A randomized trial of concurrent versus delayed smoking intervention for patients in alcohol dependence treatment.
Fear of jeopardizing drinking outcomes has resulted in a reluctance to treat tobacco dependence concurrently with alcohol dependence, in spite of the high prevalence of smoking among patients with alcohol dependence. The objective of this study was to compare the effects of smoking treatment and intensive treatment for alcohol dependence, delivered concurrently, with delayed smoking treatment on smoking and alcohol use. For the study, 1,943 patients in intensive treatment for alcohol dependence or abuse were screened for participation. Of these, 499 smokers were enrolled and randomized to concurrent (during alcohol treatment) or delayed (6 months later) smoking intervention. The smoking intervention included individual behavioral counseling and nicotine replacement. The main smoking outcome measure was 7-day point prevalent tobacco abstinence, and the main drinking outcome was 6-month prolonged abstinence from alcohol; both measured 18 months after study enrollment. Participants in the concurrent group were more likely to participate in smoking treatment than those in the delayed group (78.5% vs 64.5%, p = .005), but there was no significant difference in cessation rates at 18 months (12.4% vs 13.7%). Prolonged, 6-month abstinence from alcohol was worse in the concurrent group than in the delayed group at 6, 12 and 18 months (41% vs 56%, p =.001; 33% vs 42%,p = .06; 41% vs 48%, p = .14, respectively), and 30-day prolonged alcohol abstinence was also worse in the concurrent treatment group (51% vs 64%, p = .004; 46% vs 53%, p = .11; 48% vs 60%, p = .01, respectively). These data show that patients in alcohol treatment are interested in smoking cessation, participate in treatment and demonstrate success; but there was no benefit of concurrent treatment. Drinking outcomes were worse with concurrent tobacco treatment. These findings suggest that smoking cessation intervention should be provided to patients after intensive alcohol treatment; however, the data require confirmation because they are not consistent with the existing literature.


The impact of hospital-acquired conditions on Medicare program payments.
Hospital-acquired conditions, or HACs, often result in additional Medicare payments, generated during the initial hospitalization and in subsequent health care encounters. The purpose of this article is to estimate the incremental cost to Medicare, as measured by Medicare program payments, of six HACs. The researchers used a matched case-control design to determine the incremental increase in Medicare payments attributable to each HAC. For each HAC patient, five comparison patients were matched on diagnosis group, sex, race, and age. Using the matched sample, we estimated a hospital fixed effects log-linear regression on total Medicare payments for the episode of care, further controlling for co-morbid conditions. Care episodes included the initial hospitalization and all inpatient, outpatient, physician, home health, and hospice care that occurred within 90 days of hospital discharge. All Medicare fee-for-service patients discharged alive from a hospital between October 2008 and June 2010 with one of six HACs-severe pressure ulcer, fracture, catheter-associated urinary tract infection, vascular catheter-associated infection, surgical site infection following certain orthopedic procedures, or deep vein thrombosis/ pulmonary embolism following certain orthopedic procedures-were included in the sample and matched to five similar patients without the HACs. The multivariate analysis suggests that Medicare paid an additional $146 million per year across these HAC care episodes compared with what would have been paid without the HACs. HACs create a significant financial burden for the Medicare program. We compare the incremental Medicare payments for these six HACs to the current and upcoming Medicare HAC payment penalties.


Bilateral effects of unilateral cerebellar lesions as detected by voxel based morphometry and diffusion imaging.
Over the last decades, the importance of cerebellar processing for cortical functions has been acknowledged and consensus was reached on the strict functional and structural cortico-cerebellar interrelations. From an anatomical point of view strictly contralateral interconnections link the cerebellum to the cerebral cortex mainly through the middle and superior cerebellar peduncle. Diffusion MRI (dMRI) based tractography has already been applied to address cortico-cerebellar-cortical loops in healthy subjects and to detect diffusivity alteration patterns in patients with neurodegenerative pathologies of the cerebellum. In the present study we used dMRI-based tractography to determine the degree and pattern of pathological changes of cerebellar white matter microstructure in patients with focal cerebellar lesions. Diffusion imaging and high-resolution volumes were obtained in patients with left cerebellar lesions and in normal controls. Middle cerebellar peduncles and superior cerebellar peduncles were reconstructed by multi fiber diffusion tractography. From each tract, measures of microscopic damage were assessed, and despite the presence of unilateral lesions, bilateral diffusivity differences in white matter tracts were found comparing patients with normal controls. Consistently, bilateral alterations were also evidenced in specific brain regions linked to the cerebellum and involved in higher-level functions. This could be in line with the evidence that in the presence of unilateral cerebellar lesions, different cognitive functions can be affected and they are not strictly linked to the side of the cerebellar lesion.


Direct effects of TNF-α on local fuel metabolism and cytokine levels in the placebo-controlled, bilaterally infused human leg: increased insulin sensitivity, increased net protein breakdown, and increased IL-6 release.
Tumor necrosis factor-α (TNF-α) has widespread metabolic actions. Systemic TNF-α administration, however, generates a complex hormonal and metabolic response. Our study was designed to test whether regional, placebo-controlled TNF-α infusion directly affects insulin resistance and protein breakdown. We studied eight healthy volunteers once with bilateral femoral vein and artery catheters during a 3-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. One artery was perfused with saline and one with TNF-α. During the clamp, TNF-α perfusion increased glucose arteriovenous differences (0.91 ± 0.17 vs. 0.74 ± 0.15 mmol/L, P = 0.012) and leg glucose uptake rates. Net phenylalanine release was increased by TNF-α perfusion with concomitant increases in appearance and disappearance rates. Free fatty acid kinetics was not affected by TNF-α, whereas interleukin-6 (IL-6) release increased. Insulin and protein signaling in muscle biopsies was not affected by TNF-α. TNF-α directly increased net muscle protein loss, which may contribute to cachexia and general protein loss during severe illness. The finding of increased insulin sensitivity, which could relate to IL-6, is of major clinical interest and may concurrently act to provide adequate tissue fuel supply and contribute to the occurrence of systemic hypoglycemia. This distinct metabolic feature places TNF-α among the rare insulin mimetics of human origin.


A gene expression atlas of embryonic neurogenesis in Drosophila reveals complex spatiotemporal regulation of lncRNAs.
Cell type specification during early nervous system development in Drosophila melanogaster requires precise regulation of gene expression in time and space. Resolving the programs driving neurogenesis has been a major challenge owing to the complexity and rapidity with which distinct cell populations arise. To resolve the cell type-specific gene expression dynamics in early nervous system development, we have sequenced the transcriptomes of purified neurogenic cell types across consecutive time points covering crucial events in neurogenesis. The resulting gene expression atlas comprises a detailed resource of global transcriptome dynamics that permits systematic analysis of how cells in the nervous system acquire distinct fates. We resolve known gene expression dynamics and uncover novel expression signatures for hundreds of genes among diverse neurogenic cell types, most of which remain unstudied. We also identified a set of conserved long noncoding RNAs (lncRNAs) that are regulated in a tissue-specific manner and exhibit spatiotemporal expression during neurogenesis with exquisite specificity. lncRNA expression is highly dynamic and demarcates specific subpopulations within neurogenic cell types. Our spatiotemporal transcriptome atlas provides a comprehensive resource for investigating the function of coding genes and noncoding RNAs during crucial stages of early neurogenesis.


Neurofeedback for ADHD: a review of current evidence.
Considerable scientific effort has been directed at developing effective treatments for attention-deficit/hyperactivity disorder (ADHD). Among alternative treatment approaches, neurofeedback has gained some promising empirical support in recent years from controlled studies as a treatment of core ADHD symptoms. However, a recent stringent meta-analysis of 8 randomized controlled trials published in 2013 found that the effects were stronger for unblinded measures and 3 recent subsequently published well-controlled trials found no effects for the most blinded ADHD outcome. Firmer conclusions must await upcoming evidence from larger controlled studies and future meta-analyses contrasting different forms of neurofeedback and different outcome measures.


Testing hypotheses of mitochondrial gene-tree paraphyly: unravelling mitochondrial capture of the Streak-breasted Scimitar Babbler (Pomatorhinus ruficollis) by the Taiwan Scimitar Babbler (Pomatorhinus musicus).
Species-level paraphyly inferred from mitochondrial gene trees is a prevalent phenomenon in taxonomy and systematics, but there are several potential causes that are not easily explained by currently used methods. This study aimed to test the underlying causes behind the observed paraphyly of Streak-breasted Scimitar Babbler (Pomatorhinus ruficollis) via statistical analyses of four mitochondrial (mtDNA) and nine nuclear (nuDNA) genes. Mitochondrial gene trees show paraphyly of P. ruficollis with respect to the Taiwan Scimitar Babbler (Pomatorhinus musicus), but nuclear genealogies support a sister-group relationship. Predictive coalescent simulations imply several hypothetical explanations, the most likely being mitochondrial capture of P. ruficollis by P. musicus for the observed cyto-nuclear incongruence. Further approximate Bayesian computation suggests a unidirectional introgression model with substantial level of gene flow from P. ruficollis to P. musicus during their initial divergence during the Late Pleistocene. This specific observation frames several potential causes for incongruent outcomes of mitochondrial and nuclear introgression in general, and on the whole, our results underscore the strength of multiple independent loci for species delimitation and importance of testing hypotheses that explain disparate causes of mitochondrial gene-tree paraphyly.


Rare event molecular dynamics simulations of plasma induced surface ablation.
The interaction of thermal Ar plasma particles with Si and W surfaces is modeled using classical molecular dynamics (MD) simulations. At plasma energies above the threshold for ablation, the ablation yield can be calculated directly from MD. For plasma energies below threshold, the ablation yield becomes exponentially low, and direct MD simulations are inefficient. Instead, we propose an integration method where the yield is calculated as a function of the Ar incident kinetic energy. Subsequent integration with a Boltzmann distribution at the temperature of interest gives the thermal ablation yield. At low plasma temperatures, the ablation yield follows an Arrhenius form in which the activation energy is shown to be the threshold energy for ablation. Interestingly, equilibrium material properties, including the surface and bulk cohesive energy, are not good predictors of the threshold energy for ablation. The surface vacancy formation energy is better, but is still not a quantitative predictor. An analysis of the trajectories near threshold shows that ablation occurs by different mechanisms on different material surfaces, and both the mechanism and the binding of surface atoms determine the threshold energy.


