Characteristics of complaints resulting in disciplinary actions against Danish GPs.
The risk of being disciplined in connection with a complaint case causes distress to most general practitioners. The present study examined the characteristics of complaint cases resulting in disciplinary action. The Danish Patients' Complaints Board's decisions concerning general practice in 2007 were examined. Information on the motives for complaining, as well as patient and general practitioner characteristics, was extracted and the association with case outcome (disciplinary or no disciplinary action) was analysed. Variables included complaint motives, patient gender and age, urgency of illness, cancer diagnosis, healthcare settings (daytime or out-of-hours services), and general practitioner gender and professional seniority. Cases where the complaint motives involved a wish for placement of responsibility (OR = 2.35, p = 0.01) or a wish for a review of the general practitioner's competence (OR = 1.95, p = 0.02) were associated with increased odds of the general practitioner being disciplined. The odds of discipline decreased when the complaint was motivated by a feeling of being devalued (OR = 0.39, p = 0.02) or a request for an explanation (OR = 0.46, p = 0.01). With regard to patient and general practitioner characteristics, higher general practitioner professional seniority was associated with increased odds of discipline (OR = 1.97 per 20 additional years of professional seniority, p = 0.01). None of the other characteristics was statistically significantly associated with discipline in the multiple logistic regression model. Complaint motives and professional seniority were associated with decision outcomes. Further research is needed on the impact of professional seniority on performance.


Aptamers as therapeutics in cardiovascular diseases.
With many advantages over other therapeutic agents such as monoclonal antibodies, aptamers have recently emerged as a novel and powerful class of ligands with excellent potential for diagnostic and therapeutic applications. Typically generated through Systematic Evolution of Ligands by EXponential enrichment (SELEX), aptamers have been selected against a wide range of targets such as proteins, phospholipids, sugars, nucleic acids, as well as whole cells. DNA/RNA aptamers are single-stranded DNA/RNA oligonucleotides (with a molecular weight of 5-40 kDa) that can fold into well-defined 3D structures and bind to their target molecules with high affinity and specificity. A number of strategies have been adopted to synthesize aptamers with enhanced in vitro/in vivo stability, aiming at potential therapeutic/diagnostic applications in the clinic. In cardiovascular diseases, aptamers can be developed into therapeutic agents as anti-thrombotics, anti-coagulants, among others. This review focuses on aptamers that were selected against various molecular targets involved in cardiovascular diseases: von Willebrand factor (vWF), thrombin, factor IX, phospholamban, P-selectin, platelet-derived growth factor, integrin α(v)β(3), CXCL10, vasopressin, among others. With continued effort in the development of aptamer-based therapeutics, aptamers will find their niches in cardiovascular diseases and significantly impact clinical patient management.


A microscopic Kondo lattice model for the heavy fermion antiferromagnet CeIn3.
Electrons at the border of localization generate exotic states of matter across all classes of strongly correlated electron materials and many other quantum materials with emergent functionality. Heavy electron metals are a model example, in which magnetic interactions arise from the opposing limits of localized and itinerant electrons. This remarkable duality is intimately related to the emergence of a plethora of novel quantum matter states such as unconventional superconductivity, electronic-nematic states, hidden order and most recently topological states of matter such as topological Kondo insulators and Kondo semimetals and putative chiral superconductors. The outstanding challenge is that the archetypal Kondo lattice model that captures the underlying electronic dichotomy is notoriously difficult to solve for real materials. Here we show, using the prototypical strongly-correlated antiferromagnet CeIn3, that a multi-orbital periodic Anderson model embedded with input from ab initio bandstructure calculations can be reduced to a simple Kondo-Heisenberg model, which captures the magnetic interactions quantitatively. We validate this tractable Hamiltonian via high-resolution neutron spectroscopy that reproduces accurately the magnetic soft modes in CeIn3, which are believed to mediate unconventional superconductivity. Our study paves the way for a quantitative understanding of metallic quantum states such as unconventional superconductivity.


