RESUMO
PURPOSE: The objective is to clarify the practical problem of the preimplantation genetic testing (PGT) for myotonic dystrophy type 1 (DM1) in Japanese subjects. METHODS: For the 32 couples who consented to participate in PGT for DM1, CTG repeats number on the unaffected alleles was analyzed. Based on the allele combination, they were classified into 3 groups by the number of diagnostic allelic pattern; "full informative," "semi informative," and "noninformative." According to the Japan Society of Obstetrics and Gynecology (JSOG) principle, PGT was performed using the direct diagnosis to the 288 embryos from the 17 couples who received the ethical approval from both our institution and JSOG. RESULTS: In the 32 couples, the frequency of CTG repeats on the unaffected alleles showed bimodal distribution. The "full informative," "semi informative," and "noninformative" couples accounted for 46.9% (15/32 couples), 46.9% (15/32 couples) and 6.2% (2/32 couples), respectively. The transferable embryos accounted for 28.9% (33/114 embryos) in the "full informative" couples, although it was limited to 12.6% (22/174 embryos) in the "semi informative" couples. CONCLUSION: The loss of unaffected embryos which cannot be diagnosed as transferable was a clinically major problem and implied an increase in oocyte retrieval, especially for "semi informative" couples.
RESUMO
Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection.
Assuntos
Criptococose/imunologia , Cryptococcus gattii/imunologia , Células Dendríticas/transplante , Cápsulas Fúngicas/imunologia , Vacinas Fúngicas/imunologia , Animais , Células da Medula Óssea/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Criptococose/prevenção & controle , Células Dendríticas/imunologia , Cápsulas Fúngicas/genética , Células Gigantes/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Necrose Tumoral alfa/imunologia , VacinaçãoRESUMO
We treated a 37-year-old Japanese woman with moyamoya disease who developed cerebral infarction in the early period after pregnancy and had undergone infertility treatment. After being adequately informed, including regarding the risk of stroke in the perinatal period and the option to prioritize the treatment of moyamoya disease even if the pregnancy was interrupted, the patient decided to continue the pregnancy and underwent surgical treatment after a full-term delivery by caesarean section. No new stroke was observed throughout the perinatal period or postoperative course. Since serious stroke during the perinatal period has also been reported in moyamoya disease, it is important to plan "tailored" treatment by sufficiently informing patients considering individual backgrounds and for multiple medical departments, including obstetrics, neurology, and neurosurgery departments, to carry out close outpatient follow-up in the perinatal period and carefully careful medication usage and radiological examinations.
Assuntos
Infarto Cerebral , Revascularização Cerebral , Doença de Moyamoya , Complicações na Gravidez , Humanos , Feminino , Adulto , Doença de Moyamoya/complicações , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/cirurgia , Infarto Cerebral/complicações , Infarto Cerebral/diagnóstico , Infarto Cerebral/cirurgia , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/cirurgia , Cesárea , Gravidez , Resultado do TratamentoRESUMO
1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high-sodium (8% NaCl) diet and heminephrectomy on PAC were examined. 2. Feeding of the high-sodium diet for 12 weeks similarly decreased PAC in TG and wild-type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high-sodium diet, but had no effect on PAC in WT rats fed a high-sodium diet. 3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high-sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not. 4. Nephrin and podocin mRNA levels, as determined by real-time quantitative reverse transcription-polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)-1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO-1 mRNA levels in TG rats. 5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.
