Novel acoustic radiation force impulse imaging methods for visualization of rapidly moving tissue.
Acoustic radiation force impulse (ARFI) imaging has been demonstrated to be capable of visualizing changes in local myocardial stiffness through a normal cardiac cycle. As a beating heart involves rapidly-moving tissue with cyclically-varying myocardial stiffness, it is desirable to form images with high frame rates and minimize susceptibility to motion artifacts. Three novel ARFI imaging methods, pre-excitation displacement estimation, parallel-transmit excitation and parallel-transmit tracking, were implemented. Along with parallel-receive, ECG-gating and multiplexed imaging, these new techniques were used to form high-quality, high-resolution epicardial ARFI images. Three-line M-mode, extended ECG-gated three-line M-mode and ECG-gated two-dimensional ARFI imaging sequences were developed to address specific challenges related to cardiac imaging. In vivo epicardial ARFI images of an ovine heart were formed using these sequences and the quality and utility of the resultant ARFI-induced displacement curves were evaluated. The ARFI-induced displacement curves demonstrate the potential for ARFI imaging to provide new and unique information into myocardial stiffness with high temporal and spatial resolution.


Do voluntary strength, proprioception, range of motion, or postural sway predict occurrence of lateral ankle sprain?
Prevention of ankle sprain, the most common sporting injury, is only possible once risk factors have been identified. Voluntary strength, proprioception, postural sway, and range of motion are possible risk factors. A systematic review was carried out to investigate these possibilities. Eligible studies were those with longitudinal design investigating ankle sprain in subjects aged > or = 15 years. The studies had to have measured range of motion, voluntary strength, proprioception, or postural sway before monitoring incidence of lateral ankle sprain. Dorsiflexion range strongly predicted risk of ankle sprain. Postural sway and possibly proprioception were also predictors. Therefore the preliminary evidence suggests that people with reduced ankle dorsiflexion range may be at increased risk of ankle sprain.


'Educator talk' and patient change: some insights from the DESMOND (Diabetes Education and Self Management for Ongoing and Newly Diagnosed) randomized controlled trial.
To determine whether differences in the amount of time educators talk during a self-management education programme relate to the degree of change in participants' reported beliefs about diabetes. Educators trained to be facilitative and non-didactic in their approach were observed delivering the DESMOND self-management programme for individuals newly diagnosed with Type 2 diabetes. Observers used 10-s event coding to estimate the amount of time educators spoke during different sessions in the programme. Facilitative as opposed to didactic delivery was indicated by targets for levels of educator talk set for each session. Targets were based on earlier pilot work. Using the revised Illness Perceptions Questionnaire (IPQ-R) and the Diabetes Illness Representations Questionnaire (DIRQ), participants completed measures of: perceived duration of diabetes (timeline IPQ-R), understanding of diabetes (coherence IPQ-R), personal responsibility for influencing diabetes (personal responsibility IPQ-R), seriousness of diabetes (seriousness DIRQ) and impact on daily life (impact DIRQ), before and after the education programme. Where data from the event coding indicated educators were talking less and meeting targets for being less didactic, a greater change in reported illness beliefs of participants was seen. However, educators struggled to meet targets for most sessions of the programme. The amount of time educators talk in a self-management programme may provide a practical marker for the effectiveness of the education process, with less educator talk denoting a more facilitative/less didactic approach. This finding has informed subsequent improvements to a comprehensive quality development framework, acknowledging that educators need ongoing support to facilitate change to their normal educational style.


Heterotopic ossification of degenerating rat skeletal muscle induced by adenovirus-mediated transfer of bone morphogenetic protein-2 gene.
In vivo gene transfer is a recently developed device for efficient delivery of a therapeutic recombinant protein. We formulated the hypothesis that a high level of expression of bone morphogenetic protein 2 (BMP-2) could be a future therapeutic modality in terms of inducing substantial bone formation in vivo. First, to test this hypothesis, adenoviruses carrying BMP-2 gene were directly injected into the soleus muscle of adult rat. The BMP-2 gene was successfully overexpressed in the target muscle by adenovirus-mediated transfer, whereas bone formation in and around the muscle failed to occur in this case. Second, to recruit putative osteoprogenitor cells, we then induced ischemic degeneration of the target muscle by orthotopically grafting it simultaneously with the gene transfer. The combination of BMP-2 gene transfer and orthotopic muscle grafting resulted in successful ossification of almost the whole grafted muscle, whereas neither muscle grafting alone nor the combination of muscle grafting and adenovirus-mediated transfer of reporter gene LacZ induced any bone formation in the muscle. The ossification process was evident by positive von Kossa staining of the histological sections and roentgenographical radio-opacity of the region. It was also found that the BMP-2 transgene overexpressed in grafted muscles inhibited muscle regeneration, which should otherwise follow the muscle degeneration. We further demonstrated an up-regulation of BMP receptor type IA in grafted muscles, suggesting its involvement in the bone-formation process. In conclusion, overexpression of BMP-2 gene induced massive heterotopic ossification in skeletal muscles under graft-induced ischemic degeneration, which possibly up-regulates osteoprogenitor cells in situ.


Late cortical tracking of ignored speech facilitates neural selectivity in acoustically challenging conditions.
Listening requires selective neural processing of the incoming sound mixture, which in humans is borne out by a surprisingly clean representation of attended-only speech in auditory cortex. How this neural selectivity is achieved even at negative signal-to-noise ratios (SNR) remains unclear. We show that, under such conditions, a late cortical representation (i.e., neural tracking) of the ignored acoustic signal is key to successful separation of attended and distracting talkers (i.e., neural selectivity). We recorded and modeled the electroencephalographic response of 18 participants who attended to one of two simultaneously presented stories, while the SNR between the two talkers varied dynamically between +6 and -6 dB. The neural tracking showed an increasing early-to-late attention-biased selectivity. Importantly, acoustically dominant (i.e., louder) ignored talkers were tracked neurally by late involvement of fronto-parietal regions, which contributed to enhanced neural selectivity. This neural selectivity, by way of representing the ignored talker, poses a mechanistic neural account of attention under real-life acoustic conditions.


Rapid cytolysis of Mycobacterium tuberculosis by faropenem, an orally bioavailable β-lactam antibiotic.
Recent clinical studies indicate that meropenem, a β-lactam antibiotic, is a promising candidate for therapy of drug-resistant tuberculosis. However, meropenem is chemically unstable, requires frequent intravenous injection, and must be combined with a β-lactamase inhibitor (clavulanate) for optimal activity. Here, we report that faropenem, a stable and orally bioavailable β-lactam, efficiently kills Mycobacterium tuberculosis even in the absence of clavulanate. The target enzymes, L,D-transpeptidases, were inactivated 6- to 22-fold more efficiently by faropenem than by meropenem. Using a real-time assay based on quantitative time-lapse microscopy and microfluidics, we demonstrate the superiority of faropenem to the frontline antituberculosis drug isoniazid in its ability to induce the rapid cytolysis of single cells. Faropenem also showed superior activity against a cryptic subpopulation of nongrowing but metabolically active cells, which may correspond to the viable but nonculturable forms believed to be responsible for relapses following prolonged chemotherapy. These results identify faropenem to be a potential candidate for alternative therapy of drug-resistant tuberculosis.


Adherence to antipsychotic medication among homeless adults in Vancouver, Canada: a 15-year retrospective cohort study.
The purpose of this study was to investigate the level of adherence to antipsychotic prescription medication in a well-defined homeless cohort over a 15-year period. We hypothesized that adherence would be well below the recommended threshold for clinical effectiveness (80 %), and that it would be strongly associated with modifiable risk factors in the social environment in which homeless people live. Linked baseline data (including comprehensive population-level administrative prescription records) were examined in a subpopulation of participants from two pragmatic-randomized trials that investigated Housing First for homeless and mentally ill adults. Adherence to antipsychotic medication was operationalized using the medication possession ratio. Multivariable logistic regression was used to estimate effect sizes between socio-demographic, homelessness-related and illness factors, and medication possession ratio. Among the 290 participants who met inclusion criteria for the current analysis, adherence to antipsychotic prescription was significantly associated with: history of psychiatric hospitalization; receipt of primary medical services; long-acting injectable antipsychotic formulations; and duration of homelessness. Mean medication possession ratio in the pre-randomization period was 0.41. Socio-demographic characteristics previously correlated with antipsychotic non-adherence were not significantly related to medication possession ratio. This is the first study to quantify the very low level of adherence to antipsychotic medication among homeless people over an extended observation period of 15 years. Each of the four factors found to be significantly associated with adherence presents opportunities for intervention. Strategies to end homelessness for this population may represent the greatest opportunity to improve adherence to antipsychotic medication.


The relationships between low levels of urine fluoride on children's intelligence, dental fluorosis in endemic fluorosis areas in Hulunbuir, Inner Mongolia, China.
There has been public concern about children's intellectual performance at high levels of fluoride exposure, but few studies provide data directly to the question of whether low fluoride exposure levels less than 3.0 mg/L in drinking water adversely associated with children's intelligence. In this survey, we investigated the effects of low fluoride exposure on children's intelligence and dental fluorosis. 331 children aged from 7 to 14 were randomly recruited from four sites in Hulunbuir City, China. Intelligence was assessed using Combined Raven Test-The Rural in China while dental fluorosis was diagnosed with Dean's index. Mean value of fluoride in drinking water was 1.31±1.05 mg/L (range 0.24-2.84). Urine fluoride was inversely associated with IQ in the multiple linear regression model when children's age as a covariate variable was taken into account (P<0.0001). Each increase in 1 mg/L of urine fluoride associated with 0.59-point decrease in IQ (P=0.0226). Meanwhile, there was a dose-response relationship between urine fluoride and dental fluorosis (P<0.0001). In conclusion, our study suggested that low levels of fluoride exposure in drinking water had negative effects on children's intelligence and dental health and confirmed the dose-response relationships between urine fluoride and IQ scores as well as dental fluorosis.


