[A multi-center epidemiological study on pneumococcal meningitis in children from 2019 to 2020]. / 2019­2020å¹´160ä¾‹å„¿ç«¥è‚ºç‚Žé“¾çƒèŒè„‘è†œç‚Žä¸´åºŠæµè¡Œç— å­¦å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the clinical characteristics and prognosis of pneumococcal meningitis (PM), and drug sensitivity of Streptococcus pneumoniae (SP) isolates in Chinese children. METHODS: A retrospective analysis was conducted on clinical information, laboratory data, and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country. RESULTS: Among the 160 children with PM, there were 103 males and 57 females. The age ranged from 15 days to 15 years, with 109 cases (68.1%) aged 3 months to under 3 years. SP strains were isolated from 95 cases (59.4%) in cerebrospinal fluid cultures and from 57 cases (35.6%) in blood cultures. The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87) and 27% (21/78), respectively. Fifty-five cases (34.4%) had one or more risk factors for purulent meningitis, 113 cases (70.6%) had one or more extra-cranial infectious foci, and 18 cases (11.3%) had underlying diseases. The most common clinical symptoms were fever (147 cases, 91.9%), followed by lethargy (98 cases, 61.3%) and vomiting (61 cases, 38.1%). Sixty-nine cases (43.1%) experienced intracranial complications during hospitalization, with subdural effusion and/or empyema being the most common complication [43 cases (26.9%)], followed by hydrocephalus in 24 cases (15.0%), brain abscess in 23 cases (14.4%), and cerebral hemorrhage in 8 cases (5.0%). Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old, with rates of 91% (39/43) and 83% (20/24), respectively. SP strains exhibited complete sensitivity to vancomycin (100%, 75/75), linezolid (100%, 56/56), and meropenem (100%, 6/6). High sensitivity rates were also observed for levofloxacin (81%, 22/27), moxifloxacin (82%, 14/17), rifampicin (96%, 25/26), and chloramphenicol (91%, 21/23). However, low sensitivity rates were found for penicillin (16%, 11/68) and clindamycin (6%, 1/17), and SP strains were completely resistant to erythromycin (100%, 31/31). The rates of discharge with cure and improvement were 22.5% (36/160) and 66.2% (106/160), respectively, while 18 cases (11.3%) had adverse outcomes. CONCLUSIONS: Pediatric PM is more common in children aged 3 months to under 3 years. Intracranial complications are more frequently observed in children under 1 year old. Fever is the most common clinical manifestation of PM, and subdural effusion/emphysema and hydrocephalus are the most frequent complications. Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates. Adverse outcomes can be noted in more than 10% of PM cases. SP strains are high sensitivity to vancomycin, linezolid, meropenem, levofloxacin, moxifloxacin, rifampicin, and chloramphenicol.

Mesenchymal stem cell-derived extracellular vesicles for treatment of bone loss within periodontitis in pre-clinical animal models: a meta-analysis.

BACKGROUND: Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) represent an effective and promising strategy for periodontitis, although studies remain pre-clinical. Herein, a meta-analysis was conducted to assess the efficacy of MSC-EVs in animal models of periodontitis. METHODS: The PubMed, Web of Science, and Embase electronic databases were searched up to Dec 2022 to retrieve preclinical studies examining the use of MSC-EVs for periodontitis treatment. Meta-analyses and sub-group analyses were performed to assess the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) or the distance between the cementoenamel junction and alveolar bone crest (CEJ-ABC) in pre-clinical animal models of periodontitis. RESULTS: 11 studies published from Mar 2019 to Oct 2022 met the inclusion criteria. Overall, MSC-EVs contributed to periodontal bone regeneration in the inflammatory bone loss area due to periodontitis, as represented by a weighted mean difference (WMD) of 14.07% (95% CI = 6.73, 21.41%, p < 0.001) for BV/TV and a WMD of -0.12 mm (95% CI= -0.14, -0.11 mm, p < 0.001) for CEJ-ABC. However, sub-analysis suggested that there was no significant difference in CEJ-ABC between studies with bioactive scaffolds and studies without bioactive scaffolds (p = 0.60). CONCLUSIONS: The present study suggests that MSC-EVs may represent an attractive therapy for the treatment of inflammatory bone loss within periodontitis.

