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Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a new group of NO-donating ripasudil derivatives

AimsThe cost of drug regimens prescribed to Chinese patients has not been evaluated. This study aims to evaluate the medical costs and hypoglycemic agents for diabetes mellitus patients with or without chronic respiratory disease in Beijing, and to investigate the changes in the costs and number of antidiabetic medications used for diabetes patients with chronic respiratory disease from 2016 to 2018.MethodsThis observational, retrospective study included diabetes patients with outpatient medication records from Beijing Medical Insurance between 2016 and 2018. The medications, including hypoglycemic and nonhypoglycemic drugs, insulin dosage, comorbidities, diabetes-related complications, treatment strategies, and annual medical costs, were recorded.ResultsThis study included 2,853,036 diabetes patients from 2016 to 2018. About 18.95%–20.53% of patients with chronic respiratory disease were predominantly distributed among those aged 45–84 years (88.7%–89.1%). Diabetes patients with chronic respiratory disease used more medications (4.48 ± 2.41 vs. 3.76 ± 2.33) and had higher total annual drug costs (¥12,286 ± 10,385 vs. ¥9700 ± 9202) to treat more comorbidities (2.52 ± 1.53 vs. 2.05 ± 1.85) than those without chronic respiratory disease (p ConclusionsIn summary, diabetes patients with chronic respiratory disease had more comorbidities, required more hypoglycemic drugs, and had higher medical costs. During 2016–2018, diabetes patients with chronic respiratory disease used more medications and spent less money on medical care.

The current meta-analysis aimed to evaluate the association of thyroid dysfunction and autoimmunity with gestational diabetes mellitus (GDM). A comprehensive search from PubMed, Embase, MEDLINE, and Cochrane databases until November 2020 was conducted. Fixed-effect model was used to combine the results when I2 was 50%. A total of 44 studies were included in the meta-analysis. Low FT4 levels were closely related with GDM in the first and second trimesters of gestation. Hypothyroxinemia (OR: 1.45; 95% CI: 1.25, 1.68; P

The assessment method of iodine nutrition for pregnant women lacks strong evidence-based medicine. The prevalence of iodine deficiency in pregnant women may be overestimated using urinary iodine concentration (UIC). The reference intervals of UIC-to-urinary creatinine concentration ratio (UIC/UCr) were established using a self-sequential longitudinal study of pregnant women with singleton gestation who were recruited using the criteria of the National Academy of Clinical Biochemistry in Dandong City, which is a long-term iodine-replete area. Nine thousand one hundred sixty-four pregnant women in the first trimester from Dalian City, Dandong City, and Shenyang City were included to verify our proposed reference intervals. UIC and concentrations of urinary creatinine, serum iodine, TSH, FT4, TPOAb, and TgAb were measured. The reference intervals of UIC/UCr were 38.63-489.46 μg/g for the first trimester, 58.48-644.03 μg/g for the second trimester, and 56.27-644.93 μg/g for the third trimester. The prevalence of iodine deficiency was 49.50% using UIC as the indicator ( 150 μg/L), while the prevalence was 3.28% using UIC/UCr ( 38.63 μg/g). The prevalence of iodine excess was 3.21% using UIC as the indicator ( 500 μg/L) while the prevalence was 1.45% using UIC/UCr ( 489.46 μg/g). The highest prevalence of overt hypothyroidism and positive thyroid antibodies was in the group with UIC/UCr 38.63 μg/g. In contrast to the place of residence and age, BMI was an influencing factor for UIC/UCr. The reference intervals of UIC/UCr were established. UIC/UCr may eliminate the effect of urine volume and reflect the actual prevalence of iodine deficiency in pregnant women.

The microenvironment plays a vital role in tumor progression, and hypoxia is a typical microenvironment feature in nearly all solid tumors. In this study, we focused on elucidating the effect of canagliflozin (CANA), a new class of antidiabetic agents, on hepatocarcinoma (HCC) tumorigenesis under hypoxia, and demonstrated that CANA could significantly inhibit hypoxia-induced metastasis, angiogenesis, and metabolic reprogramming in HCC. At the molecular level, this was accompanied by a reduction in VEGF expression level, as well as a reduction in the epithelial-to-mesenchymal transition (EMT)-related proteins and glycolysis-related proteins. Next, we focused our study particularly on the modulation of HIF-1α by CANA, which revealed that CANA decreased HIF-1α protein level by inhibiting its synthesis without affecting its proteasomal degradation. Furthermore, the AKT/mTOR pathway, which plays an important role in HIF-1α transcription and translation, was also inhibited by CANA. Thus, it can be concluded that CANA decreased metastasis, angiogenesis, and metabolic reprogramming in HCC by inhibiting HIF-1α protein accumulation, probably by targeting the AKT/mTOR pathway. Based on our results, we propose that CANA should be evaluated as a new treatment modality for liver cancer.

