Development and validation of a risk assessment model for prediabetes in China national diabetes survey.

BACKGROUND: Prediabetes risk assessment models derived from large sample sizes are scarce. AIM: To establish a robust assessment model for prediabetes and to validate the model in different populations. METHODS: The China National Diabetes and Metabolic Disorders Study (CNDMDS) collected information from 47325 participants aged at least 20 years across China from 2007 to 2008. The Thyroid Disorders, Iodine Status and Diabetes Epidemiological Survey (TIDE) study collected data from 66108 participants aged at least 18 years across China from 2015 to 2017. A logistic model with stepwise selection was performed to identify significant risk factors for prediabetes and was internally validated by bootstrapping in the CNDMDS. External validations were performed in diverse populations, including populations of Hispanic (Mexican American, other Hispanic) and non-Hispanic (White, Black and Asian) participants in the National Health and Nutrition Examination Survey (NHANES) in the United States and 66108 participants in the TIDE study in China. C statistics and calibration plots were adopted to evaluate the model's discrimination and calibration performance. RESULTS: A set of easily measured indicators (age, education, family history of diabetes, waist circumference, body mass index, and systolic blood pressure) were selected as significant risk factors. A risk assessment model was established for prediabetes with a C statistic of 0.6998 (95%CI: 0.6933 to 0.7063) and a calibration slope of 1.0002. When externally validated in the NHANES and TIDE studies, the model showed increased C statistics in Mexican American, other Hispanic, Non-Hispanic Black, Asian and Chinese populations but a slightly decreased C statistic in non-Hispanic White individuals. Applying the risk assessment model to the TIDE population, we obtained a C statistic of 0.7308 (95%CI: 0.7260 to 0.7357) and a calibration slope of 1.1137. A risk score was derived to assess prediabetes. Individuals with scores ≥ 7 points were at high risk of prediabetes, with a sensitivity of 60.19% and specificity of 67.59%. CONCLUSION: An easy-to-use assessment model for prediabetes was established and was internally and externally validated in different populations. The model had a satisfactory performance and could screen individuals with a high risk of prediabetes.

Two-Years Prospective Follow-Up Study of Subacute Thyroiditis.

Purpose: The aim of the present prospective follow-up study was to explore the early indicators of hypothyroidism and the final changes in thyroid volume in subacute thyroiditis (SAT) patients. Methods: We enrolled 61 SAT patients and followed them up for 2 years to assess the incidence of hypothyroidism and changes in thyroid volume. Binary logistic regression and receiver operating characteristic (ROC) curves were used for data analysis. Results: During the 2 years follow-up period, we found that the volumes of the thyroid gland in SAT patients at 1 and 2 years were significantly smaller than those in the healthy control group, which were significantly smaller compared to the initial thyroid volumes after SAT onset (p < 0.001). Also, the thyroid volumes of SAT patients with hypothyroidism were significantly smaller than those of SAT patients without hypothyroidism. The early maximum thyroid-stimulating hormone (TSH) values (within 3 months after SAT onset) were closely related to the incidence of hypothyroidism at 2 years. The OR value was 1.18 (95% CI = 1.01-1.38, p = 0.032). The early maximum TSH value had a maximum area under the ROC curve (AUC) of 0.866 for the development of hypothyroidism 2 years after SAT onset vs. euthyroidism (p < 0.001). Conclusions: The thyroid volumes of patients increased significantly after the onset of SAT, while during the follow-up these volumes decreased; the thyroid volumes at 1 and 2 years were significantly smaller than those of normal healthy subjects, especially in SAT patients with hypothyroidism. Furthermore, the early maximum TSH value could be used as an effective indicator of the development of hypothyroidism 2 years after the onset of SAT.

Novel frameshift mutation causes early termination of the thyroxine-binding globulin protein and complete thyroxine-binding globulin deficiency in a Chinese family: A case report.

