Aβ Amyloid Fibers Drastically Alter the Topography and Mechanical Properties of Lipid Membranes.
Alzheimer's disease (AD) is related to the fibrillation of the Aβ peptides at neuronal membranes, a process that depends on the lipid composition and may impart different physical states to the membrane. In the present work, we study the properties of the Aβ peptide when mixed with a zwitterionic lipid (DMPC), using the Langmuir monolayer technique as an approach to control membrane physical conditions. First, we build on previous characterizations of pure Aβ monolayers and observe that, in addition to high shear, these films present a pronounced compressional hysteresis. When Aβ is assembled with DMPC in a binary film, the resulting membranes become heterogeneous, with a peptide-enriched phase distributed in a network-like pattern, and they exhibit a lateral transition that depends on the Aβ content. At lower peptide proportions, the films segregate into two well-defined phases: one consisting of lipids and another enriched with peptides. The reflectivity of these phases differs from that obtained for pure Aβ films. Thus, the formed fibers effectively cover most of the interface area and remain stable at higher pressures (from 20 to 30 mN m-1 depending on Aβ content) compared to pure peptide films (17 mN m-1). Furthermore, such structures induce a compressional hysteresis in the film, similar to that of pure peptide films (which is nonexistent in the pure lipid monolayer), even at low peptide proportions. We claim that the mechanical properties at the interface are governed by the size of the fibril-like structures. Based on the low molar fractions and surface packing at which these phenomena were observed, we postulate that as a consequence of peptide intermolecular interactions, Aβ may have drastic effects on the molecular arrangement and mechanical properties of a lipid membrane.


Transfer hydrogenation of carbon dioxide and bicarbonate from glycerol under aqueous conditions.
The transfer hydrogenation of CO2 from glycerol to afford formic and lactic acid is a highly attractive path to valorizing two waste streams and is a significantly more thermodynamically favorable process than direct CO2 hydrogenation. We report the first homogeneous catalyst for this transformation consisting of a water-soluble Ru N-heterocyclic carbene complex. The catalyst affords lactic and formic acid selectively in the presence of a base at temperatures between 150 and 225 °C. Carbonate salts can also be utilized in place of CO2, affording the same products at higher rates.


Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group.
Misoprostol is effective for ulcers associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs) but is often poorly tolerated because of diarrhea and abdominal pain. We compared the efficacy of omeprazole and misoprostol in healing and preventing ulcers associated with NSAIDs. In a double-blind study, we randomly assigned 935 patients who required continuous NSAID therapy and who had ulcers or more than 10 erosions in the stomach or duodenum (or both) to receive 20 mg or 40 mg of omeprazole orally in the morning or 200 microg of misoprostol orally four times daily. Patients were treated for four weeks or, in the absence of healing, eight weeks. Treatment success was defined as the absence of ulcers and the presence of fewer than five erosions at each site and not more than mild dyspepsia. We then randomly reassigned 732 patients in whom treatment was successful to maintenance therapy with 20 mg of omeprazole daily, 200 microg of misoprostol twice daily, or placebo for six months. At eight weeks, treatment was successful in 76 percent of the patients given 20 mg of omeprazole (233 of 308), 75 percent of those given 40 mg of omeprazole (237 of 315), and 71 percent of those given misoprostol (212 of 298). The rates of gastric-ulcer healing were significantly higher with 20 mg of omeprazole (but not 40 mg of omeprazole) than with misoprostol. Healing rates among patients with duodenal ulcers were higher with either dose of omeprazole than with misoprostol, whereas healing rates among patients with erosions alone were higher with misoprostol. More patients remained in remission during maintenance treatment with omeprazole (61 percent) than with misoprostol (48 percent, P=0.001) and with either drug than with placebo (27 percent, P<0.001). There were more adverse events during the healing phase in the misoprostol group than in the groups given 20 mg and 40 mg of omeprazole (59 percent, 48 percent, and 46 percent, respectively). The overall rates of successful treatment of ulcers, erosions, and symptoms associated with NSAIDs were similar for the two doses of omeprazole and misoprostol. Maintenance therapy with omeprazole was associated with a lower rate of relapse than misoprostol. Omeprazole was better tolerated than misoprostol.


Facial colliculus syndrome due to a Herpes simplex virus infection following Herpes labialis.
The facial colliculus is an elevated area that is formed by fibers from the motor nucleus of the 7`th cranial nerve as they loop over the abducens nucleus. Clinical signs and symptoms of facial colliculus lesions occur primarily due to injury to the abducens nerve nucleus, the facial nerve fibers around the abducens nucleus, paramedian pontine reticular formation, and the medial longitudinal fasciculus. The etiology of facial colliculus lesions varies by age. While tumors, demyelinating lesions, and viral infections can be involved in young individuals` etiology, vascular ischemia is a common causative factor in older people. In this paper, we present a case of facial colliculus syndrome due to its rare occurrence in a young patient; who developed the signs and symptoms after a herpes infection. Facial colliculus syndrome is rare and the treatment is based on etiology.


Extreme Phenotype Approach Suggests Taste Transduction Pathway for Carotid Plaque in a Multi-Ethnic Cohort.
Carotid plaque is a heritable trait and a strong predictor of vascular events. Several loci have been identified for carotid plaque, however, studies in minority populations are lacking. Within a multi-ethnic cohort, we have identified individuals with extreme total carotid plaque area (TCPA), that is, higher or lower TCPA than expected based on traditional vascular risk factors (age, sex, smoking, diabetes mellitus, hypertension, etc). We hypothesized that these individuals are enriched with genetic variants accounting for the plaque burden that cannot be explained by traditional vascular risk factors. Herein, we sought to identify the genetic basis for TCPA using the multi-ethnic cohort. Three hundred forty participants (170 from each extreme group) from 3 race/ethnic groups (53% Hispanic, 29% non-Hispanic Black, and 18% non-Hispanic White) were genotyped using a genome-wide single-nucleotide polymorphism (SNP) array and imputed using 1000Genome data. SNP-based analyses using logistic regression and gene-based analyses using VEGAS2 were performed within each race/ethnic group and then meta-analyzed. Genes with P<0.001 were included in an overrepresentation enrichment pathway analysis using WebGestalt. Promising findings were tested for association with ischemic stroke using the MEGASTROKE Consortium data set. No SNP or gene reached genome-wide significance. In the pathway analysis, GO:0050913 (sensory perception of bitter taste) gene set was significantly enriched (P=4.5×10-6, false discovery rate=0.04), which was confirmed in MEGASTROKE (P=0.01). Within the GO:0050913 gene set, 3 genes were associated with extreme TCPA in our study (P<0.001): TAS2R20, TAS2R50, and ITPR3. In TAS2R50, rs1376251 is the top SNP and has been associated with myocardial infarction by others. In ITPR3, a SNP with high regulatory potential (rs3818527, RegulomeScore=1f), and ITPR3 itself were among the top SNP-based and gene-based results and showed consistent evidence for association in all ethnic groups (P<0.05). Extreme TCPA analysis identified new candidate genes for carotid plaque in understudied populations.


Three-dimensional forces in GPC-based counterpropagating-beam traps.
We theoretically investigate the three-dimensional (3D) trapping force acting on a microsphere held in a pair of counterpropagating beams produced by the generalized phase contrast (GPC) method. In the case of opposing beams of equal power, we identify the range of beam waist separation s that results in a stable 3D optical potential-well by assessing the dependence of the axial and transverse force curves on s. We also examine how the force curves are influenced by other parameters such as size and refractive index of the microsphere. Aside from force curves of beam tandems with equal powers, we also numerically calculate force curves for cases of beam pairs having disparate relative strengths. These calculations enable us to elucidate the large dynamic range for axial position control of microparticles in GPC-based counterpropagting-beam traps.


Retinal light distributions, the Stiles-Crawford effect and apodization.
Analysis of retinal image formation for beams of coherent and incoherent radiation emphasizes the role of the Poynting vector's inclination with respect to the retinal image plane. Coherent beams interfere and give rise to a single Poynting vector that highlights the unique direction of incidence of energy flow, whereas multiple incoherent beams, especially incoherent extended sources in the pupil, generate electro-magnetic disturbances in the image plane each characterized by Poynting vectors of their own. As a result, the Stiles-Crawford diminution of luminant efficiency adds differently depending on the coherence of the entering light. Two practical considerations follow: first, in performing diffraction calculations for the retinal image from known wavefronts in the pupil plane, apodization terms should not be factored in, and, second, in principle, for perfect imaging in standard target viewing, Stiles-Crawford integration with increasing pupil diameter is not expected.


Particle ejection from the cytoproct of Tetrahymena.
Egestion of carmine particle-containing food vacuoles from the cytoproct of Tetrahymena pyriformis has been analyzed by high-speed cinemicrography. The vacuole may enter into position in the cytoproct approximately 7 sec before ejection, and forms a distinct bulge beyond the outline of the cell surface for over 2 sec prior to ejection. The ejection process itself requires 20-80 msec.


Amyloid transition of ubiquitin on silver nanoparticles produced by pulsed laser ablation in liquid as a function of stabilizer and single-point mutations.
The interaction of nanoparticles with proteins has emerged as a key issue in addressing the problem of nanotoxicity. We investigated the interaction of silver nanoparticles (AgNPs), produced by laser ablation with human ubiquitin (Ub), a protein essential for degradative processes in cells. The surface plasmon resonance peak of AgNPs indicates that Ub is rapidly adsorbed on the AgNP surface yielding a protein corona; the Ub-coated AgNPs then evolve into clusters held together by an amyloid form of the protein, as revealed by binding of thioflavin T fluorescent dye. Transthyretin, an inhibitor of amyloid-type aggregation, impedes aggregate formation and disrupts preformed AgNP clusters. In the presence of sodium citrate, a common stabilizer that confers an overall negative charge to the NPs, Ub is still adsorbed on the AgNP surface, but no clustering is observed. Ub mutants bearing a single mutation at one edge β strand (i.e. Glu16Val) or in loop (Glu18Val) behave in a radically different manner.


