[Home therapeutic adherence of pelvic floor muscle exercises in urinary incontinence].
Urinary incontinence (UI) is a medical and social problem that has a great impact on the quality of life of women. Pelvic floor muscle strengthening exercises have been shown to be a form of conservative treatment. However, there is still high failure in this treatment. To analyze the factors associated with low home therapeutic adherence to pelvic floor exercises in patients with UI. An analytical cross-sectional prolective study was carried out in women aged 20-85 years, with UI and under conservative treatment with pelvic floor muscle exercises. They were questioned about their demographic data; the Morisky Green therapeutic adherence questionnaire and the Likert-type satisfaction scale were applied on the results of the questionnaire. 235 women with UI and with a prescription for pelvic floor muscle exercises, with a median of 55 (46-64) years, were analyzed. The lack of adherence to pelvic floor exercises was observed in 130 (55.32%), whose causes were their work (37.69%), forgetfulness (23.08%) and lack of interest (12.08%). The risk factors for non-adherence were having 3 or less children (OR 1.81 [95% CI 1.10-3.23], p = 0.02), and not feeling satisfied with the exercises (OR 6.70 [95% CI 3.75-11.97], p < 0.001. The factors associated with low home therapeutic adherence to pelvic floor exercises in patients with urinary incontinence were having 3 or less children and not being satisfied with the results.


Dealloyed Ruthenium Film Catalysts for Hydrogen Generation from Chemical Hydrides.
Thin-film ruthenium (Ru) and copper (Cu) binary alloys have been prepared on a Teflon™ backing layer by cosputtering of the precious and nonprecious metals, respectively. Alloys were then selectively dealloyed by sulfuric acid as an etchant, and their hydrogen generation catalysts performances were evaluated. Sputtering time and power of Cu atoms have been varied in order to tailor the hydrogen generation performances. Similarly, dealloying time and the sulfuric acid concentration have also been altered to tune the morphologies of the resulted films. A maximum hydrogen generation rate of 35 mL min-1 was achieved when Cu sputtering power and time were 200 W and 60 min and while acid concentration and dealloying time were 18 M and 90 min, respectively. It has also been demonstrated that the Ru content in the alloy after dealloying gradually increased with the increasing the sputtering power of Cu. After 90 min dealloying, the Ru to Cu ratio increased to about 190 times that of bare alloy. This is the key issue for observing higher catalytic activity. Interestingly, we have also presented template-free nanoforest-like structure formation within the context of one-step alloying and dealloying used in this study. Last but not least, the long-time hydrogen generation performances of the catalysts system have also been evaluated along 3600 min. During the first 600 min, the catalytic activity was quite stable, while about 24% of the catalytic activity decayed after 3000 min, which still makes these systems available for the development of robust catalyst systems in the area of hydrogen generation.


Nanobiotechnology advanced antifouling surfaces for the continuous electrochemical monitoring of glucose in whole blood using a lab-on-a-chip.
In the current work we have developed a lab-on-a-chip containing embedded amperometric sensors in four microreactors that can be addressed individually and that are coated with crystalline surface protein monolayers to provide a continuous, stable, reliable and accurate detection of blood glucose. It is envisioned that the microfluidic device will be used in a feedback loop mechanism to assess natural variations in blood glucose levels during hemodialysis to allow the individual adjustment of glucose. Reliable and accurate detection of blood glucose is accomplished by simultaneously performing (a) blood glucose measurements, (b) autocalibration routines, (c) mediator-interferences detection, and (d) background subtractions. The electrochemical detection of blood glucose variations in the absence of electrode fouling events is performed by integrating crystalline surface layer proteins (S-layer) that function as an efficient antifouling coating, a highly-oriented immobilization matrix for biomolecules and an effective molecular sieve with pore sizes of 4 to 5 nm. We demonstrate that the S-layer protein SbpA (from Lysinibacillus sphaericus CCM 2177) readily forms monomolecular lattice structures at the various microchip surfaces (e.g. glass, PDMS, platinum and gold) within 60 min, eliminating unspecific adsorption events in the presence of human serum albumin, human plasma and freshly-drawn blood samples. The highly isoporous SbpA-coating allows undisturbed diffusion of the mediator between the electrode surface, thus enabling bioelectrochemical measurements of glucose concentrations between 500 μM to 50 mM (calibration slope δI/δc of 8.7 nA mM(-1)). Final proof-of-concept implementing the four microfluidic microreactor design is demonstrated using freshly drawn blood. Accurate and drift-free assessment of blood glucose concentrations (6. 4 mM) is accomplished over 130 min at 37 °C using immobilized enzyme glucose oxidase by calculating the difference between autocalibration (10 mM glc) and background measurements. The novel combination of biologically-derived nanostructured surfaces with microchip technology constitutes a powerful new tool for multiplexed analysis of complex samples.


The involvement of micro-opioid receptors in the central nervous system in the worsening of allergic airway inflammation by psychological stress in mice.
Psychological stress has a recognized association with asthma symptoms. However, the mechanisms linking stress to the exacerbation of asthma are not well defined. mu-Opioid receptors (MOR) have been shown to be involved in the shift of the immune system toward a Th2-predominant response caused by psychological stress. To test the hypothesis that MOR play a role in the worsening of allergic airway inflammation evoked by psychological stress. Sensitized mice were exposed to restraint stress followed by antigen challenge. The levels of corticosterone and ovalbumin (OVA)-specific IgE in the blood and the levels of inflammatory cells and cytokine contents in bronchoalveolar lavage fluid were compared between stressed and nonstressed mice. The effects of MOR gene deletion and MOR antagonists/agonists were also investigated. Stress exposure was confirmed by an increase in corticosterone levels. Although OVA-specific IgE levels were not significantly different, the numbers of inflammatory cells and Th2 cytokine levels after antigen challenge in stressed mice were significantly higher than in nonstressed mice. MOR gene deletion ameliorated the stress-induced worsening of antigen-induced airway inflammation, and the administration of morphine, a MOR agonist, reproduced the stress-induced antigen-induced airway inflammation. Selective blocking of MOR in the central nervous system (CNS) significantly reduced stress-induced inflammatory exacerbation, but the blocking of peripheral MOR did not. MOR in the CNS are involved in psychological stress-induced aggravation of allergic airway inflammation.


Enforced expression of Bcl-XS induces differentiation and sensitizes chronic myelogenous leukemia-blast crisis K562 cells to 1-beta-D-arabinofuranosylcytosine-mediated differentiation and apoptosis.
Human chronic myelogenous leukemia-blast crisis K562 cells have been demonstrated to be relatively resistant to antileukemic drug-induced apoptosis. This has been attributed to the activity of p210bcr-abl tyrosine kinase present in the K562 cells, which is known to suppress drug-induced apoptosis. Recently, K562 cells have been shown to express the antiapoptosis Bcl-xL but not Bcl-2 proteins. To investigate the contribution of Bcl-xL toward resistance to drug-induced apoptosis, we created K562/Bcl-xS and K562/neo cells by electroporating the expression plasmids pSFFVneo-Bcl-xS and pSFFVneo, containing the bcl-xS and neomycin resistance genes, respectively, into K562 cells. K562/Bcl-xS but not K562/neo cells expressed the bcl-xS mRNA and p19Bcl-xS protein. In contrast, both cell types expressed equivalent levels of Bcl-xL, Bax, Bcl-2, Myc, retinoblastoma, p21cbor-abl, and p145abl proteins. A significant increase in the hemoglobin levels was observed in the K562/Bcl-xS compared with the K562/neo cells (P < 0.05). In addition, K562/Bcl-xS cells were significantly more sensitive than K562/neo cells to undergoing erythroid differentiation induced by low-dose 1-beta-D-arabinofuranosylcytosine (ara-C) and hexamethyl bisacetamide (P < 0.05), but not by all-trans-retinoic acid. Low-dose ara-C- or hexamethyl bisacetamide-induced differentiation was not associated with apoptosis of K562/Bcl-xS or K562/neo cells. Low-dose ara-C-induced erythroid differentiation was accompanied by conversion of the retinoblastoma protein to predominantly its underphosphorylated isoform as well as by down-regulation of Myc levels in K562/Bcl-xS and K562/neo cells. Importantly, exposure to high-dose ara-C (HIDAC; 100 microM ara-C for 4 h) caused internucleosomal DNA fragmentation and the morphological features of apoptosis in K562/Bcl-xS cells. These effects were modestly enhanced by cotreatment with HIDAC plus herbimycin A. In contrast, K562/neo cells were completely resistant to HIDAC- and herbimycin A-induced apoptosis. These results indicate that the expression of Bcl-xS induces erythroid differentiation and partially sensitizes chronic myelogenous leukemia-blast crisis-derived K562 cells to ara-C-induced differentiation and apoptosis.


Current Status, Time Trends and Outcomes of Combination Therapy With Oral Anticoagulant and Antiplatelet Drug in Patients With Atrial Fibrillation - The Fushimi AF Registry.
The combination of oral anticoagulant (OAC) and antiplatelet drug (APD) increases the bleeding risk in atrial fibrillation (AF). Non-vitamin K antagonist OAC (NOAC) have been increasingly used since 2011. We investigated current status, time trends and outcomes of AF patients using combination therapy in 2011-2017. Methods and Results: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. Of 2,378 patients with OAC at enrollment, 521 (22%) received combination therapy, while 1,857 (78%) received OAC alone. When compared with OAC alone, combination therapy patients had more comorbidities, but approximately 30% had no atherosclerotic disease. From 2011 to 2017, the prevalence of combination therapy decreased from 26% to 14%. The prevalence of NOAC increased in those on combination therapy. Off-label under-dosing of NOAC increased year by year, especially in combination therapy. During follow-up, the incidence of major bleeding (hazard ratio [HR], 1.42; 95% CI: 1.03-1.95) and stroke/systemic embolism (HR, 1.48; 95% CI: 1.09-2.00) was higher in the combination therapy than in the OAC alone group. In Japanese AF patients receiving OAC, the prevalence of combination therapy decreased, with the proportion of NOAC use increasing in 2011-2017. Many patients, however, received off-label NOAC under-dosing, especially in the combination therapy group. Patients with combination therapy had higher incidences of major bleeding as well as stroke/systemic embolism, compared with OAC monotherapy.


