Abnormal brain structure in atopic dermatitis: Evidence from Mendelian randomization study.

BACKGROUND: Structural abnormalities in the brain of patients with atopic dermatitis (AD) have been reported; however, the cause has not been determined yet. Herein, we used Mendelian randomization (MR) to reveal the causal effect of AD on brain structure. METHODS: This study utilized summary statistics from genome-wide association studies (GWASs) to investigate a collection of cerebral structural measures, encompassing cortical thickness (CT), cortical surface area (CA), and subcortical volumes in T1 images. A comprehensive GWAS meta-analysis identified a total of 20 independent single nucleotide polymorphisms linked to AD, surpassing the genome-wide significance threshold (p < 5 × 10⁻8). MR estimates were aggregated through the application of the inverse variance weighted method. Additional complementary analyses (i.e., MR-Egger and weighted median approaches) were conducted to further assess the robustness of the obtained results. Sensitivity analysis and multivariate MR (MVMR) while adjusting for brain structural changes risk factors (i.e., depression and anxiety) were performed to assess the reliability and stability of observed causality. RESULTS: Genetically determined AD exhibited a causal link with reduced caudate volumes (IVW-MR: ß = -0.186, p = 0.001, p-corrected = 0.009). Furthermore, we identified potential causal associations between AD and reduced CT in the cingulate region (posterior cingulate, IVW-MR: ß = -0.065, p = 0.018, p-corrected = 0.551; isthmus cingulate, IVW-MR: ß = -0.086, p = 0.003, p-corrected = 0.188), as well as abnormal cortical surface area (CA) in the supramarginal (IVW-MR: ß = -0.047, p = 0.044, p-corrected = 0.714) and isthmus cingulate (IVW-MR: ß = 0.053, p = 0.018, p-corrected = 0.714). Additional supplementary analyses yielded consistent outcomes. There was no evidence of horizontal pleiotropy. MVMR analysis showed that the causal effects of AD on abnormal brain structure remained significant while adjusting for depression and anxiety. CONCLUSION: This MR study provided suggestive evidence that decreased caudate nucleus, posterior cingulate cortex, isthmus cingulate cortex and supramarginal gyrus are suggestively associated with higher AD risk. Future investigation into the brain regions is recommended, which helps to clarify the underlying mechanisms and point to new therapies against AD.

Ivermectin inhibits the growth of glioma cells by inducing cell cycle arrest and apoptosis in vitro and in vivo.

Glioma, the most predominant primary malignant brain tumor, remains uncured due to the absence of effective treatments. Hence, it is imperative to develop successful therapeutic agents. This study aimed to explore the antitumor effects and mechanisms of ivermectin (IVM) in glioma cells in vitro and in vivo. The effects of IVM on cell viability, cell cycle arrest, apoptosis rate, and morphological characteristics were determined respectively by MTT assay/colony formation assay, flow cytometry, and transmission electron microscope. In addition, the expression levels of cycle-related and apoptosis-associated proteins were individually examined by Western blot analysis. Moreover, cell proliferation and apoptosis analyses were carried out by TUNEL, Ki-67, cleaved caspase-3, and cleaved caspase-9 immunostaining assay. Our results demonstrated that IVM has a potential dosage-dependent inhibition effect on the apoptosis rate of glioma cells. Meanwhile, the results also revealed that IVM induced apoptosis by increasing caspase-3 and caspase-9 activity, upregulating the expressions of p53 and Bax, downregulating Bcl-2, activating cleaved caspase-3 and cleaved caspase-9, and blocking cell cycle in G0/G1 phase by downregulating levels of CDK2, CDK4, CDK6, cyclin D1, and cyclin E. These findings suggest that IVM has an inhibition effect on the proliferation of glioma cells by triggering cell cycle arrest and inducing cell apoptosis in vitro and in vivo, and probably represents promising agent for treating glioma.

Topical treatment of green tea polyphenols emulsified in carboxymethyl cellulose protects against acute ultraviolet light B-induced photodamage in hairless mice.