BACKGROUND: Thyroxine-binding globulin (TBG; the gene product of SERPINA7) is the main transporter of thyroid hormones in humans. Mutations in the TBG gene may lead to inherited TBG deficiency. There have been 28 reported mutations that associate with complete TBG deficiency (TBG-CD). Here we identified a novel frameshift mutation causing early termination of the TBG protein and TBG-CD in a Chinese family. CASE SUMMARY: A 46-year-old Chinese man was referred to our hospital with normal free thyroxine, free triiodothyronine, thyrotropin, but lower total thyroxine and total triiodothyronine, and undetectable serum TBG, indicative of TBG-CD. Blood samples were obtained from the patient's family members and thyroid function and serum TBG were evaluated. Genomic DNA from peripheral blood was sequenced to detect possible TBG mutation(s). Quantitative PCR high-resolution melting curve analysis was used to screen TBG-Poly (L283F) among 117 Chinese men. A novel mutation of TBG (p.Phe135Alafs*21), a 19-nucleotide insertion in exon 1, was identified, which resulted in a truncated TBG protein product and caused TBG-CD. The other mutation, identified in the proband's father, is a known polymorphism, TBG-Poly (L283F). The frequency of the TBG-Poly allele among 117 unrelated Han Chinese men from northeast China was 21.37%. CONCLUSION: A novel mutation in the TBG gene associated with the TBG-CD phenotype was identified in a Chinese family. Additionally, it was found that 21.37% of Chinese males had TBG-Poly (L283F).

Association between iron deficiency and prevalence of thyroid autoimmunity in pregnant and non-pregnant women of childbearing age: a cross-sectional study.

BACKGROUND: Thyroid autoimmunity (TAI) is prevalent among women of reproductive age and associated with adverse pregnancy outcomes. This study aimed to investigate the association between iron nutritional status and the prevalence of TAI in women during the first trimester of pregnancy and in non-pregnant women of childbearing age. METHODS: Cross-sectional analysis of 7463 pregnant women during the first trimester of pregnancy and 2185 non-pregnant women of childbearing age nested within the sub-clinical hypothyroid in early pregnancy study, a prospective collection of pregnant and non-pregnant women's data, was conducted in Liaoning province of China between 2012 and 2015. Serum thyrotropin, free thyroxine, thyroid peroxidase antibodies (TPOAbs), thyroglobulin antibodies (TgAbs), serum ferritin, and urinary iodine were measured. Iron deficiency (ID) was defined as serum ferritin <15 µg/L and iron overload (IO) was defined as ferritin >150 µg/L. TPOAb-positive was defined as >34 U/mL and TgAb-positive was defined as >115 U/mL. Multilevel logistic regression was conducted to examine the association between TAI and different iron nutritional status after adjusting for potential confounders. RESULTS: The prevalence of isolated TPOAb-positive was markedly higher in women with ID than those without ID, in both pregnant and non-pregnant women (6.28% vs. 3.23%, χ = 10.264, P = 0.002; 6.25% vs. 3.70%, χ = 3,791, P = 0.044; respectively). After adjusting for confounders and the cluster effect of hospitals, ID remained associated with TPOAb-positive in pregnant and non-pregnant women (odds ratio [OR]: 2.111, 95% confidence interval [CI]: 1.241-3.591, P = 0.006; and OR: 1.822, 95% CI: 1.011-3.282, P = 0.046, respectively). CONCLUSION: ID was associated with a higher prevalence of isolated TPOAbs-positive, but not with isolated TgAb-positive, in both pregnant women during the first trimester of pregnancy and non-pregnant women of childbearing age, while IO was not associated with either isolated TPOAb-positive or isolated TgAb-positive. CLINICAL TRIAL REGISTRATION: ChiCTR-TRC-13003805, http://www.chictr.org.cn/index.aspx.

Intralesional and topical glucocorticoids for pretibial myxedema: A case report and review of literature.

Pretibial myxedema (PTM), an uncommon manifestation of Graves' disease (GD), is a local autoimmune reaction in the cutaneous tissue. The treatment of PTM is a clinical challenge. We herein report on a patient with PTM who achieved complete remission by multipoint subcutaneous injections of a long-acting glucocorticoid and topical glucocorticoid ointment application for a self-controlled study. A 53-year-old male presented with a history of GD for 3.5 years and a history of PTM for 1.5 years. Physical examination revealed slight exophthalmos, a diffusely enlarged thyroid gland, and PTM of both lower extremities. One milliliter of triamcinolone acetonide (40 mg) was mixed well with 9 mL of 2% lidocaine in a 10 mL syringe. Multipoint intralesional injections into the skin lesions of the right lower extremity were conducted with 0.5 mL of the premixed solution. A halometasone ointment was used once daily for PTM of the left lower extremity until the PTM had remitted completely. The patient's PTM achieved complete remission in both legs after an approximately 5-mo period of therpy that included triamcinolone injections once a week for 8 wk and then once a month for 2 mo for the right lower extremity and halometasone ointment application once daily for 8 wk and then once 3-5 d for 2 mo for the left lower extremity. The total dosage of triamcinolone acetonide for the right leg was 200 mg. Our experience with this patient suggests that multipoint subcutaneous injections of a long-acting glucocorticoid and topical glucocorticoid ointment application are safe, effective, and convenient treatments. However, the topical application of a glucocorticoid ointment is a more convenient treatment for patients with PTM.

