Sprouting angiogenesis in engineered pseudo islets.
Despite the recent achievements in cell-based therapies for curing type-1 diabetes (T1D), capillarization in beta (β)-cell clusters is still a major roadblock as it is essential for long-term viability and function of β-cells in vivo. In this research, we report sprouting angiogenesis in engineered pseudo islets (EPIs) made of mouse insulinoma βTC3 cells and rat heart microvascular endothelial cells (RHMVECs). Upon culturing in three-dimensional (3D) constructs under angiogenic conditions, EPIs sprouted extensive capillaries into the surrounding matrix. Ultra-morphological analysis through histological sections also revealed presence of capillarization within EPIs. EPIs cultured in 3D constructs maintained their viability and functionality over time while non-vascularized EPIs, without the presence of RHMVECs, could not retain their viability nor functionality. Here we demonstrate angiogenesis in engineered islets, where patient specific stem cell-derived human beta cells can be combined with microvascular endothelial cells in the near future for long-term graft survival in T1D patients.


Spinal pethidine for elective caesarean section.
Pethidine (meperidine) is a unique member of the opioid family. In addition to its analgesic activity, it also has significant local anaesthetic activity. This property enables it to be used as the sole agent for spinal anaesthesia. We describe the successful use of intrathecal pethidine 1 mg/kg for an elective lower segment caesarean section in a patient presumed to be allergic to amide local anaesthetics. There were no significant adverse effects in either the mother or the newborn.


Advances in analysis of low signal-to-noise images link dynamin and AP2 to the functions of an endocytic checkpoint.
Numerous endocytic accessory proteins (EAPs) mediate assembly and maturation of clathrin-coated pits (CCPs) into cargo-containing vesicles. Analysis of EAP function through bulk measurement of cargo uptake has been hampered due to potential redundancy among EAPs and, as we show here, the plasticity and resilience of clathrin-mediated endocytosis (CME). Instead, EAP function is best studied by uncovering the correlation between variations in EAP association to individual CCPs and the resulting variations in maturation. However, most EAPs bind to CCPs in low numbers, making the measurement of EAP association via fused fluorescent reporters highly susceptible to detection errors. Here, we present a framework for unbiased measurement of EAP recruitment to CCPs and their direct effects on CCP dynamics. We identify dynamin and the EAP-binding α-adaptin appendage domain of the AP2 adaptor as switches in a regulated, multistep maturation process and provide direct evidence for a molecular checkpoint in CME.


Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model.
The metabolic preference of malignant glioma for glycolysis as an energy source is a potential therapeutic target. As a result of the cellular heterogeneity of these tumors, however, the relation between glycolytic preference, tumor formation, and tumor cell clonogenicity has remained unknown. To address this issue, we analyzed the metabolic profiles of isogenic glioma-initiating cells (GICs) in a mouse model. GICs were established by overexpression of H-Ras(V12) in Ink4a/Arf-null neural stem cells. Subpopulations of these cells were obtained by single-cell cloning, and clones differing in extracellular acidification potential were assessed for metabolic characteristics. Tumors formed after intracranial implantation of these clones in mice were examined for pathological features of glioma and expression of glycolytic enzymes. Malignant transformation of neural stem cells resulted in a shift in metabolism characterized by an increase in lactic acid production. However, isogenic clonal populations of GICs manifested pronounced differences in glucose and oxygen consumption, lactate production, and nucleoside levels. These differences were paralleled by differential expression of glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2, with this differential expression also being evident in tumors formed by these clones in vivo. The metabolic characteristics of glioma cells appear early during malignant transformation and persist until the late stages of tumor formation. Even isogenic clones may be heterogeneous in terms of metabolic features, however, suggesting that a more detailed understanding of the metabolic profile of glioma is imperative for effective therapeutic targeting.


Ambulance diversion and emergency department offload delay: resource document for the National Association of EMS Physicians position statement.
The emergency medical services (EMS) system is a component of a larger health care safety net and a key component of an integrated emergency health care system. EMS systems, and their patients, are significantly impacted by emergency department (ED) crowding. While protocols designed to limit ambulance diversion may be effective at limiting time on divert status, without correcting overall hospital throughput these protocols may have a negative effect on ED crowding and the EMS system. Ambulance offload delay, the time it takes to transfer a patient to an ED stretcher and for the ED staff to assume the responsibility of the care of the patient, may have more impact on ambulance turnaround time than ambulance diversion. EMS administrators and medical directors should work with hospital administrators, ED staff, and ED administrators to improve the overall efficiency of the system, focusing on the time it takes to get ambulances back into service, and therefore must monitor and address both ambulance diversions and ambulance offload delay. This paper is the resource document for the National Association of EMS Physicians position statement on ambulance diversion and ED offload time. Key words: ambulance; EMS; diversion; bypass; offload; delay.


Senescence-Associated Molecules and Tumor-Immune-Interactions as Prognostic Biomarkers in Colorectal Cancer.
The initiation of cellular senescence in response to protumorigenic stimuli counteracts malignant progression in (pre)malignant cells. Besides arresting proliferation, cells entering this terminal differentiation state adopt a characteristic senescence-associated secretory phenotype (SASP) which initiates alterations to their microenvironment and effects immunosurveillance of tumorous lesions. However, some effects mediated by senescent cells contribute to disease progression. Currently, the exploration of senescent cells' impact on the tumor microenvironment and the evaluation of senescence as possible target in colorectal cancer (CRC) therapy demand reliable detection of cellular senescence in vivo. Therefore, specific immunohistochemical biomarkers are required. Our aim is to analyze the clinical implications of senescence detection in colorectal carcinoma and to investigate the interactions of senescent tumor cells and their immune microenvironment in vitro and in vivo. Senescence was induced in CRC cell lines by low-dose-etoposide treatment and confirmed by Senescence-associated β-galactosidase (SA-β-GAL) staining and fluorescence activated cell sorting (FACS) analysis. Co-cultures of senescent cells and immune cells were established. Multiple cell viability assays, electron microscopy and live cell imaging were conducted. Immunohistochemical (IHC) markers of senescence and immune cell subtypes were studied in a cohort of CRC patients by analyzing a tissue micro array (TMA) and performing digital image analysis. Results were compared to disease-specific survival (DSS) and progression-free survival (PFS). Varying expression of senescence markers in tumor cells was associated with in- or decreased survival of CRC patients. Proximity analysis of p21-positive senescent tumor cells and cytotoxic T cells revealed a significantly better prognosis for patients in which these cell types have the possibility to directly interact. In vitro, NK-92 cells (mimicking natural killer T cells) or TALL-104 cells (mimicking both cytotoxic T cells and natural killer T cells) led to dose-dependent specific cytotoxicity in >75 % of the senescent CRC cells but <20 % of the proliferating control CRC cells. This immune cell-mediated senolysis seems to be facilitated via direct cell-cell contact inducing apoptosis and granule exocytosis. Counteracting tumorigenesis, cellular senescence is of significant relevance in CRC. We show the dual role of senescence bearing both beneficial and malignancy-promoting potential in vivo. Absence as well as exceeding expression of senescence markers are associated with bad prognosis in CRC. The antitumorigenic potential of senescence induction is determined by tumor micromilieu and immune cell-mediated elimination of senescent cells.


Somatostatin-28(1-12)-like immunoreactivity is reduced in Alzheimer's disease cerebral cortex.
A deficiency in somatostatin is the most consistently described neurochemical alteration in Alzheimer's disease (AD) attributable to intrinsic cortical neurons. Somatostatin-28 (SOM-28), an N-terminal-extended form of somatostatin, can be cleaved to form somatostatin-28(1-12)(SOM-28(1-12) ) and somatostatin-14 (SOM-14). We have measured concentrations of SOM-28(1-12)-like immunoreactivity in 8 cortical regions from 12 patients with AD and 13 controls. Significant reductions (P less than 0.001) were found in all cortical regions examined with the largest decrease in temporal lobe. Reductions were significantly correlated with decreases in somatostatin-14-like immunoreactivity in the same regions. The similar reductions of two prosomatostatin-derived peptides in AD cerebral cortex supports the contention that decreased somatostatin immunoreactivity in AD is caused by a degeneration of somatostatin cortical neurons and terminals.


Antibacterial Activity and Untargeted Metabolomics Profiling of Acalypha arvensis Poepp.
The search for potent antimicrobial compounds is critical in the face of growing antibiotic resistance. This study explores Acalypha arvensis Poepp. (A. arvensis), a Caribbean plant traditionally used for disease treatment. The dried plant powder was subjected to successive extractions using different solvents: hexane (F1), dichloromethane (F2), methanol (F3), a 50:50 mixture of methanol and water (F4), and water (F5). Additionally, a parallel extraction was conducted using a 50:50 mixture of methanol and chloroform (F6). All the fractions were evaluated for their antimicrobial activity, and the F6 fraction was characterized using untargeted metabolomics using SPME-GC×GC-TOFMS. The extracts of A. arvensis F3, F4, and F5 showed antibacterial activity against Staphylococcus aureus ATCC 25923 (5 mg/mL), MRSA BA22038 (5 mg/mL), and Pseudomonas aeruginosa ATCC 27853 (10 mg/mL), and fraction F6 showed antibacterial activity against Staphylococcus aureus ATCC 29213 (2 mg/mL), Escherichia coli ATCC 25922 (20 mg/mL), Pseudomonas aeruginosa ATCC 27853 (10 mg/mL), Enterococcus faecalis ATCC 29212 (10 mg/mL), Staphylococcus aureus 024 (2 mg/mL), and Staphylococcus aureus 003 (2 mg/mL). Metabolomic analysis of F6 revealed 2861 peaks with 58 identified compounds through SPME and 3654 peaks with 29 identified compounds through derivatization. The compounds included methyl ester fatty acids, ethyl ester fatty acids, terpenes, ketones, sugars, amino acids, and fatty acids. This study represents the first exploration of A. arvensis metabolomics and its antimicrobial potential, providing valuable insights for plant classification, phytochemical research, and drug discovery.