Ultraviolet (UV) radiation causes skin injury and inflammation resulting in impaired immune response and increased risk of skin cancer. It has been shown that green tea polyphenols (GTPs) enhanced intracellular antioxidant defense and promoted the downregulation of proapoptotic genes, and they could be used to protect against the damage induced by UV irradiation. However, the high instability and poor bioavailability of GTPs impose restrictions on their potential pharmacological use. Here we show that carboxymethyl cellulose sodium (CMC-Na) had a stabilizing effect on GTPs under aqueous conditions and topical application of GTPs (emulsified in CMC-Na) had a strong photoprotective effect against acute UVB induced photodamage in uncovered (Uncv) hairless mice skin. After 8 h of incubation at 50 °C with CMC-Na, a percentage i.e. 93% of GTPs was preserved, while in the absence of CMC-Na, a percentage of only 61% was preserved. Topical treatment of emulsified GTPs effectively inhibited acute UVB-induced infiltration of inflammatory cells, increase of skin thickness, oxidative stress such as depletion of antioxidant enzymes and lipid oxidation, and induced nuclear accumulation of Nrf2 in the mice skin. We also discovered the ability of GTPs to simultaneously trigger accumulation of nuclear Nrf2 and export of nuclear Bach1. Altogether, our findings reinforced the putative application of GTPs in the prevention/minimization of the deleterious effects of UV on the skin.

Risk Factors for Infections Related to Lumbar Drainage in Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: A solid knowledge associated with lumbar drainage (LD)-related infections in spontaneous subarachnoid hemorrhage (SAH) patients is necessary and that would be useful in taking effective measures to cope with this complication. We aimed to describe incidence rates and risk factors associated with LD-related infections in SAH patients. METHODS: A retrospective review was performed on SAH patients who underwent LD between July 2010 and August 2015. Patient charts were reviewed to retrieve demographic, clinical, and laboratory data. LD-related infections were defined based on culture results of cerebrospinal fluid in combination with clinical symptoms. Infection rates were calculated, and a logistic regression model was developed to identify risk factors. RESULTS: A total of 629 SAH patients (25-82 years age range, 42.8 % male) were treated with LD in the period. LD-related infections were identified in 36 patients (5.7 %). Longer duration of LD (≥4 days: p = 0.0037) and puncture site leakage (p < 0.0001) appeared to be risk factors for infection. The infection rate increased with length of the hospital stay (16-20 days: p = 0.0032; ≥21 days: p = 0.0007). 84.6 % of the isolated bacteria were Gram-positive, and the most commonly associated pathogens were Methicillin-resistant coagulase-negative Staphylococcus (MRCNS, 61.5 %). CONCLUSIONS: The patients with LD for more than 4 days or with puncture site leakage had more risk of infection. Infected patients were more likely to stay longer in the hospital. MRCNS were identified as the most frequent causal pathogens. And the use of antibiotics during LD did not appear to reduce the risk of infection.

Human amniotic epithelial stem cells inhibit microglia activation through downregulation of tumor necrosis factor-α, interleukin-1ß and matrix metalloproteinase-12 in vitro and in a rat model of intracerebral hemorrhage.

BACKGROUND AIMS: The molecular mechanisms by which stem cell transplantation improves functional recovery after intracerebral hemorrhage (ICH) are not well understood. Accumulating evidence suggests that microglia cells are activated shortly after ICH and that this activation contributes to secondary ICH-induced brain injury. We studied the effect of human amniotic epithelial stem cells (HAESCs) on microglia activation. METHODS: To study the effect of HAESCs in vitro, we used thrombin to activate the microglia cells. Twenty-four hours after thrombin treatment, the levels of tumor necrosis factor-α and interleukin-1ß were measured by enzyme-linked immunosorbent assay. In vivo, the HAESCs were transplanted into the rat striatum 1 day after collagenase-induced ICH. The expression levels of matrix metalloproteinase (MMP)-12 and microglia infiltration in the peri-hematoma tissues were determined 7 days after ICH through the use of reverse transcriptase-polymerase chain reaction and immunohistochemical analysis, respectively. RESULTS: Thrombin-activated microglia expression of tumor necrosis factor-α, interleukin-1ß and MMP-12 was significantly reduced through contact-dependent and paracrine mechanisms when the HAESCs were co-cultured with microglia cells. After transplantation of HAESCs in rat brains, the expression levels of MMP-12 and microglia infiltration in the peri-hematoma tissues were significantly reduced. CONCLUSIONS: Our observations suggest that microglia activation could be inhibited by HAESCs both in vitro and in vivo, which may be an important mechanism by which the transplantation of HAESCs reduces brain edema and ameliorates the neurologic deficits after ICH. Therefore, we hypothesize that methods for suppressing the activation of microglia and reducing the inflammatory response can be used for designing effective treatment strategies for ICH.

