Demonstration of a direct interaction between β2-adrenergic receptor and insulin receptor by BRET and bioinformatics.
Glucose metabolism is under the cooperative regulation of both insulin receptor (IR) and β(2)-adrenergic receptor (β(2)AR), which represent the receptor tyrosine kinases (RTKs) and seven transmembrane receptors (7TMRs), respectively. Studies demonstrating cross-talk between these two receptors and their endogenous coexpression have suggested their possible interactions. To evaluate the effect of IR and prospective heteromerization on β(2)AR properties, we showed that IR coexpression had no effect on the ligand binding properties of β(2)AR; however, IR reduced β(2)AR surface expression and accelerated its internalization. Additionally, both receptors displayed a similar distribution pattern with a high degree of colocalization. To test the possible direct interaction between β(2)AR and IR, we employed quantitative BRET(2) saturation and competition assays. Saturation assay data suggested constitutive β(2)AR and IR homo- and heteromerization. Calculated acceptor/donor (AD50) values as a measure of the relative affinity for homo- and heteromer formation differed among the heteromers that could not be explained by a simple dimer model. In heterologous competition assays, a transient increase in the BRET(2) signal with a subsequent hyperbolical decrease was observed, suggesting higher-order heteromer formation. To complement the BRET(2) data, we employed the informational spectrum method (ISM), a virtual spectroscopy method to investigate protein-protein interactions. Computational peptide scanning of β(2)AR and IR identified intracellular domains encompassing residues at the end of the 7th TM domain and C-terminal tail of β(2)AR and a cytoplasmic part of the IR β chain as prospective interaction domains. ISM further suggested a high probability of heteromer formation and homodimers as basic units engaged in heteromerization. In summary, our data suggest direct interaction and higher-order β(2)AR:IR oligomer formation, likely comprising heteromers of homodimers.


Degradation of microcrystalline cellulose: synergism between different endoglucanases of Cellulomonas sp. ATCC 21399.
Three immunologically and enzymatically distinct endoglucanases of Cellulomonas sp. ATCC 21399 were purified previously. Endoglucanase A and endoglucanase B acted synergistically on microcrystalline cellulose (Avicel), whereas no synergistic action was observed between endoglucanase B or endoglucanase C. Only endoglucanase A was capable of hydrolyzing Avicel when acting alone and this enzyme resulted in "short fiber formation" when acting on Avicel. The end product of hydrolysis of acid swollen Avicel produced by the three endoglucanases was in all cases dominated by cellobiose and showed lower content of glucose and cellotriose. Higher cellodextrins appeared as transient end products. The results indicate that the function of endoglucanase A in the cellulase system of Cellulomonas might be very similar to the function of the cellobiohydrolases of Trichoderma reesei.


Clinical and etiological studies of chlamydial conjunctivitis in Sapporo, Japan.
Chlamydia trachomatis was isolated from 21.5% (61/284 cases) of the patients with conjunctivitis seen in an eye clinic in Sapporo, Japan, during a recent 4-year period. The frequency was the highest in newborn babies and the 20- to 29-year-old age group. The early incidence of neonatal conjunctivitis suggested that transmission had occurred at delivery. Isolation by tissue culture is the most sensitive method for detection of this condition but the Micro Trak direct fluorescence antibody test is more practical. The detection of a specific IgG antibody and IgA antibody against chlamydia in human sera and in tears showed that patients with chlamydial conjunctivitis had the antibody before the onset of conjunctivitis.


Analyzing Mitochondrial Morphology Through Simulation Supervised Learning.
The quantitative analysis of subcellular organelles such as mitochondria in cell fluorescence microscopy images is a demanding task because of the inherent challenges in the segmentation of these small and morphologically diverse structures. In this article, we demonstrate the use of a machine learning-aided segmentation and analysis pipeline for the quantification of mitochondrial morphology in fluorescence microscopy images of fixed cells. The deep learning-based segmentation tool is trained on simulated images and eliminates the requirement for ground truth annotations for supervised deep learning. We demonstrate the utility of this tool on fluorescence microscopy images of fixed cardiomyoblasts with a stable expression of fluorescent mitochondria markers and employ specific cell culture conditions to induce changes in the mitochondrial morphology.


Pair-potential approach to accurate dispersion energies between group 12 (Zn, Cd, Hg) clusters.
Dispersion interactions between group 12 (Zn, Cd, Hg) metal clusters are studied at the CCSD(T) level with triple-ζ basis sets. We use atomic orientation dependent C6 dispersion coefficients derived from simple model systems to calculate the intermolecular dispersion energy between larger metal clusters. By using an atomic pair-potential model, we are able to obtain highly accurate results comparable to the CCSD(T) level of theory. For all the systems studied, our method results in a robust description of the dispersion energy at long distances, and it is able to outperform the examined dispersion corrected DFT calculations.


Effect of repeated induced airway collapse during total liquid ventilation.
Negative pressure generated during the expiratory phase of total liquid ventilation (TLV) may induce airway collapse. Evaluation of the effect of repeated airway collapse is crucial to optimize this technique. A total of 24 New Zealand White rabbits were randomly divided into four groups. Ventilation was performed for 6 hours with different strategies: conventional gas ventilation, TLV without airway collapse, and TLV with collapse induced in either 75 or 150 sequential breaths. In the treated groups, airway collapse was induced by increasing the perfluorocarbon drainage velocity while maintaining the minute ventilation constant. Airway pressure, gas exchange, and blood pressure were monitored at 30-minute intervals. At the end of the experiment, airway and lung parenchyma specimens were processed for light microscopy. No evidence of fluorothorax was noticed in any of the four groups at autopsy examination. Minimal signs of inflammation were noticed in all airway and lung parenchyma specimens, but no evident structural alteration was visible. Adequate gas exchange and systemic blood pressure were maintained during all the studies. Repeated airway collapse is not associated with structural changes in the respiratory system and does not alter the gas exchange ability of the lungs.


Understanding the stress responses of Kluyveromyces marxianus after an arrest during high-temperature ethanol fermentation based on integration of RNA-Seq and metabolite data.
The thermotolerant Kluyveromyces marxianus is a potential candidate for high-temperature ethanol fermentation. Although K. marxianus exhibited high ethanol productivity at 45 °C during the early fermentation stage, we observed a fermentation arrest due to the accumulated inhibitors. The stress responses of K. marxianus during high-temperature fermentation were revealed based on integration of RNA sequencing (RNA-Seq) and metabolite data. High temperature stimulated mitochondrial respiration but repressed the tricarboxylic acid (TCA) cycle, leading to increased generation of reactive oxygen species (ROS) and a lowered ratio of reduced nicotinamide adenine dinucleotide (NADH)/oxidized nicotinamide adenine dinucleotide (NAD+). Glycerol production was enhanced during the early fermentation stage, which might contribute to NADH reoxidation and ROS generation. Excess ROS could be neutralized by reduced nicotinamide adenine dinucleotide phosphate (NADPH) that might be reserved in the following ways: (1) decreased biosynthesis of branched-chain amino acids (BCAAs) reduced NADPH consumption; (2) enhanced acetic acid production increased NADPH regeneration. The degree of fatty acid unsaturation was also reduced to adapt to high temperature. In addition, stress responses were also observed after the fermentation arrest at 45 °C. Genes related to peroxidase activity, iron-sulfur cluster assembly, and flavin mononucleotide (FMN) binding were downregulated, while genes associated with DNA repair and lipid composition of the plasma were upregulated. The yeast also produced more ergosterol to deal with ethanol stress. This study gains comprehensive insights into the K. marxianus transcriptome under various stresses during high-temperature ethanol fermentation, providing rich information for further metabolic engineering towards improved stress tolerance and ethanol production.


[Biogenic elements and sulfate reduction in a flooded oil carbonate stratum].
Biogenous sulphate reduction and accumulation of secondary H2S were caused by the action of pumping waters with a low content of mineral elements on carbonate collectors with a high concentration of relict H2S during long periods of time. The amount of sulphates, phosphates, and ammonium nitrogen in water from layers of various mineralization is sufficient for active sulphate reduction. Sulphates and phosphates are eliminated from rocks of layers with diluted waters. The maximum increase of SO42- in waters was 1545 mg/litre, that of HPO42- was 0.34 mg/litre. The amount of ammonium decreases with mineralization of the layer waters, remaining within the range of 129-7 mg/litre. The content of CO2 and HCO3- increases in diluted waters to 197 and 695 mg/litre, respectively, correlating with biogenous processes. The highest number of sulphate reducing bacteria (dozens of thousands of the cells per ml) was found in water with mineralization of 19 g/litre. Curves for the content of SO42-, HPO42-, NH4+, and CO2 have a common maximum in waters of the Polaznensky deposit with a salinity of 62 g/litre.


The impact of accelerated high frequency rTMS on brain neurochemicals in treatment-resistant depression: Insights from 1H MR spectroscopy.
Although accelerated repetitive transcranial magnetic stimulation (rTMS) designs seem to be able to alleviate mood over a relatively short period of time, no studies yet examined the cellular effects on neurochemicals with regard to working mechanisms, safety and neural integrity. Eighteen right-handed antidepressant-free unipolar treatment resistant depressed (TRD) patients participated in this sham-controlled accelerated high frequency (aHF)-rTMS 1H MR spectroscopy study applied to the left dorsolateral prefrontal cortex (DLPFC). Baseline measurements were compared to eighteen age- and gender-matched healthy controls. We explicitly focused on neurochemical concentrations in the bilateral DLPFC and rostral anterior cingulate cortex (rACC). Compared to healthy individuals, TRD patients displayed significantly lower baseline glutamatergic (sum absolute concentrations glutamate and glutamine) concentrations in the left DLPFC. aHF-rTMS does not significantly alter neurochemical concentrations in the three predefined brain regions. Clinical improvement was related to significant GABA concentration increases in the left DLPFC. Accelerated HF-rTMS treatment did not affect neural integrity in the examined regions. The observed GABA concentration increases suggest that the immediate therapeutic effects of aHF-rTMS could be mediated through a locally increased GABAergic inhibitory neurotransmission. Although more statistical power is needed for reaching firm conclusions, aHF-rTMS does not appear to negatively influence neural integrity.


