Prevalence of, risk factors for, and target organ damage from metabolic syndrome among people living with HIV on ART: A cross-sectional analysis in Chongqing, China.

INTRODUCTION: The incidence of metabolic syndrome (MetS) in people living with HIV is significantly higher than in people without HIV. MetS is not only a major driver of cardiovascular disease (CVD) but is also closely related to the development of chronic kidney disease (CKD). The aim of this study was to investigate the prevalence of and risk factors for MetS and to further understand the degree of damage to target organs. METHODS: This was a cross-sectional descriptive study conducted at Chongqing Public Health Medical Center, China. Information was collected via questionnaire survey, physical examination, and laboratory tests. We used the China Diabetes Society guidelines to define MetS. Pooled cohort equations were calculated to compare CVD risk in the next 10 years in people living with HIV aged ≥40 years with or without MetS. We used Student's t-test, the chi-squared test, Fisher's exact test, binary logistic regression, and multiple linear regression in the statistical analysis. RESULTS: The study included 979 people living with HIV, including 13 who have experienced CVD, receiving antiretroviral therapy (ART). The median age was 43.0 years, 20.9% were female, and the median ART time was 45.0 months. The prevalence of MetS was 33.9%. The components of MetS criteria were hyperglycaemia (50.4%), hypertriglyceridaemia (48.4%), hypertension (46.8%), low concentrations of high-density lipoprotein cholesterol (28.2%), and abdominal obesity (25.0%). Higher body mass index (odds ratio [OR] 1.266; 95% confidence interval [CI] 1.203-1.333), higher total cholesterol (OR 1.267; 95% CI 1.011-1.588), high alcohol consumption (OR 1.973; 95% CI 1.009-3.859), and family history of diabetes (OR 1.726; 95% CI 1.075-2.770) were independent risk factors for MetS. Compared with the non-MetS group, the MetS group had a higher rate of urine albumin (23.8% vs 14.8%, p = 0.001), and the estimated glomerular filtration rate <90 mL/min/1.73 m2 (18.37% vs. 12.8%, p = 0.020) and ß2-microglobin (p = 0.004) increased more markedly in the MetS group. Regarding the risk of developing CVD events in the next 10 years, 38.5% of those in the MetS group were at high or very high risk, which was significantly higher than in the non-MetS group (p < 0.001). In addition, age (p < 0.001) and sex (p = 0.002) are independent risk factors for developing CVD events in the next 10 years. CONCLUSIONS: The prevalence of MetS in people living with HIV on ART is high in Chongqing, China. Risk factors for the development of MetS are high alcohol consumption, family history of diabetes, higher body mass index, and higher total cholesterol levels. In addition, MetS is associated with a risk of CKD and the incidence of 10-year CVD.

Lumbar Scheuermann's disease found in a patient with osteogenesis imperfecta (OI) caused by a heterozygous mutation in COL1A2 (c.4048G > A): a case report.

BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder characterized by increased bone fragility and a series of extraskeletal manifestations. Approximately 90 % of OI cases are caused by type I collagen variants encoded by the collagen type I alpha 1 (COL1A1) or type I alpha 2 (COL1A2) gene. Lumbar Scheuermann's disease is an atypical type of Scheuermann's disease accompanied by Schmorl's nodes and irregular endplates but without pronounced kyphosis. Although the etiology of Scheuermann's disease is unclear, genetic and environmental factors are likely. CASE PRESENTATION: Here, we report a 32-year-old male patient who experienced multiple brittle fractures. Gene sequencing revealed a heterozygous mutation, c.4048G > A (p.G1350S), in the COL1A2 gene, and the patient was diagnosed with OI. Magnetic resonance imaging of his thoracolumbar spine revealed multiple Schmorl's nodes. CONCLUSIONS: This is the first reported case of OI coexisting with the spinal presentation of Scheuermann's disease. It is speculated that the COL1A2 gene mutation might be an underlying novel genetic cause of Scheuermann's disease. In conclusion, this case demonstrates the relationship between Scheuermann's disease and OI for the first time and enriches the genotype-phenotype spectrum of OI.

