Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies.
The Large(myd) mouse has a loss-of-function mutation in the putative glycosyltransferase gene Large. Mutations in the human homolog (LARGE) have been described in a form of congenital muscular dystrophy (MDC1D). Other genes (POMT1, POMGnT1, fukutin, and FKRP) that encode known or putative glycosylation enzymes are also causally associated with human congenital muscular dystrophies. All these diseases are associated with hypoglycosylation of the membrane protein alpha-dystroglycan (alpha-DG) and consequent loss of extracellular ligand binding. Hence, they are termed dystroglycanopathies. A paralogous gene for LARGE (LARGE2 or GYLTL1B) may also have a role in DG glycosylation. Using database interrogation and reverse-transcriptase polymerase chain reaction (RT-PCR), we identified vertebrate orthologs of each of these LARGE genes in many vertebrates, including human, mouse, dog, chicken, zebrafish, and pufferfish. However, within invertebrate genomes, we were able to identify only single homologs. We suggest that vertebrate LARGE orthologs be referred to as LARGE1. RT-PCR, dot-blot, and northern analysis indicated that LARGE2 has a more restricted tissue-expression profile than LARGE1. Using epitope-tagged proteins, we show that both LARGE1 and LARGE2 localize to the Golgi apparatus. The high similarity between the LARGE paralogs suggests that LARGE2 may also act on DG. Overexpression of LARGE2 in mouse C2C12 myoblasts results in increased glycosylation of alpha-DG accompanied by an increase in laminin binding. Thus, there may be functional redundancy between LARGE1 and LARGE2. Consistent with this idea, we show that alpha-DG is still fully glycosylated in kidney (a tissue that expresses a high level of LARGE2 mRNA) of Large(myd) mutant mice.


During viral infection of the respiratory tract, CD27, 4-1BB, and OX40 collectively determine formation of CD8+ memory T cells and their capacity for secondary expansion.
Independent studies have shown that CD27, 4-1BB, and OX40 can all promote survival of activated CD8+ T cells. We have therefore compared their impact on CD8+ memory T cell formation and responsiveness within one, physiologically relevant model system. Recombinant mice, selectively lacking input of one or two receptors, were challenged intranasally with influenza virus, and the immunodominant virus-specific CD8+ T cell response was quantified at priming and effector sites. Upon primary infection, CD27 and (to a lesser extent) 4-1BB made nonredundant contributions to accumulation of CD8+ virus-specific T cells in draining lymph nodes and lung, while OX40 had no effect. Interestingly though, in the memory response, accumulation of virus-specific CD8+ T cells in spleen and lung critically depended on all three receptor systems. This was explained by two observations: 1) CD27, 4-1BB, and OX40 were collectively responsible for generation of the same memory CD8+ T cell pool; 2) CD27, 4-1BB, and OX40 collectively determined the extent of secondary expansion, as shown by adoptive transfers with standardized numbers of memory cells. Surprisingly, wild-type CD8+ memory T cells expanded normally in primed OX40 ligand- or 4-1BB ligand-deficient mice. However, when wild-type memory cells were generated in OX40 ligand- or 4-1BB ligand-deficient mice, their secondary expansion was impaired. This provides the novel concept that stimulation of CD8+ T cells by OX40 and 4-1BB ligand during priming imprints into them the capacity for secondary expansion. Our data argue that ligand on dendritic cells and/or B cells may be critical for this.


Differential sensitivity to rotations of facial features in the Thatcher illusion.
A developmental study is presented in which participants must detect the Thatcher illusion in order to match unfamiliar faces on identity. 114 participants between 6 and 67 years of age completed a matching task whereby face pairs were presented upright or under inversion. At all ages, participants were more accurate matching upright than inverted faces. In an altered version of the Thatcher task, where only the eyes or mouth were inverted, all participants were more accurate and faster to detect eye manipulations than mouth manipulations. The results are discussed in terms of the developmental significance of face inversion, the Thatcher illusion, and the salience for protection from the Thatcher illusion.


Peeling plaids apart: context counteracts cross-orientation contrast masking.
Contrast discrimination for an image is usually harder if another image is superimposed on top. We asked whether such contrast masking may be enhanced or relieved depending on cues promoting integration of both images as a single pattern, versus segmentation into two independent components. Contrast discrimination thresholds for a foveal test grating were sharply elevated in the presence of a perfectly overlapping orthogonally-oriented mask grating. However thresholds returned to the unmasked baseline when a surround grating was added, having the same orientation and phase of either the test or mask grating. Both such masking and 'unmasking' effects were much stronger for moving than static stimuli. Our results suggest that common-fate motion reinforces the perception of a single coherent plaid pattern, while the surround helps to identify each component independently, thus peeling the plaid apart again. These results challenge current models of early vision, suggesting that higher-level surface organization influences contrast encoding, determining whether the contrast of a grating may be recovered independently from that of its mask.


Toxoplasma gondii and subversion of the immune system.
Toxoplasma gondii is an intracellular obligate parasite that enters the host via the gastrointestinal tract. The parasite is able to evade or subvert the immune response of its host via various mechanisms. Here, we discuss a recent in vitro study by Eric Denkers and colleagues that focused on the modulation of gene transcription of host macrophages stimulated by lipopolysaccharide (LPS) following infection with T. gondii. The parasite was able to block the response of macrophages to LPS, a major immunostimulatory component of Gram negative bacteria, thus possibly avoiding the hyperinflammatory response of the host to gut microflora, among which Gram negative bacteria are abundant.


An uncommon presentation of metastatic melanoma: a case report.
Metastases to the spleen are rare and are generally part of a multi-visceral metastatic disease. The most common sources of splenic metastases include breast, lung and colorectal malignancies as well as melanoma and ovarian carcinoma. Solitary splenic metastasis is very uncommon. We present a case of a 44-year-old man who presented at our department for gallstones symptoms. He had a past medical history of neck cutaneous melanoma (T3bN0M0--Stage IIb). He had not attended follow-up schedule for personal reasons. However, abdominal ultrasound revealed the presence of a solitary solid lesion in the spleen. Preoperative workup was completed with CT scan that confirmed the presence of a large splenic lesion with subcapsular fluid collection, also compatible with a post-traumatic lesion.Preoperative findings could not exclude malignancy and patient was therefore submitted to surgery. At laparoscopy, a condition of peritoneal melanosis was present. Splenectomy was carried out. Histological report confirmed the peritoneal melanosis and the diagnosis of metastatic spleen lesion from melanoma. Patient was observed, but died of metastatic disease 14 months after surgery. Splenic metastases are uncommon. Isolated metastases from melanoma are rare and could be found several months after primary diagnosis of melanoma. Surgery remains the most effective treatment, especially for metachronous disease, offering the best chance of long-term survival. Prognosis remains poor, as metachronous disease is indicative of aggressive widespread of the disease.


Writing Together to Get AHEAD: an interprofessional boot camp to support scholarly writing in the health professions.
Writing for publication is an integral skill for both sharing research findings and career advancement, yet many faculty lack expertise, support, and time to author scholarly publications. Health professions educators identified writing as an area in which a new educators' academy could offer support. To address this need, a writing task force was formed consisting of a librarian, a School of Medicine faculty member, and a School of Nursing faculty member. The task force launched two initiatives to motivate and support faculty writing and publication over two academic years. In the first year, a structured interprofessional "boot camp" consisting of a sequenced, modularized approach to manuscript completion was offered. In the second year, community building, in-person writing sessions, and incentives were added to the structured tasks. In year one, twenty participants enlisted in the boot camp, nine of whom completed a manuscript for submission by the end of the program. Qualitative feedback indicated potential improvements, which were put in place in the second program. In year two, twenty-eight participants enrolled, and eleven submitted thirteen manuscripts for publication by the end of the program. Structured tasks, frequent deadlines, and professional editorial assistance were highly valued by participants. Time remains a barrier for faculty seeking to complete manuscripts. As experts in many facets of the publication process, librarians are well positioned to partner with others to facilitate faculty and staff development in writing.


The Effect of Iron-Fortified Lentils on Blood and Cognitive Status among Adolescent Girls in Bangladesh.
Iron deficiency is highly prevalent in South Asia, especially among women and children in Bangladesh. Declines in cognitive performance are among the many functional consequences of iron deficiency. We tested the hypothesis that, over the course of a 4-month iron fortification trial, cognitive performance would improve, and that improvement would be related to improvements in iron status. Participants included 359 adolescent girls attending Bangladesh Rural Advancement Committee (BRAC) clubs as a subsample of a larger double-blind, cluster-randomized community trial in which participants were assigned to one of three conditions: a condition in which no lentils were supplied (NL, n = 118, but which had the usual intake of lentils), a control (non-fortified) lentil condition (CL, n = 124), and an iron-fortified lentil condition (FL, n = 117). In the FL and CL conditions, approximately 200 g of cooked lentils were served five days per week for a total of 85 feeding days. In addition to biomarkers of iron status, five cognitive tasks were measured at baseline (BL) and endline (EL): simple reaction time task (SRT), go/no-go task (GNG), attentional network task (ANT), the Sternberg memory search Task (SMS), and a cued recognition task (CRT). Cognitive performance at EL was significantly better for those in the FL relative to the CL and NL conditions, with this being true for at least one variable in each task, except for the GNG. In addition, there were consistent improvements in cognitive performance for those participants whose iron status improved. Although there were overall declines in iron status from BL to EL, the declines were smallest for those in the FL condition, and iron status was significantly better for those in FL condition at EL, relative to those in the CL and NL conditions. the provision of iron-fortified lentils provided a protective effect on iron status in the context of declines in iron status and supported higher levels of cognitive performance for adolescent girls at-risk of developing iron deficiency.


[Is your patient correctly sedated? Monitoring patients by means of the bispectral index].
The use of sedatives is relatively frequent in hospital care. However the evaluation of the effects of sedatives continues to be carried out in a non-standardized manner. There are two forms to do so, either by use of subjective evaluation scales like Ramsay or RASS, among others, or by means of an objective evaluation instrument, the bispectral index or BIS, produced by Aspect. BIS monitoring permits medical personnel to measure objectively the degree of anesthesia. This technology make it possible to administer an adequate anesthesia to patients and thus prevent unnecessary overdoses, since the evaluation scales are ineffective on patients treated with muscle relaxants. BIS is especially recommended for patients who have undergone neurological surgery since it is essential to maintain a high degree of comfort plus an adequate sedation in order to practice an adequate clinical evaluation, avoiding an inappropriate sedation which could hide signs and symptoms.