This meta-analysis mainly examined the effect size of exposure and response prevention (ERP) for obsessive-compulsive disorder (OCD) when compared with different control conditions, and the difference in the efficacy of different variants of ERP in the treatment of OCD. Thirty studies were included, involving 39 randomized controlled trials with 1793 participants, from 30 studies up to January 18, 2022. Hedge's g was calculated using random-effects models. The results showed that ERP had a definite effect on OCD (g = 0.37), and its effect was significant when the control condition was placebo (g = 0.97) or drug (g = 0.59). However, ERP did not show statistical differences with other therapies in improving OCD (g = -0.07). In addition, we found that both therapist and self-controlled exposure (at the same time as the therapist controls, self-control is exercised after the therapy session) and total response prevention can better improve OCD symptoms. In addition, compared with the control group, ERP reduced depression (g = 0.15) and anxiety symptoms (g = 0.23) in patients with OCD. Meta-regression results showed that the longer the length of sessions, the better the treatment effect (t = 2.41, p = 0.022).

Chemokine receptor 2 (CXCR2) is the receptor of glutamic acid–leucine–arginine sequence-contained chemokines CXCs (ELR+ CXCs). In recent years, CXCR2-target treatment strategy has come a long way in cancer therapy. CXCR2 antagonists could block CXCLs/CXCR2 axis, and are widely used in regulating immune cell migration, tumor metastasis, apoptosis and angiogenesis. Herein, two series of new CXCR2 small-molecule inhibitors, including 1,2,4-triazol-3-one derivatives 1–11 and pyridazinone derivatives 12–22 were designed and synthesized based on the proof-to-concept. The pyridazinone derivative 18 exhibited good CXCR2 antagonistic activity (69.4 ± 10.5 %Inh at 10 μM) and demonstrated its significant anticancer metastasis activity in MDA-MB-231 cells and remarkable anti-angiogenesis activity in HUVECs. Furthermore, noteworthy was that 18 exhibited an obvious synergistic effect with Sorafenib in anti-proliferation assay in MDA-MB-231 cells. Moreover, 18 showed a distinct reduction of the phosphorylation levels of both PI3K and AKT proteins in MDA-MB-231 cells, and also affected the expression levels of other PI3K/AKT signaling pathway-associated proteins. The molecular docking studies of 18 with CXCR2 also verified the rationality of our design strategy. All of these results revealed pyridazinone derivative 18 as a promising CXCR2 antagonist for future cancer therapy.

Purpose The aim of this study was to describe the genetic and clinical characteristics of Chinese patients with autosomal recessive bestrophinopathy (ARB). Methods This study presents a retrospective observational case series. Twenty-one ARB patients and 25 clinically healthy family members were recruited. The coding regions and adjacent intronic regions of BEST1 were analysed via Sanger sequencing. Clinical examinations, including ultrasound biomicroscopy, A-scan, optical coherence tomography, fundus autofluorescence, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA) and visual electrophysiology, were reviewed. Results Six novel mutations (c.380C>T, p.T127M; c.397A>G, p.N133D; c.500A>G, p.E167G; c.817G>A, p.V273M; c.174_176del, p.Q58del; and c.950_955del, p.S318_L319) and 8 previously reported mutations were identified. The p.R255W mutation had the highest frequency in our cohort. Twenty patients had serous retinal detachment with multifocal subretinal vitelliform deposits in the posterior poles. One patient exhibited chorioretinal atrophy. FFA revealed peripheral vascular leakage in 10 patients, and ICGA revealed hyperfluorescent spots in 8 patients. Visual electrophysiology was abnormal in all patients. Fifteen patients with angle closure (AC) or angle-closure glaucoma (ACG) had shallower anterior chambers and shorter axial lengths than the patients with open angle, contributing to their risk of developing AC/ACG. One patient developed AC during the 7-year follow-up period. The misdiagnosis and missed rates were 35.3% and 58.8%, respectively. Conclusion The six novel mutations and high frequency of p.R255W suggest ethnical differences in the BEST1 mutation spectrum among Chinese patients. BEST1 gene screening and detailed clinical examinations help establishing a diagnosis of ARB. Clinical evaluations of the risk of developing AC/ACG are recommended for ARB patients.