Natural variation in teosinte at the domestication locus teosinte branched1 (tb1).
The teosinte branched1(tb1) gene is a major QTL controlling branching differences between maize and its wild progenitor, teosinte. The insertion of a transposable element (Hopscotch) upstream of tb1 is known to enhance the gene's expression, causing reduced tillering in maize. Observations of the maize tb1 allele in teosinte and estimates of an insertion age of the Hopscotch that predates domestication led us to investigate its prevalence and potential role in teosinte. We assessed the prevalence of the Hopscotch element across an Americas-wide sample of 837 maize and teosinte individuals using a co-dominant PCR assay. Additionally, we calculated population genetic summaries using sequence data from a subset of individuals from four teosinte populations and collected phenotypic data using seed from a single teosinte population where Hopscotch was found segregating at high frequency. Genotyping results indicate the Hopscotch element is found in a number of teosinte populations and linkage disequilibrium near tb1 does not support recent introgression from maize. Population genetic signatures are consistent with selection on the tb1 locus, revealing a potential ecological role, but a greenhouse experiment does not detect a strong association between the Hopscotch and tillering in teosinte. Our findings suggest the role of Hopscotch differs between maize and teosinte. Future work should assess tb1 expression levels in teosinte with and without the Hopscotch and more comprehensively phenotype teosinte to assess the ecological significance of the Hopscotch insertion and, more broadly, the tb1 locus in teosinte.


Canadian Study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE study): a cohort study protocol examining the mechanisms of obesity in survivors of childhood brain tumours.
Childhood obesity has reached epidemic proportions and is impacting children's health globally. In adults, obesity is associated with chronic low-grade inflammation that leads to insulin resistance, which is one of the important mechanisms through which dysregulation of metabolism occurs. There is limited information available about the contribution of inflammation to metabolic health in obese children, and how individual and lifestyle factors impact this risk. One of the paediatric groups at risk of higher rates of obesity includes the survivors of childhood brain tumours. The aim of this study was to evaluate the mechanisms that contribute to inflammation in obese survivors of childhood brain tumours. This is a prospective cohort study. We will recruit lean and obese survivors of childhood brain tumours, and a control group composed of lean and obese children with no history of tumours. We will measure circulating and urinary cytokine levels and cytokine gene expression in monocytes. In addition, the methylation patterns of cytokine genes and that of toll-like receptor genes will be evaluated. These will be correlated with individual and lifestyle factors including age, sex, ethnicity, puberty, body mass index, fasting lipid levels, insulin sensitivity, diet, exercise, sleep, stress and built environment. The sample size calculation showed that we need 25 participants per arm This study has received ethics approval from the institutional review board. Once completed, we will publish this work in peer-reviewed journals and share the findings in presentations and posters in meetings. This study will permit the interrogation of inflammation as a contributor to obesity and its complications in obese survivors of childhood brain tumours and compare them with lean survivors and lean and obese controls with no history of tumours, which may help identify therapeutic and preventative interventions to combat the rising tide of obesity.


A Study of Dip-Coatable, High-Capacitance Ion Gel Dielectrics for 3D EWOD Device Fabrication.
We present a dip-coatable, high-capacitance ion gel dielectric for scalable fabrication of three-dimensional (3D) electrowetting-on-dielectric (EWOD) devices such as an n × n liquid prism array. Due to the formation of a nanometer-thick electric double layer (EDL) capacitor, an ion gel dielectric offers two to three orders higher specific capacitance (c ≈ 10 μF/cm²) than that of conventional dielectrics such as SiO₂. However, the previous spin-coating method used for gel layer deposition poses several issues for 3D EWOD device fabrication, particularly when assembling multiple modules. Not only does the spin-coating process require multiple repetitions per module, but the ion gel layer also comes in risks of damage or contamination due to handling errors caused during assembly. In addition, it was observed that the chemical formulation previously used for the spin-coating method causes the surface defects on the dip-coated gel layers and thus leads to poor EWOD performance. In this paper, we alternatively propose a dip-coating method with modified gel solutions to obtain defect-free, functional ion gel layers without the issues arising from the spin-coating method for 3D device fabrication. A dip-coating approach offers a single-step coating solution with the benefits of simplicity, scalability, and high throughput for deposition of high-capacitance gel layers on non-planar EWOD devices. An ion gel solution was prepared by combining the [EMIM][TFSI] ionic liquid and the [P(VDF-HFP)] copolymer at various wt % ratios in acetone solvent. Experimental studies were conducted to fully understand the effects of chemical composition ratios in the gel solution and how varying thicknesses of ion gel and Teflon layers affects EWOD performance. The effectiveness and potentiality of dip-coatable gel layers for 3D EWOD devices have been demonstrated through fabricating 5 × 1 arrayed liquid prisms using a single-step dip-coating method. Each prism module has been individually controlled to achieve spatial beam steering without the need for bulky mechanical moving parts.


Responses of dietary ileal amino acid digestibility to consumption of different cultivars of potatoes and conventional fibers in grower pigs fed a high-fat basal diet.
Whereas dietary fibers are well recognized for nutritional management of human health issues, fiber is also known to be one of the dietary factors potentially affecting digestive use of dietary proteins. As a staple food, potato (Solanum tuberosum) may be a significant dietary fiber source. The objective of this study was to examine effects of dietary supplementation of six potato cultivar-genotype samples that differ in soluble fiber content and two conventional fiber components (i.e., cellulose and guar gum) on the apparent ileal AA digestibility in pigs fed a high-fat basal diet. The basal diet was formulated as a zero-fiber negative control (NC) to contain 41.5% poultry meal, 4% casein, 15% animal fat-oil blend, 2.8% sucrose, 31% corn (Zea mays) starch, 0.50% salt, and 0.40% trace mineral-vitamin supplement with fat contributing to 47% of the dietary GE. The two fiber diets were formulated by respectively diluting the basal diet with 10% guar gum and 10% cellulose at the expense of corn starch. Six other test diets were formulated by including 8.5% guar gum and further diluting the basal diet with 25.1% one of the six cultivar-genotype samples of dehydrated potato tuber powder to contain about 10% total dietary fiber at the expense of corn starch. Eighty-one 25-kg barrows were fitted with a simple T-cannula at the distal ileum and fed the diets according to a completely randomized block design with each block lasting 28 d. Compared with the NC, the ileal digestibility of Ala, Gly, and Pro were decreased (P < 0.05) by 10% guar gum whereas the digestibility of Gly was reduced (P < 0.05) by 10% cellulose. The ileal digestibility of several AA was decreased (P < 0.05) by the test potatoes plus 8.5% guar gum compared with the NC. Our results suggest that dietary inclusion of fiber at 10% from guar gum and cellulose and contributed by potatoes may adversely affect digestive use of dietary protein.


The Relationship Between Hikikomori Risk and Internet Use During COVID-19 Restrictions.
This study explores the phenomenon of hikikomori, or extreme social isolation, which for the past 20 years has been associated with a range of negative outcomes, including psychological, financial, and social. As hikikomori is associated with marked social withdrawal in one's home and increased Internet use, it has been suggested that the social and technological changes brought about by COVID-19 restrictions may exacerbate the risk of hikikomori in young adults. This study, therefore, sought to identify the relationship between hikikomori risk and changes in Internet use for young people aged 16-24 years during COVID-19 restrictions. An international sample of 826 participants completed an online survey consisting of questions about demographics, experience of lockdown restrictions in the previous 12 months, changes to Internet use in the previous 12 months and a hikikomori risk scale. Higher hikikomori risk was associated with being male, greater time spent in lockdown, and leaving the house less frequently. An increase in Internet use during lockdown was associated with reduced risk of hikikomori. Findings are discussed in relation to gender differences in the type of Internet use engaged in by males and females. It is concluded that online social interaction may be a means of mitigating hikikomori risk in post-COVID-19 societies.


[Analysis of clinical features of community-acquired pneumonia caused by pediatric respiratory syncytial virus and human metapneumovirus].
We retrospectively reviewed the background, clinical features, blood tests, and complications in the 720 children seen for acute respiratory tract infection from July 2004 to December 2005. Of these, 75 (10.5%) were diagnosed with pneumonia due to respiratory syncytial virus (RSV) and 19 (2.6%) with pneumonia due to human metapneumovirus (hMPV) based on multiplex PCR analysis of nasopharyngeal samples. RSV was PCR-positive mostly in winter, -from November to January-, and hMPV mostly in spring, -from March to June. The mean RSV pneumonia group age was 1.3 +/- 1.4 years and in the hMPV pneumonia group 3.0 +/- 3.1 years, showing a statistically significant differences in the age of virus onset. Clinically the RSV group showed more rhinorrhea and wheezing (p < 0.05) and the hMPV group a higher maximum body temperature and a longer wheezing duration (p < 0.05). Fever, cough, vomiting, diarrhea, fever frequency, and C-reactive protein level were similar in both groups (p > 0.05). Complication prevalence was 49.3% in the RSV group and 42.1% in the hMPV group. Acute otitis media was seen more often in the RSV group (32.0%) and febrile convulsion more often in the hMPV group (15.8%) (p > 0.05). These findings may be helpful in clinically diagnosing community-acquired pneumonia due to RSV or hMPV.


Improvements to the ABSINTH Force Field for Proteins Based on Experimentally Derived Amino Acid Specific Backbone Conformational Statistics.
We present an improved version of the ABSINTH implicit solvation model and force field paradigm (termed ABSINTH-C) by incorporating a grid-based term that bootstraps against experimentally derived and computationally optimized conformational statistics for blocked amino acids. These statistics provide high-resolution descriptions of the intrinsic backbone dihedral angle preferences for all 20 amino acids. The original ABSINTH model generates Ramachandran plots that are too shallow in terms of the basin structures and too permissive in terms of dihedral angle preferences. We bootstrap against the reference optimized landscapes and incorporate CMAP-like residue-specific terms that help us reproduce the intrinsic dihedral angle preferences of individual amino acids. These corrections that lead to ABSINTH-C are achieved by balancing the incorporation of the new residue-specific terms with the accuracies inherent to the original ABSINTH model. We demonstrate the robustness of ABSINTH-C through a series of examples to highlight the preservation of accuracies as well as examples that demonstrate the improvements. Our efforts show how the recent experimentally derived and computationally optimized coil-library landscapes can be used as a touchstone for quantifying errors and making improvements to molecular mechanics force fields.


