Detection Test for Language Impairments in Adults and the Aged-A New Screening Test for Language Impairment Associated With Neurodegenerative Diseases: Validation and Normative Data.
To date, there is no quick screening test that could be used during routine office visits to accurately assess language disorders in neurodegenerative diseases. To fill this important gap, we developed the Detection Test for Language impairments in Adults and the Aged (DTLA), a quick, sensitive, standardized screening test designed to assess language disorders in adults and the elderly individuals. In Study 1, we describe the development of the DTLA. In Study 2, we report data on the DTLA's validity and reliability. Finally, in Study 3, we establish normative data for the test. The DTLA has good convergent and discriminant validity as well as good internal consistency and test-retest reliability. Norms for the DTLA obtained from a sample of 545 healthy, community-dwelling, French-speaking adults from 4 French-speaking countries (Belgium, Canada (Quebec), France, and Switzerland) are provided. The development, validation, and standardization of the DTLA constitute a significant effort to meet the need for a language screening test adapted to neurodegenerative diseases.


Reverse-proton-exchange in stoichiometric lithium tantalate.
Buried waveguides with nearly symmetrical refractive index profile and high homogeneity were obtained by applying the reverse-proton-exchange technique to MgO doped stoichiometric lithium tantalate, a promising nonlinear material due to its low coercive field and high damage threshold. By characterizing several samples fabricated under different experimental conditions, we identified a fabrication procedure in which the annealing and the reverse-exchange processes are performed at the same temperature, and the diffusion of hydrogen ions towards the substrate is negligible during the burial step. These fabrication conditions are simpler than the conventional ones used for lithium niobate. Accurate empirical laws were found, relating the fabrication conditions to the optical parameters.


Diagnostic usefulness of cognitive auditory event-related p300 subcomponents in patients with Alzheimers disease?
Early diagnosis of Alzheimers disease (AD) would be of great clinical value. Auditory event-related P300 mainly generated in temporoparietal regions is related to the pathophysiology of AD. A former study revealed that reliable separation of P300 subcomponents by dipole source analysis increased sensitivity (86.7%) and specificity (76.7%) in correctly detecting AD patients from healthy subjects. Aim of the present study was to replicate this interesting finding on a different sample. Auditory event-related P300 was recorded in unmedicated patients with mild to moderate AD and age- and sex-matched healthy volunteers. The subcomponents of the P300, P3a and P3b, were determined by dipole source analysis (Brain Electric Source Analysis program). As in the first study, AD patients were again characterized by a diminished P3b amplitude and longer P3a latency and reaction time. Using these three parameters, sensitivity was 81.3% to detect patients with AD from healthy controls with a specificity of 83.3%. This successful replication of the first study suggests that recording and determining P300 subcomponents together with other putative neurobiological markers may be useful to enhance the individual diagnostic accuracy in AD at an early stage.


The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak.
Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. Based on the large number of infected people that were exposed to the wet animal market in Wuhan City, China, it is suggested that this is likely the zoonotic origin of COVID-19. Person-to-person transmission of COVID-19 infection led to the isolation of patients that were subsequently administered a variety of treatments. Extensive measures to reduce person-to-person transmission of COVID-19 have been implemented to control the current outbreak. Special attention and efforts to protect or reduce transmission should be applied in susceptible populations including children, health care providers, and elderly people. In this review, we highlights the symptoms, epidemiology, transmission, pathogenesis, phylogenetic analysis and future directions to control the spread of this fatal disease.


Shoulder ultrasound: diagnostic accuracy for impingement syndrome, rotator cuff tear, and biceps tendon pathology.
We sought to determine the accuracy of ultrasound for the preoperative evaluation of shoulder impingement syndrome, rotator cuff tear, and abnormalities of the long head of the biceps tendon. The findings in 42 consecutive surgical cases were compared with the preoperative sonographic readings. Ultrasound detected all of the 10 full-thickness cuff tears identified at surgery (sensitivity 1.0, specificity 0.97) but detected only 6 of 13 partial-thickness cuff tears (sensitivity 0.46, specificity 0.97). A full-thickness tear was falsely diagnosed in one case of severe cuff abrasion. Dynamic scan criteria correctly diagnosed impingement in 27 of 34 cases (sensitivity 0.79, positive predictive value 0.96). Abnormalities of the long head of the biceps were accurately diagnosed with the exception of low-grade tendinitis and the superior labral tear, anterior to posterior, lesion. We concluded that ultrasound is a sensitive and accurate method of identifying patients with full-thickness tears of the rotator cuff, extracapsular biceps tendon pathology, or both. Dynamic ultrasound can help confirm, but not exclude, a clinical diagnosis of impingement.


Template-directed synthesis of metal-organic materials.
This tutorial review details the emergence of template-directed synthesis of metal-organic materials (MOMs) with emphasis upon reports of MOMs in which the template is retained, template@MOMs, and structurally characterized. Such MOMs enable analysis of the nature of the intermolecular interactions that occur between the template and the resulting host framework. The utilization of such understanding can enable template-directed synthesis to serve as a crystal engineering tool for the preparation of new MOMs, especially those that cannot be accessed without the use of a template. We anticipate that this review will guide future research by delineating several rules for identifying appropriate templates and molecular building blocks to afford MOMs with targeted structures and properties.


Hypoxia modulates the expression of leucine zipper-positive MYPT1 and its interaction with protein kinase G and Rho kinases in pulmonary arterial smooth muscle cells.
We have shown previously that acute hypoxia downregulates protein kinase G (PKG) expression and activity in ovine fetal pulmonary vessels and pulmonary arterial smooth muscle cells (SMC). Here, we report that acute hypoxia also reduces the expression of leucinezipper-positive MYPT1 (LZ(+)MYPT1), a subunit of myosin light chain (MLC) phosphatase, in ovine fetal pulmonary arterial SMC. We found that in hypoxia, there is greater interaction between LZ(+) MYPT1 and RhoA and Rho kinase 1 (ROCK1)/Rho kinase 2 (ROCK2) and decreased interaction between LZ(+) MYPT1 and PKG, resulting in increased MLC(20) phosphorylation, a higher pMLC(20)/MLC(20) ratio and SMC contraction. In normoxic SMC PKG overexpression, LZ(+) MYPT1 expression is upregulated while PKG knockdown had an opposite effect. LZ(+) MYPT1 overexpression enhanced the interaction between PKG and LZ(+) MYPT1. Overexpression of a mutant LZ(-) MYPT1 isoform in SMC mimicked the effects of acute hypoxia and decreased pMLC(20)/MLC(20) ratio. Collectively, our data suggest that hypoxia downregulates LZ(+) MYPT1 expression by suppressing PKG levels, reduces the interaction of LZ(+) MYPT1 with PKG and promotes LZ(+) MYPT1 interaction with RhoA or ROCK1/ROCK2, thereby promoting pulmonary arterial SMC contraction.


Real-time observation of the conformational dynamics of mitochondrial Hsp70 by spFRET.
The numerous functions of the important class of molecular chaperones, heat shock proteins 70 (Hsp70), rely on cycles of intricate conformational changes driven by ATP-hydrolysis and regulated by cochaperones and substrates. Here, we used Förster resonance energy transfer to study the conformational dynamics of individual molecules of Ssc1, a mitochondrial Hsp70, in real time. The intrinsic dynamics of the substrate-binding domain of Ssc1 was observed to be uncoupled from the dynamic interactions between substrate- and nucleotide-binding domains. Analysis of the fluctuations in the interdomain separation revealed frequent transitions to a nucleotide-free state. The nucleotide-exchange factor Mge1 did not induce ADP release, as expected, but rather facilitated binding of ATP. These results indicate that the conformational cycle of Ssc1 is more elaborate than previously thought and provide insight into how the Hsp70s can perform a wide variety of functions.


Structural characterization of a dimer of RNA duplexes composed of 8-bromoguanosine modified CGG trinucleotide repeats: a novel architecture of RNA quadruplexes.
Fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS) are neurodegenerative disorders caused by the pathogenic expansion of CGG triplet repeats in the FMR1 gene. FXTAS is likely to be caused by a 'toxic' gain-of-function of the FMR1 mRNA. We provide evidence for the existence of a novel quadruplex architecture comprising CGG repeats. The 8-bromoguanosine ((Br)G)-modified molecule GC(Br)GGCGGC forms a duplex in solution and self-associates via the major groove to form a four-stranded, antiparallel (GC(Br)GGCGGC)4 RNA quadruplex with (Br)G3:G6:(Br)G3:G6 tetrads sandwiched between mixed G:C:G:C tetrads. Self-association of Watson-Crick duplexes to form a four-stranded structure has previously been predicted; however, no experimental evidence was provided. This novel four-stranded RNA structure was characterized using a variety of experimental methods, such as native gel electrophoresis, NMR spectroscopy, small-angle X-ray scattering and electrospray ionization mass spectrometry.


Organophosphoric acid-derived CoP quantum dots@S,N-codoped graphite carbon as a trifunctional electrocatalyst for overall water splitting and Zn-air batteries.
Developing highly efficient, low-cost, and multifunctional electro-catalysts to replace noble metals is of significant importance for energy storage and conversion systems. Herein, we demonstrate a facile strategy for the preparation of CoP quantum dots (QDs) embedded in S,N-codoped graphite carbon (CoP@SNC) by using organophosphoric acid as both phosphorus and carbon sources. Benefiting from the strong coupling and synergistic effect between CoP QDs and highly conductive S,N-codoped carbon, well-structured porosity and high specific surface area, the resulting CoP@SNC exhibits excellent activities for oxygen evolution reaction (OER), hydrogen evolution reaction (HER), and oxygen reduction reaction (ORR), making it a trifunctional electro-catalyst for overall water splitting and rechargeable Zn-air batteries. When CoP@SNC is used for overall water splitting, a cell voltage as low as 1.64 V is required to reach the current density of 10 mA cm-2; the obtained rechargeable Zn-air battery with CoP@SNC as the air cathode exhibits a high open-circuit voltage of 1.45 V, a very low discharge-charge voltage gap (0.83 V at 10 mA cm-2), and a long cycle life (up to 180 cycles). This work not only offers a new strategy for the synthesis of CoP@SNC but also presents its huge potential as a trifunctional electro-catalyst for clean energy systems.


