Establishing hierarchy: the chain of events leading to the formation of silicalite-1 nanosheets.
In applying a multi-scale spectroscopic and computational approach, we demonstrate that the synthesis of stacked zeolite silicalite-1 nanosheets, in the presence of a long-tail diquaternary ammonium salt surfactant, proceeds through a pre-organised phase in the condensed state. In situ small-angle X-ray scattering, coupled to paracrystalline theory, and backed by electron microscopy, shows that this phase establishes its meso-scale order within the first five hours of hydrothermal synthesis. Quasi in situ vibrational and solid-state NMR spectroscopy reveal that this meso-shaped architecture already contains some elementary zeolitic features. The key to this coupled organisation at both micro- and meso-scale, is a structure-directing agent that is ambifunctional in shaping silica at the meso-scale whilst involved in molecular recognition at the micro-scale. The latter feature is particularly important and requires the structure-directing agent to reside within the silica matrix already at early stages of the synthesis. From here, molecular recognition directs stabilization of precursor species and their specific embedding into a lattice, as shown by force-field molecular dynamics calculations. These calculations, in line with experiment, further show how it is possible to subtly tune both the zeolite topology and aspect ratio of the condensating crystals, by modifying the headgroup of the structure-directing agent.


All Our Babies Cohort Study: recruitment of a cohort to predict women at risk of preterm birth through the examination of gene expression profiles and the environment.
Preterm birth is the leading cause of perinatal morbidity and mortality. Risk factors for preterm birth include a personal or familial history of preterm delivery, ethnicity and low socioeconomic status yet the ability to predict preterm delivery before the onset of preterm labour evades clinical practice. Evidence suggests that genetics may play a role in the multi-factorial pathophysiology of preterm birth. The All Our Babies Study is an on-going community based longitudinal cohort study that was designed to establish a cohort of women to investigate how a women's genetics and environment contribute to the pathophysiology of preterm birth. Specifically this study will examine the predictive potential of maternal leukocytes for predicting preterm birth in non-labouring women through the examination of gene expression profiles and gene-environment interactions. Collaborations have been established between clinical lab services, the provincial health service provider and researchers to create an interdisciplinary study design for the All Our Babies Study. A birth cohort of 2000 women has been established to address this research question. Women provide informed consent for blood sample collection, linkage to medical records and complete questionnaires related to prenatal health, service utilization, social support, emotional and physical health, demographics, and breast and infant feeding. Maternal blood samples are collected in PAXgene™ RNA tubes between 18-22 and 28-32 weeks gestation for transcriptomic analyses. The All Our Babies Study is an example of how investment in clinical-academic-community partnerships can improve research efficiency and accelerate the recruitment and data collection phases of a study. Establishing these partnerships during the study design phase and maintaining these relationships through the duration of the study provides the unique opportunity to investigate the multi-causal factors of preterm birth. The overall All Our Babies Study results can potentially lead to healthier pregnancies, mothers, infants and children.


Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma.
To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. Thirty-one angiogenic-related genes were significantly associated with survival (q≤0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p=0.01, HR=0.8), CD44 (q=0.003; TCGA p=0.05, HR=0.9), EPHB2 (q=0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q=0.02; TCGA p=0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q=0.03; GSE26712 p=0.01, HR=3.1); PF4 (q=0.02; GSE26712 p=0.01, HR=3.0); NRP1 (q=0.02; GSE26712 p<0.04, HR>1.4); COL4A3 (q=0.04; GSE26712 p=0.03, HR=1.3); and ANGPTL3 (q=0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.


Blocking IL-1α but not IL-1β increases susceptibility to chronic Mycobacterium tuberculosis infection in mice.
IL-1α and IL-1β are potent inflammatory cytokines and important mediators of immune responses to intracellular pathogens such as Mycobacterium tuberculosis (Mtb). Here, we investigated the role of IL-1α and IL-1β during chronic Mtb infection and spontaneous reactivation in mice. For long-term neutralization of IL-1α, IL-1β or both, mice were immunized with virus-like particles (VLPs) displaying either of the cytokines, inducing strong and long-lasting neutralizing IgG responses. Blocking of IL-1α but not of IL-1β resulted in increased susceptibility to chronic infection with Mtb. Neutralizing either IL-1α or IL-1β alone did not lead to increased reactivation of latent tuberculosis. The generation of antibodies neutralizing both IL-1α and IL-1β simultaneously, did not influence weight gain during Mtb reactivation and the slight increase in pulmonary bacillary counts were not significant when compared to control-immunized group. Thus, the results suggest that IL-1α is the major mediator of the IL-1RI-dependent and protective innate immune responses to Mtb in mice.


Cross-correlation spin noise spectroscopy of heterogeneous interacting spin systems.
Interacting multi-component spin systems are ubiquitous in nature and in the laboratory. As such, investigations of inter-species spin interactions are of vital importance. Traditionally, they are studied by experimental methods that are necessarily perturbative: e.g., by intentionally polarizing or depolarizing one spin species while detecting the response of the other(s). Here, we describe and demonstrate an alternative approach based on multi-probe spin noise spectroscopy, which can reveal inter-species spin interactions--under conditions of strict thermal equilibrium--by detecting and cross-correlating the stochastic fluctuation signals exhibited by each of the constituent spin species. Specifically, we consider a two-component spin ensemble that interacts via exchange coupling, and we determine cross-correlations between their intrinsic spin fluctuations. The model is experimentally confirmed using "two-color" optical spin noise spectroscopy on a mixture of interacting Rb and Cs vapors. Noise correlations directly reveal the presence of inter-species spin exchange, without ever perturbing the system away from thermal equilibrium. These non-invasive and noise-based techniques should be generally applicable to any heterogeneous spin system in which the fluctuations of the constituent components are detectable.


Pituitary function in children with hydrocephalus before and after the first shunting operation.
Children with shunted hydrocephalus experience slow linear growth in prepuberty, accelerated pubertal maturation and a reduced final height. A substantial proportion of these patients have a poor growth hormone (GH) response to stimulation and reduced pituitary volume. The basic mechanisms behind these phenomena are still unknown, but one can hypothesize that an unphysiological intracranial pressure (ICP) may be involved. This study was undertaken to investigate the effect of increased ICP on pituitary function. Twenty-one children (nine males) aged 4 months to 15 years were evaluated for pituitary function before and after their first shunting operation. A clinical examination was performed, bone age was determined and a combined pituitary stimulation test was performed to evaluate GH, luteinizing hormone, follicle-stimulating hormone, cortisol, thyrotropin and prolactin secretion. GH concentrations were significantly higher 10 and 15 min before the operation (P=0.04 and P=0.03 respectively) than after it. The basal levels of insulin-like growth factor-I (IGF-I) tended to be higher before the operation than afterwards and those of its binding protein-3 (IGFBP-3) were significantly so (P<0.01). The higher GH response to GH releasing hormone and circulating IGFBP-3 levels in children with hydrocephalus before compared with after their first shunting operation raise the possibility that the reduced GH secretion and retarded linear growth observed in children with shunted hydrocephalus may be a consequence of decreased ICP and/or the lack of physiological pressure variations.


Self-evaluation as a moderating factor of strategy change in directed forgetting benefits.
In list method directed forgetting, instructing people to forget a studied word list usually results in better recall for a newly studied list. Sahakyan and Delaney (2003) have suggested that these benefits are due to a change in encoding strategy that occurs between the study of the first list and the study of the second list. To investigate what might mediate such strategy change decisions, in two experiments we induced both forget and remember participants to evaluate their memory performance on the two lists. In Experiment 1, they were asked to explicitly recall the items from the first list before studying the second list. In Experiment 2, after the study of the first list, the participants provided a rapid aggregate judgment of learning. Evaluation eliminated the differences between the forget and remember groups for the second list in both experiments, because the remember group achieved recall levels comparable to those for the forget group. The role of performance evaluation in mediating directed forgetting benefits is discussed.


Joint spectrum of photon pairs measured by coincidence Fourier spectroscopy.
We propose and demonstrate a method for measuring the joint spectrum of photon pairs via Fourier spectroscopy. The biphoton spectral intensity is computed from a two-dimensional interferogram of coincidence counts. The method has been implemented for a type-I downconversion source using a pair of common-path Mach-Zehnder interferometers based on Soleil compensators. The experimental results agree well with calculated frequency correlations that take into account the effects of coupling into single-mode fibers. The Fourier method is advantageous over scanning spectrometry when detectors exhibit high dark count rates leading to dominant additive noise.


β-Ocimene, a Key Floral and Foliar Volatile Involved in Multiple Interactions between Plants and Other Organisms.
β-Ocimene is a very common plant volatile released in important amounts from the leaves and flowers of many plant species. This acyclic monoterpene can play several biological functions in plants, by potentially affecting floral visitors and also by mediating defensive responses to herbivory. The ubiquity and high relative abundance of β-ocimene in the floral scents of species from most plant families and from different pollination syndromes (ranging from generalism to specialism) strongly suggest that this terpenoid may play an important role in the attraction of pollinators to flowers. We compiled abundant evidence from published studies that supports β-ocimene as a generalist attractant of a wide spectrum of pollinators. We found no studies testing behavioural responses of pollinators to β-ocimene, that could directly demonstrate or deny the function of β-ocimene in pollinator attraction; but several case studies support that the emissions of β-ocimene in flowers of different species follow marked temporal and spatial patterns of emission, which are typical from floral volatile organic compound (VOC) emissions that are involved in pollinator attraction. Furthermore, important β-ocimene emissions are induced from vegetative plant tissues after herbivory in many species, which have relevant functions in the establishment of tritrophic interactions. We thus conclude that β-ocimene is a key plant volatile with multiple relevant functions in plants, depending on the organ and the time of emission. Experimental behavioural studies on pure β-ocimene conducted with pollinating insects will be necessary to prove the assumptions made here.


