Case report: A rare DLST mutation in patient with metastatic pheochromocytoma: clinical implications and management challenges.

Background: Pheochromocytoma is one of the most hereditary human tumors with at least 20 susceptible genes undergoing germline and somatic mutations, and other mutations less than 1% -2%. In recent years, other rare mutations have gradually been discovered to be possibly related to the pathogenesis and metastasis of pheochromocytoma. Most patients with pheochromocytoma experience common symptoms like headaches, palpitations, and sweating, while some may have less common symptoms. The diversity of symptoms, genetic mutations, and limited treatment options make management challenging. Case presentation: A 53-year-old woman was hospitalized after experiencing episodic epigastric pain for one month. A mass was found in her right adrenal gland and she underwent robot-assisted laparoscopic surgery, revealing a pheochromocytoma. At the 16-month follow-up, multiple metastatic lesions consistent with metastatic pheochromocytoma were found. A germline mutation in the dihydrolipoamide succinyltransferase (DLST) gene (c.330 + 14A>G) was detected, and despite trying chemotherapy and adjuvant therapy, the patient had a limited response with an overall survival of 27 months. Conclusions: DLST mutation is one of the rare pheochromocytoma-related mutated genes, and genetic sequencing is crucial for effective clinical management.

Neurexin dysfunction in neurodevelopmental and neuropsychiatric disorders: a PRIMSA-based systematic review through iPSC and animal models.

Background: Neurexins, essential synaptic proteins, are linked to neurodevelopmental and neuropsychiatric disorders like autism spectrum disorder (ASD) and schizophrenia. Objective: Through this systematic review, we aimed to shed light on the relationship between neurexin dysfunction and its implications in neurodevelopmental and neuropsychiatric manifestations. Both animal and human-induced pluripotent stem cell (hiPSC) models served as our primary investigative platforms. Methods: Utilizing the PRISMA 2020 guidelines, our search strategy involved scouring articles from the PubMed and Google Scholar databases covering a span of two decades (2003-2023). Of the initial collection, 27 rigorously evaluated studies formed the essence of our review. Results: Our review suggested the significant ties between neurexin anomalies and neurodevelopmental and neuropsychiatric outcomes, most notably ASD. Rodent-based investigations delineated pronounced ASD-associated behaviors, and hiPSC models derived from ASD-diagnosed patients revealed the disruptions in calcium dynamics and synaptic activities. Additionally, our review underlined the integral role of specific neurexin variants, primarily NRXN1, in the pathology of schizophrenia. It was also evident from our observation that neurexin malfunctions were implicated in a broader array of these disorders, including ADHD, intellectual challenges, and seizure disorders. Conclusion: This review accentuates the cardinal role neurexins play in the pathological process of neurodevelopmental and neuropsychiatric disorders. The findings underscore a critical need for standardized methodologies in developing animal and hiPSC models for future studies, aiming to minimize heterogeneity. Moreover, we highlight the need to expand research into less studied neurexin variants (i.e., NRXN2 and NRXN3), broadening the scope of our understanding in this field. Our observation also projects hiPSC models as potent tools for bridging research gaps, promoting translational research, and fostering the development of patient-specific therapeutic interventions.

Experimental and Numerical Investigation of the Tensile and Failure Response of Multiple-Hole-Fiber-Reinforced Magnesium Alloy Laminates under Various Temperature Environments.

In this paper, the tensile mechanical behavior and progressive damage morphology of glass-fiber-reinforced magnesium alloy laminate for different numbers of holes in a temperature range of 25-180 °C were investigated. In addition, based on extensive tensile tests, the tensile mechanical behavior and microscopic damage morphology of porous-glass-fiber-reinforced magnesium alloy laminates at different temperatures were observed by finite element simulation and scanning electron microscopy (SEM). Finally, the numerical simulation and experimental results were in good accordance with the prediction of mechanical properties and fracture damage patterns of the laminates, the average difference between the residual strength values of the specimens at ambient temperature was 5.57%, and the stress-strain curves were in good agreement. The experimental and finite element analysis results showed that the damaged area of the bonded layer tended to expand with the increase in the number of holes, which has a lesser effect on the ultimate tensile strength. As the temperature increased, the specimens changed from obvious fiber breakage (pull-out) and the resin matrix damage mode to matrix softening damage and interfacial delamination fracture damage. As the testing temperature of the specimens increased from 25 °C to 180 °C, the tensile strength of the specimens decreased by an average of 51.59%, while the tensile strength of the specimens showed a nonlinear decreasing trend. The damage mechanism of porous-glass-fiber-reinforced magnesium alloy laminates at different temperatures is discussed in this paper, which can provide a reference for engineering applications and design.