Successful Treatment of Cutaneous Protothecosis Due to Prototheca wickerhamii with Terbinafine.

Protothecosis, an infrequent human infection, is caused by achlorophyllic algae belonging to the genus Prototheca, particularly Prototheca wickerhamii. The skin stands as the most commonly affected organ. This report documents a case involving an 82-year-old male with Protothecosis. Histopathological analysis revealed granulomatous inflammation in the dermis, exhibiting necrotic features and hosting numerous non-budding spherical organisms. These organisms were positively stained using methenamine silver and periodic acid-Schiff stains, confirming identification as P. wickerhamii after validation through tissue culture and sequencing procedures. Initially, the patient received oral itraconazole at a dosage of 200 mg daily, accompanied by topical 1% naftifine-0.25% ketoconazole cream for a duration of 4 weeks, resulting in significant improvement. Subsequently, due to gastrointestinal discomfort presumably linked to itraconazole, terbinafine was administered. Over a span of 3 months, the patient received oral terbinafine at a dosage of 250 mg/day alongside the application of topical 1% naftifine-0.25% ketoconazole cream, leading to complete healing of the skin lesion, leaving behind a fibrotic scar.

Risk Factors for Seizures After Titanium Cranioplasty: Five-Year Experience from a Single Institution.

OBJECTIVE: Seizures are one of the complications that can occur after cranioplasty (CP). In some regions, titanium mesh remains the material of choice for CP. However, risk factors for seizures after titanium CP have been less studied. The purpose of this study was to identify potential risk factors for early seizures (≤7 days) and late seizures (>8 days) after titanium CP in a single institution. METHODS: A retrospective review was conducted of 241 consecutive patients who received titanium CP at the First Affiliated Hospital of Harbin Medical University from January 2016 to December 2020. Univariate and multivariable logistic regression analyses were performed to determine the independent risk factors for new-onset seizures after titanium CP. RESULTS: Fifteen patients (6.22%) experienced early post-CP seizures, and late post-CP seizures were observed in 81 patients (33.61%). A flaccid concave cranial defect (P = 0.042) was associated with early post-CP seizures, whereas hypertension (P < 0.001) was the only significant predictor for late seizures after titanium CP. CONCLUSIONS: Seizure is a common complication after titanium CP, especially in patients who do not receive prophylactic antiepileptic drugs before the procedure. Risk factors for new-onset seizures at different periods after titanium CP were found to be different. In addition, radiologic factors before titanium CP may play a role in early new-onset seizures after titanium CP and should not be ignored.

Exploring the causal association between genetically determined circulating metabolome and hemorrhagic stroke.

Background: Hemorrhagic stroke (HS), a leading cause of death and disability worldwide, has not been clarified in terms of the underlying biomolecular mechanisms of its development. Circulating metabolites have been closely associated with HS in recent years. Therefore, we explored the causal association between circulating metabolomes and HS using Mendelian randomization (MR) analysis and identified the molecular mechanisms of effects. Methods: We assessed the causal relationship between circulating serum metabolites (CSMs) and HS using a bidirectional two-sample MR method supplemented with five ways: weighted median, MR Egger, simple mode, weighted mode, and MR-PRESSO. The Cochran Q-test, MR-Egger intercept test, and MR-PRESSO served for the sensitivity analyses. The Steiger test and reverse MR were used to estimate reverse causality. Metabolic pathway analyses were performed using MetaboAnalyst 5.0, and genetic effects were assessed by linkage disequilibrium score regression. Significant metabolites were further synthesized using meta-analysis, and we used multivariate MR to correct for common confounders. Results: We finally recognized four metabolites, biliverdin (OR 0.62, 95% CI 0.40-0.96, PMVMR = 0.030), linoleate (18. 2n6) (OR 0.20, 95% CI 0.08-0.54, PMVMR = 0.001),1-eicosadienoylglycerophosphocholine* (OR 2.21, 95% CI 1.02-4.76, PMVMR = 0.044),7-alpha-hydroxy-3 -oxo-4-cholestenoate (7-Hoca) (OR 0.27, 95% CI 0.09-0.77, PMVMR = 0.015) with significant causal relation to HS. Conclusion: We demonstrated significant causal associations between circulating serum metabolites and hemorrhagic stroke. Monitoring, diagnosis, and treatment of hemorrhagic stroke by serum metabolites might be a valuable approach.

