Examining the effects of one- and three-dimensional spatial filtering analyses in magnetoencephalography.
Spatial filtering, or beamforming, is a commonly used data-driven analysis technique in the field of Magnetoencephalography (MEG). Although routinely referred to as a single technique, beamforming in fact encompasses several different methods, both with regard to defining the spatial filters used to reconstruct source-space time series and in terms of the analysis of these time series. This paper evaluates two alternative methods of spatial filter construction and application. It demonstrates how encoding different requirements into the design of these filters has an effect on the results obtained. The analyses presented demonstrate the potential value of implementations which examine the timeseries projections in multiple orientations at a single location by showing that beamforming can reconstruct predominantly radial sources in the case of a multiple-spheres forward model. The accuracy of source reconstruction appears to be more related to depth than source orientation. Furthermore, it is shown that using three 1-dimensional spatial filters can result in inaccurate source-space time series reconstruction. The paper concludes with brief recommendations regarding reporting beamforming methodologies in order to help remove ambiguity about the specifics of the techniques which have been used.


Contribution of IL-18 to Th1 response and host defense against infection by Mycobacterium tuberculosis: a comparative study with IL-12p40.
The present study was conducted to critically determine the protective role of IL-18 in host response to Mycobacterium tuberculosis infection. IL-18-deficient (knockout (KO)) mice were slightly more prone to this infection than wild-type (WT) mice. Sensitivity of IL-12p40KO mice was lower than that of IL-12p40/IL-18 double KO mice. IFN-gamma production caused by the infection was significantly attenuated in IL-18KO mice compared with WT mice, as indicated by reduction in the levels of this cytokine in sera, spleen, lung, and liver, and its synthesis by spleen cells restimulated with purified protein derivatives. Serum IL-12p40 level postinfection and its production by peritoneal exudate cells stimulated with live bacilli were also significantly lower in IL-18KO mice than WT mice, suggesting that attenuated production of IFN-gamma was secondary to reduction of IL-12 synthesis. However, this was not likely the case, because administration of excess IL-12 did not restore the reduced IFN-gamma production in IL-18KO mice. In further studies, IL-18 transgenic mice were more resistant to the infection than control littermate mice, and serum IFN-gamma level and its production by restimulated spleen cells were increased in the former mice. Taken together, our results indicate that IL-18 plays an important role in Th1 response and host defense against M. tuberculosis infection although the contribution was not as profound as that of IL-12p40.


[Synergism of energy-dependent calcium fluxes through smooth muscle cell membrane].
Some peculiarities of Ca2+ exchange in the vesiculate fraction of myometrium sarcolemma during separate and combined functioning of the Ca-pump and Na(+)-Ca2+ antiporter in the presence of initial physiologically significant transmembrane gradients of Ca2+ and Na+ were studied. The effect of synergistic activation of the transfer substrate accumulation inside the vesicles was demonstrated. This effect was observed both in the presence of inside-out directed Ca2+ gradient and in its absence. At Ca2+ concentrations in the extravesicular space equimolar to those in contracted myocytes (5 x 10(-6)-10(-5) M), the co-functioning of the cationic antiporter and Ca-pump provided for effective translocation of the transfer substrate to the vesicles which fully prevented the dissipation of the initial oppositely directed Ca2+ gradient. The synergism of energy-dependent calcium fluxes seemed to be unrelated to changes in the chemical composition of the ATP-containing incubation medium responsible for the induction of Mg2+, ATP- and Na(+)-dependent Ca2+ transfer (addition to the medium of Mg2+ and isotonic replacement of Na+ for choline+, respectively). It is concluded that the observed synergism is due to the stimulating effect of the Na+ gradient on the turnover number of the myometrium sarcolemma Ca-pump.


Thyroid eye disease.
Thyroid eye disease is the most common cause of unilateral and bilateral proptosis in adults. It occurs most frequently in women aged 30 to 50 years. Clinical features include eyelid retraction, periorbital edema, conjunctival injection and chemosis, proptosis, extraocular muscle restriction, exposure keratopathy, and optic nerve compromise. Thyroid eye disease differs from idiopathic orbital myositis in that the latter is characterized by a more acute onset, more severe pain, and a rapid response to systemic corticosteroid therapy. Echography and computed tomography in thyroid eye disease reveal enlarged extraocular muscle bellies with relative sparing of the tendons. Despite evidence of an immune-mediated cause, the precise pathophysiologic mechanisms of thyroid eye disease remain unknown.


Rapid endothelialization of small diameter vascular grafts by a bioactive integrin-binding ligand specifically targeting endothelial progenitor cells and endothelial cells.
Establishing and maintaining a healthy endothelium on vascular and intravascular devices is crucial for the prevention of thrombosis and stenosis. Generating a biofunctional surface on vascular devices to recruit endothelial progenitor cells (EPCs) and endothelial cells (ECs) has proven efficient in promoting in situ endothelialization. However, molecules conventionally used for EPC/EC capturing generally lack structural stability, capturing specificity, and biological functionalities, which have limited their applications. Discovery of effective, specific, and structurally stable EPC/EC capturing ligands is desperately needed. Using the high-throughput One-Bead One-Compound combinatorial library screening technology, we recently identified a disulfide cyclic octa-peptide LXW7 (cGRGDdvc), which possesses strong binding affinity and functionality to EPCs/ECs, weak binding to platelets, and no binding to inflammatory cells. Because LXW7 is cyclic and 4 out of the 8 amino acids are unnatural D-amino acids, LXW7 is highly proteolytically stable. In this study, we applied LXW7 to modify small diameter vascular grafts using a Click chemistry approach. In vitro studies demonstrated that LXW7-modified grafts significantly improved EPC attachment, proliferation and endothelial differentiation and suppressed platelet attachment. In a rat carotid artery bypass model, LXW7 modification of the small diameter vascular grafts significantly promoted EPC/EC recruitment and rapidly achieved endothelialization. At 6 weeks after implantation, LXW7-modified grafts retained a high patency of 83%, while the untreated grafts had a low patency of 17%. Our results demonstrate that LXW7 is a potent EPC/EC capturing and platelet suppressing ligand and LXW7-modified vascular grafts rapidly generate a healthy and stable endothelial interface between the graft surface and the circulation to reduce thrombosis and improve patency. STATEMENT OF SIGNIFICANCE: In this study, One-Bead One-Compound (OBOC) technology has been applied for the first time in discovering bioactive ligands for tissue regeneration applications. Current molecules used to modify artificial vascular grafts generally lack EPC/EC capturing specificity, biological functionalities and structural stability. Using OBOC technology, we identified LXW7, a constitutionally stable disulfide cyclic octa-peptide with strong binding affinity and biological functionality to EPCs/ECs, very weak binding to platelets and no binding to inflammatory cells. These characteristics are crucial for promoting rapid endothelialization to prevent thrombosis and improve patency of vascular grafts. LXW7 coating technology could be applied to a wide range of vascular and intravascular devices, including grafts, stents, cardiac valves, and catheters, where a "living" endothelium and healthy blood interface are needed.


Bayesian estimation and modeling: Editorial to the second special issue on Bayesian data analysis.
This editorial accompanies the second special issue on Bayesian data analysis published in this journal. The emphases of this issue are on Bayesian estimation and modeling. In this editorial, we outline the basics of current Bayesian estimation techniques and some notable developments in the statistical literature, as well as adaptations and extensions by psychological researchers to better tailor to the modeling applications in psychology. We end with a discussion on future outlooks of Bayesian data analysis in psychology. (PsycINFO Database Record


Problem-solving models and search strategies for pattern recognition.
Noting the major limitations of multivariate statistical classification and syntactic pattern recognition models, this paper presents an overview of some recent work using alternate representations for multistage and nearest neighbor multiclass classification, and for structural analysis and feature extraction. These alternate representations are based on generalizations of state-space and AND/OR graph models and search strategies developed in artificial intelligence (AI). The paper also briefly touches on other current interactions and differences between artificial intelligence and pattern recognition.


Characterization of Salmonella enterica subspecies I genovars by use of microarrays.
Subspecies 1 of Salmonella enterica is responsible for almost all Salmonella infections of warm-blooded animals. Within subspecies 1 there are over 2,300 known serovars that differ in their prevalence and the diseases that they cause in different hosts. Only a few of these serovars are responsible for most Salmonella infections in humans and domestic animals. The gene contents of 79 strains from the most prevalent serovars were profiled by microarray analysis. Strains within the same serovar often differed by the presence and absence of hundreds of genes. Gene contents sometimes differed more within a serovar than between serovars. Groups of strains that share a distinct profile of gene content can be referred to as "genovars" to distinguish them from serovars. Several misassignments within the Salmonella reference B collection were detected by genovar typing and were subsequently confirmed serologically. Just as serology has proved useful for understanding the host range and pathogenic manifestations of Salmonella, genovars are likely to further define previously unrecognized specific features of Salmonella infections.


Between ethylene and polyenes--the non-adiabatic dynamics of cis-dienes.
Using Ab Initio Multiple Spawning (AIMS) with a Multi-State Multi-Reference Perturbation theory (MS-MR-CASPT2) treatment of the electronic structure, we have simulated the non-adiabatic excited state dynamics of cyclopentadiene (CPD) and 1,2,3,4-tetramethyl-cyclopentadiene (Me4-CPD) following excitation to S1. It is observed that torsion around the carbon-carbon double bonds is essential in reaching a conical intersection seam connecting S1 and S0. We identify two timescales; the induction time from excitation to the onset of population transfer back to S0 (CPD: -25 fs, Me4-CPD: -71 fs) and the half-life of the subsequent population transfer (CPD: -28 fs, Me4-CPD: -48 fs). The longer timescales for Me4-CPD are a kinematic consequence of the inertia of the substituents impeding the essential out-of-plane motion that leads to the conical intersection seam. A bifurcation is observed on S1 leading to population transfer being attributable, in a 5 : 2 ratio for CPD and 7 : 2 ratio for Me4-CPD, to two closely related conical intersections. Calculated time-resolved photoelectron spectra are in excellent agreement with experimental spectra validating the simulation results.


