Association of sleep characteristics with cardiovascular disease risk in adults over 40 years of age: a cross-sectional survey.

Background: The relationship between sleep characteristics and cardiovascular disease (CVD) risk has yet to reach a consistent conclusion, and more research needs to be carried out. This study aimed to explore the relationship between snoring, daytime sleepiness, bedtime, sleep duration, and high-risk sleep patterns with CVD risk. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) 2015-2018 were collected and analyzed. Multivariable logistic regression was used to evaluate the relationship between snoring, daytime sleepiness, bedtime, sleep duration, high-risk sleep patterns, and CVD risk. Stratified analysis and interaction tests were carried out according to hypertension, diabetes and age. Results: The final analysis contained 6,830 participants, including 1,001 with CVD. Multivariable logistic regression suggested that the relationship between snoring [OR = 7.37,95%CI = (6.06,8.96)], daytime sleepiness [OR = 11.21,95%CI = (9.60,13.08)], sleep duration shorter than 7 h [OR = 9.50,95%CI = (7.65,11.79)] or longer than 8 h [OR = 6.61,95%CI = (5.33,8.19)], bedtime after 0:00 [OR = 13.20,95%CI = (9.78,17.80)] compared to 22:00-22:59, high-risk sleep patterns [OR = 47.73,95%CI = (36.73,62.04)] and CVD risk were statistically significant. Hypertension and diabetes interacted with high-risk sleep patterns, but age did not. Conclusions: Snoring, daytime sleepiness, excessive or short sleep duration, inappropriate bedtime, and high-risk sleep patterns composed of these factors are associated with the CVD risk. High-risk sleep patterns have a more significant impact on patients with hypertension and diabetes.

Association between different insulin resistance surrogates and all-cause mortality in patients with coronary heart disease and hypertension: NHANES longitudinal cohort study.

BACKGROUND: Studies on the relationship between insulin resistance (IR) surrogates and long-term all-cause mortality in patients with coronary heart disease (CHD) and hypertension are lacking. This study aimed to explore the relationship between different IR surrogates and all-cause mortality and identify valuable predictors of survival status in this population. METHODS: The data came from the National Health and Nutrition Examination Survey (NHANES 2001-2018) and National Death Index (NDI). Multivariate Cox regression and restricted cubic splines (RCS) were performed to evaluate the relationship between homeostatic model assessment of IR (HOMA-IR), triglyceride glucose index (TyG index), triglyceride glucose-body mass index (TyG-BMI index) and all-cause mortality. The recursive algorithm was conducted to calculate inflection points when segmenting effects were found. Then, segmented Kaplan-Meier analysis, LogRank tests, and multivariable Cox regression were carried out. Receiver operating characteristic (ROC) and calibration curves were drawn to evaluate the differentiation and accuracy of IR surrogates in predicting the all-cause mortality. Stratified analysis and interaction tests were conducted according to age, gender, diabetes, cancer, hypoglycemic and lipid-lowering drug use. RESULTS: 1126 participants were included in the study. During the median follow-up of 76 months, 455 participants died. RCS showed that HOMA-IR had a segmented effect on all-cause mortality. 3.59 was a statistically significant inflection point. When the HOMA-IR was less than 3.59, it was negatively associated with all-cause mortality [HR = 0.87,95%CI (0.78, 0.97)]. Conversely, when the HOMA-IR was greater than 3.59, it was positively associated with all-cause mortality [HR = 1.03,95%CI (1.00, 1.05)]. ROC and calibration curves indicated that HOMA-IR was a reliable predictor of survival status (area under curve = 0,812). No interactions between HOMA-IR and stratified variables were found. CONCLUSION: The relationship between HOMA-IR and all-cause mortality was U-shaped in patients with CHD and hypertension. HOMA-IR was a reliable predictor of all-cause mortality in this population.

USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart.

BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. METHODS: The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. RESULTS: Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. CONCLUSIONS: Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.

Targeting SDCBP2 in acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a biologically heterogeneous disease with high morbidity and mortality under the existing treatment strategies. Our previous study showed that E2A might be a potential therapeutic target for AML, but the underlying mechanism was unclear. Here, we found that SDCBP2 might be a target gene of E2A through RNA-seq combined ChIP-seq screening. This was also demonstrated by Co-IP experiment. Furthermore, the expression of E2A and SDCBP2 were increased in both AML cell lines and patient samples. Downregulation of SDCBP2 expression suppressed proliferation and induced differentiation of AML cells. In human xenograft mouse leukemia model, inhibiton of SDCBP2 expression delayed AML progression. Overall, the above results confirmed that SDCBP2 might be a target gene of E2A and a potential therapeutic target for AML.