The external (combination) rhinoplasty approach for the problem nose.
The external (combination) rhinoplasty approach has gradually gained acceptance as an approach to expose the nasal infrastructure. Its wide exposure has sharpened diagnostic skills by correlating pre-operative clinical impressions with specific anatomic deformities found at surgery. Its wide access has greatly increased as well as simplified the range of surgical maneuvers used in reconstruction. Following a review of the external approach, attention is focused on some of the problem nasal deformities where this approach has been helpful in obtaining good results. Nasal valve obstruction, nasal tip problems, nasal pyramid depression, and the crooked nose are discussed in terms of pathological anatomy and techniques of repair.


The epidermal growth factor-induced migration of rat liver epithelial cells is associated with a transient inhibition of DNA synthesis.
Epidermal growth factor (EGF) is a potent mitogen for most cultured cells and has previously been shown to induce the migration of rat liver epithelial cells. We have now demonstrated that under migration-inducing conditions EGF does not stimulate cell proliferation, but causes instead a transient inhibition of DNA synthesis. Analysis at the single-cell level by [3H]thymidine autoradiography indicated that in 40-50% of the EGF-treated cell population the entry into S phase is delayed. The simultaneous demonstration of migration tracks by laminin immunofluorescence revealed that the transient inhibition of DNA synthesis is not restricted to the migratory cells. The effect is also observed with the stationary subpopulation and appears, therefore, to be independent of the induction of migration. The independence of both processes was further supported by showing that induction of migration by EGF proceeds undisturbed in cells blocked in S phase by aphidicolin. These results indicated that for rat liver epithelial cells the induction of migration by EGF has priority over cell proliferation. The data also emphasize the need for a time-course analysis when studying factors that stimulate or inhibit DNA synthesis or cell proliferation.


Comparative genomics of a vertically transmitted thiotrophic bacterial ectosymbiont and its close free-living relative.
Thiotrophic symbioses between sulphur-oxidizing bacteria and various unicellular and metazoan eukaryotes are widespread in reducing marine environments. The giant colonial ciliate Zoothamnium niveum, however, is the only host of thioautotrophic symbionts that has been cultivated along with its symbiont, the vertically transmitted ectosymbiont Candidatus Thiobius zoothamnicola (short Thiobius). Because theoretical predictions posit a smaller genome in vertically transmitted endosymbionts compared to free-living relatives, we investigated whether this is true also for an ectosymbiont. We used metagenomics to recover the high-quality draft genome of this bacterial symbiont. For comparison we have also sequenced a closely related free-living cultured but not formally described strain Milos ODIII6 (short ODIII6). We then performed comparative genomics to assess the functional capabilities at gene, metabolic pathway and trait level. 16S rRNA gene trees and average amino acid identity confirmed the close phylogenetic relationship of both bacteria. Indeed, Thiobius has about a third smaller genome than its free-living relative ODIII6, with reduced metabolic capabilities and fewer functional traits. The functional capabilities of Thiobius were a subset of those of the more versatile ODIII6, which possessed additional genes for oxygen, sulphur and hydrogen utilization and for the acquisition of phosphorus illustrating features that may be adaptive for the unstable environmental conditions at hydrothermal vents. In contrast, Thiobius possesses genes potentially enabling it to utilize lactate and acetate heterotrophically, compounds that may be provided as byproducts by the host. The present study illustrates the effect of strict host-dependence of a bacterial ectosymbiont on genome evolution and host adaptation.


Human Creativity and Consciousness: Unintended Consequences of the Brain's Extraordinary Energy Efficiency?
It is proposed that both human creativity and human consciousness are (unintended) consequences of the human brain's extraordinary energy efficiency. The topics of creativity and consciousness are treated separately, though have a common sub-structure. It is argued that creativity arises from a synergy between two cognitive modes of the human brain (which broadly coincide with Kahneman's Systems 1 and 2). In the first, available energy is spread across a relatively large network of neurons, many of which are small enough to be susceptible to thermal (ultimately quantum decoherent) noise. In the second, available energy is focussed on a smaller subset of larger neurons whose action is deterministic. Possible implications for creative computing in silicon are discussed. Starting with a discussion of the concept of free will, the notion of consciousness is defined in terms of an awareness of what are perceived to be nearby counterfactual worlds in state space. It is argued that such awareness arises from an interplay between memories on the one hand, and quantum physical mechanisms (where, unlike in classical physics, nearby counterfactual worlds play an indispensable dynamical role) in the ion channels of neural networks, on the other. As with the brain's susceptibility to noise, it is argued that in situations where quantum physics plays a role in the brain, it does so for reasons of energy efficiency. As an illustration of this definition of consciousness, a novel proposal is outlined as to why quantum entanglement appears to be so counter-intuitive.


Macroscopic theory for capillary-pressure hysteresis.
In this article, we present a theory of macroscopic contact angle hysteresis by considering the minimization of the Helmholtz free energy of a solid-liquid-gas system over a convex set, subject to a constant volume constraint. The liquid and solid surfaces in contact are assumed to adhere weakly to each other, causing the interfacial energy to be set-valued. A simple calculus of variations argument for the minimization of the Helmholtz energy leads to the Young-Laplace equation for the drop surface in contact with the gas and a variational inequality that yields contact angle hysteresis for advancing/receding flow. We also show that the Young-Laplace equation with a Dirichlet boundary condition together with the variational inequality yields a basic hysteresis operator that describes the relationship between capillary pressure and volume. We validate the theory using results from the experiment for a sessile macroscopic drop. Although the capillary effect is a complex phenomenon even for a droplet as various points along the contact line might be pinned, the capillary pressure and volume of the drop are scalar variables that encapsulate the global quasistatic energy information for the entire droplet. Studying the capillary pressure versus volume relationship greatly simplifies the understanding and modeling of the phenomenon just as scalar magnetic hysteresis graphs greatly aided the modeling of devices with magnetic materials.


Dust Exposures in Swedish Soft Tissue Paper Mills.
Paper dust has previously been linked to adverse health effects. However, a comprehensive dataset of paper dust exposures does not appear to have been published previously. Our study was intended to address this need by describing a large dataset of measurements made in Swedish soft tissue paper mills. We compiled personal and area total dust exposure measurements collected from a range of operations by our research staff at four soft tissue paper mills in Sweden. We also compiled measurements made by the occupational health staff at each mill and the Swedish Work Environment Authority. We analyzed these measurements to describe patterns and trends in exposures and used mixed-effects regression models to identify measurement characteristics that predicted exposure levels. We compiled 1578 measurements from 1971 to 2009, of which 1026 (65%) were personal samples. Statistically significant differences were found between measurements made by research, mill, and Swedish Work Environment Authority staff, as well as between personal and area measurements. The measurement data suggest that, beginning in the 1980s, exposures declined at three of the four mills, but that overexposures were still common at the end of the period. Papermaking and converting operations had the highest observed dust exposures. One mill had significantly lower exposures than the others. Type of measurement (personal versus area) and source of measurement (research staff, company, or regulatory agency) were not significant predictors of measured total dust exposure after controlling for mill, operation, and time. Our analysis of measured paper dust exposures may be useful for historical and contemporary exposure assessment in our own and other epidemiological studies. We have identified specific characteristics (i.e. papermaking operations and mill) and time trends that are important data features to consider, and documented continuing overexposure situations. Our results highlight the ongoing need for application of exposure controls to reduce paper dust exposures in the soft tissue paper industry.


Status, taste and distinction in consumer culture: acknowledging the symbolic dimensions of inequality.
The relationship between social position and health has been the focus of extensive public health debate. In the UK and elsewhere, most researchers have focused on physical aspects of health, using indicators such as mortality and morbidity to draw a picture of profound and widening social inequalities. This paper draws attention to the (neglected) influence of contemporary culture on wellbeing, arguing that the social meanings created within consumer culture possess symbolic force that can add to wider inequalities. The possession of greater material and cultural resources by people of higher social status enables them to label their preferred forms of consumption and lifestyle as desirable and legitimate, thus conveying messages about superior taste and social distinction. Symbolic rather than material forms of inequality are implicated here, with consequences for the psychological wellbeing of disadvantaged people. This paper argues that analyses of inequality need broadening to include such considerations. However, there are implications for efforts to address health inequalities because this analysis suggests that if some forms of social inequality are removed, elements within society would be motivated to invent new forms to replace them. Therefore, this article suggests processes whereby people can develop the self-awareness needed to resist the glossy illusions of the good life represented by modern consumer capitalism.


Nurse Coaching and Mobile Health Compared With Usual Care to Improve Diabetes Self-Efficacy for Persons With Type 2 Diabetes: Randomized Controlled Trial.
Type 2 diabetes is a growing public health problem amenable to prevention and health promotion. As healthy behaviors have an impact on disease outcomes, approaches to support and sustain diabetes self-management are vital. This study aimed to evaluate the effectiveness of a nurse coaching program using motivational interviewing paired with mobile health (mHealth) technology on diabetes self-efficacy and self-management for persons with type 2 diabetes. This randomized controlled trial compared usual care with an intervention that entailed nurse health coaching and mHealth technology to track patient-generated health data and integrate these data into an electronic health record. The inclusion criteria were as follows: (1) enrolled at 1 of 3 primary care clinics, (2) aged 18 years or above, (3) living with type 2 diabetes, and (4) English-speaking. We collected outcome measures at baseline, 3 months, and 9 months. The primary outcome was diabetes self-efficacy; secondary outcomes were depressive symptoms, perceived stress, physical functioning, and emotional distress and anxiety. Linear regression mixed modeling estimated the population trends and individual differences in change. We enrolled 319 participants; 287 participants completed the study (155 control and 132 intervention). The participants in the intervention group had significant improvements in diabetes self-efficacy (Diabetes Empowerment Scale, 0.34; 95% CI -0.15,0.53; P<.01) and a decrease in depressive symptoms compared with usual care at 3 months (Patient Health Questionnaire-9; 0.89; 95% CI 0.01-1.77; P=.05), with no differences in the other outcomes. The differences in self-efficacy and depression scores between the 2 arms at 9 months were not sustained. The participants in the intervention group demonstrated a significant increase in physical activity (from 23,770 steps per week to 39,167 steps per week at 3 months and 32,601 per week at 9 months). We demonstrated the short-term effectiveness of this intervention; however, by 9 months, although physical activity remained above the baseline, the improvements in self-efficacy were not sustained. Further research should evaluate the minimum dose of coaching required to continue progress after active intervention and the potential of technology to provide effective ongoing automated reinforcement for behavior change. ClinicalTrials.gov NCT02672176; https://clinicaltrials.gov/ct2/show/NCT02672176.


