To pilot an in-home unintentional injury hazard assessment tool and to quantify potential injury risks for young children in a low-income urban setting.
Two low-income neighbourhoods in Karachi, Pakistan, were mapped, and families with at least one child between the ages of 12 and 59 months were identified. Using existing available home injury risk information, an in-home injury risk assessment tool was drafted and tailored to the local setting. Home injury assessments were done in June–July 2010 after obtaining informed consent.
Approximately 75.4% of mothers were educated through at least grade 12. The main risks identified were stoves within the reach of the child (n=279, 55.5%), presence of open buckets in the bathroom (n=240, 47.7%) within the reach of the child, and pedestal fans accessible to the child (n=242, 48.1%). In terms of safety equipment, a first-aid box with any basic item was present in 70% of households, but only 4.8% of households had a fire extinguisher in the kitchen.
This was the first time that an in-home, all-unintentional injury risk assessment tool was tailored and applied in the context of a low-income community in Pakistan. There was a significant burden of hazards present in the homes in these communities, representing an important opportunity for injury prevention. This pilot may have future relevance to other LMICs where child injury prevention is a critical need.
The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly (P < 0.05) decreased the AUC0−t and Cmax of imatinib. AUC0−t and the Cmax of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect.
Azygos vein aneurysm is very rare and most cases are detected incidentally. We report a safe resection of azygos vein aneurysm by video-assisted thoracoscopic surgery (VATS) under preoperative evaluation of thrombus by multidetector computed tomography (MDCT). A 60-year old woman presented to our department due to a mediastinal mass revealed by enhanced CT. A dynamic enhanced-CT scan showed a dilated azygos vein with great enhancement in the early phase. Under the diagnosis of azygos vein aneurysm, we analysed the aneurysm by MDCT and confirmed that there was no thrombus within the aneurysm. The resection of the aneurysm by VATS was performed safely. She was discharged 4 days after surgery.
Azygos vein aneurysm; Multidetector computed tomography; Video-assisted thoracic surgery
Ser/Thr- and Tyr-Protein kinases constitute a key switch underlying the dynamic nature and graded regulation of signal transduction and pathway activities in cellular organization. Here we describe the identification and characterization of Dusty, a single-copy gene that arose in metazoan evolution and encodes a putative dual Ser/Thr and Tyr protein kinase with unique structural features. Dusty is widely expressed in vertebrates, broadly distributed in the central nervous system, and deregulated in certain human cancers. Confocal imaging of transiently expressed human Dusty-GFP fusion proteins showed a cytoplasmic distribution. Dusty proteins from lower to higher species display an increasing degree of sequence conservation from the N-terminal non-catalytic domain to C-terminal catalytic domain. The non-catalytic region has eight conserved cysteine residues, multiple potential kinasedocking motifs and phosphorylation sites, whereas the catalytic domain is divergent and about equally distant of Ser/Thr and Tyr protein kinases. Homology analyses identified the essential catalytic residues, suggesting that Dusty homologues all possess the enzymatic activity of a protein kinase. Taken together, Dusty is a unique evolutionarily selected group of divergent protein kinases that may play important functional roles in the brain and other tissues of vertebrates.
Dusty protein kinase; Tissue specificity; Protein structure; Gene evolution; Vertebrate animals; Human cancer
Arenaviruses are enveloped, negative-stranded RNA viruses that belong to the family Arenaviridae. This diverse family can be further classified into OW (Old World) and NW (New World) arenaviruses based on their antigenicity, phylogeny, and geographical distribution. Many of the NW arenaviruses are highly pathogenic viruses that cause systemic human infections characterized by hemorrhagic fever and/or neurological manifestations, constituting public health problems in their endemic regions. NW arenavirus infection induces a variety of host innate immune responses, which could contribute to the viral pathogenesis and/or influence the final outcome of virus infection in vitro as well as in vivo. On the other hand, NW arenaviruses have also developed several strategies to counteract the host innate immune response. We will review current knowledge regarding the interplay between the host innate immune response and NW arenavirus infection in vitro and in vivo, with emphasis on viral-encoded proteins and their effect on the type I interferon response.
