Risk Factors for Tremor in a Population of Patients with Severe Mental Illness: An 18-year Prospective Study in a Geographically Representative Sample (The Curacao Extrapyramidal Syndromes Study XI).
The aim was to assess incidence, prevalence and risk factors of medication-induced tremor in African-Caribbean patients with severe mental illness (SMI). A prospective study of SMI patients receiving care from the only mental health service of the previous Dutch Antilles. Eight clinical assessments, over 18 years, focused on movement disorders, medication use, and resting tremor (RT) and (postural) action tremor (AT). Risk factors were modeled with logistic regression for both current (having) tremor and for tremor at the next time point (developing). The latter used a time-lagged design to assess medication changes prior to a change in tremor state. Yearly tremor incidence rate was 2.9% and mean tremor point prevalence was 18.4%. Over a third of patients displayed tremor during the study. Of the patients, 5.2% had AT with 25% of cases persisting to the next time point, while 17.1% of patients had RT of which 65.3% persisted. When tremor data were examined in individual patients, they often had periods of tremor interspersed with periods of no tremor. Having RT was associated with age (OR=1.07 per year; 95% confidence interval 1.03-1.11), sex (OR=0.17 for males; 0.05-0.78), cocaine use (OR=10.53; 2.22-49.94), dyskinesia (OR=0.90; 0.83-0.97), and bradykinesia (OR=1.16; 1.09-1.22). Developing RT was strongly associated with previous measurement RT (OR=9.86; 3.80-25.63), with previous RT severity (OR=1.22; 1.05-1.41), and higher anticholinergic load (OR= 1.24; 1.08-1.43). Having AT was associated with tremor-inducing medication (OR= 4.54; 1.90-10.86), cocaine use (OR=14.04; 2.38-82.96), and bradykinesia (OR=1.07; 1.01-1.15). Developing AT was associated with, previous AT severity (OR=2.62 per unit; 1.64-4.18) and tremor reducing medication (OR=0.08; 0.01-0.55). Long-stay SMI patients are prone to developing tremors, which show a relapsing-remitting course. Differentiation between RT and AT is important as risk factors differ and they require different prevention and treatment strategies.


Facial Action Recognition Combining Heterogeneous Features via Multikernel Learning.
This paper presents our response to the first international challenge on facial emotion recognition and analysis. We propose to combine different types of features to automatically detect action units (AUs) in facial images. We use one multikernel support vector machine (SVM) for each AU we want to detect. The first kernel matrix is computed using local Gabor binary pattern histograms and a histogram intersection kernel. The second kernel matrix is computed from active appearance model coefficients and a radial basis function kernel. During the training step, we combine these two types of features using the recently proposed SimpleMKL algorithm. SVM outputs are then averaged to exploit temporal information in the sequence. To evaluate our system, we perform deep experimentation on several key issues: influence of features and kernel function in histogram-based SVM approaches, influence of spatially independent information versus geometric local appearance information and benefits of combining both, sensitivity to training data, and interest of temporal context adaptation. We also compare our results with those of the other participants and try to explain why our method had the best performance during the facial expression recognition and analysis challenge.


Imagery rehearsal therapy and/or mianserin in treatment of refugees diagnosed with PTSD: Results from a randomized controlled trial.
Sleep disturbances are frequently part of the symptomatology in refugees with post-traumatic stress disorder (PTSD). It has been suggested that targeting sleep disturbances may enhance the outcome of PTSD treatment. However, randomized studies on the effect of treatment focusing on sleep disturbances in refugees with PTSD are lacking. The aim of this study was to examine add-on treatment with imagery rehearsal therapy (IRT) and/or mianserin against treatment as usual (TAU) alone in a sample of trauma-affected refugees with PTSD at 8-12 months follow-up. In a randomized controlled trial, 219 adult refugees diagnosed with PTSD and suffering from sleep disturbances were randomized to four groups (1:1:1:1) receiving, respectively, TAU, TAU + mianserin, TAU + IRT, and TAU + IRT + mianserin. The primary outcome was subjective sleep quality (Pittsburgh Sleep Quality Index) and the secondary outcomes included PTSD and depression symptoms, level of functioning and subjective well-being. The data were analysed using mixed models. The only significant effect of IRT was on level of functioning (p = .040, ES 0.44), whereas there was no significant effect of mianserin on any of the measured outcomes. Low adherence to both IRT (39%) and mianserin (20%) was observed. Contrary to our hypothesis, we did not find IRT or mianserin to be superior to TAU. The low adherence may potentially cause an underestimation of the effect of IRT and mianserin and indicates a necessity to further analyse the complex factors that may impact the motivation and ability of trauma-affected refugees to participate in and profit from available treatment options.


Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo.
Substantial evidence indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have potential as chemopreventative/therapeutic agents. However, these agents cannot be universally recommended for prevention purposes due to their potential side-effect profiles. Here, we compared the growth inhibitory and mechanistic activity of aspirin to two novel analogues, diaspirin (DiA) and fumaryl diaspirin (F-DiA). We found that the aspirin analogues inhibited cell proliferation and induced apoptosis of colorectal cancer cells at significantly lower doses than aspirin. Similar to aspirin, we found that an early response to the analogues was a reduction in levels of cyclin D1 and stimulation of the NF-κB pathway. This stimulation was associated with a significant reduction in basal levels of NF-κB transcriptional activity, in keeping with previous data for aspirin. However, in contrast to aspirin, DiA and F-DiA activity was not associated with nucleolar accumulation of RelA. For all assays, F-DiA had a more rapid and significant effect than DiA, identifying this agent as particularly active against colorectal cancer. Using a syngeneic colorectal tumour model in mice, we found that, while both agents significantly inhibited tumour growth in vivo, this effect was particularly pronounced for F-DiA. These data identify two compounds that are active against colorectal cancer in vitro and in vivo. They also identify a potential mechanism of action of these agents and shed light on the chemical structures that may be important for the antitumour effects of aspirin.


Effector-Dependent and -Independent Molecular Mechanisms of Soybean-Microbe Interaction.
Soybean is a pivotal staple crop worldwide, supplying the main food and feed plant proteins in some countries. In addition to interacting with mutualistic microbes, soybean also needs to protect itself against pathogens. However, to grow inside plant tissues, plant defense mechanisms ranging from passive barriers to induced defense reactions have to be overcome. Pathogenic but also symbiotic micro-organisms effectors can be delivered into the host cell by secretion systems and can interfere with the immunity system and disrupt cellular processes. This review summarizes the latest advances in our understanding of the interaction between secreted effectors and soybean feedback mechanism and uncovers the conserved and special signaling pathway induced by pathogenic soybean cyst nematode, Pseudomonas, Xanthomonas as well as by symbiotic rhizobium.


Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor.
Reprofiling of existing drugs to treat conditions not originally targeted is an attractive means of addressing the problem of a decreasing stream of approved drugs. To determine if 3D shape similarity can be used to rationalize an otherwise serendipitous process, we employed 3D shape-based virtual screening to reprofile existing FDA-approved drugs. The study was conducted in two phases. First, multiple histamine H(1) receptor antagonists were identified to be used as query molecules, and these were compared to a database of approved drugs. Second, the hits were ranked according to 3D similarity and the top drugs evaluated in a cell-based assay. The virtual screening methodology proved highly successful, as 13 of 23 top drugs tested selectively inhibited histamine-induced calcium release with the best being chlorprothixene (IC(50) 1 nM). Finally, we confirmed that the drugs identified using the cell-based assay were all acting at the receptor level by conducting a radioligand-binding assay using rat membrane.


Polarization effects in optically bound particle arrays.
Sub-micron polystyrene spheres spontaneously assemble into twodimensional arrays in the evanescent field of counterpropagating laser beams at the silica-water interface. The symmetry and dynamics of these arrays depends on the particle size and the polarization of the two laser beams. Here we describe the polarization effects for particles with diameters of 390-520 nm, which are small enough to form regular 2-D arrays yet large enough to be readily observed with an optical microscope. We report the observation of rectangular arrays, three different types of hexagonal arrays and a defective array in which every third row is missing. The structure of the arrays is determined by both optical trapping and optical binding. Optical binding can overwhelm optical trapping and give rise to an array that is incommensurate with the interference fringes formed by two laser beams of the same polarization.


A framework to identify contributing genes in patients with Phelan-McDermid syndrome.
Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.


Localised to intraligand charge-transfer states in cyclometalated platinum complexes: an experimental and theoretical study into the influence of electron-rich pendants and modulation of excited states by ion binding.
The neopentyl ester of 1,3-di(2-pyridyl)benzene-5-boronic acid (dpy-B) is a useful intermediate in the divergent synthesis of N;C;N-coordinating, 1,3-di(2-pyridyl)benzene ligands, HL(n), that carry aryl substituents at the 5-position of the central ring. The platinum(ii) complexes, PtL(n)Cl, of several such ligands have been prepared, incorporating pendant anisoles, arylamines, an oxacrown, and an azacrown, all of which are strongly luminescent in solution at 298 K. The emission of the complexes is partially quenched by oxygen, and all of the compounds are very efficient sensitisers of singlet oxygen. The quantum yields of (1)O(2) formation have been measured on the basis of the intensity of the O(2)(1)Delta(g) emission at 1270 nm, and are in the range 0.25-0.65. Density functional theory (DFT) calculations have been carried out that include the effect of the solvent, on the unsubstituted complex PtL(1)Cl and on the derivatives incorporating p-dimethylaminophenyl and phenyl-15-mono-N-azacrown-5 pendants (PtL(9)Cl and PtL(12)Cl respectively). Absorption spectra have been simulated on the basis of the calculated singlet excitations: they closely resemble the experimental spectra. In particular, the DFT successfully accounts for the appearance of low-energy absorption bands that accompany the introduction of the aryl pendants, indicating the participation of the aryl group in the HOMO but not significantly in the LUMO. The calculated lowest energy triplet excitation of PtL(1)Cl is close to the observed 0-0 emission maximum of this complex in solution. Taking together data for this series of complexes and related compounds previously studied, the energies of the lowest-energy spin-allowed absorption bands are shown to correlate approximately linearly with the oxidation peak potential. The emission energies show a similar correlation in toluene, but in CH2Cl2 the value for PtL(9)Cl is anomalously low. The differing emission properties of this complex in the two solvents suggest a switch to a TICT-like state in CH2Cl2 (TICT = twisted intramolecular charge transfer), stabilised in the more polar environment. Transient DC photoconductivity measurements confirm that the dipole moment of the triplet excited state is larger in CH2Cl2 than in toluene. The azacrown PtL(12)Cl displays similar behaviour. Binding of metal ions such as Ca2+ to the azacrown unit of this complex leads to a pronounced blue shift in the emission, which can be readily understood in terms of the large increase in the TICT energy that will accompany the binding of the metal ion to the lone pair of the azacrown nitrogen atom.