Mitral Leaflet Changes Following Myocardial Infarction: Clinical Evidence for Maladaptive Valvular Remodeling.
Ischemic mitral regurgitation (MR) is classically ascribed to functional restriction of normal leaflets, but recent studies have suggested post-myocardial infarction (MI) mitral valve (MV) leaflet fibrosis and thickening, challenging valve normality. Progression of leaflet thickness post-MI has not been studied. We hypothesized that excessive MV remodeling post-MI contributes to MR. Our objectives are to characterize MV changes after MI and relate them to MR. Three groups of 40 patients with serial echocardiograms over a mean of 23.4 months were identified from an echocardiography database: patients first studied early (6±12 days) and late (12±7 years) after an inferior MI and normal controls. MV thickness was correlated with MR. We studied the mechanisms for MV changes in a sheep model (6 apical MI versus 6 controls) followed for 8 weeks, with MV cellular and histopathologic analyses. Early post-MI, leaflet thickness was found to be similar to controls (2.6±0.5 vs 2.5±0.4 mm; P=0.23) but significantly increased over time (2.5±0.4 to 2.9±0.4 mm; P<0.01). In this group, patients tolerating maximal doses of renin-angiotensin blocking agents had less thickening (25% of patients; P<0.01). The late-MI group had increased thickness (3.2±0.5 vs 2.5±0.4 mm; P<0.01) without progression. At follow-up, 48% of post-MI patients had more than mild MR. Increased thickness was independently associated with MR. Experimentally, 8 weeks post-MI, MVs were 2-fold thicker than controls, with increased collagen, profibrotic transforming growth factor-β, and endothelial-to-mesenchymal transformation, confirmed by flow cytometry. MV thickness increases post-MI and correlates with MR, suggesting an organic component to ischemic MR. MV fibrotic remodeling can indicate directions for future therapy.


A heterologous reductase affects the redox balance of recombinant Saccharomyces cerevisiae.
Recombinant Saccharomyces cerevisiae harbouring the xylose reductase (XR) gene XYL1 from Pichia stipitis was grown in anoxic chemostat culture at two different dilution rates. At each dilution rate a transient experiment, encompassing a shift in the sugar content of the medium from glucose to glucose plus xylose was performed. The steady states at the beginning and the end of the transients were compared in terms of specific product fluxes from glucose metabolism. At both dilution rates, the specific glycerol flux decreased and the specific acetate and CO2 fluxes increased. The specific ethanol flux was not affected. At the lower dilution rate, the production of biomass decreased during the transient, but at the higher dilution rate it increased. The changes in product pattern can be explained as being due to the redox perturbation caused by the consumption of reduced cofactors in the XR-catalysed reaction. Regeneration of NAD partly through xylose reduction instead of glycerol production decreased the formation of glycerol. Additionally, xylose reduction activated those pathways which produce reduced cofactors, such as acetate formation and the pentose phosphate pathway, indicated by increased acetate and CO2 production. The dual cofactor specificity of XR, with a preference for NADPH over NADH, was evident from the effects of xylose reduction on product fluxes. Comparison of the xylose reduction rates at low and high glucose flux indicated that the supply of reduced cofactors partly controlled the reaction rate. At the higher dilution rate, control by some other factor such as xylose transport or XR activity increased. Calculation of carbon balances at the steady states showed that all substrate carbon was recovered in biomass or products. Based on the specific product fluxes, calculations of quantitative cofactor balances at the steady states was attempted. However, sensitivity calculations showed that analysis errors in the range of 5% caused substantial errors in the cofactor balance, without affecting the carbon balance.


[Pancreatic cancer. An appraisal of 147 cases (author's transl)].
Out of 147 exocrine cancers of the pancreas 17 (11.6%) were considered as inoperable. Extensive lesions are frequent: liver metastasis (33%) invasion of surrounding tissues (duodenum-portal vein - mesenteric vessels) 29%, regional lymph nodes metastases (25%), peritoneal carcinomatosis (13%). For these reasons, non curative operations were the most frequent: bilio-intestinal anastomosis (56.4%), exploratory laparotomy (14.9%). Our resection rate is low: 16% (21 cases), with performance of 15 pancreatico-duodenal resections (71%), 5 total pancreatectomies (24%) and 1 left pancreatic resection. We note a mortality rate of 19%: 20% four resections, 17% after palliative anastomosis. The mean survival rate was 11.5 months following pancreatico duodenal resections and 4,8 months following anastomotic procedures. No survival after 5 years is registered.