Activation of GluR6-containing kainate receptors induces ubiquitin-dependent Bcl-2 degradation via denitrosylation in the rat hippocampus after kainate treatment.
We previously showed that Bcl-2 (B-cell lymphoma 2) is down-regulated in a kainate (KA)-induced rat epileptic seizure model. The underlying mechanism had remained largely unknown, but we here report for the first time that denitrosylation and ubiquitination are involved. Our results show that the S-nitrosylation levels of Bcl-2 are down-regulated after KA injection and that the GluR6 (glutamate receptor 6) antagonist NS102 can inhibit the denitrosylation of Bcl-2. Moreover, the ubiquitin-dependent degradation of Bcl-2 was found to be promoted after KA treatment, which could be suppressed by the proteasome inhibitor MG132 and the NO donors, sodium nitroprusside and S-nitrosoglutathione. In addition, experiments based on siRNA transfections were performed in the human SH-SY5Y neuroblastoma cell line to verify that the stability of Bcl-2 is causal to neuronal survival. At the same time, it was found that the exogenous NO donor GSNO could protect neurons when Bcl-2 is targeted. Subsequently, these mechanisms were morphologically validated by immunohistochemistry, cresyl violet staining, and in situ TUNEL staining to analyze the expression of Bcl-2 as well as the survival of CA1 and CA3/DG pyramidal neurons. NS102, GSNO, sodium nitroprusside, and MG132 contribute to the survival of CA1 and CA3/DG pyramidal neurons by attenuating Bcl-2 denitrosylation. Taken together, our data reveal that Bcl-2 ubiquitin-dependent degradation is induced by Bcl-2 denitrosylation during neuronal apoptosis after KA treatment.


The social development model: An integrated approach to delinquency prevention.
This paper describes a comprehensive developmental approach to preventing youth crime based on the social development model, an integration of social control theory and social learning theory. The model asserts that the most important units of socialization, family, schools, peers, and community, influence behavior sequentially. Positive socialization is achieved when youths have the opportunity within each unit to be involved in conforming activities, when they develop skills necessary to be successfully involved, and when those with whom they interact consistently reward desired behaviors. These conditions should increase attachment to others, commitment to conforming behavior, and belief in the conventional order. These social bonds to conventional society inhibit association with delinquent pers and, in turn, prevent delinquent behavior. The paper describes prevention approaches consistent with the model. Rigorous evaluation of the delinquency prevention effects of these interventions is needed.


Iris-fixated posterior chamber intraocular lenses in children.
To report the short-term outcomes and complications of iris-fixated posterior chamber intraocular lenses (PCIOL) in the pediatric population. Retrospective, observational case study. Twelve consecutive pediatric patients (17 eyes) underwent placement of foldable iris-sutured PCIOLs between September 1, 2004 and September 30, 2007 by two anterior segment surgeons at a single academic center. Outcome measures included change in visual acuity (VA) and complications. In our series, there was a higher rate of dislocation of iris-sutured IOLs in patients with a history of ectopia lentis resulting from Marfan syndrome or hereditary or idiopathic causes than in patients being treated for aphakia resulting from other causes (45% vs 0%). Mean final VA improved by 0.23 logarithm of the minimum angle of resolution units from preoperative baseline. One eye of a Marfan patient sustained a retinal detachment eight months after dislocation of the PCIOL, and one patient experienced iris capture of the IOL after surgery. Iris-fixated IOLs are reasonable alternative to transsclerally sutured IOLs to correct aphakia in pediatric patient. Dislocation of the IOLs can occur, however, and there is concern for suture degradation over time. The procedure should be considered with caution in pediatric patients.


Perinatal expression of adenylyl cyclase subtypes in rat brown adipose tissue.
The ability of norepinephrine to stimulate adenylyl cyclase (AC) activity increases during the perinatal period in rat brown adipose tissue (BAT), and this increase is associated with changes in the activities of both GS alpha and AC. The purpose of this study was to determine which AC subtypes are present in neonatal BAT and to examine whether the perinatal increase in AC activity corresponds to an increase in the expression of a particular AC subtype. Analysis of AC mRNAs by nuclease protection assay demonstrated the presence of mRNAs encoding AC-III, AC-IV, AC-VI, and AC-IX in embryonic and postnatal BAT. Of the subtypes detected, only AC-III mRNA levels increased substantially during the perinatal period. The increase in AC-III expression was paralleled by an increase in isoproterenol-stimulated AC activity. Treatment of neonates was the sympathetic neurotoxin 6-hydroxydopamine abolished the perinatal increase in both AC activity and AC-III mRNA levels but had no effect on the expression of other AC subtypes. These results strongly indicate that the increase in AC activity during the perinatal period is due to an increase in the expression of AC-III.


[Management of patients with recurrent purulent sinusitis caused by structural anomaly of the unciform process].
We have examined and treated 14 patients suffering from recurrent bacterial sinusitis (RBS) in abnormal unciform process (UP). The duration of the disease was 1 to 3 years, mean 1.9 years. The patients had UP hypoplasia (n=7), UP perforation (n=4), defects due to endonasal surgical intervention (n=3). We made surgical remodeling of the UP by two original techniques. After follow-up for 1-1.5 years the results of the treatment in patients with recurrent bacterial maxillary ethmoiditis were satisfactory in 12 (85.7%) patients and unsatisfactory in 2 (14.3%) patients.


Comparative Trophic Levels of Phragmocone-Bearing Cephalopods (Nautiloids, Ammonoids and Sepiids).
Cephalopods are among many marine animals that through some combination of habit and/or habitat have proven difficult to study, especially understanding their trophic positions in marine communities. Stable isotope analyses have provided powerful tools for discovering quantitative aspects about the ecology and food sources of many cephalopod species. Here, we present new gut content and isotopic data (carbon and nitrogen isotopes) from phragmocone-bearing cephalopods (both ectocochleates, as well as those with internal, hard part buoyancy maintenance apparatuses). To this, we also include observations from baited remote underwater video systems (BRUVS) to describe feeding habits and potential prey types to correlate with gut contents analyses. These data come from extant Allonautilus, Nautilus, and Sepia species, as well as from extinct nautiloids and ammonites. Extant nautiloids occupy a different isotopic niche than all other cephalopod groups where such data have been published to date. We conclude that these species are obligate scavengers rather than predators on any living species in their environments. Extant Nautilus and Allonautilus also demonstrate different patterns of functional allometry of nitrogen isotope values over ontogeny than do most other cephalopods (or animals in general), by showing decreasing nitrogen isotope levels during ontogeny. This pattern is shown to be different in Sepia and the yet small number of ammonite cephalopods studied to date, supporting the increasingly accepted view that ammonites were far closer to coleoids in basic biology than nautiloids. Overall, phragmocone-bearing cephalopods appear fundamentally different ecologically than cephalopods without this kind of buoyancy system. Of these groups, nautiloids appear to live a low-energy existence that allows them to subsist on energy-poor food sources, such as crustacean molts, as well as being able to scavenge in low oxygen basins where rare food-falls, such as dead fish, remain unobtainable by most other animals.


Patterns of denial in sex offenders: a replication study.
To assess whether a robust typology of sex offenders could be established based on the patterns of denial displayed, a previously developed semistructured interview method was used to assess denial in a mixed group of convicted rapists and child molesters. Cluster analysis was used to establish homogeneous groups of sex offenders based on the pattern of denial in each case, with a three-cluster solution emerging as the most appropriate, confirming previous research. The denial groups were compared in relation to objective offense characteristics to assess whether a consistent typology of offenders emerged. Each of the four groups of offenders identified (three groups emerging from the cluster analysis and an "absolute denier" group) corresponded closely with the previously identified typology. However, the authors failed to replicate previously identified differences between the denial groups in relation to independent variables such as offense type. Each group contained both rapists and child molesters and was found to differ quantitatively rather than qualitatively in the pattern of the denial expressed, with attributional style being the most consistent form of denial present in all groups. The authors conclude that denial consists of at least two continuous dimensions, rather than being a dichotomous phenomenon. Differences in the patterns of denial displayed by rapists and child molesters were found to be primarily quantitative rather than qualitative.


Acute Right Ventricular Geometric Change Predicts Outcomes in HeartMate 3 Patients.
The physiological response of the right ventricle (RV) following left ventricular assist device (LVAD) implantation is difficult to predict. We aimed to investigate RV geometric and functional changes after LVAD insertion and their effects on clinical outcomes. We retrospectively reviewed 188 patients who underwent HeartMate 3 implantation at our center between November 2014 and September 2021. The RV end-diastolic diameter (RVEDD) and area (RVEDA) were measured on preoperative and pre-discharge transthoracic echocardiography. The non-adapted group included patients with increased RVEDD and RVEDA at discharge. The composite outcome was defined as death or readmission due to worsening right heart failure. There were 82 patients (44%) who had a non-adapted and 106 (56%) who had an adapted RV. Preoperatively, the non-adapted group had smaller RVEDD (46 vs. 49 mm, p < 0.001) and RVEDA (27 vs. 31 cm2, p < 0.001). At discharge, the non-adapted group had larger RVEDD (51 vs. 43 mm, p < 0.001) and RVEDA (33 vs. 27 cm2, p < 0.001). Kaplan-Meier analysis demonstrated worse 3-year survival (77% vs. 91%, p = 0.006) and freedom from composite outcome (58% vs. 85%, p < 0.001) in the non-adapted group. A multivariable Cox proportional hazards model showed that non-adaption (HR 3.09, 95% CI 1.29-7.40 p = 0.01) and age (HR 3.73, 95% CI 1.42-9.77, p = 0.007) were independent predictors of composite outcome. Acute RV dimensional changes after LVAD insertion may represent intrinsic RV function and may be a useful prognostic marker.


