High-intensity interval exercise training for public health: a big HIT or shall we HIT it on the head?
The efficacy of high-intensity interval training for a broad spectrum of cardio-metabolic health outcomes is not in question. Rather, the effectiveness of this form of exercise is at stake. In this paper we debate the issues concerning the likely success or failure of high-intensity interval training interventions for population-level health promotion. Biddle maintains that high-intensity interval training cannot be a viable public health strategy as it will not be adopted or maintained by many people. This conclusion is based on an analysis of perceptions of competence, the psychologically aversive nature of high-intensity exercise, the affective component of attitudes, the less conscious elements of motivated behaviour that reflect our likes and dislikes, and analysis using the RE-AIM framework. Batterham argues that this appraisal is based on a constrained and outmoded definition of high-intensity interval training and that truly practical and scalable protocols have been - and continue to be - developed. He contends that the purported displeasure associated with this type of exercise has been overstated. Biddle suggests that the way forward is to help the least active become more active rather than the already active to do more. Batterham claims that traditional physical activity promotion has been a spectacular failure. He proposes that, within an evolutionary health promotion framework, high-intensity interval training could be a successful population strategy for producing rapid physiological adaptations benefiting public health, independent of changes in total physical activity energy expenditure. Biddle recommends that we focus our attention elsewhere if we want population-level gains in physical activity impacting public health. His conclusion is based on his belief that high-intensity interval training interventions will have limited reach, effectiveness, and adoption, and poor implementation and maintenance. In contrast, Batterham maintains that there is genuine potential for scalable, enjoyable high-intensity interval exercise interventions to contribute substantially to addressing areas of public health priority, including prevention and treatment of Type 2 diabetes and cardiovascular disease.


Use of motivational interviewing in behavioural interventions among adults with obesity: A systematic review and meta-analysis.
This review aimed to identify whether motivational interviewing (MI) (a counselling approach for supporting behaviour change [BC]) helps to reduce bodyweight and BMI in an adult obesity context. This included evaluating effectiveness of MI interventions within this population and reporting the methodology used, including theoretical underpinnings and identification of BC and MI techniques. Eight databases were searched using controlled vocabulary. Eligible studies included adults with obesity (BMI ≥30 kg/m2 ), author-reported interventions using MI aiming to reduce body weight or BMI, and comparator groups not receiving an MI intervention. Data extraction and quality appraisal tools were used to identify study characteristics, intervention content was coded for techniques, and random-effects meta-analysis were conducted to investigate effects. Meta-analysis of 12 studies indicated no overall pooled effect on bodyweight and BMI outcomes between intervention and control groups (SMD = -0.01 [95%CI -0.13 to 0.12, P = .93]). Findings were limited by multiple sources accounting for risk of bias, and poor reporting of intervention fidelity and content. Intervention and control content descriptions indicated similar techniques, with social support, goal setting (behaviour) and self-monitoring of behaviour occurring most frequently across both. Findings do not contribute additional evidence for MI use in this context, however methodological limitations were identified which must be resolved to better identify the intervention effects on obesity-related outcomes.


A new physiologic model for dynamic process of creatine kinase activity after acute myocardial infarction and estimation of infarct size.
A new physiologic model for dynamic process of Creatine Kinase (CK) after acute myocardial infarction is proposed. The fundamental hypotheses are tested. The new model is better than the log-normal model in goodness of fit. With this new model, the infarct size of complicated cases with double or multiple peak CK curve can be estimated as well as that of uncomplicated cases. To estimate parameters, a nomographic algorithm and a computer program have been designed. In most cases, the initial values for parameters estimated with Marquardt's method can be determined from individual CK data.


Biophysical investigation of the mode of inhibition of tetramic acids, the allosteric inhibitors of undecaprenyl pyrophosphate synthase.
Undecaprenyl pyrophosphate synthase (UPPS) catalyzes the consecutive condensation of eight molecules of isopentenyl pyrophosphate (IPP) with farnesyl pyrophosphate (FPP) to generate the C(55) undecaprenyl pyrophosphate (UPP). It has been demonstrated that tetramic acids (TAs) are selective and potent inhibitors of UPPS, but the mode of inhibition was unclear. In this work, we used a fluorescent FPP probe to study possible TA binding at the FPP binding site. A photosensitive TA analogue was designed and synthesized for the study of the site of interaction of TA with UPPS using photo-cross-linking and mass spectrometry. The interaction of substrates with UPPS and with the UPPS.TA complex was investigated by protein fluorescence spectroscopy. Our results suggested that tetramic acid binds to UPPS at an allosteric site adjacent to the FPP binding site. TA binds to free UPPS enzyme but not to substrate-bound UPPS. Unlike Escherichia coli UPPS which follows an ordered substrate binding mechanism, Streptococcus pneumoniae UPPS appears to follow a random-sequential substrate binding mechanism. Only one substrate, FPP or IPP, is able to bind to the UPPS.TA complex, but the quaternary complex, UPPS.TA.FPP.IPP, cannot be formed. We propose that binding of TA to UPPS significantly alters the conformation of UPPS needed for proper substrate binding. As the result, substrate turnover is prevented, leading to the inhibition of UPPS catalytic activity. These probe compounds and biophysical assays also allowed us to quickly study the mode of inhibition of other UPPS inhibitors identified from a high-throughput screening and inhibitors produced from a medicinal chemistry program.


Ticagrelor or prasugrel vs. clopidogrel in combination with anticoagulation for treatment of acute coronary syndrome in patients with atrial fibrillation.
For patients with atrial fibrillation (AF) and acute coronary syndrome (ACS), it is often challenging to find the optimal balance between the risk for ischemic and hemorrhagic complication when using both antiplatelet therapy and oral anticoagulation (OAC) with vitamin K antagonist (VKA) or direct oral anticoagulants (DOACs). Current guidelines recommended: (I) double therapy with a P2Y12 inhibitor and dose adjusted VKA is reasonable post-stenting; (II) double therapy with clopidogrel and low-dose rivaroxaban (15 mg daily) may be reasonable post-stenting; (III) double therapy with a P2Y12 inhibitor and dabigatran 150 mg twice daily is reasonable post-stenting. In the AUGUSTUS trial, most patients were given clopidogrel as part a DAPT regimen, however prasugrel and ticagrelor use allowed albeit in a small percentage of the trial population, underestimating its effect. Ticagrelor and prasugrel are known to have a stronger antiplatelet effect compared to clopidogrel, however randomized studies have not been adequately powered to date allowing comparisons between ticagrelor, prasugrel and clopidogrel together in the setting of anticoagulation for the treatment of patients with ACS and AF. Careful consideration should be given to this scenario to avoid falling into the concept of sacrificing efficacy for safety.


Multilocus interactions restrict gene introgression in interspecific populations of polyploid Gossypium (cotton).
Experimental advanced-generation backcross populations contain individuals with genomic compositions similar to those resulting from interspecific hybridization in nature. By applying a detailed restriction fragment length polymorphism (RFLP) map to 3662 BC3F2 plants derived from 24 different BC1 individuals of a cross between Gossypium hirsutum and G. barbadense, large and widespread deficiencies of donor (G. barbadense) chromatin were found, and seven independent chromosomal regions were entirely absent. This skewed chromatin transmission is best accounted for by multilocus epistatic interactions affecting chromatin transmission. The observed frequencies of two-locus genotypes were significantly different from Mendelian expectations about 26 times more often than could be explained by chance (P < or = 0.01). For identical pairs of loci, different two-locus genotypes occurred in excess in different BC3 families, implying the existence of higher-order interlocus interactions beyond the resolution of these data. Some G. barbadense markers occurred more frequently than expected by chance, indicating that genomic interactions do not always favor host chromatin. A preponderance of interspecific allelic interactions involved one locus each in the two different subgenomes of (allotetraploid) Gossypium, thus supporting several other lines of evidence suggesting that intersubgenomic interactions contribute to unique features that distinguish tetraploid cotton from its diploid ancestors.


Reflex modulation of carotid sinus baroreceptor activity in the dog.
Carotid sinus baroreceptor (CBR) sensitivity may be increased by electrical stimulation of sympathetic nerves passing to the carotid sinus region. It remains unknown if reflexly induced changes in efferent sympathetic discharge affect CBR function. In 17 anesthetized dogs, we reflexly induced alterations in sympathetic discharge and recorded CBR activity originating from a vascularly isolated carotid sinus. The stimulus to the baroreceptors was pulsatile with constant mean and pulse pressure. Occlusion of the contralateral common carotid artery (n = 6) resulted in a reflex increase in arterial pressure (116 +/- 10 to 153 +/- 14 mmHg) and an increase (121 +/- 2% of control) in baroreceptor activity (P less than 0.05). Inferior vena caval occlusion (n = 6), which induced a reduction in arterial pressure (145 +/- 19 to 75 +/- 21 mmHg), also provoked an increase (141 +/- 10% of control) in baroreceptor discharge (P less than 0.05). Raising pressure (to 200 mmHg) in the contralateral carotid sinus (n = 7) resulted in a reflex decrease in arterial pressure (169 +/- 16 to 129 +/- 13 mmHg) and a reduction (82 +/- 3% of control) in baroreceptor activity (P less than 0.05). The changes in baroreceptor discharge were abolished by ipsilateral cervical sympathectomy or ganglionic blockade (n = 4). Our findings demonstrate that reflexly induced alterations in the activity of sympathetic fibers innervating the carotid sinuses can modulate baroreceptor discharge.


Early postnatal development of laminar characteristics in the dorsal lateral geniculate nucleus of the tree shrew.
Three characteristics distinguish the six layers of the adult tree shrew dorsal lateral geniculate nucleus (LGN). First, interlaminar spaces divide the nucleus into cell layers. Second, input from the two eyes projects to the nucleus such that two layers (1 and 5) receive input from the ipsilateral retinal and four layers (2, 3, 4, and 6) receive input from the contralateral retina. Finally, distinct cytological features characterize individual layers. In this report, we describe the postnatal development of LGN layers in the tree shrew in terms of the development of these three characteristics. At birth, the nucleus appears homogenous in Nissl-stained sections. Thus, no interlaminar spaces are present and all cells look similar in shape, size, and staining intensity. However, autoradiographic data show that, at birth, retinal afferents are segregated in an adult-like pattern. Interlaminar spaces begin to be evident between layers innervated by opposite eyes on postnatal day 2. Several days later, interlaminar spaces between layers innervated by the same eye (i.e., the borders of layer 3) appear, while the others continue to widen. Although some cytological maturation begins before interlaminar space formation, it is not until interlaminar spaces are apparent that features such as differential staining intensity and cell size can be used to distinguish individual layers. The results suggest that the three characteristics that define LGN layers in the tree shrew may be temporally separate events in the developing nucleus. Thus, retinal afferents are segregated prior to interlaminar space formation which, in turn, is initiated prior to final maturation of the cytological features that characterize the cell layers. This may indicate a degree of developmental independence among these maturational events.


Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria.
Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. We report that in significant human pathogens Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia spp., the differences in antibiotic resistance are largely defined by their penetration into the cell. For all tested antibiotics, the intracellular penetration was determined by a synergistic relationship between active efflux and the permeability barrier. We found that the outer membrane (OM) and efflux pumps select compounds on the basis of distinct properties and together universally protect bacteria from structurally diverse antibiotics. On the basis of their interactions with the permeability barriers, antibiotics can be divided into four clusters that occupy defined physicochemical spaces. Our results suggest that rules of intracellular penetration are intrinsic to these clusters. The identified specificities in the permeability barriers should help in the designing of successful therapeutic strategies against antibiotic-resistant pathogens.IMPORTANCE Multidrug-resistant strains of Gram-negative pathogens rapidly spread in clinics. Significant efforts worldwide are currently directed to finding the rules of permeation of antibiotics across two membrane envelopes of these bacteria. This study created the tools for analysis of and identified the major differences in antibacterial activities that distinguish the permeability barriers of P. aeruginosa, A. baumannii, Burkholderia thailandensis, and B. cepacia We conclude that synergy between active efflux and the outer membrane barrier universally protects Gram-negative bacteria from antibiotics. We also found that the diversity of antibiotics affected by active efflux and outer membrane barriers is broader than previously thought and that antibiotics cluster according to specific biological determinants such as the requirement of specific porins in the OM, targeting of the OM, or specific recognition by efflux pumps. No universal rules of antibiotic permeation into Gram-negative bacteria apparently exist. Our results suggest that antibiotic clusters are defined by specific rules of permeation and that further studies could lead to their discovery.


Effect of Substrate Conversion on Performance of Microbial Fuel Cells and Anodic Microbial Communities.
Performance of microbial fuel cells (MFCs) was monitored during the influent nutrient change from lactate to glucose/acetate/propionate and then to lactate. Meanwhile, anodic microbial communities were characterized by culture-independent molecular biotechnologies. Results showed MFC performance recovered rapidly when the lactate was replaced by one of its metabolic intermediates acetate, while it needed a longer time to recover if lactate substrate was converted to glucose/propionate or acetate to lactate. Secondary lactate feed enhanced the enrichment of bacterial populations dominating in first lactate feed. Electricity-producing bacteria, Geobacter spp., and beneficial helpers, Anaeromusa spp. and Pseudomonas spp., revived from a low abundance as lactate secondary supply, but microbial communities were hard to achieve former profiles in structure and composition. Hence, microbial community profiles tended to recover when outside environmental condition were restored. Different substrates selected unique functional microbial populations.


In Vitro Inhibition of Phosphodiesterase 3B (PDE 3B) by Anthocyanin-Rich Fruit Juice Extracts and Selected Anthocyanins.
Phosphodiesterases (PDEs) are essential enzymes for the regulation of pathways mediated by cyclic adenosine monophosphate (cAMP). Secondary plant compounds like anthocyanins (ACs) can inhibit PDE activity and, consequently, may be beneficial for lipid metabolism. This study investigated 18 AC-rich juice extracts and pure reference compounds from red fruits for potential inhibitory effects on PDE 3B activity. Extracts were obtained through adsorption on Amberlite® XAD 7 resin. Based on this screening, the chokeberry, blueberry, pomegranate, and cranberry extracts were active, with half maximal inhibitory concentrations (IC50) ranging from 163 ± 3 µg/mL to 180 ± 3 µg/mL. The ACs in these extracts, peonidin-3-glucoside and cyanidin-3-arabinoside, were the most active single compounds (IC50 = 56 ± 20 µg/mL, 108 ± 6 µg/mL). All extracts comprised high amounts of phenolic compounds, as determined by the Folin-Ciocalteu assay, ranging from 39.8 ± 1.5 to 73.5 ± 4.8 g gallic acid equivalents (GAE)/100 g extract. Pomegranate and chokeberry extracts exhibited the largest amounts of polyphenols (72.3 ± 0.7 g GAE/100 g, 70.6 ± 4.1 g GAE/100 g, respectively). Overall, our results showed that fruit juice extracts and their ACs can inhibit PDE activity. Any potential health benefits in vivo will be investigated in the future.


[Retinal ganglion cell neuroprotection in culture].
To study the pig retinal ganglion cell (RGC) survival in culture, analysing the possible neuroprotective effect of retinal Müller glia (RMG) and brain-derived neurotrophic factor (BDNF). Adult pig retina were dissociated and cultured under different conditions: 1) on laminin/poly-D-lysine-coated coverslips in chemically defined medium (CDM); 2) on laminin/poly-D-lysine-coated coverslips in CMD supplemented with BDNF; 3) on confluent monolayer cultures of RMG in CDM; 4) on laminin/poly-D-lysine substrate in conditioned medium obtained from RMG. RGCs were identified by immunocytochemistry using antibody against 68 kDa neurofilament and observed under an fluorescent microscope. RGCs were classified on the basis of the size, number and length of neurites, and their survival was assayed for each treatment. Confluent RMG substrates and RMG conditioned medium significantly increased the survival of cultured pig RGC. Moreover these two conditions increased the mean area of RGCs and enhanced neurite growth and elongation. Addition of BDNF to culture medium did not modify survival but increased RGC size, neurite number and neurite length. These findings demonstrate that factor(s) secreted by RMG exert beneficial effects on adult RGC survival and neurite regeneration in vitro, and might constitute important agent(s) for RGC neuroprotection. BDNF also increases the mean area of RGCs and enhances neurite growth but it does not increase the survival of RGCs.


Proteolytic processing of the Aplysia egg-laying hormone and R3-14 neuropeptide precursors.
A number of animal behaviors are influenced by the actions of neuropeptides that arise from the processing of complex protein precursors. In this report we investigate the proteolytic processing of neuropeptide precursors expressed in the Aplysia californica bag cells, which govern egg-laying, and neurons R3-14, which mediate aspects of cardiac output. Peptides were purified by fractionation on 2 high-pressure liquid chromatography systems followed by determination of amino acid compositions. Most of these compositions are indicative of processing products derived from the egg-laying hormone (ELH) and R3-14 precursors by cleavage at basic residues. We characterized 9 peptides that arise from the ELH precursor by cleavage of the signal sequence, as well as 7 out of 8 dibasic residues and at least 1 single Arg residue. The peptides range in size from 5 to about 60 amino acids. The R3-14 neuropeptide precursor is cleaved at 2 internal dibasic residues in addition to the signal sequence, resulting in 3 peptides. Shortened forms of several peptides probably result from amino- and carboxy-terminal peptidase action. It is likely that the complex mixtures of neuropeptides arising from these single protein precursors are co-secreted.


α-Galactosylceramide and its analog OCH differentially affect the pathogenesis of ISO-induced cardiac injury in mice.
Immunotherapies for cancers may cause severe and life-threatening cardiotoxicities. The underlying mechanisms are complex and largely elusive. Currently, there are several ongoing clinical trials based on the use of activated invariant natural killer T (iNKT) cells. The potential cardiotoxicity commonly associated with this particular immunotherapy has yet been carefully evaluated. The present study aims to determine the effect of activated iNKT cells on normal and β-adrenergic agonist (isoproterenol, ISO)-stimulated hearts. Mice were treated with iNKT stimulants, α-galactosylceramide (αGC) or its analog OCH, respectively, to determine their effect on ISO-induced cardiac injury. We showed that administration of αGC (activating both T helper type 1 (Th1)- and T helper type 2 (Th2)-liked iNKT cells) significantly accelerated the progressive cardiac injury, leading to enhanced cardiac hypertrophy and cardiac fibrosis with prominent increases in collagen deposition and TGF-β1, IL-6, and alpha smooth muscle actin expression. In contrast to αGC, OCH (mainly activating Th2-liked iNKT cells) significantly attenuated the progression of cardiac injury and cardiac inflammation induced by repeated infusion of ISO. Flow cytometry analysis revealed that αGC promoted inflammatory macrophage infiltration in the heart, while OCH was able to restrain the infiltration. In vitro coculture of αGC- or OCH-pretreated primary peritoneal macrophages with primary cardiac fibroblasts confirmed the profibrotic effect of αGC and the antifibrotic effect of OCH. Our results demonstrate that activating both Th1- and Th2-liked iNKT cells is cardiotoxic, while activating Th2-liked iNKT cells is likely cardiac protective, which has implied key differences among subpopulations of iNKT cells in their response to cardiac pathological stimulation.


Exploration of the Synergy Between 2D Nanosheets and a Non-2D Filler in Mixed Matrix Membranes for Gas Separation.
Dual-filler MMMs have attracted special interests in recent years because of the possibility of producing synergetic effect. This study is aimed at exploring the underlying synergy between two-dimensional (2D) nanosheets and a non-2D filler in mixed matrix membranes for gas separation. MXene or graphene oxide (GO) as typical nanosheet filler is selected to be in pair with a non-2D filler, SiO2 or halloysite nanotubes (HNTs), with Pebax as the polymer matrix. In this way, four pairs of binary fillers are designed and the corresponding four groups of MMMs are fabricated. By tuning the mass ratio of binary fillers, synergetic effect is found for each group of MMMs. However, the two 2D fillers found different preferential non-2D partners. GO works better with HNTs than SiO2, while MXene prefers SiO2 to HNTs. To be noted, GO/HNTs renders the membranes the maximum enhancement of CO2 permeability (153%) and CO2/N2 selectivity (72%) compared to Pebax control membrane, while each of them as single filler only brought about very limited enhancement of CO2 separation performance. The possible mechanisms are thoroughly discussed in terms of filler dispersion, nanosheet flexibility, and the tortuosity and connectivity of the surface diffusion pathways along nanosheets.