Pseudomonas syringae lytic transglycosylases coregulated with the type III secretion system contribute to the translocation of effector proteins into plant cells.
Pseudomonas syringae translocates virulence effector proteins into plant cells via a type III secretion system (T3SS) encoded by hrp (for hypersensitive response and pathogenicity) genes. Three genes coregulated with the Hrp T3SS system in P. syringae pv. tomato DC3000 have predicted lytic transglycosylase domains: PSPTO1378 (here designated hrpH), PSPTO2678 (hopP1), and PSPTO852 (hopAJ1). hrpH is located between hrpR and avrE1 in the Hrp pathogenicity island and is carried in the functional cluster of P. syringae pv. syringae 61 hrp genes cloned in cosmid pHIR11. Strong expression of DC3000 hrpH in Escherichia coli inhibits bacterial growth unless the predicted catalytic glutamate at position 148 is mutated. Translocation tests involving C-terminal fusions with a Cya (Bordetella pertussis adenylate cyclase) reporter indicate that HrpH and HopP1, but not HopAJ1, are T3SS substrates. Pseudomonas fluorescens carrying a pHIR11 derivative lacking hrpH is poorly able to translocate effector HopA1, and this deficiency can be restored by HopP1 and HopAJ1, but not by HrpH(E148A) or HrpH(1-241). DC3000 mutants lacking hrpH or hrpH, hopP1, and hopAJ1 combined are variously reduced in effector translocation, elicitation of the hypersensitive response, and virulence. However, the mutants are not reduced in secretion of T3SS substrates in culture. When produced in wild-type DC3000, the HrpH(E148A) and HrpH(1-241) variants have a dominant-negative effect on the ability of DC3000 to elicit the hypersensitive response in nonhost tobacco and to grow and cause disease in host tomato. The three Hrp-associated lytic transglycosylases in DC3000 appear to have overlapping functions in contributing to T3SS functions during infection.


Permafrost Dynamics Observatory-Part I: Postprocessing and Calibration Methods of UAVSAR L-Band InSAR Data for Seasonal Subsidence Estimation.
Interferometric synthetic aperture radar (InSAR) has been used to quantify a range of surface and near surface physical properties in permafrost landscapes. Most previous InSAR studies have utilized spaceborne InSAR platforms, but InSAR datasets over permafrost landscapes collected from airborne platforms have been steadily growing in recent years. Most existing algorithms dedicated toward retrieval of permafrost physical properties were originally developed for spaceborne InSAR platforms. In this study, which is the first in a two part series, we introduce a series of calibration techniques developed to apply a novel joint retrieval algorithm for permafrost active layer thickness retrieval to an airborne InSAR dataset acquired in 2017 by NASA's Uninhabited Aerial Vehicle Synthetic Aperture Radar over Alaska and Western Canada. We demonstrate how InSAR measurement uncertainties are mitigated by these calibration methods and quantify remaining measurement uncertainties with a novel method of modeling interferometric phase uncertainty using a Gaussian mixture model. Finally, we discuss the impact of native SAR resolution on InSAR measurements, the limitation of using few interferograms per retrieval, and the implications of our findings for cross-comparison of airborne and spaceborne InSAR datasets acquired over Arctic regions underlain by permafrost.


A case for Planetary Health/GeoHealth.
Concern has been spreading across scientific disciplines that the pervasive human transformation of Earth's natural systems is an urgent threat to human health. The simultaneous emergence of "GeoHealth" and "Planetary Health" signals recognition that developing a new relationship between humanity and our natural systems is becoming an urgent global health priority-if we are to prevent a backsliding from the past century's great public health gains. Achieving meaningful progress will require collaboration across a broad swath of scientific disciplines as well as with policy makers, natural resource managers, members of faith communities, and movement builders around the world in order to build a rigorous evidence base of scientific understanding as the foundation for more robust policy and resource management decisions that incorporate both environmental and human health outcomes.


Spatial heterogeneity of methanotrophs: a geostatistical analysis of pmoA-based T-RFLP patterns in a paddy soil.
Despite numerous studies on methanotrophs, virtually nothing is known about their spatial heterogeneity in nature. These patterns, however, have strong influences on the interpretations made from analysing microbial processes and community structure. Here we report the first use of geostatistics to analyse the spatial heterogeneity of methanotrophs in a rice field soil (Vercelli, Italy). We used the gene encoding the particulate methane monooxygenase, pmoA, for terminal restriction fragment length polymorphism (T-RFLP) analysis. The profiles obtained were compared using a pseudo-variogram analysis to study autocorrelation as a function of distance. We demonstrated that there was no large-scale spatial structure at this study site, but a micro-scale spatial structure could not be excluded. A species accumulation curve with all terminal restriction fragments revealed that even 75 samples were insufficient to cover the diversity of methanotrophs in a rice field. However, a species accumulation curve of methanotrophs defined as operational taxonomic units validated from a clone library with 90% coverage demonstrated saturation after approximately 15 samples. The results of this study have consequences for studying the diversity and function of methanotrophs. In this agroecosystem population structure showed no spatial pattern implying that both a systematic and random sampling design would be adequate.


Effects of Exercises on a Hard, Soft, and Sand Surface on Functional Outcomes of Community-Dwelling Older Individuals: A Randomized Controlled Trial.
This single-blind, randomized controlled trial compared the effects of Thai dance exercise training on hard, soft, and sand surfaces on the functional outcomes of 120 community-dwelling older adults (40 subjects/group). The subjects were involved in a Thai dance exercise program on each surface, according to their groups, for 50 min/day, 3 days/week, for 6 weeks. The functional outcomes were assessed prior to training, at Week 3, and Week 6 after training. Subjects showed a significant improvement in all functional tests at 3 and 6 weeks after training, particularly in those who were trained on a sand surface and a soft surface (7-30% improvement, p < .05). The improvement was especially demonstrated in the complex and demanding motor activities after exercise on a soft and sand surface. Aside from attempting to modify training programs on a hard surface, the current findings suggest an alternative and cost-effective program to promote the levels of independence and safety that can be applied easily in clinical, home-based, and community settings.


HIV/AIDS policy agenda setting in Iran.
HIV/AIDS control are one of the most important goals of the health systems. The aim of this study was to determine how HIV/AIDS control was initiated among policy makers' agenda setting in Iran. A qualitative research (semi-structured interview) was conducted using Kingdon's framework (problem, policy and politics streams, and policy windows and policy entrepreneurs) to analysis HIV/AIDS agenda setting in Iran. Thirty-two policy makers, managers, specialists, and researchers were interviewed. Also, 30 policy documents were analyzed. Framework analysis method was used for data analysis. the increase of HIV among Injecting drug users (IDUs) and Female Sex Workers (FSWs), lack of control of their high-risk behaviors, and exceeding the HIV into concentrated phase were examples of problem stream. Policy stream was evidence-based solutions that highlighted the need for changing strategies for dealing with such a problem and finding technically feasible and acceptable solutions. Iran's participation in United Nations General Assembly special sessions on HIV/AIDS (UNGASS), the establishment of National AIDS Committee; highlighting AIDS control in Iran's five years development program and the support of the judiciary system of harm reduction policies were examples of politics stream. Policy entrepreneurs linking these streams put the HIV/AIDS on the national agenda (policy windows) and provide their solutions. There were mutual interactions among these three streams and sometimes, they weakened or reinforced each other. Future studies are recommended to understand the interactions between these streams' parts and perhaps develop further Kingdon's framework, especially in the health sector.


Assessment of anorexia nervosa.
Standardized assessment of anorexia nervosa (AN) is essential in research and can dramatically enhance clinical practice as well. This article highlights conceptual and practical considerations pertaining to the establishment and administration of an assessment battery for AN. Commonly utilized assessment measures are described briefly, and recommendations for advancing assessment of AN are provided.


Linagliptin ameliorated interleukin-29-induced reduction of extracellular matrix genes through the nuclear factor erythroid 2-related factor 2 (Nrf2)/sry-type high-mobility-group box (SOX)-9 axis in an in vitro study on C-28/I2 chondrocytes.
Osteoarthritis (OA) is a severe orthopedic disease commonly observed in the elderly population and is closely related to the degradation of extracellular matrix (ECM) in cartilage tissues. Interleukin-29 (IL-29) is a cytokine that has been recently linked with the progression of OA. However, the physiological roles of IL-29 in ECM genes and function are unknown. Linagliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor recently reported to exert significant anti-inflammatory properties. In this study, we used IL-29 to stimulate C-28/I2 chondrocytes to build an inflammatory injury model. We aimed to investigate the protective effect of Linagliptin on IL-29-induced degradation of ECM. We found that IL-29 stimulation reduced the expressions of Col2a1 and Acan in C-28/I2 chondrocytes, and this effect was mediated by SRY-related high-mobility group box gene-9 (SOX-9), as we showed that overexpression of SOX-9 could rescue the reduction of Col2a1 and Acan. Interestingly, we found that IL-29 stimulation pronouncedly promoted the expression of DPP-4. Treatment with 100 nM of the DPP-4 inhibitor Linagliptin ameliorated IL-29-induced expressions of SOX-9, Col2a1, and Acan. Lastly, the nuclear level of nuclear factor erythroid 2-related factor 2 (Nrf2) was dramatically declined in IL-29-challenged chondrocytes and the protective effects of Linagliptin on the expressions of SOX-9, Col2a1, and Acan were abolished by the knockdown of Nrf2. Taken together, our data reveal that Linagliptin ameliorated IL-29-induced reduction of ECM genes partially through the Nrf2/SOX-9 axis in C-28/I2 chondrocytes. Further in vivo and clinical studies will be done to clarify the protective benefits of Linagliptin in OA.


The transforming capacity of collaborative institutions: Belief change and coalition reformation in conflicted wildlife management.
The aim of this study is to examine the transformative capacity of top-down imposed collaborative institutions on participants' beliefs and coordination patterns. First, do collaborative arenas enhance learning in terms of belief change and belief convergence among participating actors? Second, what types of beliefs are changed and, third, how are changes in beliefs reflected in the formation of coalitions? To answer these questions, a longitudinal study encompassing three collaborative decision-making arenas in the highly adversarial system for wildlife management in Sweden is performed. The empirical analysis indicates both stability and change within the new management system that confirms, as well as challenges, the theoretical assumptions guiding the analysis. While beliefs overall are rather stable, we note, surprisingly, how some participants' more normatively oriented policy core beliefs have been slightly modified over time. A more expected result was that these adjustments in normative policy core beliefs were accompanied by a reformed coalition structure within the studied decision-making arenas. The study contributes to our understandings of policy beliefs and coalitions in conflicted policy areas; it underlines the mixed results of collaborative institutions found in previous research; yet, lends a modest support in favor of the transformative capacity of collaborative institutions.