Effective treatment with intravenous immunoglobulins reduces autoreactive T-cell response in patients with CIDP.
To investigate changes in autoreactive T-cell responses against PMP-22 and P2 antigen as well as a T-cell memory repertoire in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) induced by repeated intravenous immunoglobulin (IVIg) treatment. In an observational trial, we prepared cryopreserved human peripheral blood monocytes from blood from 34 patients with CIDP (18 treatment naïve and 16 maintenance IVIg treatment) and from 14 healthy controls (non-immune neuropathy and healthy control). Treatment response was defined by clinical evaluation. The autoantigen-specific T-cell response was analysed by enzyme linked immunosorbent spot (ELISPOT) assay before IVIg start (baseline) and at follow-up. The T-cell memory subsets were analysed by using flow cytometric analysis. Myelin-derived P2-specific and PMP-22-specific IFN-γ producers were increased in IVIg responders compared with non-responders before treatment, which decreased by repeated IVIg infusion cycles. Treatment responders but not non-responders showed higher frequencies of CD4 T effector memory (TEM) and T central memory frequencies at baseline compared with maintenance IVIg treatment patients and controls. In addition, IVIg treatment was associated with a significant reduction in CD8 TEM at follow-up. Our data demonstrate that immunomodulatory treatment with IVIgs on a long-term basis reduces the autoreactive T-cell response against PMP-22 and P2-antigens, which may be influenced by the altered maintenance of CD8 and CD4 effector/memory T-cell subsets towards a more anti-inflammatory immune status. Elevated PMP-22 and P2-specific T-cell responses may serve as predictors for treatment responsiveness to IVIgs warranting validation in larger studies.


Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis.
Monoclonal antibodies (mAbs) against the cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule are used as an adjuvant to experimental tumor immunization protocols in the treatment of malignant melanomas and ovarian cancers. Aside from noted early therapeutic successes, a spectrum of adverse effects, including severe gastroenteritis, has been reported. We report herein our observations of 5 patients who developed severe gastrointestinal toxicity affecting the gastric, small intestinal, and colonic mucosa. The endoscopic findings were variable, ranging from normal to diffusely erythematous and ulcerated mucosa. The constant histologic findings included a lymphoplasmacytic expansion of the lamina propria with increase in intraepithelial lymphocytes. Increased epithelial apoptosis was also a distinctive feature. Cryptitis and glandular inflammation were observed in the colon, ileum, and stomach, whereas villous blunting was present in the ileal and duodenal mucosa. Immunohistochemical analysis revealed a marked increase of all T-cell subsets (CD3+, CD4+, and CD8+) and of CD4CD25 regulatory T cells. We conclude that the panenteritis associated with injection of alpha-CTLA-4 mAbs demonstrates histology resembling autoimmune enteropathy. Furthermore, although the pathogenesis of immune dysregulation after the infusion of alpha-CTLA-4 mAbs remains unclear, we suspect that the increased number of regulatory T cells in the gastrointestinal mucosa may play a role in the pathogenicity.


Predicting Viscosity and Surface Tension at High Temperature of Porcelain Stoneware Bodies: A Methodological Approach.
The shear viscosity and the glass-vapor surface tension at high temperature are crucial to understand the viscous flow sintering kinetics of porcelain stoneware. Moreover, the pyroplastic deformation depends on the viscosity of the whole body, which is made up of a suspension of crystals dispersed in the melt. The existing fundamental theoretical background, along with semi-empirical constitutive laws for viscous flow sintering and glass densification, can be exploited through different approaches to estimate the physical properties at high temperatures starting from amount and chemical composition of the melt. In this work, a comprehensive attempt to predict the properties of the liquid phase is proposed by means of a detailed overview of existing models for viscosity and surface tension of glasses and melts at high temperature. The chemical composition of the vitreous phase and its physical properties at high temperature are estimated through an experimental approach based on the qualitative and quantitative chemical and phase analyses (by Rietveld refinement of X-ray powder diffraction patterns) of different porcelain-like materials. Repercussions on the firing behavior of ceramic bodies, are discussed. Comparative examples are provided for porcelain stoneware tiles, vitreous china and porcelain bodies, disclosing differences in composition and properties but a common sintering mechanism.


Patterned activation of unpaired median neurons during fictive crawling in manduca sexta larvae
The unpaired median neurons are common to the segmental ganglia of many insects. Although some of the functional consequences of their activation, among them the release of octopamine to modulate muscle contraction, have been described, less is understood about how and when these neurons are recruited during movement. The present study demonstrates that peripherally projecting unpaired median neurons in the abdominal and thoracic ganglia of the larval tobacco hornworm Manduca sexta are recruited rhythmically during the fictive crawling motor activity that is produced by the isolated central nervous system in response to pilocarpine. Regardless of the muscles to which they project, the efferent unpaired median neurons in all segmental ganglia are depolarized together during the phase of the crawling cycle when the thoracic leg levator motoneurons are active. During fictive crawling, therefore, the unpaired median neurons are not necessarily active in synchrony with the muscles to which they project. The rhythmical synaptic drive of the efferent unpaired median neurons is derived, at least in part, from a source within the subesophageal ganglion, even when the motor pattern is evoked by exposing only the more posterior ganglia to pilocarpine. In pairwise intracellular recordings from unpaired median neurons in different ganglia, prominent excitatory postsynaptic potentials, which occur with an anterior-to-posterior delay in both neurons, are seen to underlie the rhythmic depolarizations. One model consistent with these findings is that one or more neurons within the subesophageal ganglion, which project posteriorly to the segmental ganglia and ordinarily provide unpatterned synaptic inputs to all efferent unpaired median neurons, become rhythmically active during fictive crawling in response to ascending information from the segmental pattern-generating network.


Expression of a mutated ras gene in Dictyostelium discoideum alters the binding of cyclic AMP to its chemotactic receptor.
Dictyostelium discoideum cells contain a ras gene that codes for a polypeptide that is highly homologous to the human ras proteins. Extra copies of the wild-type gene or a gene carrying a missense mutation in codon 12 (ras-Gly12 and ras-Thr12, respectively) have been introduced into Dictyostelium cells by transformation. We have investigated the properties of the chemotactic cell surface cyclic AMP receptor in crude membrane preparations of wild-type Dictyostelium cells and ras-Gly12 and ras-Thr12 transformants. In vitro, an ATP- and Ca2+-dependent reduction of the number of cyclic AMP receptors was observed in membranes from all three cell types. The number of available receptors was decreased maximally by about 50%. In the presence of ATP the half-maximal Ca2+ concentration required for this process was about 10(-5) M in wild-type and ras-Gly12 membranes, and less than 10(-7) M in ras-Thr12 membranes. Addition of GTP (but not GDP) or the phorbol ester PMA (phorbol-12-myristate-13-acetate) reduced the Ca2+ requirement of the process in wild-type and ras-Gly12 membranes to the physiological level of less than 10(-7) M. In membranes derived from ras-Thr12 cells addition of GTP or PMA had no effect. The results indicate that D. discoideum cells contain a cyclic AMP receptor-controlling pathway that can be activated in vitro and involves a GTP-binding protein and a Ca2+ plus ATP-dependent activity, possibly protein kinase C. It is concluded that the ras protein specifically interacts with this pathway; the pathway appears to be constitutively activated by the mutated ras gene product.


Super-swelled lyotropic single crystals.
Lipids self-assemble into diverse supramolecular structures that exhibit thermotropic and/or lyotropic behavior. Lyotropic mesophases, where membranes conform to periodic minimal surfaces dividing two nonpenetrating aqueous subspaces, are arguably one of the most intriguing phases of lipid materials. Traditional 3D bicontinuous cubic lipid materials appear as a polycrystal of varying degrees of order. When exposed to water, the properties of the molecular building blocks of the membrane determine specific swelling limits setting the lattice dimensions at about 15 nm. This limited swelling severely impairs their application as delivery vehicles of large drugs or as matrices for guiding protein crystallization. We report the discovery of self-assembly strategies leading to the emergence of lipid bicontinuous single crystals with unprecedented swelling capacity. The conventional strategy to increase unit cell size is tweaking membrane composition to include charged building blocks, a process to achieve electrostatic-driven swelling. In this paper, we demonstrate that controlling self-assembly external conditions when coupled to membrane composition yields 3D bicontinuous cubic phases that swell up to lattice dimensions of 68 nm. Importantly, and contrary to what is perceived for soft lyotropic materials in general, the self-assembly methodology enables the development of large super-swelled monocrystals. Utilizing small-angle X-ray scattering and cryoelectron microscopy, we underpin three crucial factors dictating the stabilization of super-swelled lipid bicontinuous cubic single crystals: (i) organic solvent drying speed, (ii) membrane charge density, and (iii) polyethylene glycol-conjugated lipids amount.


Inhibition of starch synthesis results in overproduction of lipids in Chlamydomonas reinhardtii.
Starch and neutral lipids are two major carbon storage compounds in many microalgae and plants. Lipids are more energy rich and have often been used as food and fuel feedstocks. Genetic engineering of the lipid biosynthesis pathway to overproduce lipid has achieved only limited success. We hypothesize that through blocking the competing pathway to produce starch, overproduction of neutral lipid may be achieved. This hypothesis was tested using the green microalga Chlamydomonas reinhardtii and its low starch and starchless mutants. We discovered that a dramatic increase in neutral lipid content and the neutral lipid/total lipid ratio occurred among the mutants under high light and nitrogen starvation. BAFJ5, one of the mutants defective in the small subunit of ADP-glucose pyrophosphorylase, accumulated neutral and total lipid of up to 32.6% and 46.4% of dry weight (DW) or 8- and 3.5-fold higher, respectively, than the wild-type. These results confirmed the feasibility of increasing lipid production through redirecting photosynthetically assimilated carbon away from starch synthesis to neutral lipid synthesis. However, some growth impairment was observed in the low starch and starchless mutants, possibly due to altered energy partitioning in PSII, with more excitation energy dissipated as heat and less to photochemical conversion. This study demonstrated that biomass and lipid production by the selected mutants can be improved by physiological manipulation.


