Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: results of a randomized, vehicle-controlled, multicenter clinical trial.
The safety and efficacy of topical E6005, a novel phosphodiesterase 4 inhibitor, in Japanese adults with atopic dermatitis were evaluated. A total of 78 patients were randomized to receive either the 0.2% E6005 ointment or vehicle control (without E6005) at an allocation ratio of 2:1. The randomization phase of 4 weeks was followed by an extension phase of 8 weeks. In the extension phase, all 67 subjects who completed the randomization phase were treated with 0.2% E6005 ointment. The 4-week application of topical E6005 twice daily was safe and well tolerated. The safety profile for up to 12 weeks was similar to that for the first 4 weeks. No deaths or other serious adverse effects were observed during the entire study period of 12 weeks. Plasma E6005 was undetectable in all subjects at all sampling points while very low plasma concentrations of an E6005 metabolite were detected in 47% of subjects receiving E6005 treatment. At the end of week 4, Eczema Area and Severity Index (EASI), Severity Scoring Atopic Dermatitis (SCORAD)-objective, SCORAD-C (visual analog scales for pruritus and sleep loss), itch Behavioral Rating Scale, and the severity of the targeted eczematous lesions in the topical E6005 group showed trends toward improvement compared with those in the vehicle group (not statistically significant). However, the group receiving topical E6005 for 12 weeks showed significant score reductions from baselines for EASI (P = 0.030), SCORAD-objective (P < 0.001) and SCORAD-C (P = 0.038). These results further support the development of topical E6005 for the treatment of atopic dermatitis.


Isometric versus isotonic contractions: Sex differences in the fatigability and recovery of isometric strength and high-velocity contractile parameters.
The purpose of this study was to investigate potential sex differences in the fatigue- and recovery-induced responses of isometric strength and power, as well as select dynamic contractile parameters after isometric and isotonic plantar flexor (PF) contractions. Healthy males (n = 12; age = 21.8 ± 2.2 years) and females (n = 14; age = 21.4 ± 2.5 years) performed a 2-min maximal voluntary isometric contraction and 120 concentric isotonic (30% peak isometric torque) contractions of the PFs on separate visits. Isometric strength, isotonic power, as well as torque- and velocity-related parameters were recorded before, immediately after, and throughout 10 min of recovery. Rate of EMG rise (RER) for the medial gastrocnemius (MG) and soleus was also obtained. All measures responded similarly between sexes after both fatiguing modalities (p > 0.05), except RER of the MG which, in males demonstrated both, a greater decrease during isotonic contractions (p = 0.038, ηp2 = 0.174) and more rapid recovery after isometric exercise (p = 0.043, ηp2 = 0.166). Although not significant, a nearly large effect size was demonstrated for the fatigue-induced decrease in isometric strength (p = 0.061; d = 0.77) due to relative decreases tending to be greater in males (-29% vs. -17%). Regardless of fatiguing modality, sex differences were minimal for fatigue and recovery-related responses in muscle function for the PFs, although the difference for RER may indicate a unique origin of fatigue. Further support for the disassociation between the response in isometric strength and power after fatiguing exercise was also demonstrated.


Ten Rules for Antibiotic Prescribing.
Antibiotic use has come under increased scrutiny because of the emergence of multidrug-resistant organisms.Many have called for restricting use of antibiotics in humans and animals, finding strategies to reduce the spreadof resistant organisms and development of new anti-infectives. The challenge for many clinicians is identifyingwhen antibiotics are needed, which ones to use and how long to use them. This article offers practical advice foridentifying when antibiotics are beneficial and curbing inappropriate use.


Epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in advanced nonsmall-cell lung cancer.
Classic activating mutations in the form of deletions in exon 19 or a missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict dramatic responses to EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib. We review here the clinical benefits of targeted therapy with erlotinib and gefitinib in white and Asian nonsmall-cell lung cancer patients. Two separate analyses of pooled data from small phase II prospective studies show that therapy with gefitinib and erlotinib induces responses in over 70% of nonsmall-cell lung cancer patients harboring classic EGFR mutations, with progression-free survival ranging from 9 to 13 months and median survival of around 23 months. Two separate studies in white and Asian patients have recently confirmed that these subgroups of patients attain response rates of 70% with erlotinib and gefitinib, including complete responses, progression-free survival of up to 14 months, and median survival of up to 27 months. The serial monitoring of EGFR mutations in the blood will permit the assessment of molecular responses and be an important tool for the surveillance of clinical progression. Nonsmall-cell lung cancer with EGFR mutations constitute a new entity with a unique opportunity for further refinement of different genetic subgroups among patients with EGFR mutations, requiring different personalized treatment strategies. Despite the impressive outcomes attained with EGFR tyrosine kinase inhibitors, patients with EGFR mutations at present require continuous treatment, and only a fraction of these patients will reach sustainable long-term survival.


Simvastatin inhibits catecholamine secretion and synthesis induced by acetylcholine via blocking Na+ and Ca2+ influx in bovine adrenal medullary cells.
Simvastatin, an inhibitor of HMG-CoA reductase, is a potent inhibitor of cholesterol biosynthesis and has beneficial effects in the primary and secondary prevention of cardiovascular diseases. In this study, we report the effects of simvastatin on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells used as a model of sympathetic neurons. Simvastatin inhibited catecholamine secretion induced by acetylcholine, an agonist of the nicotinic acetylcholine receptor; by veratridine, an activator of voltage-dependent Na(+) channels; and by high K(+), an activator of voltage-dependent Ca(2+) channels (IC(50) = 3.8, 7.8, and 6.1 microM, respectively). Simvastatin also suppressed acetylcholine-induced (22)Na(+) influx (IC(50) = 4.3 microM) and (45)Ca(2+) influx (IC(50) = 6.1 microM), veratridine-induced (22)Na(+) influx (IC(50) = 6.6 microM) and (45)Ca(2+) influx (IC(50) = 12 microM), and high K(+)-induced (45)Ca(2+) influx (IC(50) = 11 microM). The reduction of catecholamine secretion caused by simvastatin was not overcome by increasing the concentration of acetylcholine or by treatment with mevalonate, the first metabolite of HMG-CoA. The inhibitory effect of simvastatin on histamine-induced secretion of catecholamines was observed in the presence of extracellular Ca(2+), but not in a Ca(2+)-free medium, suggesting that simvastatin does not interfere with histamine receptors nonselectively. Simvastatin also suppressed acetylcholine-induced [(14)C]catecholamine synthesis from [(14)C]tyrosine as well as tyrosine hydroxylase activity. These findings suggest that simvastatin inhibits catecholamine secretion and synthesis induced by acetylcholine through suppression of Na(+) and Ca(2+) influx in the adrenal medulla and probably in the sympathetic neurons.


The accuracy of self-reported weights.
The accuracy of self-reported weights was assessed by comparing reported weights with measured weights of 1302 subjects at eight different medical and nonmedical sites across two countries (United States and Denmark), across ages, sexes, and different purposes for the weight measurements. Self-reported weights were remarkably accurate across all these variables in the American sample, even among obese people, and may obviate the need for measured weights in epidemiological investigations. Danish reports were somewhat less accurate, particularly among women over 40 yr of age.


It is all in the face: carotenoid skin coloration loses attractiveness outside the face.
Recently, the importance of skin colour for facial attractiveness has been recognized. In particular, dietary carotenoid-induced skin colour has been proposed as a signal of health and therefore attractiveness. While perceptual results are highly consistent, it is currently not clear whether carotenoid skin colour is preferred because it poses a cue to current health condition in humans or whether it is simply seen as a more aesthetically pleasing colour, independently of skin-specific signalling properties. Here, we tested this question by comparing attractiveness ratings of faces to corresponding ratings of meaningless scrambled face images matching the colours and contrasts found in the face. We produced sets of face and non-face stimuli with either healthy (high-carotenoid coloration) or unhealthy (low-carotenoid coloration) colour and asked participants for attractiveness ratings. Results showed that, while for faces increased carotenoid coloration significantly improved attractiveness, there was no equivalent effect on perception of scrambled images. These findings are consistent with a specific signalling system of current condition through skin coloration in humans and indicate that preferences are not caused by sensory biases in observers.


Genetic structure of the shrub Daphne laureola across the Baetic Ranges, a Mediterranean glacial refugium and biodiversity hotspot.
Distribution margins constitute areas particularly prone to random and/or adaptive intraspecific differentiation in plants. This trend may be particularly marked in species discontinuously distributed across mountain ranges, where sharp geographic isolation gradients and habitat boundaries will enhance genetic isolation among populations. In this study, we analysed the level of neutral genetic differentiation among populations of the long-lived shrub Daphne laureola (Thymelaeaceae) across the Baetic Ranges, a glacial refugium and biodiversity hotspot in the western Mediterranean Basin. Within this area, core and marginal populations of D. laureola were compared with regard to their spatial isolation, size, genetic diversity and differentiation. A spatially explicit analysis conducted on the vast majority of the species' known populations in the study area (N = 111) showed that marginal populations (western and eastern) present larger spatial isolation than core populations, but are not smaller. We compared genetic diversity and differentiation between core and marginal populations using a subsample of 15 populations and 225 amplified fragment length polymorphism (AFLP) markers. Core and marginal populations did not differ in genetic diversity, probably because of the occurrence of large populations on the local margins. Western populations were strongly differentiated from the other populations. In addition, spatial and genetic differentiation among populations was larger on the western margin. Eastern populations constituted a genetically homogeneous group closely related to core populations, despite their greater spatial isolation. Results suggest that studies on phenotypic differentiation between core and marginal populations of D. laureola, and presumably other species having discontinuous distributions across the Baetic ranges, should take into account geographical differences in levels of genetic differentiation between the different distribution borders.


Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study.
Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation.


A behavioral measure of basilar-membrane nonlinearity in listeners with normal and impaired hearing.
This paper examines the possibility of estimating basilar-membrane (BM) nonlinearity using a psychophysical technique. The level of a forward masker required to mask a brief signal was measured for conditions where the masker was either at, or one octave below, the signal frequency. The level of the forward masker at masked threshold provided an indirect measure of the BM response to the signal, as follows. Consistent with physiological studies, it was assumed that the BM responds linearly to frequencies well below the characteristic frequency (CF). Thus the ratio of the slopes of the masking functions between a masker at the signal frequency and a masker well below the signal frequency should provide an estimate of BM compression at CF. Results obtained from normally hearing listeners were in quantitative agreement with physiological estimates of BM compression. Furthermore, differences between normally hearing listeners and listeners with cochlear hearing impairment were consistent with the physiological effects of damage to the cochlea. The results support the hypothesis that BM nonlinearity governs the nonlinear growth of the upward spread of masking, and suggest that this technique provides a straightforward method for estimating BM nonlinearity in humans.