A network pharmacology and molecular docking investigation on the mechanisms of Shanyaotianhua decoction (STT) as a therapy for psoriasis.

Psoriasis is an immune-mediated inflammatory skin disease with a complex etiology involving environmental and genetic factors. Psoriasis patients often require long-term treatment. Shanyaotianua decoction (STT), a typical traditional Chinese medicine prescription, positively affects psoriasis, although its molecular targets remain unknown. To elucidate its molecular mechanisms, a combination of network pharmacology, bioinformatics analysis, and drug similarity comparisons were employed. Participants were separated into 3 groups: non-lesional (NL), lesions after medication (LM), and psoriasis lesion groups (LS). Based on the Gene Ontology/kyoto encyclopedia of genes and genomes enrichment analyses, the key targets were mainly enriched for biological processes (immuno-inflammatory responses, leukocyte differentiation, lipid metabolic disorders, and viral infection) with the relevant pathways (Janus kinase/signal transducers and activators of transcription and adipocytokine signaling and T-helper 17 cell differentiation), thus identifying the possible action mechanism of STT against psoriasis. Target prediction for 18 STT compounds that matched the screening criteria was performed. Then, the STT compounds were intersected with the differentially expressed genes of the psoriatic process, and 5 proteins were potential targets for STT. Based on the open-source toolkit RDKit and DrugBank database, and through molecular docking and drug similarity comparisons, spinasterol, diosgenin, and 24-Methylcholest-5-enyl-3belta-O-glucopyranoside_qt may be potential drugs for psoriasis.

Bilateral Adult-Onset Orbital Xanthogranuloma: A Case Report.

Adult-onset xanthogranuloma (AOX) is one of the four rare syndromes collectively referred to as adult xanthogranulomatous disease (AXD). It primarily occurs in the orbit and ocular adnexa and displays distinctive histopathological features, characterized by the infiltration of non-Langerhans-derived foam-like histiocytes and Touton giant cells. The presence of diffuse yellow plaques on the eyelids serves as a highly indicative feature. In this report, we present a compelling case of bilateral periorbital AOX. Initially, the patient received a diagnosis of necrotizing xanthogranuloma (NBX) and underwent treatment with dapsone, which yielded a poor response. Subsequently, through repeated biopsy, immunoprotein electrophoresis, and high-throughput sequencing, the diagnosis was revised to AOX. Subsequently, the patient's treatment was modified to include oral hormone therapy, and no further progression of the periorbital plaque was observed. Notably, the patient's sister was diagnosed with xanthelasma palpebrarum (XP), suggesting a potential genetic association between AOX and XP. Unfortunately, the sister declined further histologic examination and genetic sequencing of her skin lesions, impeding the acquisition of additional evidence regarding the genetic link between these two disorders. Despite the divergent pathological features, pathogenesis, and clinical presentation of AOX and xanthelasma palbrarum, clinicians should remain cognizant of the plausible genetic correlation between these two conditions and pursue further investigations when feasible.

Effect of doramectin on programmed cell death pathway in glioma cells.

PURPOSE: Doramectin (DRM) is a kind of avermectin drugs, and it has been shown that DRM has anti-cancer effects. However, the molecular mechanism of DRM in programmed cell death (PCD) aspects is still unclear. The objective of this study was to confirm whether DRM induced PCD in glioma cells. METHODS: In this experiment, the MTT assay and Ki-67 assay were used to detect in vitro cell viability and in vivo tumor proliferation. Then, the effect of DRM on PCD was analyzed by transcriptome comparison. Next, Endogenous apoptosis was detected by transmission electron microscopy (TEM), the DNA gel electrophoresis, JC-1 assay, western blotting and qRT-PCR. Meanwhile, necroptosis was detected by TEM, Hoechst 33342, FITC and PI staining assay, western blotting. RESULTS: We found DRM induced apoptosis through Bcl-2/Bax/Caspase-3 pathway. And, DRM induced ROS overproduction, then ROS caused necroptosis through RIPK1/RIPK3/MLKL pathway, Mitochondria acted as a bridge between the two pathways. CONCLUSION: Our research provided new insight with the function of anti-cancer of DRM. These results demonstrated DRM may be used as potential therapeutic agents inducing apoptosis and necroptosis for cancer therapy.

The causal effects between gut microbiota and hemorrhagic stroke: a bidirectional two-sample Mendelian randomization study.

