Fabrication and physical and biological properties of fibrin gel derived from human plasma.
The fast development of tissue engineering and regenerative medicine drives the old biomaterials, for example, fibrin glue, to find new applications in these areas. Aiming at developing a commercially available hydrogel for cell entrapment and delivery, in this study we optimized the fabrication and gelation conditions of fibrin gel. Fibrinogen was isolated from human plasma by a freeze-thaw circle. Gelation of the fibrinogen was accomplished by mixing with thrombin. Absorbance of the fibrinogen/thrombin mixture at 550 nm as a function of reaction time was monitored by UV-VIS spectroscopy. It was found that the clotting time is significantly influenced by the thrombin concentration and the temperature, while less influenced by the fibrinogen concentration. After freeze-drying, the fibrin gel was characterized by scanning electron microscopy (SEM), revealing fibrous microstructure. Thermal gravimetric analysis found that the degradation temperature of the crosslinked fibrin gel starts from 288 degrees C, which is about 30 degrees C higher than that of the fibrinogen. The hydrogel has an initial water-uptake ratio of approximately 50, decreased to 30-40 after incubation in water for 11 h depending on the thrombin concentration. The fibrin gels lost their weights in PBS very rapidly, while slowly in DMEM/fetal bovine serum and DMEM. In vitro cell culture found that human fibroblasts could normally proliferate in the fibrin gel with spreading morphology. In conclusion, the fibrin gel containing higher concentration of fibrinogen (20 mg ml(-1)) and thrombin (5 U ml(-1)) has suitable gelation time and handling properties, and thus is applicable as a delivery vehicle for cells such as fibroblasts.


Theta rhythms: state of consciousness.
The role of midline frontal theta in human is discussed, with reference to its relation on consciousness. Clinical observations of the appearance of this theta activity under various conditions are reviewed. These include simulated diving, brain tumour, chemical intoxication, exercise, mental calculation, sleep and medication. The mechanism of generation of this frontal midline theta activity is discussed.


Effect of tranexamic acid administration on intraoperative blood loss during peritonectomy: a single-center retrospective observational study.
The efficacy of tranexamic acid in elective major invasive abdominal surgeries has not yet been established. We investigated the effect of tranexamic acid administration on intraoperative blood loss during peritoneal resection of pseudomucinoma and cancerous peritoneal dissemination. Patients aged ≥ 20 years old who underwent peritoneal resection for pseudomucinoma or cancerous peritoneal dissemination at the Kishiwada Tokushukai Hospital were included in this single-center retrospective observational study. The tranexamic acid group received 1000 mg of tranexamic acid at the start of the operation, while the control group received the same intraoperative management as the tranexamic acid group, except for the tranexamic acid administration. The primary endpoint was intraoperative blood loss, and a multivariate analysis of the contributing factors was performed. The median volume of intraoperative blood loss was 1372 [interquartile range, 842 - 1877] mL and 907 [516 - 1537] mL in the control and tranexamic acid groups, respectively (p < 0.01). The total volume of blood transfusion during the operation was 2040 [1480 - 2380] mL and 1560 [1000 - 2120] mL in the control and tranexamic acid groups, respectively (p = 0.02). Postoperative blood test results revealed D-dimer values of 7.5 [4.1 - 10.7] µg/mL and 1.8 [1.0 - 3.3] µg/mL in the control and tranexamic acid groups, respectively (p < 0.01). Multivariate analysis showed that tranexamic acid administration was significantly associated with decreased intraoperative blood loss (p = 0.02). Tranexamic acid administration may be useful in reducing intraoperative blood loss and blood transfusion volume during highly-invasive surgeries such as peritoneal resection of pseudomucinoma and cancerous peritoneal dissemination.


The mitochondrial Ca 2+ channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation.
The mitochondrial uniporter (MCU) Ca 2+ ion channel represents the primary means for Ca 2+ uptake into mitochondria. Here we employed in vitro and in vivo models with MCU genetically eliminated to understand how MCU contributes to tumor formation and progression. Transformation of primary fibroblasts in vitro was associated with increased MCU expression, enhanced mitochondrial Ca 2+ uptake, suppression of inactivating-phosphorylation of pyruvate dehydrogenase, a modest increase of basal mitochondrial respiration and a significant increase of acute Ca 2+ -dependent stimulation of mitochondrial respiration. Inhibition of mitochondrial Ca 2+ uptake by genetic deletion of MCU markedly inhibited growth of HEK293T cells and of transformed fibroblasts in mouse xenograft models. Reduced tumor growth was primarily a result of substantially reduced proliferation and fewer mitotic cells in vivo , and slower cell proliferation in vitro associated with delayed progression through S-phase of the cell cycle. MCU deletion inhibited cancer stem cell-like spheroid formation and cell invasion in vitro , both predictors of metastatic potential. Surprisingly, mitochondrial matrix Ca 2+ concentration, membrane potential, global dehydrogenase activity, respiration and ROS production were unchanged by genetic deletion of MCU in transformed cells. In contrast, MCU deletion elevated glycolysis and glutaminolysis, strongly sensitized cell proliferation to glucose and glutamine limitation, and altered agonist-induced cytoplasmic Ca 2+ signals. Our results reveal a dependence of tumorigenesis on MCU, mediated by a reliance on mitochondrial Ca 2+ uptake for cell metabolism and Ca 2+ dynamics necessary for cell-cycle progression and cell proliferation.


EELS performance measurements on a new high energy resolution imaging filter.
In this paper we characterize the spectroscopy performance of a new high resolution electron energy-loss spectrometer for transmission electron microscopy, recently installed in our lab. With the event of commercially available monochromated transmission electron microscopes, equipped with improved spectrometers, experiments became feasible that allow the study of chemical bonding and electronic structures of atoms and solids at the nanometer level with an energy resolution in the range of 0.2-0.3 eV. This significant enhancement in resolution, however, can only be fully harnessed with an optimized microscope and spectrometer setup and in a suitable local environment. We attempt to quantify some of the limiting factors on our system with emphasis on spectrum mixing, spectrometer aberrations and transmissivity and we sketch proper working conditions in order to achieve the desired performance.


Review: amino acid domains involved in constitutive activation of G-protein-coupled receptors.
Guanine nucleotide-binding protein-coupled receptors may attain an active conformation in the absence of agonist by spontaneous isomerization and thus yield constitutive, agonist-independent, activity. This has mainly been demonstrated for isolated membranes and recombinant wild-type receptors, and mutant receptors. They generally show remarkable increases in the sensitivity of a biological response. The location of activating mutations both within a single receptor and across receptors is widespread, with changes reported in the seven-transmembrane domains, the second and third intracellular loop. For most of these receptors, examples of ligands defined as inverse agonists have been documented. Regulation of these receptors by inverse agonists opposite to that observed by agonists, and the therapeutic potential of inverse agonists is underlined.


Protective effect of hesperidin on oxidative and histological liver damage following carbon tetrachloride administration in Wistar rats.
In the current study, the protective effect of hesperidin (HP) on carbon tetrachloride (CCl4)-induced hepatotoxicity in rats was investigated. Twenty-eight rats were divided equally into four groups. The first group was kept as a control and given only vehicle. In the second, rats were orally administered 50 mg/kg/day HP for 10 days. Carbon tetrachloride was given in a single intraperitoneal injection at the dose of 2 ml/kg in the third group. In the fourth group, the rats were treated with equal doses of CCl4 and HP. It was found that CCl4 induced oxidative stress via a significant increase in the formation of thiobarbituric acid-reactive substances (TBARS) and caused a significant decline in the levels of glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) in rats. In contrast, HP blocked these toxic effects induced by CCl4, causing an increase in GSH, CAT and SOD levels and decreased formation of TBARS (p < 0.01). In addition, histopathological damage increased with CCl4 treatment. In contrast, HP treatment eliminated the effects of CCl4 and stimulated anti-apoptotic events, as characterized by reduced caspase-3 activation. The current study demonstrated that CCl4-induced hepatotoxicity can be prevented with HP treatment. Thus, co-administration of HP with CCl4 may be useful for attenuating the negative effects of CCl4 on the liver.


Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation.
Carbon monoxide (CO), a product of heme degradation by heme oxygenase, induces cytoprotection against ischemia/reperfusion (I/R) injury in a variety of organs such as the heart, lung, kidney, and small intestine. We examined whether CO would protect liver grafts against cold I/R injury associated with transplantation. Orthotopic liver transplantation (OLT) was performed in syngeneic Lewis rats with 18 hours preservation in cold University of Wisconsin solution. Recipients were exposed to air or CO (100 ppm) for 1 hour before and 24 hours after OLT. Recipients were sacrificed 0.5 to 48 hours post-transplant. CO inhalation significantly decreased serum aspartate aminotransferase and alanine aminotransferase levels and suppressed hepatic necrosis formation and neutrophil accumulation at 6 to 48 hours after OLT, compared with air control. The expressions of tumor necrosis factor alpha, intercellular adhesion molecule 1, and inducible nitric oxide synthase messenger RNA in the liver graft were significantly inhibited in the CO-treated group at 1 hour after reperfusion. Hepatic nuclear factor-kappaB activation did not differ between the groups. The results demonstrate that exogenous CO treatment suppresses early proinflammatory gene expression and neutrophil infiltration, and efficiently ameliorates hepatic I/R injury. The possible mechanism by which CO protects the liver against cold I/R does not seem to be associated with downregulation of the nuclear factor-kappaB-signaling pathway.


A comparative study for hybrid UASB reactor performance using polyethylene media and luffa sponge as biofilm support.
This paper study the performance of a lab-scale hybrid up-flow anaerobic sludge blanket (UASB) reactor treating low-strength synthetic wastewater using different biofilm supporting materials. Two identical reactors are constructed and operated at constant up-flow velocity of 0.1 m/hr., inflow rate of 9.76 L/d, and hydraulic retention time (HRT) of 8.26 hours. The Start-up phase, using seed sludge for existing wastewater treatment plant, lasted until the efficiency of chemical oxygen demand (COD) removal of both reactors reached 80%. Polyethylene (PE) media are added to one of the reactors and luffa sponge is used in the second reactor. Results show increased COD removal efficiency up to about 90% at 20 °C and biogas production rates from 3.8*10-3 till 7.5*10-3 m3 CH4/kg CODr using PE media. The COD removal efficiency reaches about 95% at 20 °C using luffa sponge and biogas production rates up to 6.5*10 -3 m3 CH4/kg CODr are achieved before clogging problem is observed. Effect of HRT reduction, from 8.26 to 4.13 hours, on removing clogging is investigated. Reduction in COD removal efficiencies is observed at low ambient temperatures during seasonal variations of 15-25 °C. AFM and SEM analysis are used to examine sludge granulation and biofilm formation.


