Harnessing Protein Hydrolysates and Peptides for Hyperuricemia Management: Insights into Sources, Mechanisms, Techniques, and Future Directions.

Hyperuricemia (HUA) is a metabolic disorder characterized by an imbalance in uric acid production and excretion, frequently leading to gout and various chronic conditions. Novel bioactive compounds offer effective alternatives for managing HUA, reducing side effects of traditional medications. Recent studies have highlighted the therapeutic potential of protein hydrolysates and peptides in managing HUA. This review focuses on preparing and applying protein hydrolysates to treat HUA and explores peptides for xanthine oxidase inhibition. Particularly, we discuss their origins, enzymatic approaches, and mechanisms of action in detail. The review provides an updated understanding of HUA pathogenesis, current pharmacological interventions, and methodologies for the preparation, purification, identification, and assessment of these compounds. Furthermore, to explore the application of protein hydrolysates and peptides in the food industry, we also address challenges and propose solutions related to the safety, bitterness, oral delivery, and the integration of artificial intelligence in peptide discovery. Bridging traditional pharmacological approaches and innovative dietary interventions, this study paves the way for future research and development in HUA management, contributing to the utilization of proteins from different food sources. In conclusion, protein hydrolysates and peptides show significant promise as safe agents and dietary interventions for preventing and treating HUA.

MDM2 is essential to maintain the homeostasis of epithelial cells by targeting p53.

INTRODUCTION: MDM2 is known as the primary negative regulator of p53, MDM2 promotes lung cancer fibrosis and lung injury through p53-dependent and p53-independent pathways. However, the mechanism by which MDM2 influences the pathogenesis of asthma is unknown. In this study, we investigated the function of MDM2 in lung epithelial cells in type 2 lung inflammation. METHODS: We used type II alveolar epithelial cell-specific heterozygous knockout of Mdm2 mice to validate its function. Then papain-induced asthma model was established, and changes in inflammation were observed by measuring immunohistochemistry and flow cytometry analysis. RESULTS: In this study, we knockdown the mouse Mdm2 gene in type 2 alveolar epithelial cells. We demonstrated that heterozygous Mdm2 gene-deleted mice were highly susceptible to protease allergen papain-induced pulmonary inflammation characterized by increased ILC2 numbers, IL-5 and IL-13 cytokine levels, and lung pathology. A mechanistic study showed that following the decreased expression of Mdm2 in lung epithelial cells and A549 cell line, p53 was overactivated, and the expression of its downstream genes p21, Puma, and Noxa was elevated, which resulted in apoptosis. After Mdm2 knockdown, the mRNA expression of inflammation-related gene IL-25, HMGB1 and TNF-α were increased, which further amplified the downstream ILC2 response and lung inflammation. CONCLUSION: These results indicate that Mdm2 maintains the homeostasis of lung epithelial cells by targeting P53, and regulate the function of lung epithelial cells under type 2 lung inflammation.

FEFA: Frequency Enhanced Multi-Modal MRI Reconstruction with Deep Feature Alignment.

Integrating complementary information from multiple magnetic resonance imaging (MRI) modalities is often necessary to make accurate and reliable diagnostic decisions. However, the different acquisition speeds of these modalities mean that obtaining information can be time consuming and require significant effort. Reference-based MRI reconstruction aims to accelerate slower, under-sampled imaging modalities, such as T2-modality, by utilizing redundant information from faster, fully sampled modalities, such as T1-modality. Unfortunately, spatial misalignment between different modalities often negatively impacts the final results. To address this issue, we propose FEFA, which consists of cascading FEFA blocks. The FEFA block first aligns and fuses the two modalities at the feature level. The combined features are then filtered in the frequency domain to enhance the important features while simultaneously suppressing the less essential ones, thereby ensuring accurate reconstruction. Furthermore, we emphasize the advantages of combining the reconstruction results from multiple cascaded blocks, which also contributes to stabilizing the training process. Compared to existing registration-then-reconstruction and cross-attention-based approaches, our method is end-to-end trainable without requiring additional supervision, extensive parameters, or heavy computation. Experiments on the public fastMRI, IXI and in-house datasets demonstrate that our approach is effective across various under-sampling patterns and ratios. Our code will be available at: https://github.com/chenxm12394/FEFA.