Multimodal Image Fusion for X-ray Grating Interferometry.

X-ray grating interferometry (XGI) can provide multiple image modalities. It does so by utilizing three different contrast mechanisms-attenuation, refraction (differential phase-shift), and scattering (dark-field)-in a single dataset. Combining all three imaging modalities could create new opportunities for the characterization of material structure features that conventional attenuation-based methods are unable probe. In this study, we proposed an image fusion scheme based on the non-subsampled contourlet transform and spiking cortical model (NSCT-SCM) to combine the tri-contrast images retrieved from XGI. It incorporated three main steps: (i) image denoising based on Wiener filtering, (ii) the NSCT-SCM tri-contrast fusion algorithm, and (iii) image enhancement using contrast-limited adaptive histogram equalization, adaptive sharpening, and gamma correction. The tri-contrast images of the frog toes were used to validate the proposed approach. Moreover, the proposed method was compared with three other image fusion methods by several figures of merit. The experimental evaluation results highlighted the efficiency and robustness of the proposed scheme, with less noise, higher contrast, more information, and better details.

Low depression literacy exacerbates the development and progression of depressive mood in Chinese adult social media users during COVID-19: A 3-month observational online questionnaire-based study with multiple cross-sectional analyses.

Background: The main purpose of this study was to explore the relationship between depression literacy (D-Lit) and the development and progression of depressive mood. Methods: This longitudinal study with multiple cross-sectional analyses used data from a nationwide online questionnaire administered via the Wen Juan Xing survey platform. Eligible participants were 18 years or older and had subjectively experienced mild depressive moods at the time of their initial enrollment in the study. The follow-up time was 3 months. Spearman's rank correlation test was used to analyze the predictive role of D-Lit on the later development of depressive mood. Results: We included 488 individuals with mild depressive moods. No statistically significant correlation between D-Lit and Zung Self-rating Depression Scale (SDS) at baseline was observed (adjusted rho = 0.001, p = 0.974). However, after 1 month (adjusted rho = -0.449, p < 0.001) and after 3 months (adjusted rho = -0.759, p < 0.001), D-Lit was significantly and negatively correlated with SDS. Limitations: The targeted subjects were limited to the Chinese adult social media users; meanwhile, China's current management policies for COVID-19 differ from most of the other countries, limiting the generalizability of this study. Conclusion: Despite the limitations, our study provided novel evidence supporting that low depression literacy may be associated with exacerbated development and progression of depressive mood, which, if not appropriately and promptly controlled, may ultimately lead to depression. In the future, we encourage further research to explore the practical and efficient ways to enhance public depression literacy.

Knowledge, attitude and practice toward oral anticoagulants among patients with atrial fibrillation.

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of stroke and other cardiovascular complications. Oral anticoagulants (OACs) are effective in reducing this risk. To investigate the knowledge, attitude and practice (KAP) toward OACs among patients with AF. Methods: This web-based cross-sectional study was conducted at local Hospital between April 2023 and May 2023, and enrolled AF patients. Results: A total of 491 valid questionnaires were collected, with 293 (59.67%) male and 73.93% resided in urban areas. The KAP scores were 4.64 ± 3.28, 21.09 ± 2.33 and 26.18 ± 2.15, respectively. Multivariate logistic regression analysis showed that junior high school [odd ratio (OR) = 0.346, 95% confidence interval (CI) = 0.145-0.825, P = 0.017], junior college/bachelor and above (OR = 6.545, 95% CI = 2.863-14.963, P < 0.001), monthly income ≥5,000 (OR = 2.343, 95% CI = 1.074-5.111, P = 0.032), never taken OACs (OR = 0.015, 95% CI = 0.004-0.059, P < 0.001), and having been diagnosed AF (6-10 months, OR = 4.003, 95% CI = 1.653-9.692, P = 0.002;over 20 months, OR = 4.046, 95% CI = 1.753-9.340, P = 0.001) were independently associated with knowledge. Knowledge (OR = 1.376, 95% CI = 1.162-1.629, P < 0.001), junior high school (OR = 0.258, 95% CI = 0.084-0.792, P = 0.018), monthly income ≥5,000 (OR = 5.486, 95% CI = 1.834-16.412, P = 0.002), and never undergone AF ablation (OR = 0.214, 95% CI = 0.097-0.471, P < 0.001) were independently associated with attitude. Knowledge (OR = 1.128, 95% CI = 1.030-1.235, P = 0.009), 70-79 years (OR = 2.193, 95% CI = 1.166-4.124, P = 0.015) and ≥80 years (OR = 4.375, 95% CI = 2.034-9.411, P < 0.001) were independently associated with proactive practice. Conclusion: Patients with AF had inadequate knowledge, suboptimal attitude and inactive practice towards AF and OACs. Improving patient education, especially among those with lower education levels, enhances understanding and management of AF and OACs.

Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators.

In the current study, we designed and synthesised a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon (CRBN) modulators. The results of the CCK8 assay revealed potent antiproliferative activity for the selected compound 10a against NCI-H929 (IC50=2.25 µM) and U239 (IC50=5.86 µM) cell lines. Compound 10a also can inhibit the TNF-α level (IC50=0.76 µM) in LPS stimulated PMBC and showed nearly no toxicity to this normal human cell line. The TR-FRET assay showed compound 10a having potent inhibitory activity against CRBN (IC50=4.83 µM), and the docking study confirmed a nice fitting of 10a into the active sites of CRBN. Further biology studies revealed compound 10a can increase the apoptotic events, arrest the NCI-H929 cells at G0/G1 cell cycle, and induce the ubiquitination degradation of IKZF1 and IKZF3 proteins by CRL4CRBN. These preliminary results suggested that compound 10a could serve as a potential antitumor drug and worthy of further investigation.

Occurrence of Chordoid Glioma With Sodium Ion Metabolism Disorder 5 Years After Meningioma Surgery and Whole-Exome Sequencing: A Case Report and Literature Review.

Chordoid glioma (CG), a rare slow-growing brain tumor, mainly occurs in the region of the third ventricle. Although its degree of malignancy is relatively low, its clinical prognosis is poor due to obscure clinical manifestations and the particular growing position. Currently, gross total resection is the best available method for treatment of CG. However, the tumor is located in the deep structure of the brain and close to neurovascular structure so it is difficult to remove completely. This study reported a case of CG of the third ventricle 5 years after surgery of right frontal parietal fibrous meningioma, accompanied with peri and post-operative sodium ion metabolism disorder. Whole-exome sequencing (WES) revealed 25 gene mutations shared by meningioma and CG. In addition, the PRKCA D463H CG marker gene mutation also existed in this patient. We reviewed the latest literature on this rare brain tumor, summarized its clinical manifestations, imaging and pathological characteristics, and discussed the mechanism related to its occurrence and the reasons for sodium ion disorder.

N-TFA-Gly-Bt-Based Stereoselective Synthesis of Substituted 3-Amino Tetrahydro-2H-pyran-2-ones via an Organocatalyzed Cascade Process.

Chiral-substituted 3-amino tetrahydro-2H-pyran-2-ones were prepared in excellent enantioselectivities (up to 99% ee) via an organo-catalyzed cascade procedure with N-TFA-Gly-Bt and α,ß-unsaturated aldehydes as the substrates. The corresponding tetrahydro-2H-pyran-2-ones can be used for further synthetic transformations that furnish chiral-substituted 3-aminopiperidin-2-ones with high levels of stereoselectivity.

Synthesis, Characterization, and Evaluation of Triptolide Cell-Penetrating Peptide Derivative for Transdermal Delivery of Triptolide.

