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Taiwan has witnessed a surge in the incidence of colorectal cancer (CRC), of which 40–60% metastasize. Continuous updating of cytoreductive strategies in metastatic CRC (mCRC) has contributed to median overall survival reaching 40 months. In this changing scenario, to standardize the approaches across Taiwan, a group of experts from the Taiwan Society of Colon and Rectal Surgeons (TSCRS) convened to establish evidence- and opinion-based recommendations for defining the criteria of “resectability” in mCRC. Over the course of one-on-one consultations, lasting 30–40 min each, with 30 medical specialists (19 colorectal surgeons, 4 general surgeons, and 7 medical oncologists) from 16 hospitals in Taiwan followed by a 2-h meeting with 8 physician experts (3 general surgeons, 4 colorectal surgeons, and 1 thoracic surgeon), 12 key questions on cytoreduction were addressed. This was further contextualized based on published literature. The final consensus includes eight recommendations regarding the criteria for metastasis resection, role of local control treatment in liver potentially resectable patients, management of synchronous liver metastases, approach for peritoneal metastasis, place for resection in multiple-organ metastasis, and general criteria for resectability. mCRC patients undergoing R0 resection have the greatest survival advantage following surgery. Our role as a multidisciplinary team (MDT) should be to treat potentially resectable mCRC patients as rapidly and safely as possible, and achieve R0 resection as far as possible and for as long as possible (continuum of care). This TSCRS consensus statement aims to help build clinical capacity within the MDTs, while making better use of existing healthcare resources.

A clickable connective hub 1-bromo-2-triazolethane-1-sulfonyl fluoride BTESF (1) was developed and successfully applied for the fluorosulfonylvinylation of a host of primary and secondary cyclic or acyclic amines including amino acids and pharmaceuticals. Further antimicrobial experiments revealed that vinyl sulfonyl fluoride functionalized norfloxacin (3ak), ciprofloxacin (3am), and lomefloxacin (3an) exhibited 4-fold improved antimicrobial activity against Gram-positive bacteria compared to their parent drugs.

Air embolism is a rare complication of upper endoscopy and potentially causes life-threatening events. A 67-year-old man with a history of surgery of cardiac carcinoma and pancreatic neuroendocrine tumor underwent painless upper endoscopy because of tarry stools. During the procedure, air embolism developed, which caused decreased pulse oxygen saturation and delayed sedation recovery. He recovered with some weakness of the left upper limb in the intensive care unit without hyperbaric oxygen therapy. The etiology, clinical manifestations, and treatments of air embolism are discussed based on the literature reports. Although air embolism is uncommon in endoscopic examinations, the patients' outcomes could be improved if clinicians are alert to this potential complication, and promptly start proper diagnostic and therapeutic measures.

Oxytetracycline is one of the tetracycline antibiotics for feeding pig or cow, tetracycline antibiotics are the most widely used in animals and veterinary medicine as growth promoters and antibacte...

Mobilization of terrestrial-derived and recalcitrant black carbon (BC), including char and soot, from land to ocean exerts a significant influence on the global carbon cycle. This study elaborated the occurrence and spatial distributions of BC, char, and soot concentrations, as well as their burial fluxes, in the estuarine-inner shelf surface sediments of the East China Sea (ECS), an epicontinental sea adjacent to Chinese high-intensity BC emission source regions. Using a combination of BC measurements in the Yangtze River water and coastal ECS aerosol samples, a preliminary BC budget was concurrently constrained. The spatial distribution of char concentrations resembled largely that of BC, but differed significantly from that of soot, indicating that char and soot exhibited different geochemical behaviors. In contrast to concentrations, BC, char, and soot burial fluxes exhibited highly consistent spatial patterns, and all declined as the distance from the coastline increased. For the coastal ECS, riverine discharge dominated (~92%) the total BC input, with the Yangtze River alone accounting for as high as ~72%. The area-integrated sedimentary BC sink flux (630 ± 728 Gg/yr) in the coastal ECS was equivalent to the total BC influx (670 ± 153 Gg/yr), which coincided well with the regional sediment budget. This suggested that the terrestrial-derived and recalcitrant BC could be regarded as an alternative geochemical proxy for tracing the sediment source-to-sink processes in this region. Comparisons between BC and co-generated polycyclic aromatic hydrocarbons (PAHs) budgets in the coastal ECS revealed similarities in their input pathways, but dramatic differences in their ultimate fates. Despite these, the ECS estuarine-inner shelf could serve as a major sink of these terrestrial-based materials in the global ocean.

