Abnormal blood concentration changes in a 71-year-old female who survived a 10,000mg overdose of clozapine: a case report.

BACKGROUND: Clozapine is a highly effective second-generation antipsychotic with few extrapyramidal reactions, making it a preferred choice among clinicians. However, instances of acute clozapine poisoning resulting from suicide attempts and misuse have been reported. Through our review of existing literature, we identified that we believe to be the highest recorded overdose of clozapine in elderly patients, resulting in a nonfatal outcome. CASE PRESENTATION: The case report involves a 71-year-old female with a history of depression who ingested a dose of 10,000 mg of clozapine. Approximately 6 h after the overdose, the clozapine level was 5,200 µg/L, significantly surpassing the recommended therapeutic concentration range of 350-600 µg/L. After gastric lavage and hemoperfusion, the blood level dropped to 1847.11 µg/L. Notably, during therapeutic drugs monitoring (TDM), we found a perplexing spike in the patient's blood level to 5554.15 µg/L after the second hemoperfusion. CONCLUSION: In this case we mainly focused on the abnormal fluctuations in the concentration of clozapine. We conducted a comprehensive analysis of potential factors contributing to this abnormal phenomenon in terms of the patient's age, clinical symptoms, various laboratory test indexes, and the pharmacokinetics of clozapine. Our findings underscore the importance of timely TDM and the precision of results in managing elderly patients experiencing high-dose clozapine poisoning.

Lactococcus garvieae exerts a critical role in inducing inflammation in dairy mastitis by triggering NLRP3 inflammasome-mediated pyroptosis in MAC-T cells.

Lactococcus garvieae (L. garvieae) is a pathogenic bacterium that is Gram-positive and catalase-negative (GPCN), and it is capable of growing in a wide range of environmental conditions. This bacterium is associated with significant mortality and losses in fisheries, and there are concerns regarding its potential as a zoonotic pathogen, given its presence in cattle and dairy products. While we have identified and characterized virulent strains of L. garvieae through phenotyping and molecular typing studies, their impact on mammary tissue remains unknown. This study aims to investigate the pathogenicity of strong and weak virulent strains of L. garvieae using in vivo mouse models. We aim to establish MAC-T cell model to examine potential injury caused by the strong virulent strain LG41 through the TLR2/NLRP3/NF-kB pathway. Furthermore, we assess the involvement of NLRP3 inflammasome-mediated pyroptosis in dairy mastitis by silencing NLRP3. The outcomes of this study will yield crucial theoretical insights into the potential mechanisms involved in mastitis in cows caused by the L. garvieae-induced inflammatory response in MAC-T cells.

Research Progress on the Immune-Inflammatory Mechanisms of Posttraumatic Epilepsy.

Posttraumatic epilepsy (PTE) is a severe complication arising from a traumatic brain injury caused by various violent actions on the brain. The underlying mechanisms for the pathogenesis of PTE are complex and have not been fully defined. Approximately, one-third of patients with PTE are resistant to antiepileptic therapy. Recent research evidence has shown that neuroinflammation is critical in the development of PTE. This article reviews the immune-inflammatory mechanisms regarding microglial activation, astrocyte proliferation, inflammatory signaling pathways, chronic neuroinflammation, and intestinal flora. These mechanisms offer novel insights into the pathophysiological mechanisms of PTE and have groundbreaking implications in the prevention and treatment of PTE. Immunoinflammatory cross-talk between glial cells and gut microbiota in posttraumatic epilepsy. This graphical abstract depicts the roles of microglia and astrocytes in posttraumatic epilepsy, highlighting the influence of the gut microbiota on their function. TBI traumatic brain injury, AQP4 aquaporin-4, Kir4.1 inward rectifying K channels.

COVID-19 vaccination for patients with epilepsy: A Chinese expert consensus.