[Establishment of a risk model for severe adenovirus pneumonia and prospective study of the timing of intravenous immunoglobulin therapy in children]. / å„¿ç«¥é‡ç—‡è ºç— æ¯’æ€§è‚ºç‚Žé£Žé™©æ¨¡åž‹çš„æž„å»ºåŠé™è„‰æ³¨å°„å ç–«çƒè›‹ç™½æ²»ç–—æ—¶æœºçš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To develop a risk prediction model for severe adenovirus pneumonia (AVP) in children, and to explore the appropriate timing for intravenous immunoglobulin (IVIG) therapy for severe AVP. METHODS: Medical data of 1 046 children with AVP were retrospectively analyzed, and a risk prediction model for severe AVP was established using multivariate logistic regression. The model was validated with 102 children with AVP. Then, 75 children aged ≤14 years who were considered at risk of developing severe AVP by the model were prospectively enrolled and divided into three groups (A, B and C) in order of visit, with 25 children in each group. Group A received symptomatic supportive therapy only. With the exception of symptomatic supportive therapy, group B received IVIG treatment at a dose of 1g/(kg·d) for 2 consecutive days, before progressing to severe AVP. With the exception of symptomatic supportive therapy, group C received IVIG treatment at a dose of 1 g/(kg·d) for 2 consecutive days after progressing to severe AVP. Efficacy and related laboratory indicators were compared among the three groups after treatment. RESULTS: Age<18.5 months, underlying diseases, fever duration >6.5 days, hemoglobin level <84.5 g/L, alanine transaminase level >113.5 U/L, and co-infection with bacteria were the six variables that entered into the risk prediction model for severe AVP. The model had an area under the receiver operating characteristic curve of 0.862, sensitivity of 0.878, and specificity of 0.848. The Hosmer-Lemeshow test showed good consistency between the predicted values and the actual observations (P>0.05). After treatment, group B had the shortest fever duration and hospital stay, the lowest hospitalization costs, the highest effective rate of treatment, the lowest incidence of complications, the lowest white blood cell count and interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10 levels, and the highest level of tumor necrosis factor alpha (P<0.05). CONCLUSIONS: The risk model for severe AVP established in this study has good value in predicting the development of severe AVP. IVIG therapy before progression to severe AVP is more effective in treating AVP in children.

Investigation on the mechanisms of human sperm DNA damage based on the proteomics analysis by SWATH-MS.

BACKGROUND: Spermatozoa have the task of delivering an intact paternal genome to the oocyte and supporting successful embryo development. The detection of sperm DNA fragmentation (SDF) has been emerging as a complementary test to conventional semen analysis for male infertility evaluation, but the mechanism leading to SDF and its impact on assisted reproduction remain unclear. Therefore, the study identified and analyzed the differentially expressed proteins of sperm with high and low SDF. METHODS: Semen samples from men attended the infertility clinic during June 2020 and August 2020 were analyzed, and sperm DNA fragmentation index (DFI) was detected by the sperm chromatin structure assay. Semen samples with low DFI (< 30%, control group) and high DFI (≥ 30%, experimental group) were optimized by density gradient centrifugation (DGC), and the differentially expressed proteins of obtained sperm were identified by the Sequential Window Acquisition of All Theoretical Mass Spectra Mass Spectrometry (SWATH-MS) and performed GO and KEGG analysis. RESULTS: A total of 2186 proteins were identified and 1591 proteins were quantified, of which 252 proteins were identified as differentially expressed proteins, including 124 upregulated and 128 downregulated. These differentially expressed proteins were involved in metabolic pathways, replication/recombination/repair, acrosomal vesicles, kinase regulators, fertilization, tyrosine metabolism, etc. Western blotting results showed that the expression levels of RAD23B and DFFA proteins and the levels of posttranslational ubiquitination and acetylation modifications in the experimental group were significantly higher than those in the control group, which was consistent with the results of proteomics analysis. CONCLUSIONS: Proteomic markers of sperm with high DNA fragmentation can be identified by the SWATH-MS and bioinformatic analysis, and new protein markers and posttranslational modifications related to sperm DNA damage are expected to be intensively explored. Our findings may improve our understanding of the basic molecular mechanism of sperm DNA damage.