Myoepithelial molecular markers in human breast carcinoma PMC42-LA cells are induced by extracellular matrix and stromal cells.
The microenvironment plays a key role in the cellular differentiation of the two main cell lineages of the human breast, luminal epithelial, and myoepithelial. It is not clear, however, how the components of the microenvironment control the development of these cell lineages. To investigate how lineage development is regulated by 3-D culture and microenvironment components, we used the PMC42-LA human breast carcinoma cell line, which possesses stem cell characteristics. When cultured on a two-dimensional glass substrate, PMC42-LA cells formed a monolayer and expressed predominantly luminal epithelial markers, including cytokeratins 8, 18, and 19; E-cadherin; and sialomucin. The key myoepithelial-specific proteins alpha-smooth muscle actin and cytokeratin 14 were not expressed. When cultured within Engelbreth-Holm- Swarm sarcoma-derived basement membrane matrix (EHS matrix), PMC42-LA cells formed organoids in which the expression of luminal markers was reduced and the expression of other myoepithelial-specific markers (cytokeratin 17 and P-cadherin) was promoted. The presence of primary human mammary gland fibroblasts within the EHS matrix induced expression of the key myoepithelial-specific markers, alpha-smooth muscle actin and cytokeratin 14. Immortalized human skin fibroblasts were less effective in inducing expression of these key myoepithelial-specific markers. Confocal dual-labeling showed that individual cells expressed luminal or myoepithelial proteins, but not both. Conditioned medium from the mammary fibroblasts was equally effective in inducing myoepithelial marker expression. The results indicate that the myoepithelial lineage is promoted by the extracellular matrix, in conjunction with products secreted by breast-specific fibroblasts. Our results demonstrate a key role for the breast microenvironment in the regulation of breast lineage development.


Experiencing Burnout: John Henryism, Gender Role Conflict, and Anxiety Among Incarcerated Black Men.
At the intersection of race and gender, Black men encounter conflicting and often stress-inducing gender norms. Research suggests Black men may utilize John Henryism Active Coping (JHAC), a culturally-relevant strategy to manage stress. However, little is known about how incarcerated Black men cope with gender role conflict (GRC) and resulting psychological distress. To better understand stressors and coping strategies among Black male prisoners, the current study examined the relationships between GRC, anxiety, and JHAC among N = 193 incarcerated Black men nearing community reentry. Hierarchical linear regression results showed length of incarceration, GRC, and anxiety were all negatively associated with JHAC. Full-time employment prior to incarceration was positively associated with JHAC. Moderation analyses indicated anxiety increased the strength of the negative association between GRC and JHAC. Implications highlight incarcerated Black men may benefit from interventions that encourage active coping strategies to manage gender-related stress and anxiety.


Utility of biomarkers in adult Fontan patients with decompensated heart failure.
The incidence of heart failure is increasing within the Fontan population. The use of serological markers, including B-type natriuretic peptide, has been limited in this patient population. This was a single-centre retrospective study of Fontan patients in acute decompensated heart failure. Fontan patients underwent a 1:2 match with non-Fontan patients for each heart failure hospitalisation for comparative analysis. A univariate logistic regression model was used to assess associations between laboratory and echocardiographic markers and a prolonged length of stay of 7 days or greater. B-type natriuretic peptide levels were significantly lower in Fontan patients admitted for heart failure than that in non-Fontan patients [390.9 (±378.7) pg/ml versus 1245.6 (±1160.7) pg/ml, respectively, p < 0.0001] and were higher in Fontan patients with systemic ventricular systolic or diastolic dysfunction than that in Fontan patients with normal systemic ventricular function [833.6 (±1547.2) pg/ml versus 138.6 (±134.0) pg/ml, p = 0.017]. The change from the last known outpatient value was smaller in Fontan patients in comparison with non-Fontan patients [65.7 (±185.7) pg/ml versus 1638.0 (±1444.7) pg/ml, respectively, p < 0.0001]. Low haemoglobin and high blood urea nitrogen levels were associated with a prolonged length of stay. B-type natriuretic peptide levels do not accurately reflect decompensated heart failure in Fontan patients when compared to non-Fontan heart failure patients and should, therefore, be used with caution in this patient population.


Dentistry as a prospective career choice in india.
Career choice is a complex decision in a student's life. The opportunity to participate in dental education in many countries, especially in the developing ones, is limited to a small percentage of the community. There is a wide range of options for students to choose as a career in general family, gender, personal interest; outcome expectancies can affect the decision in choosing it. Many studies showed that many individuals find themselves in occupations not really knowing why they made that particular decision. The changing nature of the dental workforce and the need to retain the services of future members has made it important to understand why current dental students have chosen dentistry as their career. However, the choice of dentistry becomes forceful at times by peer pressure, cultural thrust or inability to procure medicine. It is of interest to evaluate dentistry as a prospective career choice in India. The participants answered a questionnaire based online survey and the results were collected and analysed statistically. Analyses of data from the survey shows that majority (36.72%) of students had chosen dentistry as a career choice having missed entry or selection into medicine.


Policy Coherence and Interplay between Climate Change Adaptation Policies and the Forestry Sector in Nepal.
Least Developed Countries are likely to be hit the hardest by climate change and need focused efforts towards adaptation. Nepal recognizes that it needs to integrate climate change adaptation into various policies, but limited understanding of how to make these policies coherent is among the factors that hinder effective adaptation action. This can lead to wasted resources and lost opportunities. This paper applies concepts from policy coherence for development frameworks and policy content analysis to examine coherence in Nepal's climate and forest policies-and discusses the factors hindering effective implementation. The policies are analyzed at the horizontal/external level at three layers-motivation, measures, and planned implementation process. The paper finds that policies are more consistent on motivation level and adaptation measures, but are less coherent on implementation. The National Adaptation Programme of Action (NAPA) is more explicit in identifying institutions, organizations, roles and responsibilities, resource allocation (financial), and a monitoring and evaluation plan for climate change adaptation while other policies such as Climate Change Policy 2011, National Biodiversity Strategy and Action Plan 2014-2020, Forest Policy 2015, and Forest Sector Strategy 2016 have critical gaps in this area. This paper conclude that formulation of a policy, articulating targets, and mobilizing financial resources are in themselves not sufficient to effectively address climate change adaptation. Policy-based legislation is required, together with development of a supportive collaborative multi-stakeholder approach at different levels of governance, backed up by effective, collaborative monitoring and enforcement.


High temporal and inter-individual variation detected in the human ileal microbiota.
The diversity and temporal stability of the predominant bacteria in the human ileum was studied with the use of ileal effluent samples of seven individuals with Brooke ileostomies. The total number of bacteria within the ileal effluent was in the range of 10⁷ -10⁸ bacteria per gram (wet weight). The diversity of the bacteria in the ileal effluent showed marked differences compared with that in faecal samples from age-matched healthy adults. The ileal effluent had a higher relative abundance of species within the orders Lactobacillales and Clostridiales, mainly Streptococcus bovis-related species, and the Veillonella group, and a lower proportion of species related to Ruminococcus gnavus, R. obeum and Bacteroides plebeius. In addition, inter-individual differences were found, indicative of a highly personal ileal microbiota profile. Furthermore, temporal profiles showed large fluctuations per individual over a period of 9-28 days (average similarity over a period of 9 days was as low as 44%), and differences between morning and afternoon profiles were observed. Parallel cloning and sequencing efforts revealed several phylotypes that were not identified in previous studies (12 out of 65 phylotypes showed less than 97% sequence similarity with previously reported sequences). Achaea were found to be below detection limit by quantitative PCR. Overall, the results indicate that the microbiota of the human ileum is relatively unstable, less complex and consisting of different dominating phylotypes when compared with the colonic microbiota.


Assessing the Validity of a a priori Patient-Trial Generalizability Score using Real-world Data from a Large Clinical Data Research Network: A Colorectal Cancer Clinical Trial Case Study.
Existing trials had not taken enough consideration of their population representativeness, which can lower the effectiveness when the treatment is applied in real-world clinical practice. We analyzed the eligibility criteria of Bevacizumab colorectal cancer treatment trials, assessed their a priori generalizability, and examined how it affects patient outcomes when applied in real-world clinical settings. To do so, we extracted patient-level data from a large collection of electronic health records (EHRs) from the OneFlorida consortium. We built a zero-inflated negative binomial model using a composite patient-trial generalizability (cPTG) score to predict patients' clinical outcomes (i.e., number of serious adverse events, [SAEs]). Our study results provide a body of evidence that 1) the cPTG scores can predict patient outcomes; and 2) patients who are more similar to the study population in the trials that were used to develop the treatment will have a significantly lower possibility to experience serious adverse events.


Roles of DNA repair enzyme OGG1 in innate immunity and its significance for lung cancer.
Cytokines are pivotal mediators of the immune response, and their coordinated expression protects host tissue from excessive damage and oxidant stress. Nevertheless, the development of lung pathology, including asthma, chronic obstructive pulmonary disease, and ozone-induced lung injury, is associated with oxidant stress; as evidence, there is a significant increase in levels of the modified guanine base 7,8-dihydro-8-oxoguanine (8-oxoG) in the genome. 8-OxoG is primarily recognized by 8-oxoguanine glycosylase 1 (OGG1), which catalyzes the first step in the DNA base excision repair pathway. However, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, including NF-κB, to their cognate sites to enable expression of cytokines and chemokines, with ensuing recruitments of inflammatory cells. Hence, defective OGG1 will modulate the coordination between innate and adaptive immunity through excessive oxidant stress and cytokine dysregulation. Both oxidant stress and cytokine dysregulation constitute key elements of oncogenesis by KRAS, which is mechanistically coupled to OGG1. Thus, analysis of the mechanism by which OGG1 modulates gene expression helps discern between beneficial and detrimental effects of oxidant stress, exposes a missing functional link as a marker, and yields a novel target for lung cancer.