Sirolimus inhibits platelet-derived growth factor-induced collagen synthesis in rat vascular smooth muscle cells.
Vascular smooth muscle cell (VSMC) proliferation and extracellular matrix (ECM) accumulation play key roles in the development and the progression of vascular remodeling such as transplant arteriosclerosis and restenosis. The present study examined the effects of sirolimus (SRL) on platelet-derived growth factor (PDGF)-induced fibronectin secretion, collagen synthesis, and the related signaling pathways including reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPK) in rat VSMCs. Primary rat VSMCs were isolated from male Sprague-Dawley rats. Growth arrested, synchronized cells were treated with various concentrations of SRL before the addition of PDGF at 10 ng/mL. Proliferating cell nuclear antigen expression, fibronectin secretion, and the activation of extracellular signal-regulated protein kinase (ERK) and p38 MAPK were assessed by Western blot analysis, collagen synthesis by [(3)H]-proline incorporation, and cellular ROS by flow cytometry. PDGF (10 ng/mL) increased VSMC proliferation by 1.7-fold, fibronectin secretion by 1.5-fold, collagen synthesis by 2.1-fold, cellular ROS by 1.6-fold, and activation of ERK and p38 MAPK by 3.3- and 3.9-fold compared to controls. SRL above 1 nmol/L inhibited PDGF-induced VSMC proliferation and collagen synthesis but not PDGF-induced fibronectin secretion, cellular ROS, and activation of ERK and p38 MAPK. These data demonstrated that PDGF increased ECM synthesis as well as proliferation through cellular ROS and subsequent MAPK activation and that SRL inhibited PDGF-induced VSMC proliferation and collagen synthesis in a cellular ROS- and MAPK activation-independent way.


IgE reactivity to vaccine components in dogs that developed immediate-type allergic reactions after vaccination.
Allergic reactions after vaccination are considered as an important practical problem in dogs; however, their immunological mechanism has not been well understood. The present study was designed to investigate the relationship between IgE reactivity to the vaccines and immediate-type allergic reactions after vaccination in dogs. Sera from 10 dogs that developed immediate-type allergic reactions such as circulatory collapse, cyanosis, dyspnea, facial edema, and vomiting within 1h after vaccination with non-rabies monovalent or combined vaccines and sera from 50 dogs that did not develop allergic reactions after vaccination were collected. Serum IgE reactivity to the injected vaccines was measured by fluorometric ELISA using a mouse monoclonal anti-dog IgE antibody. Then, IgE reactivity to fetal calf serum (FCS) and stabilizer proteins (gelatin, casein, and peptone) included in the vaccines was measured in sera that had high levels of IgE to the vaccines. Levels of serum specific IgE to the vaccines in dogs with immediate-type allergic reactions (59-4173 fluorescence units [FU], mean +/- S.D.: 992.5 +/- 1181.9 FU) were significantly higher than those in control dogs (38-192 FU, 92.4 +/- 43.3 FU) (P < 0.001). Of the eight dogs that developed immediate-type allergic reactions and had high levels of serum specific IgE to the vaccines, seven had specific IgE directed to FCS. The IgE reactivity to the vaccines in sera from these dogs was almost completely inhibited by FCS. The other one dog had serum IgE directed to gelatin and casein included in the vaccine as stabilizers. The results obtained in this study suggest that immediate-type allergic reactions after vaccination in dogs were induced by type I hypersensitivity mediated by IgE directed to vaccine components. In addition, FCS, gelatin, and casein included in vaccines could be the causative allergens that induced immediate-type allergic reactions after vaccination in dogs.


Role of Gabapentin in Managing Mucositis Pain in Patients Undergoing Radiation Therapy to the Head and Neck.
Oral mucositis (OM) is a painful and debilitating side effect that affects 80%-100% of patients undergoing radiation therapy for head and neck cancer. This dose-limiting side effect may potentially lead to pain, dehydration, malnutrition, infection, and treatment breaks. Treatment breaks can lead to decreased disease control and suboptimal patient outcomes. No primary prevention exists for OM, and management is focused on pain control. Compelling evidence exists that OM pain has somatic and neuropathic components. This article reviews the existing literature on the use of gabapentin (Neurontin®) as a co-analgesic in treating the neuropathic pain in OM. A literature search was performed using CINAHL® and PubMed with the search terms gabapentin and oral mucositis. The selected articles were briefly screened for relevance, and three were included in this review. No systematic reviews exist on the role of gabapentin for neuropathic pain in radiation-induced OM. Two retrospective studies concluded that gabapentin reduced escalation of opioid doses and unplanned treatment breaks. One retrospective study demonstrated favorable swallowing outcomes. Pain and OM are nursing-sensitive outcomes that can be significantly affected by evidence-based nursing interventions.


Analysis of serum miRNA profiles of myasthenia gravis patients.
Myasthenia gravis (MG) is an autoimmune disease characterized by the presence of autoantibodies, mainly against the acetylcholine receptor (AChR). The mechanisms triggering and maintaining this chronic disease are unknown. MiRNAs are regulatory molecules that play a key role in the immune system and are altered in many autoimmune diseases. The aim of this study was to evaluate miRNA profiles in serum of 61 AChR MG patients. We studied serum from patients with early onset MG (n = 22), late onset MG (n = 27) and thymoma (n = 12), to identify alterations in the specific subgroups. In a discovery cohort, we analysed 381 miRNA arrays from 5 patients from each subgroup, and 5 healthy controls. The 15 patients had not received any treatment. We found 32 miRNAs in different levels in MG and analysed 8 of these in a validation cohort that included 46 of the MG patients. MiR15b, miR122, miR-140-3p, miR185, miR192, miR20b and miR-885-5p were in lower levels in MG patients than in controls. Our study suggests that different clinical phenotypes in MG share common altered mechanisms in circulating miRNAs, with no additional contribution of the thymoma. MG treatment intervention does not modify the profile of these miRNAs. Novel insights into the pathogenesis of MG can be reached by the analysis of circulating miRNAs since some of these miRNAs have also been found low in MG peripheral mononuclear cells, and have targets with important roles in B cell survival and antibody production.


Mosquito-Derived Anophelin Sulfoproteins Are Potent Antithrombotics.
The anophelins are small protein thrombin inhibitors that are produced in the salivary glands of the Anopheles mosquito to fulfill a vital role in blood feeding. A bioinformatic analysis of anophelin sequences revealed the presence of conserved tyrosine residues in an acidic environment that were predicted to be post-translationally sulfated in vivo. To test this prediction, insect cell expression of two anophelin proteins, from Anopheles albimanus and Anopheles gambiae, was performed, followed by analysis by mass spectrometry, which showed heterogeneous sulfation at the predicted sites. Homogeneously sulfated variants of the two proteins were subsequently generated by chemical synthesis via a one-pot ligation-desulfurization strategy. Tyrosine sulfation of the anophelins was shown to significantly enhance the thrombin inhibitory activity, with a doubly sulfated variant of the anophelin from A. albimanus exhibiting a 100-fold increase in potency compared with the unmodified homologue. Sulfated anophelins were also shown to exhibit potent in vivo anticoagulant and antithrombotic activity.


Whole-Genome Linkage Scan Combined With Exome Sequencing Identifies Novel Candidate Genes for Carotid Intima-Media Thickness.
Carotid intima-media thickness (cIMT) is an established heritable marker for subclinical atherosclerosis. In this study, we aim to identify rare variants with large effects driving differences in cIMT by performing genome-wide linkage analysis of individuals in the extremes of cIMT trait distribution (>90th percentile) in a large family-based study from a genetically isolated population in the Netherlands. Linked regions were subsequently explored by fine-mapping using exome sequencing. We observed significant evidence of linkage on chromosomes 2p16.3 [rs1017418, heterogeneity LOD (HLOD) = 3.35], 19q13.43 (rs3499, HLOD = 9.09), 20p13 (rs1434789, HLOD = 4.10), and 21q22.12 (rs2834949, HLOD = 3.59). Fine-mapping using exome sequencing data identified a non-coding variant (rs62165235) in PNPT1 gene under the linkage peak at chromosome 2 that is likely to have a regulatory function. The variant was associated with quantitative cIMT in the family-based study population (effect = 0.27, p-value = 0.013). Furthermore, we identified several genes under the linkage peak at chromosome 21 highly expressed in tissues relevant for atherosclerosis. To conclude, our linkage analysis identified four genomic regions significantly linked to cIMT. Further analyses are needed to demonstrate involvement of identified candidate genes in development of atherosclerosis.


Radiological assessment of type II Stafne idiopathic bone cyst in a patient undergoing implant therapy: a case report.
This paper is intended to describe the confirmative role of radiology in the diagnosis of Stafne Idiopathic bone Cyst (SIBC) without the need for histopathology especially when dental implants are considered so as to avoid unnecessary invasive surgical exploration of this benign pathology. Other pathologies may present not unlike SIBC and as such it is mandatory to rule out such possibilities especially prior to dental implant therapy. The use of orthopanthomogram and non-sialographic computed tomography (CT) scan in the reported case together with a review of CT scan confirmatory role in the diagnosis of SIBC from the literature was the basis for this clinical report. Based on the CTscan findings of the jaw in this case and review of the literature, the implant procedure was commenced without the need of histopathology and/or for invasive surgical exploration of this pathology. All pathologic lesions of the jawbone seen on the orthopanthomogram should be confirmed prior to commencement of implant procedure even when such pathologies are seen in areas remote from the proposed implant site. The pre-implant radiological assessment utilizing non-sialographic CT scan alone is confirmatory of SIBC.


Multi-criteria anomaly detection in urban noise sensor networks.
The growing concern of citizens about the quality of their living environment and the emergence of low-cost microphones and data acquisition systems triggered the deployment of numerous noise monitoring networks spread over large geographical areas. Due to the local character of noise pollution in an urban environment, a dense measurement network is needed in order to accurately assess the spatial and temporal variations. The use of consumer grade microphones in this context appears to be very cost-efficient compared to the use of measurement microphones. However, the lower reliability of these sensing units requires a strong quality control of the measured data. To automatically validate sensor (microphone) data, prior to their use in further processing, a multi-criteria measurement quality assessment model for detecting anomalies such as microphone breakdowns, drifts and critical outliers was developed. Each of the criteria results in a quality score between 0 and 1. An ordered weighted average (OWA) operator combines these individual scores into a global quality score. The model is validated on datasets acquired from a real-world, extensive noise monitoring network consisting of more than 50 microphones. Over a period of more than a year, the proposed approach successfully detected several microphone faults and anomalies.


Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif.
Various members of the tumor necrosis factor (TNF) receptor superfamily activate nuclear factor kappaB (NF-kappaB) and the c-Jun N-terminal kinase (JNK) pathways through their interaction with TNF receptor-associated factors (TRAFs) and NF-kappaB-inducing kinase (NIK). We have previously shown that the cytoplasmic domain of receptor activator of NF-kappaB (RANK) interacts with TRAF2, TRAF5, and TRAF6 and that its overexpression activates NF-kappaB and JNK pathways. Through a detailed mutational analysis of the cytoplasmic domain of RANK, we demonstrate that TRAF2 and TRAF5 bind to consensus TRAF binding motifs located in the C terminus at positions 565-568 and 606-611, respectively. In contrast, TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. Furthermore, transfection experiments with RANK and its deletion mutants in human embryonic 293 cells revealed that the TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation. Moreover, a kinase mutant of NIK (NIK-KM) inhibited RANK-induced NF-kappaB activation. However, RANK-mediated JNK activation required a distal portion (427-603) of RANK containing the TRAF2-binding domain. Thus, our results indicate that RANK interacts with various TRAFs through distinct motifs and activates NF-kappaB via a novel TRAF6 interaction motif, which then activates NIK, thus leading to NF-kappaB activation, whereas RANK most likely activates JNK through a TRAF2-interacting region in RANK.


"Building" a history rather than "taking" one: a perspective on information sharing during the medical interview.
Patients and physicians enter the medical encounter with unique perspectives on the illness experience. These perspectives influence the way that information is shared during the initial phase of the interview. Previous research has demonstrated that patients who are able to fully share their perspective often achieve better outcomes. However, studies of patient-physician communication have shown that the patient's perspective is often lost. Researchers and educators have responded with calls for practitioners to adopt a "narrative-based medicine" approach to the medical interview. In this article, we review the literature on narrative-based medicine with an emphasis on information sharing during the medical interview. We suggest a framework of skills and attitudes that can act as a foundation for future work in educating practitioners and researching the medical interview.


The p53 response during DNA damage: impact of transcriptional cofactors.
Defects in the DNA damage response pathways can lead to tumour development. The tumour suppressor p53 is a key player in the DNA damage response, and the precise regulation of p53 is critical for the suppression of tumorigenesis. DNA damage induces the activity of p53, via damage sensors such as ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia-related), which leads to the transcriptional regulation of a variety of genes involved in cell cycle control and apoptosis. p53 is therefore tightly controlled, and its activity is regulated at a multiplicity of levels. An increasing array of cofactors are now known to influence p53 activity. Here we will discuss several of the cofactors that impact on p53 activity, specifically those involved in the function of the two novel p53 cofactors JMY (junction-mediating and regulatory protein) and Strap (serine/threonine-kinase-receptor-associated protein).


Nephelometric activity as a criterion of adequate antisera for use in immunofluorescence.
We have characterized monospecific sheep antisera to human IgG, IgA and IgM using Ouchterlony double diffusion, immunoelectrophoresis, quantitative precipitation and nephelometric activity. The antisera were conjugated at high and low F/P ratios, absorbed and subsequently evaluated in both direct and indirect immunofluorescence. Antisera which exhibited excellent reactivity in double diffusion, IEP and quantitative precipitation but gave a poor nephelometric response (Ab dilution greater than 1/25 gave no measurable response in the Technicon Fluoronephelometer) showed a marked decreased effectiveness in both direct and indirect fluorescence. Antisera which exhibited a strong nephelometric response were invariably excellent in double diffusion, IEP and quantitative precipitation and gave strong positive fluorescence at reasonable dilutions in both direct and indirect fluorescence. We suggest nephelometry prior to conjugation is the method of choice in screening antisera usable in immunofluorescence.


Herbal-drug interaction induced rhabdomyolysis in a liposarcoma patient receiving trabectedin.
Rhabdomyolysis is an uncommon side effect of trabectedin which is used for the second line therapy of metastatic sarcoma after anthracycline and ifosfamide failure. This side effect may be due to pharmacokinetic interactions caused by shared mechanisms of metabolism involving the cytochrome P450 (CYP) system in the liver. Here, for the first time in literature, we describe the unexpected onset of heavy toxicity, including rhabdomyolysis, after the fourth course of trabectedin in a patient with retroperitoneal liposarcoma who at the same time was taking an alternative herbal medicine suspected of triggering this adverse event. This is the case of a 56 year old Caucasian man affected by a relapsed de-differentiated liposarcoma who, after the fourth cycle of second-line chemotherapy with trabectedin, complained of sudden weakness, difficulty walking and diffuse muscle pain necessitating complete bed rest. Upon admission to our ward the patient showed grade (G) 4 pancytopenia and a marked increase in liver lytic enzymes, serum levels of myoglobin, creatine phosphokinase (CPK) and lactate dehydrogenase. No cardiac or kidney function injuries were present. Based on these clinical and laboratory features, our conclusive diagnosis was of rhabdomyolysis induced by trabectedin.The patient did not report any trauma or muscular overexertion and no co-morbidities were present. He had not received any drugs during treatment with trabectedin, but upon further questioning the patient informed us he had been taking a folk medicine preparation of chokeberry (Aronia melanocarpa) daily during the last course of trabectedin and in the 2 subsequent weeks.One week after hospitalization and cessation of intake of chokeberry extract, CPK and other markers of myolysis slowly returned to standard range, and the patient noted a progressive recovery of muscle strength.The patient was discharged on day 14 when a blood transfusion and parenteral hydration gradually lowered general toxicity. Progressive mobilization of the patient was obtained as well as a complete normalization of the laboratory findings. The level of evidence of drug interaction leading to the adverse event observed in our patient was 2 (probable). Thus our case underlines the importance of understanding rare treatment-related toxicities such as trabectedin-induced rhabdomyolysis and the possible role of the drug-drug interactions in the pathogenesis of this rare side effect. Furthermore, this report draws attention to a potential problem of particular concern, that of nutritional supplements and complementary and alternative drug interactions. These are not widely recognized and can cause treatment failure.


Controlling turbulent drag across electrolytes using electric fields.
Reversible in operando control of friction is an unsolved challenge that is crucial to industrial tribology. Recent studies show that at low sliding velocities, this control can be achieved by applying an electric field across electrolyte lubricants. However, the phenomenology at high sliding velocities is yet unknown. In this paper, we investigate the hydrodynamic friction across electrolytes under shear beyond the transition to turbulence. We develop a novel, highly parallelised numerical method for solving the coupled Navier-Stokes Poisson-Nernst-Planck equation. Our results show that turbulent drag cannot be controlled across dilute electrolytes using static electric fields alone. The limitations of the Poisson-Nernst-Planck formalism hint at ways in which turbulent drag could be controlled using electric fields.


School-based internet-tailored fruit and vegetable education combined with brief counselling increases children's awareness of intake levels.
Children's fruit/vegetable intake is still below recommended levels. This study applied Internet-tailored advice for schoolchildren and Internet-supported brief dietary counselling (with child and parent) within preventive health care to promote fruit/vegetable intake. The study involved 30 seventh-grade classes (16 in the intervention group and 14 in the control group) with a total of 675 children aged 9-12 years, of whom 495 were allowed to participate. A cluster-randomised baseline-post-test experimental design was applied. During school hours, all children completed Internet-administered questionnaires on fruit/vegetable intake and related determinants. Children in the intervention group received immediate online individually tailored nutrition feedback. For each child in the intervention group, a nurse received information concerning the assessment of fruit/vegetable intake via the Internet to support a 5 min counselling protocol to promote fruit/vegetable intake. Children completed a similar post-test questionnaire 3 months after the first assessment. Intention-to-treat analyses were conducted using multilevel regression analyses. A total of 486 children (98% of 495) participated (263 in the intervention group, 223 in the control group); 240 child-parent couples in the intervention group attended the counselling. Awareness of inadequate fruit intake (odds ratio (OR) = 3.0; 95% confidence interval (CI) = 1.8-5.3) and knowledge of recommended vegetable intake levels (OR = 2.7; 95% CI = 1.8-4.1) were significantly more likely at post-test in the intervention group than in the control group. No significant effects were found on intake or other determinants. A compact, integrated two-component intervention can induce positive changes in knowledge and awareness of intake levels of fruit/vegetables among schoolchildren. To induce changes in intake levels, more comprehensive interventions may be needed.


Altered cellular metabolism following traumatic brain injury: a magnetic resonance spectroscopy study.
Experimental studies have reported early reductions in pH, phosphocreatine, and free intracellular magnesium following traumatic brain injury using phosphorus magnetic resonance spectroscopy. Paradoxically, in clinical studies there is some evidence for an increase in the pH in the subacute stage following traumatic brain injury. We therefore performed phosphorus magnetic resonance spectroscopy on seven patients in the subacute stage (mean 9 days postinjury) following traumatic brain injury to assess cellular metabolism. In areas of normal-appearing white matter, the pH was significantly alkaline (patients 7.09 +/- 0.04 [mean +/- SD], controls 7.01 +/- 0.04, p = 0.008), the phosphocreatine to inorganic phosphate ratio (PCr/Pi) was significantly increased (patients 4.03 +/- 1.18, controls 2.64 +/- 0.71, p = 0.03), the inorganic phosphate to adenosine triphosphate ratio (Pi/ATP) was significantly reduced (patients 0.37 +/- 0.10, controls 0.56 +/- 0.19, p = 0.04), and the PCr/ATP ratio was nonsignificantly increased (patients 1.53 +/- 0.29, controls 1.34 +/- 0.19, p = 0.14) in patients compared to controls. Furthermore, the calculated free intracellular magnesium was significantly increased in the patients compared to the controls (patients 0.33 +/- 0.09 mM, controls 0.22 +/- 0.09 mM, p = 0.03)). Proton spectra, acquired from similar regions showed a significant reduction in N-acetylaspartate (patients 9.64 +/- 2.49 units, controls 12.84 +/- 2.35 units, p = 0.03) and a significant increase in choline compounds (patients 7.96 +/- 1.02, controls 6.67 +/- 1.01 units, p = 0.03). No lactate was visible in any patient or control spectrum. The alterations in metabolism observed in these patients could not be explained by ongoing ischemia but might be secondary to a loss of normal cellular homeostasis or a relative alteration in the cellular population, in particular an increase in the glial cell density, in these regions.