Auto-reverse nuclear migration in bipolar mammalian cells on micropatterned surfaces.
A novel assay based on micropatterning and time-lapse microscopy has been developed for the study of nuclear migration dynamics in cultured mammalian cells. When cultured on 10-20-microm wide adhesive stripes, the motility of C6 glioma and primary mouse fibroblast cells is diminished. Nevertheless, nuclei perform an unexpected auto-reverse motion: when a migrating nucleus approaches the leading edge, it decelerates, changes the direction of motion, and accelerates to move toward the other end of the elongated cell. During this process, cells show signs of polarization closely following the direction of nuclear movement. The observed nuclear movement requires a functioning microtubular system, as revealed by experiments disrupting the main cytoskeletal components with specific drugs. On the basis of our results, we argue that auto-reverse nuclear migration is due to forces determined by the interplay of microtubule dynamics and the changing position of the microtubule organizing center as the nucleus reaches the leading edge. Our assay recapitulates specific features of nuclear migration (cell polarization, oscillatory nuclear movement), while it allows the systematic study of a large number of individual cells. In particular, our experiments yielded the first direct evidence of reversive nuclear motion in mammalian cells, induced by attachment constraints.


Expression of C-5 sterol desaturase from an edible mushroom in fisson yeast enhances its ethanol and thermotolerance.
Bioethanol is an environment friendly and renewable source of energy produced by the fermentation of agricultural raw material by a variety of microorganisms including yeast. Obtaining yeast strains that are tolerant to stresses like high levels of ethanol and high temperature is highly desirable as it reduces cost and increases yield during bioethanol production. Here, we report that heterologous expression of C-5 Sterol desaturase (FvC5SD)-an ergosterol biosynthesis enzyme from an edible mushroom Flammulina velutipes in fission yeast, not only imparts increased thermotolerance but also tolerance towards high ethanol concentration and low pH. This tolerance could be attributed to an increase of ≈1.5 fold in the level of ergosterol and oleic acid (C-18 unsaturated fatty acid) as analysed by gas chromatography- mass spectrometry. FvC5SD is a membrane localized iron binding enzyme that introduces double bond at C-5 position into the Δ7-sterol substrates to yield Δ5, 7- sterols as products. In F. velutipes, FvC5SD transcript was observed to be upregulated by ≈5 fold under low pH condition and by ≈ 9 folds and ≈5 fold at 40°C and 4°C respectively when compared to normal growth temperature of 23°C. Besides, susceptibility to cell wall inhibiting drugs like Congo red and Calcoflour white was also found to increase in FvC5SD expressing S. pombe strain. Alteration in membrane sterol and fatty acid composition could also lead to increase in susceptibility to cell wall inhibiting drugs. Thus, this study has immense industrial application and can be employed to ensure competitiveness of fermentation process.


[Diagnostic value of interleukin-27 in tuberculous pleural effusion].
To explore the diagnostic value of interleukin-27 (IL-27) in tuberculous pleural effusion. A total of 76 patients of pleural effusion treated at Shandong Provincial Hospital from March 2013 to February 2014 in accordance with the natures of effusion fluid were divided into: (1) Tuberculosis group of tuberculous pleural effusion (n = 40), including 22 males and 18 females; aged 19 to 73 years; (2) Malignant group of malignant pleural effusion (n = 36), including 20 males and 16 females; aged 33 to 78 years old; including lung cancer (n = 28), lymphoma (n = 3), esophageal (n = 1) and uncertain primary tumor site (n = 4). The effusion and serum levels of IL-27 were detected by enzyme-linked immunosorbent assay (ELISA) and the results analyzed. And the curve of receiver operating characteristic (ROC) was employed to determine the diagnostic value of IL-27 in tuberculous pleural effusion. The level of IL-27 was (1 402 ± 321) ng/L in tuberculous pleural effusion and it was significantly higher than those in malignant pleural effusion (556 ± 133) ng/L and sera (499 ± 88) ng/L (both P < 0.05). According to the ROC curve, the cut-off value of IL-27 was 838 ng/L in diagnosing tuberculous pleural effusion. And the rates of diagnostic sensitivity, specificity and accuracy of IL-27 were 95.0%, 97.2% and 96.1% respectively. Detection of pleural effusion IL-27 concentration is of great importance in the diagnosis of tuberculous pleural effusion. And it is worthy of wider clinical promotion.


Effects of ACE inhibition and beta-blockade on female genital structures in spontaneously hypertensive rats.
This study evaluated the possible differences between an angiotensin converting enzyme (ACE) inhibitor and a beta-blocker concerning their potential protective role on female external genitalia in spontaneously hypertensive rats (SHR). Morphological changes in the clitoris after antihypertensive treatments. For 6 months, SHR received no treatment; SHR + ramipril (RAM), SHR + atenolol (AT), and control Wistar Kyoto (WKY) rats received no treatment. Clitorises were processed for immunohistochemistry using anti-alpha-smooth muscle actin (alpha-SMA), anti-collagen I and III, anti-transforming growth factor beta(1) (TGFbeta(1)), and anti-endothelial nitric oxide synthase (eNOS) antibodies. SHR + RAM and SHR + AT presented significantly lower blood pressure in both groups vs. untreated SHR. Compared with WKY, alpha-SMA was increased in the arteries and in the cavernous spaces of the clitoris together with a marked increase in wall/lumen ratio in clitoral vessels in untreated SHR. All these alterations were diminished in SHR + AT (P < 0.01). SHR + RAM presented differences with respect to SHR + AT in the reduction of these variables. TGFbeta(1) expression in the vessel wall from the clitoris and collagen I and III deposition in the interstitium from the clitoris in untreated SHR were significantly more (P < 0.01) than in WKY. While SHR + AT showed a mild decrease in these variables, SHR + RAM presented a significant reduction (P < 0.01) in TGFbeta(1) expression interstitial fibrosis and in both types of collagens. Positive immunostaining of eNOS in the sinusoidal endothelium from the clitoris was less (P < 0.01) in untreated SHR (3.4 +/- 1.3%) and SHR + AT (5.1 +/- 1.2%) than in SHR + RAM (17.2 +/- 1.6%) and WKY (15.9 +/- 1.7%). Untreated SHR and SHR + AT presented more surrounding connective tissue at the perineurium in the clitoris (P < 0.01) than SHR + RAM. ACE inhibition provided a considerable protective role on the female external genitalia structures in SHR by a mechanism that may be, at least in part, independent of the degree of blood pressure lowering.


Complexity analysis of yeast proteome network.
Topological and compositional complexity of protein-protein networks is assessed in a variety of ways making use of graph theory and information theory. The methodology used is borrowed from mathematical chemistry and includes complexity descriptors such as substructure count, overall connectivity, walk count, and information on various vertex distributions. The approach is applied to the (incomplete) proteome of Saccharomyces cerevisiae containing 232 protein complexes of a total of 1,440 proteins. The proteome network and each of its nine functional subsets of protein complexes are disconnected graphs, containing a number of noninteracting species and a major component. A weighted edge between two vertices in these graphs stands for the number of shared proteins between the respective complexes. The major component is a highly connected, 'small-world' network, in which the average vertex distance between protein complexes does not exceed 2.2 (2.4 for the entire proteome), whereas the maximum distance does not exceed 4 (or 5 for the proteome). The vertex degree distribution in the major proteome component with 199 complexes follows the power law P(k) approximately k(-gamma), with gamma approximately = 1.7. The analysis of the functional organization of the yeast proteome has shown that, for any pair of biological functions, there always exist many proteins that can perform both functions. The potential application of the quantitative proteome descriptors discussed includes quantitative relationships between the structure and biological action of dynamic protein complexes in changing environment, identification of targets for markers/drugs, as well as system analysis and comparative studies of proteomes.


Induction of apoptosis in peripheral blood lymphocytes following treatment in vitro with hydroxychloroquine.
Defective regulation of apoptosis may be central to the development of autoimmune disorders. This study investigated the possibility that the antirheumatic effect of hydroxycholoroquine (HCQ) may be achieved by up-regulation of apoptosis. Peripheral blood lymphocytes collected from normal controls and patients with systemic lupus erythematosus (SLE) were cultured in the presence or absence of a range of concentrations of HCQ. Cells undergoing apoptosis were identified by several standard methods, including morphologic changes, DNA fragmentation, and flow cytometry. For some experiments, lymphocytes were simultaneously stained with antibodies to T cell surface markers and with propidium iodide for dual-stain flow cytometric studies. HCQ was able to induce apoptosis in peripheral blood lymphocytes in a dose- and time-dependent manner. HCQ induced these changes in all T cell subpopulations studied. There was no significant difference between the controls and patients with SLE in terms of the percentage of apoptotic cells detected following treatment with HCQ. The present study demonstrated that HCQ induces apoptosis in peripheral blood lymphocytes, which leads to the speculation that HCQ may exert its antirheumatic effect through this mechanism.


Transfer factor--a lymphocyte cell surface component.
An attempt was made to locate the biologically active component of the DLE in lymphocytes. The test was based on the recovery of sheep cell-rosetting capacity in trypsinized human lymphocytes (recovery assay). Comparisons of the extract from trypsinized leukocytes and the leukocyte supernatant (after trypsination ) yielded the following results: The peptide fraction detached from the cell surface by trypsin (30 min with 0.5 g trypsin/l at 37 degrees C) accounts for most of the TF activity of the whole lymphocytes. Of the two TF activities (fractions II and III), fraction III obviously stems from the cell interior because it cannot be liberated by trypsin. Fraction III is characterized by an unusually high UV absorption quotient (A 260/280), probably due to a large nucleotide content. Trypsination leads to the biologically active TF fraction going into the supernatant. Fraction II consists almost entirely of cell surface peptides. It is relatively easy to separate it cleanly, and it has a high level of biological activity (1 microgram/ml is still detectable).


