Generalized multiple kernel learning with data-dependent priors.
Multiple kernel learning (MKL) and classifier ensemble are two mainstream methods for solving learning problems in which some sets of features/views are more informative than others, or the features/views within a given set are inconsistent. In this paper, we first present a novel probabilistic interpretation of MKL such that maximum entropy discrimination with a noninformative prior over multiple views is equivalent to the formulation of MKL. Instead of using the noninformative prior, we introduce a novel data-dependent prior based on an ensemble of kernel predictors, which enhances the prediction performance of MKL by leveraging the merits of the classifier ensemble. With the proposed probabilistic framework of MKL, we propose a hierarchical Bayesian model to learn the proposed data-dependent prior and classification model simultaneously. The resultant problem is convex and other information (e.g., instances with either missing views or missing labels) can be seamlessly incorporated into the data-dependent priors. Furthermore, a variety of existing MKL models can be recovered under the proposed MKL framework and can be readily extended to incorporate these priors. Extensive experiments demonstrate the benefits of our proposed framework in supervised and semisupervised settings, as well as in tasks with partial correspondence among multiple views.


Electronic structures of bent lanthanide(III) complexes with two N-donor ligands.
Low coordinate metal complexes can exhibit superlative physicochemical properties, but this chemistry is challenging for the lanthanides (Ln) due to their tendency to maximize electrostatic contacts in predominantly ionic bonding regimes. Although a handful of Ln2+ complexes with only two monodentate ligands have been isolated, examples in the most common +3 oxidation state have remained elusive due to the greater electrostatic forces of Ln3+ ions. Here, we report bent Ln3+ complexes with two bis(silyl)amide ligands; in the solid state the Yb3+ analogue exhibits a crystal field similar to its three coordinate precursor rather than that expected for an axial system. This unanticipated finding is in opposition to the predicted electronic structure for two-coordinate systems, indicating that geometries can be more important than the Ln ion identity for dictating the magnetic ground states of low coordinate complexes; this is crucial transferable information for the construction of systems with enhanced magnetic properties.


Post-transcriptional regulation of gene expression in innate immunity.
Innate immune responses combat infectious microorganisms by inducing inflammatory responses, antimicrobial pathways and adaptive immunity. Multiple genes within each of these functional categories are coordinately and temporally regulated in response to distinct external stimuli. The substantial potential of these responses to drive pathological inflammation and tissue damage highlights the need for rigorous control of these responses. Although transcriptional control of inflammatory gene expression has been studied extensively, the importance of post-transcriptional regulation of these processes is less well defined. In this Review, we discuss the regulatory mechanisms that occur at the level of mRNA splicing, mRNA polyadenylation, mRNA stability and protein translation, and that have instrumental roles in controlling both the magnitude and duration of the inflammatory response.


1,3-Dimethylamylamine (DMAA) in supplements and geranium products: natural or synthetic?
1,3-Dimethylamylamine (DMAA) is a stimulant existing in various pre-workout supplements and often labelled as part of geranium plants. The safety and origin of DMAA in these supplements is the subject of intense debate. In this study, the enantiomeric and diastereomeric ratios of two different known synthetic DMAA compounds, as well as the total concentrations of DMAA and its stereoisomeric ratios in 13 different supplements, were determined by gas chromatography. The stereoisomeric ratios of DMAA in the synthetic standards and in all the commercial supplements were indistinguishable. Eight different commercial geranium extracts of different geographical origins (China and the Middle East) were examined for the presence of DMAA by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS). No DMAA was detected in any of the eight geranium products with a limit of detection of 10 parts per billion (w/w).


Safe use of radioisotopes.
The use of radioisotopes to label specific molecules in a defined way has greatly furthered the discovery and dissection of biochemical pathways. The development of methods to synthesize such tagged biological compounds inexpensively on an industrial scale has enabled them to be used routinely in laboratory protocols, including many detailed in this manual. Although most of these protocols involve the use of only microcurie amounts of radioactivity, some (particularly those describing the metabolic labeling of proteins or nucleic acids within cells) require amounts on the order of millicuries. In all cases where radioisotopes are used, depending on the quantity and nature of the isotope, certain precautions must be taken to ensure the safety of the scientist. It is essential to use good safety practices and proper protection to handle radioactive substances. This unit discusses handling, storage, and disposal of the isotopes most frequently used in biological research.


A CT-Based Simulation Study to Compare the Risk of Facet Joint Violation by the Cervical Pedicle Screw Between Degenerative and Nondegenerative Cervical Spines.
A retrospective case-control study. This study aimed (A) to compare entry points and trajectories of the cervical pedicle screw (CPS) between degenerative and nondegenerative spines, and (B) to evaluate the risk of facet joint violation by the CPS according to the degree of facet degeneration. Entry point, trajectories, and risk of misplacement of the CPS have been widely researched; however, its application to degenerative cervical spine has to be elucidated. Sixty patients who underwent cervical surgeries at our institution were classified into two groups according to cervical facet joint degeneration. A simulation program with 0.7-mm thickness axial computed tomographic images was used to evaluate facet joint violation by the CPS from C3 to C6. Horizontal and vertical offsets of entry points were measured from two different anatomical landmarks on lateral mass, namely the lateral notch and the center of the superior ridge. The transverse and sagittal angles of the screws were also measured. Facet joint violation was evaluated and classified into either "minor" (<50% of screw diameter) or "major" (≥50% of screw diameter). The mean transverse and sagittal angles showed no difference between the two groups. However, a more superior vertical offset from the superior ridge in terms of entry point was observed in the degenerative cervical spine group at all levels (P = 0.001-0.026). In addition, facet joint violation was more frequently found in severely degenerated facet joints than in mild to moderately degenerated facet joints (P = 0.011). The entry point of CPS was moved more superiorly in the degenerative cervical spine in this study, which increased the risk of facet joint violation in our patients. Thus, surgeons need to modify the insertion technique of the CPS or to insert lateral mass screw instead of the CPS when it is considered to insert screws at the uppermost vertebra in the degenerative cervical spine. 4.


Effect of human stem cells labeled with ferumoxides-poly-L-lysine on hematologic and biochemical measurements in rats.
To determine whether ferumoxides-poly-l-lysine (PLL) complex-labeled mesenchymal stem cells (MSCs) or ferumoxides-PLL complex alone alters hematologic, blood chemistry, renal function, and/or liver function measurements after being intravenously infused into rats. Twenty-five rats (group 1) received intravenous injections of labeled MSCs, and 25 additional rats (group 2) received intravenous injections of ferumoxides-PLL complex only. Complete blood counts, liver and renal function test results, and serum electrolyte and iron concentrations were measured for 42 days after the injections and compared with those measured in five control rats (group 3). To determine the duration of labeled MSCs in the circulation, venous blood was serially drawn from five additional rats (group 4) that were injected with labeled MSCs. Analyses of variance (ANOVA) followed by Fisher protected least significant difference post hoc tests were used to statistically analyze results. P < .05 was considered to indicate significance in all analyses. Administration of neither labeled MSCs nor ferumoxides-PLL complex had a significant effect on hematologic or blood chemistry indicators of organ function. Of the parameters measured, only hemoglobin concentration and mean corpuscular volume (MCV) in the rats injected with labeled MSCs, as well as MCV and hemoglobin, alkaline phosphatase, aspartate aminotransferase, and direct bilirubin concentrations in the rats injected with ferumoxides-PLL complex, varied significantly during the 42-day postinjection period (P < .05, ANOVA). No other measurements, including serum electrolyte and iron concentrations, changed significantly during the test period (P > .05). Furthermore, injected labeled MSCs had cleared from the peripheral circulation by 15 minutes after injection. Results indicate that infusing cells that are magnetically labeled with ferumoxides-PLL complex into rats does not alter biochemical or hematologic measures of organ function in a clinically relevant or preclusive manner.


Effect of inactivation of carotid sinus nerve by cold block on phrenic nerve activity in cats.
The effect of the elimination of input via the carotid chemoreceptor on respiratory output was examined quantitatively in anesthetized, vagotomized, and paralyzed cats. The integrated phrenic nerve activity (PNA) was recorded as an indication of output of the respiratory center. Also, the elimination of the carotid chemoreflex drive was repeatedly done by a cold block of the carotid sinus nerve at various PCO2 levels during hyperoxia, normoxia, and hypoxia. The blockade induced a reduction in PNA at each PCO2 level in every PO2 group. If the highest PNA value recorded at a high PCO2 in each PO2 condition was assigned a value of 100%, the reduction of the PNA by the blockade, i.e., the respiratory effect of the carotid chemoreflex drive, would be slightly larger during normoxia (16%) than during hyperoxia (8.7%), but would be independent of PCO2. During hypoxia, this chemoreflex effect was about 40% of a low PCO2, and decreased with increments of PCO2, finally reaching about 20% of a high PCO2 level. Furthermore, the relative contribution of the carotid chemoreceptor to respiratory output, expressed as the ratio of the PNA reduction during blockade to the PNA before blockade, was inversely proportional to both PO2 and PCO2. It is concluded that the interaction of the peripheral and central chemoreceptor drive is hypoadditive at moderate and high PCO2 levels in anesthetized cats, and this interaction is emphasized by central hypoxia.


Establishment and validation of symptomatic patients colorectal screening score for predicting colorectal neoplasia risk.
Currently, most colorectal neoplasia (CRN) screening strategies target asymptomatic individuals. However, studies on patients with non-specific gastrointestinal symptoms (NSGS) are limited. We aimed to develop a CRN risk score specifically for patients with NSGS. We prospectively enrolled patients who underwent initial colonoscopy between June 2020 and June 2021. A new risk scoring system was constructed and its applicability was evaluated. A total of 1522 consecutive patients were enrolled, among whom 1016 symptomatic patients were randomly divided into a training cohort and a validation cohort at a ratio of 7:3. The constructed Symptomatic Patients Colorectal Screening (SPCS) score showed higher diagnostic efficacy and sensitivity than several previous scoring systems. Using the SPCS score, the patients were divided into a low-risk group (-2 to 3 points) and a high-risk group (4-10 points) for CRN. Additionally, the detection rate of CRN in the training and validation cohorts of the high-risk group were 41.7% and 37.0%, respectively. The SPCS score detected 79.3% (188/237) of CRN and 87.5% (42/48) of advanced CRN in the high-risk group, which reduced the workload of colonoscopy to 45.9% (466/1016). An effective CRN risk scoring system was established and validated for symptomatic patients, which accurately classified individuals into low-risk and high-risk groups for CRN and might be used to optimize colonoscopic resource allocation.