Perspectives of pharmacy employees on an inappropriate use of antimicrobials in Kathmandu, Nepal.
Unregulated antimicrobial use is common in both hospital and community settings of low- and middle-income countries (LMICs). However, discrete data regarding the use/misuse of antimicrobials at pharmacies in LMICs are limited. This study was conducted to understand knowledge, attitude, and practice of pharmacy employees on antimicrobial dispensing in Nepal. We conducted a cross-sectional survey using a structured questionnaire on 801 pharmacy employees working in community and hospital pharmacies located in Lalitpur metropolitan city (LMC) of Kathmandu, Nepal between April 2017 and March 2019. A majority (92%) of respondents agreed that demand for non-prescription antimicrobials was common. Asking for prescription before dispensing was ranked as the first preference by majority (69%) of participants. Suspected respiratory tract infection was the most common reason demanding for non-prescription antimicrobials with the highest mean rank of 1.5. Azithromycin was the most commonly prescribed and sold antimicrobial, as reported by 46% and 48% of participants respectively. A majority (87%) of respondents agreed on antimicrobial resistance (AMR) to be a global public health threat; and misuse/overuse of antimicrobials was perceived as the most common cause of AMR with a mean rank of 1.93. Our study revealed that unfounded dispensing and use of antimicrobials is prevalent among pharmacies in Kathmandu, Nepal. This over reliance on antimicrobials, notably azithromycin, may escalate burden of AMR. We identified several drivers of inappropriate antimicrobial dispensing practice in pharmacies, which will aid public health authorities in addressing these issues. Further studies considering role of other stakeholders, such as doctors, veterinarians, general public, and policy makers are required to obtain a more holistic perspectives on practices of antimicrobial use so to curb the extant AMR crisis.


Molecular characterization of a trafficking organelle: dissecting the axonal paths of calsyntenin-1 transport vesicles.
Kinesin motors play crucial roles in the delivery of membranous cargo to its destination and thus for the establishment and maintenance of cellular polarization. Recently, calsyntenin-1 was identified as a cargo-docking protein for Kinesin-1-mediated axonal transport of tubulovesicular organelles along axons of central nervous system neurons. To further define the function of calsyntenin-1, we immunoisolated calsyntenin-1 organelles from murine brain homogenates and determined their proteome by MS. We found that calsyntenin-1 organelles are endowed with components of the endosomal trafficking machinery and contained the β-amyloid precursor protein (APP). Detailed biochemical analyses of calsyntenin-1 immunoisolates in conjunction with immunocytochemical colocalization studies with cultured hippocampal neurons, using endosomal marker proteins for distinct subcompartments of the endosomal pathways, indicated that neuronal axons contain at least two distinct, nonoverlapping calsyntenin-1-containing transport packages: one characterized as early-endosomal, APP positive, the other as recycling-endosomal, APP negative. We postulate that calsyntenin-1 acts as a general mediator of anterograde axonal transportation of endosomal vesicles. In this role, calsyntenin-1 may actively contribute to axonal growth and pathfinding in the developing as well as to the maintenance of neuronal polarity in the adult nervous system; further, it may actively contribute to the stabilization of APP during its anterograde axonal trajectory.


Are referral centers for non-muscle-invasive bladder cancer compliant to EAU guidelines? A report from the vesical antiblastic therapy Italian study.
Adherence to international guidelines is viewed as a prerequisite for optimal medical care delivery. Previously reported surveys for non-muscle-invasive bladder cancer (NMIBC) employed mailed questionnaires to urologists or patients resulting in conflicting degrees of agreement with existing guidelines. In the current study, contemporary information on the management of NMIBC was generated from a sample of italian centers. Eight Italian referral centers for the treatment of NMIBC were asked to collect information relative to all consecutive patients with a histology-proven NMIBC undergoing a transurethral resection from January 1 to March 31, 2009. The primary study objective was to verify the level of adherence of disease management with European guidelines. 344 patients resulted in being evaluable. 49.2% of high-risk patients underwent a repeat transurethral resection. Bacillus Calmette-Guérin was employed in 35% of cases, while chemotherapy was in 22%. An early single regimen was adopted in 136 patients and only in 1 out of 3 low-risk patients. High-risk NMIBC received bacillus Calmette-Guérin and chemotherapy as first-line therapy in 66 and 12.5% respectively. After 3 months, cystoscopy had been reported for 82.5% of patients with a recurrence rate of 13%. Adherence of Italian Institutions to EAU guidelines was optimal when reporting baseline variables. Significant degrees of discrepancy emerged in treatment choices.


A single-stage optical load-balanced switch for data centers.
Load balancing is an attractive technique to achieve maximum throughput and optimal resource utilization in large-scale switching systems. However current electronic load-balanced switches suffer from severe problems in implementation cost, power consumption and scaling. To overcome these problems, in this paper we propose a single-stage optical load-balanced switch architecture based on an arrayed waveguide grating router (AWGR) in conjunction with fast tunable lasers. By reuse of the fast tunable lasers, the switch achieves both functions of load balancing and switching through the AWGR. With this architecture, proof-of-concept experiments have been conducted to investigate the feasibility of the optical load-balanced switch and to examine its physical performance. Compared to three-stage load-balanced switches, the reported switch needs only half of optical devices such as tunable lasers and AWGRs, which can provide a cost-effective solution for future data centers.


Significant reduction in advanced breast cancer. Results of the first seven years of mammography screening in Kopparberg, Sweden.
A population-based, randomized, controlled breast cancer screening trial with single-view mammography as the only means of primary detection has been under way in Kopparberg county, Sweden, since October 1977. The 7-year results of the study show (1) a significant change in the stage distribution of breast cancers in the cohort invited to undergo screening (ASP) as compared to the control group. (2) This change is seen as an initial decrease in the proportion of advanced (stage II and more advanced) cancers in the ASP as compared to the control population, followed in the second and third round of screening by a significant decrease in the absolute number of these advanced cancers in the ASP relative to the control group. (3) A thorough follow-up of both populations will answer whether these preliminary findings will result in decreased breast cancer mortality in the population invited to screening.


Cooee bitumen: chemical aging.
We study chemical aging in "Cooee bitumen" using molecular dynamic simulations. This model bitumen is composed of four realistic molecule types: saturated hydrocarbon, resinous oil, resin, and asphaltene. The aging reaction is modelled by the chemical reaction: "2 resins → 1 asphaltene." Molecular dynamic simulations of four bitumen compositions, obtained by a repeated application of the aging reaction, are performed. The stress autocorrelation function, the fluid structure, the rotational dynamics of the plane aromatic molecules, and the diffusivity of each molecule are determined for the four different compositions. The aging reaction causes a significant dynamics slowdown, which is correlated to the aggregation of asphaltene molecules in larger and dynamically slower nanoaggregates. Finally, a detailed description of the role of each molecule types in the aggregation and aging processes is given.


Chirped dissipative soliton absorption spectroscopy.
We present analytical theory of dissipative soliton absorption spectroscopy. A dissipative soliton formed in an all-normal-dispersion oscillator with a narrowband intracavity absorber acquires spectral features that follow the index of refraction of the absorber, as confirmed by numerical simulations and experimental evidence. In contrast to the soliton absorption spectroscopy in an anomalous dispersion regime, we anticipate resonant enhancement of a modulation signal near the pulse spectrum edges that results in an additional signal gain. We further show that the pulse acquires a nanosecond-long tail in the time domain and provide simple formula for estimation of its energy content.


Probing prokaryotic social behaviors with bacterial "lobster traps".
Bacteria are social organisms that display distinct behaviors/phenotypes when present in groups. These behaviors include the abilities to construct antibiotic-resistant sessile biofilm communities and to communicate with small signaling molecules (quorum sensing [QS]). Our understanding of biofilms and QS arises primarily from in vitro studies of bacterial communities containing large numbers of cells, often greater than 10(8) bacteria; however, in nature, bacteria often reside in dense clusters (aggregates) consisting of significantly fewer cells. Indeed, bacterial clusters containing 10(1) to 10(5) cells are important for transmission of many bacterial pathogens. Here, we describe a versatile strategy for conducting mechanistic studies to interrogate the molecular processes controlling antibiotic resistance and QS-mediated virulence factor production in high-density bacterial clusters. This strategy involves enclosing a single bacterium within three-dimensional picoliter-scale microcavities (referred to as bacterial "lobster traps") defined by walls that are permeable to nutrients, waste products, and other bioactive small molecules. Within these traps, bacteria divide normally into extremely dense (10(12) cells/ml) clonal populations with final population sizes similar to that observed in naturally occurring bacterial clusters. Using these traps, we provide strong evidence that within low-cell-number/high-density bacterial clusters, QS is modulated not only by bacterial density but also by population size and flow rate of the surrounding medium. We also demonstrate that antibiotic resistance develops as cell density increases, with as few as ~150 confined bacteria exhibiting an antibiotic-resistant phenotype similar to biofilm bacteria. Together, these findings provide key insights into clinically relevant phenotypes in low-cell-number/high-density bacterial populations.