Effects of Maternal Marginal Iodine Deficiency on Interactions between Cerebellar Bergmann Glia Cells and Purkinje Cells in Rat Offspring.

Iodine deficiency (ID) during early pregnancy has an adverse effect on children's psychomotor and motor function but the mechanism has not been clarified. Therefore, our aim was to study the effect of maternal marginal ID on cerebellar neurodevelopment and the underlying mechanism. After obtaining marginal ID rats, we examined interactions between Bergmann glia cells (BGs) and Purkinje cells (PCs) using immunofluorescence and expression of the glutamate transporter and receptor by western blot. Our results showed that marginal ID reduced the number of contacted points between BGs and PCs, and disturbed expression of the glutamate transporter and receptor. Our results support the hypothesis that marginal ID inhibits interactions of BGs-PCs, which may be involved in abnormal regulation of the glutamate transporter and receptor.

Distribution of zinc and zinc transporters in the mouse ovarian follicles and corpus luteum.

Zinc is essential for female reproduction and it plays a role in sexual development, ovulation, menstruation and estrous cycles. Zinc deficiency may lead to female reproductive system dysfunction. The present study aimed to investigate the expression and distribution patterns of free zinc and the members of zinc transporter (ZnT) family, with zinc autometallographic (AMG), immunohistochemistry and real-time PCR, to explore the relationship of zinc homeostasis in the development and function of the ovary in the mouse. Our data revealed that the free zinc ions and ZnTs are predominantly distributed in the mouse ovarian follicles and corpus luteum. Specifically, AMG staining presented in various stages of the ovarian follicles and corpus luteum. ZnT1-9 mRNA was variously expressed, whereas ZnT10 mRNA was almost undetectable in the ovary. Moreover, the immunoreactivity of all the tested ZnTs, except for ZnT10, was detected with various intensity in the mouse primordial follicles, primary follicles, secondary follicles and antral follicles. In the corpus luteum, the immunoreactivity of ZnT1-5, 7, 8, 10, was abundantly observed in the granular and theca lutein cells and interstitial cells. Collectively, our results suggest that ZnT family proteins are differently distributed and might exert different biological functions in controlling cellular zinc levels, which regulate ovarian development and function in the mouse ovary.

Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer's disease.

Increasing evidence indicates that a disturbance of normal iron homeostasis and an amyloid-ß (Aß)-iron interaction may contribute to the pathology of Alzheimer's disease (AD), whereas iron chelation could be an effective therapeutic intervention. In the present study, transgenic mice expressing amyloid precursor protein (APP) and presenilin 1 and watered with high-dose iron served as a model of AD. We evaluated the effects of intranasal administration of the high-affinity iron chelator deferoxamine (DFO) on Aß neuropathology and spatial learning and memory deficits created in this AD model. The effects of Fe, DFO, and combined treatments were also evaluated in vitro using SHSY-5Y cells overexpressing the human APP Swedish mutation. In vivo, no significant differences in the brain concentrations of iron, copper, or zinc were found among the treatment groups. We found that high-dose iron (deionized water containing 10 mg/mL FeCl(3)) administered to transgenic mice increased protein expression and phosphorylation of APP695, enhanced amyloidogenic APP cleavage and Aß deposition, and impaired spatial learning and memory. Chelation of iron via intranasal administration of DFO (200 mg/kg once every other day for 90 days) inhibited iron-induced amyloidogenic APP processing and reversed behavioral alterations. DFO treatment reduced the expression and phosphorylation of APP protein by shifting the processing of APP to the nonamyloidogenic pathway, and the reduction was accompanied by attenuating the Aß burden, and then significantly promoted memory retention in APP/PS1 mice. The effects of DFO on iron-induced amyloidogenic APP cleavage were further confirmed in vitro. Collectively, the present data suggest that intranasal DFO treatment may be useful in AD, and amelioration of iron homeostasis is a potential strategy for prevention and treatment of this disease.

