Effects of small intestinal nutrient infusion on appetite and pyloric motility are modified by age.
The mechanisms responsible for the reduction in appetite and slowing of gastric emptying in older persons are unknown. The aims of this study were to evaluate the effects of aging on small intestinal regulation of appetite and pyloric motility. Eight healthy older (age 65-75 yr) and seven healthy young (age 20-34 yr) male subjects received isocaloric (2.9 kcal/min) intraduodenal infusions of lipid and glucose for 120 min, each on separate days. During the intraduodenal infusions, perceptions of hunger, desire to eat, and fullness were assessed by visual analog scales. Pyloric motility (isolated pyloric pressure waves and tonic pyloric pressure) was measured by manometry during the intraduodenal lipid infusion. On each day, after completion of the intraduodenal nutrient infusion the subject was offered a buffet meal and food intake was quantified. Before intraduodenal nutrient infusions, sensations of hunger (P < 0.01) and desire to eat (P < 0.05) were less in the older compared with the young subjects. In the young, intraduodenal lipid suppressed hunger to a greater extent than intraduodenal glucose (P < 0.05). In older persons, neither intraduodenal nutrient infusion suppressed hunger. Intraduodenal lipid and glucose increased fullness in both age groups (P < 0.05 for both), with no significant difference between the two nutrients. There was no significant difference in food intake from the buffet meal between the elderly and young subjects. Intraduodenal lipid infusion stimulated phasic pyloric pressure waves in both age groups (P < 0.01 for both), and this response was greater (P < 0.05) in older persons. There was an increase (P < 0.01) in tonic pyloric pressure during intraduodenal lipid infusion that was not significantly different between the two age groups. We conclude that the effect of small intestinal lipid infusion on hunger is attenuated, and the stimulation of phasic pyloric pressure waves increased in healthy older persons compared with healthy young males. Increased feedback from small intestinal nutrients does not appear to be responsible for the physiological anorexia of aging.


Ex vivo computed tomography evaluation of loading position on morphometry of the caudal cervical intervertebral disk spaces of dogs.
OBJECTIVE To provide an objective, quantitative morphometric description of the caudal cervical intervertebral disk (IVD) spaces of dogs. SAMPLE Vertebral specimens consisting of C4 through C7 from 5 medium-sized dogs. PROCEDURES CT images were obtained with the specimens positioned in neutral, flexion, extension, and lateral bending positions. Size and shape of the cranial and caudal end plates, angle between the end plates (IVD wedge angle), and craniocaudal distance (IVD width) between end plates for the 4 loading positions were measured and compared for the 3 segments (C4-5, C5-6, and C6-7). RESULTS End plate size and shape, IVD wedge angle, and IVD width were not significantly different among the 3 segments. Caudal cervical end plates were consistently larger than cranial cervical end plates. The IVD wedge angle ranged from -4.8° to 15.2°. Flexion induced a reduction in IVD width in the ventral portion of the IVD, whereas extension induced a decrease in width in the dorsal portion of the IVD. Central IVD width remained unchanged among the loading positions. CONCLUSIONS AND CLINICAL RELEVANCE Unique morphometric and dynamic characteristics of the caudal cervical IVD space of dogs were detected. These findings may help investigators when designing IVD prostheses for dogs with cervical spondylomyelopathy.


High-resolution, real-time 3D absolute coordinate measurement based on a phase-shifting method.
We describe a high-resolution, real-time 3D absolute coordinate measurement system based on a phase-shifting method. It acquires 3D shape at 30 frames per second (fps), with 266K points per frame. A tiny marker is encoded in the projected fringe pattern, and detected by software from the texture image and the gamma map. Absolute 3D coordinates are obtained from the detected marker position and the calibrated system parameters. To demonstrate the performance of the system, we measure a hand moving over a depth distance of approximately 700 mm, and human faces with expressions. Applications of such a system include manufacturing, inspection, entertainment, security, medical imaging.


Cervical spinal cord injury associated with near-drowning does not increase pneumonia risk or mortality.
Body surfing accidents (BSA) can cause cervical spinal cord injuries (CSCIs) that are associated with near-drowning (ND). The submersion injury from a ND can result in aspiration and predispose to pulmonary complications. We predicted a worse outcome (particularly the development of pneumonia) in patients with CSCIs associated with ND. A retrospective review was performed of patients who were treated at Eastern Virginia Medical School for a CSCI resulting from a blunt mechanism. Data collected included basic demographic data, data regarding injury and in-hospital outcomes, and discharge data, including discharge disposition. Statistics were performed using χ(2) and Student t test. In 2003 to 2008, 141 patients were treated for CSCIs with inclusion criteria. Thirty patients (21%) had an associated ND (BSA) and 111 patients (79%) did not (BLT). The cohorts were similar in mean age (BSA, 45 years; BLT, 50 years; P = 0.16) and male gender distribution (BSA, 93%; BLT, 79%; P = 0.13). The cohorts were similar in injury severity using Injury Severity Score (BSA, 22; BLT, 24; P = 0.65). The cohorts were similar in rates of developing pneumonia (BSA, 3%; BLT, 12%; P = 0.31). The rate of infection was significantly higher in the cohort without an associated near-drowning (BSA, 10%; BLT, 32%; P = 0.033). The mean intensive care unit stay (BSA, 3.5 days; BLT, 11.3 days; P = 0.057) and the rate of mortality were similar (BSA, 10%; BLT, 10% P = 0.99). Those patients with an associated ND had a shorter hospital stay (BSA, 5.7 days; BLT, 22.2 days; P = 0.007) and a better chance of being discharged home (BSA, 57%; BLT, 27%; P = 0.004). CSCIs after a BSA do better than their counterparts without an associated ND. CSCIs associated with ND appear to be isolated injuries with minimal pulmonary involvement despite submersion injuries.


102 W monolithic single frequency Tm-doped fiber MOPA.
We demonstrate a high power all-fiber single frequency Tm-doped fiber amplifier. The maximum output power reached 102 W and the central wavelength was 1.97 μm. The single frequency laser signal from a seed laser was amplified based on a monolithic master oscillator power amplifier (MOPA) configuration. The slope efficiency was about 50% against the absorbed pump power. Neither parasitic lasing nor nonlinear effect was observed in the monolithic fiber amplifier. The SBS threshold of the single frequency Tm-doped fiber amplifier was analyzed and estimated. The output power is not limited by the SBS threshold and could be further improved by increasing the pump power. To the best of our knowledge, this is the first demonstration of average power exceeding 100 W from monolithic all-fiber laser near 2 μm wavelength.


The reliability and validity of the Japanese version of the Levels of Emotional Awareness Scale (LEAS-J).
The Levels of Emotional Awareness Scale (LEAS) was developed to assess five levels of emotional awareness: bodily sensations, action tendencies, single emotions, blends of emotion, and combinations of blends. It is a paper and pencil performance questionnaire that presents 20 emotion-evoking scenes. We developed a Japanese version of the LEAS (LEAS-J), and its reliability and validity were examined. The LEAS-J level was independently assessed by two researchers who scored each response according to the LEAS scoring manual. High inter-rater reliability and internal consistency were obtained for the LEAS-J. Measures were socioeconomic status, LEAS-J, Toronto Alexithymia Scale-20 (TAS-20), Interpersonal Reactivity Index (IRI), and NEO Five-Factor Inventory (NEO-FFI). TAS-20, IRI and NEO-FFI were the measures used to explore the construct validity of LEAS-J, as it was predicted that higher scores on the LEAS-J would be related to fewer alexithymic features, greater empathetic ability, and a greater sense of cooperation with others. Questionnaires were completed by 344 university students. The criterion-referenced validity was determined: a significant negative relationship was found with the externally-oriented thinking scores of TAS-20, and positive relationships were found with fantasy, perspective taking, and empathic concern on IRI and with extraversion, openness to experience, and agreeableness on NEO-FFI. Consistent with our expectations, the findings provide evidence that the LEAS-J has good reliability and validity. In addition, women had significantly higher scores than men on LEAS-J, showing that the gender difference identified in the original LEAS was cross-culturally consistent.


The growth and reproductive endocrinology of adult triploid Pacific salmonids.
This paper describes the effect of triploidy on growth and reproductive endocrinology in the months leading up to and including spawning in rainbow trout,Salmo gairdneri, and pink salmon,Oncorhynchus gorbuscha. Growth rates were the same for diploid and triploid rainbow trout, but triploid female pink salmon were smaller than maturing diploid females and diploid and triploid males of the same age. Triploid males of both species developed typical secondary sexual characteristics and had normal endocrine profiles, although their cycle appeared to be delayed by about one month. Triploid females remained silvery in appearance and showed no endocrine signs of maturation, even at the level of the pituitary. Thus, although triploids of both sexes are genetically sterile, only the females do not undergo physiological maturation.


Enteropathogenicity of Vibrio parahaemolyticus in the ligated rabbit ileum.
The enteropathogenicity of Vibrio parahaemolyticus was investigated by contrasting the effects of whole cells, cell fragments, cell-free preparations, and media constituents injected into rabbit ileal loops. Three of 20 cultures utilized were Kanagawa-negative strains from seawater and sea fish. The remaining 17 cultures included both Kanagawa-positive and -negative strains from Japanese victims of gastroenteritis. Broth culture filtrates concentrated 10-fold by dialysis against 30% Carbowax were unreactive, whereas lyophilized filtrates, regardless of Kanagawa type, as well as all sterile broth preparations containing greater than or equal to 5% NaCl gave positive reactions in the rabbit gut. In contrast, crude lysates derived from broth cultures of Kanagawa-positive strains caused loop dilatation; lysate supernatants were unreactive. Lysates of cells washed from brain heart infusion agar were more reactive than lysates from Trypticase soy agar-grown cells. When agar-grown cell lysates prepared by disruption in saline were dialyzed against distilled water, they were devoid of gut reactivity. Reactivity was restored in dialysands resuspended in saline and in dialysates concentrated 10-fold. The agar-grown cell lysates exhibited Kanagawa-type hemolysis. Our data support the conclusion that the rabbit loop reactivity observed with lyophilized, cell-free culture filtrates may result from excessively elevated NaCl concentrations, and that a toxic factor associated with large-cell particles may be dialyzable, depends on saline for expression, and resembles the Kanagawa hemolysin.