Prevention of early-onset pneumonia in surgical patients by chemoprophylaxis.
The purpose of this study was to explore the impact of surgical antimicrobial chemoprophylaxis on the prevention of early-onset postsurgical pneumonia (EOPP) using a logistic regression model that included the principal risk or confusion factors associated with incidence of early-onset postsurgical pneumonia. The sample chosen corresponded to 13 years during which the epidemiological surveillance system was in place in the general and digestive surgery department (N = 13,024 patients) and was designed as a prospective cohort study. Risk factors associated with EOPP development were analyzed using a cohort-nested case-control study. Cumulative incidence of EOPP in this series of patients was .6%, accounting for 24.7% of total nosocomial pneumonias. The multivariate model showed the following risks or confusion factors for EOPP: age, emergency admission, type of surgery, duration of surgical intervention, infection on admission, and antimicrobial chemoprophylaxis (administered, odds ratio = .18; 95% confidence interval, .09-.33). Surgical antimicrobial chemoprophylaxis was associated as an independent factor with incidence reduction of early-onset postsurgical pneumonia, and, aside from its known effect on surgical site infection, its administration, where indicated, is useful for the prevention of early-onset postsurgical pneumonia.


Systemic meloxicam reduces tactile allodynia development after L5 single spinal nerve injury in rats.
Although recent evidence suggests that cyclooxygenase-2 (COX-2) may contribute to the development and management of neuropathic pain, the efficacy of COX-2 inhibitor against neuropathic pain is still unclear. In this study, we investigated the effects of the systemic administration of the selective COX-2 inhibitor meloxicam at an early stage after nerve injury on the development of tactile allodynia in L5 single spinal-nerve injury in rats. Twenty-four young male Sprague-Dawley rats received L5 single spinal-nerve injury. Nerve-injured rats (6 per group) received repeated intraperitoneal administrations of meloxicam (1, 2, or 4 mg/kg) or vehicle 0, 12, 24, and 36 hours after nerve injury. Tactile allodynia was quantified for 4 weeks by use of von Frey filaments. In animals given 2 mg/kg and 4 mg/kg, hind-paw withdrawal thresholds 4 weeks after nerve injury were significantly higher compared with those of the vehicle-treated animals. The area under the time-effect curve from preinjury to 4 weeks after nerve injury values were significantly higher in animals treated with 4 mg/kg of meloxicam compared with animals treated with vehicle. Systemic administration of 2 mg/kg and 4 mg/kg of meloxicam at an early stage after nerve injury attenuated the development of tactile allodynia. These results suggest that COX-2 may be at least in part involved in the development of tactile allodynia in an L5 single spinal-nerve injury model.


Reduced lipoxygenase and cyclooxygenase mediated signaling in PBMC of atopic dermatitis patients.
Lipoxygenases (LOX) and cyclooxygenases (COX) are the main enzymes for poly-unsaturated fatty acid (PUFA) metabolism to highly bioactive prostaglandins, leukotrienes, thromboxanes and protectins. LOX and COX pathways are highly important for the regulation of pro- and anti-inflammatory active metabolite synthesis and metabolism in various inflammatory diseases like atopic diseases (AD). In this study using QRT-PCR, we found that in PBMCs the expression of 5-LOX, 12-LOX, 15-LOX and COX pathways and further enzymatic pathways like various leukotriene-hydoxylases, leukotriene-, prostaglandin-, and thromboxane-synthases as well as various of their membrane based receptors are mainly significantly down-regulated in AD-patients vs. healthy volunteers. In addition, using HPLC MS-MS we determined up to 19 different metabolites originating from eicosapentaenoic acid (EPA), docosapentaenoic acid (DHA) and arachidonic acid (AA) ranging from hydroxylated-PUFA derivatives and further bioactive derivatives like thromboxanes, leukotrienes, prostaglandins and protectins originating from LOX and COX metabolism. In PBMCs from AD-patients LOX and COX pathways were down-regulated. We conclude from this study, that in PBMCs from AD-patients in comparison to healthy volunteers, a systemic down-regulation of LOX- and COX-responses occurs to generally reduce eicosanoid/docosanoid synthesis during the current allergic inflammatory status.


Effects of ring contraction on the conformational preferences of α-substituted proline analogs.
The structural consequences derived from the incorporation of either a methyl or a phenyl group at the α carbon of proline were recently investigated by quantum mechanical calculations (J Org Chem 2008, 73, 3418). In this work, the effect produced by contraction of the pyrrolidine ring on such α-substituted proline analogs has been explored using the same computational methods. Specifically, the intrinsic conformational preferences of the N-acetyl-N'-methylamide derivatives of the lower proline homolog L-azetidine-2-carboxylic acid (Aze), characterized by a four- instead of a five-membered ring, and its α-methyl (αMeAze) and α-phenyl (αPhAze) derivatives have been determined using quantum mechanical calculations and compared to those observed before for the proline counterparts. Replacement of the pyrrolidine ring by an azetidine cycle leads to a reduction of the conformational flexibility, especially for the Aze and αMeAze derivatives, which should be attributed to the quasi-planar geometry of the four-membered ring. Furthermore, the azetidine nitrogen shows pyramidalization, which depending on the peptide backbone conformation favors the formation of an attractive N-H···N interaction or alleviates a severe steric hindrance. Calculations on different environments predict that the tendency of αMeAze to adopt γ-turns is higher than that of unsubstituted Aze and α-methylproline, this feature being in full agreement with the experimental observations available.


Development of an implementation plan for the 6-PACK falls prevention programme as part of a randomised controlled trial: protocol for a series of preimplementation studies.
Inhospital falls cause morbidity, staff burden and increased healthcare costs. It is unclear if the persistent problem of inhospital falls is due to the use of ineffective interventions or their suboptimal implementation. The 6-PACK programme appears to reduce fall injuries and a randomised controlled trial (RCT) was undertaken to confirm effects. This paper describes the protocol for the preimplementation studies that aimed to identify moderators of the effective use of the 6-PACK programme to inform the development of an implementation plan to be applied in the RCT. The 6-PACK project included five preimplementation studies: (1) a profile of safety climate; (2) review of current falls prevention practice; (3) epidemiology of inhospital falls; (4) acceptability of the 6-PACK programme; and (5) barriers and enablers to implementation of the 6-PACK programme. The Theoretical Domain Framework that includes 12 behaviour change domains informed the design of these studies that involved 540 staff and 8877 patients from 24 wards from six Australian hospitals. Qualitative and quantitative methods were applied with data collected via: structured bedside observation; daily nurse unit manager verbal report of falls; audit of medical records, incident reporting and hospital administrative data; surveys of ward nurses; focus groups with ward nurses; and key informant interviews with senior staff. Information on contextual, system, intervention, patient and provider level factors is critical to the development of an implementation plan. Information gained from these studies was used to develop a plan applied in the RCT that addressed the barriers and harnessed enablers. The RCT is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000332921.


Genome Sequencing and Characterization of an Avian Orthoavulavirus 1 VG/GA-like Isolate with a Unique Fusion Cleavage Site Motif.
A complete genome sequence of a VG/GA -like strain of avian orthoavulavirus 1 (AOAV-1) was identified by nontargeted next-generation sequencing of an oropharyngeal swab sample collected from a carcass of a 12-mo-old backyard chicken. The isolate has a fusion (F) protein cleavage site motif consistent with a low virulent AOAV-1, but it has a unique motif with phenylalanine at position 117 (112G-R-Q-G-R↓F117), which is typical for virulent AOAV-1 strains. The one nucleotide difference at the cleavage site compared to other low-virulence viruses made the isolate detectable by F-gene-specific real-time reverse transcription-PCR (rRT-PCR) developed as a diagnostic test to specifically detect virulent strains. The mean death time determined in eggs and intracerebral pathogenicity index determined in chickens classified the isolate as lentogenic. This is the first report of a lentogenic VG/GA-like virus with a phenylalanine residue at position 117 of the F protein cleavage site in the United States. In addition to concern for potential pathogenic shift of the virus through additional changes at the cleavage site, our finding warrants increased awareness of diagnosticians of potential false positive F-gene rRT-PCR tests.


Disruption of the mitotic kinesin Eg5 gene (Knsl1) results in early embryonic lethality.
Eg5, a member of the widely conserved kinesin-5 family, is a plus-end-directed motor involved in separation of centrosomes, and in bipolar spindle formation and maintenance during mitosis in vertebrates. To investigate the requirement for Eg5 in mammalian development, we have generated Eg5 deficient mice by gene targeting. Heterozygous mice are healthy, fertile, and show no detectable phenotype, whereas Eg5(-/-) embryos die during early embryogenesis, prior to the implantation stage. This result shows that Eg5 is essential during early mouse development and cannot be compensated by another molecular motor.


Activated status of basophils in chronic urticaria leads to interleukin-3 hyper-responsiveness and enhancement of histamine release induced by anti-IgE stimulus.
Basophils and mast cells are the main target cells in chronic idiopathic urticaria (CIU). Besides the basopenia, intrinsic defects of the anti-IgE cross-linking signalling pathway of basophils have been described in CIU. We sought to investigate the profile of expression of activation markers on basophils of patients with CIU and to explore the effect of interleukin (IL)-3 priming upon anti-IgE cross-linking stimuli through expression of activation markers and basophil histamine releasability. Evaluation of the surface expression of FcepsilonRIalpha, CD63, CD203c and CD123 on whole blood basophils of patients with CIU undergoing autologous serum skin test (ASST) was performed by flow cytometry. The effect of pretreatment with IL-3 in the anti-IgE response was analysed by the expression of basophil activation markers and histamine release using enzyme-linked immunosorbent assay. Blood basophils of patients with CIU were reduced in number and displayed increased surface expression of FcepsilonRIalpha, which was positively correlated with the IgE serum levels. Upregulation of expression of both surface markers CD203c and CD63 was verified on basophils of patients with CIU, regardless of ASST response. High expression of IL-3 receptor on basophils was detected only in ASST+ patients with CIU. Pretreatment with IL-3 upregulated CD203c expression concomitantly with the excreting function of blood basophils and induced a quick hyper-responsiveness to anti-IgE cross-linking on basophils of patients with CIU compared with healthy controls. Basophils of patients with CIU showed an activated profile, possibly due to an in vivo priming. Functionally, basophils have high responsiveness to IL-3 stimulation, thereby suggesting that defects in the signal transduction pathway after IgE cross-linking stimuli are recoverable in subjects with chronic urticaria.