Multi-modality imaging on multiple evanescent white dot syndrome-A Spectralis Study.

AIM: To present retinal microstructure, metabolism and function abnormalities in the course of multiple evanescent white dot syndrome (MEWDS) by Heidelberg spectralis modality imaging platform and observe its outcome by EDI-SD-OCT and two wavelength autofluorescence. METHODS: A case of multiple evanescent white dot syndrome in a 23-year-old female presented initially with a 15-day history of floaters and a central scotoma in the right eye. To establish the diagnosis, multimodality imaging was performed, namely, blue light-fundus autofluorescence (BL-FAF, excitation 488nm, emission >500nm), near-infrared fundus autofluorescence (NIR-FAF, excitation 787nm, emission >800nm) using a confocal scanning laser ophthalmoscope, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), spectrum-domain enhance depth imaging optical coherence tomography (SD-EDI-OCT), multifocal electroretinography (mf-ERG) and fundus photogragh were performed and followed up at the eighth month after initially visiting. RESULTS: Optical coherence tomography (OCT) showed a transient disruption of the foveal photoreceptor outer segments in correspondence to foveal granularity. NIR-FAF showed hypoautofluorescent areas, ≤40µm in size, mostly concentrated around the posterior pole and its temporal side less than that in BL-FAF. Mf-ERG show pinnacle disappeared in fovea and macula and responses decreased markedly compared with the follow eye. At the eighth month follow up, hyperfluorescence in BL-FAF were disappear, while, NIR-FAF Hypofluorescent spots in early stage of such lesion were reduced. But OCT demonstrated the structure was recovered in residual Hypofluorescent area in NIR-FAF. The subfoveal choroidal thickness was decreased from 372µm to 307µm slightly and cost line was recovered. CONCLUSION: MEWDS is a benign self-healing disease and there is no pathological evidence to investigate the natural course of such disease. SD-OCT allows highly detailed images approaching histopathology to certify the microstructural changes. Two-wave length FAF and mf-ERG provide more information about metabolism in outer retina especial RPE and photoreceptor. Spectralis OCT combined with two-wavelength FAF and mf-ERG provide a new way to analyze this disease and offer more details for therapy and follow-up.

[Effects of selenium supplementation on antibodies of autoimmune thyroiditis].

OBJECTIVE: To evaluate the effects of selenium (Se) supplementation on concentrations of thyroid peroxidase antibodies (TPOAb) and TPOAb IgG subclasses in autoimmune thyroiditis (AIT) patients with different thyroid functional status. METHODS: A blind and placebo-controlled prospective study was performed for a total of 134 cases with AIT and thyroid peroxidase antibodies above 300 U/ml. Their mean age was 41 years (range: 15-70). All of them were recruited from Department of Endocrinology, First Affiliated Hospital of China Medical University from June 2008 to June 2009 and divided into 2 groups according to thyroid function: euthyroidism or subclinical hypothyroidism (n = 89) and hypothyroidism (n = 45). Then they were randomized into 2 groups: selenium-treated and placebo-treated. And 49 cases in subclinical autoimmune thyroiditis group and 28 cases in hypothyroidism group received 200 µg oral selenium yeast daily for 6 months while others placebo. Serum concentrations of TPOAb, TPOAb IgG subclasses, thyroid-stimulating hormone (TSH), free thyroxine (FT(4)) and Se were measured at baseline and after 3 and 6 months of follow-up. RESULTS: The TPOAb levels showed an overall decrease of 4.3% at 3 months and of 12.6% at 6 months (both P < 0.05) post-supplementation in subclinical autoimmune thyroiditis patients. In overt hypothyroidism patients, the overall decrease of TPOAb concentrations was 21.9% at 3 months and 20.4% at 6 months (both P < 0.05) compared with those at pre-treatment. The predominant TPOAb IgG subclasses in sera from the AIT patients were IgG1, IgG3 and IgG4 and the positive percentages 72%, 41% and 72% respectively. The positive rate and concentrations of IgG3 in the patients with hypothyroidism were significantly higher than those of subclinical autoimmune thyroiditis (P < 0.05). Significant decreases in IgG1 and IgG3 levels were noted in subclinical autoimmune thyroiditis group at 6 months post-supplementation (P < 0.05). IgG1 levels in overt hypothyroidism decreased significantly compared with those at pre-supplementation (P < 0.05). In all patients with supplementation (n = 77), the TPOAb levels decreased in 52 at 6 months while increase or no change occurred in 25. The positive percentage and concentrations of IgG1 in patients whose TPOAb levels decreased at 6 months post-supplementation were markedly higher than those whose TPOAb levels increased (P < 0.05). CONCLUSION: Se is effective in reducing TPOAb concentrations and the predominant decreasing TPOAb IgG subclasses are IgG1 and IgG3. And a high level of IgG1 subclass may explain the difficult decline of TPOAb.

