Auditory language comprehension in children with developmental dyslexia: evidence from event-related brain potentials.
In the present study, event-related brain potentials (ERPs) were used to compare auditory sentence comprehension in 16 children with developmental dyslexia (age 9-12 years) and unimpaired controls matched on age, sex, and nonverbal intelligence. Passive sentences were presented, which were either correct or contained a syntactic violation (phrase structure) or a semantic violation (selectional restriction). In an overall sentence correctness judgment task, both control and dyslexic children performed well. In the ERPs, control children and dyslexic children demonstrated a similar N400 component for the semantic violation. For the syntactic violation, control children demonstrated a combined pattern, consisting of an early starting bilaterally distributed anterior negativity and a late centro-parietal positivity (P600). Dyslexic children showed a different pattern that is characterized by a delayed left lateralized anterior negativity, followed by a P600. These data indicate that dyslexic children do not differ from unimpaired controls with respect to semantic integration processes (N400) or controlled processes of syntactic reanalyses (P600) during auditory sentence comprehension. However, early and presumably highly automatic processes of phrase structure building reflected in the anterior negativity are delayed in dyslexic children. Moreover, the differences in hemispheric distribution of the syntactic negativity indicate different underlying processes in dyslexic children and controls. The bilateral distribution in controls suggests an involvement of right hemispherically established prosodic processes in addition to the left hemispherically localized syntactic processes, supporting the view that prosodic information may be used to facilitate syntactic processing during normal comprehension. The left hemispheric distribution observed for dyslexic children, in contrast, suggests that these children do not rely on information about the prosodic contour during auditory sentence comprehension as much as controls do. This finding points toward a phonological impairment in dyslexic children that might hamper the development of syntactic processes.


Do invasive mussels restrict offshore phosphorus transport in Lake Huron?
Dreissenid mussels were first documented in the Laurentian Great Lakes in the late 1980s. Zebra mussels (Dreissena polymorpha) spread quickly into shallow, hard-substrate areas; quagga mussels (Dreissena rostriformis bugensis) spread more slowly and are currently colonizing deep, offshore areas. These mussels occur at high densities, filter large water volumes while feeding on suspended materials, and deposit particulate waste on the lake bottom. This filtering activity has been hypothesized to sequester tributary phosphorus in nearshore regions reducing offshore primary productivity. We used a mass balance model to estimate the phosphorus sedimentation rate in Saginaw Bay, a shallow embayment of Lake Huron, before and after the mussel invasion. Our results indicate that the proportion of tributary phosphorus retained in Saginaw Bay increased from approximately 46-70% when dreissenids appeared, reducing phosphorus export to the main body of Lake Huron. The combined effects of increased phosphorus retention and decreased phosphorus loading have caused an approximate 60% decrease in phosphorus export from Saginaw Bay to Lake Huron. Our results support the hypothesis that the ongoing decline of preyfish and secondary producers including diporeia (Diporeia spp.) in Lake Huron is a bottom-up phenomenon associated with decreased phosphorus availability in the offshore to support primary production.


Anti-fibrotic effects of neferine on carbon tetrachloride-induced hepatic fibrosis in mice.
The effects of neferine, a bisbenzylisoquinline alkaloid extracted from the seed embryo of the Chinese traditional medicine Nelumbo nucifera Gaertn, on carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice were evaluated. Adult male Kunming mice were administered with CCl4 1 ml/kg via intraperitoneal injection twice a week for 8 weeks. At the beginning of the 9th week, mice were treated with normal saline, colchicine (0.1 mg/kg), and neferine (5, 10, 20 mg/kg) via intraperitoneal injection once a day for 2 weeks. The liver index and histological examination, plasma ALT/AST levels, hydroxyproline and TGF-β1 content of liver tissue were examined. In the model group, the liver index, the hydroxyproline content of liver tissue and plasma ALT/AST levels were increased, and a high expression of TGF-β1 was observed. The abnormal changes could be improved by neferine in a dose-dependent manner. Our data showed that neferine had an antifibrosis effect on CCl4-induced hepatic fibrosis in mice, possibly partly due to the decreased expression of TGF-β1 in the liver.


Treatment for patients with unknown primary carcinoma and unfavorable prognostic factors.
The treatment for patients with unknown primary carcinoma, particularly those with unfavorable prognosis factors, has changed in the last decade, and continues to evolve. Empiric chemotherapy trials reported since 2000 with the newer drugs have improved the overall survival compared to retrospective historical data and prospective clinical trials reported from 1967 to 2000. Long-term survival (1, 2, 3 years and beyond) has been documented for a small minority of patients by several recent clinical trials. The survival of patients with a number of other advanced adenocarcinomas of known primary sites (colon, rectum, lung, pancreas) has been improved by the use of chemotherapy alone or combined with targeted drugs (bevacizumab, erlotinib), and about 60% of the patients with unknown primary adenocarcinomas harbor occult lesions of the colon, rectum, lung, or pancreas. Many of these patients have benefited from the newer broad-spectrum chemotherapy regimens. Several of these regimens appear about the same and currently represent the treatment of choice for the majority of these patients. Improvements in diagnostic pathology and molecular characterization of these carcinomas are likely to soon help select more appropriate and tailored therapies for many of these patients.


Atypical clinical presentation of systemic juvenile idiopathic arthritis or Still's disease: a report of two cases.
Juvenile idiopathic arthritis (JIA) constitutes a group of arthritis of unknown origin that begins before the age of 16 years. Still´s disease is the systemic form of this condition. Its clinical presentation is marked by fever, rash and sometimes joint pain, in the absence of evidence of another aetiology of the fever. We present the cases of two boys aged 4 and 10 years admitted for fever, with a cerebral origin for the first and no infectious site for the second. Fever persisted after antimalarial treatment and adequate antibiotics. Ferritinaemia, elevated sedimentation rate, lactate dehydrogenase (LDH), triglycerides, and increased serum transaminases, all in the absence of evidence of other inflammatory or malignant diseases were suggestive of Still's disease. Both children received a corticosteroid therapy with progressive dose reduction associated to methotrexate during treatment. Fever disappeared within a few hours after initiation of corticosteroid therapy, with considerable improvement in clinical state. To the best of our knowledge, these cases are among the rare cases of childhood Still disease reported in sub-Saharan Africa. These cases highlight the importance of investigating non-infectious causes of persistent fever in children, in a context of infectious disease endemicity.


Health Workers' Practices in Assessment and Management of Children with Respiratory Symptoms in Primary Care Facilities in Uganda: A FRESH AIR Descriptive Study.
Globally, acute lower respiratory infections are the leading cause of mortality among children under 5 years. Following World Health Organization primary care guidelines, pneumonia is diagnosed based on cough/difficult breathing and fast breathing. We aimed to describe the practices of healthcare workers in primary care health facilities in Uganda in the management of young children with respiratory symptoms especially regarding asthma as opposed to pneumonia. Health workers were observed during clinical consultations with children 1-59 months of age presenting with cough and/or difficult breathing at recruitment. Afterward, an exit interview with the caregiver was conducted. Health center availability of clinical guidelines, equipment and supplies for management of children with respiratory symptoms was assessed systematically. A total of 218 consultations with 50 health workers at six health centers were included. Median consultation time was 4 min. Health workers asked history relevant to distinguishing asthma from pneumonia in 16% of consultations. The respiratory rate was counted in 10%. Antibiotics were prescribed to 32% of all the children and to 39% of children diagnosed with pneumonia. Caregivers reported being informed of findings and possible diagnosis in 5% of cases. Medicine and equipment needed for diagnosing and treating asthma were generally unavailable. Clinical practices among Ugandan health workers in primary care are insufficient to distinguish between main causes of respiratory symptoms, especially asthma as opposed to pneumonia, in children under five. Irrational use of antibiotics is widespread. Clear communication with caregivers is lacking. This could be due to lack of relevant competencies, medicines, time and supplies. Globally, the most frequent cause of death for children under five is infections in the lower airways. The World Health Organization recommends that in local health clinics this is defined as cough/difficult breathing and fast breathing. This article focuses on the practices of local health workers in Uganda and how they in practice diagnose and treat children under five with these symptoms. In addition, we try to estimate how much the caregivers of the children understand from the consultation. This is done by observing the healthcare workers (HCWs) and by interviewing the caregivers. In general, we found that the consultations were too short, that too few of the health workers looked for important signs for lower airways disease such as fast breathing and that antibiotics were prescribed in too many of the consultations. Also, the length and quality of the consultations and the supplies at the local health clinics were not sufficient to diagnose and treat asthma, which can often be mistaken for an infection. We believe that it is an important problem that too few children with asthma are being diagnosed correctly and that antibiotics are being prescribed too frequently, the latter being an important cause of antibiotic resistance. Relevant action must be taken to improve this.


Structures of Merkel cell polyomavirus VP1 complexes define a sialic acid binding site required for infection.
The recently discovered human Merkel cell polyomavirus (MCPyV or MCV) causes the aggressive Merkel cell carcinoma (MCC) in the skin of immunocompromised individuals. Conflicting reports suggest that cellular glycans containing sialic acid (Neu5Ac) may play a role in MCPyV infectious entry. To address this question, we solved X-ray structures of the MCPyV major capsid protein VP1 both alone and in complex with several sialylated oligosaccharides. A shallow binding site on the apical surface of the VP1 capsomer recognizes the disaccharide Neu5Ac-α2,3-Gal through a complex network of interactions. MCPyV engages Neu5Ac in an orientation and with contacts that differ markedly from those observed in other polyomavirus complexes with sialylated receptors. Mutations in the Neu5Ac binding site abolish MCPyV infection, highlighting the relevance of the Neu5Ac interaction for MCPyV entry. Our study thus provides a powerful platform for the development of MCPyV-specific vaccines and antivirals. Interestingly, engagement of sialic acid does not interfere with initial attachment of MCPyV to cells, consistent with a previous proposal that attachment is mediated by a class of non-sialylated carbohydrates called glycosaminoglycans. Our results therefore suggest a model in which sialylated glycans serve as secondary, post-attachment co-receptors during MCPyV infectious entry. Since cell-surface glycans typically serve as primary attachment receptors for many viruses, we identify here a new role for glycans in mediating, and perhaps even modulating, post-attachment entry processes.