Psychotic denial of pregnancy: legal and treatment considerations for clinicians.
The authors examine the legal questions raised by the involuntary medical and psychiatric treatment of a patient with psychotic denial of pregnancy. A case is presented, and psychotic denial of pregnancy is defined. Legal cases are reviewed that set precedent for state intervention on behalf of either the pregnant mother or the fetus when the mother refuses care. Included are specific cases that have a bearing on the rights of pregnant women with co-morbid mental illness. A distinction is made between cases in which the mother is competent versus incompetent to make treatment decisions, and particular attention is paid to California law. The authors conducted systematic Westlaw and LexisNexis searches of relevant case law and legal precedent. Laws that address the rights of pregnant women are complex, and courts have allowed medical interventions against objection in cases of both competent and incompetent mothers. No clear legal precedent was found to guide decision-making in the specific case of a woman with psychotic denial of pregnancy. The principles of substituted judgment and best interest may help guide clinicians in making decisions about the treatment of pregnant patients in the absence of clear legal precedent.


Partial Range of Motion Exercise Is Effective for Facilitating Muscle Hypertrophy and Function Through Sustained Intramuscular Hypoxia in Young Trained Men.
Goto, M, Chikako, M, Hirayama, T, Terada, S, Nirengi, S, Kurosawa, Y, Nagano, A, and Hamaoka, T. Partial range of motion exercise is effective for facilitating muscle hypertrophy and function through sustained intramuscular hypoxia in young trained men. J Strength Cond Res 33(5): 1286-1294, 2019-The acute response to and long-term effects of partial range of motion exercise (PRE) and full range of motion exercise (FRE) of elbow extensors were compared in young trained men. The PRE was expected to increase the intramuscular hypoxic environment, which was theorized to enhance muscular hypertrophy. Forty-four resistance-trained men were divided into 2 training groups, PRE (n = 22) or FRE (n = 22) group, and performed the PRE or FRE acute exercise protocol. The PRE (elbow range from 45° to 90°) and FRE (from 0° to 120°) acute protocols consisted of 3 sets of 8 repetitions, with an 8RM, and an equivalent workload. After the initial testing, the training program for each group, comprised 3 training sessions per week for 8 weeks, was started. The acute responses of area under the oxygenated hemoglobin (Oxy-Hb) curve, blood lactate concentration, and root mean square of electromyography were significantly higher both before and after PRE than FRE training. Long-term effects were produced by both PRE and FRE, with significant (p ≤ 0.05) increases in cross-sectional area (CSA) of triceps brachii and isometric strength. The CSA increased significantly greater after PRE (48.7 ± 14.5%) than after FRE (28.2 ± 10.9%). Furthermore, during the PRE program, a positive correlation was detected between the percent increase in CSA and area under the Oxy-Hb curves before and after 8-week exercise training (before 8-week exercise training: r = 0.59, after 8-week exercise training: r = 0.70, p < 0.01). These results suggest that intramuscular hypoxia might facilitate muscular hypertrophy with PRE being more effective than FRE.


Graphite/InP and graphite/GaN Schottky barriers with electrophoretically deposited Pd or Pt nanoparticles for hydrogen detection.
Large attention has been devoted worldwide to the investigation of hydrogen sensors based on various Schottky diodes. We prepared graphite semimetal Schottky contacts on polished n-InP and n-GaN wafers partly covered with nanoparticles of catalytic metals Pd or Pt by applying colloidal graphite. Metal nanoparticles were deposited electrophoretically from colloids prepared beforehand. Deposited nanoparticles were imaged by scanning electron microscopy, atomic force microscopy, and scanning tunneling microscopy on the as-made and annealed-in-vacuum samples. Current-voltage characteristics of prepared Schottky diodes had very high rectification ratios, better than 107 at 1 V. It was shown that the barrier heights of these diodes were equal to the difference between the electron affinity of InP or GaN and the electron work function of the metal Pd or Pt (Schottky-Mott limit). That was a good precondition for the high sensitivity of the diodes to hydrogen, and indeed, high sensitivity to hydrogen, with the detection limit better than 1 ppm, was proved.


Detection of sinusoidal amplitude modulated sounds: deficits after bilateral lesions of auditory cortex in the rat.
The ability of rats to detect the presence of sinusoidal amplitude modulation (AM) of a broadband noise carrier was determined before and after bilateral ablation of auditory cortex. The rats were trained to withdraw from a drinking spout to avoid a shock when they detected a modulation of the sound. Sensitivity was evaluated by testing the rats at progressively smaller depths of modulation. Psychophysical curves were produced to describe the limits of detection at modulation rates of 10, 100 and 1000Hz. Performance scores were based on the probability of withdrawal from the spout during AM (warning periods) relative to withdrawal during the un-modulated noise (safe periods). A threshold was defined as the depth of modulation that produced a score halfway between perfect avoidance and no avoidance (performance score=0.5). Bilateral auditory cortical lesions resulted in significant elevations in threshold for detection of AM at rates of 100 and 1000Hz. No significant shift was found at a modulation rate of 10Hz. The magnitude of the deficit for AM rates of 100 and 1000Hz was positively correlated with the size of the cortical lesion. Substantial deficits were found only in animals with lesions that included secondary as well as primary auditory cortical areas. The results show that the rat's auditory cortex is important for processing sinusoidal AM and that its contribution is most apparent at high modulation rates. The data suggest that the auditory cortex is a crucial structure for maintaining normal sensitivity to temporal modulation of an auditory stimulus.


Post stroke depression.
Comorbidity of depression and stroke significantly reduces the quality of life of patients after the stroke. Squeal after stroke also determines the quality of life and have impact on the occurrence of depression after the stroke. In our study we investigated the occurrence of depression in patients after different types and subtypes of stroke measured by the Hamilton scale compared to the level of disability measured by NIHSS scale. The goal was to make a comparative analysis of depression after stroke, according to gender and age, side of the lesion and the severity of neurological deficit. Material for our work are 210 patients with stroke treated at the Neurology Clinic, Clinical Center of Sarajevo University in 2012, 105 male and 105 female. The mean age of the patients was 67.12 +/- 9.5 years. Ischemic stroke was present in 65% cases. There was no statistically significant difference between ischemic and hemorrhagic stroke among genders. In case of hemorrhagic M-56.7%, F-43.3%; ischemic M-48.3%, F-51.7% (chi-square = 6.563, p = 0.082). Depression was more prevalent among younger patients (52-60 years) with 39.2% then in the group of older patients (61-70 years) with 32% of depressed. In relation to gender there was significantly more patients with depression among women compared to men (63.8:27.2%, chi-square = 14.38, p = 0.00019). Depression was more frequent in patients with stroke in the left hemisphere medial localization (63%). NIHSS scale average was 16.07 with the minimum of 11 and maximum of 22, F = 52.56, p = 0.001. We can conclude that depression after stroke is more frequent in younger patients, female patients, patients with localized stroke in the medial left hemisphere and with higher disability score.


Changes in antigen-specific IgG1 Fc N-glycosylation upon influenza and tetanus vaccination.
Antibody effector functions have been shown to be influenced by the structure of the Fc N-glycans. Here we studied the changes in plasma or serum IgG Fc N-glycosylation upon vaccination of 10 Caucasian adults and 10 African children. Serum/plasma IgG was purified by affinity chromatography prior to and at two time points after vaccination. Fc N-glycosylation profiles of individual IgG subclasses were determined for both total IgG and affinity-purified anti-vaccine IgG using a recently developed fast nanoliquid chromatography-electrospray ionization MS (LC-ESI-MS) method. While vaccination had no effect on the glycosylation of total IgG, anti-vaccine IgG showed increased levels of galactosylation and sialylation upon active immunization. Interestingly, the number of sialic acids per galactose increased during the vaccination time course, suggesting a distinct regulation of galactosylation and sialylation. In addition we observed a decrease in the level of IgG1 bisecting N-acetylglucosamine whereas no significant changes were observed for the level of fucosylation. Our data indicate that dependent on the vaccination time point the infectious agent will encounter IgGs with different glycosylation profiles, which are expected to influence the antibody effector functions relevant in immunity.


Photoreactivity of aged human RPE melanosomes: a comparison with lipofuscin.
To determine whether aging is accompanied by changes in aerobic photoreactivity of retinal pigment epithelial (RPE) melanosomes isolated from human donors of different ages, and to compare the photoreactivity of aged melanosomes with that of RPE lipofuscin. Human RPE pigment granules were isolated from RPE cells pooled into groups according to the age of the donors. Photoreactivity was determined by blue-light-induced oxygen uptake and photogeneration of reactive oxygen species. Short-lived radical intermediates were detected by spin-trapping, hydrogen peroxide by an oxidase electrode, singlet oxygen by cholesterol assay, and lipid hydroperoxides by iodometric assay. Blue-light photoexcitation of melanosomes resulted in age-related increases in both oxygen uptake and the accumulation of superoxide anion spin adducts. The efficiencies of these processes, however, were still significantly lower than that induced by photoexcited lipofuscin. During irradiation of melanosomes, a substantial amount of oxygen was converted into hydrogen peroxide, whereas for lipofuscin, hydrogen peroxide accounted for not more than 3% of oxygen consumed. In contrast to lipofuscin, photoexcited melanosomes did not substantially increase the rate of oxidative reactions in the presence of polyunsaturated lipids or albumin. However, oxygen uptake was significantly elevated in the presence of ascorbate. Thus, the rate of photo-induced oxygen uptake in samples containing both ascorbate and melanosomes approached that observed in lipofuscin samples. Blue-light-induced photoreactivity of melanosomes increases with age, perhaps providing a source of reactive oxygen species and leading to depletion of vital cellular reductants, which, together with lipofuscin, may contribute to cellular dysfunction.