Genome sequence analysis and organization of the Hyphantria cunea granulovirus (HycuGV-Hc1) from Turkey.
The fall webworm (Hyphantria cunea) impacts a wide variety of crops and cultivated broadleaf plant species. The pest is native to North America, was introduced to Europe and has since spread further as far as central Asia. Despite several attempts to control its distribution, the pest continues to spread causing damage all over the world. A naturally occurring baculovirus, Hyphantria cunea granulovirus (HycuGV-Hc1), isolated from the larvae of H. cunea in Turkey appears to have a potential as microbial control agent against this pest. In this report we describe the complete genome sequence and organization of the granulovirus isolate (HycuGV-Hc1) that infects the larval stages and compare it to other baculovirus genomes. The HycuGV-Hc1 genome is a circular double-stranded DNA of 114,825 bp in size with a nucleotide distribution of 39.3% G + C. Bioinformatics analysis predicted 132 putative open reading frames of (ORFs) ≥ 150 nucleotides. There are 24 ORFs with unknown function. Seven homologous repeated regions (hrs) and two bro genes (bro-1 and bro-2) were identified in the genome. Comparison to other baculovirus genomes, HycuGV-Hc1 revealed some differences in gene content and organization. Gene parity plots and phylogenetics confirmed that HycuGV-Hc1 is a Betabaculovirus and is closely related to Plutella xylostella granulovirus. This study expands our knowledge on the genetic variation of HycuGV isolates and provides further novel knowledge on the nature of granuloviruses.


Suppression of Alzheimer's Disease-Like Pathology Progression by Mitochondria-Targeted Antioxidant SkQ1: A Transcriptome Profiling Study.
Alzheimer's disease (AD) is the most common type of dementia, with increasing prevalence and no disease-modifying treatment available yet. There is increasing evidence-from interventions targeting mitochondria-that may shed some light on new strategies for the treatment of AD. Previously, using senescence-accelerated OXYS rats that simulate key characteristics of sporadic AD, we have shown that treatment with mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) from age 12 to 18 months (that is, during active progression of AD-like pathology)-via improvement of mitochondrial function-prevented the neuronal loss and synaptic damage, enhanced neurotrophic supply, and decreased amyloid-β 1-42 protein levels and tau hyperphosphorylation in the hippocampus. In the present study, we continued to explore the mechanisms of the anti-AD effects of SkQ1 in an OXYS rat model through deep RNA sequencing (RNA-seq) and focused upon the cell-specific gene expression alterations in the hippocampus. According to RNA-seq results, OXYS rats had 1,159 differentially expressed genes (DEGs) relative to Wistar rats (control), and 6-month treatment with SkQ1 decreased their number twofold. We found that 10.5% of all DEGs in untreated (control) OXYS rats were associated with mitochondrial function, whereas SkQ1 eliminated differences in the expression of 76% of DEGs (93 from 122 genes). Using transcriptome approaches, we found that the anti-AD effects of SkQ1 are associated with an improvement of the activity of many signaling pathways and intracellular processes. SkQ1 changed the expression of genes in neuronal, glial, and endothelial cells, and these genes are related to mitochondrial function, neurotrophic and synaptic activity, calcium processes, immune and cerebrovascular systems, catabolism, degradation, and apoptosis. Thus, RNA-seq analysis yields a detailed picture of transcriptional changes during the development of AD-like pathology and can point to the molecular and genetic mechanisms of action of the agents (including SkQ1) holding promise for the prevention and treatment of AD.


Early detection of acute lung injury uncoupled to hypoxemia in pigs using ultrasound lung comets.
Oleic acid-induced lung injury is an established experimental model of acute lung injury in pigs and is considered to reproduce the early exudative phase of acute respiratory distress syndrome. Ultrasound lung comets are an echographic sign of extravascular lung water, originating from thickened interlobular septa. The objective of this study was to evaluate the timing and relationship between the number of ultrasound lung comets, the Pao2/Fio2 ratio, and the static respiratory compliance in an experimental model of oleic acid-induced lung injury in pigs. Laboratory experiment. Research institute. Ten anesthetized pigs. Acute lung injury was induced by injection of oleic acid (0.1 mL/kg, intravenously). Ultrasound lung comets, Pao2/Fio2, and static respiratory compliance were measured at baseline and at 15, 30, 60, and 90 mins after the injection of oleic acid. We evaluated ultrasound lung comets by transthoracic echography (7.5-MHz vascular probe), scanning on right and left hemithoraxes at 12 predefined scanning sites. Acute lung injury/acute respiratory distress syndrome was present in all pigs at 90 mins. The number of ultrasound lung comets increased over time and was consistently earlier than the decrease in Pao2/Fio2. At 15 mins, ultrasound lung comets were markedly increased, but no significant changes in Pao2/Fio2 were observed. Accordingly, static respiratory compliance was dramatically reduced at 15 mins compared with baseline (17.04 +/- 1.82 vs. 34.84 +/- 2.62 mL/cm H2O, p < .05). Ultrasound lung comets, assessed by transthoracic echography, detected extravascular lung water accumulation very early in the course of the oleic acid lung injury in pigs, in the presence of a normal Pao2/Fio2. These results suggest that ultrasound lung comets could be a very early, noninvasive, and simple method to detect and quantify pulmonary edema in acute lung injury.


Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain.
There has been a trend over recent years for combining a nonsteroidal antiinflammatory drug (NSAID) with paracetamol (acetaminophen) for pain management. However, therapeutic superiority of the combination of paracetamol and an NSAID over either drug alone remains controversial. We evaluated the efficacy of the combination of paracetamol and an NSAID versus either drug alone in various acute pain models. A systematic literature search of Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and PubMed covering the period from January 1988 to June 2009 was performed to identify randomized controlled trials in humans that specifically compared combinations of paracetamol with various NSAIDs versus at least 1 of these constituent drugs. Identified studies were stratified into 2 groups: paracetamol/NSAID combinations versus paracetamol or NSAIDs. We analyzed pain intensity scores and supplemental analgesic requirements as primary outcome measures. In addition, each study was graded for quality using a validated scale. Twenty-one human studies enrolling 1909 patients were analyzed. The NSAIDs used were ibuprofen (n = 6), diclofenac (n = 8), ketoprofen (n = 3), ketorolac (n = 1), aspirin (n = 1), tenoxicam (n = 1), and rofecoxib (n = 1). The combination of paracetamol and NSAID was more effective than paracetamol or NSAID alone in 85% and 64% of relevant studies, respectively. The pain intensity and analgesic supplementation was 35.0% +/- 10.9% and 38.8% +/- 13.1% lesser, respectively, in the positive studies for the combination versus paracetamol group, and 37.7% +/- 26.6% and 31.3% +/- 13.4% lesser, respectively, in the positive studies for the combination versus the NSAID group. No statistical difference in median quality scores was found between experimental groups. Current evidence suggests that a combination of paracetamol and an NSAID may offer superior analgesia compared with either drug alone.


Evidence-based medicine and general practice.
Evidence-based medicine (EBM) aids clinical decision making in all fields of medicine, including primary care. General practice is characterized by particular emphasis on the doctor-patient relationship and on biomedical, personal and contextual perspectives in diagnosis. Most evidence available to general practitioners (GPs) addresses only the bio-medical perspective and is often not directly applicable to primary care, as it derives from secondary or tertiary care. Emphasis on the biomedical domain and the randomized controlled trial (RCT) alone reflects a reductionist approach that fails to do justice to the philosophy of general practice. The art of medicine is founded on context, anecdote, patient stories of illness and personal experience, and we should continue to blend this with good quality and appropriate research findings in patient care.


Regulation of locomotion and cell-cell contact area by the LFA-1 and ICAM-1 adhesion receptors.
We demonstrate complementary differences in the behavior of B lymphoblastoid cells adhering to LFA-1 or its counter-receptor ICAM-1. The interaction of B lymphoblastoid cells with glass-supported planar bilayers bearing LFA-1 or ICAM-1 was observed by time-lapse video microscopy, and the distribution of adhesion receptors on cells interacting with the planar bilayers was studied by immunofluorescence microscopy. B lymphoblasts formed a large contact area and crawled rapidly (up to 25 microns/min) on planar bilayers bearing ICAM-1. In contrast, these cells attached to planar bilayers bearing LFA-1 through a fixed point about which the cells actively pivoted, using a single stalk-like projection. Phorbol ester-stimulated lymphoblasts, which adhere more strongly to ICAM-1-bearing substrates than unstimulated lymphoblasts, were still capable of locomotion on ICAM-1. Phorbol ester stimulation of B lymphoblasts on planar bilayers bearing LFA-1 promoted a rapid conversion from "stalk" attachment to symmetrical spreading of the cell on the substrate. Cellular LFA-1 remained uniformly distributed on the cell surface during interaction with bilayers bearing purified ICAM-1 as determined by immunofluorescence. In contrast, ICAM-1 was concentrated in the stalk-like structure through which the unstimulated B lymphoblasts adhered to LFA-1 in planar bilayers, but ICAM-1 immunofluorescence became more uniformly distributed over the cell surface within minutes of phorbol ester addition. Neither LFA-1 or ICAM-1 colocalized with the prominent staining of filamentous actin in the ruffling membrane regions. Interaction through cell surface LFA-1 and ICAM-1, 2, or 3 promotes different cellular morphologies and behaviors, the correlation of which with previously observed patterns of lymphocyte interaction with different cell types is discussed.


White-emitting Protein-Metal Nanocluster Phosphors for Highly Performing Biohybrid Light-Emitting Diodes.
This work presents a simple in situ synthesis and stabilization of fluorescent gold nanoclusters (AuNCs) with different sizes using engineered protein scaffolds in water. The protein-AuNC hybrids show a dual emission (450 and 700 nm) with a record photoluminescence quantum yield of 20%. These features impelled us to apply them to biohybrid light-emitting diodes as color down-converting filters or biophosphors. Efficient white emission (x/y CIE color coordinates of 0.31/0.29) and stabilities of more than 800 h were achieved. This represents a 2 orders of magnitude enhancement compared to the prior art. Besides the outstanding performance, the protein scaffold also infers a unique anisotropic emission character that is considered as a proof-of-concept of high interest for single-point lighting and display.