Perceived barriers to physical activity among North Carolinians with arthritis: findings from a mixed-methodology approach.
A goal of the North Carolina Arthritis Plan is to reduce arthritis burden through regular physical activity. We identified community and personal factors that influence physical activity in individuals with arthritis. In 2004 and 2005, 2479 individuals (53% self-reported arthritis) from 22 North Carolina communities completed a telephone survey (59.5% response rate) assessing health status, neighborhood characteristics, health attitudes, and demographic variables. Qualitative discussions (N=32) were conducted to further examine understanding of community and health and were enhanced with photographs. Descriptive analyses were conducted. A 2-sided binomial test (for each reason given for not being physically active) was used to test for significance between individuals with arthritis and the general population, using a Bonferroni test for multiple comparisons. Interviews and photographs were analyzed using qualitative software ATLAS.ti Version 5.0. Quantitative results show similar community-level reasons for physical inactivity (rural environment, heavy traffic, and lack of sidewalks) despite arthritis status. Yet personal reasons differed as individuals with arthritis more often cited physical inability and illness. In qualitative discussions, walking surfaces emerged as a primary barrier for those with arthritis. Findings from this exploratory study may have limited generalization and warrant further study. The built environment and personal barriers should be considered when examining physical activity in individual with arthritis.


Assessing decisional balance for smoking cessation among Southeast Asian males in the US.
This study examines the relationship of positive and negative perceptions of smoking to self-reported readiness to quit smoking among Southeast (SE) Asian males of Cambodian, Laotian or Vietnamese descent. In order to investigate this relationship, measures of decisional balance constructs (i.e. the pros and cons of smoking) appropriate for these ethnic groups were developed. Decisional balance was calculated by subtracting the cons from the pros. Following the criteria established by Prochaska and DiClemente, subjects were categorized into four levels of readiness to quit smoking (precontemplation, contemplation, preparation/action and maintenance). The expected pattern of relationship between decisional balance and stages of change included: (1) the cons of smoking being of less importance than the pros of smoking for those smokers in the precontemplation stage, (2) the pros and cons intersecting at the contemplation stage, and (3) the cons being of greater importance than the pros in the later stages of change. The SE Asian men in this study did not exhibit these decisional balance patterns, although mean decisional balance scores for precontemplators and contemplators were significantly more positive than mean scores for those in the preparation/action and maintenance stages. Decisional balance patterns differed across the three ethnic groups included in the sample.


Activation of enteric nerve pathways in the guinea-pig duodenum by cholecystokinin octapeptide and pentagastrin.
The action and mechanism of action of cholecystokinin octapeptide (CCK-8) and pentagastrin on isolated segments of guinea-pig duodenum were examined using contractility studies and by intracellular recordings made from smooth muscle cells. Both CCK-8 and pentagastrin caused an excitatory contractile response. The threshold concentration ranged from 5 X 10(-11) to 10(-9) M for CCK-8 and 5 X 10(-10) to 10(-8) M for pentagastrin. The excitatory response was abolished by tetrodotoxin (3.1 X 10(-6) M) and atropine (1.5 X 10(-6) M) and inhibited by d-tubocurarine (up to 2.9 X 10(-5) M). In the presence of atropine a proportion of preparations relaxed in response to CCK-8 (nineteen of thirty-one) and pentagastrin (thirteen of seventeen). This response was only seen at high concentrations of the peptides (10(-8)-10(-7) M) and was abolished by tetrodotoxin (3 X 10(-6) M). Intracellular recordings from duodenal smooth muscle revealed multiple excitatory junction potentials (e.j.p.s) in response to CCK-8 and to pentagastrin. These e.j.p.s were identical to those evoked by transmural nerve stimulation and were abolished by atropine (1.5 X 10(-7) M) and by tetrodotoxin (3 X 10(-6) M). Inhibitory junction potentials (i.j.p.s) were not recorded in response to the peptides except on one occasion. It is suggested that CCK-8 and pentagastrin cause an increase in duodenal motility by the selective activation of excitatory pathways in the enteric nervous system.


Shape-preserving and unidirectional frequency conversion by four-wave mixing.
In this work, we investigate the properties of four-wave mixing Bragg scattering driven by orthogonally polarized pumps in a birefringent waveguide. This configuration enables a large signal conversion bandwidth, and allows strongly unidirectional frequency conversion as undesired Bragg-scattering processes are suppressed by waveguide birefringence. Moreover, we show that this form of Bragg scattering preserves the (arbitrary) signal pulse shape, even when driven by pulsed pumps.


Clausa, a tomato mutant with a wide range of phenotypic perturbations, displays a cell type-dependent expression of the homeobox gene LeT6/TKn2.
Class I knox genes play an important role in shoot meristem function and are thus involved in the ordered development of stems, leaves, and reproductive organs. To elucidate the mechanism underlying the expression pattern of these homeobox genes, we studied a spontaneous tomato (Lycopersicon esculentum) mutant that phenotypically resembles, though is more extreme than, transgenic plants misexpressing class I knox genes. This mutant was found to carry a recessive allele, denoted clausa:shootyleaf (clau:shl)-a newly identified allele of clausa. Mutant plants exhibited abnormal leaf and flower morphology, epiphyllus inflorescences, fusion of organs, calyx asymmetry, and navel-like fruits. Analysis by scanning electron microscopy revealed that such fruits carried ectopic ovules, various vegetative primordia, as well as "forests" of stalked glandular trichomes. In situ RNA hybridization showed a peculiar expression pattern of the class I knox gene LeT6/TKn2; expression was restricted to the vascular system and palisade layer of mature leaves and to the inner part of ovules integuments. We conclude that CLAUSA regulates various aspects of tomato plant development, at least partly, by rendering the LeT6/TKn2 gene silent in specific tissues during development. Considering the expression pattern of LeT6/TKn2 in the clausa mutant, we suggest that the control over a given homeobox gene is maintained by several different regulatory mechanisms, in a cell type-dependent manner.


Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose.
Exogenous ketone drinks may improve athletic performance and recovery, but information on their gastrointestinal tolerability is limited. Studies to date have used a simplistic reporting methodology that inadequately represents symptom type, frequency, and severity. Herein, gastrointestinal symptoms were recorded during three studies of exogenous ketone monoester (KME) and salt (KS) drinks. Study 1 compared low- and high-dose KME and KS drinks consumed at rest. Study 2 compared KME with isocaloric carbohydrate (CHO) consumed at rest either when fasted or after a standard meal. Study 3 compared KME+CHO with isocaloric CHO consumed before and during 3.25 hr of bicycle exercise. Participants reported symptom type and rated severity between 0 and 8 using a Likert scale at regular intervals. The number of visits with no symptoms reported after ketone drinks was n = 32/60 in Study 1, n = 9/32 in Study 2, and n = 20/42 in Study 3. Following KME and KS drinks, symptoms were acute but mild and were fully resolved by the end of the study. High-dose KS drinks caused greater total-visit symptom load than low-dose KS drinks (13.8 ± 4.3 vs. 2.0 ± 1.0; p < .05) and significantly greater time-point symptom load than KME drinks 1-2 hr postdrink. At rest, KME drinks caused greater total-visit symptom load than CHO drinks (5.0 ± 1.6 vs. 0.6 ± 0.4; p < .05). However, during exercise, there was no significant difference in total-visit symptom load between KME+CHO (4.2 ± 1.0) and CHO (7.2 ± 1.9) drinks. In summary, exogenous ketone drinks cause mild gastrointestinal symptoms that depend on time, the type and amount of compound consumed, and exercise.


Characterization of peripheral and mucosal immune responses in rhesus macaques on long-term tenofovir and emtricitabine combination antiretroviral therapy.
The goal of antiretroviral therapy (ART) is to suppress virus replication to limit immune system damage. Some have proposed combining ART with immune therapies to boost antiviral immunity. For this to be successful, ART must not impair physiological immune function. We studied the impact of ART (tenofovir and emtricitabine) on systemic and mucosal immunity in uninfected and simian immunodeficiency (SIV)-infected Chinese rhesus macaques. Subcutaneous ART was initiated 2 weeks after tonsillar inoculation with SIVmac239. There was no evidence of immune dysregulation as a result of ART in either infected or uninfected animals. Early virus-induced alterations in circulating immune cell populations (decreased central memory T cells and myeloid dendritic cells) were detected, but normalized shortly after ART initiation. ART-treated animals showed marginal SIV-specific T-cell responses during treatment, which increased after ART discontinuation. Elevated expression of CXCL10 in oral, rectal, and blood samples and APOBEC3G mRNA in oral and rectal tissues was observed during acute infection and was down regulated after starting ART. ART did not impact the ability of the animals to respond to tonsillar application of polyICLC with increased CXCL10 expression in oral fluids and CD80 expression on blood myeloid dendritic cells. Early initiation of ART prevented virus-induced damage and did not impede mucosal or systemic immune functions.


A 3D similarity method for scaffold hopping from known drugs or natural ligands to new chemotypes.
A primary goal of 3D similarity searching is to find compounds with similar bioactivity to a reference ligand but with different chemotypes, i.e., "scaffold hopping". However, an adequate description of chemical structures in 3D conformational space is difficult due to the high-dimensionality of the problem. We present an automated method that simplifies flexible 3D chemical descriptions in which clustering techniques traditionally used in data mining are exploited to create "fuzzy" molecular representations called FEPOPS (feature point pharmacophores). The representations can be used for flexible 3D similarity searching given one or more active compounds without a priori knowledge of bioactive conformations or pharmacophores. We demonstrate that similarity searching with FEPOPS significantly enriches for actives taken from in-house high-throughput screening datasets and from MDDR activity classes COX-2, 5-HT3A, and HIV-RT, while also scaffold or ring-system hopping to new chemical frameworks. Further, inhibitors of target proteins (dopamine 2 and retinoic acid receptor) are recalled by FEPOPS by scaffold hopping from their associated endogenous ligands (dopamine and retinoic acid). Importantly, the method excels in comparison to commonly used 2D similarity methods (DAYLIGHT, MACCS, Pipeline Pilot fingerprints) and a commercial 3D method (Pharmacophore Distance Triplets) at finding novel scaffold classes given a single query molecule.