[Thoracic Endovascular Aortic Repair for Mycotic Thoracic Aortic Aneurysm After BCG Intravesical Therapy].
Bacille Calmette-Guérin( BCG) intravesical therapy is an effective and safe treatment for bladder cancer; however, mycotic aneurysms have been reported as a rare complication. Case 1:A 64-year-old man with a history of BCG intravesical therapy underwent emergent thoracic endovascular aortic repair (TEVAR) for a ruptured thoracic aortic aneurysm (TAA). He was diagnosed with BCG infection by hemosputum specimen culture five months later;then, antituberculous therapy was initiated. However, his follow-up computed tomography scan revealed stent-graft infection and new aneurysm formation. Therefore, we performed a repeated TEVAR with abdominal 4-vessel debranching. There was no recurrence of infection for six years while continuing postoperative antituberculous therapy. Case 2:A 72-year-old man who had undergone BCG intravesical therapy underwent TEVAR for a rapidly enlarging mycotic TAA. He received anti-tuberculous therapy for one year with no recurrent infection for one year. TEVAR may be an effective alternative to the open surgical procedure;however, multidisciplinary treatment including anti-tuberculous therapy and careful long-term follow up are required.


Palladium and gold-palladium catalysts for the direct synthesis of hydrogen peroxide.
Today hydrogen peroxide is produced by an indirect process in which an alkyl anthraquinone is sequentially hydrogenated and oxidized. In this way hydrogen and oxygen are kept separate during the manufacturing process. A process where molecular oxygen is directly hydrogenated could be preferred if control of the sequential hydrogenation can be achieved, particularly if high rates can be attained under intrinsically safe, non-explosive conditions. Herein we describe recent progress in the direct synthesis of hydrogen peroxide using supported palladium and gold-palladium alloy catalysts and consider some of the problems that have to be overcome.


Size Resolved High Temperature Oxidation Kinetics of Nano-Sized Titanium and Zirconium Particles.
While ultrafine metal particles offer the possibility of very high energy density fuels, there is considerable uncertainty in the mechanism by which metal nanoparticles burn, and few studies that have examined the size dependence to their kinetics at the nanoscale. In this work we quantify the size dependence to the burning rate of titanium and zirconium nanoparticles. Nanoparticles in the range of 20-150 nm were produced via pulsed laser ablation, and then in-flight size-selected using differential electrical mobility. The size-selected oxide free metal particles were directly injected into the post flame region of a laminar flame to create a high temperature (1700-2500 K) oxidizing environment. The reaction was monitored using high-speed videography by tracking the emission from individual nanoparticles. We find that sintering occurs prior to significant reaction, and that once sintering is accounted for, the rate of combustion follows a near nearly (diameter)(1) power-law dependence. Additionally, Arrhenius parameters for the combustion of these nanoparticles were evaluated by measuring the burn times at different ambient temperatures. The optical emission from combustion was also used to model the oxidation process, which we find can be reasonably described with a kinetically controlled shrinking core model.


Functional effects of neuropeptide Y receptors on blood flow and nitric oxide levels in the human nose.
The aim of this study was to examine dose-dependent effects of intranasal application of neuropeptide Y (NPY) on nasal mucosal blood flow, blood content, and intranasal nitric oxide (NO) concentration. Blood flow was measured by laser Doppler flowmetry (LDF) and blood content by rhinomanometry. Mucosal biopsies were taken for investigation of Y1 and Y2 receptor mRNA expression, using the reverse transcriptase-polymerase chain reaction (RT-PCR). Intranasal application of NPY evoked a dose-dependent reduction of nasal mucosal blood flow. Maximal vasoconstriction, seen at 12 nmol, was -37.5 +/- 6.2%, p < 0.05 (n = 9). The vasoconstrictive effect developed within 2 to 4 min and lasted > 17 min. NPY evoked a dose-dependent reduction of nasal airway resistance (NAR) on the ipsilateral side. Maximal decrease was -24.0 +/- 10.0% at 12 nmol, p < 0.05 (n = 9). There was a decrease in nasal NO production on the ipsilateral side after application of NPY 12 nmol (-7.4 +/- 1.2%, p < 0.05, n = 8). RT-PCR products corresponding to Y1 receptor but not Y2 receptor mRNA were obtained from biopsies of the nasal mucosa. In conclusion, NPY is a potent vasoconstrictor in the human nose reducing mucosal blood flow, as well as the blood content. The effect is probably mediated via Y1 receptors. NPY receptor agonists may prove beneficial in the treatment of the congested nose in allergic or vasomotor rhinitis.


Secondary abdominal compartment syndrome after severe extremity injury: are early, aggressive fluid resuscitation strategies to blame?
Secondary abdominal compartment syndrome (ACS) is the development of ACS in the absence of abdominal injury. The development of secondary ACS has been viewed by some authors as an unavoidable sequela of the aggressive crystalloid resuscitation often employed in the treatment of severe shock. We hypothesized that poor resuscitation techniques, including early and excessive crystalloid administration, places patients with extremity injuries at risk for developing secondary ACS. The Trauma Registry of the American College of Surgeons database was queried for all patients with an extremity Abbreviated Injury Scale (AIS) score of 3 or greater and abdominal AIS score of 0 treated at our institution between January 1, 2001 and December 31, 2005. The study group included those patients who developed secondary ACS, whereas the comparison cohort included those who did not develop secondary ACS. Forty-eight patients developed secondary ACS and were compared with 48 randomly selected patients who had an extremity AIS score of 3 or greater and an abdomen AIS score of 0. There were no differences between the groups with respect to age, sex, race, or individual AIS scores. However, the secondary ACS group had a slightly higher Injury Severity Score (25.6 vs. 21.4, p = 0.02), significantly higher operating room crystalloid administration (9.9 L vs. 2.7 L, p < 0.001), and more frequent use of a rapid infuser (12.5% vs. 0.0%, p = 0.01). Multiple logistic regression identified prehospital and emergency department crystalloid as predictors of secondary ACS. Aggressive resuscitation techniques, often begun in the prehospital setting, appear to increase the likelihood of patients with severe extremity injuries developing secondary ACS. Early, large volume crystalloid administration was the greatest predictor of secondary ACS.


Growth hormone synthesis and secretion by a somatomammotroph cell line derived from normal adult pituitary of the rat.
A somatomammotroph cell line derived from male rat anterior pituitary (rPCO) has been established without the use of transforming agents and has been maintained in culture for more than 1 yr (45 passages) using Minimum Essential Medium supplemented with 10% horse serum, 5 nM T3, 2 nM corticosterone, and 0.1 nM GH-releasing hormone (GRH). Peroxidase and immunofluorescent staining revealed immunoreactive GH in 99% of rPCO cells and immunoreactive PRL in 72% of cells. Within individual cells, GH and PRL appear to be colocalized. The storage capacity for GH in rPCO cells represented 40% of the daily hormone production. In serum-free medium containing 5 nM cortisol, GH secretion was stimulated 10- and 25-fold by 50 pM and 50 nM T3, respectively. GRH (1 nM) stimulated GH secretion 8-fold in the absence of T3, although no effect was observed in the presence of 50 nM T3. Qualitatively similar changes occurred in GH mRNA responses to T3 and GRH. Other secretory proteins were detected on sodium dodecyl sulfate-polyacrylamide gel electrophoresis of culture medium, several of which were present in concentrations similar to that of GH. Nine separate cell lines were cloned from rPCO cells by limiting dilution, all of which secreted GH and PRL. GH secretion varied 6-fold between clones, and the GH to PRL ratio varied more than 200-fold. These rPC cell lines provide a new model for studying the control of GH and PRL gene expression, including hormone synthesis, processing, and secretion. They may also be useful for identifying other pituitary secretory products and as a source for the production of protein hormones.


Comparative physiology investigations support a role for histidine-containing dipeptides in intracellular acid-base regulation of skeletal muscle.
Histidine containing dipeptides (HCDs: carnosine, anserine and balenine) have numerous therapeutic and ergogenic properties, but there is a lack of consensus on the mechanistic pathways through which they function. Potential roles include intracellular buffering, neutralisation of reactive species, and calcium regulation. Comparative investigations of the HCD content of various species provide unique insight into their most likely mechanisms of action. This review chronologically describes how the comparative physiology studies, conducted since the beginning of the 20th century, have shaped our understanding of the physiological roles of HCDs. The investigation of a wide range of physiologically distinct species indicates that those species with a strong reliance on non-oxidative forms of energy production are abundant in HCDs. These include: whales who experience long periods of hypoxia while diving; racehorses and greyhound dogs who have highly developed sprint abilities, and chickens and turkeys whose limited capacity for flight is largely fuelled by their white, glycolytic, muscle. Additionally, a higher HCD content in the Type 2 muscle fibres of various species (which have greater capacity for non-oxidative metabolism) was consistently observed. The pKa of the HCDs render them ideally suited to act as intracellular physicochemical buffers within the pH transit range of the skeletal muscle. As such, their abundance in species which show a greater reliance on non-oxidative forms of energy metabolism, and which experience regular challenges to acid-base homeostasis, provides strong evidence that intracellular proton buffering is an important function of the HCDs in skeletal muscle.