The Brazilian version of the Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity in dementia.
Patients with dementia may be unable to describe their symptoms, and caregivers frequently suffer emotional burden that can interfere with judgment of the patient's behavior. The Neuropsychiatric Inventory-Clinician rating scale (NPI-C) was therefore developed as a comprehensive and versatile instrument to assess and accurately measure neuropsychiatric symptoms (NPS) in dementia, thereby using information from caregiver and patient interviews, and any other relevant available data. The present study is a follow-up to the original, cross-national NPI-C validation, evaluating the reliability and concurrent validity of the NPI-C in quantifying psychopathological symptoms in dementia in a large Brazilian cohort. Two blinded raters evaluated 312 participants (156 patient-knowledgeable informant dyads) using the NPI-C for a total of 624 observations in five Brazilian centers. Inter-rater reliability was determined through intraclass correlation coefficients for the NPI-C domains and the traditional NPI. Convergent validity included correlations of specific domains of the NPI-C with the Brief Psychiatric Rating Scale (BPRS), the Cohen-Mansfield Agitation Index (CMAI), the Cornell Scale for Depression in Dementia (CSDD), and the Apathy Inventory (AI). Inter-rater reliability was strong for all NPI-C domains. There were high correlations between NPI-C/delusions and BPRS, NPI-C/apathy-indifference with the AI, NPI-C/depression-dysphoria with the CSDD, NPI-C/agitation with the CMAI, and NPI-C/aggression with the CMAI. There was moderate correlation between the NPI-C/aberrant vocalizations and CMAI and the NPI-C/hallucinations with the BPRS. The NPI-C is a comprehensive tool that provides accurate measurement of NPS in dementia with high concurrent validity and inter-rater reliability in the Brazilian setting. In addition to universal assessment, the NPI-C can be completed by individual domains.


Probing the Nanoscale Heterogeneous Mixing in a High-Performance Polymer Blend.
The blend of polyetheretherketone (PEEK) and polybenzimidazole (PBI) produces a high-performance blend (PPB) that is a potential replacement material in several industries due to its high temperature stability and desirable tribological properties. Understanding the nanoscale structure and interface of the two domains of the blend is critical for elucidating the origin of these desirable properties. Whilst achieving the physical characterisation of the domain structures is relatively uncomplicated, the elucidation of structures at the interface presents a significant experimental challenge. In this work, we combine atomic force microscopy (AFM) with an IR laser (AFM-IR) and thermal cantilever probes (nanoTA) to gain insights into the chemical heterogeneity and extent of mixing within the blend structure for the first time. The AFM-IR and nanoTA measurements show that domains in the blend are compositionally different from those of the pure PEEK and PBI polymers, with significant variations observed in a transition region several microns wide in proximity to domain boundary. This strongly points to physical mixing of the two components on a molecular scale at the interface. The versatility intrinsic to the combined methodology employed in this work provides nano- and microscale chemical information that can be used to understand the link between properties of different length scales across a wide range of materials.


A functional analysis of recombinant soluble CD46 in vivo and a comparison with recombinant soluble forms of CD55 and CD35 in vitro.
The human cell surface complement regulatory proteins CD46 (MCP), CD55 (DAF) and CD35 (CR1) protect autologous cells from complement-mediated damage by inhibiting C3 and C5 convertases. This regulatory potential has previously been exploited in the treatment of some models of inflammatory injury by the generation of recombinant soluble (rs) proteins, such as rsCD55 and rsCD35 . More recently, we have shown that rsCD46 inhibits complement activation in the fluid phase. In this report, the ability of rsCD46, rsD55 and rsCD35 to regulate human complement activation mediated by the classical pathway in vitro was clearly demonstrated by all three soluble proteins; however, rsCD35 was a more effective inhibitor than either rsCD46 or rsCD55. A combination of rsCD46+ rsCD55 was more potent than either of these proteins alone. Cell lysis via alternative pathway activation in vitro was efficiently regulated by rsCD46 and rsCD35 to a similar extent, whereas rsCD55 was not effective. Assays of rsCD46 in vivo have previously not been possible due to difficulties in expressing sufficient quantities of protein. This limitation has been overcome and now we report the ability of rsCD46 to inhibit immune complex-mediated inflammation in a rat using the reverse passive Arthus reaction model. Administration of rsCD46 significantly reduced the size of lesion, and histological examination showed a reduction in inflammatory infiltrate and edema. These data suggest that rsCD46, in addition to rsCd55 and rsCD35, may be useful a therapeutic agent.


Joint probabilistic-logical refinement of multiple protein feature predictors.
Computational methods for the prediction of protein features from sequence are a long-standing focus of bioinformatics. A key observation is that several protein features are closely inter-related, that is, they are conditioned on each other. Researchers invested a lot of effort into designing predictors that exploit this fact. Most existing methods leverage inter-feature constraints by including known (or predicted) correlated features as inputs to the predictor, thus conditioning the result. By including correlated features as inputs, existing methods only rely on one side of the relation: the output feature is conditioned on the known input features. Here we show how to jointly improve the outputs of multiple correlated predictors by means of a probabilistic-logical consistency layer. The logical layer enforces a set of weighted first-order rules encoding biological constraints between the features, and improves the raw predictions so that they least violate the constraints. In particular, we show how to integrate three stand-alone predictors of correlated features: subcellular localization (Loctree [J Mol Biol 348:85-100, 2005]), disulfide bonding state (Disulfind [Nucleic Acids Res 34:W177-W181, 2006]), and metal bonding state (MetalDetector [Bioinformatics 24:2094-2095, 2008]), in a way that takes into account the respective strengths and weaknesses, and does not require any change to the predictors themselves. We also compare our methodology against two alternative refinement pipelines based on state-of-the-art sequential prediction methods. The proposed framework is able to improve the performance of the underlying predictors by removing rule violations. We show that different predictors offer complementary advantages, and our method is able to integrate them using non-trivial constraints, generating more consistent predictions. In addition, our framework is fully general, and could in principle be applied to a vast array of heterogeneous predictions without requiring any change to the underlying software. On the other hand, the alternative strategies are more specific and tend to favor one task at the expense of the others, as shown by our experimental evaluation. The ultimate goal of our framework is to seamlessly integrate full prediction suites, such as Distill [BMC Bioinformatics 7:402, 2006] and PredictProtein [Nucleic Acids Res 32:W321-W326, 2004].


Rapid Detection of Recurrent Non-Muscle Invasive Bladder Cancer in Urine Using ATR-FTIR Technology.
Non-muscle Invasive Bladder Cancer (NMIBC) accounts for 80% of all bladder cancers. Although it is mostly low-grade tumors, its high recurrence rate necessitates three-times-monthly follow-ups and cystoscopy examinations to detect and prevent its progression. A rapid liquid biopsy-based assay is needed to improve detection and reduce complications from invasive cystoscopy. Here, we present a rapid spectroscopic method to detect the recurrence of NMIBC in urine. Urine samples from previously-diagnosed NMIBC patients (n = 62) were collected during their follow-up visits before cystoscopy examination. Cystoscopy results were recorded (41 cancer-free and 21 recurrence) and attenuated total refraction Fourier transform infrared (ATR-FTIR) spectra were acquired from urine samples using direct application. Spectral processing and normalization were optimized using parameter grid searching. We assessed their technical variability through multivariate analysis and principal component analysis (PCA). We assessed 35 machine learning models on a training set (70%), and the performance was evaluated on a held-out test set (30%). A Regularized Random Forests (RRF) model achieved a 0.92 area under the receiver operating characteristic (AUROC) with 86% sensitivity and 77% specificity. In conclusion, our spectroscopic liquid biopsy approach provides a promising technique for the early identification of NMIBC with a less invasive examination.


Schwann cells, but not Oligodendrocytes, Depend Strictly on Dynamin 2 Function.
Myelination requires extensive plasma membrane rearrangements, implying that molecules controlling membrane dynamics play prominent roles. The large GTPase dynamin 2 (DNM2) is a well-known regulator of membrane remodeling, membrane fission, and vesicular trafficking. Here, we genetically ablated Dnm2 in Schwann cells (SCs) and in oligodendrocytes of mice. Dnm2 deletion in developing SCs resulted in severely impaired axonal sorting and myelination onset. Induced Dnm2 deletion in adult SCs caused a rapidly-developing peripheral neuropathy with abundant demyelination. In both experimental settings, mutant SCs underwent prominent cell death, at least partially due to cytokinesis failure. Strikingly, when Dnm2 was deleted in adult SCs, non-recombined SCs still expressing DNM2 were able to remyelinate fast and efficiently, accompanied by neuropathy remission. These findings reveal a remarkable self-healing capability of peripheral nerves that are affected by SC loss. In the central nervous system, however, we found no major defects upon Dnm2 deletion in oligodendrocytes.


Garlic essential oil protects against obesity-triggered nonalcoholic fatty liver disease through modulation of lipid metabolism and oxidative stress.
This study investigated the protective properties of garlic essential oil (GEO) and its major organosulfur component (diallyl disulfide, DADS) against the development of nonalcoholic fatty liver disease (NAFLD). C57BL/6J mice were fed a normal or high-fat diet (HFD) with/without GEO (25, 50, and 100 mg/kg) or DADS (10 and 20 mg/kg) for 12 weeks. GEO and DADS dose-dependently exerted antiobesity and antihyperlipidemic effects by reducing HFD-induced body weight gain, adipose tissue weight, and serum biochemical parameters. Administration of 50 and 100 mg/kg GEO and 20 mg/kg DADS significantly decreased the release of pro-inflammatory cytokines in liver, accompanied by elevated antioxidant capacity via inhibition of cytochrome P450 2E1 expression during NAFLD development. The anti-NAFLD effects of GEO and DADS were mediated through down-regulation of sterol regulatory element binding protein-1c, acetyl-CoA carboxylase, fatty acid synthase, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase, as well as stimulation of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1. These results demonstrate that GEO and DADS dose-dependently protected obese mice with long-term HFD-induced NAFLD from lipid accumulation, inflammation, and oxidative damage by ameliorating lipid metabolic disorders and oxidative stress. The dose of 20 mg/kg DADS was equally as effective in preventing NAFLD as 50 mg/kg GEO containing the same amount of DADS, which demonstrates that DADS may be the main bioactive component in GEO.