Effect of plasticizer and antimicrobial agents on functional properties of bionanocomposite films based on corn starch-chitosan for food packaging applications.
The aim of this study was to evaluate the influence plasticizer (glycerol (GLY)/sorbitol (SOR)) and antimicrobial (potassium sorbate (KS)/grapefruit seed extract (GFSE)) agents on crystallinity, water barrier, mechanical, thermal and anti-fungal properties of prepared with corn starch (CS)-chitosan (CH) nanoclay (Na-MMT) bionanocomposite films. Results showed that CS/CH/nanoclay/SOR/GFSE films exhibit a higher crystallinity than any other bionanocomposite films. Molecular miscibility among corn starch, chitosan (COOH, NH) and nanoclay (AlOH, SiOSi) was exhibited in XRD. Films plasticized with SOR showed the highest tensile strength, lowest film solubility, lowest water vapor permeability and thermal stability. Fourier transform infrared spectroscopy (FTIR) confirmed that the main interactions among the components in a bionanocomposite film are due to hydrogen bonding. Bionanocomposite films containing GFSE showed a maximum zone of inhibition against Aspergillus niger. Synthetic plastic films exhibited fungal growth on 6th day whereas CS/CH/nanoclay/SOR/GFSE films did not show the same up to 20 days when bread samples were packed at 25 °C and 59% RH. CS/CH/nanoclay/SOR/GFSE film could potentially be useful for active packaging in extend the shelf life; maintain its quality and safety of food products thus substituting synthetic plastic packaging materials.


Parallel frequency-domain optical coherence tomography scatter-mode imaging of the hamster cheek pouch using a thermal light source.
We use a parallel frequency-domain optical coherence tomography (FDOCT) system to generate a scatter-mode image of the hamster cheek pouch epithelium. To our knowledge, this is the first optical coherence tomography (OCT) image of a biological sample obtained using a thermal light source in the frequency domain. The system employs an imaging spectrometer to acquire depth-resolved profiles from adjacent spatial points without the need for any scanning. To enable this imaging modality, we have considered that signals originating from multiple depths combine in a different manner in FDOCT compared to time-domain optical coherence tomography (TDOCT). Because a multicomponent FDOCT signal is a coherent sum, it is necessary to limit the number of modes that contribute to the detected signal. Conversely, multicomponent TDOCT signals can be represented as incoherent sums, where increasing the number of modes improves the signal.


Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics.
Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. We describe here a new human peptide deformylase (Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previously not thought to be necessary in mammalian cells. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. We designed and synthesized 33 chemical analogs of actinonin; all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner; removal of actinonin led to a recovery of the membrane potential consistent with indirect effects on the electron transport chain. In animal models, oral or parenteral actinonin was well tolerated and inhibited human prostate cancer and lung cancer growth. We conclude that HsPDF is a new human mitochondrial enzyme that may provide a novel selective target for anticancer therapy by use of actinonin-based antibiotics.


Accuracy of matching optic discs with visual fields: the European Structure and Function Assessment Trial (ESAFAT).
To determine the ability of ophthalmologists across Europe to match stereoscopic optic disc photographs to visual fields of varying severity. Evaluation and comparison of 2 diagnostic tests. A total of 109 of 260 invited ophthalmologists in 11 European countries. These had participated in the previous European Optic Disc Assessment Trial (EODAT), a trial on glaucoma diagnostic accuracy based on optic discs only. Each participant matched stereo optic disc photographs of 40 healthy and 48 glaucomatous eyes to a visual field chosen from 4 options per disc. The 4 presented visual fields included the corresponding one and 3 other visual fields, varying in severity. The matching accuracy and any inaccuracy per disease severity were calculated. Classification accuracy (as glaucomatous or healthy) was compared with EODAT data. Duplicate slides allowed for the assessment of intraobserver agreement. Accuracy of matching optic discs with their corresponding visual field and of classifying them as healthy or glaucomatous; intraobserver agreement (κ). The overall accuracy of ophthalmologists for correctly matching stereoscopic optic disc photographs to their visual fields was 58.7%. When incorrectly matched, the observers generally overestimated the visual field severity (P<0.001), notably in eyes with early glaucoma. The intraobserver agreement was, on average, moderate (0.52). European ophthalmologists correctly matched stereoscopic optic disc photographs to their corresponding visual field in only approximately 59% of cases. In most mismatches, the clinicians overestimated the visual field damage.


Penile verrucous carcinoma: a clinicopathologic, human papillomavirus typing and flow cytometric analysis.
The relationship of various verruciform squamous cell proliferations of the penis such as verrucous carcinoma, with or without anaplasia and giant condyloma, is uncertain. We conducted clinicopathologic, flow cytometric, and HPV typing studies on 15 cases of penile verrucous carcinoma to investigate its place in the spectrum of genital squamous proliferations. The results show a high degree of morphologic uniformity with respect to Ackerman's original diagnostic criteria, as well as to several other histopathologic features evaluated. The latter include polygonal squamous cells with glassy cytoplasm, centrally located vesicular nuclei, intercellular edema, well-formed cellular bridges, and absence or paucity of koilocytes, true fibrovascular cores, and keratohyalin granules. Intraepithelial abscesses and crust-formation were present in many cases. Four cases contained microscopic foci of cellular anaplasia. These hybrid verrucous-squamous carcinomas presented and behaved similarly to the pure verrucous carcinomas. Tumor recurrence was correlated with extent of initial surgical management. DNA ploidy analysis by flow cytometry performed on eight pure and two hybrid tumors showed uniform diploid populations with similar G1/G2 fractions in both groups. Eight pure and two hybrid tumors evaluated for HPV by isotopic in situ hybridization were uniformly negative for HPV types 6, 11, 16, 18, and 31. The results show that penile verrucous carcinoma demonstrates characteristic and uniform morphologic features and does not contain the HPV types typically associated with condyloma acuminatum, giant condyloma of Buschke-Löwenstein, and condylomatous carcinoma.


Composition and antimicrobial activity of the essential oil of Heracleum thomsonii (Clarke) from the cold desert of the western Himalayas.
Volatile oil composition of hydro-distilled (HD) and supercritical carbon dioxide (SC-CO(2)) essential oil of freshly collected aerial parts of Heracleum thomsonii (Umbeliferae) from the western Himalayas was studied by GC-FID and GC-MS. Results revealed qualitative and quantitative dissimilarity in the composition of hydro-distilled and SC-CO(2) extracted oils. Nineteen constituents, which accounted for 89.32% of total constituents in HD oil, represented by limonene (4.31%), (Z)-β-ocimene (3.69%), terpinolene (22.24%), neryl acetate (36.19%), nerol (9.51%) and p-cymene-8-ol (2.61%) were identified. In SC-CO(2) extracted oil, 24 constituents representing 89.95% of total constituents were identified. Terpinolene (5.08%), germacrene D (2.17%), neryl acetate (51.62%), nerol (9.78%), geranyl acetate (2.06%), α-bisabolol (2.48%) and 1-nonadecanol (4.96%) were the dominating constituents. In vitro antimicrobial activity of hydro-distilled oil was conducted against microrobial strains including two Gram-positive (Staphylococcus aureus and Bacillus subtilis) and five Gram-negative (Burkholderia cepacia, Escherichia coli, Enterobacter cloacae, Klebseilla pneumoniae and Pseudomonas aeruginosa) bacteria as well as seven fungi (Candida albicans, Issatchenkia orientalis, Aspergillus flavus, Aspergillus niger, Aspergillus parasiticus, Aspergillus sydowii and Trichophyton rubrum) using broth microdilution method. The results of bioassay showed that the oil exhibited moderate to high antimicrobial activity against fungi C. albicans (MIC 625 µg ml(-1)), A. parasiticus (MIC 312.5 µg ml(-1)), A. sydowii (MIC 312.5 µg ml(-1)), T. rubrum (MIC 625 µg ml(-1)), Gram-positive bacteria B. subtilis (MIC 625 µg ml(-1)) and Gram-negative bacteria P. aeruginosa (MIC 312.5 µg ml(-1)).


Azithromycin in control of trachoma.
Trachoma is the leading cause of preventable blindness. Programmes to prevent blindness due to trachoma are based on community-wide treatment with topical tetracycline. We assessed the potential of community-wide azithromycin treatment for trachoma control. Pairs of villages in trachoma endemic areas of Egypt, The Gambia, and Tanzania were matched on trachoma rates in 1-10-year-old children. Villages were randomly assigned community-wide oral azithromycin treatment (three doses with intervals of 1 week) or treatment with 1% topical tetracycline (once daily for 6 weeks). Clinical examinations were done at baseline, 2-4.5 months, and 12-14 months after treatment. Chlamydia trachomatitis was identified by ligase chain reaction (LCR). Analyses were by intention to treat. Univariate comparisons and multivariate analyses were used to compare outcomes. LCR positivity was correlated with clinical severity, but about 30% of Egyptian and Gambian villagers with no active disease were LCR positive. Village-wide LCR positivity ranged from 16.5% (Tanzania) to 43.6% (Egypt). Treatment compliance was over 90% except in the tetracycline treatment village in Egypt. Of the participants initially LCR positive, 866 (95%) of 924 who received at least one azithromycin dose and 482 (82%) of 587 who received 28 days or more topical tetracycline, were negative at follow-up. At 1 year, village-wide LCR positivity rates were substantially lower than at baseline with both treatments; the decreases were greater with azithromycin than with tetracycline (93% vs 77% in Egypt, 78 vs 66% in The Gambia, 64 vs 55% in Tanzania). Similarly, greater reduction in clinical activity occurred after azithromycin. In multivariate analyses, factors associated with being LCR positive at 1 year were: not receiving azithromycin; age under 10 years; and LCR positivity at baseline. Community-wide treatment with oral azithromycin markedly reduces C. trachomatis infection and clinical trachoma in endemic areas and may be an important approach to control of trachoma.


Predictive value of developmental testing in the second year for cognitive development at five years of age.
There is mixed evidence about the predictive validity of the Griffiths mental developmental scales. This study aimed to assess the predictive value of developmental assessments of children in their second year using the Griffiths mental development scales for neuro-developmental status at five years using the Wechsler preschool and primary scale of intelligence, revised (WPPSI-R). In a longitudinal study 253 children were assessed in their second year of life using the Griffiths scales and again at five years using the WPPSI-R. The scores were compared and the predictability of the WPPSI-R outcome on the basis of Griffiths scores was assessed. The WPPSI-R full scale IQ and the performance IQ at age five could be predicted moderately by the Griffiths general quotient (GQ) and by the personal/social scale. The Griffiths GQ was not a significant predictor of verbal IQ at age 5. The Griffiths performance scale predicted subsequent WPPSI-R performance IQ, and marginally the Full Scale IQ. For the early identification of children at risk for language delay, the Griffiths scales may not be suitable. However, a shortened form would be useful to predict overall cognitive development from the second year to school entry, focussing on the personal-social and performance scales.