Triptolide (TP) has been used as one of the most common systemic treatments for various diseases since the 1960s. However, TP displays diverse side effects on various organs, which limits its clinical application. To overcome this issue, numerous C-14-hydroxyl group derivatives of TP have been synthesized. In this research, the C-14-hydroxyl group of TP is modified by a cell-penetrating peptide polyarginine (R7). The derivative TP-disulfide-CR7 (TP-S-S-CR7) containing a disulfide linkage between TP and R7 possesses less toxicity at various concentrations on the immortal human keratinocyte (HaCaT) cell line by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay compared with free TP. Treating HaCaT cells with TP (100 nM) could increase intracellular ROS (reactive oxygen species) and decrease the activity of SOD (superoxide dismutase). Meanwhile, treating HaCaT cells with equimolar concentration of TP-S-S-CR7 did not cause both of the above TP-induced alterations. In addition, TP-S-S-CR7 did not show significant dermal toxicity on guinea pigs and could efficiently overcome the barrier of corneum and then reach epidermis and dermis within 2 h of transdermal administration. In addition, there was a relatively lower concentration of TP in blood indicating less toxicity on organs. Such results suggest that topical therapy using polyarginine is possible by the transdermal delivery of TP.

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway.

Pyrazinamide (PZA) causes serious hepatotoxicity, but little is known about the exact mechanism by which PZA induced liver injury. The peroxisome proliferator-activated receptors alpha (PPARα) is highly expressed in the liver and modulates the intracellular lipidmetabolism. So far, the role of PPARα in the hepatotoxicity of PZA is unknown. In the present study, we described the hepatotoxic effects of PZA and the role of PPARα and its target genes in the downstream pathway including L-Fabp, Lpl, Cpt-1b, Acaa1, Apo-A1 and Me1 in this process. We found PZA induced the liver lipid metabolism disorder and PPARα expressionwas down-regulated which had a significant inverse correlation with liver injury degree. These changeswere ameliorated by fenofibrate, the co-treatment that acts as a PPARα agonist. In contrast, short-termstarvation significantly aggravated the severity of PZA-induced liver injury. In conclusion, this study demonstrated the critical role played by PPARα in PZA-induced hepatotoxicity and provided a better understanding of the molecular mechanisms underlying PZA-induced liver injury. Copyright © 2016 John Wiley & Sons, Ltd.

An Organocatalytic Asymmetric Friedel-Crafts Addition/Fluorination Sequence: Construction of Oxindole-Pyrazolone Conjugates Bearing Vicinal Tetrasubstituted Stereocenters.

A highly efficient and practical one-pot sequential process, consisting of an organocatalytic enantioselective Friedel-Crafts-type addition of 4-nonsubstituted pyrazolones to isatin-derived N-Boc ketimines and a subsequent diastereoselective fluorination of the pyrazolone moiety, is developed. This reaction sequence delivers novel oxindole-pyrazolone adducts featuring vicinal tetrasubstituted stereocenters with a 0.5 mol % catalyst loading in high yield with excellent enantio- and diastereocontrol. Notably, chloro, bromo, and thioether functionalities can be readily incorporated, rendering a broad diversity of the product.

Organocatalytic enantioselective α-amination of 5-substituted rhodanines: an efficient approach to chiral N,S-acetals.

We report a highly efficient approach to constructing chiral N,S-acetals using 5-substituted rhodanines as sulfur-bound pronucleophiles catalyzed by natural cinchona alkaloids quinine or quinidine. This α-amination reaction has a broad substrate scope, and the products featuring both rhodanine and N,S-acetal structural motifs were obtained in high yields and excellent enantioselectivities.

Novel tartrate-derived guanidine-catalyzed highly enantio- and diastereoselective Michael addition of 3-substituted oxindoles to nitroolefins.

The Michael addition of 3-substituted oxindoles to nitroolefins was catalyzed by a novel tartrate-derived guanidine in high yield with excellent diastereo- and enantioselectivity. This method showed an extraordinarily broad substrate scope in terms of both reaction partners.

Analysis of therapeutic effect and safety of target-dose metoprolol in the treatment of patients with diabetes mellitus with chronic heart failure.

