis on thyroids from both wild-type and TRbeta(PV/PV) mice revealed elevation of activated AKT in TRbeta(PV/PV) mice. Immunohistochemistry and confocal microscopy reveal activated AKT in both the thyroid and metastatic lesions of TRbeta(PV/PV) mice. Whereas all three AKT isoforms were overexpressed in primary tumors from TRbeta(PV/PV) mice in the cytoplasm of thyroid cancer cells, only AKT1 was also found in the nucleus, matching the localization of activated AKT in a pattern similar to human follicular thyroid cancer. In the metastases, all AKT isoforms correlated with phosphorylated AKT nuclear localization. We created primary thyroid cell lines derived from TRbeta(PV/PV) mice and found reduction of phosphorylated AKT levels or AKT downstream targets diminishes cell motility. Activated AKT is common to both human and mouse follicular thyroid cancer and is correlated with increased cell motility in vitro and metastasis in vivo. Thus, TRbeta(PV/PV) mice could be used to further dissect the detailed pathways underlying the progression and metastasis of follicular thyroid carcinoma.