Acute systemic knockdown of Atg7 is lethal and causes pancreatic destruction in shRNA transgenic mice.
The notion that macroautophagy/autophagy is a potentially attractive therapeutic target for a variety of diseases, including cancer, largely stems from pre-clinical mouse studies. Most of these examine the effects of irreversible and organ confined autophagy deletion using site specific Cre-loxP recombination of the essential autophagy regulating genes Atg7 or Atg5. Model systems with the ability to impair autophagy systemically and reversibly at all disease stages would allow a more realistic approach to evaluate the consequences of authophagy inhibition as a therapeutic concept and its potential side effects. Here, we present shRNA transgenic mice that via doxycycline (DOX) regulable expression of a highly efficient miR30-E-based shRNA enabled knockdown of Atg7 simultaneously in the majority of organs, with the brain and spleen being noteable exceptions. Induced animals deteriorated rapidly and experienced profound destruction of the exocrine pancreas, severe hypoglycemia and depletion of hepatic glycogen storages. Cessation of DOX application restored apparent health, glucose homeostasis and pancreatic integrity. In a similar Atg5 knockdown model we neither observed loss of pancreatic integrity nor diminished survival after DOX treatment, but identified histological changes consistent with steatohepatitis and hepatic fibrosis in the recovery period after termination of DOX. Regulable Atg7-shRNA mice are valuable tools that will enable further studies on the role of autophagy impairment at various disease stages and thereby help to evaluate the consequences of acute autophagy inhibition as a therapeutic concept.Abbreviations: ACTB: actin, beta; AMY: amylase complex; ATG4B: autophagy related 4B, cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; Cag: CMV early enhancer/chicken ACTB promoter; Col1a1: collagen, type I, alpha 1; Cre: cre recombinase; DOX: doxycycline; GCG: glucagon; GFP: green fluorescent protein; INS: insulin; LC3: microtubule-associated protein 1 light chain 3; miR30-E: optimized microRNA backbone; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; PNLIP: pancreatic lipase; rtTA: reverse tetracycline transactivator protein; SQSTM1/p62: sequestome 1; TRE: tetracycline responsive element.


Addressing the challenges of diagnostics demand and supply: insights from an online global health discussion platform.
Several barriers challenge development, adoption and scale-up of diagnostics in low and middle income countries. An innovative global health discussion platform allows capturing insights from the global health community on factors driving demand and supply for diagnostics. We conducted a qualitative content analysis of the online discussion 'Advancing Care Delivery: Driving Demand and Supply of Diagnostics' organised by the Global Health Delivery Project (GHD) (http://www.ghdonline.org/) at Harvard University. The discussion, driven by 12 expert panellists, explored what must be done to develop delivery systems, business models, new technologies, interoperability standards, and governance mechanisms to ensure that patients receive the right diagnostic at the right time. The GHD Online (GHDonline) platform reaches over 19 000 members from 185 countries. Participants (N=99) in the diagnostics discussion included academics, non-governmental organisations, manufacturers, policymakers, and physicians. Data was coded and overarching categories analysed using qualitative data analysis software. Participants considered technical characteristics of diagnostics as smaller barriers to effective use of diagnostics compared with operational and health system challenges, such as logistics, poor fit with user needs, cost, workforce, infrastructure, access, weak regulation and political commitment. Suggested solutions included: health system strengthening with patient-centred delivery; strengthened innovation processes; improved knowledge base; harmonised guidelines and evaluation; supply chain innovations; and mechanisms for ensuring quality and capacity. Engaging and connecting different actors involved with diagnostic development and use is paramount for improving diagnostics. While the discussion participants were not representative of all actors involved, the platform enabled a discussion between globally acknowledged experts and physicians working in different countries.


Concentration-dependent color tunability of nitrogen-doped carbon dots and their application for iron(III) detection and multicolor bioimaging.
Nitrogen doping can effectly adjust the compositions and structures of carbon dots and hence enhance their fluorescence. In this work, we report a fast and low-cost route for synthesis of nitrogen-doped carbon dots (N-CDs) by microwave pyrolysis of citric acid and ammonium within 7 min. The as-prepared N-CDs contain plentiful oxygen and nitrogen functional groups, and dispaly intense fluorescence with high quantum yield of ca. 44.3% and have an average size of 1.8 nm. The obtained N-CDs exhibit highly stable against photobleaching, ionic strengths, and can be used for selective and sensitive detection of Fe(III). It is postulated that the Fe3+-mediated fluorescence quenching is attributed to the charge transfer between N-CDs and Fe3+. In particular, the emission peaks from blue to red region can be tuned by interparticle distance of N-CDs, simply by increasing the concentration of N-CDs in aqueous solution, which indicates its potential applications as a promising optical image probe in multicolor cellular imaging.


[Ultrasound characteristics of partially cystic thyroid nodules and their relationship with differential diagnosis of the lesions].
To explore the ultrasound (US) findings of partially cystic thyroid nodules (PCTNs) and to analyze their relationship with differential diagnosis of benign and malignant lesions. 265 cases of PCTNs confirmed by needle biopsy or surgical pathology were included in this study. Their ultrasound characteristics were reviewed and their significance in differential diagnosis was analyzed. In the 265 PTCNs, 53 cases were malignant and 212 cases were benign lesions. According to the comparison of ultrasound and pathology results, there were 51 true-positive cases, 208 true negative cases, four false-positive cases and two false negative cases;the sensitivity was 96.2% (51/53), specificity was 98.1% (208/212), positive predictive value (PPV) was 92.7% (51/55), negative predictive values (NPV) was 99.0% (208/210), and accuracy rate was 97.7% (259/265). In terms of the PTCNs, internal structure, shape and margin were significantly associated with malignant or benign nature (P < 0.001); the aspect ratio ≥ 1, spiculated or micro-lobulated margin were significantly associated with malignancy; while the smooth margin, spongiform structure were significantly associated with benign nature. In terms of the internal solid portion of the nodules, the configuration, free margin, echogenecity, and calcification were significantly associated with malignant or benign nature (P < 0.001). The eccentric configuration with an acute angle, non-smooth free margin, hypoechogenecity, marked hypoechogenecity and micro-calcification were significantly associated with malignancy; while concentric configuration, smooth free margin, hyper/isoechogenicity, free margin of the solid component, and macro-calcifications were significantly associated with benign nature (P < 0.01). The results of logistic regression analysis showed that the echogenicity, free margin, configuration and calcification of the solid component were important predictive factors of malignant lesions (P < 0.05), that the hypoechogenecity, marked hypoechogenecity, eccentric configuration with an acute angle, non-smooth free margin and micro-calcification of the internal solid portion of the nodules were predictors for malignant PTCNs (P < 0.01). Understanding the characteristics of US findings of partially cystic thyroid nodules is of great importance to make an accurate diagnosis of malignant nodules.


Long-acting reversible contraception use among residents in obstetrics/gynecology training programs.
The objective of the study was to estimate the personal usage of long-acting reversible contraception (LARC) among obstetrics and gynecology (Ob/Gyn) residents in the United States and compare usage between programs with and without a Ryan Residency Training Program (Ryan Program), an educational program implemented to enhance resident training in family planning. We performed a web-based, cross-sectional survey to explore contraceptive use among Ob/Gyn residents between November and December 2014. Thirty-two Ob/Gyn programs were invited to participate, and 24 programs (75%) agreed to participate. We divided respondents into two groups based on whether or not their program had a Ryan Program. We excluded male residents without a current female partner as well as residents who were currently pregnant or trying to conceive. We evaluated predictors of LARC use using bivariate analysis and multivariable Poisson regression. Of the 638 residents surveyed, 384 (60.2%) responded to our survey and 351 were eligible for analysis. Of those analyzed, 49.3% (95% confidence interval [CI]: 44.1%, 54.5%) reported current LARC use: 70.0% of residents in Ryan Programs compared to 26.8% in non-Ryan Programs (RRadj 2.14, 95% CI 1.63-2.80). Residents reporting a religious affiliation were less likely to use LARC than those who described themselves as non-religious (RRadj 0.76, 95% CI 0.64-0.92). Of residents reporting LARC use, 91% were using the levonorgestrel intrauterine device. LARC use in this population of women's health specialists is substantially higher than in the general population (49% vs. 12%). Ob/Gyn residents in programs affiliated with the Ryan Program were more likely to use LARC.


OXBench: a benchmark for evaluation of protein multiple sequence alignment accuracy.
The alignment of two or more protein sequences provides a powerful guide in the prediction of the protein structure and in identifying key functional residues, however, the utility of any prediction is completely dependent on the accuracy of the alignment. In this paper we describe a suite of reference alignments derived from the comparison of protein three-dimensional structures together with evaluation measures and software that allow automatically generated alignments to be benchmarked. We test the OXBench benchmark suite on alignments generated by the AMPS multiple alignment method, then apply the suite to compare eight different multiple alignment algorithms. The benchmark shows the current state-of-the art for alignment accuracy and provides a baseline against which new alignment algorithms may be judged. The simple hierarchical multiple alignment algorithm, AMPS, performed as well as or better than more modern methods such as CLUSTALW once the PAM250 pair-score matrix was replaced by a BLOSUM series matrix. AMPS gave an accuracy in Structurally Conserved Regions (SCRs) of 89.9% over a set of 672 alignments. The T-COFFEE method on a data set of families with <8 sequences gave 91.4% accuracy, significantly better than CLUSTALW (88.9%) and all other methods considered here. The complete suite is available from http://www.compbio.dundee.ac.uk. The OXBench suite of reference alignments, evaluation software and results database provide a convenient method to assess progress in sequence alignment techniques. Evaluation measures that were dependent on comparison to a reference alignment were found to give good discrimination between methods. The STAMP Sc Score which is independent of a reference alignment also gave good discrimination. Application of OXBench in this paper shows that with the exception of T-COFFEE, the majority of the improvement in alignment accuracy seen since 1985 stems from improved pair-score matrices rather than algorithmic refinements. The maximum theoretical alignment accuracy obtained by pooling results over all methods was 94.5% with 52.5% accuracy for alignments in the 0-10 percentage identity range. This suggests that further improvements in accuracy will be possible in the future.