Identification of a rat model for usher syndrome type 1B by N-ethyl-N-nitrosourea mutagenesis-driven forward genetics.
The rat is the most extensively studied model organism and is broadly used in biomedical research. Current rat disease models are selected from existing strains and their number is thereby limited by the degree of naturally occurring variation or spontaneous mutations. We have used ENU mutagenesis to increase genetic variation in laboratory rats and identified a recessive mutant, named tornado, showing aberrant circling behavior, hyperactivity, and stereotypic head shaking. More detailed analysis revealed profound deafness due to disorganization and degeneration of the organ of Corti that already manifests at the onset of hearing. We set up a single nucleotide polymorphism (SNP)-based mapping strategy to identify the affected gene, revealing strong linkage to the central region of chromosome 1. Candidate gene resequencing identified a point mutation that introduces a premature stopcodon in Myo7a. Mutations in human MYO7A result in Usher syndrome type 1B, a severe autosomal inherited recessive disease that involves deafness and vestibular dysfunction. Here, we present the first characterized rat model for this disease. In addition, we demonstrate proof of principle for the generation and cloning of human disease models in rat using ENU mutagenesis, providing good perspectives for systematic phenotypic screens in the rat.


Sent Home versus Being Arrested: The Relative Influence of School and Police Intervention on Drug Use.
Prior research has demonstrated that school disciplinary practices lead to juvenile justice intervention or the "school-to-prison pipeline" and that juvenile justice intervention leads to adversities, including drug-using behavior, in adolescence and adult life. Yet, it is not clear which form of official intervention, school suspension and expulsion or police arrest, is more predictive of drug use among young people. Using data from the Rochester Youth Developmental Study, we examined both the immediate, concurrent influence of school and police intervention on drug use during adolescence and the long-term, cumulative impact of school and police intervention during adolescence on subsequent drug use in young established adulthood. The results indicate that school exclusionary practices appeared to be more predictive of drug use than police arrest during both adolescence and young adulthood. Additionally, such negative effects mainly exhibited among minority subjects, and the effects by gender appeared contingent on developmental stages.


Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination.
We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a severe deficit in contextual fear if made 1 d, but not 28 d, after fear conditioning (). As such, the hippocampus seems to play a time-limited role in the consolidation of contextual fear conditioning. Here, we examine retrograde amnesia of contextual fear produced by DH lesions in a within-subjects design. Unlike our previous reports, rats had both a remote and recent memory at the time of the lesion. Rats were given 10 tone-shock pairings in one context (remote memory) and 10 tone-shock pairings in a distinct context (with a different tone) 50 d later (recent memory), followed by DH or sham lesions 1 d later. Relative to controls, DH-lesioned rats exhibited no deficit in remote contextual fear, but recent contextual fear memory was severely impaired. They also did not exhibit deficits in tone freezing. This highly specific deficit in recent contextual memory demonstrated in a within-subjects design favors mnemonic over performance accounts of hippocampal involvement in fear. These findings also provide further support for a time-limited role of the hippocampus in memory storage.


Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
Wnt/β-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote β-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC(50) of ∼10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.


Selection, recombination and demographic history in Drosophila miranda.
Selection, recombination, and the demographic history of a species can all have profound effects on genomewide patterns of variability. To assess the impact of these forces in the genome of Drosophila miranda, we examine polymorphism and divergence patterns at 62 loci scattered across the genome. In accordance with recent findings in D. melanogaster, we find that noncoding DNA generally evolves more slowly than synonymous sites, that the distribution of polymorphism frequencies in noncoding DNA is significantly skewed toward rare variants relative to synonymous sites, and that long introns evolve significantly slower than short introns or synonymous sites. These observations suggest that most noncoding DNA is functionally constrained and evolving under purifying selection. However, in contrast to findings in the D. melanogaster species group, we find little evidence of adaptive evolution acting on either coding or noncoding sequences in D. miranda. Levels of linkage disequilibrium (LD) in D. miranda are comparable to those observed in D. melanogaster, but vary considerably among chromosomes. These patterns suggest a significantly lower rate of recombination on autosomes, possibly due to the presence of polymorphic autosomal inversions and/or differences in chromosome sizes. All chromosomes show significant departures from the standard neutral model, including too much heterogeneity in synonymous site polymorphism relative to divergence among loci and a general excess of rare synonymous polymorphisms. These departures from neutral equilibrium expectations are discussed in the context of nonequilibrium models of demography and selection.


Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain.
Nine voltage-gated sodium channels are expressed in complex patterns in mammalian nerve and muscle. Three channels, Na(v)1.7, Na(v)1.8, and Na(v)1.9, are expressed selectively in peripheral damage-sensing neurons. Because there are no selective blockers of these channels, we used gene ablation in mice to examine the function of Na(v)1.7 (PN1) in pain pathways. A global Na(v)1.7-null mutant was found to die shortly after birth. We therefore used the Cre-loxP system to generate nociceptor-specific knockouts. Na(v)1.8 is only expressed in peripheral, mainly nociceptive, sensory neurons. We knocked Cre recombinase into the Na(v)1.8 locus to generate heterozygous mice expressing Cre recombinase in Na(v)1.8-positive sensory neurons. Crossing these animals with mice where Na(v)1.7 exons 14 and 15 were flanked by loxP sites produced nociceptor-specific knockout mice that were viable and apparently normal. These animals showed increased mechanical and thermal pain thresholds. Remarkably, all inflammatory pain responses evoked by a range of stimuli, such as formalin, carrageenan, complete Freund's adjuvant, or nerve growth factor, were reduced or abolished. A congenital pain syndrome in humans recently has been mapped to the Na(v)1.7 gene, SCN9A. Dominant Na(v)1.7 mutations lead to edema, redness, warmth, and bilateral pain in human erythermalgia patients, confirming an important role for Na(v)1.7 in inflammatory pain. Nociceptor-specific gene ablation should prove useful in understanding the role of other broadly expressed genes in pain pathways.


On-road measurement of gas and particle phase pollutant emission factors for individual heavy-duty diesel trucks.
Pollutant concentrations in the exhaust plumes of individual diesel trucks were measured at high time resolution in a highway tunnel in Oakland, CA, during July 2010. Emission factors for individual trucks were calculated using a carbon balance method, in which pollutants measured in each exhaust plume were normalized to measured concentrations of carbon dioxide. Pollutants considered here include nitric oxide, nitrogen dioxide (NO(2)), carbon monoxide, formaldehyde, ethene, and black carbon (BC), as well as optical properties of emitted particles. Fleet-average emission factors for oxides of nitrogen (NO(x)) and BC respectively decreased 30 ± 6 and 37 ± 10% relative to levels measured at the same location in 2006, whereas a 34 ± 18% increase in the average NO(2) emission factor was observed. Emissions distributions for all species were skewed with a small fraction of trucks contributing disproportionately to total emissions. For example, the dirtiest 10% of trucks emitted half of total NO(2) and BC emissions. Emission rates for NO(2) were found to be anticorrelated with all other species considered here, likely due to the use of catalyzed diesel particle filters to help control exhaust emissions. Absorption and scattering cross-section emission factors were used to calculate the aerosol single scattering albedo (SSA, at 532 nm) for individual truck exhaust plumes, which averaged 0.14 ± 0.03.


Are babies conceived during Ramadan born smaller and sooner than babies conceived at other times of the year? A Born in Bradford Cohort Study.
It is not known whether infants exposed to intermittent maternal fasting at conception are born smaller or have a higher risk of premature birth than those who are not. Doctors are therefore unsure about what advice to give women about the safety of Ramadan fasting. This cohort study aimed to investigate these questions in Muslim mother-infant pairs to inform prenatal care. Routinely collected data accessed from maternity records were the source for information. Mothers were considered exposed if they were Muslim and Ramadan overlapped with their infant conception date, estimated to be 14 days after the last menstrual period. Infants were included as exposed if their estimated conception date was in the first 21 days of Ramadan or 7 days prior to Ramadan. After adjusting for gestational age, maternal age, infant gender, maternal body mass index at booking, smoking status, gestational diabetes, parity and year of birth, there was no significant difference in birth weight between infants born to Muslim mothers who were conceived during Ramadan (n=479) and those who were not (n=4677) (adjusted mean difference =24.3 g, 95% CI -16.4 to 64.9). There was no difference in rates of premature births in exposed and unexposed women (5.2% vs 4.9%; OR=1.08, 95% CI 0.71 to 1.65). Healthy Muslim women considering becoming pregnant prior to, or during Ramadan, can be advised that fasting does not seem to have a detrimental effect on the size (weight) of their baby and it appears not to increase the likelihood of giving birth prematurely.


Imported malaria and artemisinin-based combination therapy failure in travellers returning to Belgium: A retrospective study.
Malaria (Plasmodium spp) remains a top cause of travel-associated morbidity among European residents. Here, we describe recent trends of imported malaria to Belgium and characterize the first cases of P.falciparum failure to artemisinin-based combination therapy (ACT). National surveillance data and registers from national reference laboratory were used to investigate malaria cases and ACT failures in the past 20 years. Recurrent infections were confirmed by pfmsp genotyping and polymorphisms in drug resistance-associated genes pfk13, pfcrt, pfmdr1, pfpm2, pfap2mu and pfubp1 were determined by sequencing or quantitative PCR. Annual malaria cases steadily increased in the last decade, reaching 428 in 2017 (all species). An estimated 15% of P.falciparum cases were severe. Between 2014 and 2017, 727 P.falciparum cases were reported and six non-immune travellers presented late recurrence. Five had hyperparasitaemia and/or signs of severe malaria at initial consultation. No mutations in ACT drug resistance markers were detected, although pfcrt-pfmdr1 haplotypes associated with lumefantrine tolerance were common. The upward trend in imported malaria, the substantial proportion of severe cases and the emergence of ACT failures are sources of concern, although late failures were infrequent. Genetic analysis did not support parasitological resistance to ACT, suggesting prospective pharmacokinetic studies should assess adequacy of partner drug dosage and duration of treatment in non-immune populations.