Feasibility of tablet computer screening for opioid abuse in the emergency department.
Tablet computer-based screening may have the potential for detecting patients at risk for opioid abuse in the emergency department (ED). Study objectives were a) to determine if the revised Screener and Opioid Assessment for Patients with Pain (SOAPP®-R), a 24-question previously paper-based screening tool for opioid abuse potential, could be administered on a tablet computer to an ED patient population; b) to demonstrate that >90% of patients can complete the electronic screener without assistance in <5 minutes and; c) to determine patient ease of use with screening on a tablet computer. This was a cross-sectional convenience sample study of patients seen in an urban academic ED. SOAPP®-R was programmed on a tablet computer by study investigators. Inclusion criteria were patients ages ≥18 years who were being considered for discharge with a prescription for an opioid analgesic. Exclusion criteria included inability to understand English or physical disability preventing use of the tablet. 93 patients were approached for inclusion and 82 (88%) provided consent. Fifty-two percent (n=43) of subjects were male; 46% (n=38) of subjects were between 18-35 years, and 54% (n=44) were >35 years. One hundred percent of subjects completed the screener. Median time to completion was 148 (interquartile range 117.5-184.3) seconds, and 95% (n=78) completed in <5 minutes. 93% (n=76) rated ease of completion as very easy. It is feasible to administer a screening tool to a cohort of ED patients on a tablet computer. The screener administration time is minimal and patient ease of use with this modality is high.


Bounded diffusion for multiscale edge detection using regularized cubic B-spline fitting.
This paper shows that in edge detection the regularization factor alpha is a better scale parameter than the standard deviation (sigma) of the Gaussian pre-filter. The alpha scale space, which exhibits the evolutionary behaviour of an edge in various scales, is the basis for the design of a multiscale edge detector (MRCBS). In MRCBS, the scale is determined adaptively according to the local noise level; the thresholds which control the amount of edge details are adjusted according to the scale; and the anisotropic diffusion is applied in the finest scale to further suppress noise.


Does growth impairment underlie the adverse effects of dexamethasone on development of noradrenergic systems?
Glucocorticoids are given in preterm labor to prevent respiratory distress but these agents evoke neurobehavioral deficits in association with reduced brain region volumes. To determine whether the neurodevelopmental effects are distinct from growth impairment, we gave developing rats dexamethasone at doses below or within the therapeutic range (0.05, 0.2 or 0.8 mg/kg) at different stages: gestational days (GD) 17-19, postnatal days (PN) 1-3 or PN7-9. In adolescence and adulthood, we assessed the impact on noradrenergic systems in multiple brain regions, comparing the effects to those on somatic growth or on brain region growth. Somatic growth was reduced with exposure in all three stages, with greater sensitivity for the postnatal regimens; brain region growth was impaired to a lesser extent. Norepinephrine content and concentration were reduced depending on the treatment regimen, with a rank order of deficits of PN7-9 > PN1-3 > GD17-19. However, brain growth impairment did not parallel reduced norepinephrine content in magnitude, dose threshold, sex or regional selectivity, or temporal pattern, and even when corrected for reduced brain region weights (norepinephrine per g tissue), the dexamethasone-exposed animals showed subnormal values. Regression analysis showed that somatic growth impairment accounted for an insubstantial amount of the reduction in norepinephrine content, and brain growth impairment accounted for only 12%, whereas specific effects on norepinephrine accounted for most of the effect. The adverse effects of dexamethasone on noradrenergic system development are not simply related to impaired somatic or brain region growth, but rather include specific targeting of neurodifferentiation.


Insulation break of the ventricular lead in a dog with a pacemaker.
A 10-year-old female spayed mixed breed dog that had a transvenous pacemaker implanted four years prior was presented for the evaluation of episodes of transient loss of consciousness without any history of trauma that were unresponsive to anticonvulsant therapies. Intermittent failure to capture coupled with low impedance and high capture threshold were noted upon interrogation of the pacemaker. Radiography and fluoroscopy demonstrated a possible break in the insulation of the lead. After the placement of another transvenous pacemaker, the dog had no additional syncopal episodes, and anticonvulsants were tapered off. The dog developed an implant infection from the newly placed pacemaker, which prompted the removal of the infected pacemaker and the implantation of an epicardial pacemaker. However, the epicardial lead dislodged seven days after placement, and the dog was euthanized. During necropsy, the first transvenous lead was removed, and the insulation break was visually confirmed. Although an insulation break is a rare delayed complication of pacemaker implantation, this report shows how the diagnosis, suspected by typical interrogation findings, can be aided by radiographic and fluoroscopic investigations.


Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches.
In its 33 years, ADDR has published regularly on the po5tential of oral delivery of biologics especially peptides and proteins. In the intervening period, analysis of the preclinical and clinical trial failures of many purported platform technologies has led to reflection on the true status of the field and reigning in of expectations. Oral formulations of semaglutide, octreotide, and salmon calcitonin have completed Phase III trials, with oral semaglutide being approved by the FDA in 2019. The progress made with oral peptide formulations based on traditional permeation enhancers is against a background of low and variable oral bioavailability values of ~1%, leading to a current perception that only potent peptides with a viable cost of synthesis can be realistically considered. Desirable features of candidates should include a large therapeutic index, some stability in the GI tract, a long elimination half-life, and a relatively low clearance rate. Administration in nanoparticle formats have largely disappointed, with few prototypes reaching clinical trials: insufficient particle loading, lack of controlled release, low epithelial particle uptake, and lack of scalable synthesis being the main reasons for discontinuation. Disruptive technologies based on engineered devices promise improvements, but scale-up and toxicology aspects are issues to address. In parallel, medicinal chemists are synthesizing stable hydrophobic macrocyclic candidate peptides of lower molecular weight and with potential for greater oral bioavailability than linear peptides, but perhaps without the same requirement for elaborate drug delivery systems. In summary, while there have been advances in understanding the limitations of peptides for oral delivery, low membrane permeability, metabolism, and high clearance rates continue to hamper progress.


Cost-Effectiveness Analysis of Afatinib versus Gefitinib for First-Line Treatment of Advanced EGFR-Mutated Advanced Non-Small Cell Lung Cancers.
The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial for first-line treatment of advanced EGFR mutation-positive NSCLCs. Afatinib and gefitinib costs and patients' outcomes in France were assessed. A partitioned survival model was designed to assess the cost-effectiveness of afatinib versus gefitinib for EGFR mutation-positive NSCLCs. Outcomes and safety were taken primarily from the LUX-Lung 7 trial. Resource use and utilities were derived from that trial, an expert-panel questionnaire, and published literature, limiting expenditures to direct costs. Incremental cost-effectiveness ratios (ICERs) were calculated over a 10-year time horizon for the entire population, and EGFR exon 19 deletion or exon 21 L858R mutation (L858R) subgroups. Deterministic and probabilistic sensitivity analyses were conducted. For all EGFR mutation-positive NSCLCs, the afatinib-versus-gefitinib ICER of was €45,211 per quality-adjusted life-year (QALY) (0.170 QALY gain for an incremental cost of €7697). ICERs for EGFR exon 19 deletion and L858R populations were €38,970 and €52,518, respectively. Afatinib had 100% probability to be cost-effective at a willingness-to-pay threshold of €70,000/QALY for patients with common EGFR mutations. First-line afatinib appears cost-effective compared with gefitinib for patients with EGFR mutation-positive NSCLCs.


Regional glucose utilization in infarcted and remote myocardium: its relation to coronary anatomy and perfusion.
We studied the relationship between coronary anatomy, perfusion and metabolism in myocardial segments exhibiting transient and persistent perfusion defects on stress/rest 99Tcm-MIBI single photon emission tomography in 35 patients (31 males, 4 females, mean age 56 +/- 7 years) with a previous myocardial infarction. Quantitative coronary angiography and assessment of myocardial perfusion reserve and glucose metabolism were performed within 1 week of one another. Perfusion was assessed by SPET after the intravenous injection of 740 MBq of 99Tcm-MIBI at rest and after exercise. Regional myocardial glucose metabolism was assessed by position emission tomography at rest (200 MBq of 18F-2-deoxyglucose, FDG) after an overnight fast with no glucose loading. All 35 patients exhibited persistent perfusion defects consistent with the clinically identified infarct site, and 27 (77%) also showed various degrees of within-infarct FDG uptake; 11 patients developed exercise-induced transient perfusion defects within, or in the vicinity of, 15 infarct segments and resting FDG uptake was present in 10 of these segments (67%). Five patients also showed exercise-induced transient perfusion defects in nine segments remote from the site of infarct: resting FDG uptake was present in six of these regions (67%). Finally, nine patients had increased glucose uptake in non-infarcted regions not showing transient perfusion defects upon exercise testing and perfused by coronary arteries with only minor irregularities. Our results confirm the presence of viable tissue in a large proportion of infarct sites. Moreover, FDG uptake can be seen in regions perfused by coronary arteries showing minor irregularities, not necessarily resulting in detectable transient perfusion defects on a MIBI stress scan. Since the clinical significance of such findings is not clear, further studies should be conducted to assess the long-term evolution of perfusion, function and metabolism in non-revascularized patients of those remote areas which are apparently normally perfused, but show abnormal fasting FDG uptake after myocardial infarction. Such studies may have important implications for the management of post-infarct patients, as the preservation of coronary vasodilator reserve and myocardial metabolism in remote myocardium may be seen as an additional goal in the treatment of such patients.