Krüppel-like factor 15 in liver diseases: Insights into metabolic reprogramming.

Liver diseases, characterized by metabolic disorder, have become a global public health problem with high morbidity and mortality. Krüppel-like factor 15 (KLF15) is a zinc-finger transcription factor mainly enriched in liver. Increasing evidence suggests that hepatic KLF15 is activated rapidly during fasting, and contributes to the regulation of gluconeogenesis, lipid, amino acid catabolism, bile acids, endobiotic and xenobiotic metabolism. This review summarizes the latest advances of KLF15 in metabolic reprogramming, and explore the function of KLF15 in acute liver injury, hepatitis B virus, and autoimmune hepatitis. which aims to evaluate the potential of KLF15 as a therapeutic target and prognostic biomarker for liver diseases.

Minocycline Activates the Nucleus of the Solitary Tract-Associated Network to Alleviate Lipopolysaccharide-Induced Neuroinflammation.

Objective To examine the neuroanatomical substrates underlying the effects of minocycline in alleviating lipopolysaccharide (LPS)-induced neuroinflammation. Methods Forty C57BL/6 male mice were randomly and equally divided into eight groups. Over three conse-cutive days, saline was administered to four groups of mice and minocycline to the other four groups. Immediately after the administration of saline or minocycline on the third day, two groups of mice were additionally injected with saline and the other two groups were injected with LPS. Six or 24 hours after the last injection, mice were sacrificed and the brains were removed. Immunohistochemical staining across the whole brain was performed to detect microglia activation via Iba1 and neuronal activation via c-Fos. Morphology of microglia and the number of c-Fo-positive neurons were analyzed by Image-Pro Premier 3D. One-way ANOVA and Fisher's least-significant differences were employed for statistical analyses. Results Minocycline alleviated LPS-induced neuroinflammation as evidenced by reduced activation of microglia in multiple brain regions, including the shell part of the nucleus accumbens (Acbs), paraventricular nucleus (PVN) of the hypothalamus, central nucleus of the amygdala (CeA), locus coeruleus (LC), and nucleus tractus solitarius (NTS). Minocycline significantly increased the number of c-Fo-positive neurons in NTS and area postrema (AP) after LPS treatment. Furthermore, in NTS-associated brain areas, including LC, lateral parabrachial nucleus (LPB), periaqueductal gray (PAG), dorsal raphe nucleus (DR), amygdala, PVN, and bed nucleus of the stria terminali (BNST), minocycline also significantly increased the number of c-Fo-positive neurons after LPS administration. Conclusion Minocycline alleviates LPS-induced neuroinflammation in multiple brain regions, possibly due to increased activation of neurons in the NTS-associated network.

Immune Cell Landscape in Gastric Cancer.

BACKGROUND: The tumor-infiltrating immune cells are closely associated with the prognosis of gastric cancer (GC). This article is aimed at determining the composition change of immune cells and immune regulatory factors in GC and normal tissues, depicting their prognosis value in GC, and revealing the relationship between them and GC clinical parameters. METHODS: We used CIBERSORT to calculate the proportion of 22 immune cells in the GC or normal tissues; a t-test was applied to assess the expression difference of immune cells and immune regulatory factors in normal and GC tissues. The relationship of the immune cells, immune regulatory factors, and GC patients' clinical characteristics was assessed by univariate analysis. RESULTS: In this study, we found that the proportion of macrophages increased, while plasma cells and monocytes decreased in GC tissues. In these immune fractions, Tregs and naïve B cells were found to be correlated with GC patients' prognosis. Interestingly, the expression of immune regulatory factors was ambiguous with their classical function in GC tissues. For example, TIM-3, FOXP3, and CMTM6 were overexpressed, while CD27 and PD-1 were underexpressed in GC tissues. We also found that IDO1, PD-1, TIGIT, and TIM-3 were highly expressed in high-grade GC tissues, the HERC2 expression level was related to patients' gender, and the TIGIT expression level was sensitive to targeted therapy. Furthermore, our results suggested that the infiltration of Tregs and naive B cells was strongly correlated with the T stage, radiation therapy, targeted molecular therapy, and the expression levels of TIM-3 and FOXP3 in GC. CONCLUSION: The expression pattern of tumor-infiltrating immune cells and immune regulatory factors was systematically depicted in the GC tumor microenvironment, indicating that individualized treatment based on the tumor-infiltrating immune cells and immune regulatory factors may be beneficial to GC patients.

