New insights into the all-testis differentiation in zebrafish with compromised endogenous androgen and estrogen synthesis.

The regulatory mechanism of gonadal sex differentiation, which is complex and regulated by multiple factors, remains poorly understood in teleosts. Recently, we have shown that compromised androgen and estrogen synthesis with increased progestin leads to all-male differentiation with proper testis development and spermatogenesis in cytochrome P450 17a1 (cyp17a1)-/- zebrafish. In the present study, the phenotypes of female-biased sex ratio were positively correlated with higher Fanconi anemia complementation group L (fancl) expression in the gonads of doublesex and mab-3 related transcription factor 1 (dmrt1)-/- and cyp17a1-/-;dmrt1-/- fish. The additional depletion of fancl in cyp17a1-/-;dmrt1-/- zebrafish reversed the gonadal sex differentiation from all-ovary to all-testis (in cyp17a1-/-;dmrt1-/-;fancl-/- fish). Luciferase assay revealed a synergistic inhibitory effect of Dmrt1 and androgen signaling on fancl transcription. Furthermore, an interaction between Fancl and the apoptotic factor Tumour protein p53 (Tp53) was found in vitro. The interaction between Fancl and Tp53 was observed via the WD repeat domain (WDR) and C-terminal domain (CTD) of Fancl and the DNA binding domain (DBD) of Tp53, leading to the K48-linked polyubiquitination degradation of Tp53 activated by the ubiquitin ligase, Fancl. Our results show that testis fate in cyp17a1-/- fish is determined by Dmrt1, which is thought to stabilize Tp53 by inhibiting fancl transcription during the critical stage of sexual fate determination in zebrafish.

Use of All-Male cyp17a1-Deficient Zebrafish (Danio rerio) for Evaluation of Environmental Estrogens.

Natural and synthetic environmental estrogens (EEs) are widespread and have received extensive attention. Our previous studies demonstrated that depletion of the cytochrome P450 17a1 gene (cyp17a1) leads to all-testis differentiation phenotype in zebrafish and common carp. In the present study, cyp17a1-deficient zebrafish with defective estrogen biosynthesis were used for the evaluation of EEs, as assessed by monitoring vitellogenin (vtg) expression. A rapid and sensitive assessment procedure was established with the 3-day administration of estradiol (E2), followed by examination of the transcriptional expression of vtgs in our cyp17a1-deficient fish. Compared with the control fish, a higher E2-mediated vtg upregulation observed in cyp17a1-deficient zebrafish exposed to 0.1 µg/L E2 is known to be estrogen receptor-dependent and likely due to impaired in vivo estrogen biosynthesis. The more responsive vtg expression in cyp17a1-deficient zebrafish was observed when exposed to 200 and 2000 µg/L bisphenol A (BPA) and perfluoro-1-octanesulfonate (PFOS). The estrogenic potentials of E2, BPA, and PFOS were compared and assessed by the feminization effect on ovarian differentiation in cyp17a1-deficient zebrafish from 18 to 50 days postfertilization, based on which a higher sensitivity of E2 in ovarian differentiation than BPA and PFOS was concluded. Collectively, through the higher sensitivity to EEs and the capacity to distinguish chemicals with different estrogenic potentials exhibited by the all-male cyp17a1-deficient zebrafish with impaired estrogen biosynthesis, we demonstrated that they can be used as an excellent in vivo model for the evaluation of EEs. Environ Toxicol Chem 2024;43:1062-1074. © 2024 SETAC.

Androgen signaling inhibits de novo lipogenesis to alleviate lipid deposition in zebrafish.

Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males. However, the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood, especially in teleosts. In this study, cyp17a1-/- zebrafish ( Danio rerio) exhibited excessive visceral adipose tissue (VAT), lipid content, and up-regulated expression and activity of hepatic de novo lipogenesis (DNL) enzymes. The assay for transposase accessible chromatin with sequencing (ATAC-seq) results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/- fish compared to cyp17a1+/+ male fish, including stearoyl-CoA desaturase ( scd) and fatty acid synthase ( fasn). Androgen response element (ARE) motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+ male fish but not in cyp17a1-/- fish. Both androgen receptor ( ar)-/- and wild-type (WT) zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue, lipid content, and up-regulated expression and activity of hepatic de novo lipogenesis enzymes. The Ar agonist BMS-564929 reduced the content of VAT and lipid content, and down-regulated acetyl-CoA carboxylase a ( acaca), fasn, and scd expression. Mechanistically, the rescue effect of testosterone on cyp17a1-/- fish in terms of phenotypes was abolished when ar was additionally depleted. Collectively, these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish, thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.