Luteolin limits infarct size and improves cardiac function after myocardium ischemia/reperfusion injury in diabetic rats.
The present study was to investigate the effects and mechanism of Luteolin on myocardial infarct size, cardiac function and cardiomyocyte apoptosis in diabetic rats with myocardial ischemia/reperfusion (I/R) injury. Diabetic rats underwent 30 minutes of ischemia followed by 3 h of reperfusion. Animals were pretreated with or without Luteolin before coronary artery ligation. The severity of myocardial I/R induced LDH release, arrhythmia, infarct size, cardiac function impairment, cardiomyocyte apoptosis were compared. Western blot analysis was performed to elucidate the target proteins of Luteolin. The inflammatory cytokine production were also examined in ischemic myocardium underwent I/R injury. Our results revealed that Luteolin administration significantly reduced LDH release, decreased the incidence of arrhythmia, attenuated myocardial infarct size, enhanced left ventricular ejection fraction and decreased myocardial apoptotic death compared with I/R group. Western blot analysis showed that Luteolin treatment up-regulated anti-apoptotic proteins FGFR2 and LIF expression, increased BAD phosphorylation while decreased the ratio of Bax to Bcl-2. Luteolin treatment also inhibited MPO expression and inflammatory cytokine production including IL-6, IL-1a and TNF-a. Moreover, co-administration of wortmannin and Luteolin abolished the beneficial effects of Luteolin. This study indicates that Luteolin preserves cardiac function, reduces infarct size and cardiomyocyte apoptotic rate after I/R injury in diabetic rats. Luteolin exerts its action by up-regulating of anti-apoptotic proteins FGFR2 and LIF expression, activating PI3K/Akt pathway while increasing BAD phosphorylation and decreasing ratio of Bax to Bcl-2.


How psoriasis patients perceive, obtain, and use biologic agents: Survey from an academic medical center.
The availability of new biologic agents for the treatment of psoriasis provides hope for improved quality of life outcomes. However, the way patients come to use biologics, the potential barriers they encounter, and their attitudes towards using these medications are still not well studied. Here, we conducted a survey of 106 psoriasis patients at an academic medical center to discern patient attitudes towards biologics. We found that most patients learn of biologics through their physician and perform follow-up research using the Internet. Most patients did not find it difficult to make the decision to start a biologic. Difficulty in obtaining biologics was associated with age less than 55 (p = 0.01), lower income level (p = 0.007), and lack of insurance (p = 0.04). Patients were found to have high satisfaction and compliance rates on biologics. Of patients who missed a dose of their biologic, this was mainly due to logistical reasons such as not having the medication or forgetting to take it, rather than being depressed or overwhelmed. Patients with lower income levels had increased cut backs in personal expenses due to co-payments (p = 0.001). Among respondents, the mean annual out-of-pocket expense for a biologic was $557.12 per year, with a range of $0-7000.


Progression of breast cancer cells was enhanced by endocrine-disrupting chemicals, triclosan and octylphenol, via an estrogen receptor-dependent signaling pathway in cellular and mouse xenograft models.
In the present study, we determined whether two endocrine-disrupting chemicals (EDCs), triclosan (TCS) and octylphenol (OP), are able to alter the expression of two cell cycle regulators, cyclin D1 and p21, in both in vitro and mouse breast cancer models. In addition, we determined whether the stimulatory effects of OP or TCS on breast cancer progression may be associated with an estrogen receptor (ER)-mediated signaling pathway. Altered expressions of cyclin D1 and p21 were observed in MCF-7 human breast cancer cells treated with TCS and OP, which is linked to the G1/S transition of cell cycle, leading to cell proliferation. In a xenograft mouse model, breast tumor masses were established following exposure to TCS and OP for 8 weeks. In these animals, the tumor cells with BrdU-positive nuclei were increased by treatment with 17β-estradiol (E2), OP, and TCS compared to that of a control (corn oil), suggesting that TCS and OP increase DNA synthesis during the S phase in tumor cells. Increased level of cyclin D1 protein by TCS and OP was also observed in vivo, implying that the effects of these EDCs possessing estrogenic activity alter the expression of genes related to cancer progression. It was of interest that the effects of TCS and OP were reversed by ICI 182,780, an ER antagonist, indicating that EDC-induced activities are mediated by an ER-dependent signaling pathway. Taken together, these results suggest that TCS and OP may promote breast cancer progression, via an ER-mediated signaling cascade.


SU-E-T-384: An Easy Use Anthropomorphic Phantom for Lung IMRT QA.
Even though lung IMRT plans are calculated based on patient CT with heterogeneity correction, patient-specific validations are often performed by using measurements in homogeneous solid media. In this study we developed heterogeneous phantoms for measurement-based validation of lung IMRT. Three slabs from thorax region of anthropomorphic RANDO phantom and virtual water (VW) slabs were used to construct two versions of heterogeneous phantom, "Hetero-1" and "Hetero-2". The RANDO slabs are 2.5 cm thick. A two-dimensional diode array detector, MapCHECK and an ion chamber were used for measurements. "Hetero-1" consisted of three RANDO slabs placed horizontally on the MapCHECK plus a 3cm VW on the top. Hetero-2 was constructed by inserting a 2 cm VW with a chamber cavity on top of the first RANDO slab above the MapCHECK. Two lung-IMRT plans were generated using Pinnacle TPS, including a plan for the RPC Lung-Phantom. The point doses were compared with ion chamber measurements and planar dose were compared with MapCHECK measurements. The MapCHECK measurements were performed using "Hetero-1" on a beam-by-beam basis for the two IMRT plans. Passing rates under 3%/3mm Gamma criteria of were from 93.5% to 98.5% for all beams. Accumulative measurements were performed using "Hetero-2" and the passing rates under same criteria for two IMRT plans were 96.9% and 96.3% respectively, and 95.2% and 98.5% for measurements with 5cm lateral-IsoCenter-shift including more lung material. The differences between Ion-chamber- measurements and TPS-calculations were 1.2% and 1.71% for two IMRT plans. In vivo results obtained from RPC-report for two TLDs inside the PTV were 98% and 99% between measurements and calculations. An easy-to-setup heterogonous phantom for Lung IMRT QA can be constructed by adopting thorax region slabs of anthropomorphic-type phantoms. It can be implemented as a convenient and efficient tool for lung IMRT QA in a routine clinic.


Association between Coffee Consumption and Renal Impairment in Korean Women with and without Diabetes: Analysis of the Fourth Korea National Health and Nutrition Examination Survey in 2008.
Recent studies suggest that coffee consumption has an influence on kidney function. This study investigated the relationship between habitual coffee consumption and renal impairment in Korean women, in consideration of diabetic status. This study involved 2,673 women aged 35 to 84 years who had participated in the Fourth Korea National Health and Nutrition Examination Surveys, conducted in 2008. Habitual coffee consumption was classified into three categories: less than 1 cup per day, 1 cup per day, and 2 or more cups per day. Renal function impairment was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) by the Modification of Diet in Renal Disease equation. The prevalence of diabetes and renal function impairment was higher in women who drank < 1 cup of coffee per day. Compared with drinking < 1 cup of coffee per day, the odds ratio (OR) for renal function impairment was significantly lower (OR, 0.59; 95% confidence interval [CI], 0.37 to 0.95; P = 0.03) in those who habitually drank ≥ 2 cups per day after adjusting for multiple confounding factors. When data were stratified according to the presence of diabetes, coffee consumption ≥ 2 cups of coffee per day showed an inverse association with renal function impairment in only diabetic women (OR, 0.14; 95% CI, 0.02 to 0.88; P = 0.04), compared with consumption < 1 cup of coffee per day. In a representative sample of Korean women, coffee consumption was significantly associated with a decreased risk of renal impairment especially in middle and elderly-aged diabetic women.


Effect of Pre-Procedural Beta-Blocker on Clinical Outcome after Percutaneous Coronary Intervention in Acute Coronary Syndrome.
The efficacy of pre-procedural beta-blocker use in patients with acute coronary syndrome (ACS) is not well established in the current percutaneous coronary intervention (PCI) era. We investigate the effect of pre-procedural beta-blocker use on clinical outcomes in patients with ACS undergoing PCI. Among 44,967 consecutive cases of PCI enrolled in the nationwide, retrospective, multicenter registry (K-PCI registry), 31,040 patients with ACS were selected and analyzed. We classified patients into pre-procedural beta-blocker group (n = 8,678) and pre-procedural no-beta-blocker group (n = 22,362) according to the use of beta-blockers at least for two weeks before index PCI. Propensity score-matching analysis was performed and resulted in 7,445 pairs. The primary outcome was in-hospital cardiac death. In propensity score-matched populations, the pre-procedural beta-blocker group had a lower incidence of in-hospital cardiac death compared with the pre-procedural no-beta-blocker group (1.1% versus 2.0%, unadjusted odds ratio [OR]: 0.56, 95% confidence interval [CI]: 0.42-0.73, P < 0.01). In subgroup analysis, the pre-procedural beta-blocker group had a lower incidence of in-hospital cardiac death, compared with the pre-procedural no-beta-blocker group in ST-segment elevation myocardial infarction subpopulation (3.1% versus 6.1%, unadjusted OR: 0.49, 95% CI: 0.34-0.71, P < 0.01) and non-ST-segment elevation myocardial infarction subpopulation (1.5% versus 2.9%, unadjusted OR: 0.51, 95% CI: 0.33-0.79, P < 0.01). However, in unstable angina subpopulation, the in-hospital cardiac death rate was comparable between both groups. In conclusion, the use of pre-procedural beta-blocker was associated with a lower risk of in-hospital cardiac death in patients with ACS undergoing PCI. This result adds to the body of evidence that use of pre-procedural beta-blocker in patients with ACS might be reasonable.