Adaptive multichannel FES neuroprosthesis with learning control and automatic gait assessment.
FES (Functional Electrical Stimulation) neuroprostheses have long been a permanent feature in the rehabilitation and gait support of people who had a stroke or have a Spinal Cord Injury (SCI). Over time the well-known foot switch triggered drop foot neuroprosthesis, was extended to a multichannel full-leg support neuroprosthesis enabling improved support and rehabilitation. However, these neuroprostheses had to be manually tuned and could not adapt to the persons' individual needs. In recent research, a learning controller was added to the drop foot neuroprosthesis, so that the full stimulation pattern during the swing phase could be adapted by measuring the joint angles of previous steps. The aim of this research is to begin developing a learning full-leg supporting neuroprosthesis, which controls the antagonistic muscle pairs for knee flexion and extension, as well as for ankle joint dorsi- and plantarflexion during all gait phases. A method was established that allows a continuous assessment of knee and foot joint angles with every step. This method can warp the physiological joint angles of healthy subjects to match the individual pathological gait of the subject and thus allows a direct comparison of the two. A new kind of Iterative Learning Controller (ILC) is proposed which works independent of the step duration of the individual and uses physiological joint angle reference bands. In a first test with four people with an incomplete SCI, the results showed that the proposed neuroprosthesis was able to generate individually fitted stimulation patterns for three of the participants. The other participant was more severely affected and had to be excluded due to the resulting false triggering of the gait phase detection. For two of the three remaining participants, a slight improvement in the average foot angles could be observed, for one participant slight improvements in the averaged knee angles. These improvements where in the range of 4circat the times of peak dorsiflexion, peak plantarflexion, or peak knee flexion. Direct adaptation to the current gait of the participants could be achieved with the proposed method. The preliminary first test with people with a SCI showed that the neuroprosthesis can generate individual stimulation patterns. The sensitivity to the knee angle reset, timing problems in participants with significant gait fluctuations, and the automatic ILC gain tuning are remaining issues that need be addressed. Subsequently, future studies should compare the improved, long-term rehabilitation effects of the here presented neuroprosthesis, with conventional multichannel FES neuroprostheses.


Effects of Speech Output on Maintenance of Requesting and Frequency of Vocalizations in Three Children with Developmental Disabilities.
We evaluated the role of digitized speech output on the maintenance of requesting and frequency of vocalizations in three children with developmental disabilities. The children were taught to request access to preferred objects using an augmentative communication speech-generating device (SGD). Following acquisition, rates of requesting and vocalizations were compared across two conditions (speech output on versus speech output off) that were alternated on a session-by-session basis. There were no major or consistent differences across the two conditions for the three children, suggesting that access to preferred objects was the critical variable maintaining use of the SGDs. The results also suggest that feedback in the form of digitized speech from the SGD did not inhibit vocalizations. One child began to speak single words during the latter part of the study, suggesting that in some cases AAC intervention involving SGDs may facilitate speech.


Effects and Mechanisms of Transcutaneous Electrical Acustimulation on Postoperative Recovery After Elective Cesarean Section.
To explore the effects and mechanisms of transcutaneous electrical acustimulation (TEA) on postoperative recovery after cesarean section (CS). A total of 108 women who underwent CS were randomized to receive TEA or sham-TEA. Four hours after CS, electrogastrogram (EGG) and electrocardiogram (ECG) were recorded for 30 min to assess gastric slow waves and autonomic functions, respectively. TEA at ST36 or sham-TEA at non-acupoints was performed for one hour right after recording ECG and EGG and then twice daily from postoperative days (POD) 1 to 3. In the morning of POD4, the EGG and ECG were recorded again for 30 min. TEA enhanced postoperative recovery associated with lower GI motility, reflected as a reduction in time of first flatus (p = 0.002) and time of first defecation (p < 0.001), an increase in the Bristol stool score (p < 0.001) and the number of SBMs (p < 0.001) in comparison with sham-TEA. TEA reduced symptoms associated with upper GI motility, including a reduction in time to resume semifluid (p = 0.008), and the total score of loss of appetite (p = 0.003) and belching (p = 0.038) from POD1 to POD3. Physiologically, TEA but not sham-TEA increased the percentage of normal gastric slow waves on POD4 compared with POD0 (p = 0.001). TEA reduced the visual analogue scale (VAS) pain score from POD1 to POD3 (p < 0.001). TEA but not sham-TEA increased vagal activity (p = 0.013) and decreased sympathetic activity (p = 0.013) on POD4 compared with POD0. Two factors were found to be independent predictors of shortened time of the first defecation: the use of TEA and a shorter surgical duration. Needleless non-invasive TEA at ST36 is effective in promoting both lower and upper GI symptoms after CS by enhancing vagal and suppressing sympathetic activities [Correction added on 23 June 2020, after first online publication: The first word of the preceded sentence has been corrected.].


Integration of statistical inferences and machine learning algorithms for prediction of metritis cure in dairy cows.
The study's objectives were to identify cow-level and environmental factors associated with metritis cure to predict metritis cure using traditional statistics and machine learning algorithms. The data set used was from a previous study comparing the efficacy of different therapies and self-cure for metritis. Metritis was defined as fetid, watery, reddish-brownish discharge, with or without fever. Cure was defined as an absence of metritis signs 12 d after diagnosis. Cows were randomly allocated to receive a subcutaneous injection of 6.6 mg/kg of ceftiofur crystalline-free acid (Excede, Zoetis) at the day of diagnosis and 3 d later (n = 275); and no treatment at the time of metritis diagnosis (n = 275). The variables days in milk (DIM) at metritis diagnosis, treatment, season of the metritis diagnosis, month of metritis diagnostic, number of lactation, parity, calving score, dystocia, retained fetal membranes, body condition score at d 5 postpartum, vulvovaginal laceration score, the rectal temperature at the metritis diagnosis, fever at diagnosis, milk production from the day before to metritis diagnosis, and milk production slope up to 5, 7, and 9 DIM were offered to univariate logistic regression. Variables included in the multivariable logistic regression model were selected from the univariate analysis according to P-value. Variables were offered to the model to assess the association between these factors and metritis cure. Additionally, the univariate logistic regression variables were offered to a recursive feature elimination to find the optimal subset of features for a machine learning algorithms analysis. Cows without vulvovaginal laceration had 1.91 higher odds of curing of metritis than cows with vulvovaginal laceration. Cows that developed metritis at >7 DIM had 2.09 higher odds of being cured than cows that developed metritis at ≤7 DIM. For rectal temperature, each degree Celsius above 39.4°C led to lower odds to be cured than cows with rectal temperature ≤39.4°C. Furthermore, milk production slope and milk production difference from the day before to the metritis diagnosis were essential variables to predict metritis cure. Cows that had reduced milk production from the day before to the metritis diagnosis had lower odds to be cured than cows with moderate milk production increase. The results from the multivariable logistic regression and receiver operating characteristic analysis indicated that cows developing metritis at >7 DIM, with increase in milk production, and with a rectal temperature ≤39.40°C had increased likelihood of cure of metritis with an accuracy of 75%. The machine learning analysis showed that in addition to these variables, calving-related disorders, season, and month of metritis event were needed to predict whether the cow will cure or not from metritis with an accuracy ≥70% and F1 score (harmonic mean between precision and recall) ≥0.78. Although machine learning algorithms are acknowledged as powerful tools for predictive classification, the current study was unable to replicate its potential benefits. More research is needed to optimize predictive models of metritis cure.


Lack of Rule-Adherence During Mountain Gorilla Tourism Encounters in Bwindi Impenetrable National Park, Uganda, Places Gorillas at Risk From Human Disease.
Mountain gorillas (Gorilla beringei beringei) are an endangered primate species, with ~43% of the 1,063 individuals that remain on the planet today residing in Bwindi Impenetrable National Park (BINP) in southwestern Uganda. These primates are at the heart of a growing tourism industry that has incentivized their continued protection, but close proximity between humans and gorillas during such encounters presents well-documented risks for disease transmission. The Uganda Wildlife Authority (UWA) has developed rules to help protect the health of the gorillas, limiting each habituated gorilla group to a single 60 min visit each day by a group of no more than 8 tourists, and emphasizing that humans maintain a >7 m distance from gorillas at all times. A number of studies have documented that not all tour groups respect these rules. This project assesses rule-adherence during gorilla tourism encounters at BINP using both observational and survey-based data collected during the tourism high season between May and August, 2014. Observational data from 53 treks reveal that groups of 1-11 tourists engaged in gorilla viewing encounters between 46 and 98 min in duration. Although 96% of pre-trek briefings conducted by park rangers emphasized the need to maintain >7 m human-gorilla spacing, the 7 m distance rule was violated in over 98% (52 out of 53) of the tours examined in this study. Observational data were collected at 2 min intervals during gorilla-viewing encounters, documenting the nearest distance between any tourist and a gorilla (n = 1,604), of which 1,094 observations (68.2%) took place at a distance less than or equal to 7 m. Importantly, the 7 m rule was violated in visits to all of the gorilla groups habituated during the time of the study. In 224 observations (~14%, per 1,604 total), human-gorilla spacing was 3 m or less. Survey data (n = 243) revealed promising opportunities to improve tourist understanding of and adherence to park rules, with 73.6% of respondents indicating that they would be willing to utilize a precautionary measure of wearing a face-mask during encounters to protect gorilla health.


Macromolecular structure of cellulose studied by second-harmonic generation imaging microscopy.
The macromolecular structure of purified cellulose samples is studied by second-harmonic generation (SHG) imaging microscopy. We show that the SHG contrast in both Valonia and Acetobacter cellulose strongly resembles that of collagen from animal tissues, both in terms of morphology and polarization anisotropy. Polarization analysis shows that microfibrils in each lamella are highly aligned and ordered and change directions by 90 degrees in adjacent lamellae. The angular dependence of the SHG intensity fits well to a cos2 theta distribution, which is characteristic of the electric dipole interaction. Enzymatic degradation of Valonia fibers by cellulase is followed in real time by SHG imaging and results in exponential decay kinetics, showing that SHG imaging microscopy is ideal for monitoring dynamics in biological systems.


Effects of ursolic acid on glucose metabolism, the polyol pathway and dyslipidemia in non-obese type 2 diabetic mice.
Ursolic acid (UA) is a pentacyclic triterpenoid compound that naturally occurs in fruits, leaves and flowers of medicinal herbs. This study investigated the dose-response efficacy of UA (0.01 and 0.05%) on glucose metabolism, the polyol pathway and dyslipidemia in streptozotocin/nicotinamide-induced diabetic mice. Supplement with both UA doses reduced fasting blood glucose and plasma triglyceride levels in non-obese type 2 diabetic mice. High-dose UA significantly lowered plasma free fatty acid, total cholesterol and VLDL-cholesterol levels compared with the diabetic control mice, while LDL-cholesterol levels were reduced with both doses. UA supplement effectively decreased hepatic glucose-6-phosphatase activity and increased glucokinase activity, the glucokinase/glucose-6-phosphatase ratio, GLUT2 mRNA levels and glycogen content compared with the diabetic control mice. UA supplement attenuated hyperglycemia-induced renal hypertrophy and histological changes. Renal aldose reductase activity was higher, whereas sorbitol dehydrogenase activity was lower in the diabetic control group than in the non-diabetic group. However, UA supplement reversed the biochemical changes in polyol pathway to normal values. These results demonstrated that low-dose UA had preventive potency for diabetic renal complications, which could be mediated by changes in hepatic glucose metabolism and the renal polyol pathway. High-dose UA was more effective anti-dyslipidemia therapy in non-obese type 2 diabetic mice.