innate immunity; arenavirus; interferon; cytokine interferon antagonist
Obesity is prevalent worldwide, and is highly associated with metabolic disorders, such as insulin resistance, hyperlipidemia and steatosis. Ginseng has been used as food and traditional herbal medicine for the treatment of various metabolic diseases. However, the molecular mechanisms how ginseng and its components participate in the regulation of lipogenesis are still largely unclear. Here, we identified that protopanaxatriol (PPT), a major ginseng constituent, inhibited rosiglitazone-supported adipocyte differentiation of 3T3-L1 cells by repressing the expression of lipogenesis-related gene expression. In high-fat diet-induced obesity (DIO) mice, PPT reduced body weight and serum lipid levels, improved insulin resistance, as well as morphology and lipid accumulation, particular macrovesicular steatosis, in the livers. These effects were confirmed with genetically obese ob/ob mice. A reporter gene assay showed that PPT specifically inhibited the transactivity of PPARγ, but not PPAR α, β/δ and LXR α, β. TR-FRET assay revealed that PPT was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study. Our data demonstrate that PPT is a novel PPARγ antagonist. The inhibition of PPARγ activity could be a promising therapy for obesity and steatosis. Our findings shed new light on the mechanism of ginseng in the treatment of metabolic syndrome.
Cymbidium is a genus of 68 species in the orchid family, with extremely high ornamental value. Marker-assisted selection has proven to be an effective strategy in accelerating plant breeding for many plant species. Analysis of cymbidiums genetic background by molecular markers can be of great value in assisting parental selection and breeding strategy design, however, in plants such as cymbidiums limited genomic resources exist. In order to obtain efficient markers, we deep sequenced the C. ensifolium transcriptome to identify simple sequence repeats derived from gene regions (genic-SSR).
The 7,936 genic-SSR markers were identified. A total of 80 genic-SSRs were selected, and primers were designed according to their flanking sequences. Of the 80 genic-SSR primer sets, 62 were amplified in C. ensifolium successfully, and 55 showed polymorphism when cross-tested among 9 Cymbidium species comprising 59 accessions. Unigenes containing the 62 genic-SSRs were searched against Non-redundant (Nr), Gene Ontology database (GO), eukaryotic orthologous groups (KOGs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The search resulted in 53 matching Nr sequences, of which 39 had GO terms, 18 were assigned to KOGs, and 15 were annotated with KEGG. Genetic diversity and population structure were analyzed based on 55 polymorphic genic-SSR data among 59 accessions. The genetic distance averaged 0.3911, ranging from 0.016 to 0.618. The polymorphic index content (PIC) of 55 polymorphic markers averaged 0.407, ranging from 0.033 to 0.863. A model-based clustering analysis revealed that five genetic groups existed in the collection. Accessions from the same species were typically grouped together; however, C. goeringii accessions did not always form a separate cluster, suggesting that C. goeringii accessions were polyphyletic.
The genic-SSR identified in this study constitute a set of markers that can be applied across multiple Cymbidium species and used for the evaluation of genetic relationships as well as qualitative and quantitative trait mapping studies. Genic-SSR’s coupled with the functional annotations provided by the unigenes will aid in mapping candidate genes of specific function.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0124-5) contains supplementary material, which is available to authorized users.
Cymbidium ensifolium; Genic-SSR; Genetic diversity; Population structure
Heart failure is a complex disease that involves genetic, environmental, and physiological factors. As a result, current medication and treatment for heart failure produces limited efficacy, and better medication is in demand. Although mammalian models exist, simple and low-cost models will be more beneficial for drug discovery and mechanistic studies of heart failure. We previously reported that aristolochic acid (AA) caused cardiac defects in zebrafish embryos that resemble heart failure. Here, we showed that cardiac troponin T and atrial natriuretic peptide were expressed at significantly higher levels in AA-treated embryos, presumably due to cardiac hypertrophy. In addition, several human heart failure drugs could moderately attenuate the AA-induced heart failure by 10%–40%, further verifying the model for drug discovery. We then developed a drug screening assay using the AA-treated zebrafish embryos and identified three compounds. Mitogen-activated protein kinase kinase inhibitor (MEK-I), an inhibitor for the MEK-1/2 known to be involved in cardiac hypertrophy and heart failure, showed nearly 60% heart failure attenuation. C25, a chalcone derivative, and A11, a phenolic compound, showed around 80% and 90% attenuation, respectively. Time course experiments revealed that, to obtain 50% efficacy, these compounds were required within different hours of AA treatment. Furthermore, quantitative polymerase chain reaction showed that C25, not MEK-I or A11, strongly suppressed inflammation. Finally, C25 and MEK-I, but not A11, could also rescue the doxorubicin-induced heart failure in zebrafish embryos. In summary, we have established two tractable heart failure models for drug discovery and three potential drugs have been identified that seem to attenuate heart failure by different mechanisms.