Investigation of the mechanisms leading to human sperm DNA damage based on transcriptome analysis by RNA-seq techniques.

RESEARCH QUESTION: What are the molecular mechanisms leading to human sperm DNA damage? DESIGN: Semen samples were collected and the sperm DNA fragmentation index (DFI) was assessed. Differentially expressed RNA in spermatozoa with a high (DFI ≥30%, experimental group) or normal (DFI <30%, control group) DFI were identified by RNA-sequencing (RNA-seq) technology, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed. Three differentially expressed RNA related to sperm DNA damage and repair, namely PMS1, TP53BP1 and TLK2, were validated using real-time quantitative (RT-qPCR). RESULTS: A total of 19,970 expressed RNA were detected in the two groups. Compared with the control group, the expression levels of 189 RNA in the experimental group were significantly increased and those of 163 genes decreased. Gene Ontology enrichment analysis showed that these RNA were mainly concentrated in the ATPase-dependent transmembrane transport complex, extracellular exosome, somatic cell DNA recombination, protein binding, cytoplasm and regulation of localization. KEGG pathway analysis showed that these RNA were mainly related to the PI3K-Akt signalling pathway, endocytosis, p53 signalling pathway and cGMP-PKG signalling pathway. The RT-qPCR results showed that the expression levels of PMS1, TP53BP1 and TLK2 in the experimental group were significantly lower than in the control group (P = 0.01, 0.015 and 0.004, respectively), which was identical to the results of RNA sequencing. CONCLUSIONS: Differentially expressed RNA related to sperm DNA damage and repair may be identified by RNA-seq technology, which provides new insights into the understanding of sperm DNA damage and repair, and will help to discover new biomarkers related to sperm DNA damage.

Mitochondria-Targeting Boron Dipyrromethene Based Photosensitizers for Enhanced Photodynamic Therapy: Synthesis, Optical Properties, and in†vitro Biological Activity.

Increasing Investigations show that photosensitizers (PSs) which target mitochondria are useful for enhancing photodynamic therapy (PDT) efficacy. Herein, we carefully designed and synthesized four triphenylphosphonium (TPP)-modified boron dipyrromethene (BDP)-based PSs through Cu(I)-assisted "3+2" cycloaddition reaction. All of them exhibit intense red light absorption with maxima between 659 and 663 nm, considerable fluorescence emission with quantum yields of 0.16-0.23, high singlet oxygen generation efficiency ranging from 0.22 to 0.34, excellent mitochondria-targeting ability, and good biocompatibility. Upon illumination, they induce significant cancer cell death through a mitochondria-related apoptosis pathway. The IC50 values of these BDP dyes against MCF-7 cells were determined to be as low as 0.046-0.113 µM under rather low dosage of light irradiation (1.5 J ⋅ cm-2 ).

Research progress on the hedgehog signalling pathway in regulating bone formation and homeostasis.

Bone formation is a complex regeneration process that was regulated by many signalling pathways, such as Wnt, Notch, BMP and Hedgehog (Hh). All of these signalling have been demonstrated to participate in the bone repair process. In particular, one promising signalling pathway involved in bone formation and homeostasis is the Hh pathway. According to present knowledge, Hh signalling plays a vital role in the development of various tissues and organs in the embryo. In adults, the dysregulation of Hh signalling has been verified to be involved in bone-related diseases in terms of osteoarthritis, osteoporosis and bone fracture; and during the repair processes, Hh signalling could be reactivated and further modulate bone formation. In this chapter, we summarize our current understanding on the function of Hh signalling in bone formation and homeostasis. Additionally, the current therapeutic strategies targeting this cascade to coordinate and mediate the osteogenesis process have been reviewed.