Human reference gut microbiome catalog including newly assembled genomes from under-represented Asian metagenomes.
Metagenome sampling bias for geographical location and lifestyle is partially responsible for the incomplete catalog of reference genomes of gut microbial species. Thus, genome assembly from currently under-represented populations may effectively expand the reference gut microbiome and improve taxonomic and functional profiling. We assembled genomes using public whole-metagenomic shotgun sequencing (WMS) data for 110 and 645 fecal samples from India and Japan, respectively. In addition, we assembled genomes from newly generated WMS data for 90 fecal samples collected from Korea. Expecting genome assembly for low-abundance species may require a much deeper sequencing than that usually employed, so we performed ultra-deep WMS (> 30 Gbp or > 100 million read pairs) for the fecal samples from Korea. We consequently assembled 29,082 prokaryotic genomes from 845 fecal metagenomes for the three under-represented Asian countries and combined them with the Unified Human Gastrointestinal Genome (UHGG) to generate an expanded catalog, the Human Reference Gut Microbiome (HRGM). HRGM contains 232,098 non-redundant genomes for 5414 representative prokaryotic species including 780 that are novel, > 103 million unique proteins, and > 274 million single-nucleotide variants. This is an over 10% increase from the UHGG. The new 780 species were enriched for the Bacteroidaceae family, including species associated with high-fiber and seaweed-rich diets. Single-nucleotide variant density was positively associated with the speciation rate of gut commensals. We found that ultra-deep sequencing facilitated the assembly of genomes for low-abundance taxa, and deep sequencing (e.g., > 20 million read pairs) may be needed for the profiling of low-abundance taxa. Importantly, the HRGM significantly improved the taxonomic and functional classification of sequencing reads from fecal samples. Finally, analysis of human self-antigen homologs on the HRGM species genomes suggested that bacterial taxa with high cross-reactivity potential may contribute more to the pathogenesis of gut microbiome-associated diseases than those with low cross-reactivity potential by promoting inflammatory condition. By including gut metagenomes from previously under-represented Asian countries, Korea, India, and Japan, we developed a substantially expanded microbiome catalog, HRGM. Information of the microbial genomes and coding genes is publicly available ( www.mbiomenet.org/HRGM/ ). HRGM will facilitate the identification and functional analysis of disease-associated gut microbiota.


Acc homoeoloci and the evolution of wheat genomes.
The DNA sequences of wheat Acc-1 and Acc-2 loci, encoding the plastid and cytosolic forms of the enzyme acetyl-CoA carboxylase, were analyzed with a view to understanding the evolution of these genes and the origin of the three genomes in modern hexaploid wheat. Acc-1 and Acc-2 loci from each of the wheats Triticum urartu (A genome), Aegilops tauschii (D genome), Triticum turgidum (AB genome), and Triticum aestivum (ABD genome), as well as two Acc-2-related pseudogenes from T. urartu were sequenced. The 2.3-2.4 Mya divergence time calculated here for the three homoeologous chromosomes, on the basis of coding and intron sequences of the Acc-1 genes, is at the low end of other estimates. Our clock was calibrated by using 60 Mya for the divergence between wheat and maize. On the same time scale, wheat and barley diverged 11.6 Mya, based on sequences of Acc and other genes. The regions flanking the Acc genes are not conserved among the A, B, and D genomes. They are conserved when comparing homoeologous genomes of diploid, tetraploid, and hexaploid wheats. Substitution rates in intergenic regions consisting primarily of repetitive sequences vary substantially along the loci and on average are 3.5-fold higher than the Acc intron substitution rates. The composition of the Acc homoeoloci suggests haplotype divergence exceeding in some cases 0.5 Mya. Such variation might result in a significant overestimate of the time since tetraploid wheat formation, which occurred no more than 0.5 Mya.


Obstructive sleep apnea and metabolic syndrome: alterations in glucose metabolism and inflammation.
Metabolic syndrome (MS), the commonly used term for the clustering of obesity, insulin resistance, hypertension, and dyslipidemia, affects millions of people worldwide, and is associated with an increased risk of cardiovascular disease and type 2 diabetes. Recently, it has been suggested that obstructive sleep apnea (OSA), an increasingly prevalent condition, may contribute to the development of MS and diabetes. Despite substantial evidence from both clinical and population studies to suggest an independent link between OSA and metabolic abnormalities, the issue still remains controversial. Obesity, particularly visceral obesity, is an important factor in the assessment of adverse metabolic outcome in OSA. Further prospective and interventional studies, with adequate sample sizes and longer follow-up, rigorous control for adiposity, and, ideally, randomization and control for any therapeutic intervention, are clearly needed to address the direction of causality. There are multiple mechanistic pathways involved in the interaction between OSA, obesity, and metabolic derangements. Chronic intermittent hypoxia and sleep fragmentation with sleep loss in OSA are likely key triggers that initiate or contribute to the sustenance of inflammation as a prominent phenomenon, but their complex interplay remains to be elucidated. In summary, OSA may represent a novel risk factor for MS and diabetes, and thus clinicians should be encouraged to systematically evaluate the presence of metabolic abnormalities in OSA and vice versa.


Severe Cervicothoracic Kyphoscoliosis in Neurofibromatosis - A Failure Of Posterior-Only Instrumentation: A Case Report.
Treatment of severe spinal deformities associated with neurofibromatosis has proven to be challenging. An 11-year-old girl, with neurofibromatosis and severe cervicothoracic kyphoscoliosis, was initially treated with posterior instrumentation and fusion. Implant failure developed within a year, requiring an anterior stabilisation and fusion with a non-vascularised fibular strut graft for better stability and increased likelihood of achieving union. The posterior instrumentation was removed due to its prominence and wound breakdown. Following the removal of the posterior implant, the fibular graft fractured. The patient was maintained on a cervical collar until union was achieved. Posterior spinal fusion alone in severe spinal deformities in neurofibromatosis has a high risk of failure. A combined anterior and posterior fusion may increase the chance of success, with better stability and union rate.


Thyroid function tests: a review.
In this paper, we review the tests that are executed to aid the diagnosis of thyroid dysfunction. Thyroid function tests provide information at physiological, pathological and anatomical levels. Along with history and physical examination they owe to many specific findings that are associated with thyroid functioning. So an attempt has been made to put forward a gist of thyroid function tests. Serum tests of thyroid function are serum total thyroxine (T4), serum total triiodothyronin (T3), free thyroxine (FT4), free triiodothyronin (FT3), reverse triiodothyronin (rT3), thyroid stimulating hormone (TSH), serum calcitonin and protein thyroglobulin (Tg). The serological tests are antithyroglobulin antibodies (ATA) and antimicrosomal antibodies (AMA). An invasive test for histologic examination is done by fine needle aspiration cytology (FNAC) and noninvasive test includes ultrasonography, magnetic resonance imaging, and positron emission tomography. Further molecular study provides molecular markers for thyroid cancer. These tests can provide greater sensitivity and specificity that enhance the likelihood of early detection of ambiguous thyroid disease with only minimal clinical findings. Lastly, in vivo tests are thyroidal radioiodine and iodide uptake is also done.


Analysis of gut microbiota profiles and microbe-disease associations in children with autism spectrum disorders in China.
Autism spectrum disorder (ASD) is a set of complex neurodevelopmental disorders. Recent studies reported that children with ASD have altered gut microbiota profiles compared with typical development (TD) children. However, few studies on gut bacteria of children with ASD have been conducted in China. Here, in order to elucidate changes of fecal microbiota in children with ASD, 16S rRNA sequencing was conducted and the 16S rRNA (V3-V4) gene tags were amplified. We investigated differences in fecal microbiota between 35 children with ASD and 6 TD children. At the phylum level, the fecal microbiota of ASD group indicated a significant increase of the Bacteroidetes/Firmicutes ratio. At the genus level, we found that the relative abundance of Sutterella, Odoribacter and Butyricimonas was much more abundant in the ASD group whereas the abundance of Veillonella and Streptococcus was decreased significantly compared to the control group. Functional analysis demonstrated that butyrate and lactate producers were less abundant in the ASD group. In addition, we downloaded the association data set of microbe-disease from human microbe-disease association database and constructed a human disease network including ASD using our gut microbiome results. In this microbe-disease network based on microbe similarity of diseases, we found that ASD is positively correlated with periodontal, negatively related to type 1 diabetes. Therefore, these results suggest that microbe-based disease analysis is able to predict novel connection between ASD and other diseases and may play a role in revealing the pathogenesis of ASD.


Maltose chemoreceptor of Escherichia coli: interaction of maltose-binding protein and the tar signal transducer.
The maltose chemoreceptor in Escherichia coli consists of the periplasmic maltose-binding protein (MBP) and the Tar signal transducer, which is localized in the cytoplasmic membrane. We previously isolated strains containing malE mutations that cause specific defects in the chemotactic function of MBP. Four of these mutations have now been characterized by DNA sequence analysis. Two of them replace threonine at residue 53 of MBP with isoleucine (MBP-TI53), one replaces an aspartate at residue 55 with asparagine (MBP-DN55), and the fourth replaces threonine at residue 345 with isoleucine (MBP-TI345). The chemotactic defects of MBP-TI53 and MBP-DN55, but not of MBP-TI345, are suppressed by mutations in the tar gene. Of the tar mutations, the most effective suppressor (isolated independently three times) replaces Arg-73 of Tar with tryptophan. Two other tar mutations that disrupt the aspartate chemoreceptor function of Tar also suppress the maltose taxis defects associated with MBP-TI53 and MBP-DN55. One of these mutations introduces glutamine at residue 73 of Tar, the other replaces arginine at residue 69 of Tar with cysteine. These results suggest that regions of MBP that include residues 53 to 55 and residue 345 are important for the interaction with Tar. In turn, arginines at residues 69 and 73 of Tar must be involved in the recognition of maltose-bound MBP and/or in the production of the attractant signal generated by Tar in response to maltose-bound MBP.


Structures and dynamic properties of the LiPF6 electrolytic solution under electric fields - a theoretical study.
Fluorinated carbonates have attracted increasing attention in high-voltage lithium ion battery applications. Under free and electric fields, their structure-related solvent dynamic properties such as charge and discharge rate, however, are rarely reported. Herein, solutions including linear fluorinated carbonates have been simulated using joint MD/DFT calculations. For the first time, the dielectric constants of the four pure fluorinated carbonates have been predicted to be ca. 5.4 (4: ethyl-2,2,2-trifluoroethyl carbonate)-12.1 (7: di-1,1,2,2,2-pentafluoroethyl carbonate), which are dependent on the number of fluorine atoms. Minor difference in the solvation free energies and few contact ion associations were observed in the ETFEC and DTFEC solvents. Their comparable viscosity values were found through calculations of ion diffusivity and conductivity. In the electric fields, the Li+ mobilities in the two solutions have similar values, showing that the dynamic properties of the electrolytic solutions are almost independent of the number of fluorine atoms on these carbonates. There emerges an oriented and ordered arrangement of the solvent molecules and thus the largely decreased dielectric constants under the electric fields, even though the field strength is very low. These interesting phenomena should be relevant in the formation of contact and aggregate ion pairs, leading to unexpected reduction of the charge-discharge rate-related ion mobility in mixed solvents.