CYP1B1-AS1 Is a Novel Biomarker in Glioblastoma by Comprehensive Analysis.

OBJECTIVE: Growing evidence shows that enhancer RNAs (eRNAs) are pivotal for tumor progression. In this research, our team aimed to identify the survival-related eRNAs and further explore their potential function in glioblastoma (GBM). METHODS: RNA-sequencing data in 31 tumor types were acquired from TCGA datasets. The survival-related eRNAs were identified by the use of Kaplan-Meier survival analyses and Spearman's correlation analyses. KEGG pathway enrichment analysis was completed to investigate the underlying signal paths of the critical eRNA. Pancancer assays were applied to explore the association between CYP1B1-AS1 and CYP1B1. RESULTS: We identified 74 survival-related eRNAs and focused on CYP1B1-AS1 which displayed the greatest cor value. CYP1B1 was identified as a regulatory target of CYP1B1-AS1. KEGG analyses suggested that CYP1B1-AS1 might play an essential role through CK-CKR mutual effect, complement and coagulation cascades, TNF signal path, and JAK-STAT signal path. The pancancer verification outcomes revealed that CYP1B1-AS1 was related to survival in 4 cancers, i.e., LIHC, KIRP, KICH, and KIRC. Association was discovered between CYP1B1-AS1 and the targeted gene, CYP1B1, in 29 cancer types. CONCLUSION: The outcomes herein provided the first evidence that overexpression of CYP1B1-AS1 might be a potential molecular biomarker for predicting the prognosis of patients with GBM.

DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo.

Fibroblast growth factor receptor (FGFR) is a promising anticancer target. Currently, most FGFR inhibitors lack sufficient selectivity and have nonnegligible activity against kinase insert domain receptor (KDR), limiting their feasibility due to the serious side effects. Notably, compensatory activation occurs among FGFR1-4, suggesting the urgent need to develop selective pan-FGFR1-4 inhibitors. Here, we explored the antitumor activity of DW14383, a novel irreversible FGFR1-4 inhibitor. DW14383 exhibited equivalently high potent inhibition against FGFR1, 2, 3 and 4, with IC50 values of less than 0.3, 1.1, less than 0.3, and 0.5 nmol/L, respectively. It is a selective FGFR inhibitor, exhibiting more than 1100-fold selectivity for FGFR1 over recombinant KDR, making it one of the most selective FGFR inhibitors over KDR described to date. Furthermore, DW14383 significantly inhibited cellular FGFR1-4 signaling, inducing G1/S cell cycle arrest, which in turn antagonized FGFR-dependent tumor cell proliferation. In contrast, DW14383 had no obvious antiproliferative effect against cancer cell lines without FGFR aberration, further confirming its selectivity against FGFR. In representative FGFR-dependent xenograft models, DW14383 oral administration substantially suppressed tumor growth by simultaneously inhibiting tumor proliferation and angiogenesis via inhibiting FGFR signaling. In summary, DW14383 is a promising selective irreversible pan-FGFR inhibitor with pan-tumor spectrum potential in FGFR1-4 aberrant cancers, which has the potential to overcome compensatory activation among FGFR1-4.

[FOXO3a signaling pathway in prostate cancer: Progress in studies].

FOXO3a is an important member of the FOXO subfamily of Forkhead transcription factors, which plays an important role in promoting cell apoptosis, inducing cell cycle arrest, inhibiting cell proliferation and suppressing tumor metastasis through phosphorylation, ubiquitination-mediated degradation and microRNA. Studies show that upregulated expression of FOXO3a can inhibit the growth of PCa cells. This review summarizes the advances in the studies of the FOXO3a signaling pathway in PCa, aiming to provide some new ideas on the clinical diagnosis and targeted therapy of the malignancy.

Transcatheter mitral valve implantation using a novel system: preclinical results.