Despite advances in the characterization of colorectal cancer (CRC), it still faces a poor prognosis. There is growing evidence that gut microbiota and their metabolites potentially contribute to the development of CRC. Thus, microbial dysbiosis and their metabolites associated with CRC, based on stool samples, may be used to advantage to provide an excellent opportunity to find possible biomarkers for the screening, early detection, prevention, and treatment of CRC. Using 16S rRNA amplicon sequencing coupled with statistical analysis, this study analyzed the cause–effect shift of the microbial taxa and their metabolites that was associated with the fecal gut microbiota of 17 healthy controls, 21 polyps patients, and 21 cancer patients. The microbial taxonomic shift analysis revealed striking differences among the healthy control, polyps and cancer groups. At the phylum level, Synergistetes was reduced significantly in the polyps group compared to the healthy control and cancer group. Additionally, at the genus level and in association with the cancer group, a total of 12 genera were highly enriched in abundance. In contrast, only Oscillosprira was significantly higher in abundance in the healthy control group. Comparisons of the polyps and cancer groups showed a total of 18 significantly enriched genera. Among them, 78% of the genera associated with the cancer group were in higher abundance, whereas the remaining genera showed a higher abundance in the polyps group. Additionally, the comparison of healthy control and polyp groups showed six significantly abundant genera. More than 66% of these genera showed a reduced abundance in the polyps group than in healthy controls, whereas the remaining genera were highly abundant in the polyps group. Based on tumor presence and absence, the abundance of Olsenella and Lactobacillus at the genus level was significantly reduced in the patient group compared to healthy controls. The significant microbial function prediction revealed an increase in the abundance of metabolites in the polyps and cancer groups compared to healthy controls. A correlation analysis revealed a higher contribution of Dorea in the predicted functions. This study showed dysbiosis of gut microbiota at the taxonomic level and their metabolic functions among healthy subjects and in two stages of colorectal cancer, including adenoma and adenocarcinoma, which might serve as potential biomarkers for the early diagnosis and treatment of CRC.

Magnolia officinalis, as a well-known herb worldwide, has been widely used to treat multiple diseases for a long time. In this study, the petroleum ether extract from M. officinalis showed effective antifungal activity against seven plant pathogens (particularly against R. solani with an inhibition rate of 100.00% at 250 μg/mL). Honokiol and magnolol, isolated by the bioassay-guided method, exhibited greater antifungal activity than tebuconazole (EC50 = 3.07 μg/mL, p ≤ 0.001) against R. solani, which EC50 values were 2.18 μg/mL and 3.48 μg/mL, respectively. We used transcriptomics to explore the mechanism of action of honokiol against R. solani. Results indicated that honokiol may exert antifungal effects by blocking the oxidative phosphorylation metabolic pathway. Further studies indicated that honokiol induced ROS overproduction, disrupted the mitochondrial function, affected respiration, and blocked the TCA cycle, which eventually inhibited ATP production. Besides, honokiol also damaged cell membranes and caused morphological changes. This study demonstrated that the lignans isolated from M. officinalis possess the potential to be developed as botanical fungicides.

Non-invasive positive pressure ventilation (NIPPV) is a life-saving approach which was developed to reduce the complications of endotracheal intubation and invasive ventilation in patients with chronic obstructive pulmonary disease (COPD). However, it has a certain probability of invalid. Failure of NIPPV will lead to an increase in mortality, which highlights the importance of rational diagnosis about the need for NIPPV therapy. In order to avoid delaying endotracheal intubation, we proposed a hybrid model which combine tree-based feature transformation with Bayesian non-parametric classification, to predict whether the patient should adopt NIPPV based on the their own physical condition. We delved into the feature importance and justified the rationality of using tree-based feature transformation. The proposed gaussian process classification (GPC) with gradient boosting decision tree (GBDT) feature transformation model has shown state-of-the-art results on both the NIPPV dataset and two simulated datasets with larger sample size. For critically ill COPD patients, the proposed method provides diagnostic assistance for physicians' decision making and avoids delaying endotracheal intubation or mechanical ventilation.

Direct synthesis of alkynes from inexpensive, abundant alcohols was achieved in high yields (greater than 40 examples, up to 95% yield) through a SO2F2-promoted dehydration and dehydrogenation process. This straightforward transformation of sp3-sp3 (C-C) bonds to sp-sp (C≡C) bonds requires only inexpensive and readily available reagents (no transition metals) under mild conditions. The crude alkynes are sufficiently free of impurities to permit direct use in further transformations, as illustrated by regioselective Huisgen alkyne-azide cycloaddition reactions with PhN3 to give 1,4-substituted 1,2,3-traiazoles (16 examples, up to 92% yield) and Sonogashira couplings (10 examples, up to 77% yield).

Elemental carbon (EC), the highly recalcitrant carbonaceous material released exclusively from fossil fuel combustion and biomass burning, is a preferred geochemical agent for evaluating anthropogenic activities. We investigated the spatiotemporal trends of EC and char/soot ratios (char and soot, the two subtypes of EC, differ in formation mechanisms and physicochemical characteristics) in five sediment cores from eastern China marginal seas, spatially spanning from inshore coastal mud areas to offshore remote mud areas. The temporal profiles of EC depositional fluxes closely tracked socioeconomic development in China over the past ∼150 years, with the most pronounced increasing trend beginning in the early 1980s, commensurate with the implementation of national policy of Reform and Open in 1978. The temporal EC profiles in China differed significantly from those in European/American countries, reflecting their different socioeconomic development stages. The spatiotemporal trends of char/soot ratios were also highly informative. Temporally, they decreased from bottom to subsurface layers, indicating the switch of China from an agricultural economy to an industrial economy during the 20th century. Spatially, they decreased from inshore to offshore areas, suggesting the differential transport patterns of EC among these sampling regimes.