Functional analysis of thyroid peroxidase gene mutations resulting in congenital hypothyroidism.

OBJECTIVE: Thyroid peroxidase (TPO) is essential for thyroid hormone biosynthesis. TPO mutations might lead to congenital hypothyroidism. In the present study, we analysed the function of a compound heterozygous TPO mutation in a Chinese family. DESIGN: We studied a 23-year-old Chinese girl with a history of growth retardation and severe constipation from the age of 3 months, who was diagnosed as having congenital hypothyroidism. METHODS: Genomic DNA was extracted from peripheral blood samples obtained from the patient's family members. The genomic DNA was sequenced to detect mutations in a panel of genes associated with congenital hypothyroidism. Bioinformatic analysis and structural modelling predicted the potential disease-causing potential mutant genes and the microstructure of the mutant protein, respectively. Western blotting and ELISA were used to measure protein expression, and guaiacol oxidation assay measured the TPO activity of the mutant protein. RESULTS: We identified a compound heterozygous mutation (c.C1993T, c.T2473C) in the TPO gene. Bioinformatic analysis predicted that the TPO mutations were potentially disease causing. Structural modelling predicted damage to the microstructure of the mutant TPO protein. Western blotting and ELISA showed reduced protein levels of the mutant TPO protein compared with that of the wild-type protein. The mutant TPO protein showed weaker activity compared with that of the wild-type protein. CONCLUSIONS: A novel compound heterozygous mutation of TPO gene was identified in a Chinese family. This mutation might alter the extracellular microstructure of TPO, and decrease its expression and the activity, resulting in congenital hypothyroidism.

A negative association between urinary iodine concentration and the prevalence of hyperuricemia and gout: a cross-sectional and population-based study in Mainland China.

BACKGROUND AND AIMS: Iodine is one of the most important trace elements in the human body. It is not only the main component of thyroid hormones but also has extrathyroid biological functions. To date, there have been no large-scale epidemiological studies on the relationship between hyperuricemia and iodine intake, although both are closely related to health. A population-based epidemiological survey in China offers such an opportunity. METHODS: This population-based cross-sectional study recruited 75,653 adults aged ≥ 18 years from 2015 to 2017 with a randomized, multistage, stratified sampling strategy. Serum uric acid levels and urinary iodine concentrations (UICs) were measured. RESULTS: Stratified by UIC, the prevalence of hyperuricemia was 17.8%, 18.8%, 16.0% and 13.7% in the UIC < 100, 100-199, 200-299, and ≥ 300 µg/L groups, respectively; the prevalence of gout was 4.0%, 3.4%, 2.4% and 1.7%, respectively. The prevalence of gout decreased significantly as the UIC increased. The prevalence of hyperuricemia and gout were markedly higher in postmenopausal females than in the premenopausal population (hyperuricemia: 15.9% vs. 8.3%, X2 = 520.072, p < 0.001; gout: 3.6% vs. 1.3%, X2 = 219.889, p < 0.001), and the prevalence decreased as the UIC increased. Subjects in the more than adequate and excessive iodine groups had lower likelihoods of having hyperuricemia [aOR = 0.81 (95% CI 0.77-0.85), aOR = 0.68 (95% CI 0.64-0.72)] and lower odds of having gout than subjects in the adequate iodine (AI) group [aOR = 0.77 (95% CI 0.68-0.86), aOR = 0.59 (95% CI 0.51-0.68)]. CONCLUSIONS: UIC was inversely associated with the occurrence of hyperuricemia and gout. More in-depth research and prospective studies are needed to explore the molecular mechanisms and confirm the observed association.

Thyroid hormone receptor sumoylation is required for preadipocyte differentiation and proliferation.