Antibiotics prescription for targeted therapy of pediatric invasive pneumococcal diseases in China: a multicenter retrospective study.

BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) is a major cause of bacterial meningitis, septicemia and pneumonia in children. Inappropriate choice of antibiotic can have important adverse consequences for both the individual and the community. Here, we focused on penicillin/cefotaxime non-susceptibility of S. pneumoniae and evaluated appropriateness of targeted antibiotic therapy for children with IPD (invasive pneumococcal diseases) in China. METHODS: A multicenter retrospective study was conducted in 14 hospitals from 13 provinces in China. Antibiotics prescription, clinical features and resistance patterns of IPD cases from January 2012 to December 2017 were collected. Appropriateness of targeted antibiotics therapy was assessed. RESULTS: 806 IPD cases were collected. The non-susceptibility rates of S. pneumoniae to penicillin and cefotaxime were 40.9% and 20.7% respectively in 492 non-meningitis cases, whereas those were 73.2% and 43.0% respectively in 314 meningitis cases. Carbapenems were used in 21.3% of non-meningitis cases and 42.0% of meningitis cases for targeted therapy. For 390 non-meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were used in 17.9% and 8.7% of cases respectively for targeted therapy. For 179 meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were prescribed in 55.3% and 15.6% of cases respectively. Overall, inappropriate targeted therapies were identified in 361 (44.8%) of 806 IPD cases, including 232 (28.8%) cases with inappropriate use of carbapenems, 169 (21.0%) cases with inappropriate use of vancomycin and 62 (7.7%) cases with inappropriate use of linezolid. CONCLUSIONS: Antibiotic regimens for IPD definite therapy were often excessive with extensive prescription of carbapenems, vancomycin or linezolid in China. Antimicrobial stewardship programs should be implemented to improve antimicrobial use.

Contribution of Mitophagy to Cell-Mediated Mineralization: Revisiting a 50-Year-Old Conundrum.

Biomineralization in vertebrates is initiated via amorphous calcium phosphate (ACP) precursors. These precursors infiltrate the extracellular collagen matrix where they undergo phase transformation into intrafibrillar carbonated apatite. Although it is well established that ACP precursors are released from intracellular vesicles through exocytosis, an unsolved enigma in this cell-mediated mineralization process is how ACP precursors, initially produced in the mitochondria, are translocated to the intracellular vesicles. The present study proposes that mitophagy provides the mechanism for transfer of ACP precursors from the dysfunctioned mitochondria to autophagosomes, which, upon fusion with lysosomes, become autolysosomes where the mitochondrial ACP precursors coalesce to form larger intravesicular granules, prior to their release into the extracellular matrix. Apart from endowing the mitochondria with the function of ACP delivery through mitophagy, the present results indicate that mitophagy, triggered upon intramitochondrial ACP accumulation in osteogenic lineage-committed mesenchymal stem cells, participates in the biomineralization process through the BMP/Smad signaling pathway.

NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina.

Photoreceptor cell death is recognized as the key pathogenesis of retinal degeneration, but the molecular basis underlying photoreceptor-specific cell loss in retinal damaging conditions is virtually unknown. The N-myc downstream regulated gene (NDRG) family has recently been reported to regulate cell viability, in particular NDRG1 has been uncovered expression in photoreceptor cells. Accordingly, we herein examined the potential roles of NDRGs in mediating photoreceptor-specific cell loss in retinal damages. By using mouse models of retinal degeneration and the 661 W photoreceptor cell line, we showed that photoreceptor cells are indeed highly sensitive to light exposure and the related oxidative stress, and that photoreceptor cells are even selectively diminished by phototoxins of the alkylating agent N-Methyl-N-nitrosourea (MNU). Unexpectedly, we discovered that of all the NDRG family members, NDRG2, but not the originally hypothesized NDRG1 or other NDRG subtypes, was selectively expressed and specifically responded to retinal damaging conditions in photoreceptor cells. Furthermore, functional experiments proved that NDRG2 was essential for photoreceptor cell viability, which could be attributed to NDRG2 control of the photo-oxidative stress, and that it was the suppression of NDRG2 which led to photoreceptor cell loss in damaging conditions. More importantly, NDRG2 preservation contributed to photoreceptor-specific cell maintenance and retinal protection both in vitro and in vivo. Our findings revealed a previously unrecognized role of NDRG2 in mediating photoreceptor cell homeostasis and established for the first time the molecular hallmark of photoreceptor-specific cell death as NDRG2 suppression, shedding light on improved understanding and therapy of retinal degeneration.