Three-dimensional solution structure of the complex of alpha-bungarotoxin with a library-derived peptide.
The solution structure of the complex between alpha-bungarotoxin (alpha-BTX) and a 13-residue library-derived peptide (MRYYESSLKSYPD) has been solved using two-dimensional proton-NMR spectroscopy. The bound peptide adopts an almost-globular conformation resulting from three turns that surround a hydrophobic core formed by Tyr-11 of the peptide. The peptide fills an alpha-BTX pocket made of residues located at fingers I and II, as well as at the C-terminal region. Of the peptide residues, the largest contact area is formed by Tyr-3 and Tyr-4. These findings are in accord with the previous data in which it had been shown that substitution of these aromatic residues by aliphatic amino acids leads to loss of binding of the modified peptide with alpha-BTX. Glu-5 and Leu-8, which also remarkably contribute to the contact area with the toxin, are present in all the library-derived peptides that bind strongly to alpha-BTX. The structure of the complex may explain the fact that the library-derived peptide binds alpha-BTX with a 15-fold higher affinity than that shown by the acetylcholine receptor peptide (alpha185-196). Although both peptides bind to similar sites on alpha-BTX, the latter adopts an extended conformation when bound to the toxin [Basus, V., Song, G. & Hawrot, E. (1993) Biochemistry 32, 12290-12298], whereas the library peptide is nearly globular and occupies a larger surface area of alpha-BTX binding site.


Application of polyimide films as a nuclear track detector (1): A systematic study of track registration sensitivity.
This paper reports the variation of track registration sensitivity as a function of the stopping power of heavy ions in UPILEX-S® films, which is known as the most radiation tolerant polyimide (PI). The detection thresholds in the stopping power for etch pit formation are determined as 4,000, 4,100, 4,800, and 5600 keV/μm for 40Ar, 84Kr, 132Xe and 238U ions, respectively. Furthermore, we investigate the latent track structure in two kinds of PI films (UPILEX-S® and Kapton) by means of FT-IR spectroscopy. At the similar stopping power value, the radiation chemical yields (G value) for heavier ions are lower than those of lighter ions. This is due to the difference of the radial dose distribution for low and high velocity ions.


Nuclear protein import is decreased by engineered mutants of nuclear transport factor 2 (NTF2) that do not bind GDP-Ran.
Nuclear transport factor 2 (NTF2) is associated with the translocation stage of nuclear protein import and binds both to nuclear pore proteins (nucleoporins) containing phenylalanine-rich repeats and to the Ras family GTPase Ran. In this study we probed the role of the NTF2-Ran interaction in nuclear protein import using site-directed mutants of NTF2 that interfere with its interaction with GDP-Ran. The design of these mutants was based on the X-ray crystal structure of NTF2 and was concentrated on conserved residues in and around the molecule's hydrophobic cavity. The mutant NTF2 cDNAs were expressed in Escherichia coli. Purified mutant proteins retained the interaction with FxFG-repeat nucleoporins, but several mutants in the negatively charged residues that surround the NTF2 cavity or in residues in the cavity itself were unable to bind GDP-Ran in vitro. The crystal structure of the E42K mutant protein showed significant structural changes only in this side-chain, indicating that it participated directly in the interaction with GDP-Ran. In permeabilised cell nuclear protein import assays, only wild-type NTF2 and mutants that bound GDP-Ran were functional. Furthermore, when the NTF2 E42K and D92N/D94N NTF2 mutants that failed to bind GDP-Ran in vitro were substituted for the chromosomal yeast NTF2, the yeast cells became non-viable, whereas yeast substituted with wild-type human NTF2 remained viable. We conclude that interaction between NTF2 and GDP-Ran is important for efficient nuclear protein import.


Nickel-catalyzed Mizoroki-Heck reaction of aryl sulfonates and chlorides with electronically unbiased terminal olefins: high selectivity for branched products.
Achieving high selectivity in the Heck reaction of electronically unbiased alkenes has been a longstanding challenge. Using a nickel-catalyzed cationic Heck reaction, we were able to achieve excellent selectivity for branched products (≥19:1 in all cases) over a wide range of aryl electrophiles and aliphatic olefins. A bidentate ligand with a suitable bite angle and steric profile was key to obtaining high branched/linear selectivity, whereas the appropriate base suppressed alkene isomerization of the product. Although aryl triflates are traditionally used to access the cationic Heck pathway, we have shown that, by using triethylsilyl trifluoromethanesulfonate, we can effect a counterion exchange of the catalytic nickel complex, such that cheaper and more stable aryl chlorides, mesylates, tosylates, and sulfamates can be used to yield the same branched products with high selectivity.


Metabolic costs imposed by hydrostatic pressure constrain bathymetric range in the lithodid crab Lithodes maja.
The changing climate is shifting the distributions of marine species, yet the potential for shifts in depth distributions is virtually unexplored. Hydrostatic pressure is proposed to contribute to a physiological bottleneck constraining depth range extension in shallow-water taxa. However, bathymetric limitation by hydrostatic pressure remains undemonstrated, and the mechanism limiting hyperbaric tolerance remains hypothetical. Here, we assess the effects of hydrostatic pressure in the lithodid crab Lithodes maja (bathymetric range 4-790 m depth, approximately equivalent to 0.1 to 7.9 MPa hydrostatic pressure). Heart rate decreased with increasing hydrostatic pressure, and was significantly lower at ≥10.0 MPa than at 0.1 MPa. Oxygen consumption increased with increasing hydrostatic pressure to 12.5 MPa, before decreasing as hydrostatic pressure increased to 20.0 MPa; oxygen consumption was significantly higher at 7.5-17.5 MPa than at 0.1 MPa. Increases in expression of genes associated with neurotransmission, metabolism and stress were observed between 7.5 and 12.5 MPa. We suggest that hyperbaric tolerance in Lmaja may be oxygen-limited by hyperbaric effects on heart rate and metabolic rate, but that Lmaja's bathymetric range is limited by metabolic costs imposed by the effects of high hydrostatic pressure. These results advocate including hydrostatic pressure in a complex model of environmental tolerance, where energy limitation constrains biogeographic range, and facilitate the incorporation of hydrostatic pressure into the broader metabolic framework for ecology and evolution. Such an approach is crucial for accurately projecting biogeographic responses to changing climate, and for understanding the ecology and evolution of life at depth.


Interhospital variability in time to discharge to rehabilitation among insured trauma patients.
Hospital costs are partly a function of length of stay (LOS), which can be impacted by the local availability of postacute care (PAC) resources (inpatient rehabilitation and skilled nursing facilities), particularly for injured patients. We hypothesized that LOS for trauma patients destined for PAC would be variable based on insurance type and hospitals from which they are discharged. We used the 2014 to 2015 National Inpatient Sample from the Healthcare Cost and Utilization Project. We included all adult admissions with a primary diagnosis of trauma (International Classification of Diseases, 9th Revision, Clinical Modification codes), who were insured and discharged to PAC. We then ranked hospitals based upon mean LOS and divided them into quartiles to determine differences. The primary outcome was inpatient LOS; secondary outcome was cost. There are 958,005 trauma patients that met the inclusion criteria. Mean LOS varied based upon insurance type (Medicaid vs. Private vs. Medicare: 12.7 days vs. 8.8 days and 5.7 days; p < 0.001). Shortest LOS hospitals had a marginal variation in LOS (Medicaid vs. Private vs. Medicare: 5.5 days vs. 4.8 days vs. 4.2 days; p < 0.001). Longest LOS hospitals had mean LOS that varied substantially (16.4 days vs. 11.0 days vs. 6.7 days; p < 0.001). Multivariate regression controlling for patient and hospital characteristics revealed that Medicaid patients spent Medicaid patients spent an additional 0.4 days in shortest LOS hospitals and an additional 2.6 days in longest LOS hospitals (p < 0.001). The average daily cost of inpatient care was US $3,500 (SD, US $132). Even with conservative estimates, Medicaid patients at hospitals without easy access to rehabilitation incur significant additional inpatient costs over $10,000 in some hospitals. Prolonged LOS is likely a function of access to postacute facilities, which is largely out of the hands of trauma centers. Efficiencies in care are magnified by access to postacute beds, suggesting that increased availability of rehabilitation facilities, particularly for Medicaid patients, might help to reduce LOS. Epidemiologic, level III; care management, level IV.


Primary prevention of drink driving by the large-scale use of alcolocks in commercial vehicles.
Alcolocks are commercial breath test devices that prevent a motor vehicle from starting when a driver's blood alcohol concentration (BAC) is elevated. This report is an evaluation of the experiences and BAC data from the first use of alcolocks in commercial vehicles as a primary prevention strategy. In most applications, the alcolock is imposed only after an impaired driving conviction. This study, implemented in Sweden, estimates drink driving on a large scale in a variety of commercial vehicles. Officials from 118 companies were interviewed representing 3689 alcolock-equipped vehicles used by 9614 professional drivers, an 80% compliance rate. In a contrast group of 230 transport businesses without alcolocks the interview compliance rate was 57%. Survey results probed motivation for and experience with alcolocks. Analysis of BAC test patterns showed alcohol consumption among employees through prevalence estimates of drink-driving attempts at the rate of BAC> or =the legal limit 0.020%. Before alcolock installation, 64% of the employers suspected alcohol problems among their employees and their motive for installing alcolocks (cost averaged 1700 euro/vehicle) was to improve the transport quality. Several companies had technical problems with the alcolocks; but 98% recommended that other companies install alcolocks. Among 600, heavy vehicles, 0.19% of all starts were prevented by elevated BAC; most during weekends and mornings. Daytime Saturday and Sunday mornings 0.72% of the drivers had elevated BAC. The prevalence of drink driving among professional drivers is probably similar to that among drivers in general. Alcolocks would improve the safety margin and reduce public risk. Provided that the entire fleet of trucks, buses, and taxis in Sweden had installed alcolocks that would correspond to about half a million drink driving trips being prevented every year.