Standard precautions and infection control, medical students' knowledge and behavior at a Saudi university: the need for change.
No previous studies have reported the knowledge of Saudi medical students about Standard Precautions (SPs) and infection control. The objectives of this study were to assess medical students' knowledge in clinical years at King Faisal University, Saudi Arabia about SPs' and to explore their attitudes toward the current curricular/training in providing them with effective knowledge and necessary skills with regard to SPs. This cross sectional study targeted students in clinical stage at College of Medicine, King Faisal University, Saudi Arabia. A pre-tested anonymous self administered data collection form was used. Inquires about students' characteristics, general concepts of infection control/SPs, hand hygiene, personal protective equipment, sharp injuries and disposal, and care of health providers were included. The main source of information for each domain was also inquired. The second part dedicated to explore the attitudes toward the curricular and teaching relevant to SPs. A total of 251 students were included. Knowledge scores in all domains were considerably low, 67 (26.7%) students scored ? 24 (out of 41points) which was considered as an acceptable level of knowledge, 22.2% in 4th year, 20.5% in 5th year and 36.8% in 6th year. Sharp injuries, personal protective equipment and health care of the providers showed the least knowledge scores. The main sources of knowledge were self learning, and informal bed side practices The majority of students' believed that the current teaching and training are insufficient in providing them with the necessary knowledge and skills regarding SPs. The overall knowledge scores for SPs were low especially in the domains of hand hygiene, sharp management, and personal protective equipment reflecting insufficient and ineffective instructions received by medical students through the current curriculum posing them vulnerable to health facilities related infections. Proper curricular reform and training are required to protect students and their patients.


Annotation of the Giardia proteome through structure-based homology and machine learning.
Large-scale computational prediction of protein structures represents a cost-effective alternative to empirical structure determination with particular promise for non-model organisms and neglected pathogens. Conventional sequence-based tools are insufficient to annotate the genomes of such divergent biological systems. Conversely, protein structure tolerates substantial variation in primary amino acid sequence and is thus a robust indicator of biochemical function. Structural proteomics is poised to become a standard part of pathogen genomics research; however, informatic methods are now required to assign confidence in large volumes of predicted structures. Our aim was to predict the proteome of a neglected human pathogen, Giardia duodenalis, and stratify predicted structures into high- and lower-confidence categories using a variety of metrics in isolation and combination. We used the I-TASSER suite to predict structural models for ∼5,000 proteins encoded in G. duodenalis and identify their closest empirically-determined structural homologues in the Protein Data Bank. Models were assigned to high- or lower-confidence categories depending on the presence of matching protein family (Pfam) domains in query and reference peptides. Metrics output from the suite and derived metrics were assessed for their ability to predict the high-confidence category individually, and in combination through development of a random forest classifier. We identified 1,095 high-confidence models including 212 hypothetical proteins. Amino acid identity between query and reference peptides was the greatest individual predictor of high-confidence status; however, the random forest classifier outperformed any metric in isolation (area under the receiver operating characteristic curve = 0.976) and identified a subset of 305 high-confidence-like models, corresponding to false-positive predictions. High-confidence models exhibited greater transcriptional abundance, and the classifier generalized across species, indicating the broad utility of this approach for automatically stratifying predicted structures. Additional structure-based clustering was used to cross-check confidence predictions in an expanded family of Nek kinases. Several high-confidence-like proteins yielded substantial new insight into mechanisms of redox balance in G. duodenalis-a system central to the efficacy of limited anti-giardial drugs. Structural proteomics combined with machine learning can aid genome annotation for genetically divergent organisms, including human pathogens, and stratify predicted structures to promote efficient allocation of limited resources for experimental investigation.


Global trade in ornamental fish from an Australian perspective: the case for revised import risk analysis and management strategies.
Over 1 billion ornamental fish comprising more than 4000 freshwater and 1400 marine species are traded internationally each year, with 8-10 million imported into Australia alone. Compared to other commodities, the pathogens and disease translocation risks associated with this pattern of trade have been poorly documented. The aim of this study was to conduct an appraisal of the effectiveness of risk analysis and quarantine controls as they are applied according to the Sanitary and Phytosanitary (SPS) agreement in Australia. Ornamental fish originate from about 100 countries and hazards are mostly unknown; since 2000 there have been 16-fold fewer scientific publications on ornamental fish disease compared to farmed fish disease, and 470 fewer compared to disease in terrestrial species (cattle). The import quarantine policies of a range of countries were reviewed and classified as stringent or non-stringent based on the levels of pre-border and border controls. Australia has a stringent policy which includes pre-border health certification and a mandatory quarantine period at border of 1-3 weeks in registered quarantine premises supervised by government quarantine staff. Despite these measures there have been many disease incursions as well as establishment of significant exotic viral, bacterial, fungal, protozoal and metazoan pathogens from ornamental fish in farmed native Australian fish and free-living introduced species. Recent examples include Megalocytivirus and Aeromonas salmonicida atypical strain. In 2006, there were 22 species of alien ornamental fish with established breeding populations in waterways in Australia and freshwater plants and molluscs have also been introduced, proving a direct transmission pathway for establishment of pathogens in native fish species. Australia's stringent quarantine policies for imported ornamental fish are based on import risk analysis under the SPS agreement but have not provided an acceptable level of protection (ALOP) consistent with government objectives to prevent introduction of pests and diseases, promote development of future aquaculture industries or maintain biodiversity. It is concluded that the risk analysis process described by the Office International des Epizooties under the SPS agreement cannot be used in a meaningful way for current patterns of ornamental fish trade. Transboundary disease incursions will continue and exotic pathogens will become established in new regions as a result of the ornamental fish trade, and this will be an international phenomenon. Ornamental fish represent a special case in live animal trade where OIE guidelines for risk analysis need to be revised. Alternatively, for countries such as Australia with implied very high ALOP, the number of species traded and the number of sources permitted need to be dramatically reduced to facilitate hazard identification, risk assessment and import quarantine controls.


Role of Coronary Artery Calcium Score of Zero and Other Negative Risk Markers for Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis (MESA).
Limited attention has been paid to negative cardiovascular disease (CVD) risk markers despite their potential to improve medical decision making. We compared 13 negative risk markers using diagnostic likelihood ratios (DLRs), which model the change in risk for an individual after the result of an additional test. We examined 6814 participants from the Multi-Ethnic Study of Atherosclerosis. Coronary artery calcium score of 0, carotid intima-media thickness <25th percentile, absence of carotid plaque, brachial flow-mediated dilation >5% change, ankle-brachial index >0.9 and <1.3, high-sensitivity C-reactive protein <2 mg/L, homocysteine <10 µmol/L, N-terminal pro-brain natriuretic peptide <100 pg/mL, no microalbuminuria, no family history of coronary heart disease (any/premature), absence of metabolic syndrome, and healthy lifestyle were compared for all and hard coronary heart disease and all CVD events over the 10-year follow-up. Models were adjusted for traditional CVD risk factors. Among all negative risk markers, coronary artery calcium score of 0 was the strongest, with an adjusted mean DLR of 0.41 (SD, 0.12) for all coronary heart disease and 0.54 (SD, 0.12) for CVD, followed by carotid intima-media thickness <25th percentile (DLR, 0.65 [SD, 0.04] and 0.75 [SD, 0.04], respectively). High-sensitivity C-reactive protein <2 mg/L and normal ankle-brachial index had DLRs >0.80. Among clinical features, absence of any family history of coronary heart disease was the strongest (DLRs, 0.76 [SD, 0.07] and 0.81 [SD, 0.06], respectively). Net reclassification improvement analyses yielded similar findings, with coronary artery calcium score of 0 resulting in the largest, most accurate downward risk reclassification. Negative results of atherosclerosis-imaging tests, particularly coronary artery calcium score of 0, resulted in the greatest downward shift in estimated CVD risk. These results may help guide discussions on the identification of individuals less likely to receive net benefit from lifelong preventive pharmacotherapy.


NaHCO3- and NaCl-Type Hot Springs Enhance the Secretion of Inflammatory Cytokine Induced by Polyinosinic-Polycytidylic Acid in HaCaT Cells.
Background: Hot springs have been traditionally used as an alternative treatment for a wide range of diseases, including rheumatoid arthritis, bronchial asthma, diabetes, hypertension, psoriasis and atopic dermatitis. However, the clinical effects and therapeutic mechanisms associated with hot springs remain poorly defined. The purpose of this study was to demonstrate the different effects of hot springs on cellular viability and secretion of inflammatory cytokines on keratinocyte in two geographically representative types of hot springs: NaHCO3-type and NaCl-type, which are the most common types in South Korea. We performed WST-1, BrdU measurements, human inflammatory cytokine arrays and enzyme-linked immunosorbent assay in HaCaT cells stimulated with toll-like receptor 3 by polyinosinicpolycytidylic acid. The interaction effects of cell viability and cell proliferation were not significantly different regardless of polyinosinic-polycytidylic acid stimulation and cultured hot springs type. Cytokine array and enzymelinked immunosorbent assay analysis showed increased expression of inflammatory cytokines such as interleukin6 and granulocyte-macrophage colony-stimulating factor by polyinosinic-polycytidylic acid stimulation, with expression levels differing according to hot springs hydrochemical composition. Cytokine reduction was not significant. The effects and mechanisms of hot springs treatment in keratinocytes were partially elucidated.


Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses.
More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18-55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n = 20) or half-dose (SD/LD D56; n = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials.