First Direct Measurement Constraining the ^{34}Ar(α,p)^{37}K Reaction Cross Section for Mixed Hydrogen and Helium Burning in Accreting Neutron Stars.
The rate of the final step in the astrophysical αp process, the ^{34}Ar(α,p)^{37}K reaction, suffers from large uncertainties due to a lack of experimental data, despite having a considerable impact on the observable light curves of x-ray bursts and the composition of the ashes of hydrogen and helium burning on accreting neutron stars. We present the first direct measurement constraining the ^{34}Ar(α,p)^{37}K reaction cross section, using the Jet Experiments in Nuclear Structure and Astrophysics gas jet target. The combined cross section for the ^{34}Ar,Cl(α,p)^{37}K,Ar reaction is found to agree well with Hauser-Feshbach predictions. The ^{34}Ar(α,2p)^{36}Ar cross section, which can be exclusively attributed to the ^{34}Ar beam component, also agrees to within the typical uncertainties quoted for statistical models. This indicates the applicability of the statistical model for predicting astrophysical (α,p) reaction rates in this part of the αp process, in contrast to earlier findings from indirect reaction studies indicating orders-of-magnitude discrepancies. This removes a significant uncertainty in models of hydrogen and helium burning on accreting neutron stars.


Medical jurisprudence in the local context.
Medical jurisprudence in the local context would require the examination of a wide area. This paper focuses on liability producing conduct arising from the providing of medical services, other than liability for criminal negligent conduct. It examines the circumstances in which the physician-patient relationship emerges, in medical jurisprudence as against practice by medical practitioners. Tort law is the dominant legal theory, and reference is made to some intentional and miscellaneous torts. Implied contracts creating the relationship are touched upon, besides the reference to vicarious liability. Insanity and diminished responsibility in the criminal law, particularly the issue of whether the status quo is satisfactory and reliance on medical reports for purposes of treatment under drug laws are examined. Where abortion is performed, the question whether the husband has any right to prevent his wife from having a lawful abortion is discussed in the local context. Some thoughts on the medical (therapy, education and research) Act 1972 are expressed in relation to the living body, the corpse and the parts of the human body. The patient's right to determination and information in the light of the above legislation is also discussed.


Caveolae promote successful abscission by controlling intercellular bridge tension during cytokinesis.
During cytokinesis, the intercellular bridge (ICB) connecting the daughter cells experiences pulling forces, which delay abscission by preventing the assembly of the ESCRT scission machinery. Abscission is thus triggered by tension release, but how ICB tension is controlled is unknown. Here, we report that caveolae, which are known to regulate membrane tension upon mechanical stress in interphase cells, are located at the midbody, at the abscission site, and at the ICB/cell interface in dividing cells. Functionally, the loss of caveolae delays ESCRT-III recruitment during cytokinesis and impairs abscission. This is the consequence of a twofold increase of ICB tension measured by laser ablation, associated with a local increase in myosin II activity at the ICB/cell interface. We thus propose that caveolae buffer membrane tension and limit contractibility at the ICB to promote ESCRT-III assembly and cytokinetic abscission. Together, this work reveals an unexpected connection between caveolae and the ESCRT machinery and the first role of caveolae in cell division.


Molecular origins of pediatric embryonal tumors.
The different but distinctly related lines of investigation discussed during this workshop are likely to provide important insights into the molecular events that initiate and mediate the oncogenic process. Pediatric embryonal tumors were the first malignancies in which chemotherapeutic responses were recognized, and they have been singularly important clinical models for the development of many important principles of cancer treatment. Judging from the emerging insights into the pathogenesis of these tumors, it seems likely that they will also serve as important models for designing novel approaches to cancer treatment.


Perceptual Learning in Children With Infantile Nystagmus: Effects on Visual Performance.
To evaluate whether computerized training with a crowded or uncrowded letter-discrimination task reduces visual impairment (VI) in 6- to 11-year-old children with infantile nystagmus (IN) who suffer from increased foveal crowding, reduced visual acuity, and reduced stereopsis. Thirty-six children with IN were included. Eighteen had idiopathic IN and 18 had oculocutaneous albinism. These children were divided in two training groups matched on age and diagnosis: a crowded training group (n = 18) and an uncrowded training group (n = 18). Training occurred two times per week during 5 weeks (3500 trials per training). Eleven age-matched children with normal vision were included to assess baseline differences in task performance and test-retest learning. Main outcome measures were task-specific performance, distance and near visual acuity (DVA and NVA), intensity and extent of (foveal) crowding at 5 m and 40 cm, and stereopsis. Training resulted in task-specific improvements. Both training groups also showed uncrowded and crowded DVA improvements (0.10 ± 0.02 and 0.11 ± 0.02 logMAR) and improved stereopsis (670 ± 249″). Crowded NVA improved only in the crowded training group (0.15 ± 0.02 logMAR), which was also the only group showing a reduction in near crowding intensity (0.08 ± 0.03 logMAR). Effects were not due to test-retest learning. Perceptual learning with or without distractors reduces the extent of crowding and improves visual acuity in children with IN. Training with distractors improves near vision more than training with single optotypes. Perceptual learning also transfers to DVA and NVA under uncrowded and crowded conditions and even stereopsis. Learning curves indicated that improvements may be larger after longer training.


Management of Dyslipidemia in Individuals with Low-to-Moderate Cardiovascular Risk: Role of Nutraceuticals.
Cardiovascular diseases (CVDs) are the leading cause of premature deaths globally and in Ukraine. Dyslipidemia is a recognized risk factor for the development of CVD. Therefore, early detection and appropriate management of dyslipidemia are essential for the primary prevention of CVDs. However, currently, there is a lack of Ukraine-specific guideline recommendations focusing on the management of dyslipidemia in individuals with low-to-moderate CV risk, thus creating an urgent need for structured and easily implementable clinical recommendations/guidelines specific to the country. An expert panel of cardiologists, endocrinologists, and family physicians convened in Ukraine in March 2019. The expert panel critically reviewed and analyzed the current literature and put forth the following recommendations for the management of dyslipidemia in individuals with low-to-moderate risk of CVDs specific to Ukraine: (1) family physicians have the greatest opportunities in carrying out primary prevention; (2) lipid-lowering interventions are essential for primary prevention as per guidelines; (3) a number of nutraceuticals and nutraceutical combinations with clinically established lipid-lowering properties can be considered for primary prevention; they also have a suggested role as an alternative therapy for statin-intolerant patients; (4) on the basis of clinical evidence, nutraceuticals are suggested by guidelines for primary prevention; (5) red yeast rice has potent CV-risk-lowering potential, in addition to lipid-lowering properties; (6) in patients with low-to-moderate cardiovascular risk, a nutraceutical combination of low-dose red yeast rice and synergic lipid-lowering compounds can be used as integral part of guideline-recommended lifestyle interventions for effective primary prevention strategy; (7) nutraceutical combination can be used in patients aged 18 to 75+ years; its use is particularly appropriate in the age group of 18-44 years; (8) it is necessary to attract the media (websites, etc.) to increase patient awareness on the importance of primary prevention; and (9) it is necessary to legally separate nutraceuticals from dietary supplements. These consensus recommendations will help physicians in Ukraine effectively manage dyslipidemia in individuals with low-to-moderate CV risk.


Hypermucoviscosity as a virulence factor in experimental Klebsiella pneumoniae endophthalmitis.
Klebsiella pneumoniae is a common cause of endogenous bacterial endophthalmitis, a disease that frequently results in a poor visual outcome. Hypermucoviscosity has been identified as a virulence factor among clinical bacteremia isolates of K. pneumoniae. In this study, an experimental murine model of K. pneumoniae endophthalmitis was established, and the role of hypermucoviscosity in its pathogenesis was analyzed. C57BL/6J mice were intravitreously injected with 100 CFU of hypermucoviscous (HMV+) or nonhypermucoviscous (HMV-) K. pneumoniae. Intraocular bacterial growth, retinal function, gross pathology, and inflammatory responses were monitored every 3 hours until the eyes lost significant (>90%) retinal function, or the infection appeared to clear. The HMV+ strain grew logarithmically in eyes until approximately 15 hours postinfection (PI), reaching a stationary phase of growth at approximately 8.0 log(10) CFU/eye. The HMV- strain grew logarithmically to approximately 7.6 log(10) by 18 hours, but bacterial count declined to approximately 6.4 log(10) CFU/eye by 21 hours PI. Eyes infected with the HMV+ strain retained approximately 35% a-wave and <10% b-wave function by 18 hours PI. These eyes also had a cumulative clinical score of 14+ by 18 hours and underwent phthisis between 21 and 24 hours. Eyes infected with the HMV- strain had a cumulative clinical score of <6 and retained >60% a-wave and >50% b-wave function throughout 21 hours. Five of 7 eyes had <100 CFU HMV- K. pneumoniae at 27 hours PI. The findings demonstrate the site-threatening consequences of K. pneumoniae endophthalmitis and the importance of the hypermucoviscosity phenotype in the pathogenesis of experimental K. pneumoniae endophthalmitis.