Analysis of the stimulation-inhibition paradox exhibited by lymphocytes exposed to concanavalin A.
High doses of Concanavalin A (Con A), which normally inhibit T-lymphocyte stimulation as measured by increases in DNA synthesis, cause these lymphocytes to become committed to mitogenesis while also generating a dominant but reversible negative growth signal. The observed response to the stimulatory signal as measured by the rate of commitment to enter the S phase (i.e., the rate at which the stimulation becomes lectin independent) increases with lectin concentration even in the inhibitory range. The generation of this positive signal is prevented by treating the cells with colchicine. Cells that have become committed but are also simultaneously blocked from entering the S phase by the high doses of Con A can begin synthesizing DNA if the lectin is released by adding a competitive inhibitor of binding. Experiments done in agarose cultures in which lymphocytes are kept from contact with each other suggest that the reversible inhibitory signal is mediated by structures in the individual cells rather than as a result of agglutination. Continuously dividing cells of the lymphoid line P388 are also individually and reversibly inhibited by Con A. These findings are considered in terms of the relation of the inhibitory signal to the microtubular components of cell surface modulating assemblies made up of submembranous arrays of microtubules, microfilaments, and associated proteins.


Adjudicating bleeding events in a platelet dose study: impact on outcome results and challenges.
In the SToP platelet dose study, the World Health Organization (WHO) bleeding grade was assigned using adjudication. This study describes the challenges associated with adjudicating bleeding events and compares the adjudicated and bedside results for bleeding grade. To categorize bleeding, the following information was provided to adjudicators: daily bleeding assessments, interventions to stop or control bleeding, daily blood counts, and transfused blood components. Each daily assessment was sent to two adjudicators who independently assigned a grade and anatomic site of bleeding. Discordant cases where disagreement occurred were sent to a third adjudicator and subsequently to a fourth or fifth adjudicator in an attempt to reach agreement. Disagreement after five adjudicators was resolved by consensus. The final adjudicated grade was compared with the grade of bleeding assigned at the bedside by study personnel. A total of 1150 case report forms were adjudicated. Disagreement on grade of bleeding was common: 31.2% after the first two adjudicators, 4.0% after the third adjudicator, 0.7% after four, and 0.05% after five. Disagreement on anatomic site was less but still occurred in 17% of cases after two adjudicators. The frequency of bleeding (≥ Grade 2) based on adjudication was higher than bedside grading (standard-dose arm, 47.5% vs. 34.4%; low-dose arm, 50.0% vs. 43.1%). The frequency of WHO bleeding varies depending on the method used to assign grade. Adjudication to assign bleeding grade resulted in significant disagreement when two adjudicators were used.


Targeting the seeds of small cell lung cancer.
The concept of antibody drug conjugates (ADCs), which includes the delivery of cytotoxic drugs to antigen-expressing tumor cells by harnessing the antigen-selectivity of a monoclonal antibody, has the potential to redefine the landscape of translational medicine. With the advent of patient derived xenograft (PDX) models and sophisticated genomic technologies, the identification of a selective antigen can be accurately validated within the appropriate tumor milieu. However, a major biological hurdle in cancer translational medicine is the inherent tumoral heterogeneity, underscoring the importance of targeting the 'right' sub-population of cancer cells. Herein, we review a seminal work highlighting the ability to target a key 'stem-like' cancer sub-population called tumor initiating cells (TICs) using engineered ADCs. While the promise of this approach needs to be validated in the clinical setting, TIC-targeted ADCs offer great hope for circumventing current limitations with conventional ADC therapy.


Combustion of dried animal dung as biofuel results in the generation of highly redox active fine particulates.
The burning of biomass in the developing world for heating and cooking results in high indoor particle concentrations. Long-term exposure to airborne particulate matter (PM) has been associated with increased rates of acute respiratory infections, chronic obstructive lung disease and cancer. In this study we determined the oxidative activity of combustion particles derived from the biomass fuel dung cake by examining their capacity to deplete antioxidants from a model human respiratory tract lining fluid (RTLF). For comparison, the observed oxidative activity was compared with that of particles derived from industrial and vehicular sources. Incubation of the dung cake particle suspensions in the RTLF for 4 h resulted in a mean loss of ascorbate of 72.1 +/- 0.7 and 89.7 +/- 2.5% at 50 and 100 microg/ml, respectively. Reduced glutathione was depleted by 49.6 +/- 4.3 and 63.5 +/- 22.4% under the same conditions. The capacity of these samples to deplete ascorbate was in excess of that observed with diesel or gasoline particles, but comparable to that seen with residual oil fly ash and considerably in excess of all three control particles in terms of glutathione depletion. Co-incubation with the metal chelator diethylenetriaminepentaacetate inhibited these losses, whilst minimal inhibition was seen with superoxide dismutase and catalase treatment. The majority of the activity observed appeared to be contained within aqueous particle extracts. These data demonstrate that biomass derived particles have considerable oxidative activity, largely attributable to their transition metal content.


Switching of Receptor Binding Poses between Closely Related Enteroviruses.
Echoviruses, for which there are currently no approved vaccines or drugs, are responsible for a range of human diseases, for example echovirus 11 (E11) is a major cause of serious neonatal morbidity and mortality. Decay-accelerating factor (DAF, also known as CD55) is an attachment receptor for E11. Here, we report the structure of the complex of E11 and the full-length ectodomain of DAF (short consensus repeats, SCRs, 1-4) at 3.1 Å determined by cryo-electron microscopy (cryo-EM). SCRs 3 and 4 of DAF interact with E11 at the southern rim of the canyon via the VP2 EF and VP3 BC loops. We also observe an unexpected interaction between the N-linked glycan (residue 95 of DAF) and the VP2 BC loop of E11. DAF is a receptor for at least 20 enteroviruses and we classify its binding patterns from reported DAF/virus complexes into two distinct positions and orientations, named as E6 and E11 poses. Whilst 60 DAF molecules can attach to the virion in the E6 pose, no more than 30 can attach to E11 due to steric restrictions. Analysis of the distinct modes of interaction and structure and sequence-based phylogenies suggests that the two modes evolved independently, with the E6 mode likely found earlier.


Mexico's methamphetamine precursor chemical interventions: impacts on drug treatment admissions.
To help counter problems related to methamphetamine, Mexico has implemented interventions targeting pseudoephedrine and ephedrine, the precursor chemicals commonly used in the drug's synthesis. This study examines whether the interventions impacted methamphetamine treatment admissions-an indicator of methamphetamine consequences. Quasi-experiment: autoregressive integrated moving average (ARIMA)-based intervention time-series analysis. precursor chemical restrictions implemented beginning November 2005; major rogue precursor chemical company closed (including possibly the largest single drug-cash seizure in history) March 2007; precursor chemicals banned from Mexico (North America's first precursor ban) August 2008. Mexico and Texas (1996-2008). Monthly treatment admissions for methamphetamine (intervention series) and cocaine, heroin and alcohol (quasi-control series). The precursor restriction was associated with temporary methamphetamine admissions decreases of 12% in Mexico and 11% in Texas. The company closure was associated with decreases of 56% in Mexico and 48% in Texas; these decreases generally remained to the end of the study period. Neither intervention was associated with significant changes in the Mexico or Texas quasi-control series. The analysis of Mexico's ban was indeterminate due largely to a short post-ban series. This study, one of the first quasi-experimental analyses of an illicit-drug policy in Mexico, indicates that the country's precursor interventions were associated with positive impacts domestically and in one of the Unites States' most populous states--Texas. These interventions, coupled with previous US and Canadian interventions, amount to a new, relatively cohesive level of methamphetamine precursor control across North America's largest nations, raising the possibility that the impacts found here could continue for an extended period.


Human V-ATPase a-subunit isoforms bind specifically to distinct phosphoinositide phospholipids.
V-ATPases are highly conserved multi-subunit enzymes that maintain the distinct pH of eukaryotic organelles. The integral membrane a-subunit is encoded by tissue and organelle specific isoforms, and its cytosolic N-terminal domain (aNT) modulates organelle specific regulation and targeting of V-ATPases. Organelle membranes have specific phosphatidylinositol phosphate (PIP) lipid enrichment linked to maintenance of organelle pH. In yeast, the aNT domains of the two a-subunit isoforms bind PIP lipids enriched in the organelle membranes where they reside; these interactions affect activity and regulatory properties of the V-ATPases containing each isoform. Humans have four a-subunit isoforms. We hypothesize that the aNT domains of the human isoforms will also bind to specific PIP lipids. The a1 and a2 isoforms of human V-ATPase a-subunits are localized to endolysosomes and Golgi, respectively. Bacterially expressed Hua1NT and Hua2NT bind specifically to endolysosomal PIP lipids PI(3)P and PI(3,5)P2 and Golgi enriched PI(4)P, respectively. Despite the lack of canonical PIP binding sites, potential binding sites in the HuaNT domains were identified by sequence comparisons and existing subunit structures and models. Mutations at a similar location in the distal loops of both HuaNT isoforms compromise binding to their cognate PIP lipids, suggesting that these loops encode PIP specificity of the a-subunit isoforms. These data also suggest a mechanism through which PIP lipid binding could stabilize and activate V-ATPases in distinct organelles.


In vitro evidence of two-component system phosphorylation between the Mycobacterium tuberculosis TrcR/TrcS proteins.
Two-component regulatory proteins, histidine kinases and response regulators, function in bacteria as sensing and adaptive factors in response to a wide range of environmental stimuli. Conserved histidine and glycine regions of histidine kinase sensor proteins were used to design degenerate oligonucleotide primers for amplification of DNA fragments from Mycobacterium tuberculosis. Two adjacent genes, trcR and trcS, which encode a response regulator and a histidine kinase, respectively, have been identified. Full-length and truncated TrcR and TrcS proteins have been expressed in Escherichia coli. Difficulties in expressing recombinant full-length TrcS and a truncated N -terminal form of TrcS reveal that the transmembrane domains are toxic to E. coli. Overexpressed truncated C-terminal transmitter domains of TrcS have been autophosphorylated in vitro and have transphosphorylated both the full-length recombinant TrcR protein and the N -terminal receiver/regulator domain of TrcR. In vitro autophosphorylation of TrcS requires the presence of Mn2+or Ca2+as a divalent cation cofactor and subsequent transphosphorylation of TrcR is evident in the presence of TrcS-phosphate and Ca2+. Transphosphorylation between these two proteins provides evidence that these M. tuberculosis genes encode functional two-component system regulatory proteins that are members of a signal transduction circuit.