Coronavirus disease-2019 (COVID-19) first emerged in late 2019 and has since spread worldwide. More than 600 million people have been diagnosed with COVID-19, and over 6 million have died. Vaccination against COVID-19 is one of the best ways to protect humans. Epilepsy is a common disease, and there are approximately 10 million patients with epilepsy (PWE) in China. However, China has listed "uncontrolled epilepsy" as a contraindication for COVID-19 vaccination, which makes many PWE reluctant to get COVID-19 vaccination, greatly affecting the health of these patients in the COVID-19 epidemic. However, recent clinical practice has shown that although a small percentage of PWE may experience an increased frequency of seizures after COVID-19 vaccination, the benefits of COVID-19 vaccination for PWE far outweigh the risks, suggesting that COVID-19 vaccination is safe and recommended for PWE. Nonetheless, vaccination strategies vary for different PWE, and this consensus provides specific recommendations for PWE to be vaccinated against COVID-19.

Research progress on the pathogenesis of CDKL5 pathogenic variants and related encephalopathy.

Cyclin-dependent kinase-like 5 (CDKL5) is a gene encoding a serine/threonine kinase that possesses an N-terminal catalytic domain and a large C-terminal domain and is located on the short arm of the X-chromosome at position 22 (Xp22). CDKL5 regulates neuronal migration, axonal growth, dendritic morphogenesis, and synaptic development and affects synaptic function. Pathogenic variants include deletions, truncations, splice variants, and missense variants. The specificity of CDKL5 is mainly determined by the shared sequence of amino acid residues, which is the phosphorylation site of the target protein with the motif Arg-Pro-X-Ser/Thr-Ala/Pro/Gly/Ser (R-P-X-[S/T]-[A/G/P/S]). Developmental encephalopathy caused by pathogenic variants of CDKL5 has a variety of nervous system symptoms, such as epilepsy, hypotonia, growth retardation, dyskinesia, cortical visual impairment, sleep disorders, and other clinical symptoms. This review summarizes the mechanism of CDKL5-induced allogeneic lesions in the nervous system and the clinical manifestations of related encephalopathy.   Conclusion: This review clarifies CDKL5's participation in neurodevelopmental diseases as well as its crucial function in dividing cells, cultured neurons, knockout mice, and human iPSC-derived neurons. CDKL5 variants help identify clinical diagnostic biomarkers. Although a few direct substrates of CDKL5 have been identified, more must be found in order to fully comprehend the signaling pathways connected to CDKL5 in the brain and the mechanisms that underlie its activities.

Assessment of Cognitive Function with Sleep Spindle Characteristics in Adults with Epilepsy.

Objective: Epilepsy may cause chronic cognitive impairment by disturbing sleep plasticity. Sleep spindles play a crucial role in sleep maintenance and brain plasticity. This study explored the relationship between cognition and spindle characteristics in adult epilepsy. Methods: Participants underwent one-night sleep electroencephalogram recording and neuropsychological tests on the same day. Spindle characteristics during N2 sleep were extracted using a learning-based system for sleep staging and an automated spindle detection algorithm. We investigated the difference between cognitive subgroups in spindle characteristics. Multiple linear regressions were applied to analyze associations between cognition and spindle characteristics. Results: Compared with no/mild cognitive impairment, epilepsy patients who developed severe cognitive impairment had lower sleep spindle density, the differences mainly distributed in central, occipital, parietal, middle temporal, and posterior temporal (P < 0.05), and had relatively long spindle duration in occipital and posterior temporal (P < 0.05). Mini-Mental State Examination (MMSE) was associated with spindle density (pars triangularis of the inferior frontal gyrus (IFGtri): ß = 0.253, P = 0.015, and P.adjust = 0.074) and spindle duration (IFGtri: ß = -0.262, P = 0.004, and P.adjust = 0.030). Montreal Cognitive Assessment (MoCA) was associated with spindle duration (IFGtri: ß = -0.246, P = 0.010, and P.adjust = 0.055). Executive Index Score (MoCA-EIS) was associated with spindle density (IFGtri: ß = 0.238, P = 0.019, and P.adjust = 0.087; parietal: ß = 0.227, P = 0.017, and P.adjust = 0.082) and spindle duration (parietal: ß = -0.230, P = 0.013, and P.adjust = 0.065). Attention Index Score (MoCA-AIS) was associated with spindle duration (IFGtri: ß = -0.233, P = 0.017, and P.adjust = 0.081). Conclusions: The findings suggested that the altered spindle activity in epilepsy with severe cognitive impairment, the associations between the global cognitive status of adult epilepsy and spindle characteristics, and specific cognitive domains may relate to spindle characteristics in particular brain regions.