Protein-Observed Fluorine NMR Is a Complementary Ligand Discovery Method to 1H CPMG Ligand-Observed NMR.
To evaluate its potential as a ligand discovery tool, we compare a newly developed 1D protein-observed fluorine NMR (PrOF NMR) screening method with the well-characterized ligand-observed 1H CPMG NMR screen. We selected the first bromodomain of Brd4 as a model system to benchmark PrOF NMR because of the high ligandability of Brd4 and the need for small molecule inhibitors of related epigenetic regulatory proteins. We compare the two methods' hit sensitivity, triaging ability, experiment speed, material consumption, and the potential for false positives and negatives. To this end, we screened 930 fragment molecules against Brd4 in mixtures of five and followed up these studies with mixture deconvolution and affinity characterization of the top hits. In selected examples, we also compare the environmental responsiveness of the 19F chemical shift to 1H in 1D-protein observed 1H NMR experiments. To address concerns of perturbations from fluorine incorporation, ligand binding trends and affinities were verified via thermal shift assays and isothermal titration calorimetry. We conclude that for the protein understudy here, PrOF NMR and 1H CPMG have similar sensitivity, with both being effective tools for ligand discovery. In cases where an unlabeled protein can be used, 1D protein-observed 1H NMR may also be effective; however, the 19F chemical shift remains significantly more responsive.


Assessment of 19 Genes and Validation of CRM Gene Panel for Quantitative Transcriptional Analysis of Molecular Rejection and Inflammation in Archival Kidney Transplant Biopsies.
Background: There is an urgent need to develop and implement low cost, high-throughput standardized methods for routine molecular assessment of transplant biopsies. Given the vast archive of formalin-fixed and paraffin-embedded (FFPE) tissue blocks in transplant centers, a reliable protocol for utilizing this tissue bank for clinical validation of target molecules as predictors of graft outcome over time, would be of great value. Methods: We designed and optimized assays to quantify 19 target genes, including previously reported set of tissue common rejection module (tCRM) genes. We interrogated their performance for their clinical utility for detection of graft rejection and inflammation by analyzing gene expression microarrays analysis of 163 renal allograft biopsies, and subsequently validated in 40 independent FFPE archived kidney transplant biopsies at a single center. Results: A QPCR (Fluidigm) and a barcoded oligo-based (NanoString) gene expression platform were compared for evaluation of amplification of gene expression signal for 19 genes from degraded RNA extracted from FFPE biopsy sections by a set protocol. Increased expression of the selected 19 genes, that reflect a combination of specific cellular infiltrates (8/19 genes) and a graft inflammation score (11/19 genes which computes the tCRM score allowed for segregation of kidney transplant biopsies with stable allograft function and normal histology from those with histologically confirmed acute rejection (AR; p = 0.0022, QPCR; p = 0.0036, barcoded assay) and many cases of histological borderline inflammation (BL). Serial biopsy shaves used for gene expression were also processed for in-situ hybridization (ISH) for a subset of genes. ISH confirmed a high degree of correlation of signal amplification and tissue localization. Conclusions: Target gene expression amplification across a custom set of genes can identify AR independent of histology, and quantify inflammation from archival kidney transplant biopsy tissue, providing a new tool for clinical correlation and outcome analysis of kidney allografts, without the need for prospective kidney biopsy biobanking efforts.


[A brest-feeding study].
As an introduction the authors consider the advantages of breast-feeding, describing the social-economic causes which are influencing, the abandonment of this practice in the world. Following this they describe and comment on the results of a research project carried out with a group of mothers, which had as its objective to study some aspects relative to breast-feeding children.


