The inflammatory microenvironment of nasal polyps in patients with chronic rhinosinusitis and the relationship of this microenvironment with the nasal microbiome.
We investigated the characteristics of the microbial community of the nasal sinuses in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and identified the correlations of the nasal microbiome with the inflammatory microenvironment of the nasal cavity. We collected matched nasal secretion and polyp tissue samples from 77 CRSwNP patients. Then, we extracted microbial DNA from cotton swabs, used high-throughput sequencing technology based on 16S ribosomal RNA (rRNA) to detect the bacterial community composition, and detected cytokines such as interleukin (IL)-5, IL-8, IL-17a, IL-17e, IL-18, IL-27 and interferon (INF)-gamma in the polyp tissue samples using Luminex. Eosinophils and neutrophils in the peripheral blood and polyp tissue were counted, and the relationships between inflammatory factors or inflammatory cell counts and nasal microbial diversity were analyzed. Among the inflammatory factors evaluated, IL-5 had a positive rate of 32.47%, IFN-γ had a positive rate of 84.42%, IL-17A and IL-17E had positive rates of 75.32%, IL-18 had a positive rate of 94.81%, IL-27 had a positive rate of 68.83%, and IL-8 had a positive rate of 100%. IL-17a and IL-27 were negatively correlated with both Enterobacter and Anaerococcus, IL-8 was negatively correlated with both Enterobacter and Staphylococcus, IL-18 was positively correlated with Candidatus Arthromitus and negatively correlated with Haemophilus, and IL-27 was positively correlated with Faecalibaculum. Lactobacillus and Enterococcus were positively correlated with the degree of neutrophil infiltration in nasal polyp tissue. In Southwest China, inflammation of the nasal polyps exhibits a variety of patterns. Enterobacteria and anaerobic bacteria may be correlated with the inflammatory pattern of nasal polyps. The neutrophil-mediated inflammatory response plays an important role in patients with CRSwNP in Southwest China.


In vitro characteristics and in vivo immunosuppressive activity of compact bone-derived murine mesenchymal progenitor cells.
In contrast to the considerable amount of data that documents the biological properties of mesenchymal progenitor cells from human and other species, there is still paucity of information about mouse counterparts, as their purification and culture expansion procedures remain rudimentary. In the present study, murine mesenchymal progenitor cell (muMPC) culture was developed by explant culture of collagenase-digested bone fragments after removal of the released cells. During cultivation, fibroblastoid cells sprouted and migrated from the fragments, followed by adherent monolayer development. The cells exhibited homogenous surface antigen profile and presented in vitro multipotential differentiation along osteocyte, chondrocyte, and adipocyte lineages, as evaluated by matched cell or matrix staining and reverse transcription polymerase chain reaction techniques. Also, the surface antigenic epitope changed and potential of proliferation and multidifferentiation decreased with successive subculturing. Functional investigations demonstrated that these cells supported in vitro hematopoiesis and suppressed lymphocyte cell proliferation triggered by ConA or allogeneic splenocytes. Furthermore, muMPCs prolonged the mean survival time of skin grafts across the major histocompatibility barrier (H2(b) --> H2(d)), suggestive of the immunosuppressive effects in vivo. The findings demonstrate that muMPCs obtained with this simple protocol are similar in property to their marrow counterparts, and thus, the protocol described here could be used for further investigations in mouse physiological and pathological models.


The effect of fixation condition manipulations on antisaccade performance in schizophrenia: studies of diagnostic specificity.
This series of studies evaluated (1) hypotheses that poor antisaccade performance is attributable to confounding variables (e.g., visual attention deficits, incomplete understanding of task demands) and (2) the specificity of poor antisaccade performance to schizophrenia. In addition to self-correcting errors before being cued to do so, schizophrenia patients also showed the expected saccadic reaction time changes to fixation condition manipulations: decreased latencies for gap and increased latencies for overlap trials. These data suggest that schizophrenia patients are adequately engaged in and understand the antisaccade task. Schizophrenia patients made fewer correct antisaccade responses than other psychiatric patients (obsessive-compulsive and bipolar disorder) and normal subjects. The first-degree relatives of schizophrenia patients also generated a decreased proportion of correct antisaccade responses compared with normal subjects. For schizophrenia patients who performed below the range of normal subjects, 26% of their relatives also performed below the normal range. Conversely, patients who performed normally did not have a single poor-performing relative. These data suggest that increased antisaccade error rates may index a liability for schizophrenia within a subset of families.


Establishing smoke-free hospitals in Vietnam: a pilot project.
In Vietnam, a pilot 'smoke-free hospital' model was implemented in nine hospitals in 2009-2010 to supply lessons learned that would facilitate a replication of this model elsewhere. This study aimed to assess smoking patterns among health professionals and to detect levels of second-hand smoke (SHS) exposure within hospital premises before and after the 'smoke-free hospital' model implementation. A pre- and post-intervention cross-sectional study was conducted in nine purposively selected hospitals. Air nicotine levels were measured using passive nicotine monitors; smoking evidence was collected through on-site observations; and smoking patterns were assessed through interviews with health workers. Despite the 'smoke-free hospital' intervention, smoking continued among health-care workers who were former smokers. Specifically, self-reported smoking prevalence significantly decreased post-intervention, but the number of daily cigarettes smoked at workplaces among male health workers remained unchanged. Post-intervention, smoking was more likely to take place outside buildings and cafeterias. However, air nicotine levels in the doctors' lounges and in emergency departments did not change post-intervention. Air nicotine levels at other sites decreased minimally. Tailored tobacco cessation programmes, targeting current smokers and mechanisms to enforce non-smoking, should be established to meet requirements of Vietnam's comprehensive National Tobacco Control Law effective in May 2013.


The oral ecology of patients with severe Sjögren's syndrome.
An investigation of the commensal microflora, salivary flow rate, pH, and the degree of atrophy of the oral mucosa in ten patients with severe Sjögren's syndrome and ten control subjects, revealed a number of differences. The numbers of Streptococcus salivarius, Neisseria pharyngis, Veillonella species and Micrococcus mucilagenosus isolated from patients with Sjögren's syndrome were significantly reduced, while the numbers of Candida spp. and Staphylococcus aureus were significantly increased when compared with control subjects. In addition the salivary pH of the Sjögren's group was significantly reduced and the degree of mucosal atrophy increased compared with controls.


Antifungal effect of voriconazole on intracellular Candida glabrata, Candida krusei and Candida parapsilosis in human monocyte-derived macrophages.
Infections caused by Candida species other than Candida albicans are increasingly common, and decreased susceptibility to azoles has made them more difficult to treat. Since phagocytic killing is important in elimination of Candida infections, intracellular killing of fluconazole-resistant Candida glabrata, Candida krusei and Candida parapsilosis (four strains each) by voriconazole was investigated in human monocyte-derived macrophages (MDMs). MDMs were infected with Candida, and voriconazole was then added. MDMs were lysed at 0, 24 or 48 h after infection, and viable Candida in the lysates enumerated. Compared to the starting inoculum, the number of viable intracellular C. parapsilosis and C. glabrata in untreated MDMs increased to 28,121 and 351 %, respectively, in 48 h. In contrast, the number of C. krusei decreased to 42 %. In MDMs treated with voriconazole, the decrease in viable count was dependent upon drug concentration. At 48 h, C. glabrata was killed only at 5x MIC (P < 0.05), C. krusei was killed at all voriconazole concentrations, while C. parapsilosis was inhibited at 0.5 and 1x MIC and killed at > or = 2.5x MIC (P < 0.05). The data show that intracellular growth and survival of these Candida species in the absence or presence of voriconazole vary markedly. The activity of voriconazole depends on the concentration of the drug and the time of exposure. For the 12 Candida strains studied, regression curves show that the maximum intracellular anticandidal activity of voriconazole was reached at 3.5-5x MIC.


Pediatric Professional Medical Associations and Industry Guideline Compliance.
There has been an increasing focus on the relationship between pediatric prescribers and the biomedical industry. There is a lack of research, however, on the biomedical industry's relationship with the professional medical associations (PMAs) of pediatric prescribers. We developed a systematic method to assess this relationship by evaluating PMA transparency and compliance with a set of 2009 best practice guidelines (BPGs). Nine PMAs rated as having the greatest influence on pediatric prescribers were examined. Two researchers independently coded publicly accessible information from the PMAs' Web sites for transparency and compliance with 36 BPG recommendations. Using the coded data, an industry relationship index (IRI) score was developed to systematize comparisons across PMAs. The PMAs demonstrated transparency and compliance with less than one-half of the 2009 BPGs (mean ± SD: 30.2 ± 15.6; range: 8-51 on the 66-point IRI scale). Two PMAs clustered in the high IRI (more transparent and compliant) group, 3 in the medium group, and 4 in the low group. There was no significant association of IRI group status and the PMAs' number of members or age. PMAs were least compliant with recommendations that prohibit or limit financial relationships with industry. PMAs with influence on pediatric prescribers have achieved only limited transparency and compliance with a set of 2009 BPGs, particularly with respect to financial separation from industry. Use of quantifiable standards of conduct facilitates comparisons between organizations and may enhance public trust in PMAs, preserving their ability to achieve organizational goals.


Investigating the occurrence of persistent organic pollutants (POPs) in the arctic: their atmospheric behaviour and interaction with the seasonal snow pack.
POPs in the Arctic are the focus of international concern due to their occurrence and accumulation in Arctic food webs. This paper presents an overview of the major pathways into the Arctic and details contemporary studies that have focused on the occurrence and transfer of POPs between the major Arctic compartments, highlighting areas where there is a lack of quantitative information. The behaviour of these chemicals in the Arctic atmosphere is scrutinised with respect to long-term trends and seasonal behaviour. Subtle differences between the PCBs and OC pesticides are demonstrated and related to sources outside of the Arctic as well as environmental processes within the Arctic. Unlike temperate regions, contaminant fate is strongly affected by the presence of snow and ice. A description of the high Arctic snow pack is given and the physical characteristics that determine chemical fate, namely the specific surface area of snow and wind driven ventilation, are discussed. Using a well-characterised fresh snow event observed at Alert (Canadian high Arctic) [Atmos. Environ. 36(2002) 2767] the flux of gamma-HCH out of the snow is predicted following snow ageing. Under conditions of wind (10 m/s) it is estimated that approximately 75% of the chemical may be re-emitted to the atmosphere within 24 h following snowfall, compared with just approximately 5% under conditions of no wind. The implications of this are raised and areas of further research suggested.