Functional activity of anti-C6 antibodies elicited in C6-deficient rats reconstituted by liver allografts. Ability to inhibit hyperacute rejection of discordant cardiac xenografts.
A critical role of the complement membrane attack complex (C5b-9) in mediating hyperacute rejection has been demonstrated previously in fully C6-deficient PVG (C-)(RT1c) rats that reject guinea pig cardiac xenografts at a delayed tempo (45 +/- 9 hr; n=16) compared with C6-sufficient PVG (C+)(RT1c) hosts (0.5 +/- 2 hr; n=6). We have investigated whether selective depletion of C6 from Lewis rats by antibody therapy prevents hyperacute rejection. A polyclonal rat-antirat C6 antibody was induced in PVG (C-) recipients by orthotopic liver transplants from congenic PVG (C+) donors. These liver grafts produced high levels of C6 that reconstituted the complement function of PVG (C-) hosts by 7 days, but the recipients responded within 28 days with the synthesis of an IgG1 antibody to rat C6. The antiserum inhibited hemolytic complement activity of Lewis (RT1(1)) rats in vivo and in vitro. The effect of C6 depletion on Xg survival was investigated by injecting Lewis rats with 2 ml of rat-antirat C6 antiserum before and 1 ml after reperfusion of the guinea pig cardiac xenograft. Lewis rats rejected guinea pig cardiac xenografts after treatment with this rat-antirat C6 antiserum in 38 +/ -11 hr (n=3). Treatment with normal control sera from PVG (C-) rats did not prolong guinea pig cardiac xenograft survival in the Lewis rats (1 +/- 0.7 hr; n=3)(P<0.0043). Injection of 3 ml of the IgG fraction purified from the rat-antirat C6 antibody (33 mg/ml) prolonged xenograft survival to 13.6 +/- 4 hr (n=4) compared with the survival of 0.61 +/- 0.3 hr (n=4) after injection of control rat IgG (33 mg/ml) (P<0.005). These results demonstrate that specific depletion of C6 by antibody therapy has a significant effect on guinea pig cardiac xenograft survival in the Lewis rat. These findings further suggest that C6 depletion may be beneficial to patients undergoing hyperacute rejection of xenografts or allografts.


Effects of exposure to the UV-filter 4-MBC during Solea senegalensis metamorphosis.
Many personal care products integrate UV-filters, such as 4-methylbenzylidene camphor (4-MBC), a compound frequently detected in aquatic habitats, including coastal areas. However, the potential effects of 4-MBC to saltwater species have been poorly studied. Therefore, the main objective of this work is to study the effects of 4-MBC exposure on Solea senegalensis during metamorphosis, a sensitive life stage of this flatfish. To achieve this, fish were exposed to 4-MBC (0.2-2.0 mg L-1) for 48 h at the beginning of metamorphosis (13 days after hatching, dah). After this period, the fish were transferred to a clean medium. They were fed and maintained until more than 80% of individuals in the control group completed the metamorphosis (24 dah). Mortality, malformations, and metamorphic progression were studied daily. Growth, behavior, and biochemical markers of neurotransmission (acetylcholinesterase, AChE), oxidative stress (catalase, CAT; lipid peroxidation, LPO), detoxification (glutathione S-transferase, GST), and anaerobic metabolism (lactate dehydrogenase, LDH) were also determined at the end of the experiment. An acceleration of metamorphosis progression was observed during and 2 days after the 4-MBC exposure in all concentrations tested. In addition, reduced length, inhibition of CAT activity, and induction of oxidative damage were observed (lowest observed effect concentration, LOEC = 0.928 mg L-1 4-MBC for length, CAT, and LPO). Short-term exposure to 4-MBC at the onset of metamorphosis affected S. senegalensis at several levels of organization, even after 9 days in a clean medium, including growth and metamorphic progression, suggesting possible long-term adverse effects in this species.


[Clinical questions of extremal processing of Mirizzi syndrome].
In this article two clinical cases of Mirizzi syndrome is presented. In the observation examined reactive processing of Mirizzi syndrome I with severe overall system reaction to endogenous infection. The data characterizing the current version of Mirizzi syndrome V b is considered in the second observation. Timely diagnosis of Mirizzi syndrome and determination of the most appropriate method of treatment can reduce the risk of intraoperative injury.


Management of anterolateral foramen magnum meningiomas: surgical vs conservative decision making.
Anterolateral meningiomas of the foramen magnum (FMMs) represent a neurosurgical challenge because they grow in close contact with osteoarticular, nervous, and vascular structures that cannot be sacrificed or retracted. To evaluate our strategy and results in 26 patients with FMMs and analyze factors affecting the decision-making process, resection, and outcome. Among 26 consecutive symptomatic FMM (10 anterior, 16 lateral) patients (16 women, 10 men, ages 28-82 years), 4 older than 70 years of age were untreated. Twenty-two were operated on using a posterolateral approach, with the vertebral artery transposed in 19 and the occipital condyle drilled in 10. We analyzed the characteristics and outcome of untreated cases, the utility of THE occipital condyle drilled, the difficulties of microdissection, morbidity and total removal rates, the outcome of tumor residues, and the literature on radiosurgery. Three of 4 untreated patients remained clinically stable at 2 to 5 years. After systematic vertebral artery medial transposition and occipital condyle drilled in 6 cases, our technique evolved with experience in the next 16 (vertebral artery transposed in 13 of 16; occipital condyle drilled in 4 of 13) for dissecting anteriorly beyond midline (anterior FMMs). Retrocondylar access was sufficient for lateral FMMs. Tumors were totally removed in 16 of 22 (73%). One patient died, and 4 had permanent deficits. Follow-up of more than 5 years in 12 patients showed no C0-1 instability, and slight increase of tumor residue size 7 years after surgery. In the literature, 15 FMMs treated with radiosurgery are reported, 13 at diagnosis and 2 at recurrence, with short-term clinical and radiological safety and efficacy. We currently recommend (1) aiming for subtotal removal in difficult cases, (2) remaining conservative in asymptomatic or elderly patients with mild symptoms, and (3) considering radiosurgery at diagnosis for small (<30 mm) symptomatic FMMs or as an adjunct for evolving residues/recurrences in poor candidates for resection.


Dissimilarity in mother and adolescent illness representations of type 1 diabetes and negative emotional adjustment.
The study explored how two measures of mother-adolescent dissimilarity in illness representations relate to negative emotional adjustment in mothers and adolescents. Eighty-four adolescents with type 1 diabetes (age 11.5-17.5) and their mothers completed the Revised Illness Perceptions Questionnaire and measures of negative emotional adjustment. Adolescents viewed diabetes as less chronic, containing fewer negative emotional representations, and that mother had less control over the illness than did mothers. Mother-adolescent mean differences in representations were not associated with negative adjustment for adolescents; mean differences in coherence were related to negative adjustment for mothers, when controlling the individual's own representations. A measure of dissimilarity based on the sum of squared differences between mother and adolescent was associated with negative adolescent adjustment when controlling adolescent's own representations, but no relations were found for mothers. Dyadic approaches to coping with chronic illness will benefit by understanding how dissimilarity in illness representations between patient and caregiver relate to adjustment.


Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis: results from the Dallas Heart Study.
Although IL-18 promotes atherogenesis in animal studies and predicts cardiovascular risk in humans, it is unknown whether elevated IL-18 levels are associated with coronary atherosclerosis in the general population. IL-18 plasma levels were determined by ELISA in 2231 subjects from the Dallas Heart Study. In univariable analysis, IL-18 levels associated with traditional cardiovascular risk factors and particularly with components of the metabolic syndrome (MS, P<0.01 for trend across the number of MS components); IL-18 also associated with coronary artery calcium (CAC) scores measured by electron beam computed tomography and aortic plaque measured by MRI (P<0.01 for each). In multivariable analyses, IL-18 remained associated with multiple components of the MS but not with CAC or aortic plaque. In a large population-based sample, elevated IL-18 plasma levels associated with risk factors for atherosclerosis and with the metabolic syndrome. The association between IL-18 and atherosclerosis diminished after accounting for traditional cardiovascular risk factors. These data suggest that IL-18 does not add independently to detection of atherosclerotic burden in asymptomatic individuals.


Contracture development in anoxia: the importance of asynchrony.
Several studies have reported a linear correlation between ATP levels, measured on isolated adult heart cells exposed to anoxia, and cellular configuration. The case is presented here for the viewpoint that these results can best be explained by an asynchronous decline in cellular ATP levels. By asynchrony we mean that an individual cell maintains a constant high level of ATP for a lag period until some point when, over a short period of time, the ATP level suddenly drops to near zero; the time spread of the decline in total measured ATP then arises from a spread in lag periods amongst the cells. By contrast, the synchronous view assumes that the time spread of the decline in total measured ATP reflects the simultaneous slow decline of ATP levels within each cell. These viewpoints have important consequences for elucidating the etiology of cell death.


Amniotic 17-alpha hydroxyprogesterone and HLA typing for the prenatal diagnosis of 21-alpha hydroxylase deficiency--congenital adrenal hyperplasia.
We have investigated a family with one child affected with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Prenatal determination of 17-alpha hydroxyprogesterone (17OHP) in amniotic fluid (AF) and HLA typing of amniotic fibroblasts from a pregnancy at risk showed that the fetus was not affected. A healthy cousin with HLA haplotypes identical to those of the proposita (only one being identical by descent) had a normal plasma level of 17OHP. The prenatal diagnosis of a fetus affected with 21-hydroxylase deficiency CAH may be established by the determination of 17OHP in AF. This is a relatively quick procedure that can be confirmed by the HLA genotype, and is mandatory in families with a parent homozygous for an HLA haplotype and in certain recombinant haplotypes in the fetus.


Study protocol: a clinical trial for improving mental health screening for Aboriginal and Torres Strait Islander pregnant women and mothers of young children using the Kimberley Mum's Mood Scale.
Improving the rates of, and instruments used in, screening for perinatal depression and anxiety among Aboriginal and Torres Strait Islander women are important public health priorities. The Kimberley Mum's Mood Scale (KMMS) was developed and later validated as an effective and acceptable perinatal depression and anxiety screening tool for the Kimberley region under research conditions. Other regions have expressed interest in using the KMMS with perinatal Aboriginal and Torres Strait Islander women. It is, however, important to re-evaluate the KMMS in a larger Kimberley sample via a real world implementation study, and to test for applicability in other remote and regional environments before recommendations for wider use can be made. This paper outlines the protocol for evaluating the process of implementation and establishing the 'real world' validity and acceptability of the KMMS in the Kimberley, Pilbara and Far North Queensland in northern Australia. The study will use a range of quantitative and qualitative methods across all sites. KMMS validation/revalidation internal consistency of Part 1 will be determined using Cronbach's alpha. Equivalence for identifying risk of depression and anxiety compared to a standard reference assessment will be determined from receiver operating characteristic curves. Sensitivity and specificity will be determined based on these cut-points. Qualitative methods of phenomenology will be used to explore concepts of KMMS user acceptability (women and health professionals). Additional process evaluation methods will collate, assess and report on KMMS quality review data, consultations with health service administrators and management, field notes, and other documentation from the research team. This information will be reported on using the Dynamic Sustainability Framework. This project is contributing to the important public health priority of screening Aboriginal and Torres Strait Islander women for perinatal depression and anxiety with tools that are meaningful and responsive to cultural and clinical needs. Identifying and addressing barriers to implementation contributes to our understanding of the complexity of improving routine clinical practie. The study was registered retrospectively on 15/05/2019 with the Australian and New Zealand Clinical Trial registry (ACTRN12619000580178).