Student learning preferences reflect curricular change.
This study measured the learning preference profile development and readiness for self-directed learning over time of two undergraduate student cohorts experiencing different curricular presentations of essentially the same syllabus. The results from three measurement points are reported following each cohort through their first half of the BSc (Honours) Physiotherapy Course, Cardiff. At intake both cohorts preferred a concrete, fact-based learning environment, which was teacher structured. Over time, the cohorts responded significantly differently to their curricula in respect of the student-structured learning preference (LP) variable (p < 0.05), and displayed trends (p < 0.1) towards response difference for the concrete, interpersonal and individual LP variables. Cohort differences are discussed in terms of the planned curriculum changes made during the intervening revalidation exercise. It is suggested that curricula mould students' learning profile development. The impact of this statement on future curriculum development is discussed and educational research-in-action promoted.


Chitosan enhances gene delivery of oligonucleotide complexes with magnetic nanoparticles-cell-penetrating peptide.
Gene-based therapies, including the delivery of oligonucleotides, offer promising methods for the treatment of cancer cells. However, they have various limitations including low efficiency. Herein, cell-penetrating peptides (CPPs)-conjugated chitosan-modified iron oxide magnetic nanoparticles (CPPs-CTS@MNPs) with high biocompatibility as well as high efficiency were tested for the delivery of oligonucleotides such as plasmid pGL3, splice correction oligonucleotides, and small-interfering RNA. A biocompatible nanocomposite, in which CTS@MNPs was incorporated in non-covalent complex with CPPs-oligonucleotide, is developed. Modifying the surface of magnetic nanoparticles with cationic chitosan-modified iron oxide improved the performance of magnetic nanoparticles-CPPs for oligonucleotide delivery. CPPs-CTS@MNPs complexes enhance oligonucleotide transfection compared to CPPs@MNPs or CPPs. The hydrophilic character of CTS@MNPs improves complexation with plasmid pGL3, splice correction oligonucleotides, and small-interfering RNA payload, which consequently resulted in not only strengthening the colloidal stability of the constructed complex but also improving their biocompatibility. Transfection using PF14-splice correction oligonucleotides-CTS@MNPs showed sixfold increase of the transfection compared to splice correction oligonucleotides-PF14 that showed higher transfection than the commercially available lipid-based vector Lipofectamine™ 2000. Nanoscaled CPPs-CTS@MNPs comprise a new family of biomaterials that can circumvent some of the limitations of CPPs or magnetic nanoparticles.


A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development.
The involvement of interleukin-1 (IL-1) in inflammation, tumor growth, and metastasis makes it an attractive target for therapeutic intervention. Here, we show that a continuous delivery of a low, but steady-state level of the naturally occurring IL-1 receptor antagonist (IL-1Ra) reduced inflammatory responses and inhibited tumor development in mice, phenomena that are induced by IL-1, mainly secretable IL-1beta. The IL-1Ra was delivered from microencapsulated genetically engineered cells, which overexpress and secrete this mediator. For a tumor model, we used fibrosarcoma cell line, which secretes high levels of IL-1beta; when injected s.c. into mice, the cells developed into large tumors characterized by very active angiogenic patterns. The proangiogenic features of IL-1beta were manifested at low levels of the cytokine, and release of 25 ng per day of the IL-1Ra was needed to oppose its effects and inhibit tumor development. The continuous delivery of the IL-1Ra contributed to improved biocompatibility of the microencapsulated cell systems; the fibrotic sac surrounding the systems was much thinner with significantly less blood capillaries and inflammatory cells. Not only do our findings point to the antiangiogenic properties of IL-1Ra in inflammation and tumor growth, but they also provide a more efficient and convenient way for treating diseases involving IL-1.