Cytotoxicity and antimicrobial activity of isolated compounds from Monsonia angustifolia and Dodonaea angustifolia.
Monsonia angustifolia is traditionally used to treat anthrax, heartburn, diarrhea, eye infections and hemorrhoids. Dodonaea angustifolia is frequently used as a treatment for dental pain, microbial infections and jungle fever. The two plant species were selected due to the presence of secondary metabolites such as coumarins, flavonoids, terpenoids, saponins and polyphenolics from the crude extracts, which exhibit pharmacological significance. The pure isolated compounds from the crude extracts are known for their diverse structures and interesting pharmacophores. To isolate and identify antibacterial and antifungal chemical constituents from Monsonia angustifolia and Dodonaea angustifolia plant extracts and evaluate the cytotoxicity of pure compounds from the crude extracts. Extractives from M. angustifolia and D. angustifolia plants were isolated using chromatographic techniques and structures were elucidated based on NMR, IR and MS spectroscopic techniques. A microplate serial dilution method was used to evaluate the antibacterial activity of extracts and pure compounds against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and antifungal activity against Candida albicans and Cryptococcus neoformans. The cytotoxicity was determined using the 3-(4, 5-dimethylthiazol)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The dichloromethane, ethyl acetate and methanol crude extracts from the plants exhibited significant inhibition of microbial growth. The phytochemical investigation of these active crude extracts led to the isolation of five pure active compounds, 5-methoxyjusticidin A (1), cis-phytyl diterpenoidal fatty acid ester (2), stigmasterol (3), β-sitosterol (4) and 5-hydroxy-7,4'-dimethoxyflavone (5). Stigmasterol (3) showed good antifungal activity against Cryptococcus neoformans with a minimum inhibition concentration (MIC) of 25 μg/mL and Candida albicans (MIC = 50 μg/mL). Compounds (1-5) isolated from Monsonia angustifolia and Dodonaea angustifolia showed antibacterial and antifungal activities and were non-toxic against Madin-Darby canine kidney (MDCK) cells and VERO monkey kidney (VERO) cells.


Aberrant Kynurenine Signaling Modulates DNA Replication Stress Factors and Promotes Genomic Instability in Gliomas.
Metabolism of the essential amino acid L-tryptophan (TRP) is implicated in a number of neurological conditions including depression, neurodegenerative diseases, and cancer. The TRP catabolite kynurenine (KYN) has recently emerged as an important neuroactive factor in brain tumor pathogenesis, with additional studies implicating KYN in other types of cancer. Often highlighted as a modulator of the immune response and a contributor to immune escape for malignant tumors, it is well-known that KYN has effects on the production of the coenzyme nicotinamide adenine dinucleotide (NAD(+)), which can have a direct impact on DNA repair, replication, cell division, redox signaling, and mitochondrial function. Additional effects of KYN signaling are imparted through its role as an endogenous agonist for the aryl hydrocarbon receptor (AhR), and it is largely through activation of the AhR that KYN appears to mediate malignant progression in gliomas. We have recently reported on the ability of KYN signaling to modulate expression of human DNA polymerase kappa (hpol κ), a translesion enzyme involved in bypass of bulky DNA lesions and activation of the replication stress response. Given the impact of KYN on NAD(+) production, AhR signaling, and translesion DNA synthesis, it follows that dysregulation of KYN signaling in cancer may promote malignancy through alterations in the level of endogenous DNA damage and replication stress. In this perspective, we discuss the connections between KYN signaling, DNA damage tolerance, and genomic instability, as they relate to cancer.


Efficacy of decalcified freeze-dried bone allograft in the regeneration of small osseous defect: A comparative study.
To access the efficacy of decalcified freeze-dried bone allograft (DFDBA) in the regeneration of bone following small osseous defect in minor oral surgery. To evaluate the ability of DFDBA to enhance the rate of wound healing and assess radiographic bone density, pain, and infection preoperatively and postoperatively. Twenty patients with cysts were assessed. Ten patients were filled with DFDBA (Group 1) and ten without bone graft (Group 2), respectively. Radiographic bone density was assessed on preoperative, intraoperative, and postoperative radiographs on 1st day, 3rd month, and at 6th month using Adobe Photoshop CS6 - Grayscale histogram. Bone density in Group 1 was found to be significantly higher than in Group 2 on 3rd and 6th month postoperatively with a P = 0.024 and P = 0.016 which was statistically significant. The percentage increase in bone density between both the group was determined and yielded no difference over a period of time, but the difference in percentage increase was markedly higher in Group 1 compared to Group 2 at all the time intervals. Bone formed as depicted by bone density is significantly higher when DFDBA is used in small bony defects.


Surgically implantable long-term antipsychotic delivery systems for the treatment of schizophrenia.
Non-adherence with medication remains a major correctable cause for poor outcome in schizophrenia. We describe a surgically implantable preparation of haloperidol with the aim that patients will have superior outcomes with improved medication adherence from implants. In contrast to depot formulations, implantable pellets could last many months, providing symptomatic improvement for periods of time never before possible. Additionally, in the event of unacceptable side effects, implants could be removed, offering a degree of reversibility not available with depot formulations. A surgically-implantable formulation of haloperidol has been created using biodegradable polymers. Implants have been characterized for in-vitro kinetics, as well as in-vivo bioactivity in rodents. Haloperidol implants demonstrate steady release of drug for 5 months. Animals treated with haloperidol implants display increased striatal D2 receptor expression as well as increased apomorphine stimulated locomotion. Surgically-implantable formulations are a viable approach to provide long-term delivery of antipsychotic medications to patients with psychotic disorders.


[Intraoperative radiotherapy in abdominal-pelvic cancer surgery].
Intraoperative radiotherapy consists in the irradiation of the affected area, exposed using anesthesiological and laparotomic procedures, following the removal of a neoplasia using palliative or macroscopically radical surgical. This increases local tumour control and augments the selectivity of treatment between healthy and neoplastic tissues, thus obtaining a marked improvement in survival or palliation. The authors analyse the data reported in international literature regarding the possible use of intraoperative radiotherapy in patients undergoing abdomino-pelvic oncological surgery. The aim of the study was to evaluate this method for use in selected and combined treatment in which surgery represents an obligatory step. Studies were carried out in a few highly specialised centres given that special technical, logistic and professional skills were required. The populations studied were often very small with a marked prevalence of feasibility studies compared to random studies. In spite of this intraoperative radiotherapy is undoubtedly indicated in locally advanced gastric, rectal and vesical neoplasia, it represents a valid palliative solution in pancreatic neoplasia and in pelvic recidivation, and an effective alternative solution to mutilating surgery in the initial stages of vesical cancer. Positive results are obtained in prostate and uterine cancer, but they are reported by non-conclusive studies. Toxicity is acceptable and non-limiting within a given range of doses and irradiated volume. The "repercussion" in terms of knowledge, experience, scientific integration between oncological surgeons and radiotherapists is basic, with a marked improved in the management of cancer treatment.


Strengthening Theoretical Testing in Criminology Using Agent-based Modeling.
The Journal of Research in Crime and Delinquency (JRCD) has published important contributions to both criminological theory and associated empirical tests. In this article, we consider some of the challenges associated with traditional approaches to social science research, and discuss a complementary approach that is gaining popularity-agent-based computational modeling-that may offer new opportunities to strengthen theories of crime and develop insights into phenomena of interest. Two literature reviews are completed. The aim of the first is to identify those articles published in JRCD that have been the most influential and to classify the theoretical perspectives taken. The second is intended to identify those studies that have used an agent-based model (ABM) to examine criminological theories and to identify which theories have been explored. Ecological theories of crime pattern formation have received the most attention from researchers using ABMs, but many other criminological theories are amenable to testing using such methods. Traditional methods of theory development and testing suffer from a number of potential issues that a more systematic use of ABMs-not without its own issues-may help to overcome. ABMs should become another method in the criminologists toolbox to aid theory testing and falsification.


Role of motility in the colonization of uropathogenic Escherichia coli in the urinary tract.
Uropathogenic Escherichia coli (UPEC) causes most uncomplicated urinary tract infections (UTIs) in humans. Flagellum-mediated motility and chemotaxis have been suggested to contribute to virulence by enabling UPEC to escape host immune responses and disperse to new sites within the urinary tract. To evaluate their contribution to virulence, six separate flagellar mutations were constructed in UPEC strain CFT073. The mutants constructed were shown to have four different flagellar phenotypes: fliA and fliC mutants do not produce flagella; the flgM mutant has similar levels of extracellular flagellin as the wild type but exhibits less motility than the wild type; the motAB mutant is nonmotile; and the cheW and cheY mutants are motile but nonchemotactic. Virulence was assessed by transurethral independent challenges and cochallenges of CBA mice with the wild type and each mutant. CFU/ml of urine or CFU/g bladder or kidney was determined 3 days postinoculation for the independent challenges and at 6, 16, 48, 60, and 72 h postinoculation for the cochallenges. While these mutants colonized the urinary tract during independent challenge, each of the mutants was outcompeted by the wild-type strain to various degrees at specific time points during cochallenge. Altogether, these results suggest that flagella and flagellum-mediated motility/chemotaxis may not be absolutely required for virulence but that these traits contribute to the fitness of UPEC and therefore significantly enhance the pathogenesis of UTIs caused by UPEC.


Cloning and expression of UDP-glucose: flavonoid 3-O-glucosyltransferase gene in peach flowers.
To elucidate the connection between flower coloration and the expression of genes associated with anthocyanin biosynthesis, a gene encoding UDP-glucose: flavonoid 3-O-glucosyltransferase (UFGT) was isolated, and the expression of the last four genes in the anthocyanin biosynthetic pathway during peach flower development was determined. The nucleotide sequence of the peach UFGT (GenBank accession No. JX149550) is highly similar to its homologs in other plants. Total anthocyanin content initially increased during peach flower development, and then decreased over time. Expression of the four anthocyanin biosynthesis genes increased until the full-bloom stage, and then decreased during late florescence. Expression of F3H, DFR, and UFGT increased dramatically at the full-bloom stage, coinciding with an increase in anthocyanin concentration. The UFGT gene may not be the only gene of the anthocyanin pathway to be differentially controlled in red peach flower tissues. Further studies are needed to genetically and physiologically characterize these genes and enzymes in peach flowers and to gain a better understanding of their functions and relationships with flower coloration.