Summary High expression of the inhibitory receptor programmed cell death ligand 1 (PD-L1) on tumor cells and tumor stromal cells have been found to play a key role in tumor immune evasion in several human malignancies. However, the expression of PD-L1 on bone marrow mesenchymal stem cells (BMSCs) and whether the programmed cell death 1 (PD-1)/PD-L1 signal pathway is involved in the BMSCs versus T cell immune response in multiple myeloma (MM) remains poorly defined. In this study, we explored the expression of PD-L1 on BMSCs from newly diagnosed MM (NDMM) patients and the role of PD-1/PD-L1 pathway in BMSC-mediated regulation of CD8+ T cells. The data showed that the expression of PD-L1 on BMSCs in NDMM patients was significantly increased compared to that in normal controls (NC) (18·81 ± 1·61 versus 2·78± 0·70%; P

BackgroundIron deficiency (ID) is concerned as the most common nutritional deficiency worldwide. The effects of ID on thyroid function and autoimmunity in pregnant women and reproductive-age women are controversial. The aim of the current study was to summarize the evidences and evaluate the relationship between ID and thyroid disorders.MethodsIn this systematic review and meta-analysis, studies published on the Cochrane, Embase, Medline, and PubMed databases by October 2020 were searched. A total of 636 studies which discussed the correlation between ID and thyroid disorders were eligible in the initial search. Pooled mean differences (MD) and 95% confidence intervals (CI) were calculated for the assessment of thyrotropin (TSH) and free thyroxine (FT4) levels. Combined odd ratios (OR) and 95% CI were calculated for the assessment of the prevalence of overt and subclinical hypothyroidism, positive thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb).ResultsFor women of reproductive age, ID could significantly increase the risk of positive TPOAb (OR: 1.89; 95% CI: 1.17, 3.06:P= 0.01) and both positive TPOAb and TgAb (OR: 1.48; 95% CI: 1.03, 2.11:P= 0.03). The meta-analysis of pregnant women showed that pregnant women with ID had increased serum TSH levels (MD: 0.12; 95% CI: 0.07, 0.17; P < 0.00001) and decreased FT4 levels (MD: −0.73; 95% CI: −1.04, −0.41; P < 0.00001). Meanwhile, the prevalence of overt (OR: 1.60; 95% CI: 1.17, 2.19; P = 0.004) and subclinical (OR: 1.37; 95% CI: 1.13, 1.66; P = 0.001) hypothyroidism in pregnant women with ID was significantly increased.ConclusionsID may adversely affect thyroid function and autoimmunity of pregnant and reproductive-age women and it is very necessary for monitoring iron nutritional status and early treatment of ID for them.

Noncoding RNA (ncRNA) is involved in the occurrence, development, metastasis, and drug resistance of tumors and involves a variety of biological functions. In addition, miRNA can regulate proliferation and migration and even regulate epigenetics to promote the development of multiple myeloma (MM). However, the mechanism of ncRNA involved in MM is still unclear, and there are many unknown ncRNAs to be explored. This research is aimed at discovering the unknown lncRNA in MM through high-throughput sequencing and to study the mechanism and role of competitive endogenous RNA (ceRNA) involved in the pathogenesis of MM for the development of novel molecular markers and potential new targeted drugs. We screened out 262 new lncRNAs with statistical differences by RNA sequencing and selected the lncRNA MSTRG.29039.1 according to the expression and function of lncRNAs and their target genes in MM. We verified that MSTRG.29039.1 and its target gene OSMR were highly expressed in MM. After knockdown of MSTRG.29039.1 in MM cell lines, the expression of OSMR was decreased, and the expression of hsa-miR-12119 was upregulated which can also promote cell apoptosis and inhibit proliferation. Then, we knocked down hsa-miR-12119 and MSTRG.29039.1, we found that apoptosis of MM cells was reduced, and cell proliferation was increased compared with just knocking down hsa-miR-12119. We further verified the direct binding relationship between MSTRG.29039.1 and OSMR by the dual-luciferase reporter assay system. Thus, MSTRG.29039.1 can competitively bind with miRNA to counteract the inhibitory effect of miRNA on OSMR, which regulates cell proliferation and apoptosis through the JAK2/STAT3 pathway. In a conclusion, lncRNA MSTRG.29039.1 could promote proliferation by sponging hsa-miR-12119 via the JAK2/STAT3 pathway in multiple myeloma. This may be a molecular marker and a potential therapeutic target for MM.