Distinct synaptic mechanisms create parallel S-ON and S-OFF color opponent pathways in the primate retina.
Anatomical and physiological approaches are beginning to reveal the synaptic origins of parallel ON- and OFF-pathway retinal circuits for the transmission of short (S-) wavelength sensitive cone signals in the primate retina. Anatomical data suggest that synaptic output from S-cones is largely segregated; central elements of synaptic triads arise almost exclusively from the "blue-cone" bipolar cell, a presumed ON bipolar, whereas triad-associated contacts derive primarily from the "flat" midget bipolar cell, a hyperpolarizing, OFF bipolar. Similarly, horizontal cell connectivity is also segregated, with only the H2 cell-type receiving numerous contacts from S-cones. Negative feedback from long (L-) and middle (M-) wavelength sensitive cones via the H2 horizontal cells elicits an antagonistic surround in S-cones demonstrating that S versus L + M or "blue-yellow" opponency is first established in the S-cone. However, the S-cone output utilizes distinct synaptic mechanisms to create color opponency at the ganglion cell level. The blue-cone bipolar cell is presynaptic to the small bistratified, "blue-ON" ganglion cell. S versus L + M cone opponency arises postsynaptically by converging S-ON and LM-OFF excitatory bipolar inputs to the ganglion cell's bistratified dendritic tree. The common L + M cone surrounds of the parallel S-ON and LM-OFF cone bipolar inputs appear to cancel resulting in "blue-yellow" antagonism without center-surround spatial opponency. By contrast, in midget ganglion cells, opponency arises by the differential weighting of cone inputs to the receptive field center versus surround. In the macula, the "private-line" connection from a midget ganglion cell to a single cone predicts that S versus L + M opponency is transmitted from the S-cone to the S-OFF midget bipolar and ganglion cell. Beyond the macula, OFF-midget ganglion cell dendritic trees enlarge and collect additional input from multiple L and M cones. Thus S-OFF opponency via the midget pathway would be expected to become more complex in the near retinal periphery as L and/or M and S cone inputs sum to the receptive field center. An important goal for further investigation will be to explore the hypothesis that distinct bistratified S-ON versus midget S-OFF retinal circuits are the substrates for human psychophysical detection mechanisms attributed to S-ON versus S-OFF perceptual channels.


A comparison of the effect of honey, dextromethorphan, and diphenhydramine on nightly cough and sleep quality in children and their parents.
Coughing is a prevalent symptom of upper respiratory infections (URIs) that cause disturbance in the sleep of children and their parents. There is as yet no reliable treatment to control URIs and their related cough; however, drugs such as dextromethorphan (DM) and diphenhydramine (DPH) are now mainly used in the world. The aim of this study is to compare the effect of honey, DM, and DPH on the nightly cough and sleep quality of children and their parents. This was a clinical trial study in which 139 children aged 24-60 months suffering from coughing due to URIs were selected and assigned randomly to 4 groups. The first group received honey (HG), the second one DM (DMG), the third DPH (DPHG), but the fourth group or control group (CG) was assigned to a supportive treatment. After approximately a 24-hour intervention, the 4 groups were reexamined and their cough frequency, cough severity, and sleep quality in children and their parents were recorded by using the questionnaire with Likert-type questions. The mean of cough frequency score HG is 4.09 +/- 0.72 and 1.93 +/- 0.65 before and after the intervention, respectively, while these figures for the CG are 4.11 +/- 0.78 and 3.11 +/- 0.57, respectively. After the intervention, the difference of the mean score of the variables in all groups became statistically significant. The mean score of all variables in HG has stood significantly higher than those in other groups. There is also a significant relationship between the DMG and CG groups, even though there is no statistically difference between DMG and DPHG groups. The result of the study demonstrated that receiving a 2.5-mL dose of honey before sleep has a more alleviating effect on URIs-induced cough compared with DM and DPH doses.


Development and validation of a clinical model to predict the presence of β-lactam resistance in viridans group streptococci causing bacteremia in neutropenic cancer patients.
Concern for serious infection due to β-lactam-resistant viridans group streptococci (VGS) is a major factor driving empiric use of an anti-gram-positive antimicrobial in patients with febrile neutropenia. We sought to develop and validate a prediction model for the presence of β-lactam resistance in VGS causing bloodstream infection (BSI) in neutropenic patients. Data from 569 unique cases of VGS BSI in neutropenic patients from 2000 to 2010 at the MD Anderson Cancer Center were used to develop the clinical prediction model. Validation was done using 163 cases from 2011 to 2013. In vitro activity of β-lactam agents was determined for 2011-2013 VGS bloodstream isolates. In vitro resistance to β-lactam agents commonly used in the empiric treatment of febrile neutropenia was observed only for VGS isolates with a penicillin minimum inhibitory concentration (MIC) of ≥ 2 µg/mL. One hundred twenty-nine of 732 patients (17%) were infected with VGS strains with a penicillin MIC ≥ 2 µg/mL. For the derivation and validation cohorts, 98% of patients infected by VGS with a penicillin MIC of ≥ 2 µg/mL had at least 1 of the following risk factors: current use of a β-lactam as antimicrobial prophylaxis, receipt of a β-lactam antimicrobial in the previous 30 days, or nosocomial VGS BSI onset. Limiting empiric anti-gram-positive therapy to neutropenic patients having at least 1 of these 3 risk factors would have reduced such use by 42%. Simple clinical criteria can assist with targeting of anti-gram-positive therapy to febrile neutropenic patients at risk of serious β-lactam-resistant VGS infection.


Tumor-stroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma.
Tumor-stroma ratio (TSR) has been identified as a new and practicable prognostic histological characteristic of solid tumors. The aim of this study was to evaluate the prognostic value of TSR in resected esophageal squamous cell carcinoma (ESCC). A total of 95 patients who underwent esophagectomy for ESCC were included in this study. TSR was assessed visually on the hematoxylin-eosin-stained tissue sections of surgical specimens by two independent observers. Patients with more than 50% intratumor stroma were quantified as the stroma-rich group and those with less than 50% as the stroma-poor group. No significant differences were observed in patient, tumor, and treatment characteristics between the stroma-rich and stroma-poor groups. The 3-year overall survival and disease-free survival rates were 64% and 57%, respectively, in the stroma-poor group, and 23% and 23%, respectively, in the stroma-rich group. Both 3-year overall and disease-free survival rates in the stroma-poor group were significantly better than those in the stroma-rich group (p < 0.01). In a multivariate analysis, TSR was identified as a highly significant prognostic factor for 3-year overall survival (hazard ratio 3.450; p = 0.001) and 3-year disease-free survival (hazard ratio 2.995; p = 0.001), independent of pTNM stage and radicality of the primary tumor. Stroma-rich tumors were associated with poor prognosis and an increased risk of relapse, which may serve as a new prognostic histological characteristic in ESCC. TSR is simple and quick to determine, is reproducible, and could be easily incorporated in routine histological evaluation.


Implementation of an ergonomics intervention in a Swedish flight baggage handling company-A process evaluation.
To conduct a process evaluation of the implementation of an ergonomics training program aimed at increasing the use of loading assist devices in flight baggage handling. Feasibility related to the process items recruitment, reach, context, dose delivered (training time and content); dose received (participants' engagement); satisfaction with training; intermediate outcomes (skills, confidence and behaviors); and barriers and facilitators of the training intervention were assessed by qualitative and quantitative methods. Implementation proved successful regarding dose delivered, dose received and satisfaction. Confidence among participants in the training program in using and talking about devices, observed use of devices among colleagues, and internal feedback on work behavior increased significantly (p<0.01). Main facilitators were self-efficacy, motivation, and perceived utility of training among the trainees. Barriers included lack of peer support, opportunities to observe and practice behaviors, and follow-up activities; as well as staff reduction and job insecurity. In identifying important barriers and facilitators for a successful outcome, this study can help supporting the effectiveness of future interventions. Our results suggest that barriers caused by organizational changes may likely be alleviated by recruiting motivated trainees and securing strong organizational support for the implementation.


Considering the flanking region variants of nonbinary SNP and phenotype-informative SNP to constitute 30 microhaplotype loci for increasing the discriminative ability of forensic applications.
The flanking region variants of nonbinary SNPs and phenotype-informative SNPs (piSNPs) have been observed, which may greatly improve the discriminative ability after constituting microhaplotype. In this study, 30 microhaplotype loci based on the nonbinary SNPs and piSNPs (shown to be related to phenotypes such as hair and eye color) were selected. Genotyping were conducted on 100 unrelated northern Han Chinese, and the 26 populations from the 1000 Genome Project were also included for comparison of populations differentiation. The simulated study was conducted for evaluating the efficiency of kinship testing. These 30 microhaplotype loci we selected had good polymorphism, with a mean effective number of alleles (Ae) of 3.46. The average Ae increase was 1.27 compared with the target SNPs. The populations from the five regions worldwide could also be distinguished using these loci. The results of kinship testing showed that these microhaplotype loci had the similar ability as 15 STR loci of AmpFlSTRR IdentifilerR PCR Amplification Kit to identify the biological parent and a stronger ability to exclude the nonbiological parents. So, these 30 microhaplotype loci may be multifunctional for forensic application, including the ability of personal identification and kinship testing equivalent to 15 STR loci, and the power of ancestry inference for distinguishing the main intercontinental population. Moreover, our selected phenotypic microhaplotype loci may theoretically have phenotype prediction capabilities. But the phenotype prediction efficiency of these phenotypic microhaplotype loci may be worse than that of piSNPs and the detailed prediction accuracy of different populations needs to be further studied.


Ablative neurosurgery for mental disorders: is there still a role in the 21st century? A personal perspective.
The author presents his personal perspective on ablative neurosurgical techniques used to perform bilateral anterior cingulotomy (BACI) and bilateral anterior capsulotomy (BACA) for ameliorating the symptoms of refractory obsessive-compulsive disorder (OCD) and treatment refractory depression (TRD). With depression predicted to be the second most common cause of disability in the world by the year 2020 and the birth of electric neurostimulation representing an attractive alternative treatment option for TRD and OCD, it is desirable to revisit the pros and cons of these treatment options. The author reviewed the surgical methods and outcome (including neuroimaging findings) in all cases in which ablative neurosurgery was performed at Ninewells Hospital and Medical School over the last 2 decades. The advantages of ablative procedures (BACI and BACA) from patients' and psychiatrists' perspectives are that the ablative procedures are one-off procedures that do not require lifelong commitment to program the stimulation devices, fix hardware failures, or change exhausted batteries. From the perspective of healthcare funding bodies, the relatively low cost of these treatments is an advantage. The main disadvantages of BACI and BACA are the perceived higher complication rates, the irreversibility of the surgical lesions, and the stigma associated with brain destruction in psychiatric patients that are still unpalatable in the community at large. However, some patients still choose a one-off procedure in preference to any other options presented to them. There is still place for BACI and BACA in modern neurosurgery for mental disorders, at least in the short term for those who do not want to commit to lifelong device programming and maintenance.


Active Sets for Explicitly Constrained Evolutionary Optimization.
Active-set approaches are commonly used in algorithms for constrained numerical optimization. We propose that active-set techniques can beneficially be employed for evolutionary black-box optimization with explicit constraints and present an active-set evolution strategy. We experimentally evaluate its performance relative to those of several algorithms for constrained optimization and find that the active-set evolution strategy compares favourably for the problem set under consideration.