Mechanical recanalization for clot occlusion of venous access ports: experimental study using ports with clot occlusion.
To test the hypothesis that mechanical injection of saline is safe and effective in restoring patency of totally implantable venous access ports (TIVAPs) with clot occlusion. We devised an experimental port model for the evaluation of mechanical TIVAP recanalization prior to its clinical application. The clot TIVAP occlusion model was constructed by filling the catheter with swine blood and incubating it at 37.5°C. The model was incubated for different lengths of time ranging from 1 day to 7 days. Each incubation time point included 20 ports. Total catheter occlusion of the TIVAPs was assessed with a 10-mL saline syringe equipped with a non-coring needle. Occlusion was defined as no passage of saline through the catheter when it was aspirated and infused gently with the 10-mL saline syringe. Pressure was evaluated during recanalization with an indeflator. Histological examination was performed on the clot obtained during recanalization. Among the 140 total experimental ports, 65 occlusions (46.4%) were detected. Of these 65 occlusions, 56 (86.1%) were recanalized by mechanical saline pressure via the indeflator. The indeflator pressure ranged from 29 pound per square-inch (psi) to 265 psi at mechanical catheter recanalization (mean: 110 psi). Histologically, all specimens from the model ports exhibited a similar appearance; specifically, erythrocytes, cells, and fibrin were evenly scattered throughout the clot. Our data indicate that it is feasible to generate a TIVAP clot occlusion model with swine blood. Moreover, mechanical recanalization was suitable for resolving occluded catheters without thrombolytic agents.


A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders.
Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.


Classification of various sources of error in range assessment using proton radiography and neural networks in head and neck cancer patients.
This study evaluates the suitability of convolutional neural networks (CNNs) to automatically process proton radiography (PR)-based images. CNNs are used to classify PR images impaired by several sources of error affecting the proton range, more precisely setup and calibration curve errors. PR simulations were performed in 40 head and neck cancer patients, at three different anatomical locations (fields A, B and C, centered for head and neck, neck and base of skull coverage). Field sizes were 26 × 26cm2for field A and 4.5 × 4.5cm2for fields B and C. Range shift maps were obtained by comparing an unperturbed reference PR against a PR where one or more sources of error affected the proton range. CT calibration curve errors in soft, bone and fat tissues and setup errors in the anterior-posterior and inferior-superior directions were simulated individually and in combination. A CNN was trained for each type of PR field, leading to three CNNs trained with a mixture of range shift maps arising from one or more sources of range error. To test the full/partial/wrong agreement between predicted and actual sources of range error in the range shift maps, exact, partial and wrong match percentages were computed for an independent test dataset containing range shift maps arising from isolated or combined errors, retrospectively. The CNN corresponding to field A showed superior capability to detect isolated and combined errors, with exact matches of 92% and 71% respectively. Field B showed exact matches of 80% and 54%, and field C resulted in exact matches of 77% and 41%. The suitability of CNNs to classify PR-based images containing different sources of error affecting the proton range was demonstrated. This procedure enables the detection of setup and calibration curve errors when they appear individually or in combination, providing valuable information for the interpretation of PR images.


Insights on Aboriginal peoples' views of cancer in Australia.
Although the incidence of cancer in Indigenous peoples is similar to its incidence in the overall Australian population, Indigenous peoples are less likely to access early detection and medical interventions resulting in higher mortality and morbidity rates. To explore and address this discrepancy, the National Health and Medical Research Council funded a research study to examine Indigenous peoples' views of cancer and cancer treatments with an end goal of developing an innovative model of Indigenous Palliative Care. Seventy-two participants were interviewed from four geographical areas within the Northern Territory (Australia) including patients, caregivers, Indigenous and non-Indigenous health care workers, and interpreters. Indigenous peoples' views of cancer have to be examined within a historical, socio-political, and cultural context. There is no Indigenous word for cancer and the Western biomedical language that semantically constructs the notion of cancer is not widely understood. Additionally, for many Indigenous people, the aetiology of cancer is embedded in beliefs about the spiritual world of curses and payback from perceived misdeeds. The paper advocates for cross-cultural education initiatives, stressing the importance of a two way education strategy incorporating a process whereby medical and nursing personnel would improve their understanding of Indigenous peoples' view of cancer and Indigenous peoples would learn more about prevention and treatment of cancer from a biomedical perspective.


Actual practices in nephropathology: a survey and comparison with best practices.
Nephropathology is a specialized field requiring routine tissue evaluation by immunofluorescence (IF), electron microscopy (EM), and light microscopy, and has published standards of best practice. Actual practices are less well documented. We therefore evaluated actual practices in nephropathology and their divergence from best practices. One hundred and twenty Renal Pathology Society members were given questionnaires regarding tissue handling, processing, and staining. Appropriate statistics for each question were calculated from results compiled into Microsoft Excel. Responses from 75 members showed that most received 16 or 18 gauge core biopsies, examined 9 slides for native kidneys, 8 slides for transplant kidneys, and for both used hematoxylin and eosin, periodic acid-Schiff, trichrome, and silver stains. For native kidney biopsies, most collected for IF and EM if tissue was adequate, while clinical input could influence the rest. Almost all performed IF on adequate samples, with a minimum of 8 antibodies, including both light chains, those from Europe sometimes without proof of adequacy. Half performed EM unconditionally, the remainder based on specimen adequacy or clinical input. For transplant kidney biopsies, most collected tissue for IF and EM only with specific clinical indications, performed C4d IF on frozen tissue if available, but few used the native kidney IF panel. Very few performed EM unconditionally, but most would if given specific indications. We conclude that actual nephropathology practices within the Renal Pathology Society are geographically uniform and similar to published best practices, with divergence in performing IF and EM on the basis of specimen adequacy and clinical input, particularly in transplant biopsies.


Estimation of the impact of genital warts on health-related quality of life.
One of the two new human papillomavirus (HPV) vaccines protects against HPV types 6 and 11, which cause over 95% of genital warts, in addition to protecting against HPV types 16 and 18. In anticipation of HPV vaccine implementation, the impact of genital warts on health-related quality of life (HRQoL) was measured to assess the potential benefits of the quadrivalent over the bivalent vaccine. Genitourinary medicine clinic patients aged 18 years and older with a current diagnosis of genital warts were eligible; 81 consented and were interviewed by a member of the research team. A generic HRQoL questionnaire, the EQ-5D (comprising EQ-5D index and EQ visual analogue scale (VAS) scores) and a disease-specific HRQoL instrument, the CECA10, were administered. Previously established UK population norms were used as a control group for EQ-5D comparisons. Cases (with genital warts) had lower EQ VAS and EQ-5D index scores than controls. After adjusting for age a mean difference between cases and controls 30 years of age and under (n = 70) of 13.9 points (95% CI 9.9 to 17.6, p<0.001) for the EQ VAS and 0.039 points (95% CI 0.005 to 0.068, p = 0.02) on the EQ-5D index (also adjusted for sex) was observed. The difference between cases and controls for the EQ VAS was especially notable in young women. Genital warts are associated with a significant detriment to HRQoL. The potential added benefit of preventing most cases of genital warts by HPV vaccination should be considered in decisions about which HPV vaccine to implement in the United Kingdom.


Serum level of VEGF-D in patients with primary lymphedema.
Recent studies have indicated that vascular endothelial growth factor-D (VEGF-D) stimulates lymphangiogenesis in humans. Furthermore, mutations of vascular endothelial growth factor receptor 3 (VEGFR-3) have been observed in families with hereditary lymphedema. The lack of stimulation of lymphangiogenesis could lead to production of even more VEGF-D to obtain stimulation of lymphangiogenesis resulting in a high serum level of VEGF-D. The aim of the present study was to compare the serum level of VEGF-D in patients with primary lymphedema with healthy controls. In a prospective study, the serum level of VEGF-D was determined by a solid phase ELISA in patients with primary lymphedema and compared with healthy controls. In the group of patients with primary lymphedema the serum level of VEGF-D was significantly higher compared with controls (p=0.0047). The increased levels of VEGF-D observed in the present study suggest that primary lymphedema may be based on defective stimulation of VEGFR-3.


Molecular insights into mammalian end-binding protein heterodimerization.
Microtubule plus-end tracking proteins (+TIPs) are involved in many microtubule-based processes. End binding (EB) proteins constitute a highly conserved family of +TIPs. They play a pivotal role in regulating microtubule dynamics and in the recruitment of diverse +TIPs to growing microtubule plus ends. Here we used a combination of methods to investigate the dimerization properties of the three human EB proteins EB1, EB2, and EB3. Based on Förster resonance energy transfer, we demonstrate that the C-terminal dimerization domains of EBs (EBc) can readily exchange their chains in solution. We further document that EB1c and EB3c preferentially form heterodimers, whereas EB2c does not participate significantly in the formation of heterotypic complexes. Measurements of the reaction thermodynamics and kinetics, homology modeling, and mutagenesis provide details of the molecular determinants of homo- versus heterodimer formation of EBc domains. Fluorescence spectroscopy and nuclear magnetic resonance studies in the presence of the cytoskeleton-associated protein-glycine-rich domains of either CLIP-170 or p150(glued) or of a fragment derived from the adenomatous polyposis coli tumor suppressor protein show that chain exchange of EBc domains can be controlled by binding partners. Extension of these studies of the EBc domains to full-length EBs demonstrate that heterodimer formation between EB1 and EB3, but not between EB2 and the other two EBs, occurs both in vitro and in cells as revealed by live cell imaging. Together, our data provide molecular insights for rationalizing the dominant negative control by C-terminal EB domains and form a basis for understanding the functional role of heterotypic chain exchange by EBs in cells.