[Usefulness of chest CT in diagnosing pneumonia].
The usefulness of chest CT in diagnosing pneumonia was evaluated by a retrospective review of 110 pneumonia cases in which both plain chest radiograph and CT were obtained. Detection of abnormal opacities on chest radiograph was difficult or impossible in 9 cases (8.2%), requiring CT to detect them. The opacities which appeared consolidative, nodular, small nodular or cavitary on chest radiograph were shown as opacities of similar character on CT. On the other hand, many opacities of patchy, ground-glass or linear/reticular character on chest radiograph were shown as opacities of different character on CT. One case out of 3 of mycoplasma pneumonia, one case each of influenza viral pneumonia and pneumocystis carinii pneumonia and showed rather typical appearance on CT. Detection of pleural effusion on chest radiograph was difficult in 17 (58.6%) of 29 cases in which it was easily detected on CT. In conclusion, CT is useful in diagnosing pneumonia in limited cases, as follows: (1) indistinct abnormal opacity on chest radiograph despite positive clinical signs of pneumonia, (2) patchy, ground-glass or linear/reticular opacities on chest radiograph, (3) confirmation of pleural effusion, (4) close observation of sequential changes of opacity after starting treatment of pneumonia. In contrast, CT is not generally useful in evaluating consolidative opacities on chest radiograph.


Resin-bonded prosthodontics. An update.
First-generation designs that covered a large area of enamel but had minimal retentive features still provided sufficient longevity to be classified as "permanent" type restorations. The goal of long-term service can be realized more consistently by incorporating second-generation designs with the ease of adhesive bonding.


Evaluation of the New BD Max GC Real-Time PCR Assay, Analytically and Clinically as a Supplementary Test for the BD ProbeTec GC Qx Amplified DNA Assay, for Molecular Detection of Neisseria gonorrhoeae.
The new BD Max GC real-time PCR assay showed high clinical and analytical sensitivity and specificity. It can be an effective and accurate supplementary test for the BD ProbeTec GC Qx amplified DNA assay, which had suboptimal specificity, and might also be used for initial detection of Neisseria gonorrhoeae.


The unique activity of saponin: Induction of cytotoxicity in HTLV-1 infected cells.
Infection with the retrovirus human T-cell leukemia virus type 1 (HTLV-1) sometimes causes diseases that are difficult to cure. To find anti-HTLV-1 natural compounds, we opted to screen using the HTLV-1-infected T-cell line, MT-2. Based on our results, an extract of the pulp/seeds of Akebia quinata Decaisne fruit killed MT-2 cells but did not affect the Jurkat cell line that was not infected with virus. To determine the active ingredients, seven saponins with one-six sugar moieties were isolated from A. quinata seeds, and their activities against the two cell lines were examined. Both cell lines were killed in a similar manner by Akebia saponins A and B. Further, Akebia saponins D, E, PK and G did not exhibit cytotoxicity. Akebia saponin C had a similar activity to the extract found in the screening. This compound was found to enhance Gag aggregation, induce the abnormal cleavage of Gag, suppress virion release, and preferentially kill HTLV-1 infected cells; however, their relationship remains elusive. Our findings may lead to the development of new therapies for infectious diseases based on the removal of whole-virus-infected cells.


[Phlebotomine sandflies and transmission of disease agents around the Mediterranean basin].
Around 800 species of phlebotomine sandflies are widely distributed in tropical and temperate areas. Some sand flies are documented vectors of human disease agents including parasitic protozoa, (Leishmania spp), bacteria (Bartonella bacilliformis) and viruses (phlebovirus). In addition to presenting morphologic, taxonomic and biologic aspects of Phlebotomine sandflies, this report focuses on ecologic, epidemiologic, ethologic, and anthropic factors contributing to the proliferation of sand flies as exemplified by zoonotic cutaneous and visceral leishmaniases around the Mediterranean basin.


Peritonitis in children on chronic peritoneal dialysis: analysis at 10 years.
Peritoneal dialysis is the major form of renal replacement therapy for children awaiting renal transplantation. Peritonitis is the major associated morbidity. We retrospectively identified the pathogens, co-morbid factors and outcome of peritonitis in children on peritoneal dialysis from 1980-1989. Seventy-three children, mean age 12.4 years, received 1,234 patient months of chronic peritoneal dialysis. Twenty-four patients (33%) remained peritonitis free until their dialysis catheters were removed after transplantation. Forty-nine children (67%) developed 219 episodes of peritonitis. Peritoneal fluid cultures were positive in 169 episodes (77%). Of the pathogens identified, 73% were gram positive cocci, 22% gram negative rods, 3% were fungus, and 2% other organisms. The incidence of peritonitis was one episode per 5.6 months. Over a 10 year period: 1) 67% of children on peritoneal dialysis developed peritonitis; 2) gram positive cocci accounted for most episodes; 3) the incidence in children was higher than that reported for adults; 4) there were no deaths attributable to peritonitis.


Mutations in BTD gene causing biotinidase deficiency: a regional report.
Biotinidase deficiency is an autosomal recessive inborn error of biotin metabolism. Children with biotinidase deficiency cannot cleave biocytin and, therefore, cannot recycle biotin. Untreated individuals become secondarily biotin deficient, which in turn results in decreased activities of the biotin-dependent carboxylases and the subsequent accumulation of toxic metabolites causing clinical symptoms. Biotinidase deficiency is characterized by neurological, cutaneous manifestations and metabolic abnormalities. The worldwide incidence of profound biotinidase deficiency has been estimated at 1:112,271. The human biotinidase gene is located on chromosome 3p25 and consists of four exons with a total length of 1629 base pairs. To date, more than 100 mutations in the biotinidase gene known to cause biotinidase deficiency have been reported. The vast majority of mutations are homozygous or compound heterozygous. Finding known mutations can be correlated with the biochemical enzymatic results. This report summarizes the demographic features of patients identified as biotinidase deficient from August of 2012 through August of 2013 and mutation analysis results for 20 cases in the southeast region of Turkey.


Ultrasonography-Derived Elasticity Estimation of Live Porcine Oral Mucosa.
To investigate the biomechanical properties of porcine oral tissues with in vivo ultrasonography and to compare the difference between oral alveolar mucosa and gingival tissue concerning compressional and tensile mechanical strain. Sinclair minipigs (6 females and 4 males, 6 to 18 months of age) were anesthetized for ultrasonography. In vivo high-frequency tissue harmonic ultrasound (12/24 MHz) cine-loops were obtained while inducing mechanical tissue stress (0 to 1 N). Post-processing strain analysis was performed in a cardiac speckle tracking software (EchoInsight®). Region of interest (ROI) was placed for gingival and alveolar mucosa tissues for longitudinal (compressional) and tensile strain analyses. A calibrated gel pad was employed to determine the absolute force (pressure) for the measured tissue strain response function. The resulting elasticity data was statistically analyzed using custom Matlab scripts. In total, 38 sonography cine-loops around the third premolars were included in the investigation. The longitudinal strain of alveolar mucosa ε AM L $$ {\varepsilon}_{AM}^L $$ was found to be significantly (P < .05) larger than that of gingiva ε G L $$ {\varepsilon}_G^L $$ . Across the measured force range, ε AM L $$ {\varepsilon}_{AM}^L $$ ~ 1.7 × ε G L $$ {\varepsilon}_G^L $$ . Significant differences between alveolar mucosa and gingiva tissues were found for all forces. The tensile strain of the alveolar mucosa ε AM T $$ {\varepsilon}_{AM}^T $$ was found to be ~2 × ε G T $$ {\varepsilon}_G^T $$ (on the epithelial surface of the gingiva). Both were statistically significantly different for forces exceeding ~0.08 N. At depth, that is, 500 and 1000 μm below the epithelial surface, the gingiva was found to have less ability to stretch contrary to the alveolar mucosa. Gingival tissue at 500 μm depth has significantly less tensile strain than at its surface and more than at 1000 μm depth. In contrast, the tensile strain of alveolar mucosa is largely independent of depth. Ultrasonography can reveal significant differences in oral alveolar mucosal and gingival elastic properties, such as compressional and tensile strain. Under minute forces equivalent to 10 to 40 g, these differences can be observed. As dental ultrasound is a chairside, and noninvasive modality, obtaining real-time images might soon find clinical utility as a new diagnostic tool for the objective and quantitative assessment of periodontal and peri-implant soft tissues in clinical and research realms. As ultrasound is a safe modality with no known bioeffects, longitudinal monitoring of areas of concern would be particularly attractive.


Nanoscopic confinement through self-assembly: crystallization within micellar cores exhibits simple Gibbs-Thomson behavior.
It is well known that liquids confined to small nanoscopic pores and droplets exhibit thermal behavior very different from bulk samples. Less is known about liquids spontaneously confined through self-assembly into micellar structures. Here we demonstrate, using a very well-defined n-alkyl-poly(ethylene oxide) polymer system with a tunable structure, that n-alkane(s) forming 2-3 nm small micellar cores are affected considerably by confinement in the form of melting point depressions. Moreover, comparing the reduction in melting points, ΔT_{m}, determined through volumetric and calorimetric methods with the micellar core radius, R_{c}, obtained from small-angle x-ray scattering, we find excellent agreement with the well-known Gibbs-Thomson equation, ΔT_{m}∼R_{c}^{-1}. This demonstrates that the reduced size, i.e., the Laplace pressure, is the dominant parameter governing the melting point depression in micellar systems.


Cross-organ sensitization between the prostate and bladder in an experimental rat model of lipopolysaccharide (LPS)-induced chronic pelvic pain syndrome.
The aim of the current study was to investigate the effects of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) on bladder function via prostate-to-bladder cross-sensitization in a rat model of lipopolysaccharide (LPS)-induced prostate inflammation. Male rats were intraprostatically injected with LPS or saline, serving as control. Micturition parameters were examined in a metabolic cage 10 or 14 days later. Subsequently, to evaluate bladder function, cystometry was performed. Micturition cycles were induced by saline infusion and cholinergic and purinergic contractile responses were measured by intravenous injection with methacholine and ATP, respectively. Thereafter, the prostate and bladder were excised and assessed histopathologically for possible inflammatory changes. Metabolic cage experiments showed increased urinary frequency in rats with LPS-induced CP/CPPS. Cystometry showed a significant increase in the number of non-voiding contractions, longer voiding time and lower compliance in CP/CPPS animals compared to controls. Induction of CP/CPPS led to significantly reduced cholinergic and purinergic bladder contractile responses. Histopathological analysis demonstrated prostatic inflammation in CP/CPPS animals. There were no significant differences between the groups regarding the extent or the grade of bladder inflammation. Prostate weight was not significantly different between the groups. The present study shows that prostate-to-bladder cross-sensitization can be triggered by an infectious focus in the prostate, giving rise to bladder overactivity and alterations in both afferent and efferent signalling. Future studies are required to fully understand the underlying mechanisms.