Baculovirus-driven protein expression in insect cells: A benchmarking study.
Baculovirus-insect cell expression system has become one of the most widely used eukaryotic expression systems for heterologous protein production in many laboratories. The availability of robust insect cell lines, serum-free media, a range of vectors and commercially-packaged kits have supported the demand for maximizing the exploitation of the baculovirus-insect cell expression system. Naturally, this resulted in varied strategies adopted by different laboratories to optimize protein production. Most laboratories have preference in using either the E. coli transposition-based recombination bacmid technology (e.g. Bac-to-Bac®) or homologous recombination transfection within insect cells (e.g. flashBAC™). Limited data is presented in the literature to benchmark the protocols used for these baculovirus vectors to facilitate the selection of a system for optimal production of target proteins. Taking advantage of the Protein Production and Purification Partnership in Europe (P4EU) scientific network, a benchmarking initiative was designed to compare the diverse protocols established in thirteen individual laboratories. This benchmarking initiative compared the expression of four selected intracellular proteins (mouse Dicer-2, 204 kDa; human ABL1 wildtype, 126 kDa; human FMRP, 68 kDa; viral vNS1-H1, 76 kDa). Here, we present the expression and purification results on these proteins and highlight the significant differences in expression yields obtained using different commercially-packaged baculovirus vectors. The highest expression level for difficult-to-express intracellular protein candidates were observed with the EmBacY baculovirus vector system.


Referenceless segmentation of flaws in woven fabrics.
The automatic segmentation of flaws in woven fabrics is achieved by applying Fourier analysis to the image of the sample under inspection, without considering any reference image. No prior information about the fabric structure or the defect is required. The algorithm is based on the structural feature extraction of the weave repeat from the Fourier transform of the sample image. These features are used to define a set of multiresolution bandpass filters, adapted to the fabric structure, that operate in the Fourier domain. Inverse Fourier transformation, binarization, and merging of the information obtained at different scales lead to the output image that contains flaws segmented from the fabric background. The whole process is fully automatic and can be implemented either optically or electronically. Experimental results are presented and discussed for a variety of fabrics and defects.


Sucrose transport through maltoporin mutants of Escherichia coli.
Maltoporin (LamB) and sucrose porin (ScrY) reside in the bacterial outer membrane and facilitate the passive diffusion of maltodextrins and sucrose, respectively. To gain further insight into the determinants of solute specificity, LamB mutants were designed to allow translocation of sucrose, which hardly translocates through wild-type LamB. Three LamB mutants were studied. (a) Based on sequence and structure alignment of LamB with ScrY, two LamB triple mutants were generated (R109D, Y118D,D121F; R109N,Y118D,D121F) to mimic the ScrY constriction. The crystal structure of the first of these mutants was determined to be 3.2 A and showed an increased ScrY-like cross-section except for D109 that protrudes into the channel. (b) Based on this crystal structure a double mutant was generated by truncation of the two residues that obstruct the channel most in LamB (R109A,Y118A). Analysis of liposome swelling and in vivo sugar uptake demonstrated substantial sucrose permeation through all mutants with the double alanine mutant performing best. The triple mutants did not show a well-defined binding site as indicated by sugar-induced ion current noise analysis, which can be explained by remaining steric interference as deduced from the crystal structure. Binding, however, was observed for the double mutant that had the obstructing residues truncated to alanines.


Effect of antipyrine on the gastric emptying of liquid in rats.
Antipyrine (At) and dipyrone (Dp) delay gastric emptying (GE) in rats. The objective of the present study was to assess the effects of intravenous (iv) and intracerebroventricular (icv) administration of At and Dp on the GE of liquid by rats. GE was assessed in male Wistar rats (5-10 in each group) 10 min after the icv or iv drug injection by measuring percent gastric retention (%GR) of a saline test meal labeled with phenol red 10 min after administration by gavage. The At iv group was significantly higher (64.4 +/- 2.6%) compared to control (33.4 +/- 1.5%) but did not differ from the Dp group (54.3 +/- 3.8%). After icv administration of At, %GR (34.2 +/- 2%) did not differ from control (32.6 +/- 1.9%), but was significantly higher after Dp (54.5 +/- 2.3%). Subdiaphragmatic vagotomy significantly reduced %GR in the At group (30.2 +/- 0.7%) compared to the sham group, but was significantly higher than in the controls (23.0 +/- 0.5%). In the animals treated with At iv, baclofen significantly reduced %GR (28.3 +/- 2.4%) compared to vehicle-treated animals (55.2 +/- 3.2%). The same occurred in the animals treated iv with vehicle and icv with baclofen. Although vagotomy and baclofen reduced %GR per se, the reduction was twice more marked in the animals treated with At. The results suggest that At administered iv, but not icv, delays GE of liquid in rats with the participation, at least in part, of the vagus nerve and that this phenomenon is blocked by the activation of GABA B receptors in the central nervous system.


Nicotinamide does not protect islet B-cell metabolism against alloxan toxicity.
Nicotinamide, a poly(ADP-ribose)synthetase inhibitor, protected NMRI mice against alloxan-induced hyperglycemia when given 10 min before, but not 10 min after, the injection of the drug. Pretreatment in vivo with nicotinamide induced hyperglycemia at the time of alloxan injection, and this could account for the protective action of nicotinamide against alloxan diabetes. Exposure of islets to alloxan (2 mM) in vitro caused a marked inhibition of both glucose-stimulated proinsulin biosynthesis and insulin release, and this was not affected by the action of nicotinamide. Alloxan-impaired islet glucose oxidation was partly restored by nicotinamide. The decreased islet content of NADH plus NAD, which was observed after alloxan treatment, could be prevented by nicotinamide. Glucose-stimulated islet oxygen uptake was abolished after treatment with alloxan, and nicotinamide had no protective effect in this process. Leucine (10 mM) plus glutamine (10 mM), however, were still able to evoke an islet respiratory response after alloxan exposure. Alloxan caused an immediate increase in the islet efflux of radiolabeled nucleotides, which was followed after about 5 min by a further increase. This latter increase of the radio efflux was inhibited by the addition of nicotinamide. The inability of nicotinamide to prevent the alloxan-induced impairment of proinsulin biosynthesis, insulin release, and oxygen uptake, together with the failure of nicotinamide to prevent the development of diabetes when given after alloxan, does not support a current hypothesis that the major cytotoxic effect of alloxan is primarily due to DNA damage. The present data suggest that organelles other than the nuclei, e.g., the mitochondria or the plasma membrane, are the primary sites of B-cell injury by alloxan.(ABSTRACT TRUNCATED AT 250 WORDS)


Consistent implementation of decisions in the brain.
Despite the complexity and variability of decision processes, motor responses are generally stereotypical and independent of decision difficulty. How is this consistency achieved? Through an engineering analogy we consider how and why a system should be designed to realise not only flexible decision-making, but also consistent decision implementation. We specifically consider neurobiologically-plausible accumulator models of decision-making, in which decisions are made when a decision threshold is reached. To trade-off between the speed and accuracy of the decision in these models, one can either adjust the thresholds themselves or, equivalently, fix the thresholds and adjust baseline activation. Here we review how this equivalence can be implemented in such models. We then argue that manipulating baseline activation is preferable as it realises consistent decision implementation by ensuring consistency of motor inputs, summarise empirical evidence in support of this hypothesis, and suggest that it could be a general principle of decision making and implementation. Our goal is therefore to review how neurobiologically-plausible models of decision-making can manipulate speed-accuracy trade-offs using different mechanisms, to consider which of these mechanisms has more desirable decision-implementation properties, and then review the relevant neuroscientific data on which mechanism brains actually use.


Intracellular diffusion restrictions in isolated cardiomyocytes from rainbow trout.
Restriction of intracellular diffusion of adenine nucleotides has been studied intensively on adult rat cardiomyocytes. However, their cause and role in vivo is still uncertain. Intracellular membrane structures have been suggested to play a role. We therefore chose to study cardiomyocytes from rainbow trout (Oncorhynchus mykiss), which are thinner and have fewer intracellular membrane structures than adult rat cardiomyocytes. Previous studies suggest that trout permeabilized cardiac fibers also have diffusion restrictions. However, results from fibers may be affected by incomplete separation of the cells. This is avoided when studying permeabilized, isolated cardiomyocytes. The aim of this study was to verify the existence of diffusion restrictions in trout cardiomyocytes by comparing ADP-kinetics of mitochondrial respiration in permeabilized fibers, permeabilized cardiomyocytes and isolated mitochondria from rainbow trout heart. Experiments were performed at 10, 15 and 20 degrees C in the absence and presence of creatine. Trout cardiomyocytes hypercontracted in the solutions used for mammalian cardiomyocytes. We developed a new solution in which they retained their shape and showed stable steady state respiration rates throughout an experiment. The apparent ADP-affinity of permeabilized cardiomyocytes was different from that of fibers. It was higher, independent of temperature and not increased by creatine. However, it was still about ten times lower than in isolated mitochondria. The differences between fibers and cardiomyocytes suggest that results from trout heart fibers were affected by incomplete separation of the cells. However, the lower ADP-affinity of cardiomyocytes compared to isolated mitochondria indicate that intracellular diffusion restrictions are still present in trout cardiomyocytes despite their lower density of intracellular membrane structures. The lack of a creatine effect indicates that trout heart lacks mitochondrial creatine kinase tightly coupled to respiration. This argues against diffusion restriction by the outer mitochondrial membrane. These results from rainbow trout cardiomyocytes resemble those from other low-performance hearts such as neonatal rat and rabbit hearts. Thus, it seems that metabolic regulation is related to cardiac performance, and it is likely that rainbow trout can be used as a model animal for further studies of the localization and role of diffusion restrictions in low-performance hearts.


HPLC method for the quantification of procyanidins in cocoa and chocolate samples and correlation to total antioxidant capacity.
Monomeric and oligomeric procyanidins present in cocoa liquors and chocolates were separated and quantified in four different laboratories using a normal-phase high-performance liquid chromatography (HPLC) method with fluorescence detection. Procyanidin standards through decamers were obtained by extraction from cocoa beans, enrichment by Sephadex LH-20 gel permeation chromatography, and final purification by preparative normal-phase HPLC. The purity of each oligomeric fraction was assessed using HPLC coupled to mass spectrometry. A composite standard was then prepared, and calibration curves were generated for each oligomeric class using a quadratic fit of area sum versus concentration. Results obtained by each of the laboratories were in close agreement, which suggests this method is reliable and reproducible for quantification of procyanidins. Furthermore, the procyanidin content of the samples was correlated to the antioxidant capacity measured using the ORAC assay as an indicator for potential biological activity.