Functional connectivity in the normal and injured brain.
The brain is neither uniform nor composed of similar modules but is rather a mosaic of different and highly interconnected regions. Accordingly, knowledge of functional connectivity between brain regions is crucial to understanding perception, cognition, and behavior. Functional connectivity methods estimate similarities between activity recorded in different regions of the brain. They are often applied to resting state activity, thus providing measures that are by nature task independent. The spatial patterns revealed by functional connectivity are not only shaped by the underlying anatomical structure of the brain but also partially depend on the history of task-driven coactivations. Inter-subject differences in functional connectivity may, at least to some degree, underlie variability observed in task performance across healthy subjects and in behavioral impairments in neurological patients. In this respect, recent studies have demonstrated that behavioral deficits in patients with brain injury are not only due to local tissue damage but also due to altered functional connectivity among structurally intact regions connected to the damaged site. Studies based on functional connectivity have the potential to advance basic understanding of how brain lesions induce neuropsychological syndromes. Furthermore, they may eventually suggest improved rehabilitation strategies for patients with brain injury, through the design of individualized treatment and recovery protocols.


The halotolerance and phylogeny of cyanobacteria with tightly coiled trichomes (Spirulina Turpin) and the description of Halospirulina tapeticola gen. nov., sp. nov.
The morphologies, halotolerances, temperature requirements, pigment compositions and 16S rRNA gene sequences of five culture collection strains and six novel isolates of cyanobacteria with helical, tightly coiled trichomes were investigated. All strains were very similar morphologically and could be assigned to the genus Spirulina (or section Euspirulina sensu Geitler), according to traditional classification. However, the isolates showed significantly different requirements for salinity and temperature, which were in accordance with their respective environmental origins. The genetic divergence among the strains investigated was large. The results indicate the drastic underestimation of the physiological and phylogenetic diversity of these cyanobacteria by the current morphology-based classification and the clear need for new taxa. Three of the isolates originated from hypersaline waters and were similar with respect to their high halotolerance, broad euryhalinity and elevated temperature tolerance. By phylogenetic analyses, they were placed in a tight monophyletic cluster apart from all other cyanobacteria. Thus it is proposed to reclassify highly halotolerant cyanobacteria with tightly coiled trichomes in Halospirulina gen. nov., with the type species Halospirulina tapeticola sp. nov.


The Relationship of Coronary Artery Calcium and Clinical Coronary Artery Disease with Cognitive Function: A Systematic Review and Meta-Analysis.
Coronary artery disease (CAD) and cognitive impairment are common in the elderly, with evidence for shared risk factors and pathophysiological processes. The coronary artery calcium (CAC) score is a marker of subclinical CAD, which may allow early detection of individuals prone to cognitive decline. Prior studies on associations of CAC and clinical CAD with cognitive impairment had discrepant results. This systematic review aims to evaluate the association of (sub)clinical CAD with cognitive function, cognitive decline, and diagnosis of mild cognitive impairment (MCI) or dementia. A systematic search was conducted in MEDLINE, Embase, and Web of Science until February 2019, supplemented with citations tracking. Two reviewers independently screened studies and extracted information including odds ratios (ORs) and hazard ratios (HRs). Forty-six studies, 10 on CAC and 36 on clinical CAD, comprising 1,248,908 participants were included in the systematic review. Studies about associations of (sub)clinical CAD with cognitive function and cognitive decline had heterogeneous methodology and inconsistent findings. Two population-based studies investigated the association between CAC and risk of dementia over 6-12.2 years using different CAC scoring methods. Both found a tendency toward higher risk of dementia as CAC severity increased. Meta-analysis in 15 studies (663,250 individuals) showed an association between CAD and MCI/dementia (pooled OR 1.32, 95%CI 1.17-1.48) with substantial heterogeneity (I2=87.0%, p<0.001). Pooled HR of CAD for incident MCI/dementia over 3.2-25.5 years in six longitudinal studies (70,060 individuals) was 1.51 (95%CI 1.24-1.85), with low heterogeneity (I2=14.1%, p=0.32). Sensitivity analysis did not detect any study that was of particular influence on the pooled OR or HR. Limited evidence suggests the CAC score is associated with risk of dementia. In clinical CAD, risk of MCI and dementia is increased by 50%, as supported by stronger evidence.


Lineages of acidophilic archaea revealed by community genomic analysis.
Novel, low-abundance microbial species can be easily overlooked in standard polymerase chain reaction (PCR)-based surveys. We used community genomic data obtained without PCR or cultivation to reconstruct DNA fragments bearing unusual 16S ribosomal RNA (rRNA) and protein-coding genes from organisms belonging to novel archaeal lineages. The organisms are minor components of all biofilms growing in pH 0.5 to 1.5 solutions within the Richmond Mine, California. Probes specific for 16S rRNA showed that the fraction less than 0.45 micrometers in diameter is dominated by these organisms. Transmission electron microscope images revealed that the cells are pleomorphic with unusual folded membrane protrusions and have apparent volumes of <0.006 cubic micrometer.


Two components of the delayed rectifier potassium current, IK, in rabbit sino-atrial node cells.
The delayed rectifier current was studied in rabbit isolated sino-atrial (SA) node cells using the whole-cell voltage clamp technique with amphotericin-permeabilized patches. The envelope of tails test indicated that in SA node cells the decay of IK (IK.tall) comprises two distinct current components similar to the specific fast and slow components of IK (IKr and JKs) that have been found in atrial and ventricular myocytes. Dofetilide, a Class III antiarrhythmic agent and a selective blocker of IKr. separated the delayed rectifier current into drug-sensitive current (IKr) and drug-insensitive current (IKs). The dofetilide-sensitive current activated rapidly and it showed two components of deactivation, the larger of which was very slow, while the dofetilide-insensitive current activated more slowly and deactivated quickly. The effects of propofol, an IKs blocker, on the delayed rectifier current were also investigated. The results show that IKs contributes to IK.tall and that the more positive the membrane potential, the more the contribution of IKs. The ratio of IKs to IKr in tail currents at -40 mV after a 1 s clamp pulse to +40 mV was 0.3-0.4:1. Dofetilide slowed spontaneous activity, suggesting that IKr contributes to the pacemaker activity of the SA node cell.


Discrete states of synaptic strength in a stochastic model of spike-timing-dependent plasticity.
A stochastic model of spike-timing-dependent plasticity (STDP) postulates that single synapses presented with a single spike pair exhibit all-or-none quantal jumps in synaptic strength. The amplitudes of the jumps are independent of spiking timing, but their probabilities do depend on spiking timing. By making the amplitudes of both upward and downward transitions equal, synapses then occupy only a discrete set of states of synaptic strength. We explore the impact of a finite, discrete set of strength states on our model, finding three principal results. First, a finite set of strength states limits the capacity of a single synapse to express the standard, exponential STDP curve. We derive the expression for the expected change in synaptic strength in response to a standard, experimental spike pair protocol, finding a deviation from exponential behavior. We fit our prediction to recent data from single dendritic spine heads, finding results that are somewhat better than exponential fits. Second, we show that the fixed-point dynamics of our model regulate the upward and downward transition probabilities so that these are on average equal, leading to a uniform distribution of synaptic strength states. However, third, under long-term potentiation (LTP) and long-term depression (LTD) protocols, these probabilities are unequal, skewing the distribution away from uniformity. If the number of states of strength is at least of order 10, then we find that three effective states of synaptic strength appear, consistent with some experimental data on ternary-strength synapses. On this view, LTP and LTD protocols may therefore be saturating protocols.


Spot Form of Net Blotch Resistance in a Diverse Set of Barley Lines in Australia and Canada.
The responses of 95 barley lines and cultivars to spot form of net blotch (SFNB) caused by Pyrenophora teres f. maculata were analyzed as seedlings and adults in Australia and Canada. Cluster analyses revealed complex reaction responses. Only 2 lines (Esperance Orge 289 and TR3189) were resistant to all isolates at the seedling stage, whereas 15 lines and cultivars (81-82/033, Arimont, BYDV-018, CBSS97M00855T-B2-M1-Y1-M2-Y-1M-0Y, CI9776, Keel, Sloop, Torrens, TR326, VB0111, Yarra, VB0229, WI-2477, WI2553, and Wisconsin Pedigree) were resistant toward the two Canadian isolates and mixture of Australian isolates at the adult stages. In Australian field experiments, the effectiveness of SFNB resistance in three barley cultivars (Barque, Cowabbie, and Schooner) and one breeding line (VB9104) with a different source of resistance was tested. Barque, which possessed a resistance gene that provided complete resistance to SFNB, was the most effective and showed no effect on grain yield or quality in the presence of inoculum. Generally, cultivars with seedling or adult resistance had less disease and better grain quality than the susceptible control, Dash, but they were not as effective as Barque. A preliminary differential set of 19 barley lines and cultivars for P. teres f. maculata is proposed.


Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth.
Regular physical activity protects against the development of breast and colon cancer, since it reduces the risk of developing these by 25-30%. During exercise, humoral factors are released from the working muscles for endocrinal signaling to other organs. We hypothesized that these myokines mediate some of the inhibitory effects of exercise on mammary cancer cell proliferation. Serum and muscles were collected from mice after an exercise bout. Incubation with exercise-conditioned serum inhibited MCF-7 cell proliferation by 52% and increased caspase activity by 54%. A similar increase in caspase activity was found after incubation of MCF-7 cells with conditioned media from electrically stimulated myotubes. PCR array analysis (CAPM-0838E; SABiosciences) revealed that seven genes were upregulated in the muscles after exercise, and of these oncostatin M (OSM) proved to inhibit MCF-7 proliferation by 42%, increase caspase activity by 46%, and induce apoptosis. Blocking OSM signaling with anti-OSM antibodies reduced the induction of caspase activity by 51%. To verify that OSM was a myokine, we showed that it was significantly upregulated in serum and in three muscles, tibialis cranialis, gastronemius, and soleus, after an exercise bout. In contrast, OSM expression remained unchanged in subcutaneous and visceral adipose tissue, liver, and spleen (mononuclear cells). We conclude that postexercise serum inhibits mammary cancer cell proliferation and induces apoptosis of these cells. We suggest that one or more myokines secreted from working muscles may be mediating this effect and that OSM is a possible candidate. These findings emphasize that role of physical activity in cancer treatment, showing a direct link between exercise-induced humoral factors and decreased tumor cell growth.