Time-dependent risk reduction of ventricular tachyarrhythmias in cardiac resynchronization therapy patients: a MADIT-RIT sub-study.
Data on the time-dependent benefit of cardiac resynchronization therapy with defibrillator (CRT-D) compared with a dual-chamber implantable cardioverter-defibrillator (ICD) to reduce death or ventricular tachycardia (VT) or ventricular fibrillation (VF) are limited. We aimed to evaluate the time-related risk of death or sustained VT or VF in patients receiving CRT-D vs. ICD in the MADIT-RIT trial. Kaplan-Meier survival analyses and multivariate Cox regression models were utilized to compare the incidence and the risk of death or sustained VT/VF in the CRT-D and ICD subgroups by the elapsed time after device implantation (6 months). Of the ICD (n = 742) and CRT-D (n = 757) patients enrolled, the risk of death was lower in CRT-D vs. in ICD early after device implantation [hazard ratio (HR) = 0.42, 95% confidence interval (CI): 0.17-1.03, P = 0.058] and beyond 6 months of follow-up (HR = 0.39, 95% CI: 0.21-0.73, P = 0.004), with the 6-month interaction P = 0.899. The overall risk of sustained VT/VF was reduced in CRT-D vs. ICD patients (HR = 0.73, 95% CI: 0.52-1.03, P = 0.07). However, the risk was similar in the first 6 months (HR = 1.00, 95% CI: 0.62-1.62, P = 0.988), and a lower risk emerged 6 months after CRT-D implantation (HR = 0.58, 95% CI: 0.38-0.88, P = 0.011), with the 6-month interaction P = 0.059. The reduced mortality risk of CRT-D compared with an ICD alone began early after device implantation and was sustained during long-term follow-up; the reduced risk for ventricular tachyarrhythmias did not emerge until 6 months after device implantation. http://clinicaltrials.gov/ct2/show/NCT00947310.


Zika Virus Infection: A Vector-Borne Threat to Pregnant Women and Infants.
Zika virus (ZIKV) is an emergent flavivirus, transmitted predominately by Aedes genus mosquitos that recently reached the Americas and was soon implicated in an increase in microcephaly and other serious birth defects. This report provides updated information and recommendations on testing, screening, and care for pregnant women and infants affected by ZIKV. Current published recommendations from the Centers for Disease Control and Prevention, the World Health Organization, and the American Academy of Pediatrics were reviewed and included in this report. Although largely a self-limiting disease usually without symptoms, pregnant women and their fetuses are at greatest risk. Maternal transmission of ZIKV to the fetus can lead to congenital Zika infection with potentially devastating sequelae to the infant. The available evidence suggests that infection during the first trimester of pregnancy, in which the fetus' central nervous system is being formed, is associated with higher risk of brain abnormalities and perinatal loss. Uncertainties remain about the course of the disease, and the full spectrum of effects of the virus on the developing infant is not yet understood. Infants with congenital Zika syndrome need coordinated follow-up and long-term specialty care, as well as support for the family. There is no known cure for ZIKV infection and no vaccine is currently available. The full spectrum of developmental disabilities and other adverse early childhood outcomes associated with congenital ZIKV infection needs to be studied.


Further evidence for enhancing effects of NO on monosynaptic and polysynaptic spinal reflexes in cats.
There are a number of studies on the effects of different NO donors and inhibitors on spinal cord with quite contradictory results. The aim of this study was to investigate the effects of sodium nitroprusside (SNP), a NO donor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, on monosynaptic and polysynaptic spinal reflexes in anesthetized and spinalized cats. After a dorsal laminectomy between L5 and S1, monosynaptic and polysynaptic spinal reflexes were evoked by stimulation of gastrocnemius nerves. Following control recordings, administration of L-NAME in 100, 200, 500 microM (local) and 10, 20, 50 mg/kg (i.v.) doses decreased significantly the monosynaptic and polysynaptic reflex amplitudes in a dose-dependent manner. Administration of SNP in 100, 200, 500 microM (local) and 100, 200, 500 microg/kg (i.v.) doses enhanced significantly the both reflex amplitudes in a dose-dependent manner. In another series of experiments it has been observed that the maximal decrease in reflex amplitudes caused by 500 microM local L-NAME administration in the 15th minute was reversed by locally administered SNP (500 microM). Our results support the hypothesis stating that NO may play a role in the modulation of mono- and polysynaptic spinal reflexes and the NO appears to have an enhancing role on these responses.


GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice.
GABA has been proposed to inhibit insulin secretion through GABAB receptors (GABABRs) in pancreatic beta-cells. We investigated whether GABABRs participated in the regulation of glucose homeostasis in vivo. The animals used in this study were adult male and female BALB/C mice, mice deficient in the GABAB1 subunit of the GABABR (GABAB(-/-)), and wild types (WT). Blood glucose was measured under fasting/fed conditions and in glucose tolerance tests (GTTs) with a Lifescan Glucose meter, and serum insulin was measured by ELISA. Pancreatic insulin content and islet insulin were released by RIA. Western blots for the GABAB1 subunit in islet membranes and immunohistochemistry for insulin and GABAB1 were performed in both genotypes. BALB/C mice preinjected with Baclofen (GABABR agonist, 7.5 mg/kg ip) presented impaired GTTs and decreased insulin secretion compared with saline-preinjected controls. GABAB(-/-) mice showed fasting and fed glucose levels similar to WT. GABAB(-/-) mice showed improved GTTs at moderate glucose overloads (2 g/kg). Baclofen pretreatment did not modify GTTs in GABAB(-/-) mice, whereas it impaired normal glycemia reinstatement in WT. Baclofen inhibited glucose-stimulated insulin secretion in WT isolated islets but was without effect in GABAB(-/-) islets. In GABAB(-/-) males, pancreatic insulin content was increased, basal and glucose-stimulated insulin secretion were augmented, and impaired insulin tolerance test and increased homeostatic model assessment of insulin resistance index were determined. Immunohistochemistry for insulin demonstrated an increase of very large islets in GABAB(-/-) males. Results demonstrate that GABABRs are involved in the regulation of glucose homeostasis in vivo and that the constitutive absence of GABABRs induces alterations in pancreatic histology, physiology, and insulin resistance.


Enamel bond strengths of pairs of adhesives from the same manufacturer.
Most manufacturers of dental adhesives have both a total-etch adhesive and a simplified self-etching adhesive available on the market. This study measured the enamel microtensile bond strengths of five pairs of enamel adhesives as a function of enamel roughness. The proximal surfaces of 25 extracted mandibular molars were sectioned with a diamond saw to obtain 50 enamel rectangles with an area of 8x4 mm2. The enamel rectangles were divided in two equal parts via a groove to obtain 4x4 mm2 squared bonding surfaces. One half was roughened with a coarse diamond bur under water for five seconds, while the other half was kept intact. The enamel surfaces were randomly assigned to 10 enamel adhesives grouped into five pairs. Each pair included one self-etch adhesive and one total-etch adhesive from the same manufacturer: Adper Prompt and Adper Single Bond (PLP and SB, 3M ESPE); AdheSE and Excite (ADH and EXC, Ivoclar Vivadent); OptiBond Solo Plus SE and OptiBond Solo Plus (OPTSE and OPT, Kerr); Tyrian SPE/One-Step Plus and One-Step (TYR and OST, BISCO, Inc); Xeno III and Prime&Bond NT (XEN and PBNT, Dentsply). The adhesives were applied according to the manufacturers' instructions. Buildups were constructed with Filtek Z250 (3M ESPE). The specimens were sectioned in sticks with a cross section of 0.8+/-0.2 mm2 and tested to failure in tension at a crosshead speed of 1 mm/minute. Two-way ANOVA followed by Duncan's post-hoc test at p<0.05 was computed. The highest mean bond strengths were obtained with total-etch adhesives. For "roughened enamel," three pairs of materials had statistically different means in which the total-etch adhesive resulted in statistically higher bond strengths (MPa) than the corresponding self-etch adhesive: EXC (36.6) > ADH (23.0) at p<0.026; OPT (34.5) > OPTSE (25.3) at p<0.028; PBNT (36.6) > XEN (19.5) at p<0.0001. For "intact enamel," four pairs of materials resulted in statistically different means: SB (31.7) > PLP (20.9) at p<0.049; EXC (37.9) > ADH (16.3) at p<0.0001; OST (30.1) > TYR (18.0); PBNT (43.8) > XEN (16.0) at p<0.0001. When the same adhesive was compared on intact vs roughened enamel, all the self-etch materials resulted in lower bond strengths on intact enamel, but this difference was only significant for TYR (p<0.042) and ADH (p<0.050). For total-etch materials, only OPT resulted in statistically lower bond strengths when applied on intact enamel p<0.011).


Complications of the canalith repositioning procedure.
To describe the conversion of benign paroxysmal positional vertigo involving the posterior canal into benign paroxysmal positional vertigo involving the anterior or horizontal canals after treatment using the canalith repositioning maneuver. Retrospective study of outcome. Outpatient clinic. Consecutive sample of 85 patients diagnosed as having benign paroxysmal positional vertigo affecting the posterior canal. Identification of posterior canal involvement was based on the observation of the direction of the vertical component of nystagmus after the Hallpike-Dix maneuver. Canalith repositioning maneuver. Eye movements were observed about 1 week after the treatment. The direction of nystagmus elicited after movement of the patient into the Hallpike-Dix position indicated which canal was involved in the patients who had not responded to treatment. Of the 85 patients studied who originally had posterior canal benign paroxysmal positional vertigo, five (6%) had anterior canal (n=2) or horizontal canal (n=3) positional vertigo after undergoing this maneuver. Careful observation of the direction of the nystagmus is necessary for correct identification of which canal is involved in patients who do not respond to the initial treatment using the canalith repositioning maneuver.