Primary care patients' expectations regarding medical appointments and their experiences during a visit: does age matter?
There is evidence that meeting patients' expectations toward health care correlates with involvement in the treatment they receive. The most important patient expectations concern certain types of information: explanation of disease and treatment, health promotion, and improvement in quality of life. Other demands include proper rapport and emotional support. The aim of this paper was to examine different patient groups over the age of 50 years and their expectations toward medical visits, evaluated before a visit and after the visit. The study group consisted of 4,921 primary health-care patients. The patients received self-administered questionnaires that they filled in before and after the appointment with the doctor. Interviews with patients were conducted individually by specially trained interviewers. The PRACTA Patient Expectations Scale was used to measure the appointment-related expectations of the patients. We observed differences related to age in patients' expectations before medical visits regarding the following factors: disease explanation, treatment explanation, quality of life, rapport, and emotional support. The same differences were not observed on health promotion. Evaluation of patients' appointment-related experiences after the visit showed that there were significant differences between the age-groups regarding all types of expectations included in the study. Differences between previsit and postvisit measurements were statistically significant in all age-groups. Patients who received less than they expected from doctors outnumbered those who received what they expected or more in all the groups. Patients' expectations toward medical visits are conditioned by age. Therefore, doctors should pay more attention to requirements related to age in their effort to identify and satisfy expectations. This is particularly important in light of the discrepancy between previsit expectations and the actual experiences of patients evaluated after the visit.


Cerebral hemodynamics during treatment with sodium nitroprusside versus labetalol in malignant hypertension.
In patients with malignant hypertension, immediate blood pressure reduction is indicated to prevent further organ damage. Because cerebral autoregulatory capacity is impaired in these patients, a pharmacologically induced decline of blood pressure reduces cerebral blood flow with the danger of cerebral hypoperfusion. We compared the reduction in transcranial Doppler-determined middle cerebral artery blood velocity during blood pressure lowering with sodium nitroprusside with that of labetalol. Therefore, in 15 patients, fulfilling World Health Organization criteria for malignant hypertension, beat-to-beat mean arterial pressure, systemic vascular resistance (Modelflow), mean middle cerebral artery blood velocity, and cerebrovascular resistance index (mean blood pressure:mean middle cerebral artery blood flow velocity ratio), were monitored during treatment with sodium nitroprusside (n=8) or labetalol (n=7). The reduction in mean arterial blood pressure with sodium nitroprusside (-28+/-3%; mean+/-SEM) and labetalol (-28+/-4%) was comparable. With labetalol, both systemic and cerebral vascular resistance decreased proportionally (-13+/-10% and -17+/-5%), whereas with sodium nitroprusside, the decline in systemic vascular resistance was larger than that in cerebral vascular resistance (-53+/-4% and -7+/-4%). The rate of reduction in middle cerebral artery blood velocity was smaller with labetalol than with sodium nitroprusside (0.45+/-0.05% versus 0.78+/-0.04% cm.s(-1).%mm Hg(-1); P<0.05). In conclusion, sodium nitroprusside reduced systemic vascular resistance rather than cerebral vascular resistance with a larger rate of reduction in middle cerebral artery blood velocity, suggesting a preferential blood flow to the low resistance systemic vascular bed rather than the cerebral vascular bed.


Evaluation of the Auxotab Enteric 1 System for identification of Enterobacteriaceae.
An evaluation of the accuracy and convenience of the Auxotab Enteric 1 System for identification of Enterobacteriaceae was performed with 160 bacteria. Identification at the species level was correct in 134 (83.8%) instances and at the generic level in 144 (90%) instances. Sixty strains failed to achieve the minimal concentration of organisms required to complete the identification process within 7 hr. The system was judged to be laborious and to present a potential hazard to those working with it.


Persistent expression of CD94/NKG2 receptors by virus-specific CD8 T cells is initiated by TCR-mediated signals.
Subsets of CD8 T cells express receptors that are critical in regulating the activity of NK cells. To characterize the expression of these receptors on CD8 T cells we made use of transgenic mice that express a H-2Kb restricted TCR specific for the immunodominant epitope located within the HSV-1 glycoprotein B (gB). Few naive gB-specific T cells express Ly49 or CD94/NKG2 receptors. Following acute infection of C57BL/6 mice with either HSV-1 or a recombinant influenza virus that encodes the gB determinant, gB-specific T cells showed a dramatic upregulation of CD94/NKG2 receptors. Moreover, gB-specific CD8 T cells that expressed CD94/NKG2 receptors were also found to express another NK receptor, KLRG1. We established that while Ag-stimulated gB-specific CD8 T cells primarily express inhibitory isoforms of CD94/NKG2 receptors, these cells remain capable of producing gammaIFN upon peptide stimulation. While peak CD94/NKG2 expression on gB-specific cells was reached 2-3 days following infection, it remained elevated beyond 60 days post-infection with either HSV-1 or a gB-expressing recombinant influenza virus. The data imply that the prolonged expression was not due to persistence of replicating virus and suggest that while recognition of the cognate Ag is necessary to trigger expression of CD94/NKG2 receptors, it is not required for their continued expression on memory T cells.


Neural Oscillations and a Nascent Corticohippocampal Theory of Reference.
The ability to use words to refer to the world is vital to the communicative power of human language. In particular, the anaphoric use of words to refer to previously mentioned concepts (antecedents) allows dialogue to be coherent and meaningful. Psycholinguistic theory posits that anaphor comprehension involves reactivating a memory representation of the antecedent. Whereas this implies the involvement of recognition memory or the mnemonic subroutines by which people distinguish old from new, the neural processes for reference resolution are largely unknown. Here, we report time-frequency analysis of four EEG experiments to reveal the increased coupling of functional neural systems associated with referentially coherent expressions compared with referentially problematic expressions. Despite varying in modality, language, and type of referential expression, all experiments showed larger gamma-band power for referentially coherent expressions compared with referentially problematic expressions. Beamformer analysis in high-density Experiment 4 localized the gamma-band increase to posterior parietal cortex around 400-600 msec after anaphor onset and to frontotemporal cortex around 500-1000 msec. We argue that the observed gamma-band power increases reflect successful referential binding and resolution, which links incoming information to antecedents through an interaction between the brain's recognition memory networks and frontotemporal language network. We integrate these findings with previous results from patient and neuroimaging studies, and we outline a nascent corticohippocampal theory of reference.


Functional correlation of trophinin expression with the malignancy of testicular germ cell tumor.
Trophinin is a membrane protein that is potentially involved in human embryo implantation by mediating homophillic cell adhesion between trophoblastic cells and endometrial cells. Trophinin expression by maternal cells may be induced by the embryo that secretes human chorionic gonadotropin (hCG). Because the process of tumor metastasis resembles that of trophoblast invasion and proliferation during embryo implantation, we hypothesized that testicular cancers that synthesize hCG express trophinin thus becoming aggressive trophoblast-like cells. We screened paraffin-embedded orchiectomy specimens of 158 patients with testicular germ cell tumor by immunohistochemistry using antitrophinin antibody. This screening identified trophinin-positive specimens with the frequencies 39 of 91 (43%) in stage I, 14 of 24 (58%) in stage II, and 41 of 43 (95%) in stage III (P < 0.001). Thus, trophinin expression positively correlates with clinical stage. Remarkably, trophinin was found in all of the cases (33 of 33) with lung metastasis. The levels of serum hCG-beta were significantly higher in the patients with trophinin-positive tumors than those with trophinin-negative tumors (P = 0.004). To determine whether trophinin promotes aggressiveness of the cell, trophinin-negative human seminona cell line JKT-1 was stably transfected with a mammalian expression vector containing trophinin cDNA. In vitro assays revealed that trophinin-expressing JKT-1-Tro cells are more invasive than JKT-1-mock cells, whereas there are no differences between JKT-1-Tro and JKT-1-mock in their proliferation activity. Upon orthotopic inoculation to athymic nude mice, JKT-1-Tro cells exhibited i.p. metastases in all of the mice (n = 5), whereas JKT-1-mock produced no metastases (n = 5). These results suggest strongly that trophinin enhances invasiveness of the cells and promotes metastasis of testicular germ cell tumor.


Study of acute localised inflammation of the gastrointestinal tract: the effluent lymph.
The effect of localised acute inflammation, produced by a small intestinal anastomosis on the effluent lymph of the gastrointestinal tract and on the efferent lymph of the mesenteric lymph glands has been studied in rats. There is a progressive increase in the output of lymph from the gastrointestinal tract in rats with an intact anastomosis, but a decreased output in animals with a disrupted anastomosis causing either generalised peritonitis or a localised para-anastomotic abscess. The total white cell output is increased on the second day after constructing an intact intestinal anastomosis and this increase is principally due to neutrophil polymorphonuclear leucocytes. The neutrophil polymorphonuclear leucocyte response is prolonged, but has returned to normal values at four weeks. Although the output of cells of the mononuclear phagocytic series which are esterase positive is increased it is not statistically significant. An intact anastomosis does not produce any alteration in the lymphocyte output. The neutrophil polymorphonuclear leucocyte response to an intestinal anastomosis is decreased by a factor of two and the non-lymphocytic non-specific esterase positive cell response is decreased by a factor of six by the mesenteric lymph glands which may be functioning in a 'filtering' capacity dealing with agents originating at the anastomosis and noxious to the body,


Capillary hemangioma of the scrotum mimicking an epididymal tumor: case report.
We report a case of capillary hemangioma of the scrotum. A 52-year-old male presented with a left scrotum swelling that had arisen suddenly two months before. Scrotal ultrasound revealed a dishomogeneous mass in the left scrotum. The mass demonstrated blood flow in the color Doppler mode. Scrotal mass excision was performed. Pathological evaluation revealed a capillary hemangioma.