Thyroid hormone and thyroid hormone receptor (TR) play an essential role in metabolic regulation. However, the role of TR in adipogenesis has not been established. We reported previously that TR sumoylation is essential for TR-mediated gene regulation and that mutation of either of the two sites in TRα or any of the three sites in TRß reduces TR sumoylation. Here, we transfected TR sumoylation site mutants into human primary preadiocytes and the mouse 3T3L1 preadipocyte cell line to determine the role of TR sumoylation in adipogenesis. Reduced sumoylation of TRα or TRß resulted in fewer and smaller lipid droplets and reduced proliferation of preadipocytes. TR sumoylation mutations, compared with wild-type TR, results in reduced C/EBP expression and reduced PPARγ2 mRNA and protein levels. TR sumoylation mutants recruited NCoR and disrupted PPARγ-mediated perilipin1 (Plin1) gene expression, associated with impaired lipid droplet formation. Expression of NCoRΔID, a mutant NCoR lacking the TR interaction domain, partially "rescued" the delayed adipogenesis and restored Plin1 gene expression and adipogenesis. TR sumoylation site mutants impaired Wnt/ß-catenin signaling pathways and the proliferation of primary human preadipocytes. Expression of the TRß K146Q sumoylation site mutant down-regulated the essential genes required for canonical Wnt signal-mediated proliferation, including Wnt ligands, Fzds, ß-catenin, LEF1, and CCND1. Additionally, the TRß K146Q mutant enhanced the canonical Wnt signaling inhibitor Dickkopf-related protein 1 (DKK1). Our data demonstrate that TR sumoylation is required for activation of the Wnt canonical signaling pathway during preadipocyte proliferation and enhances the PPARγ signaling that promotes differentiation.

Relationship Between Serum Thyrotropin Levels and Metabolic Diseases in Older Adults.

CONTEXT: Subclinical hypothyroidism is associated with metabolic diseases; however, it remains controversial in older individuals. OBJECTIVE: This work aimed to investigate the relationship between thyrotropin (TSH) levels and metabolic diseases. METHODS: In this cross-sectional study, sampling was conducted from nationally representative general communities from 31 provinces in mainland China. A total of6791 older (aged ≥65 years) and 55 303 young participants (aged 18-64 years) were selected after excluding individuals with overt hyperthyroidism or overt hypothyroidism. According to the kit, TSH reference range (0.27-4.2 mU/L) and the age-specific TSH range previously formulated (an upper limit of 8.86 mU/L for older adults and 6.57 mU/L for young adults), the older adults and young adults were separately divided into 4 groups based on their TSH levels. Main outcome measures included anthropometric assessments, serum concentrations of thyroid functions, and various metabolic parameters. RESULTS: In contrast to young adults, there was no significant increase in the prevalence of any metabolic disorders assessed in the slightly elevated TSH group (TSH 4.21-8.86 mU/L) compared to the euthyroid group (TSH 0.27-4.2 mU/L) among older adults. After adjusting for interference factors, a TSH level higher than 8.86 mU/L was found to be an independent risk factor for low high-density lipoprotein cholesterol (OR, 1.84; 95% CI, 1.14-2.98) and dyslipidemia (OR, 1.49; 95% CI, 1.09-2.04) when compared to the euthyroid group in older adults. CONCLUSION: Slightly elevated TSH levels are not associated with an increased risk of metabolic diseases in older adults. Therefore, we recommend raising the upper limit of the TSH range for individuals aged 65 years and older.

Elevated COX2 expression and PGE2 production by downregulation of RXRα in senescent macrophages.

Increased systemic level of inflammatory cytokines leads to numerous age-related diseases. In senescent macrophages, elevated prostaglandin E2 (PGE2) production contributes to the suppression of T cell function with aging, which increases the susceptibility to infections. However, the regulation of these inflammatory cytokines and PGE2 with aging still remains unclear. We have verified that cyclooxygenase (COX)-2 expression and PGE2 production are higher in LPS-stimulated macrophages from old mice than that from young mice. Downregulation of RXRα, a nuclear receptor that can suppress NF-κB activity, mediates the elevation of COX2 expression and PGE2 production in senescent macrophages. We also have found less induction of ABCA1 and ABCG1 by RXRα agonist in senescent macrophages, which partially accounts for high risk of atherosclerosis in aged population. Systemic treatment with RXRα antagonist HX531 in young mice increases COX2, TNF-α, and IL-6 expression in splenocytes. Our study not only has outlined a mechanism of elevated NF-κB activity and PGE2 production in senescent macrophages, but also provides RXRα as a potential therapeutic target for treating the age-related diseases.