Widespread expression of zinc transporter ZnT (SLC30) family members in mouse endocrine cells.

Zinc is abundant in most endocrine cell types, and plays a pivotal role in the synthesis and secretion of many hormones. Recent studies have demonstrated the expression of numerous zinc transporter (ZnT) family members in the pancreas, thyroid, and adrenal glands, suggesting a role for ZnTs in regulating cellular zinc homeostasis in endocrine cells. However, the cellular distribution of ZnTs in the endocrine organs has not been well established. In the present study, the mRNA expression level, cellular distribution of ZnTs as well as liable zinc ions were examined in the mouse pituitary, adrenal glands, thyroid, and pancreas. In general, ZnT1-10 mRNA was expressed to various degrees in the detected endocrine organs, with no detectable ZnT10 mRNA in the pancreas. In the anterior pituitary, both the acidophilic and basophilic cells were immunopositive to ZnT1-5, 7, 8, except for ZnT10. In the adrenal cortex, the immunoreactivity of all the tested ZnTs, including ZnT1-5, 7, 8, 10, was observed in the zona fasciculata, and some ZnTs were detected in the zona glomerulosa, zona reticularis, and the adrenal medulla. Both the follicle epithelial cells and parafollicular cells in the thyroid gland were immunostained with ZnT1-5, 7, 8, but not ZnT10. In the endocrine pancreas, the immunoreactivity of tested ZnTs was observed to various degrees except for ZnT10 in the cytoplasm of islet cells. Furthermore, autometallographic staining showed that liable zinc was observed in the endocrine cells, such as the adrenal cortical cells, thyroid follicle epithelial cells, and the pancreatic islet cells. All together, the wide distribution of liable zinc and the phenomenon that numerous ZnT family members are partially overlapped in a subset of endocrine cells suggest an important role for the ZnT family in controlling cellular zinc levels and subsequently regulating the synthesis and secretion of hormones in the endocrine system.

Clioquinol reduces zinc accumulation in neuritic plaques and inhibits the amyloidogenic pathway in AßPP/PS1 transgenic mouse brain.

Metal dyshomeostasis in the brain helps promote amyloid-ß (Aß) deposition in Alzheimer's disease (AD). Therefore, targeting the interactions between metal and Aß is a potential therapeutic approach for AD. The metal chelator, clioquinol (CQ), is thought to reduce Aß deposits in the AD transgenic mouse brain, and attenuate the clinical symptoms of AD patients. However, whether oral administration of CQ reduces zinc accumulation in Aß plaques and inhibits the amyloidogenic pathway have not been properly established in AD transgenic mice. By means of autometallographic analysis, we show for the first time that both the number and size of the zinc-containing plaques were significantly reduced in the brain of amyloid-ß protein precursor (AßPP)/presenilin 1 (PS1) double transgenic mice treated with CQ (30 mg/kg/day) orally for 2 months. This was accompanied by a reduction in Aß burden in the CQ-treated mouse brain. Furthermore, CQ treatment markedly reduced the expression levels of AßPP protein, the ß-site of AßPP cleaving enzyme 1 (BACE1), PS1, and the secreted ß-secretase-derived fragments of AßPP (sAßPPß). The present data indicate that CQ is able to reduce zinc accumulation in the neuritic plaques and inhibit amyloidogenic AßPP processing in the AßPP/PS1 mouse brain.

[Sex hormone-binding globulin of gestational diabetes mellitus pregnant women with well-controlled glucose and pregnancy outcomes].