Service area size assessment for evaluating the spatial scale of solid waste recovery chains: A territorial perspective.
Waste recovery is an integrated part of municipal solid waste management systems but its strategic planning is still challenging. In particular, the service area size of facilities is a sensitive issue since its calculation depends on various factors related to treatment technologies (output products) and territorial features (sources waste production and location). This work presents a systemic approach for the estimation of a chain's service area size, based on a balance between costs and recovery profits. The model assigns a recovery performance value to each source, which can be positive, neutral or negative. If it is positive, the source should be included in the facility's service area. Applied to the case of Montreal for food waste recovery by anaerobic digestion, the approach showed that at most 23 out of the 30 districts should be included in the service area, depending on the indicator, which represents around 127,000 t of waste recovered/year. Due to the systemic approach, these districts were not necessarily the closest to the facility. Moreover, for the Montreal case, changing the facility's location did not have a great influence on the optimal service area size, showing that the distance to the facility was not a decisive factor at this scale. However, replacing anaerobic digestion by a composting plant reduced the break-even transport distances and, thus, the number of sources worth collecting (around 68,500 t/year). In this way, the methodology, applied to different management strategies, gave a sense of the spatial dynamics involved in the recovery chain's design. The map of optimal supply obtained could be used to further analyse the feasibility of multi-site and/or multi-technology systems for the territory considered.


Show me the child at seven: the consequences of conduct problems in childhood for psychosocial functioning in adulthood.
This paper seeks to extend research into the adult sequelae of childhood conduct problems by investigating the associations between conduct problems in middle childhood and psychosocial outcomes in adulthood. Data were gathered during the course of a 25-year longitudinal study of a birth cohort of New Zealand young people. Information was collected on: a) parent and teacher reports of child conduct problems at ages 7, 8 and 9 years; b) measures of crime, substance use, mental health, sexual/partner relationships, education/employment; c) confounding factors, including childhood, family and educational characteristics. There were statistically significant associations between childhood conduct problems from 7-9 years and risks of adverse outcomes across all domains of functioning. After control for confounding factors the associations between conduct problems and education/employment outcomes became statistically non-significant. Associations persisted for other outcomes (crime, substance dependence, mental health and sexual/partner relationships). Children in the most disturbed 5% of the cohort had rates of these outcomes that were between 1.5 and 19 times higher than rates for the least disturbed 50% of the cohort. The associations between conduct problems and adult outcomes were similar for males and females. Childhood conduct problems were associated with a wide range of adverse psychosocial outcomes (crime, substance use, mental health, sexual/partner relationships) even after control for confounding factors. The results reinforce the need for greater investment into interventions to address these problems.


The science of making drug-addicted animals.
Research involving animal models of drug addiction can be viewed as a sort of reverse psychiatry. Contrary to clinicians who seek to treat addicted people to become and remain abstinent, researchers seek to make drug-naïve animals addicted to a drug with known addictive properties in humans. The goals of this research are to better understand the neuroscience of drug addiction and, ultimately, to translate this knowledge into effective treatments for people with addiction. The present review will not cover the vast literature that has accumulated over the past 50 years on animal models of drug addiction. It is instead more modestly devoted to recent research spanning the past decade on drug self-administration-based models of addiction in the rat (the animal species most frequently used in the field), with a special focus on current efforts to model compulsive cocaine use as opposed to nonaddictive use. Surprisingly, it turns out that modeling compulsive cocaine use in rats is possible but more difficult than previously thought. In fact, it appears that resilience to cocaine addiction is the norm in rats. As in human cocaine users, only few individual rats would be vulnerable. This conclusion has several important implications for future research on the neuroscience of cocaine addiction and on preclinical medication development.


A new era of atopic eczema research: Advances and highlights.
Atopic eczema (AE) is an inflammatory skin disease with involvement of genetic, immunological and environmental factors. One hallmark of AE is a skin barrier disruption on multiple, highly interconnected levels: filaggrin mutations, increased skin pH and a microbiome dysbiosis towards Staphylococcus aureus overgrowth are observed in addition to an abnormal type 2 immune response. Extrinsic factors seem to play a major role in the development of AE. As AE is a first step in the atopic march, its prevention and appropriate treatment are essential. Although standard therapy remains topical treatment, powerful systemic treatment options emerged in the last years. However, thorough endotyping of the individual patients is still required for ideal precision medicine approaches in future. Therefore, novel microbial and immunological biomarkers were described recently for the prediction of disease development and treatment response. This review summarizes the current state of the art in AE research.


Liver transplantation.
From March 1963 through June 1976, 111 patients received orthotopic liver homografts. Forty-two of the recipients had congenital biliary atresia. Other common diagnoses were chronic aggressive hepatitis, Laennec's cirrhosis, and primary hepatic malignancy. There were also other assorted, less common diagnoses. Thirty-one of the 111 patients (28%) lived at least one year and 15 are still alive with follow-ups of 2 1/2 to 8 1/2 years. Seven of the patients lived for more than five years, and 6 of these 7 are still alive. In 1975 and 1976, clinical-pathologic correlations on all these patients were carried out with Professor K.A. Porter of London. The most common causes for failure were technical misadventures, including biliary tract problems, vascular thromboses, and the use of ischemically damaged livers. Rejection was less of a problem than had been realized. In view of these findings, improvements in intraoperative and postoperative management were made with particular reference to biliary tract drainage and to the use of microvascular techniques. Treatment of a new series of 30 patients was begun in July 1976, and completed in December 1977. After 6 to 22 months, 15 of the 30 most recently treated patients are alive, all living outside the hospital. Thus, the outlook after transplantation appears to have greatly improved, and a one-year survival rate of 50% is projected.


Palliative care nurses' views on euthanasia.
In debates on euthanasia legalization in Belgium, the voices of nurses were scarcely heard. Yet studies have shown that nurses are involved in the caring process surrounding euthanasia. Consequently, they are in a position to offer valuable ideas about this problem. For this reason, the views of these nurses are important because of their palliative expertise and their daily confrontation with dying patients. The aim of this paper is to report a study of the views of palliative care nurses about euthanasia. A grounded theory approach was chosen, and interviews were carried out with a convenience sample of 12 palliative care nurses in Flanders (Belgium). The data were collected between December 2001 and April 2002. The majority of the nurses were not a priori for or against euthanasia, and their views were largely dependent on the situation. What counted was the degree of suffering and available palliative options. Depending on the situation, we noted both resistance and acceptance towards euthanasia. The underlying arguments for resistance included respect for life and belief in the capabilities of palliative care; arguments underlying acceptance included the quality of life and respect for patient autonomy. The nurses commented that working in palliative care had a considerable influence on one's opinion about euthanasia. In light of the worldwide debate on euthanasia, it is essential to know how nurses, who are confronted with terminally ill patients every day, think about it. Knowledge of these views can also contribute to a realistic and qualified view on euthanasia itself. This can be enlightening to the personal views of caregivers working in a diverse range of care settings.


Avidity of antineurocytoskeletal antibodies in Alzheimer's disease patients.
To optimise the ELISA method for the avidity of IgG antibodies against neurofilament heavy chain (NfH) and to determine the levels and avidity of anti-NfH antibodies in patients with Alzheimer's disease (AD) and a healthy control group. Various dilutions of sera and concentrations of urea and sodium chloride as chaotropic reagents were tested in the process of the ELISA optimisation. The levels and avidity of anti-NfH antibodies were determined in 30 patients with Alzheimer's disease and 30 age-matched cognitively normal elderly adults. Sera dilution 1:200 and urea as a chaotrope in a concentration 6 mol/L were chosen to be the most suitable for the avidity assay of anti-NfH antibodies by ELISA. The results showed no differences in either level or avidity of IgG anti-NfH antibodies between AD patients and cognitively normal persons. The levels of anti-NfH IgG antibodies inversely correlated with their avidities. We optimised the ELISA method for the determination of anti-NfH antibody avidity determination which is suitable for research of anti-NfH antibody avidity in patients with neurological diseases associated with neurocytoskeletal defects. The determination of serum anti-NfH antibody avidity in AD patients seems to have limited diagnostic significance.


Mimotopes of tumor-associated T-cell epitopes for cancer vaccines determined with combinatorial peptide libraries.
Cytotoxic T-cells are the most important effector cells in immune responses against tumors. The identification of tumor-associated epitopes for these cells, therefore, has become a key aspect of the development of cancer vaccines. Here, we describe a new approach to the determination of tumor-associated T-cell epitopes which employs combinatorial peptide libraries with singly defined sequence positions in a randomized context. The analysis of the responses of a T-cell clone to these libraries yields the amino acid constituents of the epitope which can be combined to obtain mimotopes that are suitable as vaccine antigens for the induction of tumor-specific responses.


Emergency Department Length of Stay for Critical Care Admissions. A Population-based Study.
Hospital emergency department (ED) strain is common in North America. Excessive strain may result in prolonged ED length of stay and may lead to worse outcomes for patients admitted to intensive care units (ICUs). To describe patient, ED, and hospital characteristics associated with prolonged ED length of stay for adult patients admitted from EDs to ICUs. We conducted a population-based cohort study in the Province of Ontario, Canada, including patients admitted to an adult ICU from an ED and excluding only interhospital transfers and scheduled visits. Using regression modeling, we examined associations between patient- and hospital-level characteristics and two ED performance measures: length of stay in the ED of more than 6 hours and 90-day mortality. From April 2007 to March 2012, 261,274 adults presented to 118 EDs in Ontario, generating 314,836 ICU admissions. This activity represented 4.1% of all adult ED visits (incidence, 1,374 ICU admissions/100,000 ED visits). Median (interquartile range) ED length of stay was 7 (4-13) hours. Less than half (41.4%; 95% confidence interval [CI], 41.2-41.5) of these patients had an ED length of stay of 6 hours or less, whereas 10.5% (95% CI, 10.4-10.6) stayed 24 hours or longer. Hospital characteristics associated with ED length of stay more than 6 hours included shift-level ED crowding (mean length of stay of patients of similar acuity registering during same 8 h epoch) (odds ratio [OR], 1.19/h; 95% CI, 1.19-1.19), ED annual visit volume (OR, 1.01/1,000 patients; 95% CI, 1.01-1.01), time of ED presentation (00:00-07:59) (OR, 1.41; 95% CI, 1.38-1.45), and ICU functioning at greater than 20% above the average annual census (OR, 1.10; 95% CI, 1.08-1.12). ED length of stay more than 6 hours was not associated with 90-day mortality after adjustment for selected confounders (OR, 0.99; 95% CI, 0.97-1.02). In this population-based study, less than half of adult ED patients were admitted to an ICU 6 hours or less after arrival to an ED, an internationally recognized performance indicator for ED care quality. ED and ICU strain generated by time-varying demand on capacity was an important determinant of ED length of stay. However, prolonged length of stay in an ED did not measurably reduce 90-day mortality.