Endometrial Cancer Risk Among Germline BRCA1/2 Pathogenic Variant Carriers: Review of Our Current Understanding and Next Steps.
To review the literature exploring endometrial cancer (EC) risk among surgical candidates with germline BRCA1/2 pathogenic variants (PVs) to guide decisions around risk-reducing (rr) hysterectomy in this population. A comprehensive review was conducted of the current literature that influences clinical practice and informs expert consensus. We present our understanding of EC risk among BRCA1/2 PV carriers, the risk-modifying factors specific to this patient population, and the available research technology that may guide clinical practice in the future. Limitations of the existing literature are outlined. Patients with BRCA1/2 PVs, those with a personal history of tamoxifen use, those who desire long-term hormone replacement therapy, and/or have an elevated BMI are at higher risk of EC, primarily endometrioid EC and/or uterine papillary serous carcinoma, and may benefit from rr-hysterectomy. Although prescriptive clinical guidelines specific to BRCA1/2 PV carriers could inform decisions around rr-hysterectomy, limitations of the current literature prevent more definitive guidance at this time. A large population-based study of a contemporary cohort of BRCA1/2 PV carriers with lifetime follow-up compared with cancer-gene negative controls would advance this topic and facilitate care decisions. This review validates a potential role for rr-hysterectomy to address EC risk among surgical candidates with BRCA1/2 PVs. Evidence-based clinical guidelines for rr-hysterectomy in BRCA1/2 PV carriers are essential to ensure equitable access to this preventive measure, supporting insurance coverage for patients with either BRCA1 or BRCA2 PVs to pursue rr-hysterectomy. Overall, this review highlights the complexity of EC risk in BRCA1/2 PV carriers and offers a comprehensive framework to shared decision making to inform rr-hysterectomy for BRCA1/2 PV carriers.


Correlation between the electrocardiogram amplitude detected by an implantable cardiac monitor and the implantation depth.
Implantable cardiac monitors (ICMs) primarily use R-R intervals in subcutaneous electrocardiograms (ECGs) to detect arrhythmias. Therefore, reliable detection of R-wave amplitude by an ICM is vital. Since ICMs detect subcutaneous ECGs, the impact of the implantation depth should be assessed. This study investigated the influence of ICM depth on R-wave (ICM-R) amplitude on an ECG generated by an ICM (JOT Dx; Abbott). Overall, 53 patients who underwent ICM implantation at Kamagaya General Hospital from May 2022 to April 2023 were retrospectively reviewed. The depth-position was measured using ultrasound imaging after implantation. The depth of the ICM did not show any correlation with ICM-R amplitude (r = -.0141, p = .294). However, the distance between the ICM and the heart surface showed a significant correlation with ICM-R amplitude (r = -.581, p < .001). Body weight (r = -.0283, p = .033) and body mass index (r = -.0342, p = .009) were associated with ICM-R amplitude. S wave in the V1 -lead was also associated with ICM-R amplitude (r = .481, p < .001). After multivariate analysis, the distance between the ICM and heart surface and the S wave in V1 were independent determinants for the ICM-R amplitude. The ICM-R amplitude may be higher with the ICM implanted deeper.


Persistence of antibody response to SARS-CoV-2 in a cohort of haemodialysis patients with COVID-19.
Haemodialysis patients are extremely vulnerable to COVID-19. Their immune response after infection is unclear. We have found high seroconversion rates in this population with 95% developing antibodies. It is unclear if and how long these antibodies persist. Here we investigate this with serial antibody testing. We identified haemodialysis patients who had confirmed SARS-CoV-2 between March-May 2020 and measured monthly antibodies (IgG/IgM) in those who survived. We used a semi-quantitative cut-off index (COI) to create a qualitative result and plotted optical density (OD) over time. We used linear regression to examine the slope, as well as noting peak OD and time to peak OD. We correlated these against baseline demographics, markers of illness severity, and comorbidities. 122 patients were analysed. All remained antibody positive during follow-up; for a minimum of 148 days. 71% had a positive gradient indicating increasing antibody positivity over time. We found that age (p = 0.01), duration of PCR positivity (p = 0.06) and presence of symptoms (p = 0.05) were associated with a longer time to peak OD. Immunosuppression did not alter peak OD but did lead to a non-significant increase in time to peak OD and more patients had a subsequent fall in Ab levels (p = 0.02). Diabetic patients were more likely to have a positive slope (OR 2.26). These results indicate that haemodialysis patients have a robust and sustained antibody response after confirmed COVID-19 infection with no suggestion that immunosuppression weakens this response. Although unclear what protection these antibodies confer, this encouraging that haemodialysis patients should respond to vaccination.


Early biochemical predictors of survival in intermediate and high-risk prostate cancer treated with radiation and androgen deprivation therapy.
To identify early biochemical predictors of survival in intermediate- and high-risk prostate cancer patients with a pre-treatment PSA <20 ng/mL following definitive radiation therapy (RT) and androgen deprivation therapy (ADT). A single-institution review of 2566 intermediate and high-risk prostate cancer patients treated with definitive RT and neoadjuvant and concurrent ADT from 1990 to 2012 was performed. The first prostate-specific antigen (PSA) value within three months of ADT initiation (post-ADT PSA) and the first PSA within three months after RT completion (post-RT PSA) were recorded. 1275 had baseline PSA <20 ng/mL and either post-ADT or post-RT PSA available. Median follow-up was 7.6 years. The relationship between post-treatment PSA kinetics and biochemical relapse (BR), distant metastasis (DM), prostate cancer specific death (PCSD) and overall survival (OS) was modeled using Cox regression univariate and multivariate analysis (MVA). MVA demonstrated a strong association between a post-RT PSA ≥0.09 ng/mL and a significantly higher risk of BR (HR: 1.93; 95% CI: 1.45-2.57; p < 0.001), DM (HR: 2.97; 95% CI: 2.01-4.39; p < 0.001), PCSD (HR: 2.99; 95% CI: 1.73-5.15; p < 0.001) and OS (HR: 1.49; 95% CI: 1.18-1.86; p < 0.001). Post-RT PSA reduction of ≥95% relative to the baseline PSA was associated with a significantly lower risk of BR (MVA HR: 0.58; 95% CI: 0.41-0.83; p = 0.003) and DM (MVA HR: 0.47; 95% CI: 0.30-0.76; p = 0.002). A PSA value ≥0.09 ng/mL early after RT completion is associated with significantly worse prognosis across all clinical outcomes, and an early PSA reduction of ≥95% is associated with reduced risk of BR and DM. These findings may identify patients who require early aggressive systemic management for high-risk disease.


Clinically Translatable Solid-State Dye for NIR-II Imaging of Medical Devices.
Medical devices are commonly implanted underneath the skin, but how to real-time noninvasively monitor their migration, integrity, and biodegradation in human body is still a formidable challenge. Here, the study demonstrates that benzyl violet 4B (BV-4B), a main component in the FDA-approved surgical suture, is found to produce fluorescence signal in the first near-infrared window (NIR-I, 700-900 nm) in polar solutions, whereas BV-4B self-assembles into highly crystalline aggregates upon a formation of ultrasmall nanodots and can emit strong fluorescence in the second near-infrared window (NIR-II, 1000-1700 nm) with a dramatic bathochromic shift in the absorption spectrum of ≈200 nm. Intriguingly, BV-4B-involved suture knots underneath the skin can be facilely monitored during the whole degradation process in vivo, and the rupture of the customized BV-4B-coated silicone catheter is noninvasively diagnosed by NIR-II imaging. Furthermore, BV-4B suspended in embolization glue achieves hybrid fluorescence-guided surgery (hybrid FGS) for arteriovenous malformation. As a proof-of-concept study, the solid-state BV-4B is successfully used for NIR-II imaging of surgical sutures in operations of patients. Overall, as a clinically translatable solid-state dye, BV-4B can be applied for in vivo monitoring the fate of medical devices by NIR-II imaging.


Granuloma annulare mimicking multicentric reticulohistiocytosis.
We describe a patient with granuloma annulare (GA) who presented with firm periungual papules mimicking "coral beads", a characteristic sign of multicentric reticulohistiocytosis (MRH). We highlight the importance of distinguishing between GA and MRH because the prognoses differ significantly.


Call for a national plan for rare diseases.
Australia requires a national plan, similar to plans developed internationally, to address the impacts of rare diseases on individuals, the community and health services. Rare diseases often present in childhood, many are chronic, some life threatening and others associated with significant disability. However, diagnosis is often delayed, because of lack of knowledge and experience of health professionals and uncertainty about where to refer. Specialised health services are frequently lacking and specific therapies are often not available, partly because of lack of research funding directed towards rare diseases. A national plan would facilitate a coordinated response to service development, carer support, and health professional and community education, and would promote research and advocacy for affected children and their families.


Effectiveness of seasonal influenza vaccine in Australia, 2015: An epidemiological, antigenic and phylogenetic assessment.
A record number of laboratory-confirmed influenza cases were notified in Australia in 2015, during which type A(H3) and type B Victoria and Yamagata lineages co-circulated. We estimated effectiveness of the 2015 inactivated seasonal influenza vaccine against specific virus lineages and clades. Three sentinel general practitioner networks conduct surveillance for laboratory-confirmed influenza amongst patients presenting with influenza-like illness in Australia. Data from the networks were pooled to estimate vaccine effectiveness (VE) for seasonal trivalent influenza vaccine in Australia in 2015 using the case test-negative study design. There were 2443 eligible patients included in the study, of which 857 (35%) were influenza-positive. Thirty-three and 19% of controls and cases respectively were reported as vaccinated. Adjusted VE against all influenza was 54% (95% CI: 42, 63). Antigenic characterisation data suggested good match between vaccine and circulating strains of A(H3); however VE for A(H3) was low at 44% (95% CI: 21, 60). Phylogenetic analysis indicated most circulating viruses were from clade 3C.2a, rather than the clade included in the vaccine (3C.3a). VE point estimates were higher against B/Yamagata lineage influenza (71%; 95% CI: 57, 80) than B/Victoria (42%, 95% CI: 13, 61), and in younger people. Overall seasonal vaccine was protective against influenza infection in Australia in 2015. Higher VE against the B/Yamagata lineage included in the trivalent vaccine suggests that more widespread use of quadrivalent vaccine could have improved overall effectiveness of influenza vaccine. Genetic characterisation suggested lower VE against A(H3) influenza was due to clade mismatch of vaccine and circulating viruses.