NPY Y2 and Y4 receptors selective ligands: promising anti-obesity drugs?
Neuropeptide Y (NPY), a potent orexigen peptide widely produced and distributed in arcuate neurons in the hypothalamus, is a promising candidate for the control of appetitive ingestive behavior. In mammals, the signaling is mediated via at least five different cell surface receptors, denoted as Y(1), Y(2), Y(4), Y(5) and Y(6). Obesity is an important public health problem in the world, particularly in developed societies, and has taken on pandemic proportions. The therapeutics of obesity, including appetite suppressants, has increased 453% over the past decade, although issues concerning safety, efficacy, and little knowledge of the pharmacological activity result in the still modest effects of the anti-obesity drugs presently used. Ligands for Y receptors may be of benefit for the treatment of obesity, and recent findings have indicated a promising role of Y(2) and Y(4) in protecting against diet-induced obesity. This review highlights the supporting evidence therapeutic potential of Y(2) and Y(4) receptors antagonists as additional intervention to treat human obesity.


Carbamoyl phosphate synthetase (glutamine-hydrolyzing): increased activity in cancer cells.
The specific activity of carbamoyl phosphate synthetase (glutamine-hydrolyzing), the first and rate-limiting enzyme of de novo uridine 5'-triphosphate biosynthesis, was increased in 13 transplantable hepatomas, particularly in the rapidly growing tumors (5.7- to 9.5-fold), and the rise was correlated with tumor growth rates. Thus, synthetase activity was linked with both hepatic neoplastic transformation and progression. Synthetase specific activity was so elevated in a transplantable sarcoma (18-fold) and a kidney adenocarcinoma (5-fold). The increased activity should enhance the capacity of the pathway and should confer selective advantages to cancer cells.


Lessons Learned from Mechanical Thrombectomy of an Acute Occlusion of a Duplicated Middle Cerebral Artery: A Case Report.
Detection of acute arterial occlusion in an anomalous middle cerebral artery (MCA) is challenging in an emergency setting because of its rarity. We report an 81-year-old woman who presented with acute occlusion of a duplicated middle cerebral artery (DMCA). Although the absence of the superior trunk of the left MCA was identified on preoperative imaging, initial angiography showed no typical sign of the occluded vessel. Repeated angiography eventually revealed retrograde arterial flow parallel to the other visible MCA trunk, which raised the possibility of a DMCA. The occlusion occurred at the origin of the DMCA originating from the internal carotid artery terminus, which obscured its presence. Mechanical thrombectomy was performed and achieved complete recanalization. The DMCA had two trunks of approximately equal size. The patient completely recovered within 90 days. Comprehensive knowledge of cerebrovascular anomalies is essential to identify the occluded branch faster and accurately and to avoid thrombectomy-related complications in endovascular recanalization therapy. Relevant DMCA anatomy and tips for identifying an occluded DMCA are discussed.


Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody.
Selecting the dose for efficacy and first-in-human studies of bispecific antibodies (BsAbs) is a challenging process. Herein, positron emission tomography (PET) imaging with 89Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with 89Zr, we aimed to assess the pharmacokinetics (PK), safety, and target engagement of IBI322 with dose escalation dynamic PET imaging in humanized transgenic animal models bearing MC38 tumors (knock-in of hCD47 and hPDL1). 89Zr-labeled IBI322 specifically accumulated in tumors with a tumor-to-muscle ratio of 12.37 ± 1.42 at 168 h (0.22 mg/kg) and the biodistribution of normal tissues from PET imaging could be used for preliminary safety prediction. According to the Pearson correlation analysis between the ELISA-quantified serum concentration and heart uptake (%ID/g) (r = 0.980), a modified Patlak model was proposed. The exploratory target-mediated 50% (0.38 mg/kg) and 90% (0.63 mg/kg) inhibitory mass doses were calculated with the current modified Patlak model. The preliminary pharmacodynamics (PD) study with 0.34 mg/kg revealed that the dose prediction was rational. In conclusion, dose escalation PET imaging with 89Zr-labeled antibodies is promising for PK/PD modeling and safety prediction, and helpful for determining rational dosing for preclinical and clinical trials of BsAbs.


Mortality in patients with biopsy-proven giant cell arteritis: a south australian population-based study.
To compare mortality rates and cause of death in patients with biopsy-proven giant cell arteritis (GCA) with those in the general population. Patients with biopsy-proven GCA were identified from pathology reports of temporal artery biopsies in South Australia, from January 1, 1992, to December 31, 2006. All patients with biopsy-proven GCA were linked to the South Australian Births, Death and Marriage Registry to identify deaths until December 31, 2006. Standardized mortality ratios and relative survival (ratio of observed survival in GCA group to expected survival of general South Australian population, matched by age, sex, and calendar time) were calculated. The cause of death recorded on the death certificate was also documented. There were 225 cases of biopsy-proven GCA (163 women and 62 men). The mean age at diagnosis of GCA was 78.2 years. The mean followup period was 66.2 months (SD 47.1 mo). During the followup period, there were 71 deaths in the GCA group (50 women, 21 men). The standardized mortality ratio was 0.99 (95% CI 0.77-1.25). The relative survival for different followup periods demonstrates that patients with GCA experienced similar mortality to the general population (age-matched and sex-matched). Death from cardiovascular causes (45%) was the most common, followed by infection (17%) and cancer (17%). Infection was a significantly more common cause of death in the first year (chi-squared, p = 0.0002). Our population-based cohort study did not demonstrate any increased mortality risk for patients diagnosed with biopsy-proven GCA. The risk of death from infection early in the disease may be increased.


Oncogenic Gq/11 signaling acutely drives and chronically sustains metabolic reprogramming in uveal melanoma.
Metabolic reprogramming has been shown to occur in uveal melanoma (UM), the most common intraocular tumor in adults. Mechanisms driving metabolic reprogramming in UM are poorly understood. Elucidation of these mechanisms could inform development of new therapeutic strategies for metastatic UM, which has poor prognosis because existing therapies are ineffective. Here, we determined whether metabolic reprogramming is driven by constitutively active mutant α-subunits of the heterotrimeric G proteins Gq or G11 (Gq/11), the oncogenic drivers in ∼90% of UM patients. Using PET-computed tomography imaging, microphysiometry, and GC/MS, we found that inhibition of oncogenic Gq/11 with the small molecule FR900359 (FR) attenuated glucose uptake by UM cells in vivo and in vitro, blunted glycolysis and mitochondrial respiration in UM cell lines and tumor cells isolated from patients, and reduced levels of several glycolytic and tricarboxylic acid cycle intermediates. FR acutely inhibited glycolysis and respiration and chronically attenuated expression of genes in both metabolic processes. UM therefore differs from other melanomas that exhibit a classic Warburg effect. Metabolic reprogramming in UM cell lines and patient samples involved protein kinase C and extracellular signal-regulated protein kinase 1/2 signaling downstream of oncogenic Gq/11. Chronic administration of FR upregulated expression of genes involved in metabolite scavenging and redox homeostasis, potentially as an adaptive mechanism explaining why FR does not efficiently kill UM tumor cells or regress UM tumor xenografts. These results establish that oncogenic Gq/11 signaling is a crucial driver of metabolic reprogramming in UM and lay a foundation for studies aimed at targeting metabolic reprogramming for therapeutic development.


Treatment Outcomes of Interdisciplinary Care on Speech and Health-Related Quality of Life Outcomes in Adults With Cleft Palate.
Individuals born with a cleft palate with or without a cleft lip (CP ± L) often experience functional, aesthetic, and psychosocial consequences well into adulthood. This study aimed to investigate outcomes of speech and health-related quality of life (HRQoL) in adults with a CP ± L who received interdisciplinary cleft care at the Ghent University Hospital using valid, reliable, and condition-specific instruments. Thirteen Belgian Dutch-speaking participants with a CP ± L with a mean age of 25.4 years (SD = 5.1, range: 20-33 years) and an age- and gender-matched control group of 13 participants without a CP ± L with a mean age of 25.2 years (SD = 4.8, range: 20-32 years) were included in this study. Speech characteristics were evaluated perceptually and instrumentally. HRQoL was assessed through standardized patient-reported outcome measures. Outcomes were compared with those of the control group and to normative data where available. Participants with a CP ± L in this sample demonstrated significantly lower speech acceptability (p < .001) and higher rates of hypernasality (p = .015) and nasal turbulence (p = .005) than the control group. They showed significantly higher satisfaction with appearance of the cleft scar compared with norms of adults with a CP ± L (p = .047). No other differences in speech characteristics, sociodemographics, or HRQoL were found between participants with and without a CP ± L. The reduced speech acceptability and the presence of resonance and nasal airflow disorders may indicate the need for standardized long-term outcome measurement and interdisciplinary follow-up for speech characteristics and velopharyngeal insufficiency in young and middle adulthood in future clinical practice. Additional research is necessary to further substantiate these findings and to determine predictors for these continuing complications in adults with a CP ± L. https://doi.org/10.23641/asha.24243901.


PI3K/mTOR inhibition markedly potentiates HDAC inhibitor activity in NHL cells through BIM- and MCL-1-dependent mechanisms in vitro and in vivo.
The aim of this study is to explore the efficacy and define mechanisms of action of coadministration of the PI3K/mTOR inhibitor BEZ235 and pan-HDAC inhibitor panobinostat in diffuse large B-cell lymphoma (DLBCL) cells. Various DLBCL cells were exposed to panobinostat and BEZ235 alone or together after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Genetic strategies defined the functional significance of such changes, and xenograft mouse models were used to assess tumor growth and animal survival. Panobinostat and BEZ235 interacted synergistically in ABC-, GC-, and double-hit DLBCL cells and MCL cells but not in normal CD34(+) cells. Synergism was associated with pronounced AKT dephosphorylation, GSK3 dephosphorylation/activation, Mcl-1 downregulation, Bim upregulation, increased Bcl-2/Bcl-xL binding, diminished Bax/Bak binding to Bcl-2/Bcl-xL/Mcl-1, increased γH2A.X phosphorylation and histone H3/H4 acetylation, and abrogation of p21(CIP1) induction. BEZ235/panobinostat lethality was not susceptible to stromal/microenvironmental forms of resistance. Genetic strategies confirmed significant functional roles for AKT inactivation, Mcl-1 downregulation, Bim upregulation, and Bax/Bak in synergism. Finally, coadministration of BEZ235 with panobinostat in immunocompromised mice bearing SU-DHL4-derived tumors significantly reduced tumor growth in association with similar signaling changes observed in vitro, and combined treatment increased animal survival compared with single agents. BEZ235/panobinostat exhibits potent anti-DLBCL activity, including in poor-prognosis ABC- and double-hit subtypes, but not in normal CD34(+) cells. Synergism is most likely multifactorial, involving AKT inactivation/GSK3 activation, Bim upregulation, Mcl-1 downregulation, enhanced DNA damage, and is operative in vivo. Combined PI3K/mTOR and HDAC inhibition warrants further attention in DLBCL.