Marijuana use by middle-aged and older adults in the United States, 2015-2016.
Marijuana use is increasing among middle-aged and older adults in the US, but little is understood of its pattern of use by this population. We performed a cross-sectional analysis of responses from 17,608 adults aged ≥50 years from the 2015 and 2016 administrations of the National Survey on Drug Use and Health. Prevalence of past-year marijuana use was estimated and compared between middle-aged adults (age 50-64) and older adults (≥65). Characteristics of past-year marijuana users including demographics, substance use, chronic disease, and emergency room use, were compared to non-marijuana users and stratified by age group. Marijuana use characteristics were also compared between middle-aged and older adults. We used multivariable logistic regression to determine correlates of past-year marijuana use. Prevalence of past-year marijuana use was 9.0% among adults aged 50-64 and 2.9% among adults aged ≥65. Prevalence of past-year alcohol use disorder (AUD), nicotine dependence, cocaine use, and misuse of prescription medications (i.e., opioids, sedatives, tranquilizers) were higher among marijuana users compared to non-users. In adjusted models, initiation of marijuana use <19 years of age [adjusted odds ratio (AOR) = 13.43, 95% confidence interval (CI) 9.60, 18.78)], AUD (AOR = 2.11, 95% CI 1.51, 2.94), prescription opioid misuse (AOR 2.49, 95% CI 1.61, 3.85), nicotine dependence (AOR = 1.90, 95% CI 1.59, 2.26), and cocaine use (AOR 7.43, 95% CI 4.23, 13.03), were all associated with increased odds of past-year marijuana use. Marijuana use is becoming more prevalent in this population and users are also at high risk for other drug use.


Factors affecting the quality of life of gastric cancer survivors.
The number of gastric cancer survivors has been increasing, and such survivors experience various changes in their lives post-recovery. Adapting to these changes requires appropriate interventions that can improve their quality of life (QoL). This study was conducted to investigate the factors affecting the QoL of gastric cancer survivors and provide basic data for effective intervention. Data were collected between September 8 and September 29, 2017, from the Gastric Cancer Center at a tertiary hospital. Questionnaire surveys were conducted using the EORTC QLQ-C30/STO22, Self-Efficacy-Scale, Multidimensional Scale of Perceived Social Support, and Quality of Life-Cancer Survivors Questionnaire on gastric cancer survivors who were followed up for 3 years after gastrectomy. Data were analyzed using descriptive statistics, t test, ANOVA, Pearson's correlation coefficient, and multiple regression analysis. A total of 136 gastric cancer survivors completed the questionnaire survey. There were significant positive correlations of QoL with self-efficacy, functional status, and social support (r = .35, p < .001; r = .53, p < .001; r = .26, p < .001, respectively). There were significant negative correlations of QoL with general symptoms (r = - .39, p < .001) and gastric cancer-specific symptoms (r = - .51, p < .001). The regression model explained 48.3% of the QoL, and the affecting factors were gastric cancer-specific symptoms (β = - .397, p < .001), religious belief (β = .299, p < .001), functional status (β = .251, p = .003), and self-efficacy (β = .191, p = .004). This study confirmed that gastric cancer-specific symptoms, spiritual well-being, self-efficacy, and functional status affect the QoL of gastric cancer survivors. Hence, these factors should be considered in the interventions to improve the QoL of gastric cancer survivors.


Simple chemiluminescent detector for the screening of foodstuffs for the presence of volatile nitrosamines.
The construction and subsequent evaluation of an apparatus for the detection of trace amounts of nitrosamines is described. The apparatus consists of a gas chromatograph, a catalytic chamber to generate nitric oxide from eluted nitrosamines, and a chemiluminescent detector to measure the infra-red emission resulting from interaction of this gas with ozone. Examples of the use of the system for determining the nitrosamine concentration in food extracts and other materials are given.


Stationarity in moment closure and quasi-stationarity of the SIS model.
Previous epidemiological studies on SIS model have only considered the dynamic evolution of the mean value and the variance of the infected individuals. In this paper, through cumulant neglection, we use the dynamic equations of all the moments of infected individuals to develop a recursive method to compute the equilibria manifold of the moment closure ODE's. Specifically, we use the stable equilibria of the moment closure ODE's to obtain good approximations of the quasi-stationary states of the SIS model. This is a crucial step when the quasi-stationary distribution is highly skewed.


Postoperative systemic adjuvant chemotherapy for bladder cancer.
Forty-six patients with bladder cancer without distant metastasis (M0) were treated by chemotherapy as an adjuvant after total cystectomy using three protocols (protocol I: adriamycin 50 mg/m2, cyclophosphamide 500 mg/m2, and cis-platinum 50 mg/m2 i.v., starting at least 2 weeks after surgery every 3 weeks for three cycles; protocol II: adriamycin 30 mg/m2 on the 1st postoperative day, cyclophosphamide 300 mg/m2 on the 1st and the 7th days; protocol III: FT-207 60 mg/m2, p.o. every day for 1 year). Average follow-up periods after surgery by protocol were 18 months for protocol I, 31 for protocol II, and 43 for protocol III. Analysis of the survival curves showed no statistically significant differences among the three groups or between a historical control group of 106 patients and the entire patient population examined in the present study. The histopathological grades recorded in the 46 patients were G1, G2, and G3 in 1, 22, and 23, respectively. However, from a study of 48 pT3 and pT4 cases, the survival rate of 10 patients receiving protocol I therapy was statistically significantly higher than those of 12 patients treated according to protocol II and of 26 historical controls, at 1 year and 2 years, respectively. Toxic effects, with gastrointestinal symptoms including nausea and vomiting and myelosuppression (including leukopenia and anemia) were more frequent with protocol I. Alopecia occurred in about 80%-90% of patients treated according to either protocol I or II. Almost all patients could tolerate adjuvant chemotherapy, and none of them died as a result of these regimens. The results recorded in this study justify the evaluation of combination adjuvant chemotherapy with adriamycin, cyclophosphamide and cis-platinum in a prospectively randomized trial.


Focused antithrombotic therapy: novel anti-platelet salicylates with reduced ulcerogenic potential and higher first-pass detoxification than aspirin in rats.
The use of aspirin as an anti-platelet drug is limited by its propensity to induce gastric injury and by its adverse effect on vascular prostacyclin formation. Two phenolic non-steroidal anti-inflammatory drugs (salicylic acid and diflunisal) were modified by esterification with a series of O-acyl moieties. The short-term ulcerogenic in vitro and in vivo anti-platelet properties, pharmacodynamic profiles, and extent of hepatic extraction of these phenolic esters were compared with aspirin (acetylsalicylic acid). The more lipophilic esters (longer carbon chain length in O-acyl group) show significantly less gastrotoxicity in stressed rats than does aspirin after a single oral dose. The in vitro and in vivo anti-platelet studies show that these phenolic esters inhibited (1) arachidonate-triggered human platelet aggregation and (2) thrombin-stimulated rat serum thromboxane A2 production by platelets in the clotting process almost as effectively as aspirin. The hepatic extractions of these O-acyl derivatives are significantly higher than those of aspirin. The pharmacodynamic studies show that these O-acyl derivatives of salicylic acid and diflunisal probably bind to, or combine with, the same site on the platelet cyclooxygenase as aspirin. Replacing the O-acetyl group with longer chain O-acyl moiety in this series of phenolic esters markedly reduced the potential of these agents to induce short-term gastric injury but did not lessen their activity as inhibitors of platelet aggregation. These non-acetyl salicylates may therefore represent a novel class of anti-platelet drugs with less ulcerogenic potential.


Measurement and interpretation of Q0 and Q1 band property changes of two cationic metalloporphyrins upon binding with B-DNA: electronic MCD, CD, and optical absorption.
Room-temperature Q-band electronic MCD, CD, and optical spectra are reported for the first time for two free and nucleic acid-bound cationic metalloporphyrins. Metalloporphyrins are the high-symmetry (C4v or D4h), four-coordinate tetragonal type MP(X) [M = CuII and PtII; P(X) = meso-tetrakis(X-N-methylpyridyl)porphine; X = 2 or 4], and the nucleic acid is native, B-form calf thymus DNA (CT DNA). For intercalation system PtP(4)/CT DNA, large optical (lambda 0, epsilon max) and MCD (lambda peak, lambda trough, A(aj), A(aj)/D(aj), and delta[theta]Mp-t/epsilon max) band parameter shifts, as well as a single negative (-) induced CD peak for each of Q0 and Q1, were observed upon binding of the porphyrin to chiral DNA. The directions and magnitudes of these changes are comparable to those observed for the Soret (B0) band of this system. Decreases of MCD/optical ratio delta[theta]Mp-t/epsilon max (varies; is directly proportional to A(aj)/D(aj)) of 30% (Q0) and 50% (Q1) upon intercalation indicate substantial reductions of the Q0[1Eu(a) (0,0), approximately 1a1u1 4eg1] and Q1[1Eu(a)(0,1), approximately 1a1u1 4eg1] excited state angular momenta, <Lj>. It is of additional interest that intercalation leads to intensity cancellation of one of the four A-term lobes, the (+)lobe of the Q0 MCD (+)pseudo-A-term, which was also observed previously for intercalation systems PdP(4)/poly(G-C)2 and /CT DNA. Application of the CD sector method to the constituent x- and y-polarized porphyrin edtms, square root of D(aj), of the Q0 (edtms mu0x and mu0y) and Q1 (edtms mu1x and mu1y) CD bands leads to the conclusion that PtP(4) is symmetrically intercalated between adjacent GC base pairs, specifically at 5'GC3' sites, with each of two adjacent 4-N-methylpyridyl groups extending into each of the major and minor grooves. For outside binder CuP(2), small optical and MCD band parameter shifts and smaller, single positive (+) induced CD peaks are observed for Q0 and Q1 upon interaction with CT DNA, similar to what is found for B0. Little or no change in the MCD/optical ratio, delta[theta]Mp-t/epsilon max, informs that external binding has only small effects on the excited state angular momenta, <Lj>, of these bands. The composite of MCD, CD, and optical spectra are consistent with CuP(2) binding to CT DNA by one or both of two competing external modes, i.e., by an AT-specific, edge-on minor groove mode at 5'TA3' sites and/or a face-on major groove mode with high selectivity for 5'AT3' or 5'CG3' sites. For Q0 and Q1 of each of the CuP(2)/CT DNA and PtP(4)/CT DNA systems, we observe that the genuine MCD (+) A-terms of these free MP(X)s retain their (+) sign on becoming pseudo-A-terms upon binding to the low-symmetry, asymmetric DNA sites, and this indicates that the external and intercalative modes result in the 4eg splitting, or delta LUMO, being less than the magnitude of 1a1u-3a2u energy separation, or delta HOMO.