BACKGROUND: This preclinical study in sheep sought to demonstrate the initial safety and feasibility of a novel transcatheter mitral valve system (Mi-thos valve) composed of a self-expanding frame and a bovine pericardial tissue bioprosthesis. METHODS: The valve was implanted in 26 sheep using a transapical approach for short- and long-term evaluation. The technical feasibility, safety, durability, and valve function were evaluated during and 6 months after the procedure using intracardiac and transthoracic echocardiography, multisliced computed tomography, histological analysis, and electron microscopy. RESULTS: The success rate of valve implantation was 100%, and the immediate survival rate after surgery was 84%. Five animals died within 90 min after the development of the prosthetic valve due to an acute left ventricular outflow tract obstruction (n = 2) and sudden intraoperative ventricular fibrillation (n = 3). Twelve animals died within 1 month due to acute left heart dysfunction. Mild (n = 5) and moderate (n = 2) paravalvular leakage occurred in seven animals, and two moderate PVL animals died of chronic heart failure within three months. Multimodality imaging studies of the remaining seven animals showed excellent function and alignment of the valves, with no coronary artery obstruction, no left ventricular outflow tract obstruction, no severe transvalvular gradients and no paravalvular leakage. Macroscopic evaluation demonstrated stable, secure positioning of the valve, with full endothelialization of the valve leaflets without injury to the ventricular or atrial walls. Histological and electron microscopic examinations at six months showed no obvious macro- or microcalcification in the leaflets. CONCLUSIONS: Preclinical studies indicate that transcatheter implantation of the Mi-thos valve is technically safe and feasible. The durability, functionality, and lack of leaflet calcification were all verified in animal experiments. The information from these preclinical studies will be applied to patient selection criteria and the first-in-human studies.

Compound amino acid combined with high-dose vitamin B6 attenuate traumatic coagulopathy via inhibiting inflammation by HMGB1/TLR4/NF-κB pathway.

BACKGROUND: Traumatic coagulopathy (TC) arises primarily from coagulation system failure to maintain adequate hemostasis after serious blood loss or trauma. Circulatory homeostasis restoration is the mainstay of the therapeutic approach to TC, but the effects are significantly inhibited by coagulopathy. OBJECTIVE: To identify the therapeutic effects and underlying mechanism of compound amino acid (CAA) combined with high-dosage of vitamin B6 (VB6) on TC. METHODS: Rabbit traumatic model and cellular model were used to evaluate the effect of CAA combined with high-dosage of VB6 in TC. Blood concentrations of AST and ALT were measured using the Vitros 250 device while blood APTT, PT and TT concentrations were measured using commercial diagnostics kits. Furthermore, qRT-PCR, ELISA and Western blotting were used to determine the expression of clotting factor (II, VII, IX, X and XI), inflammatory factors (TNF-α, IL-6 and IL-1ß) and HMGB1/TLR4/NF-κB signaling-related proteins, respectively. RESULTS: In the rabbit traumatic model, CAA combined with high-dosage of VB6 therapy inhibited the high expression of AST and ALT, but increased the expression of coagulation factors. Additionally, in both the rabbit trauma model and cellular injury model, CAA combined with high-dosage of VB6 inhibited the expression of inflammatory factors (IL-6, TNF-α and IL-1ß) and proteins (HMGB1, TLR4 and p-p65) in HMGB1/TLR4/NF-κB pathway. Most importantly, over-expression of HMGB1 reversed the effect of CAA and VB6 in HUVECs and EA.hy926 cells injury model. CONCLUSION: CAA combined with high-dosage of VB6 alleviated TC and inhibited the expression and secretion of inflammatory factors by inhibiting HMGB1-mediated TLR4/NF-κB pathway.

Targeting ferroptosis contributes to ATPR-induced AML differentiation via ROS-autophagy-lysosomal pathway.

Ferroptosis, a newly discovered form of non-apoptotic cell death, is induced by an excessive degree of iron-dependent lipid peroxide. ATPR, a novel all-trans retinoic acid (ATRA) derivative, has been extensively developed to show superior anticancer effect than ATRA in acute myeloid leukemia (AML). However, whether ferroptosis exists during ATPR treatment of AML remains unclear. Herein, we found that ferroptosis occurred in an AML xenograft mouse model of ATPR treatment. In vitro, ATPR was verified to induce ferroptosis in a dose-dependent manner by proferroptotic protein marker, lipid peroxidation, and lipid ROS, which could be significantly reversed by ferrostatin-1. Using lysosomal inhibitor chloroquine and iron chelator desferrioxamine, we further revealed that ATPR-induced ferroptosis was regulated by autophagy via iron homeostasis, especially Nrf2. Furthermore, targeting ferroptosis contributes to ATPR-induced AML differentiation. In conclusion, these results indicated that ferroptosis play an important role in ATPR-induced differentiation, and suggested that ATPR would provide a potential therapeutic value for AML treatment.