2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus.
To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.


Structural basis of folding cooperativity in model proteins: insights from a microcanonical perspective.
Two-state cooperativity is an important characteristic in protein folding. It is defined by a depletion of states that lie energetically between folded and unfolded conformations. There are different ways to test for two-state cooperativity; however, most of these approaches probe indirect proxies of this depletion. Generalized-ensemble computer simulations allow us to unambiguously identify this transition by a microcanonical analysis on the basis of the density of states. Here, we present a detailed characterization of several helical peptides obtained by coarse-grained simulations. The level of resolution of the coarse-grained model allowed to study realistic structures ranging from small α-helices to a de novo three-helix bundle without biasing the force field toward the native state of the protein. By linking thermodynamic and structural features, we are able to show that whereas short α-helices exhibit two-state cooperativity, the type of transition changes for longer chain lengths because the chain forms multiple helix nucleation sites, stabilizing a significant population of intermediate states. The helix bundle exhibits signs of two-state cooperativity owing to favorable helix-helix interactions, as predicted from theoretical models. A detailed analysis of secondary and tertiary structure formation fits well into the framework of several folding mechanisms and confirms features that up to now have been observed only in lattice models.


Sequence, transcriptional, and functional analyses of the valine (branched-chain amino acid) dehydrogenase gene of Streptomyces coelicolor.
The gene encoding the valine (branched-chain amino acid) dehydrogenase (Vdh) from Streptomyces coelicolor has been characterized as follows. The vdh gene was identified by hybridization to a specific oligodeoxynucleotide that was synthesized on the basis of the N-terminal amino acid sequence of purified Vdh. Nucleotide sequence analysis predicts that the vdh gene contains a 364-amino-acid open reading frame that should produce a 38,305-M(r) protein. The deduced amino acid sequence of the Vdh protein is significantly similar to those of several other amino acid dehydrogenases, especially the leucine and phenylalanine dehydrogenases from Bacillus spp. The vdh gene is apparently transcribed from a single major transcriptional start point, separated by only 8 bp from the 5' end of a divergent transcript and located 63 bp upstream from the vdh translational start point. Mutants with a disrupted vdh gene have no detectable Vdh activity and have lost the ability to grow on valine, leucine, or isoleucine as the sole nitrogen source. This vdh mutation does not significantly affect growth or actinorhodin production in a minimal medium, yet the addition of 0.2% L-valine to the medium provokes approximately 32 and 80% increases in actinorhodin production in vdh+ and vdh strains, respectively.


On the effect of confined fluid molecular structure on nonequilibrium phase behaviour and friction.
A detailed understanding of the behaviour of confined fluids is critical to a range of industrial applications, for example to control friction in engineering components. In this study, a combination of tribological experiments and confined nonequilibrium molecular dynamics simulations has been used to investigate the effect of base fluid molecular structure on nonequilibrium phase behaviour and friction. An extensive parameter study, including several lubricant and traction fluid molecules subjected to pressures (0.5-2.0 GPa) and strain rates (104-1010 s-1) typical of the elastohydrodynamic lubrication regime, reveals clear relationships between the friction and flow behaviour. Lubricants, which are flexible, broadly linear molecules, give low friction coefficients that increase with strain rate and pressure in both the experiments and the simulations. Conversely, traction fluids, which are based on inflexible cycloaliphatic groups, give high friction coefficients that only weakly depend on strain rate and pressure. The observed differences in friction behaviour can be rationalised through the stronger shear localisation which is observed for the traction fluids in the simulations. Higher pressures lead to more pronounced shear localisation, whilst increased strain rates lead to a widening of the sheared region. The methods utilised in this study have clarified the physical mechanisms of important confined fluid behaviour and show significant potential in both improving the prediction of elastohydrodynamic friction and developing new molecules to control it.


In vivo TCR Signaling in CD4(+) T Cells Imprints a Cell-Intrinsic, Transient Low-Motility Pattern Independent of Chemokine Receptor Expression Levels, or Microtubular Network, Integrin, and Protein Kinase C Activity.
Intravital imaging has revealed that T cells change their migratory behavior during physiological activation inside lymphoid tissue. Yet, it remains less well investigated how the intrinsic migratory capacity of activated T cells is regulated by chemokine receptor levels or other regulatory elements. Here, we used an adjuvant-driven inflammation model to examine how motility patterns corresponded with CCR7, CXCR4, and CXCR5 expression levels on ovalbumin-specific DO11.10 CD4(+) T cells in draining lymph nodes. We found that while CCR7 and CXCR4 surface levels remained essentially unaltered during the first 48-72 h after activation of CD4(+) T cells, their in vitro chemokinetic and directed migratory capacity to the respective ligands, CCL19, CCL21, and CXCL12, was substantially reduced during this time window. Activated T cells recovered from this temporary decrease in motility on day 6 post immunization, coinciding with increased migration to the CXCR5 ligand CXCL13. The transiently impaired CD4(+) T cell motility pattern correlated with increased LFA-1 expression and augmented phosphorylation of the microtubule regulator Stathmin on day 3 post immunization, yet neither microtubule destabilization nor integrin blocking could reverse TCR-imprinted unresponsiveness. Furthermore, protein kinase C (PKC) inhibition did not restore chemotactic activity, ruling out PKC-mediated receptor desensitization as mechanism for reduced migration in activated T cells. Thus, we identify a cell-intrinsic, chemokine receptor level-uncoupled decrease in motility in CD4(+) T cells shortly after activation, coinciding with clonal expansion. The transiently reduced ability to react to chemokinetic and chemotactic stimuli may contribute to the sequestering of activated CD4(+) T cells in reactive peripheral lymph nodes, allowing for integration of costimulatory signals required for full activation.


Design, synthesis and binding properties of a fluorescent α₉β₁/α₄β₁ integrin antagonist and its application as an in vivo probe for bone marrow haemopoietic stem cells.
The α9β1 and α4β1 integrin subtypes are expressed on bone marrow haemopoietic stem cells and have important roles in stem cell regulation and trafficking. Although the roles of α4β1 integrin have been thoroughly investigated with respect to HSC function, the role of α9β1 integrin remains poorly characterised. Small molecule fluorescent probes are useful tools for monitoring biological processes in vivo, to determine cell-associated protein localisation and activation, and to elucidate the mechanism of small molecule mediated protein interactions. Herein, we report the design, synthesis and integrin-dependent cell binding properties of a new fluorescent α9β1 integrin antagonist (R-BC154), which was based on a series of N-phenylsulfonyl proline dipeptides and assembled using the Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) reaction. Using transfected human glioblastoma LN18 cells, we show that R-BC154 exhibits high nanomolar binding affinities to α9β1 integrin with potent cross-reactivity against α4β1 integrin under physiological mimicking conditions. On-rate and off-rate measurements revealed distinct differences in the binding kinetics between α9β1 and α4β1 integrins, which showed faster binding to α4β1 integrin relative to α9β1, but more prolonged binding to the latter. Finally, we show that R-BC154 was capable of binding rare populations of bone marrow haemopoietic stem and progenitor cells when administered to mice. Thus, R-BC154 represents a useful multi-purpose fluorescent integrin probe that can be used for (1) screening small molecule inhibitors of α9β1 and α4β1 integrins; (2) investigating the biochemical properties of α9β1 and α4β1 integrin binding and (3) investigating integrin expression and activation on defined cell phenotypes in vivo.


Global research trends of World Health Organization's top eight emerging pathogens.
On December 8th, 2015, World Health Organization published a priority list of eight pathogens expected to cause severe outbreaks in the near future. To better understand global research trends and characteristics of publications on these emerging pathogens, we carried out this bibliometric study hoping to contribute to global awareness and preparedness toward this topic. Scopus database was searched for the following pathogens/infectious diseases: Ebola, Marburg, Lassa, Rift valley, Crimean-Congo, Nipah, Middle Eastern Respiratory Syndrome (MERS), and Severe Respiratory Acute Syndrome (SARS). Retrieved articles were analyzed to obtain standard bibliometric indicators. A total of 8619 journal articles were retrieved. Authors from 154 different countries contributed to publishing these articles. Two peaks of publications, an early one for SARS and a late one for Ebola, were observed. Retrieved articles received a total of 221,606 citations with a mean ± standard deviation of 25.7 ± 65.4 citations per article and an h-index of 173. International collaboration was as high as 86.9%. The Centers for Disease Control and Prevention had the highest share (344; 5.0%) followed by the University of Hong Kong with 305 (4.5%). The top leading journal was Journal of Virology with 572 (6.6%) articles while Feldmann, Heinz R. was the most productive researcher with 197 (2.3%) articles. China ranked first on SARS, Turkey ranked first on Crimean-Congo fever, while the United States of America ranked first on the remaining six diseases. Of retrieved articles, 472 (5.5%) were on vaccine - related research with Ebola vaccine being most studied. Number of publications on studied pathogens showed sudden dramatic rise in the past two decades representing severe global outbreaks. Contribution of a large number of different countries and the relatively high h-index are indicative of how international collaboration can create common health agenda among distant different countries.