LINE-1s are active human DNA parasites that are agents of genome dynamics in evolution and disease. These streamlined elements require host factors to complete their lifecycles, whereas hosts have developed mechanisms to combat retrotransposition’s mutagenic effects. As such, endogenous L1 expression levels are extremely low, creating a roadblock for detailed interactomic analyses. Here we describe a system to express and purify highly active L1 RNP complexes from human suspension cell culture and characterize the co-purified proteome, identifying 37 high-confidence candidate interactors. These datasets include known interactors PABPC1 and MOV10 and, with in-cell imaging studies, suggest existence of at least three types of compositionally and functionally distinct L1 RNPs. Among the novel findings, UPF1, a key nonsense-mediated decay factor, and PCNA, the polymerase-delta-associated sliding DNA clamp, were identified and validated. PCNA interacts with ORF2p via a PIP box motif; mechanistic studies suggest this occurs during or immediately after target-primed reverse transcription.
In this work, a DNA inter-strand replacement strategy for therapeutic activity has been successfully designed for multimodal therapy. In this multimodal therapy, chlorin e6 (Ce6) photosensitizer molecules are used for photodynamic therapy (PDT), while aptamer-AuNRs, are used for selective binding to target cancer cells and for photothermal therapy (PTT) with near infrared (NIR) laser irradiation. Aptamer Sgc8, which specifically targets leukemia T cells, is conjugated to an AuNR by a thiol-Au covalent bond. and then hybridized with a Ce6-labeled photosensitizer/reporter to form a DNA double helix. When target cancer cells are absent, Ce6 is quenched and shows no PDT effect. However, when target cancer cells are present, the aptamer changes structure to release Ce6 to produce singlet oxygen for PDT upon light irradiation. Importantly, by combining photosensitizer and photothermal agents, PTT/PDT dual therapy supplies a more effective therapeutic outcome than either therapeutic modality alone.
aptamer; gold nanorods; photosensitizer; multimodal therapy
As natural experiments, famines provide a unique opportunity to test the health consequences of nutritional deprivation during the critical period of early life. Using data on 4,972 Chinese born between 1956 and 1963 who participated in a large mental health epidemiology survey conducted between 2001 and 2005, we investigated the potential impact of famine exposure in utero and during the early postnatal life on adult mental illness. The risk of mental illness was assessed with the 12-item General Health Questionnaire (GHQ-12) and eight other risk factors, and the famine impact on adult mental illness was estimated by difference-in-difference models. Results show that compared with women born in 1963, women born during the famine years (1959–1961) had higher GHQ scores (increased by 0.95 points; CI: 0.26, 1.65) and increased risk of mental illness (OR= 2.80; CI: 1.23, 6.39); those born in 1959 were the most affected and had GHQ scores 1.52 points higher (CI: 0.42, 2.63) and an OR for mental illness of 4.99 (CI: 1.68, 14.84). Compared to men in the 1963 birth cohort, men born during the famine had lower GHQ scores (decreased by 0.89 points; CI: −1.59, −0.20) and a nonsignificant decrease in the risk of mental illness (OR = 0.60; CI: 0.26, 1.40). We speculate that the long-term consequences of early-life famine exposure include both the selection of the hardiest and the enduring deleterious effects of famine on those who survive. The greater biological vulnerability and stronger natural selection in utero of male versus female fetuses during severe famine may result in a stronger selection effect among men than women, obscuring the deleterious impact of famine exposure on the risk of mental illness in men later in life.