Species differences take shape at nanoparticles: protein corona made of the native repertoire assists cellular interaction.
Cells recognize the biomolecular corona around a nanoparticle, but the biological identity of the complex may be considerably different among various species. This study explores the importance of protein corona composition for nanoparticle recognition by coelomocytes of the earthworm Eisenia fetida using E. fetida coelomic proteins (EfCP) as a native repertoire and fetal bovine serum (FBS) as a non-native reference. We have profiled proteins forming the long-lived corona around silver nanoparticles (75 nm OECD reference materials) and compared the responses of coelomocytes to protein coronas preformed of EfCP or FBS. We find that over time silver nanoparticles can competitively acquire a biological identity native to the cells in situ even in non-native media, and significantly greater cellular accumulation of the nanoparticles was observed with corona complexes preformed of EfCP (p < 0.05). An EfCP-nanoparticle mimicry made with a recombinant protein, lysenin, revealed its critical contribution in the observed cell-nanoparticle response. This confirms the determinant role of the recognizable biological identity during invertebrate in vitro testing of nanoparticles. Our finding shows a case of species-specific formation of biomolecular coronas, and this suggests that the use of representative species may need careful consideration in assessing the risks associated with nanoparticles.


A negative regulator of HO transcription, SIN1 (SPT2), is a nonspecific DNA-binding protein related to HMG1.
The SIN1 gene was initially identified because mutations in SIN1 bypass the need for SWI1 to activate transcription of the yeast HO gene. We show here that transcription of HO in swi1 sin1 cells efficiently utilizes the normal start site. We have cloned SIN1 and found that it is identical to the previously identified gene SPT2, mutations in which allow transcription from certain mutated regulatory regions. The predicted SIN1/SPT2 protein has a distinctive amino acid composition (45% charged residues, 25% basic and 20% acidic) and has similarity to the mammalian HMG1 protein, a nonhistone component of chromatin. We show that SIN1 is concentrated in the nucleus and binds to DNA with little or no sequence specificity in vitro. It thus exhibits properties of an HMG protein. Addition of random DNA segments to a test promoter alters regulation by SIN1 in a manner similar to addition of a segment from the HO upstream region. Functional analysis of certain SIN1 mutations suggests that SIN1 may be part of a multiprotein complex. On the basis of these results, we propose that SIN1 is a nonhistone component of chromatin which creates the proper context for transcription. Because sin1 mutants exhibit increased loss of chromosome III, SIN1 may also play a role in fidelity of chromosome segregation.


Characterization of a human alpha 1-antitrypsin null allele involving aberrant mRNA splicing.
alpha 1-Antitrypsin (alpha 1AT) is a major protease inhibitor present in high concentrations in the plasma. Inheritance of alpha 1AT deficiency or null alleles (alleles associated with no detectable serum alpha 1AT) is associated with an increased risk for emphysema. In contrast to beta zero-thalassemia variants in which RNA splicing and promoter mutations constitute more than 40% of beta zero-thalassemia variants, all nine alpha 1AT null variants identified are the result of mutations involving the protein coding region of the alpha 1AT gene. During routine screening of individuals applying for enrollment in the USA alpha 1AT Deficiency Registry we identified an individual with emphysema and a Protease Inhibitor (PI*) type heterozygous for a novel alpha 1AT null allele. Direct DNA sequencing of this individual's alpha 1AT alleles demonstrated one normal and one novel allele, designated PI*QOwest, characterized by a single G-->T base substitution at position 1 of intron II, a highly conserved nucleotide position in vertebrate splice donor sites. Metabolic labeling of NIH-3T3 cells transfected with a plasmid vector containing an alpha 1AT minigene with the QOwest mutation demonstrated an absence of detectable immunoprecipitable alpha 1AT confirming that the G-->T mutation is responsible for the observed null phenotype. QOwest alpha 1AT minigene transfected cells expressed 25-100 fold less alpha 1AT mRNA than a normal control. DNA sequencing of polymerase chain reaction amplified mRNA obtained from transfected cells demonstrated the use of a cryptic splice site 84 bases upstream from the normal splice site.(ABSTRACT TRUNCATED AT 250 WORDS)


Folding and misfolding of the collagen triple helix: Markov analysis of molecular dynamics simulations.
Folding and misfolding of the collagen triple helix are studied through molecular dynamics simulations of two collagenlike peptides, [(POG)(10)](3) and [(POG)(4)POA(POG)(5)](3), which are models for wild-type and mutant collagen, respectively. To extract long time dynamics from short trajectories, we employ Markov state models. By analyzing thermodynamic and kinetic quantities calculated from the Markov state models, we examine folding mechanisms of the collagen triple helix and consequences of glycine mutations. We find that the C-to-N zipping of the collagen triple helix must be initiated by a nucleation event consisting of formation of three stable hydrogen bonds, and that zipping through a glycine mutation site requires a renucleation event which also consists of formation of three stable hydrogen bonds. Our results also suggest that slow kinetics, rather than free energy differences, is mainly responsible for the stability of the collagen triple helix.


Increasing adherence to the Mediterranean diet and lifestyle is associated with reduced fecal calprotectin and intra-individual changes in microbial composition of healthy subjects.
The Mediterranean diet (MED) is associated with the modification of gut microbial composition. In this pilot study, we investigate the feasibility of a microbiota-targeted MED-based lifestyle intervention in healthy subjects. MED intervention integrating dietary counseling, a supporting mobile application, and daily physical activity measurement using step trackers was prospectively applied for 4 weeks. Blood and fecal samples were collected at baseline, after the 4-week intervention, and at 6 and 12 months. Blood counts, inflammatory markers, microbial and eukaryotic composition were analyzed. Dietary adherence was assessed using daily questionnaires. All 20 healthy participants (females 65%, median age 37), completed the 4-week intervention. Adherence to MED increased from 15.6 ± 4.1 (baseline) to 23.2 ± 3.6 points (4 weeks), p < .01, reflected by increased dietary fiber and decreased saturated fat intake (both p < .05). MED intervention modestly reduced fecal calprotectin, white blood cell, neutrophil, and lymphocyte counts, within the normal ranges (P < .05). Levels of butyrate producers including Faecalibacterium and Lachnospira were positively correlated with adherence to MED and the number of daily steps. Bacterial composition was associated with plant-based food intake, while fungal composition with animal-based food as well as olive oil and sweets. Increasing adherence to MED correlated with increased absolute abundances of multiple beneficial gut symbionts. Therefore, increasing adherence to MED is associated with reduction of fecal calprotectin and beneficial microbial alterations in healthy subjects. Microbiota targeted lifestyle interventions may be used to modify the intestinal ecosystem with potential implications for microbiome-mediated diseases.


Systematic analysis reveals distinct roles of USF family proteins in various cancer types.
Upstream stimulatory factors (USFs) are members of the basic helix-loop-helix leucine zipper transcription factor family, including USF1, USF2, and USF3. The first two members have been well studied compared to the third member, USF3, which has received scarce attention in cancer research to date. Despite a recently reported association of its alteration with thyroid carcinoma, its expression has not been previously analyzed. We comprehensively analyzed differential levels of USFs expression, genomic alteration, DNA methylation, and their prognostic value across different cancer types and the possible correlation with tumor-infiltrating immune cells and drug response by using different bioinformatics tools. Our findings established that USFs play an important role in cancers related to the urinary system and justify the necessity for further investigation. We implemented and offer a useful ShinyApp to facilitate researchers' efforts to inquire about any other gene of interest and to perform the analysis of drug response in a user-friendly fashion at http://zzdlab.com:3838/Drugdiscovery/.


Common acute lymphoblastic leukemia Ph+ following Langerhans cell histiocytosis in a multi-malformed child with INV (9) (p12;q13) (mat): case report.
The occurrence of Langerhans cell histiocytosis (LCH) and another malignancy in the same patient is infrequent but has been recognized. The genetic changes that could be responsible for LCH and/or concomitant leukemia development are obscure. To the best of our knowledge, this is the first description of constitutional maternally derived inv (9) (p12;q13) in an LCH patient, and also of the development of common ALL Ph after LCH diagnosis and therapy. The potential significance of these findings [inv (9)+LCH+ALL Ph+] and their mutual relationship are unknown. Therefore, cooperative studies of large numbers of patients are needed to identify the common risk factors, if any.


1 alpha,25-Dihydroxyvitamin D3 markedly enhances chemically-induced transformation in BALB 3T3 cells.
1 alpha,25-Dihydroxyvitamin D3, a hormonally active form of vitamin D3, enhanced methylcholanthrene-induced transformation in BALB 3T3 cells to a much greater extent than 12-O-tetradecanoylphorbol-13-acetate. This enhancement was probably mediated by a cytosol receptor for 1 alpha,25-dihydroxyvitamin D3 which has an equilibrium constant of 28.4pM and a maximum binding of 32.6 fmol/mg protein.


Credit and Recognition for Contributions to Data-Sharing Platforms Among Cohort Holders and Platform Developers in Europe: Interview Study.
The European Commission is funding projects that aim to establish data-sharing platforms. These platforms are envisioned to enhance and facilitate the international sharing of cohort data. Nevertheless, broad data sharing may be restricted by the lack of adequate recognition for those who share data. The aim of this study is to describe in depth the concerns about acquiring credit for data sharing within epidemiological research. A total of 17 participants linked to European Union-funded data-sharing platforms were recruited for a semistructured interview. Transcripts were analyzed using inductive content analysis. Interviewees argued that data sharing within international projects could challenge authorship guidelines in multiple ways. Some respondents considered that the acquisition of credit for articles with extensive author lists could be problematic in some instances, such as for junior researchers. In addition, universities may be critical of researchers who share data more often than leading research. Some considered that the evaluation system undervalues data generators and specialists. Respondents generally looked favorably upon alternatives to the current evaluation system to potentially ameliorate these issues. The evaluation system might impede data sharing because it mainly focuses on first and last authorship and undervalues the contributor's work. Further movement of crediting models toward contributorship could potentially address this issue. Appropriate crediting mechanisms that are better aligned with the way science ought to be conducted in the future need to be developed.