Quantitative and qualitative assessment of an all-inclusive postpartum human papillomavirus vaccination program.
A postpartum human papillomavirus vaccination program was locally implemented to address low initiation rates among young adults. Within 20 months, the program achieved high vaccine initiation and series completion rates. Based on the program's success, it was expanded to all 36 counties served by a public hospital. This study aimed to conduct a quantitative and qualitative evaluation to examine the success and limitations of the program when expanded from 1 county to 36 counties, many of which are home to rural and medically underserved communities. Patient navigators reviewed the electronic medical records and immunization registry records of women aged ≤26 years, who delivered an infant at the public hospital, to determine whether they needed to initiate or complete the human papillomavirus vaccine series. Eligible women were counseled and offered the human papillomavirus vaccine during their hospital stay. Patient navigators scheduled follow-up injections in addition to the mother's postpartum or her infant's well-child visits, made reminder phone calls, and rescheduled missed appointments. Descriptive statistics, including frequencies and proportions, were used for patients approached in the initial and expansion programs. Frequencies from the initial and expansion programs were examined separately. Qualitative interviews were conducted with the clinic staff to evaluate the program. The qualitative analyses were conducted using NVivo (QSR International, Melbourne, Australia, version 10). Both initial and expanded programs achieved vaccine completion rates above 70%. Of the 2631 eligible postpartum women enrolled in the initial program, 785 (30%) had already been fully vaccinated. Of the remaining 1846 women, 1265 (69%) women received their first dose, and 196 (11%) women received their second or third dose on the postpartum unit. Of the 1461 women who received at least 1 dose through the initial program, 1124 (77%) completed all 3 doses. Of the 4330 eligible postpartum women enrolled in the expanded program, 886 (21%) had already been fully vaccinated. Of the remaining 3444 women, 2284 (66%) received their first dose, and 343 (10%) received their second or third dose on the postpartum unit. Of the 2627 women receiving at least 1 dose through the expanded program, 1932 (74%) completed all 3 doses. Clinic staff interviewed felt the program benefited the postpartum unit and clinics, because it increased patient knowledge of the vaccine, increased patient volume for vaccination, and gave healthcare providers more time to focus on other tasks. Human papillomavirus vaccination on the postpartum unit is an effective way to increase catchup rates and is well accepted by healthcare providers. High completion rates can be achieved if adequate support is provided, even among patients residing in rural or underserved areas who need extensive support to access primary healthcare services. Although this particular program may be considered costly, it is overall effective because the vaccine prevents 5 different types of cancer in women. The inclusion of human papillomavirus vaccination in routine postpartum care is a relatively easy way to reach many adults not vaccinated at a younger age and could help address low vaccination rates among young women in the United States, including hard-to-reach populations.


First-trimester use of paroxetine and congenital heart defects: a population-based case-control study.
There is a need for case-control studies of the effect of paroxetine on the occurrence of specific heart defects. We performed a case-control study with data from a population-based birth defects registry in the Netherlands. All the children born between 1997 and 2006 were selected. Cases were defined as fetuses and children with isolated heart defects, and the controls were fetuses and children with a genetic disorder with no heart defect. We excluded children for whom there was no information on maternal medication use and deceased children and fetuses who were not examined postmortem. First-trimester exposure to paroxetine was compared between cases and controls by calculating adjusted odds ratios (AOR). We included 678 cases with isolated heart defects and 615 controls. The first trimester exposure rate was 1.5% for cases and 1.0% for controls. After excluding mothers who used paroxetine outside the first trimester, or who had used another SSRI, we found no significantly increased risk for heart defects overall (10 exposed cases; AOR, 1.5; 95% confidence interval [CI], 0.5-4.0), but we did find a significantly increased risk for atrium septum defects (three exposed cases; AOR, 5.7; 95% CI, 1.4-23.7). Our results suggest that the use of paroxetine in early pregnancy is associated with an increased risk of atrium septum defects. The results stress the importance of studying possible teratogenic effects of a drug, preferably in regard to well-specified malformations.


FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress.
Transcriptional regulatory mechanisms of cardiac oxidative stress resistance are not well defined. FoxO transcription factors are critical mediators of oxidative stress resistance in multiple cell types, but cardioprotective functions have not been reported previously. FoxO function in oxidative stress resistance was investigated in cultured cardiomyocytes and in mice with cardiomyocyte-specific combined deficiency of FoxO1 and FoxO3 subjected to myocardial infarction (MI) or acute ischemia/reperfusion (I/R) injury. Induction of oxidative stress in cardiomyocytes promotes FoxO1 and FoxO3 nuclear localization and target gene activation. Infection of cardiomyocytes with a dominant-negative FoxO1(Δ256) adenovirus results in a significant increase in reactive oxygen species and cell death, whereas increased FoxO1 or FoxO3 expression reduces reactive oxygen species and cell death. Mice generated with combined conditional deletion of FoxO1 and FoxO3 specifically in cardiomyocytes were subjected to I/R or MI. Loss of FoxO1 and FoxO3 in cardiomyocytes results in a significant increase in infarct area with decreased expression of the antiapoptotic molecules, PTEN-induced kinase1 (PINK1) and CBP/P300-interacting transactivator (CITED2). Expressions of the antioxidants catalase and manganese superoxide dismutase-2 (SOD2) and the autophagy-related proteins LC3II and Gabarapl1 also are decreased following I/R compared with controls. Mice with cardiomyocyte-specific FoxO deficiency subjected to MI have reduced cardiac function, increased scar formation, induction of stress-responsive signaling, and increased apoptotic cell death relative to controls. These data support a critical role for FoxOs in promoting cardiomyocyte survival during conditions of oxidative stress through induction of antioxidants and cell survival pathways.


Cardiac tamponade as manifestation of advanced thymic carcinoma.
Thymic carcinoma, a malignant thymoma, is rare in the anterior mediastinum. Typically it occurs after age 40 years, presents as an asymptomatic disorder for prolonged periods of time, and is incidentally detected by chest radiograph. Symptomatic patients often complain of a dull ache or chest pain. Cardiac tamponade as the first manifestation of these advanced thymomas is unusual. We now report the case of a 47-year-old man who experienced sudden onset syncope because of cardiac tamponade and massive pleural and pericardial effusions resulting from a huge thymic tumor. Emergency pericardiocentesis and thoracentesis terminated the life-threatening episode. The tumor and lung lesion were resected. Pathologic examination showed a moderately differentiated squamous cell carcinoma. Postoperative radiotherapy and chemotherapy were introduced. The patient has subsequently done well for the past 10 months.


Somatic pairing, endomitosis and chromosome aberrations in snakes (Viperidae and Colubridae).
The positioning of macrochromosomes of Bothrops jararaca and Bothrops insularis (Viperidae) was studied in undistorted radial metaphases of uncultured cells (spermatogonia and oogonia) not subjected to spindle inhibitors. Colchicinized metaphases from uncultured (spleen and intestine) and cultured tissues (blood) were also analyzed. We report two antagonic non-random chromosome arrangements in untreated premeiotic cells: the parallel configuration with homologue chromosomes associated side by side in the metaphase plate and the antiparallel configuration having homologue chromosomes with antipolar distribution in the metaphase ring. The antiparallel aspect also appeared in colchicinized cells. The spatial chromosome arrangement in both configurations is groupal size-dependent and maintained through meiosis. We also describe, in untreated gonia cells, endomitosis followed by reductional mitosis which restores the diploid number. In B. jararaca males we observed that some gonad regions present changes in the meiotic mechanism. In this case, endoreduplicated cells segregate the diplochromosomes to opposite poles forming directly endoreduplicated second metaphases of meiosis with the suppression of first meiosis. By a successive division, these cells form nuclei with one set of chromosomes. Chromosome doubling in oogonia is known in hybrid species and in parthenogenetic salamanders and lizards. This species also presented chromosome rearrangements leading to aneuploidies in mitosis and meiosis. It is suggested that somatic pairing, endomitosis, meiotic alterations, and chromosomal aberrations can be correlated processes. Similar aspects of nuclei configurations, endomitosis and reductional mitosis were found in other Viperidae and Colubridae species.


One hundred base pairs of 5' flanking sequence of a vaccinia virus late gene are sufficient to temporally regulate late transcription.
A vaccinia virus late gene coding for a major structural polypeptide of 11 kDa was sequenced. Although the 5' flanking gene region is very A+T rich, it shows little homology either to the corresponding region of vaccinia early genes or to consensus sequences characteristic of most eukaryotic genes. Three DNA fragments (100, 200, and 500 base pairs, respectively), derived from the flanking region and including the late gene mRNA start site, were inserted into the coding sequence of the vaccinia virus thymidine kinase (TK) early gene by homologous in vivo recombination. Recombinants were selected on the basis of their TK- phenotype. Cells were infected with the recombinant viruses and RNA was isolated at 1-hr intervals. Transcripts initiating either from the TK early promoter, or from the late gene promoter at its authentic position, or from the translocated late gene promoters within the early gene were detected by nuclease S1 mapping. Early after infection, only transcripts from the TK early promoter were detected. Later in infection, however, transcripts were also initiated from the translocated late promoters. This RNA appeared at the same time and in similar quantities as the RNA from the late promoter at its authentic position. No quantitative differences in promoter efficiency between the 100-, 200-, and 500-base-pair insertions were observed. We conclude that all necessary signals for correct regulation of late-gene expression reside within only 100 base pairs of 5' flanking sequence.


Efficacy and safety of intravenous chemotherapy during intensive treatment phase in patients with newly diagnosed pulmonary tuberculosis.
The purpose of our study was to examine the efficacy and safety of intravenous chemotherapy during intensive treatment phase for patients with newly diagnosed pulmonary tuberculosis (pulmonary TB). The study involved 92 patients with newly diagnosed pulmonary TB aged between 20 years and 68 years. All patient with newly diagnosed pulmonary TB and chemosensitive tuberculosis were enrolled in this study. The patients were allocated to two groups. The first (control) group of 46 patients received standard chemotherapy orally. The second (main) group consisted of 46 patients who were prescribed isoniazid, rifampin, ethambutol by i / v transfusion, and pyrazinamide orally as a part of the standard treatment. Symptoms of intoxication in pulmonary TB patients from the second group were eliminated faster (1.42±0.35) of a month than the same symptoms of the group 1-(2.96±0.24) of the months,p < 0.05; disappearance of respiratory symptoms of the group 2-(1.34±0.29) of a month, group 1-(2.65±0.43) of the months,p < 0.05. In the group 2, the bacterioexcretion time was reducing faster and up to 2 months it reached 37(80.43±5.85%) while the time for the control group reached 25(54.35±7.34%),p < 0.05. Destruction healing and healing frequency of destruction cavities up to 4 months amounted to 38(82.61±5.59%) (in control group - 28(60.87±7.20%),p < 0.05) and residual changes were reducing (small changes or absence of even minimal radiological changes were found in 29(63.04 ±7.12%) patients versus 18(39.13±7.20%) of the group 1, and large residual changes accordingly in 17(36.96±7.12%) and 28(60.87±7.20%),p < 0.05. Thanks to i/v chemotherapy clinical manifestations of the in patients with pulmonary TB were eliminated faster, severe side effects to anti-TB drugs were not noticed, time of bacterial excretion and healing destruction reduced, healing frequency of destruction cavities increased and the residual changes decreased.