A simple spatial working memory and attention test on paired symbols shows developmental deficits in schizophrenia patients.

People with neuropsychiatric disorders such as schizophrenia often display deficits in spatial working memory and attention. Evaluating working memory and attention in schizophrenia patients is usually based on traditional tasks and the interviewer's judgment. We developed a simple Spatial Working Memory and Attention Test on Paired Symbols (SWAPS). It takes only several minutes to complete, comprising 101 trials for each subject. In this study, we tested 72 schizophrenia patients and 188 healthy volunteers in China. In a healthy control group with ages ranging from 12 to 60, the efficiency score (accuracy divided by reaction time) reached a peak in the 20-27 age range and then declined with increasing age. Importantly, schizophrenia patients failed to display this developmental trend in the same age range and adults had significant deficits compared to the control group. Our data suggests that this simple Spatial Working Memory and Attention Test on Paired Symbols can be a useful tool for studies of spatial working memory and attention in neuropsychiatric disorders.

Prevalence and risk factors of hypothyroidism after universal salt iodisation: a large cross-sectional study from 31 provinces of China.

OBJECTIVES: To investigate the prevalence and risk factors of hypothyroidism after universal salt iodisation for 20 years in mainland China. DESIGN: Nationwide, cross-sectional survey. SETTING AND PARTICIPANTS: The Thyroid Disorders, Iodine Status and Diabetes epidemiological study included adults from 31 provinces of China. Data included demographic, physical characteristics, urine, serum thyroid-stimulating hormone (TSH), thyroid-peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb) and thyroid ultrasonography. Subclinical hypothyroidism (SCH) was classified into severe SCH (TSH >10 mU/L) and mild SCH (TSH 4.2-9.9 mU/L). A total of 78 470 (38 182 men and 40 288 women) participants were included in the final analysis. RESULTS: The prevalence of hypothyroidism was 13.95%. The prevalence rates of overt hypothyroidism (OH) and SCH were 1.02% and 13.93%, which mild SCH was significantly higher than severe SCH (12.18% vs 0.75%). Prevalence was higher in women than in men, and this gender difference was noted among all age groups. The prevalence of mild SCH, severe SCH and OH increases by 1.16%, 1.40% and 1.29% for every 10 years older. TPOAb or/and TgAb positive were significantly associated with OH and severe SCH (OR 15.9, p<0.001). However, SCH was positively correlated with increased urine iodine concentration, but this correlation was only in antibody-negative female patients. In non-autoimmune and male populations, there was a U-shaped relationship between severe SCH and OH and urine iodine concentration. CONCLUSIONS: Mild SCH is the most common form of hypothyroidism, which is related to iodine intake. Severe SCH is more similar to OH which autoimmune is the main cause. The various effects of iodine on hypothyroidism depend on thyroid autoimmune and gender.

The different outcomes in the elderly with subclinical hypothyroidism diagnosed by age-specific and non-age-specific TSH reference intervals: a prospectively observational study protocol.