Singular Points of Polarizations in the Momentum Space of Photonic Crystal Slabs.
Bound states in the continuum (BICs), circularly polarized states (C points) and degenerate states are all of three types of singular points of polarization in the momentum space. For photonic crystal slabs (PhCSs) with linearly polarized far fields, BICs were found to be the centers of polarization vortices and attracted more attention in the previous studies. Here, we theoretically demonstrate that the far fields of PhCSs can exhibit remarkably diverse polarizations due to the robust existences of C points in the continuum. Only a pair of C points with identical handedness and opposite topological charge can be annihilated together. Continuously fine tuning of the structure parameters of PhCSs without breaking their symmetry, a pair of C points with identical topological charge and opposite handedness are able to merge into a BIC, then the BIC splits into C points again. Interestingly, a Dirac-degenerate BIC with one-half of topological charge is observed when two pairs of C points with identical topological charge from the upper and lower band, respectively, simultaneously merge at the Dirac-degenerate point. The law of topological charge conservation is verified to play an important role in the evolutions and interconversions between different types of polarization singularities. Our findings might shed light on the origin of singular points of polarization, could open a gateway towards the applications of them in the generation and manipulation of vector beams.


Cutting edge: TCR revision occurs in germinal centers.
Mouse CD4(+)Vbeta5(+) T cells recognize a peripherally expressed superantigen encoded by an endogenous retrovirus. Ag encounter tolerizes the mature CD4 T cell compartment, either by deletion of autoreactive cells or by TCR revision. This latter process is driven by TCRbeta rearrangement through RAG activity and results in the rescue of cells expressing novel TCRs that no longer recognize the tolerogen. Consistent with the notion that revising T cells represent a distinct peripheral T cell population, we now show that these lymphocyte blasts express a hybrid effector/memory phenotype and are not undergoing cell division. A population of revising T cells is CD40(+), expresses the germinal center (GC) marker CXCR5, and is Vbeta5(low)Thy-1(low). Histology reveals that, consistent with their surface Ag phenotype, T cells undergoing TCR revision are enriched in splenic GCs. These data demonstrate that TCR revision is a multistep tolerance pathway supported by the unique microenvironment provided by GCs.


[Analysis of gene loci and epistasis for drought tolerance in seedling stage of rice (Oryza sativa L.)].
Drought tolerance of rice is important because a considerable proportion of the world rice area is not irrigated and is prone to water deficit. In this study, an indica variety, Zhai Ye Qing 8 (ZYQ8), and a japonica variety, Jing Xi 17 (JX17), and their double haploid (DH) population were used for genetic study of drought tolerance. Water supply was stopped in seedling period for 15 days and then drought tolerance of the DH population and their parents were investigated. Mapping quantitative trait loci (QTLs) was undertaken base on the constructed molecular linkage map of this population. Two QTLs (qDR-5 and qDR-12) for drought tolerance were identified, they were in the region of GA41-GA257 on chromosome 5 and RG457-Y12817R on chromosome 12, respectively. The tolerance alleles of both QTLs were from the indica parent, ZYQ8. In the meantime two genes for drought tolerance near GA257 and Y12817R were detected too by using Epistat software, that is in accordance with the result by using Mapmaker/QTL. In addition, three loci (RG541, G318 and G192 on chromosome 1, 4 and 8, respectively) were found interacting with GA257 by Epistat software, while one locus (CT234 on chromosome 3) found interacting with Y12817R were also detected by Epistat software.


Lymphocytic Hypophysitis Mimicking Pituitary Macroadenoma.
Lymphocytic hypophysitis is an inflammatory /autoimmune disorder that primarily involves the pituitary gland and the pituitary stalk. The common clinical presentations include headache, nausea, vomiting, fatigue, features of hypopituitarism and diabetes insipidus as well as diplopia, orbital pain and bitemporal hemianopia. We report a case of lymphocytic hypophysitis which presented as hemichorea. Neuroimaging showed a mass in the sella tursica region which, on histopathological examination was suggestive of lymphocytic hypophysitis. After excision of this mass, patient showed marked improvement in his symptoms albeit he developed panhypopituitarism. The patient was treated with pituitary hormonal replacement therapy and is currently asymptomatic.


Nickel-responsive regulation of two novel Helicobacter pylori NikR-targeted genes.
Nickel is an essential transition metal for the survival of Helicobacter pylori in the acidic human stomach. The nickel-responsive transcriptional regulator HpNikR is important for maintaining healthy cytosolic nickel concentrations through the regulation of multiple genes, but its complete regulon and role in nickel homeostasis are not well understood. To investigate potential gene targets of HpNikR, ChIP sequencing was performed using H. pylori grown at neutral pH in nickel-supplemented media and this experiment identified HPG27_866 (frpB2) and HPG27_1499 (ceuE). These two genes are annotated to encode a putative iron transporter and a nickel-binding, periplasmic component of an ABC transporter, respectively. In vitro DNA-binding assays revealed that HpNikR binds both gene promoter sequences in a nickel-responsive manner with affinities on the order of ∼10(-7) M. The recognition sites of HpNikR were identified and loosely correlate with the HpNikR pseudo-consensus sequence (TATTATT-N11-AATAATA). Quantitative PCR experiments revealed that HPG27_866 and HPG27_1499 are transcriptionally repressed following growth of H. pylori G27 in nickel-supplemented media, and that this response is dependent on HpNikR. In contrast, iron supplementation results in activation of HPG27_1499, but no impact on the expression of HPG27_866 was observed. Metal analysis of the Δ866 strain revealed that HPG27_866 has an impact on nickel accumulation. These studies demonstrate that HPG27_866 and HPG27_1499 are both direct targets of HpNikR and that HPG27_866 influences nickel uptake in H. pylori.


Controlling the Phase Behavior of Low and Negative Thermal Expansion ReO3-Type Fluorides using Interstitial Anions: Sc1-xZrxF3+x.
Density measurements suggest that the incorporation of ZrF4 into the cubic ReO3-type structure of Sc1-xZrxF3+x is associated with the creation of anion interstitials. X-ray total scattering measurements are consistent with the conversion of corner-sharing octahedra to edge-sharing polyhedra as the solid solutions become richer in ZrF4. The cubic (Pm3̅m) to rhombohedral (R3̅c) cooperative octahedral tilting transition seen for ScF3 moves to a higher pressure as increasing amounts of zirconium are added, and it is eventually suppressed completely (x = 0.4 and 0.5) so that the cubic phase persists to high pressure until an amorphization occurs. All the samples studied (x = 0.0, 0.1, 0.2, 0.3, 0.4, and 0.5) display pressure-induced softening, and increasing the zirconium content leads to a higher zero-pressure bulk modulus. The incorporation of "excess fluoride" into ReO3-type fluorides is a powerful tool for suppressing the generally unwanted phase transitions seen when subjecting these materials to stress.


Strategy difficulty effects in young and older adults' episodic memory are modulated by inter-stimulus intervals and executive control processes.
Efficient execution of strategies is crucial to memory performance and to age-related differences in this performance. Relative strategy complexity influences memory performance and aging effects on memory. Here, we aimed to further our understanding of the effects of relative strategy complexity by looking at the role of cognitive control functions and the time-course of the effects of relative strategy complexity. Thus, we manipulated inter-stimulus intervals (ISI) and assessed executive functions. Results showed that (a) performance as a function of the relative strategy difficulty of the current and previous trial was modulated by ISI, (b) these effects were modulated by inhibition capacities, and (c) significant age differences were found in the way ISI modulates relative strategy difficulty. These findings have important implications for understanding the relationships between aging, executive control, and strategy execution in episodic memory.


Applications of Nonenzymatic Catalysts to the Alteration of Natural Products.
The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogues of natural products by this approach is then described as a quintessential "late-stage functionalization" exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this Review is on the recent studies of nonenzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C-H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C-C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates, and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.


Design and Evaluation of a Training Protocol for a Photographic Method of Visual Estimation of Fruit and Vegetable Intake among Kindergarten Through Second-Grade Students.
To design a replicable training protocol for visual estimation of fruit and vegetable (FV) intake of kindergarten through second-grade students through digital photography of lunch trays that results in reliable data for FV served and consumed. Protocol development through literature and researcher input was followed by 3 laboratory-based trainings of 3 trainees. Lunchroom data collection sessions were done at 2 elementary schools for kindergarten through second-graders. Intraclass correlation coefficients (ICCs) were used. By training 3, ICC was substantial for amount of FV served and consumed (0.86 and 0.95, respectively; P < .05). The ICC was moderate for percentage of fruits consumed (0.67; P = .06). In-school estimates for ICCs were all significant for amounts served at school 1 and percentage of FV consumed at both schools. The protocol resulted in reliable estimation of combined FV served and consumed using digital photography. The ability to estimate FV intake accurately will benefit intervention development and evaluation.


The clinical significance and management of microleakage. Part one.
This research reviews relevant articles related to microleakage from 1966 to the present. The review discusses what the sensation of microleakage is clinically; how dentin permeability is related to microleakage; how the quality of dentin affects permeability and microleakage; what the effects of bacterial infiltration from microleakage can be, as well as the body's defenses against bacterial infiltration within the tooth complex; how caries and microleakage are related; and how various materials and procedures can be used to limit microleakage.


Personality as a mediator of autistic traits and internalizing symptoms in two community samples.
Autism spectrum disorder (ASD) is characterized by deficits in social functioning and is comorbid with internalizing disorders and symptoms. While personality is associated with these symptoms and social functioning in non-ASD samples, its role mediating the relationship between ASD traits and internalizing symptoms is not clear. We studied the mediating effect of personality on the correlations between ASD traits and internalizing symptoms (i.e., depression, anxiety, stress) in two samples. Additionally, we explored the moderating effect of gender. Analyses were applied to a small (Study 1; N = 101) undergraduate sample. A broader sample recruited via an online crowdsourcing platform (Study 2; N = 371) was used to validate the results. Study 1's mediation analyses revealed that neuroticism was the only significant mediator. Study 2 replicated these results by finding extraversion to be an additional mediator for anxiety and extraversion, openness, and agreeableness as additional mediators for stress. Moderation analyses revealed that gender was never a significant moderator. These results support the effects of personality on the relationship between autism traits and internalizing symptoms. Future research should explore these effects in clinical samples to better understand the role of personality in symptomatology and the need to address it as part of intervention.