Supplemental selenium source on gut health: insights on fecal microbiome and fermentation products of growing puppies.
Selenium is an essential trace element that can modulate the gut microbiome with an impact on host health. The present study aimed to evaluate the effects of organic (selenium-enriched yeast) vs inorganic (sodium selenite) selenium source on fecal end-fermentation products and gut microbiome of puppies from 20 to 52 weeks of age. Alpha and beta diversity of the gut bacterial community were affected by age but not by gender or selenium source. The relative abundance of taxa was differently affected by age, and the DNA concentration of all selected bacterial groups increased with age, although total volatile fatty acids (VFA), acetate, propionate, caproate and lactate concentrations decreased. Organic selenium was associated with a higher concentration of total VFA, propionate and butyrate, a higher number of DNA copies of Lactobacillus, and a trend to lower DNA copies of Escherichia coli. Effects on fecal microbiome during growth differed with selenium source. Females had higher fecal end-fermentation products related to protein degradation, whereas males had higher DNA concentration of Bifidobacterium. Organic selenium might be beneficial over inorganic for dog food supplementation due to the positive modulation of the gut microbiome observed in puppies.


Measurement of Electroretinograms and Visually Evoked Potentials in Awake Moving Mice.
The development of new treatments for intractable retinal diseases requires reliable functional assessment tools for animal models. In vivo measurements of neural activity within visual pathways, including electroretinogram (ERG) and visually evoked potential (VEP) recordings, are commonly used for such purposes. In mice, the ERG and VEPs are usually recorded under general anesthesia, a state that may alter sensory transduction and neurotransmission, but seldom in awake freely moving mice. Therefore, it remains unknown whether the electrophysiological assessment of anesthetized mice accurately reflects the physiological function of the visual pathway. Herein, we describe a novel method to record the ERG and VEPs simultaneously in freely moving mice by immobilizing the head using a custom-built restraining device and placing a rotatable cylinder underneath to allow free running or walking during recording. Injection of the commonly used anesthetic mixture xylazine plus ketamine increased and delayed ERG oscillatory potentials by an average of 67.5% and 36.3%, respectively, compared to unanesthetized mice, while having minimal effects on the a-wave and b-wave. Similarly, components of the VEP were enhanced and delayed by up to 300.2% and 39.3%, respectively, in anesthetized mice. Our method for electrophysiological recording in conscious mice is a sensitive and robust means to assess visual function. It uses a conventional electrophysiological recording system and a simple platform that can be built in any laboratory at low cost. Measurements using this method provide objective indices of mouse visual function with high precision and stability, unaffected by anesthetics.


Safety and efficacy of donepezil hydrochloride in patients with mild to moderate Alzheimer's disease: Findings of an observational study.
Alzheimer's disease (AD), a progressive brain disorder, is the most common cause of dementia among the elderly. Donepezil hydrochloride is a potent, reversible, and highly selective inhibitor of acetylcholinesterase (AChE). It is chemically distinct from other cholinesterase (ChE) inhibitors which are effective in the treatment of AD. To evaluate the safety and efficacy of donepezil hydrochloride therapy over a 12 weeks period in patients with mild to moderate AD in Indian population. In this post-marketing study, patients with mild to moderate AD received oral donepezil hydrochloride 5 mg/day for 4 weeks followed by 10 mg/day for 8 weeks. Patients were assessed 4 times weekly for cognition on 'Mini Mental Status Examination (MMSE) scale', and function on 'Activities of Daily Living (ADL) index'. Clinicians and caregivers assessment of safety and efficacy was assessed on a 5-point rating scale. One hundred and seventy two of one hundred and eighty two patients completed 12 weeks of study period. MMSE score significantly improved (P<0.0001) from 16.72 at baseline to 19.77 after 12 weeks, and there was significant improvement (P<0.05) in ADL index in 13 of 17 domains after 12 weeks. Caregivers and clinicians rated the therapy as very good to good in >80% and >90% patients, respectively. Adverse events were consistent with the known pharmacological and safety profile of donepezil. Donepezil is well tolerated in Indian patients with mild to moderate AD with significant improvement in cognition and function.


Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases.
The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activity are currently in clinical use for treatment of multiple myeloma and other cancers, and the deubiquitinase activity associated with the proteasome is also a valid target for anticancer agents. Recent studies suggested that zinc pyrithione, an FDA-approved antidandruff agent, may have antitumor activity, but the detailed molecular mechanisms remain unclear. Here we report that zinc pyrithione (ZnPT) targets the proteasome-associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes. Furthermore, ZnPT exhibits cytotoxic effects against various cancer cell lines in vitro, selectively kills bone marrow cells from leukemia patients ex vivo, and efficiently inhibits the growth of lung adenocarcinoma cancer cell xenografts in nude mice. This study has identified zinc pyrithione, an FDA-approved pharmacological agent with potential antitumor properties as a proteasomal DUB inhibitor.


Tolerance induction in hemophilia A animal models: battling inhibitors with antigen-specific immunotherapies.
Hemophilia A is an X-linked recessive bleeding disorder due to either a lack of or greatly reduced activity in the blood coagulation protein factor VIII (FVIII), due to mutations in the F8 gene. This poses significant challenges for FVIII replacement therapy since hemophilic patients are not immunologically tolerant to the protein. Thus, a proportion of patients who receive plasma-derived or recombinant FVIII replacement therapy develop anti FVIII neutralizing antibodies, known as "inhibitors." These patients require long-term regimens of high dose FVIII administration, which has varying success rates and prohibitive costs. Therefore, therapeutics for tolerance induction in such patients with inhibitors are desired. In this review, we address the current progress of immunotherapies for inducing FVIII specific tolerance in animal models of hemophilia A. Specifically we discuss the beneficial effects of B-cell depletion on immune tolerance induction (ITI), B-cell mediated gene therapy, antigen-coupled lymphocyte therapy, and regulatory T-cell epitopes (Tregitopes).


Gender Disparities in Surgical Treatment of Axis Fractures in Older Adults.
Retrospective cohort study. Gender appears to play in important role in surgical outcomes following acute cervical spine trauma, with current literature suggesting males have a significantly higher mortality following spine surgery. However, no well-adjusted population-based studies of gender disparities in incidence and outcomes of spine surgery following acute traumatic axis injuries exist to our knowledge. We hypothesized that females would receive surgery less often than males, but males would have a higher 1-year mortality following isolated traumatic axis fractures. We performed a retrospective cohort study using Medicare claims data that identified US citizens aged 65 and older with ICD-9 (International Classification of Diseases, Ninth Revision) code diagnosis corresponding to isolated acute traumatic axis fracture between 2007 and 2014. Our primary outcome was defined as cumulative incidence of surgical treatment, and our secondary outcome was 1-year mortality. Propensity weighted analysis was performed to balance covariates between genders. Our institutional review board approved the study (IRB #16-0533). There was no difference in incidence of surgery between males and females following acute isolated traumatic axis fractures (7.4 and 7.5 per 100 fractures, respectively). Males had significantly higher 1-year weighted mortality overall (41.7 and 28.9 per 100 fractures, respectively, P < .001). Our well-adjusted data suggest there was no significant gender disparity in incidence of surgical treatment over the study period. The data also support previous observations that males have worse outcomes in comparison to females in the setting of axis fractures and spinal trauma regardless of surgical intervention.


Parallax360: Stereoscopic 360° Scene Representation for Head-Motion Parallax.
We propose a novel 360° scene representation for converting real scenes into stereoscopic 3D virtual reality content with head-motion parallax. Our image-based scene representation enables efficient synthesis of novel views with six degrees-of-freedom (6-DoF) by fusing motion fields at two scales: (1) disparity motion fields carry implicit depth information and are robustly estimated from multiple laterally displaced auxiliary viewpoints, and (2) pairwise motion fields enable real-time flow-based blending, which improves the visual fidelity of results by minimizing ghosting and view transition artifacts. Based on our scene representation, we present an end-to-end system that captures real scenes with a robotic camera arm, processes the recorded data, and finally renders the scene in a head-mounted display in real time (more than 40 Hz). Our approach is the first to support head-motion parallax when viewing real 360° scenes. We demonstrate compelling results that illustrate the enhanced visual experience - and hence sense of immersion-achieved with our approach compared to widely-used stereoscopic panoramas.


Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease.
In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15-30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15-30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control subjects, we estimated the likelihood that a given measurement reflects corticospinal tract degeneration. Therefore, intermuscular coherence has potential as a quantitative test of subclinical upper motor neuron involvement in motor neuron disease.


[Diagnosis and therapy of acute cholecystitis in liver cirrhosis].
The article deals with information on 12 patients with acute cholecystitis and cirrhosis of the liver (class A--with maintained hepatic function in 3, class B--with subcompensated hepatic function in 8, and class C--with decompensated stage of cirrhosis of the liver in one patient). The clinical picture was atypical and the course severe (purulent complications, hepatic insufficiency). Nonoperative management of the attack should be limited to 24 hours. Sparing decompression (laparoscopic or laparocentetic cholecystostomy) is the optimal method of treatment of class B and C patients. The tactics in class A patients does not differ from the commonly accepted tactics. Unfavorable outcomes (3) were linked with performance of emergency cholecystectomy in patients with disturbed hepatic function.