Changes in knee shape and geometry resulting from total knee arthroplasty.
Changes in knee shape and geometry resulting from total knee arthroplasty can affect patients in numerous important ways: pain, function, stability, range of motion, and kinematics. Quantitative data concerning these changes have not been previously available, to our knowledge, yet are essential to understand individual experiences of total knee arthroplasty and thereby improve outcomes for all patients. The limiting factor has been the challenge of accurately measuring these changes. Our study objective was to develop a conceptual framework and analysis method to investigate changes in knee shape and geometry, and prospectively apply it to a sample total knee arthroplasty population. Using clinically available computed tomography and radiography imaging systems, the three-dimensional knee shape and geometry of nine patients (eight varus and one valgus) were compared before and after total knee arthroplasty. All patients had largely good outcomes after their total knee arthroplasty. Knee shape changed both visually and numerically. On average, the distal condyles were slightly higher medially and lower laterally (range: +4.5 mm to -4.4 mm), the posterior condyles extended farther out medially but not laterally (range: +1.8 to -6.4 mm), patellofemoral distance increased throughout flexion by 1.8-3.5 mm, and patellar thickness alone increased by 2.9 mm (range: 0.7-5.2 mm). External femoral rotation differed preop and postop. Joint line distance, taking cartilage into account, changed by +0.7 to -1.5 mm on average throughout flexion. Important differences in shape and geometry were seen between pre-total knee arthroplasty and post-total knee arthroplasty knees. While this is qualitatively known, this is the first study to report it quantitatively, an important precursor to identifying the reasons for the poor outcome of some patients. Using the developed protocol and visualization techniques to compare patients with good versus poor clinical outcomes could lead to changes in implant design, implant selection, component positioning, and surgical technique. Recommendations based on this sample population are provided. Intraoperative and postoperative feedback could ultimately improve patient satisfaction.


Patient consultations during SARS-CoV-2 pandemic: a mixed-method cross-sectional study in 16 European countries.
Remote consultations help reduce contact between people and prevent cross-contamination. Little is known about the changes in consultation in European rural primary care during the SARS-CoV-2 (COVID-19) pandemic. The purpose of this mixed-methods cross-sectional study was to find out more about the effects of the pandemic on changes in patient consultations in European rural primary care. A key informant survey from 16 member countries of the European Rural and Isolated Practitioners Association (EURIPA) was undertaken using a self-developed questionnaire. The steering committee of this project, called EURIPA Covid-19 study, developed a semi-structured questionnaire with 68 questions, 21 of which included free-text comments. Proportions were calculated for dichotomized or categorized data, and means were calculated for continuous data. Multivariate analysis by logistic regression model was used to assess the association of multiple variables. A total of 406 questionnaires from primary care providers (PCPs) in 16 European countries were collected; 245 respondents (60.5%) were females, 152 PCPs were rural (37.5%), 124 semi-rural (30.5%). Mean age of the respondents was 45.9 years (standard deviation (SD) 11.30) while mean seniority (length of experience) was 18.2 years (SD 11.6). A total of 381 (93.8%) respondents were medical doctors. Significant differences were found between countries in adopting alternative arrangements to face-to-face consultation: remote teleconsultation is well appreciated by both healthcare professionals and patients, but the most common way of remote consultation remains telephone consultation. A factor significantly inversely associated with the adoption of video consultation was the seniority of the PCP (odds ratio 1.19, 95% confidence interval 1.02-1.40, p=0.03). Telephone consultation is the most common form of remote consultation. The adoption of video-consultation is inversely related to the seniority of the informants.


The acetic acid test in evaluation of subclinical genital papillomavirus infection: a comparative study on penoscopy, histopathology, virology and scanning electron microscopy findings.
To evaluate colposcopic criteria in acetowhite lesions of the penis ("penoscopy") for the diagnosis of subclinical genitoanal papillomavirus infection (GPVI) compared with histopathological criteria of HPV involvement and to various hybridisation assays for HPV DNA detection, and to depict typical lesions by scanning electron microscopy. The study included 101 randomly selected male partners of females with known GPVI, or with penile symptoms such as itching, burning and dyspareunia who did not exhibit overt genital warts but appeared to be afflicted with acetowhite penile lesions after topical application of 5% acqueous acetic acid. Lesions were judged by penoscopy as either typical, conspicuous or nontypical for underlying HPV infection. Biopsy specimens from 91 men were examined by light microscopy and by either Southern blot (SB), polymerase chain reaction (PCR) and/or in situ hybridisation (ISH) assays for the presence of HPV DNA of the HPV types 6, 11, 16, 18, 31, 33 and 42 (Group A). From another ten men lesions clinically typical for GPVI were also examined topographically by scanning electronic microscopy (Group B). The STD out-patient clinic of the Department of Dermatovenereology of Karolinska Hospital, Stockholm, Sweden. Group A Seventy eight (86%) of the biopsied lesions met the penoscopy criteria of being either typical of or conspicuous for GVPI. The agreement between penoscopy and histopathology was fairly good, as HPV diagnosis was made by both methods in 56 (62%) of the cases. The reliability of applying strict colposcopic hallmarks was further substantiated by the finding that 55 (60%) of the biopsy specimens taken from penoscopically typical/conspicuous lesions contained HPV DNA. However, there are diagnostic pitfalls for the acetic acid test. Coexistence of an eczematoid reaction with changes indicative of HPV influence was detected in six (7%) of the cases, while an inflammatory response only occurred in 17 (19%) of the specimens. Additional histopathological diagnoses (normal epithelium, lichen sclerosus et atrophicus, balanitis circinata parakeratotica, verruca plana) were established in another eight (9%) of the cases. Among the HPV DNA positive cases, all of the HPV types tested for were detected with the exception of HPV 18. A severe penile intraepithelial neoplasia (PIN III) was revealed in five (5%) of biopsies; HPV 16 was present in two and HPV 42 in one of these biopsy specimens. Scanning electron microscopy depiction harmonised with the penoscopy findings showing that subclinical GPVI characteristically exhibits a well demarcated, slightly elevated border and that the central area of lesions often displays a "groove" in which the epithelium appears to be thin with protrusions from beneath that probably represent capillaries. Use of the acetic acid test for evaluation of GPVI should be combined with a colposcopic evaluation based on strict topographic hallmarks, followed by a directed biopsy for light microscopic evaluation. We found that the positive predictive value of colposcopy was as high when correlated with histopathological findings (72%) as when virological methods were used, whether HPV DNA hybridisation testing was performed with the well established SB and ISH assays (45%), or by applying the newly introduced and highly sensitive PCR assay as well (71%). False positivity from the acetic acid test occurs and is mainly due to inflammatory conditions but also to the presence of other conditions. Epithelial fissures are evidently associated with some subclinical GPVI lesions and may potentially represent loci minores for infectious stimuli and perhaps facilitate the transmission of some blood-borne STDs. We prose that the term "papillomavirus balanoposthitis" should be used for penile HPV infection associated with inflammatory responses. Our study indicates that PIN III frequently occurs in a subclinical form and may be associated with not only previously identified "high-risk" HPV types such as type 16, but also with the HPV type 42 that has not previously been considered as oncogenic.


Adsorbate-driven reactive interfacial Pt-NiO1-x nanostructure formation on the Pt3Ni(111) alloy surface.
The origin of the synergistic catalytic effect between metal catalysts and reducible oxides has been debated for decades. Clarification of this effect, namely, the strong metal-support interaction (SMSI), requires an understanding of the geometric and electronic structures of metal-metal oxide interfaces under operando conditions. We show that the inherent lattice mismatch of bimetallic materials selectively creates surface segregation of subsurface metal atoms. Interfacial metal-metal oxide nanostructures are then formed under chemical reaction environments at ambient pressure, which thus increases the catalytic activity for the CO oxidation reaction. Our in situ surface characterizations using ambient-pressure scanning tunneling microscopy and ambient-pressure x-ray photoelectron spectroscopy exhibit (i) a Pt-skin layer on the Pt-Ni alloyed surface under ultrahigh vacuum, (ii) selective Ni segregation followed by the formation of NiO1-x clusters under oxygen gas, and (iii) the coexistence of NiO1-x clusters on the Pt-skin during the CO oxidation reaction. The formation of interfacial Pt-NiO1-x nanostructures is responsible for a highly efficient step in the CO oxidation reaction. Density functional theory calculations of the Pt3Ni(111) surface demonstrate that a CO molecule adsorbed on an exposed Pt atom with an interfacial oxygen from a segregated NiO1-x cluster has a low surface energy barrier of 0.37 eV, compared with 0.86 eV for the Pt(111) surface.


Insights into the prostanoid pathway in the ovary development of the penaeid shrimp Penaeus monodon.
The prostanoid pathway converts polyunsaturated fatty acids (PUFAs) into bioactive lipid mediators, including prostaglandins, thromboxanes and prostacyclins, all of which play vital roles in the immune and reproductive systems in most animal phyla. In crustaceans, PUFAs and prostaglandins have been detected and often associated with female reproductive maturation. However, the presence of prostanoid biosynthesis genes remained in question in these species. In this study, we outlined the prostanoid pathway in the black tiger shrimp Penaeus monodon based on the amplification of nine prostanoid biosynthesis genes: cytosolic phospholipase A2, hematopoietic prostaglandin D synthase, glutathione-dependent prostaglandin D synthase, prostaglandin E synthase 1, prostaglandin E synthase 2, prostaglandin E synthase 3, prostaglandin F synthase, thromboxane A synthase and cyclooxygenase. TBLASTX analysis confirmed the identities of these genes with 51-99% sequence identities to their closest homologs. In addition, prostaglandin F2α (PGF2α), which is a product of the prostaglandin F synthase enzyme, was detected for the first time in P. monodon ovaries along with the previously identified PUFAs and prostaglandin E2 (PGE2) using RP-HPLC and mass-spectrometry. The prostaglandin synthase activity was also observed in shrimp ovary homogenates using in vitro activity assay. When prostaglandin biosynthesis was examined in different stages of shrimp ovaries, we found that the amounts of prostaglandin F synthase gene transcripts and PGF2α decreased as the ovaries matured. These findings not only indicate the presence of a functional prostanoid pathway in penaeid shrimp, but also suggest a possible role of the PGF2α biosynthesis in shrimp ovarian development.


Terahertz-Range Polar Modes in Domain-Engineered BiFeO_{3}.
The dielectric permittivity and properties of electrically active lattice resonances in nanotwinned BiFeO_{3} crystals have been studied theoretically using an earlier established interatomic potential. The results suggest that an array of 71° domain walls with about 2-5 nm spacing enhances the static permittivity of BiFeO_{3} by more than an order of magnitude. This enhancement is associated with an electrically active excitation, corresponding to a collective vibration of pinned domain walls at a remarkably high frequency of about 0.3 THz.