Memory-Based Cross-Modal Semantic Alignment Network for Radiology Report Generation.

Generating radiology reports automatically reduces the workload of radiologists and helps the diagnoses of specific diseases. Many existing methods take this task as modality transfer process. However, since the key information related to disease accounts for a small proportion in both image and report, it is hard for the model to learn the latent relation between the radiology image and its report, thus failing to generate fluent and accurate radiology reports. To tackle this problem, we propose a memory-based cross-modal semantic alignment model (MCSAM) following an encoder-decoder paradigm. MCSAM includes a well initialized long-term clinical memory bank to learn disease-related representations as well as prior knowledge for different modalities to retrieve and use the retrieved memory to perform feature consolidation. To ensure the semantic consistency of the retrieved cross modal prior knowledge, a cross-modal semantic alignment module (SAM) is proposed. SAM is also able to generate semantic visual feature embeddings which can be added to the decoder and benefits report generation. More importantly, to memorize the state and additional information while generating reports with the decoder, we use learnable memory tokens which can be seen as prompts. Extensive experiments demonstrate the promising performance of our proposed method which generates state-of-the-art performance on the MIMIC-CXR dataset.

MonoAux: Fully Exploiting Auxiliary Information and Uncertainty for Monocular 3D Object Detection.

Monocular 3D object detection plays a pivotal role in autonomous driving, presenting a formidable challenge by requiring the precise localization of 3D objects within a single image, devoid of depth information. Most existing methods in this domain fall short of harnessing the limited information available in monocular 3D detection tasks. They typically provide only a single detection outcome, omitting essential uncertainty analysis and result post-processing during model inference, thus limiting overall model performance. In this paper, we propose a comprehensive framework that maximizes information extraction from monocular images while encompassing diverse depth estimation and incorporating uncertainty analysis. Specifically, we mine additional information intrinsic to the monocular 3D detection task to augment supervision, thereby addressing the information scarcity challenge. Moreover, our framework handles depth estimation by recovering multiple sets of depth values from calculated visual heights. The final depth estimate and 3D confidence are determined through an uncertainty fusion process, effectively reducing inference errors. Furthermore, to address task weight allocation in multi-task training, we present a versatile training strategy tailored to monocular 3D detection. This approach leverages measurement indicators to monitor task progress, adaptively adjusting loss weights for different tasks. Experimental results on the KITTI and Waymo dataset confirm the effectiveness of our approach. The proposed method consistently provides enhanced performance across various difficulty levels compared to the original framework while maintaining real-time efficiency.

Meta-lasso: new insight on infection prediction after minimally invasive surgery.

Surgical site infection (SSI) after minimally invasive lung cancer surgery constitutes an important factor influencing the direct and indirect economic implications, patient prognosis, and the 5-year survival rate for early-stage lung cancer patients. In the realm of predictive healthcare, machine learning algorithms have been instrumental in anticipating various surgical outcomes, including SSI. However, accurately predicting infection after minimally invasive surgery remains a clinical challenge due to the multitude of physiological and surgical factors associated with it. Furthermore, clinical patient data, in addition to being high-dimensional, often exists the long-tail problem, posing difficulties for traditional machine learning algorithms in effectively processing such data. Based on this insight, we propose a novel approach called meta-lasso for infection prediction following minimally invasive surgery. Our approach leverages the sparse learning algorithm lasso regression to select informative features and introduces a meta-learning framework to mitigate bias towards the dominant class. We conducted a retrospective cohort study on patients who had undergone minimally invasive surgery for lung cancer at Shanghai Chest Hospital between 2018 and 2020. The evaluation encompassed key performance metrics, including sensitivity, specificity, precision (PPV), negative predictive value (NPV), and accuracy. Our approach has surpassed the performance of logistic regression, random forest, Naive Bayes classifier, gradient boosting decision tree, ANN, and lasso regression, with sensitivity at 0.798, specificity at 0.779, precision at 0.789, NPV at 0.798, and accuracy at 0.788 and has greatly improved the classification performance of the inferior class.

Salvianolic acid B attenuates liver fibrosis by targeting Ecm1 and inhibiting hepatocyte ferroptosis.

Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.

Prevalence and molecular characteristics of heterogeneous vancomycin intermediate Staphylococcus aureus in a tertiary care center of northern China.

The use of glycopeptide medications may decline in line with the annual decline in methicillin-resistant Staphylococcus aureus (MRSA) detection rates in China. The rate of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA)detection may be impacted by this. However, there is currently a dearth of information on the incidence of hVISA in China. This study aims to analyze the recent epidemiology and molecular characteristics of hVISA strains in Beijing, China. A total of 175 non-duplicate MRSA strains from various infection sites were collected from a medical center between January 2018 and May 2023 and underwent molecular typing and susceptibility testing (Vitek2). Vancomycin and teicoplanin MICs were also evaluated by standard broth microdilution method and agar dilution method, respectively. Isolates growing on screening agar (BHIV4 and BHIT5, brain heart infusion agar containing 4 µg/ml vancomycin and 5 µg/ml teicoplanin, respectively) were characterized further by analysis of macro-Etest (MET) and population analysis profiling with area under the curve (PAP-AUC). The proportion of hVISA among MRSA isolates was 8.6 %. BHIT5 could select all hVISA strains while BHIV4 and MET only selected two hVISA strains. Compared with vancomycin- susceptible Staphylococcus aureus (VSSA), hVISA isolates were less susceptible to erythromycin and clindamycin. In addition, hVISA frequency was MIC-independent despite using different detection methods. In total, 11 types of STs, 28 types of spa typing, four types of SCCmec typing, and two types of agr typing were identified and the predominant type in both MRSA and hVISA isolates was ST239-t030-SCCmecIII-agr I. The analysis of biofilm formation, growth, and virulence genes in hVISA strains revealed sparse information. The dataset presented in this study provided the prevalence and molecular characteristics of hVISA in hospital settings and the combination of BHIT5 and PAP-AUC may identify hVISA efficiently. The result of genotyping suggested the genotype of hVISA was mainly consistent with that of local MRSA. Additional studies on the characteristics of hVISA strains were necessary.

Resistance phenotype and genetic features of a heterogeneous vancomycin intermediate-resistant Staphylococcus aureus strain from an immunocompromised patient.

Strain C1 was successfully isolated from an immunosuppressed patient with persistent bacteremia, who had not previously been exposed to glycopeptide antibiotics. This strain was found to be a heterogeneous vancomycin intermediate-resistant Staphylococcus aureus (hVISA). It is noteworthy that, following a brief period of vancomycin treatment, strains C6, C8, and C9, which were obtained from blood and other body parts, exhibited a significant reduction in heterogeneity as determined by population analysis profile-area under the curve (PAP-AUC) detection. Genotyping analysis revealed that these bacterial strains belonged to the same SCCmecIVa-ST59-t437-agrI genotype and shared the same virulome and resistome. In this study, a comparative genomics analysis was conducted between strain C1 and strain N315 to identify potential hVISA-associated mutations. Ultimately, a total of 205 mutation sites in 19 candidate genes, likely associated with the hVISA phenotype, were identified.

Evaluation of commercial assays for the assessment of SARS-CoV-2 antibody response in hemodialysis patients.

BACKGROUND: Hemodialysis patients exhibit variable immunogenicity following administration of the SARS-CoV-2 mRNA vaccine. The aim of the current study was to evaluate the use of two commercial assays in the assessment of SARS-CoV-2 antibody response in hemodialysis patients and to compare their utility to commonly used SARS-CoV-2 serological assays developed in Canada. METHODS: We evaluated serologic antibody response in 85 hemodialysis patients up to 6 months after receiving both doses of the Pfizer-BioNTech BNT162b2 COVID-19 mRNA vaccine. In addition, antibody response was assessed in 46 chronic kidney disease patients and 40 COVID-19 naïve health care workers (HCW) up to 3 months and 9 months, respectively. Anti-spike (S) and anti-nucleocapsid (N) levels were measured using Elecsys anti-SARS-CoV-2 immunoassays on the Roche analyzer and compared to ELISA-based detection of anti-S, anti-receptor binding domain (RBD), and anti-N. RESULTS: The Elecsys anti-N immunoassay showed 93 % concordance with the anti-N ELISA. The Elecsys anti-S immunoassay showed 97 % concordance with the anti-S ELISA and 89 % concordance with the anti-RBD ELISA. HCWs exhibited significantly higher anti-S levels relative to hemodialysis patients. Anti-S levels decreased significantly over a 6-month period (p < 0.001) in patients receiving maintenance hemodialysis. In addition, anti-S levels decreased significantly over a 9-month (p < 0.001) and 3-month period (p < 0.001) in HCWs and CKD patients, respectively. CONCLUSIONS: There is high concordance between commercial SARS-CoV-2 serological assays and SARS-CoV-2 serological assays developed in Canada. Hemodialysis patients exhibited varying immunogenicity following two doses of the COVID-19 mRNA vaccine with anti-S levels decreasing over time.