Background: Recent studies have suggested that the composition of gut microbiota (GM) may change after intracerebral hemorrhage. However, the causal inference of GM and hemorrhagic stroke is unknown. Mendelian Randomization (MR) is an effective research method that removes confounding factors and investigates the causal relationship between exposure and outcome. This study intends to explore the causal relationship between GM and hemorrhagic stroke with the help of MR. Methods: Univariable and multivariable MR analyses were performed using summary statistics of the GM (n = 18,340) in the MiBioGen consortium vs. the FinnGen consortium R9 summary statistics (intracerebral hemorrhage, subarachnoid hemorrhage, and nontraumatic intracranial hemorrhage). Causal associations between gut microbiota and hemorrhagic stroke were analyzed using inverse variance weighted, MR-Egger regression, weighted median, weighted mode, simple mode, and MR-PRESSO. Cochran's Q statistic, MR-Egger regression, and leave-one-out analysis were used to test for multiplicity and heterogeneity of instrumental variables. Separate reverse MR analyses were performed for microbiota found to be causally associated with hemorrhagic stroke in the forward MR analysis. Also, multivariate MR analyses were conducted after incorporating common confounders. Results: Based on the results of univariable and multivariate MR analyses, Actinobacteria (phylum) (OR, 0.80; 95%CI, 0.66-0.97; p = 0.025) had a protective effect against hemorrhagic stroke, while Rikenellaceae RC9 gut group (genus) (OR, 0.81; 95%CI, 0.67-0.99; p = 0.039) had a potential protective effect. Furthermore, Dorea (genus) (OR, 1.77; 95%CI, 1.27-2.46; p = 0.001), Eisenbergiella (genus) (OR, 1.24; 95%CI, 1.05-1.48; p = 0.013) and Lachnospiraceae UCG008 (genus) (OR, 1.28; 95%CI, 1.01-1.62; p = 0.041) acted as potential risk factors for hemorrhagic stroke. The abundance of Dorea (genus) (ß, 0.05; 95%CI, 0.002 ~ 0.101; p = 0.041) may increase, and that of Eisenbergiella (genus) (ß, -0.072; 95%CI, -0.137 ~ -0.007; p = 0.030) decreased after hemorrhagic stroke according to the results of reverse MR analysis. No significant pleiotropy or heterogeneity was detected in any of the MR analyses. Conclusion: There is a significant causal relationship between GM and hemorrhagic stroke. The prevention, monitoring, and treatment of hemorrhagic stroke through GM represent a promising avenue and contribute to a deeper understanding of the mechanisms underlying hemorrhagic stroke.

Erratum: Moxidectin induces Cytostatic Autophagic Cell Death of Glioma Cells through inhibiting the AKT/mTOR Signalling Pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.46697.].

Novel roles of METTL1/WDR4 in tumor via m7G methylation.

As one of the prevalent posttranscriptional modifications of RNA, N7-methylguanosine (m7G) plays essential roles in RNA processing, metabolism, and function, mainly regulated by the methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) complex. Emerging evidence suggests that the METTL1/WDR4 complex promoted or inhibited the processes of many tumors, including head and neck, lung, liver, colon, bladder cancer, and teratoma, dependent on close m7G methylation modification of tRNA or microRNA (miRNA). Therefore, METTL1 and m7G modification can be used as biomarkers or potential intervention targets, providing new possibilities for early diagnosis and treatment of tumors. This review will mainly focus on the mechanisms of METTL1/WDR4 via m7G in tumorigenesis and the corresponding detection methods.

The MAI score: A novel score to early predict shunt-dependent hydrocephalus in patients with aneurysmal subarachnoid hemorrhage after surgery.