T-cell responses and previous exposure to hepatitis C virus in indeterminate blood donors.
Blood donors are routinely screened for hepatitis C virus infection. Some individuals have weak or restricted virus-specific antibody responses, and are classed as indeterminate. Such donors are almost always negative for viral RNA in blood. We postulated that previous transient virus exposure might account for some of these cases. With sensitive ex-vivo analyses of T-cell responses, we identified virus-specific responses in 15 of 30 indeterminate blood donors tested, compared with none in controls (p=0.0013). Additionally, these responses were typically focused on core-derived peptides. These findings suggest previous exposure to the virus in many indeterminate blood donors.


μ-Opioid Receptor Gene A118 G Variants and Persistent Pain Symptoms Among Men and Women Experiencing Motor Vehicle Collision.
The μ-opioid receptor 1 (OPRM1) binds endogenous opioids. Increasing evidence suggests that endogenous OPRM1 agonists released at the time of trauma may contribute to the development of posttraumatic musculoskeletal pain (MSP). In this prospective observational study, we evaluated the hypothesis that individuals with an AG or GG genotype at the OPRM1 A118 G allele, which results in a reduced response to opioids, would have less severe MSP 6 weeks after motor vehicle collision (MVC). Based on previous evidence, we hypothesized that this effect would be sex-dependent and most pronounced among women with substantial peritraumatic distress. European American men and women ≥ 18 years of age presenting to the emergency department after MVC and discharged to home after evaluation (N = 948) were enrolled. Assessments included genotyping and 6-week evaluation of overall MSP severity (0-10 numeric rating scale). In linear regression modeling, a significant A118 G Allele × Sex interaction was observed: an AG/GG genotype predicted reduced MSP severity among women with substantial peritraumatic distress (β = -.925, P = .014) but not among all women. In contrast, men with an AG/GG genotype experienced increased MSP severity at 6 weeks (β = .827, P = .019). Further studies are needed to understand the biologic mechanisms mediating observed sex differences in A118 G effects. These results suggest a sex-dependent mechanism by which an emotional response to trauma (distress) contributes to a biologic mechanism (endogenous opioid release) that increases MSP in the weeks after stress exposure. These results also support the hypothesis that endogenous opioids influence pain outcomes differently in men and women.


Hypoxic preconditioning protects against ischemic brain injury.
Animals exposed to brief periods of moderate hypoxia (8% to 10% oxygen for 3 hours) are protected against cerebral and cardiac ischemia between 1 and 2 days later. This hypoxia preconditioning requires new RNA and protein synthesis. The mechanism of this hypoxia-induced tolerance correlates with the induction of the hypoxia-inducible factor (HIF), a transcription factor heterodimeric complex composed of inducible HIF-1alpha and constitutive HIF-1beta proteins that bind to the hypoxia response elements in a number of HIF target genes. Our recent studies show that HIF-1alpha correlates with hypoxia induced tolerance in neonatal rat brain. HIF target genes, also induced following hypoxia-induced tolerance, include vascular endothelial growth factor, erythropoietin, glucose transporters, glycolytic enzymes, and many other genes. Some or all of these genes may contribute to hypoxia-induced protection against ischemia. HIF induction of the glycolytic enzymes accounts in part for the Pasteur effect in brain and other tissues. Hypoxia-induced tolerance is not likely to be equivalent to treatment with a single HIF target gene protein since other transcription factors including Egr-1 (NGFI-A) have been implicated in hypoxia regulation of gene expression. Understanding the mechanisms and genes involved in hypoxic tolerance may provide new therapeutic targets to treat ischemic injury and enhance recovery.


'Ignorance is bliss sometimes': constraints on the emergence of the 'informed patient' in the changing landscapes of health information.
In this paper we describe and analyse results from an empirical study designed to provide insight into factors facilitating and/or inhibiting the emergence of the much-heralded 'informed patient' and its sociological equivalent, the 'reflexive patient' or 'reflexive consumer'. In particular, we seek to examine the relationship between information and empowerment in a healthcare context and assess the significance of the Internet in mediating this relationship. The paper draws on data from interviews with 32 mid-life women concerned to know about HRT for the relief of menopausal symptoms. Having analysed these women's 'information practices', we conclude that constraints on the emergence of the informed patient identity exist within both patient and practitioner communities and within the space occupied by both in the medical encounter. In particular, in this paper we identify a tension caused by the emphasis on 'information for choice' in the informed patient discourse which itself obscures the potential conflict between lay and expert/medical knowledges in the clinical encounter.


Development and validation of a ReaxFF reactive force field for Fe/Al/Ni alloys: molecular dynamics study of elastic constants, diffusion, and segregation.
We have developed a ReaxFF force field for Fe/Al/Ni binary alloys based on quantum mechanical (QM) calculations. In addition to the various bulk phases of the binary alloys, the (100), (110) and (111) surface energies and adatom binding energies were included in the training set for the force field parametrization of the Fe/Al/Ni binary alloys. To validate these optimized force fields, we studied (i) elastic constants of the binary alloys at finite temperatures, (ii) diffusivity of alloy components in Al/Ni alloy, and (iii) segregation on the binary alloy surfaces. First, we calculated linear elastic constants of FeAl, FeNi(3), and Ni(3)Al in the temperature range 300 to 1100 K. The temperature dependences of the elastic constants of these three alloys, showing a decrease in C(11), C(12), and C(44) as temperature increases, were in good agreement with the experimental results. We also performed ReaxFF molecular dynamics (MD) simulations for Al or Ni diffusion in the system modeled as Al/Ni mixed layers with the linear composition gradients. At 1000 K, Al diffusivity at the pure Al end was 2 orders of magnitude larger than that in the Al trace layers, probably explaining the nature of different diffusion behavior between molten metals and alloys. However, the diffusivity of Ni at the pure Ni end was only slightly larger than that in the Ni trace layers at the system temperature much lower than the melting temperature of Ni. Third, we investigated the surface segregation in L1(2)-Fe(3)Al, Fe(3)Ni, and Ni(3)Al clusters at high temperature (2500 K). From the analysis of composition distribution of the alloy components from the bulk to the surface layer, it was found that the degree of segregation depended on the chemical composition of the alloy. Al surface segregation occurred most strongly in Fe(3)Al, whereas it occurred most weakly in Ni(3)Al. These results may support the segregation mechanism that surface segregation results from the interplay between the energetic stability of the ordered bulk phase and the surface reconstruction. In addition, the surface segregation induced the depletion layers of segregating metal species (Al in Fe(3)Al and Ni(3)Al, and Ni in Fe(3)Ni) next to the segregation layers. These simulation results qualitatively agreed with early experimental observations of segregation in Fe/Al/Ni binary alloys.


Observation of spontaneous toroidal rotation inversion in Ohmically heated Tokamak plasmas.
Bulk plasma toroidal rotation is observed to invert spontaneously from counter to cocurrent direction in TCV (Tokamak à Configuration Variable) Ohmically heated discharges, in low confinement mode, without momentum input. The inversion occurs in high current discharges, when the plasma electron density exceeds a well-defined threshold. The transition between the two rotational regimes has been studied by means of density ramps. The results provide evidence of a change of the balance of nondiffusive momentum fluxes in the core of a plasma without an external drive.


Benefits and Shortcomings of Laboratory Model Systems in the Development of Genetic Therapies.
Gene therapeutic approaches promise treatment or even a cure of diseases that were previously untreatable. Retinal gene therapies tested in clinical trials comprise a wide range of different strategies, including gene supplementation therapies, in vivo gene editing, modulation of splicing mechanisms, or the suppression of gene expression. To guarantee efficient transfer of genetic material into the respective target cells while avoiding major adverse effects, the development of genetic therapies requires appropriate in vitro model systems that allow tests of efficacy and safety of the gene therapeutic approach. In this review, we introduce various in vitro models of different levels of complexity used in the development of genetic therapies and discuss their respective benefits and shortcomings using the example of adeno-associated virus-based retinal gene therapy.


An assessment of the impact of thimerosal on childhood neurodevelopmental disorders.
The prevalence of autism in the US has risen from 1 in approximately 2500 in the mid-1980s to 1 in approximately 300 children in the mid-1990s. The purpose of this study was to evaluate whether mercury from thimerosal in childhood vaccines contributed to neurodevelopmental disorders. Neurodevelopmental disorder dose-response curves for increasing mercury doses of thimerosal in childhood vaccines were determined based upon examination of the Vaccine Adverse Events Reporting System (VAERS) database and the 2001 US' Department of Education Report. The instantaneous dosage of mercury children received in comparison to the Food and Drug Administration (FDA)'s maximum permissible dose for the oral ingestion of methylmercury was also determined. The dose-response curves showed increases in odds ratios of neurodevelopmental disorders from both the VAERS and US Department of Education data closely linearly correlated with increasing doses of mercury from thimerosal-containing childhood vaccines and that for overall odds ratios statistical significance was achieved. Similar slopes and linear regression coefficients for autism odds ratios in VAERS and the US Department of Education data help to mutually validate each other. Controls employed in the VAERS and US Department of Education data showed minimal biases. The evidence presented here shows that the occurrence of neurodevelopmental disorders following thimerosal-containing childhood vaccines does not appear to be coincidental.


Degarelix for the treatment of advanced prostate cancer compared with GnRh-Agonists: a systematic review and meta-analysis.
Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer. We performed a systematic review to compare safety, efficacy and effectiveness of degarelix, a new gonadotropin-releasing hormone (GnRH) antagonist (blocker), versus gonadotropin-releasing hormone (GnRH) agonists. MEDLINE, Web of Science and the Cochrane library were searched to identify all of the published Randomized Controlled Trials (RCTs) that used degarelix versus gonadotropin-releasing hormone agonists with or without anti-androgen therapy for the treatment of prostate cancer. We performed meta-analysis of extracted data on safety and efficacy of the target medication. Six studies were included. They involved a total of 2296 patients which were used in the meta-analysis. Follow-up times after treatment were between 12 weeks and 12 months. Three of six RCTs compared degarelix with goserelin and the others compared it with leuprolide. Meta-analysis on safety outcomes revealed that the only statistically significant difference between the degarelix treated group and GnRH agonists treated group was complication in the injection site which was higher in degarelix-treated group (OR= 46.34, 95% CI: 15.79 to 136, p<0.001). Although general mortality rate was lower in degarelix-treated group (OR= 2.06, 95% CI: 1.08 to 3.93, p=0.03); mortality due to the drug side effects was not different. Meta-analysis of efficacy data also showed that International Prostate Symptom Score (IPSS) reduction at week 12, (MD=-1.85, 95% CI: -2.97 to - 0.72, p=0.001) and Testosterone reduction between day 1-28, (OR=11.58, 95% CI: 5.77 to 23.22, p<0.001) was statistically higher in degarelix-treated group. Testosterone reduction after day 28 and prostate volume reduction did not have significant difference. Our meta-analysis indicates that, compared with GnRH agonists, degarelix has significantly more effects on lower urinary tract symptoms and also Prostate Specific Antigen (PSA) and testosterone reduction in the first month of the treatment. Except minor complications in the injection site like pain, erythema and swelling, there is no increase in major side effects and mortality due to degarelix. This is while the effect on testosterone and PSA after the first month of treatment is not statistically different between the two groups.