Famine; mental health; selection effect; natural selection in utero; China; life course
Although interferon (IFN) signaling induces genes that limit viral infection, many pathogenic viruses overcome this host response. As an example, 2′-O methylation of the 5′ cap of viral RNA subverts mammalian antiviral responses by evading restriction of Ifit1, an IFN-stimulated gene that regulates protein synthesis. However, alphaviruses replicate efficiently in cells expressing Ifit1 even though their genomic RNA has a 5′ cap lacking 2′-O methylation. We show that pathogenic alphaviruses use secondary structural motifs within the 5′-untranslated region (UTR) of their RNA to alter Ifit1 binding and function. Mutations within the 5′-UTR affecting RNA structural elements enabled restriction by or antagonism of Ifit1 in vitro and in vivo. These results identify an evasion mechanism by which viruses use RNA structural motifs to avoid immune restriction.
An increased mean platelet volume (MPV) is an early marker of platelet activation. MPV was also shown to be associated with the pathophysiological characteristics of various types of cancer. A previous study demonstrated that MPV was significantly associated with the overall survival (OS) of patients with advanced non-small-cell lung cancer (NSCLC). However, there has been no analysis of the prognostic effect of MPV on patients with resected NSCLC. The aim of this study was to evaluate the contribution of MPV to the survival of patients with completely resected NSCLC. We retrospectively analyzed 308 consecutive patients with NSCLC who underwent curative resection at Kitano Hospital. The associations between MPV and clinicopathological factors were assessed. We also evaluated the effect of MPV on survival, using the two-tailed log-rank test and the Cox proportional hazards model. A MPV value of 8.50 fl was considered to be the optimal cut-off value for prognosis. A low MPV was not associated with any other clinicopathological factors. The two-tailed log-rank test demonstrated that patients with a low MPV experienced a shorter disease-free survival (DFS) and overall survival (OS) (P=0.011 and 0.001, respectively), compared to those with a high MPV. The multivariate analysis demonstrated that a low MPV was an independent unfavorable prognostic factor for DFS and OS [hazard ratio (HR)=1.713; 95% confidence interval (CI): 1.070–2.742, P=0.025; and HR=2.835; 95% CI: 1.304–6.163, P=0.009, respectively)]. Therefore, we demonstrated that a low MPV predicted an unfavorable prognosis in patients with NSCLC following curative resection.
lung cancer; mean platelet volume; overall survival; disease-free survival; curative resection; prognosis
Patients with esophageal squamous cell carcinoma generally present at an advanced stage at the time of diagnosis. The most common sites of visceral metastasis are the lung, liver and bone, but brain and bone marrow involvement is exceedingly rare. Herein, we report a 62-year-old man with a 4-wk history of progressive low back pain with radiation to bilateral lower legs, dysphagia and body weight loss. Esophageal squamous cell carcinoma with regional lymph node, liver and bone metastases was diagnosed. He underwent concurrent chemoradiotherapy and got a partial response. Four months later, he complained of headache, diplopia and severe hearing impairment in the left ear. There was no evidence for bacterial, fungal, tuberculous infection or neoplastic infiltration. Magnetic resonance imaging of the brain demonstrated thickening and enhancement of bilateral pachymeninges and multiple enhancing masses in bilateral skull. Dural metastasis was diagnosed and he received whole brain irradiation. In addition, laboratory examination revealed severe thrombocytopenia and leucopenia, and bone marrow study confirmed the diagnosis of metastatic squamous cell carcinoma. This is the first described case of esophageal squamous cell carcinoma with dural and bone marrow metastases. We also discuss the pathogenesis of unusual metastatic diseases and differential diagnosis of pachymeningeal thickening.
Esophageal cancer; Squamous cell carcinoma; Dural metastasis; Bone marrow metastasis
Recent advances have shown that histology and genetic biomarkers are important
in patient selection, which have led to significantly better outcomes for lung
cancer patients. However, most new treatments only apply to adenocarcinoma or
non-squamous, and in squamous carcinoma there is little breakthrough. In a phase
III trial nab-paclitaxel plus carboplatin showed superior response rate over
paclitaxel and carboplatin. In subgroup analysis the squamous histology appeared
to be a predictive factor to nab-paclitaxel treatment.