[A retrospective study about 11 cases of Esthesioneuroblastomas treated in Hospital Santa Creu i Sant Pau between 2000 and 2008 and literature review].
INTRODUCTION. Esthesioneuroblastoma (ENB) is a very uncommon malignant tumor with a neuroectodermal origin that usually involves the anterior cranial fossa and nasal cavity. OBJECTIVES. To review our experience in the management of ENB and assess the validity of the histopathological diagnosis, modality of treatment and prognostic factors of the disease comparing our findings with the literature. METHODS. A retrospective study of 11 cases with the diagnosis of esthesioneuroblastoma treated in our hospital between 2000 and 2008. Statistical analysis was performed in search for prognostic factors. The bibliography about ENB published between 1990 and 2009 was reviewed RESULTS. There were 3 women and 8 men, with a mean age of 42 years old (range 20-71y). Their symptoms upon admission were nasal obstruction (81%), epistaxis (27%), visual loss (18%), headache and others. According to the Kadish Stage, 2 were stage B and 9 were stage C. Dulguerov and Calcaterra Classification was also used: 2 were T2, 3 were T3 and 6 were T4. The hystopathological result according to the Hyams classification was: 2 cases in stage I, 4 in stage II, 3 in stage III and 2 in stage IV. The two cases classified in stage IV changed the diagnosis to undifferenciate tumor in the second biopsy. A subcranial approach was performed in 8 cases combined with endonasal endoscopy to confirm the total removal, followed by radiotherapy in all and chemotherapy in one case, resulting on 62% (5 patients) being alive without disease, 12,5% (1 p) alive with disease, and 25% (2 p) dead of disease. Another patient was operated by a single endonasal endoscopic approach and a subtotal removal was achieved. This patient is alive without disease. The other 2 patients were treated by biopsy plus radiotherapy and chemotherapy, because they were considered unresectable, and one of them is alive with disease and the other one is dead of disease. Radiotherapy was performed in all cases and chemotherapy in 5 cases. The hystopathological grading system of Hyams was considered statistically significant as a prognostic factor of disease-free survival. CONCLUSIONS. When the hystopathological diagnosis of ENB is considered, the Hyams classification can be valid considering grade IV as an advanced stage that is sometimes difficult to differentiate from other undiferentiated tumors. The subcranial approach or craneofacial resection in advanced stages (Kadish C and some B) should be considered as the first treatment of choice. Radiotherapy is indicated in all cases and chemotherapy in selected cases. Hyams' classification was the only staging system that proved useful as a prognostic factor in our series.


ERS statement on chest imaging in acute respiratory failure.
Chest imaging in patients with acute respiratory failure plays an important role in diagnosing, monitoring and assessing the underlying disease. The available modalities range from plain chest X-ray to computed tomography, lung ultrasound, electrical impedance tomography and positron emission tomography. Surprisingly, there are presently no clear-cut recommendations for critical care physicians regarding indications for and limitations of these different techniques.The purpose of the present European Respiratory Society (ERS) statement is to provide physicians with a comprehensive clinical review of chest imaging techniques for the assessment of patients with acute respiratory failure, based on the scientific evidence as identified by systematic searches. For each of these imaging techniques, the panel evaluated the following items: possible indications, technical aspects, qualitative and quantitative analysis of lung morphology and the potential interplay with mechanical ventilation. A systematic search of the literature was performed from inception to September 2018. A first search provided 1833 references. After evaluating the full text and discussion among the committee, 135 references were used to prepare the current statement.These chest imaging techniques allow a better assessment and understanding of the pathogenesis and pathophysiology of patients with acute respiratory failure, but have different indications and can provide additional information to each other.


Affective Response to Exercise and Preferred Exercise Intensity Among Adolescents.
Little information exists as to the exercise intensity that adolescents enjoy and whether identifiable subgroups of adolescents will choose higher-intensity exercise. Healthy adolescents (N = 74; mean age = 11.09 years) completed a cardiorespiratory fitness test, a moderate-intensity exercise task, and an exercise task at an intensity that felt "good." Heart rate (HR), work rate (WR), and ratings of perceived exertion (RPE) were assessed every 3 minutes. During the "feels good" task, adolescents exercised at a HR recognized as beneficial for cardiovascular health (mean HR = 66% to 72% of HR at VO2peak). Adolescents who experienced a positive affective shift during the moderate-intensity task engaged in higher-intensity exercise during the feels-good task as compared with those whose affective response to moderate-intensity exercise was neutral or negative (76% of peak HR vs. 70% of peak HR, P < .01).There was no difference between groups in RPE. Adolescents tend to select an exercise intensity associated with fitness benefits when afforded the opportunity to choose an intensity that feels good. An identified subgroup engaged in higher-intensity exercise without a commensurate perception of working harder. Encouraging adolescents to exercise at an intensity that feels good may increase future exercise without sacrificing fitness.


Analytical Model and Numerical Analysis of Composite Wrap System Applied to Steel Pipeline.
Composite overwraps are a cost-effective repair technology, appropriate for corrosion defects, dents, and gouges for both onshore and offshore steel pipelines. The main benefit of polymer-based sleeves is safe installation without taking the pipeline out of service. This paper presents a new calculation procedure proposed in the form of an algorithm for the sizing of composite repairs of corroded pipelines when the sleeve is applied at zero internal pressure. The main objective of the presented methodology is determination of the effective thickness of the composite repair without its overestimation or underestimation. The authors used a non-linear finite element method with constitutive models allowing analysis of the steel, putty, and composite structures. The validation of the results of numerical computations compared to the experimental ones showed an appropriate agreement. The numerical calculations were applied to compare the analytical results in relation to those obtained by the standards ASME PCC-2 or ISO/TS 24817. The comparison showed that the proposed solution confirmed its effectiveness in reducing the thickness of the sleeve significantly, thus, showing that the current industrial standards provide a considerably excessive composite wrap around the steel pipe corroded area, which leads to an unnecessary increase in the repair costs.


Physiological stress in batch cultures of Pseudomonas putida 54G during toluene degradation.
Physiological stress associated with toluene exposure in batch cultures of Pseudomonas putida 54G was investigated. P. putida 54G cells were grown using a continuous vapor phase feed stream containing 150 ppmv or 750 ppmv toluene as the sole carbon and energy source. Cells were enumerated on non-selective (R2A agar plates) and a selective minimal medium incubated in the presence of vapor phase toluene (HCMM2). Differential recovery on the two media was used to evaluate bacterial stress, culturability and loss of toluene-degrading capability. A majority of the bacteria were reversibly stressed and could resume active colony formation on selective medium after passage on non-selective medium. A small fraction of the bacterial cells suffered an irreversible loss of toluene degradation capability and were designated as Tol- variants. Numbers of stressed organisms increased with duration of toluene exposure and toluene concentration and coincided with accumulation of metabolic intermediates from incomplete toluene degradation. Respiring cell numbers in the batch cultures decreased as injury increased, indicating a possible relationship between respiring and injured cells. Rate expressions for injury, for formation of Tol- variants and for growth of Tol- variants were determined by calibrating a theoretical model to the results obtained. These rate expressions can be used to calibrate bioreactor models, and provide a basis for better design and control of bioremediation systems.


Is the GehD lipase from Staphylococcus epidermidis a collagen binding adhesin?
The opportunistic human pathogen Staphylococcus epidermidis is the major cause of nosocomial biomaterial infections. S. epidermidis has the ability to attach to indwelling materials coated with extracellular matrix proteins such as fibrinogen, fibronectin, vitronectin, and collagen. To identify the proteins necessary for S. epidermidis attachment to collagen, we screened an expression library using digoxigenin-labeled collagen as well as two monoclonal antibodies generated against the Staphylococcus aureus collagen-adhesin, Cna, as probes. These monoclonal antibodies recognize collagen binding epitopes on the surface of S. aureus and S. epidermidis cells. Using this approach, we identified GehD, the extracellular lipase originally found in S. epidermidis 9, as a collagen-binding protein. Despite the monoclonal antibody cross-reactivity, the GehD amino acid sequence and predicted structure are radically different from those of Cna. The mature GehD circular dichroism spectra differs from that of Cna but strongly resembles that of a mammalian cell-surface collagen binding receptor, known as the alpha(1) integrin I domain, suggesting that they have similar secondary structures. The GehD protein is translated as a preproenzyme, secreted, and post-translationally processed into mature lipase. GehD does not have the conserved LPXTG C-terminal motif present in cell wall-anchored proteins, but it can be detected in lysostaphin cell wall extracts. A recombinant version of mature GehD binds to collagens type I, II, and IV adsorbed onto microtiter plates in a dose-dependent saturable manner. Recombinant, mature GehD protein and anti-GehD antibodies can inhibit the attachment of S. epidermidis to immobilized collagen. These results provide evidence that GehD may be a bi-functional molecule, acting not only as a lipase but also as a cell surface-associated collagen adhesin.


The effect of social experience on serotonergic modulation of the escape circuit of crayfish.
The neuromodulator serotonin has widespread effects in the nervous systems of many animals, often influencing aggression and dominance status. In crayfish, the effect of serotonin on the neural circuit for tailflip escape behavior was found to depend on the animal's social experience. Serotonin reversibly enhanced the response to sensory stimuli of the lateral giant (LG) tailflip command neuron in socially dominant crayfish, reversibly inhibited it in subordinate animals, and persistently enhanced it in socially isolated crayfish. Serotonin receptor agonists had opposing effects: A vertebrate serotonin type 1 receptor agonist inhibited the LG neurons in dominant and subordinate crayfish and had no effect in isolates, whereas a vertebrate serotonin type 2 receptor agonist enhanced the LG neurons' responses in all three types of crayfish. The LG neurons appear to have at least two populations of serotonin receptors that differ in efficacy in dominant, subordinate, and socially isolate crayfish.