Use of the Principles of Design Thinking to Address Limitations of Digital Mental Health Interventions for Youth: Viewpoint.
Numerous reviews and meta-analyses have indicated the enormous potential of technology to improve the appeal, effectiveness, cost, and reach of mental health interventions. However, the promise of digital mental health interventions for youth has not yet been realized. Significant challenges have been repeatedly identified, including engagement, fidelity, and the lack of personalization. We introduce the main tenets of design thinking and explain how they can specifically address these challenges, with an entirely new toolbox of mindsets and practices. In addition, we provide examples of a new wave of digital interventions to demonstrate the applicability of design thinking to a wide range of intervention goals. In the future, it will be critical for scientists and clinicians to implement their scientific standards, methods, and review outlets to evaluate the contribution of design thinking to the next iteration of digital mental health interventions for youth.


Reimbursement and value-based pricing: stratified cost-effectiveness analysis may not be the last word.
During recent discussions, it has been argued that stratified cost-effectiveness analysis has a key role in reimbursement decision-making and value-based pricing (VBP). It has previously been shown that when manufacturers are price-takers, reimbursement decisions made in reference to stratified cost-effectiveness analysis lead to a more efficient allocation of resources than decisions based on whole-population cost-effectiveness analysis. However, we demonstrate that when manufacturers are price setters, reimbursement or VBP based on stratified cost-effectiveness analysis may not be optimal. Using two examples - one considering the choice of thrombolytic treatment for specific patient subgroups and the other considering the extension of coverage for a cancer treatment to include an additional indication - we show that combinations of extended coverage and reduced price can be identified that are advantageous to both payers and manufacturers. The benefits of a given extension in coverage and reduction in price depend both upon the average treatment benefit in the additional population and its size relative to the original population. Negotiation regarding trade-offs between price and coverage may lead to improved outcomes both for health-care systems and manufacturers compared with processes where coverage is determined conditional simply on stratified cost-effectiveness at a given price.


Feedback for simulation-based procedural skills training: a meta-analysis and critical narrative synthesis.
Although feedback has been identified as a key instructional feature in simulation based medical education (SBME), we remain uncertain as to the magnitude of its effectiveness and the mechanisms by which it may be effective. We employed a meta-analysis and critical narrative synthesis to examine the effectiveness of feedback for SBME procedural skills training and to examine how it works in this context. Our results demonstrate that feedback is moderately effective during procedural skills training in SBME, with a pooled effect size favoring feedback for skill outcomes of 0.74 (95 % CI 0.38-1.09; p < .001). Terminal feedback appears more effective than concurrent feedback for novice learners' skill retention. Multiple sources of feedback, including instructor feedback, lead to short-term performance gains although data on long-term effects is lacking. The mechanism by which feedback may be operating is consistent with the guidance hypothesis, with more research needed to examine other mechanisms such as cognitive load theory and social development theory.


Striatal infusion of cholesterol promotes dose-dependent behavioral benefits and exerts disease-modifying effects in Huntington's disease mice.
A variety of pathophysiological mechanisms are implicated in Huntington's disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre-symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol-loaded brain-permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini-pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and rate-controlled manner. All tested doses prevented cognitive decline, while amelioration of disease-related motor defects was dose-dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose-dependent, disease-modifying effect and may be therapeutically relevant in HD.


Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence. To review available evidence on corticosteroid treatment of boys with Duchenne dystrophy. Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification, and areas for future research are defined. Seven class I studies and numerous less rigorous trials all demonstrated that corticosteroid treatment for 6 months with prednisone (0.75 or 1.5 mg/kg/day) increased muscle strength, performance, and pulmonary function and significantly slowed the progression of weakness. Two class I trials examined the effect of lower dosage of prednisone (0.30 and 0.35 mg/kg/day), demonstrated lesser but similar benefits, and showed a lower frequency of side effects (e.g., weight gain). The only significant side effects in all class I trials were weight gain and development of a cushingoid facial appearance. One longer-term trial of daily prednisone (0.3 to 0.7 mg/kg/day), a class III study, showed prolongation of functional ability and slower progression of weakness in patients during 3 years of treatment. One class IV, open trial of alternate-day prednisone (2 mg/kg for 2 months, then two-thirds dose every other day) extended ambulation by approximately 2 years in treated compared with untreated patients. Deflazacort, a corticosteroid similar in structure to prednisone, produced similar improvement in muscle strength and function with a similar side effect profile. Prednisone has been demonstrated to have a beneficial effect on muscle strength and function in boys with Duchenne dystrophy and should be offered (at a dose of 0.75 mg/kg/day) as treatment. If side effects require a decrease in prednisone, tapering to dosages as low as 0.3 mg/kg/day gives less robust but significant improvement. Deflazacort (0.9 mg/kg/day) can also be used for the treatment of Duchenne dystrophy in countries in which it is available. Benefits and side effects of corticosteroid therapy need to be monitored. The offer of treatment with corticosteroids should include a balanced discussion of potential risks.


Descriptions of pain in elderly patients following orthopaedic surgery.
The aims of this study were to investigate what words elderly patients, who had undergone hip surgery, used to describe their experience of pain in spoken language and to compare these words with those used in the Short-Form McGill Pain Questionnaire (SF-MPQ) and Pain-O-Meter (POM). The study was carried out at two orthopaedic and two geriatric clinical departments at a large university hospital in Sweden. Altogether, 60 patients (mean age =77) who had undergone orthopaedic surgery took part in the study. A face-to-face interview was conducted with each patient on the second day after the operation. This was divided into two parts, one tape-recorded and semi-structured in character and one structured interview. The results show that a majority of the elderly patients who participated in this study verbally stated pain and spontaneously used a majority of the words found in the SF-MPQ and in the POM. The patients also used a number of additional words not found in the SF-MPQ or the POM. Among those patients who did not use any of the words in the SF-MPQ and the POM, the use of the three additional words 'stel' (stiff), 'hemsk' (awful) and 'rad(d)(sla)' (afraid/fear) were especially marked. The patients also combined the words with a negation to describe what pain was not. To achieve a more balanced and nuanced description of the patient's pain and to make it easier for the patients to talk about their pain, there is a need for access to a set of predefined words that describe pain from a more multidimensional perspective than just intensity. If the elderly patient is allowed, and finds it necessary, to use his/her own words to describe what pain is but also to describe what pain is not, by combining the words with a negation, then the risk of the patient being forced to choose words that do not fully correspond to their pain can be reduced. If so, pain scales such as the SF-MPQ and the POM can create a communicative bridge between the elderly patient and health care professionals in the pain evaluation process.


Police killings and their spillover effects on the mental health of black Americans: a population-based, quasi-experimental study.
Police kill more than 300 black Americans-at least a quarter of them unarmed-each year in the USA. These events might have spillover effects on the mental health of people not directly affected. In this population-based, quasi-experimental study, we combined novel data on police killings with individual-level data from the nationally representative 2013-15 US Behavioral Risk Factor Surveillance System (BRFSS) to estimate the causal impact of police killings of unarmed black Americans on self-reported mental health of other black American adults in the US general population. The primary exposure was the number of police killings of unarmed black Americans occurring in the 3 months prior to the BRFSS interview within the same state. The primary outcome was the number of days in the previous month in which the respondent's mental health was reported as "not good". We estimated difference-in-differences regression models-adjusting for state-month, month-year, and interview-day fixed effects, as well as age, sex, and educational attainment. We additionally assessed the timing of effects, the specificity of the effects to black Americans, and the robustness of our findings. 38 993 (weighted sample share 49%) of 103 710 black American respondents were exposed to one or more police killings of unarmed black Americans in their state of residence in the 3 months prior to the survey. Each additional police killing of an unarmed black American was associated with 0·14 additional poor mental health days (95% CI 0·07-0·22; p=0·00047) among black American respondents. The largest effects on mental health occurred in the 1-2 months after exposure, with no significant effects estimated for respondents interviewed before police killings (falsification test). Mental health impacts were not observed among white respondents and resulted only from police killings of unarmed black Americans (not unarmed white Americans or armed black Americans). Police killings of unarmed black Americans have adverse effects on mental health among black American adults in the general population. Programmes should be implemented to decrease the frequency of police killings and to mitigate adverse mental health effects within communities when such killings do occur. Robert Wood Johnson Foundation and National Institutes of Health.


A Survey on an Energy-Efficient and Energy-Balanced Routing Protocol for Wireless Sensor Networks.
Wireless sensor networks (WSNs) form an important part of industrial application. There has been growing interest in the potential use of WSNs in applications such as environment monitoring, disaster management, health care monitoring, intelligence surveillance and defence reconnaissance. In these applications, the sensor nodes (SNs) are envisaged to be deployed in sizeable numbers in an outlying area, and it is quite difficult to replace these SNs after complete deployment in many scenarios. Therefore, as SNs are predominantly battery powered devices, the energy consumption of the nodes must be properly managed in order to prolong the network lifetime and functionality to a rational time. Different energy-efficient and energy-balanced routing protocols have been proposed in literature over the years. The energy-efficient routing protocols strive to increase the network lifetime by minimizing the energy consumption in each SN. On the other hand, the energy-balanced routing protocols protract the network lifetime by uniformly balancing the energy consumption among the nodes in the network. There have been various survey papers put forward by researchers to review the performance and classify the different energy-efficient routing protocols for WSNs. However, there seems to be no clear survey emphasizing the importance, concepts, and principles of load-balanced energy routing protocols for WSNs. In this paper, we provide a clear picture of both the energy-efficient and energy-balanced routing protocols for WSNs. More importantly, this paper presents an extensive survey of the different state-of-the-art energy-efficient and energy-balanced routing protocols. A taxonomy is introduced in this paper to classify the surveyed energy-efficient and energy-balanced routing protocols based on their proposed mode of communication towards the base station (BS). In addition, we classified these routing protocols based on the solution types or algorithms, and the input decision variables defined in the routing algorithm. The strengths and weaknesses of the choice of the decision variables used in the design of these energy-efficient and energy-balanced routing protocols are emphasised. Finally, we suggest possible research directions in order to optimize the energy consumption in sensor networks.