Site-directed cross-linking studies on the E. coli tRNA-ribosome complex: determination of sites labelled with an aromatic azide attached to the variable loop or aminoacyl group of tRNA.
tRNA(Phe) from E. coli, modified with the photoreactive label N-(p-azidobenzoyl)-glycine (ABG) either at the naturally occurring nucleotide 3-(3-amino-3-carboxy-propyl) uridine (acp3U47) or the alpha-amino group of Phe-tRNA(Phe), was bound nonenzymatically to 70S ribosomes in the presence of poly (U) or short synthetic mRNA molecules prepared by T7 transcription. The noncovalent complexes were subjected to a mild ultraviolet irradiation treatment and the sites of photo-incorporation were analysed. When the photo-affinity label was attached to the aminoacyl group cross-linking was observed from both A- and P-site bound tRNA and involved exclusively the 50S subunit. In both cases the major target of cross-linking was a single site in 23S RNA, localized to position A-2439. A lower yield of cross-linking to L27 from both P- and A-sites was also observed. In contrast, cross-linking from the acp3U47 derivative was specific for P-site bound tRNA and involved mainly (but not exclusively) the 50S subunit. In this case rRNA and ribosomal protein were labelled in approximately equal yields, the sites of cross-linking involving A-2309 in 23S RNA and L33. These results are discussed in the light of our present knowledge concerning the structural arrangement of the tRNA-ribosome complex.


Clinician knowledge and utilization of empirically-supported treatments for maltreated children.
Efforts to disseminate empirically-supported treatments (ESTs) for maltreated children are confronted with numerous challenges, and the success of these efforts is unclear. The current study reports on the results of a nationwide survey of 262 clinicians serving maltreated children in the United States. From a provided list, clinicians were asked to identify interventions they believed possessed adequate empirical support, as well as the interventions they commonly used, were trained to use, or would like to receive training to use. Results showed that clinicians generally are unable to identify ESTs, and many of the interventions clinicians reported most commonly using and being trained to use are not typically considered to be empirically-supported (with the exception of Trauma-Focused Cognitive-Behavioral Therapy). Greater ability to accurately identify ESTs was predicted by favorable attitudes toward evidence-based practice; however, beliefs that non-ESTs were empirically-supported were best predicted by training background (e.g., professional discipline, education level, and theoretical orientation). Finally, regression analyses found that the interventions clinicians identified as empirically-supported predicted the interventions in which clinicians received training, which in turn predicted the interventions commonly used. Implications of these findings for dissemination and policy are discussed.


Kinematics of cervical spine discectomy with and without bone grafting: quantitative evaluation of late fusion in a sheep model.
This study was conducted to evaluate the kinematic response of late fusion results for cervical spine discectomies with and without bone grafting. Fifteen Barbados Black Belly sheep underwent sham operations (Group A, n = 5), C2-C3 discectomies only (Group B, n = 5), and C2-C3 discectomies with autologous iliac bone grafting (Group C, n = 5). Ten months after surgery, the animals were killed. Fresh ligamentous spines (C1-C5) were subjected to the relevantly applied loads through a loading frame attached to the C1. Each vertebra (from C2 to C4) was attached with a set of three infrared light-emitting diodes to record the spatial location relating to each load application using a Selspot II system (Selcom Selective Electronics, Inc., Valdese, NC). The load-deformation data of the C2-C3 and C3-C4 motion segments were recorded and analyzed for the three groups. At the C2-C3 motion segment, the results indicated that Group B displayed larger motion ranges of rotation and lateral bending loads than did the other two groups. Significantly larger motion ranges of rotation loads were found in Group B than in Group C (P<0.05, for both comparisons). In contrast, Group C had the smallest motion ranges of flexion, lateral bending, and rotation loads. At the C3-C4 motion segment, both groups that had undergone discectomies had a significantly larger motion range of flexion load compared with Group A (P<0.05, for both comparisons). A significant increase in the motion range of right axial rotation was found in Group B (P<0.05), but not in Group C, compared with Group A. Group B exhibited larger motion ranges responding to all six tested loads than did Group C. The results indicate that anterior fusion after C2-C3 cervical discectomies, regardless of the presence or absence of bone grafting, decreases the motion range of flexion load at the C2-C3 motion segment, and contrary data were seen at the C3-C4 motion segment. For axial rotation loads, discectomies without bone grafting resulted in increased motion ranges of both C2-C3 and C3-C4 motion segments whereas discectomies with bone grafting did not. The data may have clinical relevance regarding the role of bone grafting in cases of cervical spine disease.


The do-not-resuscitate order: outpatient experience and decision-making preferences.
Do-not-resuscitate (DNR) orders have become a widespread part of modern medical practice. This study examined patient experience and decision-making preferences regarding cardiopulmonary resuscitation. A random sample of 800 outpatients (one half aged over 70 years) was surveyed by questionnaire, with a 51% response rate. While only 11% of patients had ever discussed resuscitation with a physician, 67% had thought about the issue, and 44% had discussed it with someone other than a physician. Patients overwhelmingly preferred to preserve a good quality of life, even if it meant not living longer (93.9%). When asked who they would have help them with DNR decisions, physicians were most often selected, while spouses were the most valued advisors. In a series of scenarios such factors as dementia, drug or alcohol use, age, and pain had a significant effect on a patient's decision about resuscitation. Discussions about DNR issues in the outpatient setting should be encouraged, as patient interest is strong, and greater physician awareness of patients' values and preferences can prevent unwanted resuscitation in the acute setting.


Electrochemical metallization switching with a platinum group metal in different oxides.
In a normal electrochemical metallization (ECM) switch, electrochemically active metals, such as Ag and Cu are used to provide mobile ions for the conducting filament. In both ECM and valence change memory (VCM) devices, platinum group metals, such as Pt and Pd, are typically used as the counter electrode and assumed to be chemically and physically inert. In this study, we explore whether the so-called inert metal itself can form a conducting filament and result in repeatable resistance switching. Pd and different oxide host matrices are used for this purpose. We have observed that the transport of oxygen anions dominates over Pd metal cations in ALD deposited AlOx and HfOx. However, in sputtered SiOx, Pd cation transport was revealed, accompanied by the formation of nano-crystalline Pd filament(s) in the junctions. Based on these observations, memristors with reversible and repeatable switching were obtained by using Pd doped SiOx as the switching material.


[Characteristics of ambient air quality in office chambers and its influence on workers' state].
Increasing health complaints of office workers are associated with exposure to indefinite risk factors. Many discussions involve ano-particles (size less than 100 nm) in air of non-industrial chambers containing contemporary office equipment. Complex study covered quality of air in offices (microclimate, organic and inorganic pollutants, dust particles). New approach to assessment of non- industrial working environment is evaluation of air pollution by ultrasmall (nano) particles through their quantity and surface square. Polling method helped to study the state of office workers.


Alcohol and smoking.
The WHO ranks smoking and alcohol consumption as the first and third leading causes of the global burden of disease in industrialized countries, using disability-adjusted life years (DALYs) as a combined measure of premature death and disability. Smoking is responsible for 12.2% of all DALYs and alcohol consumption for 9.2%. For example in Germany, annually 110,000-140,000 humans die prematurely because of cigarette smoking and 40,000 because of alcohol drinking. In Europe and the USA, more than 20% of all hospitalized men and more than 9% of all hospitalized women suffer from alcohol-associated diseases. In Germany, about 2.0 million people in the age group 18-64 years (3.8% of all Germans) are alcohol abusers and 1.3 million people (2.4%) are alcohol-dependent. Alcohol can cause acute as well as chronic damage in nearly all body organs. Smoking damages also nearly every human body organ and is worldwide the most important single preventable health risk factor as well as the main cause for premature mortality in industrial countries. One third of the adult Germans as well as of the world population are active smokers; men smoke more frequently than women (34.0 vs. 25.1%). In this review a short overview will be given on the most important deleterious effects of alcohol and smoking. The most recent data about the pathophysiological relevance of non-alcoholic compounds of alcoholic beverages will also be discussed.


Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma.
Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated skin cancer. Robust cellular immune responses are associated with excellent outcomes in patients with MCC, but these responses are typically absent. We determined the prevalence and reversibility of major histocompatibility complex class I (MHC-I) downregulation in MCC, a potentially reversible immune-evasion mechanism. Cell-surface MHC-I expression was assessed on five MCC cell lines using flow cytometry as well as immunohistochemistry on tissue microarrays representing 114 patients. Three additional patients were included who had received intralesional IFN treatment and had evaluable specimens before and after treatment. mRNA expression analysis of antigen presentation pathway genes from 35 MCC tumors was used to examine the mechanisms of downregulation. Of note, 84% of MCCs (total n = 114) showed reduced MHC-I expression as compared with surrounding tissues, and 51% had poor or undetectable MHC-I expression. Expression of MHC-I was lower in polyomavirus-positive MCCs than in polyomavirus-negative MCCs (P < 0.01). The MHC-I downregulation mechanism was multifactorial and did not depend solely on HLA gene expression. Treatment of MCC cell lines with ionizing radiation, etoposide, or IFN resulted in MHC-I upregulation, with IFNs strongly upregulating MHC-I expression in vitro, and in 3 of 3 patients treated with intralesional IFNs. MCC tumors may be amenable to immunotherapy, but downregulation of MHC-I is frequently present in these tumors, particularly those that are positive for polyomavirus. This downregulation is reversible with any of several clinically available treatments that may thus promote the effectiveness of immune-stimulating therapies for MCC.