Introduction: Subclinical hypothyroidism (SCH) is a common endocrine disorder characterized by elevated thyroid-stimulating hormone (TSH) levels and normal free thyroxine (FT4) levels. The overdiagnosis and overtreatment of SCH in elderly patients have become concerns as TSH levels naturally increase with age. Studies have shown that many elderly patients with SCH can recover without treatment, and the administration of levothyroxine (L-T4) does not improve their prognosis. Therefore, It is necessary to establish age-specific reference ranges for TSH in elderly individuals to aid in clinical decision-making and prevent overdiagnosis. Methods: This is a multicenter prospective study that focuses on Chinese elderly patients with SCH who have TSH levels below 10 mU/L. After obtaining the informed consent of the patients, their initial diagnosis information will be registered, and they will be asked to fill out questionnaires such as the Montreal Cognitive Assessment-Basic (MoCA-B), Hamilton Depression Scale (HAMD), Hypothyroidism Symptom Questionnaire (SRQ), frail scale(FRAIL), fatigue scale, and EQ-5D. In addition, thyroid function tests, blood lipid analysis, carotid artery ultrasound, and thyroid ultrasound examinations will be conducted. Patients will also be grouped according to FT4 levels, the changes in FT4 and its relationship with TSH can also be described. For patients over 80 years old, a decrease in FT4 will be used as an endpoint event, while for patients between 60-80 years old, TSH levels greater than or equal to 10mIU/L or a decline in FT4 will be used as the endpoint event. The TSH reference intervals of the general and elderly populations will be used to calculate medical costs associated with multiple follow-ups of patients, and a social-economic analysis will also be conducted. Discussion: This study will prospectively observe elderly patients with SCH who are screened using both age-specific and non-age-specific TSH reference ranges for the elderly population. We will compare the results of elderly patients diagnosed with SCH using different reference ranges and analyze their association with FT4 to identify meaningful SCH patients and reduce over diagnosis and over treatment of elderly SCH. Ethics: The Medical Science Research Ethics Committee of the First Affiliated Hospital of China Medical University approved this study (ID: AF-SOP-07-1.1-01). The results will be published in an open-access journal. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2300070831.

Changing Iodine Status and the Incidence of Thyroid Disease in Mainland China: A Prospective 20-Year Follow-Up Study.

Background: We aimed to assess the long-term effects of the transition in iodine status on the incidence of thyroid disorders over 20 years of follow-up. Methods: The original prospective cohort study, started in 1999 (n = 3761), classified three regions in north China based on iodine status (insufficient iodine, more than adequate iodine, and excessive iodine, respectively) for 5 years. Subsequently, participants were followed for up to another 15 years to assess the long-term effects of shifts to adequate iodine on the incidence of thyroid disorders. Panshan transitioned from insufficient to adequate iodine, and Huanghua transitioned from excessive to more than adequate iodine. Both regions were compared with Zhangwu, in which iodine status changed from more than adequate to adequate iodine (from 214 to 167.2 µg/L). A cluster sampling method was used to select participants in the three regions. Participants completed questionnaires and underwent thyroid ultrasonography. Urinary iodine concentrations (UICs), serum thyroid hormone concentration, and thyroid antibodies were measured. Results: When the iodine status changed from insufficient to adequate (with the median UIC increasing from 88 to 141.9 µg/L), the incidence density of subclinical hyperthyroidism, positive thyroperoxidase antibody, positive thyroglobulin antibody (TgAb), and goiter decreased significantly (p < 0.05 for all). Additionally, the cumulative incidence of subclinical hypothyroidism was significantly lower compared with the region where the iodine status changed from being more than adequate to adequate (1.9% vs. 6.0%, p < 0.001). When the iodine status changed from excessive to more than adequate (median UIC from 634 to 266.7 µg/L), a significant decrease in the incidence density of subclinical hyperthyroidism, positive thyroid antibodies, positive TgAb, and goiter (p < 0.05 for all) were also found. However, an increase in thyroid nodule incidence density (17.26 vs. 28.25 per 1000 person-years, p < 0.001) was seen. Conclusions: The incidence of thyroid disorders (except for thyroid nodules) stabilized or decreased among adults in the three communities from year 5 to year 15 of follow-up. Appropriate iodine fortification is safe and effective over the long term. Restoring urinary iodine to appropriate levels reduces population risk for thyroid disorders.

Somatic IDH1 Hotspot Variants in Chinese Patients With Pheochromocytomas and Paragangliomas.