Shoulder rotator strength in patients with stage I-II subacromial impingement: relationship to pain, disability, and quality of life.
The purpose of this study was two-fold: to determine the shoulder rotator strength in patients with stage I and II subacromial impingement syndrome and to explore its relationship with pain, disability, and quality of life. Thirteen patients with at least 2 positive tests (Neer, Hawkins, painful arc) on the dominant side and 25 unaffected control subjects were included. All individuals had an intact rotator cuff bilaterally, as evaluated by sonography. Isokinetic testing of the shoulder internal and external rotators was performed using Biodex System 3 during concentric/concentric shoulder rotations at a velocity of 60 degrees /s in the scapular plane. The Shoulder Pain and Disability Index, Simple Shoulder Test, and Nottingham Health Profile were self-reported by all subjects. Peak torque values of patients were found to be indifferent from those of controls'. External and internal rotation strength were negatively correlated with pain (r = .63, r = .66, P < .05). In spite of shoulder pain and disability, general health in stage I and II impingement patients did not show any deterioration.


Functional and nonfunctional measles virus matrix genes from lethal human brain infections.
Subacute sclerosing panencephalitis (SSPE) is a lethal disease induced by the persistence of measles virus in the human brain. In many SSPE cases, the viral matrix (M) protein cannot be detected; in others, M proteins of the expected size are found and sequence analysis of M cDNAs has confirmed that the reading frames are intact, showing only several missense mutations. To determine whether these alterations result in nonfunctional proteins, we have replaced the M gene of an infectious full-length genomic cDNA (from vaccine strain Edmonston) with different M genes derived from four patients with SSPE. One of the SSPE M genes tested proved to be functionally competent, giving rise to a virus yielding titers similar to those of viruses containing the M gene from control lytic strains. The other three SSPE M genes were not functionally competent in the same test. In all three cases, the inactivating changes resided in the carboxyl-terminal half of the M protein, as shown by the exchange of either of the two genes halves. In summary, mutational M gene alterations, which either prevent synthesis of M protein altogether or only allow synthesis of nonfunctional M protein, have been detected by us and by others in 9 of 10 SSPE cases. The one functional M gene appears to be an exception to the rule, indicating that M gene alteration might not be an absolute requirement for disease development.


Risk of stomach cancer associated with 12 workplace hazards: analysis of death certificates from 24 states of the United States with the aid of job exposure matrices.
To investigate the risk of gastric cancer associated with 12 workplace exposures suspected or discussed as aetiological agents in previous reports. A case-control study was conducted based on the death certificates of several million deaths in 24 states of the United States in 1984-96. Overall, the data base included 41,957 deaths from stomach cancer among subjects aged > or = 25 years. These were 20,878 white men, 14,125 white women, 4215 African American men, and 2739 African American women. Two controls for each case were selected from among subjects who died from non-malignant diseases, frequency matched to cases by geographic region, race, sex and 5 year age group. Each three digit occupation and industry code listed in the 1980 United States census was classified for probability and intensity of exposure to asbestos, inorganic dust, metals, lead, polycyclic aromatic hydrocarbons (PAHs), nitrogen oxides, nitrosamines, sulphuric acid, fertilisers, herbicides, other pesticides (including insecticides and fungicides), and wood dust. These job exposure matrices were subsequently applied to the occupation-industry combinations in the death certificates of study subjects, separately by sex and race. Risk of stomach cancer showed a modest association with occupational exposure to inorganic dust (odds ratio (OR) = 1.06; 95% confidence interval (95% CI) 1.03 to 1.11) with significant increasing trends by probability and intensity of exposure overall and by cross classification of the two exposure matrices. Workplace exposure to nitrosamines also showed a modest association (OR = 1.06; 95% CI 1.01 to 1.11), but the excess risk was even smaller after adjusting for inorganic dust exposure. Risk of gastric cancer was not associated with any of the other workplace exposures considered in this study. Non-differential misclassification of exposure may have caused negative findings in this study, and inorganic dust may be a partial surrogate for exposure to other unknown risk factors. Alternatively, our results suggest that occupational factors contribute little to the aetiology of gastric cancer. Inorganic dust might act through non-specific mechanisms, similar to those proposed for salt, aspirin, and heat by other authors.


Malignant adenomyoepithelioma combined with adenoid cystic carcinoma of the breast: a case report and literature review.
Malignant adenomyoepithelioma and adenoid cystic carcinoma are both rare malignant epithelial-myoepithelial tumors of the breast. We report a very rare case with a malignant adenomyoepithelioma combining with adenoid cystic carcinoma in a single mass. A 61-year-old female presented with a palpable painless mass in the right breast. Mammography revealed a large irregular dense shadow without obvious internal calcification. A simple lumpectomy was performed, and a 1.6cm well-circumscribed pale-tan nodule was presented. Histologically, the nodule was composed of two obscure lobules. One exhibited typical histological image of adenoid cystic carcinoma, the other one showed the image of epithelial-myoepithelial carcinoma of salivary gland, and support the diagnosis of biphasic malignant adenomyoepithelioma. Transition between the two lobules was gradual. Immunohistochemically, CK18 and P63 highlighted the epithelial and myoepithelial cells respectively in both lesions. CD117 was positive in the epithelial cells of adenoid cystic carcinoma, but was totally negative in malignant adenomyoepithelioma. This report is, to our knowledge, the first case that combines these two tumors in a single mass. In addition, we present a review of the literature. The histogenesis of these tumors is also discussed. The virtual slide(s) for this article can be found here: http://med.motic.com/MoticGallery/Slide?id=D562817E-23C2-4F72-9823-86EF6DA40005&user=2C69F0D6-A478-4A2B-ABF0-BB36763E8025 and http://med.motic.com/MoticGallery/Slide?id=38BB7126-6FFB-4B66-A208-B8C0F528DCA8&user=2C69F0D6-A478-4A2B-ABF0-BB36763E8025.


Transition from school to work for students with autism spectrum disorders: understanding the process and achieving better outcomes.
Individuals and their parents frequently turn to pediatricians, adolescent medicine specialists, and psychologists to answer questions about the course and outcomes of their disorder. This article provides a description of the characteristics of autism spectrum disorders (ASD) in adolescence and early adulthood. It also describes essential elements of high school programs designed to increase positive outcomes for youth with ASD and provides detailed information about various employment support models. Finally, the implications of transition programming for medical specialists and psychologists are discussed.


Supporting the emotional needs of young people in care: a qualitative study of foster carer perspectives.
Young people who have been removed from their family home and placed in care have often experienced maltreatment and there is well-developed evidence of poor psychological outcomes. Once in care, foster carers often become the adult who provides day-to-day support, yet we know little about how they provide this support or the challenges to and facilitators of promoting better quality carer-child relationships. The aim of this study was to understand how carers support the emotional needs of the young people in their care and their views on barriers and opportunities for support. Participants were 21 UK foster carers, recruited from a local authority in England. They were predominantly female (86%), aged 42-65 years old and ranged from those who were relatively new to the profession (<12 months' experience) to those with over 30 years of experience as a carer. We ran three qualitative focus groups to gather in-depth information about their views on supporting their foster children's emotional well-being. Participants also completed short questionnaires about their training experiences and sense of competence. Only half of the sample strongly endorsed feeling competent in managing the emotional needs of their foster children. While all had completed extensive training, especially on attachment, diagnosis-specific training for mental health problems (eg, trauma-related distress, depression) was less common. Thematic analysis showed consistent themes around the significant barriers carers faced navigating social care and mental health systems, and mixed views around the best way to support young people, particularly those with complex mental health needs and in relation to reminders of their early experiences. Findings have important implications for practice and policy around carer training and support, as well as for how services support the mental health needs of young people in care.


Molecular cloning of lymphadenopathy-associated virus.
Lymphadenopathy-associated virus (LAV) is a human retrovirus first isolated from a homosexual patient with lymphadenopathy syndrome, frequently a prodrome or a benign form of acquired immune deficiency syndrome (AIDS). Other LAV isolates have subsequently been recovered from patients with AIDS or pre-AIDS and all available data are consistent with the virus being the causative agent of AIDS. The virus is propagated on activated T lymphocytes and has a tropism for the T-cell subset OKT4 (ref. 6), in which it induces a cytopathic effect. The major core protein of LAV is antigenically unrelated to other known retroviral antigens. LAV-like viruses have more recently been independently isolated from patients with AIDS and pre-AIDS. These viruses, called human T-cell leukaemia/lymphoma virus type III (HTLV-III) and AIDS-associated retrovirus (ARV), seem to have many characteristics in common with LAV and probably represent independent isolates of the LAV prototype. We have sought to characterize LAV by the molecular cloning of its genome. A cloned LAV complementary DNA was used to screen a library of recombinant phages constructed from the genomic DNA of LAV-infected T lymphocytes. Two families of clones were characterized which differ in a restriction site. The viral genome is longer than any other human retroviral genome (9.1-9.2 kilobases).