Walking and rolling of crystals induced thermally by phase transition.
The mechanical motion of materials has been increasingly explored in terms of bending and expansion/contraction. However, the locomotion of materials has been limited. Here, we report walking and rolling locomotion of chiral azobenzene crystals, induced thermally by a reversible single-crystal-to-single-crystal phase transition. Long plate-like crystals with thickness gradient in the longitudinal direction walk slowly, like an inchworm, by repeated bending and straightening under heating and cooling cycles near the transition temperature. Furthermore, thinner, longer plate-like crystals with width gradient roll much faster by tilted bending and then flipping under only one process of heating or cooling. The length of the crystal is shortened above the transition temperature, which induces bending due to the temperature gradient to the thickness direction. The bending motion is necessarily converted to the walking and rolling locomotion due to the unsymmetrical shape of the crystal. This finding of the crystal locomotion can lead to a field of crystal robotics.


The encapsulation effect of UV molecular absorbers into biocompatible lipid nanoparticles.
The efficiency of a cosmetic product depends not only on the active ingredients, but also on the carrier system devoted to improve its bioavailability. This article aims to encapsulate two couples of UV molecular absorbers, with a blocking action on both UV-A and UV-B domains, into efficient lipid nanoparticles. The effect of encapsulation on the specific properties such as sun protection factor and photostability behaviour has been demonstrated. The lipid nanoparticles with size range 30-350 nm and a polydispersity index between 0.217 and 0.244 are obtained using a modified high shear homogenisation method. The nanoparticles had spherical shapes with a single crystallisation form of lipid matrices characteristic for the least ordered crystal structure (α-form). The in vitro determination of photoprotection has led to high SPF ratings, with values of about 20, which assure a good photoprotection and filtering about 95% of UV radiation. The photoprotection effect after irradiation stage was observed to be increased more than twice compared to initial samples as a result of isomerisation phenomena. All the results have shown that good photoprotection effect and improved photostability could be obtained using such sunscreen couples, thus demonstrating that UV absorbers-solid lipid nanoparticles are promising carriers for cosmetic formulations.


Characterization factors for terrestrial acidification at the global scale: a systematic analysis of spatial variability and uncertainty.
Characterization factors (CFs) are used in life cycle assessment (LCA) to quantify the potential impact per unit of emission. CFs are obtained from a characterization model which assess the environmental mechanisms along the cause-effect chain linking an emission to its potential damage on a given area of protection, such as loss in ecosystem quality. Up to now, CFs for acidifying emissions did not cover the global scale and were only representative of their characterization model geographical scope. Consequently, current LCA practices implicitly assume that all emissions from a global supply chain occur within the continent referring to the characterization method geographical scope. This paper provides worldwide 2°×2.5° spatially-explicit CFs, representing the change in relative loss of terrestrial vascular plant species due to an emission change of nitrogen oxides (NOx), ammonia (NH3) and sulfur dioxide (SO2). We found that spatial variability in the CFs is much larger compared to statistical uncertainty (six orders of magnitude vs. two orders of magnitude). Spatial variability is mainly caused by the atmospheric fate factor and soil sensitivity factor, while the ecological effect factor is the dominant contributor to the statistical uncertainty. The CFs provided in our study allow the worldwide spatially explicit evaluation of life cycle impacts related to acidifying emissions. This opens the door to evaluate regional life cycle emissions of different products in a global economy.


The "Everything About the Existence" Experiences of Turkish Women With Infertility: Solicited Diaries in Qualitative Research.
Infertility as a gynecological illness causes many psychological problems. In Turkey, only a limited number of studies have used qualitative methods to explore the experiences of infertile women. The aims of this study are to investigate the infertility experiences of women using Watson's Theory of Human Caring as a guide and to sensitize healthcare professionals to the importance of the personal stories of these women. A phenomenological approach was used to guide our exploration of the stories of infertile women during their treatment for infertility. This study involved 18 infertile women in Turkey. Data were collected using solicited diaries and were evaluated using thematic analysis. The findings identified the following themes: (a) losing control of everything, (b) facing up to the angst, (c) living with the unknown, (d) alienation from the fertile world, (e) existential faith and hope, and (f) nonhealing environment. This study identified "existentialist philosophy" as the most important aspect of the infertility experience. Participant experiences highlighted that they lived with a despair that was brought about by losses resulting from the infertility diagnosis and its treatment. Nurses should help infertile women reorganize the meaning of infertility to reach a healthy interpretation of infertility.


Experience from controlled trials of physical training in chronic heart failure. Protocol and patient factors in effectiveness in the improvement in exercise tolerance. European Heart Failure Training Group.
Beneficial effects of physical training on exercise tolerance, autonomic and skeletal muscle function and limb blood flow have been demonstrated in chronic heart failure. Because this rehabilitation is expensive, may involve risk, and has unknown effects on prognosis, the possibility of predicting benefit on the basis of individual patient data is intriguing. The most suitable exercise training programme has not yet been established. We reviewed the progress of 134 stable heart failure patients studied in randomized controlled trials of physical training. A significant training effect (+13% peak oxygen consumption, +17% exercise duration) was associated with improved autonomic indices (resting catecholamines and hormones, heart rate variability), without significant side-effects. No ventilatory, haemodynamic, autonomic or clinical factor at baseline was a predictor of outcome. Similar beneficial effects were observed in both male and female patients. The improvement in oxygen consumption after 16 weeks training was higher than after 6 weeks (+2.6 +/- 3.0 vs +0.3 +/- 3.1 ml.kg.min-1, P < 0.05). The combination of cycle ergometer with calisthenic exercises was more beneficial than cycle ergometer alone (+2.7 +/- 4.2 vs 1.2 +/- 2.0 ml.kg.min-1, P < 0.01). The presence of nonsustained ventricular tachycardia did not preclude a training effect. Patients older than 70 years were able to train, although less effectively than the younger ones. No difference in exercise gain was observed whether the patients trained in the hospital or at home. The positive effects of physical rehabilitation in chronic stable heart failure patients are confirmed. No baseline patient factor was significantly correlated with outcome. A tailored, moderate, home-based, combined cycle ergometer, plus calisthenic exercise training seems safe and beneficial in a large cohort of heart failure patients, with similar benefits in a variety of conditions and different hospital settings.


Dynamic expression of the RNA-binding protein Sam68 during mouse pre-implantation development.
The STAR protein Sam68 (KHDRBS1) is involved in several aspects of post-transcriptional mRNA metabolism. Herein, we have investigated the expression and subcellular localization of Sam68 during early mouse embryogenesis. We found that mouse oocytes express high levels of Sam68 mRNA, low levels of the transcript for Khdrbs2 (current symbol for Slm-1) and no Khdrbs3 (current symbol for Slm-2), two highly homologous STAR genes. Sam68 protein is expressed throughout oocyte meiotic maturation and early embryogenesis. It is released in the cytoplasm upon meiotic resumption and it slowly accumulates in the nucleus after fertilization. Unlike what was observed for other RNA-binding proteins, nuclear accumulation of Sam68 was independent of de novo mRNA transcription. However, we found that inhibition of mRNA translation by either cycloheximide or puromycin in one-cell embryos caused the accumulation of Sam68 in cytoplasmic granules. Analysis of these granules by deconvolution microscopy demonstrated that they are sites of accumulation for proteins involved in the initiation of mRNA translation, such as eIF4A1, eIF4E and eIF4G. These granules contained RNA and were dissolved by treatment with RNase A. Other proteins expressed by the zygote, like the splicing factor SC35 or the cytoplasmic kinase ERK2, did not accumulate in such structures after treatment with inhibitors of mRNA translation, indicating that the localization of Sam68 and of the translation initiation factors in these granules is a specific event. These results indicate that Sam68 is involved in translational regulation of maternal mRNAs in the zygote and in the early signaling events triggered by fertilization.


Stimulation of renin release by intrarenal calcium infusion.
The effects of intrarenal infusions of calcium gluconate (10 and 100 micrograms Ca/kg/min) on renin secretion were studied in anesthetized mongrel dogs. In one group, the two doses of calcium were infused for 30 minutes each (1 ml/min). In a second group, the same doses were administered 30 minutes after the start of infusion of prostaglandin synthesis inhibitors (indomethacin 10 micrograms/kg/min intrarenal or injection of meclofenamate 5 mg/kg i.v. bolus). Mean arterial pressure, renal blood flow, and glomerular filtration rate remained unchanged during the infusion of calcium in both groups. The infusion of 10 micrograms Ca/kg/min increased renin secretion 77% and sodium excretion 123%. During the infusion of 100 micrograms Ca/kg/min, renin secretion was not different from precalcium values, whereas urinary 6-keto-PGF1 alpha, urine flow, sodium, potassium, and calcium excretion rates were increased (p less than 0.05). During the administration of prostaglandin synthesis inhibitors, the urinary 6-keto-PGF1 alpha levels were reduced, and the infusion of 10 micrograms Ca/kg/min failed to increase renin secretion, sodium excretion, or 6-keto-PGF1 alpha excretion rates. The infusion of 100 micrograms Ca/kg/min during prostaglandin synthesis inhibition did not modify urine flow or sodium excretion; however, potassium and calcium excretions increased. It is concluded that 1) the intrarenal infusion of small doses of calcium gluconate is capable of stimulating renin secretion through a prostaglandin-mediated mechanism, and 2) the stimulation of renin secretion as well as the increase in sodium excretion induced by calcium are independent of hemodynamic alterations.


Extracellular matrix production by adipose-derived stem cells: implications for heart valve tissue engineering.
A key challenge in tissue engineering a heart valve is to reproduce the major tissue structures responsible for native valve function. Here we evaluated human adipose-derived stem cells (ADSCs) as a source of cells for heart valve tissue engineering investigating their ability to synthesize and process collagen and elastin. ADSCs were compared with human bone marrow mesenchymal stem cells (BmMSCs) and human aortic valve interstitial cells (hVICs). ADSCs and BmMSCs were stretched at 14% for 3 days and collagen synthesis determined by [(3)H]-proline incorporation. Collagen and elastin crosslinking was assessed by measuring pyridinoline and desmosine respectively, using liquid chromatography/mass spectrometry. Three-dimensional culture was obtained by seeding cells onto bovine collagen type I scaffolds for 2-20 days. Expression of matrix proteins and processing enzymes was assessed by Real Time-PCR, immunofluorescence and transmission electron microscopy. Stretch increased the incorporation of [(3)H]-proline in ADSCs and BmMSCs, however only ADSCs and hVICs upregulated COL3A1 gene. ADSCs produced collagen and elastin crosslinks. ADSCs uniformly populated collagen scaffolds after 2 days, and fibrillar-like collagen was detected after 20 days. ADSCs sense mechanical stimulation and produce and process collagen and elastin. These novel findings have important implications for the use of these cells in tissue engineering.