Background Demographic, systemic and ocular factors may impact macular ganglion cell–inner plexiform layer (GCIPL) thickness measurements. This study aimed to investigate the influences of multiple potential determinants of macular GCIPL thickness in normal Chinese adults. Methods This was a retrospective study conducted on 225 normal eyes from 225 healthy Chinese adults. GCIPL thickness were obtained using Cirrus high-definition optical coherence tomography (OCT). The age, gender, laterality, spherical equivalent (SE) refractive error, intraocular pressure (IOP), axial length (AL), central cornea thickness (CCT), circumpapillary retinal nerve fibre layer (pRNFL) thickness and OCT signal strength were recorded and their respective effect on GCIPL thickness parameters were evaluated. Results The mean (± SD) average, minimum, superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal GCIPL thickness was 84.56 ± 5.36, 81.32 ± 5.58, 83.08 ± 5.37, 85.70 ± 5.95, 87.15 ± 6.26, 85.07 ± 6.11, 82.46 ± 5.76, and 83.88 ± 5.59 μm, respectively. Determinants of thinner GCIPL thickness were older age (P = 0.001–0.117; effects enhanced if age over 40 years), thinner pRNFL (all P P P = 0.069–0.842), and between right eyes and the left eyes (P = 0.160–0.875) except that of superonasal GCIPL thickness (P P = 0.135–0.968). Conclusions Individual determinants associated with thinner GCIPL thickness were older age (particularly over 40 years of age), thinner pRNFL, and weaker OCT signal strength. This is relevant in comprehensively understanding the normative data and differentiating normal aging from abnormalities.

Various psychiatric disorders are treated with mindfulness-based interventions (MBIs), although the efficacy of MBIs in patients with social anxiety disorder (SAD) is unclear. In this meta-analysis, we investigated the efficacy of MBIs on SAD symptoms. Systematic searches were performed in various databases, and 11 eligible randomized controlled trials (RCTs) and 5 single-arm trials were identified. The between-groups analysis of the 11 RCTs showed that Hedges' g = 0.00, while the within-group analysis showed a large pre-post effect size (g = 1.20).MBIs were superior to the no-treatment comparator (g = 0.89), equivalent to specific active treatment (g = –0.19), and less effective than evidence-based treatment (i.e., cognitive behavioral therapies) (g = –0.29).MBIs significantly alleviated depressive symptoms and improved mindfulness, quality of life, and self-compassion. Meta-regression analysis showed a dose–response relationship between the alleviation of SAD symptoms and the duration of the MBIs (β = 0.659). Follow-up analysis showed that the effects of MBIs on SAD persisted for 12 months (g = 0.231). An analysis of the 5 single-arm trials found that MBIs had a medium effect in alleviating SAD symptoms (g = 0.48). Future research is needed regarding the design of large RCTs of MBIs on SAD patients.

Primary angle-closure glaucoma (PACG) and retinitis pigmentosa (RP) can co-occur, but the mechanism of their association is not yet established. The purpose of this study was to investigate the differences in ocular biometry parameters and molecular genetics in patients with PACG with or without RP, and to determine the association between PACG and RP. Patients with early-onset PACG (age of onset