Hfq Globally Binds and Destabilizes sRNAs and mRNAs in Yersinia pestis.
Hfq is a ubiquitous Sm-like RNA-binding protein in bacteria involved in physiological fitness and pathogenesis, while its in vivo binding nature remains elusive. Here we reported genome-wide Hfq-bound RNAs in Yersinia pestis, a causative agent of plague, by using cross-linking immunoprecipitation coupled with deep sequencing (CLIP-seq) approach. We show that the Hfq binding density is enriched in more than 80% mRNAs of Y. pestis and that Hfq also globally binds noncoding small RNAs (sRNAs) encoded by the intergenic, antisense, and 3' regions of mRNAs. An Hfq U-rich stretch is highly enriched in sRNAs, while motifs partially complementary to AGAAUAA and GGGGAUUA are enriched in both mRNAs and sRNAs. Hfq-binding motifs are enriched at both terminal sites and in the gene body of mRNAs. Surprisingly, a large fraction of the sRNA and mRNA regions bound by Hfq and those downstream are destabilized, likely via a 5'P-activated RNase E degradation pathway, which is consistent with a model in which Hfq facilitates sRNA-mRNA base pairing and the coupled degradation in Y. pestis These results together have presented a high-quality Hfq-RNA interaction map in Y. pestis, which should be important for further deciphering the regulatory role of Hfq-sRNAs in Y. pestis IMPORTANCE Discovered in 1968 as an Escherichia coli host factor that was essential for replication of the bacteriophage Qβ, the Hfq protein is a ubiquitous and highly abundant RNA-binding protein in many bacteria. With the assistance of Hfq, small RNAs in bacteria play important roles in regulating the stability and translation of mRNAs by base pairing. In this study, we want to elucidate the Hfq-assisted sRNA-mRNA regulation in Yersinia pestis A global map of Hfq interaction sites in Y. pestis was obtained by sequencing cDNAs converted from the Hfq-bound RNA fragments using UV cross-linking coupled immunoprecipitation technology. We demonstrate that Hfq could bind to hundreds of sRNAs and the majority of mRNAs in Y. pestis The enriched binding motifs in sRNAs and mRNAs are complementary to each other, suggesting a general base-pairing mechanism for sRNA-mRNA interaction. The Hfq-bound sRNA and mRNA regions were both destabilized. The results suggest that Hfq binding facilitates sRNA-mRNA base pairing and coordinates their degradation, which might enable Hfq to surveil the homeostasis of most mRNAs in bacteria.


Pseudo-insular glioma syndrome: illustrative cases.
Lower-grade insular gliomas often appear as expansile and infiltrative masses on magnetic resonance imaging (MRI). However, there are nonneoplastic lesions of the insula, such as demyelinating disease and vasculopathies, that can mimic insular gliomas. The authors report two patients who presented with headaches and were found to have mass lesions concerning for lower-grade insular glioma based on MRI obtained at initial presentation. However, on the immediate preoperative MRI obtained a few weeks later, both patients had spontaneous and complete resolution of the insular lesions. Tumor mimics should always be in the differential diagnosis of brain masses, including those involving the insula. The immediate preoperative MRI (within 24-48 hours of surgery) must be compared carefully with the initial presentation MRI to assess interval change that suggests tumor mimics to avoid unnecessary surgical intervention.


Automatic collision notification availability and emergency response times following vehicle collision-an analysis of the 2017 crash investigation sampling system.
To determine whether occupants of collisions involving at least one vehicle with an available Automatic Collision Notification (ACN) system have quicker times from collision to 1) Emergency Medical Services (EMS) notification and 2) arrival to a medical center. Using data from the 2017 Crash Investigation Sampling System, vehicles were categorized as whether ACN was available using data from the CISS's dataset of crash avoidance system availability (in which ACN is included though notably not a crash avoidance system). A Cox proportional hazards model-overall and stratified by urbanization-was used to compare the time from collision to both EMS notification and EMS arrival to a medical center. A total of 2,034 collisions (weight n: 2,775,512) involving 4235 occupants (weighted n: 4,987,669) were included. An estimated 259,021 (9.3%) and 546,223 occupants (11.0%) were in a collision in which one vehicle had ACN equipped. The median time to EMS notification was longer for collisions in which no involved vehicles had ACN available (median 4, IQR 2-9 minutes) than ACN-exposed collisions (median 2, IQR 1-5 minutes). There was a marginally significant higher hazard (i.e., instantaneous risk) of EMS notification for collisions with at least one vehicle having ACN available (HR 1.77, 95% CI 0.99-3.15). Likewise, there was a higher instantaneous risk of medical center arrival for occupants (HR 1.80, 95% CI 1.41-2.30) involved in collisions in which at least one vehicle had ACN available. ACN was associated with quicker EMS notification only in urban areas (HR 3.06, 95% CI 1.57-5.97) and associated with a greater reduction in time to medical facility in less urban areas (median 36 vs 45 minutes, HR 2.12, 95% CI 1.22-3.63). This is the first study to directly compare EMS response-related times between collisions involving vehicles with and without ACN available. The current data corroborate prior literature reporting quicker EMS notification times among collisions involving ACN-equipped vehicles. This is the first study to find that ACN is also associated to quicker times to medical center arrival, particularly for collisions occurring in less urban areas. Future research examining whether these decreased times are associated with better clinical outcomes are needed in order to fully assess ACN's ability to prevent trauma-related mortality and morbidity.


"Giant surfactants" created by the fast and efficient functionalization of a DNA tetrahedron with a temperature-responsive polymer.
Copper catalyzed azide-alkyne cycloaddition (CuAAC) was employed to synthesize DNA block copolymers (DBCs) with a range of polymer blocks including temperature-responsive poly(N-isoproylacrylamide) (poly(NIPAM)) and highly hydrophobic poly(styrene). Exceptionally high yields were achieved at low DNA concentrations, in organic solvents, and in the absence of any solid support. The DNA segment of the DBC remained capable of sequence-specific hybridization: it was used to assemble a precisely defined nanostructure, a DNA tetrahedron, with pendant poly(NIPAM) segments. In the presence of an excess of poly(NIPAM) homopolymer, the tetrahedron-poly(NIPAM) conjugate nucleated the formation of large, well-defined nanoparticles at 40 °C, a temperature at which the homopolymer precipitated from solution. These composite nanoparticles were observed by dynamic light scattering and cryoTEM, and their hybrid nature was confirmed by AFM imaging. As a result of the large effective surface area of the tetrahedron, only very low concentrations of the conjugate were required in order for this surfactant-like behavior to be observed.


Obesity is not associated with increased difficulty placing peripheral IVs in trauma activation patients.
Previous studies have identified obesity as a risk factor for difficult IV access, but this has not been studied in the acute trauma setting. The primary objective was to determine if obesity is associated with increased difficulty placing peripheral IVs in trauma patients. Secondary analysis evaluated IV difficulty and associations with nursing self-competence ratings, trauma experience, and patient demographics. Prospective, observational study at academic level I trauma center with 58,000 annual visits. Trauma activation patients between January and October of 2016 were included. Each nurse who attempted IV placement, completed anonymous 7 question survey, including trauma experience (years), self-competence and IV difficulty (Likert scales 1-5), and attempts. Demographic and clinical information was retrospectively collected from the EMR and nursing surveys. Descriptive statistics, chi-square tests, and spearman correlations were used. 200 patients included in the study with 185 BMI calculations. 110 overweight (BMI > 25) and 48 obese (BMI > 30). 70 (35%) female, 149 (75%) white, average age 48. Increased BMI and IV difficulty displayed spearman correlation (ρ) of 0.026 (P = 0.72) suggesting against significant association. Increased trauma experience and self-competence ratings significantly correlated with decreased IV difficulty, ρ = -0.173 and -0.162 (P = 0.010 and 0.014). There was no statistically significant association with IV difficulty in regards to patient race, age, sex, or location of IV placement. Obesity was not associated with increased difficulty in placing peripheral IVs in trauma activation patients. Nurses with greater trauma experience and higher self-competence ratings, had less difficulty inserting IVs.


Evolution of adrenoleukodystrophy model systems.
X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder affecting the adrenal glands, testes, spinal cord and brain. The disease is caused by mutations in the ABCD1 gene resulting in a defect in peroxisomal degradation of very long-chain fatty acids and their accumulation in plasma and tissues. Males with ALD have a near 100% life-time risk to develop myelopathy. The life-time prevalence to develop progressive cerebral white matter lesions (known as cerebral ALD) is about 60%. Adrenal insufficiency occurs in about 80% of male patients. In adulthood, 80% of women with ALD also develop myelopathy, but adrenal insufficiency or cerebral ALD are very rare. The complex clinical presentation and the absence of a genotype-phenotype correlation are complicating our understanding of the disease. In an attempt to understand the pathophysiology of ALD various model systems have been developed. While these model systems share the basic genetics and biochemistry of ALD they fail to fully recapitulate the complex neurodegenerative etiology of ALD. Each model system recapitulates certain aspects of the disorder. This exposes the complexity of ALD and therefore the challenge to create a comprehensive model system to fully understand ALD. In this review, we provide an overview of the different ALD modeling strategies from single-celled to multicellular organisms and from in vitro to in vivo approaches, and introduce how emerging iPSC-derived technologies could improve the understanding of this highly complex disorder.


[Surgical therapy of cone-shaped epiphyses of the proximal interphalangeal joints in tricho-rhino-phalangeal syndrome type I: a survey among three successive generations of a single family].
Report on 6 individuals, occurring in three successive generations of a single family, who were affected by "classical" tricho-rhino-phalangeal syndrome type I. Besides pear-shaped noses, enlarged philtrum, hypotrichosis, premature alopecia, coned epiphysis at the proximal interphaleangeal joints with consecutive ulnar deviation of the long fingers, dysostotic feet, Perthes-like hip dysplasia with multilocated joint laxity and hyposomia were impressing. Height was 168 cm, corresponding to the 50 (th) percentile. Radiographs and 3D-reconstruction of both hands showed asymmetrical brachymetacarpia, brachymesophalangia and painful invaginations of the middle phalanx bases (type 12 according to Giedion). Angular deformities are seen predominantly in the index finger decreasing to the ring finger. Painful cone-shaped epiphyses with ulnar dislocation of the PIP joints were stabilized following resection arthrodesis with tension band osteosynthesis. At reexamination 48 months postoperatively a painfree and powerful pinch grip function of both hands was restored. All family members who showed the phenotypical features of TRPS type I revealed in genetic analysis also identical mutations. Inside the exon 4 in position 1831 there was a nonsens mutation C --> T. Non-afflicted relatives did not show this mutation.