Rapid assessment of Opisthorchis viverrini IgG antibody in serum: A potential diagnostic biomarker to predict risk of cholangiocarcinoma in regions endemic for opisthorchiasis.
Opisthorchiasis is caused by an infection with fish-borne liver flukes of the genus Opisthorchis. Opisthorchiasis frequently leads to chronic inflammation in the biliary tract and is classified as a group 1 biological carcinogen by the International Agency for Research on Cancer: a definitive risk for cholangiocarcinoma (CCA). We used the rapid immunochromatographic test (ICT) to detect anti-Opisthorchis viverrini IgG and IgG4 subclass antibodies in sera of patients with CCA. The ICT kits were developed based on soluble antigens excreted and secreted by O. viverrini adult worms. ICT indicated sera was positive for IgG and IgG4 antibodies, respectively, in 22 (61.1%) and 15 (41.6%) participants of the 36 study participants diagnosed with CCA (P > 0.05). Our study also included groups with other cancers and with liver cirrhosis, where the IgG ICT and IgG4 ICT kits were 27.7% (13/47) and 25.5% (12/47) positive, respectively (P > 0.05). Neither total the IgG ICT nor the IgG4 ICT yielded positive results in a control group of 20 healthy participants. Moreover, the percentage positivity rate using the ICT for total IgG between the CCA group and the other cancers and liver cirrhosis group was significantly different (P < 0.05). By contrast, no significant difference between these groups was apparent in the ICT for IgG4 antibody. The CCA group was 6.53 times more likely to have positive anti-O. viverrini IgG antibody (odds ratio 6.53, P < 0.001) and 3.27 times more likely to have positive anti-O. viverrini IgG4 antibody (odds ratio 3.27, P = 0.010) than the non-CCA group. This information is of potential value for the development of a diagnostic biomarker to predict risk for O. viverrini infection-associated CCA.


Fine mapping and comparative genomics integration of two quantitative trait loci controlling resistance to powdery mildew in a Spanish barley landrace.
The intervals containing two major quantitative trait loci (QTL) from a Spanish barley landrace conferring broad spectrum resistance to Blumeria graminis were subjected to marker saturation. First, all the available information on recently developed marker resources for barley was exploited. Then, a comparative genomic analysis of the QTL regions with other sequenced grass model species was performed. As a result of the first step, 32 new markers were added to the previous map and new flanking markers closer to both QTL were identified. Next, syntenic integration revealed that the barley target regions showed homology with regions on chromosome 6 of rice (Oryza sativa), chromosome 10 of Sorghum bicolor and chromosome 1 of Brachypodium distachyon. A nested insertion of ancestral syntenic blocks on Brachypodium chromosome 1 was confirmed. Based on sequence information of the most likely candidate orthologous genes, 23 new barley unigene-derived markers were developed and mapped within the barley target regions. The assessment of colinearity revealed an inversion on chromosome 7HL of barley compared to the other three grass species, and nearly perfect colinearity on chromosome 7HS. This two-step marker enrichment allowed for the refinement of the two QTL into much smaller intervals. Inspection of all predicted proteins for the barley unigenes identified within the QTL intervals did not reveal the presence of resistance gene candidates. This study demonstrates the usefulness of sequenced genomes for fine mapping and paves the way for the use of these two loci in barley breeding programs.


Autonomy, discourse, and power: a postmodern reflection on principlism and bioethics.
In recent years there has been an increasing critique of the philosophically based reasoning in bioethics which is known as principlism. This article seeks to make a postmodern contribution to this emerging debate by using notions of power and discourse to highlight the limits and superficiality of this abstract, rationalistic mode of reflection. The focus of the discussion will be on the principle of autonomy. Recent doctoral research on a hospice organization (Karuna Hospice Service) will be used to contextualize the debate to end-of life ethical dilemmas. The conclusion will be reached that the discursive richness of this organization's notion of autonomy or choice, which incorporates a holistic respect for the individual and the active creation of alternatives, can provide important insights to our understanding of autonomy in bioethics. The concern is raised that if autonomy is reified as a principle outside of the context of discourse, it may only complement the hegemonic power of biomedicine.


Genetic structure of fragmented populations of a threatened endemic percid of the Rhône river: Zingel asper.
Zingel asper is an endemic percid of the Rhône basin considered to be critically endangered. This species was continuously distributed throughout the Rhône in 1900, but today only occupies 17% of its initial area. In the present study, five microsatellite loci were used to assess the level of genetic variability within and among populations localized in different sub-basins. Contrasting results were obtained for the three main populations from the Rhône. A reduced allelic diversity was observed for the two populations displaying the lowest patch sizes (length of the river system occupied); of these, a recent genetic bottleneck was detected for the population showing a particularly low density. However, the third population was characterized by a relatively large spatial extent, high local fish concentrations and an allelic diversity that was twice as high and associated with an equilibrium between mutation and drift. Thus, this population shows an apparently better evolutionary potential for long-term survival. Since 1930, a marked fragmentation of the whole Rhône system has appeared, related to the development of dams, and we assume that the significant genetic differentiation detected between the populations could mainly reflect the impact of this fragmentation. The high turnover of the Z. asper populations, and the major role of dispersal in population persistence (highlighted in a recent population dynamics study), indeed suggest that the differentiation observed could mainly have arisen from habitat fragmentation in recent history.


Comparison of psychometric properties of GOHAI, OHIP-14, and OHIP-EDENT as measures of oral health in complete edentulous patients aged 60 years and more.
To compare the psychometric properties of three OHRQoL indicators (GOHAI, OHIP-14, and OHIP-EDENT) in a group of complete edentulous subjects and to explore the ability of these instruments to distinguish between individuals with different prosthetic and oral health status. This was a cross-sectional study. Edentulous individuals aged 60 years and more were recruited between January 2019 and February 2020 in a medical and dental care centers. The Lebanese versions of GOHAI, OHIP-14, and OHIP-EDENT were used. External and internal consistencies were assessed using intraclass correlation coefficient (ICC) and Cronbach alpha, respectively. The concurrent validity was evaluated by testing the indicators against a proxy measure of a similar concept. To test their discriminative abilities, the ADD (GOHAI and OHIP) and SC (GOHAI and OHIP) scores were dichotomized according to the 25th and 75th percentile, respectively, and multivariate analyses were performed using sociodemographic, clinical, and subjective health parameters as explanatory variables. Two hundred and two edentulous subjects (age: 72.94 ± 7.378 years) were included. The proportion of subjects with no impact was lower for OHIP-EDENT (7.9%) compared to GOHAI (28.2%) and OHIP-14 (38.6%). Reproducibility was satisfactory for all OHRQoL tools since they were able to reproduce the results consistently in time (ICC > 0.80). The Cronbach alpha values were greater than 0.8 indicating acceptable internal consistency. The concurrent validity of the three tools was acceptable since subjects with lower OHRQoL score were less satisfied with their dentures and reported a higher need for self-rated therapy. Concerning the discriminant validity, OHIP-EDENT was more discriminant than OHIP-14 and GOHAI, since it was more able to identify patients with poor prosthetic issues or using instable denture. The OHIP-EDENT was more effective in identifying edentulous individuals with oral and prosthetic problems. Our results can help decide which dental instrument to use to assess the perception of oral health in edentulous individuals. More prospective studies are required to compare their evaluative properties.


[Zearalenone in food].
The research project "Methods of Analysis and occurrence of important Fusarium toxins (deoxynivalenol and zearalenone) as well as the intake of these toxins by the German consumer" supported by the Federal Ministry of Consumer Protection, Food and Agriculture (BMVEL) is processed by the institutions mentioned above. This work represents a comprehensive summary of the contamination of food by zearalenone (ZEA).


Acute and chronic effects of sublethal neonicotinoid thiacloprid to Asian honey bee (Apis cerana cerana).
Pesticide pollution is one of the most important factors for global bee declines. Despite many studies have revealed that the most important Chinese indigenous species,Apis cerana, is presenting a high risk on exposure to neonicotinoids, the toxicology information on Apis cerana remain limited. This study was aimed to determine the acute and chronic toxic effects of thiacloprid (IUPAC name: {(2Z)-3-[(6-Chloro-3-pyridinyl)methyl]-1,3-thiazolidin-2-ylidene}cyanamide) on behavioral and physiological performance as well as genome-wide transcriptome in A. cerana. We found the 1/5 LC50 of thiacloprid significantly impaired learning and memory abilities after both acute and chronic exposure, nevertheless, has no effects on the sucrose responsiveness and phototaxis climbing ability of A. cerana. Moreover, activities of detoxification enzyme P450 monooxygenases and CarE were increased by short-term exposure to thiacloprid, while prolonged exposure caused suppression of CarE activity. Neither acute nor chronic exposure to thiacloprid altered honey bee AChE activities. To further study the potential defense molecular mechanisms in Asian honey bee under pesticide stress, we analyzed the transcriptomes of honeybees in response to thiacloprid stress. The transcriptomic profiles revealed consistent upregulation of immune- and stress-related genes by both acute or chronic treatments. Our results suggest that the chronic exposure to thiacloprid produced greater toxic effects than a single administration to A. cerana. Altogether, our study deepens the understanding of the toxicological characteristic of A. cerana against thiacloprid, and could be used to further investigate the complex molecular mechanisms in Asian honey bee under pesticide stress.


Segmental neurofibromatosis in childhood.
Segmental neurofibromatosis refers to individuals who have manifestations of neurofibromatosis type 1 (NF-1) limited to one area of the body. It results from a post-conceptional mutation in the NF-1 gene leading to somatic mosaicism. Although it is generally considered a rare condition, this report of 39 children with segmental NF-1 demonstrates that it is commonly seen in a pediatric NF-1 referral center. The mean age at diagnosis was 7.8 years (range: 2-25 years). Twenty-nine patients had only pigmentary manifestations of segmental NF-1, including seven who had only café-au-lait macules and 22 who had café-au-lait macules and freckling. Two patients had isolated plexiform neurofibromas; a third patient had a plexiform neurofibroma of the eyelid in addition to ipsilateral dysplasia of the sphenoid wing and Lisch nodules. A 12-year-old girl had an isolated tibial pseudarthrosis. An 8-year-old boy had an isolated optic pathway tumor, which behaved both biologically and radiographically as an NF1-associated tumor. While most children with segmental NF-1 have only localized pigmentary changes, some children will have isolated plexiform neurofibromas, pseudarthroses, or optic pathway tumors. Accurate diagnosis of segmental NF-1 is crucial for both management and genetic counseling.