[Role of p38MAPK signaling pathway in autophagy of Henle-407 cells induced by spvB of Salmonella typhimurium].

OBJECTIVE: To investigate the role of p38MAPK signaling pathway in autophagy of intestinal epithelial cells induced by spvB of S.typhimurium. METHODS: Henle-407 cells in exponential growth were infected with wild-type S.typhimurium strain STM-211 (with spvB gene), spvB mutated strain STM-delata;spvB, or with delata;spvB-complemented strain STM-c-spvB after treatment of the cells with the p38MAPK inhibitor SB203580. At different time points of co-culture, the cells were collected and the intracellular bacteria were counted. Western blotting was performed to detect the expressions of phosphorylated p38 and autophagy-related proteins LC3 and p62; immunofluorescence staining was used to observe the expression and distribution of LC3. RESULTS: At 1, 2 and 4 h after the infection, the phosphorylation levels of p38 in STM-211 group and STM-c-spvB group were significantly lower than that in STM-delata;spvB group (P<0.05). At 2 and 4 h of co-culture, the intracellular bacterial counts were significantly greater in STM-211 and STM-c-spvB infection groups than in STM-delata;spvB group (P<0.05). Pretreatment with p38 inhibitor SB203580 did no significantly affect the expression levels of LC3 II or P62 in STM-211 and STM-c-spvB groups, but caused significant reduction in their expressions in STM-delata;spvB group at 1 h (P<0.05), and such changes were more obvious at 3 h (P<0.05). CONCLUSION: The inhibitory effect of spvB gene on autophagy in intestinal epithelial cells is related with the negative regulation of p38MAPK signaling pathway.

Pediatric huaiyangshan virus infection: A case report with literature review.

To define the clinical manifestations and laboratory characteristics of pediatric severe fever with thrombocytopenia syndrome (SFTS) case caused by a novel bunyavirus. we retrospectively analyzed a pediatric case of viral SFTS in a 13 year old successfully managed and confirmed to be due to the novel bunyavirus now referred to as Huaiyangshan virus. A literature review of related cases was performed.Our pediatric case was a 13.3-year-old middle school student no underlying disease. Major clinical features included a fever with chills, headache, and dizziness. The patient's epidemiology showed he had close contact with his grandfather who had a confirmed, novel bunyavirus infection. Symptomatic theraphy were given at admission. The patient's temperature and platelet count returned to normal by days 7 and 10, respectively, and he was discharged from the hospital with an improved condition. A literature search was performed using "severe fever with thrombocytopenia syndrome" and "bunyavirus" as keywords, but few relevant reports were found. Novel bunyavirus infection can be transmitted through close contact. Confirmed cases should be kept in isolation. Clinical manifestations were characterized by aspecific symptoms, such as fever and chills. In some cases, platelet counts may remain normal in the early phase of the disease, and fever may not present throughout the entire illness period. Thus, misdiagnosis is possible. Surveillance and vigorous follow-up should be carried out in children with tick bites or in close contact with an index patient in high-risk areas during peak season.

Preparation and In Vitro Photodynamic Activity of Glucosylated Zinc(II) Phthalocyanines as Underlying Targeting Photosensitizers.