A single receptor binds both insulin-like growth factor II and mannose-6-phosphate.
Amino acid sequences deduced from rat complementary DNA clones encoding the insulin-like growth factor II (IGF-II) receptor closely resemble those of the bovine cation-independent mannose-6-phosphate receptor (Man-6-P receptorCI), suggesting they are identical structures. It is also shown that IGF-II receptors are adsorbed by immobilized pentamannosyl-6-phosphate and are specifically eluted with Man-6-P. Furthermore, Man-6-P specifically increases by about two times the apparent affinity of the purified rat placental receptor for 125I-labeled IGF-II. These results indicate that the type II IGF receptor contains cooperative, high-affinity binding sites for both IGF-II and Man-6-P-containing proteins.


Conferone, a coumarin from Ferula flabelliloba, induced toxic effects on adult T-cell leukemia/lymphoma cells.
Adult T-cell leukemia/lymphoma (ATL) is a lymphoid malignancy caused by HTLV-1 infection, with distinct geographical distribution. Despite advances in cancer treatment, the average survival rate of ATL is low. Conferone is a natural coumarin extracted from Ferula species with a wide range of pharmaceutical effects. In search for a novel chemotherapeutic agent, we investigated the cytotoxicity of conferone on ATL cells. To obtain conferone, the methanolic extract of the roots of F. flabelliloba was subjected to silica gel column chromatography, followed by 1H- and 13C-NMR to confirm its structure. For cytotoxicity assay, MT-2 cells were treated with different concentrations of conferone (2.5, 5, 10, 20, and 40 µM) for 24, 48, and 72 h, and viability was evaluated by a colorimetric assay using alamarBlue. Cell cycle was analyzed by PI staining and flow cytometry, and qPCR was used to study the expression of candidate genes. Obtained findings indicated that conferone induced considerable cytotoxic effects on MT-2 cells in a time- and dose-dependent manner. In addition, accumulation of cells in the sub-G1 phase of the cell cycle was detected upon conferone administration. Moreover, conferone reduced the expression of CDK6, c-MYC, CFLIPL, and NF-κB (Rel-A) in MT-2 cells. Accordingly, conferone could be considered as a potent agent against ATL, although complementary investigations are required to define more precisely its mechanism of action.


Blood leukocyte Alu and LINE-1 methylation and gastric cancer risk in the Shanghai Women's Health Study.
Recent data suggest a link between blood leukocyte DNA methylation, and cancer risk. However, reports on DNA methylation from a prospective study are unavailable for gastric cancer. We explored the association between methylation in pre-diagnostic blood leukocyte DNA and gastric cancer risk in a case-control study nested in the prospective Shanghai Women's Health Study cohort. Incident gastric cancer cases (n=192) and matched controls (n=384) were included in the study. Methylation of Alu and long interspersed nucleotide elements (LINE)-1 were evaluated using bisulphite pyrosequencing. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated from logistic regression adjusting for potential confounders. Alu methylation was inversely associated with gastric cancer risk, mainly among cases diagnosed one or more years after blood collection. After excluding cases diagnosed during the first year of follow-up, the ORs for the third, second, and first quartiles of Alu methylation compared with the highest quartile were 2.43 (1.43-4.13), 1.47(0.85-2.57), and 2.22 (1.28-3.84), respectively. This association appeared to be modified by dietary intake, particularly isoflavone. In contrast, LINE-1 methylation levels were not associated with gastric cancer risk. Evidence from this prospective study is consistent with the hypothesis that DNA hypomethylation in blood leukocytes may be related to cancer risk, including risk of gastric cancer.


Highly Sensitive and Selective Detection of Steroid Hormones Using Terahertz Molecule-Specific Sensors.
Discrimination and quantification of trace amounts of steroid hormones in biological specimens are needed to elucidate their changing expression because their biological functions are responsible for the development and prevention of endocrine disorders. Although mass-spectrometry-based assays are most commonly recommended, development of a new type of highly sensitive and selective detection methods in clinical practices is needed. Here, we introduce a label-free type of terahertz molecule sensor capable of sensing and identifying progesterone and 17α-OH-progesterone selectively. Nanoslot-array-based sensing chips were used as launching pads for absorption cross-section enhancement of molecules at a reliable terahertz frequency. With use of nanoslots with resonances at 1.17 THz corresponding to intrinsic THz absorption resonance mode for progesterone and at 1.51 THz for 17α-OH-progesterone, respectively, each steroid shows prominent transmittance change in terms of its amount. In particular, the sensing performance has been much improved by controlling evaporation speed, in turn resulting in an efficient, homogeneous distribution of the molecules onto a sensing hot spot.


A toxic shock syndrome toxin-1 peptide that shows homology to mycobacterial heat shock protein 18 is presented as conventional antigen to T cells by multiple HLA-DR alleles.
We observe that PBMC from most adults (16 of 18 subjects tested) show a small but significant in vitro proliferative response to a 30-amino acid-long peptide (peptide 2, amino acids 34-63) derived from toxic shock syndrome toxin. By contrast, PBMC from newborn blood and thymocytes do not proliferate to this peptide, and furthermore, peptide 2 did not displace the binding of radiolabeled TSST-1 to MHC class II positive cells, nor did it induce IL-1 beta mRNA in monocytes, indicating that this peptide does not behave as a superantigen. Proliferation of PBMC to peptide 2 could be blocked by anti-HLA-DR, but not by anti-HLA-DP or DQ mAb, suggesting that HLA-DR molecules are the restriction elements for the recognition of this peptide by T cells. This premise was further confirmed by demonstrating that mouse L cells transfected with human HLA-DR, but not HLA-DP or DQ molecules, supported the proliferation of purified T cells to peptide 2. Studies with subjects of known HLA-DR types showed that all types tested are capable of responding to this peptide, PBMC from adults exposed to mycobacterial Ag showed significantly better proliferative response to peptide 2 than unexposed adults. Studies with truncations of this peptide suggest that a "core" region of eight amino acids that is conserved between low m.w. heat shock proteins and peptide 2 may be critical to T cell recognition of this peptide. The universal presentation of peptide 2 by HLA-DR molecules may contribute to the widespread natural immunity observed against toxic shock syndrome toxin.


The new clinical classification of metastatic spinal malignancies serves as a vital reference for surgical management: a retrospective case-control study.
It is commonly accepted that surgical treatment is an essential component of the comprehensive management of metastatic spinal malignancies. However, up until now, the clinical classification of metastatic spinal malignancies has not been well-structured. After IRB approval, 86 patients with metastatic spinal malignancies were adopted. According to the vascular distribution, stability of vertebrae, and degree of nerve compression, metastatic spinal malignancies can be classified into five types. Tumors classified as type I typically appear in the vertebral body. Type II tumors are those that develop in the transverse processes, superior and inferior articular processes, and spinal pedicles. Type III denotes malignancies that are present in the spinous process and vertebral plate. Types IVa and IVb are included in type IV. Type IVa combines type I and type II, whereas type IVb combines type II and type III. Type V tumors are those of types I, II, and III that co-occur and spread in different directions into the spinal canal. 20 of included 86 patients who did not receive segmental arterial embolization were set as the non-embolization group. The embolization group included 24 patients who received segmental arterial embolization on both sides of the diseased vertebrae. 42 patients were included in the offending embolization group after receiving responsible arterial embolization. A surgical intervention was performed within 24 h following an embolization. Surgical intervention with the purpose of removing as much of the tumor as possible and providing an effective reconstruction of the spinal column. In comparison with the non-embolization group and embolization group, the offending embolization group presented unique advantages in terms of bleeding volume (p<0.001), operation time (p<0.001), and local recurrence rate within 12 months (p=0.006). By significantly reducing surgical trauma and local recurrence rate (12 months), responsible arterial vascular embolization procedures together with associated surgical protocols developed on the basis of the clinical classification of metastatic spinal malignancies, are worthy of clinical dissemination.


Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels.
Small molecule inhibitors of site-specific O-glycosylation by the polypeptide N-acetylgalactosaminyltransferase (ppGalNAc-T) family are currently unavailable but hold promise as therapeutics, especially if selective against individual ppGalNAc-T isozymes. To identify a compound targeting the ppGalNAc-T3 isozyme, we screened libraries to find compounds that act on a cell-based fluorescence sensor of ppGalNAc-T3 but not on a sensor of ppGalNAc-T2. This identified a hit that subsequent in vitro analysis showed directly binds and inhibits purified ppGalNAc-T3 with no detectable activity against either ppGalNAc-T2 or ppGalNAc-T6. Remarkably, the inhibitor was active in two medically relevant contexts. In cell culture, it opposed increased cancer cell invasiveness driven by upregulated ppGalNAc-T3 suggesting the inhibitor might be anti-metastatic. In cells and mice, it blocked ppGalNAc-T3-mediated glycan-masking of FGF23 thereby increasing its cleavage, a possible treatment of chronic kidney disease. These findings establish a pharmacological approach for the ppGalNAc-transferase family and suggest that targeting specific ppGalNAc-transferases will yield new therapeutics.


Axillary artery thrombosis resulting in upper limb amputation as a COVID-19 sequela.
Novel COVID-19 continues to intrigue medical professionals with its varied presentations. Though it affects the respiratory tract primarily, thrombogenesis has been the Achilles' heel. A 44-year-old man diagnosed with COVID-19 presented with upper limb pain at a local hospital and was found to have thrombosis of the right axillary artery. Despite a successful embolectomy at the local hospital, there was re-occlusion of the axillary artery and the limb became ischaemic. He was referred to our institution by which time the limb became gangrenous above the elbow and had to be amputated. Extensive sloughing of the nerves was also seen in the local area. Hypercoagulability presenting with various manifestations is common in COVID-19 and needs early anticoagulation. We present this asymptomatic patient who lost a limb to this COVID-19 sequelae.