Cyclic AMP-modulated potassium channels in murine B cells and their precursors.
A voltage-dependent potassium current (the delayed rectifier) has been found in murine B cells and their precursors with the whole-cell patch-clamp technique. The type of channel involved in the generation of this current appears to be present throughout all stages of pre-B-cell differentiation, since it is detected in pre-B cell lines infected with Abelson murine leukemia virus; these cell lines represent various phases of B-cell development. Thus, the presence of this channel is not obviously correlated with B-cell differentiation. Although blocked by Co2+, the channel, or channels, does not appear to be activated by Ca2+ entry. It is, however, inactivated by high intracellular Ca2+ concentrations. In addition, elevation of intracellular adenosine 3', 5'-monophosphate induces at all potentials a rapid decrease in the peak potassium conductance and increased rates of activation and inactivation. Therefore, potassium channels can be physiologically modulated by second messengers in lymphocytes.


Protective care-receiving: the active role of care-recipients.
Historical and contemporary conceptualizations of caregiving have not addressed the active role of care recipients within caregiver-care-recipient relationships. Using an interpretive synthesis method, the authors developed the concept of protective care-receiving from three qualitative studies of different groups of care receivers (older adults with chronic illnesses, persons with AIDS, and persons in treatment for active cancer). This paper describes the focus of care recipients' protective care-receiving efforts, the goals they hoped to achieve, and the strategies they used to assist themselves in attaining their goals. Examples of their efforts and strategies are illustrated with quotations from the data. These findings extend what is known about care recipients' selfcare activities. Moreover, the findings reveal a new dimension in the role of care recipients--protective care given by care recipients to their professional care providers, family and friend caregivers, and other care recipients. The concept of protective care-receiving advances our understanding of caregiving relationships and presents researchers with the opportunity to investigate the complex encounter between caregiver and care recipient. Recognizing and facilitating care recipients' protective care-receiving is an ethical imperative for a 'caring' profession such as nursing.


Breakage and re-growth of flocs formed by charge neutralization using alum and polyDADMAC.
The formation, breakage and re-growth of flocs were investigated using alum and polyDADMAC to explore the reversibility of floc breakage. There is a significant reversibility of the breakage process, i.e. the broken flocs can re-grow to the size before breakage, when charge neutralization dominates the coagulation mechanism. However, for higher alum dosage, the break-up process displayed a distinct irreversibility. When coagulated in charge neutralization, the re-growth process of alum was nearly the same as that of polyDADMAC. The average size, coagulation rate and fractal dimension of flocs before and after breakage were nearly the same, including alum and polyDADMAC. While at higher alum dosage, the average size, coagulation rate and fractal dimension of flocs after breakage were much lower than that before breakage. Most important is that the number of small flocs after breakage and re-growth was much less than before breakage when charge neutralization dominated the coagulation mechanism. On the contrary, at higher alum dosage, the small flocs, after breakage and re-growth, increased. The fractal dimension of flocs with alum increased as coagulation time increased until a limiting floc size was reached, while for higher alum dosage, it decreased, whether before or after breakage. The determining parameter for floc re-growth is probably not the fractal dimension, but rather the chemical characteristics of the flocs surface.


Acupuncture on the day of embryo transfer: a randomized controlled trial of 635 patients.
This prospective, randomized, controlled and double-blinded trial studied whether acupuncture in relation to embryo transfer could increase the ongoing pregnancy rates and live birth rates in women undergoing assisted reproductive therapy. A total of 635 patients undergoing IVF or intracytoplasmic sperm injection (ICSI) were included. In 314 patients, embryo transfer was accompanied by acupuncture according to the principles of traditional Chinese medicine. In the control group, 321 patients received placebo acupuncture using a validated placebo needle. In the acupuncture group and the placebo group, the ongoing pregnancy rates were 27% (95% CI 22-32) and 32% (95% CI 27-37), respectively. Live birth rates were 25% (95% CI 20-30) in the acupuncture group and 30% (95% CI 25-30) in the placebo group. The differences were not statistically significant. These results suggest that acupuncture administered in relation to embryo transfer has no effect on the outcome of IVF and ICSI.


C-erbB-2/ HER-2 upregulates fascin, an actin-bundling protein associated with cell motility, in human breast cancer cell lines.
The over-expression of c-erbB-2/ HER-2, a receptor tyrosine kinase, correlates with poor prognosis in patients with breast and ovarian cancer. In the human breast cancer cell line, MDA-MB-435, c-erbB-2 over-expression results in increased chemoinvasion and higher metastatic properties in nude mice. However, the mechanisms by which c-erbB-2 increases the malignant potential of cells remains unclear. We have determined that over-expression of c-erbB-2 in MDA-MB-435 cells, and in some additional breast cancer cell lines, is associated with graphic increases in mRNA and protein levels of the actin bundling protein fascin. Heightened fascin expression has been observed in other systems to result in greatly increased cell motility, and indeed, our work employing semi-automated time-lapse microscopy demonstrates that MDA-MB-435 cells over-expressing c-erbB-2 exhibit significantly heightened cellular dynamics and locomotion, while visualization of bundled microfilaments within fixed cells revealed enhanced formation of dendritic-like processes, microspikes and other dynamic actin based structures. To address the means by which c-erbB-2 over-expression might result in elevated fascin levels, we identified multiple perfect match TCF and NF-kappaB consensus sites in fascin's promoter and first intron, which appeared consistent with the greater endogenous transcriptional activities of TCF and NF-kappaB in c-erbB-2 over-expressing MDA-MB-435 cells. While such transcriptional modulation may occur in the context of the intact gene/chromatin, subsequent tests using reporter constructs did not support involvement of these signaling pathways. In conclusion, highly increased fascin levels were observed in MDA-MB-435 over-expressing c-erbB-2, likely contributing to these cells' altered actin dynamics, and increased cell motility and malignancy. Studies in progress aim to discern the means by which c-erbB-2 over-expression leads to transcriptional activation of the fascin gene.


Myelin basic proteins in myelin subfractions from normal and quaking mice.
The relative proportions of four myelin basic proteins (preL, L, preS,S) were determined in myelin subfractions prepared from the forebrains of quaking and littermate control mice. The distribution pattern of each protein was similar in both mutant and control fractions. The S component was the only basic protein present in low amounts in myelin from the mutant.


Examining physician-patient-caregiver encounters: the case of Alzheimer's disease patients and family physicians in Israel.
This study examines the characteristics of physician-patient-caregiver encounters in the presence of dementia and how sociodemographic and professional characteristics of family physicians, and severity of symptoms in patients with dementia affect these encounters. Phone interviews were conducted with 141 Israeli-Jewish family physicians (representing a 66% response rate), who were presented with one of two vignettes describing a 76-year old women with dementia. The two vignettes were identical, except that in the first it was stated that the woman sits quietly and cooperates during the examination whereas in the second she is agitated and uncooperative. Participants were asked to what extent they would ask questions to, inform and involve the patient and caregiver respectively when presented with one of the two vignettes. Findings showed that physicians would address the caregiver more than the patient (both with respect to questions, information and involvement). Moreover, it was found that physicians, who were older and had a higher number of years in the profession, would address the caregiver to a higher degree (compared to the patient) than younger and less experienced physicians. Findings provide direction for understanding medical encounters in the presence of dementia. Theoretical implications for dementia care, for medical encounters, and practical implications are discussed.


Drought Legacy Effects on the Composition of Soil Fungal and Prokaryote Communities.
It is increasingly acknowledged that climate change is influencing terrestrial ecosystems by increased drought and rainfall intensities. Soil microbes are key drivers of many processes in terrestrial systems and rely on water in soil pores to fulfill their life cycles and functions. However, little is known on how drought and rainfall fluctuations, which affect the composition and structure of microbial communities, persist once original moisture conditions have been restored. Here, we study how simulated short-term drying and re-wetting events shape the community composition of soil fungi and prokaryotes. In a mesocosm experiment, soil was exposed to an extreme drought, then re-wetted to optimal moisture (50% WHC, water holding capacity) or to saturation level (100% WHC). Composition, community structure and diversity of microbes were measured by sequencing ITS and 16S rRNA gene amplicons 3 weeks after original moisture content had been restored. Drying and extreme re-wetting decreased richness of microbial communities, but not evenness. Abundance changes were observed in only 8% of prokaryote OTUs, and 25% of fungal OTUs, whereas all other OTUs did not differ between drying and re-wetting treatments. Two specific legacy response groups (LRGs) were observed for both prokaryotes and fungi. OTUs belonging to the first LRG decreased in relative abundance in soil with a history of drought, whereas OTUs that increased in soil with a history of drought formed a second LRG. These microbial responses were spread among different phyla. Drought appeared to be more important for the microbial community composition than the following extreme re-wetting. 16S profiles were correlated with both inorganic N concentration and basal respiration and ITS profiles correlated with fungal biomass. We conclude that a drying and/or an extreme re-wetting history can persist in soil microbial communities via specific response groups composed of members with broad phylogenetic origins, with possible functional consequences on soil processes and plant species. As a large fraction of OTUs responding to drying and re-wetting belonged to the rare biosphere, our results suggest that low abundant microbial species are potentially important for ecosystem responses to extreme weather events.