Quantitative oxygenation venography from MRI phase.
To demonstrate acquisition and processing methods for quantitative oxygenation venograms that map in vivo oxygen saturation (SvO2 ) along cerebral venous vasculature. Regularized quantitative susceptibility mapping (QSM) is used to reconstruct susceptibility values and estimate SvO2 in veins. QSM with ℓ1 and ℓ2 regularization are compared in numerical simulations of vessel structures with known magnetic susceptibility. Dual-echo, flow-compensated phase images are collected in three healthy volunteers to create QSM images. Bright veins in the susceptibility maps are vectorized and used to form a three-dimensional vascular mesh, or venogram, along which to display SvO2 values from QSM. Quantitative oxygenation venograms that map SvO2 along brain vessels of arbitrary orientation and geometry are shown in vivo. SvO2 values in major cerebral veins lie within the normal physiological range reported by (15) O positron emission tomography. SvO2 from QSM is consistent with previous MR susceptometry methods for vessel segments oriented parallel to the main magnetic field. In vessel simulations, ℓ1 regularization results in less than 10% SvO2 absolute error across all vessel tilt orientations and provides more accurate SvO2 estimation than ℓ2 regularization. The proposed analysis of susceptibility images enables reliable mapping of quantitative SvO2 along venograms and may facilitate clinical use of venous oxygenation imaging.


Photic resetting of the human circadian pacemaker in the absence of conscious vision.
Ocular light exposure patterns are the primary stimuli for entraining the human circadian system to the local 24-h day. Many totally blind persons cannot use these stimuli and, therefore, have circadian rhythms that are not entrained. However, a few otherwise totally blind persons retain the ability to suppress plasma melatonin concentrations after ocular light exposure, probably using a neural pathway that includes the site of the human circadian pacemaker, suggesting that light information is reaching this site. To test definitively whether ocular light exposure could affect the circadian pacemaker of some blind persons and whether melatonin suppression in response to bright light correlates with light-induced phase shifts of thecircadian system, the authorsperformed experiments with 5 totally blind volunteers using a protocol known to induce phase shifts of the circadian pacemaker in sighted individuals. In the 2 blind individuals who maintained light-induced melatonin suppression, the circadian system was shifted by appropriately timed bright-light stimuli. These data demonstrate that light can affect the circadian pacemaker of some totally blind individuals--either by altering the phase of the circadian pacemaker or by affecting its amplitude. They are consistent with data from animal studies demonstrating that there are different neural pathways and retinal cells that relay photic information to the brain: one for conscious light perception and the other for non-image-forming functions.


Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.
Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt uses a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivation domains of ERG, but it inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia in which DUX4 deregulation results in loss of function of ERG, either by deletion or induced expression of an isoform that is a dominant-negative inhibitor of wild-type ERG function.


Role of adherence in pathogenesis of Enterococcus faecalis urinary tract infection and endocarditis.
Enterococcus faecalis strains isolated from urinary tract infections (UTIs) and endocarditis were analyzed for their ability to adhere to urinary tract epithelial cells (ECs) and Girardi heart (GH) and human embryonic kidney (HEK) cell cultures. UTI isolates adhered to urinary tract ECs more efficiently than to the cultured cells, at the same time showing the least affinity for GH cells. In contrast, endocarditis isolates adhered to GH cell cultures more readily than to urinary tract ECs. Moreover, although strains isolated from endocarditis adhered to GH cells more efficiently than those derived from UTI, the latter strains adhered to urinary tract cells better than the former. Studies of the ability of GH and HEK cells to internalize E. faecalis showed that for UTI isolates, 9 to 74% of adhered bacteria were internalized, while for endocarditis isolates, the percentage varied from 76 to 82%. All strains were able to associate with human neutrophils; endocarditis strains, however, associated less efficiently than UTI isolates. Growth in serum raised the adherence of all tested strains by at least 1.5- to 3-fold, with the greatest increase being observed in UTI strain adherence to GH cells (8-fold). In contrast, the association of serum-grown cells with polymorphonuclear leukocytes was reduced by two- to fivefold. In both cases, the observed serum-dependent alterations were cancelled by a few subcultures in brain heart infusion broth. These results indicate that adhesive properties are important virulence factors in the pathogenesis of UTI and endocarditis and also suggest that UTI strains showing the highest invasion and adhesive potential invade the kidneys, cause bacteremia, and, after having expressed the serum-dependent surface modification, colonize the heart.


Neuroanatomical, Clinical and Cognitive Correlates of Post-Stroke Dysphagia.
About half of the dysphagic stroke patients have persistent swallowing dysfunction after 7 days from symptom onset. The aim of the study was to evaluate incidence, prognosis, clinical and neuroradiological correlates of post-stroke dysphagia. We prospectively examined consecutive patients with acute ischemic or hemorrhagic stroke. Patients' clinical and neuroradiological data were collected. Swallowing function was assessed by the water swallow test upon admission and after 14 days; patients were then classified as persistent dysphagic, non-persistent dysphagic or non-dysphagic. We recruited 275 patients, 121 of whom were dysphagic upon admission and 254 patients attended follow-up at 14 days; 141 never presented dysphagia, 21 had a non-persistent pattern of dysphagia and 92 had a persistent one. Stroke type, leukoaraiosis degree, previous cognitive impairment and stroke severity upon admission independently predicted the occurrence of dysphagia after stroke and its persistence as well. At receiver operating characteristic (ROC) analysis, the National Institutes of Health Stroke Scale (NIHSS) score of 11.5 was the best predictive value of persistent dysphagia, with a specificity of 90.1% and a sensitivity of 72.4%. Stroke severity is an important predictor of a persistent pattern of dysphagia, with a suggested NIHSS cutoff value of ≥12. An independent correlation was observed with leukoaraiosis and with previous cognitive impairment.


Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.
Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant over-expression on synapse formation and function in cultured rodent hippocampal neurons. Δex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPδ that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling because their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPδ/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients.


Inositol hexakisphosphate mobilizes an endomembrane store of calcium in guard cells.
myo-Inositol hexakisphosphate (InsP6) is the most abundant inositol phosphate in cells, yet it remains the most enigmatic of this class of signaling molecule. InsP6 plays a role in the processes by which the drought stress hormone abscisic acid (ABA) induces stomatal closure, conserving water and ensuring plant survival. Previous work has shown that InsP6 levels in guard cells are elevated in response to ABA, and InsP6 inactivates the plasma membrane inward K+ conductance (IK,in) in a cytosolic calcium-dependent manner. The use of laser-scanning confocal microscopy in dye-loaded patch-clamped guard cell protoplasts shows that release of InsP6 from a caged precursor mobilizes calcium. Measurement of calcium (barium) currents ICa in patch-clamped protoplasts in whole cell mode shows that InsP6 has no effect on the calcium-permeable channels in the plasma membrane activated by ABA. The InsP6-mediated inhibition of IK,in can also be observed in the absence of external calcium. Thus the InsP6-induced increase in cytoplasmic calcium does not result from calcium influx but must arise from InsP6-triggered release of calcium from endomembrane stores. Measurements of vacuolar currents in patch-clamped isolated vacuoles in whole-vacuole mode showed that InsP6 activates both the fast and slow conductances of the guard cell vacuole. These data define InsP6 as an endomembrane-acting calcium-release signal in guard cells; the vacuole may contribute to InsP6-triggered Ca2+ release, but other endomembranes may also be involved.


Moving your head reduces perisaccadic compression.
Flashes presented around the time of a saccade appear to be closer to the saccade endpoint than they really are. The resulting compression of perceived positions has been found to increase with the amplitude of the saccade. In most studies on perisaccadic compression the head is static, so the eye-in-head movement is equal to the change in gaze. What if moving the head causes part of the change in gaze? Does decreasing the eye-in-head rotation by moving the head decrease the compression of perceived positions? To find out, we asked participants to shift their gaze between two positions, either without moving their head or with the head contributing to the change in gaze. Around the time of the saccades we flashed bars that participants had to localize. When the head contributed to the change in gaze, the duration of the saccade was shorter and compression was reduced. We interpret this reduction in compression as being caused by a reduction in uncertainty about gaze position at the time of the flash. We conclude that moving one's head can reduce the systematic mislocalization of flashes presented around the time of saccades.


Opening the climate envelope reveals no macroscale associations with climate in European birds.
Predicting how species distributions might shift as global climate changes is fundamental to the successful adaptation of conservation policy. An increasing number of studies have responded to this challenge by using climate envelopes, modeling the association between climate variables and species distributions. However, it is difficult to quantify how well species actually match climate. Here, we use null models to show that species-climate associations found by climate envelope methods are no better than chance for 68 of 100 European bird species. In line with predictions, we demonstrate that the species with distribution limits determined by climate have more northerly ranges. We conclude that scientific studies and climate change adaptation policies based on the indiscriminate use of climate envelope methods irrespective of species sensitivity to climate may be misleading and in need of revision.


Electrozymographic evaluation of the attenuation of arsenic induced degradation of hepatic SOD, catalase in an in vitro assay system by pectic polysaccharides of Momordica charantia in combination with curcumin.
Momordica charantia (MC) fruit known as bitter gourd, is of potential nutritional and medicinal value. The objectives of the present in vitro study were to evaluate the efficacy of bioactive pectic polysaccharides (CCPS) of MC along with another well-known bioactive compound curcumin in the abrogation of hepatocellular oxidative stress persuaded by sodium arsenite. Electrozymographic method was developed for the assessment of superoxide dismutase (SOD) and catalase activities of liver tissues maintained under an in vitro system. A significant association of CCPS of MC in combination with curcumin was found in the alleviation of oxidative stress induced by sodium arsenite in liver slice. Generated data pointed out that CCPS of MC and curcumin separately or in combination can offer significant protection against alterations in malondialdehyde (MDA), conjugated diene (CD) and antioxidative defense (SOD, CAT) markers. Furthermore, results of hepatic cell DNA degradation strongly supported that both these co-administrations have efficacy in preventing cellular damage. This is the first information of extracted polysaccharides from MC preventing arsenic induced damage in a liver slice of rat.