The TMA-93: A New Memory Test for Alzheimer's Disease in Illiterate and Less Educated People.
The present study aimed at validating the Memory Associative Test of the district of Seine-Saint-Denis (TMA)-93, a new test of episodic memory. The TMA-93 was proposed to mostly less educated and multicultural elderly population composed of 376 healthy controls (HC) and 94 patients with Alzheimer's disease (AD). The construct validity was checked by studying correlations with a widely used memory test (the Free and Cued Selective Reminding Test [FCSRT]) in the subsample of literate patients. Results showed that (i) all the TMA-93 scores of the patients with AD were lower than those of the HC, (ii) the TMA-93 total score identified patients with AD with a high sensitivity (88%) and very high specificity (97%), and (iii) the TMA-93 total score was strongly correlated with both free recall and total recall scores of the FCSRT. Taken together, results showed that the TMA-93 is a reliable tool to assess episodic memory in a multicultural, less educated, or illiterate population, with good construct validity for AD diagnostic accuracy.


Integration of swimming kinematics and ram suspension feeding in a model American paddlefish, Polyodon spathula.
Ram suspension-feeding fishes swim with an open mouth to force water through the oral cavity and extract prey items that are too small to be pursued individually. Recent research has indicated that, rather than using a dead-end mechanical sieve, American paddlefish (Polyodon spathula) employ vortical cross-step filtration. In this filtration mechanism, vortical flow that is generated posterior to the branchial arches organizes crossflow filtration processes into a spatial structure across the gill rakers. Despite the known impact of locomotor kinematics on fluid flow around the bodies of swimming fish, the effects of locomotor kinematics on filtration mechanisms in ram suspension feeders are unknown. Potential temporal organization of filtration mechanisms in ram suspension-feeding fish has not been studied previously. We investigated the effects of locomotor kinematics associated with undulatory swimming on intra-oral flow patterns and food particle transport. A mechanized model of the oral cavity was used to simulate the swimming kinematics of suspension-feeding paddlefish. We recorded fluctuations of flow speed and pressure within the model, which occurred at a frequency that corresponded with the frequency of the model's strides. Using the mechanized model in a flow tank seeded with Artemia cysts, we also showed that swimming kinematics aided the transport of this simulated food to the posterior margins of the gill slots, although the time scale of this transport is expected to vary with prey parameters such as size and concentration. Dye stream experiments revealed that, although stable vortical flow formed because of flow separation downstream of backward-facing steps in control trials, vortical flow structures in mechanized trials repeatedly formed and shed. These findings suggest strong integration between locomotor and feeding systems in ram suspension-feeding fishes.


Effect of epithelial cell injury on anterior corneal oxygen flux.
The aerobic response of epithelial metabolism to cellular injury or disease was studied with a three-layer model of the cornea. Nonclassical (Michaelis-Menten) respiratory kinetics were assumed, and predicted fluxes validated by reference to known estimates. The model indicates that epithelial oxygen flux is linearly related to epithelial oxygen consumption, and is therefore a direct index of epithelial aerobic metabolism. Injury leading to de-epithelialization decreases total anterior corneal oxygen flux. The decreases reported experimentally with a polarographic oxygen sensor on the denuded stroma in vivo are greater than theoretically predicted. This effect is due to a limited capture depth of the technique, which "sees" only the anterior stroma.


Curative effect of 18β-glycyrrhetinic acid in experimental visceral leishmaniasis depends on phosphatase-dependent modulation of cellular MAP kinases.
We earlier showed that 18β-glycyrrhetinic acid (GRA), a pentacyclic triterpenoid from licorice root, could completely cure visceral leishmaniasis in BALB/c mouse model. This was associated with induction of nitric oxide and proinflammatory cytokine production through the up regulation of NF-κB. In the present study we tried to decipher the underlying cellular mechanisms of the curative effect of GRA. Analysis of MAP kinase pathways revealed that GRA caused strong activation of p38 and to a lesser extent, ERK in bone marrow-derived macrophages (BMDM). Almost complete abrogation of GRA-induced cytokine production in presence of specific inhibitors of p38 and ERK1/2 confirmed the involvement of these MAP kinases in GRA-mediated responses. GRA induced mitogen- and stress-activated protein kinase (MSK1) activity in a time-dependent manner suggested that GRA-mediated NF-κB transactivation is mediated by p38, ERK and MSK1 pathway. As kinase/phosphatase balance plays an important role in modulating infection, the effect of GRA on MAPK directed phosphatases (MKP) was studied. GRA markedly reduced the expression and activities of three phosphatases, MKP1, MKP3 and protein phosphatase 2A (PP2A) along with a substantial reduction of p38 and ERK dephosphorylation in infected BMDM. Similarly in the in vivo situation, GRA treatment of L. donovani-infected BALB/c mice caused marked reduction of spleen parasite burden associated with concomitant decrease of individual phosphatase levels. However, activation of kinases also played an important role as the protective effect of GRA was significantly abrogated by pharmacological inhibition of p38 and ERK pathway. Curative effect of GRA may, therefore, be associated with restoration of proper cellular kinase/phosphatase balance, rather than modulation of either kinases or phosphatases.


Community rating and sustainable individual health insurance markets in New Jersey.
The New Jersey Individual Health Coverage Program (IHCP) was implemented in 1993; key provisions included pure community rating and guaranteed issue/renewal of coverage. Despite positive early evaluations, the IHCP appears to be heading for collapse. Using unique administrative and survey data, we examined trends in IHCP enrollment and premiums. We found the stability of the IHCP to be fragile in light of improving opportunities for job-related health insurance. We also found that it is retaining high-risk enrollees. Institutional realities and the difficulty of identifying a control group preclude attributing causality to the plan's pure community rating and open enrollment provisions.


Spectral gain control using shaped pump pulses in a counter-pumped cascaded fiber Raman amplifier.
We investigate the Raman gain spectra produced from pulse-pumping a highly nonlinear fiber with shaped optical pulses delivered from a Yb-doped fiber MOPA pump source. Cascaded Raman wavelength shifting up to seven Stokes orders is demonstrated and the counter-propagating gain is measured across all seven Stokes orders. Step-shaped optical pulses with varying instantaneous powers are then used to pump the highly nonlinear fiber, generating a controllable gain spectrum across multiple Stokes orders. Furthermore, we extend this work by using multiple pump wavelengths along with step-shaped pulses to increase the bandwidth of the Raman gain spectrum.


Asplenia in a patient with Fanconi's anemia-like congenital aplastic anemia.
Fanconi's anemia (FA) is an autosomal recessive disease manifested by pancytopenia resulting from bone marrow failure, variable physical anomalies and cancer susceptibility. A seven-year-old girl with Fanconi's anemia-like congenital aplastic anemia and concurrent asplenia without the congenital heart defects or the abdominal heterotaxia is reported. Asplenia was indicated using denatured red cells labelled with 51Cr, abdominal ultrasonography and computerized tomography. Immunological studies showed immunoglobulins (IgG, IgA, IgM), C3 and C4 levels within normal limits and the percentage of CD3, and C4 cells and the CD4/CD8 ratio decreased. The patient had not been exposed to recurrent pneumococcal infections. We think that isolated asplenia may occur in patients with Fanconi's anemia-like congenital aplastic anemia without the congenital heart diseases or abdominal heterotaxia.


Psychological consequences of child trafficking: An historical cohort study of trafficked children in contact with secondary mental health services.
Child trafficking is the recruitment and movement of people aged younger than 18 for the purposes of exploitation. Research on the mental health of trafficked children is limited, and little is known about the use of mental health services by this group. This study aimed to investigate the mental health and service use characteristics of trafficked children in contact with mental health services in England. The study employed an historical cohort design. Electronic health records of over 250,000 patients were searched to identify trafficked children, and a matched cohort of non-trafficked children was randomly selected. Data were extracted on the socio-demographic and clinical characteristics, abuse history, and trafficking experiences of the trafficked children. Logistic and linear random effects regression models were fitted to compare trafficked and non-trafficked children on their clinical profiles and service use characteristics. Fifty-one trafficked children were identified, 78% were female. The most commonly recorded diagnoses for trafficked children were post-traumatic stress disorder (PTSD) (22%) and affective disorders (22%). Records documented a high prevalence of physical violence (53%) and sexual violence (49%) among trafficked children. Trafficked children had significantly longer duration of contact with mental health services compared to non-trafficked controls (b = 1.66, 95% CI 1.09-2.55, p<0.02). No significant differences were found, however, with regards to pathways into care, prevalence of compulsory psychiatric admission, length of inpatient stays, or changes in global functioning. Child trafficking is associated with high levels of physical and sexual abuse and longer duration of contact with mental health services. Research is needed on most effective interventions to promote recovery for this vulnerable group.


The Academic Collaborative Center Older Adults: A Description of Co-Creation between Science, Care Practice and Education with the Aim to Contribute to Person-Centered Care for Older Adults.
Long-term care for older adults is in transition. Organizations offering long-term care for older adults are expected to provide person-centered care (PCC) in a complex context, with older adults aging in place and participating in society for as long as possible, staff shortages and the slow adoption of technological solutions. To address these challenges, these organizations increasingly use scientific knowledge to evaluate and innovate long-term care. This paper describes how co-creation, in the sense of close, intensive, and equivalent collaboration between science, care practice, and education, is a key factor in the success of improving long-term care for older adults. Such co-creation is central in the Academic Collaborative Center (ACC) Older Adults of Tilburg University. In this ACC, Tilburg University has joined forces with ten organizations that provide care for older adults and CZ zorgkantoor to create both scientific knowledge and societal impact in order to improve the quality of person-centered care for older adults. In the Netherlands, a "zorgkantoor" arranges long-term (residential) care on behalf of the national government. A zorgkantoor makes agreements on cost and quality with care providers and helps people that are in need of care to decide what the best possible option in their situation is. The CZ zorgkantoor arranges the long-term (residential) care in the south and southwest of the Netherlands. This paper describes how we create scientific knowledge to contribute to the knowledge base of PCC for older adults by conducting social scientific research in which the perspectives of older adults are central. Subsequently, we show how we create societal impact by facilitating and stimulating the use of our scientific knowledge in daily care practice. In the closing section, our ambitions for the future are discussed.