SUMMARY CNS cortical histogenesis depends on polarity signaling pathways that regulate cell adhesion and motility. Here we report that conditional deletion of the Rho GTPase Cdc42 in cerebellar granule cell precursors (GCPs) results in abnormalities in cerebellar foliation revealed by iDISCO clearing methodology, a loss of columnar organization of proliferating GCPs in the external germinal layer (EGL), disordered parallel fiber organization in the molecular layer (ML), and a failure to extend a leading process and form a neuron-glial junction during migration along Bergmann glia (BG). Notably, GCPs lacking Cdc42 had a multi-polar morphology and slowed migration rate. In addition, secondary defects occurred in BG development and organization, especially in the lateral cerebellar hemispheres. By phosphoproteomic analysis, affected Cdc42 targets included regulators of the cytoskeleton, cell adhesion and polarity. Thus, Cdc42 signaling pathways are critical regulators of GCP polarity and the formation of neuron-glial junctions during cerebellar development., Graphical abstract

Introduction Ventricular tachycardia (VT) acceleration due to antitachycardia pacing (ATP) therapy could be often observed in patients with implantable cardioverter defibrillator (ICD), which usually results in additional shock. However, few studies focused on the risk factors for VT acceleration caused by ATP therapy. The purpose of this study was to investigate risk factors for VT acceleration due to ATP delivery. Methods We retrospectively reviewed 1056 ATP episodes in 33 patients with structural heart diseases, of whom clinical characteristics and episodes details were evaluated. Results At individual patient level, number of VT morphologies recorded in electrograms during follow‐up was a risk factor with cutoff point of 1 (AUC 0.79, sensitivity 72.7%, specificity 77.3%, P

Xiaofei Cao,* Shijiang Liu,* Jie Sun, Min Yu, Yin Fang, Zhengnian Ding Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China *These authors contributed equally to this work Background: Respiratory depression is a complication of intravenous fentanyl administration. The effect of pregnancy on respiratory depression following opioid administration is unclear. This study investigated the effect of pregnancy on fentanyl-induced respiratory depression.Patients and methods: Female patients were divided into three groups (n=20 per group): control group (non-pregnant and scheduled for laparoscopic surgery), early pregnancy group (pregnant for 45–60days and scheduled for abortion), and postpartum group (5–7days postpartum scheduled for complete curettage of uterine cavity). All patients received an intravenous infusion of fentanyl 2µg/kg. Respiratory rate (RR), end-tidal pressure of carbon dioxide (PETCO2), and pulse oxygen saturation (SpO2) were recorded continuously from just before fentanyl infusion to 15min after commencing infusion. Plasma levels of progesterone were measured.Results: SpO2 levels in the early pregnancy and postpartum groups were significantly higher and the levels of RR and PETCO2 were significantly lower than the control group. RR and SpO2 levels were significantly decreased in all groups, whereas PETCO2 was significantly increased after fentanyl infusion. The rates of RR increase and SpO2 decrease were significantly faster in the control group than in the other groups. The lowest SpO2 after intravenous fentanyl administration was significantly positively correlated with plasma progesterone levels.Conclusion: Pregnancy improves fentanyl-induced respiratory depression, which may be associated with the increased levels of plasma progesterone. Keywords: fentanyl, pregnancy, respiratory depression, progesterone&nbsp

Comparative transcriptomics between differentiating human pluripotent stem cells (hPSC) and developing mouse neurons offers a powerful approach to compare genetic and epigenetic pathways in human and mouse neurons. To analyze human Purkinje cell (PC) differentiation, we optimized a protocol to generate hPSC-PCs that formed synapses when cultured with mouse cerebellar glia and granule cells and fired large calcium currents, measured with the genetically encoded calcium indicator jRGECO1a. To directly compare global gene expression of hPSC-PCs with developing mouse PCs, we used translating ribosomal affinity purification (TRAP). As a first step, we used Tg(Pcp2-L10a-Egfp) TRAP mice to profile actively transcribed genes in developing postnatal mouse PCs, and used metagene projection to identify the most salient patterns of PC gene expression over time. We then created a transgenic Pcp2-L10a-Egfp TRAP hESC line to profile gene expression in differentiating hPSC-PCs, finding that the key gene expression pathways of differentiated hPSC-PCs most closely matched those of late juvenile, mouse PCs (P21). Comparative bioinformatics identified classical PC gene signatures as well as novel mitochondrial and autophagy gene pathways during the differentiation of both mouse and human PCs. In addition, we identified genes expressed in hPSC-PCs but not mouse PCs and confirmed protein expression of a novel human PC gene, CD40LG, expressed in both hPSC-PCs and native human cerebellar tissue. This study therefore provides the first direct comparison of hPSC-PC and mouse PC gene expression and a robust method for generating differentiated hPSC-PCs with human-specific gene expression for modeling developmental and degenerative cerebellar disorders.Significance StatementTo compare global gene expression features of differentiating human pluripotent stem cell-derived Purkinje cells (hPSC-PC) and developing mouse Purkinje cells (PC) we derived hPSC-PCs and compared gene expression datasets from human and mouse PCs. We optimized a differentiation protocol that generated hPSC-PCs most similar in gene expression to mouse P21 PCs. Metagene projection analysis of mouse PC gene expression over postnatal development identified both classical PC marker genes as well as novel mitochondrial and autophagy gene pathways. These key gene expression patterns were conserved in differentiating hPSC-PCs. We further identified differences in timing and expression of key gene sets between mouse and hPSC-PCs and confirmed expression of a novel human PC marker, CD40LG, in human cerebellar tissue.