Graded response to GABA by native extrasynaptic GABA receptors.
GABA is the main inhibitory neurotransmitter in the mammalian CNS. GABA in the brain is commonly associated with a fast, point-to-point form of signalling called synaptic transmission (phasic inhibition), but there is growing evidence that GABA participates in another, slower and more diffuse form of signalling often referred to as tonic inhibition. Unresolved questions regarding tonic neuronal inhibition concern activation and functional properties of extrasynaptic GABAA receptors (GABARex) present on neurones. Extrasynaptic receptors are exposed to submicromolar GABA concentrations and may modulate the overall excitability of neurones and neuronal networks. Here, we examined GABA-activated single-channel currents in dentate gyrus granule neurones in rat hippocampal slices. We activated three types (I, II, III) of GABARex channels by nanomolar GABA concentrations (EC50 I: 27 +/- 12; II: 4 +/- 3; III: 43 +/- 19 nm). The channels opened after a delay and the single-channel conductance was graded (gammamax I: 61 +/- 3; II: 85 +/- 8, III: 40 +/- 3 pS). The channels were differentially modulated by 1 microm diazepam, 200 nm zolpidem, 1 microm flumazenil and 50 nm THDOC (3alpha, 21-dihydroxy-5alpha-pregnan-20-one), consistent with the following minimal subunit composition of GABARex I alpha1betagamma2, GABARex II alpha4betagamma2 and GABARex III alphabetadelta channels.


Assessment of the integral membrane protein topology in living cells.
The bimolecular fluorescence complementation (BiFC) phenomenon has been successfully applied for in vivo protein-protein interaction studies and protein tagging analysis. Here we report a novel BiFC-based technique for investigation of integral membrane protein topology in living plant cells. This technique relies on the formation of a fluorescent complex between a non-fluorescent fragment of the yellow fluorescent protein (YFP) targeted into a specific cellular compartment and a counterpart fragment attached to the integral membrane protein N- or C-terminus or inserted into the internal loop(s). We employed this technique for topological studies of beet yellows virus-encoded p6 membrane-embedded movement protein, a protein with known topology, and the potato mop-top virus-encoded integral membrane TGBp2 protein with predicted topology. The results confirm that p6 is a type III integral transmembrane protein. Using a novel method, the central hydrophilic region of TGBp2 was localized into the ER lumen, whereas the N- and C-termini localized to the cytosol. We conclude that the BiFC-based reporter system for membrane protein topology analysis is a relatively fast and efficient method that can be used for high-throughput analysis of proteins integrated into the endoplasmic reticulum in living plant cells.


Service duplication within urban hospital clusters.
Approximately 80% of multihospital system member hospitals in U.S. urban areas are clustered with other same-system member hospitals located in the same market area. A key argument for clustering is the potential for reducing service duplication across cluster members. The aim of this study is to examine the effects of characteristics of hospital clusters on service duplication within 339 hospital clusters in U.S. metropolitan statistical areas and adjacent counties in 2002. Ordinary least squares regression is used to estimate the relationship between cluster characteristics in 1998 and duplicated services per cluster member in 2002. Duplication is higher in hospitals clusters with higher case mix index and higher bed size range. Duplication is lower in hospital clusters with more members, for-profit ownership, and more geographic dispersion. Increases in the size of hospital clusters allow more opportunities for service rationalization. For-profit clusters may be innovators in rationalization activity, and they should be studied in this regard. Clusters with a higher case mix, lower geographic dispersion, and hub-and-spoke design (with high bed-size range) may find service reallocation less feasible.


Properties of growth hormone receptors in relation to the adipose conversion of 3T3 cells.
Cultured preadipose 3T3 cells undergo a process of differentiation in which they convert to adipose cells. Growth hormone promotes this conversion. Since 3T3 sublines vary in their susceptibility to adipose conversion, it was of interest to examine the properties of the growth hormone receptors in relation to that susceptibility. It was found that preadipose 3T3-F442A cells, which are able to convert to adipose cells with high frequency, are able to bind about 10(4) growth hormone molecules per cell with Kd approximately 10(-9) M. After adipose conversion, no appreciable change in hormone binding was detected. The binding of growth hormone to 3T3-C2 cells (a line virtually insusceptible to adipose conversion) was indistinguishable from that to 3T3-F442A cells. Internalization and degradation of the hormone were also similar in the two cell lines. Susceptibility to adipose conversion is therefore not determined by the relative ability of the cells to bind or degrade the hormone, but must instead depend on some response, as yet unidentified, that follows binding of the hormone.


Study protocol for a randomised controlled trial of humanoid robot-based distraction for venipuncture pain in children.
Intravenous insertion (IVI) is a very common procedure in the emergency department (ED). IVI is often painful and stressful for both children and their families. Currently, distraction therapy is not used as a standard of care for IVI in North America. We propose that interaction with a humanoid robot may effectively distract children during IVI thereby reducing their pain and distress. This randomised controlled superiority trial will be conducted in a Canadian paediatric ED. We plan to recruit 80 patients. Children will be eligible if they (1) are 6 to 11 years of age, (2) need an IVI, (3) are fully conscious and alert, (4) have sufficient knowledge of the English language to understand and complete the study assessments and (5) are accompanied by a legal guardian. Our primary objective is to compare patient-reported pain and distress with the use of distraction (via a humanoid robot) versus standard care in children. The primary outcomes will be (1) self-reported pain, as measured by the Faces Pain Scale-Revised and (2) observed distress, as measured by the Observational Scale of Behavioural Distress-Revised. Secondary outcomes will include (1) measuring parental anxiety, (2) examining the association between parental anxiety and child outcomes and (3) children's degree of engagement with the humanoid robot via the Intrinsic Motivation Inventory tool. First enrolment occurred in April 2017 and is ongoing. This study has been approved by the Health Research Ethics Board (University of Alberta). Informed consent to participate will be obtained from all participants' parents/guardian, in conjunction with assent from the participant themselves. This study data will be submitted for publication regardless of results. Purchase of the robot was facilitated through a Stollery Children's Hospital Foundation donation. Recruitment costs are supported by the Women and Children's Health Research Institute. NCT02997631; Pre-results.


The effects of standardized trauma training on prehospital pain control: have pain medication administration rates increased on the battlefield?
The US Military has served in some of the most austere locations in the world. In this ever-changing environment, units are organized into smaller elements operating in very remote areas. This often results in longer evacuation times, which can lead to a delay in pain management if treatment is not initiated in the prehospital setting. Early pain control has become an increasingly crucial military prehospital task and must be controlled from the pain-initiating event. The individual services developed their standardized trauma training based on the recommendations by Frank Butler and the Defense Health Board Committee on Tactical Combat Casualty Care. This training stresses evidence-based treatment modalities, including pain control, derived from casualty injury analysis. Inadequate early pain control may lead to multiple acute and potentially chronic effects. These effects encompass a wide range from changes in blood pressure to delayed wound healing and posttraumatic stress disorder. Therefore, it is essential that pain be addressed in the prehospital environment. Institutional Review Board approval was obtained to conduct a retrospective Joint Theater Trauma Registry comparative study evaluating whether standardized trauma training increased prehospital pain medication administration between 2007 and 2009. These years were selected on the basis of mandatory training initiation dates and available Joint Theater Trauma Registry records. Records were analyzed for all US prehospital trauma cases with documented pain medication administration from Operations Enduring Freedom and Iraqi Freedom for the specified years. Data analysis revealed 232 patients available for review (102 for 2007 and 130 for 2009). A statistically significant prehospital pain treatment increase was noted, from 3.1% in 2007 to 6.7% in 2009 (p < 0.0005; 95% confidence interval, 2.39-4.93). Standardized trauma training has increased the administration of prehospital pain medication and the awareness of the importance of early pain control.


[Serum neopterin in hemorrhagic vasculitis].
Out of 12 patients with hemorrhagic vasculitis (HV) having the disease for 3-3.2 years (5 males and 7 females aged 18-55 years, mean age 34 +/- 13.8 years) renal affection was found in 3 (25%) patients. Renal function was normal in all the patients. One patient had nephrotic and two had mixed nephritis. One patient had gastrointestinal lesions. Serum neopterin was measured by radioimmunoassay. Mean concentration of serum neopterin was significantly higher than in donors (9.15 +/- 6.82 nmol/l and 5.2 +/- 2.1 nmol/l, respectively). A high neopterin level was found in 2 (67%) of 3 patients with nephritis and in 1(11%) of 9 patients free of nephritis. Mean neopterin was significantly higher in 3 patients with renal disorders than in the comparison group. A positive correlation existed between neopterin level and the clinical activity index, ESR, IgA, IgG CIC concentrations.


[A comparative study of the efficacy of Vermox, albendazole and medamine in an experimental model of trichocephaliasis in mice].
A comparison of the efficacy of albendazole, medamine, and Vermox using an experimental model of Trichocephalus muris in DBA-2 mice showed that Vermox was most effective at all stages of the parasite development. The therapeutic activity of albendazole and medamine depends on daily dose, its dividing through the day and the duration of the treatment. At larval stages of T. muris complete recovery might be achieved using a daily dose of 25 mg/kg for albendazole and 150 mg/kg for medamine, but at the adult stage the doses of the drugs should be 3-4 times higher to achieve 100% effect. The resistance of T. muris to the drugs especially increases at the beginning of egg production.


Characterization of anxiolytic and neuropharmacological activities of Silexan.
Silexan is an essential oil produced from Lavandula angustifolia flowers with proven clinical efficacy for the treatment of anxiety disorders. The present study was conducted to assess its anxiolytic activity and to screen for neuropharmacological properties in rats and mice of either sex. Silexan (3, 10, and 30 mg/kg, intraperitoneally), lorazepam (5 mg/kg, p.o.), or diazepam (3 mg/kg, p.o.) were administered once daily for 7 consecutive days. Experiments were conducted 1 h after the last drug or vehicle administration. All the three doses of Silexan showed significant and dose-dependent anxiolytic activity in the used pharmacological models (open-field test, elevated plus-maze test, elevated zero-maze test, social interaction test, and novelty-induced suppressed feeding latency test), which was comparable to that of the standard anxiolytic agent lorazepam. In addition, Silexan amplified pentobarbital-induced sleeping time, but in contrast to diazepam was found to be devoid of any significant effect on locomotor activity and muscle-grip performance.