Ultrabroad terahertz bandpass filter by hyperbolic metamaterial waveguide.
We propose and demonstrate an ultrabroad terahertz (THz) bandpass filter (BPF) by integrating two different-sized tapered hyperbolic metamaterial (HMM) waveguides, each of which has wide but different absorption and transmission bands, into a unit cell. With proper structural design of each HMM waveguide to control the absorption and transmission bands, we numerically demonstrate the designed BPF is capable of operating with a broad passband in the THz domain. A typical TM-polarized HMM BPF has a peak transmission of 37% at 3.3 THz with the passband bandwidth of 2.2 THz ranging from 2.97 to 5.17 THz. The co-designed three-dimensional HMM BPF also shows the capability of operating with independence to the polarization of incident light because of the structural symmetry and has sharp bandedge transitions of 22.6 and 17.6 dB/THz to the stop bands, respectively. The presented results here hold great promise for developing practical THz BPF with various applications in THz field.


Therapy options in irritable bowel syndrome.
Numerous meta-analyses have recently assessed the overall clinical benefit of single therapy options and groups of therapies in the irritable bowel syndrome (IBS). By large, this should enable physicians to select from a number of therapy options available. We entered dichotomous outcome data from 121 IBS trials published over the last 35 years with different groups and subgroups of drugs (antispasmodics, motility-affecting agents, antidepressants, peppermint oil), dietary interventions (bran, probiotics), and psychotherapy (cognitive behavioral, psychodynamic, hypnotherapy, relaxation techniques) into meta-analytic tools and estimate the overall efficacy (odds ratio, number needed to treat). Highest efficacy is currently found for peppermint oil, followed by psychotherapeutic and psychopharmacological interventions and probiotics. Traditional antispasmodic therapy has a moderate efficacy, whereas the list of (partially failed or cancelled) motility affecting drugs yielded weak clinical results, and therapies by bran and fibers are of no value in IBS. Evidence-based therapy in IBS provides a number of effective treatment options beyond the fact that many novel compounds under development have failed to reach the market. An algorithm for clinical therapy decision is proposed.


The vitronectin RGD motif regulates TGF-β-induced alveolar epithelial cell apoptosis.
Transforming growth factor-β (TGF-β) is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGF-β, which regulates changes in the cellular and matrix makeup of the lung during the repair and fibrosis phase. TGF-β can also initiate alveolar epithelial cell (AEC) apoptosis. Injury leads to destruction of the laminin-rich basement membrane, which is replaced by a provisional matrix composed of arginine-glycine-aspartate (RGD) motif-containing plasma matrix proteins, including vitronectin and fibronectin. To determine the role of specific matrix proteins on TGF-β-induced apoptosis, we studied primary AECs cultured on different matrix conditions and utilized mice with deletion of vitronectin (Vtn(-/-)) or mice in which the vitronectin RGD motif is mutated to nonintegrin-binding arginine-glycine-glutamate (RGE) (Vtn(RGE/RGE)). We found that AECs cultured on fibronectin and vitronectin or in wild-type mouse serum are resistant to TGF-β-induced apoptosis. In contrast, AECs cultured on laminin or in serum from Vtn(-/-) or Vtn(RGE/RGE) mice undergo robust TGF-β-induced apoptosis. Plasminogen activator inhibitor-1 (PAI-1) sensitizes AECs to greater apoptosis by disrupting AEC engagement to vitronectin. Inhibition of integrin-associated signaling proteins augments AEC apoptosis. Mice with transgenic deletion of PAI-1 have less apoptosis after bleomycin, but deletion of vitronectin or disruption of the vitronectin RGD motif reverses this protection, suggesting that the proapoptotic function of PAI-1 is mediated through vitronectin inhibition. Collectively, these data suggest that integrin-matrix signaling is an important regulator of TGF-β-mediated AEC apoptosis and that PAI-1 functions as a natural regulator of this interaction.


Challenges of improving the evidence base in smaller surgical specialties, as highlighted by a systematic review of gastroschisis management.
To identify methods of improving the evidence base in smaller surgical specialties, using a systematic review of gastroschisis management as an example. Operative primary fascial closure (OPFC), and silo placement with staged reduction and delayed closure (SR) are the most commonly used methods of gastroschisis closure. Relative merits of each are unclear. A systematic review and meta-analysis was performed comparing outcomes following OPFC and SR in infants with simple gastroschisis. Primary outcomes of interest were mortality, length of hospitalization and time to full enteral feeding. 751 unique articles were identified. Eight met the inclusion criteria. None were randomized controlled trials. 488 infants underwent OPFC and 316 underwent SR. Multiple studies were excluded because they included heterogeneous populations and mixed intervention groups. Length of stay was significantly longer in the SR group (mean difference 8.97 days, 95% CI 2.14-15.80 days), as was number of post-operative days to complete enteral feeding (mean difference 7.19 days, 95%CI 2.01-12.36 days). Mortality was not statistically significantly different, although the odds of death were raised in the SR group (OR 1.96, 95%CI 0.71-5.35). Despite showing some benefit of OPFC over SR, our results are tempered by the low quality of the available studies, which were small and variably reported. Coordinating research through a National Paediatric Surgical Trials Unit could alleviate many of these problems. A similar national approach could be used in other smaller surgical specialties.


Results after treatment of craniopharyngiomas: further experiences with 73 patients since 1997.
The authors report surgical and endocrinological results of a series of 73 cases of craniopharyngioma that they treated surgically since 1997 to demonstrate their change in treatment strategy and its effect on outcome compared with a previous series and results reported in the literature. A total of 73 patients underwent surgery for craniopharyngiomas between May 1997 and January 2005. In patients with poor clinical or neuropsychological condition, even following pretreatment, only stereotactic cyst aspiration took place (8 cases). In the remaining patients, gross-total resection (GTR) was intended and appeared to be possible. The most frequent approaches were subfrontal (27 cases) and transsphenoidal (26 cases); in some cases, a multistep approach was used. The rate of GTR, complications, and functional outcome (comparing pre- and postoperative endocrine and neuropsychological testing) were evaluated. The mean duration of follow-up was 25.2 months. Gross-total resection was achieved in 88.5% of cases in which a transsphenoidal approach was used and 79.5% of those in which a transcranial approach was used (85.2% of those in which a subfrontal approach was used and 72.7% of those in which a frontolateral approach was used). In the total series, GTR was achieved in 83.1% of cases (vs 49.3% in the authors' former series). The complication rate was 13.8% without any mortality. New endocrine deficits were observed more frequently in patients treated with transcranial approaches over the years (16.3%-66.7% vs 2.6%-50.0%) but were less frequent after transsphenoidal approaches (5.2%-19.2% vs 2.9%-45.7%). Open surgery with intended total resection remains the treatment of choice in most patients. Initial stereotactic cyst aspiration or medical pretreatment to improve the patients' condition and adequate choice of surgical approach(es) are essential to achieve that goal. Nevertheless, a moderate increase in endocrinological deficits has to be accepted. The authors recommend using radiotherapy only in cases in which there are tumor remnants or disease progression after surgery.


Brief induction chemotherapy followed by involved-field irradiation for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.
In an attempt to assess the effects and toxicity of brief induction chemotherapy plus involved-field irradiation for localized intermediate- and high-grade non-Hodgkin's lymphoma, we conducted a single-arm prospective trial between May 1987 and July 1991. Patients received four cycles of a five-drug chemotherapy regimen consisting of cyclophosphamide, doxorubicin, vincristine, prednisolone, and bleomycin (CHOP-Bleo) followed by involved-field irradiation of 30 Gy. Of 32 patients consecutively enrolled, 30 patients had measurable and/or evaluable disease, while two had no evaluable disease, as their major tumors had been surgically removed. All the patients were in complete remission at the conclusion of all treatment. Four patients have relapsed so far and one died of the disease at 17 months. With a median follow-up time of 33 months (range, 8 to 58), the actuarial disease-free survival rate was 82% and the overall survival rate was 96%. The toxicity was generally mild and all the patients received the planned treatment course. This treatment modality appeared to be safe and effective for localized intermediate- and high-grade non-Hodgkin's lymphoma.


Prognostic significance of plasma scatter factor/hepatocyte growth factor levels in patients with metastatic hormone- refractory prostate cancer: results from cancer and leukemia group B 150005/9480.
Scatter factor, also known as hepatocyte growth factor (SF/HGF), is a polypeptide growth factor thought to be important in the growth and spread of prostatic carcinoma. Scatter factor/HGF levels in pretreatment plasma samples from 171 men with metastatic hormone-refractory prostate cancer enrolled in CALGB 9480 were quantified by solid-phase, enzyme-linked immunosorbent assay. The Cox proportional hazards model was used to assess the prognostic importance of SF/HGF with adjustment for established prognostic factors. Median SF/HGF was 991 pg/mL (range, 212-2733 pg/mL). In a univariate analysis, although plasma SF/HGF levels above versus below the median value did not reach statistical significance (P = 0.0862), the cutoff point of > 935 pg/mL was associated with a significant reduction in overall survival (P = 0.0334). Patients with SF/HGF levels > 935 pg/mL experienced a median survival of 15 months compared with 19 months for men with SF/HGF levels < or = 935 pg/mL. In a multivariate analysis, adjusting for SF/HGF, prostate-specific antigen, lactate dehydrogenase, and performance status, only plasma alkaline phosphatase was significantly associated with overall survival (hazard ratio, 1.7; 95% confidence interval, 1.2-2.5; P = 0.0017). Higher plasma levels of SF/HGF in men with hormone-refractory prostate cancer are associated with a decreased patient survival. Currently, SF/HGF levels do not appear to be of value as a contributor to multivariate models for prediction of outcome, but the association with decreased survival suggests that SF/HGF might be a potential target for therapy.


Single molecule analysis of Trypanosoma brucei DNA replication dynamics.
Eukaryotic genome duplication relies on origins of replication, distributed over multiple chromosomes, to initiate DNA replication. A recent genome-wide analysis of Trypanosoma brucei, the etiological agent of sleeping sickness, localized its replication origins to the boundaries of multigenic transcription units. To better understand genomic replication in this organism, we examined replication by single molecule analysis of replicated DNA. We determined the average speed of replication forks of procyclic and bloodstream form cells and we found that T. brucei DNA replication rate is similar to rates seen in other eukaryotes. We also analyzed the replication dynamics of a central region of chromosome 1 in procyclic forms. We present evidence for replication terminating within the central part of the chromosome and thus emanating from both sides, suggesting a previously unmapped origin toward the 5' extremity of chromosome 1. Also, termination is not at a fixed location in chromosome 1, but is rather variable. Importantly, we found a replication origin located near an ORC1/CDC6 binding site that is detected after replicative stress induced by hydroxyurea treatment, suggesting it may be a dormant origin activated in response to replicative stress. Collectively, our findings support the existence of more replication origins in T. brucei than previously appreciated.


Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life.
The gut microbiota is central to human health, but its establishment in early life has not been quantitatively and functionally examined. Applying metagenomic analysis on fecal samples from a large cohort of Swedish infants and their mothers, we characterized the gut microbiome during the first year of life and assessed the impact of mode of delivery and feeding on its establishment. In contrast to vaginally delivered infants, the gut microbiota of infants delivered by C-section showed significantly less resemblance to their mothers. Nutrition had a major impact on early microbiota composition and function, with cessation of breast-feeding, rather than introduction of solid food, being required for maturation into an adult-like microbiota. Microbiota composition and ecological network had distinctive features at each sampled stage, in accordance with functional maturation of the microbiome. Our findings establish a framework for understanding the interplay between the gut microbiome and the human body in early life.


[Radiation treatment of early stage supraglottic cancer].
The management of early-stage squamous cell carcinoma (SCC) of the supraglottic larynx is still controversial. Supraglottic laryngectomy as well as irradiation alone is correlated with good oncological and functional results. In order to evaluate the results and prognostic factors influencing the successful using radiotherapy (RT), the authors performed a retrospective study of 100 consecutive T1-T2 N0 M0 cases of SCC of the supraglottic larynx, treated at a single institution between 1983 and 1992. RT was delivered with 60Co or 6 MeV photons through two lateral parallel opposed portals encompassing the primary laryngeal tumor and the upper and mid-neck nodes (Robbins' levels II, III and V). Supraclavicular nodes (level IV) were electively irradiated in 54 patients with T2 N0 tumors only, using an anterior field with midline block. Sixty-three patients received conventional fractionation (2 Gy/fraction, once-a-day, five times a week), while 37 patients were irradiated according to a twice-a-day fractionation regimen (1.5 Gy/fraction, twice a day with six-hour interval, five days a week). The median total tumor dose delivered was 67 Gy. A multivariate analysis showed that performance status, tumor grade and fractionation modality were the only statistically significant variables influencing disease-free survival. Acute and late radiation reactions were relatively low. This retrospective study confirms that conservative management of T1-T2 N0 supraglottic cancer using RT can achieve good cure rates with the possibility of larynx preservation for the majority of the patients. The decision between different conservative treatment modalities may be influenced by several factors correlated to the patient's conditions, tumor characteristics, but especially treatment modalities.


Predicting adherence to use of remote health monitoring systems in a cohort of patients with chronic heart failure.
It is unclear whether subgroups of patients may benefit from remote monitoring systems (RMS) and what user characteristics and contextual factors determine effective use of RMS in patients with heart failure (HF). The study was conducted to determine whether certain user characteristics (i.e. personal and clinical variables) predict use of RMS using advanced machine learning software algorithms in patients with HF. This pilot study was a single-arm experimental study with a pre- (baseline) and post- (3 months) design; data from the baseline measures were used for the current data analyses. Sixteen patients provided consent; only 7 patients (mean age 65.8 ± 6.1, range 58-83) accessed the RMS and transmitted daily data (e.g. weight, blood pressure) as instructed during the 12 week study duration. Baseline demographic and clinical characteristics of users and non-users were comparable for a majority of factors. However, users were more likely to have no HF specialty based care or an automatic internal cardioverter defibrillator. The precision accuracy of decision tree, multilayer perceptron (MLP) and k-Nearest Neighbor (k-NN) classifiers for predicting access to RMS was 87.5%, 90.3%, and 94.5% respectively. Our preliminary data show that a small set of baseline attributes is sufficient to predict subgroups of patients who had a higher likelihood of using RMS. While our findings shed light on potential end-users more likely to benefit from RMS-based interventions, additional research in a larger sample is warranted to explicate the impact of user characteristics on actual use of these technologies.


Mesenchymal stem cells are injured by complement after their contact with serum.
Despite the potent immunosuppressive activity that mesenchymal stem cells (MSCs) display in vitro, recent clinical trial results are disappointing, suggesting that MSC viability and/or function are greatly reduced after infusion. In this report, we demonstrated that human MSCs activated complement of the innate immunity after their contact with serum. Although all 3 known intrinsic cell-surface complement regulators were present on MSCs, activated complement overwhelmed the protection of these regulators and resulted in MSCs cytotoxicity and dysfunction. In addition, autologous MSCs suffered less cellular injury than allogeneic MSCs after contacting serum. All 3 complement activation pathways were involved in generating the membrane attack complex to directly injure MSCs. Supplementing an exogenous complement inhibitor, or up-regulating MSC expression levels of CD55, one of the cell-surface complement regulators, helped to reduce the serum-induced MSC cytotoxicity. Finally, adoptively transferred MSCs in complement deficient mice or complement-depleted mice showed reduced cellular injury in vivo compared with those in wild type mice. These results indicate that complement is integrally involved in recognizing and injuring MSCs after their infusion, suggesting that autologous MSCs may have ad-vantages over allogeneic MSCs, and that inhibiting complement activation could be a novel strategy to improve existing MSC-based therapies.


KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype.
Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice. In this study, we further elucidated the in vivo roles of the epidermal proteases in NS using a set of mouse models individually or simultaneously deficient for KLK5 and KLK7 on the genetic background of a novel NS-mouse model. We show that although the ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality allowing mice to reach adulthood with fully functional skin and normal hair growth. We report that not only KLK5 but also KLK7 plays an important role in the inflammation and defective differentiation in NS and KLK7 activity is not solely dependent on activation by KLK5. Altogether, these findings show that unregulated activities of KLK5 and KLK7 are responsible for NS development and both proteases should become targets for NS therapy.


Fluorine-18 fluorodeoxyglucose splenic uptake from extramedullary hematopoiesis after granulocyte colony-stimulating factor stimulation.
Two patients with sarcoma, one with recurrent osteosarcoma of the spine and the other with metastatic synovial cell sarcoma, were treated with high-dose chemotherapy that produced severe leukopenia. The patients received granulocyte colony-stimulating factor (G-CSF) to stimulate the bone marrow (480 mg given subcutaneously twice daily for 5 to 7 days); their responses were seen as a marked increase in peripheral leukocyte count with no change in the erythrocyte or platelet counts. The patients had fluorine-18 fluorodeoxyglucose (F-18 FDG) imaging 24 hours after the end of G-CSF treatment. Diffusely increased uptake of F-18 FDG was seen in the bone marrow in both patients. In addition, markedly increased uptake in the spleen was noted in both, indicating that the spleen was the site of extramedullary hematopoiesis. The patients had no evidence of splenic metastases. The first patient had a history of irradiation to the dorsal spine, which was less responsive to G-CSF administration than was the nonirradiated lumbar spine.


Theoretical and observational assessments of flare efficiencies.
Flaring of waste gases is a common practice in the processing of hydrocarbon (HC) materials. It is assumed that flaring achieves complete combustion with relatively innocuous byproducts such as CO2 and H2O. However, flaring is rarely successful in the attainment of complete combustion, because entrainment of air into the region of combusting gases restricts flame sizes to less than optimum values. The resulting flames are too small to dissipate the amount of heat associated with 100% combustion efficiency. Equations were employed to estimate flame lengths, areas, and volumes as functions of flare stack exit velocity, stoichiometric mixing ratio, and wind speed. Heats released as part of the combustion process were then estimated from a knowledge of the flame dimensions together with an assumed flame temperature of 1200 K. Combustion efficiencies were subsequently obtained by taking the ratio of estimated actual heat release values to those associated with 100% complete combustion. Results of the calculations showed that combustion efficiencies decreased rapidly as wind speed increased from 1 to 6 m/sec. As wind speeds increased beyond 6 m/sec, combustion efficiencies tended to level off at values between 10 and 15%. Propane and ethane tend to burn more efficiently than do methane or hydrogen sulfide because of their lower stoichiometric mixing ratios. Results of theoretical predictions were compared to nine values of local combustion efficiencies obtained as part of an observational study into flaring activity conducted by the Alberta Research Council (ARC). All values were obtained during wind speed conditions of less than 4 m/sec. There was generally good agreement between predicted and observed values. The mean and standard deviation of observed combustion efficiencies were 68 +/- 7%. Comparable predicted values were 69 +/- 7%.


Nonlinear compensation of chromatic dispersion for phase- and intensity-modulated signals in the presence of amplified spontaneous emission noise.
We numerically study the evolution of nonsoliton signals in fiber links in the presence of the Kerr effect, chromatic dispersion, and the amplified spontaneous emission of optical amplifiers. Conditions in which the amplified spontaneous emission noise does not deeply affect the signal propagation are found, and the nonlinear Kerr compensation of the distortion induced by the chromatic dispersion is shown.


Roles of topoisomerases in maintaining steady-state DNA supercoiling in Escherichia coli.
DNA supercoiling is essential for bacterial cell survival. We demonstrated that DNA topoisomerase IV, acting in concert with topoisomerase I and gyrase, makes an important contribution to the steady-state level of supercoiling in Escherichia coli. Following inhibition of gyrase, topoisomerase IV alone relaxed plasmid DNA to a final supercoiling density (sigma) of -0.015 at an initial rate of 0.8 links min(-1). Topoisomerase I relaxed DNA at a faster rate, 5 links min(-1), but only to a sigma of -0.05. Inhibition of topoisomerase IV in wild-type cells increased supercoiling to approximately the same level as in a mutant lacking topoisomerase I activity (to sigma = -0.08). The role of topoisomerase IV was revealed by two functional assays. Removal of both topoisomerase I and topoisomerase IV caused the DNA to become hyper-negatively supercoiled (sigma = -0.09), greatly stimulating transcription from the supercoiling sensitive leu-500 promoter and increasing the number of supercoils trapped by lambda integrase site-specific recombination.