Major active components in grapefruit, orange, and apple juices responsible for OATP2B1-mediated drug interactions.
We aimed to explore the major active components in grapefruit juice (GFJ), orange juice (OJ), and apple juice (AJ) that are responsible for OATP2B1-mediated drug interactions, by means of in vitro studies using Xenopus oocytes expressing OATP2B1 with a typical OATP2B1 substrate, estrone-3-sulfate. All three juices inhibited OATP2B1-mediated estrone-3-sulfate uptake with half-maximum inhibition (IC50 ) values of 0.222% (GFJ), 0.807% (OJ), and 2.27% (AJ). Eight major flavonoids (naringin, naringenin, hesperidin, hesperetin, phloridzin, phloretin, quercetin, and kaempferol) contained in the juices inhibited OATP2B1-mediated estrone-3-sulfate uptake with IC50 values of 4.63, 49.2, 1.92, 67.6, 23.2, 1.31, 9.47, and 21.3 μM, respectively. When the concentration-IC50 ratios ([C]/IC50 ) of these flavonoids in GFJ, OJ, and AJ were calculated, values of [C]/IC50 ≥ 100 were obtained for naringin in GFJ and hesperidin in OJ. No flavonoid in AJ showed a ratio higher than unity. However, significant inhibition of OATP2B1 was observed with a mixture of phloridzin, phloretin, hesperidin, and quercetin at the concentrations present in AJ. In conclusion, our results indicate that naringin and hesperidin are the major OATP2B1 inhibitors in GFJ and OJ, respectively, whereas a combination of multiple components appears to be responsible for OATP2B1 inhibition by AJ.


Infinite coordination polymer networks: metallogelation of aminopyridine conjugates and in situ silver nanoparticle formation.
Herein we report silver(i) directed infinite coordination polymer network (ICPN) induced self-assembly of low molecular weight organic ligands leading to metallogelation. Structurally simple ligands are derived from 3-aminopyridine and 4-aminopyridine conjugates which are composed of either pyridine or 2,2'-bipyridine cores. The cation specific gelation was found to be independent of the counter anion, leading to highly entangled fibrillar networks facilitating the immobilization of solvent molecules. Rheological studies revealed that the elastic storage modulus (G') of a given gelator molecule is counter anion dependent. The metallogels derived from ligands containing a bipyridine core displayed higher G' values than those with a pyridine core. Furthermore, using single crystal X-ray diffraction studies and 1H-15N two-dimensional (2D) correlation NMR spectroscopy, we show that the tetracoordination of silver ions enables simultaneous coordination polymerization and metallosupramolecular cross-linking. The resulting metallogels show spontaneous, in situ nanoparticle (d < 2-3 nm) formation without any additional reducing agents. The silver nanoparticle formation was followed using spectroscopic studies, and the self-assembled fibrillar networks were imaged using transmission electron microscopy (TEM) imaging.


The streaming liver.
Twenty male adult rats weighing 200 g were injected with tritiated thymidine (3HTdR). The animals were then killed in groups of five, at the following times: 1 h, 1, 3 and 5 weeks. Autoradiograms of sections through the liver were prepared. The distances between labelled cells and the portal space rim were measured. One hour after labelling most labelled cells were confined to a region extending from the portal space rim up to a distance of 700 micron, which roughly corresponds to Rappaport's hepatic acinus zones-1 and -2. Throughout the experiment lasting 5 weeks labelled cells entered zone-3 and advanced toward the terminal hepatic vein. Hepatocytes travelled at a daily velocity of 1.44 micron, covering daily 0.324% of the acinus diameter. During the experiment acinus size did not change appreciably. The estimated mean hepatocyte cell cycle time was 37 days and its life expectation, 201 days. These experiments show that the liver is essentially a slowly renewing cell population. Hepatocytes nascent at the portal space gradually stream toward the terminal hepatic vein where they are probably eliminated by apoptosis. Their journey lasts 201 days. Since hepatocytes are glued together with tight junctions, all have to advance toward their terminal hepatic veins en masse. During their voyage, they traverse the three acinus zones, and since in each they produce different enzymes, each zone represents a differentiation state of the advancing cell. It is suggested further that the streaming hepatocyte carries with it its nerve supply and is accompanied by sinusoidal endothelium and Kupffer cells.


The relationship between ultrasound-based TIRADS and BETHESDA categories in patients undergoing thyroid biopsy.
The TIRADS is a scoring system used for the selection of nodules for FNA and classification of the risk of malignancy based on ultrasound characteristics. The BETHESDA is a standard reporting system used for the classification of FNA results based on six criteria with risks for malignancy. The objective of this study was to evaluate the relationship between TIRADS and BSRTC classifications in patients undergoing thyroid biopsy. A total of 350 consecutive patients were retrospectively evaluated using TIRADS and BETHESDA reporting systems for determining preoperative diagnosis of thyroid nodules. Patients' demographics, size, echogenicity and contour status of the nodules, TIRADS and BETHESDA scores were recorded and analyzed. Data obtained in this study were expressed as mean, standard deviation, frequency and percentage descriptive statistics. The mean age of the patients was 49.03 ± 17.58 years. The mean nodule size was measured as 20.56 ± 10.47 mm. TIRADS TR3 category was found in 165 (47.14%), TR4 in 154 (44%) and TR5 in 31 (8.86%) patients, while BETHESDA II category was found in 288 (82.28%), BETHESDA III category in 1 (0.29%), BETHESDA IV category in 19 (5.43%), BETHESDA V in 37 (10.57%) and BETHESDA VI in 5 (1.43%) patients. There was a general concordance between BETHESDA and TRIADS categories. The most significant concordance was found between BETHESDA IV and TR4 categories (84.21%). Combined use of TRIADS and BETHESDA can be efficiently used to provide the most accurate results for making preoperative diagnosis of thyroid nodules and to determine the risk of malignancy.


Outcomes among African-Americans and Caucasians in colon cancer adjuvant therapy trials: findings from the National Surgical Adjuvant Breast and Bowel Project.
African-Americans generally have lower survival rates from colon cancer than Caucasian Americans. This disparity has been attributed to many sources, including diagnosis at later disease stage and other unfavorable disease features, inadequate treatment, and socioeconomic factors. The randomized clinical trial setting ensures similarity in disease stage and a uniform treatment plan between blacks and whites. In this study, we evaluated survival and related end points for African-American and Caucasian patients with colon cancer participating in randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine whether outcomes were less favorable for African-Americans. The study included African-American (n = 663) or Caucasian (n = 5969) patients from five serially conducted, randomized clinical trials of the NSABP. We compared recurrence-free survival, disease-free survival (recurrence, new primary cancer, or death), and survival (death from any cause) between blacks and whites by using statistical modeling to account for differences in patient and disease characteristics between the groups. Statistical tests were two-sided. Dukes' stage and number of positive lymph nodes were remarkably similar between African-American and Caucasian patients in each trial. Over all trials combined, an 8% (95% confidence interval [CI] = -6% to 25%; P =.27) excess risk of colon cancer recurrence that was not statistically significant was observed for blacks. A greater disparity in survival was seen, with blacks experiencing a statistically significant 21% (95% CI = 6%-37%; P =.004) greater risk of death. Treatment efficacy appeared similar between the groups. While the overall survival prognosis was less favorable for African-Americans compared with Caucasians in these trials, other outcomes measured were considerably more similar than those seen in the population at large, suggesting that earlier detection and adjuvant therapy could appreciably improve colon cancer prognosis for African-Americans. Continued investigations into causes of the deficits noted are warranted.


Sedation monitoring during open muscle biopsy in children by Comfort Score and Bispectral Index - a prospective analysis.
Open muscle biopsies in children are generally performed under general anesthesia. Alternatively, deep sedation and analgesia may be required. The aim of our study was to compare the Bispectral Index (BIS) and Comfort Score (CS) with respect to their clinical significance for sedation/analgesia in children undergoing open muscle biopsy. Thirty pediatric patients subjected to open muscle biopsy for diagnosis of their underlying disease were prospectively enrolled. Sedation/analgesia was performed in all patients using remifentanil and propofol. The patients were simultaneously monitored using the CS and BIS. All sedations and muscle biopsies were performed uneventfully. The CS and BIS were significantly correlated (R = 0.589; P < 0.01). Receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.918 with a maximum cut-off point of BIS 70.5 (sensitivity 0.9; specificity 0.785) for adequate sedation. Sensitivity of 100% was achieved at BIS 60. Accordingly, all patients with BIS ≤60 had CS within the target range of 10-14. The BIS showed substantial intra- and interindividual variability (30 points and 58 points, respectively) during sedation, whereas CS varied only within close ranges during sedation. In 25 patients, sedatives were reduced according to low BIS values (<60). No unintended anesthesia awareness was noted during the study period. Bispectral Index provides an additional helpful tool to guide sedation/analgesia in minor surgical procedures in children. BIS values ≤60 correlated with sufficient depth of sedation and prevented unintended awareness. Additionally, BIS measurement allowed for distinct regulation of depth of sedation without prolonged sedation/analgesia due to unintended overdose.