An inferior sinus venosus interatrial communication associated with a secundum atrial septal defect, clinically presenting in an adult patient: autopsy report.
Atrial septal defects (ASD) are the most common congenital cardiac lesion in adults, representing up to 40% of acyanotic shunt lesions in patients older than 40 years. Secundum ASD comprises defects in the area of the oval fossa, and may be associated with other types of interatrial communications. We present a case of a 25 year-old female patient who was asymptomatic until the age 22 when she started presenting exertion dyspnea and lower limbs edema, during her third pregnancy. The patient was admitted in the emergency department because of a febrile respiratory distress syndrome dying in less than 36 hours after her arrival. The autopsy examination revealed pneumonia and a secundum ASD, associated with a rare form of interatrial communication, the inferior sinus venosus defect, which is characterized by an anomalous connection of the right pulmonary veins to the inferior caval vein at its opening in the right atrial cavity, while retaining partially their connection to the left atrium. A dysplastic and thickened mitral valve was also present. Signs of pulmonary hypertension confirm the Eisenmenger syndrome in this adult patient.


Comparison of insertion characteristics of two types of hydroxyapatite-coated and uncoated positive profile transfixation pins in the third metacarpal bone of horses.
To determine the effect of 2 hydroxyapatite pin coatings on heat generated at the bone-pin interface and torque required for insertion of transfixation pins into cadaveric equine third metacarpal bone. Third metacarpal bone pairs from 27 cadavers of adult horses. Peak temperature of the bone at the cis-cortex and the hardware and pin at the trans-cortex was measured during insertion of a plasma-sprayed hydroxyapatite (PSHA)-coated, biomimetic hydroxyapatite (BMHA)-coated, or uncoated large animal transfixation pin. End-insertional torque was measured for each pin. The bone-pin interface was examined grossly and histologically for damage to the bone and coating. The BMHA-coated transfixation pins had similar insertion characteristics to uncoated pins. The PSHA-coated pins had greater mean peak bone temperature at the cis-cortex and greater peak temperature at the trans-cortex (70.9 +/- 6.4(o)C) than the uncoated pins (38.7 +/- 8.4(o)C). The PSHA-coated pins required more insertional torque (10,380 +/- 5,387.8 Nmm) than the BMHA-coated pins (5,123.3 +/- 2,296.9 Nmm). Four of the PSHA-coated pins became immovable after full insertion, and 1 gross fracture occurred during insertion of this type of pin. The PSHA coating was not feasible for use without modification of presently available pin hardware. The BMHA-coated pins performed similarly to uncoated pins. Further testing is required in an in vivo model to determine the extent of osteointegration associated with the BMHA-coated pins in equine bone.


Do inquiries into health system failures lead to change in clinical governance systems?
This paper reports the first part of a case study investigation to examine the changes at King Edward Memorial Hospital (KEMH) following an inquiry established to review the quality of obstetric and gynaecological services. Common findings from a range of health inquiries in recent times include that there have been inadequate adverse event reporting systems, the absence of transparent systems for staff and patients to report concerns about quality of patient care, and an ineffective medical credentialing and performance review system. The similarity of findings from many health inquiries raises the question of whether an inquiry does lead to changes to improve patient care and safety. There has been very little reported in the literature about this. Using a case study strategy the areas of medical credentialing, performance review and involvement of consumers in care were chosen as the KEMH clinical governance processes to be examined for changes post inquiry. Documents, archives and interviews were used as data sources for this case study. Documents were examined using a normative analytic approach and the Miles and Huberman framework was used for data analysis of the interviews. There were significant changes in the area of credentialing and performance review evident in analysis of all sources of data. There were some improvements in the processes of involving consumers in care, but deficits were identified in regard to the provision of training and upskilling for clinicians to improve their communication skills and interactions with patients and families.


Exploring the associations between spiritual well-being, burden, and quality of life in family caregivers of cancer patients.
The spiritual dimension is important in the process of coping with stress and may be of special relevance for those caring for cancer patients in the various phases of caregivership, although current attention is most prevalent at the end of life. This study explores the associations among spiritual well-being (SWB), caregiver burden, and quality of life (QoL) in family caregivers of patients with cancer during the course of the disease. This is a cross-sectional study. All participants (n = 199) underwent the following self-report questionnaires: the SWB-Index, the Medical Outcomes Study Short Form, and the Caregiver Burden Inventory (CBI). SWB scores were dichotomized at a cutoff corresponding to the 75th percentile. Statistical analyses were made using the Student t or by chi-square test to compare high and low SWB groups.ResultThe high SWB group reported significantly better Medical Outcomes Study Short Form scores in bodily pain (p = 0.035), vitality (p < 0.001), social activities (p = 0.001), mental health (p < 0.001), and in standardized mental component subscales (p < 0.001) than the low SWB group. No significant differences were detected between the two SWB groups in physical activity, physical role, general health, emotional status, and standardized physical component scale. The high SWB group also had better CBI scores in the physical (p = 0.049) and developmental burden (p = 0.053) subscales. There were no significant differences in the other CBI scores (overall and sections).Significance of resultsThis study points out that high SWB caregivers have a more positive QoL and burden. Knowledge of these associations calls for more attention on the part of healthcare professionals toward spiritual resources among family cancer caregivers from the moment of diagnosis and across the entire cancer trajectory.


[KCNQ 1 (KvLQT1) missense mutation causing congenital long QT syndrome (Jervell-Lange-Nielsen) in a Mexican family].
Long QT syndromes (LQTS) are inherited cardiac disorders caused by mutations in the genes that encode sodium or potassium transmembrane ion channel proteins. More than 200 mutations, in at least six genes, have been found in these patients. The Jervell and Lange-Nielsen (JLN) syndrome is the recessive form of the disease and is associated with deafness. Few families with JLN syndrome and genetic studies are reported in the literature. The KCNQ1 (KvLQT1) gene in a Mexican family with Jervell-Lange-Nielsen long QT syndrome was analyzed using an automated sequence method. A missense mutation was found in the three affected individuals. This mutation is associated with complete loss of channel function. Correlation with the phenotype showed a prolonged QTc interval and deafness in the two siblings homozygous to the mutation. The mother, who was heterozygous for the mutation, also had prolonged QTc interval without deafness. The father and younger brother had normal QTc intervals. The mutation was not found in 50 healthy controls studied. We describe for the first time a mutation in the KCNQ1 gene in a Mexican family with JLN long QT syndrome. This mutation produces an amino acid change (Gly-Arg) at protein level at the 168 residue. This mutation has been previously reported in Caucasian families with LQTS.


Effect of masticating chewing gum on postural stability during upright standing.
The purpose of this study was to investigate the effect of masticating chewing gum on postural stability during upright standing. To address this issue, 12 healthy subjects performed quiet standing on a force platform for the posturography study. The subjects were instructed to stand as stable as possible on the force platform in order to record the trajectory of the center-of-pressure (COP). After measuring the postural sway in the initial condition (pre-condition), the subjects were asked to stand while masticating chewing gum (gum-condition). Following the gum-condition, quiet standing without mastication was evaluated (post-condition) to ensure the effect of masticating chewing gum on postural stability. The trajectory and velocity of the COP were analyzed for each condition. We found that the postural stability tended to enhance during mastication of chewing gum. The rectangle area of the COP trajectory significantly diminished in the gum-condition and significantly enlarged in the post-condition. A similar effect was observed in the maximum velocity and standard deviation (SD) of the fore-aft amplitude of the COP trajectory. The values were significantly smaller in the gum-condition compared to those in the post-condition. These findings suggest that mastication of chewing gum affects the postural control by enhancing the postural stability during upright standing.


Comparative analysis of oocyte transcript profiles reveals a high degree of conservation among species.
Cross-species comparison of gene expression is a powerful approach for discovering genes that have been conserved throughout evolution. Conserved genes are presumably very important in the mechanisms related to the unique molecular functions in oocytes. The objective of this study was to identify genes expressed in the oocyte and conserved across three diverse vertebrate species. We report the global gene expression profiles of Bos taurus and Xenopus laevis oocytes on an NIA mouse development microarray that consists of 60-mer oligonucleotide probes representing more than 20,000 mouse transcripts derived from stem cell, oocyte, and early embryo cDNA libraries. Analysis based on intensity values revealed that 9853 and 10,046 genes are expressed in bovine and Xenopus oocytes respectively. Furthermore, previously published microarray data on preimplantation development in the mouse were used for a comparative analysis of global oocyte gene expression profiles. Interestingly, a substantial proportion of the genes expressed in mouse oocytes is conserved between the three species (74%, 7275 genes). Moreover, functional annotation of these conserved oocyte-expressed genes confirmed that certain functions are conserved among the three species. RNA metabolism and cell cycle were among the over-represented Gene Ontology terms in the biological process category. Finally, a pattern-matching analysis identified 208 conserved maternally expressed genes. Results from these cross-species hybridizations allowed numerous genes expressed in oocytes and conserved between Mus musculus, B. taurus, and X. laevis to be identified. This comparative analysis of oocyte transcript profiles revealed a high degree of conservation among species.


Increased circulating CSF-1 (M-CSF) in myeloproliferative disease: association with myeloid metaplasia and peripheral bone marrow extension.
Myeloproliferative disease (MPD) is heterogeneous in phenotypic expression and may display features consistent with expansion and activation of the monocyte/macrophage population during its course. The role of colony-stimulating factor-1 (CSF-1) in the pathophysiology of MPD was investigated by measuring circulating CSF-1 levels and examining their relationship to disease phenotype. Serum CSF-1 concentrations, measured by radioimmunoassay, were elevated in all MPD phenotypes. CSF-1 levels differed significantly between groups of patients with essential thrombocythemia, polycythemia vera, and postpolycythemic or agnogenic myeloid metaplasia (in ascending order). CSF-1 serum levels were positively correlated with spleen size and the degree of peripheral bone marrow extension, determined by scintigraphy using a macrophage-seeking isotope. There was no correlation between CSF-1 concentration and circulating levels of erythrocytes, neutrophils or platelets, or the presence of bone marrow fibrosis. Elevated serum CSF-1 levels appear to be associated with an expanded monocyte/macrophage population in MPD. In view of the known cooperativity between CSF-1 and other growth factors in regulating hematopoiesis, the finding of increased serum CSF-1 concentrations and its association with myeloid metaplasia and bone marrow extension may indicate a pathophysiologic role for CSF-1 in determining the phenotypic expression of MPD.