Estrogen Signaling Inhibits the Expression of anti-Müllerian hormone (amh) and gonadal-soma-derived factor (gsdf) during the Critical Time of Sexual Fate Determination in Zebrafish.

The mechanism of fish gonadal sex differentiation is complex and regulated by multiple factors. It has been widely known that proper steroidogenesis in Leydig cells and sex-related genes in Sertoli cells play important roles in gonadal sex differentiation. In teleosts, the precise interaction of these signals during the sexual fate determination remains elusive, especially their effect on the bi-potential gonad during the critical stage of sexual fate determination. Recently, all-testis phenotypes have been observed in the cyp17a1-deficient zebrafish and common carp, as well as in cyp19a1a-deficient zebrafish. By mating cyp17a1-deficient fish with transgenic zebrafish Tg(piwil1:EGFP-nanos3UTR), germ cells in the gonads were labelled with enhanced green fluorescent protein (EGFP). We classified the cyp17a1-deficient zebrafish and their control siblings into primordial germ cell (PGC)-rich and -less groups according to the fluorescence area of the EGFP labelling. Intriguingly, the EGFP-labelled bi-potential gonads in cyp17a1+/+ fish from the PGC-rich group were significantly larger than those of the cyp17a1-/- fish at 23 days post-fertilization (dpf). Based on the transcriptome analysis, we observed that the cyp17a1-deficient fish of the PGC-rich group displayed a significantly upregulated expression of amh and gsdf compared to that of control fish. Likewise, the upregulated expressions of amh and gsdf were observed in cyp19a1a-deficient fish as examined at 23 dpf. This upregulation of amh and gsdf could be repressed by treatment with an exogenous supplement of estradiol. Moreover, tamoxifen, an effective antagonist of both estrogen receptor α and ß (ERα and Erß), upregulates the expression of amh and gsdf in wild-type (WT) fish. Using the cyp17a1- and cyp19a1a-deficient zebrafish, we provide evidence to show that the upregulated expression of amh and gsdf due to the compromised estrogen signaling probably determines their sexual fate towards testis differentiation. Collectively, our data suggest that estrogen signaling inhibits the expression of amh and gsdf during the critical time of sexual fate determination, which may broaden the scope of sex steroid hormones in regulating gonadal sex differentiation in fish.

ASSOCIATION OF DIABETIC MACULAR EDEMA WITH QUALITY OF LIFE IN PATIENTS WITH TYPE 2 DIABETES: The Fushun Diabetic Retinopathy Cohort Study.

PURPOSE: To report the vision-related quality of life in patients with diabetic macular edema (DME) in a population-based study. METHODS: In this cross-sectional study, we analyzed 1,659 subjects with type 2 diabetes. Questionnaires were administered to assess the patient's vision-related quality of life. Diabetic macular edema severity was graded according to the established protocols. A subject's DME score ranged from 1 (no DME in either eye) to 7 (severe bilateral DME) using predefined criteria. RESULTS: Composite 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) scores for participants with DME were 88.9 (interquartile range [IQR]: 76.2-94.9) compared with 92.0 (IQR: 82.7-96.0) for those without DME ( P < 0.001). Locally weighted scatterplot smoothing plots depicted a consistent decline in composite NEI-VFQ-25 scores corresponding to the escalation of bilateral DME severity: starting from 88.59 for no DME in either eye, progressing through 86.65, 85.83, 85.31, 84.91, 83.85, and culminating at 82.71 for bilateral severe DME. Notably, the locally weighted scatterplot smoothing plots highlighted significant NEI-VFQ-25 composite score reduction at unilateral mild DME (slope m = -1.94). CONCLUSION: Significant changes in vision-related quality of life manifest in the early stage of DME. Therefore, early identification and intervention for these patients are crucial clinical objectives.

Disease Burden of Colorectal Cancer in China from 1990 to 2019: Age- and Sex-Specific Time Trends and 10-Year Forecast.