The modification effect of fasting blood glucose level on the associations between short-term ambient air pollution and blood lipids.

The association between short-term ambient air pollution (AAP) exposure and blood lipids is inconsistent across populations. This study aimed to investigate the modifying effects of fasting blood glucose (FBG) levels on the associations between short-term AAP exposure and blood lipids in 110,637 male participants from Beijing, China. The results showed that FBG modified the association between short-term AAP exposure and blood lipids, especially low-density lipoprotein cholesterol (LDL-C). In the hyperglycemia group, a 10-µg/m3 increase in particles with diameters ≤ 2.5 µm (PM2.5), particles with diameters ≤ 10 µm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), or a 1-mg/m3 increase in carbon monoxide (CO) was associated with a 0.454%, 0.305%, 1.507%, 0.872%, or 3.961% increase in LDL-C, respectively. In the nonhyperglycemic group, short-term increases in air pollutants were even associated with small decreases in LDL-C. The findings demonstrate that lipids in hyperglycemic individuals are more vulnerable to short-term AAP exposure than those in normal populations.

Lactococcus lactis, a bacterium with probiotic functions and pathogenicity.

Lactococcus lactis (L. lactis) is the primary organism for lactic acid bacteria (LAB) and is a globally recognized safe microorganism for the regulation of the intestinal micro-ecological balance of animals and improving the immune performance of the host. L. lactis is known to play a commercially important role in feed fortification, milk fermentation, and vaccine production, but pathogenic L. lactis has been isolated from many clinical cases in recent years, such as the brain of silver carp with Lactococcosis, the liver and spleen of diseased waterfowl, milk samples and padding materials with cow mastitis, and blood and urine from human patients with endocarditis. In dairy farming, where L. lactis has been used as a probiotic in the past, however, some studies have found that L. lactis can cause mastitis in cows, but the lack of understanding of the pathogenesis of mastitis in cows caused by L. lactis has become a new problem. The main objective of this review is to analyze the increasingly serious clinical mastitis caused by L. lactis and combined with the wide application of L. lactis as probiotics, to comprehensively discuss the characteristics and diversity of L. lactis.

Exome and RNA-Seq analyses of an incomplete penetrance variant in USP9X in female-specific syndromic intellectual disability.

Pathogenic variants in USP9X, on X chromosome, have been implicated in syndromic intellectual disability (ID) in both males and females with distinct craniofacial features. We report a truncating variant, c.885_889delAAAAG, p.(Lys296Serfs*4), in the USP9X gene with incomplete penetrance in two nontwin female siblings with phenotypic resemblance to female-specific syndromic ID (MIM 300969, also known as MRX99F). To investigate the possible genetic etiology of the reduced penetrance, X-inactivation, RNA-Seq, and full quad exome analyses were attempted, but failed to identify a promising candidate modifier. While the penetrance of pathogenic variants in USP9X in female appears to be high (95%) and the variants frequently occur de novo, incomplete penetrance should be considered.

The Association between Dietary Protein Intake and the Risk of Pancreatic Cancer: Evidence from 14 Publications.