Solar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary-lung axis.

The immunomodulatory effects of ultraviolet B (UVB) radiation in human diseases have been described. Whether type 2 lung inflammation is directly affected by solar ultraviolet (UV) radiation is not fully understood. Here, we show a possible negative correlation between solar UVB radiation and asthmatic inflammation in humans and mice. UVB exposure to the eyes induces hypothalamus-pituitary activation and α-melanocyte-stimulating hormone (α-MSH) accumulation in the serum to suppress allergic airway inflammation by targeting group 2 innate lymphoid cells (ILC2) through the MC5R receptor in mice. The α-MSH/MC5R interaction limits ILC2 function through attenuation of JAK/STAT and NF-κB signaling. Consistently, we observe that the plasma α-MSH concentration is negatively correlated with the number and function of ILC2s in the peripheral blood mononuclear cells (PBMC) of patients with asthma. We provide insights into how solar UVB radiation-driven neuroendocrine α-MSH restricts ILC2-mediated lung inflammation and offer a possible strategy for controlling allergic diseases.

Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis.

The objective was to examine the pooled effects of antibiotic-probiotic combinations by examining the cure rate and recurrence rate for bacterial vaginosis (BV). A systematic literature search was conducted from electronic databases. All parallel randomized controlled trials (RCTs) that focused on the effects of antibiotics combined with intravaginal probiotics were included. Cure rate and recurrence rate were the primary and secondary outcomes to be analyzed. Meta-analysis was conducted following the Cochrane handbook for Systematic Reviews of Interventions. As a result, of 923 studies identified, 11 articles involving 1,493 BV patients met the inclusion criteria and nine were available for meta-analysis. A meta-analysis of two studies evaluated the recurrence rate 12-16 weeks after treatment. Results showed a statistically significant difference favoring the antibiotics plus probiotics group vs the antibiotics plus placebo group (relative risk 0.62, 95% confidence interval [CI]: 0.45-0.85). The narrative review in one study indicated that the cure rate was higher in the antibiotics plus probiotics group, giving a significant HR ratio of 0.73 (95% CI 0.54-0.98) (p = 0.042). In conclusion, vaginal application of Lactobacillus in combination with antibiotics for the treatment of BV could be a promising method for both reducing the recurrence rate and relieving symptoms of BV.

The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation.

The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FINmajor (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.

Group 2 innate lymphoid cells boost CD8+ T-cell activation in anti-tumor immune responses.

Group 2 innate lymphoid cells (ILC2s) are essential for orchestrating type 2 immune responses during allergic airway inflammation and infection. ILC2s have been reported to play a regulatory role in tumors; however, this conclusion is controversial. In this study, we showed that IL-33-activated ILC2s could boost CD8+ T-cell function through direct antigen cross-presentation. After activation by IL-33, ILC2s showed an enhanced potential to process antigens and prime CD8+ T cell activation. Activated ILC2s could phagocytose exogenous antigens in vivo and in vitro, promoting antigen-specific CD8+ T cell function to enhance antitumor immune responses. Administration of OVA-loaded ILC2s induces robust antitumor effects on the OVA-expressing tumor model. These findings suggested that the administration of tumor antigen-loaded ILC2s might serve as a potential strategy for cancer treatment.

Dual consistent pseudo label generation for multi-source domain adaptation without source data for medical image segmentation.