Determination of Chlorinated Solvent Sorption by Porous Material-Application to Trichloroethene Vapor on Cement Mortar.
Experiments have been performed to investigate the sorption of trichloroethene (TCE) vapor by concrete material or, more specifically, the cement mortar component. Gas-flow experiments were conducted using columns packed with small pieces of cement mortar obtained from the grinding of typical concrete material. Transport and retardation of TCE at high vapor concentrations (500 mg L-1) was compared to that of a non-reactive gas tracer (Sulfur Hexafluoride, SF6). The results show a large magnitude of retardation (retardation factor = 23) and sorption (sorption coefficient = 10.6 cm3 g-1) for TCE, compared to negligible sorption for SF6. This magnitude of sorption obtained with pollutant vapor is much bigger than the one obtained for aqueous-flow experiments conducted for water-saturated systems. The considerable sorption exhibited for TCE under vapor-flow conditions is attributed to some combination of accumulation at the air-water interface and vapor-phase adsorption, both of which are anticipated to be significant for this system given the large surface area associated with the cement mortar. Transport of both SF6 and TCE was simulated successfully with a two-region physical non-equilibrium model, consistent with the dual-medium structure of the crushed cement mortar. This work emphasizes the importance of taking into account sorption phenomena when modeling transport of volatile organic compounds through concrete material, especially in regard to assessing vapor intrusion.


Engineering highly effective antimicrobial selenium nanoparticles through control of particle size.
The overuse of antibiotics has induced the rapid development of antibiotic resistance in bacteria. As a result, antibiotic efficacy has become limited, and infection with multidrug-resistant bacteria is considered to be one of the largest global human health threats. Consequently, new, effective and safe antimicrobial agents need to be developed urgently. One promising candidate to address this requirement is selenium nanoparticles (Se NPs), which are made from the essential dietary trace element Se and have antimicrobial activity against Gram-positive bacteria. The size of nanomaterials can strongly affect their biophysical properties and functions; however, the effects of the size of Se NPs on their antibacterial efficacy has not been systematically investigated. Therefore, in this work, spherical Se NPs ranging from 43 to 205 nm in diameter were fabricated, and their mammalian cytotoxicity and antibacterial activity as a function of their size were systematically studied. The antibacterial activity of the Se NPs was shown to be strongly size dependent, with 81 nm Se NPs showing the maximal growth inhibition and killing effect of methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA). The Se NPs were shown to have multi-modal mechanisms of action that depended on their size, including depleting internal ATP, inducing ROS production, and disrupting membrane potential. All the Se NPs were non-toxic towards mammalian cells up to 25 μg mL-1. Furthermore, the MIC value for the 81 nm particles produced in this research is 16 ± 7 μg mL-1, significantly lower than previously reported MIC values for Se NPs. This data illustrates that Se NP size is a facile yet critical and previously underappreciated parameter that can be tailored for maximal antimicrobial efficacy. We have identified that using Se NPs with a size of 81 nm and concentration of 10 μg mL-1 shows promise as a safe and efficient way to kill S. aureus without damaging mammalian cells.


Relationship between mammographic features and hormone receptor content in patients with breast cancer.
Recurrences of breast cancer are more responsive to hormone therapy if the tumors are positive for estrogen receptors or progesterone receptors. To assess the relationship between hormone receptor content, mammographic tumor morphology, and breast parenchymal patterns, we reviewed charts and mammograms of 210 patients with primary unilateral breast cancer. Mammograms of tumors in 97 patients were divided morphologically into five groups: (1) spiculated mass, (2) architectural distortion, (3) calcifications only, (4) circumscribed mass, and (5) tumor not visible. Estrogen receptor positivity was 81% (39/48) in group 1, 37% (7/19) in group 2, 17% (2/12) in group 3, 31% (4/13) in group 4, and 60% (3/5) in group 5 (P less than .001). Mean estrogen receptor content was also significantly different among groups (P less than .001). There was no statistically significant association between tumor morphology and progesterone receptors, or between calcifications and receptor status. In all 210 patients, hormone-receptor-positive tumors showed no association with mammographic parenchymal pattern. When direct assay of estrogen receptors is unavailable, mammographic appearance of the tumor may suggest the estrogen receptor status.


Neuroprotection and free radical scavenging effects of Osmanthus fragrans.
The ethanol extract of dried flowers Osmanthus fragrans (OFE) was assessed for free radical scavenging effects measured by the bleaching of the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical, scavenging of the hydroxyl anion, investigation of the ferric reducing/antioxidant power (FRAP) and lipid-peroxidation inhibition in rat tissues. OFE contained a high amount of total flavonoid and polyphenol. OFE presented the effects in the metal reducing power, FRAP assay with IC(50) values of 0.23 microg/ml, and 7.74 microg/ml, respectively. OFE presented similar activities toward the DPPH and hydroxyl anion scavenging ability with IC(50) values of 10 microg/ml. OFE with IC(50 )values between 46 and 97 microg/ml inhibited lipid peroxidation initiated by ferrous chloride in rat brain, liver, heart and kidney mitochodrias. Moreover, the neuroprotective activity of OFE was investigated under different insults (glutamate, arachidonic acid, and 6-hydroxydopamine) in Wistar rat primary cortical neurons. OFE with EC(50 )values between 66 and 165 microg/ml attenuated the neurotoxicity on MTT and LDH assays. In addition, the AKT protein expression of excitotoxicity and oxidative stress was displayed by western blotting analysis. OFE could up-regulate the glutamate and 6-OHDA decreased AKT expression. This is the first demonstration of the neuroprotective, free radical scavenging and anti-oxidative effects of O. fragrans.


Linkage of nanosecond protein motion with enzymatic methyl transfer by nicotinamide N-methyltransferase.
Nicotinamide N-methyltransferase (NNMT), a key cytoplasmic protein in the human body, is accountable to catalyze the nicotinamide (NCA) N1-methylation through S-adenosyl-L-methionine (SAM) as a methyl donor, which has been linked to many diseases. Although extensive studies have concerned about the biological aspect, the detailed mechanism study of the enzyme function, especially in the part of protein dynamics is lacking. Here, wild-type nicotinamide N-methyltransferase together with the mutation at position 20 with Y20F, Y20G, and free tryptophan were carried out to explore the connection between protein dynamics and catalysis using time-resolved fluorescence lifetimes. The results show that wild-type nicotinamide N-methyltransferase prefers to adapt a less flexible protein conformation to achieve enzyme catalysis.


Modifiable risk factors and thyroid cancer.
To evaluate the association between modifiable patient risk factors including tobacco use, alcohol consumption, body mass index (BMI), and thyroid cancer. Retrospective study with chart review. Midwest university hospital. Retrospective study comparing Midwest patients with thyroid cancer from our Thyroid Tumor and Cancer Registry with Midwest controls without a personal history of cancer. Descriptive statistics were created from patient questionnaires and chart reviews. Odds ratios (ORs) were reported for significant associations. There were 467 patients with cancer and 255 controls. The thyroid cancer group included 404 papillary, 47 follicular, 13 medullary, and 3 anaplastic cancers. When comparing all patients with cancer with controls, smoking more than 100 lifetime cigarettes was associated with a reduced cancer risk (OR, 0.68; 95% confidence interval [CI], 0.50-0.94). Secondhand smoke exposure did not show a statistically significant relationship to thyroid cancer. Compared with never drinking, current drinking was associated with a reduced cancer risk (OR, 0.46; 95% CI, 0.29-0.73) as was consuming 1 to 2 drinks daily compared to drinking <1 drink daily (OR, 0.58; 95% CI, 0.34-0.89). There was no difference between median BMI at age 20 years, lifetime maximum BMI, or current BMI between patients with cancer and controls. Our data showed no positive correlation between tobacco use, alcohol consumption, or obesity and thyroid cancer risk. Our data suggest that tobacco use and mild alcohol consumption may be associated with a slightly reduced risk of thyroid cancer. There was no association between BMI and thyroid cancer in our study population.


Functional forms for photon spectra of clinical linacs.
Specifying photon spectra of clinical linacs using a functional form is useful for many applications, including virtual source modelling and spectral unfolding from dosimetric measurements such as transmission data or depth-dose curves. In this study, 11 functional forms from the literature are compiled and quantitatively compared. A new function is proposed which offers improvements over existing ones. The proposed function is simple, physics-based and has four free parameters, one of which is the mean incident electron kinetic energy. A comprehensive benchmark set of validated, high-precision Monte Carlo spectra is generated and used to evaluate the strengths and limitations of different functions. The benchmark set has 65 spectra (3.5-30 MV) from Varian, Elekta, Siemens, Tomotherapy, Cyberknife and research linacs. The set includes spectra on- and off-axis from linacs with and without a flattening filter, and in treatment and imaging modes. The proposed function gives the lowest spectral deviations among all functions. It reproduces the energy fluence values in each bin for the benchmark set with a normalized root-mean-square deviation of 1.7%. The mean incident electron kinetic energy, maximum photon energy, most-probable energy and average energy are reproduced, on average, within 1.4%, 4.3%, 3.9% and 0.6% of their true values, respectively. The proposed function is well behaved when used for spectral unfolding from dosimetric data. The contribution of the 511 keV annihilation peak and the energy spread of the incident electron beam can be added as additional free parameters.