Mortality due to schistosomiasis mansoni: a field study in Sudan.
Although schistosomiasis affects 200 million persons, 20 million of whom have advanced disease, little is known about the mortality pattern in areas of endemic schistosomiasis mansoni. In an attempt to assess the mortality rates in an endemic area in Sudan, we conducted two demographic surveys in a village in the Gezira area. Clinical, sonographic, and parasitologic examinations were performed in a randomly selected sample of 25% of the population in 1987 and 1994. One of us asked each head of household about the names, sex, and age of family members. Particularly, we asked about death in the family if any, history of schistosomiasis, abdominal swelling, and hematemesis. Possible causes of death were ascertained by reviewing medical records in the village dispensary and the district hospital. There were 42 deaths in the village. Four males died of hematemesis secondary to portal fibrosis. The crude mortality rate of schistosomiasis was is 51/100,000/year. The overall schistosomiasis fatality rate per year was 1/1,000 infected persons, but was as high as 11/100/infected patients with bleeding varices. These findings showed the impact of schistosomiasis on public health in this economically important region of Sudan.


An Exercise in Resistance: Inoculation Messaging as a Strategy for Protecting Motivation During a Monotonous and Controlling Exercise Class.
Sustained attention has been devoted to studying the factors that support (or thwart) individuals' enjoyment of, interest in, and value judgments regarding their exercise activities. We employed a resistance-inducing (i.e., inoculation theory) messaging technique with the aim of protecting these desirable perceptions in the face of environmental conditions designed to undermine one's positive exercise experiences. Autonomously motivated exercisers (N = 146, Mage = 20.57, SD = 4.02) performed a 25-min, group-based, instructor-led exercise circuit, in which the activities were deliberately monotonous, and during which the confederate instructor acted in a disinterested, unsupportive, and critical manner. Shortly before the session, participants received either a control message containing general information about the exercise class or an inoculation message containing a forewarning about potential challenges to participants' enjoyment/interest/value perceptions during the class, as well as information about how participants might maintain positive perceptions in the face of these challenges. Despite there being no between-conditions differences in presession mood or general exercise motives, inoculated (relative to control) participants reported greater interest/enjoyment in the exercise session and higher perceptions of need support from the instructor. Perceptions of need support mediated the relationship between message condition and interest/enjoyment.


An Improved Isotropic Periodic Sum Method That Uses Linear Combinations of Basis Potentials.
Isotropic periodic sum (IPS) is a technique that calculates long-range interactions differently than conventional lattice sum methods. The difference between IPS and lattice sum methods lies in the shape and distribution of remote images for long-range interaction calculations. The images used in lattice sum calculations are identical to those generated from periodic boundary conditions and are discretely positioned at lattice points in space. The images for IPS calculations are "imaginary", which means they do not explicitly exist in a simulation system and are distributed isotropically and periodically around each particle. Two different versions of the original IPS method exist. The IPSn method is applied to calculations for point charges, whereas the IPSp method calculates polar molecules. However, both IPSn and IPSp have their advantages and disadvantages in simulating bulk water or water-vapor interfacial systems. In bulk water systems, the cutoff radius effect of IPSn strongly affects the configuration, whereas IPSp does not provide adequate estimations of water-vapor interfacial systems unless very long cutoff radii are used. To extend the applicability of the IPS technique, an improved IPS method, which has better accuracy in both homogeneous and heterogeneous systems has been developed and named the linear-combination-based isotropic periodic sum (LIPS) method. This improved IPS method uses linear combinations of basis potentials. We performed molecular dynamics (MD) simulations of bulk water and water-vapor interfacial systems to evaluate the accuracy of the LIPS method. For bulk water systems, the LIPS method has better accuracy than IPSn in estimating thermodynamic and configurational properties without the countercharge assumption, which is used for IPSp. For water-vapor interfacial systems, LIPS has better accuracy than IPSp and properly estimates thermodynamic and configurational properties. In conclusion, the LIPS method can successfully estimate homogeneous and heterogeneous systems of polar molecular systems with good accuracy.


Discriminative face alignment.
This paper proposes a discriminative framework for efficiently aligning images. Although conventional Active Appearance Models (AAMs)-based approaches have achieved some success, they suffer from the generalization problem, i.e., how to align any image with a generic model. We treat the iterative image alignment problem as a process of maximizing the score of a trained two-class classifier that is able to distinguish correct alignment (positive class) from incorrect alignment (negative class). During the modeling stage, given a set of images with ground truth landmarks, we train a conventional Point Distribution Model (PDM) and a boosting-based classifier, which acts as an appearance model. When tested on an image with the initial landmark locations, the proposed algorithm iteratively updates the shape parameters of the PDM via the gradient ascent method such that the classification score of the warped image is maximized. We use the term Boosted Appearance Models (BAMs) to refer to the learned shape and appearance models, as well as our specific alignment method. The proposed framework is applied to the face alignment problem. Using extensive experimentation, we show that, compared to the AAM-based approach, this framework greatly improves the robustness, accuracy, and efficiency of face alignment by a large margin, especially for unseen data.


Awareness and Attitudes Towards Telemedicine Among Medical Students in the United States.
Telemedicine (TM) or telehealth is defined as the delivery of healthcare services at a distance using electronic means. It is a rapidly growing field of medicine that uses telecommunication to provide healthcare services to patients such as the elderly and those in rural locations who may otherwise be unable to make it to the hospital or physician's office. With the rise in the popularity of TM, educating future physicians on this technology will become vital. This study aimed to explore medical students' experiences and opinions regarding TM. An online survey was sent to 287 medical students in 20 different allopathic medical schools in the United States. The survey consisted of 14 questions that included demographic information, information regarding TM exposure, interest in TM, and plans for future utilization. The result of this study indicated that only 17.4% of medical students had prior exposure to TM. However, the increased exposure to TM helped not only to increase awareness of the technology but also helped students form opinions on TM. Lastly, students in all intended specialties had interests in utilizing TM in the future with specialties such as pathology, psychiatry, ophthalmology, and dermatology indicating the highest levels of interest. As medicine continues to incorporate technology into the care of patients, training institutions need to expose future physicians to the modalities of care they will be utilizing. The results of this survey suggest that the development of education and exposure to TM will become increasingly important as more medical students indicate interest in utilizing this technology.


Stargazin-related protein γ₇ is associated with signalling endosomes in superior cervical ganglion neurons and modulates neurite outgrowth.
The role(s) of the newly discovered stargazin-like γ-subunit proteins remains unclear; although they are now widely accepted to be transmembrane AMPA receptor regulatory proteins (TARPs), rather than Ca²⁺ channel subunits, it is possible that they have more general roles in trafficking within neurons. We previously found that γ₇ subunit is associated with vesicles when it is expressed in neurons and other cells. Here, we show that γ₇ is present mainly in retrogradely transported organelles in sympathetic neurons, where it colocalises with TrkA-YFP, and with the early endosome marker EEA1, suggesting that γ₇ localises to signalling endosomes. It was not found to colocalise with markers of the endoplasmic reticulum, mitochondria, lysosomes or late endosomes. Furthermore, knockdown of endogenous γ₇ by short hairpin RNA transfection into sympathetic neurons reduced neurite outgrowth. The same was true in the PC12 neuronal cell line, where neurite outgrowth was restored by overexpression of human γ₇. These findings open the possibility that γ₇ has an essential trafficking role in relation to neurite outgrowth as a component of endosomes involved in neurite extension and growth cone remodelling.


Risk Factors for Suicide and Suicidal Behavior Relevant to Emergency Health Care Settings: A Systematic Review of Post-2007 Reviews.
Suicide is a global public health problem, and with recent economic and societal changes, there may be emerging risk factors unrecognized by health care professionals. The aim of this systematic review was to update existing suicide risk factor literature applicable to emergency health care settings. A total of 35 articles identified from PsycINFO, CINAHL, and Medline met the inclusion criteria. Results supported the significance of existing suicide risk factors and identified emerging risk factors. The review provides a high-quality update of risk factor literature that could be applied to emergency health care settings; however, further research is needed to confirm emerging risk factors.


The alpha-helical neck region of human lung surfactant protein D is essential for the binding of the carbohydrate recognition domains to lipopolysaccharides and phospholipids.
We have expressed the carbohydrate recognition domains (CRDs) of human lung surfactant protein D (SP-D) in Escherichia coli as a trimeric structure held together by the alpha-helical neck region of the molecule. The DNA sequence coding for the neck-region peptide and the CRD of SP-D was subcloned and expressed as a fusion protein containing the E. coli maltose binding protein (MBP). After removal of the MBP, the recombinant structure, containing three CRDs of SP-D, was found to be comparable to native SP-D in terms of carbohydrate binding specificity, the binding to lipopolysaccharides (LPSs) of Gram-negative bacteria, and interaction with phospholipids. The CRD of SP-D, without the neck region peptide, was also expressed and shown to behave as a monomer that showed a very weak affinity for maltose-agarose, LPSs and phospholipids. The alpha-helical neck region on its own showed affinity for phospholipids and thus might contribute to the binding of SP-D to these structures. However, the possibility that hydrophobic patches, which are exposed only in the isolated neck region and not in the intact SP-D, plays a role in neck region-phospholipid interaction, cannot be excluded. The results confirm the importance of the neck region as a trimerizing agent in bringing together three CRDs and suggest that multivalency is important in the strong binding of SP-D to carbohydrate targets.