INTRODUCTION: Colorectal cancer (CRC) is the third most prevalent malignant tumor worldwide and the second leading cause of cancer-related death. This study aimed at reporting the disease burden of CRC in China from 1990 to 2019 and predicting the trend of mortality burden over the next 10 years. METHODS: The age-period-cohort model was implemented to analyze the trends of mortality from CRC in China from 1990 to 2019, and the autoregressive integrated moving average (ARIMA) model was used to predict the trends of CRC incidence and mortality from 2020 to 2029. RESULTS: From 1990 to 2019, the incidence of CRC in China increased from 105,911 cases (95% uncertainty interval [UI]: 93,808-119,021) to 607,900 cases (95% UI: 521,805-708,420). The age-standardized incidence rate increased from 12.52 per 100,000 (95% UI: 11.15-14.03) to 30.55 per 100,000 (95% UI: 26.37-35.5), with an estimated annual percentage change (EAPC) of 3.66 (95% confidence interval [CI]: 3.37-3.95), showing an upward trend. The age-standardized mortality rate increased from 10.18 per 100,000 (95% UI: 9.03-11.37) to 13.86 per 100,000 (95% UI: 11.92-16.01), with an EAPC of 1.39 (95% CI: 1.14-1.63), also showing an upward trend. The age group with the highest incidence and mortality in 2019 was 65-69 years old for both sexes, and the age group with the highest mortality was 70-74 years old. Males had higher relative risks of incidence and mortality than females. Low-calcium diet was the risk factor for both sexes and females alone in 1990, while low-milk diet was the risk factor in 2019; however, smoking remained the risk factor for males. The ARIMA model predicted an increase in both disease and mortality burden of CRC over the next 10 years. CONCLUSION: The disease and mortality burden of CRC in China showed an overall upward trend from 1990 to 2019, with higher burden in males than females, and the situation remains extremely severe in the next decade.

Undiagnosed diabetic retinopathy in Northeast China: prevalence and determinants.

Objective: To report the prevalence and contributing factors of undiagnosed diabetic retinopathy (DR) in a population from Northeastern China. Subjects/Methods: A total of 800 subjects from the Fushun Diabetic Retinopathy Cohort Study were enrolled. A questionnaire assessing incentives and barriers to diagnosis of DR was administered. Logistic regression was used to identify clinical and sociodemographic factors associated with undiagnosed DR. In a prespecified subgroup analysis, we divided patients into vision-threatening diabetic retinopathy (VTDR) and non-VTDR (NVTDR) subgroups. Results: Among 800 participants with DR, 712 (89.0%) were undiagnosed. Among 601 with NVTDR, 566 (94.2%) were undiagnosed. Among 199 with VTDR, 146 (73.4%) were undiagnosed. The risk factors affecting the timely diagnosis of NVTDR and VTDR exhibit significant disparities. In multivariate models, factors associated with undiagnosed VTDR were age over 60 years (OR = 2.966; 95% CI = 1.205-7.299; P = 0.018), duration of diabetes over 10 years (OR = 0.299; 95% CI = 0.118-0753; P = 0.010), visual impairment or blindness (OR = 0.310; 95% CI = 0.117-0.820; P = 0.018), receiving a reminder to schedule an eye examination (OR = 0.380; 95% CI = 0.163-0.883; P = 0.025), and the belief that "people with diabetes are unlikely to develop an eye disease" (OR = 4.691; 95% CI = 1.116-19.724; P = 0.035). However, none of the factors were associated with undiagnosed NVTDR (all P ≥ 0.145). Conclusion: Our research has uncovered a disconcerting trend of underdiagnosis in cases of DR within our population. Addressing determinants of undiagnosed DR may facilitate early detection.

The food safety assessment of all-female common carp (Cyprinus carpio) (cyp17a1+/-;XX genotype) generated using genome editing technology.

There are several technical challenges and public issues concerning genome editing applications before they become viable in commercial aquaculture. Recently, we developed a novel strategy to generate all-female (AF) common carp, which exhibited a growth advantage over the control carp, using genetic editing through single gene-targeting manipulation. Here, we found that the body weight of the AF common carp was higher by 22.58% than that of the control common carp. Because the genotype of the AF common carp was cyp17a1+/-;XX, the contents of sex steroids were normally synthesized, as they were comparable to that of the control female carp. To evaluate the food safety of the AF carp, Wistar rats were fed a diet containing control female carp (control, C) or all-female (AF) carp at an incorporation rate of 5, 10 and 20% (w/w) for 90 days. Compared with those fed control carp, the rats fed AF common carp exhibited no significant difference in body weight, food intake, feed conversion ratio, hematology, serum biochemistry, urine test, relative organ weight, gross necropsy, and histopathological examination. This is the first food safety assessment of the farmed fish strain cultured using CRISPR/Cas9, which will further advance the fishery development of genome-edited animals.