Growing-finishing performance and carcass characteristics of pigs fed normal and genetically modified low-phytate corn.
A genetically modified corn hybrid homozygous for the lpa1 allele, containing low phytate (LP), and its nearly isogenic equivalent hybrid (normal) were compared in two experiments with growing-finishing swine. In Exp. 1, 210 barrows (27 kg) were allotted to one of six dietary treatments with two corn hybrids (LP and normal) and three P feeding regimens. There were five replicate pens (seven pigs/pen) per treatment. Treatments consisted of diets that were supplemented with P throughout the growing-finishing period (.2% P and .15% supplemental P during growing and finishing phases, respectively) or only during the growing phase (.2% supplemental P) or that were not supplemented with P throughout the growing-finishing period. Performance at the end of the growing phase was based on a 2 x 2 factorial arrangement of treatments with two corn hybrids and two levels of added P (0 and .2%). This resulted in 10 replicates for the treatments supplemented with .2% P. The finishing phase (73 to 112 kg) was a 2 x 3 factorial arrangement of treatments with the two types of corn and three regimens of added P during the finishing period. Breaking load (BL) and ash of the fourth metacarpal were evaluated from one pig/pen at the end of the growing phase and from all pigs after slaughter. Pigs fed the LP corn diet without added P had greater body weight gain, feed efficiency, BL, and ash content of the fourth metacarpal than pigs fed the normal corn diet without added P. Performance was similar between pigs fed the LP diet without added P and pigs fed LP and normal corn with added P. In Exp. 2, 1,092 gilts (34 kg body weight) were allotted by weight in a commercial facility to one of three treatments: 1) normal corn/soybean meal diet containing .29% and .22% available P during the growing and finishing phases, respectively; 2) LP corn/soybean meal diet with the same available P level as Treatment 1; and 3) same as Treatment 2 for 8 wk, then no inorganic P supplementation during the finishing phase. All pigs were slaughtered at approximately 122 kg. There were no significant differences in growing-finishing performance or BL among treatments. However, pigs fed diets containing LP corn possessed carcasses with less backfat and a higher percentage of lean (P < .01). These results confirm that the P in LP corn is available to the pig and suggest that pigs fed diets containing this genetically modified corn will have more desirable carcasses.


Cosaliency Detection Based on Intrasaliency Prior Transfer and Deep Intersaliency Mining.
As an interesting and emerging topic, cosaliency detection aims at simultaneously extracting common salient objects in multiple related images. It differs from the conventional saliency detection paradigm in which saliency detection for each image is determined one by one independently without taking advantage of the homogeneity in the data pool of multiple related images. In this paper, we propose a novel cosaliency detection approach using deep learning models. Two new concepts, called intrasaliency prior transfer and deep intersaliency mining, are introduced and explored in the proposed work. For the intrasaliency prior transfer, we build a stacked denoising autoencoder (SDAE) to learn the saliency prior knowledge from auxiliary annotated data sets and then transfer the learned knowledge to estimate the intrasaliency for each image in cosaliency data sets. For the deep intersaliency mining, we formulate it by using the deep reconstruction residual obtained in the highest hidden layer of a self-trained SDAE. The obtained deep intersaliency can extract more intrinsic and general hidden patterns to discover the homogeneity of cosalient objects in terms of some higher level concepts. Finally, the cosaliency maps are generated by weighted integration of the proposed intrasaliency prior, deep intersaliency, and traditional shallow intersaliency. Comprehensive experiments over diverse publicly available benchmark data sets demonstrate consistent performance gains of the proposed method over the state-of-the-art cosaliency detection methods.


Automated identification and classification of single particle serial femtosecond X-ray diffraction data.
The first hard X-ray laser, the Linac Coherent Light Source (LCLS), produces 120 shots per second. Particles injected into the X-ray beam are hit randomly and in unknown orientations by the extremely intense X-ray pulses, where the femtosecond-duration X-ray pulses diffract from the sample before the particle structure is significantly changed even though the sample is ultimately destroyed by the deposited X-ray energy. Single particle X-ray diffraction experiments generate data at the FEL repetition rate, resulting in more than 400,000 detector readouts in an hour, the data stream during an experiment contains blank frames mixed with hits on single particles, clusters and contaminants. The diffraction signal is generally weak and it is superimposed on a low but continually fluctuating background signal, originating from photon noise in the beam line and electronic noise from the detector. Meanwhile, explosion of the sample creates fragments with a characteristic signature. Here, we describe methods based on rapid image analysis combined with ion Time-of-Flight (ToF) spectroscopy of the fragments to achieve an efficient, automated and unsupervised sorting of diffraction data. The studies described here form a basis for the development of real-time frame rejection methods, e.g. for the European XFEL, which is expected to produce 100 million pulses per hour.


Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy.
Skeletal muscle atrophy is a common and debilitating condition that remains poorly understood at the molecular level. To better understand the mechanisms of muscle atrophy, we used mouse models to search for a skeletal muscle protein that helps to maintain muscle mass and is specifically lost during muscle atrophy. We discovered that diverse causes of muscle atrophy (limb immobilization, fasting, muscle denervation, and aging) strongly reduced expression of the enzyme spermine oxidase. Importantly, a reduction in spermine oxidase was sufficient to induce muscle fiber atrophy. Conversely, forced expression of spermine oxidase increased muscle fiber size in multiple models of muscle atrophy (immobilization, fasting, and denervation). Interestingly, the reduction of spermine oxidase during muscle atrophy was mediated by p21, a protein that is highly induced during muscle atrophy and actively promotes muscle atrophy. In addition, we found that spermine oxidase decreased skeletal muscle mRNAs that promote muscle atrophy (e.g., myogenin) and increased mRNAs that help to maintain muscle mass (e.g., mitofusin-2). Thus, in healthy skeletal muscle, a relatively low level of p21 permits expression of spermine oxidase, which helps to maintain basal muscle gene expression and fiber size; conversely, during conditions that cause muscle atrophy, p21 expression rises, leading to reduced spermine oxidase expression, disruption of basal muscle gene expression, and muscle fiber atrophy. Collectively, these results identify spermine oxidase as an important positive regulator of muscle gene expression and fiber size, and elucidate p21-mediated repression of spermine oxidase as a key step in the pathogenesis of skeletal muscle atrophy.


Integration of replication-defective R68.45-like plasmids into the Pseudomonas aeruginosa chromosome.
R68.45 and other similar broad-host-range (IncP) plasmids carrying a tandem repeat of the 2.1 kb insertion element IS21 mobilize the chromosome of many different Gram-negative bacteria. To analyse the structure of R68.45-chromosome cointegrates, whose involvement in the mobilization process had been postulated previously, we selected for the stable integration of R68.45-like plasmids into the Pseudomonas aeruginosa chromosome. Two plasmids were chosen: pME28, a transfer-deficient, mobilizable RP1 derivative with an inactive replication control (trfA) gene, and pME487, an R68.45 derivative with a trfA(ts) mutation causing temperature-sensitive replication. Chromosomally integrated pME28 and pME487 were found to be flanked by single IS21 elements. This structure is in agreement with a 'cut-and-paste' mode of R68.45 transposition. pME28 and pME487 showed a low specificity of insertion but rarely (less than 0.1%) induced auxotrophic mutations. Hfr (high-frequency-of-recombination) donors of P. aeruginosa could be obtained by chromosomal integration of pME487 or pME28; in the latter case, the transfer functions lacking from pME28 had to be provided in trans on an autonomous plasmid. Hfr donors gave higher conjugational linkage and transferred longer stretches of the P. aeruginosa chromosome than did R68.45 donors. This suggests that the integration of R68.45 into the donor chromosome is short-lived in P. aeruginosa.


A multibiomarker approach to the assessment of pollution impacts in two Baltic Sea coastal areas in Sweden using caged mussels (Mytilus trossulus).
Blue mussels (Mytilus trossulus) were transplanted in cages for three months in two Swedish coastal areas in the Bothnian Sea (northern Baltic Sea) to investigate the interactions between analysed environmental chemicals and biological responses. A wide array of biological parameters (biomarkers) including antioxidant and biotransformation activity, geno-, cyto- and neurotoxic effects, phagocytosis, bioenergetic status and heart rate were measured to detect the possible effects of contaminants. Integrated Biomarker Response index and Principal Component Analysis performed on the individual biological response data were able to discriminate between the two study areas as well as the contaminated sites from their respective local reference sites. The two contaminated sites outside the cities of Sundsvall (station S1) and Gävle (station G1) were characterised by different biomarker response patterns. Mussels at station S1 showed a low condition index, increased heart rate recovery time and phagocytosis activity coinciding with the highest tissue concentrations of some trace metals, polycyclic aromatic hydrocarbons and organotins. At station G1 the highest organochlorine pesticide concentration was recorded as well as elevations in glutathione S-transferase activity, thiamine content and low lysosomal membrane stability. Significant variability in the geno- and cytotoxic responses and bioenergetic status was also observed at the different caging stations. The results obtained suggest that different chemical mixtures present in the study areas cause variable biological response patterns in organisms.


Waldenström macroglobulinemia.
Waldenström macroglobulinemia (WM) is an indolent low-grade lymphoma characterized by bone marrow infiltration with lymphoplasmacytic cells associated with a monoclonal immunoglobulin M protein. It is considered incurable. The 5-year survival rate for patients with symptomatic WM is 87% for those with low-risk disease, 68% for those with intermediate-risk disease, and 36% for those with high-risk disease. Owing to recent advances in therapy with new targeted treatment options, relative survival has improved. Insights into mutations in MYD88 L265P and the WHIM-like CXCR4 have been shown to be significant not just in terms of their diagnostic and prognostic value, but also as potential targets for therapy. For patients with symptomatic WM, the different classes of agents used to treat WM include alkylating agents (eg, cyclophosphamide and chlorambucil), nucleoside analogues (eg, cladribine and fludarabine) and monoclonal antibodies (eg, rituximab and alemtuzumab). With an increasing number of novel treatment options available including everolimus, bendamustine, bortezomib, ibrutinib, carfilzomib, lenalidomide, and panobinostat, the optimal timing and introduction of these options in the absence of phase 3 trials remains controversial. A treatment algorithm based on Mayo Stratification for Macroglobulinemia and Risk-Adapted Therapy (mSMART) and a comparison of important clinical trials in WM is provided.