This is an open-label, randomized, active controlled phase II trial. A total
of 120 untreated advanced squamous lung cancer patients are randomized at a 1:1
ratio to receive nab-paclitaxel (135 mg/m2, d1, 8, q3w)
plus carboplatin (AUC 5, d1, q3w) or gemcitabine
(1,250 mg/m2, d1, 8, q3w) and carboplatin (AUC 5, d1,
q3w). The primary endpoint is objective response rate and the second endpoints are
progression free survival, overall survival, safety and biomarkers associated with
nab-paclitaxel. The treatment will continue up to six cycles or intolerable
This ongoing trial will be the first prospective randomized trial to explore
the efficacy of nab-paclitaxel as the first-line treatment specifically in
squamous carcinoma of lung.
Clinicaltrials.gov reference: NCT01236716
Nab-paclitaxel; Carboplatin; Gemcitabine; Squamous; Carcinoma; Lung
7-Ketocholesterol (7-KC) is found at an elevated level in patients with cancer and chronic liver disease. The up-regulation of an efflux pump, P-glycoprotein (P-gp) leads to drug resistance. To elucidate the effect of 7-KC on P-gp, P-gp function and expression were investigated in hepatoma cell lines Huh-7 and HepG2 and in primary hepatocyte-derived HuS-E/2 cells. At a subtoxic concentration, 48-h exposure to 7-KC reduced the intracellular accumulation and cytotoxicity of P-gp substrate doxorubicin in hepatoma cells, but not in HuS-E/2 cells. In Huh-7 cells, 7-KC elevated efflux function through the activation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. 7-KC activated the downstream protein synthesis initiation factor 4E-BP1 and induced P-gp expression post-transcriptionally. The stimulation of efflux was reversible and could not be prevented by N-acetyl cysteine. Total cellular ATP content remained the same, whereas the lactate production was increased and fluorescence lifetime of protein-bound NADH was shortened. These changes suggested a metabolic shift to glycolysis, but glycolytic inhibitors did not eliminate 7-KC-mediated P-gp induction. These results demonstrate that 7-KC induces P-gp through PI3K/mTOR signaling and decreased the cell-killing efficacy of doxorubicin in hepatoma cells.
7-ketocholesterol; P-glycoprotein; PI3K/mTOR; glycolysis; hepatoma
Wood formation in tree species is regulated by multiple factors at various layers. Alternative splicing (AS) occurs within a large number of genes in wood formation. However, the functional implications and conservation of the AS occurrence are not well understood.
In this study, we profiled AS events in wood-forming tissues of Populus and Eucalyptus, and analyzed their functional implications as well as inter-species conservation. 28.3% and 20.7% of highly expressed transcripts in the developing xylem of Populus and Eucalyptus respectively were affected by AS events. Around 42% of the AS events resulted in changes to the original reading frame. 25.0% (in Populus) and 26.8% (in Eucalyptus) of the AS events may cause protein domain modification. In the process of wood formation, about 28% of AS-occurring genes were putative orthologs and 71 conserved AS events were identified in the two species.
Through analysis of AS events in developing xylem of two tree species, this study reveals an array of new information regarding AS occurrence and function in tree development.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-780) contains supplementary material, which is available to authorized users.
Alternative splicing (AS); Comparative transcriptome; Wood formation; Conservation; Populus; Eucalyptus
To determine the role of postmastectomy radiotherapy (PMRT) in breast cancer patients with T1–2 and N1 disease.
Patients and methods.
A total of 207 postmastectomy women were enrolled. The 5-year Kaplan-Meier estimates of locoregional recurrence rate (LRR), distant recurrence rate (DRR) and overall survival (OS) were analyzed by different tumor characteristics. Multivariate analyses were performed using Cox proportional hazards modeling.
With median follow-up 59.5 months, the 5-year LRR, DRR and OS were 9.1%, 20.3% and 84.4%, respectively. On univariate analysis, age < 40 years old (p = 0.003) and Her-2/neu over-expression (p = 0.016) were associated with higher LRR, whereas presence of LVI significantly predicted higher DRR (p = 0.026). Negative estrogen status (p = 0.033), Her-2/neu overexpression (p = 0.001) and LVI (p = 0.01) were significantly correlated with worse OS. PMRT didn’t prove to reduce 5-year LRR (p = 0.107), as well as 5-year OS (p = 0.918). In subgroup analysis, PMRT showed significant benefits of improvement LRR and OS in patients with positive LVI.