Acid-base and spectroelectrochemical properties of doubly N-confused porphyrins.
The cis-doubly N-confused porphyrin, H2N2CP, containing two adjacent confused pyrrole rings has been investigated from the point of view of its acid-base and electrochemical behavior in dichloromethane. This novel porphyrin isomer can form two metal-carbon bonds in the central core, stabilizing metal ions in unusually high oxidation states. Furthermore, the two outside N-pyrrole atoms remain available for acid-base and specific solvent interactions. Protonation of the pyrrole N atoms proceeds according to two successive steps, while only a single deprotonation step has been observed in the presence of bases. Similarly, in the case of the silver and copper complexes the protonation and deprotonation of the outer pyrrole rings have been detected, confirming the structure of the metalated species as M(III)-HN2CP. The electrochemical reduction of the metal ions (III/II redox process) and oxidation of the macrocycle ring have been detected respectively at -0.9 and 1.4 V based on spectroelectrochemical measurements in conjunction with the acid/base equilibrium studies. Additional waves observed around -0.5 and 1.3 V have been assigned to redox processes involving water molecules associated with the doubly N-confused porphyrins.


MosaicNet: A deep-learning-based multi-tile biomedical image stitching method.
Multi-tile image stitching aims to merge multiple natural or biomedical images into a single mosaic. This is an essential step in whole-slide imaging and large-scale pathological imaging systems. To tackle this task, a multi-step framework is usually used by first estimating the optimal transformation for each image and then fusing them into a whole image. However, the traditional approaches are usually time-consuming and require manual adjustments. Advances in deep learning techniques provide an end-to-end solution to register and fuse information of multiple tile images. In this paper, we present a deep learning model for multi-tile biomedical image stitching, namely MosaicNet, consisting of an aligning network and a fusion network. We trained the MosaicNet network on a large simulation dataset based on the VOC2012 dataset and evaluated the model on multiple types of datasets, including simulated natural images, mouse brain T2-weighted Magnetic Resonance Imaging (T2w-MRI) data, and mouse brain polarization sensitive-optical coherence tomography (PS-OCT) data. Our method outperformed traditional approaches on both natural images and brain imaging data. The proposed method is robust to different settings of hyper-parameters and shows high computational efficiency, up to approximately 32 times faster than the conventional methods.


Mechanisms of force depression caused by different types of physical exercise studied by direct electrical stimulation of human quadriceps muscle.
Force production frequently remains depressed for several hours or even days after various types of strenuous physical exercise. We hypothesized that the pattern of force changes during the first hour after exercise can be used to reveal muscular mechanisms likely to underlie the decline in muscle performance during exercise as well as factors involved in the triggering the prolonged force depression after exercise. Nine groups of recreationally active male volunteers performed one of the following types of exercise: single prolonged or repeated short maximum voluntary contractions (MVCs); single or repeated all-out cycling bouts; repeated drop jumps. The isometric force of the right quadriceps muscle was measured during stimulation with brief 20 and 100 Hz trains of electrical pulses given before and at regular intervals for 60 min after exercise. All exercises resulted in a prolonged force depression, which was more marked at 20 Hz than at 100 Hz. Short-lasting (≤2 min) MVC and all-out cycling exercises showed an initial force recovery (peak after ~ 5 min) followed by a secondary force depression. The repeated drop jumps, which involve eccentric contractions, resulted in a stable force depression with the 20 Hz force being markedly more decreased after 100 than 10 jumps. In accordance with our hypothesis, the results propose at least three different mechanisms that influence force production after exercise: (1) a transiently recovering process followed by (2) a prolonged force depression after metabolically demanding exercise, and (3) a stable force depression after mechanically demanding contractions.


Investigation of nitriding and reduction processes in a nanocrystalline iron-ammonia-hydrogen system at 350 °C.
In this paper, the series of phase transitions occurring during the gaseous nitriding of nanocrystalline iron was studied. The nitriding process of nanocrystalline iron and the reduction process of the obtained nanocrystalline iron nitrides were carried out at 350 °C in a tubular differential reactor equipped with systems for thermogravimetric measurements and analysis of gas phase composition. The samples were reduced with hydrogen at 500 °C in the above mentioned reactor. Then the sample was nitrided at 350 °C in a stream of ammonia-hydrogen mixtures of various nitriding potentials, P = pNH3/pH2(3/2). At each nitriding potential stationary states were obtained - the nitriding reaction rate is zero and the catalytic ammonia decomposition reaction rate is constant. The reduction process of the obtained nanocrystalline iron nitrides was studied at 350 °C in the stationary states as well. The phase composition of products obtained in both reaction directions (nitriding and reduction) was different despite the identical concentration of nitrogen in the nitriding mixture. The hysteresis phenomenon, occurring at the iron nitriding degree - nitriding potential system, was explained. In the single-phase areas of α-Fe(N), γ'-Fe4N or ε-Fe3-2N, a state of chemical equilibrium between the ammonia-hydrogen mixture, nanocrystalline iron surface and volume was observed. In the multi-phase areas, between the gas phase and the iron surface a state of chemical equilibrium holds, but between the gas phase and solid phase volume a state of quasi-equilibrium exists. The model of the nitriding process of nanocrystalline iron to iron nitride (γ'-Fe4N) was presented. It was found that nanocrystallites reacted in the order of their sizes from the largest to the smallest.


The megencephaly mouse has disturbances in the insulin-like growth factor (IGF) system.
Megencephaly, enlarged brain, is a major sign in several human neurological diseases. The mouse model for megencephaly, mceph/mceph, has an enlarged brain and a lowered body weight. In addition, it displays several neurological and motoric disturbances. Previous studies suggest that the brain enlargement results from hypertrophy of the brain cells, rather than hyperplasia. No structural abnormalities, edema or increased myelination have been found. In this study, a major imbalance in the mRNA expression of molecules in the insulin-like growth factor (IGF) system was found in brains of 9-10 weeks old mceph/mceph mice compared to +/+ wild-type mice. In mceph/mceph brains, we found upregulation of IGF binding proteins (BP)-2, -4, -5, and -6 mRNA, the regulating hormone transforming growth factor (TGF)beta1 mRNA and also a local downregulation of IGFBP-5 mRNA compared to wild-type brains by in situ hybridization. The altered expression of these mRNA species is colocalized in cerebral cortex, hippocampus, amygdala and piriform/entorhinal cortex. The mceph/mceph mice express less of the myelin component proteolipid protein (PLP) mRNA in corpus callosum. No expression difference of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in brain or IGF system components in liver was found between mceph/mceph and wild-type mice. These data suggest that the IGF system has an important role in the excessive growth of the mceph/mceph brains.


The outcome of combined-modality treatments for stage I and II primary large B-cell lymphoma of the mediastinum.
Primary mediastinal large B-cell lymphoma (PML) has clinicopathologic features distinct from those of other diffuse large-cell lymphomas. However, the optimal treatment for this tumor is evolving, and in particular, the role of radiation therapy remains undefined. We conducted a retrospective review to evaluate the role of radiation therapy in this disease. The medical records of 40 consecutive patients with Ann Arbor Stage I or II PML treated at our institution from January 1980 to December 1995 were reviewed. There were 18 patients with Stage I disease and 22 patients with Stage II disease; 62.5% were women and 37.5% were men. The median age was 32.4 years (range, 17-74 years). The tumor scores were 0 in 1 patient, I in 5 patients, II in 13 patients, III in 7 patients, IV in 4 patients, and unknown in 10 patients. The International Prognostic Index (IPI) was 0 in 10 patients, I in 26 patients, II in 2 patients, and unknown in 2 patients. All patients were treated with doxorubicin-based chemotherapy, and 35 patients received radiation therapy. For most patients who received radiation therapy, an involved field or a modified-mantle field was used, and a dose of 40 Gy in 20 fractions or 39.6 Gy in 22 fractions was administered. Univariate analysis was performed to identify prognostic factors. The median follow-up in surviving patients was 56 months (range, 19-194 months). The actuarial 5-year relapse-free survival (RFS) rate and overall survival (OS) rate for all patients were 67% and 72%, respectively. Thirty-five patients achieved a complete response; 32 of these patients received radiation therapy. The patterns of failure for the complete responders were as follows: locoregional failure alone for 1 patient (at the margin of the radiation field); distant failure alone for 5 patients; and both locoregional (in-field) and distant failure for 1 patient. There were no failures after 2.5 years. None of the 5 patients who never achieved a complete response had local control, and all died with disease. Only 2 of the 5 completed the planned course of radiation therapy; both had massive mediastinal disease. There was no treatment-related death from the initial chemotherapy or radiation therapy. One patient developed a second malignancy (sarcoma) within the radiation field after 13 years. The tumor score was a significant predictor of RFS (p = 0.016) and OS (p = 0.006), but the IPI did not prove to be a significant predictor. We recommend consolidative radiation therapy in view of the excellent local control and the lack of significant toxicity. Modified mantle or involved field appears to be an adequate volume, and 39.6-40 Gy appears to be an adequate dose. The tumor score is a significant prognostic factor.


Multicolor multifocal 3D microscopy using in-situ optimization of a spatial light modulator.
Multifocal microscopy enables high-speed three-dimensional (3D) volume imaging by using a multifocal grating in the emission path. This grating is typically designed to afford a uniform illumination of multifocal subimages for a single emission wavelength. Using the same grating for multicolor imaging results in non-uniform subimage intensities in emission wavelengths for which the grating is not designed. This has restricted multifocal microscopy applications for samples having multicolored fluorophores. In this paper, we present a multicolor multifocal microscope implementation which uses a Spatial Light Modulator (SLM) as a single multifocal grating to realize near-uniform multifocal subimage intensities across multiple wavelength emission bands. Using real-time control of an in-situ-optimized SLM implemented as a multifocal grating, we demonstrate multicolor multifocal 3D imaging over three emission bands by imaging multicolored particles as well as Escherichia coli (E. coli) interacting with human liver cancer cells, at [Formula: see text] multicolor 3D volumes per second acquisition speed. Our multicolor multifocal method is adaptable across SLM hardware, emission wavelength band locations and number of emission bands, making it particularly suited for researchers investigating fast processes occurring across a volume where multiple species are involved.


Helicobacter pylori specific immune response induced by conservative flagellin linear B-cell epitope.
To testify the immunogenicity of a conservative B-cell linear epitope of Helicobacter pylori (H pylori) flagellin A. Different programs were used to analyze the secondary structure, molecular hydropathy, and surface accessibility of H pylori flagellin A. Linear B-cell epitopes were estimated based on the structural and physiochemical information. Analysis of residue divergence was proposed to screen a conservative linear epitope. The 29-peptide (Pep29mer) synthesized by chemical method, including the predicted conservative B-cell epitope and a known K2d compatible T-cell epitope, was used to immunize mice, and then H pylori-specific antibodies were detected by ELISA. Based on the analyses of divergent amino acid residues, structural and physiochemical characteristics, it was strongly suggested that the short fragment NDSDGR was the core of a conservative linear epitope in flagellin A. Animals immunized by Pep29mer acquired efficient immune response. In detail, serum H pylori-specific IgA and IgG1 increased significantly in immunized group, while IgG2a only had an insignificant change. H pylori-specific IgA in gastrointestinal flushing fluid also increased significantly. The conservative short fragment NDSDGR is the core of a linear B-cell epitope of flagellin A.