Two novel glucosylated zinc(ІІ) phthalocyanines 7a-7b, as well as the acetyl-protected counterparts 6a-6b, have been synthesized by the Cu(I)-catalyzed 1,3-dipolar cycloaddition between the propargylated phthalocyanine and azide-substituted glucoses. All of these phthalocyanines were characterized with various spectroscopic methods and studied for their photo-physical, photo-chemical, and photo-biological properties. With glucose as the targeting unit, phthalocyanines 7a-7b exhibit a specific affinity to MCF-7 breast cancer cells over human embryonic lung fibroblast (HELF) cells, showing higher cellular uptake. Upon illumination, both photosensitizers show high cytotoxicity with IC50 as low as 0.032 µM toward MCF-7 cells, which are attributed to their high cellular uptake and low aggregation tendency in the biological media, promoting the generation of intracellular reactive oxygen species (ROS). Confocal laser fluorescence microscopic studies have also revealed that they have high and selective affinities to the lysosomes, but not the mitochondria, of MCF-7 cells. The results show that these two glucosylated zinc(II) phthalocyanines are potential anticancer agents for targeting photodynamic therapy.

Baseline HBV load increases the risk of anti-tuberculous drug-induced hepatitis flares in patients with tuberculosis.

Hepatitis associated anti-tuberculous treatment (HATT) has been a main obstacle in managing patients co-infected with Mycobacterium tuberculosis and hepatitis B virus (HBV). Therefore, we evaluated the factors related to the severity of adverse effects during HATT, especially those associated with liver failure. A retrospective study was carried out at Tongji Hospital from 2007 to 2012. Increases in serum transaminase levels of >3, 5, and 10 times the upper limit of normal (ULN) were used to define liver damage as mild, moderate, and severe, respectively. Patients with elevated total bilirubin (TBil) levels that were more than 10 times the ULN (>171 µmol/L) with or without decreased (<40%) prothrombin activity (PTA) were diagnosed with liver failure. A cohort of 87 patients was analyzed. The incidence of liver damage and liver failure was 59.8% (n=52) and 25.3% (n=22), respectively. The following variables were correlated with the severity of hepatotoxicity: albumin (ALB) levels, PTA, platelet counts (PLT), and the use of antiretroviral therapies (P<0.05). Hypo-proteinemia and antiretroviral therapy were significantly associated with liver failure, and high viral loads were a significant risk factor with an odds ratio (OR) of 2.066. Judicious follow-up of clinical conditions, liver function tests, and coagulation function, especially in patients with high HBV loads and hypoalbuminemia is recommended. It may be advisable to reconsider the use of antiviral drugs failure during the course of anti-tuberculous treatment of HBV infection patients to avoid the occurrence of furious liver failure.

Double-stranded-RNA-specific adenosine deaminase 1 (ADAR1) is proposed to contribute to the adaptation of equine infectious anemia virus from horses to donkeys.

Equine infectious anemia virus (EIAV) is a member of the genus Lentivirus of the family Retroviridae. Horses are the most susceptible equids to EIAV infection and are therefore the primary hosts of this virus. In contrast, infected donkeys do not develop clinically active equine infectious anemia (EIA). This phenomenon is similar to what has been observed with HIV-1, which fails to induce AIDS in non-human primates. Interestingly, Shen et al. developed a donkey-tropic pathogenic virus strain (EIAVDV117, DV117) by serially passaging a horse-tropic pathogenic strain, EIAVLN40 (LN40), in donkeys. LN40, which was generated by passaging a field isolate in horses, displayed enhanced virulence in horses but caused no clinical symptoms in donkeys. Infection with DV117 induced acute EIA in nearly 100 % of donkeys. Genomic analysis of DV117 revealed a significantly higher frequency of A-to-G substitutions when compared to LN40. Furthermore, detailed analysis of dinucleotide editing showed that A-to-G mutations had a preference for 5'TpA and 5'ApA. These results strongly implicated the activity of the adenosine deaminase, ADAR1, in this type of mutation. Further investigation demonstrated that overexpression of donkey ADAR1 increased A-to-G mutations within the genome of EIAV. Together with our previous finding that multiple mutations in multiple genes are generated in DV117 during its adaptation from horses to donkeys, the present study suggests that ADAR1-induced A-to-G mutations occur during virus adaption to related new hosts contributing to the alteration of EIAV host tropism.