Socially flexible female choice and premating isolation in field crickets (Teleogryllus spp.).
Social influences on mate choice are predicted to influence evolutionary divergence of closely related taxa, because of the key role mate choice plays in reproductive isolation. However, it is unclear whether females choosing between heterospecific and conspecific male signals use previously experienced social information in the same manner or to the same extent that they do when discriminating among conspecific mates only. We tested this using two field cricket sister species (Teleogryllus oceanicus and Teleogryllus commodus), in which considerable information is known about the role of male calling song in premating isolation, in addition to the influence of acoustic experience on the development of reproductive traits. We manipulated the acoustic experience of replicate populations of both species and found, unexpectedly, that experience of male calling song during rearing did not change how accurate females were in choosing a conspecific over a heterospecific male song during playback trials. However, females with acoustic experience were considerably less responsive to male song compared with naïve females. Our results suggest that variation in the acoustic environment affects mate choice in both species, but that it may have a limited impact on premating isolation. The fact that social flexibility during interspecific mate discrimination does not appear to operate identically to that which occurs during conspecific mate discrimination highlights the importance of considering the context in which animals exercise socially flexible mating behaviours. We suggest an explanation for why social flexibility might be context dependent and discuss the consequences of such flexibility for the evolution of reproductive isolation.


Irinotecan synergistically enhances the antiproliferative and proapoptotic effects of axitinib in vitro and improves its anticancer activity in vivo.
To demonstrate the synergistic antiproliferative and proapoptotic activity of irinotecan and axitinib in vitro and the improvement of the in vivo effects on angiogenesis and pancreatic cancer. Proliferation and apoptotic assays were performed on human dermal microvascular endothelial cells and pancreas cancer (MIAPaCa-2, Capan-1) cell lines exposed to SN-38, the active metabolite of irinotecan, axitinib, or their simultaneous combination for 72 hours. ERK1/2 and Akt phosphorylation, the vascular endothelial growth factor (VEGF), VEGF receptor-2, and thrombospondin-1 (TSP-1) concentration were measured by ELISAs. ATP7A and ABCG2 gene expression was performed with real-time polymerase chain reaction and SN-38 intracellular concentrations were measured by high-performance liquid chromatography. Capan-1 xenografts in nude mice were treated with irinotecan and axitinib alone or in simultaneous combination. A strong synergistic effect on antiproliferative and proapoptotic activity was found with the axitinib/SN-38 combination on endothelial and cancer cells. ERK1/2 and Akt phosphorylation were significantly inhibited by lower concentrations of the combined drugs in all the cell lines. Axitinib and SN-38 combined treatment greatly inhibited the expression of the ATP7A and ABCG2 genes in endothelial and cancer cells, increasing the SN-38 intracellular concentration. Moreover, TSP-1 secretion was increased in cells treated with both drugs, whereas VEGFR-2 levels significantly decreased. In vivo administration of the simultaneous combination determined an almost complete regression of tumors and tumor neovascularization. In vitro results show the highly synergistic properties of simultaneous combination of irinotecan and axitinib on endothelial and pancreas cancer cells, suggesting a possible translation of this schedule into the clinics.


Temozolomide salvage chemotherapy for recurrent anaplastic oligodendroglioma and oligo-astrocytoma.
To evaluate the efficacy of temozolomide (TMZ) chemotherapy for recurrent anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA). A multi-center retrospective trial enrolled seventy-two patients with histologically proven AO/AOA who underwent TMZ chemotherapy for their recurrent tumors from 2006 to 2010. TMZ was administered orally (150 to 200 mg/m(2)/day) for 5 days per 28 days until unacceptable toxicity occurred or tumor progression was observed. TMZ chemotherapy cycles administered was median 5.3 (range, 1-41). The objective response rate was 24% including 8 cases (11%) of complete response and another 23 patients (32%) were remained as stable disease. Severe side effects (≥grade 3) occurred only in 9 patients (13%). Progression-free survival (PFS) of all patients was a median 8.0 months (95% confidence interval, 6.0-10.0). The time to recurrence of a year or after was a favorable prognostic factor for PFS (p<0.05). Overall survival (OS) was apparently differed by the patient's histology, as AOA patients survived a median OS of 18.0 months while AO patients did not reach median OS at median follow-up of 11.5 months (range 2.7-65 months). Good performance status of Eastern Cooperative Oncology Group 0 and 1 showed prolonged OS (p<0.01). For recurrent AO/AOA after surgery followed by radiation therapy, TMZ could be recommended as a salvage therapy at the estimated efficacy equal to procarbazine, lomustine, and vincristine (PCV) chemotherapy at first relapse. For patients previously treated with PCV, TMZ is a favorable therapeutic option as 2nd line salvage chemotherapy with an acceptable toxicity rate.


[The content of apolipoproteins in blood M and parameters of lipid metabolism in population of North Polar regions and Southern regions of Caucasus].
The study was carried out concerning the between content of apolipoproteins A and B in blood and lipid metabolism in population of North Polar regions and Southern regions of Caucasus. The differences of correlation relationships depending on concentration of apolipoproteins A and B in blood in population dwelling in territories climate geographic regions were detected.


ORIO (Online Resource for Integrative Omics): a web-based platform for rapid integration of next generation sequencing data.
Established and emerging next generation sequencing (NGS)-based technologies allow for genome-wide interrogation of diverse biological processes. However, accessibility of NGS data remains a problem, and few user-friendly resources exist for integrative analysis of NGS data from different sources and experimental techniques. Here, we present Online Resource for Integrative Omics (ORIO; https://orio.niehs.nih.gov/), a web-based resource with an intuitive user interface for rapid analysis and integration of NGS data. To use ORIO, the user specifies NGS data of interest along with a list of genomic coordinates. Genomic coordinates may be biologically relevant features from a variety of sources, such as ChIP-seq peaks for a given protein or transcription start sites from known gene models. ORIO first iteratively finds read coverage values at each genomic feature for each NGS dataset. Data are then integrated using clustering-based approaches, giving hierarchical relationships across NGS datasets and separating individual genomic features into groups. In focusing its analysis on read coverage, ORIO makes limited assumptions about the analyzed data; this allows the tool to be applied across data from a variety of experiments and techniques. Results from analysis are presented in dynamic displays alongside user-controlled statistical tests, supporting rapid statistical validation of observed results. We emphasize the versatility of ORIO through diverse examples, ranging from NGS data quality control to characterization of enhancer regions and integration of gene expression information. Easily accessible on a public web server, we anticipate wide use of ORIO in genome-wide investigations by life scientists.


Relicts in the mist: Two new frog families, genera and species highlight the role of Pantepui as a biodiversity museum throughout the Cenozoic.
The iconic mountains of the Pantepui biogeographical region host many early-diverging endemic animal and plant lineages, concurring with Conan Doyle's novel about an ancient "Lost World". While this is the case of several frog lineages, others appear to have more recent origins, adding to the controversy around the diversification processes in this region. Due to its remoteness, Pantepui is challenging for biological surveys, and only a glimpse of its biodiversity has been described, which hampers comprehensive evolutionary studies in many groups. During a recent expedition to the Neblina massif on the Brazil-Venezuela border, we sampled two new frog species that could not be assigned to any known genus. Here, we perform phylogenetic analyses of mitogenomic and nuclear loci to infer the evolutionary relationships of the new taxa and support their description. We find that both species represent single lineages deeply nested within Brachycephaloidea, a major Neotropical clade of direct-developing frogs. Both species diverged >45 Ma from their closest relatives: the first is sister to all other Brachycephaloidea except for Ceuthomantis, another Pantepui endemic, and the second is sister to Brachycephalidae, endemic to the Brazilian Atlantic Forest. In addition to these considerable phylogenetic and biogeographic divergences, external morphology and osteological features support the proposition of two new family and genus-level taxa to accommodate these new branches of the amphibian tree of life. These findings add to other recently described ancient vertebrate lineages from the Neblina massif, providing a bewildering reminder that our perception of the Pantepui's biodiversity remains vastly incomplete. It also provides insights into how these mountains acted as "museums" during the diversification of Brachycephaloidea and of Neotropical biotas more broadly, in line with the influential "Plateau theory". Finally, these discoveries point at the yet unknown branches of the tree of life that may go extinct, due to global climate change and zoonotic diseases, before we even learn about their existence, amphibians living at higher elevations being particularly at risk.


Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases.
Alzheimer, Parkinson and other neurodegenerative diseases involve a series of brain proteins, referred to as 'amyloidogenic proteins', with exceptional conformational plasticity and a high propensity for self-aggregation. Although the mechanisms by which amyloidogenic proteins kill neural cells are not fully understood, a common feature is the concentration of unstructured amyloidogenic monomers on bidimensional membrane lattices. Membrane-bound monomers undergo a series of lipid-dependent conformational changes, leading to the formation of oligomers of varying toxicity rich in beta-sheet structures (annular pores, amyloid fibrils) or in alpha-helix structures (transmembrane channels). Condensed membrane nano- or microdomains formed by sphingolipids and cholesterol are privileged sites for the binding and oligomerisation of amyloidogenic proteins. By controlling the balance between unstructured monomers and alpha or beta conformers (the chaperone effect), sphingolipids can either inhibit or stimulate the oligomerisation of amyloidogenic proteins. Cholesterol has a dual role: regulation of protein-sphingolipid interactions through a fine tuning of sphingolipid conformation (indirect effect), and facilitation of pore (or channel) formation through direct binding to amyloidogenic proteins. Deciphering this complex network of molecular interactions in the context of age- and disease-related evolution of brain lipid expression will help understanding of how amyloidogenic proteins induce neural toxicity and will stimulate the development of innovative therapies for neurodegenerative diseases.