Study of the kinetics and mechanism of rapid self-assembly in block copolymer thin films during solvo-microwave annealing.
Microwave annealing is an emerging technique for achieving ordered patterns of block copolymer films on substrates. Little is understood about the mechanisms of microphase separation during the microwave annealing process and how it promotes the microphase separation of the blocks. Here, we use controlled power microwave irradiation in the presence of tetrahydrofuran (THF) solvent, to achieve lateral microphase separation in high-χ lamellar-forming poly(styrene-b-lactic acid) PS-b-PLA. A highly ordered line pattern was formed within seconds on silicon, germanium and silicon on insulator (SOI) substrates. In-situ temperature measurement of the silicon substrate coupled to condition changes during "solvo-microwave" annealing allowed understanding of the processes to be attained. Our results suggest that the substrate has little effect on the ordering process and is essentially microwave transparent but rather, it is direct heating of the polar THF molecules that causes microphase separation. It is postulated that the rapid interaction of THF with microwaves and the resultant temperature increase to 55 °C within seconds causes an increase of the vapor pressure of the solvent from 19.8 to 70 kPa. This enriched vapor environment increases the plasticity of both PS and PLA chains and leads to the fast self-assembly kinetics. Comparing the patterns formed on silicon, germanium and silicon on insulator (SOI) and also an in situ temperature measurement of silicon in the oven confirms the significance of the solvent over the role of substrate heating during "solvo-microwave" annealing. Besides the short annealing time which has technological importance, the coherence length is on a micron scale and dewetting is not observed after annealing. The etched pattern (PLA was removed by an Ar/O2 reactive ion etch) was transferred to the underlying silicon substrate fabricating sub-20 nm silicon nanowires over large areas demonstrating that the morphology is consistent both across and through the film.


A phase 1B dose escalation trial of Scutellaria barbata (BZL101) for patients with metastatic breast cancer.
The purpose of this study was to determine the safety and maximum tolerated dose (MTD) of BZL101 (FDA IND# 59,521), an orally delivered aqueous extract from the herb Scutellaria barbata, in women with metastatic breast cancer (MBC). The trial was an open-label, phase 1B, multicenter, dose escalation study. Eligible patients had histologically confirmed breast cancer and measurable stage IV disease. The standard phase 1 "3 + 3" study design was used to determine the MTD. Primary endpoints were toxicity and MTD of BZL101. Secondary outcomes included efficacy based on RECIST criteria. A total of 27 women with a median of 2 prior chemotherapy treatments for metastatic disease were treated in four different dose cohorts. Grade 3 and 4 adverse events (AEs) were uncommon. Dose-limiting toxicities included the following: grade 4 AST elevation, grade 3 diarrhea, grade 3 fatigue, and grade 3 rib pain. Fourteen patients were evaluable according to Response Evaluation Criteria in Solid Tumors. Investigator assessment classified three patients with stable disease for >120 days (21%). One patient was on BZL101 for 449 days and remains stable for 700 + days. Independent radiology review identified three patients with objective tumor regression (>0% and <30%). The MTD was not reached, thus per protocol, the MTD was defined as the maximum administered dose of BZL101 40 g/day. In conclusion, oral administration of BZL101 was safe, well tolerated, and showed promising clinical evidence of anticancer activity in this heavily pretreated population of women with MBC.


Vitamin D levels appear to be normal in Danish patients attending secondary care for low back pain and a weak positive correlation between serum level Vitamin D and Modic changes was demonstrated: a cross-sectional cohort study of consecutive patients with non-specific low back pain.
Hypovitaminosis D has previously been reported in both the general population, in people with chronic musculoskeletal pain, and in people with low back pain (LBP). Myopathy-related symptoms such as diffuse bone and muscle pain, weakness and paresthesia in the legs, have also been observed in people with non-specific LBP and associations with low levels of Vitamin D have been suggested. The objectives of this study were to investigate (1) Vitamin D levels in patients seeking care for LBP in a Danish out-patient secondary care setting, and (2) their possible relationship with myopathy-related symptoms, Body Mass Index (BMI), and Modic changes. A total of 152 consecutive patients with non-specific LBP participated in a cross-sectional study. Participants were recruited at The Spine Centre of Southern Denmark during springtime 2011. Individual serum levels of 25-Hydroxyvitamin-D were determined using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). Information about symptoms, height, and weight were collected from electronic questionnaires completed by the participants. All patients had an MRI from which Modic changes were identified. Correlations between Vitamin D level and pain, paresthesia, weakness in the legs, BMI or Modic changes were described using correlation coefficients and odds ratios obtained from logistic regression. Two-thirds of the included patients with LBP had normal Vitamin D levels of >50 nmol/L. No correlations were seen between Vitamin D deficiency and gender, age, back pain intensity, leg pain intensity, and duration of pain. Statistically significant, but low, correlation coefficients were found between Vitamin D levels and BMI as well as Modic changes. Low Vitamin D levels and Modic changes were statistically significantly associated with an odds ratio of 0.30 (95% CI 0.12; 0.75) while weakness, paresthesia and widespread pain were not. In patients seeking care for low back pain in a Danish outpatient clinic, Vitamin D deficiency was not common. Whether patients who are overweight or who have Modic changes might represent subgroups of people for whom their LBP may be associated with Vitamin D levels, needs further investigation.


Unveiling distribution patterns of freshwater phytoplankton by a next generation sequencing based approach.
The recognition and discrimination of phytoplankton species is one of the foundations of freshwater biodiversity research and environmental monitoring. This step is frequently a bottleneck in the analytical chain from sampling to data analysis and subsequent environmental status evaluation. Here we present phytoplankton diversity data from 49 lakes including three seasonal surveys assessed by next generation sequencing (NGS) of 16S ribosomal RNA chloroplast and cyanobacterial gene amplicons and also compare part of these datasets with identification based on morphology. Direct comparison of NGS to microscopic data from three time-series showed that NGS was able to capture the seasonality in phytoplankton succession as observed by microscopy. Still, the PCR-based approach was only semi-quantitative, and detailed NGS and microscopy taxa lists had only low taxonomic correspondence. This is probably due to, both, methodological constraints and current discrepancies in taxonomic frameworks. Discrepancies included Euglenophyta and Heterokonta that were scarce in the NGS but frequently detected by microscopy and Cyanobacteria that were in general more abundant and classified with high resolution by NGS. A deep-branching taxonomically unclassified cluster was frequently detected by NGS but could not be linked to any group identified by microscopy. NGS derived phytoplankton composition differed significantly among lakes with different trophic status, showing that our approach can resolve phytoplankton communities at a level relevant for ecosystem management. The high reproducibility and potential for standardization and parallelization makes our NGS approach an excellent candidate for simultaneous monitoring of prokaryotic and eukaryotic phytoplankton in inland waters.


Advanced imaging for detection and differentiation of colorectal neoplasia: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.
1 ESGE suggests the routine use of high definition white-light endoscopy systems for detecting colorectal neoplasia in average risk populations (weak recommendation, moderate quality evidence). 2 ESGE recommends the routine use of high definition systems and pancolonic conventional or virtual (narrow band imaging [NBI], i-SCAN) chromoendoscopy in patients with known or suspected Lynch syndrome (strong recommendation, low quality evidence). 2b ESGE recommends the routine use of high definition systems and pancolonic conventional or virtual (NBI) chromoendoscopy in patients with known or suspected serrated polyposis syndrome (strong recommendation, low quality evidence). 3 ESGE recommends the routine use of 0.1 % methylene blue or 0.1 % - 0.5 % indigo carmine pancolonic chromoendoscopy with targeted biopsies for neoplasia surveillance in patients with long-standing colitis. In appropriately trained hands, in the situation of quiescent disease activity and adequate bowel preparation, nontargeted, four-quadrant biopsies can be abandoned (strong recommendation, high quality evidence). 4 ESGE suggests that virtual chromoendoscopy (NBI, FICE, i-SCAN) and conventional chromoendoscopy can be used, under strictly controlled conditions, for real-time optical diagnosis of diminutive (≤ 5 mm) colorectal polyps to replace histopathological diagnosis. The optical diagnosis has to be reported using validated scales, must be adequately photodocumented, and can be performed only by experienced endoscopists who are adequately trained and audited (weak recommendation, high quality evidence). 5 ESGE suggests the use of conventional or virtual (NBI) magnified chromoendoscopy to predict the risk of invasive cancer and deep submucosal invasion in lesions such as those with a depressed component (0-IIc according to the Paris classification) or nongranular or mixed-type laterally spreading tumors (weak recommendation, moderate quality evidence). Advanced imaging techniques will need to be applied in specific patient groups in routine clinical practice and to be taught in endoscopic training programs.


Chapter 10: Pediatric asthma: principles and treatment.
Approximately one-half of children with asthma present with symptoms before 3 years of age. The typical history describes recurrent episodes of wheezing and/or cough triggered by a viral upper respiratory infection, activity, or changes in weather or seasons. When symptoms occur after a viral respiratory infection, children with asthma often take longer than the usual week to recover fully from their respiratory symptoms. Wheezing and coughing during exercise or during laughing or crying and episodes triggered in the absence of infection suggest asthma. A trial of bronchodilator medication should show symptomatic improvement. The goal of asthma therapy is to keep children "symptom free" by preventing chronic symptoms, maintaining lung function, and allowing for normal daily activities. Avoidance of triggers identified by history, such as second-hand cigarette smoke exposure and allergens identified by skin-prick testing, can significantly reduce symptoms. According to the National Asthma Education and Prevention Program 2007 report (Expert Panel Report 3 [EPR-3]. Guidelines for the diagnosis and management of asthma: Summary report 2007. J Allergy Clin Immunol 120:S94-S138, 2007.), if impairment symptoms are present >2 days/week or 2 nights/mo, the disease process is characterized as persistent, and in all age groupings, inhaled corticosteroids (ICS) are recommended as the preferred daily controller therapy. Other controller medications such as cromolyn must be given three to four times a day and provides less efficacy than ICS. Montelukast is approved for children ≥12 months old and is often used for its ease of daily oral dosing. Long-acting beta(2)-adrenergic agonists should not be used as monotherapy (i.e., should only be used with ICS).


Spatially dispersive finite-difference time-domain analysis of sub-wavelength imaging by the wire medium slabs.
In this paper, a spatially dispersive finite-difference time-domain (FDTD) method to model wire media is developed and validated. Sub-wavelength imaging properties of the finite wire medium slabs are examined. It is demonstrated that the slab with its thickness equal to an integer number of half-wavelengths is capable of transporting images with sub-wavelength resolution from one interface of the slab to another. It is also shown that the operation of such transmission devices is not sensitive to their transverse dimensions, which can be made even comparable to the wavelength. In this case, the edge diffractions are negligible and do not disturb the image formation.


