Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production due to abnormalities in the hypothalamic-pituitary-thyroid axis, is the most common congenital endocrine disorder. We previously conducted comprehensive genetic screening of 102 patients with permanent CH born in Kanagawa Prefecture, Japan and identified mutations in several genes in 19 CH patients, including defects in genes encoding dual oxidase 2, thyroglobulin, thyrotropin receptor, thyroid peroxidase, and paired-box 8. Despite these findings, approximately 80% of cases remain unexplained. CH pedigrees unexplained by known genetic forms of CH have been reported in the literature and registered as congenital hypothyroidism, nongoitrous, 3 (CHNG3; %609893) in Online Mendelian Inheritance in Man. We also identified a Japanese pedigree of CH that was compatible with CHNG3. However, the exact genetic cause of CHNG3 was not revealed by standard analysis methods such as exome sequencing and array comparative genomic hybridization. We therefore took a combined approach and analyzed a total of 11 undiagnosed CH pedigrees by whole genome sequencing to analyze a 3-Mb linkage region, and found a disease-causing variant affecting a TTTG microsatellite in a noncoding region on chromosome 15. Further analysis revealed that 13.9% of 989 Japanese CH patients had abnormalities involving the TTTG microsatellite, with a substantial proportion (41.5%) of familial CH cases carrying these mutations. Identification of the genetic cause of CHNG3 provides new insights into the pathogenesis of CH, and highlights the need for continued exploration of noncoding genomic regions in Mendelian disorders of unknown etiology.

Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production due to abnormalities in the hypothalamic-pituitary-thyroid axis, is the most common congenital endocrine disorder. We previously conducted comprehensive genetic screening of 102 patients with permanent CH born in Kanagawa Prefecture, Japan and identified mutations in several genes in 19 CH patients, including defects in genes encoding dual oxidase 2, thyroglobulin, thyrotropin receptor, thyroid peroxidase, and paired-box 8. Despite these findings, approximately 80% of cases remain unexplained. CH pedigrees unexplained by known genetic forms of CH have been reported in the literature and registered as congenital hypothyroidism, nongoitrous, 3 (CHNG3; %609893) in Online Mendelian Inheritance in Man. We also identified a Japanese pedigree of CH that was compatible with CHNG3. However, the exact genetic cause of CHNG3 was not revealed by standard analysis methods such as exome sequencing and array comparative genomic hybridization. We therefore took a combined approach and analyzed a total of 11 undiagnosed CH pedigrees by whole genome sequencing to analyze a 3-Mb linkage region, and found a disease-causing variant affecting a TTTG microsatellite in a noncoding region on chromosome 15. Further analysis revealed that 13.9% of 989 Japanese CH patients had abnormalities involving the TTTG microsatellite, with a substantial proportion (41.5%) of familial CH cases carrying these mutations. Identification of the genetic cause of CHNG3 provides new insights into the pathogenesis of CH, and highlights the need for continued exploration of noncoding genomic regions in Mendelian disorders of unknown etiology.

Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production due to abnormalities in the hypothalamic-pituitary-thyroid axis, is the most common congenital endocrine disorder. We previously conducted comprehensive genetic screening of 102 patients with permanent CH born in Kanagawa Prefecture, Japan and identified mutations in several genes in 19 CH patients, including defects in genes encoding dual oxidase 2, thyroglobulin, thyrotropin receptor, thyroid peroxidase, and paired-box 8. Despite these findings, approximately 80% of cases remain unexplained. CH pedigrees unexplained by known genetic forms of CH have been reported in the literature and registered as congenital hypothyroidism, nongoitrous, 3 (CHNG3; %609893) in Online Mendelian Inheritance in Man. We also identified a Japanese pedigree of CH that was compatible with CHNG3. However, the exact genetic cause of CHNG3 was not revealed by standard analysis methods such as exome sequencing and array comparative genomic hybridization. We therefore took a combined approach and analyzed a total of 11 undiagnosed CH pedigrees by whole genome sequencing to analyze a 3-Mb linkage region, and found a disease-causing variant affecting a TTTG microsatellite in a noncoding region on chromosome 15. Further analysis revealed that 13.9% of 989 Japanese CH patients had abnormalities involving the TTTG microsatellite, with a substantial proportion (41.5%) of familial CH cases carrying these mutations. Identification of the genetic cause of CHNG3 provides new insights into the pathogenesis of CH, and highlights the need for continued exploration of noncoding genomic regions in Mendelian disorders of unknown etiology.

Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production due to abnormalities in the hypothalamic-pituitary-thyroid axis, is the most common congenital endocrine disorder. We previously conducted comprehensive genetic screening of 102 patients with permanent CH born in Kanagawa Prefecture, Japan and identified mutations in several genes in 19 CH patients, including defects in genes encoding dual oxidase 2, thyroglobulin, thyrotropin receptor, thyroid peroxidase, and paired-box 8. Despite these findings, approximately 80% of cases remain unexplained. CH pedigrees unexplained by known genetic forms of CH have been reported in the literature and registered as congenital hypothyroidism, nongoitrous, 3 (CHNG3; %609893) in Online Mendelian Inheritance in Man. We also identified a Japanese pedigree of CH that was compatible with CHNG3. However, the exact genetic cause of CHNG3 was not revealed by standard analysis methods such as exome sequencing and array comparative genomic hybridization. We therefore took a combined approach and analyzed a total of 11 undiagnosed CH pedigrees by whole genome sequencing to analyze a 3-Mb linkage region, and found a disease-causing variant affecting a TTTG microsatellite in a noncoding region on chromosome 15. Further analysis revealed that 13.9% of 989 Japanese CH patients had abnormalities involving the TTTG microsatellite, with a substantial proportion (41.5%) of familial CH cases carrying these mutations. Identification of the genetic cause of CHNG3 provides new insights into the pathogenesis of CH, and highlights the need for continued exploration of noncoding genomic regions in Mendelian disorders of unknown etiology.

　　This study sought to identify whether the inter-rater reliability of lower limb muscle strength measurements made using a hand-held dynamometer differs for patients with hip fracture according to the severity of their cognitive impairment. Of the 144 patients with hip fracture hospitalized at our institution, we excluded 28 from this study (18 with level III, IV, or M of independence in daily living for the demented elderly, 8 with a history of central nervous system disorders, and 2 who were transferred to another department), leaving 116 patients for analysis. These 116 patients were divided into three groups according to their severity of cognitive impairment: 44 with a normal level of independence in daily living for the demented elderly, 38 with level I independence, and 34 with level II independence. We compared the intra-class correlation coefficients and the standard error of measurement between the groups. There were no significant differences in the intra-class correlation coefficients between the groups. The standard error of measurement in the group with level II independence in daily living for the demented elderly was significantly lower than that in the other two groups. These findings indicate that the inter-rater reliability of lower limb muscle strength measurements using a hand-held dynamometer in patients with hip fracture did not differ between patients with mild or moderate cognitive impairment. Furthermore, the inter-rater reliability was high.

PURPOSE: It has been reported that the Pulse Contour Cardiac Output (PiCCO) is very useful mainly in the field of intensive care and treatment to grasp the pathophysiological conditions of pulmonary edema because of its capability of obtaining data such as Pulmonary Vascular Permeability Index (PVPI) and Extra Vascular Lung Water (EVLW). Furthermore, a high degree of usability of various markers has been reported for better understanding of the pathological conditions in cases with septicemia. MATERIALS AND METHODS: The correlation between the cardiorespiratory status based upon the PiCCO monitor (EVLW and PVPI) and inflammatory markers including C reactive protein, procalcitonin (PC), and Endotoxin Activity Assay (EAA) were evaluated in 11 severe cases that required treatment with a respirator in an intensive care unit. RESULTS: The EAA values were significantly higher in patients with abnormal EVLW at 0.46+/-0.20 compared to the normal EVLW group at 0.21+/-0.19 (p=0.0064). In a similar fashion, patients with abnormal PVPI values tended to have higher PC levels at 18.9+/-21.8 compared to normal PVPI cases at 2.4+/-2.2 (p=0.0676). On the other hand, PVPI was significantly higher in the abnormal EAA group at 3.55+/-0.48 in comparison with the normal EAA group at 1.99+/-0.68 (p=0.0029). The abnormal EAA group tended to have higher PVPI values than the normal EAA group. CONCLUSION: The EAA is a measurement method designed to estimate the activity of endotoxins in the whole blood. Our results suggest that the EAA value, which had the greatest correlation with lung disorders diagnosed by the PiCCO monitoring, reflects inflammatory reactions predominantly in the lungs.
Adult ; Aged ; Aged, 80 and over ; Cardiac Output/physiology ; Endotoxins/*blood ; Female ; Humans ; Lung Injury/*blood/*diagnosis/physiopathology ; Male ; Middle Aged ; Pulmonary Edema/blood/*diagnosis/physiopathology

Disorder of Sex Development, 46,XY/genetics* ; GATA4 Transcription Factor/genetics* ; Genetic Testing ; Heart Defects, Congenital ; Humans ; Male ; Molecular Structure ; Mutation/genetics*