Molecular and cellular characterization of a Salmonella enterica serovar Paratyphi a outbreak strain and the human immune response to infection.
Enteric fever is an invasive life-threatening systemic disease caused by the Salmonella enterica human-adapted serovars Typhi and Paratyphi. Increasing incidence of infections with Salmonella enterica serovar Paratyphi A and the spreading of its antibiotic-resistant derivates pose a significant health concern in some areas of the world. Herein, we describe a molecular and phenotypic characterization of an S. Paratyphi A strain accounted for a recent paratyphoid outbreak in Nepal that affected at least 37 travelers. Pulsed-field gel electrophoresis analysis of the outbreak isolates revealed one genetic clone (pulsotype), confirming a single infecting source. Genetic profiling of the outbreak strain demonstrated the contribution of specific bacteriophages as a prime source of genetic diversity among clinical isolates of S. Paratyphi A. Phenotypic characterization in comparison with the S. Paratyphi A ATCC 9150 reference sequenced strain showed differences in flagellar morphology and increased abilities of the outbreak strain with respect to its motility, invasion into nonphagocytic cells, intracellular multiplication, survival within macrophages, and higher induction of interleukin-8 (IL-8) secreted by host cells. Collectively, these differences suggest an enhanced virulence potential of this strain and demonstrate an interesting phenotypic variation among S. Paratyphi A isolates. In vivo profiling of 16 inflammatory cytokines in patients infected with the outbreak strain revealed a common profile of a remarkable gamma interferon (IFN-γ) induction together with elevated concentrations of tumor necrosis factor alpha (TNF-α), IL-6, IL-8, IL-10, and IL-15, but not IL-12, which was previously demonstrated as elevated in nontyphoidal Salmonella infections. This apparent profile implies a distinct immune response to paratyphoid infections.


Examining the effects of school-based drug prevention programs on drug use in rural settings: methodology and initial findings.
Although there have been substantial advances in knowledge about drug prevention over the last decade, the majority of school-based drug prevention studies have been conducted in urban settings. There is little knowledge about the effectiveness of such programs when they are implemented in rural populations. To examine the prevention effects of school-based drug prevention programs implemented in rural populations. Mixed model or 2-level meta-analysis of trials based on school-based drug prevention programs that included rural populations. A total of 182 trials were coded for urbanicity of schools and 22 separate trials were selected for the analysis conducted in this paper. A total of 435 distinct analyses were examined from these 22 trials. We found a modest but consistent beneficial impact of drug prevention programs on later use as well as level of use. Regarding later drug use, the largest impact was on those who were not using at baseline and those exposed to an interactive program; the results were much larger for marijuana and other drugs compared to alcohol or tobacco, while inhalant use was less affected than other drug categories. Regarding level of use, the impact was greatest 6 months after the trial ended, with diminishing effects thereafter. Evidence exists for a small but systematic beneficial effect of drug prevention programs in rural settings. It is likely that these programs have produced a mild reduction in new use of substances but have had little impact on those already using substances.


Occurrence of Nontuberculous Mycobacteria, Salmonella, Listeria monocytogenes, and Staphylococcus aureus in Artisanal Unpasteurized Cheeses in the State of Michoacan, Mexico.
This study investigated the presence of nontuberculous mycobacteria (NTM) for the first time in two types of unpasteurized fresh cheese produced in the state of Michoacan, Mexico. We tested for this pathogen, along with the others, to broaden the study of microbiological quality in 60 samples of cheese, 30 fresh and 30 Adobera, which were collected from six artisanal cheese factories (ACFs). The hygienic conditions of these establishments and the practices of cheese manufacture were generally poor. Although Mycobacterium bovis was not detected, four cheese samples harbored NTM isolates. The four NTM isolates were identified using three molecular markers (hsp65, rrs, and rpoB genes) that corresponded to Mycolicibacterium fortuitum (n = 3) and Mycolicibacterium mageritense (n = 1). All 60 cheese samples analyzed had unsatisfactory microbiological quality according to the Mexican Official Guideline. Regarding fresh cheeses, all 30 samples analyzed were positive for aerobic mesophilic bacteria, total coliforms, fecal coliforms, and yeasts and molds. Escherichia coli and Staphylococcus aureus were present in 23 and 21 samples, respectively. Listeria monocytogenes was identified in a sample and was isolated from a bulk milk tank in the same ACF. With regard to Adobera cheeses, all samples were positive for aerobic mesophilic bacteria, total coliforms, fecal coliforms, yeasts and molds, and S. aureus. E. coli was isolated from 28 samples. Salmonella was isolated from a sample and from a wooden shovel used in the manufacture of the cheeses in the same ACF. Thus, the consumption of unpasteurized fresh cheese may represent a public health risk. Because of this, health authorities should enforce the legislation that forbids the processing of cheese with unpasteurized milk and encourage producers to follow good manufacturing practices from original ingredients, through the production process of the cheese, to its sale to assure a safe product.


Signaling individual identity versus quality: a model and case studies with ruffs, queleas, and house finches.
We develop an evolutionary model that predicts that characters selected to signal individual identity will have properties differing from those expected for indicator signals of quality. Traits signaling identity should be highly variable, often display polymodal distributions, not be condition dependent (i.e., be cheap to produce and/or maintain), not be associated with fitness differences, exhibit independent assortment of component characters, and often occur as fixed phenotypes with a high degree of genetic determination. We illustrate the existence of traits with precisely these attributes in the ornamental, conspicuously variable, and sexually dimorphic breeding plumages of ruff sandpipers Philomachus pugnax and red-billed queleas Quelea quelea. Although ruffs lek and queleas are monogamous, both species breed in high-density aggregations with high rates of social interactions (e.g., aggression and territory defense). Under these socioecological conditions, individual recognition based on visual cues may be unusually important. In contrast to these species, we also review plumage characteristics in house finches Carpodacus mexicanus, a nonterritorial, dispersed-breeding species in which plumage ornamentation is thought to signal quality. In keeping with expectations for quality signals, house finch plumage is relatively less variable, unimodally distributed, condition dependent, correlated with fitness measures, has positively correlated component characters, and is a plastic, environmentally determined trait. We briefly discuss signals of identity in other animals.


Performance of self-reported measures for periodontitis in rheumatoid arthritis and osteoarthritis.
This study evaluates the performance of self-report against the reference standard of clinically defined periodontitis in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) after accounting for factors associated with periodontitis. Six self-report periodontitis questions were evaluated in patients with RA and OA. Questions were validated against a reference standard of severe and moderate-to-severe periodontitis based on full-mouth examination. Multivariable logistic regression was used to evaluate the performance of: 1) self-report alone; 2) age, sex, education, and smoking status; and 3) a combination of the above. Model performance was assessed using the c-statistic. Convergent validity of self-reported "bone loss/deep pockets" and "loose teeth" was assessed; associations of self-report with RA disease characteristics were explored. Self-report performed similarly in RA and OA, with individual question specificity for periodontitis ≥ 68% and sensitivity from 9.8% to 45%. Question-only models yielded c-statistics of 0.66 to 0.72, whereas risk factor-only models yielded c-statistics of 0.74 to 0.79. The highest-performing models incorporated both self-report questions and periodontitis risk factors, with c-statistics ≥ 0.79. Greater radiographic alveolar bone loss was observed among participants reporting "bone loss/deep pockets" (P < 0.001) and "loose teeth" (P < 0.001). Among patients with RA, "loose teeth," but not other self-report items, was associated with rheumatoid factor positivity (P = 0.047) and higher disease activity (P < 0.001). Patient self-report, when combined with other risk factors, performs well in identifying periodontitis among patients with RA and OA. Self-report questions related to alveolar bone loss exhibit excellent convergent validity in these patient subsets.


The tree-buttress biotope: a pathobiocenose of Leishmania braziliensis.
A total of 52,033 sandflies, comprising 33 species, was collected in tree buttresses in Panama. Of the 18,025 females collected, 1,592 (8.8%) engorged phlebotomines of 18 species contained sufficient blood for identification of their vertebrate hosts by the microcapillary precipitin method. Lutzomyia ylephiletor and Lu. trapidoi, vectors of Leishmania braziliensis, had fed predominantly on sloths (47.0% and 65.1%, respectively). Lutzomyia shannoni, a common non-anthropophilic sandfly in tree buttresses also fed most frequently on sloths (28.0%) and probably also contributes to the Leishmania transmission cycle among the edentates. Two-toed sloths (Choloepus hoffmanni), the principal reservoir of L. braziliensis in Panama, cohabit the same arboreal bioptope with these sandfly species. Leishmania braziliensis was isolated in culture from 14 of 68 (20.6%) C. hoffmanni captured in the study sites during the period of this investigation. The data illustrate that the butrresses of large trees in Panama represent potential pathobiocenose bioptopes of L. braziliensis. Other sandfly species tested for host-feeding sources included: Lu. trinidadensis, which fed preferentially on reptiles; Lu. triramula, Lu. ovallesi, and Lu. camposi fed most frequently on armadillos. The hosts of 11 additional sandfly species were identified; however, the numbers recorded were too small to discern distinct feeding patterns among the phlebotomines.


Usefulness of Contrast-enhanced Ultrasound in the Evaluation of Chronic Kidney Disease.
Contrast-enhanced ultrasound (CEUS) can provide more improved images of renal blood flow and much more information of both macro- and microcirculation of the kidney as compared to Doppler US. To investigate the usefulness of CEUS by analyzing differences in perfusion-related parameters among the three chronic kidney disease (CKD) subgroups and the control group. Thirty-eight patients with CKD and 21 controls who were age-matched (20-49 years) were included. Included CKD patients were stratified into three groups according to their eGFR: group I, eGFR ≥ 60 ml/min/1.73 m2 (GFR category I and II); group II, 30 ml/min/1.73 m2 ≤ eGFR < 60 ml/min/1.73 m2 (GFR category III); and group III, eGFR < 30 ml/min/1.73 m2 (GFR category IV and V). Comparisons with the controls (eGFR > 90 ml/min/1.73 m2) were performed. Real-time and dynamic renal cortex imaging was performed using CEUS. Time-intensity curves and several bolus model quantitative perfusion parameters were created using the VueBox® quantification software. We compared the parameters among the CKD subgroups and between the CKD and control groups. Eight patients were included in group I, 12 patients in group II, and 18 patients in group III. Significant differences were noted in the wash-in and wash-out rates between the CKD and control groups (p = 0.027 and p = 0.018, respectively), but not between those of the CKD subgroups. There were no significant differences of other perfusion parameters among the CKD subgroups and between the CKD and control groups. A few perfusion related CEUS parameters (WiR and WoR) can be used as markers of renal microvascular perfusion relating renal function. CEUS can effectively and quantitatively exhibit the renal microvascular perfusion in patients with CKD as well as normal control participants.