Baicalin inhibits toll-like receptor 2/4 expression and downstream signaling in rat experimental periodontitis.

Periodontitis is a severe inflammatory response, leading to characteristic periodontal soft tissue destruction and alveolar bone resorption. Baicalin possesses potent anti-inflammatory activity; however, it is still unclear whether baicalin regulates toll-like receptor (TLR) 2/4 expression and downstream signaling during the process of periodontitis. In this study, the cervical area of the maxillary second molars of rats was ligated and inoculated with Porphyromonas gingivalis (P. gingivalis) for 4weeks to induce periodontitis. Some rats with periodontitis were treated intragastrically with baicalin (50, 100 or 200mg/kg/day) or vehicle for 4weeks. Compared with the sham group, the levels of TLR2, TLR4 and MyD88 expression and the p38 MAPK and NF-κB activation were up-regulated in the experimental periodontitis group (EPG), accompanied by marked alveolar bone loss and severe inflammation. Treatment with 100 or 200mg/kg/day baicalin dramatically reduced the alveolar bone loss, the levels of HMGB1, TNF-α, IL-1ß, and MPO expression, and the numbers of inflammatory infiltrates in the gingival tissues. Importantly, treatment with 100 or 200mg/kg/day baicalin mitigated the periodontitis-up-regulated TLR2, TLR4 and MyD88 expression, and the p38 MAPK and NF-κB activation. Hence, the blockage of the TLR2 and TLR4/MyD88/p38 MAPK/NF-κB signaling by baicalin may contribute to its anti-inflammatory effects in rat model of periodontitis. In conclusion, these novel findings indicate that baicalin inhibits the TLR2 and TLR4 expression and the downstream signaling and mitigates inflammatory responses and the alveolar bone loss in rat experimental periodontitis. Therefore, baicalin may be a potential therapeutic agent for treatment of periodontitis.

Double-stranded RNA-specific adenosine deaminase 1 (ADAR1) promotes EIAV replication and infectivity.

Adenosine deaminases that act on RNA (ADARs) have been reported to be functional on various viruses. ADAR1 may exhibit antiviral or proviral activity depending on the type of virus. Human immunodeficiency virus (HIV)-1 is the most well-studied lentivirus with respect to its interaction with ADAR1, and variable results have been reported. In this study, we demonstrated that equine ADAR1 (eADAR1) was a positive regulator of equine infectious anemia virus (EIAV), another lentivirus of the Retroviridae family. First, eADAR1 significantly promoted EIAV replication, and the enhancement of viral protein expression was associated with the long terminal repeat (LTR) and Rev response element (RRE) regions. Second, the RNA binding domain 1 of eADAR1 was essential only for enhancing LTR-mediated gene expression. Third, in contrast with APOBEC proteins, which have been shown to reduce lentiviral infectivity, eADAR1 increased the EIAV infectivity. This study indicated that eADAR1 was proviral rather than antiviral for EIAV.

Equine viperin restricts equine infectious anemia virus replication by inhibiting the production and/or release of viral Gag, Env, and receptor via distortion of the endoplasmic reticulum.