Breast imaging with positron emission tomography and fluorine-18 fluorodeoxyglucose: use and limitations.
To evaluate the diagnostic value of positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) for the diagnosis of primary breast cancer. Preoperatively, 144 patients with masses suggestive of breast cancer underwent PET imaging of the breast. To identify breast cancer by increased metabolic activity, parametric FDG-PET images were analyzed for increased tracer uptake applying conventional image reading (CIR) and sensitive image reading (SIR). One hundred eighty-five breast tumors were evaluated by histology, revealing 132 breast carcinomas and 53 benign masses. Breast carcinomas were identified with an overall sensitivity of 64.4% (CIR) and 80.3% (SIR). The increase in sensitivity (SIR) resulted in a noticeable decrease in specificity, from 94.3% (CIR) to 75.5% (SIR). At stage pT1, only 30 (68.2%) of 44 breast carcinomas were detected, compared with 57 (91.9%) of 62 at stage pT2. A higher percentage of invasive lobular carcinomas were false-negative (65.2%) compared with invasive ductal carcinomas (23.7%). Nevertheless, positive PET scans provided a high positive-predictive value (96.6%) for breast cancer. Partial volume effects and varying metabolic activity (dependent on tumor type) seem to represent the most significant limitations for the routine diagnostic application of PET. The number of invasive procedures is therefore unlikely to be significantly reduced by PET imaging in patients presenting with abnormal mammography. However, the high positive-predictive value, resulting from the increased metabolic activity of malignant tissue, may be used with carefully selected subsets of patients as well as to determine the extent of disease or to assess therapy response.


[Simultaneous analyses of cocaine and its metabolite benzoylecgonine in urine by LC-MS/MS].
To establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous analysis of cocaine (COC) and its metabolite benzoylecgonine(BZE) in urine samples. A single dose of COC (10 mg/kg) was injected intraperitoneally into guinea pigs and urine samples were collected for 7 days. The urine samples were extracted by auto solid phase extraction (SPE), separated by the Allure PFP propyl column with a mobile phase consisting of methanol and 20 mmol/L ammonium acetate buffer [0.1% formic acid (80:20, V/V)], and then analyzed by LC-MS/MS. Multiple reaction monitoring (MRM) mode was used to analyze COC (m/z 304.2-->182.3, m/z 304.2-->150.1) and BZE (m/z 290.2-->168.3, m/z 290.2-->105.0). COC and BZE showed a fairly good linearity over the range of 2.0-100 ng/mL (r=0.9995). The detection limit was 0.5 ng/mL. The recovery rate was greater than 90% and the deviation of intra- and inter-day precision was less than 6%. BZE was the major target detected in urine samples, and its detection window was longer than COC. This newly developed method shows high sensitivity and selectivity, and is suitable for the simultaneous analysis of cocaine and benzoylecgonine in urine samples.


Signal therapy of NF1-deficient tumor xenograft in mice by the anti-PAK1 drug FK228.
PAK1, a Rac/CDC42-dependent Ser/Thr kinase, is required for the malignant growth of RAS transformants as well as both NF1-deficient and NF2-deficient cancer cells. FK228, a histone deacetylase (HDAC) inhibitor, suppresses the growth of more than 70% of human cancers in vivo including RAS transformants, breast cancers and prostate cancers by activating a set of genes including the tumor suppressors gelsolin and p21(WAF1), that block upstream and downstream of PAK1, respectively. Here we demonstrate that (1) the anti-PAK1 drug FK228 (0.1 nM) completely blocks the growth of both NF1-deficient and NF2-deficient cancer cells in vitro, and that (2) FK228 (2.5 mg/kg, i.p., twice a week) causes the complete regression of an NF1-deficient human malignant peripheral nerve sheath tumor (MPNST) xenograft in nude mice. This is the very first case where a chemical drug in clinical trials for cancers has ever worked so effectively on neurofibromatosis (experimental neurofibromas) in vivo.


Exercise Intensity during 6-Minute Walk Test in Patients with Peripheral Artery Disease.
Non-supervised ground walking has been recommended for patients with symptomatic peripheral artery disease (PAD). However, the magnitude of the effort required by this activity and the characteristics of patients whose ground walking is more intense are unclear. To determine whether ground walking exceeds the ventilatory threshold (VT), a recognized marker of exercise intensity, in patients with symptomatic PAD. Seventy patients (61.4% male and aged 40 to 85 years old) with symptomatic PAD were recruited. Patients performed a graded treadmill test for VT determination. Then, they were submitted to a 6-minute walk test so the achievement of VT during ground ambulation could be identified. Multiple logistic regression was conducted to identify predictors of VT achievement during the 6-minute walk test. The significance level was set at p < 0.05 for all analyses. Sixty percent of patients achieved VT during the 6-minute walk test. Women (OR = 0.18 and 95%CI = 0.05 to 0.64) and patients with higher cardiorespiratory fitness (OR = 0.56 and 95%CI = 0.40 to 0.77) were less likely to achieve VT during ground walking compared to men and patients with lower cardiorespiratory fitness, respectively. More than half of patients with symptomatic PAD achieved VT during the 6-minute walk test. Women and patients with higher cardiorespiratory fitness are less likely to achieve VT during the 6-minute walk test, which indicates that ground walking may be more intense for this group. This should be considered when prescribing ground walking exercise for these patients. (Arq Bras Cardiol. 2020; 114(3):486-492).


Ascorbate affects proliferation of guinea-pig vascular smooth muscle cells by direct and extracellular matrix-mediated effects.
Proliferation of smooth muscle cells and deposition of extracellular matrix proteins are important events in the formation of atherosclerotic plaques. We have investigated the direct and matrix-mediated effects of ascorbate on the proliferation rate of vascular smooth muscle cells (VSMC) isolated from the guinea-pig aorta. In the presence of ascorbate, cells showed a bi-phasic growth pattern. At 125 microM ascorbate, -3H--thymidine incorporation was stimulated 25%. However, higher concentrations of ascorbate gradually decreased cell-incorporated radioactivity up to 50% at 2 mM ascorbate. These effects of ascorbate on DNA synthesis in VSMC were paralleled by the changes in cell number and were not due to ascorbate cytotoxicity. Alpha-tocopherol (0.1 mM), individually and in combinations with 1 mm ascorbate, also inhibited DNA synthesis in VSMC. Ascorbate also influenced proliferation of smooth muscle cells through matrix-mediated effect. New VSMC culture plated on extracellular matrices deposited by smooth muscle cells in the presence of 0.1-1 mM ascorbate had up to 50% lower proliferation rate than on matrices from ascorbate-deficient cells, as assessed by [3H]-thymidine incorporation. This effect was independent from alpha-tocopherol and specific inhibitors of collagen synthesis: L-azetidine-2-carboxylic acid and pyridine-2,4-dicarboxylic acid. An ascorbate-dependent matrix effect was specific for smooth muscle cells grown on VSMC and human skin fibroblast-originated matrices, but not for human vascular endothelial cells. The possible involvement of ascorbate in the regulation of smooth muscle cells proliferation by its antioxidant/pro-oxidant effects and regulation of extracellular matrix composition are discussed.


The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy.
The introduction of anti-CD20 monoclonal antibodies such as rituximab, ofatumumab, or obinutuzumab improved the therapy of B-cell malignancies even though the precise physiological role and regulation of CD20 remains unclear. Furthermore, CD20 expression is highly variable between different B-cell malignancies, patients with the same malignancy, and even between intraclonal subpopulations in an individual patient. Several epigenetic (EZH2, HDAC1/2, HDAC1/4, HDAC6, complex Sin3A-HDAC1) and transcription factors (USF, OCT1/2, PU.1, PiP, ELK1, ETS1, SP1, NFκB, FOXO1, CREM, SMAD2/3) regulating CD20 expression (encoded by MS4A1) have been characterized. CD20 is induced in the context of microenvironmental interactions by CXCR4/SDF1 (CXCL12) chemokine signaling and the molecular function of CD20 has been linked to the signaling propensity of B-cell receptor (BCR). CD20 has also been shown to interact with multiple other surface proteins on B cells (such as CD40, MHCII, CD53, CD81, CD82, and CBP). Current efforts to combine anti-CD20 monoclonal antibodies with BCR signaling inhibitors targeting BTK or PI3K (ibrutinib, acalabrutinib, idelalisib, duvelisib) or BH3-mimetics (venetoclax) lead to the necessity to better understand both the mechanisms of regulation and the biological functions of CD20. This is underscored by the observation that CD20 is decreased in response to the "BCR inhibitor" ibrutinib which largely prevents its successful combination with rituximab. Several small molecules (such as histone deacetylase inhibitors, DNA methyl-transferase inhibitors, aurora kinase A/B inhibitors, farnesyltransferase inhibitors, FOXO1 inhibitors, and bryostatin-1) are being tested to upregulate cell-surface CD20 levels and increase the efficacy of anti-CD20 monoclonal antibodies. Herein, we review the current understanding of CD20 function, and the mechanisms of its regulation in normal and malignant B cells, highlighting the therapeutic implications.


A multilevel thoracolumbar meningioma in a young woman.
Spinal meningiomas of five or more vertebral segment long are very rare and also less common in younger patients. Under 50 years of age these tumors are more commonly genetical and have worse prognosis. A 25-year-old woman presented with back pain and progressive walking difficulty. An intradural extramedullary tumor extending from thoracal 9th to lumbar 2nd vertebral body was detected. The patient was operated and the tumor was totally removed. The histopathological diagnosis was angiomatous meningioma. Neurological symptoms and signs partially improved postoperatively. Interestingly, magnetic resonance imaging of this patient might easily be confused with ependymoma. Although we performed laminectomy and instrumentation, to maintain stability laminoplasty should be the first treatment modality for such a young patient.


Unleashing the potential of cell membrane-based nanoparticles for COVID-19 treatment and vaccination.
Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a particular coronavirus strain responsible for the coronavirus disease 2019 (COVID-19), accounting for more than 3.1 million deaths worldwide. Several health-related strategies have been successfully developed to contain the rapidly-spreading virus across the globe, toward reduction of both disease burden and infection rates. Particularly, attention has been focused on either the development of novel drugs and vaccines, or by adapting already-existing drugs for COVID-19 treatment, mobilizing huge efforts to block disease progression and to overcome the shortage of effective measures available at this point.Areas covered: This perspective covers the breakthrough of multifunctional biomimetic cell membrane-based nanoparticles as next-generation nanosystems for cutting-edge COVID-19 therapeutics and vaccination, specifically cell membrane-derived nanovesicles and cell membrane-coated nanoparticles, both tailorable cell membrane-based nanosystems enriched with the surface repertoire of native cell membranes, toward maximized biointerfacing, immune evasion, cell targeting and cell-mimicking properties.Expert opinion: Nano-based approaches have received widespread interest regarding enhanced antigen delivery, prolonged blood circulation half-life and controlled release of drugs. Cell membrane-based nanoparticles comprise interesting antiviral multifunctional nanoplatforms for blocking SARS-CoV-2 binding to host cells, reducing inflammation through cytokine neutralization and improving drug delivery toward COVID-19 treatment.