Assuntos
Aldosterona/sangue , Nefropatias/prevenção & controle , Antagonistas de Receptores de Mineralocorticoides , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Receptores de Superfície Celular/fisiologia , Espironolactona/análogos & derivados , Animais , Eplerenona , Humanos , Nefropatias/sangue , Nefropatias/etiologia , Nefropatias/metabolismo , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Nefrectomia , Ratos , Ratos Transgênicos , Receptores de Superfície Celular/genética , Cloreto de Sódio na Dieta/administração & dosagem , Espironolactona/administração & dosagem , Espironolactona/farmacologia , Espironolactona/uso terapêutico , Receptor de Pró-ReninaRESUMO
The patient was a 23-year-old man who was diagnosed with severe hypoxemia and liver dysfunction after suffering from sudden difficulty breathing. At 2 years of age, he had been diagnosed with hypopituitarism, and had received hormone-replacement until he was 18 years of age. Echocardiography using micro bubbles and pulmonary scintigraphy indicated intrapulmonary shunt and a liver biopsy showed steatohepatitis. He was diagnosed with hepatopulmonary syndrome associated with nonalcoholic steatohepatitis. Hormone-replacement therapy was re-started. After 5 months, a second liver biopsy revealed the amelioration of nonalcoholic steatohepatitis, which improved his respiratory condition. This case suggested that early effective therapy for chronic liver diseases might improve the pathological and clinical conditions of hepatopulmonary syndrome.
Assuntos
Síndrome Hepatopulmonar/complicações , Síndrome Hepatopulmonar/tratamento farmacológico , Terapia de Reposição Hormonal/métodos , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/etiologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Corticosteroides/uso terapêutico , Adulto , Hormônio do Crescimento/uso terapêutico , Humanos , Masculino , Testosterona/uso terapêutico , Hormônios Tireóideos/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Autophagy is an intracellular catabolic process contributing to the regulation of nutrient homeostasis and cellular remodeling. Studies revealed that the nuclear translocation of transcription factor EB (TFEB) plays a key role in lysosomal biogenesis and autophagic pathways. The (pro)renin receptor [(P)RR] is a multifunctional protein playing a pivotal role in regulation of the tissue renin-angiotensin system and is known as an essential constituent of vacuolar H+ -ATPase, considered to be necessary for the autophagy-lysosome pathway. On the basis of these findings, we postulated that (P)RR may also contribute to the regulation of starvation-induced autophagy. In this study, starvation increased the expression of (P)RR and autophagy-related genes, especially, in the skeletal muscles of mice. In C2C12 mouse myoblast cells, starvation increased (P)RR expression and TFEB translocation, leading to the expression of autophagy-related genes. Knockdown of (P)RR enhanced both the TFEB translocation to the nucleus and the expression of autophagy-related genes during starvation. These results suggest that (P)RR plays a buffering role in starvation-induced autophagy by affecting the nuclear translocation of TFEB. Thus, (P)RR, which increases during starvation, is one of the important factors that control autophagy in the skeletal muscles. (P)RR may act as a buffer to reduce excessive TFEB-dependent autophagy flux.
Assuntos
Autofagia , Músculo Esquelético/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Receptores de Superfície Celular/metabolismo , Inanição/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular , Núcleo Celular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , ATPases Translocadoras de Prótons/genética , Receptores de Superfície Celular/genéticaRESUMO
Antithyroid drugs are generally selected as the first-line treatment for Graves' Disease (GD); however, the existence of patients showing resistance or severe side effects to these drugs is an important issue to be solved. The (pro)renin receptor [(P)RR] is a multi-functional protein that activates the tissue renin-angiotensin system and is an essential constituent of vacuolar H+-ATPase, necessary for the autophagy-lysosome pathway. (P)RR is cleaved to soluble (s)(P)RR, which reflects the status of (P)RR expression. In this retrospective study, we aimed to investigate whether serum s(P)RR concentration can be used as a biomarker to predict the outcome of antithyroid drug treatment in GD patients. Serum s(P)RR levels were measured in 54 untreated GD patients and 47 control participants. Effects of medical treatment with antithyroid drugs on these levels were investigated in GD patients. Serum s(P)RR levels were significantly higher in patients with Graves' disease than in control subjects (P<0.005) and were significantly reduced after medical treatment for Graves' disease. High serum s(P)RR levels were associated with resistance to antithyroid drug treatment, suggesting that serum s(P)RR concentration can be used as a useful biomarker to predict the outcome of antithyroid drug treatment in these patients. Patients with Graves' disease with low body mass index showed higher levels of serum soluble (pro)renin receptor levels than those with high body mass index. In addition, in patients with Graves' disease, serum triglyceride levels were negatively correlated with serum soluble (pro)renin receptor levels. All these data indicated an association between low nutrient condition due to hyperthyroidism and increased (pro)renin receptor expression in these patients, suggesting that (pro)renin receptor expression could be increased in the process of stimulating intracellular energy production via activating autophagy function to compensate energy loss.