Physical Activity, Adiposity, and Serum Vitamin D Levels in Healthy Women: The Cooper Center Longitudinal Study.
Background: Although physical inactivity, obesity, and low serum vitamin D [25-hydroxyvitamin D, 25(OH)D] are common among women, joint associations among these biomarkers are not well-described. Materials and Methods: A total of 7553 healthy women received a comprehensive examination (2006-2018), including self-reported physical activity (PA), body mass index (BMI), waist circumference (WC), waist:height ratio (W:HT), percent body fat (%Fat), and 25(OH)D. Participants were divided into four categories of PA based on current guidelines: <500 (not meeting guidelines), 500-1000 (meeting guidelines), 1001-2500 (>1-2.5 times guidelines), and >2500 (>2.5 times guidelines) metabolic equivalent-minutes/week (MET-Min/wk), and were also classified by clinical cut points for adiposity measures and 25(OH)D. We examined trends of 25(OH)D and adiposity exposures across PA categories and calculated odds ratios (ORs) of vitamin D deficiency across categories of each adiposity exposure. We examined joint associations among PA and adiposity with 25(OH)D. Results: A positive trend was observed for 25(OH)D across PA categories (p < 0.001). Compared with normal weight status, the odds for 25(OH)D deficiency were significantly higher for overweight women within adiposity exposures (p for all <0.001). When examining joint associations, 25(OH)D was higher across PA categories within each stratum of BMI, WC, W:HT, and %Fat (p trend <0.007 for all). When examining PA and BMI as continuous variables, OR for vitamin D deficiency were 0.95 (95% confidence interval [CI]: 0.93-0.96) per 250 MET-minutes/week increment in PA, and 1.20 (95% CI: 1.17-1.23) per 2 kg/m2 increment in BMI. Conclusions: 25(OH)D levels are positively associated with PA and negatively associated with different measures of adiposity. Higher levels of PA attenuate the association between adiposity and 25(OH)D.


Relative molar sensitivities of carnosol and carnosic acid with respect to diphenylamine allow accurate quantification of antioxidants in rosemary extract.
We have been developing a high-performance liquid chromatography/photodiode array (HPLC/PDA) employing relative molar sensitivities (RMSs) and adopted it to the accurate quantification of carnosol (CL) and carnosic acid (CA) which are the antioxidants in rosemary extract. The method requires no references of CL or CA and instead uses RMSs with respect to diphenylamine (DPA) whose certified reference material is available from a reagent manufacturer. The molar and response ratios of the analytes to the reference in an artificial mixture of them were determined using 1H-quantitative nuclear magnetic resonance spectroscopy (1H-qNMR) and HPLC/PDA at a wavelength of 284 nm under isocratic condition, respectively, and then RMSs were calculated to be 0.111 for CL/DPA and 0.0809 for CA/DPA as averaged values in three HPLC-PDA instruments. The RMS values varied by up to 1.1% as relative standard deviation. To evaluate the performance of HPLC/PDA with the RMSs, the CL and CA contents in rosemary extracts were determined using DPA as a reference. The CL and CA contents were compared with those determined using calibration curves of CL and CA obtained by HPLC measurement of standard solutions prepared from their reagents whose absolute purities were determined using 1H-qNMR. The differences between the two methods for CL and CA were ≤3% as relative error. This chromatographic method with RMSs allows a simple and reliable quantification when reference of the analyte is unavailable.


Gamma Knife Radiosurgery Followed by Flow-Reductive Embolization for Ruptured Arteriovenous Malformation.
: Background: Aggressive treatment to achieve complete obliteration of brain arteriovenous malformation (AVM) is necessary in patients with a recent history of hemorrhage. The major drawback of Gamma knife radiosurgery (GKRS) alone for AVM is risk of bleeding during the latent period until the AVM occludes. At our center, patients who present with ruptured AVMs are frequently offered GKRS followed by embolization. The goal of this study was to compare outcomes of embolization for patients who have previously undergone GKRS for ruptured AVMs. A database including 150 GKRS for ruptured AVMs between November 2008 and October 2017 was reviewed. The embolized group was selected by including AVMs with post-GKRS embolization. The non-embolized group was defined as AVMs treated by GKRS alone. Outcomes including obliteration rate, incidence of repeat hemorrhage, and delayed cyst formation were compared between two groups. The predictive factors related to AVM obliteration and complications were analyzed. The study consisted of 81 patients in the non-embolized group and 17 patients in the embolized group. Statistically significant differences were detected between the two groups with respect to age, Pollock-Flickinger score, Spetzler-Martin (SM) grade, eloquence of adjacent brain, and presence of aneurysms. The embolized group included more AVMs with larger median nidus volume. The predictive factors for the obliteration of ruptured AVMs were nidus volume, SM grade, Virginia Radiosurgery AVM Scale (VRAS), and Pollock-Flickinger score and for the subsequent hemorrhage were marginal dose, nidus volume, SM grade, VRAS, and Pollock-Flickinger score. The obliteration rates and complication rates after GKRS between groups were not significantly different. However, this study demonstrated statistically significant difference in the cumulative incidence of obliteration in AVMs with SM grade III and IV (p = 0.037). Although the current study demonstrated similar results in patients who underwent GKRS with and without embolization, the embolized group included more AVMs with larger nidus volume, higher SM grade, Pollock-Flickinger score, and aneurysm, which have a lower chance of obliteration and a higher probability of repeat hemorrhage. GKRS followed by embolization appears to be a beneficial approach for the treatment of ruptured AVMs that are at risk for obliteration failure and repeat hemorrhage during the latency period after single-session GKRS alone. Further studies involving a larger number of cases and continuous follow-up are necessary to confirm our conclusions.


A cross sectional survey on health-related quality of life of elementary school students using the Korean version of the EQ-5D-Y.
The Korean version of the EQ-5D-Y was launched in 2015 by the EuroQol group. Currently, there is no HRQOL data obtained by using the EQ-5D-Y in Korea. This study aimed to measure health-related quality of life of Korean elementary school students using the EQ-5D-Y. Elementary school students were recruited from 11 primary schools in Gyungbuk, South Korea. The EQ-5D-Y was self-administered in the sample population. Demographic characteristics were collected from the subjects' parents or guardians. The percentage of respondents reporting problems and VAS scores were calculated. Feasibility of the EQ-5D-Y was assessed by analysing the proportion of missing responses. The percentage of reported problems on the dimensions and VAS score between groups were compared by demographic factors. A total of 2,494 questionnaires were collected. There were 24 (0.96%) missing responses on the EQ-5D-Y and 187 (7.5%) missing VAS score responses. The proportion of reported problems ranged from 2.3% on the mobility dimension to 9.8% on the "having pain or discomfort" dimension. There was no significant difference in the proportion of problems by age group in male participants. However, in females, the older group reported significantly more problems on the "having pain or discomfort" and "feeling worried, sad, or unhappy" dimensions compared to the younger group. Students living with parents with the lowest educational level reported significantly more problems on the "looking after myself" and "doing usual activities" dimensions than did those living with parents with higher levels of education. This study showed the distribution of health-related quality of life and explored the feasibility of the EQ-5D-Y for measuring health-related quality of life in Korean elementary school students. Further studies are required to examine other psychometric properties of the Korean EQ-5D-Y.


Genetic Association and Potential Mediators between Sarcopenia and Coronary Heart Disease: A Bidirectional Two-Sample, Two-Step Mendelian Randomization Study.
To elucidate the bidirectional correlation of sarcopenia with coronary heart disease (CHD), as well as to investigate the mediating role of cardiometabolic factors and inflammatory biomarkers, a bidirectional two-sample, two-step Mendelian randomization (MR) study was conducted. Summary statistics were obtained from genome-wide association studies (GWAS). In our bidirectional two-sample MR, genetic variants associated with sarcopenia-related traits and CHD were instrumented for the estimation of bidirectional correlations. Besides, genetic variants associated with thirteen cardiometabolic factors and six inflammatory biomarkers were selected for further mediation analyses. To confirm the consistency of the results, several sensitivity analyses were carried out. Genetically predicted higher appendicular lean mass (OR = 0.835, 95% CI: 0.790-0.882), left hand grip strength (OR = 0.703, 95% CI: 0.569-0.869), right hand grip strength (OR = 0.685, 95% CI: 0.555-0.844), and walking pace (OR = 0.321, 95% CI: 0.191-0.539) reduced CHD risk, while genetic predisposition to CHD did not affect any of the sarcopenia-related traits. Seven mediators were identified for the effects of appendicular lean mass on CHD, including waist-to-hip ratio, hip circumference, systolic blood pressure, low-density lipoprotein cholesterol, total cholesterol, triglycerides, and fasting insulin. The mediation proportion ranged from 10.23% for triglycerides to 35.08% for hip circumference. Hip circumference was found to mediate the relationships between both left (mediation proportion: 24.61%) and right-hand grip strength (24.14%) and CHD, and the link between walking pace and CHD was partially mediated by waist-to-hip ratio (31.15%) and body mass index (26.66%). Our results showed that higher appendicular lean mass, hand grip strength, and walking pace reduced CHD risk, but the causal relationship was not bidirectional. Several mediators were found to mediate the causal pathways between sarcopenia-related traits and CHD, and intervention of these factors may be helpful in terms of CHD prevention in sarcopenia patients.


Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone.
Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration-response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose-response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.


Mirena, an Italian experience.
The aim of this review was to evaluate contraceptive efficacy, compliance, effect on menstrual cycle of a levonorgestrel-releasing device (Mirena®) in an Italian setting. During the 48 months of recruitment, 128 women accepted the insertion of the LNG-IUS satisfying all inclusion criteria; 71.6% of the women completing five years of use had heavy menstrual blood loss. General and pelvic examination, including an ultrasound scan were performed at recruitment and repeated at 1, 3, 6, months postinsertion. Each subject was given a menstrual diary to report both menstrual patterns and side effects. Over the 7 308 woman/months of observation, no pregnancy occurred. Menstrual blood flow decreased in all patients, both in terms of quantity and duration. In the vast majority of cases (93.7%), spotting disappeared within six months; within the first six cycles postinsertion, amenorrhoea occurred in 29.5% of all women. In five subjects the device was removed before the planned five years of observation: two women desired a pregnancy and three, in spite of a pre-existing condition of menorrhagia, requested removal within the first nine months, because they could not tolerate amenorrhoea. Three expulsions and one dislocation of the device were also detected, all within the first eight months. Although in Italy intrauterine contraception is poorly accepted, once started on Mirena® women found that the device represents a safe and effective contraceptive modality, particularly indicated in the presence of heavy or prolonged bleeding. The only important side effect reported was breast tenderness; in addition the transient appearance of ovarian cystic images was observed.