Zebrafish gonad mutant models reveal neuroendocrine mechanisms of brain sexual dimorphism and male mating behaviors of different brain regions.

BACKGROUND: Sexually dimorphic mating behaviors differ between sexes and involve gonadal hormones and possibly sexually dimorphic gene expression in the brain. However, the associations among the brain, gonad, and sexual behavior in teleosts are still unclear. Here, we utilized germ cells-free tdrd12 knockout (KO) zebrafish, and steroid synthesis enzyme cyp17a1-deficient zebrafish to investigate the differences and interplays in the brain-gonad-behavior axis, and the molecular control of brain dimorphism and male mating behaviors. METHODS: Tdrd12+/-; cyp17a1+/- double heterozygous parents were crossed to obtain tdrd12-/-; cyp17a1+/+ (tdrd12 KO), tdrd12+/+; cyp17a1-/- (cyp17a1 KO), and tdrd12-/-; cyp17a1-/- (double KO) homozygous progenies. Comparative analysis of mating behaviors were evaluated using Viewpoint zebrafish tracking software and sexual traits were thoroughly characterized based on anatomical and histological experiments in these KOs and wild types. The steroid hormone levels (testosterone, 11-ketotestosterone and 17ß-estradiol) in the brains, gonads, and serum were measured using ELISA kits. To achieve a higher resolution view of the differences in region-specific expression patterns of the brain, the brains of these KOs, and control male and female fish were dissected into three regions: the forebrain, midbrain, and hindbrain for transcriptomic analysis. RESULTS: Qualitative analysis of mating behaviors demonstrated that tdrd12-/- fish behaved in the same manner as wild-type males to trigger oviposition behavior, while cyp17a1-/- and double knockout (KO) fish did not exhibit these behaviors. Based on the observation of sex characteristics, mating behaviors and hormone levels in these mutants, we found that the maintenance of secondary sex characteristics and male mating behavior did not depend on the presence of germ cells; rather, they depended mainly on the 11-ketotestosterone and testosterone levels secreted into the brain-gonad regulatory axis. RNA-seq analysis of different brain regions revealed that the brain transcript profile of tdrd12-/- fish was similar to that of wild-type males, especially in the forebrain and midbrain. However, the brain transcript profiles of cyp17a1-/- and double KO fish were distinct from those of wild-type males and were partially biased towards the expression pattern of the female brain. Our results revealed important candidate genes and signaling pathways, such as synaptic signaling/neurotransmission, MAPK signaling, and steroid hormone pathways, that shape brain dimorphism and modulate male mating behavior in zebrafish. CONCLUSIONS: Our results provide comprehensive analyses and new insights regarding the endogenous interactions in the brain-gonad-behavior axis. Moreover, this study revealed the crucial candidate genes and neural signaling pathways of different brain regions that are involved in modulating brain dimorphism and male mating behavior in zebrafish, which would significantly light up the understanding the neuroendocrine and molecular mechanisms modulating brain dimorphism and male mating behavior in zebrafish and other teleost fish.

Attenuated glucose uptake promotes catabolic metabolism through activated AMPK signaling and impaired insulin signaling in zebrafish.

Glucose metabolism in fish remains a controversial area of research as many fish species are traditionally considered glucose-intolerant. Although energy homeostasis remodeling has been observed in fish with inhibited fatty acid ß-oxidation (FAO), the effects and mechanism of the remodeling caused by blocked glucose uptake remain poorly understood. In this study, we blocked glucose uptake by knocking out glut2 in zebrafish. Intriguingly, the complete lethality, found in Glut2-null mice, was not observed in glut2-/- zebrafish. Approxiamately 30% of glut2-/- fish survived to adulthood and could reproduce. The maternal zygotic mutant glut2 (MZglut2) fish exhibited growth retardation, decreased blood and tissue glucose levels, and low locomotion activity. The decreased pancreatic ß-cell numbers and insulin expression, as well as liver insulin receptor a (insra), fatty acid synthesis (chrebp, srebf1, fasn, fads2, and scd), triglyceride synthesis (dgat1a), and muscle mechanistic target of rapamycin kinase (mtor) of MZglut2 zebrafish, suggest impaired insulin-dependent anabolic metabolism. Upregulated expression of lipolysis (atgl and lpl) and FAO genes (cpt1aa and cpt1ab) in the liver and proteolysis genes (bckdk, glud1b, and murf1a) in muscle were observed in the MZglut2 zebrafish, as well as elevated levels of P-AMPK proteins in both the liver and muscle, indicating enhanced catabolic metabolism associated with AMPK signaling. In addition, decreased amino acids and elevated carnitines of the MZglut2 zebrafish supported the decreased protein and lipid content of the whole fish. In summary, we found that blocked glucose uptake impaired insulin signaling-mediated anabolism via ß-cell loss, while AMPK signaling-mediated catabolism was enhanced. These findings reveal the mechanism of energy homeostasis remodeling caused by blocked glucose uptake, which may be a potential strategy for adapting to low glucose levels.