CONTEXT: IDH1 is a pheochromocytoma/paraganglioma (PPGL) susceptibility gene; however, its role, especially in the Chinese population, has not been characterized. OBJECTIVE: To determine the prevalence of somatic IDH1 hotspot variants in a large cohort of Chinese patients with PPGLs and to summarize associated phenotypes. METHODS: This retrospective cross-sectional study was based on a main cohort of 1141 patients with PPGLs from 2 tertiary-care centers in China. We included 50 cases with urinary bladder paragangliomas (UBPGLs), of whom 29 were part of the main cohort and 21 were from other centers. Two additional cases with IDH1 hotspot variants not part of the main cohort were also included for summarizing IDH1-associated phenotypes. Next-generation sequencing of tumor DNA was used to analyze a customized panel of genes. RESULTS: The overall prevalence of IDH1 hotspot variants in the main cohort was 0.5% (6/1141). Among those PPGLs without mutations in 15 common driver genes, the prevalence of IDH1 variants was 0.9% (4/455). When restricted to paraganglioma (PGL) without mutations, the prevalence reached 4.7% (4/86). Among UBPGLs, IDH1 hotspot variants accounted for 8% (4/50). Together, all 10 patients (9 PGLs and 1 pheochromocytoma) with IDH1 hotspot variants, including 3 females with concurrent EPAS1 hotspot variants, had apparently sporadic tumors, without metastasis or recurrence. There were 3 patients with biochemical data, all showing a non-adrenergic phenotype. CONCLUSIONS: The somatic IDH1 hotspot variants cause PPGL development in some Chinese patients, especially among those apparently sporadic PGLs with a non-adrenergic phenotype and without mutations in major PPGL driver genes.

Developmental Hypothyroidism Influences the Development of the Entorhinal-Dentate Gyrus Pathway of Rat Offspring.

BACKGROUND: Developmental hypothyroidism impairs learning and memory in offspring, which depend on extensive neuronal circuits in the entorhinal cortex, together with the hippocampus and neocortex. The entorhinal-dentate gyrus pathway is the main entrance of memory circuits. We investigated whether developmental hypothyroidism impaired the morphological development of the entorhinal-dentate gyrus pathway. METHODS: We examined the structure and function of the entorhinal-dentate gyrus pathway in response to developmental hypothyroidism induced using 2-mercapto-1-methylimidazole. RESULTS: 1,1´-Dioctadecyl-3,3,3´,3´-tetramethylindocarbocyanine perchlorate tract tracing indicated that entorhinal axons showed delayed growth in reaching the outer molecular layer of the dentate gyrus at postnatal days 2 and 4 in hypothyroid conditions. The proportion of fibers in the outer molecular layer was significantly smaller in the hypothyroid group than in the euthyroid group at postnatal day 4. At postnatal day 10, the pathway showed a layer-specific distribution in the outer molecular layer, similar to the euthyroid group. However, the projected area of entorhinal axons was smaller in the hypothyroid group than in the euthyroid group. An electrophysiological examination showed that hypothyroidism impaired the long-term potentiation of the perforant and the cornu ammonis 3-cornu ammonis 1 pathways. Many repulsive axon guidance molecules were involved in the formation of the entorhinaldentate gyrus pathway. The hypothyroid group had higher levels of erythropoietin-producing hepatocyte ligand A3 and semaphorin 3A than the euthyroid group. CONCLUSION: We demonstrated that developmental hypothyroidism might influence the development of the entorhinal-dentate gyrus pathway, contributing to impaired long-term potentiation. These findings improve our understanding of neural mechanisms for memory function.

Resistance to thyroid hormone beta coexisting with papillary thyroid carcinoma-two case reports of a thyroid hormone receptor beta gene mutation and a literature review.