LEC-2, a highly variable lectin in the lichen Peltigera membranacea.
Lectins are a diverse group of carbohydrate binding proteins often involved in cellular interactions. A lectin gene, lec-2, was identified in the mycobiont of the lichen Peltigera membranacea. Sequencing of lec-2 open reading frames from 21 individual samples showed an unexpectedly high level of polymorphism in the deduced protein (LEC-2), which was sorted into nine haplotypes based on amino acid sequence. Calculations showed that the rates of nonsynonymous versus synonymous nucleotide substitutions deviated significantly from the null hypothesis of neutrality, indicating strong positive selection. Molecular modeling revealed that most amino acid replacements were around the putative carbohydrate-binding pocket, indicating changes in ligand binding. Lectins have been thought to be involved in the recognition of photobiont partners in lichen symbioses, and the hypothesis that positive selection of LEC-2 is driven by variation in the Nostoc photobiont partner was tested by comparing mycobiont LEC-2 haplotypes and photobiont genotypes, as represented by the rbcLX region. It was not possible to pair up the two types of marker sequences without conflicts, suggesting that positive selection of LEC-2 was not due to variation in photobiont partners.


Multiple signaling pathways of human interleukin-8 receptor A. Independent regulation by phosphorylation.
Interleukin-8 (IL-8) receptor A (CXCR1) couples to a pertussis toxin-sensitive G protein to mediate phospholipase Cbeta (PLCbeta) activation and cellular responses. Responses to CXCR1 are attenuated by prior exposure of neutrophils to either IL-8, a cleavage product of the fifth component of complement (C5a) or n-formylated peptides (formylmethionylleucylphenylalanine, fMLP). To characterize the role of receptor phosphorylation in the regulation of the CXCR1, a phosphorylation-deficient mutant, M2CXCR1, was constructed. This receptor, stably expressed in RBL-2H3 cells, coupled more efficiently to G protein and stimulated enhanced phosphoinositide hydrolysis, cAMP production, exocytosis, and phospholipase D activation, and was resistant to IL-8-induced receptor internalization. The rate and total amount of ligand stimulated actin polymerization remained unchanged, but interestingly, chemotaxis was decreased by approximately 30% compared with the wild type receptor. To study the role of receptor phosphorylation in cross-desensitization of chemoattractant receptors, M2CXCR1 was coexpressed with cDNAs encoding receptors for either fMLP (FR), C5a (C5aR), or platelet-activating factor (PAFR). Both C5aR and PAFR were cross-phosphorylated upon M2CXCR1 activation, resulting in attenuated guanosine 5'-3'-O-(thio)triphosphate (GTPgammaS) binding in membranes. In contrast, FR and M2CXCR1 were resistant to cross-phosphorylation and cross-inhibition of GTPgammaS binding by other receptors. Despite the resistance of M2CXCR1 to cross-phosphorylation and receptor/G protein uncoupling, its susceptibility to cross-desensitization of its Ca2+ response by fMLP and C5a, was equivalent to CXCR1. Regardless of the enhancement in certain receptor functions in M2CXCR1 compared with the wild type CXCR1, the mutated receptors mediated equivalent PLCbeta3 phosphorylation and cross-desensitization of Ca2+ mobilization by FR, C5aR, and PAFR. The results herein indicate that phosphorylation of CXCR1 regulates some, but not all of the receptors functions. While receptor phosphorylation inhibits G protein turnover, PLC activation, Ca2+ mobilization and secretion, it is required for normal chemotaxis and receptor internalization. Since phosphorylation of CXCR1 had no effect on its ability to induce phosphorylation of PLCbeta3 or to mediate class-desensitization, these activities may be mediated by independently regulated pathways.


Locally Estimated Hemodynamic Response Function and Activation Detection Sensitivity in Heroin-Cue Reactivity Study.
A fixed hemodynamic response function (HRF) is commonly used for functional magnetic resonance imaging (fMRI) analysis. However, HRF may vary from region to region and subject to subject. We investigated the effect of locally estimated HRF (in functionally homogenous parcels) on activation detection sensitivity in a heroin cue reactivity study. We proposed a novel exploratory method for brain parcellation based on a probabilistic model to segregate the brain into spatially connected and functionally homogeneous components. Then, we estimated HRF and detected activated regions in response to an experimental task in each parcel using a joint detection estimation (JDE) method. We compared the proposed JDE method with the general linear model (GLM) that uses a fixed HRF and is implemented in FEAT (as a part of FMRIB Software Library, version 4.1). 1) Regions detected by JDE are larger than those detected by fixed HRF, 2) In group analysis, JDE found areas of activation not detected by fixed HRF. It detected drug craving a priori "regions-of-interest" in the limbic lobe (anterior cingulate cortex [ACC], posterior cingulate cortex [PCC] and cingulate gyrus), basal ganglia, especially striatum (putamen and head of caudate), and cerebellum in addition to the areas detected by the fixed HRF method, 3) JDE obtained higher Z-values of local maxima compared to those obtained by fixed HRF. In our study of heroin cue reactivity, our proposed method (that estimates HRF locally) outperformed the conventional GLM that uses a fixed HRF.


Hypoxia and Inactivity Related Physiological Changes (Constipation, Inflammation) Are Not Reflected at the Level of Gut Metabolites and Butyrate Producing Microbial Community: The PlanHab Study.
We explored the assembly of intestinal microbiota in healthy male participants during the run-in (5 day) and experimental phases [21-day normoxic bed rest (NBR), hypoxic bedrest (HBR)], and hypoxic ambulation (HAmb) in a strictly controlled laboratory environment, balanced fluid, and dietary intakes, controlled circadian rhythm, microbial ambiental burden, and 24/7 medical surveillance. The fraction of inspired O2 (FiO2) and partial pressure of inspired O2 (PiO2) were 0.209 and 133.1 ± 0.3 mmHg for NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg for both hypoxic variants (HBR and HAmb; ~4,000 m simulated altitude), respectively. A number of parameters linked to intestinal transit spanning Bristol Stool Scale, defecation rates, zonulin, α1-antitrypsin, eosinophil derived neurotoxin, bile acids, reducing sugars, short chain fatty acids, total soluble organic carbon, water content, diet composition, and food intake were measured (167 variables). The abundance, structure, and diversity of butyrate producing microbial community were assessed using the two primary bacterial butyrate synthesis pathways, butyryl-CoA: acetate CoA-transferase (but) and butyrate kinase (buk) genes. Inactivity negatively affected fecal consistency and in combination with hypoxia aggravated the state of gut inflammation (p < 0.05). In contrast, gut permeability, various metabolic markers, the structure, diversity, and abundance of butyrate producing microbial community were not significantly affected. Rearrangements in the butyrate producing microbial community structure were explained by experimental setup (13.4%), experimentally structured metabolites (12.8%), and gut metabolite-immunological markers (11.9%), with 61.9% remaining unexplained. Many of the measured parameters were found to be correlated and were hence omitted from further analyses. The observed progressive increase in two immunological intestinal markers suggested that the transition from healthy physiological state toward the developed symptoms of low magnitude obesity-related syndromes was primarily driven by the onset of inactivity (lack of exercise in NBR) that were exacerbated by systemic hypoxia (HBR) and significantly alleviated by exercise, despite hypoxia (HAmb). Butyrate producing community in colon exhibited apparent resilience toward short-term modifications in host exercise or hypoxia. Progressive constipation (decreased intestinal motility) and increased local inflammation marker suggest that changes in microbial colonization and metabolism were taking place at the location of small intestine.


A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced prostate-specific antigen responses.
Each year in the United States, nearly 50,000 prostate cancer patients exhibit a rise in prostate-specific antigen (PSA) levels, which can indicate disease recurrence. For patients with biochemically recurrent prostate cancer, we evaluated the effects of white button mushroom (WBM) powder on serum PSA levels and determined the tolerability and biological activity of WBM. Patients with continuously rising PSA levels were enrolled in the study. Dose escalation was conducted in cohorts of 6; this ensured that no more than 1 patient per cohort experienced dose-limiting toxicity (DLT). The primary objective was to evaluate treatment feasibility and associated toxicity. The secondary objectives were to determine WBM's effect on serum PSA/androgen levels; myeloid-derived suppressor cells (MDSCs); and cytokine levels. Thirty-six patients were treated; no DLTs were encountered. The overall PSA response rate was 11%. Two patients receiving 8 and 14 g/d demonstrated complete response (CR): their PSA declined to undetectable levels that continued for 49 and 30 months. Two patients who received 8 and 12 g/d experienced partial response (PR). After 3 months of therapy, 13 (36%) patients experienced some PSA decrease below baseline. Patients with CR and PR demonstrated higher levels of baseline interleukin-15 than nonresponders; for this group, we observed therapy-associated declines in MDSCs. Therapy with WBM appears to both impact PSA levels and modulate the biology of biochemically recurrent prostate cancer by decreasing immunosuppressive factors.


Characterization of the interaction between eupatorin and bovine serum albumin by spectroscopic and molecular modeling methods.
This study investigated the interaction between eupatorin and bovine serum albumin (BSA) using ultraviolet-visible (UV-vis) absorption, fluorescence, synchronous fluorescence, circular dichroism (CD) spectroscopies, and molecular modeling at pH 7.4. Results of UV-vis and fluorescence spectroscopies illustrated that BSA fluorescence was quenched by eupatorin via a static quenching mechanism. Thermodynamic parameters revealed that hydrophobic and electrostatic interactions played major roles in the interaction. Moreover, the efficiency of energy transfer, and the distance between BSA and acceptor eupatorin, were calculated. The effects of eupatorin on the BSA conformation were analyzed using UV-vis, CD, and synchronous fluorescence. Finally, the binding of eupatorin to BSA was modeled using the molecular docking method.