Catheter Access Management for Acute Peritoneal Dialysis.
Insertion of a peritoneal dialysis (PD) catheter is frequently done by interventional nephrologists, but these procedures are typically only performed for adults. Almost all invasive procedures in children are performed by pediatric surgeons. If a pediatric surgeon is unavailable, the initiation of PD in acute situations may be delayed, thus increasing the risk of complications and chronic kidney disease. For these patients, the main obstacle to initiating renal replacement therapy is access, even when involving central vein catheter (CVC) or peritoneal access. Here we report the case of a 10-kg baby affected by hemolytic and uremic syndrome diarrhea in whom all of the procedures to manage the complications of acute kidney injury (PD catheter insertion, PD catheter revision, CVC placement, and CVC revision) were undertaken by interventional nephrologists. This experience allowed us to rapidly treat the acute kidney injury, recover normal kidney function thereby avoiding chronic complications, and allowing us to discharge the baby from the intensive care unit.


Solute equilibration curves, crossing time for urea and glucose during peritoneal dialysis: a function of age in children.
Glucose is absorbed from the dialysate more rapidly in younger than in older children on CAPD leading to a relatively early loss of ultrafiltration during dwell time. In order to assess peritoneal permeability and in term to prescribe optimal management of CAPD, we tested peritoneal equilibration curves (EC) for urea and glucose, especially the crossing time point of these two ECs. Baseline values were obtained from 8 patients divided in two groups by age at start of CAPD: group I (N = 4) mean age 1 year 6 months, mean body weight 8.25 +/- 3.17 kg, group II (N = 4) mean age 12 years 6 months, mean body weight 33.5 +/- 1.5 kg. The crossing time point is earlier in group I (49 +/- 14 min) than in group II (101 +/- 20 min) (p less than 0.001). Followup of each patient, during a mean time of 20 months in group I and 23 months in group II, establishes that the curves crossing time point for each patient remains stable.


Increased expression of brain-derived neurotrophic factor is correlated with visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome.
Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome (IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor (BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS (IBS-D). To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology. Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 age- and sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined. The patients had a higher anxiety score [median (interquartile range), 6.0 (2.0-10.0) vs 3.0 (1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0 (44.0-61.0) vs 21.0 (17.3-30.0), P < 0.001] than controls. The defecating sensation threshold [60.0 (44.0-80.0) vs 80.0 (61.0-100.0), P = 0.009], maximum tolerable threshold [103.0 (90.0-128.0) vs 182.0 (142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0 (20.0-30.0) vs 30.0 (30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46E-2 (3.06E-2-4.44E-2) vs 3.07E-2 (2.91E-2-3.48E-2), P = 0.031] and mRNA [1.57 (1.31-2.61) vs 1.09 (0.74-1.42), P = 0.001] expression and nerve fiber density [4.12E-2 (3.07E-2-7.46E-2) vs 1.98E-2 (1.21E-2-4.25E-2), P = 0.002] were significantly elevated in the patients. Increased BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters. Elevated mucosal BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity.


Retrospective claims analysis of best supportive care costs and survival in a US metastatic renal cell population.
Survival and best supportive care (BSC) costs for patients with metastatic renal cell carcinoma (mRCC), after stopping therapy, are poorly characterized yet an important aspect of patient care. This study examined survival and costs associated with BSC after one or two lines of therapy (LOTs) for mRCC. A retrospective cohort analysis used claims data from commercially insured or Medicare Advantage Prescription Drug (MAPD) plan enrollees of a large United States health plan with an index RCC diagnosis (ICD-9-CM 189.0) between January 1, 2007 and June 30, 2010; initiating any of the following therapies 30 days pre-index date through disenrollment from plan: sunitinib, temsirolimus, sorafenib, bevacizumab, everolimus, pazopanib, cytokines. LOT was identified using prescription fill and administration dates. Health care costs represent health plan- plus patient-paid amounts. The cohort (n = 274) was 73% male, with a mean age of 63.3 years (SD 11.1), with 80% commercially insured (20% MAPD), and 68% starting BSC following one LOT. Mean BSC duration was longer following one than two LOTs (223 [SD 260], 176 [SD 163] days). Median survival from the start of BSC was similar following one and two LOTs (126 and 118 days). Total BSC costs following one and two LOTs averaged US$50,188 (SD $96,984) and $37,295 (SD $51,102). Monthly costs for BSC following one and two LOTs ($10,151 and $10,566) were not substantially lower than costs while on treatment ($14,621 and $16,957). Inpatient hospital costs represented 47% and 49% following one and two LOTs, with ambulatory costs of approximately 36% following each LOT. Our study found similar survival and monthly costs for BSC following either one or two LOTs, with almost half of the cost reflecting inpatient care. Compared to costs on treatment ($14,621 to $16,957), BSC costs can be considerable ($10,151 to $10,566).


High-Performance Organolead Halide Perovskite-Based Self-Powered Triboelectric Photodetector.
We report a MAPbI3-based self-powered photodetector (SPPD). It has a dual sensing mechanism that relies on the joint properties of a photoelectric effect and a triboelectric effect of the perovskite material. Both the photoconductivity and the surface triboelectric density of the MAPbI3-based composite thin film are significantly altered upon solar illumination, which results in considerable reduction of the output voltage. The SPPD exhibits excellent responsivity (7.5 V W(-1)), rapid response time (<80 ms), great repeatability, and broad detection range that extends from UV to visible regions. This work presents a route to designing high-performance self-powered photodetectors from the aspect of materials.


The Potential Mechanism of Curcumin in Treating Oral Squamous Cell Carcinoma Based on Integrated Bioinformatic Analysis.
This study explores the effects of curcumin as a therapeutic agent against oral squamous cell carcinoma (OSCC). We acquired the targets of curcumin from three digital databases, including the Comparative Toxicogenomics Database, Search Tool for Interactions of Chemicals, and SwissTargetPrediction. Then, we identified the differentially expressed genes (DEGs) and the weighted gene coexpression network analysis-based key modules using the expression profiles of GSE23558 to acquire the OSCC-related genes. Additionally, the GeneCards and Online Mendelian Inheritance in Man databases were also used to identify the OSCC-related genes. Finally, curcumin-OSCC interaction genes were obtained by overlapping curcumin targets and OSCC-related genes. The enrichment analysis was performed by the ClusterProfiler algorithm and Metascape, respectively. Then, a protein-protein interaction network was created, and the maximal clique centrality algorithm was used to identify the top 10 hub genes. Besides, we examined the expression levels of hub genes in OSCC using The Cancer Genome Atlas database. 927 DEGs were identified, including 308 upregulated ones and 619 downregulated ones. The cluster one-step network construction function of the WGCNA algorithm recognized a soft-thresholding power of 6, and 9083 genes were acquired. 2591 OSCC-related genes were obtained by overlapping the GSE23558-identified genes and the OSCC-related genes from disease target bases. Finally, we identified 70 candidate drug-disease interaction genes by overlapping the disease-related genes with the curcumin target. The enrichment analysis suggested that response to oxidative stress, epithelial cell proliferation, and AGE/RAGE pathway might involve in the effect of curcumin on OSCC. The topologic study identified the ten hub genes, including VEGFA, AKT1, TNF, HIF1A, EGFR, JUN, STAT3, MMP9, EGF, and MAPK3. A significant difference was observed in VEGFA, AKT1, TNF, HIF1A, EGFR, MMP9, EGF, and MAPK3 expression levels between head and neck squamous cell carcinoma and the normal controls. However, no significant difference was observed in JUN (P = 0.14) and STAT3 (P = 0.054). This study provided an overview and basis for the potential mechanism of curcumin against OSCC. The following experiments should be performed to further understand the effectiveness and safety of curcumin in treating OSCC.


Interaction of scaffolding adaptor protein Gab1 with tyrosine phosphatase SHP2 negatively regulates IGF-I-dependent myogenic differentiation via the ERK1/2 signaling pathway.
Grb2-associated binder 1 (Gab1) coordinates various receptor tyrosine kinase signaling pathways. Although skeletal muscle differentiation is regulated by some growth factors, it remains elusive whether Gab1 coordinates myogenic signals. Here, we examined the molecular mechanism of insulin-like growth factor-I (IGF-I)-mediated myogenic differentiation, focusing on Gab1 and its downstream signaling. Gab1 underwent tyrosine phosphorylation and subsequent complex formation with protein-tyrosine phosphatase SHP2 upon IGF-I stimulation in C2C12 myoblasts. On the other hand, Gab1 constitutively associated with phosphatidylinositol 3-kinase regulatory subunit p85. To delineate the role of Gab1 in IGF-I-dependent signaling, we examined the effect of adenovirus-mediated forced expression of wild-type Gab1 (Gab1(WT)), mutated Gab1 that is unable to bind SHP2 (Gab1(DeltaSHP2)), or mutated Gab1 that is unable to bind p85 (Gab1(Deltap85)), on the differentiation of C2C12 myoblasts. IGF-I-induced myogenic differentiation was enhanced in myoblasts overexpressing Gab1(DeltaSHP2), but inhibited in those overexpressing either Gab1(WT) or Gab1(Deltap85). Conversely, IGF-I-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation was significantly repressed in myoblasts overexpressing Gab1(DeltaSHP2) but enhanced in those overexpressing either Gab1(WT) or Gab1(Deltap85). Furthermore, small interference RNA-mediated Gab1 knockdown enhanced myogenic differentiation. Overexpression of catalytic-inactive SHP2 modulated IGF-I-induced myogenic differentiation and ERK1/2 activation similarly to that of Gab1(DeltaSHP2), suggesting that Gab1-SHP2 complex inhibits IGF-I-dependent myogenesis through ERK1/2. Consistently, the blockade of ERK1/2 pathway reversed the inhibitory effect of Gab1(WT) overexpression on myogenic differentiation, and constitutive activation of the ERK1/2 pathway suppressed the enhanced myogenic differentiation by overexpression of Gab1(DeltaSHP2). Collectively, these data suggest that the Gab1-SHP2-ERK1/2 signaling pathway comprises an inhibitory axis for IGF-I-dependent myogenic differentiation.