Screening extended-spectrum beta-lactamase production in Enterobacter cloacae and Serratia marcescens using antibiogram-based methods.
In Enterobacter cloacae and Serratia marcescens, AmpC beta-lactamases can confer resistance to the third-generation cephalosporins and oxacephems, but not to the fourth-generation cephalosporins. Extended-spectrum beta-lactamases (ESBL) may confer resistance to all extended-spectrum cephalosporins but not flomoxef. As difficult to detect, the ESBL phenotype of the intrinsically AmpC- producing E. cloacae and S. marcescens is not routinely screened in the clinical microbiology laboratories. The distinct antibiotic resistance phenotype between ESBL- and AmpC-producers may assist to differentiate the type of secreted beta-lactamases. Therefore, we attested the validity of an antibiogram-based method to predict the presence of ESBLs in both species. Polymerase chain reaction-based methods and antibiogram-based methods were compared for their detection of ESBL in 74 E. cloacae and 69 S. marcescens isolates recovered from patients hospitalized at two medical centers in Taiwan. Three major types of antibiogram were defined: type I (3s4s), susceptible to cefotaxime, ceftazidime, and cefepime; type II (3r4s), resistant to cefotaxime or ceftazidime, but susceptible to cefepime; and type III (3r4r), resistant to cefepime plus cefotaxime and/or ceftazidime. Furthermore, subtype-a and subtype-b were defined as being resistant and susceptible to flomoxef, respectively. Overall, ESBL producers were identified in 20 (27.0%) of Enterobacter and 11 (15.9%) of Serratia isolates by polymerase chain reaction-based methods. All type I isolates of both species (n= 49) were non-ESBL producers. In E. cloacae, all subtype IIb (n = 6) and type III (n = 6) isolates produced ESBLs, but only 8 of 17 IIa isolates produced ESBLs. The IIb and III types had the highest positive predictive value (100%) and specificity (100%) for ESBL detection. In S. marcescens, type II isolates rarely produced ESBLs (4/57 isolates), while seven of type III (n = 8) isolates produced ESBLs. Type III antibiogram had the highest positive predictive value (87.5%) and specificity (98.3%) for ESBL detection. The antibiograms of subtype IIb and type III are highly predictive for ESBL detection in E. cloacae, while type III is highly predictive for ESBL detection in S. marcescens. It is imperative to further examine ESBLs, focusing on the E. cloacae isolates with antibiogram subtype IIa.


Value of mitral valve tenting volume determined by real-time three-dimensional echocardiography in patients with functional mitral regurgitation.
This study sought to evaluate mitral valve tenting volume (TnV) as a clinical parameter using real-time 3-dimensional echocardiography in patients with functional mitral regurgitation (MR). In 27 patients with functional MR and 4 controls without mitral disease, real-time 3-dimensional echocardiographic images were obtained to measure TnV frame by frame from presystole to end-systole. The maximal and minimal TnVs during systole were identified in each patient, and mitral annular areas and tenting heights were also measured. Using 2-dimensional echocardiography, tenting area (TnA) was measured from the apical long-axis, apical 4-chamber, and apical 2-chamber views. The regurgitant orifice area was measured by the proximal isovelocity surface area method. Maximal and minimal TnVs occurred at the time of 2 +/- 6% and 78 +/- 6% of whole systolic duration, respectively, and the systolic percentage change of TnV was related to that of tenting height but not to that of mitral annular area. TnA on the long-axis images was significantly larger than that on the 4- and 2-chamber images (2.5 +/- 1.4 vs 1.7 +/- 1.3 and 1.9 +/- 1.4 cm(2), respectively, p <0.001). Regurgitant orifice area was significantly correlated with maximal TnV (r = 0.90), minimal TnV (r = 0.86), and TnA on the long-axis (r = 0.79), 4-chamber (r = 0.75), and 2-chamber (r = 0.73) images. Among minimal TnV and 3 TnAs, minimal TnV was the only independent determinant of regurgitant orifice area (p <0.001). Minimal TnV >or=3.90 ml identified significant functional MR with a sensitivity of 86% and a specificity of 100%. In conclusion, TnV derived from real-time 3-dimensional echocardiography is a preferable novel single index for assessing mitral valve tethering in functional MR to TnA that is dependent on the location of 2-dimensional planes.


Human papillomavirus genotype distribution among French women with and without cervical abnormalities.
To assess human papillomavirus (HPV) prevalence and distribution among French women with normal and pathologic cytology findings. A genomic DNA microarray assay enabling the detection of 35 different HPV genotypes was used for in vitro diagnosis, as a complement to Papanicolaou screening, to test 785 women who attended the gynecology department of a hospital in Lyon, France. Pathologic and normal cytology findings were obtained for 260 (33.1%) and 302 (38.5%) of the 785 women, respectively, whereas 223 (28.4%) results were inconclusive. HPV infection and multiple infection were significantly more prevalent (P<0.001) in the population with pathologic findings (90.0% and 41.9%, respectively) than in the population with normal cytology findings (48.3% and 20.2%, respectively). Overall, the 4 most frequent HPV genotypes were HPV-16 (14.8%), HPV-53 (9.0%), HPV-31 (8.7%), and HPV-51 (7.5%), whereas HPV-18 (3.8%), HPV-6 (2.9%), and HPV-11 (0.4%) were less common. The HPV genotypes included in the quadrivalent vaccination had a prevalence of 20.6% among all women and 30.4% among those with pathologic findings. The present data indicate a reduced direct impact of HPV vaccination in the study population owing to a low prevalence of HPV-18 and a high prevalence of HPV-53, HPV-31, and HPV-51.


Sclerosing cholangitis: biliary reconstruction with Silastic transhepatic stents.
Because of multiple areas of stricturing and small fibrotic ducts, sclerosing cholangitis has generally not been amenable to direct reconstructive procedures. In reviewing the cholangiograms of 29 patients with sclerosing cholangitis, it became apparent that despite diffuse disease, the hepatic duct bifurcation was often (22 patients) the most severely narrowed area. Because of this finding it was decided to manage patients who have sclerosing cholangitis, persistent jaundice, and hepatic duct bifurcation narrowing with a direct surgical approach. In 11 patients the extrahepatic biliary tree including the bifurcation was resected and the right and left hepatic ducts were dilated. Bilateral 6 mm silicone rubber (Silastic) transhepatic biliary stents were inserted and bilateral hepaticojejunostomy was performed. Eight patients were men, three were women, and the mean age was 41.9 years. At the time of surgery the mean serum bilirubin concentration was 15.3 mg/dl (range 1 to 50 mg/dl). The disease had been present clinically for a mean duration of 3.6 years. There was one hospital death. Nine of the ten remaining patients have responded with a decrease in serum bilirubin concentration to a mean of 2.9 mg/dl. These nine patients have returned to normal activity. The tenth patient has done poorly and awaits liver transplantation. Follow-up ranges from 4 to 36 months (mean 18 months). The stents have been left in position permanently.


Looking for symmetry: fixational eye movements are biased by image mirror symmetry.
Humans are highly sensitive to symmetry. During scene exploration, the area of the retina with dense light receptor coverage acquires most information from relevant locations determined by gaze fixation. We characterized patterns of fixational eye movements made by observers staring at synthetic scenes either freely (i.e., free exploration) or during a symmetry orientation discrimination task (i.e., active exploration). Stimuli could be mirror-symmetric or not. Both free and active exploration generated more saccades parallel to the axis of symmetry than along other orientations. Most saccades were small (<2°), leaving the fovea within a 4° radius of fixation. Analysis of saccade dynamics showed that the observed parallel orientation selectivity emerged within 500 ms of stimulus onset and persisted throughout the trials under both viewing conditions. Symmetry strongly distorted existing anisotropies in gaze direction in a seemingly automatic process. We argue that this bias serves a functional role in which adjusted scene sampling enhances and maintains sustained sensitivity to local spatial correlations arising from symmetry.


Consumer response to healthy eating, physical activity and weight-related recommendations: a systematic review.
Strong evidence linking poor diet and lack of physical activity to risk of obesity and related chronic disease has supported the development and promotion of guidelines to improve population health. Still, obesity continues to escalate as a major health concern, and so the impact of weight-related guidelines on behaviour is unclear. The aim of this review was to examine consumer response to weight-related guidelines. A systematic literature search was performed using Medline, PsycInfo, ProQuest Central and additional searches using Google and reference lists. Of the 1,765 articles identified, 46 relevant titles were included. Most studies examined attitudes towards content, source, tailoring and comprehension of dietary guidelines. Many respondents reported that guidelines were confusing, and that simple, clear, specific, realistic, and in some cases, tailored guidelines are required. Recognition of guidelines did not signify understanding nor did perceived credibility of a source guarantee utilization of guidelines. There was a lack of studies assessing: the impact of guidelines on behaviour; responses to physical activity guidelines; responses among males and studies undertaken in developing countries. Further research is needed, in particular regarding responses to physical activity guidelines and guidelines in different populations. Communication professionals should assist health professionals in the development of accurate and effective weight-related guidelines.


A System-Level Approach to Improve the Uptake of Antiestrogen Preventive Therapy among Women with Atypical Hyperplasia and Lobular Cancer In Situ.
Background: The low uptake of antiestrogen preventive therapy among women at high risk of developing breast cancer remains a challenge. We implemented a performance improvement program to increase the uptake of preventive therapy among women with atypical hyperplasia (AH) and lobular cancer in situ (LCIS).Methods: A performance improvement program was implemented at the MD Anderson Cancer Center (Houston, TX), November 2015 to February 2017, for patients with a new (<6 months) or existing (≥6 months) diagnosis of AH/LCIS. The program consisted of an audit of eligible women who were recommended and prescribed preventive therapy and the provision of clinical performance feedback to providers. The baseline uptake of preventive therapy was estimated from patients enrolled in a high-risk breast cohort.Results: Baseline uptake of preventive therapy was 44%. The program registered 408 patients with a new (n = 87) or existing diagnosis (n = 321) of AH/LCIS; mean age was 57 and 71% were non-Hispanic white. Ninety-eight percent of patients received a recommendation for preventive therapy. The overall prescribing of preventive therapy to patients with a new or existing diagnosis was 82% (monthly range, 40%-100%; Ptrend = 0.76) and 48% (monthly range, 27%-57%; Ptrend < 0.01), respectively. Adherence among patients with a new or existing diagnosis was 76% and 48% (P < 0.01) at 6 months, respectively.Conclusion: A system-level approach improved the uptake of preventive therapy. Identifying women at the time of diagnosis of AH/LCIS and offering a strong recommendation are key components for improving acceptance and adherence with preventive therapy. Cancer Prev Res; 11(5); 295-302. ©2018 AACR.