Lung and colorectal cancer treatment and outcomes in the Veterans Affairs health care system.
Lung cancer (LC) and colorectal cancer (CRC) are the second- and third-most commonly diagnosed cancers in the Veterans Affairs (VA) health care system. While many studies have evaluated the treatment quality and outcomes of various aspects of VA LC and CRC care, there are no known reviews synthesizing this information across studies. The purpose of this literature review was to describe LC and CRC treatment (ie, surgical and nonsurgical) and outcomes (eg, mortality, psychosocial, and other) in the VA health care system as reported in the existing peer-reviewed scientific literature. We identified potential articles through a search of published literature using the PubMed electronic database. Our search strategy identified articles containing Medical Subject Headings terms and keywords addressing veterans or veterans' health and LC and/or CRC. We limited articles to those published in the previous 11 years (January 1, 2003 through December 31, 2013). A total of 230 articles were retrieved through the search. After applying the selection criteria, we included 74 studies (34 LC, 47 CRC, and seven both LC and CRC). VA provides a full array of treatments, often with better outcomes than other health care systems. More work is needed to assess patient-reported outcomes.


State-specific effects of sevoflurane anesthesia on sleep homeostasis: selective recovery of slow wave but not rapid eye movement sleep.
Prolonged propofol administration does not result in signs of sleep deprivation, and propofol anesthesia appears to satisfy the homeostatic need for both rapid eye movement (REM) and non-REM (NREM) sleep. In the current study, the effects of sevoflurane on recovery from total sleep deprivation were investigated. Ten male rats were instrumented for electrophysiologic recordings under three conditions: (1) 36-h ad libitum sleep; (2) 12-h sleep deprivation followed by 24-h ad libitum sleep; and (3) 12-h sleep deprivation, followed by 6-h sevoflurane exposure, followed by 18-h ad libitum sleep. The percentage of waking, NREM sleep, and REM sleep, as well as NREM sleep δ power, were calculated and compared for all three conditions. Total sleep deprivation resulted in significantly increased NREM and REM sleep for 12-h postdeprivation. Sevoflurane exposure after deprivation eliminated the homeostatic increase in NREM sleep and produced a significant decrease in the NREM sleep δ power during the postanesthetic period, indicating a complete recovery from the effects of deprivation. However, sevoflurane did not affect the time course of REM sleep recovery, which required 12 h after deprivation and anesthetic exposure. Unlike propofol, sevoflurane anesthesia has differential effects on NREM and REM sleep homeostasis. These data confirm the previous hypothesis that inhalational agents do not satisfy the homeostatic need for REM sleep, and that the relationship between sleep and anesthesia is likely to be agent and state specific.


Stereoselective synthesis of cis-3,4-disubstituted piperidines through ring transformation of 2-(2-mesyloxyethyl)azetidines.
The reactivity of 2-(2-mesyloxyethyl)azetidines, obtained through monochloroalane reduction and mesylation of the corresponding β-lactams, with regard to different nucleophiles was evaluated for the first time, resulting in the stereoselective preparation of a variety of new 4-acetoxy-, 4-hydroxy-, 4-bromo-, and 4-formyloxypiperidines. During these reactions, transient 1-azoniabicyclo[2.2.0]hexanes were prone to undergo an S(N)2-type ring opening to afford the final azaheterocycles, which was rationalized by means of a detailed computational analysis. This approach constitutes a convenient alternative for the known preparation of 3,4-disubstituted 5,5-dimethylpiperidines, providing an easy access to the 5,5-nor-dimethyl analogues as valuable templates in medicinal chemistry. Furthermore, cis-4-bromo-3-(phenoxy or benzyloxy)piperidines were elaborated into the piperidin-3-one framework via dehydrobromination followed by acid hydrolysis.


Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation.
T cell activation requires that the cell meet increased energetic and biosynthetic demands. We showed that exogenous nutrient availability regulated the differentiation of naïve CD4(+) T cells into distinct subsets. Activation of naïve CD4(+) T cells under conditions of glutamine deprivation resulted in their differentiation into Foxp3(+) (forkhead box P3-positive) regulatory T (Treg) cells, which had suppressor function in vivo. Moreover, glutamine-deprived CD4(+) T cells that were activated in the presence of cytokines that normally induce the generation of T helper 1 (TH1) cells instead differentiated into Foxp3(+) Treg cells. We found that α-ketoglutarate (αKG), the glutamine-derived metabolite that enters into the mitochondrial citric acid cycle, acted as a metabolic regulator of CD4(+) T cell differentiation. Activation of glutamine-deprived naïve CD4(+) T cells in the presence of a cell-permeable αKG analog increased the expression of the gene encoding the TH1 cell-associated transcription factor Tbet and resulted in their differentiation into TH1 cells, concomitant with stimulation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Together, these data suggest that a decrease in the intracellular amount of αKG, caused by the limited availability of extracellular glutamine, shifts the balance between the generation of TH1 and Treg cells toward that of a Treg phenotype.


Association of behavioral inhibition with hair pigmentation in a European sample.
Behavioral inhibition, a temperamental trait signalling a predisposition to childhood and adolescent anxiety disorders, is slightly more frequent in America among Caucasian children having blue irises. This paper examines a community sample of 101 German toddlers assessed for behavioral inhibition in a standardized laboratory procedure. Hair pigmentation was found to be significantly associated with behavioral inhibition in the sense that blond children exhibited higher fear scores. As in American samples, blue-eyed children had a higher fear score than did other children, but this difference was not statistically significant.


Immunotherapy in breast cancer: Current status and future directions.
Breast cancer, one of the leading causes of death in women in the United States, challenges therapeutic success in patients due to tumor heterogeneity, treatment resistance, metastasis and disease recurrence. Knowledge of immune system involvement in normal breast development and breast cancer has led to extensive research into the immune landscape of breast cancer and multiple immunotherapy clinical trials in breast cancer patients. However, poor immunogenicity and T-cell infiltration along with heightened immunosuppression in the tumor microenvironment have been identified as potential challenges to the success of immunotherapy in breast cancer. Oncodrivers, owing to their enhanced expression and stimulation of tumor cell proliferation and survival, present an excellent choice for targeted immunotherapy development in breast cancer. Loss of anti-tumor immune response specific to oncodrivers has been reported in breast cancer patients as well. Dendritic cell vaccines have been tested for their efficacy in generating anti-tumor T-cell response against specific tumor-associated antigens and oncodrivers and have shown improved survival outcome in patients. Here, we review the current status of immunotherapy in breast cancer, focusing on dendritic cell vaccines and their therapeutic application in breast cancer. We further discuss future directions of breast cancer immunotherapy and potential combination strategies involving dendritic cell vaccines and existing chemotherapeutics for improved efficacy and better survival outcome in breast cancer.


Determinants of the higher order association of the restriction factor TRIM5alpha and other tripartite motif (TRIM) proteins.
Many tripartite motif (TRIM) proteins self-associate, forming dimers and higher order complexes. For example, dimers of TRIM5α, a host factor that restricts retrovirus infection, assemble into higher order arrays on the surface of the viral capsid, resulting in an increase in avidity. Here we show that the higher order association of different TRIM proteins exhibits a wide range of efficiencies. Homologous association (self-association) was more efficient than the heterologous association of different TRIM proteins, indicating that specificity determinants of higher order self-association exist. To investigate the structural determinants of higher order self-association, we studied TRIM mutants and chimeras. These studies revealed the following: 1) the RING domain contributes to the efficiency of higher order self-association, which enhances the binding of TRIM5α to the human immunodeficiency virus (HIV-1) capsid; 2) the RING and B-box 2 domains work together as a homologous unit to promote higher order association of dimers; 3) dimerization is probably required for efficient higher order self-association; 4) the Linker 2 region contributes to higher order self-association, independently of effects of Linker 2 changes on TRIM dimerization; and 5) for efficiently self-associating TRIM proteins, the B30.2(SPRY) domain is not required for higher order self-association. These results support a model in which both ends of the core TRIM dimer (RING-B-box 2 at one end and Linker 2 at the other) contribute to the formation of higher order arrays.


Concentration ratios of morphine to codeine in blood of impaired drivers as evidence of heroin use and not medication with codeine.
Both the illicit drug heroin and the prescription drug codeine are metabolized to morphine, which tends to complicate interpretation of opiate-positive samples. We report here the concentrations of morphine and codeine, the morphine/codeine ratios, and 6-acetylmorphine (6-AM) in blood specimens from individuals arrested for driving under the influence of drugs (DUID) in Sweden. The results were compared with positive findings of 6-AM in urine as evidence of heroin intake. In 339 DUID suspects, both blood and urine specimens were available for toxicologic analysis. In another 882 cases, only blood was available. All specimens were initially analyzed by immunoassay, and the positive results were verified by isotope-dilution gas chromatography-mass spectrometry. In routine casework, the limits of quantification (LOQs) for unconjugated opiates were 5 ng/g for blood and 20 microg/L for urine. The median concentration of morphine in blood was 30 ng/g with 2.5 and 97.5 percentiles of 5 and 230 ng/g, respectively (n = 979). This compares with a median codeine concentration of 20 ng/g and 2.5 and 97.5 percentiles of 5 and 592 ng/g, respectively (n = 784). The specific metabolite of heroin, 6-AM, was identified in only 16 of 675 blood specimens (2.3%). This compares with positive findings of 6-AM in 212 of 339 urine samples (62%) from the same population of DUID suspects. When 6-AM was identified in urine, the morphine/codeine ratio in blood was always greater than unity (median, 6.0; range, 1-66). In 18 instances, 6-AM was present in urine, although morphine and codeine were below the LOQ in blood. The morphine/codeine ratio in blood was greater than unity in 85% of DUID cases when urine was not available (n = 506), and the median morphine and codeine concentrations were 70 ng/g and 10 ng/g, respectively. When morphine/codeine ratios in blood were less than unity (n = 76), the median morphine and codeine concentrations were 10 ng/g and 180 ng/g, respectively. Only 2.3% of opiate-positive DUID suspects were verified as heroin users on the basis of positive findings of 6-AM in blood. A much higher proportion (62%) were verified heroin users from 6-AM identified in urine. When urine was not available for analysis, finding a morphine/codeine concentration ratio in blood above unity suggests heroin use and not medication with codeine. This biomarker indicated that 85% of opiate-positive DUID blood samples were from heroin users.