A review of evidence-based practice, nursing research and reflection: levelling the hierarchy.
This paper examines the evidence-based practice movement, the hierarchy of evidence and the relationship between evidence-based practice and reflective practice. Evidence-based practice is equated with effective decision making, with avoidance of habitual practice and with enhanced clinical performance. The hierarchy of evidence has promoted randomized control trials as the most valid source of evidence. However, this is problematic for practitioners as randomized control trials overlook certain types of knowledge that, through the process of reflection, provide useful information for individualized and effective practice. A literature search was undertaken using CINAHL, medline and Ovid electronic databases in early 2006. The search terms used were: evidence-based practice, research evidence, evidence for practice, qualitative research, reflective practice, reflection and evidence. Other sources included handpicking of books on evidence-based practice, reflection and research. Only material written in English was included. The hierarchy of evidence that has promoted randomized control trials as the most valid form of evidence may actually impede the use of most effective treatment because of practical, political/ideological and epistemological contradictions and limitations. Furthermore, evidence-based practice appears to share very similar definitions, aims and procedures with reflective practice. Hence, it appears that the evidence-based practice movement may benefit much more from the use of reflection on practice, rather than the use of the hierarchical structure of evidence. Evidence-based practice is necessary for nursing, but its' effective implementation may be hindered by the hierarchy of evidence. Furthermore, evidence-based practice and reflection are both processes that share very similar aims and procedures. Therefore, to enable the implementation of best evidence in practice, the hierarchy of evidence might need to be abandoned and reflection to become a core component of the evidence-based practice movement. Provides an elaborated analysis for clinical nurses on the definition and implementation of evidence in practice.


Probing the structure of the V2 domain of human immunodeficiency virus type 1 surface glycoprotein gp120 with a panel of eight monoclonal antibodies: human immune response to the V1 and V2 domains.
We have analyzed a panel of eight murine monoclonal antibodies (MAbs) that depend on the V2 domain for binding to human immunodeficiency virus type 1 (HIV-1) gp120. Each MAb is sensitive to amino acid changes within V2, and some are affected by substitutions elsewhere. With one exception, the MAbs were not reactive with peptides from the V2 region, or only poorly so. Hence their ability to bind recombinant strain IIIB gp120 depended on the preservation of native structure. Three MAbs cross-reacted with strain RF gp120, but only one cross-reacted with MN gp120, and none bound SF-2 gp120. Four MAbs neutralized HIV-1 IIIB with various potencies, and the one able to bind MN gp120 neutralized that virus. Peptide serology indicated that antibodies cross-reactive with the HxB2 V1 and V2 regions are rarely present in HIV-1-positive sera, but the relatively conserved segment between the V1 and V2 loops was recognized by antibodies in a significant fraction of sera. Antibodies able to block the binding of V2 MAbs to IIIB or MN gp120 rarely exist in sera from HIV-1-infected humans; more common in these sera are antibodies that enhance the binding of V2 MAbs to gp120. This enhancement effect of HIV-1-positive sera can be mimicked by several human MAbs to different discontinuous gp120 epitopes. Soluble CD4 enhanced binding of one V2 MAb to oligomeric gp120 but not to monomeric gp120, perhaps by inducing conformational changes in the oligomer.


Altered pattern of immunoglobulin hypermutation in mice deficient in Slip-GC protein.
We recently identified a novel germinal center GTPase, SLIP-GC, that localizes to replication factories in B cells and that, when reduced, induces DNA breaks in lymphoma B cell lines in an activation-induced deaminase (AID)-dependent manner. Herein, we generated mice deficient in SLIP-GC and examined the impact of SLIP-GC deficiency in immunoglobulin hypermutation and class switch recombination, both AID-dependent mechanisms. SLIP-GC-deficient mice experienced a substantial increase in mutations at G:C base pairs at the region downstream of JH4 in the immunoglobulin heavy chain locus. This change was reflected in the overall mutation frequency, and it was associated with an increase in transitions from G:C base pairs, a hallmark of AID-mediated deamination during replication. In addition, G:C transitions at non-immunoglobulin loci also increased in these mice. Given the intracellular localization of SLIP-GC to sites of replicating DNA, these results suggest that SLIP-GC protects replicating DNA from AID-mediated deamination of cytosines in both strands.


Creating employment opportunities for people with disabilities in healthcare: the Bristol Employment Collaborative.
Unemployment is a significant problem among working-age adults with disabilities. The Bristol Employment Collaborative (BEC), one of five Regional Employment Collaboratives in Massachusetts, brings together State agencies, community employment service providers, educational institutions, local businesses, economic development organizations, and people with disabilities to design and implement regional strategies to enhance employment opportunities and outcomes for people with disabilities. Launched in 2009, BEC has developed an innovative model to train people with disabilities to become personal assistance services workers, a healthcare occupation with high demand. The case study describes the strategic planning process undertaken by BEC partners to develop a certificate program to be offered by the local community college. The first class enrolled in September 2010 and graduated ten weeks later. Innovative approaches such as the one being pursued and developed by the BEC could help address both unemployment for people with disabilities and the labor shortages in the healthcare sector.


The annexins and exocytosis.
The annexins are a group of homologous proteins that bind phospholipids in the presence of calcium. They may provide a major pathway for communication between cellular membranes and their cytoplasmic environment. Annexins have a characteristic "bivalent" activity in the sense that they can draw two membranes together when activated by calcium. This has led to the hypothesis that certain members of this protein family may initiate contact and fusion between a secretory vesicle membrane and the plasma membrane during the process of exocytosis.


"Agar Cell-Suspension": A Novel Technique for Processing Clear Specimens.
Clear cytology specimens are processed by cytocentrifugation which is preferred over membrane filters (MF). Although both techniques are expensive, cytocentrifugation is less tedious and may cause cellular distortion. To standardize "Agar cell-suspension" (ACS) an innovative, simple, cost-effective technique to process clear specimens. About 93 clear specimens (65 urine, 15 effusion, 12 CSF, and 1 bronchial lavage) were processed by both cytocentrifugation and ACS. The sample was centrifuged in two tubes; one was used for ACS and other for cytocentrifugation. ACS smears were prepared by mixing one drop of 0.5% agar solution with the last drop of the centrifugate. Smears were fixed in methanol and stained by Papanicolaou staining method. ACS smears were compared with cytocentrifuged smears (CS) and evaluated for cellularity, cytomorphology preservation, staining quality, time, and cost. As compared to CS smears, ACS smears showed better cellularity in 16.1%, comparable in 53.7%, and less in 30.1%. All ACS smears (100%) showed well-preserved cytomorphology as compared to 96.7% CS. Staining quality was optimal in 96.7% ACS smears against 91.3% CS. Both techniques took equal time. The additional cost of ACS was only 0.03 INR compared to 12.50 INR for CS. ACS is an innovative, simple, easy, and cost-effective technique for processing clear specimens. It gives equally good results comparable to cytocentrifugation in terms of cellularity and staining quality. ACS does not cause cell distortion or air-drying as seen in some CS. Thus, ACS is a superior alternative to cytocentrifugation.


Balloon dilation performs poorly as a salvage management strategy for recurrent bulbar urethral strictures following failed urethroplasty.
The optimal management strategy for recurrent urethral stricture disease (USD) following urethroplasty remains undefined. We aim to evaluate the role and efficacy of endoscopic urethral balloon dilation in temporizing recurrent USD after failed urethroplasty. Between 2007-2018 at our institution, 80 patients underwent balloon dilation procedures for bulbomembranous urethral strictures. Balloon dilation was performed with an 8-cm, 24-French UroMax Ultra™ balloon dilator, under direct vision, guided by a 16-French flexible cystoscope. Patients who underwent concomitant open or endoscopic urethral procedures were excluded. Treatment failure was defined as the need for subsequent surgical intervention for stricture recurrence. Stricture characteristics including etiology, length, location, severity stage, and prior surgical procedures were compared between patients with and without treatment failure. Failure cases were more likely to have strictures following urethroplasty (21/27, 78%) [vs. the no-failure group (27/53, 51%)]. Among the 27/80 (33.8%) failures with a median follow-up of 8.4 months (IQR, 3.9-22.5 months), median time to recurrence was 4 months (IQR, 2-12 months). These patients had a greater incidence of prior stricture intervention in general (P=0.01) and prior urethroplasty specifically (P=0.03). On multivariable analysis, the number of prior treatments specifically independently remained associated with treatment failure. Complications of balloon dilation were uncommon (6/80, 7.5%) and minor in nature. Endoscopic balloon dilation performs poorly as a salvage strategy after failed open urethral reconstruction in addition to prior urethral dilations.


The Sensitivity of Land-Atmosphere Coupling to Modern Agriculture in the Northern Midlatitudes.
Modern agricultural land cover and management are important as regional climate forcings. Previous work has shown that land cover change can significantly impact key climate variables, including turbulent fluxes, precipitation, and surface temperature. However, fewer studies have investigated how intensive crop management can impact background climate conditions, such as the strength of land-atmosphere coupling and evaporative regime. We conduct sensitivity experiments using a state-of-the-art climate model with modified vegetation characteristics to represent modern crop cover and management, using observed crop-specific leaf area indexes and calendars. We quantify changes in land-atmosphere interactions and climate over intensively cultivated regions situated at transitions between moisture- and energy-limited conditions. Results show that modern intensive agriculture has significant and geographically varying impacts on regional evaporative regimes and background climate conditions. Over the northern Great Plains, modern crop intensity increases the model simulated precipitation and soil moisture, weakening hydrologic coupling by increasing surface water availability and reducing moisture limits on evapotranspiration. In the U.S. Midwest, higher growing season evapotranspiration, coupled with winter and spring rainfall declines, reduces regional soil moisture, while crop albedo changes also reduce net surface radiation. This results overall in reduced dependency of regional surface temperature on latent heat fluxes. In central Asia, a combination of reduced net surface energy and enhanced pre-growing season precipitation amplify the energy-limited evaporative regime. These results highlight the need for improved representations of agriculture in global climate models to better account for regional climate impacts and interactions with other anthropogenic forcings.