Molecular analysis of single circulating tumour cells following long-term storage of clinical samples.
The CellSearch® semiautomated CTC enrichment and staining system has been established as the 'gold standard' for CTC enumeration with CellSearch® CTC counts recognized by the FDA as prognostic for a number of cancers. We and others have gone on to show that molecular analysis of CellSearch® CTCs isolated shortly after CellSearch® enrichment provides another valuable layer of information that has potential clinical utility including predicting response to treatment. Although CellSearch® CTCs can be readily isolated after enrichment, the process of analysing a single CellSearch® patient sample, which may contain many CTCs, is both time-consuming and costly. Here, we describe a simple process that will allow storage of all CellSearch® -enriched cells in glycerol at -20 °C for up to 2 years without any measurable loss in the ability to retrieve single cells or in the genome integrity of the isolated cells. To establish the suitability of long-term glycerol storage for single-cell molecular analysis, we isolated individual CellSearch® -enriched cells by DEPArray™ either shortly after CellSearch® enrichment or following storage of matched enriched cells in glycerol at -20 °C. All isolated cells were subjected to whole-genome amplification (WGA), and the efficacy of single-cell WGA was evaluated by multiplex PCR to generate a Genome Integrity Index (GII). The GII results from 409 single cells obtained from both 'spike-in' controls and clinical samples showed no statistical difference between values obtained pre- and postglycerol storage and that there is no further loss in integrity when DEPArray™-isolated cells are then stored at -80 °C for up to 2 years. In summary, we have established simple yet effective 'stop-off' points along the CTC workflow enabling CTC banking and facilitating selection of suitable samples for intensive analysis once patient outcomes are known.


A Learning Sparrow Search Algorithm.
This paper solves the drawbacks of traditional intelligent optimization algorithms relying on 0 and has good results on CEC 2017 and benchmark functions, which effectively improve the problem of algorithms falling into local optimality. The sparrow search algorithm (SSA) has significant optimization performance, but still has the problem of large randomness and is easy to fall into the local optimum. For this reason, this paper proposes a learning sparrow search algorithm, which introduces the lens reverse learning strategy in the discoverer stage. The random reverse learning strategy increases the diversity of the population and makes the search method more flexible. In the follower stage, an improved sine and cosine guidance mechanism is introduced to make the search method of the discoverer more detailed. Finally, a differential-based local search is proposed. The strategy is used to update the optimal solution obtained each time to prevent the omission of high-quality solutions in the search process. LSSA is compared with CSSA, ISSA, SSA, BSO, GWO, and PSO in 12 benchmark functions to verify the feasibility of the algorithm. Furthermore, to further verify the effectiveness and practicability of the algorithm, LSSA is compared with MSSCS, CSsin, and FA-CL in CEC 2017 test function. The simulation results show that LSSA has good universality. Finally, the practicability of LSSA is verified by robot path planning, and LSSA has good stability and safety in path planning.


Clinical outcomes after local field conformal reirradiation of patients with retropharyngeal nodal metastasis.
The purpose of this study was to present our experience with retropharyngeal node reirradiation using highly conformal radiotherapy (RT). A retrospective screen of 2504 consecutively irradiated patients with head and neck malignancies between 2005 and 2015 identified 19 patients who underwent reirradiation for retropharyngeal node metastasis. Clinical and toxicity outcomes were assessed in these patients. Thirteen patients (68%) had squamous cell carcinoma. Eleven patients (58%) received conventionally fractionated intensity-modulated radiotherapy (IMRT) or proton therapy, and 8 patients (42%) received single-fractionated or hypofractionated stereotactic RT. Fourteen patients (74%) received chemotherapy. Median follow-up was 14.7 months. The 1-year local control, locoregional control, overall survival, and progression-free survival rates were 100%, 94%, 92%, and 92%, respectively. Three patients (16%) experienced acute grade 3 toxicity and occurred in those treated with IMRT. There was no late grade ≥3 toxicity. Retropharyngeal node reirradiation with conformal therapy is well tolerated and associated with excellent short-term disease control.


A parsec-scale optical jet from a massive young star in the Large Magellanic Cloud.
Highly collimated parsec-scale jets, which are generally linked to the presence of an accretion disk, are commonly observed in low-mass young stellar objects. In the past two decades, a few of these jets have been directly (or indirectly) observed from higher-mass (larger than eight solar masses) young stellar objects, adding to the growing evidence that disk-mediated accretion also occurs in high-mass stars, the formation mechanism of which is still poorly understood. Of the observed jets from massive young stars, none is in the optical regime (massive young stars are typically highly obscured by their natal material), and none is found outside of the Milky Way. Here we report observations of HH 1177, an optical ionized jet that originates from a massive young stellar object located in the Large Magellanic Cloud. The jet is highly collimated over its entire measured length of at least ten parsecs and has a bipolar geometry. The presence of a jet indicates ongoing, disk-mediated accretion and, together with the high degree of collimation, implies that this system is probably formed through a scaled-up version of the formation mechanism of low-mass stars. We conclude that the physics that govern jet launching and collimation is independent of stellar mass.


[A man with an asymmetrical thoracic wall].
A 57- year-old policeman fell during a violent arrest. He presented with pain and a hematoma in the right axillary region. Physical examination showed an asymmetrical contour of the anterior axillary fold and loss of strength during internal rotation and flexion of the right shoulder. These symptoms are specific for a pectoralis major muscle rupture.


Facial attractiveness biases the perception of eye contact.
Attractive faces are appealing: We like to look at them, and we like to be looked at by them. We presented attractive and unattractive smiling and neutral faces containing identical eye regions with different gaze directions. Participants judged whether or not a face looked directly at them. Overall, attractive faces increased participants' tendency to perceive eye contact, consistent with a self-referential positivity bias. However, attractiveness effects were modulated by facial expression and gender: For female faces, observers more likely perceived eye contact in attractive than unattractive faces, independent of expression. For male faces, attractiveness effects were limited to neutral expressions and were absent in smiling faces. A signal detection analysis elucidated a systematic pattern in which (a) smiling faces, but not highly attractive faces, reduced sensitivity in gaze perception overall, and (b) attractiveness had a more consistent impact on bias than sensitivity measures. We conclude that combined influences of attractiveness, expression, and gender determine the formation of an overall impression when deciding which individual's interest in oneself may be beneficial and should be reciprocated.


Vocal cord paralysis following central line insertion in a neonate: a review of the literature.
Acute onset stridor in a neonate following general anaesthesia is commonly attributed to laryngeal oedema secondary to anaesthetic airway trauma. The authors present a case of recurrent laryngeal nerve injury resulting in vocal cord paralysis causing stridor following central venous catheterisation under general anaesthesia in a neonate. This was managed expectantly and resolved spontaneously over a period of 6 months.


Culture of photomixotrophic soybean and pine in a modified fermentor using a novel impeller.
Photomixotrophic suspensions of Glycine max (soybean) and Pinus elliottii (slash pine) have been successfully cultured in a hybrid stirred tank photobioreactor using a novel cell-lift impeller. A cell-lift impeller exhibited cell viabilities over 90% and an average cell aggregate size of 1.0 mm or less. Flat-bladed turbines produced equivalent biomass to the cell-lift impeller, but cell viability was reduced (85%) and cell aggregate size increased (3-5 mm diameter). Maximum fresh weights of 82 g L(-1) (soybean) and 52 g L(-1) (slash pine) were achieved in 15 days using continuous lighting (90-100 microE m(-2) s(-1)) and supplemental 2% CO(2) inlet gas. Maximum biomass was achieved using an impeller speed of 60 rpm with air-flow rate of 0.2 vvm for the cell-lift impeller and the pair of flat bladed turbines. The lag and early exponential phases were characterized by (1) rapid hydrolysis of sucrose followed by preferential use of glucose and (2) a reduction in chlorophyll levels. Carbon dioxide (2%-5%) was an essential nutrient for photomixotrophic cell culture in the bioreactors.


Systemic iron metabolism and mortality from Parkinson's disease.
Six measures of systemic iron metabolism were used to predict mortality among 103 patients with Parkinson's disease and 353 controls followed in a longitudinal study. Adjusting for gender, education, ethnicity, presence of dementia, and extrapyramidal signs, transferrin receptor concentration was strongly associated with mortality in patients with PD but not controls. This increase in serum transferrin receptor concentration before death suggests that the previously observed perturbation in iron metabolism continues throughout the disease course.


Control of alternative splicing of potassium channels by stress hormones.
Many molecular mechanisms for neural adaptation to stress remain unknown. Expression of alternative splice variants of Slo, a gene encoding calcium- and voltage-activated potassium channels, was measured in rat adrenal chromaffin tissue from normal and hypophysectomized animals. Hypophysectomy triggered an abrupt decrease in the proportion of Slo transcripts containing a "STREX" exon. The decrease was prevented by adrenocorticotropic hormone injections. In Xenopus oocytes, STREX variants produced channels with functional properties associated with enhanced repetitive firing. Thus, the hormonal stress axis is likely to control the excitable properties of epinephrine-secreting cells by regulating alternative splicing of Slo messenger RNA.


On the central pattern generator for the basic breathing rhythmicity.
Recent advances in several laboratories concerning the respiration-related medullary neurons, their locations, projections, interconnections, morphological and physiological properties, and patterns of inhibitory postsynaptic potentials, excitatory postsynaptic potentials, and discharge rate, on the one hand, and the "systems behavior," on the other, have provided the basis for new hypothesis concerning the neural mechanisms underlying the central pattern generator (CPG) for breathing and its different parts. The onset of the "ramp"-like increase in inspiratory activity is due to an abrupt release of inhibition and a subsequent progressively increasing synaptic excitation of inspiratory premotor neurons. The integration of the excitatory "drive" inputs underlying the ramp inspiratory activity seems to depend on structures in the ventrorostral medulla, including nucleus paragigantocellularis. The termination of this activity by the off-switch mechanisms is actuated when a critical threshold is attained by the excitatory inputs of 1) a slowly increasing inspiration-related activity and 2) the afferent input from the pulmonary stretch receptors. The nature of the former activity is discussed. During the expiratory phase, an inhibitory activity suppresses inspiration-facilitating inputs with a slowly decaying power that controls the expiratory duration. The postinspiration activity, which brakes the rate of exhalation during the first part of the expiratory phase, depends on mechanisms separate from those responsible for the inspiratory ramp activity. The respiratory CPG seems to be organized with considerable amount of redundancy, or "degeneracity."