Confidential health care for adolescents: reconciling clinical evidence with family values.
Community debate about confidential health care for adolescents was triggered recently by the federal government's proposal to allow parents of teenagers aged 16 years and under access to their children's Health Insurance Commission data without their consent. Extensive research evidence highlights the importance of confidentiality in promoting young people's access to health care, particularly for sensitive issues such as mental and sexual health, and substance use. Involving parents is important, but evidence for any benefit from mandatory parental involvement is lacking. The law recognises the rights of mature minors to make decisions about their medical treatment and to receive confidential health care; however, the doctor must weigh up certain factors to assess maturity and ensure that confidentiality around such treatment will be in the young person's best interests. Evaluation of maturity must take into account characteristics of the young person, gravity of the proposed treatment, family factors, and statutory restrictions.


Epicutaneous antigen exposure induces a Th17 response that drives airway inflammation after inhalation challenge.
IL-17 has been implicated in a number of inflammatory diseases, but the conditions of antigen exposure that drive the generation of Th17 responses have not been well defined. Epicutaneous (EC) immunization of mice with ovalbumin (OVA), which causes allergic skin inflammation with many characteristics of the skin lesions of atopic dermatitis, was found to also drive IL-17 expression in the skin. EC, but not i.p., immunization of mice with OVA drove the generation of IL-17-producing T cells in draining lymph nodes and spleen and increased serum IL-17 levels. OVA inhalation by EC-sensitized mice induced IL-17 and CXCL2 expression and neutrophil influx in the lung along with bronchial hyperreactivity, which were reversed by IL-17 blockade. Dendritic cells trafficking from skin to lymph nodes expressed more IL-23 and induced more IL-17 secretion by naïve T cells than splenic dendritic cells. This was inhibited by neutralizing IL-23 in vitro and by intradermal injection of anti-TGFbeta neutralizing antibody in vivo. Our findings suggest that initial cutaneous exposure to antigens in patients with atopic dermatitis may selectively induce the production of IL-17, which, in turn, drives inflammation of their airways.


The torsional vibration of the CO2-N2O complex determined from its infrared spectrum.
The spectra of the weakly bound complex CO(2)-N(2)O are studied in the regions of the nu(1) and nu(3) fundamentals of N(2)O and the nu(3) fundamental of CO(2) using a rapid-scan tunable diode laser spectrometer to probe a pulsed supersonic jet expansion. Five bands are measured and analyzed, of which four have not been previously studied. Two bands at 2225.75 and 1279.58 cm(-1), with a/b-type rotational structure, are assigned to the nu(1) and nu(3) fundamentals of the N(2)O component of the complex. Small perturbations are noted in the nu(3) band, similar to those observed previously for the nonpolar dimer (N(2)O)(2) in the nu(3) and nu(1)+nu(3) regions. The previously known band at 2348.86 cm(-1) in the region of the nu(3) CO(2) stretch is analyzed in improved detail. Weaker c-type bands at 2251.46 and 2374.67 cm(-1) are assigned as combinations of the intermolecular torsional (out-of-plane) vibration plus the N(2)O nu(1) and CO(2) nu(3) stretches, respectively. The resulting torsional frequency of CO(2)-N(2)O is experimentally determined for the first time to be 25.8 cm(-1).


[Thermal physiological analysis of man in an Intravehicular Activity space suit].
To analyze the thermal physiological changes of man in a Intravehicular Activity (IVA) space suit. Combined second design was used to arrange 24 tests in 6 young male subjects wearing an IVA space suit at sea level. The relationship between common thermal physiological measurements and air ventilating parameters (air temperature, flow rate and its relative humidity) together with metabolic state (rest or work) of man were established in mathematical models. Possible applications of these models were illustrated. Metabolic heat production which influences the relations was also discussed. Thermal physiological changes of man in the space suit were properly expressed by the mathematical models in this paper.


Silent Breathlessness: A Case and Brief Review of Spontaneous Pneumomediastinum.
Spontaneous pneumomediastinum is an uncommon diagnosis defined as the presence of free air in the mediastinum without an apparent cause. It is a self-limiting disorder that most often occurs in young males without any apparent precipitating factor or underlying disease process. Its pathophysiology involves the rupture of alveoli with resultant air penetration into the mediastinum. Underlying disease processes, such as asthma, physical trauma, including yelling, contact sports, and Valsalva during labor, have also been reported to cause spontaneous pneumomediastinum. Here, we present the case of an 18-year-old male who presented to us with the chief complaint of cough and the subsequent diagnosis of spontaneous pneumomediastinum.


Identification of Nine mRNA Signatures for Sepsis Using Random Forest.
Sepsis has high fatality rates. Early diagnosis could increase its curating rates. There were no reliable molecular biomarkers to distinguish between infected and uninfected patients currently, which limit the treatment of sepsis. To this end, we analyzed gene expression datasets from the GEO database to identify its mRNA signature. First, two gene expression datasets (GSE154918 and GSE131761) were downloaded to identify the differentially expressed genes (DEGs) using Limma package. Totally 384 common DEGs were found in three contrast groups. We found that as the condition worsens, more genes were under disorder condition. Then, random forest model was performed with expression matrix of all genes as feature and disease state as label. After which 279 genes were left. We further analyzed the functions of 279 important DEGs, and their potential biological roles mainly focused on neutrophil threshing, neutrophil activation involved in immune response, neutrophil-mediated immunity, RAGE receptor binding, long-chain fatty acid binding, specific granule, tertiary granule, and secretory granule lumen. Finally, the top nine mRNAs (MCEMP1, PSTPIP2, CD177, GCA, NDUFAF1, CLIC1, UFD1, SEPT9, and UBE2A) associated with sepsis were considered as signatures for distinguishing between sepsis and healthy controls. Based on 5-fold cross-validation and leave-one-out cross-validation, the nine mRNA signature showed very high AUC.


Stable colloidal dispersions of C60 fullerenes in water: evidence for genotoxicity.
Stable aqueous suspensions of colloidal C60 fullerenes free of toxic organic solvents were prepared by two methods: ethanol to water solvent exchange (EthOH/nC60 suspensions) and extended mixing in water (aqu/nC60 suspensions). The extended mixing method resulted in the formation of larger (dp approximately 178 nm) and less negatively charged (zeta approximately -13.5 mV) nC60 colloids than nC60 prepared by ethanol to water solvent exchange (dp approximately 122 nm, zeta approximately -31.6 mV). Genotoxicity of these suspensions was evaluated with respect to human lymphocytes using single-cell gel electrophoresis assay (Comet assay). The assay demonstrated genotoxicity for both types of suspensions with a strong correlation between the genotoxic response and nC60 concentration, and with genotoxicity observed at concentrations as low as 2.2 microg/L for aqu/nC60 and 4.2 microg/L for EtOH/nC60. The Olive tail moments (OTM) for these two concentrations were 1.54 +/- 0.24 and 1.34 +/- 0.07, respectively, which in comparison to the negative control OTM of 0.98 +/- 0.17 is statistically different with a p value of at least 0.05. Aqu/nC60 suspensions elicited higher genotoxic response than EthOH/nC60 for the same nC60 concentration. The results represent the first genotoxicity data for colloidal fullerenes produced by simple mixing in water.


Causes and treatment outcome of mechanical bowel obstruction in north eastern Nigeria.
Mechanical bowel obstruction is one of the commonest surgical emergencies in the tropics. There has been a recent change in its commonest aetiology from external abdominal hernias to adhesions however data on the subject from this environment are lacking. To establish the aetiological factors, clinical presentation, treatment methods and outcome of mechanical bowel obstruction (MBO) in Maiduguri. A retrospective review of all cases of MBO that presented to the surgical services of the University of Maiduguri Teaching Hospital (UMTH) between Jan 1994 and March 2004 was under taken. There were 372 patients ranging between ages five days and 90 years with a male: female ratio of 2.4:1. The mean age was 34.5 years. Patients below 10 years and those between the third and fifth decades accounted for 227(60%) of the cases. Abdominal pain 330 (88.7%), vomiting 316 (84.8%), and constipation 293 (78.8%) were the main symptoms while tenderness and abdominal masses were common signs. Obstructed external hernias, 131 (35.0%) were the commonest cause of MBO; with indirect inguinal hernia 105, (80.1%) accounting for most hernias. Intraperitoneal adhesions 99, accounted for 26.61% of cases. Other causes in descending order were intussusception 80 (21.5%), malignant colonic obstruction 34 (9.14%) and sigmoid volvulus 11 (2.95%). There were no cases of MBO due to Ascaris worms. Adhesiolysis and bowel resection were the commonest operative procedures performed. Common postoperative complications included wound infection 57 (15.3%) and pneumonia 35 (9.4%). There were 34 deaths; giving a mortality rate of 9.14%. Strangulated external hernias remain the main cause of MBO though its incidence appears to be falling. The pattern of MBO seems to be affected by changing attitude to and availability of elective operations for external abdominal hernias.


Airway smooth muscle function in asthma.
Known to have affected around 340 million people across the world in 2018, asthma is a prevalent chronic inflammatory disease of the airways. The symptoms such as wheezing, dyspnea, chest tightness, and cough reflect episodes of reversible airway obstruction. Asthma is a heterogeneous disease that varies in clinical presentation, severity, and pathobiology, but consistently features airway hyperresponsiveness (AHR)-excessive airway narrowing due to an exaggerated response of the airways to various stimuli. Airway smooth muscle (ASM) is the major effector of exaggerated airway narrowing and AHR and many factors may contribute to its altered function in asthma. These include genetic predispositions, early life exposure to viruses, pollutants and allergens that lead to chronic exposure to inflammatory cells and mediators, altered innervation, airway structural cell remodeling, and airway mechanical stress. Early studies aiming to address the dysfunctional nature of ASM in the etiology and pathogenesis of asthma have been inconclusive due to the methodological limitations in assessing the intrapulmonary airways, the site of asthma. The study of the trachealis, although convenient, has been misleading as it has shown no alterations in asthma and it is not as exposed to inflammatory cells as intrapulmonary ASM. Furthermore, the cartilage rings offer protection against stress and strain of repeated contractions. More recent strategies that allow for the isolation of viable intrapulmonary ASM tissue reveal significant mechanical differences between asthmatic and non-asthmatic tissues. This review will thus summarize the latest techniques used to study ASM mechanics within its environment and in isolation, identify the potential causes of the discrepancy between the ASM of the extra- and intrapulmonary airways, and address future directions that may lead to an improved understanding of ASM hypercontractility in asthma.