Enhanced insulin activity achieved in VDRa/b ablation zebrafish.

Introduction: 1α,25-dihydroxyvitamin D3 (1α,25[OH]2VD3) is a hormone known for its key roles in calcium absorption and nutrient metabolism. In teleost fishes, 1α,25(OH)2VD3 insufficiency causes impaired glucose metabolism and lipid oxidation. However, the cascade and mechanisms of 1α,25(OH)2VD3 and the vitamin d receptor (VDR) signaling are unclear. Results: In this study, two genes (vdra and vdrb) encoding paralogs of VDRs were genetically knocked out in zebrafish. Growth retardation and accumulated visceral adipose tissue have been observed in vdra -/-;vdrb -/- deficient line. In the liver elevated accumulation of triglycerides and suppressed lipid oxidation were detected. Morover significantly elevated 1α,25(OH)2VD3 levels were detected in vdra-/-;vdrb-/- zebrafish due to cyp24a1 transcription repression. Furthermore VDRs ablation Enhanced insulin signaling including elevated insulin/insra trancriptional levels, glycolysis, lipogenesis and promoted AKT/mTOR activity. Discussion: In conclusion, our present studies provides a zebrafish model with an elevated 1α,25(OH)2VD3 levels in vivo. The 1α,25(OH)2VD3/VDRs signaling promote lipid oxidation activity. However 1α,25(OH)2VD3 activity of regulation of glucose homeostasis through Insulin/Insr was independent of nuclear VDRs in teleosts.

Refractive Error in a Chinese Population with Type 2 Diabetes: A Report from the Fushun Diabetic Retinopathy Cohort Study.

PURPOSE: To describe the prevalence and risk factors for refractive errors in a northeastern Chinese population with type 2 diabetes. METHODS: Subjects (age ≥30 years) from a community-based study, the Fushun Diabetic Retinopathy Cohort Study, were enrolled. All subjects underwent comprehensive ocular examinations, including autorefraction. Myopia, high myopia, and hyperopia were defined as a spherical equivalent (SE) of the right eye <-0.5 diopter (D), <-5.0D, and >0.5D, respectively. Astigmatism was defined as cylinder <-0.5D in a minus cylinder prescription. Anisometropia was defined as a difference of SE >1.0D between two eyes. RESULTS: A total of 1929 participants (790 males, 41.0%) were enrolled. The age and gender standardized prevalence of myopia, high myopia, hyperopia, astigmatism, and anisometropia were 43.1% (95% confidence interval [CI]: 40.9%-45.3%), 8.5% (95% CI: 7.3%-9.8%), 21.5% (95% CI: 19.7%-23.4%), 61.0% (95% CI: 58.9%-63.2%), and 17.2% (95% CI: 15.5%-18.9%), respectively. Advancing age was associated with a higher frequency of hyperopia, astigmatism, and anisometropia, as opposed to a lower frequency of myopia. Female (adjusted odds ratio [aOR], 1.27; 95% CI, 1.02-1.57) participants, higher intraocular pressure (aOR, 1.03; 95% CI, 1.00-1.07), and lenticular opacity (aOR, 1.53; 95% CI, 1.20-1.94) were also found to be associated with myopia. Long duration of diabetes (>15 years) was found to be a significant factor for astigmatism (aOR, 1.62; 95% CI, 1.15-2.27) and anisometropia (aOR, 1.87; 95% CI, 1.29-2.71). CONCLUSION: Nearly two-thirds of participants with type 2 diabetes had a refractive error. Age is a common factor with different types of refractive errors.

Efficacy of local hemostatic agents after endoscopic submucosal dissection: a meta-analysis.