Measuring family caregivers' experience of interprofessional care for patients and families: development of the Japanese version of the Caregivers' Experience Instrument.
Improving individuals' experience of care is now a critical goal of health care systems. Although a number of instruments have been developed to measure experience of care, few instruments measure family caregivers' experience of interprofessional care for patients and families. To develop the Japanese version of the Caregivers' Experience Instrument (J-IEXPAC CAREGIVERS) and to investigate its validity in assessing quality of integrated care for both patients with chronic conditions and their family caregivers, from the caregivers' perspective, in Japan. We used a cross-sectional questionnaire survey to test the validity and internal consistency of J-IEXPAC CAREGIVERS. Four hundred family caregivers were recruited in three municipalities. We evaluated the feasibility, structural validity, internal consistency and hypothesis testing for construct validity of the scale. A total of 274 (68.5%) questionnaires were analysed. Confirmatory factor analysis showed acceptable model fit for the hypothesized two-factor model according to fit indices, as identified for the original version: attention for the patient and attention for the caregiver. Cronbach's alpha for score in J-IEXPAC CAREGIVERS with 12 items was high (0.92). Spearman's rank correlation coefficient between overall caregiver satisfaction and J-IEXPAC CAREGIVERS score was 0.71. Family caregivers who experienced home-visit services had significantly (P = 0.001) higher total scores than those who did not. This pilot study showed that the J-IEXPAC CAREGIVERS is valid and reliable. This scale can be useful for evaluating quality of integrated care, with focus on family caregivers and patients with chronic conditions in Japan.


Corchorus pascuorum: transmission of chemically induced fruit formation with environmental change.
When Corchorus pascuorum (Tiliaceae), native to Australia, was grown in the arid region of West Pakistan, it flowered abundantly but produced no fruit. It was induced to form fruit by treatment with 25 percent sucrose solution containing indolebutyric acid (300 parts per million). When plants were raised from the induced fruits, they fruited without any further treatment and retained the ability to produce fruits in two subsequent generations, whereas those raised from the original seeds produced no fruit.


Browsing lawns? Responses of Acacia nigrescens to ungulate browsing in an African savanna.
We measured browsing-induced responses of Acacia trees to investigate "browsing lawns" as an analogy to grazing lawns in a semiarid eutrophic African savanna. During the two-year field study, we measured plant tolerance, resistance, and phenological traits, while comparing variation in leaf nitrogen and specific leaf area (SLA) across stands of Acacia nigrescens, Miller, that had experienced markedly different histories of attack from large herbivores. Trees in heavily browsed stands developed (1) tolerance traits such as high regrowth abilities in shoots and leaves, high annual branch growth rates, extensive tree branching and evidence of internal N translocation, and (2) resistance traits such as close thorn spacing. However, phenological "escape" responses were weak even in heavily browsed stands. Overall, browsing strongly affected plant morpho-functional traits and decreased both the number of trees carrying pods and the number of pods per tree in heavily browsed stands. Hence, there is experimental evidence that tolerance and resistance traits may occur simultaneously at heavily browsed sites, but this comes at the expense of reproductive success. Such tolerance and resistance traits may coexist if browsers trigger and maintain a positive feedback loop in which trees are continually investing in regrowth (tolerance), and if the plant's physical defenses (resistance) are not nutritionally costly and are long-lived. Our results confirm that chronic browsing by ungulates can maintain A. nigrescens trees in a hedged state that is analogous to a grazing lawn. Further research is needed to fully understand the long-term effects of chronic browsing on reproduction within such tree populations, as well as the overall effects on nutrient cycling at the ecosystem level.


Early diagnosis and minimally invasive treatment of occlusal caries--a clinical approach.
This report summarizes the clinical experiences and recommendations for use of the KaVo DIAGNOdent laser fluorescence device and of air abrasion (Kinetic cavity preparation). A major diagnostic problem facing clinicians today is the difficulty of achieving accurate occlusal caries diagnosis. Diagnostic accuracy is important because it determines the quality of the treatment decisions made, particularly with regard to the possibility of unnecessary operative intervention. The decrease in incidence of cavitated caries in Western countries, followed by the change in common presentation to non-cavitated caries, has made this accurate diagnosis more difficult. The deficiencies of using traditional methods of occlusal diagnosis are discussed and examined, along with the need for new, more accurate techniques. The use of the new technology of laser fluorescence is explained in detail with a discussion of the advantages and limitations of a commercial device: the KaVo DIAGNOdent. A minimal cavity outline philosophy is suggested for operative intervention, with particular emphasis on the advantages of using Kinetic cavity preparation (KCP) non-rotary method of tooth cutting. It should be noted that treatment options such as operative intervention should never precede adequate diagnosis and the use of preventive treatments such as sealants, should be utilized where indicated.


Activities of glutathione-S-transferase and ethoxycoumarin-O-deethylase in tissues of camels, sheep, goats and rats.
1. The activities of the drug metabolizing enzymes ethoxycoumarin-O-deethylase, glutathione-S-transferase, and protein concentrations were measured in vitro in the liver, kidney and duodenal mucosa of camels, sheep, goats and rats. 2. Enzyme activities were generally higher in the liver than in the kidney and duodenal mucosa in the four species studied. 3. The activities of ethoxycoumarin-O-deethylase and glutathione-S-transferase in liver of male kids were about one third and half of that in adult male goats, respectively. In the kidney and duodenal mucosa of male kids, the activity of glutathione-S-transferase was about 70% and 53% of that in the mature male goat, respectively. In the latter tissues, however, there was no detectable activity of ethoxycoumarin-O-deethylase. 4. In general, goats and sheep had similar activities of the two enzymes which were significantly higher than those found in camels and rats. 5. Some sex-related differences were noted in the activity of the two enzymes studied. Female sheep had significantly higher hepatic glutathione-S-transferase than the male: while the enzyme activity in the kidney and duodenal mucosa of male goats was significantly higher than in females. Male rats had higher hepatic ethoxycoumarin-O-deethylase activity than females.


Proximal junctional kyphosis results in inferior SRS pain subscores in adult deformity patients.
Retrospective comparative study. We aimed to examine the difference in clinical outcomes in proximal junctional kyphosis (PJK). To date, PJK has been primarily a radiographical finding. Inferior outcomes associated with PJK have not been reported. We performed an analysis of PJK in adult deformity patients to identify risk factors and to evaluate clinical outcomes. A total of 364 patients at a single institution from 2002 to 2007 with adult scoliosis, with an average 3.5 years' follow-up were analyzed. Inclusion criteria were age more than 18 years and fusion greater than 5 levels from any thoracic upper instrumented vertebrae to any lower instrumented vertebrae. Cobb measurements in the coronal and sagittal plane in addition to measurements of the PJK angle at postoperative time points were performed. Clinical assessment was performed using Scoliosis Research Society (SRS) scores and the Oswestry Disability Index. The prevalence of PJK was 39.5% (144/364). The average age in the non-PJK group (n-PJK) was 48.9 versus 53.3 in the PJK group (PJK), and, specifically, age more than 60 years posed a higher prevalence. The prevalence of osteoporosis was 9.8% versus 20.4% in the n-PJK versus PJK groups, respectively. Sex, body mass index, revision surgery, and smoking status were not different between groups. Pain was prevalent in 0.9% versus 29.4% in n-PJK versus PJK, which resulted in lower composite SRS Pain scores (mean change +1.2 vs. +0.8), despite no differences seen in other SRS domains, total SRS score, or Oswestry Disability Index. On multivariate analysis, the presence of pain of the upper back was highly predictive of PJK (odds ratio, 12.5, 95% confidence interval, 2.5-63.2). Radiographically, no differences were seen between groups. However, increasing distance of the upper instrumented vertebrae to C7 plumb line had a higher prevalence of PJK. Instrumentation type, surgical approach, and crosslink use were not different between groups. PJK results in worse clinical outcomes measured by the SRS Pain subscore. Our regression model suggests that pain in the upper back has a strong predictive value for PJK. 3.


Lung function in infants with cystic fibrosis.
Lung function was measured in 28 infants with cystic fibrosis and repeated in 17 of the infants during the first year of life. Thoracic gas volume (TGV) and specific airway conductance (sGaw) were measured plethysmographically and maximum forced expiratory flow at functional residual capacity (VmaxFRC) was derived from the partial expiratory flow-volume curve. At the time of the initial evaluation respiratory function was correlated with the clinical condition of the infants but not with age. There was a good correlation between sGaw and VmaxFRC when both were expressed as percentages of the predicted normal values. On the basis of the normal range for sGaw the infants were divided into two groups. Group A (n = 9), who had normal sGaw, were younger and had a lower clinical score and normal VmaxFRC and TGV values. Group B (n = 19), who had low sGaw, had increased TGV and decreased VmaxFRC. There was no correlation with age for any measure of lung function for the population as a whole. Repeat testing was undertaken at intervals in 17 representative infants. In most of these infants the relation between sGaw and VmaxFRC was maintained; there was no evidence that VmaxFRC was affected before sGaw. There was no functional evidence that the earliest changes in cystic fibrosis occur in small airways, as reflected by changes in VmaxFRC in infancy.


A New Surgical Model of Skeletal Muscle Injuries in Rats Reproduces Human Sports Lesions.
Skeletal muscle injuries are the most common sports-related injuries in sports medicine. In this work, we have generated a new surgically-induced skeletal muscle injury in rats, by using a biopsy needle, which could be easily reproduced and highly mimics skeletal muscle lesions detected in human athletes. By means of histology, immunofluorescence and MRI imaging, we corroborated that our model reproduced the necrosis, inflammation and regeneration processes observed in dystrophic mdx-mice, a model of spontaneous muscle injury, and realistically mimicked the muscle lesions observed in professional athletes. Surgically-injured rat skeletal muscles demonstrated the longitudinal process of muscle regeneration and fibrogenesis as stated by Myosin Heavy Chain developmental (MHCd) and collagen-I protein expression. MRI imaging analysis demonstrated that our muscle injury model reproduces the grade I-II type lesions detected in professional soccer players, including edema around the central tendon and the typically high signal feather shape along muscle fibers. A significant reduction of 30% in maximum tetanus force was also registered after 2 weeks of muscle injury. This new model represents an excellent approach to the study of the mechanisms of muscle injury and repair, and could open new avenues for developing innovative therapeutic approaches to skeletal muscle regeneration in sports medicine.