For patients with T1–2 and N1 stage breast cancer, PMRT can decrease locoregional recurrence and increase overall survival only in patients with lymphovascular invasion.
breast cancer; postmastectomy radiotherapy; overall survival; locoregional recurrence; lymphovascular invasion
The pulse oximeter is a popular instrument to monitor the arterial oxygen saturation (SPO2). Although a fingertip-type pulse oximeter is the mainstream one on the market at present, it is still inconvenient for long-term monitoring, in particular, with respect to motion. Therefore, the development of a wearable pulse oximeter, such as a finger base-type pulse oximeter, can effectively solve the above issue. However, the tissue structure of the finger base is complex, and there is lack of detailed information on the effect of the light source and detector placement on measuring SPO2. In this study, the practicability of a ring-type pulse oximeter with a multi-detector was investigated by optical human tissue simulation. The optimal design of a ring-type pulse oximeter that can provide the best efficiency of measuring SPO2 was discussed. The efficiency of ring-type pulse oximeters with a single detector and a multi-detector was also discussed. Finally, a wearable and wireless ring-type pulse oximeter was also implemented to validate the simulation results and was compared with the commercial fingertip-type pulse oximeter.
pulse oximeter; arterial oxygen saturation; finger base; optical human tissue simulation; multi-detector
To investigate the mechanisms underlying the hepatotoxicity of timosaponin A3 (TA3), a steroidal saponin from Anemarrhena asphodeloides, in rats.
Male SD rats were administered TA3 (100 mg·kg−1·d−1, po) for 14 d, and the blood and bile samples were collected after the final administration. The viability of a sandwich configuration of cultured rat hepatocytes (SCRHs) was assessed using WST-1. Accumulation and biliary excretion index (BEI) of d8-TCA in SCRHs were determined with LC-MS/MS. RT-PCR and Western blot were used to analyze the expression of relevant genes and proteins. ROS and ATP levels, and mitochondrial membrane potential (MMP) were measured. F-actin cytoskeletal integrity was assessed under confocal microscopy.
TA3 administration in rats significantly elevated the total bile acid in serum, and decreased bile acid (BA) component concentrations in bile. TA3 inhibited the viability of the SCRHs with an IC50 value of 15.21±1.73 μmol/L. Treatment of the SCRHs with TA3 (1–10 μmol/L) for 2 and 24 h dose-dependently decreased the accumulation and BEI of d8-TCA. The TA3 treatment dose-dependently decreased the expression of BA transporters Ntcp, Bsep and Mrp2, and BA biosynthesis related Cyp7a1 in hepatocytes. Furthermore, the TA3 treatment dose-dependently increased ROS generation and HO-1 expression, decreased the ATP level and MMP, and disrupted F-actin in the SCRHs. NAC (5 mmol/L) significantly ameliorated TA3-induced effects in the SCRHs, whereas mangiferin (10–200 μg/mL) almost blocked TA3-induced ROS generation.
TA3 triggers liver injury through inducing ROS generation and suppressing the expression of BA transporters. Mangiferin, an active component in Anemarrhena, may protect hepatocytes from TA3-induced hepatotoxicity.
timosaponin A3; hepatotoxicity; cholestasis; bile acid; transporter; Cyp7a1; ROS; N-acetyl-L- cysteine; mangiferin
Single-stranded DNA-binding protein (SSB) plays an important role in DNA metabolism, including DNA replication, repair, and recombination, and is therefore essential for cell survival. Bacterial SSB consists of an N-terminal ssDNA-binding/oligomerization domain and a flexible C-terminal protein-protein interaction domain. We characterized the ssDNA-binding properties of Klebsiella pneumoniae SSB (KpSSB), Salmonella enterica Serovar Typhimurium LT2 SSB (StSSB), Pseudomonas aeruginosa PAO1 SSB (PaSSB), and two chimeric KpSSB proteins, namely, KpSSBnStSSBc and KpSSBnPaSSBc. The C-terminal domain of StSSB or PaSSB was exchanged with that of KpSSB through protein chimeragenesis. By using the electrophoretic mobility shift assay, we characterized the stoichiometry of KpSSB, StSSB, PaSSB, KpSSBnStSSBc, and KpSSBnPaSSBc, complexed with a series of ssDNA homopolymers. The binding site sizes were determined to be 26 ± 2, 21 ± 2, 29 ± 2, 21 ± 2, and 29 ± 2 nucleotides (nt), respectively. Comparison of the binding site sizes of KpSSB, KpSSBnStSSBc, and KpSSBnPaSSBc showed that the C-terminal domain swapping of SSB changes the size of the binding site. Our observations suggest that not only the conserved N-terminal domain but also the C-terminal domain of SSB is an important determinant for ssDNA binding.