The purpose is to assess the diagnostic ability for early glaucoma of macular ganglion cell–inner plexiform layer (GCIPL) thickness in a Chinese population including glaucoma suspects. A total of 367 eyes with primary open-angle glaucoma (168 early glaucoma, 78 moderate glaucoma, and 121 advanced glaucoma), 52 eyes with ocular hypertension (OHT), 59 eyes with enlarged cup-to-disc ratio (C/D), and 225 normal eyes were included. GCIPL thickness (average, minimum, superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal), retinal nerve fiber layer (RNFL) thickness, and optic nerve head (ONH) parameters were measured using Cirrus high-definition optical coherence tomography (OCT) and compared. The diagnostic ability of OCT parameters was assessed by area under receiver operating characteristic curve (AUROC) in 3 distinguishing groups: normal eyes and eyes with early glaucoma, normal eyes and eyes with glaucoma regardless of disease stage, and nonglaucomatous eyes (normal eyes, eyes with OHT, and enlarged C/D) and early glaucomatous eyes. Glaucomatous eyes showed a significant reduction in GCIPL thickness compared with nonglaucomatous eyes. In all 3 distinguishing groups, best-performing parameters of GCIPL thickness, RNFL thickness, and ONH parameters were minimum GCIPL thickness (expressed in AUROC, 0.899, 0.952, and 0.900, respectively), average RNFL thickness (0.904, 0.953, and 0.892, respectively), and rim area (0.861, 0.925, and 0.824, respectively). There was no statistical significance of AUROC between minimum GCIPL thickness and average RNFL thickness (all P > .05). GCIPL thickness could discriminate early glaucoma from normal and glaucoma suspects with good sensitivity and specificity. The glaucoma diagnostic ability of GCIPL thickness was comparable to that of RNFL thickness.

A new enzymatic glucose biosensor based on reversible co-immobilization of horseradish peroxidase (HRP) and glucose oxidase (GOx) on a pH-responsive imprinted monolith is prepared. The poly(4-vinylphenylboronic acid)-grafted imprinted polymer using HRP as a template is formed via surface initiated atom transfer radical polymerization within the pores of brominated poly(glycidyl methacrylate-co-ethylene dimethacrylate) macroporous monolith contained in a 100 μm I.D. capillary column. The two enzymes conjugate is formed via the strong affinity interaction between biotin-labeled GOx and streptavidin-labeled HRP. The modulation of the external pH value enables reusability of the biosensor simply using stripping of the inactive enzymes at a low pH value and subsequent immobilization of fresh enzymes at a high pH value. Under the optimized conditions, the enzymatic biosensor features excellent performance in detection of glucose with a linear range of its concentration from 0.11 to 38.85 mmol/L and a limit of detection of 0.03 mmol/L. A relative standard deviation of 3.7% is calculated from determination of twenty glucose samples. This novel enzymatic sensing system is successfully applied for determination of glucose in human serum, and confirms an enhancement both in selectivity and specificity compared to the more traditionally clinical methods.

Purpose Trabeculectomy has been regarded as a mainstay of initial treatment in eyes of angle closure glaucoma (ACG) with peripheral anterior synechia > 180° in the Chinese population while its efficacy in secondary ACG with BEST1 gene mutation remains unclear. We set out to investigate the treatment outcome of trabeculectomy for secondary ACG in a group of patients with autosomal recessive bestrophinopathy (ARB). Methods In this retrospective case series study, 8 secondary ACG patients with ARB and their 4 recruited family members underwent a thorough ophthalmic examination including best-corrected visual acuity, Goldmann applanation tonometry, gonioscopy, and fundus examinations. Ultrasound biomicroscopy, optical coherence tomography (OCT), ultrasound A-scan, B-scan, electro-oculography (EOG), Humphrey perimetry, fundus photography, fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were also performed. Blood samples were obtained in the patients and their available family members to analyze the variants of the BEST1 gene. Trabeculectomy was performed in the 8 patients (15 eyes). Results The age of onset varied from 13 to 38 years. The average axial length (AL) of the affected eyes was 21.82 ± 0.92 mm and the average anterior chamber depth (ACD) was 2.19 ± 0.29 mm. There was marked axial shallowing of the anterior chamber in all 15 eyes after trabeculectomy, and was not improved with potent mydriatics. The IOP was elevated in 3 eyes. Variable degree of yellowish subretinal deposits was observed in the posterior retina. The FFA showed punctuate or patched hyperfluorescence suggesting retinal pigment epithelium impairment. The ICGA demonstrated dilatation of choroidal vessels. The OCT revealed diffused neuroretinal detachment in the posterior and midperipheral retina, with intraretinal fluid collections, and hyperreflective subretinal accumulations. The average subfoveal choroidal thickness of the patients was 382.36 ± 80.09 μm. All the patients and enrolled family members carried mutation in BEST1 gene. Conclusions ARB is a rare condition with fundus manifestations mimicking various diseases. Careful discrimination should be taken to exclude any secondary causes for ACG before treatment. Concerning the high incidence of postoperative shallow anterior chamber, selection of filtering surgery should be very careful in these patients.