Complementary and Alternative Medicine in Cardiac Surgery: Prevalence and Modality of use.
Complementary and alternative medicines are developing at a growing rate but their use in the hospital setting is little known, ignoring risk or benefit in practice. The objectives of the study were to quantify the prevalence of complementary and alternative medicines used by patients admitted to a cardiac surgery department. Patients and staff at the Cardiac Surgery unit of Angers University Hospital (France) were surveyed regarding their modality of complementary and alternative medicines use, between April 01, 2013, and April 18, 2014, by means of an anonymous questionnaire. Of 154 patients included in the study, 58% used a complementary and alternative medicine at least once in their lifetime, 38% during the preceding year, and 14% between the consultation and surgery. In all, 71% used them as a complement to their conventional medical treatment. Of those who used a complementary and alternative medicine during the year of their surgery procedure, only 29% informed their physicians and paramedical staff about it. Complementary and alternative medicines use among patients admitted to cardiac surgery units is common. Yet there is a real lack of knowledge regarding these health practices among physicians and paramedical staff.


Posterior lens capsule neovascularization treated with anti-VEGF complicated by phacogenic uveitis.
To report a case of neovascularization of posterior capsule (NVPC) successfully treated with intravitreal ranibizumab (Lucentis) and neodymium:YAG (Nd:YAG) capsulotomy, followed by phacogenic uveitis. We report a systemically otherwise healthy 81-year-old male presenting with unilateral NVPC and iris (NVI) occurring five years after a central retinal vein occlusion. A single intravitreal injection of ranibizumab led to complete regression of NVPC and NVI within three weeks after which a Nd:YAG capsulotomy was performed. Two weeks later, the patient returned with a severe inflammatory reaction diagnosed as phacogenic uveitis and treated with surgical capsular bag/intraocular lens complex removal and peripheral pan-retinal photocoagulation. One-year follow-up demonstrated no recurrence of NVPC. Visual acuity remained at baseline of light perception. We acknowledge that intravitreal anti-vascular endothelial growth factor treatment with Nd:YAG capsulotomy for NVPC is a rational option, but raise awareness to the rare possibility of phacogenic uveitis.


Epidemiology and Risk Factors of Melanoma.
The incidence of melanoma continues to increase worldwide. In the United States, melanoma is the fifth most common cancer in men and the sixth most common cancer in women. The risk factors contributing to melanoma have largely remained unchanged, but there is a new focus on modifiable risk factors including sun exposure and ultraviolet light. A large public initiative supported by the Centers for Disease Control focuses on educating the public on the risks of sun exposure and indoor tanning. Early detection and resection of melanoma lesions is necessary to prevent metastasis and reduce medical costs.


Primary Dermal Melanoma (PDM): Histological and Clinical Interdependence to Guide Therapy.
This study examined clinical and histological parameters of primary dermal melanoma (PDM) to aid in its distinction from dermal metastasis. Retrospective analysis of a prospective cohort of PDM patients. Includes patients fulfilling the strict histologic criteria for PDM (N = 9) and patients who did not, but clinically, unequivocally had an intradermal melanoma-clinical PDM (cPDM; N = 17).Histopathology slides were re-examined. Prognosticators and outcome measures were compared between groups. Sentinel nodes' retrieval and wide local excision (WLE) were offered to all patients as primary treatment. 26 patients identified, 15 females with a median age of 69 years (range 3.5-85). Mean Breslow was 7.9 ± 5.7 mm (median 5.8, range 1.8-25.0), and the mean mitotic rate was 4.9 ± 3.8/mm2 (median 4.0, range 0-17). Initial treatment and follow-up were as for cutaneous melanoma. One patient in each group with a palpable stage III underwent primary radical dissection. Sentinel nodes were retrieved in all 20 lymphatic mappings performed and found to be metastatic in 5 (25%) patients. Treatment consisted of completion lymph-node dissection. At a median postoperative follow-up of 62 months (range 8-132), 20 patients were disease-free, including 6 of 7 patients with stage III disease at presentation. Six patients died all of cPDM; 5 of 6 patients had primary ulcerated or epidermal-abutting melanomas. This is the first study to highlight cPDM. Diagnosis requires expert pathology review and a tight correlation to the clinical parameters. Patients seem to benefit from WLE with sentinel node retrieval and complete dissection when appropriate. However, clinical guidelines for dissection have changed since the time period of this retrospective review. Based on this series, complete nodal dissection in these melanomas is associated with better than expected outcome, for stage III disease.


Action potentials in non-tumor cells from the anterior pituitary gland.
Non-tumor cells of rat anterior pituitary gland are able, upon electrical stimulation, to generate action potentials which are based on an increase of the membrane permeability to both Na+ and Ca2+.


A Micro-Computed Tomographic Assessment of the Influence of Operator's Experience on the Quality of WaveOne Instrumentation.
Micro-computed tomographic scanning was used to evaluate the influence of operator's experience on the time and quality of instrumentation of the mesial root canals of mandibular molars using WaveOne Primary files (Dentsply Maillefer, Ballaigues, Switzerland). Thirty mandibular molars with 2 separate mesial canals were submitted to preoperative micro-CT scans. Teeth were randomly allocated to 3 groups: and experienced operator group and inexperienced groups before and after training with WaveOne files. Second scans were obtained after instrumentation. The volume of the untreated canal, the volume of dentin removed after preparation; the amount of the uninstrumented area; and transportation to the coronal, middle, and apical thirds of canals were measured. The preparation time was also recorded. Instrumentation of canals increased their volume and surface area in all groups. No significant differences between experienced and inexperienced (with and without training) groups in the apical, middle, and coronal sections were detected although coronal transportation was slightly larger in both inexperienced groups than in the experienced group. The inexperienced operator without training used significantly more time for instrumentation than the experienced operator (P < .05); after training for 1 month, the instrumentation time by the same inexperienced operator was reduced (P < .05) to close to the time of the experienced operator (P > .05). The WaveOne instrumentation technique required a short learning curve for the inexperienced user in order to master this technology.


Dose metric considerations in in vitro assays to improve quantitative in vitro-in vivo dose extrapolations.
Challenges to improve toxicological risk assessment to meet the demands of the EU chemical's legislation, REACH, and the EU 7th Amendment of the Cosmetics Directive have accelerated the development of non-animal based methods. Unfortunately, uncertainties remain surrounding the power of alternative methods such as in vitro assays to predict in vivo dose-response relationships, which impedes their use in regulatory toxicology. One issue reviewed here, is the lack of a well-defined dose metric for use in concentration-effect relationships obtained from in vitro cell assays. Traditionally, the nominal concentration has been used to define in vitro concentration-effect relationships. However, chemicals may differentially and non-specifically bind to medium constituents, well plate plastic and cells. They may also evaporate, degrade or be metabolized over the exposure period at different rates. Studies have shown that these processes may reduce the bioavailable and biologically effective dose of test chemicals in in vitro assays to levels far below their nominal concentration. This subsequently hampers the interpretation of in vitro data to predict and compare the true toxic potency of test chemicals. Therefore, this review discusses a number of dose metrics and their dependency on in vitro assay setup. Recommendations are given on when to consider alternative dose metrics instead of nominal concentrations, in order to reduce effect concentration variability between in vitro assays and between in vitro and in vivo assays in toxicology.


Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity.
The tumor suppressor gene, MMAC/PTEN, has phosphatase, C2, and PDZ-binding domains as well as potential sites of regulation by phosphorylation, including tyrosine phosphorylation, which may contribute to its ability to modulate cell growth and viability. Several obvious and significant motifs were found in MMAC/PTEN, including most notably, a catalytic domain of tyrosine phosphatase (IHCxxGxxRS/T) and several potential tyrosine phosphorylation sites. To examine the functional significance of tyrosine phosphorylation of MMAC/PTEN, retroviral constructs were generated with mutations at two putative tyrosine phosphorylation sites (Y240A/Y240F and Y315A/Y315F). Stable expression of wild-type MMAC/PTEN in U251 human glioma cells (which do not normally produce a functional MMAC/PTEN gene product) resulted in a significant reduction of tumor growth in nude mice, decreased growth rate, saturation density, and colony formation in vitro, as well as dephosphorylation of D3-phosphorylated phosphatidylinositols (PtdIns) in vitro. Mutation of Y240 or Y315 to either alanine or phenylalanine abrogated the ability of MMAC/PTEN to alter growth rate, saturation density, and colony formation in vitro. The ability of MMAC/PTEN to limit tumor growth in nude mice was markedly decreased but not abrogated by mutation of Y240 or Y315 to alanine. Thus, Y240 and Y315 are required for MMAC/PTEN to decrease tumor growth in vitro and in vivo. In contrast to wild-type MMAC/PTEN, mutant MMAC/PTEN containing Y240A or Y315A was unable to dephosphorylate D3-phosphorylated PtdIns in vitro. Thus, Y240A and Y315A are involved in the ability of MMAC/PTEN to dephosphorylate PtdIns and regulate tumor cell growth in vitro and in vivo.