Design of a randomized controlled trial of physical training and cancer (Phys-Can) - the impact of exercise intensity on cancer related fatigue, quality of life and disease outcome.
Cancer-related fatigue is a common problem in persons with cancer, influencing health-related quality of life and causing a considerable challenge to society. Current evidence supports the beneficial effects of physical exercise in reducing fatigue, but the results across studies are not consistent, especially in terms of exercise intensity. It is also unclear whether use of behaviour change techniques can further increase exercise adherence and maintain physical activity behaviour. This study will investigate whether exercise intensity affects fatigue and health related quality of life in persons undergoing adjuvant cancer treatment. In addition, to examine effects of exercise intensity on mood disturbance, adherence to oncological treatment, adverse effects from treatment, activities of daily living after treatment completion and return to work, and behaviour change techniques effect on exercise adherence. We will also investigate whether exercise intensity influences inflammatory markers and cytokines, and whether gene expressions following training serve as mediators for the effects of exercise on fatigue and health related quality of life. Six hundred newly diagnosed persons with breast, colorectal or prostate cancer undergoing adjuvant therapy will be randomized in a 2 × 2 factorial design to following conditions; A) individually tailored low-to-moderate intensity exercise with or without behaviour change techniques or B) individually tailored high intensity exercise with or without behaviour change techniques. The training consists of both resistance and endurance exercise sessions under the guidance of trained coaches. The primary outcomes, fatigue and health related quality of life, are measured by self-reports. Secondary outcomes include fitness, mood disturbance, adherence to the cancer treatment, adverse effects, return to activities of daily living after completed treatment, return to work as well as inflammatory markers, cytokines and gene expression. The study will contribute to our understanding of the value of exercise and exercise intensity in reducing fatigue and improving health related quality of life and, potentially, clinical outcomes. The value of behaviour change techniques in terms of adherence to and maintenance of physical exercise behaviour in persons with cancer will be evaluated. NCT02473003 , October, 2014.


Blood glucose, diet-based glycemic load and cognitive aging among dementia-free older adults.
Although evidence indicates that Type II Diabetes is related to abnormal brain aging, the influence of elevated blood glucose on long-term cognitive change is unclear. In addition, the relationship between diet-based glycemic load and cognitive aging has not been extensively studied. The focus of this study was to investigate the influence of diet-based glycemic load and blood glucose on cognitive aging in older adults followed for up to 16 years. Eight-hundred and thirty-eight cognitively healthy adults aged ≥50 years (M = 63.1, SD = 8.3) from the Swedish Adoption/Twin Study of Aging were studied. Mixed effects growth models were utilized to assess overall performance and change in general cognitive functioning, perceptual speed, memory, verbal ability, and spatial ability as a function of baseline blood glucose and diet-based glycemic load. High blood glucose was related to poorer overall performance on perceptual speed as well as greater rates of decline in general cognitive ability, perceptual speed, verbal ability, and spatial ability. Diet-based glycemic load was related to poorer overall performance in perceptual speed and spatial ability. Diet-based glycemic load and, in particular, elevated blood glucose appear important for cognitive performance/cognitive aging. Blood glucose control (perhaps through low glycemic load diets) may be an important target in the detection and prevention of age-related cognitive decline.


Parenteral N-3 fatty acids modulate inflammatory and immune response in rats undergoing total gastrectomy.
This study investigated the effect of n-3 fatty acid (FA)-containing parenteral nutrition on the circulatory lymphocyte subpopulation, intracellular cytokine and leukocyte adhesion molecule expression, and phagocytic activity in rats undergoing total gastrectomy. Normal rats with internal jugular catheters were assigned to normal control (NC) and two experimental groups and received total parenteral nutrition (TPN). At the same time, a total gastrectomy was performed in the experimental groups, whereas the NC group underwent a sham operation. The TPN solutions were isonitrogenous and identical in nutrient compositions except for differences in fat emulsion contents. The NC and one of the experimental groups received a soybean oil emulsion (SO), and the other experimental group received 50% soybean oil and 50% fish oil emulsion (FO). Half of the rats in each respective group were sacrificed 1 or 3 days after surgery or the sham operation to examine their immune response. The results showed that the FO group had a higher CD4 proportion and CD4/CD8 ratio than those of the SO and NC groups postoperatively. The phagocytic activity of peritoneal macrophages was higher in the FO group than in the NC group, but no difference was found between the SO and NC groups 3 days after surgery. The intracellular interferon (IFN)-gamma distribution in the FO group was higher than that of the SO group on postoperative days. Leukocyte adhesion molecule expressions and peritoneal monocyte chemotactic protein-1 levels were lower in the FO group than in the SO group on postoperative day 3. These results suggest that parenterally infused FO did not result in immunosuppression. In addition, FO administration promotes lymphocyte Th1 cytokine production, enhances peritoneal macrophage phagocytic activity, and reduces leukocyte adhesion molecule expression in rats with total gastrectomy.


Adenosine diphosphate reduces infarct size and improves porcine heart function after myocardial infarct.
Acute myocardial infarction continues to be a major cause of morbidity and mortality. Timely reperfusion can substantially improve outcomes and the administration of cardioprotective substances during reperfusion is therefore highly attractive. Adenosine diphosphate (ADP) and uridine-5-triphoshate (UTP) are both released during myocardial ischemia, influencing hemodynamics. Both mediate the release of tissue plasminogen activator (t-PA), which can reduce infarct size (IS). The objective of this study was to investigate whether exogenous ADP and UTP administration during reperfusion could reduce myocardial IS and whether this correlated to t-PA release or improvements in hemodynamic responses. Hemodynamic variables and t-PA were measured in 22 pigs before, during, and after 45 min of left anterior coronary artery occlusion. During reperfusion, the pigs were randomized to 240 min of intracoronary infusion of ADP, UTP, or control (no intervention). Ischemic area compared to the area at risk [IS/AAR] was measured. [IS/AAR] was 52 ± 11% in the control animals. ADP decreased [IS/AAR] by 19% (P < 0.05), while UTP increased [IS/AAR] by 15% (P < 0.05). Cardiac output (CO) increased from 3.4 to 3.5 L/min (P < 0.05) and mean arterial pressure (MAP) decreased from 87 to 73 mmHg in the ADP group (P < 0.05). t-PA concentration increased in the ADP and UTP group from 2.0 ng/mL to 2.5 and 2.4 ng/mL, respectively (P < 0.05) but remained unchanged in the control group. In conclusion, intracoronary ADP infusion during reperfusion reduces IS by ∼20% independently from systemic release of t-PA. ADP-induced reduction in both preload and afterload could account for the beneficial myocardial effect.


Obesity and gastrointestinal diseases.
The prevalence of obesity in the Japanese population has been increasing dramatically in step with the Westernization of lifestyles and food ways. Our study demonstrated significant associations between obesity and a number of gastrointestinal disorders in a large sample population in Japan. We demonstrated that reflux esophagitis and hiatal hernia were strongly related to obesity (BMI > 25) in the Japanese. In particular, obesity with young male was a high risk for these diseases. On the other hand, it has been reported that obesity is also associated with Barrett's esophagus and colorectal adenoma; however, obesity was not a risk factor for these diseases in our study. The difference of ethnicity of our subjects may partly explain why we found no data to implicate obesity as a risk factor for Barrett's esophagus. Arterial sclerosis associated with advanced age and hyperglycemia was accompanied by an increased risk of colorectal adenoma.


Multi-view light-sheet imaging and tracking with the MaMuT software reveals the cell lineage of a direct developing arthropod limb.
During development, coordinated cell behaviors orchestrate tissue and organ morphogenesis. Detailed descriptions of cell lineages and behaviors provide a powerful framework to elucidate the mechanisms of morphogenesis. To study the cellular basis of limb development, we imaged transgenic fluorescently-labeled embryos from the crustacean Parhyale hawaiensis with multi-view light-sheet microscopy at high spatiotemporal resolution over several days of embryogenesis. The cell lineage of outgrowing thoracic limbs was reconstructed at single-cell resolution with new software called Massive Multi-view Tracker (MaMuT). In silico clonal analyses suggested that the early limb primordium becomes subdivided into anterior-posterior and dorsal-ventral compartments whose boundaries intersect at the distal tip of the growing limb. Limb-bud formation is associated with spatial modulation of cell proliferation, while limb elongation is also driven by preferential orientation of cell divisions along the proximal-distal growth axis. Cellular reconstructions were predictive of the expression patterns of limb development genes including the BMP morphogen Decapentaplegic.


Outcomes of first-line chemotherapy in patients with advanced or metastatic leiomyosarcoma of uterine and non-uterine origin.
Although leiomyosarcomas (LMSs) form the largest subgroup of soft tissue sarcomas (STSs), the efficacy of chemotherapy in this group is largely unclear, partly because older studies are contaminated with gastrointestinal stromal tumors (GISTs). In this retrospective study we investigated the outcome of first line chemotherapy in 65 patients with unresectable or metastatic LMS. The overall response rate (ORR) was 18%; and the median progression-free (PFS) and overall survival (OS) were 3.8 and 9.7 months respectively. No statistically significant differences in outcomes for uterine and non-uterine LMS were found. In non-uterine LMS, however, the PFS and OS seemed to be longer for females than for males, potentially negatively affecting outcomes in this group. If our observations are confirmed in other series, they would suggest that studies performed in STS patients should not only stratify for histological subtype but also for uterine versus non-uterine LMS and for gender.


Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib.
In up to 5% of non-small cell lung cancer (NSCLC) patients, the EML4-ALK translocation drives tumor progression. Treatment with the ALK inhibitor crizotinib is more effective than standard chemotherapy. However, resistance to crizotinib occurs after approximately 8 months. Ceritinib is the first second-generation ALK inhibitor approved for treatment of crizotinib-resistant NSCLC. Ceritinib inhibits two of the most common ALK-mutants that confer resistance to crizotinib: L1196 M and G1269A. Cells with ALK expression are more sensitive to ceritinib than crizotinib (IC50 25 nM vs. 150 nM, respectively). Alternative second-generation ALK inhibitors such as Alectinib, Brigatinib and PF-06463922 are currently in development, each affecting different crizotinib-resistant ALK target mutations. Genetic identification of crizotinib-resistant mutants is essential for selecting the optimal treatment strategy in NSCLC patients to overcome resistance and to increase progression-free survival.