Tunisian table olive phenolic compounds and their antioxidant capacity.
For the 1st time, 4 olive cultivars, the Meski, Chemlali, Besbessi, and Tounsi, from the Tunisian market were investigated to evaluate the phenolic compounds' contribution in nutritional value of table olives. From the Meski cultivar, we have chosen 4 different samples to evaluate differences within the same cultivar. Basic characteristics and total phenolic content were evaluated in flesh and kernel. The highest value of flesh phenolic content was observed in sample M4 of the Meski cultivar; however, the lowest value was observed in the Besbessi cultivar and they were 1801 and 339 mg GA/100 g dry weight, respectively. The main simple phenolic compounds identified in flesh extracts are hydroxytyrosol, tyrosol, and vanillic acid. Oleuropein was not detected in any samples. The antioxidant activity of Tunisian olive flesh varies between 212 and 462 muM TEAC/g of dry weight. Antioxidant activity of olives was related to their phenolic content but we found a low correlation between phenolic content and TEAC.


Skin preparation with alcohol versus alcohol followed by any antiseptic for preventing bacteraemia or contamination of blood for transfusion.
Blood for transfusion may become contaminated at any point between collection and transfusion and may result in bacteraemia (the presence of bacteria in the blood), severe illness or even death for the blood recipient. Donor arm skin is one potential source of blood contamination, so it is usual to cleanse the skin with an antiseptic before blood donation. One-step and two-step alcohol based antiseptic regimens are both commonly advocated but there is uncertainty as to which is most effective. To assess the effects of cleansing the skin of blood donors with alcohol in a one-step compared with alcohol in a two-step procedure to prevent contamination of collected blood or bacteraemia in the recipient. In December 2014, for this third update, we searched the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. All randomised trials (RCTs) comparing alcohol based donor skin cleansing in a one-step versus a two-step process that includes alcohol and any other antiseptic for pre-venepuncture skin cleansing were considered. Quasi randomised trials were to have been considered in the absence of RCTs. Two review authors independently assessed studies for inclusion. No studies (RCTs or quasi RCTs) met the inclusion criteria. We did not identify any eligible studies for inclusion in this review. It is therefore unclear whether a two-step, alcohol followed by antiseptic skin cleansing process prior to blood donation confers any reduction in the risk of blood contamination or bacteraemia in blood recipients, or conversely whether a one-step process increases risk above that associated with a two-step process.


[Characteristics of hypoxia development in aged people].
The aim of the study was to investigate the peculiarities of tissue oxygen provision on the level of microcirculatory bed and to determine the significance of the indices taken separatively in pathogenesis of hypoxia in practically healthy elderly people. The study comprised 30 practically healthy people aged 60-74. It included investigation of oxygen tension in peripheral tissues, skin and bulbar microcirculation, functional state of endothelium in the group of elderly healthy people. The results obtained were compared with analogous data obtained in practically healthy young subjects. The tissue oxygen provision was found to decrease with age.


A screen for modifiers of hedgehog signaling in Drosophila melanogaster identifies swm and mts.
Signaling by Hedgehog (Hh) proteins shapes most tissues and organs in both vertebrates and invertebrates, and its misregulation has been implicated in many human diseases. Although components of the signaling pathway have been identified, key aspects of the signaling mechanism and downstream targets remain to be elucidated. We performed an enhancer/suppressor screen in Drosophila to identify novel components of the pathway and identified 26 autosomal regions that modify a phenotypic readout of Hh signaling. Three of the regions include genes that contribute constituents to the pathway-patched, engrailed, and hh. One of the other regions includes the gene microtubule star (mts) that encodes a subunit of protein phosphatase 2A. We show that mts is necessary for full activation of Hh signaling. A second region includes the gene second mitotic wave missing (swm). swm is recessive lethal and is predicted to encode an evolutionarily conserved protein with RNA binding and Zn(+) finger domains. Characterization of newly isolated alleles indicates that swm is a negative regulator of Hh signaling and is essential for cell polarity.


DNA polymerases in precise and predictable CRISPR/Cas9-mediated chromosomal rearrangements.
Recent studies have shown that, owning to its cohesive cleavage, Cas9-mediated CRISPR gene editing outcomes at junctions of chromosomal rearrangements or DNA-fragment editing are precise and predictable; however, the underlying mechanisms are poorly understood due to lack of suitable assay system and analysis tool. Here we developed a customized computer program to take account of staggered or cohesive Cas9 cleavage and to rapidly process large volumes of junctional sequencing reads from chromosomal rearrangements or DNA-fragment editing, including DNA-fragment inversions, duplications, and deletions. We also established a sensitive assay system using HPRT1 and DCK as reporters for cell growth during DNA-fragment editing by Cas9 with dual sgRNAs and found prominent large resections or long deletions at junctions of chromosomal rearrangements. In addition, we found that knockdown of PolQ (encoding Polθ polymerase), which has a prominent role in theta-mediated end joining (TMEJ) or microhomology-mediated end joining (MMEJ), results in increased large resections but decreased small deletions. We also found that the mechanisms for generating small deletions of 1bp and >1bp during DNA-fragment editing are different with regard to their opposite dependencies on Polθ and Polλ (encoded by the PolL gene). Specifically, Polθ suppresses 1bp deletions but promotes >1bp deletions, whereas Polλ promotes 1bp deletions but suppresses >1bp deletions. Finally, we found that Polλ is the main DNA polymerase responsible for fill-in of the 5' overhangs of staggered Cas9 cleavage ends. These findings contribute to our understanding of the molecular mechanisms of CRISPR/Cas9-mediated DNA-fragment editing and have important implications for controllable, precise, and predictable gene editing.


Birth by cesarean section in relation to adult offspring overweight and biomarkers of cardiometabolic risk.
Birth by Cesarean section (C-section) may increase the risk for non-communicable diseases. We aimed to examine the relation of birth by C-section with offspring overweight and markers of cardiometabolic risk in a prospective observational cohort with 20 years of follow-up. The Danish Fetal Origins Cohort enrolled 965 pregnant women in 1988-1989. In 2008, a follow-up study of the offspring was completed. The offspring were invited to participate in a clinical examination with measurements of anthropometry and a fasting blood sample (n=443). In addition, 252 offspring completed a self-administered questionnaire with questions on height and weight, leaving us with a study sample of 695 offspring. Offspring overweight at 20 years was defined as body mass index (BMI)⩾25 kg m-2. We also analyzed blood pressure and fasting blood samples for cardiometabolic risk factors including insulin, leptin and adiponectin, and lipid concentrations. In the cohort, 7% were born by C-section, and at age 20 years, 18% of the offspring had a BMI ⩾25 kg m-2. Birth by C-section was associated with increased odds of overweight or obesity at 20 years (Odds ratio=2.17 (95% confidence interval (CI): 1.10, 4.27)) after adjustment for potential confounders. Birth by C-section was also associated with higher serum concentrations of total cholesterol (8.5%, 95% CI: 1.1-16.5), low-density lipoprotein cholesterol (12.6%, 95% CI: 1.0, 25.5), leptin (73.1%, 95% CI: 5.9, 183.1) and Apolipoprotein B (0.08 g l-1, 95% CI: 0.04, 0.15). In contrast, birth by C-section was not related to blood pressure or serum concentrations of insulin, adiponectin, triglycerides, high-density lipoprotein or Apolipoprotein A. Birth by C-section was associated with higher frequency of dysmetabolic traits in offspring independently of shared risk factors. Further research aimed at replicating these findings and elucidating the underlying biological mechanisms of this relation is needed.


Effects of Coverlys TF150® on the Photosynthetic Characteristics of Grape.
Grape rain-shelter cultivation is a widely employed practice in China. At present, the most commonly used rain shelter film materials are polyvinyl chloride (PVC), polyethylene (PE), ethylene-vinyl acetate copolymer (EVA), and polyolefin (PO). Coverlys TF150® is a woven fabric with an internal antifoggy PE coating that has not yet been popularized as a rain shelter film for grapes in China. To investigate the effects of Coverlys TF150® on grapes, we measured the microdomain environment, leaf development, and photosynthetic characteristics of 'Miguang' (Vitis vinifera × V. labrusca) under rain-shelter cultivation and performed transcriptome analysis. The results showed that Coverlys TF150® significantly reduced (p < 0.05) the light intensity, temperature, and humidity compared with PO film, increased the chlorophyll content and leaf thickness (particularly palisade tissue thickness), and increased stomatal density and stomatal opening from 10:00 to 14:00. Coverlys TF150® was observed to improve the maximum efficiency of photosystem II (Fv/Fm), photochemical quenching (qP), the electron transfer rate (ETR), and the actual photochemical efficiency (ΦPSII) from 10:00 to 14:00. Moreover, the net photosynthetic rate (Pn), intercellular CO2 concentration (Ci), stomatal conductance (Gs), and transpiration rate (Tr) of grape leaves significantly increased (p < 0.05) from 10:00 to 14:00. RNA-Seq analysis of the grape leaves at 8:00, 10:00, and 12:00 revealed 1388, 1562, and 1436 differential genes at these points in time, respectively. KEGG enrichment analysis showed the occurrence of protein processing in the endoplasmic reticulum. Plant hormone signal transduction and plant-pathogen interaction were identified as the metabolic pathways with the highest differential gene expression enrichment. The psbA encoding D1 protein was significantly up-regulated in both CO10vsPO10 and CO12vsPO12, while the sHSPs family genes were significantly down-regulated in all time periods, and thus may play an important role in the maintenance of the photosystem II (PSII) activity in grape leaves under Coverlys TF150®. Compared with PO film, the PSI-related gene psaB was up-regulated, indicating the ability of Coverlys TF150® to better maintain PSI activity. Compared with PO film, the abolic acid receptacle-associated gene PYL1 was down-regulated at all time periods under the Coverlys TF150® treatment, while PP2C47 was significantly up-regulated in CO10vsPO10 and CO12vsPO12, inducing stomatal closure. The results reveal that Coverlys TF150® alleviates the stress of high temperature and strong light compared with PO film, improves the photosynthetic capacity of grape leaves, and reduces the midday depression of photosynthesis.