Antibacterial-resistance speaks to an overall alarm, particularly in regards to the flare-up of methicillin-resistance Staphylococcus aureus (MRSA), a classic reason for genuine skin and flimsy tissues diseases. Clinically noteworthy antibacterial-resistance is probably the best challenge of the 21st century. Notwithstanding, new-fangled antibiotics are right now being created at a much more slow pace than our developing requirement for such drugs. The intriguing atomic structure of indole ring makes them appropriate possibility for the drug advancement. In this scaled down survey we abridge novel indole-based derivatives potency against diverse bacterial strains. Specifically, we plot the connection between the different structures of altered indole derivatives along with its antibacterial movement against multidrug-resistance MRSA could be discussed. This prepared information may fill in as a target for the adjustment of accessible molecules to plan new powerful antibacterial agents with lesser side effects.

Aquaporin-2 (AQP2) is a molecular water channel protein responsible for water reabsorption by the kidney collecting ducts. Many water balance disorders are associated with defects in AQP2 gene expression regulated by the peptide hormone vasopressin. Here, we studied roles of Elf3 (E26 transformation-specific (Ets)-related transcription factor 3) in AQP2 gene expression in the collecting duct cells (mpkCCD). Vasopressin increased AQP2 mRNA and protein levels without affecting AQP2 mRNA degradation, indicative of transcriptional regulation. Elf3 knockdown and overexpression, respectively, reduced and increased AQP2 gene expression under basal and vasopressin-stimulated conditions. However, the vasopressin-to-basal ratios of AQP2 gene expression levels remained constant, indicating that Elf3 does not directly mediate vasopressin response but modulates the level of AQP2 gene expression inducible by vasopressin. The Elf3-modulated AQP2 gene expression was associated with AQP2 promoter activity, in line with Elf3’s ability to bind an Ets element in the AQP2 promoter. Mutation in the Ets element reduced both basal and vasopressin-stimulated AQP2 promoter activity, again without affecting vasopressin-to-basal ratios of the AQP2 promoter activity. Lithium chloride reduced both Elf3 and AQP2 mRNA in the mpkCCD cells as well as in mouse kidney inner medulla. We conclude that Elf3 modulates AQP2 promoter activity thereby gauging vasopressin-inducible AQP2 gene expression levels. Our data provide a potential explanation to lithium-induced nephrogenic diabetes insipidus where lithium reduces Elf3 and hence AQP2 abundance.

Inspired by quinine and its analogues, we designed, synthesized, and evaluated two series of quinoline small molecular compounds (a and 2a) and six series of quinoline derivatives (3a-f) for their antifungal activities. The results showed that compounds 3e and 3f series exhibited significant fungicidal activities. Significantly, compounds 3f-4 (EC50 = 0.41 μg/mL) and 3f-28 (EC50 = 0.55 μg/mL) displayed the superior in vitro fungicidal activity and the potent in vivo curative effect against Sclerotinia sclerotiorum. Preliminary mechanism studies showed that compounds 3f-4 and 3f-28 could cause changes in the cell membrane permeability, accumulation of reactive oxygen species, loss of mitochondrial membrane potential, and effective inhibition of germination and formation of S. sclerotiorum sclerotia. These results indicate that compounds 3f-4 and 3f-28 are novel potential fungicidal candidates against S. sclerotiorum derived from natural products.

It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1−/−, Mmp12−/−, and Il17a−/− mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1−/−mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.

Objective In this study, we aimed to assess the feasibility of fiberoptic intubation (FOI), using a new, self-designed, “tongue root holder” device, in combination with the jaw thrust maneuver. Methods Three hundred patients undergoing elective surgery requiring orotracheal intubation were enrolled. Patients presented at least one or more risk factors for difficult airway. The patients were randomly allocated at a 1:1 ratio to one of two groups: group L, FOI with tongue root holder, or group C, standard FOI. Orotracheal FOI was performed after commencement of anesthesia. The jaw thrust maneuver was applied in both groups to facilitate advancement of the fiberoptic bronchoscope. The primary endpoint was the feasibility of FOI. The secondary endpoints were number of attempts, time to intubation, and airway clearance at the soft palate and epiglottis levels. Results The FOI was achieved in all 150 patients in group L, significantly higher than that in group C (100% vs 95.3%; P = 0.015). Less attempts of intubation were made in group L (P = 0.039). Mean time to successful intubation on the first attempt was shorter in group L (P P = 0.011 and P P = 0.010 and P = 0.038, respectively). Conclusions This study shows that FOI is feasible with the newly introduced, self-designed, “tongue root holder” device, when combined with the jaw thrust maneuver in patients with risk factors for difficult airway. The device also provides better airway clearance, less intubation attempts, and shorter time to intubation at first attempt. Clinical relevance Fiberoptic bronchoscope has been the gold standard for routine management of difficult airway. A technique to open the airway is introduced to reduce the incidence rate of upper airway obstruction.