INTRODUCTION: Topical hemostatic agents have been used to reduce bleeding rates after endoscopic submucosal dissection (ESD) for gastric cancer. However, to date, no review has summarized evidence on their efficacy. MATERIAL AND METHODS: PubMed, Embase, ScienceDirect, CENTRAL, and Google Scholar were searched for studies comparing bleeding rates after ESD with and without local hemostatic agents. RESULTS: Eleven studies were included. The studies used polyglycolic acid (PGA) sheets and fibrin glue, fibrin glue, oxidized regenerated cellulose, polysaccharide hemostatic powder, or polyethylene oxide adhesive. Meta-analysis revealed a statistically significant reduction in the risk of delayed bleeding with the use of PGA sheets & fibrin glue (six studies; RR: 0.35 95% CI: 0.20, 0.63 p = 0.0005). However, meta-analysis of two studies showed no difference in the risk of bleeding based on the use of fibrin glue (RR: 0.44 95% CI: 0.03, 7.17 p = 0.56). Scarce data were available for the remaining hemostatic agents. CONCLUSION: A large number of different hemostatic agents have been used to reduce the risk of bleeding after ESD for gastric cancer. Observational studies indicate that the use of PGA with fibrin glue could reduce the risk of bleeding after ESD. However, evidence for other agents was too scarce to derive conclusions.

Sexual dimorphic effects of igf1 deficiency on metabolism in zebrafish.

Insulin-like growth factor 1 (IGF1) is an essential effector of the growth hormone (GH)/IGF1 axis for somatic growth regulation in mammals. However, its functions have not been thoroughly investigated in zebrafish in vivo. In this study, the igf1-deficient zebrafish model was developed using the CRISPR/Cas9 technique. In this study all the results were performed on both male and female animals. The growth of both male and female igf1-deficient zebrafish were reduced. The igf1 deficiency leads to significant complementary up-regulation of transcriptional expression levels of insulin, igf2 and igf3. This suggested that igf2 and igf3 may act with redundant functions. While the upregulation of gh1 expression can only be detected in igf1-deficient females. At the same time, significant growth retardation, fatty liver, reduced activated levels of ribosomal S6 (S6) are seen only in igf1-deficient males. On the other hand, significant hyperglycemia, elevated transcriptional expression levels of phosphenolpyruvate carboxykinase (pepck) and levels of phosphorylated extracellular signal-regulated kinase (ERK1/2), with additional reduced hepatic lactate/pyruvate (L/P) ratios can only observed in igf1-deficient females. Impaired glucose uptake has been recorded in the primary cultured hepatocytes from igf1-deficient females, but not males. Intriguingly, exposure to 17beta-estroadiol (E2) can partially ameliorated the defects of fatty liver and activation of AKT/mTOR signaling in igf1-deficient males. Our studies demonstrate the significant functions of IGF1 on somatic regulation in zebrafish, with asymmetric gender-related consequences. Our data thus suggest that the zebrafish IGF1 is preferentially required for the activation of AKT/mTOR signaling in male zebrafish, but glucose uptake in females.

Incidence, progression and regression of diabetic retinopathy in a northeastern Chinese population.

AIM: To determine the incidence, progression and regression of diabetic retinopathy (DR), with corresponding risk factors, in a northeastern Chinese population of patients with type 2 diabetes. METHODS: Among 2006 patients who completed baseline examinations in 2012-2013 and underwent re-examination after a mean interval of 21.2 months, 1392 patients with gradable fundus photographs for both baseline and follow-up examinations were included. Incidence was defined as new development of any DR among patients without DR at baseline. An increase of ≥2 scales (concatenating Early Treatment Diabetic Retinopathy Study levels of both eyes) in eyes with DR at baseline was defined as progression, while a reduction of ≥2 scales was defined as regression. RESULTS: The age- and sex-standardised incidence, progression and regression were 5.8% (95% CI 4.7% to 6.9%), 26.8% (95% CI 24.8% to 28.8%) and 10.0% (95% CI 8.6% to 11.3%), respectively. In addition to poor blood glucose control, wider central retinal venular equivalent was associated with both incidence (relative risk (RR) 2.17, 95% CI 1.09 to 4.32, for ≥250 µm vs <210 µm) and progression (RR 2.00, 95% CI 1.02 to 3.96, for ≥250 µm vs <210 µm). Patients without insulin therapy (RR 0.64, 95% CI 0.43 to 0.97) and patients with wider central retinal arteriolar equivalent (RR 1.14, 95% CI 1.02 to 1.26, per 10 µm increase) were likely to exhibit DR regression. CONCLUSION: We determined the incidence, progression and regression of DR among northeastern Chinese patients with type 2 diabetes. Retinal vessel diameters, in addition to blood glucose level, influence the natural evolution of DR.

Characterization of the Interrenal Gland and Sexual Traits Development in cyp17a2-Deficient Zebrafish.