OBJECTIVE: To explore the therapeutic effect and safety of target-dose metoprolol in treating chronic heart failure (CHF) patients complicated with diabetes mellitus (DM). Method s : One hundred and fifty-four elderly patients were randomly divided into an observation group and a control group (n=77), which were treated with target-dose metoprolol and conventional therapy, and routinely treated respectively. The New York Heart Association (NYHA) classification, left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), 6-min walking distance and medication safety of the two groups were compared. RESULTS: Compared with the results before treatment, the NYHA classification, LVESD, LVEDD, LVEF and 6-minutes walking distance of both groups were significantly improved (P<0.05), with significantly better results in the observation group than those in the control group after treatment (P<0.05). In the 6 months of follow-up, the incidence of cardiac events in the observation group (3.90%) was significantly lower than that of the control group (14.29%) (P<0.05). The levels of average fasting blood sugar and glycosylated hemoglobin in the groups showed no significant differences (P>0.05). CONCLUSION: Treating CHF patients complicated with DM with target-dose metoprolol can obviously boost the cardiac function and exercise tolerance, leading to satisfactory clinical therapeutic effect, high security and moderate tolerance.

Deoxypodophyllotoxin triggers necroptosis in human non-small cell lung cancer NCI-H460 cells.

Deoxypodophyllotoxin (DPT), a naturally occurring microtubule destabilizer, inhibits tubulin polymerization and causes cell cycle arrest at G2/M phase in tumor cells. However, the anti-tumor effect and specific mechanism of DPT in non-small cell lung cancer (NSCLC) are still poorly understood. In this study, we determined the anti-tumor effect and potential mechanism of DPT in the NSCLC cell line, NCI-H460 (H460). First, we demonstrated that DPT significantly inhibits the proliferation of H460 cells in vitro and the growth of H460 xenografts in vivo. In further studies, DPT triggered necroptosis in H460 cells with the following characteristics: (I) necrotic cell death morphology; (II) autophagy; (III) loss of plasma membrane integrity; (IV) loss of mitochondria membrane potential; (V) elevation of reactive oxygen species levels; and (VI) specific inhibition of necroptosis via a small molecule, necrostatin-1. This study also revealed that DPT has a similar effect towards the drug-sensitive cancer cell line, H460, and the drug-resistant cell line, H460/Bcl-xL. To our knowledge, this is the first report to document the induction of necroptosis by a microtubule-targeting agent to circumvent cancer drug resistance, thereby providing a new potential choice for clinical cancer therapy, especially drug-resistant cancer therapy.

Development of tartaric acid derived chiral guanidines and their application to catalytic enantioselective α-hydroxylation of ß-dicarbonyl compounds.

A novel library of chiral guanidines featuring a tartaric acid skeleton was developed from diethyl l-tartrate. These guanidines are easily accessed with tunable steric and electronic properties. The utilities of the guanidines were highlighted by their ability to catalyze the α-hydroxylation of ß-ketoesters and ß-diketones with remarkable efficiency and excellent enantioselectivity.

Friedel-Crafts-type allylation of nitrogen-containing aromatic compounds with allylic alcohols catalyzed by a [Mo3S4Pd(η3-allyl)] cluster.

With the direct use of allylic alcohols as allylating agents, the Friedel-Crafts-type allylic alkylation of nitrogen-containing aromatic compounds catalyzed by a [Mo(3)S(4)Pd(η(3)-allyl)] cluster is achieved. With a 3 mol % catalyst loading in acetonitrile at reflux or 60 °C, a variety of N,N-dialkylanilines and indoles reacted smoothly with allylic alcohols to afford the Friedel-Crafts-type allylation products in good to excellent yields with high levels of regioselectivity.

Effects of patient volume on quality of outpatient diabetes care.

In this study we aimed to evaluate the effects of practice size (patient volume) and diabetes caseload in outpatient services on the quality of diabetes care in a teaching hospital. We analyzed the medical records of 2038 diabetic patients treated at a medical center in central Taiwan between January and June 2007. Outpatient practice size (including diabetic and non-diabetic patients) per clinic decreased the odds of glycated hemoglobin (A1C) testing (13% less for every 10 increase in outpatient encounters; p<0.001), and the percentage of A1C values<7% (8% less for every 10 increase in outpatient encounters; p=0.03) in diabetic patients treated by non-endocrinologists. However, a higher caseload of patients with diabetes was associated with an increased lipid profile measurement (19% more for every 5 increase in diabetic patients; p<0.001). In diabetic patients treated by endocrinologists, a higher patient volume was associated with increased odds of low-density-lipoprotein cholesterol (LDL-C) levels<100mg/dl, although there was no effect on the measurement and values of A1C. In conclusion, our study demonstrated some evidence of patient volume-outcome relationship in the management of diabetes in different specialties. This finding can have some implications to the health care system and the referral policy.