Further studies on the topography of human platelet glycoprotein IIb. Localization of monoclonal antibody epitopes and the putative glycoprotein IIa- and fibrinogen-binding regions.
Glycoprotein IIb (GPIIb) is a major glycoprotein of the human platelet plasma membrane, which together with glycoprotein IIIa (GPIIIa) forms a Ca2(+)-dependent heterodimer, GPIIb/IIIa, which serves as the major fibrinogen receptor in activated platelets. The precise localization of the epitopes for six anti-GPIIb monoclonal antibodies (M1-M6) has been determined by a combination of enzymic and chemical cleavage procedures, peptide isolation, N-terminal sequence analysis, peptide synthesis and enzyme immunoassay. The following localizations were found: M1, beta 1-16-36, beta 2-4-24; M2, alpha 747-755; M alpha 2, alpha 837-843; M3, alpha 849-857; M4, alpha 143-151; M5, alpha 550-558; M6, alpha 657-665. Besides considerations of the degree of exposure of these epitopes, several remarkable features are readily apparent. The earliest and main chymotryptic cleavage site of GPIIb in whole platelets is between alpha cysteine-545 and alpha phenylalanine-551. The epitope for M3 was located within the same sequence (alpha 842-857) as is the epitope for PMI-1 [Loftus, Plow, Frelinger, D'Souza, Dixon, Lacy, Sorge & Ginsberg (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 7114-7118] in spite of the fact that the exposure of the latter in whole platelets is EDTA-dependent whereas that in the former is not. The epitope for M5 shares full homology with the 540-548 peptide stretch of the alpha-subunit of the vitronectin receptor, and this antibody cross-reacts with endothelial cells. The M6 epitope is located in the 25 kDa membrane-bound fragment of GPIIb, which is most epitope is destroyed at an early stage of chymotrypic digestion. This suggests that this region of GPIIb, somewhere between the epitope for M5 (alpha 550-558) and the epitope for M2 (alpha 747-755), may carry the surface of interaction of GPIIb with GPIIIa in the GPIIb/IIIa heterodimer. Finally, the sequence where the epitope for M6 has been located (alpha 657-667) was the only one found to be hydropathically complementary to the gamma 402-411 peptide of fibrinogen within the amino acid sequence of both GPIIb and GPIIIa. This complementariness, the EDTA- or thrombin-dependence of the exposure of the alpha 657-665 stretch in whole platelets to M6 and the ability of this antibody to inhibit platelet aggregation led us to postulate that this peptide stretch is a putative binding site for fibrinogen in the platelet receptor.(ABSTRACT TRUNCATED AT 400 WORDS)


Preparative fractionation of T and B lymphocytes of the Syrian golden hamster with soybean agglutinin.
T and B lymphocytes of the Syrian golden hamster were separated from spleen cell preparations on the basis of their differential agglutinability with the lectin soybean agglutinin. Only B lymphocytes were agglutinated by this lectin, and they could be separated from the unagglutinated T lymphocytes by sedimentation through 50% heat inactivated calf serum at unit gravity. The B lymphocyte aggregates could be dissociated into single cells that were viable and functional after treatment with 0.5 M galactose. The isolated cell fractions were characterized by their blastogenic response to various T cell and B cell specific mitogens and by the presence or absence of cell surface IgG.


Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site.
A common metabotropic glutamate receptor 5 (mGlu5) allosteric site is known to accommodate diverse chemotypes. However, the structural relationship between compounds from different scaffolds and mGlu5 is not well understood. In an effort to better understand the molecular determinants that govern allosteric modulator interactions with mGlu5, we employed a combination of site-directed mutagenesis and computational modeling. With few exceptions, six residues (P654, Y658, T780, W784, S808, and A809) were identified as key affinity determinants across all seven allosteric modulator scaffolds. To improve our interpretation of how diverse allosteric modulators occupy the common allosteric site, we sampled the wealth of mGlu5 structure-activity relationship (SAR) data available by docking 60 ligands (actives and inactives) representing seven chemical scaffolds into our mGlu5 comparative model. To spatially and chemically compare binding modes of ligands from diverse scaffolds, the ChargeRMSD measure was developed. We found a common binding mode for the modulators that placed the long axes of the ligands parallel to the transmembrane helices 3 and 7. W784 in TM6 not only was identified as a key NAM cooperativity determinant across multiple scaffolds, but also caused a NAM to PAM switch for two different scaffolds. Moreover, a single point mutation in TM5, G747V, altered the architecture of the common allosteric site such that 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU29) was noncompetitive with the common allosteric site. Our findings highlight the subtleties of allosteric modulator binding to mGlu5 and demonstrate the utility in incorporating SAR information to strengthen the interpretation and analyses of docking and mutational data.


Gill structure and respiratory ability of Euchiloglanis kishinouyei (Osteichthyes: Siluriformes: Sisoridae).
Glyptosternoid fishes are distributed in the torrent environment of alpine canyons, where they often leave the water to climb rocky cliffs. As one of the most primitive species of glyptosternoid fishes, Euchiloglanis kishinouyei was examined in the current study to analyse its gill microstructure and respiratory ability. We first found that the oxygen consumption rate was relatively high and negatively correlated with body mass and that the average oxygen consumption at night was higher than during the day. The asphyxiation point of E. kishinouyei (5.05 ± 0.22 g) was c. 1.93 mg/L. Subsequently, the surface morphology, gross gill tissue structure, and ultra-microstructure of gill lamellae were investigated using optical microscopy and SEM. The gills showed an overall trend of regression, with five pairs of gill arches in each gill cavity. The adjacent gill filaments had large gaps, and the gill lamellae were thick. The gill filaments were closely arranged on the gill arches, their folded respiratory surface was highly vascularized with no tiny crest, and there were obvious tiny crests, grooves, pits, and pores on the nonrespiratory surface. The gill lamellae were closely embedded on both sides of gill filaments, which were composed of flat epithelial cells, basement membrane, pillar cells, and mucous cells. The gill total respiratory area correlated positively with body mass and length, whereas the gill relative respiratory area correlated negatively with body mass. We comprehensively analysed the gill microstructure and respiratory capacity of E. kishinouyei to provide fundamental data for the adaptive evolution of the gill structures of bimodally respiring fishes and offer insights into further study on the accessory air-breathing function of skin.


Analysis of constant tissue remodeling in Syrian hamster Harderian gland: intra-tubular and inter-tubular syncytial masses.
The Syrian hamster Harderian gland (HG) has a marked sexual dimorphism and exhibits an extraordinary rate of porphyrinogenesis. The physiological oxidative stress, derived from constant porphyrin production, is so high that the HG needs additional survival autophagic mechanisms to fight against this chronic exposure, provoking the triggering of a holocrine secretion in female glands that forms two types of secretory masses: intra-tubular-syncytial and inter-tubular-syncytial masses. The aim of this work was to study the development of this inter-tubular holocrine secretion. To approach this task, we have considered that the steps developed during the formation of the so-called invasive masses consist of the growth of epithelial cells, cell detachment from the basal lamina and invasion of surrounding tissues. The presence of these masses, particularly in the female HG, are closely linked to sexual dimorphism in redox balance and to alterations in the expression of certain factors such as cytokeratins, P-cadherin, matrix metalloproteinases, cathepsin H, proliferating cell nuclear antigen, p53, CD-31 and vascular endothelial growth factor, which seem to be involved in tissue remodeling. The results document unusual mechanisms of secretion in Syrian hamster HG: an extraordinary system of massive secretion through the conjunctive tissue, disrupting the branched structure of the gland.


Zumba Fitness and Women's Cardiovascular Health: A SYSTEMATIC REVIEW.
Zumba fitness (ZF) is a well-known exercise program involving dance and fitness. Despite its increasing popularity, no analysis has been conducted on studies focusing on the cardiovascular (CV) profile of women who performed this activity. The aim of this systematic review is to provide insights into the impact of ZF on women's CV health. Five clinical databases were searched. To be included, the articles had to include (1) women with or without CV risk factors (CVRF) and (2) CV-related outcomes resulting from a ZF program. Ten studies (322 women; 181 healthy, 141 with CVRF) were included. In healthy women, low absolute effect sizes for maximal oxygen uptake ((Equation is included in full-text article.)O2max), anthropometric and body composition profile after 8 and 12 wk of ZF were found compared with nonparticipants. Moderate to large absolute effect sizes were recorded for (Equation is included in full-text article.)O2max and body composition following 40 wk of ZF. Findings proved promising but less consistent for ZF studies involving women with CVRF due to the absence of control groups. Data describe ZF as feasible for healthy women and a promising fitness option for those with CVRF. Because of the low quality of the studies on women with CVRF and the overall small sample size along with discrepancies such as the average length of the studies on healthy women, cautious interpretation of the findings is recommended. Further investigations with a standardized design are needed to verify whether ZF may be considered as an alternative fitness option in primary prevention of CV disease in women.


Managed care and patient ratings of the quality of specialty care among patients with pain or depressive symptoms.
Managed care efforts to regulate access to specialists and reduce costs may lower quality of care. Few studies have examined whether managed care is associated with patient perceptions of the quality of care provided by physician and non-physician specialists. Aim is to determine whether associations exist between managed care controls and patient ratings of the quality of specialty care among primary care patients with pain and depressive symptoms who received specialty care for those conditions. A prospective cohort study design was conducted in the offices of 261 primary physicians in private practice in Seattle in 1997. Patients (N = 17,187) were screened in waiting rooms, yielding a sample of 1,514 patients with pain only, 575 patients with depressive symptoms only, and 761 patients with pain and depressive symptoms. Patients (n = 1,995) completed a 6-month follow-up survey. Of these, 691 patients received specialty care for pain, and 356 patients saw mental health specialists. For each patient, managed care was measured by the intensity of managed care controls in the patient's health plan and primary care office. Quality of specialty care at follow-up was measured by patient rating of care provided by the specialists. Outcomes were pain interference and bothersomeness, Symptom Checklist for Depression, and restricted activity days. The intensity of managed care controls in health plans and primary care offices was generally not associated with patient ratings of the quality of specialty care. However, pain patients in more-managed primary care offices had lower ratings of the quality of specialty care from physician specialists and ancillary providers. For primary care patients with pain or depressive symptoms and who see specialists, managed care controls may influence ratings of specialty care for patients with pain but not patients with depressive symptoms.