Memory destruction affects daily life of the elderly, and dementia is an irreversible brain dysfunction. In non-pharmacological treatments of dementia, spaced retrieval training (SRT) is a memory intervention supporting memory recall and remaining memory capacity. Furthermore, it is easy to learn and execute by caregivers. Studies show interactive technology could reduce cognitive load and increase learning interest of dementia patients. However, related researches of combining interactive technology and SRT are still unclear. The conventional SRT uses typography and pictographs as training content, while employing interactive technology in SRT provides an interactive environment with an intuitive learning experience. Therefore, the objective is developing design criteria of SRT system through observation, interview, and focus group. Twelve elderly people, one social worker, and two caregivers are recruited for observation and interview to collect information for focus group. The results are utilized as design criteria for SRT system and establish foundation for future work.

The coastal margins around Southeast Asia (SE Asia) may serve as an ideal location to study the source sink process of sedimentary black carbon (BC) because SE Asia has been identified as one of the major BC emission source regions in the world. This study provides an extensive picture of recent regional-scale sedimentary BC sequestration in the Gulf of Thailand (GOT), a tropical marine system in SE Asia. Generally, the sedimentary BC concentrations (0.07-3.99 mg/g) were in the low to moderate ranges of those obtained in other coastal sediments around the world. Regional variability of the BC and its correlation with the sediment grain size and total, organic carbon (TOC) content indicated a general hydrodynamic constraint on BC occurrence in the lower Gulf in contrast to the upper Gulf with a more source dependence due to the direct land-based input. BC/TOC% values and the varied BC components (char and soot), as well as their correlations suggested that char was the predominant constituents of sedimentary BC both in the upper and lower Gulf, which could be mainly derived from biomass burning and entered into the nearshore region through direct fluvial transport and surface run-off. The estimated BC burial flux (similar to 212 mu g/cm(2)/y) and mass inventory (similar to 200 Gg/y) in the GOT on the hundred-year timescale were of the same order of magnitude compared with other oceanic margins, and thus the tropical shelf sediments from SE Asia could serve as an important sink of land-emitted BC. (C) 2015 Elsevier Ltd. All rights reserved.

Rationale: Percutaneous endoscopic lumbar discectomy (PELD) is a minimally invasive technique for removing nucleus pulposus and achieving neural decompression via a posterolateral approach. PELD is known to have a very low rate of complications during the perioperative period. Although quite rare, seizures can occur in patients undergoing PELD. Patient concerns: A 58-year-old man with severe low back pain underwent the PELD procedure under general anesthesia. During the recovery phase after general anesthesia, the patient developed a tonic-clonic seizure. Two additional episodes occurred subsequently. Diagnoses: Bilateral disc swelling indirectly supports the diagnosis of intracranial hypertension. Interventions: Midazolam and propofol were administered to control seizures. 1.0 g phenobarbital sodium was administered by intravenous injection. Ten milligrams of furosemide and 250 mL of mannitol (20%) were prescribed sequentially. Two hundred milligrams of hydrocortisone and an ice bag were used to protect the brain. Urapidil, metoprolol, and nicardipine were intermittently used to control his blood pressure. A sustained release of sodium valproate was administered and continued prophylactically for 4 weeks. Outcomes: No further seizures were recorded and the patient recovered well. Lessons: We conclude that total volume of fluid used for irrigation was considered a possible cause of seizure. This case illustrates the fact that irrigation should be performed cautiously in PELD procedure. And anesthesiologists should be familiar with the management strategies of perioperative acute seizures.

Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ)-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications., The mechanisms controlling irreversible cell cycle exit in cerebellar granule progenitors (GCPs) have not been fully elucidated. Here, the authors performed RNA-sequencing of GCPs exiting the cell cycle to identify downregulation of Brd4 activity as an early event during cell cycle exit which subsequently regulates Shh activity and is needed for proper cerebellar development

Background The anti-tumor activities of Natural compounds and their derivatives are of great interest to pharmaceutical industries. Fisetin is one of prospective natural compounds in this regard but unfortunately with poor hydrophilicity. Methods The effects of unmodified and modified fisetin in cultured ovarian cancer cells were compared by transmission electronmicroscopy to determine apoptotic bodies, MTT assay to quantitate cell numbers, and fluorescence activated cell sorting analyse of various markers to determine the apoptotic state. In addition, the efficacy of fisetin and fisetin-micelles in vivo was determined by using immunocompromised mice. Apoptosis was measured by established markers using both western blot analysis and immunochemistry. Angiogenesis in a xenograft mouse model carring SKOV3 cells was evaluated by color Doppler ultrasound and immunohistochemistry. Result Multiple lines of evidence indicated that fisetin and fisetin micelles induce apoptosis in ovarian cancer cells in a dose-dependent manner. Histological analysis, terminal deoxynucleotidyltransferase-mediated nick-end labeling assay, western blot, immunohistochemical detection and microvessel density detection demonstrated that fisetin and fisetin micelles induced increased tumor apoptosis, proliferation suppression and antiangiogenesis activities. Conclusion As far as we know, the present study is the first time to demonstrate the potency of both fisetin and fisetin micelles inducing apoptosis in ovarian cancer cells. Further studies will be needed to validate the therapeutic potential of fisetin and fisetin micelles in ovarian cancer treatment.