Appendectomy Skin Closure Technique, Randomized Controlled Trial: Changing Paradigms (ASC).
Appendectomy is the most frequent and urgent gastrointestinal surgery. Overtime, the surgical techniques have been improved upon, in order to reduce complications, get better cosmetic results, and limit the discomfort associated with this procedure, by its high impact in the surgery departments. The traditional skin closure is associated with a poor cosmetic result and it requires stitches removal, alongside the pain associated with this procedure, and no benefits were demonstrated in the literature regarding separated stitches over intradermic stitch. This is a randomized controlled trial, and our objective is to compare two different skin closure techniques in open appendectomy. A prospective randomized trial method was used, with a total number of 208 patients participating in the study, after acute appendicitis diagnosis in the emergency department. They were randomized into two groups: patients who would receive skin closure with a unique absorbable intradermic stitch (Group A) and another group that would receive the traditional closure technique, consistent in non-absorbable separated stitches (Group B). General characteristics like gender, age, Body Mass Index (BMI), comorbidities, and allergies were registered. Days of Evolution (DOE) until surgery, previous use of antibiotics, complicated or uncomplicated appendicitis, surgical time, and wound complications like skin infection, dehiscence, seroma or abscess were also registered in each case. 8 patients were excluded due to negative appendicitis during surgery and lack of follow-up. Two groups, each containing 100 patients, were formed. General characteristics and parity were compared, and no statistically significant differences were observed. Difference in the surgical time (Group A: 47.35 min vs Group B: 54.13 min, p < .001) and cases with complicated appendicitis (Group A: 58 and Group B:38, p = .005) were found to be statistically significant. Four wound complications were reported, and the incidence of seroma (Group A:0 and Group B:5, p = .02) and abscess (Group A:2 and Group B:8, p = .05) were found to have some statistical significant difference. In a multivariate analysis, a relationship was observed between BMI > 25 kg/m2 and seroma (p = .006), BMI > 25 kg/m2 and abscess (p = .02), surgical time >50 min and seroma (p < .001), >2 DOE and abscess (p = .001), and complicated appendicitis with seroma development (p = .03). Open appendectomy skin closure with a unique absorbable intradermic stitch is safe, with a reduced seroma and abscess incidence, compared to traditional closure, and an equivalent dehiscence and superficial infection incidence, allowing a lower hospital attention cost and length of hospital stay for treatment of complications. The relative risk of complications with traditional skin closure is 2.91 higher, compared to this new technique.


Simultaneous assessment of diameter and pressure waveforms in the carotid artery.
Simultaneous assessment of diameter and pressure waveforms allows the calculation of the incremental compliance, distensibility, pulse wave velocity and elastic modulus as function of the distending pressure. However, the waveforms must be obtained at the same position and acquired and processed with the same filter characteristics to circumvent possible temporal and spatial changes in amplitude and phase. In this paper, arterial diameter waveforms are assessed by means of ultrasound (US) and converted to pressure using an empirically derived exponential relationship between pressure and arterial cross-section. The derived pressure waveform is calibrated to brachial end diastolic and mean arterial pressure by iteratively changing the wall rigidity coefficient (i.e., the exponential power). Because pressure is derived directly from arterial cross-section, no phase delay is introduced due to spatial separation or different filter characteristics. The method was evaluated for the left common carotid artery of 51 healthy subjects ranging in age from 22 to 75 years old. In healthy subjects, the carotid pulse pressure is 29% lower than the brachial pulse pressure. Continuous assessment of arterial properties confirms that pulse-wave velocity and incremental elastic modulus increase, whereas distensibility and compliance decrease, as function of increasing distending blood pressure.


Lyme carditis.
Cardiovascular manifestations of Lyme disease were first reported nearly 30 years ago. This article describes Lyme carditis, its epidemiology, pathophysiology, methods of diagnosis, and treatment options.


Recovery of rat lens epithelial cells after total or partial X-irradiation.
Irradiation of whole lenses interferes with the normal mitogenic response of lens cells to stimulation by mechanical wounding. Radiation exposure causes a delay and partial suppression of cells entering the S phase of the cell cycle. When cells are irradiated 1 day before wounding, DNA synthesis begins 20 hr after wounding and peaks 10 hr later with 20% cell labelling. The return to a normal wound response is gradual when the time interval between irradiation and wounding is lengthened. By 28 days, essentially complete recovery of the wound response occurs. Examination of the beginning of mitosis shows a similar pattern of recovery. When half of the lens is irradiated 1 day before wounding, delay and suppression of the wound response in the irradiated half of the lens epithelium is observed. However, if 4 days elapse between irradiation and mechanical wounding, complete recovery of cells responding to the mitogenic stimulus occurs. Cells of the shielded half of the lens appear to compensate for the reduced number of irradiated cells entering S phase so that peak labelling of shielded cells is 70% compared with 50% for control lens cells. An evaluation of mitotic figures confirms faster recovery of the entire lens when only half the lens is irradiated. Complete recovery of the cellular response of partially irradiated lenses occurs in 4 days in contrast to almost 28 days for wholly irradiated lens.


The effects of Berberis vulgaris consumption on plasma levels of IGF-1, IGFBPs, PPAR-γ and the expression of angiogenic genes in women with benign breast disease: a randomized controlled clinical trial.
The present study was designed to investigate the effects of Berberis vulgaris (BV) juice consumption on plasma levels of insulin-like growth factor (IGF-1), IGF-binding proteins (IGFBPs), and the expression of PPAR-γ, VEGF and HIF in women with benign breast disease. This parallel design randomized, double-blind controlled clinical trial was conducted on 85 eligible patients diagnosed with benign breast disease. They were assigned randomly into either BV juice group (n = 44, BV juice: 480 ml/day) or placebo group (n = 41, BV placebo juice: 480 ml/day) for 8 weeks intervention. Participants, caregivers and those who assessed laboratory analyses were blinded to the assignments. Plasma levels of biomarkers were measured at baseline and after 8 weeks by ELISA. Quantitative real-time PCR was used to measure the fold change in the expression of each interested gene. The compliance of participants was 95.2% and 40 available subjects analyzed in each group at last. Relative treatment (RT) effects for BV juice caused 16% fall in IGF-1 concentration and 37% reduction in the ratio of IGF-1/1GFBP1. Absolute treatment effect expressed 111 ng/ml increased mean differences of IGFBP-3 between BV group and placebo. Plasma level of PPAR-γ increased in both groups but it was not significant. Fold changes in the expressions of PPAR-γ, VEGF and HIF showed down-regulation in the intervention group compared to placebos (P < 0.05). The BV juice intervention over 8 weeks was accompanied by acceptable efficacy and decreased plasma IGF-1, and IGF-1/IGFBP-1 ratio partly could be assigned to enhanced IGFBP-1 level in women with BBD. The intervention caused reductions in the expression levels of PPAR, VEGF, and HIF which are remarkable genomic changes to potentially prevent breast tumorigenesis. IRCT2012110511335N2. Registered 10 July 2013 (retrospectively registered).


[Magnetic resonance imaging. Principles and applications in the head and neck area].
Magnetic Resonance Imaging is one of the most recently developed imaging techniques of the human body. In this review the physical principles and applications for oral surgeons are discussed.


Data on optimization of production parameters on Persea Americana (Avocado) plant oil biodiesel yield and quality.
Biodiesel has continued to receive enormous patronage from world energy demand as a result of its renewable nature, low toxicity, rapid degradation, robust fuel performance and low emission characteristics and its overall environmental friendliness. Hence, these data showed the optimization of temperature, catalyst concentration and type of catalyst, alcohol type and alcohol to oil molar ratio and reaction time on Avocado plant oil biodiesel yield and quality produced via alkali-catalyzed transesterification reaction. Data on the quality of the biodiesel produced by using the American Standard for Testing Materials (ASTM) procedures for biodiesel characterization with different concentrations of alcohol and catalyst under varying temperatures and reaction durations are also provided. The tested biodiesel properties are the cold flow properties (pour point and cloud point) and the critical parameters such as kinematic viscosity at 40 °C, specific gravity at 15 °C, flash point, cetane number, calorific value, iodine value, acid number and sulphated ash percentage.


Does cardioplegia leave room for postconditioning in paediatric cardiac surgery?
Postconditioning by brief episodes of ischaemia performed just at the time of reperfusion have been shown to reduce the size of infarcts in animal models, and in the clinical setting of percutaneous cardiac intervention. The clinical applicability of postconditioning in cardiac surgery remains to be determined. We investigated the effect of postconditioning on myocardial protection in children undergoing cardiac surgery. We randomly assigned 40 patients scheduled for surgical correction of congenitally malformed hearts under cold blood cardioplegic arrest to postconditioning or control treatment. Postconditioning was performed by two cycles of 30 seconds ischaemia and 30 seconds reperfusion using aortic reclamping, and declamping started 30 seconds after cardioplegic arrest. We assayed creatine kinase-MB, troponin I, transcardiac release of lactate and neutrophil counts. The types of procedure, age, bypass and aortic cross-clamping times were similar in both groups. The postoperative peaks of creatine kinase-MB and troponin I were lower after aortic de-clamping in the postconditioned patients compared with their controls (128 +/- 48 units per liter as opposed to 199 +/- 79 units per liter, p = 0.016, and 0.34 +/- 0.21 nanograms per milliliter as opposed to 0.61 +/- 0.53 nanograms per milliliter, p = 0.05), with reduced inotropic scores in those submitted to postconditioning compared with their controls (4.8 +/- 3.1 versus 2.3 +/- 1.5, p = 0.036). Transcardiac release of lactate was reduced in the postconditioned patients compared with their controls (0.10 +/- 0.27 as opposed to 0.37 +/- 0.43 millimols per liter, p = 0.048). No differences between groups were found for transcardiac neutrophil count during reperfusion (10.8 +/- 6.3% for postconditioning versus 14.0 +/- 8.7% for controls, p = 0.48). Our study demonstrates that postconditioning may protect the myocardium of children undergoing cold blood cardioplegic arrest. These data support the need for a larger clinical trial of postconditiong in children undergoing cardiac surgery.


Determination of cefaclor by selective sample enrichment/clean-up on silica gel bonded polyelectrolyte in ion-exchange column chromatography.
A silica gel-bound cationic polyelectrolyte, poly[N-chloranil N,N,N',N'- tetramethylethylene diammonium dichloride], modified as ion-exchanger capable of molecular recognition of beta-lactam antibiotic, was used in solid phase extraction through column chromatography for a sample clean-up and enrichment of analyte from a dilute solution. The optimum and selective sorption conditions for a model antibiotic, cefaclor, were established. The high selectivity of polymer at pH 9.5 and flow rate as high as 5 ml/min were observed for the quantitative sorption of cefaclor. The desorption by 0.1 N HCl at flow rate of 0.1 ml/min and subsequent heating at 80 degrees C for 2 h allowed the antibiotic to be detected as corresponding oxazolone form in UV-spectrophotometric and differential pulse adsorptive stripping voltammetric measurements. The potential of the suggested approach was illustrated by estimating cefaclor in urine and blood plasma samples.


Radioactivity from Fukushima Dai-ichi in air over Europe; part 2: what can it tell us about the accident?
It is shown which information can be extracted from the monitoring of radionuclides emitted from the Fukushima Dai-ichi nuclear power plant and transported to Europe. In this part the focus will be on the analysis of the concentration ratios. While (131)I, (134)Cs and (137)Cs were reported by most stations, other detected radionuclides, reported by some, are (95)Nb, (129m)Te, (132)Te, (132)I, (136)Cs and (140)La. From their activity ratios a mean burn-up of 26.7 GWd/t of the fuel from which they originated is estimated. Based on these data, inventories of radionuclides present at the time of the accident are calculated. The caesium activity ratios indicate emissions from the core of unit 4 which had been unloaded into the fuel storage pool prior to the accident.