Rutaecarpine ameliorates osteoarthritis by inhibiting PI3K/AKT/NF‑κB and MAPK signalling transduction through integrin αVβ3.
Osteoarthritis (OA) is a chronic progressive articular illness which commonly affects older‑aged adults, presenting with cartilage inflammation and degradation. Rutaecarpine (RUT) has been shown to exert promising anti‑inflammatory effects; however, the efficacy of RUT in the treatment of OA is debatable. The present study investigated the potential of RUT in alleviating OA in a mouse model. Treatment with RUT inhibited the inflammatory response and extracellular matrix degradation by suppressing process regulators in interleukin (IL)‑1β‑stimulated chondrocytes. Moreover, treatment with RUT in vitro upregulated the gene expression of anabolic agents, such as collagen type II, aggrecan and SRY‑box transcription factor 9, indicating that RUT contributed to cartilage repair. Additionally, flow cytometric assays, and the measurement of β‑galactosidase levels, autophagic flux and related protein expression revealed that RUT effectively attenuated IL‑1β‑induced chondrocyte apoptosis, senescence and autophagy impairment. In addition, bioinformatics analysis and in vitro experiments demonstrated that RUT protected cartilage by mediating the phosphoinositide‑3‑kinase (PI3K)/Akt/nuclear factor‑κB (NF‑κB) and mitogen‑activated protein kinase (MAPK) pathways. The ameliorative effects of RUT on IL‑1β‑stimulated chondrocytes were abrogated when siRNA was used to knock down integrin αVβ3. Furthermore, the results of immunohistochemical analysis and microcomputed tomography confirmed the in vivo therapeutic effects of RUT in mice with OA. On the whole, the present study demonstrates that RUT attenuates the inflammatory response and cartilage degradation in mice with OA by suppressing the activation of the PI3K/AKT/NF‑κB and MAPK pathways. Integrin αVβ3 may play a pivotal role in these effects.


Urethral pressure measurement in stress incontinence: does it help?
The resting urethral pressure profile (UPP), used for the assessment of women with stress incontinence, is routine in many urodynamic units. It is time- and effort-consuming, and its diagnostic value is controversial, as well as its value in the prediction of outcome of anti-incontinence surgery. Herein, we assessed its value in the prediction of the outcome of surgery. Sixty women were randomized to fascial sling or TVT. Urodynamics were performed preoperatively, 6 months and annually thereafter. After filling and voiding cystometry, resting UPP was performed while sitting. Automated catheter pulling, at a rate of 1 mm/s, was adopted. Averaged readings were obtained. Comparison of maximum urethral closure pressure (MUCP) in success and failure, as well as in sling and TVT, was performed, utilizing ANOVA. Preoperative MUCP and functional urethral length (FUL) were 72.9 +/- 27.9 cmH2O and 2.4 +/- 0.7 cm. At last follow-up, they were 71.1 +/- 20.7 cmH2O and 2.7 +/- 0.7 cm, respectively. The differences between sling and TVT as regards value of MUCP and FUL were not significant. The relationship of the outcome of surgery and UPP parameters showed no statistical difference. No significant effect was shown for the success of surgery, duration of follow-up, and interaction of outcome and time over MUCP (P = 0.82, 0.56 and 0.69, respectively) or FUL (P = 0.82, 0.11 and 0.67, respectively). The routine use of resting UPP has no added value in terms of the prediction of success of incontinence surgery. It does not help with follow-up and adds to the time and cost of the examination.


Augmentation of angiogenic and endothelial associated gene expression by EDM50 in human chorion-derived stem cells.
The objective of this study was to investigate the angiogenic potential of human chorion-derived stem cells (CDSC) cultured in medium containing bFGF and VEGF (EDM50). Total RNA was extracted from cells cultured in FD+10% FBS and EDM50. Quantitative RT-PCR was carried out to score the differential mRNA expression of genes involve in angiogenesis and endothelial differentiation. Our finding demonstrated that all angiogenic and endothelial associated genes were expressed higher in EDM50. Expression level of ANG-1, eNOS and VEGFR2 were significantly higher in EDM50 compared to FD+10% FBS. Our results suggested that human CDSC cultured in EDM50 can be used for angiogenesis purpose in regenerative medicine.


[Distinction between anxiety state/trait in general practice: a descriptive study].
State-anxiety has been defined as a transitory emotional response involving unpleasant feelings of tension and apprehensive thoughts. Trait-anxiety, on the other hand, has been defined as a personality trait referring to individual differences in the likelihood that a person would experience state anxiety in a stressful situation. The aim of the present study was to assess trait and state-anxiety in a population of patients consulting physicians for anxious complaints. Thus, patients who stopped the benzodiazepine (BZD) treatment after three months and those who continued it for six months were compared. Included patients were evaluated at inclusion (D0), after three months (M3) and after six months (M6). The investigator filled the Covi anxiety scale, the Raskin depression scale and a CGI; patients were asked to fill the Spielberger state/trait-anxiety questionnaire. 1,112 patients have been included, 48% considered their anxiety as chronic, 50% said the evolution was progressive, 87% considered it resulting of a trigger factor, 69% received a benzodiazepine (BZD) treatment. At D0: Covi anxiety score was 5.3 +/- 2.3 points, STAI I (state-anxiety) score was 57.4 +/- 12.2 points and STAI II (trait-anxiety) score was 52.7 +/- 10.2 points. At M3, all scores decreased, and 85% were considered as ameliorated, but differences were significant (p = 0.0001) at M6. When comparing at D0 patients who stopped BZD treatment at M3 and those who continued it, some differences appeared. In fact subjects who stopped the treatment had lower score at the STAI II, presented significantly less flushes (p = 0.01), less tremor (p = 0.04) and less feverishness (p = 0.05). Their score at Covi tended to be lower (p = 0.11). The severity of the disease, evaluated with the CGI, was also lower for the patients who stopped the BZD treatment. The trait-anxiety appeared as a good predictor of the efficacy of the BZD treatment. In fact, the trait-anxiety refers to a tendency to be anxious and higher anxiety necessitates longer treatment. The treatment response was less important in the patients who continued the treatment at M3, indicating the presence of residual anxiety in these patients.


Deformation Twinning of a Silver Nanocrystal under High Pressure.
Within a high-pressure environment, crystal deformation is controlled by complex processes such as dislocation motion, twinning, and phase transitions, which change materials' microscopic morphology and alter their properties. Understanding a crystal's response to external stress provides a unique opportunity for rational tailoring of its functionalities. It is very challenging to track the strain evolution and physical deformation from a single nanoscale crystal under high-pressure stress. Here, we report an in situ three-dimensional mapping of morphology and strain evolutions in a single-crystal silver nanocube within a high-pressure environment using the Bragg Coherent Diffractive Imaging (CDI) method. We observed a continuous lattice distortion, followed by a deformation twining process at a constant pressure. The ability to visualize stress-introduced deformation of nanocrystals with high spatial resolution and prominent strain sensitivity provides an important route for interpreting and engineering novel properties of nanomaterials.


[Hepatocellular tumours in noncirrhotic liver tissue].
In recent years, the spectrum of tissue-based diagnostics of hepatocellular tumours has changed due to novel molecular pathological findings. Innovative radiographics filter out small lesions and ambiguous tumours for bioptical sampling. The spectrum of these tumours includes hepatocellular carcinoma, hepatocellular adenomas, focal nodular hyperplasia and macroregenerative nodules. Primarily, morphological analysis should identify the dignity of a lesion. After exclusion of HCC and reactive liver cell nodules, hepatocellular adenomas should be further subclassified based on immunohistochemical/molecular pathological criteria according to the WHO classification of liver tumours. This procedure provides significant additional information regarding the prognosis and therapeutic implications of hepatocellular adenomas.


Neurofeedback application in the treatment of autistic spectrum disorders (ASD).
The aim of this paper is to describe neurofeedback (NFB) treatment in Autistic spectrum disorder (ASD) children. There is no specific cure for autism and therapeutic guidelines are directed to improve the quality of life of people with autism by reducing the symptoms and by increasing their functioning. Neurofeedback is a computerized method based on tracking electrical activity of the brain (EEG) and giving a feedback about it. The method has been developed in neurophysiological labs of scientific institutes in USA and has been used very successfully for over last 20 years. It has proven its efficacy in practise, but also in scientific and clinical research. During 2010 and 2011 neurofeedback treatment was administered to 10 children (N=10, 7 males and 3 females) age range 4 to 7 years which have been diagnosed as autistic spectrum disorder (highly functional) with an unspecific impairment of speech development and trouble communicating. An evaluation of treatment was done according to estimation of changes in functioning (parents, teachers and therapists' ratings and all other experts that were monitoring the child before, during and after the treatment) and tracking of changes in electrophysiology. The results have shown most changes in behaviour (less aggressive, more cooperation, better communication), attention span and sensory motor skills. According to the assessment of parents, teachers, therapists and other experts all children have accomplished a certain degree of improvement in the level of daily functioning. Our experiences in usage of neurofeedback in Autistic spectrum disorder (ASD) children confirmed previous data that this method can be applied to this category of patients.


Pars plana vitrectomy with intravitreal triamcinolone: effect on uveitic cystoid macular oedema and treatment limitations.
To investigate the effect of pars plana vitrectomy (PPV) in combination with intraoperative intravitreal triamcinolone acetonide injection on the course of cystoid macular oedema (CME) in patients with uveitis. Patients with uveitis with CME (n = 19) not responding to systemic corticosteroids and/or immunosuppression combined with acetazolamide were retrospectively studied after PPV with additional intravitreal injection of 4 mg triamcinolone acetonide. Patients had chronic anterior uveitis (n = 4), intermediate uveitis (n = 9), posterior uveitis (n = 3) or panuveitis (n = 3). Visual acuity tests, tonometry, fluorescein angiographic appearance and postoperative complications were analysed. Mean follow-up was 14 months (SD 4.6). CME improved in 58% of the patients within the first 6 weeks postoperatively. After 12 months, CME was further improved in 44% and worsened in another 12%. Improvement of visual acuity was noted in 42% after 3 months and in 28% after 12 months. Cataract progressed in 85% of the phacic patients postoperatively. Increased intraocular pressure was detected in 27% at 2 weeks and in 11% at 12 months after surgery. Uveitic CME that is unresponsive to systemic immunosuppression and acetazolamide may improve after PPV with additional intravitreal triamcinolone application. The effect seems to be transient in many of the patients. Frequent complications were cataract formation and ocular hypertension.