Territoriality drives preemptive habitat selection in recovering wolves: Implications for carnivore conservation.
According to the ideal-free distribution (IFD), individuals within a population are free to select habitats that maximize their chances of success. Assuming knowledge of habitat quality, the IFD predicts that average fitness will be approximately equal among individuals and between habitats, while density varies, implying that habitat selection will be density dependent. Populations are often assumed to follow an IFD, although this assumption is rarely tested with empirical data, and may be incorrect when territoriality indicates habitat selection tactics that deviate from the IFD (e.g. ideal-despotic distribution or ideal-preemptive distribution). When territoriality influences habitat selection, species' density will not directly reflect components of fitness such as reproductive success or survival. In such cases, assuming an IFD can lead to false conclusions about habitat quality. We tested theoretical models of density-dependent habitat selection on a species known to exhibit territorial behaviour in order to determine whether commonly applied habitat models are appropriate under these circumstances. We combined long-term radiotelemetry and census data from grey wolves Canis lupus in the Upper Peninsula of Michigan, USA to relate spatiotemporal variability in wolf density to underlying classifications of habitat within a hierarchical state-space modelling framework. We then iteratively applied isodar analysis to evaluate which distribution of habitat selection best described this recolonizing wolf population. The wolf population in our study expanded by >1,000% during our study (~50 to >600 individuals), and density-dependent habitat selection was most consistent with the ideal-preemptive distribution, as opposed to the ideal-free or ideal-despotic alternatives. Population density of terrestrial carnivores may not be positively correlated with the fitness value of their habitats, and density-dependent habitat selection patterns may help to explain complex predator-prey dynamics and cascading indirect effects. Source-sink population dynamics appear likely when species exhibit rapid growth and occupy interspersed habitats of contrasting quality. These conditions are likely and have implications for large carnivores in many systems, such as areas in North America and Europe where large predator species are currently recolonizing their former ranges.


IL-18, VCAM-1 and P-selectin as early biomarkers in normoalbuminuric Type 2 diabetes patients.
Aim: To investigate the pathophysiological role of different biomarkers in diabetic kidney disease (DKD) among normoalbuminuric patients with a low-estimated glomerular filtration rate (eGFR). Methods: In this cross-sectional study of 200 normoalbuminuric Type 2 diabetes patients, 28 patients (14%) had a low eGFR. Results: The IL-18, VCAM-1 and P-selectin levels were significantly higher at a low eGFR. On analyzing the area under the receiver operating characteristic curve, these biomarkers had significant diagnostic value and have important pathophysiological role in the progression of DKD. Conclusion: Among normoalbuminuric Type 2 diabetes patients, IL-18, VCAM-1 and P-selectin may play a significant role in the prediction of early DKD. Further prospective studies need to be conducted to confirm this observation.


Use of insecticide treated nets among caregivers of children under five years in Makueni District, Kenya.
Insecticide treated nets (ITNs) have been identified as a key strategy in addressing malaria problem among young children and pregnant women. Their utilisation among under fives, however, have been found to be low in some areas. To identify factors affecting net utilisation (sleeping under insecticide treated net) among caregivers of under fives in Makueni District in Kenya. A cross-sectional, descriptive study. Eight sub-locations in Wote division Makueni district. Four hundred caregivers of children aged five years and below. The results indicated that 88.5% of caregivers were aware of ITNs. The proportion of households with children below five years that owned mosquito net were found to be 46.2%, and only 32.0% had at least a treated net. Slightly more than half of treated nets were used by under fives (52.2%) compared to 47.8% used by children over five years including adults. The main reason cited by majority of caregivers as a hindrance to net utilisation was lack of treated nets in households (72.3%). Utilisation of ITNs by under five children was found to be positively associated with knowledge of ITNs (p = 0.024), marital status (p = 0.018) and occupation (p = 0.043). Utilisation of ITNs by under fives was low despite high level of awareness among caregivers. Factors such as awareness of ITNs, marital status and occupation significantly affected ITNs utilisation. Although the government with support from other stakeholders has recently embarked on large scale distribution of nets in high risky districts, more interventions from various stakeholders are needed to increase availability and accessibility of subsidised permanently treated nets, including interventions to address non-compliance to proper utilisation of nets. There is also need for intensive education emphasising on their proper and consistent use. Scaling up proper use of ITNs along with other initiatives can contribute significantly in reducing malaria.


Homologous expression and characterization of Cel61A (EG IV) of Trichoderma reesei.
There are currently four proteins in family 61 of the glycoside hydrolases, from Trichoderma reesei, Agaricus bisporus, Cryptococcus neoformans and Neurospora crassa. The enzymatic activity of these proteins has not been studied thoroughly. We report here the homologous expression and purification of T. reesei Cel61A [previously named endoglucanase (EG) IV]. The enzyme was expressed in high amounts with a histidine tag on the C-terminus and purified by metal affinity chromatography. This is the first time that a histidine tag has been used as a purification aid in the T. reesei expression system. The enzyme activity was studied on a series of carbohydrate polymers. The only activity exhibited by Cel61A was an endoglucanase activity observed on substrates containing beta-1,4 glycosidic bonds, e.g. carboxymethylcellulose (CMC), hydroxyethylcellulose (HEC) and beta-glucan. The endoglucanase activity on CMC and beta-glucan was determined by viscosity analysis, by measuring the production of reducing ends and by following the degradation of the polymer on a size exclusion chromatography system. The formation of soluble sugars by Cel61A from microcrystalline cellulose (Avicel; Merck), phosphoric acid swollen cellulose (PASC), and CMC were analysed on a HPLC system. Cel61A produced small amounts of oligosaccharides from these substrates. Furthermore, Cel61A showed activity against cellotetraose and cellopentaose. The activity of Cel61A was several orders of magnitude lower compared to Cel7B (previously EG I) of T. reesei on all substrates. One significant difference between Cel61A and Cel7B was that cellotriose was a poor substrate for Cel61A but was readily hydrolysed by Cel7B. The enzyme activity for Cel61A was further studied on a large number of carbohydrate substrates but the enzyme showed no activity towards any of these substrates.


First rank symptoms for schizophrenia.
Early and accurate diagnosis and treatment of schizophrenia may have long-term advantages for the patient; the longer psychosis goes untreated the more severe the repercussions for relapse and recovery. If the correct diagnosis is not schizophrenia, but another psychotic disorder with some symptoms similar to schizophrenia, appropriate treatment might be delayed, with possible severe repercussions for the person involved and their family. There is widespread uncertainty about the diagnostic accuracy of First Rank Symptoms (FRS); we examined whether they are a useful diagnostic tool to differentiate schizophrenia from other psychotic disorders. To determine the diagnostic accuracy of one or multiple FRS for diagnosing schizophrenia, verified by clinical history and examination by a qualified professional (e.g. psychiatrists, nurses, social workers), with or without the use of operational criteria and checklists, in people thought to have non-organic psychotic symptoms. We conducted searches in MEDLINE, EMBASE, and PsycInfo using OvidSP in April, June, July 2011 and December 2012. We also searched MEDION in December 2013. We selected studies that consecutively enrolled or randomly selected adults and adolescents with symptoms of psychosis, and assessed the diagnostic accuracy of FRS for schizophrenia compared to history and clinical examination performed by a qualified professional, which may or may not involve the use of symptom checklists or based on operational criteria such as ICD and DSM. Two review authors independently screened all references for inclusion. Risk of bias in included studies were assessed using the QUADAS-2 instrument. We recorded the number of true positives (TP), true negatives (TN), false positives (FP), and false negatives (FN) for constructing a 2 x 2 table for each study or derived 2 x 2 data from reported summary statistics such as sensitivity, specificity, and/or likelihood ratios. We included 21 studies with a total of 6253 participants (5515 were included in the analysis). Studies were conducted from 1974 to 2011, with 80% of the studies conducted in the 1970's, 1980's or 1990's. Most studies did not report study methods sufficiently and many had high applicability concerns. In 20 studies, FRS differentiated schizophrenia from all other diagnoses with a sensitivity of 57% (50.4% to 63.3%), and a specificity of 81.4% (74% to 87.1%) In seven studies, FRS differentiated schizophrenia from non-psychotic mental health disorders with a sensitivity of 61.8% (51.7% to 71%) and a specificity of 94.1% (88% to 97.2%). In sixteen studies, FRS differentiated schizophrenia from other types of psychosis with a sensitivity of 58% (50.3% to 65.3%) and a specificity of 74.7% (65.2% to 82.3%). The synthesis of old studies of limited quality in this review indicates that FRS correctly identifies people with schizophrenia 75% to 95% of the time. The use of FRS to diagnose schizophrenia in triage will incorrectly diagnose around five to 19 people in every 100 who have FRS as having schizophrenia and specialists will not agree with this diagnosis. These people will still merit specialist assessment and help due to the severity of disturbance in their behaviour and mental state. Again, with a sensitivity of FRS of 60%, reliance on FRS to diagnose schizophrenia in triage will not correctly diagnose around 40% of people that specialists will consider to have schizophrenia. Some of these people may experience a delay in getting appropriate treatment. Others, whom specialists will consider to have schizophrenia, could be prematurely discharged from care, if triage relies on the presence of FRS to diagnose schizophrenia. Empathetic, considerate use of FRS as a diagnostic aid - with known limitations - should avoid a good proportion of these errors.We hope that newer tests - to be included in future Cochrane reviews - will show better results. However, symptoms of first rank can still be helpful where newer tests are not available - a situation which applies to the initial screening of most people with suspected schizophrenia. FRS remain a simple, quick and useful clinical indicator for an illness of enormous clinical variability.