Resistance to thyroid hormone beta (RTHß) is an autosomal dominant hereditary disorder that is difficult to diagnose because of its rarity and variable clinical features, which are caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies have indicated a close association between THRB mutations and human cancers, but the mechanistic role of THRB mutations in carcinogenesis is unknown. Herein, we report two cases of RTHß coexisting with papillary thyroid carcinoma (PTC) and their follow-up results. Two female patients presented with elevated serum thyroid hormone levels and nonsuppressed thyrotropin (TSH). Genetic analysis showed that each patient had a THRB gene mutation (p.P453T and p. R320H). Based on the results of ultrasound-guided fine-needle aspiration biopsy, the thyroid nodules were suspected to be PTC. Intraoperative pathology confirmed that the two patients had PTC with multifocal carcinoma of both lobes. One patient underwent total thyroidectomy and central lymph node dissection, and the other underwent total thyroidectomy alone. Following surgery, large doses of levothyroxine were administered to suppress TSH levels and prevent recurrent or persistent disease. However, it is difficult to continually suppress TSH levels below the upper limit of the normal range. To date, the two patients have experienced no recurrence of PTC on ultrasound.

Proteomic Analysis of the Intestinal Resistance to Thyroid Hormone Mouse Model With Thyroid Hormone Receptor Alpha Mutations.

Thyroid hormone is critical during the development of vertebrates and affects the function of many organs and tissues, especially the intestine. Triiodothyronine (T3) is the active form and can bind to thyroid hormone nuclear receptors (TRs) to play a vital role in the development of vertebrates. The resistance to thyroid hormone α, as seen in patients, has been mimicked by the ThraE403X mutation. To investigate the mechanisms underlying the effect of TRα1 on intestinal development, the present study employed proteomic analysis to identify differentially expressed proteins (DEPs) in the distal ileum between homozygous ThraE403X/E403X and wild-type Thra+/+ mice. A total of 1,189 DEPs were identified, including 603 upregulated and 586 downregulated proteins. Proteomic analysis revealed that the DEPs were highly enriched in the metabolic process, the developmental process, the transporter of the nutrients, and the intestinal immune system-related pathway. Of these DEPs, 20 proteins were validated by parallel reaction monitoring analysis. Our intestinal proteomic results provide promising candidates for future studies, as they suggest novel mechanisms by which TRα1 may influence intestinal development, such as the transport of intestinal nutrients and the establishment of innate and adaptive immune barriers of the intestine.

Histological, functional and transcriptomic alterations in the juvenile hippocampus in a mouse model of thyroid hormone resistance.

Background: Proper thyroid hormone signaling via the TRα1 nuclear receptor is required for normal neurodevelopmental processes. The specific downstream mechanisms mediated by TRα1 that impact brain development remain to be investigated. Methods: In this study, the structure, function and transcriptome of hippocampal tissue in a mouse model expressing the first RTHα mutation discovered in a patient, THRA E403X, were analyzed. RNAscope was used to visualize the spatial and temporal expression of Thra1 mRNA in the hippocampus of WT mice, which is corresponding to THRA1 mRNA in humans. The morphological structure was analyzed by Nissl staining, and the synaptic transmission was analyzed on the basis of long-term potentiation. The Morris water maze test and the zero maze test were used to evaluate the behavior. RNA-seq and quantitative real-time PCR were used to analyze the differentially expressed genes (DEGs) of the hippocampal tissues in the mouse model expressing the Thra E403X mutation. Results: The juvenile mutant Thra E403X mice presented with delayed neuronal migration, disordered neuronal distribution, and decreased synaptic plasticity. A total of 754 DEGs, including 361 upregulated genes and 393 downregulated genes, were identified by RNA-seq. DEG-enriched Gene Ontology (GO) and KEGG pathways were associated with PI3K-Akt signaling, ECM-receptor interaction, neuroactive ligand-receptor interaction, and a range of immune-related pathways. 25 DEGs were validated by qPCR. Conclusions: The ThraE403X mutation results in histological and functional abnormalities, as well as transcriptomic alterations in the juvenile mouse hippocampus. This study of the ThraE403X mutant offers new insights into the biological cause of RTHα-associated neurological diseases.