Jones matrix formalism for the theory of picosecond shear acoustic pulse detection.
A theoretical analysis of the transient optical reflectivity of a sample by a normalized Jones matrix is presented. The off-diagonal components of the normalized matrix are identified with the complex rotation of the polarization ellipse. Transient optical polarimetry is a relevant technique to detect shear acoustic strain pulses propagating normally to the surface of an optically isotropic sample. Moreover, polarimetry has a selective sensitivity to shear waves, as this technique cannot detect longitudinal waves that propagate normally to the sample surface.


Characterisation of testicular function and spermatogenesis in transgender women.
Does gender-affirming treatment prevent full spermatogenesis in transgender women (TW)? Adequate hormonal therapy (HT) leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. Gender-affirming treatment in transgender individuals may involve gender-affirming HT. The effects on spermatogenesis in TW remain unclear. In order to add information from a referral centre for transgender care, we wish to compare results of earlier studies with our population of TW who received a standard hormone treatment. This was a prospective cohort study part of the European Network for the Investigation of Gender Incongruence (ENIGI), conducted between 15 February 2010 and 30 September 2015. There were 162 TW were included in the ENIGI study at the Ghent University Hospital in Belgium. Participants are included in ENIGI when they first start HT, and follow-up visits occur over the next 3 years. The study included 97 TW who initiated HT with cyproterone acetate (CPA) plus oestrogens and proceeded with gonadectomy at the Ghent University Hospital. Testicular tissue retrieved during gonadectomy was processed and stained for four different germ cell markers by the Biology of the Testis lab at the Vrije Universiteit Brussel. Subsequent immunohistochemical staining was performed for melanoma-associated antigen A4 (MAGE-A4, marker for spermatogonia and early spermatocytes), boule homologue, RNA-binding protein (BOLL, marker for secondary spermatocytes and round spermatids), cAMP-responsive element modulator (CREM, marker for round spermatids) and acrosin (marker for acrosome visualization). Serum levels of sex steroids were measured prior to surgery. Suppressed testosterone levels (<50 ng/dl) were found in 92% of the participants prior to surgery. The mean time between initiation of HT and surgery was 685 days. In 88% (85/97) of the sections, MAGE-A4 staining was positive. Further staining could not reveal complete spermatogenesis in any participant. Testicular function of the participants prior to initiation of HT was not assessed, although all participants presented with cisgender male serum testosterone values before initiation of HT. The current study only reports on people using CPA at a fixed dose and may therefore not be applicable to all TW. HT leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. Serum testosterone levels are associated with the sperm maturation rate. It is important to discuss sperm preservation before the start of hormone therapy. If serum testosterone levels remain higher, spermatogenesis may still occur. D.V.S. is a post-doctoral fellow of the Fonds Wetenschappelijk Onderzoek (FWO; 12M2819N). Processing of the testis specimens was funded by the Biology of The Testes (BITE) research group (Department of Reproduction, Genetics and Regenerative medicine at Vrije Universiteit Brussel (VUB)). There are no competing interests. N/A.


Antioxidant enzymes activity and lipid peroxidation in liver and kidney of rats exposed to cadmium and ethanol.
The oxidative status of liver and kidney of rats co-exposed to cadmium (50 mg Cd/l in drinking water) and ethanol (5 g EtOH/kg body weight/24 h, intragastrically) for 12 weeks was studied. The activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) as well as the concentration of malondialdehyde (MDA), as an indicator of lipid peroxidation, were measured in homogenates of the liver and kidney. Concentrations of zinc (Zn), copper (Cu), iron (Fe) and Cd in the serum or blood, and their content in the liver and kidney as well as EtOH concentration in the whole blood were assayed. Daily Cd intake in the Cd and Cd+EtOH groups was similar and ranged from 2.39 to 4.88 mg/kg body weight/24 h and from 2.64 to 4.14 mg/kg body weight/24 h, respectively. After the administration of EtOH alone, the activity of SOD increased in the kidney and decreased in the liver, whereas the activity of CAT decreased in both these organs, and MDA concentration increased in the liver and was unchanged in the kidney. The exposure to 50 mg Cd/l led to a decrease in the activities of SOD in the liver and CAT in the liver and kidney, and an increase in the kidney activity of SOD and MDA concentration in both these organs. In the rats co-exposed to Cd and EtOH, the kidney activity of SOD and the liver concentration of MDA were lower, whereas the kidney activity of CAT was higher compared to the Cd group. The concentration of Fe in the serum and its content in the liver of rats treated with EtOH increased, whereas the concentrations of Zn and Cu in the serum and the content of Zn, Cu and Fe in the kidney and that of Zn and Cu in the liver were unchanged. In the liver and kidney of rats treated with Cd alone, the content of Fe was decreased and that of Zn and Cu was enhanced. After EtOH administration to Cd-exposed rats, a decrease in Cu serum concentration and its liver content and an increase in Fe concentration in the serum and its content in the liver and kidney, compared to the group exposed to Cd alone, were noted. Moreover, EtOH decreased the blood Cd concentration and its accumulation in the liver and kidney of these animals. EtOH alone decreased Cd content in the liver and increased in the kidney, however the whole content of Cd in these organs was unchanged compared with control. The results of this study indicate that despite the ability of Cd and EtOH to induce the oxidative stress the effect in the liver and kidney is not intensified at simultaneous exposure to both substances. The changes in the studied indicators of oxidative stress (SOD, CAT and MDA) observed in the kidney and especially in the liver of the rats co-exposed to Cd and EtOH may result from an independent effect of Cd and/or EtOH and also from their interaction. The interactive effect may involve, among others, changes in Cd accumulation and content of Zn, Cu and Fe in these organs and their concentration in serum. Since the rats treated with Cd and Cd+EtOH had reduced drinking fluids intake that might result in dehydratation, the effect of the both xenobiotics on the oxidative status of the body may be not solely due to Cd and/or EtOH, but also the modyfing influence of accompanying alterations such as reduced water intake and dehydratation. The results of the study allow us to hypothesize that Cd-exposed alcohol misusers are not at enhanced risk of liver and kidney damage due to lipid peroxidation.


Using GIS technology to identify areas of tuberculosis transmission and incidence.
BACKGROUND: Currently in the U.S. it is recommended that tuberculosis screening and treatment programs be targeted at high-risk populations. While a strategy of targeted testing and treatment of persons most likely to develop tuberculosis is attractive, it is uncertain how best to accomplish this goal. In this study we seek to identify geographical areas where on-going tuberculosis transmission is occurring by linking Geographic Information Systems (GIS) technology with molecular surveillance. METHODS: This cross-sectional analysis was performed on data collected on persons newly diagnosed with culture positive tuberculosis at the Tarrant County Health Department (TCHD) between January 1, 1993 and December 31, 2000. Clinical isolates were molecularly characterized using IS6110-based RFLP analysis and spoligotyping methods to identify patients infected with the same strain. Residential addresses at the time of diagnosis of tuberculosis were geocoded and mapped according to strain characterization. Generalized estimating equations (GEE) analysis models were used to identify risk factors involved in clustering. RESULTS: Evaluation of the spatial distribution of cases within zip-code boundaries identified distinct areas of geographical distribution of same strain disease. We identified these geographical areas as having increased likelihood of on-going transmission. Based on this evidence we plan to perform geographically based screening and treatment programs. CONCLUSION: Using GIS analysis combined with molecular epidemiological surveillance may be an effective method for identifying instances of local transmission. These methods can be used to enhance targeted screening and control efforts, with the goal of interruption of disease transmission and ultimately incidence reduction.


Coexistence of Kaposi's sarcoma and psoriasis: is there a hidden relationship?
The relationship between Kaposi's sarcoma (KS) and psoriasis is still controversial. To analyse the association between KS and psoriasis, address the hypothesis of a reciprocal influence between the two conditions relative to clinical presentation and evolution, and consider the best therapeutic approach to be used for the treatment of psoriasis in KS patients in order to avoid the typical induction or worsening of KS during immunosuppression. We retrospectively reviewed clinical records of 37 patients with KS and psoriasis. Fisher's exact test was performed in order to compare epidemiological and clinical data between subsets of patients. The prevalence of psoriasis in our KS population (n = 1407) was 2.6%. There were no statistically significant differences in terms of stage or rate of progression between KS patients with and without psoriasis, except for a higher frequency of patients with KS Stage IIB among patients with KS and psoriasis (p = 0.001). Patients with psoriasis have a risk of KS comparable to that of the general population. Psoriasis and KS do not appear to influence each other. For the treatment of psoriasis in KS patients, one should take into account the KS-inducing potential of certain anti-psoriatic drugs.


Childhood sexual abuse and psychosis: aetiology and mechanism.
The aim of this Editorial is to describe the association between child sexual abuse and psychosis, and to consider potential mechanisms for the association. The association is strongly supported by the literature. Evidence from a variety of sources is triangulated in order to create a plausible model of the link, which can then be used to direct future research. The mechanisms are certainly complex, and there is evidence of interacting contributions at genetic, neurophysiological, behavioural, cognitive and emotional levels. Child sexual abuse is an important antecedent in psychosis, both theoretically and clinically. At the theoretical level, it potentially illuminates mechanisms by which psychotic symptoms are generated, at the clinical level it opens possibilities for improving cognitive-behavioural approaches to treatment.