Unlike the Cytochrome P450, family 17, subfamily A, member 1 (Cyp17a1), which possesses both 17α-hydroxylase and 17,20-lyase activities involved in the steroidogenic pathway that produces androgens and estrogens, Cytochrome P450, family 17, subfamily A, polypeptide 2 (Cyp17a2) possesses only 17α-hydroxylase activity and is known essential for the synthesis of cortisol. Besides with expressed in testes and ovaries, where the cyp17a1 is mainly expressed, cyp17a2 is also expressed in the interrenal gland in fish. Until now, the roles of cyp17a2 in fish, especially in sexual traits development and hypothalamic-pituitary-interrenal (HPI) axis, are poorly studied. To investigate the roles of Cyp17a2 in teleosts, the cyp17a2-null zebrafish was generated and analyzed by us. The significantly decreased cortisol concentration was observed both in the cyp17a2-deficient males and females at adult stage. The interrenal gland enlargement, increased pituitary proopiomelanocortin a (pomca) expression, decreased locomotion activity and response to light-stimulated stress were observed in cyp17a2-deficient fish. Intriguingly, the cyp17a2-deficient males were fertile and with normal breeding tubercles on the pectoral fin, but females were infertile, deficient in genital papilla and with decreased gonadosomatic index (GSI). The increased progesterone (P4), 17α,20ß-dihydroxy-4-pregnen-3-one (DHP) and 11-ketotestosterone (11-KT) in the cyp17a2-deficient males and females were observed. The increased concentration of testosterone (T) and estradiol (E2) was observed in cyp17a2-/- females and cyp17a2-/- males, respectively. By examining the ovaries development of cyp17a2-deficient fish at 3 months postfertilization (mpf), we observed that the oocytes were over-activated. Taken together, our findings demonstrate that Cyp17a2 is indispensable for production and physiology of cortisol, and cyp17a2-deficiency resulted in diminished cortisol but accumulated P4 and DHP, which may result in the over-activated oocytes in cyp17a2-deficient females.

Sex-specific differences in zebrafish brains.

In this systematic review, we highlight the differences between the male and female zebrafish brains to understand their differentiation and their use in studying sex-specific neurological diseases. Male and female brains display subtle differences at the cellular level which may be important in driving sex-specific signaling. Sex differences in the brain have been observed in humans as well as in non-human species. However, the molecular mechanisms of brain sex differentiation remain unclear. The classical model of brain sex differentiation suggests that the steroid hormones derived from the gonads are the primary determinants in establishing male and female neural networks. Recent studies indicate that the developing brain shows sex-specific differences in gene expression prior to gonadal hormone action. Hence, genetic differences may also be responsible for differentiating the brain into male and female types. Understanding the signaling mechanisms involved in brain sex differentiation could help further elucidate the sex-specific incidences of certain neurological diseases. The zebrafish model could be appropriate for enhancing our understanding of brain sex differentiation and the signaling involved in neurological diseases. Zebrafish brains show sex-specific differences at the hormonal level, and recent advances in RNA sequencing have highlighted critical sex-specific differences at the transcript level. The differences are also evident at the cellular and metabolite levels, which could be important in organizing sex-specific neuronal signaling. Furthermore, in addition to having one ortholog for 70% of the human gene, zebrafish also shares brain structural similarities with other higher eukaryotes, including mammals. Hence, deciphering brain sex differentiation in zebrafish will help further enhance the diagnostic and pharmacological intervention of neurological diseases.

Assessment of Knowledge, Attitude, and Practice Regarding Diabetic Retinopathy in an Urban Population in Northeast China.

Objective: This study aimed to assess the knowledge, attitude, and practice (KAP) of diabetic subjects with diabetic retinopathy (DR) and those without DR (NDR) in an urban community in Northeast China, as well as their risk factors in subjects with DR and NDR. Methods: A community-based survey involving 1,662 subjects was conducted in Fushun, China, between July 2012 and May 2013. The subjects included diabetics with DR (n = 783) and those NDR (n = 879), and questionnaires were completed to collect information about their sociodemographic and healthcare characteristics. A Chi-square test and multiple logistic analyses were performed to analyze the data. Results: Among the DR group, 21.88% had a good knowledge of DR, 94.15% had a positive attitude, and 68.07% followed good practice, whereas 20.98% of the NDR group had a good knowledge of DR, 94.18% had a positive attitude, and 66.92% followed good practice. There was no significant difference in the KAP of the two groups of subjects. In the NDR group, a good level of knowledge was associated with a high-level of education (OR = 0.1, 0.2; p < 0.05), a good attitude was associated with retirement (OR = 0.2; p < 0.05), and good practice was associated with being female, having a high-level of education, and the type of treatment (OR = 0.5, 0.4, 2.3, 3.1; p < 0.05). In the DR group, good practice was associated with older age and retirement (OR = 0.6, 0.4; p < 0.05). Conclusions: There was no significant difference between the DR and NDR subjects in the overall levels of KAP, but both groups showed a poor level of knowledge. Age, gender, education, occupation, and type of treatment were the main factors associated with the KAP scores, more risk factors in the NDR group than in the DR group. There is an urgent need for coordinated educational campaigns with a prioritized focus on the northeast region of China, especially NDR group.