Machupo virus (MACV) is the etiological agent of Bolivian hemorrhagic fever (BHF), a reemerging and neglected tropical disease associated with high mortality. The prototypical strain of MACV, Carvallo, was isolated from a human patient in 1963, but minimal in vitro and in vivo characterization has been reported. To this end, we utilized reverse genetics to rescue a pathogenic MACV from cloned cDNAs. The recombinant MACV (rMACV) had in vitro growth properties similar to those of the parental MACV. Both viruses caused similar disease development in alpha/beta and gamma interferon receptor knockout mice, including neurological disease development and high mortality. In addition, we have identified a novel murine model with mortality and neurological disease similar to BHF disease reported in humans and nonhuman primates.
We experienced an extremely rare case of a thymoma in the middle mediastinum. A 42-year-old woman presented with a 4-cm-sized abnormal mass in the middle mediastinum by chest computed tomography. To resect this tumor, we performed surgery using the thoracoscopic lateral approach from the right side subsequently followed by a median sternotomy. After the resection of this tumor, the intraoperative quick pathological examination diagnosed this tumor as a thymoma. An extended thymectomy was performed additionally.
To assess the efficacy of antimicrobial-impregnated catheters in preventing catheter-related infections during external ventricular drainage (EVD), we performed a meta-analysis and systematic review. We systematically searched Medline, Embase, and the Cochrane Library. All randomized controlled trials (RCTs) and nonrandomized prospective studies (NPSs) related to antimicrobial-impregnated EVD catheters were included. The primary outcome was the rate of cerebrospinal fluid infection (CFI). The secondary outcomes included the rate of time-dependent CFI and catheter bacterial colonization. We further performed subgroup analysis, meta-regression analysis, and microbial spectrum analysis. Four RCTs and four NPSs were included. The overall rate of CFIs was 3.6% in the antimicrobial-impregnated catheter group and 13.7% in the standard catheter group. The pooled data demonstrated that antimicrobial-impregnated catheters were superior to standard catheters in lowering the rate of CFIs (odds ratio (OR) = 0.25, 95% confidence interval (CI) = 0.12 to 0.52, P <0.05). In survival analysis, the 20-day infection rate was significantly reduced with the use of antimicrobial-impregnated catheters (hazard ratio = 0.52, 95% CI = 0.29 to 0.95, P <0.05). Furthermore, a significantly decreased rate of catheter bacterial colonization was noticed for antimicrobial-impregnated catheters (OR = 0.37, 95% CI = 0.21 to 0.64, P <0.05). In subgroup analyses, although significant results remained for RCTs and NPSs, a subgroup difference was revealed (P <0.05). Compared with standard catheters, a significantly lower rate of CFIs was noticed for clindamycin/rifampin-impregnated catheters (OR = 0.27, 95% CI = 0.10 to 0.73, P <0.05) and for minocycline/rifampin-impregnated catheters (OR = 0.11, 95% CI = 0.06 to 0.21, P <0.05). However, no statistical significance was found when compared with silver-impregnated catheters (OR = 0.33, 95% CI = 0.07 to 1.69, P = 0.18). In microbial spectrum analysis, antimicrobial-impregnated catheters were shown to have a lower rate of Gram-positive bacterial infection, particularly the coagulase-negative Staphylococcus. In conclusion, the use of antimicrobial-impregnated EVD catheters could be beneficial for the prevention of CFI and catheter bacterial colonization. Although antibiotic-coated catheters seem to be effective, no sufficient evidence supports the efficacy of silver-impregnated catheters.