Association of short-term ambient air pollution concentrations and ventricular arrhythmias.
The authors evaluated the association between ventricular arrhythmias detected by implantable cardioverter defibrillators and ambient air pollution concentrations in the hours immediately before the arrhythmia. Patients given implantable cardioverter defibrillators at the New England Medical Center in Boston, Massachusetts, between mid-1995 and 1999 who lived within 40 km of a central monitoring site (n = 203) were followed until July 2002. The authors used a case-crossover design to study the association between ambient air pollution and up to 798 confirmed ventricular arrhythmias among 84 subjects. The authors found that interquartile range increases in 24-hour moving average particulate matter less than 2.5 mum in aerodynamic diameter and ozone were associated with 19% and 21% increased risks of ventricular arrhythmia, respectively. For each, there was evidence of a linear exposure response, and the associations appeared independent. These associations were stronger than associations with mean concentrations on the same calendar day and previous calendar days. The authors did not find associations with pollutant concentrations less than 24 hours before the arrhythmia. Cases with a prior ventricular arrhythmia within 72 hours had greater risk associated with air pollutants than did cases without a recent arrhythmia. These results confirm previous findings and suggest that matching of pollution periods to arrhythmias is important in detecting such associations.


Contextual herd factors associated with cow culling risk in Québec dairy herds: A multilevel analysis.
Several health disorders, such as milk fever, displaced abomasum, and mastitis, as well as impaired reproductive performance, are known risk factors for the removal of affected cows from a dairy herd. While cow-level risk factors are well documented in the literature, herd-level associations have been less frequently investigated. The objective of this study was to investigate the effect of cow- and herd-level determinants on variations in culling risk in Québec dairy herds: whether herd influences a cow's culling risk. For this, we assessed the influence of herd membership on cow culling risk according to displaced abomasum, milk fever, and retained placenta. A retrospective longitudinal study was conducted on data from dairy herds in the Province of Québec, Canada, by extracting health information events from the dairy herd health management software used by most Québec dairy producers and their veterinarians. Data were extracted for all lactations starting between January 1st and December 31st, 2010. Using multilevel logistic regression, we analysed a total of 10,529 cows from 201 herds that met the inclusion criteria. Milk fever and displaced abomasum were demonstrated to increase the cow culling risk. A minor general herd effect was found for the culling risk (i.e. an intra-class correlation of 1.0% and median odds ratio [MOR] of 1.20). The proportion of first lactation cows was responsible for this significant, but weak herd effect on individual cow culling risk, after taking into account the cow-level factors. On the other hand, the herd's average milk production was a protective factor. The planning and management of forthcoming replacement animals has to be taken into consideration when assessing cow culling risks and herd culling rates.


Ebselen improves ischemia-reperfusion injury after rat lung transplantation.
The heterocyclic organic compound ebselen (2-phenyl-1,2-benizsoselenazol-3(2H)-one) is a glutathione peroxidase mimick with protective properties against oxidative injury. Ebselen also has anti-inflammatory activity, including attenuation of tumor necrosis factor release and increase of interleukin-10, as shown in vivo, in inflammatory and ischemia-reperfusion injuries, including those of the lung. This study was designed to assess its effect on severe ischemia-reperfusion injury in a model of left-sided rat lung isotransplantation. Orthotopic single left-sided lung allotransplantation (Wistar to Wistar) was performed in female rats after a total ischemic time of 18 h. In nine recipients given 500 mg/kg oral ebselen 1 h before transplantation, graft PaO(2)/FiO(2) was improved 24 h after transplantation, as evidenced with a mean (standard deviation) PaO(2) of 139 (61) mmHg vs. eight controls with 65 (33) mmHg (p = 0.009). Bronchoalveolar PMN count was reduced to approximately 50% in the ebselen group compared with controls, whereas no difference in the tumor necrosis factor content was found. We conclude that the improvement of lung function in ebselen-treated transplanted rats is mainly the result of the anti-inflammatory activity of the drug during reperfusion.


Multiple mechanisms of protein insertion into and across membranes.
Protein localization in cells is initiated by the binding of characteristic leader (signal) peptides to specific receptors on the membranes of mitochondria or endoplasmic reticulum or, in bacteria, to the plasma membrane. There are differences in the timing of protein synthesis and translocation into or across the bilayer and in the requirement for a transmembrane electrochemical potential. Comparisons of protein localization in these different membranes suggest underlying common mechanisms.


An upper arm model for simulated weightlessness.
This investigation examined the effects of 4 weeks of non-dominant arm unloading on the functional and structural characteristics of the triceps brachii muscle of six normo-active college-age males (age: 23 +/- 1 years, height: 176 +/- 4 cm, weight: 76 +/- 6 kg). The primary intention of this study was to determine if arm unloading is an effective analogue for simulating the effects of weightlessness on human skeletal muscle. Subjects were tested 2-3 days preceding unloading in a standard arm sling and following removal of the sling. The sling was worn during waking hours to unload the arm. Subjects were allowed to remove the sling during sleep and bathing. Torque production (Nm) during maximal isometric extension at 90 degrees significantly declined (P < 0.05) in response to unloading (53.93 +/- 5.07 to 47.90 +/- 5.92; 12%). There was no significant change (P > 0.05) in the force-velocity attributes of the triceps over the other measured velocities (1.05, 1.57, 2.09, 3.14, 4.19, 5.24 rad.s-1). Cross-sectional muscle area (CSA) of the upper arm was smaller (44.3 +/- 2.7 to 42.4 +/- 2.5 cm2; 4%) following 4 weeks of unloading (P < 0.05). Histochemical analysis of individual muscle fibres demonstrated reductions in fibre CSA of 27 and 18% for type I and type II fibres, respectively. However, these changes were not statistically significant. Electrophoretic analysis of muscle samples revealed a significant increase (40 +/- 7 to 58 +/- 4%, pre- and post-, respectively) in myosin heavy chain (MHC) type II isoforms following unloading. Reductions in type I MHC isoform composition failed to reach statistical significance (P < 0.08). Amplitude of the integrated electromyographic (IEMG) signal during maximal isometric contraction of the long head of the triceps decreased by 21% in response to the 4-week unloading period (P < 0.05). The changes in triceps, muscle structure and function found with arm unloading are similar in magnitude and direction to data obtained from humans following exposure to real and simulated weightlessness. These findings demonstrate that arm unloading produces some of the effects seen in response to weightlessness in muscles of the upper arm and provides potential for an additional model to simulate the effects of microgravity on human skeletal muscle.


Prolonged cough presenting with diagnostic difficulty: a study of aetiological and clinical outcomes.
Prolonged cough is a common reason for referral to a respiratory physician. Some cases of prolonged cough can be a diagnostic challenge, especially when it is not accompanied by features that suggest common aetiologies. The current study examined this group of patients so as to ascertain the final aetiological and clinical outcomes. We performed a chart review of cases that had been prospectively identified. The inclusion criteria were cough lasting more than three weeks, normal chest radiograph, non-smoking status, no history of angiotensin-converting enzyme inhibitor use, normal physical examination and absence of suggestive features of asthma, gastroesophageal reflux disease and postnasal drip syndrome. We classified the final diagnoses into three categories: likely diagnosis; possible diagnosis; and no diagnosis established, and traced the clinical outcomes. A total of 54 patients met the study criteria. The median duration of cough was 16 weeks (range four weeks to five years), while the median age of the patients was 38 (range 18-73) years. A likely diagnosis was reached in 23 patients and a possible diagnosis, in 12 patients. Gastroesophageal reflux disease and postnasal drip syndrome were the commonest diagnoses. There were no cases of asthma. The cough improved completely in 44 patients. Three cases were lost to follow-up before an outcome could be documented. In most of these cases, a diagnosis could be achieved. The cough improved in the majority of patients, including those in whom a diagnosis could not be made.


Transdisciplinary stakeholder understandings of antimicrobial resistance: An integrative approach in Aotearoa New Zealand.
Antimicrobial resistance (AMR) is a complex public health issue, with a range of influences across human, animal, and environmental health. Given the complexity of the problem, the diversity of stakeholders, and the failure of current policies to curb AMR worldwide, integrative approaches are needed to identify effective actions. Underpinned by systems thinking and One Health principles, this qualitative study explored how diverse AMR experts in Aotearoa New Zealand perceive the main drivers and effects of AMR. Semi-structured interviews with clinical, academic, policy, community, and industry representatives were designed to elicit mental models of the causes and outcomes of AMR across dimensions. Thematic analysis revealed contrasting understandings of AMR causes across four domains: food-producing animals (livestock), healthcare, community, and environment. AMR was often framed as a problem of individual behaviour, despite many implicit references to underlying structural economic influences. The politics of collaboration was a further major underlying theme. The interviews highlighted fundamental connections between AMR and other complex issues, including poverty and environmental pollution. This study brings together the understandings of AMR of transdisciplinary stakeholders, providing some immediate insights for policy makers and setting the foundation for developing a collaborative system model of AMR as a basis for decision-making.


Maternal blood pressures during pregnancy and the risk of delivering a small-for-gestational-age neonate.
To determine the relationship between maternal blood pressures throughout pregnancy and the risk of delivering a small-for-gestational-age (SGA) neonate. Women were prospectively enrolled at 9-14 weeks and had serial blood pressure measurements throughout pregnancy. SGA prevalence was compared to maternal blood pressure at enrollment, average blood pressure during each trimester, and blood pressure trends throughout gestation. Blood pressure was categorized as normotension, prehypertension, or hypertension using Joint National Committee on Hypertension-7 (JNC-7) definitions. Information on preeclampsia prevalence was also obtained due to its frequent concurrence with SGA. A total of 758 women had 8438 blood pressure measurements taken (average 11.1, range 3-14) and 65 (8.6%) delivered an SGA neonate. Forty-two of 514 (8.2%) normotensive women at enrollment and 23/244 (9.4%) women with enrollment prehypertension or hypertension delivered an SGA neonate. Women with persistent hypertensive range blood pressures had an SGA rate 2-3 times higher than other women (p = 0.272) as well as a significantly higher preeclampsia rate (p < 0.001). Women with elevated enrollment blood pressures did not have an increased SGA rate if their blood pressures improved throughout pregnancy. Logistic regression identified enrollment uterine artery Doppler, pregnancy-associated plasma protein-A levels, and ethnicity as primary contributors to SGA. Blood pressure improvement throughout pregnancy decreases the preeclampsia rate without increasing SGA frequency. Theoretical risks of fetal growth delay should not prevent investigations into improved maternal blood pressure control, possibly at thresholds lower than commonly used in obstetric practice, beginning in the first trimester of pregnancy.