OBJECTIVE: To explore the relationship between sex hormone-binding globulin (SHBG) of gestational diabetes mellitus (GDM) pregnant women with well-controlled glucose and pregnancy outcomes. METHODS: Two hundred and fifty-one GDM pregnant women of 24 - 28 weeks in Shengjing Hospital of China Medical University were recruited from Mar. 2005 to Mar. 2010. Two hundred and sixteen cases of GDM with well-controlled glucose were defined as glycemic satisfied group, and they were treated by diet therapy (169 cases) or insulin therapy (47 cases). Thirty-five cases with unsatisfied glucose were defined as glycemic unsatisfied group. One hundred and ninety-two healthy pregnant women of 24 - 28 weeks were defined as healthy control group. Serum SHBG and homeostasis model analysis of insulin resistance (HOMA-IR) at 24 - 28 weeks and above 36 weeks were measured. GDM was diagnosed by "two-step" method according to the National Diabetes Data Group (NDDG) criteria. The pregnancy outcomes and complications of the three groups were recorded. RESULTS: (1) Comparison of pregnancy outcomes and complications:glycemic satisfied group was less likely to develop hypertensive disorders in pregnancy (10.6%), premature birth (8.3%), large for gestational age (LGA) (8.8%), neonatal asphyxia (3.7%) and neonatal hypoglycemia (2.3%) compared to glycemic unsatisfied group (42.9%, 34.3%, 31.4%, 22.9% and 11.4%, respectively). And the difference was statistically significant (P < 0.05 or P < 0.01). There was no significant difference for incidence of polyhydramnios, pueperal infection, postpartum hemorrhage, neonatal hyperbilirubinemia between the two groups (P > 0.05). When compared to healthy control group (7.3%, 2.1%, 4.2%, 2.1% and 1.6%), no significant difference was found for incidence of premature birth (8.3%), pueperal infection (3.2%), postpartum hemorrhage (5.1%), neonatal asphyxia (3.7%) and neonatal hypoglycemia (2.3%, P > 0.05). (2) Comparison of results of 24 - 28 weeks and above 36 weeks: serum SHBG of glycemic satisfied group [(384 ± 88), (457 ± 48) nmol/L] was significantly higher than that of glycemic unsatisfied group [(313 ± 45), (401 ± 73) nmol/L]; HOMA-IR of glycemic satisfied group (5.3 ± 1.1, 5.5 ± 1.1) was significantly lower than that of glycemic unsatisfied group (7.0 ± 1.3, 7.6 ± 1.7; P < 0.01). Serum SHBG of glycemic satisfied group was significantly lower than that of healthy control group [(492 ± 95), (565 ± 40) nmol/L]; and HOMA-IR of glycemic satisfied group (5.3 ± 1.1, 5.5 ± 1.1) was significantly higher than that of healthy control group (3.6 ± 0.6, 3.9 ± 0.5; P < 0.01). FPG of glycemic satisfied group [(5.84 ± 0.28), (5.16 ± 0.13) mmol/L] was significantly lower than that of glycemic unsatisfied group [(6.13 ± 0.16), (5.68 ± 1.14) mmol/L;P < 0.01]. FINS of glycemic satisfied group [(20.4 ± 2.1), (24.1 ± 4.2) mmol/L] was significantly lower than that of glycemic unsatisfied group [(24.7 ± 4.5), (29.9 ± 2.7) mmol/L; P < 0.01]. (3) Correlation analysis. Between 24-28 weeks, SHBG was negatively correlated with HOMA-IR in the three groups (r = -0.952, P < 0.01); and SHBG was negatively correlated with HOMA-IR in glycemic satisfied group (r = -0.903, P < 0.01). CONCLUSIONS: Well-controlled glucose can not completely improve maternal and fetal outcomes of GDM pregnant women. High insulin resistance and low serum SHBG can influence pregnancy outcomes.

Valproate reduces tau phosphorylation via cyclin-dependent kinase 5 and glycogen synthase kinase 3 signaling pathways.