Cardiac shockwave therapy (CSWT) is a potential and effective remedy to promote revascularization in the ischemic myocardium of patients with refractory coronary heart disease (CHD). The technique is both safe and non-invasive; however, the underlying molecular mechanism remains unclear. The aim of this study was to evaluate the efficacy of CSWT in treating CHD patients and investigate a potential mechanism. A total of 26 patients with CHD were enrolled in the study, and CSWT was performed over a 3-month period. The efficacy of CSWT was assessed using several clinical parameters. Peripheral blood (PB) was collected prior to and following treatment. The number of circulating endothelial progenitor cells (EPCs) in the PB was counted using a flow cytometer, and the levels of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), stromal cell-derived factor 1 and matrix metalloproteinase 9 in the PB were analyzed. Mononuclear cells were isolated from the PB and cultured in vitro. The EPCs and EPC-colony forming units (EPC-CFUs) in the PB mononuclear cell culture were counted using an inverted phase contrast microscope. Following CSWT, the tested clinical parameters were significantly improved. The levels of circulating EPCs, VEGF and IL-8 in the PB were significantly increased, as were the EPCs and EPC-CFUs from the PB mononuclear cell culture. We suggest that EPC proliferation, mediated by VEGF and IL-8 secretion, may be among the potential mechanisms associated with CSWT.

Although casein kinase 1δ (CK1δ) is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/C(Cdh1)) ubiquitin ligase, and conditional deletion of the APC/C(Cdh1) activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/C(Cdh1) also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/C(Cdh1) controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target. We thank Dr. David Rowitch (University of California, San Francisco) for providing the Atoh1-Cre deleter line and Dr. Marc Kirschner for helpful discussions and critical reading of the manuscript. We also thank all members of the Center for Therapeutic Innovation (University of Miami) and the Department of Cancer Biology (Scripps Florida) for helpful suggestions. We thank Dr. Angela MacArthur and the Department of Scientific Editing at St. Jude Children's Research Hospital for helpful suggestions. This work was supported by R21 NS056991 (N.G.A.), R01NS067289 (N.G.A. and M.E.H.), NIH grant NCI CA-096832 (M.F.R.), NIH Molecular Library Screening Center Network grant U54MH074404 (W.R.R., Hugh Rosen, PI), Core Grant CA-021765 (M.F.R., D.K., and D.F.), the Anderson Fellowship (D.K.), and the American Lebanese-Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital (M.F.R., D.K., and D.F.) as well as the Spanish Ministerio de Economia y Competitividad (MINECO, SAF2012-38215), Fundacion Ramon Areces, Comunidad de Madrid (S2010/BMD-2470), and the European Union Seventh Framework Programme (MitoSys project; HEALTH-F5-2010-241548) (M.M.). Sí

Adriamycin (ADM) is a commonly used drug in clinical breast cancer treatment. However, some breast cancer types or breast cancers subjected to repeated ADM exposure develop strong resistance to ADM thus limiting its clinical efficacy. In this study, we found for the first time that toosendanin (TSN), a triterpenoid extracted from the traditional Chinese medicine Melia toosendan Sieb et Zucc, could successfully reverse adriamycin resistance in human breast cancer cells. Immunofluorescence and HPLC analysis demonstrated that TSN promoted adriamycin accumulation in breast cancer cells, especially in the nucleus. Furthermore, TSN could significantly reduce ABCB1 expression. We then found that TSN was capable of suppressing adriamycin-induced Akt phosphorylation, probably due to downregulation of the PI3K catalytic subunits P110α and P110β, and inhibition of DNA-PKcs. Importantly, the inhibitory effect of TSN on PI3K P110α and P110β expression was specifically observed in breast cancer cells but not in normal human cells. Moreover, TSN significantly potentiated the anti-cancer effect of ADM in the 4T1 breast cancer model and its inhibition rate was nearly 90%. Thus, TSN could be used as a novel PI3K inhibitor to reverse breast cancer resistance. The combination of ADM and TSN may represent a useful strategy for human breast cancer therapy.

This study investigates the effect of the Temporary Aid to Needy Families (TANF) program on children’s health outcomes using data from the Survey of Income and Program Participation (SIPP) over the period 1994 to 2005. The TANF policies have been credited with increased employment for single mothers and a dramatic drop in welfare caseload. Our results show that these policies also had a significant effect on various measures of children’s health and medical utilization especially among low-income families. These health measures include a rating of the child’s health status reported by the parents; the number of days an illness or injury kept the child in bed; the number of times that parents consulted a doctor; and the number of nights that the child stayed in a hospital.

Embryonic Six2-positive nephron progenitor cells adjacent to ureteric bud tips ultimately give rise to nephron structures, including proximal and distal tubules, podocytes, Bowman's capsules, and the glomeruli. This process requires an internal balance between self-renew and differentiation of the nephron progenitor cells, which is mediated by numerous molecules. Recent studies have shown that the neurofibromin (Nf1) null mutant mouse embryos have an 18- to 24-h developmental delay in metanephros manifesting retardation in its cephalad repositioning and reduction number of glomeruli. However, the underlying inter-/intracellular signaling mechanisms responsible for reducing number of glomeruli during nephrogenesis remain to be fully elucidated. Here, we originally detected the Nf1 expression in developing kidney and metanephric mesenchyme cells. Surprisingly, Nf1 knockdown by small interfering RNAs in the metanephric mesenchyme cells (mK3) resulted in a decreased expression of Six2, the key marker of renal progenitor cells, while the ratio of apoptotic cells was significantly increased. Furthermore, overexpression of Six2 in mk3 cells partially rescued apoptosis phenotype. Collectively, these results implied that knockdown of Nf1 resulted in apoptosis of mK3 cells in vitro probably through down-regulation of Six2 expression. Collectively, we demonstrated that down-regulated Six2 by knockdown of Nf1 resulted in apoptosis of mK3 cells in vitro. These results implied that inhibition of Nf1 may delay metanephros development via down-regulation of Six2.