One-stop microvascular screening service: an effective model for the early detection of diabetic peripheral neuropathy and the high-risk foot.
To evaluate the feasibility of a one-stop microvascular screening service for the early diagnosis of diabetic distal symmetrical polyneuropathy, painful distal symmetrical polyneuropathy and the at-risk diabetic foot. People with diabetes attending retinal screening in hospital and community settings had their feet examined by a podiatrist. Assessment included: Toronto Clinical Neuropathy Score evaluation; a 10-g monofilament test; and two validated, objective and quick measures of neuropathy obtained using the point-of-care devices 'DPN-Check', a hand-held device that measures sural nerve conduction velocity and amplitude, and 'Sudoscan', a device that measures sudomotor function. The diagnostic utility of these devices was assessed against the Toronto Clinical Neuropathy Score as the 'gold standard'. A total of 236 consecutive people attending the retinal screening service, 18.9% of whom had never previously had their feet examined, were evaluated. The prevalence of distal symmetrical polyneuropathy, assessed using the Toronto Clinical Neuropathy Score, was 30.9%, and was underestimated by 10-g monofilament test (14.4%). The prevalence of distal symmetrical polyneuropathy using DPN-check was 51.5% (84.3% sensitivity, 68.3% specificity), 38.2% using Sudoscan foot electrochemical skin conductance (77.4% sensitivity, 68.3% specificity), and 61.9% using abnormality in either of the results (93.2% sensitivity, 52.8% specificity). The results of both devices correlated with Toronto Clinical Neuropathy Score (P<0.001). A new diagnosis of painful distal symmetrical polyneuropathy was made in 59 participants (25%), and 56.6% had moderate- or high-risk foot. Participants rated the service very highly. Combined, eye, foot and renal screening is feasible, has a high uptake, reduces clinic visits, and identifies painful distal symmetrical polyneuropathy and the at-risk foot. Combined large- and small-nerve-fibre assessment using non-invasive, quantitative and quick point-of-care devices may be an effective model for the early diagnosis of distal symmetrical polyneuropathy.


Facial pain: sinus or not?
Facial pain remains a diagnostic and therapeutic challenge for both clinicians and patients. In clinical practice, patients suffering from facial pain generally undergo multiple repeated consultations with different specialists and receive various treatments, including surgery. Many patients, as well as their primary care physicians, mistakenly attribute their pain as being due to rhinosinusitis when this is not the case. It is important to exclude non-sinus-related causes of facial pain before considering sinus surgery to avoid inappropriate treatment. Unfortunately, a significant proportion of patients have persistent facial pain after endoscopic sinus surgery (ESS) due to erroneous considerations on aetiology of facial pain by physicians. It should be taken into account that neurological and sinus diseases may share overlapping symptoms, but they frequently co-exist as comorbidities. The aim of this review was to clarify the diagnostic criteria of facial pain in order to improve discrimination between sinogenic and non-sinogenic facial pain and provide some clinical and diagnostic criteria that may help clinicians in addressing differential diagnosis.


Effects of dietary lysine intake during lactation on blood metabolites, hormones, and reproductive performance in primiparous sows.
Effects of three dietary lysine (protein) concentrations during lactation on metabolic state, protein metabolism, reproductive hormones, and performance were investigated in 36 primiparous sows. Sows were assigned randomly to one of three diets containing .4% (low lysine, LL), 1.0% (medium lysine, ML), or 1.6% (high lysine, HL) total lysine from intact protein sources. All diets contained 2.1 Mcal NE/kg and exceeded the recommended requirements for all other nutrients. Actual lysine intakes over an 18-d lactation were 16, 36, and 56 g/d for sows fed LL, ML, and HL, respectively. Fractional breakdown rate of muscle was determined on d 4 and 15 of lactation by using a three-compartment kinetic model of 3-methylhistidine metabolism. Increasing lysine intake during lactation did not affect fractional breakdown rate of muscle on d 4 of lactation but decreased it on d 15 (P < .05). Sows fed LL had a reduced number of LH pulses on d 12 and 18 (P < .05) and reduced serum estradiol (E2) concentration on d 18 of lactation compared with sows fed ML and HL treatments. However, LH pulses and E2 concentrations were similar between ML and HL treatments (P > .35). Increasing lysine intake increased serum urea nitrogen (SUN) and postprandial insulin concentrations (P < .05) during lactation but had no effect on plasma glucose concentrations (P > .20). Sows fed HL had greater serum IGF-I on d 6 and 18 than sows fed ML (P < .05). Number of LH peaks was correlated with serum insulin concentration 25 min after feeding on d 6 and 18 (r = .31 to .41; P < .1) and pre- (r = .33 to .46) and postprandial (r = .30 to .58) SUN concentrations (P < .05) during different stages of lactation. Results indicate that, compared with medium lysine intake, low lysine intake increased muscle protein degradation and decreased concentrations of insulin, SUN, and estradiol and LH pulsatility. In contrast, high lysine (protein) intake increased SUN, insulin, and IGF-I, but did not increase secretion of estradiol and LH compared with medium lysine intake. Furthermore, nutritional impacts on reproduction may be mediated in part through associated effects on circulating insulin concentration.