Random Number Generation in HIV Disease: Associations with Neuropsychological Functions and Activities of Daily Living.
HIV is associated with frontostriatal dysregulation and executive dysfunction. This study evaluated whether HIV-infected individuals evidence deficits in random number generation (RNG), which is a strategic task requiring paced, rule-guided production of digits. In total, 74 HIV+ adults and 54 seronegative comparison participants completed a comprehensive research neuropsychological battery. Participants produced a random digit sequence by avoiding any order and using numbers 1 through 10 for 100 s at a pace of 1 digit/s. Outcomes included intrusions, repetitions, seriation (1-2-3-4), and cycling (median length of gaps between repeating digits). HIV disease was associated with higher levels of seriation and cycling (ps < .05) but not intrusions or repetitions (ps > .10). Among HIV+ individuals, higher seriation was associated with neuropsychological performance including poorer auditory attention, verbal learning, and delayed memory, whereas higher cycling scores were associated with poorer delayed memory and verbal fluency (ps < .05). Higher seriation also was independently associated with self-reported declines in activities of daily living (ADLs) in the HIV+ group. Individuals living with HIV disease evidence moderate difficulties in inhibiting statistically unlikely non-random sequences, which showed medium associations with higher order verbal abilities and may contribute to greater declines in everyday functioning outcomes. Future studies might examine RNG's role in health behaviors such as medical decision-making or medication adherence.


Infliximab improves quality of life in the short-term in patients with fistulizing Crohn's disease in clinical practice.
To assess the effect of infliximab on quality of life in a series of patients with fistulizing Crohn's disease. A prospective observational study was made. A total of 25 patients with single or multiple draining abdominal or perianal fistulas were selected for the study. All received an intravenous infusion of infliximab at a dose of 5 mg per kilogram of body weight in weeks 0, 2, and 6. The clinical activity was calculated every two weeks over a 10-week follow-up. HRQOL (SF-36 and IBDQ scores) were compared at baseline and at weeks 4 and 10. Sixty-four percent of patients had a clinical response to treatment with infliximab, with complete closure of fistulas. The mean values of CDAI decreased during follow-up, with a significant difference between weeks 0 and 10 (p < 0.01). Health-related quality of life (HRQOL), as measured by means of SF-36, showed an overall improvement in the physical domain (PCS) after 4 and 10 weeks (p < 0.05). An increase was also observed in IBDQ overall score on comparing the results obtained at week 0 and week 4 (p < 0.01). The social functioning domain of IBDQ was not significantly changed with treatment. Treatment with infliximab in active fistulizing Crohn's disease results in a significant increase in the quality of life of patients at short-term.


CRISPR/Cas9 searches for a protospacer adjacent motif by lateral diffusion.
The Streptococcus pyogenes CRISPR/Cas9 (SpCas9) nuclease has been widely applied in genetic engineering. Despite its importance in genome editing, aspects of the precise molecular mechanism of Cas9 activity remain ambiguous. In particular, because of the lack of a method with high spatio-temporal resolution, transient interactions between Cas9 and DNA could not be reliably investigated. It therefore remains controversial how Cas9 searches for protospacer adjacent motif (PAM) sequences. We have developed single-molecule Förster resonance energy transfer (smFRET) assays to monitor transient interactions of Cas9 and DNA in real time. Our study shows that Cas9 interacts with the PAM sequence weakly, yet probing neighboring sequences via facilitated diffusion. This dynamic mode of interactions leads to translocation of Cas9 to another PAM nearby and consequently an on-target sequence. We propose a model in which lateral diffusion competes with three-dimensional diffusion and thus is involved in PAM finding and consequently on-target binding. Our results imply that the neighboring sequences can be very important when choosing a target in genetic engineering applications.


HOXA10 is associated with temozolomide resistance through regulation of the homologous recombinant DNA repair pathway in glioblastoma cell lines.
Temozolomide resistance is associated with multiple DNA repair pathways. We investigated homeobox (HOX) genes for their role in temozolomide resistance, focusing on the homologous recombination (HR) pathway, and we tested their therapeutic implications in conjunction with O(6)-methylguanine DNA methyltransferase (MGMT) status. Two glioblastoma cell lines with different MGMT statuses were used to test the augmented anticancer effect of temozolomide with HOXA10 inhibition. In vitro experiments, including gene expression studies with RNA interference, were performed to verify the related pathway dynamics. HOXA10 inhibition reinforced temozolomide sensitivity independent of MGMT status and was related to the impaired double-strand DNA breakage repair process resulting from the downregulation of Rad51 paralogs. Early growth response 1 (EGR1) and phosphatase and tensin homolog (PTEN) were the regulatory mediators between HOXA10 and the HR pathway. Moreover, HOXA10 inhibition selectively affected the nuclear function of PTEN without interfering with its cytoplasmic function of suppressing the phosphoinositide 3-kinase/Akt pathway. The mechanism of HR pathway regulation by HOXA10 harbors another target mechanism for overcoming temozolomide resistance in glioblastoma patients.


Reducing 9-1-1 Emergency Medical Service Calls By Implementing A Community Paramedicine Program For Vulnerable Older Adults In Public Housing In Canada: A Multi-Site Cluster Randomized Controlled Trial.
Objective: Older adults account for 38-48% of emergency medical service (EMS) calls, have more chronic diseases, and those with low income have lower quality of life. Mobile integrated health and community paramedicine may help address these health inequalities and reduce EMS calls. This study examines the effectiveness of the Community Paramedicine at Clinic (CP@clinic) program in decreasing EMS calls and improving health outcomes in low-income older adults. Methods: This was an open-label, pragmatic, cluster-randomized controlled trial conducted within subsidized public housing buildings for older adults in 5 paramedic services across Ontario, Canada. A total of 30 apartment buildings were eligible (>50 units, >60% of units occupied by older adults, unique postal code, available match for pairing). Paired buildings were randomly allocated to intervention (CP@clinic for one year) or control (usual care) via computer-generated randomization. The CP@clinic intervention is a community-based, paramedic-led, health promotion and disease prevention program held weekly in building common rooms. CP@clinic includes risk assessment with validated tools, decision support, health promotion, referrals to resources, and reports back to family doctors. All residents could participate, but only older adults (55 years and older) were included in analyses. The primary outcome was building-level EMS calls from paramedic service databases. Secondary outcomes were individual-level changes in chronic disease risk factors and quality-adjusted-life-years (QALYs). Data were analyzed using Generalized Estimating Equations to account for clustering by sites. Results: Intention-to-treat analysis showed no significant difference in EMS calls (mean difference = -0.37/100 apartment units/month, 95%CI: -0.98 to 0.24). Sensitivity analysis excluding data from 2 building pairs with eligibility changes after intervention initiation revealed a significant difference in EMS calls in favor of the intervention buildings (mean difference = -0.90/100 apartment units/month, 95%CI: -1.54 to -0.26). At the individual level, there was a significant QALY increase (mean difference = 0.06, 95%CI: 0.02 to 0.10) and blood pressure decrease (systolic mean change = 3.65 mmHg, 95%CI: 2.37 to 4.94; diastolic mean change = 2.03 mmHg, 95%CI: 1.00 to 3.06). Conclusions: CP@clinic showed a significant decrease in EMS calls, decrease in BP, and improvement in QALYs among older adults in subsidizing public housing, suggesting this simple program should be replicated in other communities with public housing. Trial Registration: Clinicaltrials.gov, Registration no. NCT02152891.


Effects of selective serotonin reuptake inhibitors on auditory processing: case study.
Auditory sensitivity and processing ability were evaluated in a patient who suffered from hyperacusis, difficulty understanding speech, withdrawn depression, lethargy, and hypersensitivity to touch, pressure, and light. Treatment with fluvoxamine and fluoxetine (selective serotonin reuptake inhibitors) reversibly alleviated complaints. Testing while medicated and unmedicated (after voluntary withdrawal from medication for several weeks) revealed no difference in pure-tone thresholds, speech thresholds, word recognition scores, tympanograms, or acoustic reflex thresholds. Medicated SCAN-A (a screening test for central auditory processing disorders) results were normal, and unmedicated results were abnormal. Unmedicated transient otoacoustic emissions and auditory brainstem response waves I, III, and V were significantly larger bilaterally. Uncomfortable loudness levels indicated greater tolerance during the medicated condition. Central processing and vigilance were evaluated with analog-synthesized three-formant consonant-vowel syllables. While medicated, responses to stimuli at each ear revealed well-defined, labeling crossovers of about 90 msec. Vowel identification matched normal subject responses; labeling of /gE/jE/ and /bE/wE/ continua was well defined but all crossover points differed from normals (p < .0001). During unmedicated testing, responses to /gE/jE/ began at medicated levels but approached chance levels for the entire continuum within 10 min; labeling of /bE/wE/ was consistent with medicated responses throughout with earlier than normal crossover points.


Investigation of acid red 88 oxidation in water by means of electro-Fenton method for water purification.
In this study, electro-Fenton method was applied to acid red 88 (AR88) containing aqueous solutions for the removal of it from water. The mineralization of AR88 has been achieved by oxidation with hydroxyl radicals. These radicals were produced simultaneously by the electro-Fenton method using an electrochemical cell including a carbon felt cathode and a platinum anode. Applied current and concentrations of catalyst and supporting electrolyte were optimized to obtain the best effective parameters of 500 mA, 0.1 mM and 75 mM, respectively. The absolute rate constant for the oxidation reaction of AR88 with hydroxyl radical was determined as (1.57 ± 0.06) x 10(10) M(-1) s(-1). Total organic carbon (TOC) analysis was performed to determine whether the organics were converted to carbon dioxide or not. A two-hour electrolysis at 500 mA is enough to remove 87% of initial TOC values of 0.25 mM AR88 solution. Electro-Fenton treatment of AR88 led to the formation of five aromatic intermediates, five short-chain carboxylic acids and three inorganic ions. Identified intermediates and complete mineralization of AR88 allowed us to propose a mineralization pathway for first time in the literature.


Comparison of open and closed book test for admission in medical school.
This article was migrated. The article was marked as recommended. Introduction: Students' learning methods are highly influenced by the type of evaluation. Consequently, evaluation is a deciding step in the learning process. Multiple Choice Format Tests (MCQs) are almost exclusive in the admission to Health studies. PluriPASS suggests an educational reform of Health studies. This research aims at analyzing docimological features of Open-book Multiple Choice Format tests (OBT) compared to other usual tests used during the first year in Health studies curriculum (CC). Methods: This educational research took place during PluriPASS year in Health studies curriculum at Angers University, during the academic period 2015-2016. The optional course « Disability and Health » (DH) was partly assessed by open-book tests with complex wording, requiring careful thought from students. Results: Out of the 1161 students enrolled in first year curriculum, 190 have chosen the DH. For the students who followed the DH, the CC and OBT distributions are respectively a Skewness score at -0.11 and -0.12 and a Kurtosis score at -0.9 and -0.22. Bland Altman test or Deming method demonstrate a concordance between both method. Conclusion: Distribution characteristics of OBT are satisfactory and allow to consider introducing this method with the objective of promoting reflection and depth learning.