SciN is an outer membrane lipoprotein required for type VI secretion in enteroaggregative Escherichia coli.
Enteroaggregative Escherichia coli (EAEC) is a pathogen implicated in several infant diarrhea or diarrheal outbreaks in areas of endemicity. Although multiple genes involved in EAEC pathogenesis have been identified, the overall mechanism of virulence is not well understood. Recently, a novel secretion system, called type VI secretion (T6S) system (T6SS), has been identified in EAEC and most animal or plant gram-negative pathogens. T6SSs are multicomponent cell envelope machines responsible for the secretion of at least two putative substrates, Hcp and VgrG. In EAEC, two copies of T6S gene clusters, called sci-1 and sci-2, are present on the pheU pathogenicity island. In this study, we focused our work on the sci-1 gene cluster. The Sci-1 apparatus is probably composed of all, or a subset of, the 21 gene products encoded on the cluster. Among these subunits, some are shared by all T6SSs identified to date, including a ClpV-type AAA(+) ATPase (SciG) and an IcmF (SciS) and an IcmH (SciP) homologue, as well as a putative lipoprotein (SciN). In this study, we demonstrate that sciN is a critical gene necessary for T6S-dependent secretion of the Hcp-like SciD protein and for biofilm formation. We further show that SciN is a lipoprotein, as shown by the inhibition of its processing by globomycin and in vivo labeling with [(3)H]palmitic acid. SciN is tethered to the outer membrane and exposed in the periplasm. Sequestration of SciN at the inner membrane by targeting the +2 residue responsible for lipoprotein localization (Gly2Asp) fails to complement an sciN mutant for SciD secretion and biofilm formation. Together, these results support a model in which SciN is an outer membrane lipoprotein exposed in the periplasm and essential for the Sci-1 apparatus function.


Multifunctionalized polyurethane-polyurea nanoparticles: hydrophobically driven self-stratification at the o/w interface modulates encapsulation stability.
Polyurethane-polyurea (PUUa) reactive prepolymers with adjusted hydrophobic and hydrophilic dangling chains to achieve multiwalled sub-30 nm nanoparticles are presented. The combination of an amphiphilic and a hydrophobic prepolymer at the oil-water interface creates a stratified shell by hydrophobic interactions. These novel nanostructures enhance the encapsulation stability of lipophilic compounds compared to monowalled nanostructures and facilitate the selective and ordered functionalization along the multiwalled shell with bioactive motifs. As proof of concept, PUUa nanoparticles have been engineered with disulfide bonds and an αvβ3 integrin-selective cyclic RGD peptide (cRGDfK) providing our system with glutathione (GSH) triggered controlled release and cell targeting specificity to U87 tumor cells.


Unpredictable visual changes cause temporal memory averaging.
Various factors influence the perceived timing of visual events. Yet, little is known about the ways in which transient visual stimuli affect the estimation of the timing of other visual events. In the present study, we examined how a sudden color change of an object would influence the remembered timing of another transient event. In each trial, subjects saw a green or red disk travel in circular motion. A visual flash (white frame) occurred at random times during the motion sequence. The color of the disk changed either at random times (unpredictable condition), at a fixed time relative to the motion sequence (predictable condition), or it did not change (no-change condition). The subjects' temporal memory of the visual flash in the predictable condition was as veridical as that in the no-change condition. In the unpredictable condition, however, the flash was reported to occur closer to the timing of the color change than actual timing. Thus, an unpredictable visual change distorts the temporal memory of another visual event such that the remembered moment of the event is closer to the timing of the unpredictable visual change.


ACID: Association Correction for Imbalanced Data in GWAS.
Genome-wide association study (GWAS) has been widely witnessed as a powerful tool for revealing suspicious loci from various diseases. However, real world GWAS tasks always suffer from the data imbalance problem of sufficient control samples and limited case samples. This imbalance issue can cause serious biases to the result and thus leads to losses of significance for true causal markers. To tackle this problem, we proposed a computational framework to perform association correction for imbalanced data (ACID) that could potentially improve the performance of GWAS under the imbalance condition. ACID is inspired by the imbalance learning theory but is particularly modified to address the task of association discovery from sequential genomic data. Simulation studies demonstrate ACID can dramatically improve the power of traditional GWAS method on the dataset with severe imbalances. We further applied ACID to two imbalanced datasets (gastric cancer and bladder cancer) to conduct genome wide association analysis. Experimental results indicate that our method has better abilities in identifying suspicious loci than the regression approach and shows consistencies with existing discoveries.


Risk for reassault in abusive female same-sex relationships.
We revised the Danger Assessment to predict reassault in abusive female same-sex relationships. We used focus groups and interviews to evaluate the assessment tool and identify new risk factors and telephone interviews at baseline and at 1-month follow-up to evaluate the revised assessment. The new assessment tool comprised 8 original and 10 new items. Predictors included increase in physical violence (relative risk ratio [RRR]=1.95; 95% confidence interval [CI]=0.84, 4.54), constant jealousy or possessiveness of abuser (RRR = 4.07; 95% CI = 0.61, 27.00), cohabitation (RRR = 1.96; 95% CI = 0.54, 7.12), threats or use of gun by abuser (RRR=1.93; 95% CI=0.79, 4.75), alcoholism or problem drinking of abuser (RRR=1.47; 95% CI=0.79, 2.71), illegal drug use or abuse of prescription medications by abuser (RRR = 1.33; 95% CI = 0.72, 2.46), stalking by abuser (RRR=1.39; 95% CI=0.70, 2.76), failure of individuals to take victim seriously when she sought help (RRR=1.66; 95% CI=0.90, 3.05), victim's fear of reinforcing negative stereotypes (RRR=1.42; 95% CI=0.73, 2.77), and secrecy of abuse (RRR=1.72; 95% CI=0.74, 3.99). Both unweighted (P < .005) and weighted (P < .004) versions of the revised assessment were significant predictors of reassault. The revised Danger Assessment accurately assesses risk of re-assault in abusive female relationships.


[Causes of emotional stress on nurses assisting critically ill children].
This is a pilot study on the causes of emotional stress on 13 nurses working in Pediatric Intensive Care Units. The Author identified, as extrinsic causes, the objectives and the environment of the units, the relations nurse-members of the working team, the family and the children's critical condition; and, as intrinsic causes, the nurses personal conditions and their attitude towards death.


[Spinal cord involvement in Burkitt-type lymphoma: report of a case].
Case report of Burkitt's type lymphoma with involvement of the spinal cord in a three years-old child. An epidural tumoral mass (T11-L1) was removed surgically (Fig. 2), and clinical conditions improved for a short period of time (1 and 1/2 months) after which symptoms reappeared. At this occasion a computerized tomography showed a tumoral mass occupying the spinal canal with high density at the L2 level. The patient died 6 months after the beginning of the disease. General considerations are made on Burkitt's lymphoma.


Myocardial bridge in a child with cardiac arrest and ventricular fibrillation: a bridge over troubled water?
Resuscitated cardiac arrest in a child triggers a comprehensive workup to identify an aetiology and direct management. The presence of a myocardial bridge does not automatically imply causation. Careful determination of the haemodynamic significance of the myocardial bridge is critical to avoid an unnecessary sternotomy and to provide appropriate treatment.


A cocktail of small molecules maintains the stemness and differentiation potential of conjunctival epithelial cells.
The conjunctival epithelial cells cultured with bovine serum or feeder cells were not suitable for clinical application. Therefore, we developed a novel serum-free and feeder cell-free culture system containing only a cocktail of three chemicals (3C) to expand the conjunctival epithelial cells. The cell proliferative ability was evaluated by counting, crystal violet staining and Ki67 immunostaining. Co-staining of K7 and MUC5AC was performed to identify goblet cells. PAS staining was used to assess the ability of cells to synthesis and secrete glycoproteins. In vivo, eye drops containing 3C was administered to verify the role of 3C in the mouse conjunctival injury model. PAS, HE and immunofluorescence staining were performed to show conjunctival epithelial repair. Compared with other small molecule groups and the serum group, the cells in 3C group showed superior morphology and proliferative ability. Meanwhile, 3C maintained the well-proliferative capacity of cells even after fifth passage. The 3C group also exhibited more K7 and MUC5AC double positive cells, and the PAS staining positive areas were present in both the cytoplasm and extracellular matrix. The cell sheets treated with 3C in air-lifted culture were obviously stratified. In vivo, more goblet cells in the conjunctival epithelium were observed in the 3C group. Overall, our culture system can expand the conjunctival epithelial cells and retain their potential to differentiate into mature goblet cells, which provided a promising source of seed cells for conjunctival reconstruction. Furthermore, this system provides new insights for the clinical treatment of ocular surface diseases.


In vitro sensitivity of Hungarian Actinobaculum suis strains to selected antimicrobials.
In vitro antimicrobial sensitivity of 12 Hungarian isolates and the type strain ATCC 33144 of Actinobaculum suis to different antimicrobial compounds was determined both by the agar dilution and by the disc diffusion method. By agar dilution, MIC50 values in the range of 0.05-3.125 micrograms/ml were determined for penicillin, ampicillin, ceftiofur, doxycycline, tylosin, pleuromutilins, chloramphenicol, florfenicol, enrofloxacin and lincomycin. The MIC50 value of oxytetracycline and spectinomycin was 6.25 and 12.5 micrograms/ml, respectively. For ofloxacin, flumequine, neomycin, streptomycin, gentamicin, nalidixic acid, nitrofurantoin and sulphamethoxazole + trimethoprim MIC50 values were in the range of 25-100 micrograms/ml. With the disc diffusion method, all strains were sensitive to penicillin, cephalosporins examined, chloramphenicol and florfenicol, tetracyclines examined, pleuromutilins, lincomycin and tylosin. Variable sensitivity was observed for fluoroquinolones (flumequine, enrofloxacin, ofloxacin), most of the strains were susceptible to marbofloxacin. Almost all strains were resistant to aminoglycosides but most of them were sensitive to spectinomycin. A strong correlation was determined for disc diffusion and MIC results (Spearman's rho 0.789, p < 0001). MIC values of the type strain and MIC50 values of other tested strains did not differ significantly. Few strains showed a partially distinct resistance pattern for erythromycin, lincomycin and ampicillin in both methods.