[A case of autoimmune hemolytic anemia diagnosed by occurrence of cardioembolic stroke].
A 79-year-old woman came to us because of sudden onset of dysarthria. She had taken apixaban due to her non-valvular atrial fibrillation. A neurological examination revealed mild facial palsy of her right side, and magnetic resonance imaging showed acute brain infarction at the left frontal lobe. There were no stenotic lesions on intracranial or extracranial magnetic resonance angiography, and she was diagnosed with cardioembolic stroke. Intravenous infusion of heparin and edaravone was initiated, and her neurological symptoms improved. However, she gradually developed jaundice and anemia. Gastro-intestinal bleeding was not observed, and her blood test met the diagnostic criteria for hemolytic anemia. Because both the direct Coombs test and cold agglutinin were positive, she was diagnosed with mixed-type autoimmune hemolytic anemia. Although her serum hemoglobin level decreased to 7.0 g/dl on the 12th hospital day, her anemia gradually improved after steroidal therapy with transfusion. It was revealed that she had shown mild anemia (hemoglobin: 9.2-10.9 g/dl) and hyperbilirubinemia (total bilirubin: 1.8-2.6 mg/dl) for 6 months. Therefore, her latent autoimmune hemolytic anemia became activated with the occurrence of cardioembolic stroke. Autoimmune hemolytic anemia might have promoted cardiac thrombus formation despite the administration of an anticoagulant in this case. It should be noted that autoimmune hemolytic anemia can develop as thrombotic disease. In the present case, autoimmune hemolytic anemia was diagnosed based on the development of cardioembolic stroke.


Deubiquitinase ubiquitin-specific peptidase 10 maintains cysteine rich angiogenic inducer 61 expression via Yes1 associated transcriptional regulator to augment immune escape and metastasis of pancreatic adenocarcinoma.
Pancreatic adenocarcinoma (PAAD) remains an extremely fatal malignancy with a high mortality rate worldwide. This study focuses on the roles of ubiquitin-specific peptidase 10 (USP10) and cysteine rich angiogenic inducer 61 (Cyr61) in macrophage polarization, immune escape, and metastasis of PAAD. USP10 showed a positive correlation with Yes1 associated transcriptional regulator (YAP1), which, according to the TCGA-PAAD database, is highly expressed in PAAD and indicates poor patient prognosis. USP10 knockdown increased ubiquitination and degradation of YAP1, which further decreased the programmed cell death ligand 1 (PD-L1) and Galectin-9 expression, suppressed immune escape, and reduced the proliferation and metastasis of PAAD cells in vitro and in vivo. Cyr61, a downstream factor of YAP1, was overexpressed in PAAD cells after USP10 silencing for rescue experiments. Overexpression of Cyr61 restored the PD-L1 and Galectin-9 expression in cells and triggered M2 polarization of macrophages, which enhanced the immune escape and maintained the proliferation and metastasis ability of PAAD cells. In conclusion, this work demonstrates that USP10 inhibits YAP1 ubiquitination and degradation to promote Cyr61 expression, which induces immune escape and promotes growth and metastasis of PAAD.


[A case of intramedullary cervical metastasis from cerebellar anaplastic oligodendroglioma without typical MR appearance for CSF dissemination].
We report a case of intramedullary cervical metastasis from cerebellar anaplastic oligodendroglioma without any MR appearance for CSF dissemination or recurrence in the primary tumor site. The case was a 73-year-old female who underwent tumor resection for cerebellar anaplastic oligodendroglioma following irradiation and TMZ chemotherapy. One year and a half later, a small nodular lesion developed at the temporal lobe. While treatment with TMZ was restarted during the course, another intramedullary cervical lesion produced additionally without any CSF dissemination or recurrence at the primary site. The histological examination obtained in spinal surgery revealed evidence of similar features consistent with a previous cerebellar tumor with anaplastic oligodendroglioma. Although CSF dissemination by malignant glioma with leptomeningeal enhancement is relatively well recognized at their terminal stage, cases with intramedullary cervical metastasis without any leptomeningeal enhancement have only been rarely described. We discussed the mechanisms of intramedullary cervical metastasis from intracranial malignant glioma.


On the predictions and limitations of the Becker-Döring model for reaction kinetics in micellar surfactant solutions.
We investigate the breakdown of a system of micellar aggregates in a surfactant solution following an order-one dilution. We derive a mathematical model based on the Becker-Döring system of equations, using realistic expressions for the reaction constants fit to results from Molecular Dynamics simulations. We exploit the largeness of typical aggregation numbers to derive a continuum model, substituting a large system of ordinary differential equations for a partial differential equation in two independent variables: time and aggregate size. Numerical solutions demonstrate that re-equilibration occurs in two distinct stages over well-separated timescales, in agreement with experiment and with previous theories. We conclude by exposing a limitation in the Becker-Döring theory for re-equilibration of surfactant solutions.


Effect of in vitro hemolysis on 25 common biochemical tests.
Clinical chemists frequently encounter hemolyzed samples. Our study examines the effects of hemolysis on the results of 25 common biochemical tests. We collected 60 15-mL blood samples from inpatients and outpatients and mechanically hemolyzed 10 mL of the samples in a two-step procedure. We classified serum from these samples as being nonhemolyzed, moderately hemolyzed, or severely hemolyzed and then performed 25 common biochemical tests. Statistical analysis of the results showed that hemolysis had the greatest effect on the lactate dehydrogenase, acid phosphatase, and potassium tests.


Green Machine: A Card Game Introducing Students to Systems Thinking in Green Chemistry by Strategizing the Creation of a Recycling Plant.
Green Machine is a competitive strategy card game facilitating a systems thinking approach to learning recycling processes and green chemistry in accordance with the United Nations Sustainable Development Goals. Players compete to be the first to be able to launch their recycling plant by collecting a series of playing cards. Players must use interpersonal skills to consider the interconnected systems while showing an appreciation for commercial awareness and versatility, as dynamic problem solving (reflecting real-world scenarios) is required to play the game successfully. The card game was implemented with 19 U.K. graduate students and 29 U.S. second-year undergraduate students. Survey feedback showed that Green Machine was an innovative resource that was enjoyable to play and engaged students in learning recycling processes through systems thinking. On the basis of pre- and post-test questions to evaluate learning gain, Green Machine is a helpful resource to introduce students not only to green chemistry and sustainability but also to taking a systems thinking approach to learning.


Allosteric modulation balances thermodynamic stability and restores function of ΔF508 CFTR.
Most cystic fibrosis is caused by a deletion of a single residue (F508) in CFTR (cystic fibrosis transmembrane conductance regulator) that disrupts the folding and biosynthetic maturation of the ion channel protein. Progress towards understanding the underlying mechanisms and overcoming the defect remains incomplete. Here, we show that the thermal instability of human ΔF508 CFTR channel activity evident in both cell-attached membrane patches and planar phospholipid bilayers is not observed in corresponding mutant CFTRs of several non-mammalian species. These more stable orthologs are distinguished from their mammalian counterparts by the substitution of proline residues at several key dynamic locations in first N-terminal nucleotide-binding domain (NBD1), including the structurally diverse region, the γ-phosphate switch loop, and the regulatory insertion. Molecular dynamics analyses revealed that addition of the prolines could reduce flexibility at these locations and increase the temperatures of unfolding transitions of ΔF508 NBD1 to that of the wild type. Introduction of these prolines experimentally into full-length human ΔF508 CFTR together with the already recognized I539T suppressor mutation, also in the structurally diverse region, restored channel function and thermodynamic stability as well as its trafficking to and lifetime at the cell surface. Thus, while cellular manipulations that circumvent its culling by quality control systems leave ΔF508 CFTR dysfunctional at physiological temperature, restoration of the delicate balance between the dynamic protein's inherent stability and channel activity returns a near-normal state.


[Intraosseous infusions in children].
Tibial intraosseous infusions can be invaluable in the management of the pediatric patient who is in cardiac arrest or severe shock when vascular access by the intravenous route is unattainable. Recently there has been renewed interest in this procedure. There is a small risk of complications.


Estrogen and progestin regulate HIF-1alpha expression in ovarian cancer cell lines via the activation of Akt signaling transduction pathway.
Our previous study revealed that estrogen regulates nm23-H1 expression thus promoting cell migration-invasion via activating PIK3/Akt pathway. In this study, we explored the effect of hormone on hypoxia-inducible factor-1 (HIF-1alpha), a key factor in cancer invasion and metastasis, via activation of Akt signaling transduction pathway. We treated two ovarian cancer cell lines ES-2 and SKOV3 with 17beta-estradiol, methoxyprogesterone acetate (MPA) only, or hormone combined with and Akt, MAPK pathway inhibitor, or transefected with siRNA targeting Akt sequenced with hormone. Expression of HIF-1alpha was measured by Western blotting. We observed the effect of hormone on nm23-H1 expression after the cells were transfected by siRNA targeting HIF-1alpha or treated with CoCl2 to induce HIF-1alpha overexpression. The 17beta-estradiol increased HIF-1alpha expression in ovarian cancer cells, and this upregulatory effect was abrogated by Akt inhibitor LY294002 (P<0.05) and Akt siRNA interference (P<0.05), but not affected by MAPK inhibitor PD980059 (P>0.05). MPA had the opposite effect. Nm23-H1 protein expression in ES-2 and SKOV3 cells were decreased after treatment with 17beta-estradiol (P<0.05), whereas MPA had the opposite effect. The effect was attenuated by HIF-1alpha siRNA (P<0.05) and enhanced by HIF-1alpha overexpression after CoCl2 treatment (P<0.05). Our data suggest that estrogen and progestin regulate HIF-1alpha expression via Akt signaling pathway, affecting nm23-H1 expression in influencing cell metastasis.