A reovirus in the brown planthopper, Nilaparvata lugens.
A new virus, belonging to the reovirus group, was found in an apparently healthy colony of the brown planthopper, Nilaparvata lugens, and was referred to as the Nilaparvata lugens reovirus (NLRV). The virus was found in the cytoplasm of the insect cells, sometimes associated with tubular structures, which is one of the characteristic features in tissues infected with reoviruses. The virus was purified by carbon tetrachloride clarification, polyethylene glycol precipitation, differential and CsCl equilibrium centrifugations. The virus has double-shelled particles approximately 65 nm in diameter, containing 10 genome segments of dsRNA. The electrophoretic profile of the dsRNA segments differed from those of viruses associated with rice planthoppers and leafhoppers. Seven proteins were detected in a purified preparation of the virus: four were associated with the core particle and three with the outer shell. A virus antigen was detected in individual insects by ELISA. The virus is retained after injection and is vertically transmitted to the offspring.


Mechanistic role of cytochrome P450 monooxygenases in oxidized low-density lipoprotein-induced vascular injury: therapy through LOX-1 receptor antagonism?
Oxidized low-density lipoprotein (oxLDL) is an important risk factor for vascular injury. Its role on coronary vasoconstriction remains speculative. Endothelial monooxygenases (cytochrome P450s [CYPs]) are regulators of vascular tonus through production of epoxy fatty acids. We investigated the effects of oxLDL on CYP monooxygenases in human arterial coronary endothelial cells and explanted healthy and atherosclerotic aortae. We found oxLDL to induce radical oxygen species production via the action of NADPH oxidase NOX4. Intracellular radical oxygen species production prompted reduced protein expression of the transcriptional regulator nuclear factor 1 (NF-1). We identified novel DNA binding sites for NF-1 in promoter regions of CYPs. DNA binding of NF-1 was confirmed by electromobility shift assays. OxLDL repressed DNA binding of NF-1 and diminished transcript level of CYP genes targeted by this factor. The production of endothelial-derived hyperpolarization factor, a key regulator of vascular tonus, was also reduced. Repression of CYP monooxygenases was reversed, and production of endothelial-derived hyperpolarization factor was normalized after treatment of endothelium with the lectin-like oxLDL receptor antagonist kappa-carrageenan or blocking of LOX-1 with a specific antibody. This suggests a mechanistic role of CYP monooxygenases in oxLDL-induced vascular injury. Therapy of endothelial dysfunction through LOX-1 receptor antagonism will be an interesting avenue to explore. The full text of this article is available online at http://www.circresaha.org.


Changes of Brain Structure in Patients With Metastatic Non-Small Cell Lung Cancer After Long-Term Target Therapy With EGFR-TKI.
Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is the routine treatment for patients with metastatic non-small cell lung cancer (NSCLC) harboring positive EGFR mutations. Patients who undergo such treatment have reported cognitive decline during follow-up. This study, therefore, aimed to evaluate brain structural changes in patients receiving EGFR-TKI to increase understanding of this potential symptom. The medical records of 75 patients with metastatic NSCLC (without brain metastasis or other co-morbidities) who received EGFR-TKI therapy from 2010 to 2017 were reviewed. The modified Scheltens Visual Scale and voxel-based morphometry were used to evaluate changes in white matter lesions (WML) and gray matter volume (GMV), respectively. The WML scores were higher at the 12-month [8.65 ± 3.86; 95% confidence interval (CI), 1.60-2.35; p < 0.001] and 24-month follow-ups (10.11 ± 3.85; 95% CI, 2.98-3.87; p < 0.001) compared to baseline (6.68 ± 3.64). At the 24-month follow-up, the visual scores were also significantly higher in younger patients (3.89 ± 2.04) than in older patients (3.00 ± 1.78; p = 0.047) and higher in female patients (3.80 ± 2.04) than in male patients (2.73 ± 1.56; p = 0.023). Additionally, significant GMV loss was observed in sub-regions of the right occipital lobe (76.71 voxels; 95% CI, 40.740-112.69 voxels), left occipital lobe (93.48 voxels; 95% CI, 37.48-149.47 voxels), and left basal ganglia (37.57 voxels; 95% CI, 21.58-53.57 voxels) (all p < 0.005; cluster-level false discovery rate < 0.05). An increase in WMLs and loss of GMV were observed in patients with metastatic NSCLC undergoing long-term EGFR-TKI treatment. This might reflect an unknown side-effect of EGFR-TKI treatment. Further prospective studies are necessary to confirm our findings.


Learned expectations and uncertainty facilitate pain during classical conditioning.
Pain spontaneously activates adaptive and dynamic learning processes affecting the anticipation of, and the responses to, future pain. Computational models of associative learning effectively capture the production and ongoing changes in conditioned anticipatory responses (eg, skin conductance response), but the impact of this dynamic process on unconditional pain responses remains poorly understood. Here, we investigated the dynamic modulation of pain and the nociceptive flexion reflex by fear learning in healthy human adult participants undergoing a classical conditioning procedure involving an acquisition, reversal and extinction phase. Conditioned visual stimuli (CS+) coterminated with a noxious transcutaneous stimulation applied to the sural nerve on 50% of trials (unconditioned stimuli). Expected pain probabilities and cue associability were estimated using computational modeling by fitting a hybrid learning model to skin conductance response elicited by the CS+. Multilevel linear regression analyses confirmed that trial-by-trial changes in expected pain and associability positively predict ongoing fluctuations in pain outcomes. Mediation analysis further demonstrated that both expected probability and associability affect pain perception through a direct effect and an indirect effect mediated by descending modulatory mechanisms affecting spinal nociceptive activity. Moderation analyses further showed that hyperalgesic effects of associability were larger in individuals reporting more harm vigilance and less emotional detachment. Higher harm vigilance was also associated with a stronger mediation of hyperalgesic effects by spinal processes. These results demonstrate how dynamic changes in pain can be explained by associative learning theory and that resilient attitudes towards fear/pain can attenuate the adverse impact of adaptive aversive learning processes on pain.


Body mass index distribution affects discrepancies in weight classifications in children.
The aim of the present study was to investigate the effect of body mass index (BMI) distribution, ethnicity and age at menarche on the consistency in the prevalence of underweight and overweight defined by the Centers for Disease Control and Prevention (CDC) and the International Obesity Task Force (IOTF) cut-off points in 2-17-year-old Chinese and US children. Data from the China Health and Nutrition Survey (CHNS) 1991 (n= 3895), CHNS 2004 (n= 1902), and the National Health and Nutrition Examination Survey (NHANES) 2003-2004 (n= 3344) were used to define the prevalence of underweight and overweight using the CDC and IOTF BMI cut-off points. An upward shift in the BMI distribution was observed from the CHNS 1991 to CHNS 2004, and between the CHNS and NHANES 2004. The prevalence of underweight defined by the IOTF cut-off points was higher than that obtained using the CDC cut-off points; absolute differences between IOTF and CDC classifiers were 7%, 5%, and 2% in boys, and 12%, 11%, and 4% in girls in the CHNS 1991, CHNS 2004, and NHANES 2004, respectively. There was a greater consistency in the prevalence of overweight. The consistency of the two classification systems increased with the higher BMI distribution and was not affected significantly by ethnicity or age at menarche. The BMI distribution of a population can affect the classification of childhood underweight and overweight differentially as defined by the CDC and IOTF cut-off points, and thus should be considered in the interpretation of results in clinical and population settings.


Establishing diagnostic criteria for Perry syndrome.
To establish international diagnostic criteria for Perry syndrome, a disorder characterised by clinical signs of parkinsonism, depression/apathy, weight loss, respiratory symptoms, mutations in the DCTN1 gene and TAR DNA-binding protein 43 (TDP-43) pathology. Data from the published literature and newly identified patients were gathered and analysed during and after the International Symposium on Perry syndrome in Tokyo to identify diagnostic criteria for Perry syndrome. Eighty-seven patients with Perry syndrome carrying DCTN1 mutations from 20 families were included in this study, and common signs of the disorder were identified, including parkinsonism (95.2% of patients), depression/apathy (71.4%), respiratory symptoms (66.7%) and weight loss (49.2%). Based on our findings, we propose the following definitive diagnostic criteria for Perry syndrome: the presence of four cardinal signs of Perry syndrome, accompanied by a mutation in DCTN1; or a family history of the disease, parkinsonism and a mutation in DCTN1; or the presence of four cardinal signs and pathological findings that include nigral neuronal loss and TDP-43 pathology. As patients with Perry syndrome present with uniform clinical, genetic and pathological features, we further propose the disorder be termed 'Perry disease.'


Renal osmoregulatory function during simulated space flight.
Experiments are described on the dynamics of the renal excretion of water and electrolytes, osmotically active substances and osmotically free water during bed rest. In short-term experiments (up to 10-14 days) renal changes are mainly associated with haemodynamic disturbances and fluid redistribution, whereas in longer duration experiments (up to 50 days) they are brought about by metabolic changes.


Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction.
To investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction. We examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe-/-) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed. ITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe-/- mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in Akkermansia and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation. We demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases.


Neural differentiation and potential use of stem cells from the human umbilical cord for central nervous system transplantation therapy.
The human umbilical cord is a rich source of autologous stem and progenitor cells. Interestingly, subpopulations of these, particularly mesenchymal-like cells from both cord blood and the cord stroma, exhibited a potential to be differentiated into neuron-like cells in culture. Umbilical cord blood stem cells have demonstrated efficacy in reducing lesion sizes and enhancing behavioral recovery in animal models of ischemic and traumatic central nervous system (CNS) injury. Recent findings also suggest that neurons derived from cord stroma mesenchymal cells could alleviate movement disorders in hemiparkinsonian animal models. We review here the neurogenic potential of umbilical cord stem cells and discuss possibilities of their exploitation as an alternative to human embryonic stem cells or neural stem cells for transplantation therapy of traumatic CNS injury and neurodegenerative diseases.