Structured communication for patient safety in emergency medical services: a legal case report.
Providers of emergency medical services (EMS) must communicate vital information during critical phases of operations. Errors in communications, for example, the failure to hear a directive, will compromise safe and effective patient care. This article presents a case that resulted in litigation because of communication failures during the interfacility transfer of a trauma patient who subsequently died in the ambulance. The communication failure involved members of a ground ambulance crew, their dispatcher, and a supervisor. The failure of the emergency medical technician (EMT) who was driving to hear from the treating EMT and her dispatcher vital information pertaining to changes in their destination and of plans to intercept another ambulance, or alternatively, the driver's ignoring this information, led to a delay in care and may have contributed to the patient's death. Factors contributing to the cause of this communication failure may have been related to the nature of the EMS setting: the physical separation between crew members (the driver, and the care provider in the back of the ambulance); the noise of the ground ambulance transport environment, most notably, the siren; and the stress of treating a patient in critical condition. The case highlights the importance of using structured forms of communication, specifically the read-back tool and the critical assertion strategy, to limit failures in communication during EMS operations and in operations in other high-risk medical settings.


Modelling chemistry and biology after implantation of a drug-eluting stent. Part I: Drug transport.
Drug-eluting stents have been used widely to prevent restenosis of arteries following percutaneous balloon angioplasty. Mathematical modelling plays an important role in optimising the design of these stents to maximise their efficiency. When designing a drug-eluting stent system, we expect to have a sufficient amount of drug being released into the artery wall for a sufficient period to prevent restenosis. In this paper, a simple model is considered to provide an elementary description of drug release into artery tissue from an implanted stent. From the model, we identified a parameter regime to optimise the system when preparing the polymer coating. The model provides some useful order of magnitude estimates for the key quantities of interest. From the model, we can identify the time scales over which the drug traverses the artery wall and empties from the polymer coating, as well as obtain approximate formulae for the total amount of drug in the artery tissue and the fraction of drug that has released from the polymer. The model was evaluated by comparing to in-vivo experimental data and good agreement was found.


Memory outcomes of temporal lobe surgery in adults aged over 45 years.
It is assumed that temporal lobe resection in older people is associated with worse seizure outcomes and potential postsurgical memory decline. We studied postsurgical memory development and surgical efficacy in patients over 45 years of age compared with younger patients. We studied 88 patients (51 male and 37 female) after temporal lobe surgery, which involved hippocampal resection. The patients were evaluated before surgery and in the first (72 patients) and/or third (57 patients) postsurgical year. The Wechsler Memory Scale III test was performed to evaluate the MQ postsurgical development. Engel's classification was used to evaluate the postsurgical seizure outcome. The presurgical MQ (median 88) in ≥45 years age group was significantly lower than in both younger groups (median MQ = 100 for ≤30 years age group, p = 0.002; median MQ = 107 for 31-44 years age group, p = 0.002). Three years after the surgery, the MQ decreased significantly in ≤30 years age group (p = 0.012), while only non-significant MQ decline was observed in both older groups. We found no significant impact of age on the surgical outcome. Higher age at the time of surgery does not significantly increase the risk for postsurgical memory decline; however, older patients are more likely to have lowered presurgical MQ. We did not find significant differences in the impact of surgery on seizure outcome among the age groups. Epilepsy surgery appears to be a safe and effective method in the age over 45 years even though an earlier surgery should be preferred.


A cross-sectional study to assess the clinical utility of modern visual function assessments in patients with inherited retinal disease: a mixed methods observational study protocol.
Treatment options for patients with inherited retinal disease are limited, although research into novel therapies is underway. To ensure the success of future clinical trials, appropriate visual function outcome measures that can assess changes resulting from therapeutic interventions are urgently required. Rod-cone degenerations are the most common type of inherited retinal disease. Visual acuity is a standard measure but is typically preserved until late disease stages, frequently making it an unsuitable visual function marker. Alternative measures are required. This study investigates the clinical utility of a range of carefully selected visual function tests and patient reported outcome measures. The aim is to identify suitable outcome measures for future clinical trials that could be considered for regulatory approval. This cross-sectional study involves two participant groups, patients with inherited retinal disease (n = 40) and healthy controls (n = 40). The study has been designed to be flexible and run alongside NHS clinics. The study is split into two parts. Part one includes examining standard visual acuity, low luminance visual acuity, the Moorfields acuity chart visual acuity, mesopic microperimetry and three separate patient reported outcome measures. Part two involves 20 min of dark adaptation followed by two-colour scotopic microperimetry. Repeat testing will be undertaken where possible to enable repeatability analyses. A subset of patients with inherited retinal disease will be invited to participate in a semi-structured interview to gain awareness of participants' thoughts and feelings around the study and different study tests. The study highlights a need for reliable and sensitive validated visual function measures that can be used in future clinical trials. This work will build on work from other studies and be used to inform an outcome measure framework for rod-cone degenerations. The study is in keeping with the United Kingdom Department of Health and Social Care research initiatives and strategies for increasing research opportunities for NHS patients as part of their NHS care. ISRCTN registry, ISRCTN24016133, Visual Function in Retinal Degeneration, registered on 18th August 2022.


Paradoxical inhibition of atrial natriuretic peptide release during pacing-induced hypotension.
1. To determine the influence of loss of atrioventricular synchrony on release of atrial natriuretic peptide (ANP), plasma ANP concentrations were measured by radioreceptor assay in 16 patients during sequential and ventricular cardiac pacing at normal heart rates. 2. Ventricular pacing induced an increase in plasma ANP concentrations (means +/- SEM) from 44 +/- 3 to 104 +/- 4 pmol/l (P less than 0.01) in 11 patients in whom systemic blood pressure was maintained. 3. In contrast, when ventricular pacing was associated with a fall in blood pressure (five patients), ANP levels (means +/- SEM) fell from 68 +/- 6 to 14 +/- 4 pmol/l (n = 5, P less than 0.05) within 5 min, despite an increase in atrial pressure. Plasma catecholamines also rose significantly in these latter patients. 4. We conclude that when loss of atrioventricular synchrony is well tolerated haemodynamically, cardiac release of ANP is increased in keeping with elevation in atrial pressure. However, the fall in plasma ANP concentration observed when ventricular pacing produces a fall in blood pressure suggests that in addition to atrial pressure, ANP release may be influenced by negative feedback mechanisms, possibly involving the baroreflex and autonomic nervous system.


The spectrum of SWI/SNF mutations, ubiquitous in human cancers.
SWI/SNF is a multi-subunit chromatin remodeling complex that uses the energy of ATP hydrolysis to reposition nucleosomes, thereby modulating gene expression. Accumulating evidence suggests that SWI/SNF functions as a tumor suppressor in some cancers. However, the spectrum of SWI/SNF mutations across human cancers has not been systematically investigated. Here, we mined whole-exome sequencing data from 24 published studies representing 669 cases from 18 neoplastic diagnoses. SWI/SNF mutations were widespread across diverse human cancers, with an excess of deleterious mutations, and an overall frequency approaching TP53 mutation. Mutations occurred most commonly in the SMARCA4 enzymatic subunit, and in subunits thought to confer functional specificity (ARID1A, ARID1B, PBRM1, and ARID2). SWI/SNF mutations were not mutually-exclusive of other mutated cancer genes, including TP53 and EZH2 (both previously linked to SWI/SNF). Our findings implicate SWI/SNF as an important but under-recognized tumor suppressor in diverse human cancers, and provide a key resource to guide future investigations.


Göteborg Metoprolol Trial: enzyme-estimated infarct size.
In 1,375 patients serum activity of heat-stable lactate dehydrogenase (LD; E.C.188.8.131.52.) was analyzed every twelfth hour for 48 to 108 hours. The mean maximum LD activity was 11.1 +/- 0.4 mu kat X 1(-1) in the metoprolol group vs 12.4 +/- 0.5 mu kat X 1(-1) in the placebo group (p = 0.054). In patients in whom treatment was started 12 hours or less after the onset of pain, a 17% reduction in LD activity was observed (p = 0.009) and similar results were found in patients randomized 8 hours or less. Groups in which the effect after metoprolol treatment was more pronounced were those with an initially higher heart rate and also those with anterior myocardial infarction.


Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development.
Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set out to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC), as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. In particular, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T cells, and increased PTPN2 levels negatively correlated with expression of PD-1, CTLA4, STAT1, and granzyme A. In vivo, T cell- and DC-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T cells, as well as CD8+ T cell infiltration and cytotoxicity in the tumor. In direct relevance to CRC treatment, T cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced antitumor memory formation upon tumor rechallenge in vivo. Our data suggest a role for PTPN2 in suppressing antitumor immunity and promoting tumor development in patients with CRC. Our in vivo results identify PTPN2 as a key player in controlling the immunogenicity of CRC, with the strong potential to be exploited for cancer immunotherapy.


Structure of Cdc42 in a complex with the GTPase-binding domain of the cell polarity protein, Par6.
Cdc42 is a small GTPase that is required for cell polarity establishment in eukaryotes as diverse as budding yeast and mammals. Par6 is also implicated in metazoan cell polarity establishment and asymmetric cell divisions. Cdc42.GTP interacts with proteins that contain a conserved sequence called a CRIB motif. Uniquely, Par6 possesses a semi-CRIB motif that is not sufficient for binding to Cdc42. An adjacent PDZ domain is also necessary and is required for biological effects of Par6. Here we report the crystal structure of a complex between Cdc42 and the Par6 GTPase-binding domain. The semi-CRIB motif forms a beta-strand that inserts between the four strands of Cdc42 and the three strands of the PDZ domain to form a continuous eight-stranded sheet. Cdc42 induces a conformational change in Par6, detectable by fluorescence resonance energy transfer spectroscopy. Nuclear magnetic resonance studies indicate that the semi-CRIB motif of Par6 is at least partially structured by the PDZ domain. The structure highlights a novel role for a PDZ domain as a structural scaffold.