Leg skinfold thicknesses and race performance in male 24-hour ultra-marathoners.
The association of skinfold thicknesses with race performance has been investigated in runners competing over distances of ≤50 km. This study investigated a potential relation between skinfold thicknesses and race performance in male ultra-marathoners completing >50 km in 24 hours. Variables of anthropometry, training, and previous performance were related to race performance in 63 male ultra-marathoners aged 46.9 (standard deviation [SD] 10.3) years, standing 1.78 (SD 0.07) m in height, and weighing 73.3 (SD 7.6) kg. The runners clocked 146.1 (SD 43.1) km during the 24 hours. In the bivariate analysis, several variables were associated with race performance: body mass (r = -0.25); skinfold thickness at axilla (r = -0.37), subscapula (r = -0.28), abdomen (r = -0.31), and suprailiaca (r = -0.30); the sum of skinfold thicknesses (r = -0.32); percentage body fat (r = -0.32); weekly kilometers run (r = 0.31); personal best time in a marathon (r = -0.58); personal best time in a 100-km ultra-run (r = -0.31); and personal best performance in a 24-hour run (r = 0.46). In the multivariate analysis, no anthropometric or training variable was related to race performance. In conclusion, in contrast to runners up to distances of 50 km, skinfold thicknesses of the lower limbs were not related to race performance in 24-hour ultra-marathoners.


Dual-target inhibitors of mycobacterial aminoacyl-tRNA synthetases among N-benzylidene-N'-thiazol-2-yl-hydrazines.
Effective treatment of tuberculosis is challenged by the rapid development of Mycobacterium tuberculosis (Mtb) multidrug resistance that presumably could be overcome with novel multi-target drugs. Aminoacyl-tRNA synthetases (AARSs) are an essential part of protein biosynthesis machinery and attractive targets for drug discovery. Here, we experimentally verify a hypothesis of simultaneous targeting of structurally related AARSs by a single inhibitor. We previously identified a new class of mycobacterial leucyl-tRNA synthetase inhibitors, N-benzylidene-N'-thiazol-2-yl-hydrazines. Molecular docking of a library of novel N-benzylidene-N'-thiazol-2-yl-hydrazine derivatives into active sites of M. tuberculosis LeuRS (MtbLeuRS) and MetRS (MtbMetRS) resulted in a panel of the best ranking compounds, which were then evaluated for enzymatic potency. Screening data revealed 11 compounds active against MtbLeuRS and 28 compounds active against MtbMetRS. The hit compounds display dual inhibitory potency as demonstrated by IC50 values for both enzymes. Compound 3 is active against Mtb H37Rv cells in in vitro bioassays.


Core-shell silica-rhodamine B nanosphere for synthetic opals: from fluorescence spectral redistribution to sensing.
Photonic crystals are a unique tool to modify the photoluminescence of light-emitting materials. A variety of optical effects have been demonstrated by infiltrating opaline structures with photoactive media. On the other hand, the fabrication of such structures includes complex infiltration steps, that often affect the opal lattice and decrease the efficiency of light emission control. In this work, silica nanospheres were directly functionalized with rhodamine B to create an emitting shell around the dielectric core. Simple tuning of the microsphere preparation conditions allows selecting the appropriate sphere diameter and polydispersity index approaching 5%. These characteristics allow facile self-assembling of the nanospheres into three-dimensional photonic crystals whose peculiar density of photonic states at the band-gap edges induces spectral redistribution of the rhodamine B photoluminescence. The possibility to employ the new stable structure as sensor is also investigated. As a proof of principle, we report the variation of light emission obtained by exposure of the opal to vapor of chlorobenzene.


Prenatal environmental exposures, epigenetics, and disease.
This review summarizes recent evidence that prenatal exposure to diverse environmental chemicals dysregulates the fetal epigenome, with potential consequences for subsequent developmental disorders and disease manifesting in childhood, over the lifecourse, or even transgenerationally. The primordial germ cells, embryo, and fetus are highly susceptible to epigenetic dysregulation by environmental chemicals, which can thereby exert multiple adverse effects. The data reviewed here on environmental contaminants have potential implications for risk assessment although more data are needed on individual susceptibility to epigenetic alterations and their persistence before this information can be used in formal risk assessments. The findings discussed indicate that identification of environmental chemicals that dysregulate the prenatal epigenome should be a priority in health research and disease prevention.


Cervicovaginal human papillomavirus (HPV)-infection before and after hysterectomy: evidence of different tissue tropism for oncogenic and nononcogenic HPV types in a cohort of HIV-positive and HIV-negative women.
Human papillomavirus (HPV) is detected in nearly all cervical cancers and approximately half of vaginal cancers. However, vaginal cancer is an order of magnitude less common than cervical cancer, not only in the general population but also among women with HIV/AIDS. It is interesting therefore that recent studies found that HPV was common in both normal vaginal and cervical tissue, with higher prevalence of nononcogenic HPV types in the vagina. In our investigation, we prospectively examined HPV infection in 86 HIV-positive and 17 HIV-negative women who underwent hysterectomy during follow-up in a longitudinal cohort. Cervicovaginal lavage specimens were obtained semi-annually and tested for HPV DNA by polymerase chain reaction. To address possible selection biases associated with having a hysterectomy, subjects acted as their own comparison group--before versus after hysterectomy. The average HPV prevalence was higher in HIV-positive than HIV-negative women both before (59% vs. 12%; p < 0.001) and after hysterectomy (56% vs. 6%; p < 0.001). Multivariate random effects models (within-individual comparisons) demonstrated significantly lower HPV prevalence [odds ratio (OR) = 0.71; 95% confidence interval (CI) = 0.59-0.85) after hysterectomy. The association of HPV prevalence with hysterectomy was similar among HIV-positive and HIV-negative women. However, hysterectomy had greater effects on oncogenic (OR = 0.48; 95% CI = 0.35-0.66) than nononcogenic HPV types (OR = 0.89; 95% CI = 0.71-1.11; P(interaction) = 0.002). Overall, we observed greater reductions in oncogenic than nononcogenic HPV prevalence after hysterectomy. If correct, these data could suggest that oncogenic HPV have greater tropism for cervical compared to vaginal epithelium, consistent with the lower incidence of vaginal than cervical cancer.


Amorphous nanoparticles by self-assembly: processing for controlled release of hydrophobic molecules.
More than 40% of newly developed drug molecules are highly hydrophobic and, thus, suffer from low bioavailability. Kinetically trapping the drug as a nanoparticle in an amorphous state enhances solubility. However, enhanced solubility can be compromised by subsequent recrystallization from the amorphous state during drying processes. We combine Flash NanoPrecipitation (FNP) to generate nanoparticles with spray-drying to produce stable solid powders. We demonstrate that the continuous nanofabrication platform for nanoparticle synthesis and recovery does not compromise the dissolution kinetics of the drug. Lumefantrine, an anti-malaria drug, is highly hydrophobic with low bioavailability. Increasing the bioavailability of lumefantrine has the potential to reduce the dose and number of required administrations per treatment, thus reducing cost and increasing patient compliance. The low melting temperature of lumefantrine (Tm = 130 °C) makes the drying of amorphous nanoparticles at elevated temperatures potentially problematic. Via FNP, we produced 200-400 nm nanoparticles using hydroxypropyl methylcellulose acetate succinate (HPMCAS), lecithin phospholipid, and zein protein stabilizers. Zein nanoparticles were spray-dried at 100 °C and 120 °C to study the effect of the drying temperature. For zein powders, at two hours the dissolution kinetics under fasted conditions reached 85% release for the 100 °C sample, but only 60% release for the 120 °C sample. Powder X-ray diffraction, differential scanning calorimetry, and solid state nuclear magnetic resonance indicate that the lumefantrine in the nanoparticle core is amorphous for samples spray-dried at 100 °C. Dissolution under fed state conditions showed similar release kinetics for both temperatures, with 90-95% release at two hours. Zein and HPMCAS nanoparticles spray-dried at 100 °C showed release profiles in fasted and fed state media that are identical to those of lyophilized samples, i.e. those dried at cryogenic conditions where no transformation to the crystalline state can occur. Thus, spray drying 30 °C below the melting transition of lumefantrine is sufficient to maintain the amorphous state. These inexpensive formulations have potential to be developed into future therapies for malaria, and the results also highlight the potential of combining FNP and spray-drying as a versatile platform to assemble and rapidly recover amorphous nanoparticles in a solid dosage form.


Impaired dermal wound healing in discoidin domain receptor 2-deficient mice associated with defective extracellular matrix remodeling.
The wounding response relies on tightly regulated crosstalk between recruited fibroblasts and the collagenous extracellular matrix (ECM). Discoidin domain receptor 2 (DDR2) is a tyrosine kinase receptor for fibrillar collagen expressed during pathologic scarring, for example wound healing, arthritis and cancer. We have previously shown that DDR2 phosphorylation drives key wounding responses in skin fibroblasts including proliferation, chemotactic migration and secretion of both metalloproteinases and fibrillar collagen. In this study we compared healing of cutaneous wounds in DDR2+/+ and DDR2-/- mice and analyzed specific fibroblast responses. Cutaneous wound healing was significantly delayed in DDR2-/- mice compared with DDR2+/+ animals. Reduced α-smooth muscle actin (αSMA) expression and matrix metalloproteinase 2 (MMP2) activity in the DDR2-/- wound extracts indicated defective recruitment of skin fibroblasts. DDR2-/- wounds showed decreased tensile strength during healing, which correlated with a significant reduction in collagen content and defective collagen crosslinking. Non-wounded skin in DDR2-/- mice expressed less mRNA of the crosslinking enzymes lysyl oxidase (LOX), lysyl hydroxylase1 (LH1) and matricellular 'secreted protein, acidic and rich in cysteine' (SPARC; also known as osteonectin). Skin fibroblasts isolated from DDR2-/- mice displayed altered mRNA expression of a cluster of collagens, proteoglycans, integrins and MMPs that have been previously correlated with DDR2 expression, and reduced LOX, LH1 and SPARC mRNA levels and proteins. Stable reconstitution of wild-type DDR2 by retroviral infection restored LOX, LH1 and SPARC mRNA and protein levels in DDR2-/- fibroblasts. Contraction of collagen gels was reduced in DDR2-/- fibroblasts, accompanied by significantly reduced phosphorylated SrcY418. Inhibition of either LOX activity by β-aminoproprionitrile or MMP activity by N-[(2R)-2-(hydroxamido carbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (GM6001) reduced collagen gel contraction by skin fibroblasts after DDR2 induction with soluble collagen type I. DDR2 contributes to skin fibroblast responses during tissue injury. Defective synthesis of collagen type I, crosslinking molecules and MMP2 predispose DDR2-/- mice to defective dermal wounding.


Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population.
Despite extensive research of genetic determinants of human adult height, the genes identified up until now allow to predict only a small proportion of the trait's variance. To identify new genes we analyzed 2,486 genotyped and phenotyped individuals in a large pedigree including 23,612 members in 18 generations. The pedigree was derived from a young genetically isolated Dutch population, where genetic heterogeneity is expected to be low and linkage disequilibrium has been shown to be increased. Complex segregation analysis confirmed high heritability of adult height, and suggested mixed model of height inheritance in this population. The estimates of the model parameters obtained from complex segregation analysis were used in parametric linkage analysis, which highlighted three genome-wide significant and additionally at least four suggestive loci involved in height. Significant peaks were located at the chromosomal regions 1p32 (LOD score = 3.35), 2p16 (LOD score = 3.29) and 16q24 (LOD score = 3.94). For the latter region, a strong association signal (FDR q < 0.05) was obtained for 19 SNPs, 17 of them were located in the CDH13 (cadherin 13) gene of which one (rs1035569) explained 1.5% of the total height variance.


Nonlinear and ROADM induced penalties in 28 Gbaud dynamic optical mesh networks employing electronic signal processing.
We report the impact of cascaded reconfigurable optical add-drop multiplexer induced penalties on coherently-detected 28 Gbaud polarization multiplexed m-ary quadrature amplitude modulation (PM m-ary QAM) WDM channels. We investigate the interplay between different higher-order modulation channels and the effect of filter shapes and bandwidth of (de)multiplexers on the transmission performance, in a segment of pan-European optical network with a maximum optical path of 4,560 km (80km x 57 spans). We verify that if the link capacities are assigned assuming that digital back propagation is available, 25% of the network connections fail using electronic dispersion compensation alone. However, majority of such links can indeed be restored by employing single-channel digital back-propagation employing less than 15 steps for the whole link, facilitating practical application of DBP. We report that higher-order channels are most sensitive to nonlinear fiber impairments and filtering effects, however these formats are less prone to ROADM induced penalties due to the reduced maximum number of hops. Furthermore, it has been demonstrated that a minimum filter Gaussian order of 3 and bandwidth of 35 GHz enable negligible excess penalty for any modulation order.


Querying phenotype-genotype relationships on patient datasets using semantic web technology: the example of Cerebrotendinous xanthomatosis.
Semantic Web technology can considerably catalyze translational genetics and genomics research in medicine, where the interchange of information between basic research and clinical levels becomes crucial. This exchange involves mapping abstract phenotype descriptions from research resources, such as knowledge databases and catalogs, to unstructured datasets produced through experimental methods and clinical practice. This is especially true for the construction of mutation databases. This paper presents a way of harmonizing abstract phenotype descriptions with patient data from clinical practice, and querying this dataset about relationships between phenotypes and genetic variants, at different levels of abstraction. Due to the current availability of ontological and terminological resources that have already reached some consensus in biomedicine, a reuse-based ontology engineering approach was followed. The proposed approach uses the Ontology Web Language (OWL) to represent the phenotype ontology and the patient model, the Semantic Web Rule Language (SWRL) to bridge the gap between phenotype descriptions and clinical data, and the Semantic Query Web Rule Language (SQWRL) to query relevant phenotype-genotype bidirectional relationships. The work tests the use of semantic web technology in the biomedical research domain named cerebrotendinous xanthomatosis (CTX), using a real dataset and ontologies. A framework to query relevant phenotype-genotype bidirectional relationships is provided. Phenotype descriptions and patient data were harmonized by defining 28 Horn-like rules in terms of the OWL concepts. In total, 24 patterns of SWQRL queries were designed following the initial list of competency questions. As the approach is based on OWL, the semantic of the framework adapts the standard logical model of an open world assumption. This work demonstrates how semantic web technologies can be used to support flexible representation and computational inference mechanisms required to query patient datasets at different levels of abstraction. The open world assumption is especially good for describing only partially known phenotype-genotype relationships, in a way that is easily extensible. In future, this type of approach could offer researchers a valuable resource to infer new data from patient data for statistical analysis in translational research. In conclusion, phenotype description formalization and mapping to clinical data are two key elements for interchanging knowledge between basic and clinical research.


STI1 promotes glioma proliferation through MAPK and PI3K pathways.
Gliomas are tumors derived from glia or their precursors within the central nervous system. Clinically, gliomas are divided into four grades and the glioblastoma multiforme (GBM), also referred as grade IV astrocytoma, is the most aggressive and the most common glioma in humans. The prognosis for patients with GBM remains dismal, with a median survival of 9-12 months. Despite their striking heterogeneity, common alterations in specific cellular signal transduction pathways occur within most GBMs. Previous work from our group identified the co-chaperone stress-inducible protein 1 (STI1) as a cell surface ligand for cellular prion (PrP(C)), which leads to the activation of several signal transduction pathways, some of which modulate cell survival. In the present work, we used thymidine incorporation assays to investigate the effect of STI1 upon proliferation of the human glioblastoma-derived cell line A172. Here we report that STI1 is secreted by and induces proliferation in tumor cells, an effect that is modulated by the Erk and PI3K pathways, and that, in contrast to glioma cells, STI1 does not induce proliferation of normal glia. In addition, our data suggest the involvement of PrP(C) in STI1-induced proliferation of A172 cells. These results provide initial evidence of a new functional role for STI1 on the physiology of human gliomas, and may lead to the identification of new therapeutic targets in these tumors.


A quiet revolution in global public health: The World Health Organization's Prequalification of Medicines Programme.
Problems with the quality of medicines abound in countries where regulatory and legal oversight are weak, where medicines are unaffordable to most, and where the official supply often fails to reach patients. Quality is important to ensure effective treatment, to maintain patient and health-care worker confidence in treatment, and to prevent the development of resistance. In 2001, the WHO established the Prequalification of Medicines Programme in response to the need to select good-quality medicines for UN procurement. Member States of the WHO had requested its assistance in assessing the quality of low-cost generic medicines that were becoming increasingly available especially in treatments for HIV/AIDS. From a public health perspective, WHO PQP's greatest achievement is improved quality of life-saving medicines used today by millions of people in developing countries. Prequalification has made it possible to believe that everyone in the world will have access to safe, effective, and affordable medicines. Yet despite its track record and recognized importance to health, funding for the programme remains uncertain.


Quantification of the antimalarial drug pyronaridine in whole blood using LC-MS/MS - Increased sensitivity resulting from reduced non-specific binding.
Malaria is one of the most important parasitic diseases of man. The development of drug resistance in malaria parasites is an inevitable consequence of their widespread and often unregulated use. There is an urgent need for new and effective drugs. Pyronaridine is a known antimalarial drug that has received renewed interest as a partner drug in artemisinin-based combination therapy. To study its pharmacokinetic properties, particularly in field settings, it is necessary to develop and validate a robust, highly sensitive and accurate bioanalytical method for drug measurements in biological samples. We have developed a sensitive quantification method that covers a wide range of clinically relevant concentrations (1.5ng/mL to 882ng/mL) using a relatively low volume sample of 100μL of whole blood. Total run time is 5min and precision is within ±15% at all concentration levels. Pyronaridine was extracted on a weak cation exchange solid-phase column (SPE) and separated on a HALO RP amide fused-core column using a gradient mobile phase of acetonitrile-ammonium formate and acetonitrile-methanol. Detection was performed using electrospray ionization and tandem mass spectrometry (positive ion mode with selected reaction monitoring). The developed method is suitable for implementation in high-throughput routine drug analysis, and was used to quantify pyronaridine accurately for up to 42days after a single oral dose in a drug-drug interaction study in healthy volunteers.


Fosfomycin in antimicrobial stewardship programs.
Due to the increase in antimicrobial resistance, strategies such as antimicrobial stewardship programs (ASP) have been developed to improve the clinical results, decrease the adverse effects and the development of resistances and ensure cost-effective therapies. Fosfomycin has a unique mechanism of action against Gram-positive and Gram-negative bacteria. Cross-resistance is uncommon; however, fosfomycin should be used in combination in severe infections to avoid selecting resistant mutations. Fosfomycin's oral formulation facilitates sequential treatment, has low toxicity and high tissue penetration, even in the central nervous system and bone. Fosfomycin is active against resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin- resistant enterococci and penicillin-resistant Streptococcus pneumoniae, as well as against resistant Gram-negative bacteria such as extended-spectrum beta-lactamase-producing and carbapenemase-producing enterobacteria. Fosfomycin is therefore useful for cases of persistent bacteremia, skin and soft tissue infections, as a glycopeptide-sparing and carbapenem-sparing drug for healthcare-associated infections and for polymicrobial infections. Published studies have demonstrated the synergy between fosfomycin and beta-lactams, daptomycin and glycopeptides against MSSA and MRSA; with linezolid in biofilm-associated infections and with aminoglycosides and colistin against Gram-negative bacteria, providing a nephroprotective effect.