Many studies have been published to assess the association about dietary protein intake on the risk of pancreatic cancer, but with inconsistent result. This meta-analysis aimed to evaluate whether protein intake could affect the risk of pancreatic cancer. A systematic literature search was performed in PubMed, EMBASE and Web of Science up to October 1, 2019. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using a random-effect model. A total of 14 studies (12 case-control studies and two cohort studies) were included. Overall, total protein intake had no significant association on the risk of pancreatic cancer (RR = 1.02, 95%CI= 0.85-1.22, I2=45.7%). Subgroup analyses showed such relationships were almost not influenced by study design and geographic location. Interestingly, when we performed the subgroup analysis by protein type, the opposite association was found in animal protein intake (RR = 1.37, 95%CI= 0.93-2.01) and vegetable protein intake (RR = 0.78, 95%CI= 0.54-1.14), although these two groups were not statistically significant. In conclusion, this meta-analysis indicated that dietary total protein intake may be not associated with the risk of pancreatic cancer. However, protein type may be affecting the result which was found from our research. Therefore, studies with detailed information, especially protein type, are warranted to further confirm these findings.

The prognosis of late-onset anti-N-methyl-D-aspartate receptor encephalitis in China.

OBJECTIVES: Early-onset anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) differs from late-onset anti-NMDARE regarding clinical characteristics. Until recently, research focusing on prognosis of elder adults has been scarce and showed inconsistent results. This study aims to evaluate the prognosis of late-onset anti-NMDARE in China. MATERIALS & METHODS: One hundred and twelve adults diagnosed as anti-NMDARE in four hospitals in China were reviewed retrospectively. Outcome data were assessed using modified Rankin Scale (mRS) score in short term (3 months after discharge) and long term (≥12 months after discharge). The relapse rate was also computed. Multivariable logistic regression was used to evaluate whether there are substantial differences in functional outcomes and recurrence rate across two groups. RESULTS: Of the 112 patients with anti-NMDARE, 81 (72.3%) were early-onset disease and 31 (27.7%) were late-onset disease. Of these, all had short-term follow-up and 70 completed long-term follow-up. Late-onset anti-NMDARE group showed better short-term (OR 2.70, 95% CI 1.09-6.71) and long-term prognoses (OR 10.25, 95% CI 1.90-55.15). Recurrence rates were statistically different between the groups (OR 4.25, 95% CI 1.22-14.75). CONCLUSION: The prognosis for anti-NMDARE in China was poorer for older adults relative to younger adults. The relapse rates were higher in late-onset group compared to early-onset group.

Association between ambient air pollution and blood sex hormones levels in men.

Concerns are growing over time on the adverse health effects of air pollution. However, the association between ambient air pollution and blood sex hormones in men is poorly understood. We included 72,917 men aged 20-55 years from February 2014 to December 2019 in Beijing, China in this study. Blood testosterone, follicle stimulating hormone, luteinizing hormone, estradiol, and prolactin levels of each participant were measured. We collected exposure data of daily ambient levels of particulate matter ≤10 µm (PM10) and ≤2.5 µm (PM2.5), nitrogen dioxide, sulfur dioxide (SO2), carbon monoxide, and ozone. Generalized linear mixed models were used to analyze the potential association between ambient air pollution exposure and blood sex hormone levels. The results showed that both immediate and short-term cumulative PM2.5, PM10, and SO2 exposure was related to altered serum sex hormone levels in men, especially testosterone. An increase of 10 µg/m3 in PM2.5 and PM10 in the current day was related to a 1.6% (95% confidence interval [CI]: 0.9%-2.3%) and 1.1% (95% CI: 0.5%-1.6%) decrease in testosterone, respectively, and a decreasing tendency of accumulated effects persisted within lag 0-30 days. The present study demonstrated that it is important to control ambient air pollution exposure to reduce effects on the reproductive health of men.

Error Performance of Amplitude Shift Keying-Type Asymmetric Quantum Communication Systems.