Prevalence and Determinants of Adequate Compliance with Antenatal Care in Peru.
To determine the adequacy of compliance with antenatal care (ANC) by pregnant women in Peru and to identify the associated factors. An analytical cross-sectional study of data from the 2019 Peruvian Demographic and Family Health Survey (Encuesta Demográfica y de Salud Familiar, ENDES, in Spanish) was conducted. The dependent variable was adequate compliance with ANC (provided by skilled health care professionals; first ANC visit during the first trimester of pregnancy; six or more ANC visits during pregnancy; ANC visits with appropriate content) by women aged 15 to 49 years in their last delivery within the five years prior to the survey. Crude and adjusted prevalence ratios and their 95% confidence intervals were calculated using a log-binomial regression model. A total of 18,386 women were analyzed, 35.0% of whom adequately complied with ANC. The lowest proportion of compliance was found with the content of ANC (42.6%). Sociodemographic factors and those related to pregnancy, such as being in the age groups of 20 to 34 years and 35 to 49 years, having secondary or higher education, belonging to a wealth quintile of the population other than the poorest, being from the Amazon region, not being of native ethnicity, having a second or third pregnancy, and having a desired pregnancy, increased the probability of presenting adequate compliance with ANC. Only 3 out of 10 women in Peru showed adequate compliance with ANC. Compliance with the content of ANC must be improved, and strategies must be developed to increase the proportion of adequate compliance with ANC.


Desorption-limited mechanism of release from polymer nanofibers.
This work examines the release of a model water-soluble compound from electrospun polymer nanofiber assemblies. Such release attracts attention in relation to biomedical applications, such as controlled drug delivery. It is also important for stem cell attachment and differentiation on biocompatible electrospun nanofiber scaffolds containing growth factors, which have been encapsulated by means of electrospinning. Typically, the release mechanism has been attributed to solid-state diffusion of the encapsulated compound from the fibers into the surrounding aqueous bath. Under this assumption, a 100% release of the encapsulated compound is expected in a certain (long) time. The present work focuses on certain cases where complete release does not happen, which suggests that solid-state diffusion may not be the primary mechanism at play. We show that in such cases the release rate can be explained by desorption of the embedded compound from nanopores in the fibers or from the outer surface of the fibers in contact with the water bath. After release, the water-soluble compound rapidly diffuses in water, whereas the release rate is determined by the limiting desorption stage. A model system of Rhodamine 610 chloride fluorescent dye embedded in electrospun monolithic poly(methylmethacrylate) (PMMA) or poly(caprolactone) (PCL) nanofibers, in nanofibers electrospun from PMMA/PCL blends, or in core-shell PMMA/PCL nanofibers is studied. Both the experimental results and theory point at the above mentioned desorption-related mechanism, and the predicted characteristic time, release rate, and effective diffusion coefficient agree fairly well with the experimental data. A practically important outcome of this surface release mechanism is that only the compound on the fiber and pore surfaces can be released, whereas the material encapsulated in the bulk cannot be freed within the time scales characteristic of the present experiments (days to months). Consequently, in such cases, complete release is impossible. We also demonstrate how the release rate can be manipulated by the polymer content and molecular weight affecting nanoporosity and the desorption enthalpy, as well as by the nanofiber structure (monolithic fibers, fibers from polymer blends, and core-shell fibers). In particular, it is shown that, by manipulating the above parameters, release times from tens of hours to months can be attained.


Embodied Medicine: Mens Sana in Corpore Virtuale Sano.
Progress in medical science and technology drastically improved physicians' ability to interact with patient's physical body. Nevertheless, medicine still addresses the human body from a Hippocratic point of view, considering the organism and its processes just as a matter of mechanics and fluids. However, the interaction between the cognitive neuroscience of bodily self-consciousness (BSC), fundamentally rooted in the integration of multisensory bodily inputs, with virtual reality (VR), haptic technologies and robotics is giving a new meaning to the classic Juvenal's latin dictum "Mens sana in corpore sano" (a healthy mind in a healthy body). This vision provides the basis for a new research field, "Embodied Medicine": the use of advanced technologies for altering the experience of being in a body with the goal of improving health and well-being. Up to now, most of the research efforts in the field have been focused upon how external bodily information is processed and integrated. Despite the important results, we believe that existing bodily illusions still need to be improved to enhance their capability to effectively correct pathological dysfunctions. First, they do not follow the suggestions provided by the free-energy and predictive coding approaches. More, they lacked to consider a peculiar feature of the human body, the multisensory integration of internal inputs (interoceptive, proprioceptive and vestibular) that constitute our inner body dimension. So, a future challenge is the integration of simulation/stimulation technologies also able to measure and modulate this internal/inner experience of the body. Finally, we also proposed the concept of "Sonoception" as an extension of this approach. The core idea is to exploit recent technological advances in the acoustic field to use sound and vibrations to modify the internal/inner body experience.


Zinc finger nuclease-based double-strand breaks attenuate malaria parasites and reveal rare microhomology-mediated end joining.
Genome editing of malaria parasites is key to the generation of live attenuated parasites used in experimental vaccination approaches. DNA repair in Plasmodium generally occurs only through homologous recombination. This has been used to generate transgenic parasites that lack one to three genes, leading to developmental arrest in the liver and allowing the host to launch a protective immune response. While effective in principle, this approach is not safe for use in humans as single surviving parasites can still cause disease. Here we use zinc-finger nucleases to generate attenuated parasite lines lacking an entire chromosome arm, by a timed induction of a double-strand break. Rare surviving parasites also allow the investigation of unconventional DNA repair mechanisms in a rodent malaria parasite. A single, zinc-finger nuclease-induced DNA double-strand break results in the generation of attenuated parasite lines that show varying degrees of developmental arrest, protection efficacy in an immunisation regime and safety, depending on the timing of zinc-finger nuclease expression within the life cycle. We also identify DNA repair by microhomology-mediated end joining with as little as four base pairs, resulting in surviving parasites and thus breakthrough infections. Malaria parasites can repair DNA double-strand breaks with surprisingly small mini-homology domains located across the break point. Timely expression of zinc-finger nucleases could be used to generate a new generation of attenuated parasite lines lacking hundreds of genes.


Breast Volume Asymmetry Value, Ratio, and Cancer Risk.
The aim of this study was to investigate the criteria for determining the cancer risk of the breast asymmetry by comparing breast volume asymmetry levels between healthy women and women with cancer. Two hundred and one women with breast cancer (group 1) were compared with 446 healthy women (group 2) who had no pathologic findings in breast sonography and mammograpy repeated with one-year interval. Data were evaluated retrospectively. Each breast volume was measured twice by Grossman-Roudner Discs. The mean value has been recorded. The amounts of volume difference between two breasts (asymmetry value) and the rates of the volume difference to the breast volume of the smaller side (asymmetry ratio) were compared in both groups. There was a statistically significant difference between two groups with regard to average age and body mass index (P < 0.01). This significance was decreased but not disappeared, when the comparison was made within the 40-69 age group (P > 0.01). The rate of cases with asymmetry value over 50 mL was significantly higher in the cancer group (P = 0.029). Unfortunately, it disappeared in the 40-69 age group (P = 0.201). The breast volume asymmetry ratio over 20% was significantly higher in the cancer group both in all ages and in the 40-69 age group (P < 0.01). Odds ratio was 2.18 in the entire (all) series and 2.01 in the 40-69 age group. Moreover, there was no significant difference with regard to the rate of tumor location between the smaller or larger side of breast. Our data show that there is a positive correlation between breast asymmetry ratio over 20% and breast cancer risk. These results need to be confirmed by prospective randomized controlled trials.


Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-9) in F344 Rats and B6C3F1 Mice(Gavage Studies).
Furan serves as an intermediate in the synthesis and preparation of numerous linear polymers used to prepare temperature-resistant structural laminates and to prepare copolymers used in machine dishwashing products as alternatives to phosphorus- and nitrogen-containing detergents. Toxicology and carcinogenesis studies were conducted by administering furan (purity > 99%) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, mouse bone marrow cells, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells. 16-Day Studies: Groups of five male rats received doses of 0, 5, 10, 20, 40, or 80 mg of furan per kg of body weight and groups of five female rats and five mice of each sex received doses of 0, 10, 20, 40, 80, and 160 mg/kg in corn oil by gavage. All male and female mice and female rats that received 160 mg/kg, all male and female rats and all male and four female mice that received 80 mg/kg, and three male mice that received 40 mg/kg died by day 8. Final mean body weights of male rats that received 20 mg/kg and of male and female rats that received 40 mg/kg were significantly lower than controls. Final mean body weights of male mice that received 10 or 20 mg/kg were significantly greater than controls. Mottled and enlarged livers were observed at necropsy in male rats that received 20, 40, or 80 mg/kg and in females that received 40, 80, or 160 mg/kg. No lesions were observed at necropsy that were considered related to furan administration in mice. 13-Week Studies: Groups of 10 rats of each sex and groups of 10 female mice received doses of 0, 4, 8, 15, 30, or 60 mg of furan per kg of body weight, and groups of 10 male mice received doses of 0, 2, 4, 8, 15, or 30 mg/kg in corn oil by gavage. Nine male and four female rats that received 60 mg/kg died before the end of the studies. There were no chemical-related deaths in mice. Final mean body weights of male rats that received 15 or 30 mg/kg and female rats that received 60 mg/kg were significantly lower than controls. Final mean body weights of male mice that received 60 mg/kg were significantly lower than controls. Relative and absolute liver weights in both sexes of rats and mice were increased in groups that received furan, as were relative and absolute kidney weights in female rats that received furan. Thymus weights were decreased in all groups of rats that received furan. Toxic lesions of the liver (bile duct hyperplasia, cholangiofibrosis, cytomegaly and degeneration of hepatocytes, and nodular hyperplasia of hepatocytes) were associated with furan administration in all dose groups of rats; the severity of the lesions increased with dose. Kidney lesions (tubule dilatation and necrosis of tubule epithelium) were present in rats that received 30 or 60 mg/kg. Thymic atrophy and testicular or ovarian atrophy were also observed in rats exposed to 60 mg/kg furan. Toxic liver lesions (cytomegaly, degeneration, and necrosis of hepatocytes) were also present in all groups of furan-exposed mice. Bile duct hyperplasia and cholangiofibrosis were observed in groups of mice receiving 30 or 60 mg/kg. Doses selected for the 2-year studies of rats and mice were based on the hepatotoxicity associated with exposure to furan. 2-Year Studies: Groups of 70 rats of each sex were administered 2, 4, or 8 mg furan per kg body weight in corn oil by gavage 5 days per week for 2 years. After 9 and 15 months of chemical exposure, 10 rats per group were evaluated for the presence of treatment-associated lesions. Groups of 50 mice of each sex received doses of 8 or 15 mg/kg furan 5 days per week for 2 years. Body Weight and Survival: Mean body weights of male rats that received 8 mg/kg furan were lower than controls from approximately week 73 to the end of the study. Survival of male and female rats that received 8 mg/kg was lower than controls from approximately week 85 to the end of the studies as a result of moribund condition associatedassociated with liver and biliary tract neoplasms and mononuclear cell leukemia. Mean body weights of male and female mice that received 15 mg/kg furan were lower than controls during the studies. Survival of low- and high-dose male and high-dose female mice was lower than controls from approximately week 80 to the end of the studies as a result of moribund condition associated with liver neoplasms. Neoplastic and Nonneoplastic Lesions: Cholangiocarcinoma of the liver occurred in all groups of dosed rats (males: control, 0/50; low dose, 43/50; mid dose, 48/50; high dose, 49/50; females: 0/50; 49/50; 50/50; 48/50) and was present in many rats of each sex at the 9- and 15-month interim evaluations (9-month: males - 0/10, 5/10, 7/10, 10/10; females - 0/10, 4/10, 9/10, 10/10; 15-month: males - 0/10, 7/10, 9/10, 6/10; females - 0/10, 9/10, 9/10, 7/10). Hepatocellular adenomas or carcinomas (combined) were significantly increased in male rats after 2 years of chemical administration (1/50, 5/50, 22/50, 35/50) and hepatocellular adenomas were significantly increased in female rats (0/50, 2/50, 4/50, 7/50); hepatocellular neoplasms were not observed at the 9- or 15-month interim evaluations. Increased incidences of numerous nonneoplastic liver lesions were present in rats administered furan. These lesions included biliary tract fibrosis, hyperplasia, chronic inflammation, and proliferation and hepatocyte cytomegaly, cytoplasmic vacuolization, degeneration, nodular hyperplasia, and necrosis. The incidence of mononuclear cell leukemia was increased in male and female rats that received 4 or 8 mg/kg furan (males: 8/50, 11/50, 17/50, 25/50; females: 8/50, 9/50, 17/50, 21/50); the incidence in the 8 mg/kg groups of each sex exceeded the historical control ranges for corn oil gavage studies. The severity of nephropathy increased with dose and the incidence was significantly increased in all groups of dosed rats; this increased severity was accompanied by an associated increased incidence of parathyroid hyperplasia (renal secondary hyperparathyroidism). The incidence of forestomach hyperplasia was increased in male and female rats (males: 1/50, 4/49, 7/50, 6/50; females: 0/50, 2/50, 5/50, 5/50) and the incidence of subacute inflammation of the forestomach was increased in female rats (0/50, 1/50, 5/50, 6/50). No forestomach neoplasms were observed in males; a squamous papilloma was present in one low-dose female. The incidences of hepatocellular adenomas and carcinomas were significantly increased in mice receiving furan (males: adenoma - 20/50, 33/50, 42/50; carcinoma - 7/50, 32/50, 34/50; females: adenoma - 5/50, 31/50, 48/50; carcinoma - 2/50, 7/50, 27/50). The incidences of numerous nonneoplastic hepatocellular lesions were increased in dosed mice. These lesions included hepatocyte cytomegaly, degeneration, necrosis, multifocal hyperplasia, and cytoplasmic vacuolization and biliary tract dilatation, fibrosis, hyperplasia, and inflammation. The incidences of benign pheochromocytoma and focal hyperplasia of the adrenal medulla were increased in low- and high-dose male and in high-dose female mice (benign pheochromocytoma: males - 1/49, 6/50, 10/50; females - 2/50, 1/50, 6/50). The incidences of squamous papilloma, focal inflammation, and papillary hyperplasia of the forestomach were increased in male mice (squamous papilloma: 0/49, 1/50, 3/50; focal inflammation: 9/49, 13/50, 21/50; papillary hyperplasia: 7/49, 14/50, 22/50). Stop-Exposure Study: A separate 2-year study was conducted in which 50 male rats were administered 30 mg/kg furan in corn oil by gavage 5 days per week for 13 weeks and then maintained for the remainder of the 2 years without additional furan administration. Groups of 10 animals were evaluated for the presence of treatment-related lesions at the end of the 13-week period of furan administration and at 9 and 15 months. Neoplastic and Nonneoplastic Lesions: Cholangiocarcinoma of the liver occurred with an overall incidence of 100% (40/40) and hepatocellular carcinoma occurred with an overall incidence of 15% (6/40) in stop-exposure male rats that survived at least 9 months. Cholangiocarcinoma was observed in all 10 males at both the 9-month and 15-month interim evaluations. Hepatocellular carcinoma was first observed in 2 males at the 15-month interim evaluation. Genetic Toxicology: Furan was negative for induction of gene mutations in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 in the presence and the absence of exogenous metabolic activation (S9). Furan was negative for the induction of sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered either by feeding or by injection. In vitro tests for genotoxicity in mammalian cells, however, were positive. Furan induced trifluorothymidine resistance in mouse L5178Y lymphoma cells in the absence of S9, and sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells, with and without S9. Furan administered to male B6C3F1 mice by intraperitoneal injection induced chromosomal aberrations but not sister chromatid exchanges in bone marrow cells. Conclusions: Under the conditions of these 2-year gavage studies there was clear evidence of carcinogenic activity of furan in male and female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver and on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms of the liver and benign pheochromocytomas of the adrenal gland. Nonneoplastic liver lesions associated with furan administration in rats and mice included biliary tract fibrosis, hyperplasia, inflammation, and proliferation, as well as hepatocellular cytomegaly, degeneration, hyperplasia, necrosis, and vacuolization. In rats, increased severity of nephropathy with an associated increased incidence of parathyroid hyperplasia was associated with exposure to furan. Synonyms: Divinylene oxide, tetrole, furfuran, oxole, 1,4-epoxy-1,3-butadiene, axole, oxacyclopentadiene


Evidence for shutter-speed variation in CR bolus-tracking studies of human pathology.
The standard pharmacokinetic model for the analysis of MRI contrast reagent (CR) bolus-tracking (B-T) data assumes that the mean intracellular water molecule lifetime (tau(i)) is effectively zero. This assertion is inconsistent with a considerable body of physiological measurements. Furthermore, theory and simulation show the B-T time-course shape to be very sensitive to the tau(i) magnitude in the physiological range (hundreds of milliseconds to several seconds). Consequently, this standard model aspect can cause significant underestimations (factors of 2 or 3) of the two parameters usually determined: K(trans), the vascular wall CR transfer rate constant, and v(e), the CR distribution volume (the extracellular, extravascular space fraction). Analyses of animal model data confirmed two predicted behaviors indicative of this standard model inadequacy: (1) a specific temporal pattern for the mismatch between the best-fitted curve and data; and (2) an inverse dependence of the curve's K(trans) and v(e) magnitudes on the CR dose. These parameters should be CR dose-independent. The most parsimonious analysis allowing for realistic tau(i) values is the 'shutter-speed' model. Its application to the experimental animal data essentially eliminated the two standard model signature inadequacies. This paper reports the first survey for the extent of this 'shutter-speed effect' in human data. Retrospective analyses are made of clinical data chosen from a range of pathology (the active multiple sclerosis lesion, the invasive ductal carcinoma breast tumor, and osteosarcoma in the leg) that provides a wide variation, particularly of K(trans). The signature temporal mismatch of the standard model is observed in all cases, and is essentially eliminated by use of the shutter-speed model. Pixel-by-pixel maps show that parameter values from the shutter-speed analysis are increased by more than a factor of 3 for some lesion regions. This endows the lesions with very high contrast, and reveals heterogeneities that are often not seen in the standard model maps. Normal muscle regions in the leg allow validation of the shutter-speed model K(trans), v(e), and tau(i) magnitudes, by comparison with results of previous careful rat leg studies not possible for human subjects.


Cannabidiol improves vasorelaxation in Zucker diabetic fatty rats through cyclooxygenase activation.
Cannabidiol (CBD) decreases insulitis, inflammation, neuropathic pain, and myocardial dysfunction in preclinical models of diabetes. We recently showed that CBD also improves vasorelaxation in the Zucker diabetic fatty (ZDF) rat, and the objective of the present study was to establish the mechanisms underlying this effect. Femoral arteries from ZDF rats and ZDF lean controls were isolated, mounted on a myograph, and incubated with CBD (10 μM) or vehicle for 2 hours. Subsequent vasorelaxant responses were measured in combination with various interventions. Prostaglandin metabolites were detected using enzyme immunoassay. Direct effects of CBD on cyclooxygenase (COX) enzyme activity were measured by oxygraph assay. CBD enhanced the maximum vasorelaxation to acetylcholine (ACh) in femoral arteries from ZDF lean rats (P < 0.01) and especially ZDF rats (P < 0.0001). In ZDF arteries, this enhancement persisted after cannabinoid receptor (CB) type 1, endothelial CB, or peroxisome proliferator-activated receptor-γ antagonism but was inhibited by CB2 receptor antagonism. CBD also uncovered a vasorelaxant response to a CB2 agonist not previously observed. The CBD-enhanced ACh response was endothelium-, nitric oxide-, and hydrogen peroxide-independent. It was, however, COX-1/2- and superoxide dismutase-dependent, and CBD enhanced the activity of both purified COX-1 and COX-2. The CBD-enhanced ACh response in the arteries was inhibited by a prostanoid EP4 receptor antagonist. Prostaglandin E2 metabolite levels were below the limits of detection, but 6-keto prostaglandin F1 α was decreased after CBD incubation. These data show that CBD exposure enhances the ability of arteries to relax via enhanced production of vasodilator COX-1/2-derived products acting at EP4 receptors.