Do ownership of mosquito nets, dwelling characteristics and mothers' socio-economic status influence malaria morbidity among children under the age of 5 in Cameroon?
This study analyzed the effect of the number of mosquito nets that are owned by households, dwelling characteristics and maternal demographic characteristics on malaria infections. The 2011 Demographic and Health Survey (DHS) data for children under 5 years of age were used. The children were subjected to haemoglobin test and rapid diagnostic test (RDT) to ascertain the presence of malaria parasites. Data were analyzed using probit regression method. It was found that 2.43% and 8.68% of the children were living in houses that were prone to landslide and flooding, respectively. Also, 19.93%, 17.08% and 16.26% of the children lived in houses without windows, with broken windows, and with a hole in the roof, respectively. Only 5.59% and 23.96% of the children lived in houses with window and door nets, respectively. Mosquito nets were owned by 64.03% of the households, where Adamawa Region had the lowest coverage (52.23%). Reasons for not owning mosquito nets by all the households included: lack of financial means (25.17%), using something else (1.80%) and not having many mosquitoes in the vicinity (5.53%). In the probit regression, variables that significantly reduced malaria infections among the children (p < 0.05) included: the number of mosquito nets, urban residence, improved toilet, ownership of a radio, residence in flood-prone area, mother's secondary education, mother's tertiary education and residence in areas with not many mosquitoes, while infections increased along with the household size, residence in areas prone to landslide, severe anaemia, moderate anaemia, mild anaemia and age of the children. Ownership of mosquito nets and dwelling characteristics are critical factors influencing infections with malaria. There is a need to ensure compliance with its use since there are disparities between access and actual usage. Also, addressing malaria problem in Cameroon should consider regional disparity in malaria incidence rates and more engagement of the media, among others, for appropriate sensitization.


Early impairment of renal hemodynamic reserve in patients with asymptomatic heart failure is restored by angiotensin II antagonism.
The early/asymptomatic stages of heart failure (HF) are characterized by sodium retention secondary to derangement of sodium reabsorption at the proximal nephron level. Because this phenomenon is reversed by ACE inhibition, abnormalities of renal sodium handling may depend on intrarenal changes of angiotensin II (AII)/nitric oxide (NO) levels. Renal hemodynamic reserve (ie, the glomerular vasodilatory response to amino acid infusion) has been proposed as a reliable test to assess in vivo AII/NO balance. In this study, the effects of 6 weeks of treatment with 5 mg/d of enalapril or with 50 mg/d of losartan on systemic hemodynamics and renal function were assessed, at baseline and after amino acid infusion (AA), in patients with mild HF (NYHA class I) and in healthy volunteers. Untreated HF patients showed a basal renal function comparable to that of healthy subjects. After AA, glomerular filtration rate and renal plasma flow significantly increased in healthy subjects (+29.0% and +30.4%, respectively), whereas no vasodilatory response was observed in HF. Although they did not affect basal renal hemodynamics, both enalapril and losartan restored a normal response to AA in HF patients. Blood pressure and heart rate were comparable in HF subjects and healthy subjects at baseline and were not modified by either treatment. Left ventricular ejection fraction was depressed in HF but did not change after either drug. Urinary excretions of cGMP and nitrate (indexes of NO activity in the kidney), comparable in healthy subjects and in HF patients, were unchanged by either enalapril or losartan and did not correlate with renal reserve. (1) Renal functional reserve is absent in patients with early/asymptomatic HF and normal renal function and (2) both enalapril and losartan restore a normal vasodilatory response to AA in these patients without affecting basal systemic and renal hemodynamics. These data suggest a major role of AII in the development of early abnormalities in patients with HF.


LYMPHOID ORGANS AND NORMAL GAMMA-GLOBULIN IN THE RAT.
Serum gamma-globulin was determined in adult rats several months after total thymectomy, subtotal splenectomy, or a combination of total thymectomy, subtotal splenectomy, and subtotallymphadenectomy. The thymus apparently is of little importance in the production of normal gamma-globulin, but it may influence the production of albumin because a reduction of serum albumin was only seen in groups where thymectomy was performed. The spleen seems to produce normal gamma-globulin to a greater extent than lymphoid tissue elsewhere in the body.


Acute effects of acamprosate and MPEP on ethanol Drinking-in-the-Dark in male C57BL/6J mice.
Recently, a simple procedure in mice, Drinking-in-the-Dark (DID), was hypothesized to have value for medication development for human alcoholism. In DID, mice are offered intermittent, limited access to ethanol over a series of days during the dark phase that results in rapid drinking to intoxication in predisposed genotypes. We measured the effects of acamprosate or MPEP, metabotropic glutamate 5 receptor (mGluR5) antagonist, on intake of 20% ethanol, plain tap water or 10% sugar water using the DID procedure in male C57BL/6J mice. Acamprosate (100, 200, 300, or 400 mg/kg) dose dependently decreased ethanol drinking with 300 mg/kg reducing ethanol intake by approximately 20% without affecting intake of plain water or 10% sugar water. MPEP (1, 3, 5, 10, 20, or 40 mg/kg) was more potent than acamprosate with 20 mg/kg reducing ethanol intake by approximately 20% and for longer duration without affecting intake of plain water or 10% sugar water. These results support the hypothesis that mGluR5 signaling plays a role in excessive ethanol intake in DID and suggest DID may have value for screening novel compounds that reduce overactive glutamate signaling for potential pharmaceutical treatment of excessive ethanol drinking behavior.


Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer.
Systemic androgen-signaling inhibition added to ongoing androgen-deprivation therapy (ADT) improved clinical outcomes in patients with nonmetastatic castration-resistant prostate cancer without detectable metastases by conventional imaging (nmCRPC). Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) detects prostate cancer with superior sensitivity to conventional imaging, but its performance in nmCRPC remains largely unknown. We characterized cancer burden in high-risk patients with nmCRPC using PSMA-PET. We retrospectively included 200 patients with nmCRPC, prostate-specific antigen (PSA) >2 ng/mL, and high risk for metastatic disease [PSA doubling time (PSADT) of ≤10 months and/or Gleason score of ≥8] from six high-volume PET centers. We centrally reviewed PSMA-PET detection rate for pelvic disease and distant metastases (M1). We further evaluated SPARTAN patients stratified by risk factors for PSMA-PET-detected M1 disease. PSMA-PET was positive in 196 of 200 patients. Overall, 44% had pelvic diseases, including 24% with local prostate bed recurrence, and 55% had M1 disease despite negative conventional imaging. Interobserver agreement was very high (κ: 0.81-0.91). PSA ≥ 5.5 ng/mL, locoregional nodal involvement determined by pathology (pN1), prior primary radiation, and prior salvage radiotherapy independently predicted M1 disease (all P < 0.05). PSMA-PET detected any disease in nearly all patients and M1 disease in 55% of patients previously diagnosed with nmCRPC, including subgroups with PSADT of ≤10 months and Gleason score of ≥8. The value of PSMA-PET imaging for treatment guidance should be tested in future studies.


Analysis of synaptic depression contributing to habituation of gill-withdrawal reflex in Aplysia californica.
1. Repeated stimulation of the siphon skin results in short-term habituation of the reflex contractions of the gill (38). The habituation, in turn, is correlated with a depression of the excitatory postsynaptic potentials (EPSPs) in motor neurons from mechanoreceptor sensory neurons (SN) (7, 16). The present study was undertaken to examine the parametric features of the synaptic depression and gain insights into the mechanisms underlying the reduced transmitter release. 2. Single sensory neuron action potentials were repeatedly elicited with depolarizing current pulses while the amplitude of the resultant EPSPs in the motor neuron was monitored. Synaptic depression varies as a complex function of interstimulus interval (ISI). At an ISI of 1 s, depression is rapid and reaches a plateau at 36% of control. In contrast, the depression at an ISI of 100 s is less pronounced, showing a gradual decay to 65% of control with the 10th EPSP. Surprisingly, there are no significant differences in time course or magnitude of depression across a broad range of intermediate ISIs (3, 10, and 30 s), although depression at these ISIs is intermediate between the 1 and 100 s ISIs. 3. There is also a complex relationship between spike interval and the depression of the second of two EPSPs. Thus, depression of the second of two EPSPs or depression of a train of EPSPs is not a monotonic function of spike interval. Indeed, the data suggest that there may be a slight underlying facilitatory process with short spike intervals. 4. The results also indicate that the recovery of synaptic depression following a train of 10 stimuli is not constant. Shorter spike intervals produce more rapid recovery. 5. These data are inconsistent with a classical depletion model (33) for synaptic depression and indicate that either a single complex function of time and ISI or multiple functions underlie synaptic depression and its recovery at the sensory neuron synapse.


Ligands internalized through coated or noncoated invaginations follow a common intracellular pathway.
Cholera toxin (CT) represents a class of ligands that binds preferentially to noncoated pits on the cell surface. In the present study, we have investigated the mechanism of endocytosis of this class of ligand and compared it to the classic coated pit mechanism. When either CT coupled to colloidal gold particles (CT-gold) or 125I-labeled CT were incubated with 3T3 L1 fibroblasts at 4 degrees C, both ligands bound in a preferential fashion to small noncoated pits on the cell surface. CT-gold surface-labeled cells were then incubated at 22 degrees C. The labeled ligand progressively moved into noncoated vesicles and a tubulovesicular compartment composed of a network of tubules and vesicles closely associated with multivesicular bodies but distinct from the Golgi complexes. The ligand next passed into multivesicular bodies. By contrast, alpha 2-macroglobulin (alpha 2m)-gold initially localized preferentially to coated pits and subsequently to coated vesicles and tubulovesicular structures before associating with multivesicular bodies. To directly compare the intracellular pathway followed by CT-gold to that followed by alpha 2m-gold, CT-gold (7 nm) was coincubated with alpha 2m-gold (15 nm). By 10 min of incubation at 22 degrees C, up to 66% of tubulovesicular units contained both ligands when analyzed in serial sections. Subsequently, both ligands were colocalized in multivesicular bodies. We conclude that CT-gold endocytosed via noncoated vesicles and alpha 2m-gold endocytosed through coated vesicles subsequently associate with the same tubulovesicular units, multivesicular bodies, and lysosomes.