Evaluation of the Accelerate Pheno System for Identification of Acinetobacter Clinical Isolates and Minocycline Susceptibility Testing.
The Accelerate Pheno system (AXDX) is a rapid phenotypic bacterial identification and susceptibility testing system which is approved for use with positive blood cultures. Acinetobacter baumannii is a nosocomial pathogen for which the limited treatment options include minocycline in the case of multidrug resistance. Here, we studied the performance of A. baumannii identification and minocycline susceptibility testing by AXDX using 101 contemporary Acinetobacter sp. clinical isolates. Overall, the sensitivity for A. baumannii and A. baumannii complex identification was 100% (73/73) and 97.6% (82/84), respectively. Specificity for A. baumannii complex identification was 86.6% (13/15). The essential agreement of minocycline susceptibility results (±1 log2 MIC agreement) of AXDX MICs with reference broth microdilution was 98.0% (96/98). There were no very major errors or major errors. Overall, 24.5% (24/98) of results yielded minor errors. AXDX reliably identified A. baumannii and predicted minocycline susceptibility results, which should help guide treatment choices in a timely manner for infections where options are limited.


Lack of antibodies against the antigen domain 2 epitope of cytomegalovirus (CMV) glycoprotein B is associated with CMV disease after renal transplantation in recipients having the same glycoprotein H serotypes as their donors.
Cytomegalovirus (CMV) reinfection of seropositive individuals has been associated with adverse outcomes in organ transplantation and is a frequent cause of congenital infection. Previously we demonstrated that mismatching of CMV glycoprotein H (gH) serotypes was associated with CMV disease after renal transplantation. Because the antigen domain 2 (AD2) epitope of glycoprotein B (gB) is conserved among CMV isolates and is one of the known targets of neutralizing antibodies, in this study we investigated whether antibodies against the epitope contribute to protection from CMV reinfection in renal transplantation, irrespective of gH serological matching. For this purpose, the gB and gH serology and clinical outcomes were analyzed retrospectively for 77 transplant recipients in the donor positive/recipient positive setting, who were managed by preemptive strategy. We found that there was a good negative correlation between the numbers of antigenemia-positive cells and the levels of antibodies against gB AD2 in the CMV-gH antibody matched group, but not in the CMV-gH antibody mismatched group. None of the recipients with antibodies against both gB AD2 and strain-specific epitopes of gH have experienced CMV disease during 6 month after transplantation, while 28% of those who lacked either/both antibody response needed preemptive therapy. Because the outcome was statistically significant, antibodies against gB AD2 can be a useful indicator to predict emergence of CMV disease for preemptive therapy, in addition to antibodies against the mismatched gH types.


Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model.
Treosulfan (L-threitol-1,4-bismethanesulfonate) is an alkylating agent with routine clinical application in the treatment of ovarian cancer. In this murine study we show that this drug also has the ability to deplete primitive hematopoietic stem cells in a dose-dependent manner as determined by the cobblestone area-forming cell assay and is similar to its parent compound busulfan. Because busulfan is frequently used as part of the conditioning regimen before stem cell transplantation, we investigated an alternative nonmyeloablative protocol in an allogeneic bone marrow transplantation model in which low-dose treosulfan was added to an immune-suppressive regimen consisting of T cell-depleting antibodies, fludarabine, and thymic irradiation. Although this treatment protocol produced minimal myelosuppression, the addition of treosulfan proved to be important for allowing stable multilineage and mixed chimerism in C57BL/6 recipients of major histocompatibility complex-mismatched B10.A bone marrow without evidence of graft-versus-host disease. Donor lymphocyte infusion performed at 10 weeks after bone marrow transplantation had the effect of transforming the state of mixed chimerism to full donor-type cells, again without evidence of graft-versus-host disease. Donor-specific immunologic tolerance in the mixed chimeric animals was indicated by the acceptance of donor-type and rejection of third-party skin grafts. Thus, low-dose treosulfan may be considered as a useful component of a truly nonmyeloablative conditioning protocol in providing for mixed hematopoietic chimerism and, consequently, in establishing a platform for adoptive immunotherapy.


Very low density lipoproteins in intestinal lymph: role in triglyceride and cholesterol transport during fat absorption.
The role of nonchylomicron very low density lipoproteins (VLDL, S(f) 20-400) in the transport of triglyceride and cholesterol was studied during lipid absorption. Various long chain fatty acids were infused intraduodenally in the form of mixed fatty acid-mono-olein-taurocholate micelles; control animals received saline or taurocholate. As compared with controls, all fatty acids (palmitic, oleic, linoleic) resulted in significant increases in chylomicron (S(f) > 400) triglyceride. In addition, palmitic acid resulted in a twofold increase in VLDL triglyceride, whereas with the absorption of oleic or linoleic acid VLDL triglyceride did not change significantly. Differences in triglyceride fatty acid composition between chylomicrons and VLDL were observed during lipid absorption. Although the absolute amount of endogenous cholesterol in intestinal lymph was not significantly affected by lipid absorption under these conditions, its lipoprotein distribution differed substantially among the lipid-infused groups. During palmitate absorption, VLDL cholesterol was similar to that in the taurocholate-infused controls, and was equal to chylomicron cholesterol. In contrast, during oleate and linoleate absorption the VLDL cholesterol fell markedly, and was less than half of the chylomicron cholesterol in these groups. The half-time of plasma survival of VLDL cholesterol-(14)C was found to be twice that of chylomicron cholesterol-(14)C. These studies demonstrate that dietary long chain fatty acids differ significantly in their effects upon the transport of triglyceride and cholesterol by lipoproteins of rat intestinal lymph. These findings, together with the observed differences in rates of removal of chylomicrons and VLDL from plasma, suggest that variations in lipoprotein production at the intestinal level may be reflected in differences in the subsequent metabolism of absorbed dietary and endogenous lipids.


Risk of fetal chromosomal anomalies in patients with elevated maternal serum alpha-fetoprotein.
When elevated maternal serum alpha-fetoprotein (MSAFP) results lead to diagnostic amniocentesis, a decision of whether to karyotype fetal cells must be made. We examined our experience with MSAFP screening in 71,563 unselected pregnancies in which karyotyping was performed when amniocentesis was done because of MSAFP elevations. A total of 727 women (1.0%) underwent amniocentesis because of elevated MSAFP values and among this group, seven chromosomal anomalies (incidence one in 104) were detected. Of the 727 women, 658 (91%) had normal amniotic fluid AFP. In this group, there were six (one in 109) chromosomally abnormal fetuses: three with triploidy, two with 47,XXX, and one with 46,XX,1q-. Among the 69 pregnancies with elevated amniotic fluid AFP, one fetal chromosomal anomaly (trisomy 13) was diagnosed. The incidence of all chromosomal anomalies observed in women undergoing amniocentesis because of elevated MSAFP is comparable to that reported in women 36 years of age undergoing testing because of advanced maternal age. We believe that chromosome analysis should be performed on amniotic fluid samples obtained because of elevated MSAFP unless there are compelling financial circumstances that preclude this. Even in such cases, cell cultures should be established until the amniotic fluid AFP result is available. Chromosome analysis is essential when the amniotic fluid AFP is elevated because of the known association between open fetal defects (spina bifida, omphalocele, and scalp defects) and trisomies 13 and 18.


Yoga Practice Among Veterans With and Without Chronic Pain: A Mixed Methods Study.
The primary aim of this study was to examine differences in yoga practice between persons with and without chronic pain. Secondarily, we describe use of the Essential Properties of Yoga Questionnaire, Short Form (EPYQ-SF) for self-report. Participants were members of an existing cohort of veterans who completed a 2015-2016 survey focused on pain and nonpharmacological health practices. Cohort members who reported yoga in the past year [n=174 (9.4%) of 1850] were eligible for the present study, which used multiple-contact mixed-mode survey methodology to collect data on yoga practices. The EPYQ-SF was used to assess properties and context of yoga practice. Practice patterns were compared for participants with and without chronic pain. To explore potential reasons for reported yoga practice patterns, focused semistructured interviews were conducted with a subset of participants. Of 174 participants contacted, 141 (82%) returned the yoga questionnaire and 110 (78% of respondents) were still practicing yoga. Among yoga practitioners, 41 (37%) had chronic pain. Practitioners with chronic pain reported gentler (2.8 vs. 3.1, 5-point scale) and less active (2.9 vs. 3.3) yoga practice than those without. Those with chronic pain attended yoga studios less frequently and reported shorter yoga practices than those without. Most yoga practice was self-directed and at home. Differences in yoga practice of persons with and without chronic pain have implications for implementation of yoga interventions for chronic pain. Future interventions should focus on alternative individual delivery formats or addressing barriers to group practice among people with chronic pain.


Chemokines in cartilage degradation.
Besides the well-known activities of the prototypical inflammatory cytokines (IL-1beta, TNFalpha), a role for chemokines and their receptors in cartilage degradation in osteoarthritis has recently been reported. Human chondrocytes can produce CC and CXC chemokines and express chemokine receptors for both chemokine subfamilies. Engagement of these receptors can induce the release of matrix degrading enzymes such as matrix metalloproteinases 1, 3, and 13, and N-acetyl-beta-D-glucosaminidase. Furthermore GROalpha, a CXC chemokine acting on CXCR2, can activate an apoptotic pathway in chondrocytes that leads to chondrocyte cell death. These findings suggest that chemokines can act as an autocrine or paracrine loop on chondrocytes and can contribute to many pathophysiological patterns present in osteoarthritis. Chemokines and their downstream signaling pathways can be considered novel therapeutic targets in osteoarthritis.


Flap prefabrication in the head and neck: a 10-year experience.
Tissue neovascularized by implanting a vascular pedicle can be transferred as a "prefabricated flap" based on the blood flow through the implanted pedicle. This technique potentially allows any defined tissue volume to be transferred to any specified recipient site, greatly expanding the armamentarium of reconstructive options. During the past 10 years, 17 flaps were prefabricated and 15 flaps were transferred successfully in 12 patients. Tissue expanders were used as an aid in 11 flaps. Seven flaps were prefabricated at a distant site and later transferred using microsurgical techniques. Ten flaps were prefabricated near the recipient site by either transposition of a local vascular pedicle or the microvascular transfer of a distant vascular pedicle. The prefabricated flaps were subsequently transferred as island pedicle flaps. These local vascular pedicles can be re-used to transfer additional neovascularized tissues. Common pedicles used for neovascularization included the descending branch of the lateral femoral circumflex, superficial temporal, radial, and thoracodorsal pedicles. Most flaps developed transient venous congestion that resolved in 36 to 48 hours. Venous congestion could be reduced by incorporating a native superficial vein into the design of the flap or by extending the prefabrication time from 6 weeks to several months. Placing a Gore-Tex sleeve around the proximal pedicle allowed for much easier pedicle dissection at the time of transfer. Prefabricated flaps allow the transfer of moderate-sized units of thin tissue to recipient sites throughout the body. They have been particularly useful in patients recovering from extensive burn injury on whom thin donor sites are limited.