How tumor markers are used in the routine follow-up of breast and colorectal cancer. A survey of 29 Italian hospitals.
The impact of tumor markers on the outcome of several malignancies is still under debate. This relative uncertainty leads to a subjective approach to their use. Monitoring the use of tumor markers is a valuable tool to identify the need for educational policies. We conducted a survey to evaluate how tumor markers are routinely used in the follow-up of patients with breast, colorectal and ovarian carcinoma. The former two malignancies are considered in the present paper. We surveyed 35 Italian hospitals; 29 (83%, accounting for 26,622 hospital beds) filled in and returned the questionnaire. Overall, 467,361 tumor marker requests were scrutinized by the surveyed hospitals. We found a wide variability in the type and number of routinely used markers, the cutoff points chosen, and the clinical decisions taken on the basis of marker results. In addition, we observed a relative lack of communication between clinicians and clinical pathologists in around 50% of the surveyed hospitals. In these cases clinical information was not provided to the laboratory and methodological aspects were not communicated to clinicians. From the findings of the present study we conclude that the cooperation between clinicians and clinical pathologists must improve before guidelines for the use of tumor marker assays can be framed and the compliance with these guidelines can be checked. Request forms for tumor marker assays should therefore be designed to contain clinical information and the quality of filling in request forms with clinical data should be carefully monitored.


SD-OCT peripapillary nerve fibre layer and ganglion cell complex parameters in glaucoma: principal component analysis.
To identify objective glaucoma-related structural features based on peripapillary (p) and macular (m) spectral domain optical coherence tomography (SD-OCT) parameters and assess their discriminative ability between healthy and glaucoma patients. Two hundred and sixty eyes (91 controls and 169 glaucoma) were included in this prospective study. After a complete examination, all participants underwent the posterior pole and the peripapillary retinal nerve fibre layer (pRNFL) protocols of the Spectralis SD-OCT. Principal component analysis (PCA), a data reduction method, was applied to identify and characterise the main information provided by the ganglion cell complex (GCC). The discriminative ability between healthy and glaucomatous eyes of the first principal components (PCs) was compared with that of conventional SD-OCT parameters (pRNFL, macular RNFL (mRNFL), macular ganglion cell layer (mGCL)and macular inner plexiform layer (mIPL)) using 10-fold cross-validated areas under the curve (AUC). The first PC explained 58% of the total information contained in the GCC and the pRNFL parameters and was the result of a general combination of almost all variables studied (diffuse distribution). Other PCs were driven mainly by pRNFL and mRNFL measurements. PCs and pRNFL had similar AUC (0.95 vs 0.96, p=0.88), and outperformed the other structural measurements: mRNFL (0.91, p=0.002), mGCL (0.92, p=0.02) and mIPL (0.92, p=0.0001). PCA identified a diffuse representation of the papillary and macular SD-OCT parameters as the most important PC to summarise structural data in healthy and glaucomatous eyes. PCs and pRNFL parameters showed the greatest discriminative ability between healthy and glaucoma cases.


Susceptibility of Prevotella intermedia/Prevotella nigrescens (and Porphyromonas gingivalis) to propolis (bee glue) and other antimicrobial agents.
Black-pigmented gram-negative anaerobes such as Porphyromonas gingivalis and Prevotella intermedia are suspected pathogens in adult periodontitis, whereas Prevotella nigrescens has been associated with health. Antimicrobial resistance among bacteria from this group has been reported in the past decade. This research aimed to evaluate and compare the susceptibility profile of 17 P. intermedia/P. nigrescens isolates recovered from patients with periodontitis and three reference strains to six antimicrobials, prescribed in dentistry in Brazil, and propolis (bee glue). The antimicrobial agents tested were tetracycline, penicillin, clindamycin, erythromycin, metronidazole, meropenem and six ethanolic extracts of propolis (EEPs) from Brazil. The reference strains P. gingivalis ATCC 33277 and P. intermedia ATCC 25611 were used for determination of minimum bactericidal concentration (MBC) and for time-kill assay to the EEPs. All of the strains were susceptible to penicillin, erythromycin, meropenem, metronidazole and 95% of them (n=19) to tetracycline. Thirty six percent (n=7) of the P. intermedia/P. nigrescens strains tested were resistant to clindamycin. As for propolis activity, all strains were susceptible and the minimum inhibitory concentration values ranged from 64 to 256 microg/mL. For the reference strains P. gingivalis ATCC 33277 and Prevotella intermedia ATCC 25611 the MBC was 256 microg/mL and death was observed within 3 h of incubation for P. gingivalis and within 6 h for P. intermedia. The action of propolis (bee glue) against suspected periodontal pathogens suggests that it may be of clinical value.


Topological resonances in scattering on networks (graphs).
We report on a hitherto unnoticed type of resonances occurring in scattering from networks (quantum graphs) which are due to the complex connectivity of the graph-its topology. We consider generic open graphs and show that any cycle leads to narrow resonances which do not fit in any of the prominent paradigms for narrow resonances (classical barriers, localization due to disorder, chaotic scattering). We call these resonances "topological" to emphasize their origin in the nontrivial connectivity. Topological resonances have a clear and unique signature which is apparent in the statistics of the resonance parameters (such as, e.g., the width, the delay time, or the wave-function intensity in the graph). We discuss this phenomenon by providing analytical arguments supported by numerical simulation, and identify the features of the above distributions which depend on genuine topological quantities such as the length of the shortest cycle (girth). These signatures cannot be explained using any of the other paradigms for narrow resonances. Finally, we propose an experimental setting where the topological resonances could be demonstrated, and study the stability of the relevant distribution functions to moderate dissipation.


Archaeology, demography and life history theory together can help us explain past and present population patterns.
Population matters. Demographic patterns are both a cause and a consequence of human behaviour in other important domains, such as subsistence, cooperation, politics and culture. Demographers interested in contemporary and recent historical populations have rich data at their fingertips; the importance of demography means many interested parties have gathered demographic data, much of which is now readily available for all to explore. Those interested in the demography of the distant past are not so fortunate, given the lack of written records. Nevertheless, the emergence in recent years of a new interest in the demography of ancient populations has seen the development of a range of new methods for piecing together archaeological, skeletal and DNA evidence to reconstruct past population patterns. These efforts have found evidence in support of the view that the relatively low long-term population growth rates of prehistoric human populations, albeit ultimately conditioned by carrying capacities, may have been owing to 'boom-bust' cycles at the regional level; rapid population growth, followed by population decline. In fact, this archaeological research may have come to the same conclusion as some contemporary demographers: that demography can be remarkably hard to predict, at least in the short term. It also fits with evidence from biology that primates, and particularly humans, may be adapted to environmental variability, leading to associated demographic stochasticity. This evidence of the fluctuating nature of human demographic patterns may be of considerable significance in understanding our species' evolution, and of understanding what our species future demographic trajectories might be. This article is part of the theme issue 'Cross-disciplinary approaches to prehistoric demography'.


Sensitivity pattern and beta-lactamase screening of Neisseria gonorrhoeae strains isolated in Zaria, Northern Nigeria.
One hundred and sixty strains of N. gonorrhoeae were studied for their in-vitro sensitivity to six different antimicrobial agents and tested for beta-lactamase production in Zaria, Northern Nigeria. While 82% of strains were sensitive to erythromycin, 70% to tetracycline and 61% to chloramphenicol, only 35%, 33% and 24% were sensitive to ampicillin, penicillin and streptomycin respectively. Penicillin is no more the drug of choice in the treatment of gonorrhoea in this environment since two thirds of strains are either partially resistant or completely resistant to penicillin and 44% of strains are beta-lactamase producers. Erythromycin/tetracycline are recommended as the drugs of choice.


Gastric tubes and airway management in patients at risk of aspiration: history, current concepts, and proposal of an algorithm.
Rapid sequence induction and intubation (RSII) and awake tracheal intubation are commonly used anesthetic techniques in patients at risk of pulmonary aspiration of gastric or esophageal contents. Some of these patients may have a gastric tube (GT) placed preoperatively. Currently, there are no guidelines regarding which patient should have a GT placed before anesthetic induction. Furthermore, clinicians are not in agreement as to whether to keep a GT in situ, or to partially or completely withdraw it before anesthetic induction. In this review we provide a historical perspective of the use of GTs during anesthetic induction in patients at risk of pulmonary aspiration. Before the introduction of cricoid pressure (CP) in 1961, various techniques were used including RSII combined with a head-up tilt. Sellick initially recommended the withdrawal of the GT before anesthetic induction. He hypothesized that a GT increases the risk of regurgitation and interferes with the compression of the upper esophagus during CP. He later modified his view and emphasized the safety of CP in the presence of a GT. Despite subsequent studies supporting the effectiveness of CP in occluding the esophagus around a GT, Sellick's early view has been perpetuated by investigators who recommend partial or complete withdrawal of the GT. On the basis of available information, we have formulated an algorithm for airway management in patients at risk of aspiration of gastric or esophageal contents. The approach in an individual patient depends on: the procedure; type and severity of the underlying pathology; state of consciousness; likelihood of difficult airway; whether or not the GT is in place; contraindications to the use of RSII or CP. The algorithm calls for the preanesthetic use of a large-bore GT to remove undigested food particles and awake intubation in patients with achalasia, and emptying the pouch by external pressure and avoidance of a GT in patients with Zenker diverticulum. It also stipulates that in patients with gastric distension without predictable airway difficulties, a clinical and imaging assessment will determine the need for a GT and in severe cases an attempt to insert a GT should be made. In the latter cases, the success of placement will indicate whether to use RSII or awake intubation. The GT should not be withdrawn and should be connected to suction during induction. Airway management and the use of GTs in the surgical correction of certain gastrointestinal anomalies in infants and children are discussed.