Can quantifying morphology and TMEM119 expression distinguish between microglia and infiltrating macrophages after ischemic stroke and reperfusion in male and female mice?
Ischemic stroke is an acquired brain injury with gender-dependent outcomes. A persistent obstacle in understanding the sex-specific neuroinflammatory contributions to ischemic brain injury is distinguishing between resident microglia and infiltrating macrophages-both phagocytes-and determining cell population-specific contributions to injury evolution and recovery processes. Our purpose was to identify microglial and macrophage populations regulated by ischemic stroke using morphology analysis and the presence of microglia transmembrane protein 119 (TMEM119). Second, we examined sex and menopause differences in microglia/macrophage cell populations after an ischemic stroke. Male and female, premenopausal and postmenopausal, mice underwent either 60 min of middle cerebral artery occlusion and 24 h of reperfusion or sham surgery. The accelerated ovarian failure model was used to model postmenopause. Brain tissue was collected to quantify the infarct area and for immunohistochemistry and western blot methods. Ionized calcium-binding adapter molecule, TMEM119, and confocal microscopy were used to analyze the microglia morphology and TMEM119 area in the ipsilateral brain regions. Western blot was used to quantify protein quantity. Post-stroke injury is increased in male and postmenopause female mice vs. premenopause female mice (p < 0.05) with differences primarily occurring in the caudal sections. After stroke, the microglia underwent a region, but not sex group, dependent transformation into less ramified cells (p < 0.0001). However, the number of phagocytic microglia was increased in distal ipsilateral regions of postmenopausal mice vs. the other sex groups (p < 0.05). The number of TMEM119-positive cells was decreased in proximity to the infarct (p < 0.0001) but without a sex group effect. Two key findings prevented distinguishing microglia from systemic macrophages. First, morphological data were not congruent with TMEM119 immunofluorescence data. Cells with severely decreased TMEM119 immunofluorescence were ramified, a distinguishing microglia characteristic. Second, whereas the TMEM119 immunofluorescence area decreased in proximity to the infarcted area, the TMEM119 protein quantity was unchanged in the ipsilateral hemisphere regions using western blot methods. Our findings suggest that TMEM119 is not a stable microglia marker in male and female mice in the context of ischemic stroke. Until TMEM119 function in the brain is elucidated, its use to distinguish between cell populations following brain injury with cell infiltration is cautioned.


Novel Metabolite Biomarkers of Huntington's Disease As Detected by High-Resolution Mass Spectrometry.
Huntington's disease (HD) is a fatal autosomal-dominant neurodegenerative disorder that affects approximately 3-10 people per 100 000 in the Western world. The median age of onset is 40 years, with death typically following 15-20 years later. In this study, we biochemically profiled post-mortem frontal lobe and striatum from HD sufferers (n = 14) and compared their profiles with controls (n = 14). LC-LTQ-Orbitrap-MS detected a total of 5579 and 5880 features for frontal lobe and striatum, respectively. An ROC curve combining two spectral features from frontal lobe had an AUC value of 0.916 (0.794 to 1.000) and following statistical cross-validation had an 83% predictive accuracy for HD. Similarly, two striatum biomarkers gave an ROC AUC of 0.935 (0.806 to 1.000) and after statistical cross-validation predicted HD with 91.8% accuracy. A range of metabolite disturbances were evident including but-2-enoic acid and uric acid, which were altered in both frontal lobe and striatum. A total of seven biochemical pathways (three in frontal lobe and four in striatum) were significantly altered as a result of HD. This study highlights the utility of high-resolution metabolomics for the study of HD. Further characterization of the brain metabolome could lead to the identification of new biomarkers and novel treatment strategies for HD.


Contraindications of video-assisted thoracoscopic surgical lobectomy and determinants of conversion to open.
Since the introduction of anatomic lung resection by video-assisted thoracoscopic surgery (VATS) was introduced 20 years ago, VATS has experienced major advances in both equipment and technique, introducing a technical challenge in the surgical treatment of both benign and malignant lung disease. The demonstrated safety, decreased morbidity, and equivalent efficacy of this minimally invasive technique has led to the acceptance of VATS as a standard surgical modality for early-stage lung cancer and increasing application to more advanced disease. However, only a minority of lobectomies are performed using the VATS technique, likely owing to concern for intraoperative complications. Optimal operative planning, including obtaining baseline pulmonary function tests with diffusion measurements, positron emission tomography and/or computed tomography scans, bronchoscopy, and endobronchial ultrasound or mediastinoscopy, can be used to anticipate and potentially prevent the occurrence of complications. With increasing focus on operative planning, as well as comfort and experience with the VATS technique, the indications for which this technique is used has grown. As such, the absolute contraindications have narrowed to inability to tolerate single lung ventilation, inability to achieve complete resection with lobectomy, T3 or T4 tumors, and N2 or N3 disease. However, as VATS lobectomy has been applied to more advanced stage disease, the rate of conversion to open thoracotomy has increased, particularly early in the surgeon's learning curve. Causes of conversion are generally classified into four categories: intraoperative complications, technical problems, anatomical problems, and oncological conditions. Though it is difficult to anticipate which patients may require conversion, it appears that these patients do not suffer from increased morbidity or mortality as a result of conversion to open thoracotomy. Therefore, with a focus on a safe and complete resection, conversion should be regarded as a means of completing resections in a traditional manner rather than as a surgical failure.


The transcription factor Sox2 is required to maintain the cell type-specific properties and innervation of type II vestibular hair cells in adult mice.
The sense of balance relies on vestibular hair cells, which detect head motions. Mammals have two types of vestibular hair cell, I and II, with unique morphological, molecular, and physiological properties. Furthermore, each hair cell type synapses on a unique form of afferent nerve terminal. Little is known about the mechanisms in mature animals that maintain the specific features of each hair cell type or its post-synaptic innervation. We found that deletion of the transcription factor Sox2 from type II hair cells in adult mice of both sexes caused many cells in utricles to acquire features unique to type I hair cells and to lose type II-specific features. This cellular transdifferentiation, which included changes in nuclear size, chromatin condensation, soma and stereocilium morphology, and marker expression, resulted in a significantly higher proportion of type I-like hair cells in all epithelial zones. Furthermore, Sox2 deletion from type II hair cells triggered non-cell autonomous changes in vestibular afferent neurons; they retracted bouton terminals (normally present on only type II cells) from transdifferentiating hair cells and replaced them with a calyx terminal (normally present on only type I cells). These changes were accompanied by significant expansion of the utricle's central zone, called the striola. Our study presents the first example of a transcription factor required to maintain the type-specific hair cell phenotype in adult inner ears. Furthermore, we demonstrate that a single genetic change in type II hair cells is sufficient to alter the morphology of their post-synaptic partners, the vestibular afferent neurons.SIGNIFICANCE STATEMENT:The sense of balance relies on two types of sensory cells in the inner ear - type I and type II hair cells. These two cell types have unique properties. Furthermore, their post-synaptic partners, the vestibular afferent neurons, have differently shaped terminals on type I versus type II hair cells. We show that the transcription factor Sox2 is required to maintain the cell-specific features of type II hair cells and their post-synaptic terminals in adult mice. This is the first evidence of a molecule that maintains the phenotypes of hair cells and, non-cell autonomously, their post-synaptic partners in mature animals.


Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection.
Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P < 0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P = 0.0178, chi-square test). HIV-infected (HIV(+)) children with autopsy-confirmed CM were older than HIV-uninfected children (median age, 99 months versus 32 months, P = 0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV(+) and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly (>9 times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly (>2-fold) greater in HIV(+) children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV(+) children exacerbates the pathological features associated with CM. IMPORTANCE : There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms causing coma and death are uncertain. Sub-Saharan Africa has a high HIV prevalence, with 3 million HIV-infected (HIV(+)) children, but the effects of HIV on CM pathogenesis and mortality are unknown. In a study of pediatric CM in Malawi, HIV prevalence was high and CM-attributed mortality was higher in HIV(+) than in HIV-uninfected children. Brain pathology in children with fatal CM was notable not only for sequestered malaria parasites but also for intravascular accumulations of monocytes and platelets that were more severe in HIV(+) children. Our findings raise the possibility that HIV(+) children at risk for malaria may benefit from targeted malaria prophylaxis and that adjunctive treatments targeting inflammation and/or coagulation may improve CM outcomes.


Characterization of deoxyribozymes that synthesize branched RNA.
We recently reported deoxyribozymes (DNA enzymes) that synthesize 2',5'-branched RNA. The in vitro-selected 9F7 and 9F21 deoxyribozymes mediate reaction of a branch-site adenosine 2'-hydroxyl on one RNA substrate with the 5'-triphosphate of another RNA substrate. Here we characterize these DNA enzymes with respect to their branch-forming activity. Both 9F7 and 9F21 are much more active with Mn(2+) than with Mg(2+). The K(d,app)(Mg(2+)) > 400 mM but K(d,app)(Mn(2+)) approximately 20-50 mM, and the ligation rates k(obs) are orders of magnitude faster with Mn(2+) than with Mg(2+) (e.g., 9F7 approximately 0.3 min(-1) with 20 mM Mn(2+) versus 0.4 h(-1) with 100 mM Mg(2+), both at pH 7.5 and 37 degrees C). Of the other tested transition metal ions Zn(2+), Ni(2+), Co(2+), and Cd(2+), only Co(2+) supports a trace amount of activity. 9F7 is more tolerant than 9F21 of varying the RNA substrate sequences. For the RNA substrate that donates the adenosine 2'-hydroxyl, 9F7 requires YUA, where Y = pyrimidine and A is the branch site. The 3'-tail emerging from the branch-site A may have indefinite length, but it must be at least one nucleotide long for high activity. The 5'-triphosphate RNA substrate requires several additional nucleotides with varying sequence requirements (5'-pppGRMWR). Outside of these regions that flank the ligation site, 9F7 and 9F21 tolerate any RNA substrate sequences via Watson-Crick covariation of the DNA binding arms that interact directly with the substrates. 9F7 provides a high yield of 2',5'-branched RNA on the preparative nanomole scale. The ligation reaction is effectively irreversible; the pyrophosphate leaving group in the ligation reaction does not induce 2',5'-cleavage, and pyrophosphate does not significantly inhibit ligation except in 1000-fold excess. Deleting a specific nucleotide in one of the DNA binding arms near the ligation junction enhances ligation activity, suggesting an interesting structure near this region of the deoxyribozyme-substrate complex. These data support the utility of deoxyribozymes in creating synthetic 2',5'-branched RNAs for investigations of group II intron splicing, debranching enzyme (Dbr) activity, and other biochemical reactions.