Purpose Apolipoprotein E knockout (apoE−/−) mouse is one of the most popular models for cardiovascular research, especially in the study of atherosclerosis. Naturally, large amount of studies try to uncover the role of apoE in atherosclerosis, and indeed apoE plays an important role in this pathogenesis. Kidney is an organ that contains lots of capillaries and also largely expresses apoE. Moreover, a protective role of apoE in kidney as an autocrine regulator has been demonstrated previously, however, the underlying mechanism is largely unknown. Experimental design In this study, comparative proteomics is for the first time used to identify the differential proteins in kidneys of apoE−/− and wild type mice, respectively, and we try to reveal the signaling network of apoE in mice kidney using bioinformatics analysis. Results Our findings show that approximately 80 proteins are significantly differentially expressed in kidneys of apoE−/− and wild type mice, and the signaling network correlated to apoE is successfully established by employing bioinformatics assay. Conclusions and clinical relevance Taken together, we originally identify the proteins with differential expression and propose an apoE correlated molecular network in mice kidney. These findings further provide evidence of the role of apoE in mice kidney and a brand new perspective in the protection and treatment of kidney disease.

Bone regeneration required suitable scaffolding materials to support the proliferation and osteogenic differentiation of bone-related cells. In this study, a kind of hybridized nanofibrous scaffold material (CNF/BG) was prepared by incorporating bioactive glass (BG) nanoparticles into carbon nanofibers (CNF) via the combination of BG sol-gel and polyacrylonitrile (PAN) electrospinning, followed by carbonization. Three types (49 s, 68 s and 86 s) of BG nanoparticles were incorporated. To understand the mechanism of CNF/BG hybrids exerting osteogenic effects, bone marrow mesenchymal stromal cells (BMSCs) were cultured directly on these hybrids (contact culture) or cultured in transwell chambers in the presence of these materials (non-contact culture). The contributions of ion release and contact effect on cell proliferation and osteogenic differentiation were able to be correlated. It was found that the ionic dissolution products had limited effect on cell proliferation, while they were able to enhance osteogenic differentiation of BMSCs in comparison with pure CNF. Differently, the proliferation and osteogenic differentiation were both significantly promoted in the contact culture. In both cases, CNF/BG(68 s) showed the strongest ability in influencing cell behaviors due to its fastest release rate of soluble silicium-relating ions. The synergistic effect of CNF and BG would make CNF/BG hybrids promising substrates for bone repairing.

The purpose of the study was to evaluate the effect of concurrent arthroscopic osteochondral lesion (OCL) treatment and lateral ankle ligament repair on the outcome of chronic lateral ankle instability. It was hypothesized that the arthroscopic OCL treatment might have some negative effect on the outcome of chronic lateral ankle instability (CLAI) by compromising the rehabilitation program. Ankle arthroscopy and anatomic lateral ankle ligament repair with suture anchors were performed for 70 patients with CLAI between 2010 and 2012. Thirty-four patients (group A), 20 males and 14 females with a median age of 30(14–54) years, received arthroscopic abrasion, curettage, drilling, or microfracture for OCLs. The splint was removed daily for joint motion exercises beginning at post-operative 2 weeks and full weight bearing was allowed between post-operative week 8 and 12. The other 36 patients (group B) with no combined OCL were followed up as controls. Pre-operative and post-operative visual analog scale (VAS) scores, American Orthopaedic Foot and Ankle Society (AOFAS) scores, Tegner scores, sprain recurrence, ankle stability, and range of motion (ROM) were evaluated and compared. The median follow-up was 46.5 (38–55) months and 44.5 (38–56) months for group A and group B, respectively. The median post-operative VAS score, AOFAS score, and Tegner score were improved from the pre-operative level for both groups with good-to-excellent results for more than 90% patients. No significant difference was found between the two groups for the subjective scores and satisfaction rate (n.s.). Recurrent sprain was found among nine patients(26.5%) of the group A and five patients (13.9%) of the group B (n.s.). The incidence of the ROM restriction of group A was significantly higher than in group B (23.5 vs 5.6%, P = 0.043). The concurrent arthroscopic treatment of OCL with lateral ankle ligament repair demonstrated no substantial negative effect on the overall mid-term outcome of the patients with CLAI except for a potential risk of ROM restriction. III.

Objective: This study was conducted to evaluate the speech perception of Malaysian Chinese adults using the Taiwanese Mandarin HINT (MHINT-T) and the Malay HINT (MyHINT). Design: The MHINT-T and the MyHINT were presented in quiet and noise (front, right and left) conditions under headphones. Results for the two tests were compared with each other and with the norms for each test. Study sample: Malaysian Chinese native speakers of Mandarin (N = 58), 18–31 years of age with normal hearing. Results: On average, subjects demonstrated poorer speech perception ability than the normative samples for these tests. Repeated measures ANOVA showed that speech reception thresholds (SRTs) were slightly poorer on the MHINT-T than on the MyHINT for all test conditions. However, normalized SRTs were poorer by 0.6 standard deviations for MyHINT as compared with MHINT-T. Conclusions: MyHINT and MHINT-T can be used as norm-referenced speech perception measures for Mandarin-speaking Chinese in Malaysia.