Constraints upon the response of fish and crayfish to environmental flow releases in a regulated headwater stream network.
In dry climate zones, headwater streams are often regulated for water extraction causing intermittency in perennial streams and prolonged drying in intermittent streams. Regulation thereby reduces aquatic habitat downstream of weirs that also form barriers to migration by stream fauna. Environmental flow releases may restore streamflow in rivers, but are rarely applied to headwaters. We sampled fish and crayfish in four regulated headwater streams before and after the release of summer-autumn environmental flows, and in four nearby unregulated streams, to determine whether their abundances increased in response to flow releases. Historical data of fish and crayfish occurrence spanning a 30 year period was compared with contemporary data (electrofishing surveys, Victoria Range, Australia; summer 2008 to summer 2010) to assess the longer-term effects of regulation and drought. Although fish were recorded in regulated streams before 1996, they were not recorded in the present study upstream or downstream of weirs despite recent flow releases. Crayfish (Geocharax sp. nov. 1) remained in the regulated streams throughout the study, but did not become more abundant in response to flow releases. In contrast, native fish (Gadopsis marmoratus, Galaxias oliros, Galaxias maculatus) and crayfish remained present in unregulated streams, despite prolonged drought conditions during 2006-2010, and the assemblages of each of these streams remained essentially unchanged over the 30 year period. Flow release volumes may have been too small or have operated for an insufficient time to allow fish to recolonise regulated streams. Barriers to dispersal may also be preventing recolonisation. Indefinite continuation of annual flow releases, that prevent the unnatural cessation of flow caused by weirs, may eventually facilitate upstream movement of fish and crayfish in regulated channels; but other human-made dispersal barriers downstream need to be identified and ameliorated, to allow native fish to fulfil their life cycles in these headwater streams.


A Pilot Study of Partner Chair Massage Effects on Perinatal Mood, Anxiety, and Pain.
Women worldwide experience perinatal mood, anxiety, and pain contributing to pregnancy and birth challenges, maternal and infant bonding, and childhood development. Perinatal women seek massage therapy for relaxation, pain management, and emotional support, but may encounter socioeconomic barriers. Prior studies demonstrated improved perinatal health by teaching partners of pregnant women a side-lying massage. This study examined health effects to perinatal mood, anxiety, and pain, by teaching partners of pregnant (PG) women a chair massage. Participant's homes in Tucson, Arizona, USA. Twelve PG women with minor mood, anxiety, and pain: 67% white, 33% Hispanic, college educated, married, aged 32 years (± 3.86 SD), 67% expecting a first child, annual incomes ≤ $50,000 (33%), > $50,000 (67%). A pre/postintervention pilot study in a single group for eight weeks. Twice weekly partner-delivered chair massage and its relation to perinatal mood, anxiety, and pain. Pre/poststudy perinatal massage effects were measured with the Edinburgh Depression Scale (mood), the STAI-AD (anxiety), and the VAS (pain). Weekly text messaging tracked dose and frequency, follow-up surveys measured sustainability, and birth outcomes were acquired by texting. Study retention was 86%, protocol compliance 94%, with couples averaging 10-minute, twice weekly chair massage over the eight-week study period. Paired-sample t tests indicated statistically significant improvements to perinatal mood and anxiety, Cohen's d, a large strength of effect size (p = .012, d = 0.87; p = .004, d = 1.03). A trend was observed for reduced pain, with a medium strength of effect size (p = .071; d = 0.58). Follow-up surveys indicated most couples were sustaining at least weekly massage. Birth outcomes showed healthy infants with no complications, mean birth weight of 7.26 pounds, and mean gestation of 39 weeks. This is the first evidence of partner chair massage as safe and effective complementary home management of perinatal mood, anxiety, and pain.


OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program.
Chronic migraine (CM) is a prevalent and disabling neurological disorder. Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program assessed efficacy and safety of onabotulinumtoxinA (BOTOX(®)) for prophylaxis of headaches in adults with CM. This secondary analysis assessed patients who received all five treatment cycles and completed the study. PREEMPT (two phase III studies: 24-week double-blind, placebo-controlled [DBPC], parallel-group phase, followed by 32-week open-label [OL] phase) evaluated the efficacy and safety of onabotulinumtoxinA in CM (≥15 days/month with headache lasting ≥4 h a day). Patients were randomized (1:1) to onabotulinumtoxinA or placebo every 12 weeks for two cycles, followed by onabotulinumtoxinA for three cycles. Multiple headache symptom measures were evaluated. Results for the completer (five cycles) subgroup of patients are reported. Of 1384 total PREEMPT patients, 1005 received all five treatment cycles (513 received onabotulinumtoxinA only [onabotulinumtoxinA/onabotulinumtoxinA (O/O)] and 492 received two cycles of placebo then three cycles of onabotulinumtoxinA [placebo/onabotulinumtoxinA (P/O)]). Demographics were similar between treatment groups. At Week 56, after all patients were treated with onabotulinumtoxinA, there continued to be significant between-group differences favoring the O/O vs P/O group for the following headache symptom measures: LS mean change from baseline in frequencies of headache days (-12.0 O/O, -11.1 P/O; P = 0.035), migraine days (-11.6 O/O, -10.7 P/O; P = 0.038), and moderate/severe headache days (-11.0 O/O, -10.1 P/O; P = 0.042). For other measures (cumulative hours of headache on headache days, frequency of headache episodes, and percentage with severe Headache Impact Test (HIT)-6 score, and total HIT-6 and Migraine-Specific Quality of Life Questionnaire scores), there were also large mean improvements from baseline. The percent of patients with a ≥50% reduction from baseline in frequency of headache days was significantly greater for the onabotulinumtoxinA-only group at Week 56 (69.6% O/O, 62.8% P/O; P = 0.023). The treatment-related adverse event rate was 28.5% for onabotulinumtoxinA vs 12.4% for placebo in the DBPC phase and 34.8% for patients treated with onabotulinumtoxinA for all five cycles throughout the 56-week trials. This subgroup analysis demonstrated improvements with onabotulinumtoxinA treatment (five cycles) vs placebo (two cycles)/onabotulinumtoxinA (three cycles) for multiple headache symptom measures and suggests that at Week 56, patients treated earlier with onabotulinumtoxinA had better outcomes. These findings demonstrate the continued need and cumulative benefit over time with continued prophylaxis, an important and clinically pragmatic observation for clinicians and patients.


Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein.
The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control. Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD? To answer this question, we combined an analysis of the RBD structure-function with an evolutionary modeling framework. Our structure-function analysis revealed that epitopes for RBD-targeting nAbs overlap one another substantially and can be evaded by escape mutants with ACE2 affinities comparable to the wild type, that are observed in sequence surveillance data and infect cells in vitro. This suggests that the fitness cost of nAb-evading mutations is low. We then used evolutionary modeling to predict the frequency of immune escape before and after the widespread presence of nAbs due to vaccines, passive immunization or natural immunity. Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection. Predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population. Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities.


Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee).
A double-blind, crossover, 8-wk study was conducted to compare effects of the tocotrienol-enriched fraction of palm oil (200 mg palmvitee capsules/day) with those of 300 mg corn oil/d on serum lipids of hypercholesterolemic human subjects (serum cholesterol 6.21-8.02 mmol/L). Concentrations of serum total cholesterol (-15%), LDL cholesterol (-8%), Apo B (-10%), thromboxane (-25%), platelet factor 4 (-16%), and glucose (-12%) decreased significantly only in the 15 subjects given palmvitee during the initial 4 wk. The crossover confirmed these actions of palmvitee. There was a carry over effect of palmvitee. Serum cholesterol concentrations of seven hypercholesterolemic subjects (greater than 7.84 mmol/L) decreased 31% during a 4-wk period in which they were given 200 mg gamma-tocotrienol/d. This indicates that gamma-tocotrienol may be the most potent cholesterol inhibitor in palmvitee capsules. The results of this pilot study are very encouraging.


The mouse p97 (CDC48) gene. Genomic structure, definition of transcriptional regulatory sequences, gene expression, and characterization of a pseudogene.
Here we present the first description of the genomic organization, transcriptional regulatory sequences, and adult and embryonic gene expression for the mouse p97(CDC48) AAA ATPase. Clones representing two distinct p97 genes were isolated in a genomic library screen, one of them likely representing a non-functional processed pseudogene. The coding region of the gene encoding the functional mRNA is interrupted by 16 introns and encompasses 20.4 kilobase pairs. Definition of the transcriptional initiation site and sequence analysis showed that the gene contains a TATA-less, GC-rich promoter region with an initiator element spanning the transcription start site. Cis-acting elements necessary for basal transcription activity reside within 410 base pairs of the flanking region as determined by transient transfection assays. In immunohistological analyses, p97 was widely expressed in embryos and adults, but protein levels were tightly controlled in a cell type- and cell differentiation-dependent manner. A remarkable heterogeneity in p97 immunostaining was found on a cellular level within a given tissue, and protein amounts in the cytoplasm and nucleus varied widely, suggesting a highly regulated and intermittent function for p97. This study provides the basis for a detailed analysis of the complex regulation of p97 and the reagents required for assessing its functional significance using targeted gene manipulation in the mouse.


Indian Society for Study of Pain, Cancer Pain Special Interest Group Guidelines on Complementary Therapies for Cancer Pain.
The Indian Society for Study of Pain (ISSP), cancer pain Special Interest Group (SIG) guidelines on complementary therapies for cancer pain in adults provides a structured, stepwise approach which will help to improve the management of cancer pain and to provide the patients with a minimally acceptable quality of life. The guidelines have been developed based on the available literature and evidence, to suit the needs, patient population, and situations in India. A questionnaire based on the key elements of each sub drafts addressing certain inconclusive areas where evidence was lacking, was made available on the ISSP website and circulated by e-mail to all the ISSP and Indian Association of Palliative Care members. We recommend that psychological interventions, including psychoeducation, are useful and should be considered in patients with cancer pain and psychological distress. Furthermore, physical and complementary treatment can be used as an adjunctive therapy for patients with cancer pain.