Friedreich's ataxia: new insights.
Friedreich ataxia (FRDA) is an inherited disease that is typically caused by GAA repeat expansion within the first intron of the FXN gene coding for frataxin. This results in the frataxin deficiency that affects mostly muscle, nervous, and cardiovascular systems with progressive worsening of the symptoms over the years. This review summarizes recent progress that was achieved in understanding of molecular mechanism of the disease over the last few years and latest treatment strategies focused on overcoming the frataxin deficiency.


A Content Analysis of Self-Reported Financial Relationships in Biomedical Research.
Financial conflicts of interest (fCOI) present well documented risks to the integrity of biomedical research. However, few studies differentiate among fCOI types in their analyses, and those that do tend to use preexisting taxonomies for fCOI identification. Research on fCOI would benefit from an empirically-derived taxonomy of self-reported fCOI and data on fCOI type and payor prevalence. We conducted a content analysis of 6,165 individual self-reported relationships from COI statements distributed across 378 articles indexed with PubMed. Two coders used an iterative coding process to identify and classify individual fCOI types and payors. Inter-rater reliability was κ = 0.935 for fCOI type and κ = 0.884 for payor identification. Our analysis identified 21 fCOI types, 9 of which occurred at prevalences greater than 1%. These included research funding (24.8%), speaking fees (20.8%), consulting fees (18.8%), advisory relationships (11%), industry employment (7.6%), unspecified fees (4.8%), travel fees (3.2%), stock holdings (3.1%), and patent ownership (1%). Reported fCOI were held with 1,077 unique payors, 22 of which were present in more than 1% of financial relationships. The ten most common payors included Pfizer (4%), Novartis (3.9%), MSD (3.8%), Bristol Myers Squibb (3.2%), AstraZeneca (3.1%), GSK (3%), Boehringer Ingelheim (2.9%), Roche (2.8%), Eli LIlly (2.5%), and AbbVie (2.4%). These results provide novel multi-domain prevalence data on self-reported fCOI and payors in biomedical research. As such, they have the potential to catalyze future research that can assess the differential effects of various types of fCOI. Specifically, the data suggest that comparative analyses of the effects of different fCOI types are needed and that special attention should be paid to the diversity of payor types for research relationships.


Does low socioeconomic status affect use of nutritional services by pre-diabetes patients?
This paper's aim is to identify whether community-level socioeconomic status (SES) predicts: screening test for pre-diabetes; actual diagnosis of pre-diabetes; or nutritional counseling. This is an analysis of 1,348,124 insured adults receiving medical care from Maccabi Healthcare Services (MHS) in 107 MHS clinics throughout Israel. The research population comprised 79 percent of the MHS members over 18 years of age in 2004-2006. Area level socioeconomic data were drawn from the Israel Central Bureau of Statistics SES index for every geographical area and each MHS clinic in the study was coded from: - 1.03 to 2.73 (- 1.03 indicating low SES and 2.73 + high SES) according to the SES index for the location. The fasting glucose laboratory test was used for analysis. Pre-diabetes diagnosis was based on a fasting glucose above 100 mg/dl. Nutritional counseling was defined by dietitian visits in the claims database. The percentage of insured individuals who underwent blood glucose testing during the study increased with age from 67 percent at ages 18-45 to92 percent for age 65 and over. The percentage of individuals diagnosed with pre-diabetes also increased with age, rising from 4 percent in the younger group to 14 percent in those aged 46-65 and to 14-16 percent of 65 and older. The percentage of individuals with pre-diabetes who visited a dietitian was 16-27 percent for those under 65 and 14-17 percent for those over 65 (males and females, respectively). Individuals living in lower socioeconomic areas were less likely to have blood tests. Among tested patients, the prevalence of pre-diabetes was higher in areas of lower SES and their dietitian visits were less frequent. In lower SES index areas, there is a need for better identification and treatment of patients. The paper shows that a proactive approach is needed both to detect pre-diabetes and to encourage patients to receive nutritional treatment.


Gamma interferon responses induced by a panel of recombinant and purified mycobacterial antigens in healthy, non-mycobacterium bovis BCG-vaccinated Malawian young adults.
We have previously shown that young adults living in a rural area of northern Malawi showed greater gamma interferon (IFN-gamma) responses to purified protein derivatives (PPD) prepared from environmental mycobacteria than to PPD from Mycobacterium tuberculosis. In order to define the mycobacterial species to which individuals living in a rural African population have been exposed and sensitized, we tested T-cell recognition of recombinant and purified antigens from M. tuberculosis (38 kDa, MPT64, and ESAT-6), M. bovis (MPB70), M. bovis BCG (Ag85), and M. leprae (65 kDa, 35 kDa, and 18 kDa) in >600 non-M. bovis BCG-vaccinated young adults in the Karonga District of northern Malawi. IFN-gamma was measured by enzyme-linked immunosorbent assay (ELISA) in day 6 supernatants of diluted whole-blood cultures. The recombinant M. leprae 35-kDa and 18-kDa and purified native M. bovis BCG Ag85 antigens induced the highest percentages of responders, though both leprosy and bovine tuberculosis are now rare in this population. The M. tuberculosis antigens ESAT-6 and MPT64 and the M. bovis antigen MPB70 induced the lowest percentages of responders. One of the subjects subsequently developed extrapulmonary tuberculosis; this individual had a 15-mm-diameter reaction to the Mantoux test and responded to M. tuberculosis PPD, Ag85, MPT64, and ESAT-6 but not to any of the leprosy antigens. We conclude that in this rural African population, exposure to M. tuberculosis or M. bovis is much less frequent than exposure to environmental mycobacteria such as M. avium, which have antigens homologous to the M. leprae 35-kDa and 18-kDa antigens. M. tuberculosis ESAT-6 showed the strongest association with the size of the Mantoux skin test induration, suggesting that among the three M. tuberculosis antigens tested it provided the best indication of exposure to, or infection with, M. tuberculosis.


DIANA-microT Web server upgrade supports Fly and Worm miRNA target prediction and bibliographic miRNA to disease association.
microRNAs (miRNAs) are small endogenous RNA molecules that are implicated in many biological processes through post-transcriptional regulation of gene expression. The DIANA-microT Web server provides a user-friendly interface for comprehensive computational analysis of miRNA targets in human and mouse. The server has now been extended to support predictions for two widely studied species: Drosophila melanogaster and Caenorhabditis elegans. In the updated version, the Web server enables the association of miRNAs to diseases through bibliographic analysis and provides insights for the potential involvement of miRNAs in biological processes. The nomenclature used to describe mature miRNAs along different miRBase versions has been extensively analyzed, and the naming history of each miRNA has been extracted. This enables the identification of miRNA publications regardless of possible nomenclature changes. User interaction has been further refined allowing users to save results that they wish to analyze further. A connection to the UCSC genome browser is now provided, enabling users to easily preview predicted binding sites in comparison to a wide array of genomic tracks, such as single nucleotide polymorphisms. The Web server is publicly accessible in www.microrna.gr/microT-v4.


Antioxidant protective effect of glibenclamide and metformin in combination with honey in pancreas of streptozotocin-induced diabetic rats.
Hyperglycemia exerts toxic effects on the pancreatic beta-cells. This study investigated the hypothesis that the common antidiabetic drugs glibenclamide and metformin, in combination with tualang honey, offer additional protection for the pancreas of streptozotocin (STZ)-induced diabetic rats against oxidative stress and damage. Diabetes was induced in male Sprague Dawley rats by a single dose of STZ (60 mg/kg; ip). Diabetic rats had significantly elevated levels of lipid peroxidation (TBARS), up-regulated activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) while catalase (CAT) activity was significantly reduced. Glibenclamide and metformin produced no significant effects on TBARS and antioxidant enzymes except GPx in diabetic rats. In contrast, the combination of glibenclamide, metformin and honey significantly up-regulated CAT activity and down-regulated GPx activity while TBARS levels were significantly reduced. These findings suggest that tualang honey potentiates the effect of glibenclamide and metformin to protect diabetic rat pancreas against oxidative stress and damage.


[(18)F]FDOPA and [(18)F]CFT are both sensitive PET markers to detect presynaptic dopaminergic hypofunction in early Parkinson's disease.
The aim of this study was to compare two PET ligands, 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) and (18)F-labeled CFT, 2beta-carbomethoxy-3beta-(4-[(18)F]-fluorophenyl)tropane ([(18)F]CFT), in detecting presynaptic dopaminergic hypofunction in early Parkinson's disease (PD). These ligands reflect different aspects of presynaptic dopaminergic function, since [(18)F]FDOPA mainly reflects 6-[(18)F]fluorodopamine (fluorodopamine) synthesis and storage whereas [(18)F]CFT uptake is related to dopamine transporter function. Eight de novo patients with PD who had never been on antiparkinsonian medication were investigated with [(18)F]FDOPA and [(18)F]CFT PET. Five healthy volunteers were studied as controls. In PD patients, both [(18)F]FDOPA and [(18)F]CFT uptakes were significantly reduced both in the contralateral and ipsilateral anterior and posterior putamen. The reduction was greatest in the contralateral posterior putamen (to 28% of control mean for [(18)F]FDOPA, P < 0.0001 and to 16% for [(18)F]CFT, P < 0.0001). Individually, all patients' [(18)F]FDOPA and [(18)F]CFT uptake values in the contralateral anterior and posterior putamen were below 3 SD of the control mean. In the caudate nucleus, the mean uptake of both tracers was significantly reduced both ipsilaterally and contralaterally, but less severely than in the putamen (to 69% of the control mean for [(18)F]FDOPA, P = 0.003 and to 60% for [(18)F]CFT, P = 0.001 contralaterally). Our results show that both [(18)F]FDOPA as well as [(18)F]CFT sensitively detect presynaptic dopaminergic hypofunction in early PD. They demonstrate a considerable reduction of tracer uptake that is greatest in the posterior putamen, followed by the anterior putamen and the caudate nucleus.


Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation.
Mycobacterium tuberculosis utilizes multiple mechanisms to evade host immune responses, and inhibition of effector CD4+ T cell responses by M. tuberculosis may contribute to immune evasion. TCR signaling is inhibited by M. tuberculosis cell envelope lipoglycans, such as lipoarabinomannan and lipomannan, but a mechanism for lipoglycans to traffic from M. tuberculosis within infected macrophages to reach T cells is unknown. In these studies, we found that membrane vesicles produced by M. tuberculosis and released from infected macrophages inhibited the activation of CD4+ T cells, as indicated by reduced production of IL-2 and reduced T cell proliferation. Flow cytometry and Western blot demonstrated that lipoglycans from M. tuberculosis-derived bacterial vesicles (BVs) are transferred to T cells, where they inhibit T cell responses. Stimulation of CD4+ T cells in the presence of BVs induced expression of GRAIL, a marker of T cell anergy; upon restimulation, these T cells showed reduced ability to proliferate, confirming a state of T cell anergy. Furthermore, lipoarabinomannan was associated with T cells after their incubation with infected macrophages in vitro and when T cells were isolated from lungs of M. tuberculosis-infected mice, confirming the occurrence of lipoarabinomannan trafficking to T cells in vivo. These studies demonstrate a novel mechanism for the direct regulation of CD4+ T cells by M. tuberculosis lipoglycans conveyed by BVs that are produced by M. tuberculosis and released from infected macrophages. These lipoglycans are transferred to T cells to inhibit T cell responses, providing a mechanism that may promote immune evasion.


Characterizing a design space for a twin-screw wet granulation process: A case study of extended-release tablets.
Twin-screw wet granulation is an emerging continuous manufacturing technology for solid oral dosage forms. This technology has been successfully employed for the commercial manufacture of immediate-released tablets. However, the higher polymer content in extended-release (ER) formulations may present challenges in developing and operating within a desired design space. The work described here used a systematic approach for defining the optimum design space by understanding the effects of the screw design, operating parameters, and their interactions on the critical characteristics of granules and ER tablets. The impacts of screw speed, powder feeding rate, and the number of kneading (KEs) and sizing elements on granules and tablets characteristics were investigated by employing a definitive screening design. A semi-mechanistic model was used to calculate the residence time distribution parameters and validated using the tracers. The results showed that an increase in screw speed decreased the mean residence time of the material within the barrel, while an increase in the powder feeding rate or number of KEs did the opposite and increased the barrel residence time. Screw design and operating parameters affected the flow and bulk characteristics of granules. The screw speed was the most significant factor impacting the tablet's breaking strength. The dissolution profiles revealed that granule characteristics mainly influenced the early phase of drug release. This study demonstrated that a simultaneous optimization of both operating and screw design parameters was beneficial in producing ER granules and tablets of desired performance characteristics while mitigating any failure risks, such as swelling during processing.


Pharmacy residency training programs: a resident's perspective.
As changes are being made in the health care system, the roles and responsibilities of the pharmacist are evolving in direct patient care. The knowledge and skills necessary to succeed in these clinical positions are obtained through postgraduate training through pharmacy practice and specialty residencies and fellowships. Residency candidates are faced with important decisions in choosing which training programs to select and planning the course of the training. This article approaches the questions and decision-making process in residency selection from pharmacy residents' points of view.


Ex vivo measurement of intravertebral pressure during vertebroplasty.
Ex vivo biomechanical study using cadaver vertebral bodies. OBJECTIVE.: To measure the increase in internal vertebral body pressure from cement injection during vertebroplasty. Theoretically, the increased force required to inject polymerizing (viscous) cement into a vertebral body during vertebroplasty could produce a concomitant increase in intravertebral pressure and cause additional damage to the vertebral body. An alternative means of reducing intravertebral pressure during injection may be needed. We placed 11-gauge cannulas bipedicularly in six vertebral bodies from each of two fresh female cadaver spines (one osteoporotic, one normal). One cannula served as the injection route; a manometer was connected to the other. After immersion of the spines in a saline bath, the vertebral bodies were injected with 10 mL of Simplex P cement by depressing the syringe plunger at a rate of 7 mm/sec using a materials testing machine. Static pressure was measured before and after injection. Peak pressure was measured during injection. Maximum pressure elevation was calculated as peak pressure minus initial static pressure. Maximum pressure elevation averaged (+/-SD) 9.4 +/- 8.5 mm Hg and 6.4 +/- 5.0 mm Hg in the osteoporotic and normal spines, respectively. In all cases (9 of 12) in which the pressure measurement system remained patent (i.e., not occluded by cement), postinjection pressure returned to the initial static pressure. The increase in intravertebral body pressure from cement injection during vertebroplasty is minimal. Alternative means of reducing intervertebral pressure before injection may not be needed.


Correlation between dynamic contrast-enhanced MRI characteristics and apparent diffusion coefficient with Ki-67-positive expression in non-mass enhancement of breast cancer.
As a remarkably specific characteristic of breast cancer observed on magnetic resonance imaging (MRI), the association between the NME type breast cancer and prognosis, including Ki-67, necessitates comprehensive exploration. To investigate the correlation between dynamic contrast-enhanced MRI (DCE-MRI) characteristics and apparent diffusion coefficient (ADC) values with Ki-67-positive expression in NME type breast cancer. A total of 63 NME type breast cancer patients were retrospectively reviewed. Malignancies were confirmed by surgical pathology. All patients underwent DCE and diffusion-weighted imaging (DWI) before surgery. DCE-MRI characteristics, including tumor distribution, internal enhancement pattern, axillary adenopathy, and time-intensity curve types were observed. ADC values and lesion sizes were also measured. The correlation between these features and Ki-67 expression were assessed using Chi-square test, Fisher's exact test, and Spearman rank analysis. The receiver operating characteristic curve and area under the curve (AUC) was used to evaluate the diagnostic performance of Ki-67-positive expression. Regional distribution, TIC type, and ipsilateral axillary lymph node enlargement were correlated with Ki-67-positive expression (χ2 = 0.397, 0.357, and 0.357, respectively; P < 0.01). ADC value and lesion size were positively correlated with Ki-67-positive expression (rs = 0.295, 0.392; P < 0.05). The optimal threshold values for lesion size and ADC value to assess Ki-67 expression were determined to be 5.05 (AUC = 0.759) cm and 0.403 × 10-3 s/mm2 (AUC = 0.695), respectively. The best diagnosis performance was the ADC combined with lesion size (AUC = 0.791). The ADC value, lesion size, regional distribution, and TIC type in NME type breast cancer were correlated with Ki-67-positive expression. These features will aid diagnosis and treatment of NME type breast cancer.


Prefrontal cortex neurons reflecting reports of a visual illusion.
When a small, focally attended visual stimulus and a larger background frame shift location at the same time, the frame's new location can affect spatial perception. For horizontal displacements on the order of 1--2 degrees, when the frame moves more than the attended stimulus, human subjects may perceive that the attended stimulus has shifted to the right or left when it has not done so. However, that misapprehension does not disable accurate eye movements to the same stimulus. We trained a rhesus monkey to report the direction that an attended stimulus had shifted by making an eye movement to one of the two report targets. Then, using conditions that induce displacement illusions in human subjects, we tested the hypothesis that neuronal activity in the prefrontal cortex (PF) would reflect the displacement directions reported by the monkey, even when they conflicted with the actual displacement, if any, of the attended stimulus. We also predicted that these cells would have directional selectivity for movements used to make those reports, but not for similar eye movements made to fixate the attended stimulus. A population of PF neurons showed the predicted properties, which could not be accounted for on the basis of either eye-movement or frame-shift parameters. This activity, termed report-related, began approximately 150 ms before the onset of the reporting saccade. Another population of PF neurons showed greater directional selectivity for saccadic eye movements made to fixate the attended stimulus than for similar saccades made to report its displacement. In view of the evidence that PF functions to integrate inputs and actions occurring at different times and places, the present findings support the idea that such integration involves movements to acquire response targets, directly, as well as actions guided by less direct response rules, such as perceptual reports.


Circumpapillary OCT-focused hybrid learning for glaucoma grading using tailored prototypical neural networks.
Glaucoma is one of the leading causes of blindness worldwide and Optical Coherence Tomography (OCT) is the quintessential imaging technique for its detection. Unlike most of the state-of-the-art studies focused on glaucoma detection, in this paper, we propose, for the first time, a novel framework for glaucoma grading using raw circumpapillary B-scans. In particular, we set out a new OCT-based hybrid network which combines hand-driven and deep learning algorithms. An OCT-specific descriptor is proposed to extract hand-crafted features related to the retinal nerve fibre layer (RNFL). In parallel, an innovative CNN is developed using skip-connections to include tailored residual and attention modules to refine the automatic features of the latent space. The proposed architecture is used as a backbone to conduct a novel few-shot learning based on static and dynamic prototypical networks. The k-shot paradigm is redefined giving rise to a supervised end-to-end system which provides substantial improvements discriminating between healthy, early and advanced glaucoma samples. The training and evaluation processes of the dynamic prototypical network are addressed from two fused databases acquired via Heidelberg Spectralis system. Validation and testing results reach a categorical accuracy of 0.9459 and 0.8788 for glaucoma grading, respectively. Besides, the high performance reported by the proposed model for glaucoma detection deserves a special mention. The findings from the class activation maps are directly in line with the clinicians' opinion since the heatmaps pointed out the RNFL as the most relevant structure for glaucoma diagnosis.


Morphological differences in semicrystalline polymers: Implications for local dynamics and chain diffusion.
Morphological differences in semicrystalline polymers due to different crystallization conditions have implications for the chain motion. The local dynamics in the noncrystalline regions of solution-crystallized linear polyethylene is lower than in a melt-crystallized sample, but the opposite is observed for chain diffusion between noncrystalline and crystalline regions. The activation enthalpy for chain diffusion, however, is the same, indicating that entropic differences in the noncrystalline regions strongly influence the chain diffusion of the same polymer in different morphologies.