Construction of a 2.5-Mb integrated physical and gene map of distal 21q22.3.
The gene-rich telomeric region of 21q harbors several loci relevant to human diseases including autoimmune polyglandular disease type I, nonsyndromic deafness, Knobloch syndrome, holoprosencephaly, and bipolar affective disorder. A contig of genomic clones in this region would facilitate the isolation of these genes. However, distal 21q22.3 has yet been poorly mapped, presumably due to the presence of sequences that are underrepresented in yeast artificial chromosome (YAC) libraries. We generated a framework of YACs and used these clones as starting points for the isolation of a combination of bacterial artificial chromosome clones, P1-derived artificial chromosome clones, and cosmid clones by chromosome walking procedures. These studies resulted in the construction of a high-resolution contig map spanning the 2.5-Mb region from PFKL to the telomere, approximately 2 Mb of which are covered by ready-to-sequence contigs. Within this map we determined the location and relative distance of 21 markers. These include 9 established genetic markers, the order of which is cen-PFKL-D21S154-D21S170-D21S171-D21S1903- D21S1897- D21S112-D21S1446-D21S1575-tel. Moreover, we established the precise map position of 13 genes and 4 ESTs including the recently isolated genes C21ORF2, SMT3H1, RNA editing deaminase 1 (ADARB1), folate transporter (SLC19A1), COL18A1, lanosterol synthase (LSS-PEN), pericentrin (PCNT), and arginine methyltransferase (HRMT1L1). This integrated map provides a useful resource for the mapping and isolation of disease genes and for the construction of a complete transcription map of distal 21q as well as for large-scale sequencing efforts.


Associations of dietary macronutrients and micronutrients with the traditional and nontraditional risk factors for cardiovascular disease among hemodialysis patients: A clinical cross-sectional study.
The current study was to examine the association of adequate intake of macronutrients and micronutrients with traditional and nontraditional cardiovascular risk factors in hemodialysis patients.A clinical cross-sectional study was conducted between September 2013 and April 2017 on 492 hemodialysis patients aged 20 years and above, received thrice-weekly hemodialysis treatment for at least 3 months, adequate dialysis quality (equilibrated Kt/V ≥ 1.2 g/kg/d) from 7 hospital-based hemodialysis centers in Taiwan. The dietary intake was evaluated by the 3-day dietary record, and a 24-hour dietary recall. Biochemical parameters were archived from laboratory tests. The cardiovascular disease (CVD) risk factors were defined by the Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines. The adequate dietary intake of macronutrients and micronutrients was recommended by the European Best Practice Guidelines, K/DOQI, and Institute of Medicine guidelines. Logistic regression analysis was used.All hemodialysis patients had CVD risks, the lowest proportion of patients with adequate intake of macronutrients and micronutrients were 8.7% and 1.8%, respectively. The adequate dietary intake associated with lower likelihood of having CVD risks in hemodialysis patient by 47% to 84%, including 39% to 58% lower hypertension, 37% to 50% lower dyslipidemia, 42% to 63% diabetes mellitus, 44% to 84% lower obesity, 58% lower low calcium, 38% lower hyperparathyroidism, 47% to 64% lower hyperhomocysteinemia, and 41% to 67% lower inflammation, 63% to 74% lower hypoalbumin, 73% lower inadequate normalized protein nitrogen appearance.Adequate dietary nutrients intake may reduce the cardiovascular risks factors, in turn, to prevent the cardiovascular morbidity and mortality.


Elucidating the multiple structures of pipecolic acid by rotational spectroscopy.
The complex conformational space of the non-proteinogenic cyclic amino acid pipecolic acid has been explored in the gas phase for the first time. Solid pipecolic acid samples were vaporized by laser ablation and expanded in a supersonic jet where the rotational spectral signatures owing to nine different conformers were observed by Fourier transform microwave spectroscopy. All species were identified by comparison of the experimental rotational and nuclear quadrupole coupling constants with those predicted theoretically. Observation of type-III conformers, leading to a difference when compared against the conformational behavior of the analog amino acid proline, has been interpreted by an increment in steric hindrance when increasing the number of carbons present in the ring.


Affect and Personality: Ramifications of Modeling (Non-)Directionality in Dynamic Network Models.
The use of dynamic network models has grown in recent years. These models allow researchers to capture both lagged and contemporaneous effects in longitudinal data typically as variations, reformulations, or extensions of the standard vector autoregressive (VAR) models. To date, many of these dynamic networks have not been explicitly compared to one another. We compare three popular dynamic network approaches-GIMME, uSEM, and LASSO gVAR-in terms of their differences in modeling assumptions, estimation procedures, statistical properties based on a Monte Carlo simulation, and implications for affect and personality researchers. We found that all three approaches dynamic networks provided yielded group-level empirical results in partial support of affect and personality theories. However, individual-level results revealed a great deal of heterogeneity across approaches and participants. Reasons for discrepancies are discussed alongside these approaches' respective strengths and limitations.


Use of Crowd Innovation to Develop an Artificial Intelligence-Based Solution for Radiation Therapy Targeting.
Radiation therapy (RT) is a critical cancer treatment, but the existing radiation oncologist work force does not meet growing global demand. One key physician task in RT planning involves tumor segmentation for targeting, which requires substantial training and is subject to significant interobserver variation. To determine whether crowd innovation could be used to rapidly produce artificial intelligence (AI) solutions that replicate the accuracy of an expert radiation oncologist in segmenting lung tumors for RT targeting. We conducted a 10-week, prize-based, online, 3-phase challenge (prizes totaled $55 000). A well-curated data set, including computed tomographic (CT) scans and lung tumor segmentations generated by an expert for clinical care, was used for the contest (CT scans from 461 patients; median 157 images per scan; 77 942 images in total; 8144 images with tumor present). Contestants were provided a training set of 229 CT scans with accompanying expert contours to develop their algorithms and given feedback on their performance throughout the contest, including from the expert clinician. The AI algorithms generated by contestants were automatically scored on an independent data set that was withheld from contestants, and performance ranked using quantitative metrics that evaluated overlap of each algorithm's automated segmentations with the expert's segmentations. Performance was further benchmarked against human expert interobserver and intraobserver variation. A total of 564 contestants from 62 countries registered for this challenge, and 34 (6%) submitted algorithms. The automated segmentations produced by the top 5 AI algorithms, when combined using an ensemble model, had an accuracy (Dice coefficient = 0.79) that was within the benchmark of mean interobserver variation measured between 6 human experts. For phase 1, the top 7 algorithms had average custom segmentation scores (S scores) on the holdout data set ranging from 0.15 to 0.38, and suboptimal performance using relative measures of error. The average S scores for phase 2 increased to 0.53 to 0.57, with a similar improvement in other performance metrics. In phase 3, performance of the top algorithm increased by an additional 9%. Combining the top 5 algorithms from phase 2 and phase 3 using an ensemble model, yielded an additional 9% to 12% improvement in performance with a final S score reaching 0.68. A combined crowd innovation and AI approach rapidly produced automated algorithms that replicated the skills of a highly trained physician for a critical task in radiation therapy. These AI algorithms could improve cancer care globally by transferring the skills of expert clinicians to under-resourced health care settings.


Multi-site implementation of nutrition screening and diagnosis in medical care units: Success of the More-2-Eat project.
Improving the detection and treatment of malnourished patients in hospital is needed to promote recovery. To describe the change in rates of detection and triaging of care for malnourished patients in 5 hospitals that were implementing an evidence-based nutrition care algorithm. To demonstrate that following this algorithm leads to increased detection of malnutrition and increased treatment to mitigate this condition. Sites worked towards implementing the Integrated Nutrition Pathway for Acute Care (INPAC), including screening (Canadian Nutrition Screening Tool) and triage (Subjective Global Assessment; SGA) to detect and diagnose malnourished patients. Implementation occurred over a 24-month period, including developmental (Period 1), implementation (Periods 2-5), and sustainability (Period 6) phases. Audits (n = 36) of patient health records (n = 5030) were conducted to identify nutrition care practices implemented with a variety of strategies and behaviour change techniques. All sites increased nutrition screening from Period 1, with three achieving the goal of 75% of admitted patients being screened by Period 3, and the remainder achieving a rate of 70% by end of implementation. No sites were conducting SGA at Period 1, and sites reached the goal of a 75% completion rate or referral for those identified to be at nutrition risk, by Period 3 or 4. By Period 2, 100% of patients identified as SGA C (severely malnourished) were receiving a comprehensive nutritional assessment. In Period 1, the nutrition diagnosis and documentation by the dietitian of 'malnutrition' was a modest 0.37%, increasing to over 5% of all audited health records. The overall use of any Advanced Nutrition Care practices increased from 31% during Period 1 to 63% during Period 6. The success of this multi-site study demonstrated that implementation of nutrition screening and diagnosis is feasible and leads to appropriate care. INPAC promotes efficiency in nutrition care while minimizing the risk of missing malnourished patients. Retrospectively registered ClinicalTrials.gov Identifier: NCT02800304, June 7, 2016.


Dysregulation of L-arginine metabolism and bioavailability associated to free plasma heme.
Severe Plasmodium falciparum malaria is associated with hypoargininemia, which contributes to impaired systemic and pulmonary nitric oxide (NO) production and endothelial dysfunction. Since intravascular hemolysis is an intrinsic feature of severe malaria, we investigated whether and by which mechanisms free heme [Fe(III)-protoporphyrin IX (FP)] might contribute to the dysregulation of L-arginine (L-Arg) metabolism and bioavailability. Carrier systems "y+" [or cationic amino acid transporter (CAT)] and "y+L" transport L-Arg into red blood cells (RBC), where it is hydrolyzed to ornithine and urea by arginase (isoform I) or converted to NO* and citrulline by endothelial nitric oxide synthase (eNOS). Our results show a significant and dose-dependent impairment of L-Arg transport into RBC pretreated with FP, with a strong inhibition of the system carrier y+L. Despite the impaired L-Arg influx, higher amounts of L-Arg-derived urea are produced by RBC preexposed to FP caused by activation of RBC arginase I. This activation appeared not to be mediated by oxidative modifications of the enzyme. We conclude that L-Arg transport across RBC membrane is impaired and arginase-mediated L-Arg consumption enhanced by free heme. This could contribute to reduced NO production in severe malaria.