Hemodynamic and serum biochemical alterations associated with intravenous administration of three types of contrast media in anesthetized dogs.
To determine the incidence and type of alterations in heart rate (HR), peak systolic blood pressure (PSBP), and serum biochemical variables (total bilirubin, BUN, and creatinine concentrations) associated with IV administration of ionic-iodinated contrast (IIC), nonionic-iodinated contrast (NIC), and gadolinium dimeglumine (GD) contrast media in anesthetized dogs. 280 anesthetized dogs undergoing cross-sectional imaging. HR and PSBP were recorded at 5-minute intervals for 20 minutes for untreated control dogs and dogs that received IIC, NIC, or GD contrast medium. The development of an HR of < 60 beats/min or > 130 beats/min that included a > or = 20% change from baseline was considered a response. The development of PSBP of < 90 mm Hg or > 160 mm Hg that included a > or = 20% change from baseline was considered a response. Pre- and postcontrast serum biochemical values were recorded. Results-Of dogs receiving IIC medium, 3% (3/91) had a response in HR and 4% (4/91) had a response in PSBP at > or = 1 time points. None of the dogs receiving NIC medium had a response in HR; 1 of 16 had a response in PSBP. Of dogs receiving GD contrast medium, 1% (1/92) had a response in HR and 4% (4/92) had a response in PSBP. Of control dogs, 2% (2/81) had a response in HR and 4% (3/81) had a response in PSBP. No serum biochemical alterations were observed. IV administration of contrast media in anesthetized dogs caused moderate bradycardia, tachycardia, hypotension, or hypertension.


Effect of modifying occlusal cement spacer on the fit accuracy of digitally manufactured zirconia crowns.
Cement spacer has a crucial influence on the adaptation of fixed restorations. Recently, digitally fabricated zirconia crowns have become more popular, but studies on the effect of occlusal cement spacer on the fit accuracy of digitally designed and milled zirconia crowns are lacking. The purpose of this in vitro study was to investigate the effect of modifying digital occlusal spacer on the marginal and internal fit of digitally manufactured zirconia crowns. A maxillary molar typodont tooth was prepared for a zirconia crown, scanned with the Medit i700 intraoral scanner (IOS), and the standard tessellation language (STL) file was used to produce 3-dimensionally (3D) printed definitive dies assigned to 3 groups (n=12). All dies were scanned with the IOS, and the obtained STL files were exported to a computer-aided design (CAD) software program for the designing and milling of 36 complete contour zirconia crowns. The zirconia crown design was identical in the 3 groups for all parameters (default parameters in the CAD software program) with a 80-µm radial spacer 1 mm from the finish lines. The occlusal cement spacer was adjusted to 80 µm, 40 µm, and 0 µm for group 80-80, group 40-80, and group 0-80 respectively. The internal and marginal fit of the crowns were measured on their corresponding definitive dies with the replica technique. The Kruskal-Wallis test followed by the Dunn test with the Bonferroni correction was used for statistical analysis of the results (α=.05). The modification of occlusal cement spacer significantly affected the marginal and internal fit of digitally manufactured crowns (P<.05). Group 0-80 and group 40-80 had similar marginal gap values, which were significantly lower than those of group 80-80 (P<.017). For internal fit accuracy, group 0-80 displayed significantly lower gap values than group 40-80 and group 80-80 for all measured areas. Group 40-80 had significantly lower gap values than group 80-80 at the mid-occlusal and axio-occlusal areas (P<.017). Modifying occlusal cement spacer significantly affected the fit of digitally fabricated zirconia crowns. Reducing or eliminating occlusal spacer resulted in significantly improved fit accuracy.


Comparison of three methods of rewarming from hypothermia: advantages of extracorporeal blood warming.
We developed a new technique, extracorporeal venovenous rewarming (EVR), to rewarm hypothermic patients in the intensive care unit or operating room. We compared this method with the active external (standard) techniques of warming blankets; heated ventilator circuits, intravenous fluids, and gastric and peritoneal lavage; and cardiopulmonary bypass. The EVR technique warmed patients' blood or additional blood products and crystalloids to 40 degrees C at 150-400 mL/min and allowed survival from a core temperature of 31.1 degrees C after massive injury. The EVR technique rewarming patients more rapidly than standard techniques and may be most appropriate in patients with multisystem trauma when rapid correction of hypothermia-related hypovolemia, coagulopathy, and arrhythmia is necessary. Cardiopulmonary bypass is required in severely hypothermic patients with cardiac arrest. Standard techniques can be used when these immediately life-threatening conditions are not present.


Marketing health care to minorities: tapping an emerging market.
A number of myths have prevented the development of a formal health care marketing strategy for the 100 million-plus racial and ethnic group members in the United States, despite their relatively greater need for health services. This market continues to grow in numbers, resources, and influence as the majority market level off. Marketers must look to minorities for new business, but traditional health care marketers have a long way to go before they are in a position to truly maximize this opportunity.


Treatment and outcomes of patients with chronic radiation proctitis. A single-center experience and review of the literature.
Chronic radiation proctitis is a frequent complication after radiotherapy for pelvic malignancies. It is reported that 1 to 5% of patients develop chronic radiation proctitis even with recent advances in external radiotherapy. Hematochezia, mucus discharge, urgency and tenesmus are common symptoms and they can vary in severity but bleeding is often the most debilitating to the patient. Different options are reported for treatment of this condition that always should keep in differential diagnosis in patients with history of pelvic radiotherapy. Treatments range from easy, with topic administration of formalina, to expensive and requiring specialized equipment such as hyperbaric oxygen therapy. Surgery is reserved to patients with failure of conservative treatments due to the high risk of leakage and high morbidity up to 60%. KEY WORDS: Argon beam, Bleeding, Formalin, Radiation, Proctitis, Sucralfate enema.


Golgi localization of carbohydrate sulfotransferases is a determinant of L-selectin ligand biosynthesis.
Sulfation of endothelial glycoproteins by the sulfotransferase GlcNAc6ST-2 is a regulatory modification that promotes binding of the leukocyte adhesion molecule L-selectin. GlcNAc6ST-2 is a member of a family of related enzymes that act on similar carbohydrate substrates in vitro but discrete glycoproteins in vivo. We demonstrate that GlcNAc6ST-1, -2, and -3 have distinct Golgi distributions, with GlcNAc6ST-1 confined to the trans-Golgi network, GlcNAc6ST-3 confined to the early secretory pathway, and GlcNAc6ST-2 distributed throughout the Golgi. Their localization was correlated with preferred activity on either N-linked or O-linked glycoproteins. A chimera comprising the localization domain of GlcNAc6ST-1 fused to the catalytic domain of GlcNAc6ST-2 was confined to the trans-Golgi network and adopted the substrate preference of GlcNAc6ST-1. We propose a model in which Golgi enzyme localization and competition orchestrate the biosynthesis of L-selectin ligands.


Understanding, Modeling and Simulating Unintended Positional Drift during Repetitive Steering Navigation Tasks in Virtual Reality.
Virtual steering techniques enable users to navigate in larger Virtual Environments (VEs) than the physical workspace available. Even though these techniques do not require physical movement of the users (e.g. using a joystick and the head orientation to steer towards a virtual direction), recent work observed that users might unintentionally move in the physical workspace while navigating, resulting in Unintended Positional Drift (UPD). This phenomenon can be a safety issue since users may unintentionally reach the physical boundaries of the workspace while using a steering technique. In this context, as a necessary first step to improve the design of navigation techniques minimizing the UPD, this paper aims at analyzing and modeling the UPD during a virtual navigation task. In particular, we characterize and analyze the UPD for a dataset containing the positions and orientations of eighteen users performing a virtual slalom task using virtual steering techniques. Participants wore a head-mounted display and had to follow three different sinusoidal-like trajectories (with low, medium and high curvature) using a torso-steering navigation technique. We analyzed the performed motions and proposed two UPD models: the first based on a linear regression analysis and the second based on a Gaussian Mixture Model (GMM) analysis. Then, we assessed both models through a simulation-based evaluation where we reproduced the same navigation task using virtual agents. Our results indicate the feasibility of using simulation-based evaluations to study UPD. The paper concludes with a discussion of potential applications of the results in order to gain a better understanding of UPD during steering and therefore improve the design of navigation techniques by compensating for UPD.


The online inverted classroom model (oICM). A blueprint to adapt the inverted classroom to an online learning setting in medical and health education.
This article was migrated. The article was marked as recommended. The idea of this paper is to offer a blueprint, with that facilitators have a guide to set up a complete digital teaching scenario according to the latest insights of didactical research. The corona pandemic forced higher education institutions all around the world to radically shift their curricula from a mix of face-to-face and remote teaching methods to a fully remote curriculum. Though challenging, this time provides opportunities to implement new educational methods and improve the quality of digital teaching. The classical concept of the inverted classroom was modified to meet the special needs of online settings. The proposed online Inverted Classroom Model (oICM) includes the following phases: (1) pre-phase, (2) self-learning-phase, (3) Synchronous online face-to-face phase, (4) transfer-phase, (5) evaluation. Recommendations and potential tools are provided for each phase. The oICM is an innovative and easy to use approach to shape digital teaching and learning processes during and after the CoVid19 pandemic. This blueprint is developed by the committee "Digitalization" of the German Association for Medical Education (GMA) for facilitators without any prior experience with the ICM, but also for those who already teach in a traditional ICM.


Thiamine triphosphate and thiamine triphosphatase activities: from bacteria to mammals.
In most organisms, the main form of thiamine is the coenzyme thiamine diphosphate. Thiamine triphosphate (ThTP) is also found in low amounts in most vertebrate tissues and can phosphorylate certain proteins. Here we show that ThTP exists not only in vertebrates but is present in bacteria, fungi, plants and invertebrates. Unexpectedly, we found that in Escherichia coli as well as in Arabidopsis thaliana, ThTP was synthesized only under particular circumstances such as hypoxia (E. coli) or withering (A. thaliana). In mammalian tissues, ThTP concentrations are regulated by a specific thiamine triphosphatase that we have recently characterized. This enzyme was found only in mammals. In other organisms, ThTP can be hydrolyzed by unspecific phosphohydrolases. The occurrence of ThTP from prokaryotes to mammals suggests that it may have a basic role in cell metabolism or cell signaling. A decreased content may contribute to the symptoms observed during thiamine deficiency.