The Association of the Prevalence of Depression in Type 2 Diabetes Mellitus with Visual-Related Quality of Life and Social Support.

AIM: To report the prevalence of depression and its association with vision-related quality of life and social support in a type 2 diabetes mellitus (T2DM) population. METHODS: Patients were recruited from a community-based study, Fushun Diabetic Retinopathy Cohort Study (FS-DIRECT), conducted between July 2012 and May 2013 in China. Depression was assessed using the Centre for Epidemiological Studies Depression Scale (CES-D). Vision-related quality of life was evaluated using the Visual Function Questionnaire-25 (VFQ-25). Social support was captured with the Social Support Rating Scale (SSRS). Generalized linear models were used to estimate the individual and joint association of VFQ-25 composite score (VFQCS) and SSRS score (SSRSS) with depression. RESULTS: A total of 1618 subjects (60.9% female) aged 61.69 ± 8.72 years in an urban district of Jiangjun Street, Fushun City, Liaoning province, Northeast China from July 2012 to May 2013 were recruited, of which, 23.36% (95% CI: 21.30-25.42%) were identified with depression. Every 14.1 increase in VFQ-25 composite score decreased the risk of depression by half (OR = 0.5; 95% CI: 0.4-0.6); with the elevation of 10.0 SSRS score the risk of depression decreased by 40% (OR = 0.6; 95% CI: 0.5-0.7). Patients with the VFQCS less than 91.3 and SSRSS less than 38.0 had 5.9 times more risk of depression (OR = 5.9; 95% CI: 3.6-9.7). Age (over 60 years) (OR = 0.6; 95% CI: 0.4-0.9) and medical history of cardiovascular disease (OR = 1.7; 95% CI: 1.1-2.5) were independently correlated with depression symptom. CONCLUSION: The prevalence of depression is high among patients with T2DM in urban district in northeast China. Vision-related quality of life and social support scores are significantly associated with depression. Measures should be taken to screen depressive symptoms in patients with type 2 diabetes patients. These patients need to be intervened with appropriate and effective treatment as early as possible. Meanwhile, behavioral health specialists should guide the patient to get and use social support sources effectively.

Prevalence of and risk factors for diabetic macular edema in a northeastern Chinese population.

AIM: To estimate the prevalence of diabetic macular edema (DME) and clinically significant macular edema (CSME), and to assess their risk factors in a population with type 2 diabetic mellitus (T2DM) located in northeast China. METHODS: Patients were included from the Fushun Diabetic Retinopathy Cohort Study (FS-DIRECT), a community-based study conducted in northeast China. The presence of DME and CSME was determined by the Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy scale of fundus photographs. The age-standardized prevalence of DME and CSME was estimated. The association between DME/CSME and risk factors was analyzed in a multivariate Logistical analysis. RESULTS: A total of 292 (15.4%) and 166 (8.8%) patients were diagnosed as DME and CSME, yielding the age and sex standardized prevalence of 13.5% (95%CI: 11.9%-15.0%), and 7.1% (95%CI: 5.9%-8.3%), respectively. Female patients had a higher prevalence of DME compared to their male counterparts (15.7% vs 10.4%, P=0.03). Multivariable Logistic regression analysis showed that younger age, insulin use, proteinuria, longer duration of diabetes, and higher glycosylated hemoglobin A1c, were associated with the prevalence of DME and CSME. Patients with higher fasting plasma glucose, systolic blood pressure, and blood urea nitrogen were also found to be associated with DME. CONCLUSION: Early fundus screening in diabetic patients is invaluable and given the relatively high prevalence of DME and CSME in this study cohort, those with a high risk of sight threatening maculopathy would invariably benefit from earlier detection.