OBJECTIVE: As a chronic complication of aneurysmal subarachnoid hemorrhage(aSAH), Shunt dependent hydrocephalus (SDHC) often leads to severe neurological deficits. At present, risk factors of SDHC after aSAH are being refined. So this study aims to investigate independent risk factors and develop a novel score to identify early the patients who require a permanent shunt. METHOD: Five hundred twenty-four patients treated in the first affiliated hospital of Harbin medical university from March 2019 to March 2021 were analyzed. We collected clinical and radiographic data of patients within 72 h after the ictus. The relevant factors were firstly analyzed by univariate analysis, and the significant factors (p < 0.05) were included in the multivariate logistic regression analysis to obtain the independent risk factors with statistical differences. The MAI score was established based on the contribution of different independent risk factors to the outcome. the new score was validated in another cohort (97 patients with aSAH from April and June 2021). RESULT: We enrolled 524 aneurysm patients and 41(7.82%) patients who underwent ventriculoperitoneal shunt (VPS) after aneurysm treatment. Based on univariate and multivariate analysis, Acute Hydrocephalus (OR 6.498,:95% confidence interval (CI) 1.98-21.33, p = 0.002), Intraventricular hemorrhage (OR 3.55,:95%CI 1.189-10.599, p = 0.023) and Modified Fisher score ≥ 3 (OR 5.846, 95%CI 2.649-12.900, p = 0.001) were independent risk factors. The novel score was assigned according to the contribution of different independent risk factors to the results. The MAI score: Modified Fisher grade ≥ 3 (1 point), Acute Hydrocephalus (1 point), Intraventricular hemorrhage (1 point). In the receiver operating characteristic curve analysis, the area under the curve (AUC) for the MAI score is 0.773 (p < 0.0001, 95%CI 0.686-0.861). Patients scoring 2-3 MAI points showed a 10-fold higher risk for shunt dependency than patients scoring 0-1 MAI points (p < 0.001). We performed internal validation of the MAI scoring system. The scoring system reliably predicted SDHC after aSAH. The AUC of the internal validation was 0.950 (p ＝ 0.002, 95%CI 0.863-1.000). CONCLUSION: We develop a novel score based on univariate and multivariate analysis. The effectiveness of the MAI score has been confirmed in this study, which can more accurately predict SDHC after aASH and can be widely used in clinical practice. Prospective studies are needed for validation in the future.

Doramectin inhibits glioblastoma cell survival via regulation of autophagy in vitro and in vivo.

Glioblastoma (GBM) is one of the most widespread and lethal types of cancer. However, there are currently no drugs or therapeutic strategies that can completely cure GBM. Doramectin (DRM) has a broad range of activities against endoparasites and ectoparasites, and is extensively used in livestock. In the present study, the effect of DRM on the induction of autophagy in U87 and C6 GBM and glioma cell lines, as well as the mechanism of autophagy, were examined. First, transmission electron microscopy, plasmid transfection and western blot analysis demonstrated that DRM could induce autophagy in U87 and C6 cells in vitro. Next, MTT and colony formation assays revealed that DRM­induced autophagy prevented U87 and C6 cell viability and colony formation ratio. In addition, DRM­induced autophagy promoted U87 and C6 cell apoptosis, as indicated by DAPI analysis and flow cytometry. Furthermore, transcriptome analysis demonstrated that DRM modulated a number of genes and pathways involved in autophagy. In a nude mouse xenograft model, immunohistochemical staining and the TUNEL assay demonstrated that the effect of DRM on the tumor was consistent with that in vivo. These data indicated that DRM induced autophagy mainly by blocking the PI3K/AKT/mTOR signaling pathway in GBM cells. DRM­induced autophagy promoted the inhibition of GBM cell proliferation and apoptosis in vitro and in vivo. The present study suggested that DRM may be an effective drug for the treatment of GBM.

Safety Analysis of Simultaneous Cranioplasty and Ventriculoperitoneal Shunt Placement.

AIM: To investigate the safety of combined cranioplasty (CP) and ventriculoperitoneal shunt (VPS) placement. Furthermore, we investigated whether the sequence of these procedures affects the postoperative complication rates associated with staged CP and VPS placement. MATERIAL AND METHODS: We retrospectively investigated patients who developed communicating hydrocephalus after decompressive craniectomy and subsequently underwent VPS placement and CP at the hospital at which this study was performed between January 2009 and December 2019. Patients were categorized into group 1 (simultaneous CP and VPS placement) and group 2 (CP and VPS placement performed separately). Group 2 was subcategorized into subgroup 2a (CP performed before VPS placement) and subgroup 2b (VPS placement performed before CP). The Student?s t and Chi square tests were used to analyze intergroup differences. RESULTS: This study included 86 patients; 22 in group 1 and 64 in group 2 (24 patients in subgroup 2a and 40 patients in subgroup 2b). No statistically significant difference was observed in the overall complication rates between groups 1 and 2 (36.4% vs. 28.1%, P=0.591). However, the incidence of infections was significantly higher in group 1 than in group 2 (22.7% vs. 4.7%, P=0.024). Subgroup analysis showed that the overall complication rate was signi?cantly lower in subgroup 2a than in subgroup 2b (12.5% vs. 37.5%, P=0.031). CONCLUSION: Simultaneous CP and VPS placement is associated with a high incidence of infections. Moreover, compared with initial CP, initial VPS placement is associated with a significantly higher risk of overall complications in patients who undergo a staged procedure.