UNLABELLED: Viperin is an endoplasmic reticulum (ER)-associated multifunctional protein that regulates virus replication and possesses broad antiviral activity. In many cases, viperin interferes with the trafficking and budding of viral structural proteins by distorting the membrane transportation system. The lentivirus equine infectious anemia virus (EIAV) has been studied extensively. In this study, we examined the restrictive effect of equine viperin (eViperin) on EIAV replication and investigated the possible molecular basis of this restriction to obtain insights into the effect of this cellular factor on retroviruses. We demonstrated that EIAV infection of primary equine monocyte-derived macrophages (eMDMs) upregulated the expression of eViperin. The overexpression of eViperin significantly inhibited the replication of EIAV in eMDMs, and knockdown of eViperin transcription enhanced the replication of EIAV in eMDMs by approximately 45.8%. Further experiments indicated that eViperin restricts EIAV at multiple steps of viral replication. The overexpression of eViperin inhibited EIAV Gag release. Both the α-helix domain and radical S-adenosylmethionine (SAM) domain were required for this activity. However, the essential motifs in SAM were different from those reported for the inhibition of HIV-1 Gag by human viperin. Furthermore, eViperin disrupted the synthesis of both EIAV Env and receptor, which consequently inhibited viral production and entry, respectively, and this disruption was dependent on the eViperin α-helix domain. Using immunofluorescence assays and electron microscopy, we demonstrated that the α-helix domain is responsible for the distortion of the endoplasmic reticulum (ER). Finally, EIAV did not exhibit counteracting eViperin at the protein level. IMPORTANCE: In previous studies, viperin was indicated as restricting virus replications primarily by the inhibition of virus budding. Here, we show that viperin may have multiple antiviral mechanisms, including the reduction of EIAV Gag budding and Env expression, and these activities are dependent on different viperin domains. We especially demonstrate that the overexpression of viperin inhibits EIAV entry by decreasing the level of virus receptor. Therefore, viperin restriction of viruses is determined largely by the dependence of virus on the cellular membrane transportation system.

[Low-dose testosterone undecanoate capsules combined with tadalafil for late-onset hypogonadism accompanied with ED].

OBJECTIVE: To observe the clinical effect of low-dose testosterone undecanoate capsules combined with tadalafil on late-onset hypogonadism (LOH) accompanied with ED. METHODS: Ninety cases of LOH accompanied with ED who met the inclusion criteria were randomly divided into a control group and a combination therapy group, the former treated with tadalafil and the latter with low-dose testosterone undecanoate capsules combined with tadalafil. The LOH symptoms, IIEF-5 scores, sexual encounter profile (SEP) scores, prostate volumes, and the levels of total testosterone (TT), free testosterone (FT) and prostatic specific antigen (PSA) were recorded and compared between the two groups before and after treatment. RESULTS: The IIEF-5 and SEP scores and the TT and FT levels were 20.6 +/- 3.8, 4.02 +/- 1.08, (15.4 +/- 3.4) nmol/L and (0.391 +/- 0.062) nmol/L, respectively, in the combination therapy group after treatment, significantly higher both than 15.7 +/- 3.9, 1.49 +/- 0.82, (10.1 +/- 1.2) nmol/L and (0.200 +/- 0.045) nmol/L before treatment (P < 0.01) and than 8.6 +/- 3.6, 3.50 +/- 1.21, (10.2 +/- 1.2) nmol/L and (0.210 +/- 0.051) nmol/L in the control group after treatment (P < 0.01). CONCLUSION: Low-dose testosterone undecanoate capsules combined with tadalafil has a definite clinical effect and no obvious adverse reactions in the treatment of LOH accompanied with ED.

[Low-dose daily de-escalatory administration of tadalafil for psychological erectile dysfunction].

OBJECTIVE: To investigate the effect of low-dose daily de-escalatory administration of tadalafil on psychological erectile dysfunction (ED). METHODS: We randomized 84 psychological ED patients into an observation and a control group of equal number to receive low-dose daily de-escalatory administration and on-demand medication of tadalafil, respectively, both for 2 months. We compared the scores on IIEF-5 and erection hardness (EHS) between the two groups before and after the treatment. RESULTS: The treatment and follow-up were accomplished for 79 cases, with 5 withdrawals in the control group. The IIEF-5 and EHS scores were remarkably improved in both the observation and control groups after treatment. The rate of therapeutic effectiveness was significantly higher in the observation group than in the control (95.2% vs 86.5%, P < 0.05). CONCLUSION: Low-dose daily de-escalatory administration of tadalafil is highly effective and even better than on-demand medication of tadalafil for psychological ED.