Extended Adjuvant Endocrine Therapy in Early Breast Cancer Patients-Review and Perspectives.
Seventy percent of all breast cancer subtypes are hormone receptor-positive. Adjuvant endocrine therapy in these patients plays a key role. Despite the traditional duration of a 5-year intake, the risk of relapse remains elevated in a substantial proportion of patients. Several trials report that the risk of late recurrence is reduced by the extension of adjuvant endocrine therapy beyond 5 years. However, the optimal duration of endocrine therapy is still a matter of debate. The newer data only show a marginal benefit resulting from extension beyond 7 to 10 years. Furthermore, extension may be associated with more side effects. Thus, the adequate selection of patients qualifying for an extended adjuvant therapy is of importance. Tools/genomic tests, which include the characteristics of the patient and the tumor, may help to better identify patients with a risk of a late relapse. Taken together, the magnitude of benefit for extended adjuvant endocrine therapy is based on the precise estimation of the risk of relapse after 5 years. This must be balanced against the long-term side effects of endocrine treatment and the competing risks. For patients with an intermediate risk, 7 years appears to be the optimal duration, and in those with high-risk features, endocrine therapy up to 10 years may be considered.


Preparative isoelectric focussing of apolipoproteins C and E from human very low density lipoproteins.
The application of isoelectric focussing on a gel-stabilized layer for the separation of the Tris-urea-soluble apolipoproteins of very low density lipoproteins has been described. This method in one step, allows the separation of most apolipoproteins, which were then analyzed and characterized. Apolipoproteins CII and CI were isolated as single protein bands with apparent pI of 5.0 and 6.5, respectively. Apolipoprotein CII was biologically active and could activate lipoprotein lipase. Apolipoprotein CIII was separated into several protein bands with pI ranging from 4.7 to 5.1 as a function of their number of sialic acid residues. Apolipoprotein E was isolated and characterized into five polymorphic bands with pI of 5.7, 5.8, 5.9, 6.0, and 6.2, respectively.


Case report: nasotracheal intubation--look before leaping to assess the laryngeal view.
To describe an airway management plan, including oral to nasal endotracheal tube exchange, when nasal intubation is required in the unanticipated difficult airway. A nasal intubation was required for a patient undergoing oropharyngeal surgery. Following loss of consciousness and paralysis, a Cormack-Lehane class 3 view was obtained, and pressure over the thyroid cartilage failed to reveal the vocal cords. An Eschmann bougie was inserted into the oropharynx and blindly entered the trachea. An orotracheal tube was advanced into the trachea over the bougie, and the patient was ventilated with 100% O2 following the bougie's removal. An endotracheal tube was then guided through the right nostril into the hypopharynx. An Eschmann bougie was inserted into the nasal tube, and advanced towards the glottic opening under laryngoscopic view. Digital pressure applied to the oral tube at the base of the tongue brought the vocal cords into view. The oral endotracheal cuff was deflated, and the bougie (inserted into the nasal tube) was advanced into the trachea alongside the orotracheal tube. The orotracheal tube was withdrawn, and the nasal tube was advanced into the trachea over the bougie. The patient's O2 saturation and end-tidal CO2 concentration remained at 99-100% and 30-33 mmHg, respectively, during these maneuvers, which required only a few minutes to perform. When nasotracheal intubation is required, a plan of airway management is required to safely secure the airway. We emphasize the importance of direct laryngoscopy prior to insertion of an endotracheal tube through the nose, and describe a strategy for oral to nasal tracheal tube exchange.


Impact of dust filter installation in ironworks and construction on brownfield area on the toxic metal concentration in street and house dust (Celje, Slovenia).
This article presents the impact of the ecological investment in ironworks (dust filter installation) and construction works at a highly contaminated brownfield site on the chemical composition of household dust (HD) and street sediment (SS) in Celje, Slovenia. The evaluation is based on two sampling campaigns: the first was undertaken 1 month before the ecological investment became operational and the second 3 years later. The results show that dust filter installations reduced the content of Co, Cr, Fe, Mn, Mo, W and Zn on average by 58% in HD and by 51% in SS. No reduction was observed at sampling points in the upwind direction from the ironworks. By contrast, the impact of the construction works on the highly contaminated brownfield site was detected by a significant increase (on average by 37%) of elements connected to the brownfield contamination in SS. Such increase was not detected in HD.


Modeling protein loops using a phi i + 1, psi i dimer database.
We present an automated method for modeling backbones of protein loops. The method samples a database of phi i + 1 and psi i angles constructed from a nonredundant version of the Protein Data Bank (PDB). The dihedral angles phi i + 1 and psi i completely define the backbone conformation of a dimer when standard bond lengths, bond angles, and a trans planar peptide configuration are used. For the 400 possible dimers resulting from 20 natural amino acids, a list of allowed phi i + 1, psi i pairs for each dimer is created by pooling all such pairs from the loop segments of each protein in the nonredundant version of the PDB. Starting from the N-terminus of the loop sequence, conformations are generated by assigning randomly selected pairs of phi i + 1, psi i for each dimer from the respective pool using standard bond lengths, bond angles, and a trans peptide configuration. We use this database to simulate protein loops of lengths varying from 5 to 11 amino acids in five proteins of known three-dimensional structures. Typically, 10,000-50,000 models are simulated for each protein loop and are evaluated for stereochemical consistency. Depending on the length and sequence of a given loop, 50-80% of the models generated have no stereochemical strain in the backbone atoms. We demonstrate that, when simulated loops are extended to include flanking residues from homologous segments, only very few loops from an ensemble of sterically allowed conformations orient the flanking segments consistent with the protein topology. The presence of near-native backbone conformations for loops from five different proteins suggests the completeness of the dimeric database for use in modeling loops of homologous proteins. Here, we take advantage of this observation to design a method that filters near-native loop conformations from an ensemble of sterically allowed conformations. We demonstrate that our method eliminates the need for a loop-closure algorithm and hence allows for the use of topological constraints of the homologous proteins or disulfide constraints to filter near-native loop conformations.


Rabies vaccination at a virus-inoculated site as an alternative option to rabies immunoglobulin.
Combined active and passive immunization has been established to be an optimal strategy for rabies post-exposure prophylaxis (PEP). Prompt administration of vaccine and rabies immunoglobulin (RIG) can reliably prevent the disease. However, RIG is unavailable and unaffordable in the majority of cases. On the basis of a model experiment using hamsters, we demonstrated that vaccine injection at the wound site in the same manner as administration of RIG provided protective efficacy that was not inferior to the current optimal PEP, a combination of vaccination and RIG. Further study is needed to determine whether it can replace the use of RIG.


[ADEM: a rare and serious demyelinating disorder of adults].
Acute Disseminated Encephalomyelitis is a serious demyelinating disorder of childhood that typically occurs following vaccination or a viral prodrome. Some etiologies remain unrecognized, and multiple mechanisms of immune response may explain the pathophysiology of this syndrome. Based on a report of two adult cases presenting with neurologic deficit and ataxia, we report our experience with this syndrome that may affect adults without evident infectious disorder. Prompt treatment is important to avoid rapid progression.


Impaired awareness in mesial temporal lobe epilepsy: Network analysis of foramen ovale and scalp EEG.
We use co-registration of foramen-ovale and scalp-EEG to investigate network alterations in temporal-lobe epilepsy during focal seizures without (aura) or with impairment of awareness (SIA). One aura and one SIA were selected from six patients. Temporal dynamic among 4 epochs, as well as the differences between aura and SIA, were analyzed through partial directed coherence and graph theory-based indices of centrality. Regarding the auras temporal evolution, fronto-parietal (FP) regions showed decreased connectivity with respect to the interictal period, in both epileptogenic (EH) and non-epileptogenic hemisphere (nEH). During SIAs, temporal dynamic showed more changes than auras: centrality of mesial temporal (mT) regions changes during all conditions, and nEH FP centrality showed the same dynamic trend of the aura (decreased centrality), until the last epoch, close to the impaired awareness, when showed increased centrality. Comparing SIA with aura, in proximity of impaired awareness, increased centrality was found in all the regions, except in nEH mT. Our findings suggested that the impairment of awareness is related to network alterations occurring first in neocortical regions and when awareness is still retained. The analysis of 'hub' alteration can represent a suitable biomarker for scalp EEG-based prediction of awareness impairment.


Ophthalmology in medical student education: philosophy, content, and process.
The level of competency in the diagnosis and treatment of common and emergency disorders needed by nonophthalmologists is assessed and then translated into explicit objectives that specify the levels of mastery to be learned. Effective and efficient methods and materials to achieve those objectives are developed; these, together with more efficient and effective use of instructors, have now been utilized in many different schools and curricular structures, with strong student acceptance.


Regulatory T-cell heterogeneity and the cancer immune response.
The frequency of circulating or tumour-infiltrating regulatory T cells (Tregs) has been associated with poor patient survival in many cancers including breast, melanoma and lung. It has been hypothesised that Tregs impact the anti-tumour function of effector T cells, resulting in worse outcomes for patients. However, high infiltrates of Tregs have been associated with a positive outcome of patients in a minority of cancers including colorectal, bladder and oesophageal. In addition, many studies have shown no impact of Tregs in patient outcome. Traditionally, research has identified Tregs as forkhead box P3 (FOXP3+) T cells in order to make such associations. Recently, it has become evident that regulatory populations are very heterogeneous, and this heterogeneity is essential for Treg function. Treg heterogeneity likely affects predictions of patient outcome, and different Treg populations may have different influences on tumours. The study of Tregs in cancer must include a better definition of the cells analysed. This review will focus primarily on colorectal cancer in humans, due to mixed data on the impact of Tregs on patient outcome in this disease.