Pharmacokinetics services in Department of Veterans Affairs medical centers.
The provision of pharmacokinetics services in Veterans Affairs (VA) medical centers was studied. In October 1992 a questionnaire was mailed to the chief of pharmacy at each of the nation's 160 VA medical centers. The survey was designed to determine the percentage of centers providing pharmacokinetics services, the general characteristics of pharmacokinetics services provided, and whether the presence of these services was associated with specific characteristics of the medical centers. Of the 160 questionnaires mailed, 148 (93%) were returned and analyzed. Pharmacokinetics services were provided by 104 (70%) of the respondents. Of the 104 services, 58 (56%) had existed for less than five years. Of the 44 VA medical centers without a pharmacokinetics service, almost two thirds planned to start one in the future. Aminoglycosides, vancomycin, and theophylline were the drugs most frequently monitored. Fifty-four percent of the pharmacokinetics services evaluated 1-24 patients per month, and another 24% evaluated 25-49 patients monthly. VA medical centers with a pharmacy residency program were more likely to have a pharmacokinetics service than centers without such a program; an association with geographic region was also identified. Nearly three fourths of responding VA medical centers indicated that they provided pharmacokinetics services.


In silico ADME prediction: data, models, facts and myths.
A critical review of a very recent work in the field of in silico ADME prediction is presented with emphasis on the work published during the period 2000-2002, and several other review articles are mentioned in order to offer a broader view of the field. We find that not much progress has been made in developing robust and predictive models, and that the lack of accurate data, together with the use of questionable modeling end-points, has greatly hindered the real progress in defining generally applicable models. Due to the largely empirical nature of QSAR/QSPR approaches, general and truly predictive models for complex phenomena, such as absorption and clearance, may still be chimeric. The development of local models for use within focused chemical series may be the most appropriate way of utilizing in silico ADME predictions, once experience and data have been gained on a given project and/or structural class.


Determination of urinary trans,trans-muconic acid using molecularly imprinted polymer in microextraction by packed sorbent followed by liquid chromatography with ultraviolet detection.
trans,trans-Muconic acid (tt-MA) has been introduced as biological exposure index for workers exposed to benzene. In the present study, for the first time, a novel and easy-to-use analytical method based on molecularly imprinted polymer (MIP) in microextraction by packed sorbent (MEPS), followed by high-performance liquid chromatography with ultra-violet detection (MIMEPS-HPLC-UV) was developed to determine tt-MA in urine samples. Fourier transform infrared spectroscopy was used for MIP characterization. The imprinting effect on the MIP was also evaluated. Furthermore, various parameters that affect the MEPS performance were investigated, including extraction cycles, sample volume, as well as the type and volume of washing and elution solvents. The optimised procedure was selective, sensitive, rapid and both user- and environmentally-friendly. A seven-point calibration curve was obtained in the range of 0.015-2μg/mL (R2=0.9986). The extraction recovery was >89.8%. The limit of detection and limit of quantitation for tt-MA were 0.015 and 0.05μg/mL, respectively. The within- and between-day precisions, given as percent relative standard deviation, were in the range of 3.4-4.7% and 3.5-6.6%, respectively. Accuracy was -8.4 to -10.2% in urine samples. The developed method is suggested as an alternative to existing conventional SPE methods for biomonitoring of benzene-exposed subjects.


[Surgical therapeutic possibilities of the elbow in chronic polyarthritis].
The natural history of rheumatoid arthritis of the elbow often includes impairment of the function of the upper extremity in advanced stages of the disease. Synovectomy performed by a large radial incision is considered a worthwhile procedure for stages 1-3 according to the classification of Larsen et al. Radiosynoviorthesis is possible in stages 0 and 1. In the authors' opinion, resection- and interposition arthroplasty remains the procedure of choice for advanced stages 4 and 5. For elbows with severe instability alloarthroplasty may be considered. The radial head should generally not be resected. Entrapment neuropathy of the ulnar and the posterior interosseus nerves is possible in rheumatoid arthritis patients. The surgical treatment consists in decompression, if necessary with transposition and synovectomy of the elbow joint.


Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness.
A PRoliferation-Inducing TNF Ligand (APRIL) costimulates B-cell activation. When overexpressed in mice, APRIL induces B-cell neoplasia, reminiscent of human B-cell chronic lymphoid leukemia (B-CLL). We analyzed APRIL expression in situ in human non-Hodgkin lymphomas. APRIL up-regulation was only observed in high-grade B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL). Up-regulation was seen in 46% and 20% of DLBCL and BL, respectively. In DLBCL, neutrophils, constitutively producing APRIL and infiltrating the tumor tissue, were the main cellular source of APRIL. Rare DLBCL cases showed a predominance of histiocytes or mesenchymal cells as APRIL source. APRIL secreted by neutrophils accumulated on tumor cells via proteoglycan binding. In addition to proteoglycans, DLBCL tumor cells expressed the APRIL signaling receptor, TACI and/or BCMA, indicating that these tumor cells are fully equipped to respond to APRIL. A retrospective clinical analysis revealed a significant correlation between high expression of APRIL in tumor lesions and decreased overall patient survival rate. Hence, APRIL produced by inflammatory cells infiltrating lymphoma lesions may increase tumor aggressiveness and affect disease outcome.


Homogenization models for thin rigid structured surfaces and films.
A homogenization method for thin microstructured surfaces and films is presented. In both cases, sound hard materials are considered, associated with Neumann boundary conditions and the wave equation in the time domain is examined. For a structured surface, a boundary condition is obtained on an equivalent flat wall, which links the acoustic velocity to its normal and tangential derivatives (of the Myers type). For a structured film, jump conditions are obtained for the acoustic pressure and the normal velocity across an equivalent interface (of the Ventcels type). This interface homogenization is based on a matched asymptotic expansion technique, and differs slightly from the classical homogenization, which is known to fail for small structuration thicknesses. In order to get insight into what causes this failure, a two-step homogenization is proposed, mixing classical homogenization and matched asymptotic expansion. Results of the two homogenizations are analyzed in light of the associated elementary problems, which correspond to problems of fluid mechanics, namely, potential flows around rigid obstacles.


Poly(N-(4-aminobutyl)-acrylamide) as mimetic polylysine for improving survival and differentiation of cerebellar granule neurons.
Poly(N-(4-aminobutyl)-acrylamide) (P4Am) and poly-d-lysine (PDL) possess the same butylamine side chain. The main difference is the peptide structure, which is in the main chain of PDL but in the side chain of P4Am. PDL has been extensively used in the preparation of neuronal cultures. We assumed neurons are sensitive enough to distinguish such structure difference so these two cationic polymers were compared at serial coating concentrations for culturing cerebellar granule neurons from 7-day-old Wistar rats in this study. Cellular viability and morphology assay showed no obvious difference for neurons cultured at high coating concentrations (>0.31 µg/mL) of these two polymers. In contrast, the difference in the peptide structure between P4Am and PDL could be distinguished by neurons at low coating concentrations (< 0.16 µg/mL). P4Am at low coating concentration could keep aggregates with three or four thick processes to support a more complete neural network with higher cellular viability than PDL. This suggests the interaction between neurons and the specific peptide structure of P4Am at low coating concentration was able to improve survival and differentiation of cultured cerebellar granule neurons. Although neural cells exhibited different morphologies and activities on high and low P4Am coating concentrations, immunofluorescence imaging confirmed most of cultured cells were functionally mature neurons, stained by neurofilament, synapsin I, and GAP43. The information should be useful for designing new biomaterials for regeneration of damaged circuits following disease or trauma. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1194-1201, 2018.


Enhanced bovine herpesvirus type 1 neutralization by multimerized single-chain variable antibody fragments regardless of differential glycosylation.
Single-chain variable antibody fragments (scFvs) with a 2-amino-acid linker capable of multimerization as di-, tri-, or tetrabodies that neutralize bovine herpesvirus type 1 (BoHV-1) in vitro were constructed and expressed in Pichia pastoris. In contrast to the monomeric form, multimeric scFvs had a higher virus neutralization potency, as evidenced by a 2-fold increase in their ability to neutralize BoHV-1 due to avidity effects. Mass spectrum (quadrupole time of flight [Q-TOF]) analyses of multimeric scFv demonstrated extensive heterogeneity due to differential cleavage, variable glycosylation (1 to 9 mannose residues), and the incorporation of minor unidentified adducts. Regardless of the differential glycosylation patterns, the scFvs recognized non-gB or -gE target viral epitopes in the BoHV-1 envelope fraction in a Western blot and also neutralized BoHV-1 in infected Madin-Darby kidney (MDBK) cells in vitro. Indirect evidence for the noncovalent multimerization of scFv was the presence of a major peak of multimerized scFv without a His tag (due to differential cleavage) in the Q-TOF profile, unlike monomeric scFv, which copurified with normally His-tagged scFv and recognized the target antigen. Overall, differentially glycosylated recombinant scFvs against BoHV-1 with a short linker (2 amino acids) are capable of assembly into functional multimers that confer high avidity, resulting in increased virus neutralization in vitro compared to that of monovalent scFv with a long (18-amino-acid) flexible linker. Overall, recombinant multimerized scFv5-2L potentially provides a high-potency therapeutic and immunodiagnostic reagent against BoHV-1, which is suitable for passive immunization and topical application.


Detoxification of cyanide by plants and hormone action.
In higher plants cyanide is a co-product of ethylene synthesis. The increase in ethylene production that occurs during the senescence of certain flowers and the ripening of climacteric fruit is accompanied by a rise in beta-cyanoalanine synthase activity. Although these events correlate temporally and spatially, the potential for cyanide detoxification in these tissues is high compared with the expected rate of cyanide formation from the ethylene pathway. However, in stigmas and styles of Petunia flowers a semi-quantitative relationship exists between the activity of beta-cyanoalanine synthase and the activity of ACC (1-aminocyclopropane-1-carboxylic acid) oxidase, the last enzyme in the ethylene pathway. To account for these observations it is proposed that ACC oxidase can react with other amino acids by a general mechanism that liberates cyanide. This hypothesis could also account for the substrate stereospecificity of ACC oxidase, for the extreme lability of this enzyme and for the high accumulation of asparagine in some tissues.