Possible mechanism of static progressive stretching combined with extracorporeal shock wave therapy in reducing knee joint contracture in rats based on MAPK/ERK pathway.
The study aimed to observe the therapeutic effect of static progressive stretching (SPS) combined with extracorporeal shock wave therapy (ESWT) on extension knee joint contracture in rats and the effect on the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway in the development of joint capsule fibrosis. Thirty-six Sprague Dawley rats were randomly divided into blank control group, immobilization model group, natural recovery group, ESWT intervention group, SPS intervention group, and SPS combined with ESWT intervention group. The left knee joints of the rats, except for the control group, were fixed with an external fixation brace for four weeks at full extension to form joint contractures. The therapeutic effect of each intervention was assessed by evaluating total and arthrogenic contracture, the number of total cells and collagen deposition in the anterior joint capsule, the protein levels of TGF-β1, FGF-2, and ERK2 in the anterior joint capsule, the mean optical density of upstream RAS and downstream ERK2 positive expression in the MAPK/ERK pathway. SPS in combination with ESWT was more effective in relieving joint contracture, improving the histopathological changes in the anterior joint capsule, and suppressing the high expression of target proteins and the overactivated MAPK/ERK pathway. The overactivated MAPK/ERK pathway was involved in the formation of extension knee joint contracture in rats. SPS in combination with ESWT was effective in relieving joint contracture and fibrosis of joint capsule. Moreover, the inhibition of the overactivated MAPK/ERK pathway may be the potential molecular mechanism for its therapeutic effect.


Central acetylcholinesterase inhibition improves hemodynamic counterregulation to severe blood loss in alcohol-intoxicated rats.
Acute alcohol intoxication results in impaired hemodynamic counterregulation to blood loss and is associated with an attenuated hemorrhage-induced release of catecholamines and AVP. We speculated that restoration of the neuroendocrine response to hemorrhage would improve mean arterial blood pressure (MABP) recovery during acute alcohol intoxication. Previously, we demonstrated that intracerebroventricular (i.c.v.) choline, a precursor of acetylcholine, transiently increases sympathetic nervous system (SNS) outflow but is not capable of improving neuroendocrine and hemodynamic compensation to hemorrhage in alcohol-treated rats. We hypothesized that prolongation of the observed effect via i.c.v. neostigmine, an acetylcholinesterase inhibitor, would enhance SNS outflow, restore the neuroendocrine response, and in turn improve hemodynamic responses to hemorrhage during acute alcohol intoxication. I.c.v. neostigmine (1 microg) increased MABP, catecholamines, and AVP within 5 min and reversed hypotension due to 40% hemorrhage and intragastric alcohol (30% wt/vol, 2.5 g/kg) administration in chronically catheterized male Sprague-Dawley rats (225-250 g body wt). Acute alcohol intoxication before 50% hemorrhage decreased basal MABP, accentuated hypotension midhemorrhage, suppressed the hemorrhage-induced release of norepinephrine and AVP, and prevented restoration of MABP to basal levels after fluid resuscitation with lactated Ringer solution. I.c.v. neostigmine (0.5 microg) produced a sustained increase in MABP beginning at 30 min of hemorrhage that persisted throughout fluid resuscitation in control and alcohol-treated animals. I.c.v. neostigmine enhanced epinephrine responses and restored the hemorrhage-induced release of norepinephrine and AVP in alcohol-treated rats. These results demonstrate that inhibition of acetylcholinesterase in the central nervous system enhances SNS outflow, restores the neuroendocrine response to severe blood loss, and thereby improves hemodynamic counterregulation during acute alcohol intoxication. This study provides evidence for a central (and not peripheral) role of alcohol in impairing hemodynamic stability during hemorrhagic shock.


Parental migration and children's dietary diversity at home: Evidence from rural China.
There is a growing literature documenting the link between parental migration and children's health. However, few studies have explained the underlying mechanism of this observed relationship. This paper examines the effect of parental migration on children's health through dietary diversity, using survey data collected in a less developed prefecture in South Central China in 2018. To overcome the potential endogeneity of parental migration, we instrument parental migration with the proportion of households with migrated labor force at the village level, and find that parental migration reduces children's dietary diversity at home. Moreover, we provide suggestive evidence that the reduction in dietary diversity may attribute to significant negative separation effects whereas minimal positive income effects in migrant-sending households. This study highlights the negative effects of labor migration on the next generation's nutrition. In those developing countries with a high prevalence of labor migration, policies that facilitate access to dietary diversity of those left-behind children are warranted.


Effect of High-Dose Allopurinol Pretreatment on Cardiac Biomarkers of Patients Undergoing Elective Percutaneous Coronary Intervention: A Randomized Clinical Trial.
Increased accumulation of reactive oxygen species contributes to pathophysiologic states such as endothelial dysfunction, metabolic and functional impairment, inflammatory activation, and other features of cardiovascular pathophysiology. Allopurinol acts as a xanthine oxidase inhibitor that reduces the amount of free radicals after reactive oxygen species generation. In this placebo-controlled randomized clinical trial, all patients admitted with coronary artery disease who are candidates for elective percutaneous coronary intervention (PCI) were included. The 254 patients were randomly divided into 2 groups. Blood samples for cardiac biomarkers (creatine kinase [CK]-MB and troponin T [cTnT]) were collected from all patients after admission (the day before PCI), and also 8 and 16 hours after intervention. In group 1 (133 patients), 600 mg allopurinol was orally administered on the day before PCI, and another same dose on the day of PCI, and the elective PCI was performed. In group 2 (121 patients), elective PCI was performed without pretreatment with allopurinol. In an unadjusted model, the serum levels of both CK-MB and cTnT, 16 hours after PCI were higher in the placebo group as compared with the allopurinol group, although it was statistically insignificant. We compared the maximum levels of CK-MB and cTnT (8 or 16 hours after PCI) and their maximum changes in both groups. After adjustment for confounders, use of allopurinol did not have any statistically significant association with the rise of cardiac-spec-fic enzymes. Allopurinol could not be effective significantly, in patients undergoing elective PCI, to decrease cardiac-specific enzymes, and seems not to be of use before PCI.


Reliability of genomic prediction for milk fatty acid composition by using a multi-population reference and incorporating GWAS results.
Large-scale phenotyping for detailed milk fatty acid (FA) composition is difficult due to expensive and time-consuming analytical techniques. Reliability of genomic prediction is often low for traits that are expensive/difficult to measure and for breeds with a small reference population size. An effective method to increase reference population size could be to combine datasets from different populations. Prediction models might also benefit from incorporation of information on the biological underpinnings of quantitative traits. Genome-wide association studies (GWAS) show that genomic regions on Bos taurus chromosomes (BTA) 14, 19 and 26 underlie substantial proportions of the genetic variation in milk FA traits. Genomic prediction models that incorporate such results could enable improved prediction accuracy in spite of limited reference population sizes. In this study, we combine gas chromatography quantified FA samples from the Chinese, Danish and Dutch Holstein populations and implement a genomic feature best linear unbiased prediction (GFBLUP) model that incorporates variants on BTA14, 19 and 26 as genomic features for which random genetic effects are estimated separately. Prediction reliabilities were compared to those estimated with traditional GBLUP models. Predictions using a multi-population reference and a traditional GBLUP model resulted in average gains in prediction reliability of 10% points in the Dutch, 8% points in the Danish and 1% point in the Chinese populations compared to predictions based on population-specific references. Compared to the traditional GBLUP, implementation of the GFBLUP model with a multi-population reference led to further increases in prediction reliability of up to 38% points in the Dutch, 23% points in the Danish and 13% points in the Chinese populations. Prediction reliabilities from the GFBLUP model were moderate to high across the FA traits analyzed. Our study shows that it is possible to predict genetic merits for milk FA traits with reasonable accuracy by combining related populations of a breed and using models that incorporate GWAS results. Our findings indicate that international collaborations that facilitate access to multi-population datasets could be highly beneficial to the implementation of genomic selection for detailed milk composition traits.


United Arab Emirates National Newborn Screening Programme: an evaluation 1998-2000.
To evaluate the United Arab Emirate National Newborn Screening Programme we compared coverage, timeliness of programme indicators (age at sampling, recall and treatment initiation, timing of specimen delivery and laboratory results) and specimen quality with international standards. Recall rate, sensitivity, specificity, positive predictive values and relative incidence rates for phenylketonuria (PKU) and congenital hypothyroidism (CH) were calculated. Investigations for hypothyroidism included thyroid function studies (T3, T4, fT4 and TSH), technetium-99m thyroid scan when possible and thyroglobulin and thyroid antibodies when indicated. PKU investigations included plasma amino acids and measurement of biopterin defects. In the 6 years before December 2000, 138,718 neonates were screened. Relative incidences for CH and for classic PKU were 1:1570 and 1:20,050 respectively.


Air-stable aryl derivatives of pentafluoroorthotellurate.
We report on two different sets of air-stable derivatives of pentafluoroorthotellurate containing fluorinated and non-fluorinated aryl groups. The acid cis-PhTeF4OH was obtained in gram scale and further transformed to Ag[cis-PhTeF4O], which was used as a cis-PhTeF4O transfer reagent to obtain [PPh4][cis-PhTeF4O]. Furthermore, the synthesis of trans-(C6F5)2TeF3OH was achieved by a selective hydrolysis of trans-(C6F5)2TeF4 in the presence of KF and subsequent protonation by aHF. Quantum-chemical calculations show a higher acidity and robustness against fluoride abstraction for trans-(C6F5)2TeF3OH compared to cis-PhTeF4OH.


Novel homozygous AIRE mutation in a German patient with severe APECED.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder typically presenting with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal failure variably accompanied by other symptoms. APECED is caused by a mutation in the autoimmune regulator gene (AIRE). Today over 60 different mutations are known world-wide, most of them localized in exons 2, 8, and 10. We report here a German girl with rheumatoid factor positive arthritis, chronic mucocutaneous candidiasis, autoimmune hepatitis, chronic diarrhea, vitiligo, hypothyroidism, hypoparathyroidism, and adrenal failure who is homozygous for a novel mutation at the end of exon 3 of the AIRE gene (c.462G>A), within the conserved splice donor sequence. This mutation probably introduces a frameshift after amino acid 154 (p.Pro154fs) by skipping exon 4. In addition, we analyzed five other family members out of three generations for the AIRE gene mutation and for polymorphisms in the cytotoxic T lymphocyte antigen 4 (CTLA4) gene region and lymphoid protein tyrosine phosphatase (PTPN22) gene, which are associated with the occurrence of sporadic autoimmune Addison's disease, type 1 diabetes mellitus, and generalized vitiligo.