[Reevaluate the effect of G-480 point mutation that determines the neurovirulence of type I vaccine polioviruses].
Whole genome sequencing of 9 type I circulating vaccine-derived polioviruses (cVDPVs) isolated in Guizhou Province in China revealed that reverse mutations did not occur in G-480 and U-525 which are known as the most important neurovirulence determinate sites, while other known neurovirulence determinate sites such as A-2438, A-2795, C-6203 and G-7441 did revert to Mahoney type. 5 type I cVDPVs were selected for neurovirulence test on PVR-Tg21 transgenic mice which express human poliovirus receptor gene based on their different nucleotide sequences, they all showed higher neurovirulence than P1/Sabin strain, and the neurovirulence of CHN8184 and CHN8229-1. 1 were comparable to that of wild type P1/Mahoney. The neurovirulence of CHN8229-1.1, CHN8229-2 and CHN8229-3 presented a trend of decreasing, but still laid in high level. There were 7 nucleotide mutations between CHN8229-1.1 and CHN8229-2, and only 2 between CHN8229-2 and CHN8229-3 in their whole genomes, but the neurovirulence among them were relatively different, showing that there must be some unknown neurovirulence determinate sites among these mutations. Computer predicted RNA secondary structure of stem-loop V of the poliovirus 5' NCR of Guizhou type I cVDPVs was relatively stable. In the situation that no reverse mutation occurred in G-480, some type I cVDPVs already showed high neurovirulence nearly equal to P1/Mahoney, it meant that the effect of G-480 point mutation that determined neurovirulence of P1/Sabin strain has been overestimated, G-480 was not the only important site to determine neurovirulence in P1/Sabin strain, others also may play the very important role. More details are needed to elucidate the mechanism of attenuation in type I polioviruses.


Autophagy: A Novel Pharmacological Target in Diabetic Retinopathy.
Autophagy is the major catabolic pathway involved in removing and recycling damaged macromolecules and organelles and several evidences suggest that dysfunctions of this pathway contribute to the onset and progression of central and peripheral neurodegenerative diseases. Diabetic retinopathy (DR) is a serious complication of diabetes mellitus representing the main preventable cause of acquired blindness worldwide. DR has traditionally been considered as a microvascular disease, however this concept has evolved and neurodegeneration and neuroinflammation have emerged as important determinants in the pathogenesis and evolution of the retinal pathology. Here we review the role of autophagy in experimental models of DR and explore the potential of this pathway as a target for alternative therapeutic approaches.


Comparison among the Quantification of Bacterial Pathogens by qPCR, dPCR, and Cultural Methods.
The demand for rapid methods for the quantification of pathogens is increasing. Among these methods, those based on nucleic acids amplification (quantitative PCRs) are the most widespread worldwide. Together with the qPCR, a new approach named digital PCR (dPCR), has rapidly gained importance. The aim of our study was to compare the results obtained using two different dPCR systems and one qPCR in the quantification of three different bacterial pathogens: Listeria monocytogenes, Francisella tularensis, and Mycobacterium avium subsp. paratuberculosis. For this purpose, three pre-existing qPCRs were used, while the same primers and probes, as well as PCR conditions, were transferred to two different dPCR systems: the QX200 (Bio-Rad) and the Quant Studio 3D (Applied Biosystems). The limits of detection and limits of quantification for all pathogens, and all PCR approaches applied, were determined using genomic pure DNAs. The quantification of unknown decimal suspensions of the three bacteria obtained by the three different PCR approaches was compared through the Linear Regression and Bland and Altman analyses. Our results suggest that, both dPCRs are able to quantify the same amount of bacteria, while the comparison among dPCRs and qPCRs, showed both over and under-estimation of the bacteria present in the unknown suspensions. Our results showed qPCR over-estimated the amount of M. avium subsp. paratuberculosis and F. tularensis cells. On the contrary, qPCR, compared to QX200 dPCR, under-estimated the amount of L. monocytogenes cells. However, the maximum difference among PCRs approaches was <0.5 Log10, while cultural methods underestimated the number of bacteria by one to two Log10 for Francisella tularensis and Mycobacterium avium subsp. paratuberculosis. On the other hand, cultural and PCRs methods quantified the same amount of bacteria for L. monocytogenes, suggesting for this last pathogen, PCRs approaches can be considered as a valid alternative to the cultural ones.


Partial recording protocols for periodontal disease assessment in epidemiological surveys.
The objective of the present study was to compare the reliability of four partial-mouth protocols for assessing shallow, moderate, and deep sites for periodontal pocket depth and clinical attachment levels. Periodontal pocket depth and clinical attachment level measurements were recorded for 156 subjects (age > or = 30). The four models of partial-mouth protocols compared were: Model I: all sites per tooth in the random half-mouth protocol randomly selecting one maxillary and mandibular quadrant, Model II: buccal sites in a full-mouth protocol, Model III: buccal sites in the random half-mouth protocol randomly selecting one maxillary and mandibular quadrant, Model IV: all sites per tooth using Community Periodontal Index teeth. In comparison with full mouth examination, Model I did not show significant differences for periodontal pocket depth and clinical attachment level parameters. Models II and III were different for some periodontal pocket depth means, and Model IV significantly overestimated all clinical parameters related to periodontal disease. Model I appears to be adequate to substitute for the full-mouth examination to assess the prevalence and severity of chronic periodontal disease in adults.


Identifying potential treatments of COVID-19 from Traditional Chinese Medicine (TCM) by using a data-driven approach.
Traditional Chinese Medicine (TCM) has been widely used as an approach worldwide. Chinese Medicines (CMs) had been used to treat and prevent viral infection pneumonia diseases for thousands of years and had accumulated a large number of clinical experiences and effective prescriptions. This research aimed to systematically excavate the classical prescriptions of Chinese Medicine (CM), which have been used to prevent and treat Pestilence (Wenbing, Wenyi, Shiyi or Yibing) for long history in China, to obtain the potential prescriptions and ingredients to alternatively treat COVID-19. We developed the screening system based on data mining, molecular docking and network pharmacology. Data mining and association network were used to mine the high-frequency herbs and formulas from ancient prescriptions. Virtual screening for the effective components of high frequency CMs and compatibility Chinese Medicine was explored by a molecular docking approach. Furthermore, network pharmacology method was used to preliminarily uncover the molecule mechanism. 574 prescriptions were obtained from 96,606 classical prescriptions with the key words to treat "Warm diseases (Wenbing)", "Pestilence (Wenyi or Yibing)" or "Epidemic diseases (Shiyi)". Meanwhile, 40 kinds of CMs, 36 CMs-pairs, 6 triple-CMs-groups existed with high frequency among the 574 prescriptions. Additionally, the key targets of SARS-COV-2, namely 3CL hydrolase (Mpro) and angiotensin-converting enzyme 2(ACE2), were used to dock the main ingredients from the 40 kinds by the LigandFitDock method. A total of 66 compounds components with higher frequency were docked with the COVID-19 targets, which were distributed in 26 kinds of CMs, among which Gancao (Glycyrrhizae Radix Et Rhizoma), HuangQin (Scutellariae Radix), Dahuang (Rhei Radix Et Rhizome) and Chaihu (Bupleuri Radix) contain more potential compounds. Network pharmacology results showed that Gancao (Glycyrrhizae Radix Et Rhizoma) and HuangQin (Scutellariae Radix) CMs-pairs could also interact with the targets involving in immune and inflammation diseases. These results we obtained probably provided potential candidate CMs formulas or active ingredients to overcome COVID-19. Prospectively, animal experiment and rigorous clinic studies are needed to confirm the potential preventive and treat effect of these CMs and compounds.


Antiepileptogenic, antioxidant and genotoxic evaluation of rosmarinic acid and its metabolite caffeic acid in mice.
Antioxidant compounds have been extensively investigated as a pharmacological alternatives to prevent epileptogenesis. Rosmarinic acid (RA) and caffeic acid (CA) are compounds with antioxidant properties, and RA has been shown to inhibit GABA transaminase activity (in vitro). Our aim was to evaluate the effect of RA and CA on seizures induced by pentylenotetrazole (PTZ) using the kindling model in mice. Male CF-1 mice were treated once every three days during 16days with RA (1, 2 or 4mg/kg; i.p.), or CA (1, 4 or 8mg/kg; i.p.), or positive controls diazepam (1mg/kg; i.p.) or vigabatrin (600mg/kg; p.o.), 30min before PTZ administration (50mg/kg; s.c.). After the last treatment, animals were sacrificed and the cortex was collected to evaluate free radicals (determined by 2',7'-dichlorofluorescein diacetate probe), superoxide dismutase (SOD) and genotoxic activity (Alkaline Comet Assay). Rosmarinic acid 2mg/kg increased latency and decreased percentage of seizures, only on the 4th day of observation. The other tested doses of RA and CA did not show any effect. Rosmarinic acid 1mg/kg, CA 4mg/kg and CA 8mg/kg decreased free radicals, but no dose altered the levels of enzyme SOD. In the comet assay, RA 4mg/kg and CA 4mg/kg reduced the DNA damage index. Some doses of rosmarinic acid and CA tested showed neuroprotective action against oxidative and DNA damage produced in the kindling epilepsy model, although they did not produce antiepileptogenic effect in vivo.


Development of alternative strategies for management of soilborne pathogens currently controlled with methyl bromide.
The current standard treatment for management of soilborne pests in some high-value crop production systems is preplant fumigation with mixtures of methyl bromide and chloropicrin. With the impending phase-out of methyl bromide, the agricultural industries that rely on soil fumigation face the need for development of alternative pest management strategies. To maintain farm productivity, immediate term research has focused on evaluation of alternative fumigants, modification of current crop production practices to accommodate their use, and improvement of application technologies to reduce the environmental effects of fumigant applications. Longer-term research goals have focused on developing a more integrated approach for pest management that incorporates the use of cultural practices to reduce pathogen pressure, host resistance to disease, and biological approaches for stimulating plant growth and control of root diseases.