Enhanced Nogo-P3 amplitudes of mothers compared with non-mother women during an emotional Go/Nogo task.
It is known that emotion regulatory responses of humans are changed by the experiences they have, but in particular, they are changed by becoming a mother. A recent study has found how a woman's emotion regulatory response to a child's crying changes after becoming a mother. However, mothers' emotion regulatory responses other than those to children and the association between emotion regulatory response and parental stress are still unknown. Eighteen healthy Japanese females (nine mothers and nine non-mothers) participated in the experiment. They performed an emotional Go/Nogo task, with facial expressions of others (angry, happy, and neutral faces) used as emotional stimuli. The percentage of correct responses, response time, and event-related potentials (ERPs) during the task was measured. This comparison revealed that the mother group had a larger P3 (Nogo-P3) amplitude than the non-mother group when Nogo trials were held. This indicates that in mothers, there was greater activation of the behavioral inhibition-related brain areas than in non-mother women when they inhibited inappropriate behavior following recognition of facial expressions of others. In addition, in the mother group, there was a negative correlation between parental stress levels and Nogo-P3 amplitudes evoked by angry faces. This suggests that there is a relation between the level of parental stress of mothers and their emotion regulatory responses to angry faces. Our results demonstrate that mothers' emotion regulatory processes may differ from those of non-mothers in response, not only to a child's crying but also to expressions of emotions by others, and also suggest that the inhibitory recognition activity of mothers can be affected by parental stress.


Aqueous extract of the bark of Uncaria tomentosa, an amazonian medicinal plant, promotes gastroprotection and accelerates gastric healing in rats.
Uncaria tomentosa Willd. DC., is used in the Amazonian region of South America, wherein ethnic groups use the plant to treat diseases, including gastric disorders. However, despite its widespread popular use, this species has yet to be assessed for its anti-ulcer effects. In this study, we aimed to evaluate the in vivo gastroprotective and gastric healing activities of an aqueous extract of the bark of Uncaria tomentosa (AEUt) and sought to gain an understanding of the pharmacological mechanisms underlying these biological effects. To verify the gastroprotective properties rats were treated with AEUt (30, 60, or 120 mg/kg) prior to inducing gastric ulceration with ethanol or piroxicam. Additionally, the involvement of nitric oxide, non-protein sulfhydryl compounds (NP-SH), α-2 adrenergic receptors, and prostaglandins was investigated. Furthermore, a pylorus ligature model was employed to investigate the antisecretory activity of AEUt. The gastric healing effects of AEUt (60 mg/kg) were examined in rats in which ulceration had been induced with 80% acetic acid, whereas the quality of healing was evaluated in mice with interleukin-induced recurrent ulcers. We also evaluated the in vivo thickness of the gastric wall using ultrasonography. Moreover, the levels of reduced glutathione (GSH) and malondialdehyde (MDA) were evaluated in ulcerated mucosa, and we determined the activities of the enzymes myeloperoxidase (MPO), N-acetyl-β-D-glycosaminidase, superoxide dismutase, catalase, and glutathione S-transferase. In addition, we assessed the effects of AEUt on cell viability and subjected the AEUt to phytochemical analyses. Administration of the AEUt (60 or 120 mg/kg) prevented ethanol- and piroxicam-induced ulceration, which was also confirmed histologically. Moreover, we observed that pre-treatment with NEM and indomethacin abolished the gastroprotective effects of AEUt, thereby indicating the involvement of NP-SH and prostaglandins in these protective effects. In addition, we found that the administration of AEUt had no appreciable effects on the volume, acidity, or peptic activity of gastric juice. Furthermore, the AEUt (60 mg/kg) accelerated the gastric healing of acetic acid-induced ulcers by 46.2% and ultrasonographic findings revealed a reduction in the gastric wall thickness in this group. The gastric healing effect of AEUt was also accompanied by a reduction in MPO activity. The AEUt (60 mg/kg) also minimized ulcer recurrence in mice exposed to IL-1β and was associated with the maintenance of GSH levels and a reduction in MDA contents. We deduce that the biological effects of AEUt could be associated with the activities of polyphenols and the alkaloids isomitraphylline and mitraphylline, identified as predominant constituents of the AEUt. Furthermore, we found no evidence to indicate that AEUt would have any cytotoxic effects. Collectively, our findings provide compelling evidence indicating the therapeutic efficacy of U. tomentosa. Our data indicate that compounds in AEUt confer gastroprotection and that this preventive effect of AEUt was accompanied by gastric healing and a reduction in gastric ulcer recurrence. Moreover, we provide evidence to indicate that the gastroprotective and gastric healing effects involve the antioxidant system and anti-inflammatory responses that contribute to preserving the gastric mucosa.


Recruitment pattern of the diaphragm and extradiaphragmatic inspiratory muscles in response to different levels of pressure support.
Inappropriate ventilator assist plays an important role in the development of diaphragm dysfunction. Ventilator under-assist may lead to muscle injury, while over-assist may result in muscle atrophy. This provides a good rationale to monitor respiratory drive in ventilated patients. Respiratory drive can be monitored by a nasogastric catheter, either with esophageal balloon to determine muscular pressure (gold standard) or with electrodes to measure electrical activity of the diaphragm. A disadvantage is that both techniques are invasive. Therefore, it is interesting to investigate the role of surrogate markers for respiratory dive, such as extradiaphragmatic inspiratory muscle activity. The aim of the current study was to investigate the effect of different inspiratory support levels on the recruitment pattern of extradiaphragmatic inspiratory muscles with respect to the diaphragm and to evaluate agreement between activity of extradiaphragmatic inspiratory muscles and the diaphragm. Activity from the alae nasi, genioglossus, scalene, sternocleidomastoid and parasternal intercostals was recorded using surface electrodes. Electrical activity of the diaphragm was measured using a multi-electrode nasogastric catheter. Pressure support (PS) levels were reduced from 15 to 3 cmH2O every 5 min with steps of 3 cmH2O. The magnitude and timing of respiratory muscle activity were assessed. We included 17 ventilated patients. Diaphragm and extradiaphragmatic inspiratory muscle activity increased in response to lower PS levels (36 ± 6% increase for the diaphragm, 30 ± 6% parasternal intercostals, 41 ± 6% scalene, 40 ± 8% sternocleidomastoid, 43 ± 6% alae nasi and 30 ± 6% genioglossus). Changes in diaphragm activity correlated best with changes in alae nasi activity (r2 = 0.49; P < 0.001), while there was no correlation between diaphragm and sternocleidomastoid activity. The agreement between diaphragm and extradiaphragmatic inspiratory muscle activity was low due to a high individual variability. Onset of alae nasi activity preceded the onset of all other muscles. Extradiaphragmatic inspiratory muscle activity increases in response to lower inspiratory support levels. However, there is a poor correlation and agreement with the change in diaphragm activity, limiting the use of surface electromyography (EMG) recordings of extradiaphragmatic inspiratory muscles as a surrogate for electrical activity of the diaphragm.


Female blue tits sing frequently: a sex comparison of occurrence, context, and structure of song.
In species with mutual mate choice, we should expect adaptive signaling in both sexes. However, the role of female sexual signals is generally understudied. A case in point is female birdsong that has received considerably less attention than male song. This holds even for well-studied species such as the blue tit (Cyanistes caeruleus), an important model in evolutionary ecology. Although there have been anecdotal reports of female song from three populations, there are no quantitative studies on female song in this species. Here, we report systematic sampling from a population of individually marked blue tits over 3 years, revealing that females sang frequently throughout the sampling period. Notably, daytime singing of females occurred in functionally similar contexts as in males (agonistic, solo song, and alarm contexts) but females had lower song output than males and were not observed singing dawn song, while males showed long singing displays at dawn before copulations take place. Female and male song overlapped substantially in acoustic structure (i.e., same song types or peak frequency) but females had smaller individual song-type repertoires, shorter trills, and lower vocal consistency. Differential selection pressures related to functional differences in male and female song might explain the observed variation in acoustic structure. With the first quantitative study of female song in such a well-studied species, we hope to stimulate further investigations into the functions of female singing, especially in the Northern temperate zones where female song may have been overlooked, not only in this but perhaps in other monomorphic species.


Identification of a Rhizobium meliloti pSym2011 region controlling the host specificity of root hair curling and nodulation.
In Rhizobium meliloti 2011 nodulation genes (nod) required to nodulate specifically alfalfa are located on a pSym megaplasmid. Nod- derivatives carrying large pSym deletions were isolated. By complementation of these strains with in vivo- and in vitro-constructed episomes containing pSym of sequences and introduction of these episomes into Agrobacterium tumefaciens, we show (i) that from a region of pSym of about 360 kilobases, genes required for specific alfalfa nodulation are clustered in a DNA fragment of less than 30 kilobases and (ii) that a nod region located between nifHDK and the common nod genes is absolutely required for alfalfa nodulation and controls the specificity of root hair curling and nodule organogenesis initiation.


[Approach to peripheral arterial disease in the elderly].
The prevalence of peripheral arterial disease, which usually develops on the basis of atherosclerosis and develops as a result of chronic arterial occlusive pathology, increases with age. Peripheral artery disease in the elderly patient population may be asymptomatic due to restrictive conditions associated with immobilization. Concurrent cerebrovascular disease and coronary artery disease risk and mortality rates are higher in elderly patients with peripheral artery disease. The life expectancy in patients with peripheral arterial disease is worse than in prostate cancer patients. Leading risk factors include advanced age, smoking, diabetes mellitus, hypertension, hyperlipidemia, hyperhomocysteinemia and hypothyroidism. The most important physical examination component is the palpation of the entire peripheral pulses. The cases in which the ankle-brachial systolic pressure index measurement for clinical diagnosis is below 0.9 are defined as peripheral arterial disease. It is aimed to completely correct or improve the existing clinical symptoms and to increase the survival rates of the patients. The existing risk factors are modified as the first step of the treatment. Smoking cessation, treatment of hypertension primarily with angiotensin-converting enzyme inhibitors, lowering of hemoglobin A1c levels below 7%, anti-hyperlipidemic treatment primarily with statin, antiaggregant therapy primarily with clopidogrel, cilostazol therapy, good foot care, controlled exercise program, if necessary, interventional or operational revascularization, amputation in the presence of irreversible effects are the main treatment components. Indications for major revascularization include the presence of resting pain in the limb and / or open and long-lasting unhealed wound in the extremity and / or severe complaints of intermittant claudication that will result in limitation in daily activities. It should not be forgotten that, all the clinical decisions to be taken in the treatment of elderly patients with peripheral arterial disease are determined by the patient's physical condition, current clinical condition and the expectation level of the patient.