A systematic approach to decipher crosstalk in the p53 signaling pathway using single cell dynamics.
The transcription factors NF-κB and p53 are key regulators in the genotoxic stress response and are critical for tumor development. Although there is ample evidence for interactions between both networks, a comprehensive understanding of the crosstalk is lacking. Here, we developed a systematic approach to identify potential interactions between the pathways. We perturbed NF-κB signaling by inhibiting IKK2, a critical regulator of NF-κB activity, and monitored the altered response of p53 to genotoxic stress using single cell time lapse microscopy. Fitting subpopulation-specific computational p53 models to this time-resolved single cell data allowed to reproduce in a quantitative manner signaling dynamics and cellular heterogeneity for the unperturbed and perturbed conditions. The approach enabled us to untangle the integrated effects of IKK/ NF-κB perturbation on p53 dynamics and thereby derive potential interactions between both networks. Intriguingly, we find that a simultaneous perturbation of multiple processes is necessary to explain the observed changes in the p53 response. Specifically, we show interference with the activation and degradation of p53 as well as the degradation of Mdm2. Our results highlight the importance of the crosstalk and its potential implications in p53-dependent cellular functions.


Noncovalent interactions of long-chain perfluoroalkyl acids with serum albumin.
Preferential distribution of long-chain perfluoroalkyl acids (PFAAs) in the liver, kidney, and blood of organisms highlights the importance of PFAA-protein interactions in PFAA tissue distribution patterns. A serum protein association constant may be a useful parameter to characterize the bioaccumulative potential and in vivo bioavailability of PFAAs. In this work, association constants (K(a)) and binding stoichiometries for PFAA-albumin complexes are quantified over a wide range of PFAA:albumin mole ratios. Primary association constants for perfluorooctanoate (PFOA) or perfluorononanoate (PFNA) with the model protein bovine serum albumin (BSA) determined via equilibrium dialysis are on the order of 10(6) M(-1) with one to three primary binding sites. PFNA was greater than 99.9% bound to BSA or human serum albumin (HSA) at a physiological PFAA:albumin mole ratio (<10(-3)), corresponding to a high protein-water distribution coefficient (log K(PW) > 4). Nanoelectrospray ionization mass spectrometry (nanoESI-MS) data reveal PFAA-BSA complexes with up to eight occupied binding sites at a 4:1 PFAA:albumin mole ratio. Association constants estimated by nanoESI-MS are on the order of 10(5) M(-1) for PFOA and PFNA and 10(4) M(-1) for perfluorodecanoate and perfluorooctanesulfonate. The results reported here suggest binding through specific high affinity interactions at low PFAA:albumin mole ratios.


Role of Interprofessional primary care teams in preventing avoidable hospitalizations and hospital readmissions in Ontario, Canada: a retrospective cohort study.
Improving health system value and efficiency are considered major policy priorities internationally. Ontario has undergone a primary care reform that included introduction of interprofessional teams. The purpose of this study was to investigate the relationship between receiving care from interprofessional versus non-interprofessional primary care teams and ambulatory care sensitive condition (ACSC) hospitalizations and hospital readmissions. Population-based administrative databases were linked to form data extractions of interest between the years of 2003-2005 and 2015-2017 in Ontario, Canada. The data sources were available through ICES. The study design was a retrospective longitudinal cohort. We used a "difference-in-differences" approach for evaluating changes in ACSC hospitalizations and hospital readmissions before and after the introduction of interprofessional team-based primary care while adjusting for physician group, physician and patient characteristics. As of March 31st, 2017, there were a total of 778 physician groups, of which 465 were blended capitation Family Health Organization (FHOs); 177 FHOs (22.8%) were also interprofessional teams and 288 (37%) were more conventional group practices ("non-interprofessional teams"). In this period, there were a total of 13,480 primary care physicians in Ontario of whom 4848 (36%) were affiliated with FHOs-2311 (17.1%) practicing in interprofessional teams and 2537 (18.8%) practicing in non-interprofessional teams. During that same period, there were 475,611 and 618,363 multi-morbid patients in interprofessional teams and non-interprofessional teams respectively out of a total of 2,920,990 multi-morbid adult patients in Ontario. There was no difference in change over time in ACSC admissions between interprofessional and non-interprofessional teams between the pre- and post intervention periods. There were no statistically significant changes in all cause hospital readmission s between the post- and pre-intervention periods for interprofessional and non-interprofessional teams. Our study findings indicate that the introduction of interprofessional team-based primary care was not associated with changes in ACSC hospitalization or hospital readmissions. The findings point for the need to couple interprofessional team-based care with other enablers of a strong primary care system to improve health services utilization efficiency.


Prenatal Clinical Assessment of sFlt-1 (Soluble fms-like Tyrosine Kinase-1)/PlGF (Placental Growth Factor) Ratio as a Diagnostic Tool for Preeclampsia, Pregnancy-induced Hypertension, and Proteinuria.
Background: Aim of the study was a critical assessment of the clinical validity of the prenatal determination of sFlt-1/PlGF for preeclampsia (PE), pregnancy-induced hypertension (PIH), and proteinuria. Our analysis was based on a specificity of 95 % and a sensitivity of 82 % for the prediction of preeclampsia, as described by Elecsys (Roche). Methods: In this retrospective study the ratio of the prenatal antiangiogenic factor sFlt-1 (soluble fms-like tyrosine kinase-1) to the proangiogenic factor PIGF (placental growth factor) was analyzed using the electrochemiluminescence immunoassay of Elecsys (Roche Diagnostics, Mannheim, Germany) in 173 pregnant women. Sixty-three women with PE, 34 women with PIH and 6 women with proteinuria were compared to 72 controls. On average, the sFlt-1/PlGF ratio was determined 8 (controls), 2.4 (PE), 3.2 (PIH) and 4.1 (proteinuria) weeks before delivery. The PE and PIH cases were further subdivided into early (< 34 weeks of gestation) and late (≥ 34 weeks of gestation) onset groups. Statistical data analysis was done using the usual descriptive statistics and logistic regression analysis. ROC curves were calculated, and the sensitivity, specificity, and negative and positive predictive value (NPV, PPV) were estimated for a threshold of 85. Results: Although the specificity of the sFlt-1/PlGF ratio was high for PE, the sensitivity was low (only 59.4 %), thus giving unsatisfying results for PE. The sensitivity only increased to 62.5 % for the early-onset PE group. Intriguingly, a high ratio was detected for the combination of IUGR (intrauterine growth restriction) and PE in the early-onset PE group (8 cases). In the control group, 4 cases exceeded the cut-off value of 85 but showed no clinical signs of PE and the birth was unremarkable. In summary, we found that the sFlt-1/PIGF ratio could not be used as a predictive test for preeclampsia but rather as an indicator for the development and estimation of the severity of PE. Thus, the test is less suitable for the reliable exclusion of PE in routine clinical practice. Recommendation: The determination of the sFlT-1/PlGF ratio is only one element for PE diagnosis in addition to the measurement of blood pressure, proteinuria, ultrasound and Doppler.


Dependence of paclitaxel sensitivity on a functional spindle assembly checkpoint.
Paclitaxel stabilizes microtubules, causing mitotic arrest and activating the spindle assembly checkpoint. We determined whether suppression of the checkpoint genes Mad2 and BubR1 affects paclitaxel resistance and whether overexpression of Mad2 protein in checkpoint-defective cells enhances paclitaxel sensitivity. Suppression of Mad2 and BubR1 in paclitaxel-treated cancer cells abolished checkpoint function, resulting in paclitaxel resistance that correlated with suppression of cyclin-dependent kinase-1 activity. In contrast, overexpression of Mad2 in cells with a checkpoint defect attributable to low Mad2 expression restored checkpoint function, resulting in enhanced paclitaxel sensitivity that correlated with enhanced cyclin-dependent kinase-1 activity. However, overexpression of Mad2 failed to enhance paclitaxel sensitivity via checkpoint activation in Mad2-independent checkpoint-defective and -intact cells. Thus, checkpoint function is required for paclitaxel sensitivity. These findings show that any molecules that could interfere with the spindle assembly checkpoint could generate paclitaxel resistance in any patient.


Surgical Management of Migraine Headaches: A Systematic Review and Meta-analysis.
The aim of the present study was to systematically review and analyze the available evidence on the role of surgery in improving outcomes in patients with migraine headaches. An electronic search of PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials), and Google Scholar databases was performed for English-language articles reporting results of peripheral nerve surgery for migraine headaches. The search strategy revealed a total of 1528 records, of which 23 studies were included in the review. A total of 1151 headache patients were treated in the included studies. The trigger site of migraine addressed varied across studies. Meta-analysis of data of 616 patients revealed that migraine surgery significantly reduces migraine headache frequency (random: mean, 9.52; 95% confidence interval, 7.14-11.9; P < 0.00001; I = 94%). Similarly, when data of 797 patients were analyzed, there was statistically significant reduction in migraine headache intensity in patients undergoing migraine headache surgery (random: mean, 3.97; 95% confidence interval, 3.31-4.62; P < 0.00001; I = 94%). On pooling of data of all 23 studies, 8.3% to 76.4% of patients reported complete elimination of headache after surgery, whereas 3.9% to 33.3% had no relief. Peripheral nerve decompression surgery is highly effective in reducing migraine headache frequency and migraine headache intensity. However, not all patients benefit from the surgical procedure, with a small subset showing no improvement. Further clinical and anatomical studies are needed to define the exact mechanism of nerve compression in migraine patients and as to why a subset of patients does not respond to surgical treatment.


Secretion of drugs in tears.
Secretion in tears has been investigated for a limited number of drugs. Transfer of the free non protein-bound fraction from plasma to tears only can be expected for unionized drugs with sufficient lipid solubility. For acid and basic drugs the correlation of tear: plasma (unbound) ratio is disturbed by variations in tear pH. Within these limitations tear sampling will not be an useful method for drug concentration measurement.


Arteriovenous lipid content difference in patients with atherosclerosis.
The total fraction of low and very low density lipoproteins (LDL, VLDL), total cholesterol (TCS) and high density lipoprotein cholesterol (CS HDL) in arterial and venous blood was determined in 42 patients with atherosclerosis affecting predominantly arteries of the pelvis and the lower extremities. The mean concentration of the above-mentioned substances in the in-flowing and outflowing blood in the affected vascular region did not practically differ. At normal blood lipid level there exists a significant negative correlation between the absolute and relative CS HDL content on the one hand and, on the other hand, the arteriovenous difference in TCS content (r = -0.414 and -0.531 respectively). At hyperlipoproteinaemia, the CS HDL content correlates with the arteriovenous LDL and VLDL difference (r = -0.511). The findings attest to the fact that a decrease in the CS HDL level is accompanied by increased uptake of atherogenic substances in the peripheral vessels.