Zebrafish-encoded 3-O-sulfotransferase-3 isoform mediates herpes simplex virus type 1 entry and spread.
Heparan sulfate proteoglycans modified by human glucosaminyl 3-O-sulfotransferase-3 (3-OST-3) isoform generates the cellular receptor for herpes simplex virus type 1 (HSV-1). Interestingly, the ability of zebrafish (ZF)-encoded 3-OST-3 isoform to modify heparan sulfate to mediate HSV-1 entry and cell-cell fusion has not been determined although it is predominantly expressed in ZF, a popular model organism to study viral infections. Here, we demonstrate that expression of ZF-encoded 3-OST-3 isoform renders the resistant Chinese hamster ovary (CHO-K1) cells to become susceptible for HSV-1 entry. The following lines of evidence support the important role of ZF-encoded 3-OST-3 isoform as the mediator of HSV-1 entry into CHO-K1 cells: (1) ZF 3-OST-3-expressing CHO-K1 cells were able to preferentially bind HSV-1 glycoprotein D, and (2) CHO-K1 cells expressing ZF-encoded 3-OST-3 acquire the ability to fuse with cells expressing HSV-1 glycoproteins. Finally, knocking down 3-OST-3 receptor by siRNA in ZF fibroblasts cells significantly reduced HSV-1 entry and glycoprotein D binding to cells. Taken together, our results provide novel insight into the significance of ZF 3-OST-3 isoform as an HSV-1 entry and fusion receptor and its potential involvement in the HSV-1 disease model of ZF.


Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572).
Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitro and suppress viremia in patients. These small molecules bind to the IN active site, causing it to disengage from the deoxyadenosine at the 3' end of viral DNA. The emergence of viral strains that are highly resistant to RAL underscores the pressing need to develop INSTIs with improved resistance profiles. Herein, we show that the candidate second-generation drug dolutegravir (DTG, S/GSK1349572) effectively inhibits a panel of HIV-1 IN variants resistant to first-generation INSTIs. To elucidate the structural basis for the increased potency of DTG against RAL-resistant INs, we determined crystal structures of wild-type and mutant prototype foamy virus intasomes bound to this compound. The overall IN binding mode of DTG is strikingly similar to that of the tricyclic hydroxypyrrole MK-2048. Both second-generation INSTIs occupy almost the same physical space within the IN active site and make contacts with the β4-α2 loop of the catalytic core domain. The extended linker region connecting the metal chelating core and the halobenzyl group of DTG allows it to enter farther into the pocket vacated by the displaced viral DNA base and to make more intimate contacts with viral DNA, compared with those made by RAL and other INSTIs. In addition, our structures suggest that DTG has the ability to subtly readjust its position and conformation in response to structural changes in the active sites of RAL-resistant INs.


FISH analysis of intrapulmonary malignant mesothelioma without a clinically detectable primary pleural lesion: an autopsy case.
Patients with malignant mesothelioma typically present with a pleural effusion or pleural thickening and masses. A rare autopsy case of mesothelioma presenting with multiple bilateral lung nodules without clinically detectable pleural lesions is presented. A definitive diagnosis of the video-assisted thoracic surgery specimen could not be made, though a pattern of fibrosis mimicking organizing pneumonia was identified. Despite corticosteroid therapy, follow-up chest computed tomography showed enlargement of multiple nodules accompanied by the appearance of pleural thickening and effusions. The patient died of respiratory failure 11 months after initial presentation. Autopsy and retrospective analysis of the video-assisted thoracic surgery specimen using a p16 fluorescence in situ hybridization assay showed p16 homozygous deletion. The final diagnosis was sarcomatoid mesothelioma, and the lung nodules were intrapulmonary metastases from a clinically undetectable pleural sarcomatoid mesothelioma. It is important both to consider the possibility of mesothelioma with unusual clinical, radiological and pathological presentations and to remember that p16 fluorescence in situ hybridization analysis can play an important role in the diagnosis of mesothelioma.


A sensitive new microculture method for diagnosis of cutaneous leishmaniasis.
A sensitive microcapillary culture method (MCM) was developed for rapid diagnosis of cutaneous leishmaniasis (CL). The MCM is superior to the traditional culture method (TCM) as determined by the smaller inoculum size, the higher sensitivity for detection of promastigotes, and the more rapid time for emergence of promastigotes. With lesion amastigote loads from grade III to 0, the positive rates and the periods for promastigote emergence were 3-4-fold higher and faster with the MCM than with the TCM, e.g., 83-97% positive in 4-7 days versus 20-40% positive in 15-30 days (P = 0.0001). The higher Pco(2) and lower Po(2) and pH presumably encourage a rapid amastigote-to-promastigote differentiation and/or the survival or growth of the latter. This MCM has the advantage of simplicity, and may be suitable for diagnostic use and for parasite retrieval in many other endemic sites where parasites are known to be difficult to grow.


Avian Influenza A Virus Pandemic Preparedness and Vaccine Development.
Influenza A viruses can infect a wide range of hosts, creating opportunities for zoonotic transmission, i.e., transmission from animals to humans, and placing the human population at constant risk of potential pandemics. In the last hundred years, four influenza A virus pandemics have had a devastating effect, especially the 1918 influenza pandemic that took the lives of at least 40 million people. There is a constant risk that currently circulating avian influenza A viruses (e.g., H5N1, H7N9) will cause a new pandemic. Vaccines are the cornerstone in preparing for and combating potential pandemics. Despite exceptional advances in the design and development of (pre-)pandemic vaccines, there are still serious challenges to overcome, mainly caused by intrinsic characteristics of influenza A viruses: Rapid evolution and a broad host range combined with maintenance in animal reservoirs, making it near impossible to predict the nature and source of the next pandemic virus. Here, recent advances in the development of vaccination strategies to prepare against a pandemic virus coming from the avian reservoir will be discussed. Furthermore, remaining challenges will be addressed, setting the agenda for future research in the development of new vaccination strategies against potentially pandemic influenza A viruses.


Attenuated mTOR Signaling and Enhanced Glucose Homeostasis by Dietary Supplementation with Lotus Seedpod Oligomeric Procyanidins in Streptozotocin (STZ)-Induced Diabetic Mice.
This study investigated the protective role of lotus seedpod oligomeric procyanidins (LSOPC) and synbiotics (Bifidobacterium Bb-12 and xylo-oligosaccharide) against high fat and streptozotocin (STZ)-induced diabetes. Administration of LSOPC or synbiotics had no effect on blood glucose in normal mice. Treatments with LSOPC for 12 weeks markedly reduced blood glucose, FFA, endotoxin, and GHbA1c and improved glucose homeostasis, lipid metabolism, and insulin levels. In addition, administration of LSOPC significantly reversed the increase of mTOR and p66Shc in liver, skeletal muscle, and white adipose tissue (WAT). LSOPC significantly increased glucose uptake and glycolysis in liver, skeletal muscle, and WAT while improving heat generation in brown adipose tissue (BAT) and inhibiting gluconeogenesis and lipogenesis in liver. Furthermore, synbiotics strengthened the improving effect of LSOPC. These findings demonstrated that LSOPC and synbiotics may regulate glucose disposal in peripheral target tissues through the p66Shc-mTOR signaling pathway.


Intraoperative ultrasound in surgery for hepatocellular carcinoma.
Imaging-guided therapeutic procedures have modified the approach to HCC both introducing new treatment modalities and also changing the policy of hepatectomies. Indeed, with intraoperative ultrasonography (IOUS) it is possible to achieve better knowledge about tumor location and staging, also with the aid of contrast-enhanced IOUS. However, IOUS also allows to minimise the rate of major hepatectomies maintaining treatment radicality and widening the indication at surgery. Indeed, precise definition of tumor-vessel relationship, intrahepatic vessel distribution and color-Doppler analysis allows performing hepatectomies otherwise not possible. This so-called "radical but conservative" policy has allowed us a safe surgical approach with minimal mortality and major morbidity and effective local treatment with no tumor relapses at the site of the resection. Techniques for safe and radical IOUS-guided liver resections for HCC are here discussed.


Heavy metals in bottled natural spring water.
New regulations regarding the presence of contaminants in bottled water went into effect in California in January 2009. These requirements include testing, reporting, and notification to regulate the presence of heavy metals in bottled natural spring water sold in California. In the study described in this article, six sources of bottled natural spring water were purchased and analyzed for silver, arsenic, barium, beryllium, cadmium, cobalt, chromium, copper, mercury, molybdenum, nickel, lead, antimony, selenium, thallium, vanadium, and zinc. All of these metals except beryllium, mercury, and thallium were detected in at least one of the bottled natural spring water sources. No concentrations were above either federal or California maximum contaminant levels but arsenic concentrations exceeded California public health goals in all six sources. Improving the California notification requirements for bottled water contaminants would result in a process more similar to the notification process for tap water and would result in better-informed consumers.


Informative Bayesian Model Selection: a method for identifying interactions in genome-wide data.
In high-dimensional genome-wide (GWA) data, a key challenge is to detect genomic variants that interact in a nonlinear fashion in their association with disease. Identifying such genomic interactions is important for elucidating the inheritance of complex phenotypes and diseases. In this paper, we introduce a new computational method called Informative Bayesian Model Selection (IBMS) that leverages correlation among variants in GWA data due to the linkage disequilibrium to identify interactions accurately in a computationally efficient manner. IBMS combines several statistical methods including canonical correlation analysis, logistic regression analysis, and a Bayesians statistical measure of evaluating interactions. Compared to BOOST and BEAM that are two widely used methods for detecting genomic interactions, IBMS had significantly higher power when evaluated on synthetic data. Furthermore, when applied to Alzheimer's disease GWA data, IBMS identified previously reported interactions. IBMS is a useful method for identifying variants in GWA data, and software that implements IBMS is freely available online from http://lbb.ut.ac.ir/Download/LBBsoft/IBMS.


