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Background@#The transcription factor paired box 8 (PAX8) was associated with type 2 congenital non-goitrous hypothyroidism (CHNG2), a clinical phenotype of congenital hypothyroidism (CH). Though studied in a few regions with different ethnicities, the incidence of PAX8 mutations varied, even among Chinese cohorts in different regions. This study aimed to identify and characterize PAX8 mutations and explore the prevalence of its mutations in another cohort of CH.@*Methods@#The 105 unrelated Chinese patients with CH were collected from four major hospitals. Exomes of the 105 samples were sequenced by Hiseq 2000 platform to identify mutations of PAX8 on genomic DNAs extracted from peripheral blood samples. Luciferase reporter assays were used to assess the effects of mutations on the transcription of thyroid peroxidase (TPO).@*Results@#Three PAX8 mutations in four subjects were identified in 105 samples. One variant, rs189229644, was detected in two subjects, and categorized as uncertain significance. The other two missense mutations (275T>C/Ile92Thr and 398G>A/Arg133Gln) were not detected in three large-scale genotyping projects, namely 1000 Genome Project, Exome Aggregation Consortium and GO Exome Sequencing Project. Functional studies for the two mutations revealed that they could impair the transcription ability of PAX8 on one of its target genes, TPO. Therefore, the two mutations were causative for the pathogenesis of CHNG2. After combining the studies of PAX8 mutations, an average frequency of 1.74% (21/1209) could be obtained in Chinese patients with CH.@*Conclusion@#The study specifically demonstrates the role of two mutations in impairing the transcription ability of PAX8, which should be considered as pathogenic variants for CH.
ABSTRACT
BACKGROUND@#The transcription factor paired box 8 (PAX8) was associated with type 2 congenital non-goitrous hypothyroidism (CHNG2), a clinical phenotype of congenital hypothyroidism (CH). Though studied in a few regions with different ethnicities, the incidence of PAX8 mutations varied, even among Chinese cohorts in different regions. This study aimed to identify and characterize PAX8 mutations and explore the prevalence of its mutations in another cohort of CH.@*METHODS@#The 105 unrelated Chinese patients with CH were collected from four major hospitals. Exomes of the 105 samples were sequenced by Hiseq 2000 platform to identify mutations of PAX8 on genomic DNAs extracted from peripheral blood samples. Luciferase reporter assays were used to assess the effects of mutations on the transcription of thyroid peroxidase (TPO).@*RESULTS@#Three PAX8 mutations in four subjects were identified in 105 samples. One variant, rs189229644, was detected in two subjects, and categorized as uncertain significance. The other two missense mutations (275T>C/Ile92Thr and 398G>A/Arg133Gln) were not detected in three large-scale genotyping projects, namely 1000 Genome Project, Exome Aggregation Consortium and GO Exome Sequencing Project. Functional studies for the two mutations revealed that they could impair the transcription ability of PAX8 on one of its target genes, TPO. Therefore, the two mutations were causative for the pathogenesis of CHNG2. After combining the studies of PAX8 mutations, an average frequency of 1.74% (21/1209) could be obtained in Chinese patients with CH.@*CONCLUSION@#The study specifically demonstrates the role of two mutations in impairing the transcription ability of PAX8, which should be considered as pathogenic variants for CH.
ABSTRACT
BACKGROUND: Capillarization of hepatic sinusoids is an inevitable part in liver fibrosis and cirrhosis, and is a characteristic lesion inducing portal hypertension. However, curcumin effects on the capillarization of hepatic sinusoids and the underlying mechanism remain unclear. OBJECTIVE: To observe the effect of curcumin (a natural polyphenolic compound derived from the rhizome of Curcuma longa)on the microstructure and secretion of hepatic sinusoidal endothelial cells(HSECs),and to further explore its intervention on sinusoidal capillarization and pharmacological action mechanism of anti-liver fibrosis and target sites. METHODS: The rat HSECs were cultured and divided into seven groups: blank control group received no intervention and cells in the other groups were activated by leptin, followed by treatment with nothing (model group), high-, medium- and low-dose of curcumin, colchicine and salvia miltiorrhiza phenolic acid B, respectively, for 48 hours. RESULTS AND CONCLUSION: Under scanning and transmission electron microscopes, with the increasing activation of leptin, the number of fenestrae in HSECs was increased and the aperture was decreased. Curcumin could increase and enlarge narrowed or disappeared fenestrae caused by leptin, attenuated the thickness and scope of extracellular basement membrane, and reduced the degree of capillarization of hepatic sinusoids in a dose-dependent manner. Real-time PCR and ELISA results showed that after activation of leptin, mRNA and protein expression levels of endothelin-1 and vascular endothelial growth factor in HSECs were significantly increased compared with the blank control group (P < 0.05), while the expressions showed a significant decrease after treatment with curcumin in a dose-dependent manner (P < 0.05). There was also a gradient reduction in the protein expression of endothelin-1 and vascular endothelial growth factor in HSECs treated with curcumin. Moreover, all above mRNA and protein expression levels in the high-dose curcumin group were significantly lower than those in the colchicine and salvia miltiorrhiza phenolic acid B groups. In summary, curcumin can significantly alleviate the sinusoidal capillarization, and thus delay the development of liver fibrosis, probably by down-regulating the expression levels of endothelin-1 and vascular endothelial growth factor.
ABSTRACT
<p><b>OBJECTIVE</b>To investigate 16 to 22-year-old young adults' perception of malocclusion, dental health and aesthetic firstly. To investigate the perception differences between young adults and orthodontists, and factors on perception difference.</p><p><b>METHODS</b>A sample of 16 to 22-year-old young adults was selected randomly in Department of Stomatology, Hospital of Nanjing Army Command College. A questionnaire, which consisted of socioeconomic status, index of orthodontic treatment need and dental health component (DHC) questionnaire, was proposed to them. Index of orthodontic treatment need comprised aesthetic component (AC) and DHC. An orthodontist measured orthodontic dental models of participants. Participants chose AC degree and DHC degree by their subjective perception. An orthodontist chose AC degree and DHC degree by their objective measurement.</p><p><b>RESULTS</b>71.08% and 70.59% of 204 participants respectively chose 'no need treatment' of AC degree and DHC degree by their subjective perception. 19.12% and 9.80% of participants were respectively chosen 'no need treatment' of AC degree and DHC degree by orthodontist's objective measurement. Objective measurement degree of orthodontist was higher than subjective perception degree of participants. Subjective perception of participants was little related to objective measurement of orthodontists. AC degree of male participants' subjective perception was lower than the female. DHC degree of urban participants' subjective perception was higher than the rural. DHC and AC degree of only child participants' subjective perception was higher than non-only child.</p><p><b>CONCLUSION</b>Perception about malocclusion, dental health and aesthetic had significant difference between 16 to 22-year-old young adults and orthodontists. Young adults tended to think that their teeth were more beautiful and healthy. The female young adults than the male tended to think that their teeth were not enough beautiful. Urban young adults were more unsatisfactory about their dental health than the rural. Only child young adults were more unsatisfactory about their dental aesthetic and health than the non-only child.</p>