The pilosebaceous unit is part of the skin immune system.
It is well established that the functional state of sebaceous glands in vivo is a tightly regulated process orchestrated through the interaction of male sex hormones and functional androgen receptors expressed on sebocytes. In the last few years, however, it has become increasingly apparent that sebocytes like epidermal keratinocytes express a variety of cytokines which are implicated in inflammatory and immune responses. For example, sebocytes in vivo have been found to highly express tumor necrosis factor alpha (TNF-alpha) as determined by immunohistochemical and electron-microscopic methods. Moreover, certain neuropeptides including vascular intestinal peptide and proopiomelanocortin (POMC) peptides as well as their receptors have been localized within the pilosebaceous unit of murine and human skin. Since POMC peptides such as alpha-melanocyte-stimulating hormone have recently been shown to exert important immunoregulatory effects by antagonizing the function of proinflammatory cytokines (e.g interleukin 1, interleukin 6 and TNF-alpha), induction of immunosuppressive cytokines (like interleukin 10), modulation of costimulatory molecule expression (e.g. B7-2) or suppression of macrophage-derived nitric oxide, complex interactions between these mediators and their target cells within the pilosebaceous gland seem to exist. The successful cultivation of sebocytes will provide a model by which the effect of these mediators can be studied in detail in order to shed light onto the various pathophysiological conditions of sebaceous glands.


Mechanical identification of layer-specific properties of mouse carotid arteries using 3D-DIC and a hyperelastic anisotropic constitutive model.
The role of mechanics is known to be of primary order in many arterial diseases; however, determining mechanical properties of arteries remains a challenge. This paper discusses the identifiability of the passive mechanical properties of a mouse carotid artery, taking into account the orientation of collagen fibres in the medial and adventitial layers. On the basis of 3D digital image correlation measurements of the surface strain during an inflation/extension test, an inverse identification method is set up. It involves a 3D finite element mechanical model of the mechanical test and an optimisation algorithm. A two-layer constitutive model derived from the Holzapfel model is used, with five and then seven parameters. The five-parameter model is successfully identified providing layer-specific fibre angles. The seven-parameter model is over parameterised, yet it is shown that additional data from a simple tension test make the identification of refined layer-specific data reliable.


Retinal and choroidal neovascularization in sickle cell disease.
Small vessel obstruction characterizes sickle cell disease and, when occurring in the peripheral retinal vessels, initiates a sequence of vascular events which may culminate in the development of proliferative sickle retinopathy (PSR). Repeated examinations of the retinal vasculature of patients with different genotypes of sickle cell disease over the last 10 years (Condon and Serjeant, 1972a, b, c; 1975; 1980a) have allowed observations on the natural history of PSR and on factors related to its development. Choroidal neovascularization has been a common complication of a trial of xenon arc photo-coagulation in PSR. Observations on the aetiology and natural history of both retinal and choroidal neovascularization are presented in this report.


Checkoffs play key role in SICU improvement.
Unit sees 25% drop in mortality following implementation of new form. Checklist not a to-do list, but enumeration of clinical, safety goals. All members of the multidisciplinary team are involved in process.


Urinary proteomics analysis based on mass spectrometry and identification of therapeutic targets of Shenkangling interventions in rats with adriamycin nephropathy using iTRAQ.
The isobaric tags for relative and absolute quantification (iTRAQ) technique for proteomic analysis was employed to identify diagnostic markers and therapeutic targets of Shenkangling intervention or prednisone tablets in rats with adriamycin nephropathy (AN). Fifty healthy, clean-grade Sprague-Dawley rats were selected, with 10 rats in the normal group and the remaining 40 rats receiving a tail vein injection of 5.5 mg/kg of adriamycin (ADR) to induce AN. Treatment began 1 week later. The normal group received gastric administration of normal saline. Forty rats with induced AN were further randomly divided into the AN modeling group (n = 10), AN modeling + prednisone treatment group (n = 10), AN modeling + Shenkangling intervention group (n = 10), and AN modeling + prednisone + Shenkangling intervention group (n = 10). iTRAQ was employed in combination with mass spectrometry to analyze the differentially expressed proteins in the urine after 3 weeks of treatment (in the fourth week of the experiment). Compared with normal rats, AN rats had 6 down-regulated proteins and 1 upregulated protein. Compared with AN rats, prednisone rats had 2 down-regulated and 6 upregulated proteins. Compared with AN rats, combined treatment rats had 2 down-regulated and 8 upregulated proteins. Compared with the AN model group, the Shenkangling treatment group had 3 down-regulated and 9 upregulated proteins. Gro, Afamin, Cystatin-related protein 2, Afamin, and isoform CRA_a were considered diagnostic markers of primary nephrotic syndrome (PNS). Telomerase was considered the therapeutic target of prednisone. Urinary protein 2, Apolipoprotein A-II, 45 kDa calcium-binding protein, Vitronectin, and Osteopontin were the therapeutic targets of the Shenkangling intervention. Afamin, isoform CRA_a, Apolipoprotein A-IV, Coagulation factor XII, Prolactin-induced protein, and Coagulation factor XII were the therapeutic targets of the Shenkangling intervention combined with prednisone. The feasibility of urinary proteomics analysis in rats using a large number of proteins with finite molecular weights is controversial. The markers screened in this study may be of clinical value for the diagnosis and treatment of nephropathy. However, these findings should be confirmed in future cohort studies.


Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro.
The synthetic pentasaccharide, fondaparinux, is the first of a new antithrombotic class: selective factor Xa inhibitors. Comparative clinical trials of fondaparinux versus heparins in prevention and treatment of venous thromboembolism are ongoing. Little is known about fondaparinux during pregnancy, as women of child-bearing potential were excluded from clinical trials. No particular safety issue, for either mother or fetus, has been reported for heparins. The objective of this study was to compare in vitro the steady state placental transfer of fondaparinux and enoxaparin at the plasma concentrations reached during acute treatment of venous thromboembolism (1.75 microg/mL and 1 anti-Xa IU/mL respectively), using antipyrine (20 mg/L) as reference. No biological activity was detectable in the fetal venous effluent during perfusion of enoxaparin-antipyrine, fondaparinux-antipyrine or control media. Furthermore, fetal venous samples did not differ significantly from fetal arterial samples. This apparent absence of placental transfer supports further evaluation of fondaparinux in pregnant women.


miRNA-34a decreases ovarian cancer cell proliferation and chemoresistance by targeting HDAC1.
This study aimed to explore the roles of miRNA-34a (miR-34a) in ovarian cancer (OC) cells and uncover possible mechanisms. The proliferation of OC cells was measured with an MTT assay and soft agar colony formation assay. TargetScan analysis, real-time PCR, and a luciferase reporter assay were used to demonstrate the downstream target of miR-34a in OC cells. HDAC1 expression levels were detected by immunoblot analysis. miR-34a inhibited the proliferation of SKOV3 and OVCA433 cells and enhanced cisplatin sensitivity in cisplatin-resistant SKOV3cp cells. The results of TargetScan analysis, real-time PCR, and luciferase reporter assay confirmed that miR-34a downregulated HDAC1 expression by directly targeting the 3'-UTR of HDAC1 mRNA. The overexpression of HDAC1 decreased cisplatin sensitivity and promoted proliferation in OC cells. MTT assay and soft agar colony formation assay showed that HDAC1 overexpression blocked the suppressive effects of miR-34a on SKOV3 cell proliferation. In addition, treatment with the miR-34a mimic partially recovered the cisplatin sensitivity of SKOV3cp cells, whereas HDAC1 overexpression blocked the above phenomena caused by treatment with the miR-34a mimic. miR-34a exhibited suppressive effects on OC cells via directly binding and downregulating HDAC1 expression, which subsequently decreased the resistance to cisplatin and suppressed proliferation in OC cells.


Synthetic array processing of ocean ambient noise for higher resolution seabed bottom loss estimation.
Predicting transmission loss in the ocean often strongly depends on the bottom loss. Bottom loss can be estimated using ocean noise and vertical array beam-forming [Harrison and Simons, J. Acoust. Soc. Am. 112, 1377-1389 (2002)]. With finite length arrays, the bottom loss estimate using this method can be smoothed due to beam widths. This paper describes how the noise coherence function can be synthetically expanded, which is similar to extending the length of an array. A full wave ocean noise model is used to demonstrate, in simulation, how this leads to improvements in the resolution of bottom loss estimates.


[Experimental and clinical studies of flomoxef in the field of obstetrics and gynecology. Representative Committee Members of the Research Team for Infections in the Field of Obstetrics and Gynecology].
Flomoxef (FMOX) has a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria; especially its potent antibacterial activity against Staphylococcus aureus is a significant advantage that may not be found with other cephem compounds. In our determination of its antibacterial potency against various clinical isolates obtained from clinical materials (amniotic fluid, intrauterine secretions, exudates of the pelvic dead space) of patients with various infections, we obtained results representing specific features of this drug. From the results, the drug may be expected to produce an excellent effect in the treatment of various infections. Our study on drug concentrations in body fluids and genital tissues demonstrated a good transfer of this drug into various tissues; in every tissue examined, the drug administered by the usual method in the usual dose yielded a concentration exceeding MIC for principal pathogens, thus promising a good clinical response. Indeed a high clinical efficacy rate of 90.1% (good to very good responses) was obtained in a clinical trial involving 222 cases. Administration of the drug in 2 g quantity daily produced a high response rate of 92.8%. It was especially noteworthy that a good response was obtained in 30 of 32 cases (93.8%) in which other cephem compounds had failed. In evaluation of the bacteriological effect, furthermore, the drug showed an excellent rate of bacterial elimination. In conclusion, this drug is expected to be greatly useful in the light of its good transfer into genital tissues and its strong antibacterial activities against Gram-positive cocci, Gram-negative bacteria and anaerobes as well as against multiple bacterial infections predominating among women with genital infections.