Exposure therapy for PTSD: A meta-analysis.
Posttraumatic stress disorder (PTSD) is associated with high morbidity and functional impairment in the absence of effective treatment. Exposure therapy for PTSD is a trauma-focused treatment that typically includes in vivo and/or imaginal exposure. The goal of this meta-analysis was to examine the overall efficacy of exposure therapy for PTSD compared to various control conditions. We also assessed the efficacy of individual exposure-based treatments and the potentially moderating impact of various demographic, clinical, and treatment-related factors. PsycINFO and Medline were searched for randomized controlled trials of exposure-based therapies for adult PTSD. A total of 934 abstracts were screened for initial eligibility; of these, 65 articles met inclusion criteria and were included in the meta-analysis (total N = 4929 patients). Exposure therapy showed large effects relative to waitlist and treatment-as-usual, a small effect relative to non-trauma-focused comparators and a negligible effect relative to other trauma-focused treatments or medication. At follow-up most effects sizes were stable, except for a medium effect favoring exposure over medication. The individual exposure-based therapies examined were similarly effective. Moderator analyses revealed larger effect sizes in studies with fewer sessions, younger samples, fewer participants diagnosed with substance use disorder, and fewer participants on psychiatric medication. Effect sizes were also larger in studies of refugees and civilians compared to military samples, studies of PTSD related to natural disasters and transportation accidents vs. other traumatic events, and studies of individual vs. group therapy. Findings support the overall efficacy of exposure therapy and highlight that there are a number of efficacious exposure-based therapies available.


Diagnosis and treatment of microscopic colitis.
Microscopic colitis (MC) designates two types of chronic diarrhea diseases, which are lymphocytic colitis and collagenous colitis. The prevalence of microscopic colitis is increasing in both Western and Eastern countries, possibly due to the high incidence of colonoscopic survey in chronic diarrhea patients. Although the overall prognosis of MC patients is mostly good, it should be noted that appropriate diagnosis and choice of treatment is required to assure a good clinical outcome for MC patients. Also, a certain population of MC patients may take a severe and refractory clinical course, and thus require advanced clinical care using medications supported by less evidence. In this review, we would like to feature the essential points regarding the diagnosis of MC, and also describe the current standard of treatments for MC patients. In addition, we would like to add some findings from the national survey and research carried out in Japan, to compare those data with the western countries.


Orthotopic bladder reconstruction in women--what we have learned over the last decade.
Approximately 10 years ago protocols for urethra-sparing cystectomy and orthotopic urinary diversion to the urethra in female patients with bladder cancer were initiated at several centers. Long-term data regarding the oncological and functional outcome are the subject of this review. Studies regarding the relationship between primary bladder cancer and secondary urethral tumors in women revealed in most studies a lower risk for women than for men in most studies. In a recent meta-analysis the incidence of urethral tumors was 6.8% in 5657 male and 3.6% in 841 female patients with transitional cell cancer of the bladder. Anatomical and functional studies revealed that smooth musculature can be found in the entire length of the female urethra. The rhabdosphincter which is the important structure for postoperative continence in low pressure intestinal reservoirs is in the midportion of the urethra which will not be touched during urethra-sparing surgery. A recent study looked at the oncological and functional results of 102 women with orthotopic urinary diversion after a follow-up ranging from one and half to 100 months (mean 26, median 24 months). There was no perioperative mortality, and an early and late complication rate requiring secondary intervention in 5 (5%) and 12 (12%) patients. With 88 of 102 patients alive and 83 of 102 patients disease free, a disease specific survival of 74% and a disease free survival of 63% was estimated at 5 years. No pelvic recurrence was seen in 81 patients with TCC. Daytime continence was 82%; nocturnal continence was 72%. Twelve patients (12%) were unable to empty their bladders completely and needed some form of catheterization. Increasing experience in recent years confirms the initial preliminary results showing that sparing the urethra at cystectomy will not compromise oncological outcome and can be satisfactorily used for orthotopic reconstruction of the lower urinary tract. Both diurnal and nocturnal continence and clean intermittent catheterization rates after 6 months justify the use of orthotopic neobladders as the procedure of choice in the majority of female patients with bladder neoplasms.


Distinct effect of CD40 and TNF-signaling on the chemokine/chemokine receptor expression and function of the human monocyte-derived dendritic cells.
A key and limiting step in the process of human monocyte-derived dendritic cells (mDCs) for clinical use is their in vitro maturation and in vivo migration. We previously observed that CD40 signal facilitated human mDC growth and maturation. To further explore this process, mDCs generated with GM-CSF and IL-4 were co-cultured with apoptotic tumor cells for 24 hours, followed by incubating with anti-CD40 monoclonal antibody or TNF-alpha for 48 hours to generate mature DCs. The chemokine/chemokine receptor expression and functions of mature DCs upon various stimuli were determined. The expression of costimulatory molecules on apoptotic tumor cell-loaded mature DCs co-cultured with either anti-CD40 antibody (anti-CD40-DCs) or TNF-alpha (TNF-DCs) were up-regulated compared to immature DCs, consistent with the abilities of these cytokine to drive DC maturation in vitro. The mRNA levels of chemokines such as stromal cell-derived factor-1alpha (SDF-1alpha), EBV-induced molecule 1 ligand chemokine (ELC), and IFN inducible protein-10 (IP-10) in anti-CD40 activated DCs were increased and the dendritic cell-specific chemokine 1 (DC-CK1) was moderately up-regulated as compared with other mature DCs. The corresponding chemokine receptors CXCR4 and CCR7 of anti-CD40-DCs were significantly expressed. The CXCR3 expression on activated T cells stimulated by anti-CD40-DCs was also increased. Moreover, the anti-CD40-DCs had a stronger ability to stimulate T cell proliferation than any other DCs. The NF-kappaB activity was much higher in anti-CD40-DCs than that of TNF-DCs. These results offer further evidence of the importance of the CD40 signal in developing efficient human DC vaccines for cancer immune therapy.


A bladder cancer microenvironment simulation system based on a microfluidic co-culture model.
A tumor microenvironment may promote tumor metastasis and progression through the dynamic interplay between neoplastic cells and stromal cells. In this work, the most representative and significant stromal cells, fibroblasts, endothelial cells, and macrophages were used as vital component elements and combined with bladder cancer cells to construct a bladder cancer microenvironment simulation system. This is the first report to explore bladder cancer microenvironments based on 4 types of cells co-cultured simultaneously. This simulation system comprises perfusion equipment, matrigel channel units, a medium channel and four indirect contact culture chambers, allowing four types of cells to simultaneously interact through soluble biological factors and metabolites. With this system, bladder cancer cells (T24) with a tendency to form a 'reticular' structure under 3 dimensional culture conditions were observed in real time. The microenvironment characteristics of paracrine interactions and cell motility were successfully simulated in this system. The phenotype change process in stromal cells was successfully reproduced in this system by testing the macrophage effector molecule Arg-1. Arg-1 was highly expressed in the simulated tumor microenvironment group. To develop "precision medicine" in bladder cancer therapy, bladder cancer cells were treated with different clinical 'neo-adjuvant' chemotherapy schemes in this system, and their sensitivity differences were fully reflected. This work provides a preliminary foundation for neo-adjuvant chemotherapy in bladder cancer, a theoretical foundation for tumor microenvironment simulation and promotes individual therapy in bladder cancer patients.


Prognostic impact of tumor-associated macrophages, lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio in diffuse large B-cell lymphoma.
Microenvironment has a prognostic influence in diffuse large B-cell lymphoma (DLBCL); among its components, tumor-associated macrophages (TAM) play a leading role. TAM can be classified into M1 (anti-tumor) and M2 (pro-tumor). Another prognostic factor could be represented by lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio (LMR and NLR). The aim of the study is to evaluate the prognostic impact of M1 and M2 TAM subtypes, LMR and NLR in DLBCL. We analyzed 37 consecutive patients between 2009 and 2013. Out of 37 patients, 28/37 (75.6%) received R-CHOP/CHOP-like regimens, 9/37 (24.4%) less intensive therapies. Immunohistochemistry was performed with antibodies against CD68 and CD163. We divided our cohort into 2 categories according to the Steidl score. TAM who coexpressed CD68 and CD163 were considered as M2. For LMR and NLR we used previously published cut-offs of 2.71 and 2.81. CR rate was 70.3%; we did not record a significant correlation between CD68+ TAM, CD163+ TAM, CD68+/CD163+ TAM, LMR, NLR and CR. We observed a reduced PFS in patients with IPI ≥ 2 and high M2 TAM expression and a trend between higher expression of CD68+ TAM and improved PFS. M2 TAM could have a prognostic role for IPI ≥ 2 DLBCL patients receiving R-CHOP, which thus warrants further investigation.


Milan system for reporting salivary gland cytopathology: Adoption and outcomes in a community setting.
Milan system for reporting salivary gland cytopathology (MSRSGC) was introduced to standardize reporting of salivary gland cytopathology. A retrospective review of ultrasound-guided fine needle biopsy of salivary gland lesions was performed between January 2018 and May 2021 at a community otolaryngology practice. Diagnostic accuracy and rate of diagnostic sialoadenectomy were calculated. A total of 203 FNAs (fine needle aspiration) were performed in 184 patients. MSRSGC was utilized in 87/203 cytopathology reports, with a diagnostic accuracy of 84%. Descriptive reporting was used in 115 FNAs, with a diagnostic accuracy of 89% (p = 0.68). Sialoadenectomy rate was 41% for MSRSGC compared to 36% in descriptive cytopathology (p = 0.48). MSRSGC is as accurate as descriptive cytopathology and the rate of diagnostic sialoadenectomy between both groups is similar in our community. The MSRSGC brings uniformity and standardization to the FNA reporting process.


The role of autoimmune testing in chronic idiopathic urticaria.
The clinical implications of autoimmune testing in chronic idiopathic urticaria (CIU) are not well established. To identify the association of autoimmune biomarkers in CIU with disease severity. We retrospectively evaluated 195 patients with a diagnosis of CIU for the presence of antinuclear antibody (ANA), anti-thyroglobulin antibody (ATG), anti-thyroperoxidase antibody (ATPO), and Chronic Urticaria (CU) Index. The patients were categorized into controlled and refractory subgroups based on their response to antihistamines with or without a leukotriene receptor antagonist. The percentage of patients with a positive test for ANA (titer>1:160), ATG, ATPO, and CU Index were 29%, 6%, 26%, and 38%, respectively. Among those tested, the percentage of patients categorized as refractory was significantly higher in those with a positive CU index (80% vs 46%; P = .01) or a positive ANA titer (50% vs 30%; P = .04) than those with negative test results; however, a similar relationship was not observed for ATPO or ATG antibodies. Odds ratios of individual or combinations of autoimmune biomarkers in CIU were examined for associations with refractoriness to antihistamines with or without a leukotriene receptor antagonist. The CU Index alone has an odds ratio of 4.5 (P = .005), whereas the combination of ANA, ATG, and ATPO has an odds ratio of 3.1 (P = .01) and ANA alone has an odds ratio of 2.3 (P = .04) for correlating with a refractory outcome. Our data indicate the CU Index independently has the strongest correlation with disease severity followed by the combination of ANA, ATG, and ATPO and the ANA alone.