Can a community of practice equip public health nutritionists to work with remote retail to improve the food supply?
This study aimed to determine the influence on practice of a community of practice designed for public health nutritionists who work with retail stores in remote Indigenous communities in Australia. A descriptive evaluation of the community of practice participants' perspectives using the most significant change technique and individual in-depth interviews was conducted. Data were analysed using thematic and content analysis with a focus on answering the evaluation questions. Twelve public health nutritionists employed to work with remote Indigenous community stores were involved. The community of practice was reported to develop competence through problem solving, knowledge sharing and building confidence for innovative work. Building competence was achieved through accessible and timely professional support. Sharing stories and being encouraged to reflect on practice was valued and supported the participant's practice. Working to improve the food supply is challenging but there is value in being supported by like-minded colleagues to stay focused on this work. Most participants perceived the community of practice intervention to be an effective strategy to improve their work. These findings provide evidence of a promising intervention for building the public health nutrition workforce in remote Indigenous community store retail settings.


Efficacy of a novel topical fipronil, (S)-methoprene, eprinomectin and praziquantel combination against naturally acquired intestinal nematode and cestode infections in cats.
The efficacy of a novel topical combination formulation of fipronil, (S)-methoprene, eprinomectin and praziquantel against naturally acquired intestinal nematode and cestode infections in cats was evaluated in seven negative control, blinded studies. Cats were selected based on a pre-treatment faecal examination indicating a patent infection with at least hookworms (two studies), Toxocara ascarids (one study), taeniid cestodes (two studies) or Dipylidium cestodes (two studies). In each study, cats were assigned randomly to blocks of two animals each, based on decreasing pre-treatment body weight and were randomly allocated to one of two groups of six to 12 cats: untreated (control) or treated with topical fipronil (8.3%, w/v), (S)-methoprene (10%, w/v), eprinomectin (0.4%, w/v) and praziquantel (8.3%, w/v) (BROADLINE(®), Merial) at 0.12 mL/kg body weight (providing a minimum of 10mg fipronil+12 mg S-methoprene+0.5mg eprinomectin+10mg praziquantel per kg body weight). The topical treatment was administered directly on the skin in the midline of the neck in a single spot once on Day 0. For parasite recovery and count, cats were euthanized humanely and necropsied seven or ten days after treatment. A single treatment with the novel topical combination product provided 91% efficacy against Ancylostoma braziliense, ≥ 99% efficacy against Ancylostoma tubaeforme, and >97% efficacy against Toxocara cati. Similarly, excellent efficacy was established against Taenia taeniaeformis, Dipylidium caninum and Diplopylidium spp. as demonstrated by >97% and up to 100% reductions of cestode counts in the treated cats when compared to the untreated controls (P<0.01). All cats accepted the treatment well based on health observations post-treatment and daily health observations. No adverse experiences or other health problems were observed throughout the studies. The results of this series of controlled studies demonstrated high efficacy and excellent acceptability of the novel topical combination formulation of fipronil, (S)-methoprene, eprinomectin and praziquantel against a broad range of feline intestinal nematode and cestode infections.


Scoliosis imaging: what radiologists should know.
Scoliosis is defined as a lateral spinal curvature with a Cobb angle of 10° or more. This abnormal curvature may be the result of an underlying congenital or developmental osseous or neurologic abnormality, but in most cases the cause is unknown. Imaging modalities such as radiography, computed tomography (CT), and magnetic resonance (MR) imaging play pivotal roles in the diagnosis, monitoring, and management of scoliosis, with radiography having the primary role and with MR imaging or CT indicated when the presence of an underlying osseous or neurologic cause is suspected. In interpreting the imaging features of scoliosis, it is essential to identify the significance of vertebrae in or near the curved segment (apex, end vertebra, neutral vertebra, stable vertebra), the curve type (primary or secondary, structural or nonstructural), the degree of angulation (measured with the Cobb method), the degree of vertebral rotation (measured with the Nash-Moe method), and the longitudinal extent of spinal involvement (according to the Lenke system). The treatment of idiopathic scoliosis is governed by the severity of the initial curvature and the probability of progression. When planning treatment or follow-up imaging, the biomechanics of curve progression must be considered: In idiopathic scoliosis, progression is most likely during periods of rapid growth, and the optimal follow-up interval in skeletally immature patients may be as short as 4 months. After skeletal maturity is attained, only curves of more than 30° must be monitored for progression.


Biochemical studies of stimulus convergence during classical conditioning in Aplysia: dual regulation of adenylate cyclase by Ca2+/calmodulin and transmitter.
Activity-dependent facilitation is a mechanism of associative synaptic plasticity that contributes to classical conditioning in Aplysia. Previous studies of activity-dependent facilitation in the mechanosensory neurons of Aplysia suggested that the Ca2+ influx during paired spike activity enhances the transmitter-stimulated, cAMP-dependent, presynaptic facilitation in these cells. Moreover, paired activity was found to potentiate the activation of the adenylate cyclase by transmitter. It was therefore proposed that the Ca2+/calmodulin-sensitive cyclase may serve as a site of interaction between the inputs from the conditioned and unconditioned stimuli. These studies were carried out to test whether a Ca2+/calmodulin-sensitive adenylate cyclase in the Aplysia CNS has the properties necessary to mediate such an associative interaction. Three lines of evidence indicate that the same cyclase molecules that are sensitive to Ca2+/calmodulin are also stimulated by receptor to facilitatory transmitter via the stimulatory G-protein, Gs: First, calmodulin inhibitors reduced stimulation of the cyclase by facilitatory transmitter. When membranes had been preexposed to one of these inhibitors, trifluoperazine, the addition of exogenous calmodulin partially reversed the inhibition. Second, when Gs had been activated by GTP gamma S, so that it persistently activated the catalytic unit of the cyclase, stimulation of the cyclase by Ca2+ was greatly amplified, suggesting that the two inputs interact in activating a common population of the enzyme. Third, solubilized cyclase activity that bound to calmodulin-Sepharose in a Ca(2+)-dependent manner was stimulated by Gs, which had been partially purified from Aplysia CNS, as well as by Ca2+/calmodulin. Having demonstrated dual activation of the cyclase, we have explored the dependence of cyclase activation on the temporal pattern of Ca2+ and transmitter addition. Optimal activation required that a pulse of Ca2+ temporally overlap the addition of facilitatory transmitter. These several results suggested that the dually regulated adenylate cyclase might underlie the temporal requirements for effective classical conditioning in this system.


Mode of delivery after epidural analgesia in a cohort of low-risk nulliparas.
Although epidural analgesia is widespread and very effective for alleviating labor pain, its use is still controversial, as the literature is inconsistent about the risk of adverse birth outcome after administration of epidural analgesia. The aim of this study was to explore associations between epidural analgesia and mode of delivery. Data were obtained from a prospective cohort from nine Danish labor wards and comprised 2,721 term nulliparous women with spontaneous onset of labor and a singleton fetus in cephalic presentation. Information about epidural analgesia, mode of delivery, and birth complications was obtained by the staff attending labor. Additional information was provided from self-administered questionnaires in gestational week 37. Multiple logistic regression analyses were used to estimate the association between epidural analgesia and birth outcomes. Results are presented as crude and adjusted odds ratios (OR [95% CI]). Of the total cohort, 21.6 percent required epidural analgesia, 8.7 percent had emergency cesarean section, and 14.9 percent had vacuum extraction. Women with epidural analgesia had a higher risk of emergency cesarean section (adjusted OR: 5.8; 95% CI: 4.1-8.1), and vacuum extraction (adjusted OR: 1.7; 95% CI: 1.3-2.2). In a subgroup of the cohort with a very low overall risk of cesarean section, 3.4 percent had emergency cesarean section and an increased risk of emergency cesarean section was also found in this group (adjusted OR: 3.5; 95% CI: 1.5-8.2). In nulliparous women of a very low-risk population, use of epidural analgesia for labor pain was associated with higher risks of emergency cesarean section and vacuum extraction.


Low-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation.
TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.


Patterns of developmental change in infants' nighttime sleep awakenings from 6 through 36 months of age.
Nighttime sleep awakenings and infant and family characteristics were measured longitudinally in more than 1,200 infants when the infants were 6, 15, 24, and 36 months old. By 6 months of age, the majority of children slept through the night, awakening their mothers only about once or twice per week. However, not all children followed this predominant developmental pattern. Using growth mixture modeling, we identified 2 distinct developmental patterns. One group, labeled Sleepers, included 66% of the children. These children showed a flat trajectory of sleep awakenings from 6 through 36 months, with mothers reporting their infant awakening from sleep about 1 night per week. The second group, labeled Transitional Sleepers, included 34% of the infants. These children had 7 reported nights of awakenings per week at 6 months, dropping to 2 nights per week at 15 months and to 1 night per week by 24 months. Compared with Sleepers, Transitional Sleepers were more likely to be boys, score higher on the 6-month difficult temperament assessment, be breastfed at 6 and 15 months old, and have more depressed mothers at 6 months old. Using 2-group structural equation modeling, we examined individual differences at different points on the individual infants' sleep trajectories. For infants in both groups, reported sleep awakenings were associated with difficult temperament measured at 6 months, breastfeeding, infant illness, maternal depression, and greater maternal sensitivity. Infant-mother attachment measures were not related to these sleep awakenings.