Selective regulation of nuclear orphan receptors 4A by adenosine receptor subtypes in human mast cells.
Nuclear orphan receptors 4A (NR4A) are early responsive genes that belong to the superfamily of hormone receptors and comprise NR4A1, NR4A2 and NR4A3. They have been associated to transcriptional activation of multiple genes involved in inflammation, apoptosis and cell cycle control. Here, we establish a link between NR4As and adenosine, a paradoxical inflammatory molecule that can contribute to persistence of inflammation or mediate inflammatory shutdown. Transcriptomics screening of the human mast cell-line HMC-1 revealed a sharp induction of transcriptionally active NR4A2 and NR4A3 by the adenosine analogue NECA. The concomitant treatment of NECA and the adenosine receptor A(2A) (A(2A)AR) selective antagonist SCH-58261 exaggerated this effect, suggesting that upregulation of these factors in mast cells is mediated by other AR subtypes (A(2B) and A(3)) and that A(2A)AR activation counteracts NR4A2 and NR4A3 induction. In agreement with this, A(2A)AR-silencing amplified NR4A induction by NECA. Interestingly, a similar A(2A)AR modulatory effect was observed on ERK1/2 phosphorylation because A(2A)AR blockage exacerbated NECA-mediated phosphorylation of ERK1/2. In addition, PKC or MEK1/2 inhibition prevented ERK1/2 phosphorylation and antagonized AR-mediated induction of NR4A2 and NR4A3, suggesting the involvement of these kinases in AR to NR4A signaling. Finally, we observed that selective A(2A)AR activation with CGS-21680 blocked PMA-induced ERK1/2 phosphorylation and modulated the overexpression of functional nuclear orphan receptors 4A. Taken together, these results establish a novel PKC/ERK/nuclear orphan receptors 4A axis for adenosinergic signaling in mast cells, which can be modulated by A(2A)AR activation, not only in the context of adenosine but of other mast cell activating stimuli as well.


Incomplete complementation of the DNA repair defect in cockayne syndrome cells by the denV gene from bacteriophage T4 suggests a deficiency in base excision repair.
Endonuclease V (denV) from bacteriophage T4 has been examined for its ability to complement the repair defect in Cockayne syndrome (CS) cells of complementation groups A and B. CS is an autosomal recessive disorder characterized by hypersensitivity to UV light and a defect in the preferential repair of UV-induced lesions in transcriptionally active DNA by the nucleotide excision repair (NER) pathway. The denV gene was introduced into non-transformed normal and CS fibroblasts transiently via a recombinant adenovirus (Ad) vector and into SV40-transformed normal and CS cells via a retroviral vector. Expression of denV in CS-A cells resulted in partial correction of the UV-sensitive phenotype in assays of gene-specific repair and cell viability, while correction of CS-B cells by expression of denV in the same assays was minimal or non-existent. In contrast, denV expression led to enhanced host cell reactivation (HCR) of viral DNA synthesis in both CS complementation groups to near normal levels. DenV is a glycosylase which is specific for cyclobutane-pyrimidine dimers (CPDs) but does not recognize other UV-induced lesions. Previous work has indicated that CS cells can efficiently repair all non-CPD UV-induced transcription blocking lesions (S.F. Barrett et al.. Mutation Res. 255 (1991) 281-291 [1]) and that denV incised lesions are believed to be processed via the base excision repair (BER) pathway. The inability of denV to complement the NER defect in CS cells to normal levels implies an impaired ability to process denV incised lesions by the BER pathway, and suggests a role for the CS genes, particularly the CS-B gene, in BER.


Inflammatory reaction and implantation: the new entries PTX3 and D6.
Successful embryonic implantation implies anchoring the conceptus in the maternal uterine wall, establishing a vascular supply to enable optimal growth and development of the conceptus, and promoting tolerance of fetal alloantigens encoded by paternal genes. To achieve these goals, complex molecular dialogues take place among the maternal endometrium, the conceptus, and the placenta. Several factors are involved in the fetal-maternal interaction, including hormones, growth factors, cytokines, chemokines, adhesion molecules, extracellular matrix components, and matrix-degrading enzymes. This complex cross-talk results in the induction of a local inflammatory response and a state of systemic inflammation, as revealed by leukocytosis, endothelium activation, increased activity of innate immune cells, and increased levels of inflammatory cytokines and chemokines. The enriched cytokine milieu associated to implantation is likely to control trophoblast migration and differentiation, leukocyte influx and activation, complement activation, as well as angiogenic and angiostatic processes in the implantation site. Finally, these mediators play a key role in tuning the immune responses to protect the fetus from infections as well as from maternal rejection. Here, the role of pro-inflammatory networks activated in implantation will be discussed. In particular, emphasis will be put on two new players involved in regulating inflammation at the maternal-fetal interface: the long pentraxin PTX3 and the decoy receptor for inflammatory chemokines D6.


The role of corpus size and syntax in deriving lexico-semantic representations for a wide range of concepts.
One of the most significant recent advances in the study of semantic processing is the advent of models based on text and other corpora. In this study, we address what impact both the quantitative and qualitative properties of corpora have on mental representations derived from them. More precisely, we evaluate models with different linguistic and mental constraints on their ability to predict semantic relatedness between items from a vast range of domains and categories. We find that a model based on syntactic dependency relations captures significantly less of the variability for all kinds of words, regardless of the semantic relation between them or their abstractness. The largest difference was found for concrete nouns, which are commonly used to assess semantic processing. For both models we find that limited amounts of data suffice in order to obtain reliable predictions. Together, these findings suggest new constraints for the construction of mental models from corpora, both in terms of the corpus size and in terms of the linguistic properties that contribute to mental representations.


Treatment options for POEMS syndrome.
POEMS syndrome is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Recognition of the complex of a combination of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes, sclerotic bone lesions, Castleman's disease, thrombocytosis, papilledema, peripheral oedema, pleural effusions, ascites, fingernail clubbing and white nails, is the first step in effectively managing the disease. More than 95% of patients will have monoclonal lambda sclerotic plasmacytoma(s) or bone marrow infiltration. In patients with a dominant sclerotic plasmacytoma, first-line therapy should include radiation to the lesion. Retrospective analysis and personal experience would dictate that systemic therapy be considered for patients with diffuse sclerotic lesions or absence of any bone lesion, and for those who have not demonstrated stabilisation of their disease 3-6 months after completing radiation therapy. For those patients with diffuse disease, systemic therapy is indicated. Useful approaches include therapy with corticosteroids, low dose alkylator therapy and high dose chemotherapy with peripheral blood stem cell transplant. Until the pathogenesis is fully understood, these are the mainstays of treatment for patients with POEMS syndrome.


Alpha 1-adrenergic receptor blockade reduces afferent and efferent glomerular arteriolar resistances in SHR.
To assess the effects of alpha 1-adrenergic receptor blockade on intrarenal hemodynamics of spontaneously hypertensive rats (SHR), terazosin (0.015 or 0.03 mg/kg body wt) or saline was injected into SHR or normotensive Wistar-Kyoto rats (WKY) (age 16-18 wk). Single-nephron glomerular filtration rate (SNGFR) and renal glomerular filtration rate were determined with [3H]inulin infusion; effective renal blood flow was measured with p-aminohippurate. Intrarenal efferent arteriolar, proximal tubular, stop-flow pressures measurements, and tubular fluid and efferent arteriolar samplings were obtained by micropuncture techniques. Terazosin reduced arterial pressure significantly in both rat strains, but only in SHR did alpha 1-inhibition decrease glomerular hydrostatic pressure (from 58.0 +/- 1.5 to 46.6 +/- 1.1 mmHg; P less than 0.05). Terazosin did not change SNGFR or single-nephron blood flow in either strain. As a result, only in SHR did efferent glomerular arteriolar resistances decrease (0.262 +/- 0.021 to 0.193 +/- 0.014 mmHg.ml-1.min; P less than 0.05). Glomerular ultrafiltration coefficient increased only in SHR (0.034 +/- 0.005 to 0.104 +/- 0.01; P less than 0.05). These results provide further support to the concept of alpha 1-adrenergic receptor hyperresponsiveness of efferent glomerular arteriolar in SHR but not WKY.


Nuclear reassembly excludes large macromolecules.
Interphase nucleus and cytoplasm are distinct compartments, whose soluble macromolecular contents mix when the nuclear envelope disassembles at mitosis. To determine how their interphase identities are reestablished, fibroblasts were loaded with fluorescent dextrans and then allowed to divide. Large dextrans (molecular weight of 40,000 or more) were excluded from condensed mitotic chromosomes and from newly formed, postmitotic interphase nuclei. Therefore, postmitotic reassembly of the nucleus as a compartment distinct from cytoplasm occurs by exclusion not only of organelles but also of soluble macromolecules. This might occur by exclusion of macromolecules from condensed chromatin throughout mitosis and completion of nuclear envelope assembly before nuclear expansion.


Microbial, chemical and sensory properties of shalgams made using different production methods.
Shalgam is a traditional Turkish lactic acid fermented beverage. This study examined the microbial, chemical and sensory characteristics of shalgams produced by various methods. Different production methods using traditional method (dough fermentation and carrot fermentation), direct method (without dough fermentation) and with the addition of starter cultures were applied to produce shalgams. The final amounts of total acidity as lactic acid (6.33-9.22 g L(-1)), pH (3.42-3.55), the counts of lactic acid bacteria (7.43-7.74 log CFU mL(-1)), total mesophilic aerobic bacteria (7.03-7.46 log CFU mL(-1)), yeasts (6.96-7.50 log CFU mL(-1)) and non-Saccharomyces yeasts (4.21-5.19 log CFU mL(-1) ) were found. Lactobacillus plantarum and then Lb. buchneri were the most frequently isolated bacteria in shalgam samples. Sensory evaluation of shalgams showed that sample produced using traditional method with starter additions obtained highest scores. This study showed that addition of starter lactic acid bacteria cultures improved the quality of shalgams. Analysis of the results indicated that the direct method for the production of shalgam is not preferable. The data obtained can be useful for industrial shalgam producers.