Valproate (VPA) is a widely used anticonvulsant and mood-stabilizing drug. Recent studies have shown that VPA could reduce amyloid-ß generation, and improve memory deficits in transgenic mouse models of Alzheimer's disease (AD). However, whether VPA affects tau phosphorylation and the underlying mechanism has not been established. Here, we showed that systemic treatment of APP and presenilin 1 double transgenic mice with VPA (50mg/kg, once a day for 12 weeks), significantly reduced the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. Meanwhile, VPA treatment markedly reduced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3ß (GSK3ß), two protein kinases involved in abnormal hyperphosphorylation of tau. In an okadaic acid-induced tau hyperphosphorylation SH-SY5Y cell model, the anti-tau-phosphorylation effect of VPA was further confirmed, accompanied by a marked decrease in the activities of CDK5 and GSK3ß. Our present data suggest that the inhibitory effects of VPA on tau hyperphosphorylation might be mediated through both CDK5 and GSK3ß signaling pathways.

Huperzine A activates Wnt/ß-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model.

Huperzine A (HupA) is a reversible and selective inhibitor of acetylcholinesterase (AChE), and it has multiple targets when used for Alzheimer's disease (AD) therapy. In this study, we searched for new mechanisms by which HupA could activate Wnt signaling and reduce amyloidosis in AD brain. A nasal gel containing HupA was prepared. No obvious toxicity of intranasal administration of HupA was found in mice. HupA was administered intranasally to ß-amyloid (Aß) precursor protein and presenilin-1 double-transgenic mice for 4 months. We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Aß levels and Aß burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway. Importantly, our results further showed that HupA inhibited GSK3α/ß activity, and enhanced the ß-catenin level in the transgenic mouse brain and in SH-SY5Y cells overexpressing Swedish mutation APP, suggesting that the neuroprotective effect of HupA is not related simply to its AChE inhibition and antioxidation, but also involves other mechanisms, including targeting of the Wnt/ß-catenin signaling pathway in AD brain.

Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model.

BACKGROUND: Although increasing evidence has indicated that brain insulin dysfunction is a risk factor for Alzheimer disease (AD), the underlying mechanisms by which insulin deficiency may impact the development of AD are still obscure. Using a streptozotocin (STZ)-induced insulin deficient diabetic AD transgenic mouse model, we evaluated the effect of insulin deficiency on AD-like behavior and neuropathology. RESULTS: Our data showed that administration of STZ increased the level of blood glucose and reduced the level of serum insulin, and further decreased the phosphorylation levels of insulin receptors, and increased the activities of glycogen synthase kinase-3α/ß and c-Jun N-terminal kinase in the APP/PS1 mouse brain. We further showed that STZ treatment promoted the processing of amyloid-ß (Aß) precursor protein resulting in increased Aß generation, neuritic plaque formation, and spatial memory deficits in transgenic mice. CONCLUSIONS: Our present data indicate that there is a close link between insulin deficient diabetes and cerebral amyloidosis in the pathogenesis of AD.

[The changes of thyrotropin level in euthyroid population: a 5-year follow-up study in communities with different iodine intakes].

OBJECTIVE: To determine the factors that influence the development of abnormal thyrotropin (TSH) level in an euthyroid population. METHODS: We conducted a follow-up study in 3 communities with different iodine status. Of the 3403 euthyroid subjects at baseline screened in 1999, 80.1% (n = 2727) was visited and sampled in 2004 for measuring TSH, thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). RESULTS: Iodine status in the 3 communities were stable. Decreased TSH level (< 0.3 mU/L) developed in 2.5% (n = 68) of sampled subjects, while raised TSH level (> 4.8 mU/L) in 2.4% (n = 64). A logistic analysis showed that risk factors for developing decreased TSH level included positive conversion of TPOAb (OR = 5.5), positive TPOAb both in 1999 and in 2004 (OR = 4.0), positive TgAb in 2004 (OR = 3.7) and TSH < 1.0 mU/L in 1999 (OR = 2.6). Risk factors involved in developing raised TSH level included iodine status of Zhangwu community (OR = 4.1), iodine status of Huanghua community (OR = 3.9), positive TgAb in 2004 (OR = 3.7), positive TPOAb both in 1999 and 2004 (OR = 3.6), positive conversion of TPOAb (OR = 2.7) and TSH > 1.9 mU/L in 1999 (OR = 2.6). CONCLUSIONS: Exposure to long-term iodine excess imposes danger of developing hypothyroidism. The risk will be even higher when exposing to iodine adequacy after correction of iodine deficiency. An interval between 1.0 and 1.9 mU/L of TSH level was optimal with the least probability of developing abnormal TSH level.