This paper was aimed to investigate the impact of the extraction from raspberry on the Alzheimer disease model protein expression. According to weight, the ovariectomized mice were randomly divided into shame operation group, model group, estrogen positive control group(0.1 g•L⁻¹) and ethyl acetate extraction part control group(in dose of 18 g•kg⁻¹). Each mouse in positive control group was subcutaneous injected of estradiol with 0.2 mL every two days. Raspberry effective parts group were given 0.01 mL•g⁻¹ raspberry ethylacetate extracts, model group and control group were given 0.01 mL•g⁻¹ saline once a day. The drug administration lasted for 32 days. Proteins from mice's hippocampus were extracted, then Nanol-ESI liquid-mass spectrometry system was used for detection and ProteinDiscovery software was used for identification to qualitative analysis different groups of hippocampal proteins by using the software of SIEVE. The results showed that model group compared with the mice of ethyl acetate extraction part control group have 66 differentially expressed proteins including heat shock protein, microtubule protein, protein involved in energy metabolism and protein of brain protection related proteins associated with AD. Those differences protein may be the target that Raspberry prevention and treatment of AD.

Rotavirus infection is one of the most common causes of severe diarrhea in China. To evaluate the economic burden associated with rotavirus infection of children in China, we combined data on the disease burden of rotavirus-associated costs for samples comprising 832 outpatients and 604 inpatients from five seaside cities. The average social costs and direct medical costs for rotavirus-associated admissions were calculated to be US $61.64 and US $40.73 for outpatients, and US $684.15 and US $559.48 for inpatients, respectively, from October 1, 2006 to December 1, 2007. On average, the private cost ranged from US $54.64 for outpatients to US $454.24 for inpatients when children suffered from rotavirus infection. Accordingly, this cost accounted for 35.19-293% of the monthly income of an unskilled or service worker. We estimated that the annual number of children with rotavirus diarrhea was 12.10 million. Consequently, the total annual direct cost, total annual social cost, and total annual private cost were US $271.4 million, US $365.0 million, and US $290.0 million, respectively. Furthermore, rotavirus diarrhea affected children's behavior and emotions, which had a great influence on the caretakers' quality of life. These data indicate the potential requirement for a safe and effective rotavirus vaccine to reduce the economic burden associated with rotavirus disease.

Background. After hemiparetic stroke, coordination of the shoulder flexor and elbow extensor muscles during a reaching movement is impaired and contributes to poor performance. Objective. The aim was to determine whether functional coupling between electromyographic signals of synergist muscles during reaching was weakened in stroke patients who had poor motor coordination. Methods. Surface electromyography (EMG) from the anterior deltoid, triceps brachii, biceps brachii, pectoralis major, supraspinatus, and latissimus dorsi of the affected upper limb in 11 stroke patients (mean Fugl-Meyer upper extremity score 27 ± 8) and in the dominant arm of 8 healthy controls were measured. Results. Coherence between the EMG of the anterior deltoid and triceps brachii, 2 synergists for reaching, was lower in patients compared with controls, in the 0- to 11-Hz range. Detailed segmented frequency-range analysis indicated significant differences in the coherence between groups in 0- to 3.9-Hz and 4- to 7.9-Hz ranges. Conclusions. This weakened functional coupling may contribute to poor reaching performance and could be a consequence of a loss of common drive at the frequency bands as a result of interruption of information flow in the corticospinal pathway.

Introduction We have developed new urethane acrylate–based root canal sealers using polycarbonate (PC) as polyol and 2,2-azobis(2-methyl)butyronitrile (AMBN) as a thermal initiator. The purpose of this study was to compare the properties among a group of seven sealers: (1) polybutyleneadipate (PBA) with 2,2-azobis-isobutyronitrile (AIBN), (2) PBA-AMBN, (3) PC-AIBN, (4) PC-AMBN, (5) AH Plus (Dentsply DeTrey GmbH, Konstanz, Germany), (6) Epiphany (Pentron Clinical Technologies, Wallingford, CT), and (7) EndoREZ (Ultradent Products, Inc, South Jordan, UT). Methods Attenuated total reflectance-Fourier transforming infrared spectroscopy was used to analyze the degree of conversion. Cytotoxicity was evaluated using MTT assay. In addition, push-out bond strength, solubility, and dimensional stability were investigated. Results Urethane acrylate–based root canal sealers behaved better than Epiphany and EndoREZ for the properties evaluated in this study. The PC-AMBN sealer exhibited the highest degree of conversion even in the apical third, and its cytotoxicity for nonsetting and aged specimens at 24 hours was comparable to AH Plus sealer. In addition, the PC-AMBN sealer with zinc oxide/thermoplastic polyurethane cones had a significantly higher bond strength than AH Plus with gutta percha. Solubility and dimensional changes of the PC-AMBN sealer conformed to the American National Standards Institute/American Dental Association (ANSI/ADA) standard 57. Conclusions The PC-AMBN sealer has great potential for use in endodontic therapy.