Melatonin inhibits testosterone secretion by acting at hypothalamo-pituitary-gonadal axis in the rat.
OBJECTIVES: We have investigated the changes in serum luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone levels together with testicular histology in both pinealectomized (PNX) and intact rats. MATERIAL and METHODS: Twenty-one animals were PNX and allowed to recover for two months. Group I was assigned as PNX, group II PNX+melatonin and group III PNX+Human Chorionic Gonadotropin (HCG). Rats in group IV were sham PNX (S-PNX). An intact group of animals was s.c. injected with melatonin (0.5 mg/kg/day), another group with a combination of melatonin+HCG (5000 IU/kg/day) for seven days. Controls received saline alone (1 ml/kg). At the end, all animals were decapitated and blood samples obtained. Serum LH and FSH levels were determined by Radioimmunoassay, testosterone values by Chemiluminescent Enzyme Immunassay. Testicular tissue was collected and processed for light microscopy. RESULTS: Serum LH levels were increased following PNX, but no such increases were seen in testosterone. In the PNX+melatonin group, serum LH and testosterone values were found to be similar to those of S-PNX group. HCG supplementation to PNX rats resulted in significant decreases in LH (p<0.005), but increased testosterone levels (p<0.001). Melatonin administration to intact animals significantly decreased both LH and testosterone levels (p<0.01). Co-administration of HCG+melatonin resulted in significant decreases in LH (p<0.001) and increases in testosterone levels (p<0.01). Serum FSH values did not show significant changes among groups. Only HCG administration significantly reduced FSH levels (p<0.01). CONCLUSIONS: Our results suggest that melatonin inhibits testosterone secretion by acting at hypothalamo-pituitary axis. There is a functional relationship and feedback regulation between the pineal gland and the testes.


Pathways for Improving Inpatient Pediatric Asthma Care (PIPA): A Multicenter, National Study.
Pathways guide clinicians through evidence-based care of specific conditions. Pathways have been demonstrated to improve inpatient asthma care but mainly in studies at large, tertiary children's hospitals. It remains unclear if these effects are generalizable across diverse hospital settings. Our objective was to improve inpatient asthma care by implementing pathways in a diverse, national sample of hospitals. We used a learning collaborative model. Pathway implementation strategies included local champions, external facilitators and/or mentors, educational seminars, quality improvement methods, and audit and feedback. Outcomes included length of stay (LOS) (primary), early administration of metered-dose inhalers, screening for secondhand tobacco exposure and referral to cessation resources, and 7-day hospital readmissions or emergency revisits (balancing). Hospitals reviewed a sample of up to 20 charts per month of children ages 2 to 17 years who were admitted with a primary diagnosis of asthma (12 months before and 15 months after implementation). Analyses were done by using multilevel regression models with an interrupted time series approach, adjusting for patient characteristics. Eighty-five hospitals enrolled (40 children's and 45 community); 68 (80%) completed the study (n = 12 013 admissions). Pathways were associated with increases in early administration of metered-dose inhalers (odds ratio: 1.18; 95% confidence interval [CI]: 1.14-1.22) and referral to smoking cessation resources (odds ratio: 1.93; 95% CI: 1.27-2.91) but no statistically significant changes in other outcomes, including LOS (rate ratio: 1.00; 95% CI: 0.96-1.06). Most hospitals (65%) improved in at least 1 outcome. Pathways did not significantly impact LOS but did improve quality of asthma care for children in a diverse, national group of hospitals.


Effect of oral progesterone and caffeine at the end of gestation on farrowing duration and piglet growth and survival.
The profitability of pig production is constrained by high incidences of peri-parturient and pre-weaning piglet mortality. Supplementing sows with either progesterone or caffeine during the last week of gestation can reduce stillbirths and improve piglet performance. However, the consequences of combining these two substances has not been investigated. The aim of the current study was to determine the effect of oral supplementation of sows with progesterone (regumate) and caffeine at the end of gestation on the timing and progression of farrowing, as well as piglet survival and growth to weaning. From days 111 to 113 of gestation, 20 Large White pregnant sows (parity 3.0±0.45) received 5 ml of Regumate Porcine (0.4 w/v oral solution; MSD Animal Health) daily on top of their morning ration. Sows were stratified according to parity and predicted farrowing date, and allocated at random to receive a diet supplemented with either 0 g caffeine/kg diet (CONT) or 2.4 g of caffeine/kg diet (CAFF) from day 113 of gestation until parturition (n=10 sows/treatment). Treatment did not affect total litter size; however, CONT sows gave birth to more live and fewer dead piglets compared with CAFF sows; 14.5±0.73 v. 11.7±1.03 and 0.7±0.20 v. 3.2±0.77; P<0.05). Mean, minimum and maximum piglet birthweight were unaffected by treatment. Compared with the control, caffeine increased the proportion of piglets with a birthweight <1 kg (0.16±0.05 v. 0.05±0.02; P=0.072) and decreased the proportion of live born piglets surviving to day 5 postpartum (0.77±0.06 v. 0.90±0.02; P<0.05) and to weaning (0.74±0.06 v. 0.90±0.02; P<0.05). Overall, the current data provided the first evidence that caffeine supplementation of sows receiving progesterone to prevent premature farrowing impaired piglet survival during, and shortly after parturition. This negative outcome may be linked to extended farrowing durations and an increase in the proportion of very light piglets at birth. These data provide compelling, albeit preliminary, evidence that caffeine and progesterone should not be used together at the end of gestation.


A herpesvirus encoded deubiquitinase is a novel neuroinvasive determinant.
The neuroinvasive property of several alpha-herpesviruses underlies an uncommon infectious process that includes the establishment of life-long latent infections in sensory neurons of the peripheral nervous system. Several herpesvirus proteins are required for replication and dissemination within the nervous system, indicating that exploiting the nervous system as a niche for productive infection requires a specialized set of functions encoded by the virus. Whether initial entry into the nervous system from peripheral tissues also requires specialized viral functions is not known. Here we show that a conserved deubiquitinase domain embedded within a pseudorabies virus structural protein, pUL36, is essential for initial neural invasion, but is subsequently dispensable for transmission within and between neurons of the mammalian nervous system. These findings indicate that the deubiquitinase contributes to neurovirulence by participating in a previously unrecognized initial step in neuroinvasion.


Older patients with diverticulitis have low recurrence rates and rarely need surgery.
In a cohort of older patients with newly diagnosed diverticulitis, we aimed to describe diverticulitis recurrence and need for an operation based on patient age and site of initial care. This retrospective, longitudinal, cohort study used data from the 5% Medicare Provider Analysis and Review inpatient and outpatient files from January 1, 2003, through December 31, 2007. An incident cohort of patients with diverticulitis was identified. Patients undergoing left colectomy, colostomy, or ileostomy were considered to have undergone diverticulitis surgery. The primary outcomes of interest were need for operative intervention and number of recurrences. We included 16,048 individuals and followed them for an average of 19.2 months; their mean age was 77.8 years. Among those with initial inpatient care, 14.0% underwent operations and 82.5% had no further recurrences. Of patients initially managed nonoperatively, 97% did not go on to have surgery. Individuals treated as outpatients upon first presentation, and patients ≥ 80, were significantly less likely to have recurrent episodes and were less likely to require an operation. The majority of elderly patients newly diagnosed with diverticulitis did not have an operation or experience recurrent episodes. The apparent benign course of this disease in this population suggests that a conservative approach to the management may be appropriate.


TOF-secondary ion mass spectrometry imaging of polymeric scaffolds with surrounding tissue after in vivo implantation.
Supramolecular polymeric materials are of increasing interest for the use as drug delivery carriers. A thorough insight in the biocompatibility and the degradation of these materials in vivo are of fundamental importance to further their development and application in medical practice. Molecular imaging techniques are powerful tools that enable the elucidation of molecular distributions in and around such polymer implants. A supramolecular polymeric hydrogel was implanted under the renal capsule to study its biocompatibility with TOF-SIMS. This results in a molecular cartography of the polymer implant combined with the cellular signature of the implantation environment. In this experiment, molecular signals are observed from cells that are involved in the biological response to the implant, e.g., macrophages. These molecular signatures are compared with macrophage standards cultured in different polarization environments. On the basis of this comparison, information can be acquired on the various macrophage differentiations that are connected to different stages in the foreign body response. Mass spectrometric imaging techniques offer the opportunity to visualize different histological phenomena in a single experiment without the need for specific immunohistochemical markers. Cellular infiltration into the polymer is visualized, offering a clear view on both biological and polymer features in a single imaging experiment.