Assuntos
Antitireóideos/uso terapêutico , Doença de Graves/sangue , Doença de Graves/tratamento farmacológico , Hipertireoidismo/sangue , Receptores de Superfície Celular/sangue , Triglicerídeos/sangue , ATPases Vacuolares Próton-Translocadoras/sangue , Biomarcadores/sangue , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/fisiologia , Estudos RetrospectivosRESUMO
Mitochondrial disease is associated with a wide variety of clinical presentations, even among patients carrying heteroplasmic mitochondrial DNA (mtDNA) mutations, probably because of variations in mutant mtDNA proportions at the tissue and organ levels. Although several case reports and clinical trials have assessed the effectiveness of various types of drugs and supplements for the treatment of mitochondrial diseases, there are currently no cures for these conditions. In this study, we demonstrated for the first time that low dose resveratrol (RSV) ameliorated mitochondrial respiratory dysfunction in patient-derived fibroblasts carrying homoplasmic mtDNA mutations. Furthermore, low dose RSV also facilitated efficient cellular reprogramming of the patient-derived fibroblasts into induced pluripotent stem cells, partly due to improved cellular viability. Our results highlight the potential of RSV as a new therapeutic drug candidate for the treatment of mitochondrial diseases.
Assuntos
Antioxidantes/metabolismo , Respiração Celular/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Estilbenos/metabolismo , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Humanos , Células-Tronco Pluripotentes/fisiologia , ResveratrolRESUMO
Objective The management of blood pressure (BP) in hypertensive patients is the key to preventing a progression of organ damage. The brachial BP (bBP) has been used as the representative method for measuring the BP. The central BP (cBP), which is, different from the bBP due to the propagation and the reflection of the pulse wave in the arterial system, has recently received attention because it can now be estimated non-invasively. We examined the relationships between the difference in the central systolic BP (csBP) and the brachial systolic BP (bsBP) (Δ) and other factors in hypertensive patients. Methods The bsBP and csBP were measured in patients with essential hypertension and the relationships between the bsBP, csBP, or Δ and background factors including age, the brain natriuretic peptide (BNP) level, the estimated glomerular filtration rate (eGFR), flow-mediated vasodilation (an index of vascular endothelial function), the cardio-ankle vascular index (CAVI, an index of arteriosclerosis), and the carotid intima-media thickness (an index of atherosis) were investigated. Results The data of 191 patients were analyzed. Although there was no significant correlation between the CAVI and the bsBP; positive correlations were observed between the CAVI and the csBP (r=0.249, p=0.001). The Δ value showed significant positive correlations with age, and the BNP, eGFR, and CAVI values. Conclusion The csBP is more strongly associated with arteriosclerosis than the bsBP. Moreover, the Δ value is more strongly associated with cardiac function, renal function, and arteriosclerosis than the bsBP or csBP. These data suggested that the Δ value may have a greater prognostic value than the bsBP or csBP and may be worth calculating in the clinical setting.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Adulto , Fatores Etários , Idoso , Índice Tornozelo-Braço , Arteriosclerose/fisiopatologia , Determinação da Pressão Arterial , Espessura Intima-Media Carotídea , Hipertensão Essencial , Feminino , Taxa de Filtração Glomerular , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Vasodilatação/fisiologiaRESUMO