We propose an amplitude shift keying-type asymmetric quantum communication (AQC) system that uses an entangled state. As a first step toward development of this system, we evaluated and considered the communication performance of the proposed receiver when applied to the AQC system using a two-mode squeezed vacuum state (TSVS), the maximum quasi-Bell state, and the non-maximum quasi-Bell state, along with an asymmetric classical communication (ACC) system using the coherent state. Specifically, we derived an analytical expression for the error probability of the AQC system using the quasi-Bell state. Comparison of the error probabilities of the ACC system and the AQC systems when using the TSVS and the quasi-Bell state shows that the AQC system using the quasi-Bell state offers a clear performance advantage under specific conditions. Additionally, it was clarified that there are cases where the universal lower bound on the error probability for the AQC system was almost achieved when using the quasi-Bell state, unlike the case in which the TSVS was used.

Simplification of the Gram Matrix Eigenvalue Problem for Quadrature Amplitude Modulation Signals.

In quantum information science, it is very important to solve the eigenvalue problem of the Gram matrix for quantum signals. This allows various quantities to be calculated, such as the error probability, mutual information, channel capacity, and the upper and lower bounds of the reliability function. Solving the eigenvalue problem also provides a matrix representation of quantum signals, which is useful for simulating quantum systems. In the case of symmetric signals, analytic solutions to the eigenvalue problem of the Gram matrix have been obtained, and efficient computations are possible. However, for asymmetric signals, there is no analytic solution and universal numerical algorithms that must be used, rendering the computations inefficient. Recently, we have shown that, for asymmetric signals such as amplitude-shift keying coherent-state signals, the Gram matrix eigenvalue problem can be simplified by exploiting its partial symmetry. In this paper, we clarify a method for simplifying the eigenvalue problem of the Gram matrix for quadrature amplitude modulation (QAM) signals, which are extremely important for applications in quantum communication and quantum ciphers. The results presented in this paper are applicable to ordinary QAM signals as well as modified QAM signals, which enhance the security of quantum cryptography.

[Mechanism of Shenling Baizhu Powder in alleviation of ulcerative colitis in mice based on high-throughput transcriptome sequencing].

High-throughput transcriptome sequencing was used to study the mechanism of Shenling Baizhu Powder(SLBZP) in the alleviation of the dextran sulfate sodium(DSS)-induced ulcerative colitis(UC) in mice. The mouse model of DDS-induced UC was treated with SLBZP by gavage. The changes in general state, disease activity index(DAI), and colon length were observed. The hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissues of mice. Enzyme-linked immunosorbent assay(ELISA) was used to determine the expression levels of tumor necrosis factor-α(TNF-α), interleukin(IL)-1ß, IL-6, IL-4, and IL-10 in the serum and tissues of mice. The differentially expressed genes in the control group, the model group, and the SLBZP group were analyzed by high-throughput transcriptome sequencing, and the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were conducted on the differentially expressed genes. The results showed that after intragastric administration of SLBZP, the symptoms of diarrhea and bloody stool were improved, and the disease active index(DAI) score was reduced. SLBZP effectively reduced the inflammatory cell infiltration and goblet cell loss in the colonic mucosal tissue, reduced the levels of TNF-α, IL-1ß, IL-6 in the serum and colon tissue, and increased the levels of IL-4 and IL-10 in the serum and colon tissue. There were 25 differential genes in SLBZP vs the model group, which were significantly enriched in immune response, immune system process, immunoglobulin production, and other biological processes. KEGG pathway analysis showed that the differential genes were enriched in signaling pathways such as neomycin, kanamycin, and gentamicin biosynthesis, cytokine-cytokine receptor interaction, primary immunodeficiency, and IgA synthesis of the intestinal immune network. This study shows that SLBZP may alleviate UC through immune regulation.

De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.

PURPOSE: Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder. METHODS: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed. RESULTS: We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing. CONCLUSION: Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.

Comprehensive RNA sequencing in primary murine keratinocytes and fibroblasts identifies novel biomarkers and provides potential therapeutic targets for skin-related diseases.