Consumptive and nonconsumptive effects of cannibalism in fluctuating age-structured populations.
Theory and empirical studies suggest that cannibalism in age-structured populations can regulate recruitment depending on the intensity of intraspecific competition between cannibals and victims and the nature of the cannibalism window, i.e., which size classes interact as cannibals and victims. Here we report on a series of experiments that quantify that window for age-structured populations of salamander larvae and paedomorphic adults. We determined body size limits on cannibalism in microcosms and then the consumptive and nonconsumptive (injuries, foraging and activity, diet, growth) effects on victims in mesocosms with seminatural levels of habitat complexity and alternative prey. We found that cannibalism by the largest size classes (paedomorphs and > or = age 3+ yr larvae) occurs mainly on young-of-the-year (YOY) victims. Surviving YOY and other small larvae had increased injuries, reduced activity levels, and reduced growth rates in the presence of cannibals. Data on YOY survival in an experiment in which we manipulated the density of paedomorphs combined with historical data on the number of cannibals in natural populations indicate that dominant cohorts of paedomorphs can cause observed recruitment failures. Dietary data indicate that ontogenetic shifts in diet should preclude strong intraspecific competition between YOY and cannibals in this species. Thus our results are consistent with previous empirical and theoretical work that suggests that recruitment regulation by cannibalism is most likely when YOY are vulnerable to cannibalism but have low dietary overlap with cannibals. Understanding the role of cannibalism in regulating recruitment in salamander populations is timely, given the widespread occurrences of amphibian decline. Previous studies have focused on extrinsic (including anthropogenic) factors that affect amphibian population dynamics, whereas the data presented here combined with long-term field observations suggest the potential for intrinsically driven population cycles.


Use of absorbable sutures in canine carotid arteries.
To study the functional and microstructural characteristics of polydioxanone sutures in vascular surgery, we created 48 vascular anastomoses in the right and left common carotid arteries of 24 mongrel dogs. In each animal, polydioxanone sutures were used in 1 carotid artery, and polypropylene sutures were used in the contralateral carotid artery. Twelve groups of 2 animals each were then formed. The 1st group was observed for 1 month, the 2nd for 2 months, the 3rd for 3 months, and so on until the 12th group, which was observed for 12 months. At the end of each observation period, reoperation was undertaken to evaluate the vascular anastomoses by means of angiography and microscopy. The polypropylene anastomoses showed a marked deformity, with tissue retraction and a foreign body reaction. In contrast, the polydioxanone anastomoses exhibited satisfactory healing, without deformity, and were well tolerated histologically. We believe that polydioxanone may be a useful, alternative vascular suture material.


Chemical implementation of neural networks and Turing machines.
We propose a reversible reaction mechanism with a single stationary state in which certain concentrations assume either high or low values dependent on the concentration of a catalyst. The properties of this mechanism are those of a McCulloch-Pitts neuron. We suggest a mechanism of interneuronal connections in which the stationary state of a chemical neuron is determined by the state of other neurons in a homogeneous chemical system and is thus a "hardware" chemical implementation of neural networks. Specific connections are determined for the construction of logic gates: AND, NOR, etc. Neural networks may be constructed in which the flow of time is continuous and computations are achieved by the attainment of a stationary state of the entire chemical reaction system, or in which the flow of time is discretized by an oscillatory reaction. In another article, we will give a chemical implementation of finite state machines and stack memories, with which in principle the construction of a universal Turing machine is possible.


Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA.
Glutathione (GSH) is a vital intracellular cysteine-containing tripeptide across all kingdoms of life and assumes a plethora of cellular roles. Such pleiotropic behavior relies on a finely tuned spatiotemporal distribution of glutathione and its conjugates, which is not only controlled by synthesis and breakdown, but also by transport. Here, we show that import of glutathione in the obligate human pathogen Haemophilus influenzae, a glutathione auxotrophe, is mediated by the ATP-binding cassette (ABC)-like dipeptide transporter DppBCDF, which is primed for glutathione transport by a dedicated periplasmic-binding protein (PBP). We have identified the periplasmic lipoprotein HbpA, a protein hitherto implicated in heme acquisition, as the cognate PBP that specifically binds reduced (GSH) and oxidized glutathione (GSSG) forms of glutathione with physiologically relevant affinity, while it exhibits marginal binding to hemin. Dissection of the ligand preferences of HbpA showed that HbpA does not recognize bulky glutathione S conjugates or glutathione derivatives with C-terminal modifications, consistent with the need for selective import of useful forms of glutathione and the concomitant exclusion of potentially toxic glutathione adducts. Structural studies of the highly homologous HbpA from Haemophilus parasuis in complex with GSSG have revealed the structural basis of the proposed novel function for HbpA-like proteins, thus allowing a delineation of highly conserved structure-sequence fingerprints for the entire family of HbpA proteins. Taken together, our studies unmask the main physiological role of HbpA and establish a paradigm for glutathione import in bacteria. Accordingly, we propose a name change for HbpA to glutathione-binding protein A.


Porous high-density polyethylene implants in auricular reconstruction.
To evaluate the ability of porous high-density polyethylene (Medpor) implants to tolerate exposure and support skin grafts when used to reconstruct defects in auricular cartilage in an animal model. Polyethylene implants placed in surgically created defects in auricular cartilage and covered with a skin flap were then exposed at either 4, 7, or 21 days after implantation. The exposed implants were then allowed to heal secondarily or received a skin graft 1 week later. The ability of polyethylene implants to tolerate exposure and support skin grafts was observed clinically and via histological study of the implantation sites. Nine adult New Zealand rabbits. Polyethylene implants demonstrated excellent ability to tolerate wound exposure as early as 4 days after implantation, with extrusion of 1 of the 36 implants placed. The degree of secondary wound healing increased as the interval from implantation to exposure increased from 4 to 21 days. Exposed polyethylene implants in all groups also supported all 18 skin grafts placed 1 week after exposure of the implant surface. Polyethylene implants are well tolerated as replacements for native cartilage in auricular reconstruction. Polyethylene implants tolerated wound exposure as early as 4 days after implantation and demonstrated the ability to heal by secondary intention and support skin grafts. This is likely because of the extent of fibrovascular ingrowth from surrounding tissue, which allows the material to behave more like native tissue and less like a foreign body in this setting.


[Effect of GDP on transducin interaction with cyclic nucleotide phosphodiesterase and rhodopsin from bovine retinal rods].
In the presence of guanyl nucleotides and rhodopsin-containing retinal rod outer segment membranes, transducin stimulates the light-sensitive cyclic nucleotide phosphodiesterase 5.5-7 times. The activation constant (Ka) for GTP and Gpp(NH)p is 0.25 microM, that for GDP and GDP beta S is 14 and 110 microM, respectively. GDP purified from other nucleotide contaminations at concentrations up to 1 mM does not stimulate phosphodiesterase but binds to transducin and inhibits the Gpp(NH)p-dependent activation of phosphodiesterase. The mode of transducin interaction with bleached rhodopsin also depends on the nature of the bound guanyl nucleotide: in the presence of GDP rhodopsin-containing membranes bind 70-100% of transducin, whereas in the presence of Gpp(NH)p the membranes bind only 13% of the protein. The experimental results suggest that GDP and GTP convert transducin into two different functional states, i.e., the transducin X GTP complex binds to phosphodiesterase causing its stimulation, while the transducin X GDP complex is predominantly bound to rhodopsin.


Commentary on "The clinical epidemiology of urachal carcinoma: results of a large, population based study." Bruins HM, Visser O, Ploeg M, Hulsbergen-van de Kaa CA, Kiemeney LA, Witjes JA, Department of Urology, Radboud University Medical Centre, Utrecht, The Netherlands: J Urol 2012;188(4):1102-7 [Epub 2012 Aug 15].
Survival data on urachal carcinoma are sparse due to the low prevalence of this cancer. We report urachal carcinoma clinical outcomes and prognostic factors in a large, population based cohort of patients with long-term followup. Data were collected from the nationwide Netherlands Cancer Registry. Urachal carcinoma cases were also cross-referenced using the PALGA (Nationwide Network and Registry of Histology and Cytopathology) database. Pathology report summaries were reviewed. A total of 152 patients diagnosed with urachal carcinoma between 1989 and 2009 were included in analysis. The Sheldon staging system was used to classify urachal carcinoma. Median followup was 9.2 years. Primary outcomes were overall and relative survival. Prognostic factors were calculated using univariate and multivariate hazard regression models. The incidence of urachal carcinoma was 0.2% of all bladder cancers. A total of 45 patients (30%) presented with lymph node or distant metastasis. Five-year overall and relative survival was 45% and 48%, respectively. On multivariate analysis prognostic factors for impaired survival were lymph node metastasis (HR 1.7, 95% CI 1.2-2.6), tumor growth in the abdominal wall, peritoneum and/or adjacent organs (HR 5.2, 95% CI 2.6-10.3), distant metastasis (HR 5.3, 95% CI 2.8-9.9) and macroscopic residual tumor (HR 5.2, 95% CI 1.2-21.8). Urachal carcinoma is rare, accounting for 0.2% of all bladder cancers. Many patients present with advanced disease. The prognosis of urachal carcinoma depends mostly on tumor stage, particularly the presence or absence of metastatic disease.


Structural changes induced by electroconvulsive therapy are associated with clinical outcome.
Electroconvulsive therapy (ECT) is the most effective treatment option for major depressive disorder, so understanding whether its clinical effect relates to structural brain changes is vital for current and future antidepressant research. To determine whether clinical response to ECT is related to structural volumetric changes in the brain as measured by structural magnetic resonance imaging (MRI) and, if so, which regions are related to this clinical effect. We also determine whether a similar model can be used to identify regions associated with electrode placement (unilateral versus bilateral ECT). Longitudinal MRI and clinical data (Hamilton Depression Rating Scale) was collected from 10 sites as part of the Global ECT-MRI research collaboration (GEMRIC). From 192 subjects, relative changes in 80 (sub)cortical areas were used as potential features for classifying treatment response. We used recursive feature elimination to extract relevant features, which were subsequently used to train a linear classifier. As a validation, the same was done for electrode placement. We report accuracy as well as the structural coefficients of regions included in the discriminative spatial patterns obtained. A pattern of structural changes in cortical midline, striatal and lateral prefrontal areas discriminates responders from non-responders (75% accuracy, p < 0.001) while left-sided mediotemporal changes discriminate unilateral from bilateral electrode placement (81% accuracy, p < 0.001). The identification of a multivariate discriminative pattern shows that structural change is relevant for clinical response to ECT, but this pattern does not include mediotemporal regions that have been the focus of electroconvulsive therapy research so far.