A potential gradient along the layer-by-layer architecture for electron transfer rectification.
Electrochemical and photochemical measurements demonstrated that dendritic phenylazomethines, which can make complexes with SnCl2 by a stepwise process, only permit an outbound electron transfer. The unique dendrimer effect allows efficient production of photo-generated radical ion pairs by suppressing their charge recombination. In sharp contrast, the phenylenevinylene or benzylether dendrimers, which lack a heteroatom or π-conjugation, did not exhibit such non-symmetric characters.


Development of a dual drug-loaded hydrogel delivery system for enhanced cancer therapy: in situ formation, degradation and synergistic antitumor efficiency.
Herein, a dual drug-loaded hydrogel delivery system was constructed using aldehyded pullulan (A-Pul), ε-poly-l-lysine (ε-PL), and branched polyethylenimine (BPEI) in an aqueous solution via a Schiff base reaction. CDDP and DOX were loaded into the network of hydrogels for combination drug therapy. Gelation time changed from 40 s to 240 s when reaction solutions were stored at different temperatures. Scanning electron microscopy images and swelling dynamics demonstrated that the hydrogels had a homogeneous porous structure and good swelling behavior. The in vitro degradation rate and drug release rate at pH 7.0 were faster than those at pH 7.4; this indicated that the hydrogels displayed controlled drug release and pH-dependent behavior. The hydrogels could be injected and formed in situ and degraded in vivo, and the dual-drug-loaded hydrogel displayed the most efficient tumor inhibition; this indicated the synergistic anticancer effect of the CDDP + DOX combination therapy in H22 liver tumor-bearing mice. Furthermore, the hydrogels displayed no cytotoxicity against Huh-7 cells and exhibited excellent security and biocompatibility in vivo. Therefore, the hydrogels have potential applications as multidrug carriers for enhanced synergistic therapy.


COVID-19 Pandemic Spurs Medical Telerobotic Systems: A Survey of Applications Requiring Physiological Organ Motion Compensation.
The coronavirus disease 2019 (COVID-19) pandemic has resulted in public health interventions such as physical distancing restrictions to limit the spread and transmission of the novel coronavirus, causing significant effects on the delivery of physical healthcare procedures worldwide. The unprecedented pandemic spurs strong demand for intelligent robotic systems in healthcare. In particular, medical telerobotic systems can play a positive role in the provision of telemedicine to both COVID-19 and non-COVID-19 patients. Different from typical studies on medical teleoperation that consider problems such as time delay and information loss in long-distance communication, this survey addresses the consequences of physiological organ motion when using teleoperation systems to create physical distancing between clinicians and patients in the COVID-19 era. We focus on the control-theoretic approaches that have been developed to address inherent robot control issues associated with organ motion. The state-of-the-art telerobotic systems and their applications in COVID-19 healthcare delivery are reviewed, and possible future directions are outlined.


Influence of leaky surface acoustic wave velocity of glass substrates on frequency variation of ZnO/glass SAW filters.
During the manufacture of ZnO/glass surface acoustic wave (SAW) filters, two kinds of problems sometimes arise. One is that the average frequency of the SAW filters changes greatly depending on the production lot of glass sheets. The other is that SAW filters made from the same production lot of glass sheets have largely separated double peaks in the frequency distribution. Previously, it had been considered that the frequency variation of ZnO/glass SAW filters depended on such factors as the ZnO film thickness and its elastic quality. The authors focused on the glass substrates as the cause of this variation and measured the leaky SAW (LSAW) velocity on the glass substrates using an ultrasonic microscope to clarify the mechanism. As a result, it was clarified that the LSAW velocities on the glass substrates showed a large variation within and between production lots of glass sheets, and the frequency of ZnO/glass SAW filters largely depended on the LSAW velocity on glass substrates. Moreover, the authors clarified the cause of the difference in the LSAW velocity between glass substrates and were able to reduce the variation of the LSAW velocity.


Domain structure and three-dimensional model of a group II intron-encoded reverse transcriptase.
Group II intron-encoded proteins (IEPs) have both reverse transcriptase (RT) activity, which functions in intron mobility, and maturase activity, which promotes RNA splicing by stabilizing the catalytically active RNA structure. The LtrA protein encoded by the Lactococcus lactis Ll.LtrB group II intron contains an N-terminal RT domain, with conserved sequence motifs RT1 to 7 found in the fingers and palm of retroviral RTs; domain X, associated with maturase activity; and C-terminal DNA-binding and DNA endonuclease domains. Here, partial proteolysis of LtrA with trypsin and Arg-C shows major cleavage sites in RT1, and between the RT and X domains. Group II intron and related non-LTR retroelement RTs contain an N-terminal extension and several insertions relative to retroviral RTs, some with conserved features implying functional importance. Sequence alignments, secondary-structure predictions, and hydrophobicity profiles suggest that domain X is related structurally to the thumb of retroviral RTs. Three-dimensional models of LtrA constructed by "threading" the aligned sequence on X-ray crystal structures of HIV-1 RT (1) account for the proteolytic cleavage sites; (2) suggest a template-primer binding track analogous to that of HIV-1 RT; and (3) show that conserved regions in splicing-competent LtrA variants include regions of the RT and X (thumb) domains in and around the template-primer binding track, distal regions of the fingers, and patches on the protein's back surface. These regions potentially comprise an extended RNA-binding surface that interacts with different regions of the intron for RNA splicing and reverse transcription.


Hepatic inferior vena cava obstructions: clinical results of treatment with percutaneous transluminal laser-assisted angioplasty.
Three cases of hepatic inferior vena cava (IVC) obstruction (two segmental and one membranous) associated with Budd-Chiari syndrome were successfully treated with percutaneous transluminal angioplasty (PTA) with use of an Nd-YAG (neodymium-yttrium, aluminum, garnet) laser. The occluded portions were canalized by advancing a ceramic-capped delivery system and delivering intermittent laser emissions. The canal was widened by simultaneous inflation of three or four Gruentzig balloon catheters. In two of the three cases, this procedure was done after unsuccessful canalization of the occluded portions by conventional means. Postoperatively, all patients showed disappearance of Budd-Chiari syndrome. One patient also showed marked regression of a huge intraluminal thrombus. There were no serious complications during and after the procedures. Use of the Nd-YAG laser seems to be of value in PTA for the treatment of hepatic IVC obstructions as well as in treatment of arteriosclerotic lesions.


Tuberization in potato involves a switch from apoplastic to symplastic phloem unloading.
Phloem unloading was studied in potato plants in real time during the early stages of tuberization using carboxyfluorescein (CF) as a phloem-mobile tracer, and the unloading pattern was compared with autoradiography of tubers that had transported (14)C assimilates. In stolons undergoing extension growth, apoplastic phloem unloading predominated. However, during the first visible signs of tuberization, a transition occurred from apoplastic to symplastic transport, and both CF and (14)C assimilates subsequently followed identical patterns of phloem unloading. It is suggested that the switch to symplastic sucrose unloading may be responsible for the upregulation of several genes involved in sucrose metabolism. A detailed analysis of sugar levels and (14)C sugar partitioning in tuberizing stolons revealed a distinct difference between the apical region of the tuber and the subapical region. Analysis of invertase activity in nontuberizing and tuberizing stolons revealed a marked decline in soluble invertase in the subapical region of swelling stolons, consistent with the switch from apoplastic to symplastic unloading. However, cell wall-bound invertase activity remained high in the apical 1 to 2 mm of tuberizing stolons. Histochemical analysis of potato lines transformed with the promoter of an apoplastic invertase gene (invGE) linked to a reporter gene also revealed discrete gene expression in the apical bud region. Evidence is presented that the apical and lateral tuber buds function as isolated domains with respect to sucrose unloading and metabolism.


Effect of patellar taping on vasti onset timing, knee kinematics, and kinetics in asymptomatic individuals with a delayed onset of vastus medialis oblique.
This randomized within-subject study investigated the effects of patellar tape on the onset of electromyographic (EMG) activity of vastus medialis obliquus (VMO) relative to vastus lateralis (VL), knee kinematics, and kinetics in 12 currently asymptomatic individuals with a VMO timing deficit and a history of patellofemoral pain. Participants were required to complete stair stepping and normal-pace and fast-pace walking tasks under three experimental conditions; no tape, control tape and therapeutic tape. EMG onsets of VMO and VL were measured by surface electrodes, stance phase knee flexion by the PEAK movement analysis system and vertical ground reaction force by a force plate. A two-way repeated measures analysis of variance showed that neither therapeutic tape nor control tape had any effect on the EMG VMO-VL onset timing difference. Therapeutic tape, but not control tape, led to significant increases in stance phase knee flexion. The first peak vertical ground reaction force was lowered by both control and therapeutic tape but only during fast walking. The results suggest that tape induced effects on neuromotor control of the vasti seen in other studies are related to reductions in pain rather than the presence of a baseline timing deficit. However, this cannot explain the improvements in stance phase knee flexion observed with tape.


Pharmacy interventions on COVID-19 in Europe: Mapping current practices and a scoping review.
The COVID-19 pandemic has put community pharmacists at the frontline of prevention, preparedness, response, and recovery efforts. Pharmacies had to reorganize and implement several different interventions and measures within a very short time frame. 1) To map the current reported practice and trends and to review the literature on pharmacy-based interventions on COVID-19 provided in Europe; 2) To identify knowledge gaps and future avenues for pharmacy research, policy, and practice in response to public health emergencies. We used a mixed methods approach combining country mapping of current practices of pharmacy interventions on COVID-19 reported by pharmacy associations in Europe with a scoping review of published literature. We mapped current practices on 31 pharmacy interventions on COVID-19 in 32 countries in Europe. Almost all preventive measures to reduce health risks have been provided in most countries. Other frequent interventions reflected preparedness for stockpiling, increased demand for services and products, and important patient care interventions exceeding dispensing role. Expanded powers granted to pharmacies and legislation passed in view of COVID-19 enabled services that improve access to medicines and relevant products, patient screening and referral including point-of-care antigen testing, support to vulnerable patients, and COVID-19 vaccination. We identified 9 studies conducted in pharmacies in 7 countries in Europe. Most studies are cross-sectional and/or descriptive. Pharmacy associations played an important supporting role by developing and updating guidance and emergency plans to assist community pharmacists. A wide array of pharmacy interventions on COVID-19 was implemented in several countries within a very short time frame. Research on pharmacy interventions on COVID-19 is still in its infancy but confirmed the wide array of interventions provided and expanded powers granted to pharmacies. These findings may provide a significant impact to improve pharmacy research, policy, and practice in response to future public health emergencies in Europe and globally.