BACKGROUND: Keratinocytes and fibroblasts represent the major cell types in the epidermis and dermis of the skin and play a significant role in maintenance of skin homeostasis. However, the biological characteristics of keratinocytes and fibroblasts remain to be elucidated. The purpose of this study was to compare the gene expression pattern between keratinocytes and fibroblasts and to explore novel biomarker genes so as to provide potential therapeutic targets for skin-related diseases such as burns, wounds, and aging. METHODS: Skin keratinocytes and fibroblasts were isolated from newborn mice. To fully understand the heterogeneity of gene expression between keratinocytes and fibroblasts, differentially expressed genes (DEGs) between the two cell types were detected by RNA-seq technology. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the known genes of keratinocytes and fibroblasts and verify the RNA-seq results. RESULTS: Transcriptomic data showed a total of 4309 DEGs (fold-change > 1.5 and q-value < 0.05). Among them, 2197 genes were highly expressed in fibroblasts and included 10 genes encoding collagen, 16 genes encoding transcription factors, and 14 genes encoding growth factors. Simultaneously, 2112 genes were highly expressed in keratinocytes and included 7 genes encoding collagen, 14 genes encoding transcription factors, and 8 genes encoding growth factors. Furthermore, we summarized 279 genes specifically expressed in keratinocytes and 33 genes specifically expressed in fibroblasts, which may represent distinct molecular signatures of each cell type. Additionally, we observed some novel specific biomarkers for fibroblasts such as Plac8 (placenta-specific 8), Agtr2 (angiotensin II receptor, type 2), Serping1 (serpin peptidase inhibitor, clade G, member 1), Ly6c1 (lymphocyte antigen 6 complex, locus C1), Dpt (dermatopontin), and some novel specific biomarkers for keratinocytes such as Ly6a (lymphocyte antigen 6 complex, locus A) and Lce3c (late cornified envelope 3C), Ccer2 (coiled-coil glutamate-rich protein 2), Col18a1 (collagen, type XVIII, alpha 1) and Col17a1 (collagen type XVII, alpha 1). In summary, these data provided novel identifying biomarkers for two cell types, which can provide a resource of DEGs for further investigations.

The performance of the chemiluminescent immunoassay for measuring serum myeloperoxidase and proteinase 3 antibodies.

BACKGROUND: Enzyme-linked immunosorbent assay (ELISA) has traditionally been used to detect myeloperoxidase (MPO) and proteinase 3 (PR3) antibodies, although it is time-consuming and physically demanding. As a novel and highly effective immunoassay, we compared chemiluminescent immunoassay (CIA) with ELISA to verify the application value of CIA in MPO and PR3 antibodies detection. METHODS: By ELISA and CIA, serum levels of anti-MPO and anti-PR3 antibodies were measured in 63 anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients (AAV group), including 47 microscopic polyangiitis (MPA) patients and 16 granulomatosis with polyangiitis (GPA) patients, in addition, 68 patients in interference control group (IC group), 19 healthy subjects in healthy control group (HC group). We compared MPO and PR3 antibodies levels and positive rates measured by these two methods among groups. Relationship and coincidence rate between ELISA and CIA were investigated. Diagnostic values for clinical outcomes for MPO and PR3 antibodies were assessed by receiver operator characteristic (ROC) curve. RESULTS: In AAV patients, when detecting anti-MPO (r = .90) and anti-PR3 (r = .81), CIA was highly correlated with ELISA, companying with highly total (88.89%, 92.06%, respectively) and positive coincidence rates (84.78%, 77.27%, respectively). In HC group, anti-PR3 positive rate detected by both immunoassay were 0, anti-MPO almost were 0, which without statistically significant difference (P = .32). In IC group, the total (76.47%, 58.82, respectively) and positive coincidence rates (48.38%, 30.00%, respectively) of anti-MPO and anti-PR3 were the lowest, but the negative coincidence rates reached 100%. By CIA, similar to ELISA, the levels of anti-MPO were significantly higher both in AAV patients (56.00; [4.40-235.30]) and MPA patients (98.00; [27.90-324.70]) compared with either IC group (3.20; [3.20-18.55) (P < .0001) or HC group (3.20; [3.20-3.20]) (P < .0001), yielded an area under curve (AUC) of 0.76 for AAV and 0.89 for MPA, the concentration of anti-PR3 in GPA group (66.65; [24.43-150.00]) was significantly higher than that in IC group (2.3; [2.3-10.95]) (P < .0001) and HC group (2.3; [2.3-2.3]) (P < .0001), with an AUC of 0.92. CONCLUSION: Similar to ELISA, CIA was competent to detect MPO and PR3 antibodies in AAV patients and healthy population, thus distinguish AAV patients from IC group and HC group and effectively diagnose MPA and GPA.