The effect of unilateral adrenalectomy on blood pressure (BP) outcome in primary aldosteronism (PA) is diverse. Therefore, we sought to investigate the preoperative factors contributing to postoperative BP outcome. Data for 96 PA patients who underwent unilateral adrenalectomy at our institution from January 2000 to February 2015 were retrospectively collected. Based on postoperative BP after a 12-month follow-up period, the patients were categorized into two groups: cured (C) (<140/90 mm Hg with no antihypertensive drug) and not cured (NC) (if not normotensive). Patient demographics, blood and urine data, data of loading tests and adrenal vein sampling were evaluated. In all, 46 patients were categorized as C and 50 patients as NC. There were significantly more males in the NC group. Age, body mass index (BMI), number of antihypertensive drugs prescribed, serum uric acid concentration and contralateral ratio (CR) after adrenocorticotropic hormone stimulation were significantly higher in the NC group. In the multivariate model, BMI and CR significantly correlated with resolution outcome. The optimal cutoff values were 23.3 kg m-2 for BMI and 0.5 for CR, and when both parameters were used as predictors, the most optimal cutoff values for BMI and CR were 25.2 kg m-2 and 0.1, respectively. BMI and CR significantly correlated with BP outcome after adrenalectomy. To our knowledge, this is the first report to show that in addition to BMI, CR is a factor in postoperative BP outcome and to determine the optimal cutoff values of BMI and CR and calculate their sensitivities and specificities.
Assuntos
Adrenalectomia , Pressão Sanguínea , Hiperaldosteronismo/cirurgia , Adulto , Idoso , Índice de Massa Corporal , Feminino , Humanos , Hiperaldosteronismo/sangue , Hiperaldosteronismo/urina , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Resultado do TratamentoRESUMO
This is a retrospective study aimingto clarify the current status of preimplantation genetic diagnosis (PGD) in Japan. Our data were collected from 12 facilities between September 2004 and September 2012, and entered into a database. A majority of PGD in Japan was performed for balanced structural chromosomal abnormalities in couples with recurrent miscarriage. PGD for monogenic diseases was performed only in two facilities. The average maternal age was 38 years for monogenic diseases and 40 years for chromosomal abnormalities. Overall there have been671 cycles to oocyte retrieval reported. Of these cycles, 85% (572 cycles)were for chromosomal abnormalities, and 15% (99 cycles) for monogenic diseases. Diagnosis rates in the current study were 70.8% for monogenic diseases and 94.0% for chromosomal abnormalities. Rates of embryo transfer of PGD were 62.7% for monogenic diseases and 25.5% for chromosomal abnormalities. Clinical pregnancy rates per embryo transfer were 12.0% for monogenic diseases and 35.6% for chromosomal abnormalities. Our study is the first PGD report from all facilities which had the approval of the ethics committee of the Japanese Society of Obstetrics and Gynecology. We have built a basis for gathering continuous PGD data in Japan.
RESUMO
To examine the involvement of (pro)renin receptor in the accelerated organ damage in streptozotocin-induced diabetic male SHRsp, the rats fed a high-salt diet were divided into 5 groups: a group treated with the vehicle, a group treated with 15 mg/kg/day of imidapril (ACEi), a group treated with 60 mg/kg/day of imidapril (High ACEi), a group treated with handle region peptide (HRP), and a group treated with both ACEi and HRP (ACEi+HRP). After 8 weeks, the arterial pressure was similar in the vehicle and HRP groups and decreased in the ACEi-treated groups. The renal angiotensin II content decreased similarly in the groups treated with ACEi and/or HRP. Urinary protein excretion also decreased in the ACEi, High ACEi, and HRP groups and significantly further decreased in the ACEi+HRP group. The heart weight of the ACEi+HRP group was significantly lower than that of any other groups, although the cardiac angiotensin II levels decreased similarly in the groups treated with ACEi and/or HRP. Thus, (pro)renin receptor contributes to the accelerated pathogenesis in the heart and kidneys of diabetic SHRsp.