ATPR triggers acute myeloid leukaemia cells differentiation and cycle arrest via the RARα/LDHB/ERK-glycolysis signalling axis.

Acute myeloid leukaemia (AML) remains a therapeutic challenge and improvements in chemotherapy are needed. 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been proven to show superior anticancer effect compared with ATRA on various cancers. However, its potential effect on AML remains largely unknown. Lactate dehydrogenase B (LDHB) is the key glycolytic enzyme that catalyses the interconversion between pyruvate and lactate. Currently, little is known about the role of LDHB in AML. In this study, we found that ATPR showed antileukaemic effects with RARα dependent in AML cells. LDHB was aberrantly overexpressed in human AML peripheral blood mononuclear cell (PBMC) and AML cell lines. A lentiviral vector expressing LDHB-targeting shRNA was constructed to generate a stable AML cells with low expression of LDHB. The effect of LDHB knockdown on differentiation and cycle arrest of AML cells was assessed in vitro and vivo, including involvement of Raf/MEK/ERK signalling. Finally, these data suggested that ATPR showed antileukaemic effects by RARα/LDHB/ ERK-glycolysis signalling axis. Further studies should focus on the underlying leukaemia-promoting mechanisms and investigate LDHB as a therapeutic target.

Antioxidant Nanotherapies for the Treatment of Inflammatory Diseases.

Reactive oxygen species (ROS) are essential in regulating various physiological functions. However, overproduction of ROS is implicated in the pathogenesis of various inflammatory diseases. Antioxidant therapy has thus represented an effective strategy for the treatment of oxidative stress relevant inflammatory diseases. Conventional anti-oxidative agents showed limited in vivo effects owing to their non-specific distribution and low retention in disease sites. Over the past decades, significant achievements have been made in the development of antioxidant nanotherapies that exhibit multiple advantages such as excellent pharmacokinetics, stable anti-oxidative activity, and intrinsic ROS-scavenging properties. This review provides a comprehensive overview on recent advances in antioxidant nanotherapies, including ROS-scavenging inorganic nanoparticles, organic nanoparticles with intrinsic antioxidant activity, and drug-loaded anti-oxidant nanoparticles. We highlight the biomedical applications of antioxidant nanotherapies in the treatment of different inflammatory diseases, with an emphasis on inflammatory bowel disease, cardiovascular disease, and brain diseases. Current challenges and future perspectives to promote clinical translation of antioxidant nanotherapies are also briefly discussed.

[A method of exosomes extraction from large-volume cell perfusate].

Objective: To establish an efficient method for extracting exosomes from large-volume cell perfusate. Methods: EA.HY926, an immortalized cell line produced by the hybridization of human umbilical vein endothelial cells and human lung adenocarcinoma cell line A549, was cultured with M199 culture medium containing 10% fetal bovine serum. Flexcell STR-4000 parallel plate flow chamber system was employed to apply shear stress to EA.HY926. And then the perfusate was collected. The cell debris was removed by centrifugation. The supernatant was freeze-dried into the dry powder and was resuspended by small-volume medium. The dialysis was used to desalt and purify the suspension. The exoEasy Maxi Kit was used to extract the exosomes. The morphology of exosomes was observed by electron microscopy. The size of exosomes was detected by nanometer particle size analyzer. The activity of exosomes was detected by PKH26 staining. BCA protein quantification method was used to detect the protein concentration of exosomes. The expressions of exosomal specific proteins CD9 and CD81 were detected by Western blot. The quantitative RT-PCR was used to detect the expression of related genes in the exosomes. Results: The exosomes extracted by this method were uniform in size, showing a typical and complete vesicle-like structure. The particle size was concentrated at 30～150 nm, and the peak value was at 97.63 nm, indicating that the size was appropriate and the purity was high. Moreover, exosomes-specific protein CD9 and CD81 were expressed. PKH26 could bind to the membranous structure of exosomes and exosomes could be efficiently taken up by cells. Endothelial cells-associated CD31, vWF mRNA, and microRNA molecules such as miR-126, miR-21, miR-155 were expressed in exosomes secreted by EA.HY926. Conclusion: This method can effectively extract structurally intact, high-concentration, high-quality exosomes from large-volume cell perfusate.