Comparison of the efficacy and safety profiles of a pelubiprofen versus celecoxib in patients with rheumatoid arthritis: a 6-week, multicenter, randomized, double-blind, phase III, non-inferiority clinical trial.
Pelubiprofen is a prodrug of 2-arylpropionic acid with relatively selective effects on cyclooxygenase-2 activity. The aim of this study was to compare the efficacy and safety profiles of pelubiprofen with those of celecoxib in patients with rheumatoid arthritis. This was a 6-week, multicenter, randomized, double-blind, double-dummy, parallel-group, phase III, non-inferiority clinical trial. The primary end point was non-inferiority of pain decrease from baseline to week-6 as determined using a 100 mm pain visual analog scale (VAS). Pelubiprofen was considered non-inferior to celecoxib if the lower limit of the 97.5% confidence interval for treatment difference [(pain reduction in pelubiprofen group) - (pain reduction in celecoxib group)] was more than -10 mm. The secondary end points were as follows: non-inferiority of (1) reduction of Korean health assessment questionnaire (KHAQ) score; (2) decreased duration of morning stiffness; and (3) decrease in the frequency and total dose of rescue drugs after 6 weeks of treatment. Seventy-seven patients in the pelubiprofen group and 68 patients in the celecoxib group started the study medication. Pelubiprofen was non-inferior to celecoxib with regard to reduction in VAS pain severity (difference, mean ± SD 5.0 ± 20.1; 97.5% CI, -2.3 to ∞). Pelubiprofen was also non-inferior to celecoxib in terms of the secondary end points, such as, decrease in KHAQ score (0.0 ± 0.5, 97.5% CI -0.2 to ∞), decrease in duration of morning stiffness (median 0.0 minute in both groups), and decrease in the frequency (0.7 ± 3.5, 97.5% CI -0.6 to ∞) and total amount (0.7 ± 3.6, 97.5% CI -0.6 to ∞) of rescue medication uses during the 6 week study period. Safety analysis revealed 31.2% patients in the pelubiprofen group and 20.6% patients in the celecoxib group experienced an adverse drug reaction (ADR). The frequency of gastrointestinal ADRs was 20.8 % and 8.8%, respectively. Pelubiprofen was found to be as effective as celecoxib at pain reduction and for relieving stiffness in RA patients. However, more patients in the pelubiprofen group experienced ADR and the frequency of gastrointestinal ADRs was higher in the pelubiprofen group. ClinialTrials.gov identifier: NCT01781702.


The perspectives of stakeholders of intellectual disability liaison nurses: a model of compassionate, person-centred care.
To investigate the experiences of patients with intellectual disabilities, family and paid carers regarding the role of liaison nurses and the delivery of compassionate, person-centred care. From this to propose a model of person-centred care embedded in these experiences. People with intellectual disabilities have a high number of comorbidities, requiring multidisciplinary care, and are at high risk of morbidity and preventable mortality. Provision of compassionate, person-centred care is essential to prevent complications and avoid death. A qualitative design was adopted with Interpretative Phenomenological Analysis for data analysis. Semistructured interviews and focus groups were conducted. Data were analysed with a focus on compassionate, person-centred care elements and components. Themes were modelled to develop a clinically meaningful model for practice. Themes identified vulnerability, presence and the human interface; information balance; critical points and broken trust; roles and responsibilities; managing multiple transitions; 'flagging up' and communication. The findings provide the first 'anatomy' of compassionate, person-centred care and provide a model for operationalising this approach in practice. The applicability of the model will have to be evaluated further with this and other vulnerable groups. This is the first study to provide a definition of compassionate, person-centred care and proposes a model to support its application into clinical practice for this and other vulnerable groups.


Voluntary ingestion of nut paste for administration of buprenorphine in rats and mice.
An adequate analgesic strategy is important to improve the postoperative recovery and welfare of laboratory rats and mice. It is desirable that the method for administering the drug is non-invasive and stress-free. We have previously validated a method for administering buprenorphine in a nut paste for voluntary ingestion. This method has many advantages over parenteral administration. To use the method in a successful way, however, it is important to prepare and administer the mix correctly. The present paper describes in detail how to implement the method, by means of habituation, presentation, adequate concentrations and amounts of buprenorphine/nut paste, and dosage of buprenorphine to rats and mice.


Medical Malpractice and Trigeminal Neuralgia: An Analysis of 49 Cases.
Our study fills the vacancy of litigation research related to trigeminal neuralgia management, giving health care providers the information needed to understand the potential litigious outcomes that follow treatment methods. We queried the Westlaw database to identify litigation cases related to trigeminal neuralgia management. Key variables extracted included medical complaints, trial outcomes, and demographics. Continuous variables were compared between cases in favor of defendant and cases in favor of plaintiff using t-test or Wilcoxon rank sum test. Categorial variables were compared using χ2 or Fisher exact test. About 49 cases met the inclusion criteria-for those cases surgical complications (42.9%) were cited as the most common reasons for malpractice claims. Cranial nerve deficits (34.7%) were the most frequent postoperative complaints. Verdicts ruled in favor of the plaintiff in 26.5% of cases with a mean payout of $1,982,428.46. Dentists were included in the most cases, 63.3%, and the average payout was $415,908, whereas neurosurgeons were involved in 20.4% of cases with an average payout of $618,775. Cases with verdicts in favor of the plaintiff were more likely to be older than cases with verdicts in favor of the defendant (P = .03). Over one-half of cases resulted in verdicts in favor of the defendant with surgical complications cited as the most common reason for litigation. Dentistry was the most common individual clinical specialty for defendants, whereas neurosurgery contributed to the largest average payout based on specialty (for n > 1). Cranial nerve deficits were the most common plaintiff postoperative complaints. These analyses may help doctor teams involved in management of trigeminal neuralgia to have a more informed discussion with the patient at every visit so that such litigations may be avoided.


Clinical Characteristics and Outcomes After Primary ACL Reconstruction and Meniscus Ramp Repair.
Satisfactory outcomes have been reported after all-inside meniscus ramp repair with combined anterior cruciate ligament reconstruction (ACLR). However, clinical outcomes after ACLR with inside-out meniscus ramp repair are limited. The purpose of this study was to evaluate patient-reported outcomes for patients who underwent ACLR and medial meniscus ramp repair compared with those who underwent isolated ACLR; patients in the 2 groups were matched for age, sex, and sport/activity. The null hypothesis was that there would be no significant differences in clinical outcomes between groups at a minimum of 2 years postoperatively. Cohort study; Level of evidence 3. Patients who underwent primary ACLR with bone-patellar tendon-bone (BPTB) autograft by a single surgeon were retrospectively identified. A subgroup of patients with combined ACLR and meniscus ramp repair with a minimum 2-year postoperative follow-up were matched to a cohort who underwent isolated ACLR. Subjective patient-reported questionnaires, knee stability, and return to level of activity/sport were collected. There were 851 patients who underwent primary ACLR; of these, 158 (18.6%) had medial meniscus ramp lesions confirmed at arthroscopy. The most common clinical characteristics in patients with ramp lesions were chronic injuries (68.4%), contact mechanism (88%), concomitant lateral meniscus tears (63.2%), and concomitant lateral meniscus posterior root tears (22.2%). Further, 50 patients who underwent combined ACLR and meniscus ramp repair with minimum 2-year follow-up were matched to patients who underwent isolated ACLR. Both groups reported significant improvements in subjective outcomes from preoperative to postoperative assessments (P < .001). No significant differences were found in postoperative outcomes for combined ACLR with ramp repair versus isolated ACLR (P > .05). Patients with meniscus ramp repair had increased preoperative knee laxity demonstrated by grade 3 Lachman (44% vs 6%) and pivot-shift (38% vs 12%) test results compared with patients who underwent isolated ACLR (P ≤ .005 for both). This study demonstrates similar clinical outcomes, knee stability on postoperative physical examination, and return-to-sport rates for patients who underwent combined ACLR with BPTB autograft and inside-out meniscus ramp repair versus a matched cohort who underwent isolated ACLR. Clinicians should have a high index of suspicion for the presence of ramp lesions in patients with ACL tears who have a contact mechanism of injury, grade 3 Lachman test result, and concomitant lateral meniscal abnormality.


Organ injuries associated with femoral fractures: implications for severity of injury in motor vehicle collisions.
To determine if motor vehicle collisions (MVCs) resulting in femoral fractures were associated with a different injury severity and pattern of injury compared with crashes in which victims did not sustain femoral fractures. Retrospective review of seriously injured motor vehicle occupants admitted to a regional trauma unit (Hamilton General Hospital) during a 69-month period (April 1991 to December 1996) for whom detailed crash details were known. Data for 733 motor vehicle occupants with Injury Severity Scores greater than 12 were available; 112 occupants (15.3%) sustained femoral fractures, and 621 occupants (84.7%) did not sustain femoral fractures. Victims with femoral fractures had a significantly higher mean Injury Severity Score (29.4 compared with 25.3 for non-femoral fracture group; p<0.001). The femoral fracture group had a higher incidence of bowel (p<0.012) and hemopneumothorax (p<0.02) injuries as well as an increased incidence of upper and lower extremity (p<0.001) and pelvic (p<0.05) fractures. The presence of a femoral fracture is strongly associated with the pattern and severity of injuries sustained by occupants in MVCs. A high index of suspicion is warranted in identifying associated organ injuries in MVC victims with concomitant femoral fractures.