Women and HIV in the Twenty-First Century: How Can We Reach the UN 2030 Goal?
Women have always been part of the HIV/AIDS epidemic. As with other populations affected by HIV, for many years the only prevention strategy available was behavior change. Behavioral interventions for women were developed and evaluated, with some success. Because women did not control the use of male condoms, efficacious interventions needed to build skills for partner negotiation. Woman-controlled technologies such as the female condom and vaginal spermicide were unable to solve the problem of male control of the condom and enable the development of safe methods for women to protect themselves. The modern era of HIV prevention has produced biomedical solutions based on highly active retroviral chemoprophylaxis, which can be hidden from the male partner and thus eliminate his possible negative reactions. Pre-exposure prophylaxis holds promise for HIV prevention among women. This article reviews the literature on HIV prevention for women, including both successes and challenges.


TLR8 Is a Sensor of RNase T2 Degradation Products.
TLR8 is among the highest-expressed pattern-recognition receptors in the human myeloid compartment, yet its mode of action is poorly understood. TLR8 engages two distinct ligand binding sites to sense RNA degradation products, although it remains unclear how these ligands are formed in cellulo in the context of complex RNA molecule sensing. Here, we identified the lysosomal endoribonuclease RNase T2 as a non-redundant upstream component of TLR8-dependent RNA recognition. RNase T2 activity is required for rendering complex single-stranded, exogenous RNA molecules detectable for TLR8. This is due to RNase T2's preferential cleavage of single-stranded RNA molecules between purine and uridine residues, which critically contributes to the supply of catabolic uridine and the generation of purine-2',3'-cyclophosphate-terminated oligoribonucleotides. Thus-generated molecules constitute agonistic ligands for the first and second binding pocket of TLR8. Together, these results establish the identity and origin of the RNA-derived molecular pattern sensed by TLR8.


Tracking Performance in Endurance Racing Sports: Evaluation of the Accuracy Offered by Three Commercial GNSS Receivers Aimed at the Sports Market.
Advances in global navigation satellite system (GNSS) technology have resulted in smaller and more accurate GNSS receivers, which have become increasingly suitable for calculating instantaneous performance parameters during sports competitions, for example by providing the difference in time between athletes at any location along a course. This study investigated the accuracy of three commercially available GNSS receivers directed at the sports market and evaluated their applicability for time analysis in endurance racing sports. The receivers evaluated were a 1 Hz wrist-worn standalone receiver (Garmin Forerunner 920XT, Gar-920XT), a 10 Hz standalone receiver (Catapult Optimeye S5, Cat-S5), and a 10 Hz differential receiver (ZXY-Go). They were validated against a geodetic, multi-frequency receiver providing differential position solutions (accuracy < 5 cm). Six volunteers skied four laps on a 3.05 km track prepared for cross-country skiing, with all four GNSS receivers measuring simultaneously. Deviations in position (horizontal plane, vertical, direction of travel) and speed (horizontal plane and direction of travel) were calculated. In addition, the positions of all receivers were mapped onto a mapping trajectory along the ski track, and a time analysis of all 276 possible pairs of laps was performed. Specifically, the time difference between any two skiers for each integer meter along the track was calculated. ZXY-Go, CAT-S5, and GAR-920XT had horizontal plane position errors of 2.09, 1.04, and 5.29 m (third quartile, Q3), and vertical precision 2.71, 3.89, and 13.35 m (interquartile range, IQR), respectively. The precision in the horizontal plane speed was 0.038, 0.072, and 0.66 m s-1 (IQR) and the time analysis precision was 0.30, 0.13, and 0.68 s (IQR) for ZXY-Go, Cat-S5, and Gar-920XT, respectively. However, the error was inversely related to skiing speed, implying that for the low speeds typically attained during uphill skiing, substantially larger errors can occur. Specifically, at 2.0 m s-1 the Q3 was 0.96, 0.36, and 1.90 s for ZXY-Go, Cat-S5, and Gar-920XT, respectively. In summary, the differential (ZXY-Go) and 10 Hz standalone (Cat-S5) receivers performed substantially better than the wrist-worn receiver (Gar-920XT) in terms of horizontal position and horizontal speed calculations. However, all receivers produced sub-second accuracy in the time analysis, except at very low skiing speeds.


Advances in the detection of as in environmental samples using low energy X-ray fluorescence in a scanning transmission X-ray microscope: arsenic immobilization by an Fe(II)-oxidizing freshwater bacteria.
Speciation and quantitative mapping of elements, organic and inorganic compounds, and mineral phases in environmental samples at high spatial resolution is needed in many areas of geobiochemistry and environmental science. Scanning transmission X-ray microscopes (STXMs) provide a focused beam which can interrogate samples at a fine spatial scale. Quantitative chemical information can be extracted using the transmitted and energy-resolved X-ray fluorescence channels simultaneously. Here we compare the relative merits of transmission and low-energy X-ray fluorescence detection of X-ray absorption for speciation and quantitative analysis of the spatial distribution of arsenic(V) within cell-mineral aggregates formed by Acidovorax sp. strain BoFeN1, an anaerobic nitrate-reducing Fe(II)-oxidizing β-proteobacteria isolated from the sediments of Lake Constance. This species is noted to be highly tolerant to high levels of As(V). Related, As-tolerant Acidovorax-strains have been found in As-contaminated groundwater wells in Bangladesh and Cambodia wherein they might influence the mobility of As by providing sorption sites which might have different properties as compared to chemically formed Fe-minerals. In addition to demonstrating the lower detection limits that are achieved with X-ray fluorescence relative to transmission detection in STXM, this study helps to gain insights into the mechanisms of As immobilization by biogenic Fe-mineral formation and to further the understanding of As-resistance of anaerobic Fe(II)-oxidizing bacteria.


The Italian version of the Fibrofatigue Scale, a reliable tool for the evaluation of fibromyalgia symptoms.
To validate a translated Italian version of the Fibrofatigue Scale (FFS). The Italian version of FFS was administered to 60 patients affected by fibromyalgia (FM) (57 patients were interviewed again 10 days later) together with the Italian version of the Fibromyalgia Impact Questionnaire (FIQ), the Stanford Health Assessment Questionnaire (HAQ) and the Medical Outcome Survey Short Form-36 (SF-36). All patients were asked about the severity of pain today (10-cm visual analogue scale) and the duration of symptoms. Test-retest reliability was assessed using Spearman correlations. Internal consistency was evaluated with Cronbach's alpha of reliability. Construct validity of the FFS was evaluated by correlations among the FFS, the FIQ and the subscales of the SF-36. Mean duration of symptoms was 7.6 years, and mean age of participants was 56.3 years. Test-retest reliability was between 0.70 and 0.95 for the single items as well as for the total FFS and other components. Internal consistency was 0.90 for the overall FFS. Significant correlations were obtained between the FFS items and the SF-36. The Italian FFS is a reliable and valid instrument for detecting and measuring functional disability and symptoms severity in Italian patients with FM.


Inhibition of androgen-independent prostate cancer cell growth is enhanced by combination therapy targeting Hedgehog and ErbB signalling.
Prostate cancer is a leading cause of male cancer specific mortality. When cure by radical prostatectomy is not possible the next line of prostate cancer treatment is androgen deprivation. However prolonged androgen deprivation often results in relapse and androgen-independent prostate cancer that is inevitably fatal despite optimal chemotherapy. The Hedgehog signalling pathway has recently been implicated in prostate cancer development and metastasis. EGFR or ErbB2 expression has been also correlated with androgen independence, shorter survival and metastasis. We determined that the Hedgehog and ErbB signalling pathways are active in circulating tumour cells isolated from androgen-independent prostate cancer patients and in the androgen-independent prostate cancer cell line LNCaP C4-2B. As a basis for synergistic chemotherapy protocols combinations of the Hedgehog specific inhibitor cyclopamine and the ErbB signalling inhibitors gefitinib or lapatinib were tested in this study. Androgen-independent prostate cancer cell growth was inhibited by a SMO inhibitor (cyclopamine) which blocks Hedgehog signalling and by ErbB inhibitors (gefitinib and lapatinib). The isobologram and combination index method of Chou and Talalay was used to evaluate drug interactions. Synergistic antiproliferation effects were observed when the Hedgehog and ErbB inhibitors were combined. Androgen-independent prostate cancer cell proliferation was associated with activity of the Hedgehog and ErbB signalling pathways. Cyclopamine, gefitinib or lapatinib treatment significantly decreased the proliferation of androgen-independent prostate cancer cells. The Hedgehog pathway therefore represents a promising new therapeutic target in androgen-independent prostate cancer. Synergistic effects were observed when Hedgehog and ErbB inhibitors were used together. This study may have clinical implications for improving the treatment of advanced prostate cancer.


Radiosurgery for parasagittal and parafalcine meningiomas.
Parasagittal and parafalcine (PSPF) meningiomas represent the second most common location for intracranial meningiomas. Involvement of the superior sagittal sinus or deep draining veins may prevent gross-total resection of these tumors without significant morbidity. The authors review their results for treatment of PSPF meningiomas with radiosurgery. The authors retrospectively reviewed the institutional review board-approved University of Virginia Gamma Knife database and identified 65 patients with 90 WHO Grade I parasagittal (59%) and parafalcine (41%) meningiomas who had a mean MRI follow-up of 56.6 months. The patients' mean age was 57 years, the median preradiosurgery Karnofsky Performance Status score was 80, and the median initial tumor and treatment volumes were 3 and 3.7 cm(3), respectively. The median prescription dose was 15 Gy, isodose line was 40%, and the number of isocenters was 5. Kaplan-Meier analysis was used to determine progression-free survival (PFS). Univariate and multivariate Cox regression analyses were used to identify factors associated with PFS. The median overall PFS was 75.6 months. The actuarial tumor control rate was 85% at 3 years and 70% at 5 years. Parasagittal location, no prior resection, and younger age were found to be independent predictors of tumor PFS. For the 49 patients with clinical follow-up (mean 70.8 months), the median postradiosurgery Karnofsky Performance Status score was 90. Symptomatic postradiosurgery peritumoral edema was observed in 4 patients (8.2%); this group comprised 3 patients (6.1%) with temporary and 1 patient (2%) with permanent clinical sequelae. Two patients (4.1%) died of tumor progression. Radiosurgery offers a minimally invasive treatment option for PSPF meningiomas, with a good tumor control rate and an acceptable complication rate comparable to most surgical series.