Domains of Brn-2 that mediate homodimerization and interaction with general and melanocytic transcription factors.
The class III POU gene brn-2, encoding the Brn-2/N-Oct-3 transcription factor, is widely expressed in the developing mammalian central nervous system. Brn-2 has also been found to regulate the melanocytic phenotype with N-Oct-3 DNA binding activity elevated in malignant melanoma, however, its mode of action is yet to be defined. The functional role of the Brn-2 transcription factor has been investigated through the analysis of protein-protein interactions it forms with a number of basal and melanocytic transcriptional regulatory proteins. In vivo interactions were tested by gene-cotransfection using the mammalian GAL4-Herpes Simplex viral protein 16 (VP16) two hybrid formation and direct protein binding by in vitro glutathione S-transferase (GST)-pull down assay. The Brn-2 protein was found to homodimerize in vivo with high affinity, using Brn-2 deletion constructs dimer complex formation was found to be dependent on the presence of both the homeodomain and linker regions of the POU-domain. However, the POU-homoedomain was dispensable for the formation of the dimerization interface in one of the partner molecules but not both, when the POU-linker region was removed the ability to interact was lost irrespective of the presence of the homeodomain. Dimerization of Brn-2/N-Oct-3 was also found to occur in DNA binding assays using melanoma cell line nuclear extracts and a recently reported dimer target sequence probe, which may have significant consequences for gene regulation in melanocytic tumours. Low affinity Brn-2 protein contacts have also been found with the basal transcription complex, including TATA binding protein (TBP) and the transcriptional coactivator p300, and with the Sox-10 and Pax-3 transcription factors that are known to play an important role in melanocyte cell formation.


[Changes in adrenergic and cholinergic innervation of the external genitalia in alcohol and drug intoxication].
Eighteen cadavers of persons, who died of acute and chronic alcohol and drug intoxication (ephedron-addiction), were used to study the changes in the spinal nerve plexuses and external genitals. The activity of acetylcholinesterase and of NADPH-diaphorase was determined histochemically; the adrenergic nerve fibers were detected by a glyoxyl-acid technique. Rectified changes in the relative density of adrenal-cholinergic- and nitroxydergic structures and in the activity of mediators in different intoxications were found. The chronic intoxication by alcohol and ephedron was accompanied by a reduced activity of enzymes involved in the metabolism of acetylcholine, nitric oxide and catecholamines. A lower density was observed in the nerve fibers that contained the examined substances. The results can be used as an additional criterion in evaluating the male sexual-function status.


Screening for postnatal depression: not a simple task.
To evaluate an established screening program for postnatal depression using the Edinburgh Postnatal Depression Scale (EPDS) in a rural Victorian shire. By protocol, all women were screened at three time points post delivery by maternal and child health nurses. The efficacy of this approach in detecting probable depression was examined and referral pathways analysed. Records for a 12-month cohort of women giving birth in the shire were audited (n = 267). Information collected included EPDS scores, parity, mother's age, reasons for non-completion, referral details and nurses' comments. Analysis was completed using database and SPSS programs. The process goal of screening on all three occasions was rarely achieved--a goal met for only 15.5% of women; 22% were never screened at all. The highest rate of screening was 50.6% at one month, falling to 38.1% at eight months. Reasons for non-screening varied, suggesting no simple remedy. The proportions of women identified as probably depressed at each screening point (3.1%, 4.8% and 9.2%) were considerably lower than statewide figures for rural women. Referrals of probably depressed women were mainly to GPs but the results were unclear. A well-established program of universal screening was not effective in detecting probable depression in women. There was little evidence of direct feedback from GPs about women referred as a result of screening and no collaborative planning for affected women. Before universal screening of women for postnatal depression can be recommended, better evidence of its feasibility and acceptability are required, alongside convincing evidence that screening leads to improved outcomes for women.


Indwelling Urinary Catheters: A Pathway to Health Care-Associated Infections.
When a urinary catheter is not inserted using proper technique, becomes unclean, or remains in place for too long, microorganisms can travel through the catheter lumen or along the outside of the catheter and infect the bladder or kidneys, resulting in a catheter-associated urinary tract infection (CAUTI). Urinary tract infections resulting from catheter use are one of the most common health care-associated infections. The insertion of a urinary catheter is considered to be routine care. Improving practices of placement and removal of urinary catheters requires education aimed at changing the habits of nurses and physicians. Clinicians should follow evidence-based guidelines, including using aseptic technique for site preparation and supplies and limiting use and duration of the placement of urinary catheters. Perioperative personnel need to be aware of the risks of catheterization and take steps to prevent CAUTIs. This article discusses CAUTIs, including causes and strategies for prevention.


[Sleep as a method of the study of epilepsy].
It has been well known from the literature that sleep and epilepsy have strong reciprocal influences and this is true for all kinds of epilepsies. The electroencephalographic paroxysmal activity increases in slow wave sleep and the localization of the primary epileptogenic area is more reliable in paradoxical sleep. The video-polygraphic recording is a mandatory methodology in the study of the different types of epilepsies.


Competition between drum and quasi-planar structures in RhB18-: motifs for metallo-boronanotubes and metallo-borophenes.
Metal-doped boron clusters provide new opportunities to design nanoclusters with interesting structures and bonding. A cobalt-doped boron cluster, CoB18-, has been observed recently to be planar and can be viewed as a motif for metallo-borophenes, whereas the D9d drum isomer as a motif for metallo-boronanotubes is found to be much higher in energy. Hence, whether larger doped boron drums are possible is still an open question. Here we report that for RhB18- the drum and quasi-planar structures become much closer in energy and co-exist experimentally, revealing a competition between the metallo-boronanotube and metallo-borophene structures. Photoelectron spectroscopy of RhB18- shows a complicated spectral pattern, suggesting the presence of two isomers. Quantum chemistry studies indicate that the D9d drum isomer and a quasi-planar isomer (Cs) compete for the global minimum. The enhanced stability of the drum isomer in RhB18- is due to the less contracted Rh 4d orbitals, which can have favorable interactions with the B18 drum motif. Chemical bonding analyses show that the quasi-planar isomer of RhB18- is aromatic with 10 π electrons, whereas the observed RhB18- drum cluster sets a new record for coordination number of eighteen among metal complexes. The current finding shows that the size of the boron drum can be tuned by appropriate metal dopants, suggesting that even larger boron drums with 5d, 6d transition metal, lanthanide or actinide metal atoms are possible.


Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease.
In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimer's disease (AD) patients underwent respectively 3- and 5-year follow-up positron emission tomography (PET) studies with N-methyl [(11)C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole ((11)C-PIB) and (18)F-fluorodeoxyglucose ((18)F-FDG) to understand the time courses in AD disease processes. Significant increase in PIB retention as well as decrease in regional cerebral metabolic rate of glucose (rCMRglc) was observed at group level in the MCI patients while no significant change was observed in cognitive function. At group level the AD patients showed unchanged high PIB retention at 5-year follow-up compared with baseline. At the individual level, increased, stable, and decreased PIB retention were observed while disease progression was reflected in significant decrease in rCMRglc and cognition. In conclusion, after a long-term follow-up with PET, we observed an increase in fibrillar amyloid load in MCI patients followed by more stable level in clinical AD patients. The rCMRglc starts to decline in MCI patients and became more pronounced in clinical stage which related to continuous decline in cognition.


Acting locally: innate mucosal immunity in resistance to HIV-1 infection in Kenyan commercial sex workers.
Cohort studies of female commercial sex workers (CSWs) in Kenya were among the first to identify highly HIV-1-exposed seronegative (HESN) individuals. As natural resistance is usually mediated by innate immune mechanisms, we focused on determining whether expression and function of innate signaling pathways were altered locally in the genital mucosa of HESN CSWs. Our results demonstrated that selected pattern-recognition receptors (PRRs) were significantly reduced in expression in cervical mononuclear cells (CMCs) from HESN compared with the new HIV-negative (HIV-N) and HIV-positive (HIV-P) groups. Although baseline levels of secreted cytokines were reduced in CMCs of HESN, they were highly stimulated following exposure to ssRNA40 in vitro. Importantly, cervical epithelial cells from HESN also expressed reduced levels of PRRs, but Toll-like receptor 3 (TLR3) and TLR7 as well as nuclear factor-κB and activator protein 1 were highly expressed and activated. Lastly, inflammatory cytokines interleukin (IL)-1β, IL-8, and RANTES (regulated and normal T cell expressed and secreted) were detected at lower levels in cervicovaginal lavage of HESN compared with the HIV-N and HIV-P groups. Overall, our study reveals a local microenvironment of HIV resistance in the genital mucosa consisting of a finely controlled balance of basal immune quiescence with a focused and potent innate anti-viral response critical to resistance to sexual transmission of HIV-1.


Chronic stimulation of mammalian muscle: enzyme changes in individual fibers.
Single fibers of rabbit fast-twitch tibialis anterior (TA) muscles were analyzed after continuous low-frequency stimulation for up to 8 wk. After 2-5 wk, every fiber showed higher levels of citrate synthase, hexokinase, and 3-oxoacid CoA-transferase than any control fiber; in some cases these levels were 2-10 times higher (well above any found even in the control soleus, a slow-twitch muscle). Average levels of malate dehydrogenase and alanine transaminase also rose dramatically, but peak single fiber levels were not much above the highest in controls. These differential effects confirm at the single fiber level that chronic stimulation can alter mitochondrial composition. Lactate dehydrogenase, fructose-bisphosphatase, and adenylate kinase declined to levels far below those of any control TA fiber, and, in the case of fructose-bisphosphatase, to within the activity range of control soleus fibers. According to their staining reaction for myofibrillar ATPase, TA fibers were initially 23% type IIA, and 74% type IIB, but by 5 wk these had been converted to a mixture of type I, IIA, and IIC fibers. At 5 wk, levels of lactate dehydrogenase, adenylate kinase, and malate dehydrogenase were characteristic of their (new) ATPase type, but 3-oxoacid CoA transferase had increased to levels 6-15 times higher than in control fibers of the same type.