Virtual reality lead extraction as a method for training new physicians: a pilot study.
It is estimated that the demand for transvenous lead extraction (TLE) has reached an annual extraction rate of nearly 24,000 patients worldwide. Despite technologic advances, TLE still has the potential for significant morbidity and mortality. Complication rates with TLE directly parallel operator experience. However, obtaining adequate training during and postfellowship can be difficult. Given the potential for catastrophic complications and the steep learning curve (up to 300 cases) associated with this procedure, we sought to validate a virtual reality (VR) lead extraction simulator as an innovative training and evaluation tool for physicians new to TLE. We randomized eight electrophysiology fellows to VR simulator versus conventional training. We compared procedural skill competency between the groups using simulator competency, tactile measurements, markers of proficiency and attitudes, and cognitive abilities battery. Practical skills and simulator complications differed significantly between the VR simulator and conventional training groups. The VR simulator group executed patient preparation and procedure performance better than the conventional group (P < 0.01). All four fellows randomized to conventional training experienced a simulator complication (two superior vena cava [SVC] tears, three right ventricle [RV] avulsions) versus one fellow in the VR simulator group (one SVC tear) (P = 0.02). Tactile measurements revealed a trend toward excess pushing versus pulling forces among the conventionally trained group. The time for lead removal was also significantly higher in the conventional training group (12.46 minutes vs 5.54 minutes, P = 0.02). There was no significant difference in baseline or posttraining cognitive ability. We contend that the implementation of alternative training tools such as a VR simulation model will improve physician training and allow for an innovative pathway to assess the achievement of competency.


The ubiquity and coexistence of two FBPases in chloroplasts of photosynthetic eukaryotes and its evolutionary and functional implications.
In photosynthetic eukaryotes, there are two well-characterized fructose-1,6-bisphosphatases (FBPases): the redox-insensitive cytosolic FBPase (cyFBPase), which participates in gluconeogenesis, and the redox-sensitive chloroplastic FBPase (cpFBPase1), which is a critical enzyme in the Calvin cycle. Recent studies have identified a new chloroplastic FBPase, cpFBPase2; however, its phylogenetic distribution, evolutionary origin, and physiological function remain unclear. In this study, we identified and characterized these three FBPase isoforms in diverse, representative photosynthetic lineages and analyzed their phylogeny. In contrast to previous hypotheses, we found that cpFBPase2 is ubiquitous in photosynthetic eukaryotes. Additionally, all cpFBPase2s from diverse lineages form a monophyly, suggesting cpFBPase2 is not a recently evolved enzyme restricted to land plants but rather evolved early in the evolution of photosynthetic organisms, and most likely, in the common ancestor of photosynthetic eukaryotes. cyFBPase was probably first duplicated to produce cpFBPase2, and then the latter duplicated to produce cpFBPase1. The ubiquitous coexistence of these two cpFBPases in chloroplasts is most likely the consequence of adaptation to different redox conditions of photosynthesis, especially those caused by recurrent changes in light conditions.


Auditory localization and its clinical applications.
Factors of significance in the localization of sound are considered. The ability of hearing-impaired subjects to localize noise in the horizontal plane was examined with and without hearing aids, and also compared with the results for normally hearing subjects. The directional hearing was not found to be improved by the hearing aids used. The ability to localize sound has been used by several investigators as a diagnostic tool: poor directional hearing may be expected in patients with lesions of the cochlear nerve or the pontine region. However, other factors are also of significance and may impair the localization of sound. These problems are discussed.


Modulation of the C1 visual event-related component by conditioned stimuli: evidence for sensory plasticity in early affective perception.
Previous research has demonstrated optimized processing of motivationally significant stimuli early in perception. In the present study, the time course and underlying mechanisms for such fast differentiation are of interest. We investigated the involvement of the primary visual cortex in affective evaluation of conditioned stimuli (CSs). In order to elicit learning within the visual system we chose affective pictures as unconditioned stimuli and used laterally presented gratings as CSs. Using high-density electroencephalography, we demonstrated modulation of the C1 visual event-related component for threat-related stimuli versus neutral stimuli, which increased with continuing acquisition of affective meaning. The differentiation between aversive and neutral visual stimuli occurred as early as 65-90 ms after stimulus onset and suggested involvement of the primary visual areas in affective evaluation. As an underlying mechanism, we discuss short-term reorganization in visual cortex, enabling sensory amplification of specific visual features that are related to motivationally relevant information.


The notion of Kapwa amid Asian hate.
In a letter to the editor, the author has expressed how a Chinese notion of ren is a powerful tool to negate the stigma of racial discrimination among Asian people. I would argue that within the Filipino psyche, the notion of kapwa or "shared self" can be an equivalent socio-normative ideal that can be utilized towards not just countering the ill effects of social discrimination but also fostering deep communal and group solidarity among people, regardless of race, color and ethnicity.


Effect of probiotic supplementation on bacterial translocation in common bile duct obstruction.
To investigate the effects of probiotics on bacterial translocation in the obstructive common bile duct with comparison to an enteral product containing arginine and glutamine. In our study, 40 Sprague-Dawley rats each weighing 250-300 g were used. Animals in Group 1 (sham) were laparatomized and fed standard chow supplemented with physiologic saline at daily doses of 2 ml through orogastric tube for 7 days. Common bile ducts of the animals in the other groups were ligated with 3/0 silk sutures. Group 2 (control group) was fed standard chow supplemented with daily doses of 2 ml physiologic saline. Group 3 (probiotic group) was fed standard chow supplemented with a probiotic solution (Acidophilus plus) containing strains of Lactobacillus acidophilus, Bifidobacterium bifidum and Lactobacillus bulgaricus at a daily doses of 2 × 10(9) colony forming units (CFU). Group 4 (formula group) was fed only an enteral solution (Stresson Multi Fiber) containing glutamine, arginine and a medium-chain fatty acid at daily doses of 2 g/kg. At the end of the 7th day, all animals were relaparatomized, and to determine bacterial translocation, aerobic, and anaerobic cultures were obtained from the specimens of mesenteric lymph nodes, intestinal mucosa, and blood samples. Smear cultures prepared from caecum were examined to determine the number of CFU. Finally, for histological examination specimens were excised from terminal ileum, and oxidative damage was assessed in liver tissues. Afterwards all animals were killed. Moderately lesser degrees of bacterial translocation, and mucosal damage were seen in Groups 3, and 4 relative to Group 2 (p < 0.05). In Group 4, any difference was not seen in the number of cecal bacteria relative to baseline values, while in Group 3, significant decrease in cecal colonization was seen. Among all groups, a significant difference between levels of malondialdehyde, and glutathione was not observed. At the end of our study, we have concluded that both probiotics, and enteral diets which contain immunomodulators such as glutamine, and arginine alleviate bacterial translocation, and impairment of intestinal mucosa.


Influences of spontaneous perspective taking on spatial and identity processing of faces.
Previous research suggests that people, when interacting with another agent, are sensitive to the other's visual perspective on the scene. The present study investigated how spontaneously another's different spatial perspective is taken into account and how this affects the processing of jointly attended stimuli. Participants viewed upright or inverted faces alone, next to another person (same spatial perspective), or opposite another person (different spatial perspectives) while electroencephalography (EEG) was recorded. The task (counting male faces) was in no way related to spatial aspects of the stimuli, and thus did not encourage perspective taking. EEG results revealed no general differences between viewing faces alone or with another person. However, when holding different perspectives (sitting opposite each other), the amplitudes of the N170 and of the N250 significantly increased for upright faces. This indicates that people spontaneously represented the other's different perspective, which led to higher demands for structural encoding (N170) and to increased allocation of attention to face recognition (N250) for stimuli that are typically processed configurally. When holding different spatial perspectives, thus, people may not merely represent that the other sees the object or scene differently, but how the object/scene looks for the other.


[Epidemiologic situation of tuberculosis in the Republic of Kazakhstan].
The tuberculosis epidemiological situation has greatly deteriorated in the Republic of Kazakhstan in recent years. Tuberculosis morbidity has annually increased by 11.1% and, but in 1995 it amounted to as much as 100 per 100,000 in some areas and mortality was 29.5%. Forty five thousand patients with active tuberculosis types are registered at tuberculosis dispensaries, among them 12 thousand patients isolate Mycobacterium tuberculosis. The main reason is sharply deteriorated socioeconomical conditions and lower volumes of antituberculous measures.


A Framework of Temporal-Spatial Descriptors-Based Feature Extraction for Improved Myoelectric Pattern Recognition.
The extraction of the accurate and efficient descriptors of muscular activity plays an important role in tackling the challenging problem of myoelectric control of powered prostheses. In this paper, we present a new feature extraction framework that aims to give an enhanced representation of muscular activities through increasing the amount of information that can be extracted from individual and combined electromyogram (EMG) channels. We propose to use time-domain descriptors (TDDs) in estimating the EMG signal power spectrum characteristics; a step that preserves the computational power required for the construction of spectral features. Subsequently, TDD is used in a process that involves: 1) representing the temporal evolution of the EMG signals by progressively tracking the correlation between the TDD extracted from each analysis time window and a nonlinearly mapped version of it across the same EMG channel and 2) representing the spatial coherence between the different EMG channels, which is achieved by calculating the correlation between the TDD extracted from the differences of all possible combinations of pairs of channels and their nonlinearly mapped versions. The proposed temporal-spatial descriptors (TSDs) are validated on multiple sparse and high-density (HD) EMG data sets collected from a number of intact-limbed and amputees performing a large number of hand and finger movements. Classification results showed significant reductions in the achieved error rates in comparison to other methods, with the improvement of at least 8% on average across all subjects. Additionally, the proposed TSDs achieved significantly well in problems with HD-EMG with average classification errors of <5% across all subjects using windows lengths of 50 ms only.