Stiff limb syndrome with lower limb myoclonus: A case report.

RATIONALE: stiff limb syndrome (SLS) is a variant of stiff-man syndrome, primarily affecting a specific limb. Its diagnosis has always been challenging due to the lack of a specific confirmation test. We present a rare case of a patient with lower limb myoclonus and rigidity. PATIENT CONCERNS: A 53-year-old male presented with a sudden onset of progressive left lower extremity myoclonus and muscle rigidity for 3 days. He rapidly showed signs of right lower limb involvement with severe joint stiffness and inability to walk. DIAGNOSIS: The symptoms nature, physical examination, careful elimination of differential diagnosis suggested a diagnosis of stiff limb syndrome. INTERVENTIONS: Intravenous infusion of gamma globulin 0.4 mg/kg coupled with baclofen and clonazepam were given after admission. He also received an injection of botulinum toxin A to relieve his muscle stiffness. OUTCOMES: The patients' condition improved after the initial treatment with complete disappearance of muscle twitching. Further improvements were seen later on after the local administration of botulinum toxin A. LESSONS: Stiff limb syndrome shares the same complex symptoms with many other conditions. Its diagnosis relies heavily on clinical presentations and on ruling out other conditions. However, unusual symptoms such as myoclonus can occur in few cases and together with the rarity of the condition, the prevalence of misdiagnosis is high. Therefore, being aware and recognizing the signs and symptoms is crucial for proper management. Additionally, EMG is a very important test if the present condition is suspected. However, a negative EMG result or a negative anti-glutamic acid decarboxylase antibody test should not exclude SLS diagnosis.

Hepatic progenitor cell activation is induced by the depletion of the gut microbiome in mice.

The homeostasis of the gut microbiome is crucial for human health and for liver function. However, it has not been established whether the gut microbiome influence hepatic progenitor cells (HPCs). HPCs are capable of self-renewal and differentiate into hepatocytes and cholangiocytes; however, HPCs are normally quiescent and are rare in adults. After sustained liver damage, a ductular reaction occurs, and the number of HPCs is substantially increased. Here, we administered five broad-spectrum antibiotics for 14 days to deplete the gut microbiomes of male C57BL/6 mice, and we measured the plasma aminotransferases and other biochemical indices. The expression levels of two HPC markers, SRY-related high mobility group-box gene 9 (Sox9) and cytokeratin (CK), were also measured. The plasma aminotransferase activities were not affected, but the triglyceride, lactate dehydrogenase, low-density lipoprotein, and high-density lipoprotein concentrations were significantly altered; this suggests that liver function is affected by the composition of the gut microbiome. The mRNA expression of Sox9 was significantly higher in the treated mice than it was in the control mice (p < 0.0001), and a substantial expression of Sox9 and CK was observed around the bile ducts. The mRNA expression levels of proinflammatory factors (interleukin [IL]-1ß, IL-6, tumor necrosis factor [TNF]-α, and TNF-like weak inducer of apoptosis [Tweak]) were also significantly higher in the antibiotic-treated mice than the levels in the control mice. These data imply that the depletion of the gut microbiome leads to liver damage, negatively impacts the hepatic metabolism and function, and activates HPCs. However, the underlying mechanisms remain to be determined.

Alternaria yunnanensis sp. nov., a New Alternaria Species Causing Foliage Spot of Rubber Tree in China.

A new species of Alternaria causing leaf spots on the rubber tree (Hevea brasiliensis) in Yunnan, China, was isolated, examined, and illustrated. Morphologically, it belongs to the section Porri of Alternaria, which produces relatively large conidia and a simple or branched, filamentous long beak. It is, however, characterized by conidiophores gradually enlarging near the apex into a clavate conidiogenous cell and long ellipsoid to obclavate, smooth-walled conidia with a long filamentous beak. Molecular phylogenetic analyses based on ITS rDNA, GAPDH, and TEF1-alpha sequences demonstrate that the phytopathogen falls in the clade of the section Porri, being most closely related to A. sidae, A. sennae, A. deseriticola, A. cyamopsidis, A. rostellata, A. nitrimali, A. crassa, and A. thunbergiae.