Introduction: Unsupervised domain adaptation (UDA) aims to adapt a model learned from the source domain to the target domain. Thus, the model can obtain transferable knowledge even in target domain that does not have ground truth in this way. In medical image segmentation scenarios, there exist diverse data distributions caused by intensity in homogeneities and shape variabilities. But multi source data may not be freely accessible, especially medical images with patient identity information. Methods: To tackle this issue, we propose a new multi-source and source-free (MSSF) application scenario and a novel domain adaptation framework where in the training stage, we only get access to the well-trained source domain segmentation models without source data. First, we propose a new dual consistency constraint which uses domain-intra and domain-inter consistency to filter those predictions agreed by each individual domain expert and all domain experts. It can serve as a high-quality pseudo label generation method and produce correct supervised signals for target domain supervised learning. Next, we design a progressive entropy loss minimization method to minimize the class-inter distance of features, which is beneficial to enhance domain-intra and domain-inter consistency in turn. Results: Extensive experiments are performed for retinal vessel segmentation under MSSF condition and our approach produces impressive performance. The sensitivity metric of our approach is highest and it surpasses other methods with a large margin. Discussion: It is the first attempt to conduct researches on the retinal vessel segmentation task under multi-source and source-free scenarios. In medical applications, such adaptation method can avoid the privacy issue. Furthermore, how to balance the high sensitivity and high accuracy need to be further considered.

[Clinical features and genetic analysis of two children with Williams-Beuren syndrome].

OBJECTIVE: To explore the clinical and genetic characteristics of two children with Williams-Beuren syndrome (WBS). METHODS: Two children who had presented at the Department of Pediatrics, General Hospital of Ningxia Medical University respectively on January 26 and March 18, 2021 were selected as the study subjects. Clinical data and results of genetic testing of the two patients were analyzed. RESULTS: Both children had featured developmental delay, characteristic facies and cardiovascular malformation. Child 1 also had subclinical hypothyroidism, whilst child 2 had occurrence of epilepsy. Genetic testing revealed that child 1 has harbored a 1.54 Mb deletion in the 7q11.23 region, whilst child 2 has a 1.53 Mb deletion in the same region, in addition with a c.158G>A variant of the ATP1A1 gene and a c.12181A>G variant of the KMT2C gene. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.158G>A and c.12181A>G variants were rated as variants of unknown significance (PM1+PM2_Supporting+PP2+PP3；PM2_Supporting). CONCLUSION: Both children had characteristic features of WBS, for which deletions of the 7q11.23 region may be accountable. For children manifesting developmental delay, facial dysmorphism and cardiovascular malformations, the diagnosis of WBS should be suspected, and genetic testing should be recommended to confirm the diagnosis.

Molecular epidemiology, antimicrobial susceptibility, and toxin production of clinical Clostridioides difficile isolates from a teaching hospital in Northern China.

To grasp the epidemiological trend and drug resistance mechanisms of Clostridioides difficile (C. diff) in Beijing, 302 C. diff isolates were obtained from patients with diarrhea. The sequence types (STs) from mainstream strains were all susceptible to metronidazole, vancomycin, piperacillin/tazobactam, meropenem, and tigecycline but almost resistant to ciprofloxacin and clindamycin. The missense mutation of GyrA/GyrB and RpoB resulted in fluoroquinolone and rifamycin resistance, respectively. Toxigenic strains from clade IV were likely to be missed due to the deficiency of tcdA gene. Four tcdC genotypes were first detected in strains from clade III and IV. The truncating mutation of TcdC disabled its function working as a toxin suppressor. In conclusion, the molecular epidemiology of C. diff in Beijing is different from other regions of China. The antimicrobial resistance patterns and toxin-producing abilities of strains with different STs varied greatly, which suggests that continuous surveillance and control are meaningful and urgent.

Effects of Omeprazole on Recurrent Clostridioides difficile Infection Caused by ST81 Strains and Their Potential Mechanisms.