Bacillus amyloliquefaciens B10 can alleviate aflatoxin B1-induced kidney oxidative stress and apoptosis in mice.

Aflatoxin B1(AFB1) widely exists in food and feed, which seriously endangers human and animal health. How to detoxify AFB1 is a research hotspot at present. This study attempts to use the Bacillus amyloliquefaciens B10, one of probiotics strain as the research object to ascertain whether it can alleviate the kidney injury induced by AFB1 in mice and its mechanism. Fifty-six mice were divided into four groups (control, AFB1, AFB1 + B10, and B10). The mice that received intragastric administration for 28 days were euthanised, and serum was collected for biochemical index detection with fresh kidney tissue taken for HE staining, TUNEL detection, and protein expression detection. Our results showed that the biochemical indices changed, significant pathological changes appeared, the number of apoptotic cells increased in the kidney tissue of the AFB1 group mice; the protein expressions of Nrf2, HO-1,AKT, P-AKT, and Bcl-2 in the AFB1 group were significantly decreased; the protein expressions of Keap-1, PTEN, Bax, Caspase-9, and Caspase-3 were significantly increased. After B. amyloliquefaciens B10 co-treatment, compared with the AFB1 group, the biochemical indices, pathological changes, and protein expressions were significantly reversed. The results indicated that B. amyloliquefaciens B10 can alleviate AFB1-induced kidney injury in mice.

Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly.

Central conducting lymphatic anomaly (CCLA) is one of the complex lymphatic anomalies characterized by dilated lymphatic channels, lymphatic channel dysmotility and distal obstruction affecting lymphatic drainage. We performed whole exome sequencing (WES) of DNA from a four-generation pedigree and examined the consequences of the variant by transfection of mammalian cells and morpholino and rescue studies in zebrafish. WES revealed a heterozygous mutation in EPHB4 (RefSeq NM_004444.4; c.2334 + 1G>C) and RNA-Seq demonstrated that the EPHB4 mutation destroys the normal donor site, which leads to the use of a cryptic splice donor that results in retention of the intervening 12-bp intron sequence. Transient co-expression of the wild-type and mutant EPHB4 proteins showed reduced phosphorylation of tyrosine, consistent with a loss-of-function effect. Zebrafish ephb4a morpholino resulted in vessel misbranching and deformities in the lymphatic vessel development, indicative of possible differentiation defects in lymphatic vessels, mimicking the lymphatic presentations of the patients. Immunoblot analysis using zebrafish lysates demonstrated over-activation of mTORC1 as a consequence of reduced EPHB4 signaling. Strikingly, drugs that inhibit mTOR signaling or RAS-MAPK signaling effectively rescued the misbranching phenotype in a comparable manner. Moreover, knock-in of EPHB4 mutation in HEK293T cells also induced mTORC1 activity. Our data demonstrate the pathogenicity of the identified EPHB4 mutation as a novel cause of CCLA and suggesting that ERK inhibitors may have therapeutic benefits in such patients with complex lymphatic anomalies.