Genome sequence of the milbemycin-producing bacterium Streptomyces bingchenggensis.

Streptomyces bingchenggensis is a soil-dwelling bacterium producing the commercially important anthelmintic macrolide milbemycins. Besides milbemycins, the insecticidal polyether antibiotic nanchangmycin and some other antibiotics have also been isolated from this strain. Here we report the complete genome sequence of S. bingchenggensis. The availability of the genome sequence of S. bingchenggensis should enable us to understand the biosynthesis of these structurally intricate antibiotics better and facilitate rational improvement of this strain to increase their titers.

Synergistic anti-candidal activity of tetrandrine on ketoconazole: an experimental study.

With the widespread use of azoles, drug resistant Candida albicans strains are increasing. The study examined the synergism of tetrandrine (TET) on ketoconazole (KCZ) candidacidal activity. The protocol M27-A2 of the Clinical and Laboratory Standards Institute (CLSI) was adopted and the minimum inhibitory concentrations (MICs) were determined for KCZ alone and in combination with a TET level that was noncytotoxic for C. albicans strains CA-1 through CA-17, with no CA-10. Colony counting techniques were used to construct time-kill curves. CA-15 was used to build the mouse candidal vaginitis model. After randomization, drugs were administered vaginally once daily from days 3-10 (both KCZ and TET were 26 mg/kg/day and 13 mg/kg/day, respectively, administered in different combinations). Mouse vaginal lavage fluid was obtained at days 2, 6, and 11 after inoculation for fungal load analysis, and vaginal tissue was obtained for pathological examination. MICs of KCZ alone and combined with 30 microg/mL TET for the C. albicans strains were 1-32 microg/mL and 0.0038-0.2500 microg/mL, respectively ( T = 24.624, p = 0.000). Time-kill curves showed that at 48 h the viable cell counts of strains treated with KCZ + TET were at least 2 log(10) CFU/mL lower compared to strains treated with corresponding doses of KCZ (p = 0.000). At day 6, the fungal load in the KCZ 26 mg/kg/day + TET 26 mg/kg/day mice was significantly lower than the KCZ 26 mg/kg/day mice (1.17 +/- 1.17 x 10(4) CFU/mL and 9.33 +/- 3.08 x 10(4) CFU/mL, respectively, p = 0.000). Mucosal and submucosal fungal clearances were complete and vaginal mucosal edema was slight with minimal inflammatory cell infiltration. We conclude that noncytotoxic doses of TET synergistically enhance KCZ candidacidal activity in vitro and in vivo.

Moxidectin induces Cytostatic Autophagic Cell Death of Glioma Cells through inhibiting the AKT/mTOR Signalling Pathway.

Moxidectin (MOX), a broad-spectrum antiparasitic drug, has been characterized as a potential anti-glioma agent. The main objective of this study was to explore autophagy induced by MOX in glioma U251 and C6 cells, and the deep underlying molecular mechanisms. In addition, the effects of autophagy on apoptosis in glioma cells were tested. Autophagy was measured by transmission electron microscopy (TEM), immunofluorescence, western blot and immunohistochemistry. Cell viability was detected with MTT and colony formation assay. The apoptosis rate was measured by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Additonally, autophagy inhibition was achieved by using 3-Methyladenine (3-MA) and chloroquine (CQ). U251-derived xenografts were established for examination of MOX-induced autophagy on glioma in vivo. Firstly, our research found that MOX stimulated autophagy of glioma cells in a dose-dependent manner. Secondly, we found that MOX induced autophagy by inhibiting the AKT/mTOR signalling pathway. Thirdly, inhibition of autophagy could reduce apoptosis in MOX-treated glioma cells. Finally, MOX induced autophagy, and autophagy increased the apoptosis effect of MOX on U251 in vivo. In conclusion, our data provide evidence that MOX can induce autophagy in glioma cells, and autophagy could increase MOX-induced apoptosis through inhibiting the AKT/mTOR signalling pathway. These findings provided a new prospect for the application of MOX and a novel targeted therapy for the treatment of gliomas.