Noncontraceptive estrogens and abnormalities of endometrial proliferation.
Use of estrogen preparations among menopausal women has been causally associated with the development of hyperplasia and adenocarcinoma of the endometrium. The magnitude of the association seems to be greater for the hyperplastic and least aggressive malignant lesions, and smaller for tumors of higher stage and grade. This observed inverse relation of estrogen use to degree of malignancy is probably due to relatively early or overly liberal diagnoses of endometrial cancer among estrogen users, but could mean simply that estrogens promote less aggressive tumors. It appears the current increased incidence of endometrial cancer in the United States will not be followed by a corresponding increase in mortality from the disease.


Novel perspectives in mammalian copper metabolism through the use of genome-wide approaches.
The transition metal copper plays an essential role in many biological processes but is highly toxic in excess. Recent studies have characterized a highly conserved set of proteins that mediate cellular copper import, distribution, sequestration, utilization, and export. Nevertheless, the pathogenesis of copper overload and copper deficiency disorders is not well understood, and we are only beginning to comprehend the results of mild copper overload or deficiency in relation to nutritional uptake and common diseases at the population level. Technological advances open the possibility to dissect the complete genome for genetic variants predisposing to copper overload or depletion and for variations in gene expression generated by either reduced or excessive copper intake. We discuss the potential of integrated genome-wide applications to advance our knowledge of copper homeostasis and to develop molecular biomarker profiles as indicators of copper status.


Azithromycin analogue CSY0073 attenuates lung inflammation induced by LPS challenge.
Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulating effects. Long-term azithromycin therapy in patients with chronic lung diseases such as cystic fibrosis has been associated with increased antimicrobial resistance, emergence of hypermutable strains, ototoxicity and cardiac toxicity. The aim of this study was to assess the anti-inflammatory effects of the non-antibiotic azithromycin derivative CSY0073. We compared the effects of CSY0073 with those of azithromycin in experiments on bacterial cultures, Pseudomonas aeruginosa biofilm, lung cells and mice challenged intranasally with P. aeruginosa LPS. In contrast to azithromycin, CSY0073 did not inhibit the growth of P. aeruginosa, Staphylococcus aureus or Haemophilus influenzae and had no effect on an established P. aeruginosa biofilm. Bronchoalveolar lavage (BAL) fluids and lung homogenates collected after the LPS challenge in mice showed that CSY0073 and azithromycin (200 mg·kg(-1), i.p.) decreased neutrophil counts at 24 h and TNF-α, CXCL1 and CXCL2 levels in the BAL fluid after 3 h and IL-6, CXCL2 and IL-1β levels in the lung after 3 h compared with the vehicle. However, only azithromycin reduced IL-1β levels in the lung 24 h post LPS challenge. CSY0073 and azithromycin similarly diminished the production of pro-inflammatory cytokines by macrophages, but not lung epithelial cells, exposed to P. aeruginosa LPS. Unlike azithromycin, CSY0073 had no antibacterial effects but it did have a similar anti-inflammatory profile to that of azithromycin. Hence, CSY0073 may have potential as a long-term treatment for patients with chronic lung diseases.


Biofeedback interventions for gastrointestinal conditions: a systematic review.
To review evidence for the efficacy of biofeedback in the treatment of gastrointestinal problems. Studies were identified through a search of MEDLINE, HealthSTAR, EMBASE, Allied and Complementary Medicine, MANTIS, PsycINFO, Social Science Citation Index, Science Citation Index, and CINAHL. Studies were selected if they used biofeedback as the intervention, addressed the treatment of a gastrointestinal condition, and included a control group. All titles (4397), articles, and/or abstracts (1362) were evaluated by 2 independent reviewers who extracted data on study design and quality, sample size, type of intervention, and outcomes. We found 16 controlled trials of biofeedback for gastrointestinal problems. Ten studies had a comparison group that did not receive biofeedback (5 studies on constipation and/or encopresis, 3 on fecal incontinence, 1 on constipation, and 1 on abdominal pain). Of the 10 studies that had a "no biofeedback" control arm, 7 provided sufficient data to calculate an effect size. Of these 7 studies, 2 favored biofeedback: 1 study revealed a reduction in fecal incontinence among adults, and the other study showed an improvement in constipation with fecal incontinence (encopresis) among children. The other 5 had nonsignificant results. Three studies had a "no biofeedback" comparison arm but insufficient data to calculate an effect size. One of these studies in adult fecal incontinence reported statistically significant improvement. The evidence is insufficient to support the efficacy of biofeedback for these gastrointestinal conditions.


Biogeographic patterns in genomic diversity among a large collection of Vibrio cholerae isolates.
Vibrio cholerae strains are capable of inhabiting multiple niches in the aquatic environment and in some cases cause disease in humans. However, the ecology and biodiversity of these bacteria in environmental settings remains poorly understood. We used the genomic fingerprinting technique enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR) to profile 835 environmental isolates from waters and sediments obtained at nine sites along the central California coast. We identified 115 ERIC-PCR genotypes from 998 fingerprints, with a reproducibility of 98.5% and a discriminatory power of 0.971. When the temporal dynamics at a subset of sampling sites were explored, several genotypes provided evidence for cosmopolitan or geographically restricted distributions, and other genotypes displayed nonrandom patterns of cooccurrence. Partial Mantel tests confirmed that genotypic similarity of isolates across all sampling events was correlated with environmental similarity (0.04 < or = r < or = 0.05), temporal proximity (r = 0.09), and geographic distance (r = 0.09). A neutral community model for all sampling events explained 61% of the variation in genotype abundance. Cooccurrence indices (C-score, C-board, and Combo) were significantly different than expected by chance, suggesting that the V. cholerae population may have a competitive structure, especially at the regional scale. Even though stochastic processes are undoubtedly important in generating biogeographic patterns in diversity, deterministic factors appear to play a significant, albeit small, role in shaping the V. cholerae population structure in this system.


Angiocardiography and magnetic resonance imaging to assess pulmonary regurgitation in repaired tetralogy of Fallot.
This study aimed to compare the results of angiocardiography and cardiovascular magnetic resonance imaging in the assessment of pulmonary regurgitation following repair of tetralogy of Fallot. We prospectively studied 37 patients with repaired tetralogy of Fallot. After routine examination cardiovascular magnetic resonance imaging (CMR) and cardiac catheterization and angiography were performed. Pulmonary regurgitation (PR) was classified according to the following criteria, using a left lateral angiogram of the main pulmonary artery; insufficiency jet is limited to right ventricular outflow tract (mild); jet reaches the body of right ventricle (moderate); jet fills the apex of the right ventricle (severe). Pulmonary regurgitation determined by angiocardiography and CMR was severe in 51.4% and 32.4%, moderate in 27% and 40.5%, and none or mild in 21.6% and 27% of patients respectively. The ability of semi-quantitative estimation of PR determined by cardiac catheterization to distinguish between mild, moderate and severe pulmonary regurgitation was shown to have significant correlation with pulmonary regurgitant fraction obtained by CMR. Angiography obtained during invasive study can be used for the diagnosis and follow-up of pulmonary regurgitation confidently in patients with repaired tetralogy of Fallot and residual pulmonary regurgitation.


Hyperglycosylated stable core immunogens designed to present the CD4 binding site are preferentially recognized by broadly neutralizing antibodies.
The HIV-1 surface envelope glycoprotein (Env) trimer mediates entry into CD4(+) CCR5(+) host cells. Env possesses conserved antigenic determinants, such as the gp120 primary receptor CD4 binding site (CD4bs), a known neutralization target. Env also contains variable regions and protein surfaces occluded within the trimer that elicit nonneutralizing antibodies. Here we engineered additional N-linked glycans onto a cysteine-stabilized gp120 core (0G) deleted of its major variable regions to preferentially expose the conformationally fixed CD4bs. Three, 6, 7, and 10 new NXT/S glycan (G) motifs were engineered into 0G to encode 3G, 6G, 7G, and 10G cores. Following purification, most glycoproteins, except for 10G, were recognized by broadly neutralizing CD4bs-directed antibodies. Gel and glycan mass spectrometry confirmed that additional N-glycans were posttranslationally added to the redesigned cores. Binding kinetics revealed high-affinity recognition by seven broadly neutralizing CD4bs-directed antibodies and low to no binding by non-broadly neutralizing CD4bs-directed antibodies. Rabbits inoculated with the hyperglycosylated cores elicited IgM and IgG responses to each given protein that were similar in their neutralization characteristics to those elicited by parental 0G. Site-specific glycan masking effects were detected in the elicited sera, and the antisera competed with b12 for CD4bs-directed binding specificity. However, the core-elicited sera showed limited neutralization activity. Trimer priming or boosting of the core immunogens elicited tier 1-level neutralization that mapped to both the CD4bs and V3 and appeared to be trimer dependent. Fine mapping at the CD4bs indicated that conformational stabilization of the cores and addition of N-glycans altered the molecular surface of Env sites of vulnerability to neutralizing antibody, suggesting an explanation for why the elicited neutralization was not improved by this rational design strategy. Major obstacles to developing an effective HIV-1 vaccine include the variability of the envelope surface glycoproteins and its high-density glycan shield, generated by incorporation of host (human) glycosylation. HIV-1 does harbor highly conserved sites on the exposed envelope protein surface of gp120, one of which is the virus receptor (CD4) binding site. Several broadly neutralizing antibodies elicited from HIV patients do target this gp120 CD4 binding site (CD4bs); however, gp120 immunogens do not elicit broadly neutralizing antibodies. In this study, we targeted the CD4bs by conformational stabilization and additional glycan masking. We used the atomic-level structure to reengineer gp120 cores to preferentially present the cysteine-stabilized CD4bs and to mask (by glycan) nonneutralizing determinants. Importantly, glycan masking did successfully focus antibody responses to the CD4bs; however, the elicited CD4bs-directed antibodies did not neutralize HIV or bind to unmodified gp120, presumably due to the structure-guided modifications of the modified gp120 core.