The importance of visual features in generic vs. specialized object recognition: a computational study.
It is debated whether the representation of objects in inferior temporal (IT) cortex is distributed over activities of many neurons or there are restricted islands of neurons responsive to a specific set of objects. There are lines of evidence demonstrating that fusiform face area (FFA-in human) processes information related to specialized object recognition (here we say within category object recognition such as face identification). Physiological studies have also discovered several patches in monkey ventral temporal lobe that are responsible for facial processing. Neuronal recording from these patches shows that neurons are highly selective for face images whereas for other objects we do not see such selectivity in IT. However, it is also well-supported that objects are encoded through distributed patterns of neural activities that are distinctive for each object category. It seems that visual cortex utilize different mechanisms for between category object recognition (e.g., face vs. non-face objects) vs. within category object recognition (e.g., two different faces). In this study, we address this question with computational simulations. We use two biologically inspired object recognition models and define two experiments which address these issues. The models have a hierarchical structure of several processing layers that simply simulate visual processing from V1 to aIT. We show, through computational modeling, that the difference between these two mechanisms of recognition can underlie the visual feature and extraction mechanism. It is argued that in order to perform generic and specialized object recognition, visual cortex must separate the mechanisms involved in within category from between categories object recognition. High recognition performance in within category object recognition can be guaranteed when class-specific features with intermediate size and complexity are extracted. However, generic object recognition requires a distributed universal dictionary of visual features in which the size of features does not have significant difference.


Lupus nephritis combined with renal injury due to thrombotic thrombocytopaenic purpura-haemolytic uraemic syndrome.
Thrombotic thrombocytopaenic purpura-haemolytic uraemic syndrome (TTP-HUS) in SLE was reported mainly in isolated case reports. The aim of this study is to investigate the clinical and pathological features, outcome and possible pathogenesis of TTP-HUS in patients with lupus nephritis. Clinical and renal histopathological data of patients with lupus nephritis were reviewed for clinical and pathological evidence of both TTP-HUS and renal thrombotic microangiopathy (TMA). Serum ADAMTS-13 activity and ADAMTS-13 autoantibodies were further studied. Seven patients with evidence of both TTP-HUS and renal TMA were identified in 353 patients with lupus nephritis. In comparison with 55 patients with lupus nephritis without TTP-HUS, those with TTP-HUS had a higher prevalence of acute renal failure and worse renal outcome. The serum ADAMTS-13 activity was significantly lower in patients with both lupus nephritis and TTP-HUS than in patients with lupus nephritis only and in normal control (40% versus 69%, P = 0.012; 40% versus 81%, P < 0.001, respectively). The prevalence of ADAMTS-13 autoantibodies was significantly higher in patients with both lupus nephritis and TTP-HUS than in patients with lupus nephritis only and in normal control (6/7, 86% versus 10/55, 18%, P < 0.001; 6/7, 86% versus 0, P < 0.001, respectively). After clinical remission, the serum ADAMTS-13 activity of the seven patients with TTP-HUS increased significantly (40% versus 63%, P < 0.001) and five out of the six patients with positive ADAMTS-13 autoantibodies turned negative. ADAMTS-13 autoantibodies might play an important role in the pathogenesis of TTP-HUS associated with lupus nephritis. The long-term outcome seems to be worse in patients with both TTP-HUS and lupus nephritis than in patients with lupus nephritis alone.


Infectious complications and therapy of bite wounds.
Bite wounds of the lower extremities present a challenge in diagnosis and management. Primary care of the initial injury remains controversial. Innocuous as these wounds may appear, severe infections are frequent. The microbial flora of the animal mouth harbor a multitude of unusual bacteria, aerobic and anaerobic, that make antibiotic selection difficult. A protocol for initial management and antibiotic selection is presented.


Articulatory Control in Childhood Apraxia of Speech in a Novel Word-Learning Task.
Articulatory control and speech production accuracy were examined in children with childhood apraxia of speech (CAS) and typically developing (TD) controls within a novel word-learning task to better understand the influence of planning and programming deficits in the production of unfamiliar words. Participants included 16 children between the ages of 5 and 6 years (8 CAS, 8 TD). Short- and long-term changes in lip and jaw movement, consonant and vowel accuracy, and token-to-token consistency were measured for 2 novel words that differed in articulatory complexity. Children with CAS displayed short- and long-term changes in consonant accuracy and consistency. Lip and jaw movements did not change over time. Jaw movement duration was longer in children with CAS than in TD controls. Movement stability differed between low- and high-complexity words in both groups. Children with CAS displayed a learning effect for consonant accuracy and consistency. Lack of change in movement stability may indicate that children with CAS require additional practice to demonstrate changes in speech motor control, even within production of novel word targets with greater consonant and vowel accuracy and consistency. The longer movement duration observed in children with CAS is believed to give children additional time to plan and program movements within a novel skill.


Importance of interferons in recovery from mousepox.
Gamma interferon is shown to be critical in recovery of C57BL/6 mice from mousepox. Anti-gamma interferon treatment of mice infected in the footpad with ectromelia virus resulted in enhanced spread to and efficient virus replication in the spleen, lungs, ovaries, and, especially, liver. All treated, infected mice died within a mean of 7 days, 2.5 days earlier than mice with severe combined immunodeficiency that were given a comparable infection. On the other hand, alpha interferon appeared not to have a major role in controlling virus replication in tissues examined, and beta interferon was important for virus clearance in the liver and ovaries but not the spleen. Either anti-alpha, beta interferon or anti-beta interferon antibody therapy resulted in only 25% mortality. Infected control mice survived but showed persistence of ectromelia virus at the site of infection (the footpad) and transient presence of the virus in the spleen, liver, lungs, and ovaries and in the fibroreticular but not lymphoid cells of the draining popliteal lymph node. Depletion of gamma interferon but not alpha and/or beta interferon resulted in a significant reduction in the numbers of splenic T (especially gamma delta-TCR+), B, and Mac-1+ cells, although the proportion of Mac-1+ cells in the spleen increased compared with control values. Depletion of alpha, beta, or gamma interferons did not severely affect the generation of virus-specific cytotoxic T-lymphocyte responses or natural killer cell cytolytic activity. This study, in which a natural virus disease model was used, underscores the crucial importance of gamma interferon in virus clearance at all stages of infection and in all tissues tested except the primary site of infection, where virus clearance appears to be delayed.


Assessing medical student knowledge and attitudes about shared decision making across the curriculum: protocol for an international online survey and stakeholder analysis.
Shared decision making (SDM) is a goal of modern medicine; however, it is not currently embedded in routine care. Barriers include clinicians' attitudes, lack of knowledge and training and time constraints. Our goal is to support the development and delivery of a robust SDM curriculum in medical education. Our objective is to assess undergraduate medical students' knowledge of and attitudes towards SDM in four countries. The first phase of the study involves a web-based cross-sectional survey of undergraduate medical students from all years in selected schools across the United States (US), Canada and undergraduate and graduate students in the Netherlands. In the United Kingdom (UK), the survey will be circulated to all medical schools through the UK Medical School Council. We will sample students equally in all years of training and assess attitudes towards SDM, knowledge of SDM and participation in related training. Medical students of ages 18 years and older in the four countries will be eligible. The second phase of the study will involve semistructured interviews with a subset of students from phase 1 and a convenience sample of medical school curriculum experts or stakeholders. Data will be analysed using multivariable analysis in phase 1 and thematic content analysis in phase 2. Method, data source and investigator triangulation will be performed. Online survey data will be reported according to the Checklist for Reporting the Results of Internet E-Surveys. We will use the COnsolidated criteria for REporting Qualitative research for all qualitative data. The study has been approved for dissemination in the US, the Netherlands, Canada and the UK. The study is voluntary with an informed consent process. The results will be published in a peer-reviewed journal and will help inform the inclusion of SDM-specific curriculum in medical education worldwide.


A molecular basis for neurofibroma-associated skeletal manifestations in NF1.
Plexiform neurofibromas (pNF) develop in children with neurofibromatosis type 1 (NF1) and can be associated with several skeletal comorbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis and skeletal mineralization. The etiology of NF-associated skeletal manifestations remains unknown. We used mouse models of NF1 neurofibromas to assess bone mineralization of skeletal structures adjacent to tumors. Expression of genes involved in pyrophosphate homeostasis was assessed in mouse and human NF tumors and Schwann cell cultures. We used dual-energy X-ray absorptiometry (DXA) to assess tumor-associated changes in bone mineral density (BMD) in an individual with NF1 following treatment with the MEK inhibitor selumetinib. We detected increased nonmineralized bone surfaces adjacent to tumors in mouse models of NF1 neurofibromas. Expression of Enpp1, a PPi-generating ectophosphatase, and ANKH, a PPi transporter, was increased in mouse and human neurofibroma-derived tissues and Schwann cells, respectively. In one patient, tumor-associated reductions in BMD were partially rescued following therapy with selumetinib. Results indicate that NF-associated skeletal pathologies in NF1 are associated with dysregulated pyrophosphate homeostasis in adjacent NF tumors and suggest that treatment of NFs with MEK inhibitors may improve skeletal manifestations of the disease.