Acute hemorrhagic leukoencephalitis during treatment for disseminated tuberculosis in a patient with AIDS.
A 45-year-old man with the acquired immune deficiency syndrome (AIDS) developed disseminated Mycobacterium tuberculosis infection and was started on isoniazid, rifampin, pyrazinamide and ethambutol. The treatment was interrupted because of side effects. On resumption of treatment be developed a rapidly progressive neurological illness characterized by left hemiparesis, right gaze preference, convulsions, coma, evidence of cerebral edema on computed tomography scan and death 9 days later. Autopsy showed the presence of miliary tuberculosis affecting the lungs, liver, spleen, lymph nodes and bone marrow. The brain showed evidence of acute hemorrhagic leukoencephalitis (AHL)-the first such case in a patient with AIDS. We speculate that treatment-induced lysis of mycobacteria with concomitant release of mycobacterial lipoproteins may have activated T-lymphocytes to cause AHL in this patient.


Neuropathic pain in HIV patients receiving ART without stavudine in an Indonesia Referral Hospital.
Lower limb neuropathic pain in HIV patients is a common manifestation of sensory neuropathy (HIV-SN), but can be seen in patients who do not meet standard definitions of HIV-SN. The drug stavudine is a risk factor for HIV-SN, but some patients treated without stavudine experience HIV-SN, and the prevalence and risk factors influencing neuropathic pain in this setting are unknown. A cross sectional study at Cipto Mangunkusumo Hospital Jakarta tested 197 HIV patients treated for >12 months without stavudine. HIV-SN was defined using the AIDS Clinical Trial Group Brief Peripheral Neuropathy Screening Test (ACTG-BPNST). A validated Indonesia translation of Douleur Neuropathique en 4 (DN4) questionnaire was used to assess lower limb neuropathic pain. Nerve conduction studies assessed large nerve fiber function and Stimulated Skin Wrinkle (SSW) tests were performed to assess small nerve fibers. The prevalence of neuropathic pain was 6.6%. BPNST+HIV-SN was diagnosed in 14.2% of the cohort and 38.5% of patients with pain. Use of protease inhibitors and ART duration <2 years associated with neuropathic pain in univariate (p = .036, p = .002, resp.) and multivariable analyses (model p < .001). SSW tests were abnormal in 53.8% of subjects with neuropathic pain and only 25.5% without pain (p = .05). Patients with pain without BPNST+HIV-SN had begun ART more recently than those with both diagnoses. Overall this preliminary study showed that neuropathic pain associated with protease inhibitors and a shorter duration of ART in Indonesian HIV patients, and may be an early symptom of small fiber neuropathy in this context.


A comparative study of NiCo2O4 catalyst supported on Ni foam and from solution residuals fabricated by a hydrothermal approach for electrochemical oxygen evolution reaction.
Residuals have rarely been granted attention when employing a hydrothermal approach to prepare binder-free supported catalysts. Using Ni foam supported NiCo2O4 catalyst for oxygen evolution reaction as an example, it was found that the catalytic activity of NiCo2O4 from the residuals loaded on glass carbon is comparable to Ni foam supported NiCo2O4, while the specific activity and turnover frequency value of the former catalyst are many times higher than that of the supported catalyst. In view of sustainability and green development, residuals should be given more attention when catalyst is prepared using the hydrothermal fabrication approach.


The Contribution to Stress Recovery and Attention Restoration Potential of Exposure to Urban Green Spaces in Low-Density Residential Areas.
This study assessed the contributions of urban green spaces on mental health with joint consideration of people's physiological and psychological responses. The psychological and physiological responses of participants aged between 22 and 28, who visited green spaces in a low-density area of Fuzhou, Fujian Province, China, were measured using Perceived Restorativeness Scale (PRS) methods and biometric wearable sensing devices, respectively. Results showed that exposure to green space led to significant changes in PRS, electrodermal activity (EDA), facial electromyography (EMG), respiration sensor (RESP), and photoplethysmography (PPG), while there is no significant impact on skin temperature (SKT). Additionally, psychological and physiological responses were highly consistent and correlated (R < 0.8). The results also indicated that green spaces with high plant species richness, a water landscape, bumpy ground, cultural landscape, and without roadways presented a high performance on stress recovery and attention restoration. At the same time, the influence of openness was negligible in the low-density area. The study provides planners and landscape designers with specific guidance for implementing urban green spaces to improve mental health in low-density residential areas.


Comparison of atypical rotaviruses from calves, piglets, lambs and man.
Some rotaviruses from calves, piglets, and lambs were detected by electron microscopic examination of faeces but not by an enzyme-linked immunosorbent assay which relies on detection of group antigen. On further examination by polyacrylamide gel electrophoresis, these viruses had 11 segments of dsRNA, as had typical rotaviruses, but arranged in atypical patterns. From humans, three rotaviruses with atypical electrophoretypes were also detected. Gnotobiotic animals were infected with atypical calf, piglet and lamb rotaviruses, and used to provide antigen and antiserum for an immunofluorescent comparison of these rotaviruses with conventional rotaviruses and other previously described atypical rotaviruses from piglets and chickens. Two atypical rotaviruses from humans failed to infect gnotobiotic piglets. The atypical rotaviruses could be tentatively categorized into two groups serologically distinct from each other and from conventional rotaviruses, and these distinctions were consistent with electrophoretypes . The atypical chicken rotavirus may form a fourth distinct group. These findings are consistent with the hypothesis that rotaviruses belong to at least four separate groups definable by serology and electrophoretype .


Association of Metabolic Phenotypes With Coronary Artery Disease and Cardiovascular Events in Patients With Stable Chest Pain.
Obesity and metabolic syndrome are associated with major adverse cardiovascular events (MACE). However, whether distinct metabolic phenotypes differ in risk for coronary artery disease (CAD) and MACE is unknown. We sought to determine the association of distinct metabolic phenotypes with CAD and MACE. We included patients from the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) who underwent coronary computed tomography (CT) angiography. Obesity was defined as a BMI ≥30 kg/m2 and metabolically healthy as less than or equal to one metabolic syndrome component except diabetes, distinguishing four metabolic phenotypes: metabolically healthy/unhealthy and nonobese/obese (MHN, MHO, MUN, and MUO). Differences in severe calcification (coronary artery calcification [CAC] ≥400), severe CAD (≥70% stenosis), high-risk plaque (HRP), and MACE were assessed using adjusted logistic and Cox regression models. Of 4,381 patients (48.4% male, 60.5 ± 8.1 years of age), 49.4% were metabolically healthy (30.7% MHN and 18.7% MHO) and 50.6% unhealthy (22.3% MUN and 28.4% MUO). MHO had similar coronary CT findings as compared with MHN (severe CAC/CAD and HRP; P > 0.36 for all). Among metabolically unhealthy patients, those with obesity had similar CT findings as compared with nonobese (P > 0.10 for all). However, both MUN and MUO had unfavorable CAD characteristics as compared with MHN (P ≤ 0.017 for all). A total of 130 events occurred during follow-up (median 26 months). Compared with MHN, MUN (hazard ratio [HR] 1.61 [95% CI 1.02-2.53]) but not MHO (HR 1.06 [0.62-1.82]) or MUO (HR 1.06 [0.66-1.72]) had higher risk for MACE. In patients with stable chest pain, four metabolic phenotypes exhibit distinctly different CAD characteristics and risk for MACE. Individuals who are metabolically unhealthy despite not being obese were at highest risk in our cohort.


Lifesaving oral cancer screening.
Each year 605 New York State residents, on average, die from oral and pharyngeal cancer. Disappointingly, the mortality rate has not changed significantly in more than 25 years. Early detection and risk factor prevention are the two best public health tools to reduce mortality. Dental care workers must play an increasingly important leadership role in the fight against oral cancer. A technique for an annual oral cancer screening is described in this article.


Early intervention of recent onset mild persistent asthma in children aged under 11 yrs: the Steroid Treatment As Regular Therapy in early asthma (START) trial.
Inhaled corticosteroids are known to be effective in persistent asthma, but their long-term effect in mild persistent disease of recent onset, which is particularly relevant in children, requires clarification. The objective of this study was to determine the long-term efficacy of regular inhaled low-dose budesonide in children aged <11 yrs with mild persistent asthma with onset within 2 yrs of enrollment. Children aged 5-10 yrs formed part of the population of the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, and they were randomized in a double-blind manner to treatment with once daily budesonide 200 microg or placebo via Turbuhaler in addition to usual clinical care and other asthma medication. The double-blind treatment phase continued for 3 yrs. Of the 1974 children, 1000 in the budesonide group and 974 in the placebo group, were analyzed for efficacy. Addition of once-daily budesonide to usual care was associated with a significant increase in the time to first severe asthma-related event (SARE) and significantly reduced risk of SARE over 3 yrs. The hazard ratio relative to usual care (placebo) was 0.60 (95% confidence interval: 0.40-0.90; p = 0.012), with a relative risk reduction of 40%. Children receiving budesonide also needed significantly less intervention with other inhaled corticosteroids (12.3% vs. 22.5% over 3 yrs; p < 0.01), with trends towards decreased usage of oral/systemic corticosteroids and inhaled short-acting beta2-agonists. Budesonide treatment also had a significant beneficial effect on lung function relative to placebo. In conclusion, early intervention adding once-daily budesonide to usual care in children with mild, persistent asthma of recent onset reduces the long-term risk and frequency of SAREs and improves lung function compared with usual care alone.