Clostridioides difficile infection (CDI) is associated with high recurrence rates that have substantial effects on patients' quality of life. To investigate the risk factors and potential mechanisms contributing to recurrent CDI (rCDI), a total of 243 cases were enrolled in this study. The history of omeprazole (OME) medication and ST81 strain infection were considered the two independent risks with the highest odds ratios in rCDI. In the presence of OME, we detected concentration-dependent increases in the MIC values of fluoroquinolone antibiotics against ST81 strains. Mechanically, OME facilitated ST81 strain sporulation and spore germination by blocking the pathway of purine metabolism and also promoted an increase in cell motility and toxin production by turning the flagellar switch to the ON state. In conclusion, OME affects several biological processes during C difficile growth, which have fundamental impacts on the development of rCDI caused by ST81 strains. Programmed OME administration and stringent surveillance of the emerging ST81 genotype are matters of considerable urgency and significance in rCDI prevention.

Vitamin B6 regulates IL-33 homeostasis to alleviate type 2 inflammation.

Interleukin-33 (IL-33) is a crucial nuclear cytokine that induces the type 2 immune response and maintains immune homeostasis. The fine-tuned regulation of IL-33 in tissue cells is critical to control of the type 2 immune response in airway inflammation, but the mechanism is still unclear. Here, we found that healthy individuals had higher phosphate-pyridoxal (PLP, an active form of vitamin B6) concentrations in the serum than asthma patients. Lower serum PLP concentrations in asthma patients were strongly associated with worse lung function and inflammation. In a mouse model of lung inflammation, we revealed that PLP alleviated the type 2 immune response and that this inhibitory effect relied on the activity of IL-33. A mechanistic study showed that in vivo, pyridoxal (PL) needed to be converted into PLP, which inhibited the type 2 response by regulating IL-33 stability. In mice heterozygous for pyridoxal kinase (PDXK), the conversion of PL to PLP was limited, and IL-33 levels were increased in the lungs, aggravating type 2 inflammation. Furthermore, we found that the mouse double minute 2 homolog (MDM2) protein, an E3 ubiquitin-protein ligase, could ubiquitinate the N-terminus of IL-33 and sustain IL-33 stability in epithelial cells. PLP reduced MDM2-mediated IL-33 polyubiquitination and decreased the level of IL-33 through the proteasome pathway. In addition, inhalation of PLP alleviated asthma-related effects in mouse models. In summary, our data indicate that vitamin B6 regulates MDM2-mediated IL-33 stability to constrain the type 2 response, which might help develop a potential preventive and therapeutic agent for allergy-related diseases.

Clinical Validation of the sFlt-1:PlGF Ratio as a Biomarker for Preeclampsia Diagnosis in a High-Risk Obstetrics Unit.

BACKGROUND: Preeclampsia is a multisystem disorder defined by new onset of hypertension with proteinuria after 20 weeks gestation. In part due to dysregulation of pro-angiogenic factors (e.g., placental growth factor [PlGF]) and anti-angiogenic factors (e.g., soluble fms-like tyrosine kinase 1 [sFlt-1]), preeclampsia results in decreased placental perfusion. An increased sFlt-1:PlGF ratio is associated with increased risk of preeclampsia. In this study, we evaluated sFlt-1:PlGF cutoffs and evaluated the clinical performance of sFlt-1:PlGF for predicting preeclampsia. METHODS: sFlt-1:PlGF results from 130 pregnant females with clinical suspicion of preeclampsia were used to evaluate the diagnostic accuracy of different sFlt-1:PlGF cutoffs and to compare the clinical performance of sFlt-1:PlGF to traditional preeclampsia markers (proteinuria and hypertension). Serum sFlt-1 and PlGF were measured using Elecsys immunoassays (Roche Diagnostics) and preeclampsia diagnosis was verified by expert chart review. RESULTS: A sFlt-1:PlGF cutoff of >38 yielded the greatest diagnostic accuracy of 90.8% (95% CI, 85.8%-95.7%). Using a cutoff of >38, sFlt-1:PlGF exhibited a greater diagnostic accuracy than traditionally used parameters such as new or worsening proteinuria or hypertension (71.9% and 68.6%, respectively). sFlt-1:PlGF >38 exhibited a negative predictive value (NPV) of 96.4% for rule-out of preeclampsia within 7 days, and a positive predictive value (PPV) of 84.8% for predicting preeclampsia within 28 days. CONCLUSIONS: Our study shows the superior clinical performance of sFlt-1:PlGF over hypertension and proteinuria alone to predict preeclampsia at a high-risk obstetrical unit.