Predator dispersal influences predator distribution but not prey diversity in pitcher plant microbial metacommunities.
The spatial distribution of predators can affect both the distribution and diversity of their prey. Therefore, differences in predator dispersal ability that affect their spatial distribution, could also affect prey communities. Here, we use the microbial communities within pitcher plant leaves as a model system to test the relationship between predator (protozoa) dispersal ability and distribution, and its consequences for prey (bacteria) diversity and composition. We hypothesized that limited predator dispersal results in clustered distributions and heterogeneous patches for prey species, whereas wide predator dispersal and distribution could homogenize prey metacommunities. We analyzed the distribution of two prominent bacterivore protozoans from a 2-year survey of an intact field of Sarracenia purpurea pitcher plants, and found a clustered distribution of Tetrahymena and homogeneous distribution of Poterioochromonas. We manipulated the sources of protozoan colonists and recorded protozoan recruitment and bacterial diversity in target leaves in a field experiment. We found the large ciliate, Tetrahymena, was dispersal limited and occupied few leaves, whereas the small flagellate Poterioochromonas was widely dispersed. However, the bacterial communities these protozoans feed on was unaffected by clustering of Tetrahymena, but likely influenced by Poterioochromonas and other bacterivores dispersing in the field. We propose that bacterial communities in this system are structured by a combination of well dispersed bacterivores, bacterial dispersal, and bottom-up mechanisms. Clustered predators could become strong drivers of prey communities if they were specialists or keystone predators, or if they exerted a dominant influence on other predators in top-down controlled systems. Linking dispersal ability within trophic levels and its consequences for trophic dynamics can lead to a more robust perspective on trophic metacommunities.


Development and Validation of a Short Food Frequency Questionnaire to Measure Dietary Intake of a Selection of Immune-Modulating Nutrients in Patients with Established Peripheral Arterial Disease.
Nutrients with the ability to modulate the immune system (immune-modulating nutrients; IMN) may help prevent the development and progression of atherosclerosis, the main disease process underlying peripheral artery disease (PAD). Currently, no screening tool exists to measure IMN intake; therefore, the aim of this project is to develop and validate a short food frequency questionnaire (FFQ) that measures dietary intake of 14 nutrients with proposed immune-modulating effects, identified by the literature (copper, iron and zinc, vitamins A, C, D and E, alpha linolenic acid, total long-chain omega-3 fatty acids, arginine, glutamic acid, isoleucine, leucine and valine) in patients with established PAD. A 21-item FFQ was developed to measure average daily intake of IMNs over the past 12 months. Participants (n = 106) were recruited from Flinders Medical Centre, where they completed the FFQ followed by the reference method, a diet history reflecting usual intake over the past week. The mean age of participants was 72 years, with 83% being male (n = 88). Bland-Altman analysis resulted in a statistically non-significant p-value (p-value > 0.05) for 12 out of 14 nutrients, demonstrating good agreement between the two methods. Additionally, over 50% of nutrients had a sensitivity or specificity >70%. Consequently, the novel 21-item FFQ was determined to be a promising measure of dietary intake of 14 IMNs in patients with PAD when compared to the reference method of a diet history, and it is recommended that further investigations of the utility against biomarkers be explored in the future.


Self-reported sleepiness and not the apnoea hypopnoea index is the best predictor of sleepiness-related accidents in obstructive sleep apnoea.
To evaluate the value of apnoea + hypopnoea index versus self-reported sleepiness at the wheel in anticipating the risk of sleepiness-related accidents in patients referred for obstructive sleep apnoea. A cross-sectional analysis of the French national obstructive sleep apnoea registry. 58,815 subjects referred for a suspicion of obstructive sleep apnoea were investigated by specific items addressing sleepiness at the wheel and sleepiness-related accidents. Apnoea + hypopnoea index was evaluated with a respiratory polygraphy or full polysomnography. Subjects had a median age of 55.6 years [45.3; 64.6], 65% were men, with a median apnoea + hypopnoea index of 22 [8; 39] events/h. Median Epworth sleepiness scale score was 9 [6; 13], 35% of the patients reported sleepiness at the wheel (n = 20,310), 8% (n = 4,588) reported a near-miss accident and 2% (n = 1,313) reported a sleepiness-related accident. Patients reporting sleepiness at the wheel whatever their obstructive sleep apnoea status and severity exhibited a tenfold higher risk of sleepiness-related accidents. In multivariate analysis, other predictors for sleepiness-related accidents were: male gender, ESS, history of previous near-miss accidents, restless leg syndrome/periodic leg movements, complaints of memory dysfunction and nocturnal sweating. Sleep apnoea per se was not an independent contributor. Self-reported sleepiness at the wheel is a better predictor of sleepiness-related traffic accidents than apnoea + hypopnoea index.


Activated Macrophages of Monocytic Origin Predominantly Express Proinflammatory Cytokine Genes, Whereas Kupffer Cells Predominantly Express Anti-Inflammatory Cytokine Genes.
In the central nervous system and in the liver, the macrophage populations are represented exclusively by descendants of the hematopoietic progenitor cells of the yolk sac. The reasons for such differential distribution of macrophages are not fully understood. We found that, as can be judged by corresponding changes in the expression of CD86 and CD163 markers, the transient macrophages of monocytic lineage are more sensitive to activating stimuli. The two macrophage populations have distinct patterns of gene expression, which is particularly noticeable for M1- and M2-associated genes. For instance, Kupffer cells more readily develop and longer maintain the elevated expression levels of Il4, Il10, and Il13 upon the activation; by contrast, the macrophages of monocytic lineage express Il1b, Il12a, and Tnfα upon the activation. The obtained results allow us to conclude that the in vitro activated Kupffer cells of the liver are committed to M2 phenotype, whereas the in vitro activated monocyte-derived macrophages show a typical M1 behavior. These observations are likely to reflect the situation in the in vivo microenvironments.


[Chronic central cyanosis in children; always an indication for further diagnosis].
A girl and a boy, both aged 4 years, had displayed a blue discolouration of the skin for several years. In the girl, electrocardiography and roentgenography of the chest revealed no abnormalities; in the boy, the cardiac murmur was attributed to an insignificant ventricular septal defect. Further examinations were performed only when the children developed sleeping problems and decrease of exercise tolerance, respectively. In both, a right-left shunt was discovered caused by a direct communication between the right pulmonary artery and the left atrium, and tetralogy of Fallot, respectively. Both patients' condition improved after operation. Chronic central cyanosis in a child constitutes an indication for consultation of a paediatric cardiologist.


Implementing electronic health records in hospitals: a systematic literature review.
The literature on implementing Electronic Health Records (EHR) in hospitals is very diverse. The objective of this study is to create an overview of the existing literature on EHR implementation in hospitals and to identify generally applicable findings and lessons for implementers. A systematic literature review of empirical research on EHR implementation was conducted. Databases used included Web of Knowledge, EBSCO, and Cochrane Library. Relevant references in the selected articles were also analyzed. Search terms included Electronic Health Record (and synonyms), implementation, and hospital (and synonyms). Articles had to meet the following requirements: (1) written in English, (2) full text available online, (3) based on primary empirical data, (4) focused on hospital-wide EHR implementation, and (5) satisfying established quality criteria. Of the 364 initially identified articles, this study analyzes the 21 articles that met the requirements. From these articles, 19 interventions were identified that are generally applicable and these were placed in a framework consisting of the following three interacting dimensions: (1) EHR context, (2) EHR content, and (3) EHR implementation process. Although EHR systems are anticipated as having positive effects on the performance of hospitals, their implementation is a complex undertaking. This systematic review reveals reasons for this complexity and presents a framework of 19 interventions that can help overcome typical problems in EHR implementation. This framework can function as a reference for implementers in developing effective EHR implementation strategies for hospitals.


Homologous desensitization to prostaglandins in rabbit ileum.
Prostaglandins (PG's) increase short-circuit current (Isc), inhibit NaCl absorption, and stimulate Cl secretion in rabbit ileum. These changes occur with the following PGs; E2, E1, nitrilo-I2 and, to a lesser extent, with A2, D2, and F2 alpha. Arachidonic acid (AA) also stimulates secretion. The PG- or AA-stimulated Isc does not persist, however, and on prolonged exposure tachyphylaxis develops. Resensitization of the Isc response to PGE2 is rapid, being essentially complete in 15 min after the PG is removed. Desensitization to AA is not reflected by diminished PG generation. PGE2 release from the mucosa after AA addition is constant, although the AA-stimulated Isc decreases. Isc measurements indicate that PGE2 at slightly below its EC50 partially desensitizes and a near-maximal concentration completely desensitizes to PGE2 but does not, however, inhibit the subsequent change in Isc caused by theophylline or vasoactive intestinal peptide (VIP). Adenosine 3',5'-cyclic monophosphate (cAMP) measurements suggest that desensitization applies to cAMP production. PGE2 (10(-5) M) increases mucosal cAMP three- to sevenfold, but this elevation is transient; a second challenge dose, which fails to elicit a Isc change, also fails to increase mucosal cAMP. Adenylate cyclase measurements from untreated and PGE2-treated enterocytes demonstrate a decrease in stimulation by PGE2 but not in stimulation by VIP, fluoride, or 5-guanylylimidodiphosphate.


[Trial of isolation of sick house syndrome and unclassified multiple chemical sensitivities--Definition of sick house syndrome, and symptoms].
This study was designed to clarify the definition of sick house syndrome (SHS). SHS was defined based on the disease related to habitation as follows. 1. The cause of the onset of a disease relates to house. 2. Symptoms appear within house. 3. Symptoms will be less serious or disappear if patient away from house. 4. If patient goes into house, symptoms will appear repeatedly. When it corresponded to all above, it was defined to SHS, and it classified as MCS (multiple chemical sensitivities) without above conditions. Even if SHS is isolated from similar disease completely, characteristic symptoms of MCS are hard to be detected because MCS are combination of two or more diseases. Based on this working hypothesis, the logistic regression by setting MCS as reference was performed so that characteristic symptoms of SHS show odds ratios with exceeding one. The odds ratios with more than two of characteristic symptoms in SHS were "nausea or vomiting" "Troublesome in everything" and the causative substances to which symptoms get worse was "The smell of a perfume and cosmetics". Characteristic symptoms of an allergy disease were detected by comparison with the allergic conjunctivitis, allergic rhinitis, and bronchial asthma, respectively. These results showed that the classification method was appropriate. This definition is not fundamentally differed from the definition of the sick-building syndrome of WHO.