An epidemiological study of the serum thyrotropin reference range and factors that influence serum thyrotropin levels in iodine sufficient areas of China.

The aims of this study performed in 2007 were to verify the selection criteria proposed by the National Academy of Clinical Biochemistry (NACB) guidelines, to investigate factors that influence thyrotropin (TSH) levels, and to determine serum TSH reference range in iodine sufficient areas of China. After excluding 291 subjects, a total of 5,348 inhabitants from three iodine sufficient areas of Liaoning province were asked to fulfill the questionnaire, and take TSH, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) measurements and a thyroid ultrasound examination. The distribution of TSH was right skewed in normal people. It has been customary to log transform the values to observe the Gaussian distribution. In the subjects 12-19 years of age, the TSH level was significantly higher than in the other age groups (p<0.001), while there were no significant difference in the TSH values of the other age groups. The TSH levels in females(1.68±1.90mIU/L) were significantly higher than in males (1.45±1.92mIU/L) (p<0.001). Therefore, the normal TSH range in males over age 20 was 0.43-4.74mIU/L, and in females the range was 0.48-5.39 mIU/L. A family history of thyroid disease, abnormal thyroid ultrasound, a thyroid antibody-positive status were the factors that influenced the TSH reference range. Non-thyroid disease did not impact the TSH reference range significantly. We recommend use of a TSH reference range 0.46-5.19mIU/L in iodine sufficient areas of China for males and females over 20 years old. We suggest using a normal thyroid ultrasound as a new criterion in addition to the NACB guidelines to determine the TSH reference range.

The relationship between serum thyrotropin and components of metabolic syndrome.

To explore the relationship between serum thyrotropin and components of metabolic syndrome in a Chinese cohort. A total of 1534 adult inhabitants in DaDong district of Shenyang were asked to fulfill the questionnaire, complete physical examination and OGTT. Blood samples were collected to test thyrotropin (TSH), fasting plasma glucose (FPG), OGTT 2h PG, fasting insulin (FINS), triglyceride (TG) and high density lipoprotein cholesterol (HDL-C). Serum TSH in metabolic syndrome group was higher than that in the non-metabolic syndrome group (2.54 mIU/L vs. 2.22 mIU/L, p<0.05). TG level increased significantly in subclinical hypothyroid group compared with euthyroid subjects (1.73±0.12 mmol/L vs. 1.47±0.03 mmol/L, p<0.05), and HDL-C decreased significantly in patients with subclinical hypothyroidism compared with euthyroid subjects (1.26±0.27 mmol/L vs. 1.33±0.27 mmol/L, p<0.05). The prevalence of hypertension was higher in the subclinical hypothyroid group than that in euthyroid group (42.86% vs. 33.2%, p<0.05). The serum TSH within the reference range was positively related with the prevalence of overweight/obesity. Slight increase in serum TSH maybe a risk factor for metabolic syndrome.

The correlation between thyrotropin and dyslipidemia in a population-based study.

This study investigated the relationship between serum thyrotrophin levels and dyslipidemia in subclinical hypothyroid and euthyroid subjects. A total of 110 subjects with subclinical hypothyroidism and 1,240 euthyroid subjects enrolled in this study. Patients with subclinical hypothyroidism had significantly lower high density lipoprotein cholesterol (HDL-C) levels than those who were euthyroid. The lipid profiles were each categorized and mean thyrotrophin levels were higher in subjects in the dyslipidemia subclasses than subjects in the normal subclasses. Thyrotrophin was positively associated with serum triglyceride and negatively associated with serum HDL-C in women. Thyrotrophin was also positively associated with total cholesterol (TC) in the overweight population along with TC and LDL-C in overweight women. In the euthyroid population, thyrotrophin was positively associated with TC in the overweight population. In conclusion, serum thyrotrophin was correlated with dyslipidemia in subclinical hypothyroid and euthyroid subjects; the correlation was independent of insulin sensitivity.