Collective judgment predicts disease-associated single nucleotide variants.
In recent years the number of human genetic variants deposited into the publicly available databases has been increasing exponentially. The latest version of dbSNP, for example, contains ~50 million validated Single Nucleotide Variants (SNVs). SNVs make up most of human variation and are often the primary causes of disease. The non-synonymous SNVs (nsSNVs) result in single amino acid substitutions and may affect protein function, often causing disease. Although several methods for the detection of nsSNV effects have already been developed, the consistent increase in annotated data is offering the opportunity to improve prediction accuracy. Here we present a new approach for the detection of disease-associated nsSNVs (Meta-SNP) that integrates four existing methods: PANTHER, PhD-SNP, SIFT and SNAP. We first tested the accuracy of each method using a dataset of 35,766 disease-annotated mutations from 8,667 proteins extracted from the SwissVar database. The four methods reached overall accuracies of 64%-76% with a Matthew's correlation coefficient (MCC) of 0.38-0.53. We then used the outputs of these methods to develop a machine learning based approach that discriminates between disease-associated and polymorphic variants (Meta-SNP). In testing, the combined method reached 79% overall accuracy and 0.59 MCC, ~3% higher accuracy and ~0.05 higher correlation with respect to the best-performing method. Moreover, for the hardest-to-define subset of nsSNVs, i.e. variants for which half of the predictors disagreed with the other half, Meta-SNP attained 8% higher accuracy than the best predictor. Here we find that the Meta-SNP algorithm achieves better performance than the best single predictor. This result suggests that the methods used for the prediction of variant-disease associations are orthogonal, encoding different biologically relevant relationships. Careful combination of predictions from various resources is therefore a good strategy for the selection of high reliability predictions. Indeed, for the subset of nsSNVs where all predictors were in agreement (46% of all nsSNVs in the set), our method reached 87% overall accuracy and 0.73 MCC. Meta-SNP server is freely accessible at http://snps.biofold.org/meta-snp.


Perspective: The promise of multi-cellular engineered living systems.
Recent technological breakthroughs in our ability to derive and differentiate induced pluripotent stem cells, organoid biology, organ-on-chip assays, and 3-D bioprinting have all contributed to a heightened interest in the design, assembly, and manufacture of living systems with a broad range of potential uses. This white paper summarizes the state of the emerging field of "multi-cellular engineered living systems," which are composed of interacting cell populations. Recent accomplishments are described, focusing on current and potential applications, as well as barriers to future advances, and the outlook for longer term benefits and potential ethical issues that need to be considered.


Metabolic control of sexual function and growth: role of neuropeptide Y and leptin.
The discovery of leptin has generated an extraordinary interest in the field of obesity but also in the understanding of the relationship between metabolic status and the neuroendocrine system. Following the initial demonstration that leptin administration to fasting mice can 'protect' neuroendocrine secretions and prevent the changes that are associated with fasting, the concept has emerged that a normal leptin secretion is a prerequisite for normal neuroendocrine secretions. Several unfavorable metabolic situations are associated with low plasma leptin, increased secretion of hypothalmic neuropeptide Y (NPY), and hypogonadism, and a causal relationship has been evoked. Severe dietary restriction in juvenile female rats is associated with low plasma leptin and sexual immaturity. Cessation of food restriction leads to immediate increase in plasma leptin followed 4 days later by vaginal opening. If food restriction is maintained, central leptin infusion can induce sexual maturation, thus demonstrating that leptin can act as a signal for the onset of puberty. In untreated type-I diabetic rats, hypogonadism is associated with very low plasma leptin and increased hypothalmic NYP synthesis and oestrous cyclicity. Fasting rapidly inhibits growth hormone (GH) secretion in association with low plasma leptin and elevated hypothalmic NPY. Central infusion of leptin to fasting rats was able to completely prevent the collapse of GH secretion and to maintain a normal low NPY synthesis. In summary, normally elevated plasma levels appear to be a prerequisite for normal GH and gonadotropin secretion in the rat. Degradation of metabolic conditions results in a rapid reduction of circulating leptin that could represent the signal for several alterations of neuroendocrine secretions. At the level of the hypothalamus, leptin could act on NPY neurons to transduce part or all of this 'metabolic' message. The possibility that changing plasma levels for leptin also affect peripheral endocrine targets, such as pituitary, ovary, adrenal or pancreas, is likely since these endocrine organs express functional long-term leptin receptors.


Application of molecularly imprinted polymers to selective removal of clofibric acid from water.
A new molecularly imprinted polymer (MIP) adsorbent for clofibric acid (CA) was prepared by a non-covalent protocol. Characterization of the obtained MIP was achieved by scanning electron microscopy (SEM) and nitrogen sorption. Sorption experimental results showed that the MIP had excellent binding affinity for CA and the adsorption of CA by MIP was well described by pseudo-second-order model. Scatchard plot analysis revealed that two classes of binding sites were formed in the MIP with dissociation constants of 7.52 ± 0.46 mg L(-1) and 114 ± 4.2 mg L(-1), respectively. The selectivity of MIP demonstrated higher affinity for CA over competitive compound than that of non-imprinted polymers (NIP). The MIP synthesized was used to remove CA from spiked surface water and exhibited significant binding affinity towards CA in the presence of total dissolved solids (TDS). In addition, MIP reusability was demonstrated for at least 12 repeated cycles without significant loss in performance.


Influence of substrates on in vitro dephosphorylation of glycogen phosphorylase a by protein phosphatase-1.
The kinetic theory of the substrate reaction during modification of enzyme activity has been applied to a study of the dephosphorylation of phosphorylase a by protein phosphatase-1 (ppase-1). On the basis of the kinetic equation of the substrate reaction in the presence of ppase-1, all the inactivation rate constants for the free enzyme and the enzyme-substrate(s) complexes have been determined. Binding of the allosteric substrate, glucose 1-phosphate, to one subunit of phosphorylase a protects completely against ppase-1 action on either the same subunit or the adjacent subunit, whereas binding of the non-allosteric substrate, glycogen, to one subunit protects this subunit partially, but has no effect on the modification on the neighbouring subunit. Analysis of the data suggests that the allosteric behaviour of phosphorylase a can be interpreted in terms of a modified concerted model. The present method also provides a novel approach for studying dephosphorylation reactions. Since the experimental conditions used resemble more closely the in vivo situation where the substrate is constantly being turned over while the enzyme is being modified, this new method would be particularly useful when the regulatory mechanism of the reversible phosphorylation reaction toward certain enzymes is being assessed.


Development of aliphatic biodegradable photoluminescent polymers.
None of the current biodegradable polymers can function as both implant materials and fluorescent imaging probes. The objective of this study was to develop aliphatic biodegradable photoluminescent polymers (BPLPs) and their associated cross-linked variants (CBPLPs) for biomedical applications. BPLPs are degradable oligomers synthesized from biocompatible monomers including citric acid, aliphatic diols, and various amino acids via a convenient and cost-effective polycondensation reaction. BPLPs can be further cross-linked into elastomeric cross-linked polymers, CBPLPs. We have shown representatively that BPLP-cysteine (BPLP-Cys) and BPLP-serine (BPLP-Ser) offer advantages over the traditional fluorescent organic dyes and quantum dots because of their preliminarily demonstrated cytocompatibility in vitro, minimal chronic inflammatory responses in vivo, controlled degradability and high quantum yields (up to 62.33%), tunable fluorescence emission (up to 725 nm), and photostability. The tensile strength of CBPLP-Cys film ranged from 3.25 +/- 0.13 MPa to 6.5 +/- 0.8 MPa and the initial Modulus was in a range of 3.34 +/- 0.15 MPa to 7.02 +/- 1.40 MPa. Elastic CBPLP-Cys could be elongated up to 240 +/- 36%. The compressive modulus of BPLP-Cys (0.6) (1:1:0.6 OD:CA:Cys) porous scaffold was 39.60 +/- 5.90 KPa confirming the soft nature of the scaffolds. BPLPs also possess great processability for micro/nano-fabrication. We demonstrate the feasibility of using BPLP-Ser nanoparticles ("biodegradable quantum dots") for in vitro cellular labeling and noninvasive in vivo imaging of tissue engineering scaffolds. The development of BPLPs and CBPLPs represents a new direction in developing fluorescent biomaterials and could impact tissue engineering, drug delivery, bioimaging.


Online variational inference for state-space models with point-process observations.
We present a variational Bayesian (VB) approach for the state and parameter inference of a state-space model with point-process observations, a physiologically plausible model for signal processing of spike data. We also give the derivation of a variational smoother, as well as an efficient online filtering algorithm, which can also be used to track changes in physiological parameters. The methods are assessed on simulated data, and results are compared to expectation-maximization, as well as Monte Carlo estimation techniques, in order to evaluate the accuracy of the proposed approach. The VB filter is further assessed on a data set of taste-response neural cells, showing that the proposed approach can effectively capture dynamical changes in neural responses in real time.


Effect of continuous positive airway pressure therapy on circadian patterns of cardiac repolarization in patients with obstructive sleep apnoea: data from a randomized trial.
Obstructive sleep apnoea (OSA) has been proposed as an independent risk factor for sudden cardiac death (SCD). This study takes advantage of a previous randomized trial and seeks to evaluate circadian patterns of the QTc-interval, a marker of cardiac repolarization and biomarker for SCD, in patients with OSA. We hypothesized that patients with OSA would exhibit longest QTc during the night-time and that continuous positive airway pressure (CPAP) therapy would reverse this. One hundred eighteen patients diagnosed with moderate-to-severe OSA were randomized to receive therapeutic or subtherapeutic CPAP for 4 weeks. Of these, 84 had full 24 h-Holter monitoring data at baseline and follow-up. Weighted means of all QTc-intervals were analysed over 24 h, during four time-periods (12 pm-6 am, 6 am-12 am, 12 am-6 pm, 6 pm-12 pm) as well as during each individual hour. A two-sided P value <0.05 was considered to be of statistical significance. QTc-intervals at baseline [mean (SD) over 24 h: 407.8 ms (36.6)] were highest from 6 pm-12 pm [411.7 ms (42.0)] and shortest from 6 am-12 am [405.4 ms (39.5)]. Overall 24 h CPAP treatment effect on QTc was -11.3 ms [95% confidence interval (CI), -22.1 to -0.6; P=0.039] and was estimated to be greater from 6 pm-12 pm than from 12 pm-6 am (P=0.068). The CPAP treatment effect on QTc was driven by those patients in the highest QTc decile at baseline (all >430 ms). In these patients, CPAP led to reductions in QTc, allowing reclassification into lower risk-associated values of QTc (<430 ms). In this exploratory study, CPAP treatment led to an overall reduction in the QTc-interval compared with subtherapeutic CPAP. This reduction seems more pronounced during evening hours and in patients with a QTc above 430 ms.