Glomerular hyperfiltration during sympathetic nervous system activation in early essential hypertension.
Glomerular hyperfiltration may be important for the development of essential hypertension. Both the renin-angiotensin system and the sympathetic nervous system influence renal hemodynamic regulation. To test the hypothesis that glomerular hyperfiltration can be unmasked by sympathetic nervous system activation, renal hemodynamics and humoral components of the renin-angiotensin system were examined at rest and during mental stress in 45 young normotensive healthy subjects and 37 young people with mild essential hypertension. GFR and renal plasma flow (RPF) were determined with inulin and para-aminohippuric acid clearance at rest and during stress. At rest, RPF, GFR, filtration fraction, plasma renin activity, angiotensin (Ang) II concentrations, and serum aldosterone values were similar in normotensive and hypertensive subjects. After stress, blood pressure increased (P < 0.01), but this was nearly identical in normotensive and hypertensive subjects (7.05 +/- 6.9 versus 7.03 +/- 4.6 mmHg, NS). The decrease in RPF (-27 +/- 54 versus -22 +/- 25 ml/min per 1.73 m2, NS) was also similar in the two groups. In contrast, the increase in GFR (+ 10.5 +/- 7.2 versus 6.08 +/- 5.7 ml/min per 1.73 m2, P < 0.001) and filtration fraction (+2.48 +/- 1.38 versus 1.82 +/- 1.49%, P < 0.05) was more marked in hypertensive than in normotensive subjects. The concomitant increase in Ang II concentrations was greater in hypertensive than in normotensive subjects (+4.6 +/- 1.0 versus -1.0 +/- 0.45 pg/ml, P < 0.001). The increase in GFR during mental stress was correlated with the increment in Ang II concentrations (r = 0.39, P < 0.001). Compared with the placebo control phase, blockade of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor attenuated the increase in GFR during stress in hypertensive (8.04 +/- 5.01 versus 10.1 +/- 5.7 ml/min per 1.73 m2, P < 0.05), but not in normotensive, subjects. Even in early essential hypertension, glomerular hyperfiltration is evident during sympathetic nervous system activation, which is mediated by postglomerular vasoconstriction. This early stress-induced glomerular hyperfiltration may contribute to, or trigger, the development of essential hypertension.


Income Attainment among Victims of Violence: Results From a Preliminary Study.
Violent victimisation may have many short-term psychological and physical outcomes. Occasionally, the negative aftermath of violence persists over time or induces other and more far-reaching consequences. Income attainment after victimisation is one of these outcomes. To date, previous studies have focussed on the income effects of violent victimisation during childhood and adolescence. Violence exposure during the early stages of the life course may frustrate processes of educational and occupational attainment and consequentially result in lower income levels. However, in addition or alternatively, many other and age-independent pathways between violent victimisation and income may be suggested. Prior studies appear to have paid little attention to this issue. Therefore, the purpose of the current study was to explore whether violent victimisation is associated with income levels several years after victimisation, irrespective of the age at which victimisation occurs. Victims of violence were recruited through the Dutch Victim Compensation Fund. To preliminary estimate the effect of violent victimisation on income, a comparable control group of non-victims was composed. The study sample contained 206 victims and 173 non-victims. Both bivariate correlational and multivariate statistical techniques suggested that violent victimisation is a significant predictor of income. Implications of the presented results were discussed with regard to future research and policy practice.


Evaluation of combination protocols of the chemotherapeutic agent FX-9 with azacitidine, dichloroacetic acid, doxorubicin or carboplatin on prostate carcinoma cell lines.
The isoquinolinamine FX-9 is a novel potential chemotherapeutic agent showing antiproliferative effects against hematologic and prostate cancer cell lines such as B- and T-acute lymphoblastic leukemia and prostate cancer (PC) of different species. Interestingly, FX-9 shows no hemolytic activity and low toxicity in benign adherent cells. The detailed FX-9 molecular mode of action is currently not fully understood. But application on neoplastic cells induces pro-apoptotic and antimitotic effects. Canine prostate cancer (cPC) represents a unique spontaneous occurring animal model for human androgen-independent PC. Human androgen-independent PC as well as cPC are currently not satisfactorily treatable with chemotherapeutic protocols. Accordingly, the evaluation of novel agent combinations bears significant potential for identifying novel treatment strategies. In this study, we combined FX-9 with the currently approved therapeutic agents doxorubicin, carboplatin, the demethylating substance azacitidine as well as further potentially antitumorigenic agents such as dichloroacetic acid (DCA) in order to evaluate the respective synergistic potential. The combinations with 1-5 μM FX-9 were evaluated regarding the effect after 72 hours on cell viability, cell count and apoptotic/necrotic cells in two human prostate cancer cell lines (LNCaP, PC-3) and a canine prostate cancer cell line (Adcarc1258) representing androgen-dependent and -independent PC/cPC forms. FX-9 in combination with azacitidine decreases cell viability and increases cell death with positive Bliss values. Furthermore, this decreases the cell count with neutral Bliss values on PC-3. Carboplatin in combination with FX-9 reduces cell viability with a neutral Bliss value and increases cell death on LNCaP with calculated positive Bliss values. DCA or doxorubicin in combination with FX-9 do not show synergistic or additive effects on the cell viability. Based on these results, azacitidine or carboplatin in combination with FX-9 offers synergistic/additive efficacy against prostate adenocarcinoma cell lines in vitro. The beneficial effects of both combinations are worth further investigation.


Arginine-lysine positional swap of the LL-37 peptides reveals evolutional advantages of the native sequence and leads to bacterial probes.
Antimicrobial peptides are essential components of the innate immune system of multicellular organisms. Although cationic and hydrophobic amino acids are known determinants of these amphipathic molecules for bacterial killing, it is not clear how lysine-arginine (K-R) positional swaps influence peptide structure and activity. This study addresses this question by investigating two groups of peptides (GF-17 and 17BIPHE2) derived from human cathelicidin LL-37. K-R positional swap showed little effect on minimal inhibitory concentrations of the peptides. However, there are clear differences in bacterial killing kinetics. The membrane permeation patterns vary with peptide and bacterial types, but not changes in fluorescent dyes, salts or pH. In general, the original peptide is more efficient in bacterial killing, but less toxic to human cells, than the K-R swapped peptides, revealing the evolutionary significance of the native sequence for host defense. The characteristic membrane permeation patterns for different bacteria suggest a possible application of these K-R positional-swapped peptides as molecular probes for the type of bacteria. Such differences are related to bacterial membrane compositions: minimal for Gram-positive Staphylococcus aureus with essentially all anionic lipids (cardiolipin and phosphatidylglycerol), but evident for Gram-negative Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli with a mixture of phosphatidylethanolamine and phosphatidylglycerol. Biophysical characterization found similar structures and binding affinities for these peptides in vesicle systems mimicking E. coli and S. aureus. It seems that interfacial arginines of GF-17 are preferred over lysines in bacterial membrane permeation. Our study sheds new light on the design of cationic amphipathic peptides.


[Changes in the care of the elderly after the enactment of the elderly statute according to professionals of a geriatric hospital].
This study was aimed at finding out how an interdisciplinary team deals with the Elderly Statute and how it interfered in the care of institutionalized elderly. The setting was a geriatric hospital in Sio Paulo where 297 elderly people reside. Thirty-five professionals from the facility's interdisciplinary team took part in the study and answered a questionnaire with open and close questions. Results were divided into categories and submitted to a descriptive analysis. It was observed that 68.6% of the professionals thought that after the enactment of the Statute there have been changes in the care provided, even if slowly, and that they occurred in the interdisciplinary staff, which went after specialization in order to improve care; in the facilities, which adapted so as to attend to the needs of the elders; and in the elderly people themselves and in their families, whom, feeling protected by the law, increased the demands for their rights.


A Chinese Chan-based mind-body intervention for patients with depression.
Given the recent growing interest and encouraging findings in studies of alternative treatments for depression, the present randomized controlled trial study aimed to compare the effect of a newly developed Chinese Chan-based Dejian Mind-Body Intervention (DMBI) with the Cognitive Behavioral Therapy (CBT) on improving depressive symptoms in patients with depression. Seventy-five participants diagnosed with major depressive disorder were randomly assigned to receive either 10-session CBT or DMBI, or placed on a waitlist. Pre-post measurements included record of anti-depressants treatment, ratings by psychiatrists who were blinded to the experimental design and self-report on mood measures, and performance in a cognitive test tapping concentration ability. Both the CBT and DMBI groups demonstrated significantly reduced overall depressive syndrome after intervention at large effect size (0.93-1.10). Furthermore, the DMBI group (p<0.05), but not the CBT or waitlist groups, demonstrated significant reduction in intake of anti-depressants, and significant improvement in specific depression-related symptoms including difficulty in concentration (p=0.002), and problems in gastrointestinal health (p=0.02) and overall sleep quality (p<0.001). This study has provided some evidence for the short-term effect of the DMBI on Chinese population. Its long-term effect on a larger sample and on Caucasian population warrants further investigation. The present findings suggest that a Chinese Chan-based Mind-Body intervention has positive effects on improving mood and health conditions of individuals with depression.


Functional reconstitution of the type IVa pilus assembly system from enterohaemorrhagic Escherichia coli.
Type 4a pili (T4aP) are long, thin and dynamic fibres displayed on the surface of diverse bacteria promoting adherence, motility and transport functions. Genomes of many Enterobacteriaceae contain conserved gene clusters encoding putative T4aP assembly systems. However, their expression has been observed only in few strains including Enterohaemorrhagic Escherichia coli (EHEC) and their inducers remain unknown. Here we used EHEC genomic DNA as a template to amplify and assemble an artificial operon composed of four gene clusters encoding 13 pilus assembly proteins. Controlled expressions of this operon in nonpathogenic E. coli strains led to efficient assembly of T4aP composed of the major pilin PpdD, as shown by shearing assays and immunofluorescence microscopy. When compared with PpdD pili assembled in a heterologous Klebsiella T2SS type 2 secretion system (T2SS) by using cryo-electron microscopy (cryoEM), these pili showed indistinguishable helical parameters, emphasizing that major pilins are the principal determinants of the fibre structure. Bacterial two-hybrid analysis identified several interactions of PpdD with T4aP assembly proteins, and with components of the T2SS that allow for heterologous fibre assembly. These studies lay ground for further characterization of the T4aP structure, function and biogenesis in enterobacteria.