PlanHab Study: Consequences of combined normobaric hypoxia and bed rest on adenosine kinetics.
Adenosine plays a role in the energy supply of cells and provokes differential, hormone-like functions in circulating cells and various tissues. Its release is importantly regulated by oxygen tension. This renders adenosine and its kinetics interesting to investigate in humans subjected to low oxygen conditions. Especially for space exploration scenarios, hypoxic conditions - together with reduced gravity - represent two foreseen living conditions when planning manned long-duration space missions or planetary habitats. The PlanHab study investigated microgravity through inactivity in bed rest and normobaric hypoxia to examine their independent or combined effect on adenosine and its kinetics. Healthy male subjects (n = 14) completed three 21-day interventions: hypoxic bed rest (HBR); hypoxic ambulatory confinement (HAMB); normoxic bed rest (NBR). The interventions were separated by 4 months. Our hypothesis of a hypoxia-triggered increase in adenosine was confirmed in HAMB but unexpectedly also in NBR. However, the highest adenosine levels were noted following HBR. Furthermore, the percentage of hemolysis was elevated in HBR whereas endothelial integrity markers stayed low in all three interventions. In summary, these data suggest that neocytolysis accounts for these effects while we could reduce evidence for microcirculatory changes.


[Analysis of KRAS status in cancer tissue with submucosal or deeper invasion in patients with familial adenomatous polyposis].
The KRAS status in cancer tissue with submucosal or deeper invasion was investigated in patients with familial adenomatous polyposis (FAP). Fifteen cancerous lesions in 10 FAP patients were subjected to analysis for KRAS status. The clinical features of FAP were the dense type in 2 patients and the sparse type in 8 patients. Of the 15 cancerous lesions, 6 (40%) were identified as having wild-type KRAS and the remaining 9 (60%), as having mutated KRAS. Of the 9 mutated lesions, the G13D mutation was recognized in 4 patients and was the most frequent pattern. With regard to the KRAS status in patients with multiple cancerous lesions, 1 patient had 3 cancerous lesions of which 2 were of the mutated type and 1 was of the wild type and another patient had 4 cancerous lesions of which 3 were of the mutated type and 1 was of the wild type. These results suggest that the frequency of wild-type KRAS in cancer associated with FAP was approximately 40%, although it was lower than that in sporadic cancer. Moreover, we need to analyze the KRAS status in all cancerous lesions in clinical practice when chemotherapy with anti-epidermal growth factor receptor (EGFR) antibody is required for the treatment of FAP patients with unresectable advanced multiple cancers.


Novelty facilitates the persistence of aversive memory extinction by dopamine regulation in the hippocampus and ventral tegmental area.
Aversive memory extinction comprises a novel learning that blocks retrieving a previously formed traumatic memory. In this sense, aversive memory extinction is an excellent tool for decreasing fear responses. However, this tool it's not effective in the long term because of original memory spontaneous recovery. Thus, searching for alternative strategies that strengthen extinction learning is essential. In the current study, we evaluated the effects of a novel context (i.e., novelty) exposure on aversive memory extinction enhancement over days and the dopaminergic system requirement. Given the purpose, experiments were conducted using 3-month-old male Wistar rats. Animals were trained in inhibitory avoidance (IA). Twenty-four hours later, rats were submitted to a weak extinction protocol. Still, 30 min before the first extinction session, animals were submitted to an exploration of a novel context for 5 min. After, memory retention and persistence were evaluated 24 h, 3, 7, 14, and 21 days later. The exposition of a novel context caused a decrease in aversive responses in all days analyzed and an increase in dopamine levels in the hippocampus. The intrahippocampal infusion of dopamine in the CA1 area or the stimulation of the ventral tegmental area (VTA) by a glutamatergic agonist (NMDA) showed similar effects of novelty. In contrast, VTA inhibition by a gabaergic agonist (muscimol) impaired the persistence of extinction learning induced by novelty exposition and caused a decrease in hippocampal dopamine levels. In summary, we show that novel context exposure promotes persistent aversive memory extinction, revealing the significant role of the dopaminergic system.


Identification of a Nosema bombycis (Microsporidia) spore wall protein corresponding to spore phagocytosis.
Life-cycle stages of the microsporidia Nosema bombycis, the pathogen causing silkworm pebrine, were separated and purified by an improved method of Percoll-gradient centrifugation. Soluble protein fractions of late sporoblasts (spore precursor cells) and mature spores were analysed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Protein spots were recovered from gels and analysed by mass spectrometry. The most abundant differential protein spot was identified by database search to be a hypothetical spore wall protein. Using immunoelectron microscopy, we demonstrated that HSWP5 is localized to the exospore of mature spores and renamed it as spore wall protein 5 (NbSWP5). Further spore phagocytosis assays indicated that NbSWP5 can protect spores from phagocytic uptake by cultured insect cells. This spore wall protein may function both for structural integrity and in modulating host cell invasion.


[A sustained response in chronic hepatitis C treated with interferon].
We analyzed 27 subjects with long-term response, from a group of 110 interferon treated patients with biopsy-proven chronic hepatitis and serum anti-HCV antibodies. The following variables were assessed as potential predictors: sex, age, ALT level before the therapy was started, liver structure, type of interferon, total amount of interferon. Total amount of administered interferon statistically correlated with long-term response by univariate analysis. Nevertheless upon stepwise logistic multivariate analysis none of them was independently predictive of long-term response. Additional studies would be needed in order to develop a model capable of predicting from pre-treatment features which patients are likely to have long-term response.


Single Lumen Alternating Micro-Batch Hemodiafiltration (SLAMB-HDF): A Device for Minimally Invasive Renal Replacement Therapy.
Blood-based RRT, such as hemodialysis, requires access to the bloodstream and adequate blood flow to enable the requisite clearance. As such, nearly all RRT systems require two lumens, enabling a blood circuit that pulls blood from one lumen or needle and returns it via another lumen or needle. The proposed single lumen alternating micro-batch (SLAMB) technique uses a small single lumen to draw a "micro" batch of blood into a single reservoir. In the reservoir, the "batch" of blood is circulated at a high blood flow rate through a hemofilter or hemodialyzer, enabling efficient small- and middle-molecule clearance. Thereafter, the "purified" blood is returned to the patient and the cycle is repeated. Each batch comprises 20-300 ml of blood, which is adjusted to the vascular access, hemodynamic status, and size of the patient. Up to 15 cycles can be done per hour, allowing this system to achieve a blood clearance level comparable to modern continuous RRT systems. Because the system can function with a small-bore single lumen, this device can work with existing central lines, thus allowing for less invasive vascular access. Because of their size and relative simplicity, SLAMB-based systems are less expensive, smaller, and have improved portability. Lastly, a similar, manual SLAMB-hemofiltration kit, which requires no electricity or battery, can be developed at low cost (<$25) for use in austere medical conditions, thus expanding the availability of RRT for patients with AKI.


Design and synthesis of new 2-arylnaphthyridin-4-ones as potent antitumor agents targeting tumorigenic cell lines.
To develop new anticancer drug candidates from 2-arylnaphthyridin-4-one (AN), we have designed and synthesized a series of 3'-hydroxy and 6-hydroxy derivatives of AN. The results of cytotoxicity screening indicated that the replacement of the 3'-methoxy moiety on the C-ring phenyl group of AN (6a-e) with 3'-hydroxy (7a-e) made no significant effect on the inhibitory activity against HL-60, Hep3B and NCI-H460 cancer cell lines. On the other hand, replacing the 6-methoxy group on the A-ring of AN (6g-i) with a 6-hydroxy group (7g-i) resulted in reduced inhibitory activity against the above three cancer cell lines. Among the above-mentioned target compounds, 2-(3-hydroxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (7a) demonstrated the greatest potency and the best selectivity toward tumorigenic cancer cell lines. In a 7a preliminary mechanism of action study in Hep3B hepatoma cells, 7a showed the effects on microtubules followed by cell cycle arrest and sequentially led to apoptosis. In addition, a phosphate prodrug (11) of 7a exhibited significant antitumor activity when tested in a Hep3B xenograft nude mice model. Since compound 11 has demonstrated good development potential, it is recommended for further preclinical studies.


Evolution of impedance field telemetry after one day of activation in cochlear implant recipients.
Changes in impedance between 24 hours and one month after cochlear implantation have never been explored due to the inability to switch on within one day. This study examined the effect of early activation (within 24 hours) on the evolution of electrode impedance with the aim of providing information on the tissue-to-electrode interface when electrical stimulation was commenced one day post implantation. We performed a retrospective review at a single institution. Patients who received a Nucleus 24RECA implant system (Cochlear, Sydney, Australia) and underwent initial switch-on within 24 hours postoperatively were included. Impedance measurements were obtained intraoperatively and postoperatively at 1 day, 1 week, 4 weeks, and 8 weeks. A significant drop in impedance was noted 1 day after an initial activation within 24 hours followed by a significant rise in impedance in all channels until 1 week, after which the impedance behaved differently in different segments. Basal and mid-portion electrodes revealed a slight increase while apical electrodes showed a slight decrease in impedance from 1 week to 8 weeks postoperatively. Impedance was relatively stable 4 weeks after surgery. This is the first study to report the evolution of impedance in all channels between initial mapping 1 day and 1 month after cochlear implantation. The underlying mechanism for the differences in behavior between different segments of the electrode may be associated with the combined effect of dynamics among the interplay of cell cover formation, electrical stimulation, and fibrotic reaction.


Clinical isolates and nasopharyngeal carriage of antibiotic-resistant Streptococcus pneumoniae in Hospital for Infectious Diseases, Sofia, Bulgaria, 1991-1993.
The antimicrobial resistance of Streptococcus pneumoniae was surveyed in 1991-1993 at the Hospital for Infectious Diseases in Sofia, Bulgaria. Pneumococcal isolates were collected from routine clinical specimens and from nasopharyngeal secretions of inpatient carriers. The incidence of penicillin-resistant S. pneumoniae (PRSP) was 24.3% among clinical samples and nasopharyngeal carriage of PRSP was as high as 40% among children. Penicillin-resistant strains were more frequently resistant to non-beta-lactam antibiotics than were penicillin-sensitive strains. More than half of the PRSP strains were multiply resistant. On the basis of MIC values of ampicillin, it was established that ampicillin was not superior to penicillin. The MICs of five cephalosporins were found to increase in parallel with the MICs of penicillin G. Some of the pneumococcal strains that were highly penicillin-resistant were also resistant to cefotaxime/ceftriaxone (MIC = 1-4 micrograms/ml), but the number of strains was small. On the basis of MIC values of cefotaxime and ceftriaxone for strains from cerebrospinal fluid, both antibiotics may be suitable alternatives for treating meningitis due to strains with resistance to penicillin.