Cost-Effectiveness Analysis of Influenza A (H1N1) Chemoprophylaxis in Brazil.
Background: Oseltamivir and zanamivir are recommended for treating and preventing influenza A (H1N1) worldwide. In Brazil, this official recommendation lacks an economic evaluation. Our objective was to assess the efficiency of influenza A chemoprophylaxis in the Brazilian context. Methods: We assessed the cost-effectiveness of oseltamivir and zanamivir for prophylaxis of influenza for high risk population, compared to no prophylaxis, in the perspective of Brazilian public health system. Quality-adjusted life years (QALY) and effectiveness data were based on literature review and costs in Brazilian real (BRL) were estimated from official sources and micro-costing of 2016's H1N1 admissions at a university hospital. We used a decision-tree model considering prophylaxis and no prophylaxis and the probabilities of H1N1, ambulatory care, admission to hospital, intensive care, patient discharge, and death. Adherence and adverse events from prophylaxis were included. Incremental cost-effectiveness ratio was converted to 2016 United States dollar (USD). Uncertainty was assessed with univariated and probabilistic sensitivity analysis. Results: Adherence to prophylaxis was 0.70 [95% confidence interval (CI) 0.54; 0.83]; adverse events, 0.09 (95% CI 0.02; 0.18); relative risk of H1N1 infection in chemoprophylaxis, 0.43 (95% CI 0.33; 0.57); incidence of H1N1, 0.14 (95% CI 0.11; 0.16); ambulatory care, 0.67 (95% CI 0.58; 0.75); hospital admission, 0.43 (CI 95% 0.39; 0.42); hospital mortality, 0.14 (CI 95% 0.12; 0.15); intensive care unit admission, 0.23 (95% CI 0.20; 0.27); and intensive care mortality, 0.40 (95% CI 0.29; 0.52). QALY in H1N1 state was 0.50 (95% CI 0.46; 0.53); in H1N1 inpatients, 0.23 (95% CI 0.18; 0.28); healthy, 0.885 (95% CI 0.879; 0.891); death, 0. Adverse events estimated to affect QALY in -0.185 (95% CI -0.290; -0.050). Cost for chemoprophylaxis was BRL 39.42 [standard deviation (SD) 17.94]; ambulatory care, BRL 12.47 (SD 5.21); hospital admission, BRL 5,727.59 (SD 7,758.28); intensive care admission, BRL 19,217.25 (SD 7,917.33); and adverse events, BRL 292.05 (SD 724.95). Incremental cost-effectiveness ratio was BRL -4,080.63 (USD -1,263.74)/QALY and -982.39 (USD -304.24)/H1N1 prevented. Results were robust to sensitivity analysis. Conclusion: Chemoprophylaxis of influenza A (H1N1) is cost-saving in Brazilian health system context.


Humidity and Strain Rate Determine the Extent of Phase Shift in the Piezoresistive Response of PEDOT:PSS.
The piezoresistive response of PEDOT:PSS is sensitive to changes in its morphology when exposed to humidity and in response to different strain rates. The piezoresistive response of as-cast PEDOT:PSS transitions from being in-phase to being out-of-phase with applied strain when the relative humidity is reduced from >50% to near zero. At >50% relative humidity, the PSS matrix swells and interrupts the connectivity of electrically conducting PEDOT domains. Stretching PEDOT:PSS at such conditions leads to an increase in resistance with strain. Under dry conditions, PEDOT domains are connected; stretching PEDOT:PSS instead leads to preferential alignment of the conducting domains and a concomitant decrease in resistance. At intermediate humidity, the piezoresistive response of PEDOT:PSS is phase shifted relative to applied strain, with it being out-of-phase at low strain rates (0.34%/min) and in-phase at high strain rates (1.12%/min). We interpret this peculiar and surprising observation as a competition between strain-induced domain separation and alignment, each having a different response time to applied strain. Postdeposition treatment of PEDOT:PSS with dichloroacetic acid removes excess PSS; PEDOT:PSS's piezoresistive response is then invariant with humidity and strain rate. Stabilizing its piezoresistive response can ensure accuracy of PEDOT:PSS-based flexible resistive sensors whose response to small strains is used to monitor environmental and human-health.


High-resolution structural characterization of Noxa, an intrinsically disordered protein, by microsecond molecular dynamics simulations.
High-resolution characterization of the structure and dynamics of intrinsically disordered proteins (IDPs) remains a challenging task. Consequently, a detailed understanding of the structural and functional features of IDPs remains limited, as very few full-length disordered proteins have been structurally characterized. We have performed microsecond-long molecular dynamics (MD) simulations of Noxa, the smallest member of the large Bcl-2 family of apoptosis regulating proteins, to characterize in atomic-level detail the structural features of a disordered protein. A 2.5 μs MD simulation starting from an unfolded state of the protein revealed the formation of a central antiparallel β-sheet structure flanked by two disordered segments at the N- and C-terminal ends. This topology is in reasonable agreement with protein disorder predictions and available experimental data. We show that this fold plays an essential role in the intracellular function and regulation of Noxa. We demonstrate that unbiased MD simulations in combination with a modern force field reveal structural and functional features of disordered proteins at atomic-level resolution.


Effect of piroxicam on gait in patients with osteoarthritis of the knee.
To determine whether the use of a nonsteroidal antiinflammatory drug (NSAID) in patients with painful osteoarthritis (OA) of the knee would result in alterations in specific biomechanical parameters of gait. Eighteen patients with symptomatic knee OA and varus knee deformity underwent initial clinical evaluation for pain and activities of daily living, and assessment of parameters of gait utilizing a well-described computerized system. All patients were then treated with piroxicam at 20 mg once daily, and clinical and gait analyses were repeated after 4 weeks. Fifteen of the 18 patients studied had a significant increase in the knee adduction moment after treatment. In the group as a whole there was a significant increase in knee adduction moment (mean percent body weight times height [%BWTH] 4.11 pretreatment versus 4.57 after 4 weeks of treatment; P < 0.01) and maximum quadriceps moment (mean %BWTH 2.13 pretreatment, 2.62 posttreatment; P < 0.01), as well as changes in other gait parameters that might be expected to be altered as a result of relief of pain. Sixteen of 18 patients experienced symptomatic relief, with a significant reduction in pain in the group as a whole after 4 weeks (P < 0.001). NSAID treatment in patients with knee OA results in a reduction in symptomatic pain and an increase in loading of the knee. Whether the increased loading is due to the analgesic effects of the treatment is unknown, but if so, the development of agents capable of relieving pain while reducing loads at the knee may be desirable.


What's in a Name? Patterns, Trends, and Suggestions for Defining Non-Perennial Rivers and Streams.
Rivers that cease to flow are globally prevalent. Although many epithets have been used for these rivers, a consensus on terminology has not yet been reached. Doing so would facilitate a marked increase in interdisciplinary interest as well as critical need for clear regulations. Here we reviewed literature from Web of Science database searches of 12 epithets to learn (Objective 1-O1) if epithet topics are consistent across Web of Science categories using latent Dirichlet allocation topic modeling. We also analyzed publication rates and topics over time to (O2) assess changes in epithet use. We compiled literature definitions to (O3) identify how epithets have been delineated and, lastly, suggest universal terms and definitions. We found a lack of consensus in epithet use between and among various fields. We also found that epithet usage has changed over time, as research focus has shifted from description to modeling. We conclude that multiple epithets are redundant. We offer specific definitions for three epithets (non-perennial, intermittent, and ephemeral) to guide consensus on epithet use. Limiting the number of epithets used in non-perennial river research can facilitate more effective communication among research fields and provide clear guidelines for writing regulatory documents.


Neuropathic Pain Related with Spinal Disorders: A Systematic Review.
Systematic literature review. To review the evidence from high-quality studies regarding the treatment of neuropathic pain originating specifically from spinal disorders. In general, treatment guidelines for neuropathic pain cover all its various causes, including medical disease, peripheral neuropathy, and cancer. However, the natural history of neuropathic pain originating from spinal disorders may differ from that of the pain originating from other causes or lesions. An expert research librarian used terms related to neuropathic pain and spinal disorders, disc herniation, stenosis, and spinal cord injury to search in MEDLINE, Embase, and Cochrane CENTRAL for primary research from January 2000 to October 2015. Among 2,313 potential studies of interest, 25 randomized controlled trials (RCTs) and 21 systematic reviews (SRs) were included in the analysis. The selection was decided based on the agreement of two orthopedic surgeons. There was a lack of evidence about medication for radiculopathy arising from disc herniation and stenosis, but intervention procedures, including epidural block, showed positive efficacy in radiculopathy and also limited efficacy in spinal stenosis. There was some evidence based on the short-term follow-up regarding surgery being superior to conservative treatments for radiculopathy and stenosis. There was limited evidence regarding the efficacy of pharmacological and electric or magnetic stimulation therapies for neuropathic pain after spinal cord injury. This review of RCTs and SRs with high-quality evidence found some evidence regarding the efficacy of various treatment modalities for neuropathic pain related specifically to spinal disorders. However, there is a need for much more supportive evidence.


Global environmental impacts of agricultural expansion: the need for sustainable and efficient practices.
The recent intensification of agriculture, and the prospects of future intensification, will have major detrimental impacts on the nonagricultural terrestrial and aquatic ecosystems of the world. The doubling of agricultural food production during the past 35 years was associated with a 6.87-fold increase in nitrogen fertilization, a 3.48-fold increase in phosphorus fertilization, a 1.68-fold increase in the amount of irrigated cropland, and a 1.1-fold increase in land in cultivation. Based on a simple linear extension of past trends, the anticipated next doubling of global food production would be associated with approximately 3-fold increases in nitrogen and phosphorus fertilization rates, a doubling of the irrigated land area, and an 18% increase in cropland. These projected changes would have dramatic impacts on the diversity, composition, and functioning of the remaining natural ecosystems of the world, and on their ability to provide society with a variety of essential ecosystem services. The largest impacts would be on freshwater and marine ecosystems, which would be greatly eutrophied by high rates of nitrogen and phosphorus release from agricultural fields. Aquatic nutrient eutrophication can lead to loss of biodiversity, outbreaks of nuisance species, shifts in the structure of food chains, and impairment of fisheries. Because of aerial redistribution of various forms of nitrogen, agricultural intensification also would eutrophy many natural terrestrial ecosystems and contribute to atmospheric accumulation of greenhouse gases. These detrimental environmental impacts of agriculture can be minimized only if there is much more efficient use and recycling of nitrogen and phosphorus in agroecosystems.