Assessment of clusters of transcription factor binding sites in relationship to human promoter, CpG islands and gene expression.
Gene expression is regulated mainly by transcription factors (TFs) that interact with regulatory cis-elements on DNA sequences. To identify functional regulatory elements, computer searching can predict TF binding sites (TFBS) using position weight matrices (PWMs) that represent positional base frequencies of collected experimentally determined TFBS. A disadvantage of this approach is the large output of results for genomic DNA. One strategy to identify genuine TFBS is to utilize local concentrations of predicted TFBS. It is unclear whether there is a general tendency for TFBS to cluster at promoter regions, although this is the case for certain TFBS. Also unclear is the identification of TFs that have TFBS concentrated in promoters and to what level this occurs. This study hopes to answer some of these questions. We developed the cluster score measure to evaluate the correlation between predicted TFBS clusters and promoter sequences for each PWM. Non-promoter sequences were used as a control. Using the cluster score, we identified a PWM group called PWM-PCP, in which TFBS clusters positively correlate with promoters, and another PWM group called PWM-NCP, in which TFBS clusters negatively correlate with promoters. The PWM-PCP group comprises 47% of the 199 vertebrate PWMs, while the PWM-NCP group occupied 11 percent. After reducing the effect of CpG islands (CGI) against the clusters using partial correlation coefficients among three properties (promoter, CGI and predicted TFBS cluster), we identified two PWM groups including those strongly correlated with CGI and those not correlated with CGI. Not all PWMs predict TFBS correlated with human promoter sequences. Two main PWM groups were identified: (1) those that show TFBS clustered in promoters associated with CGI, and (2) those that show TFBS clustered in promoters independent of CGI. Assessment of PWM matches will allow more positive interpretation of TFBS in regulatory regions.


[Neonatal lupus: clinical features and risk of congenital cardiac heart block in newborns from mothers with anti Ro/SSA antibodies]
OBJECTIVE: To assess the prevalence of Congenital Heart Block (CHB) in newborns from anti Ro/SS-A antibodies positive mothers affected by connective tissue diseases (CTD) and to evaluate the prevalence of other manifestations of Neonatal Lupus (NL) and the electrocardiographic abnormalities. METHODS: A prospective study was conducted on 100 anti Ro/SS-A positive mothers that were followed before and during their 118 pregnancies (4 twin pregnancies and 18 second pregnancies). Counterimmunoelectroforesis (CIE) and immunoblot (IB) were used to test antibodies to extractable nuclear antigens (ENA). RESULTS: Only 2 cases of CHB (1.8%) were found among the 112 living newborns. In one case the mother with primary Sjögren's Syndrome (pSS) was anti Ro 60 and 52kD positive while in the other case the mother affected by undifferentiated connective tissue disease (UCTD) was anti Ro 60kD and anti La positive. No fetal death was due to CHB. There were no cutaneous rashes at birth while mild hepatic enzyme alterations were observed in 21 (68%) of the 31 tested newborns. In 22 healthy newborns an ECG have been registered and in 4 cases (18.2%) sinus bradycardia was found. During the follow up 7 suckling showed Cutaneous Neonatal Lupus. Moreover a six month girl developed Kawasaki Syndrome. CONCLUSIONS: The risk of delivering a child with CHB is 1.8% in anti Ro/SS-A positive mothers with CTD. This finding is extremely important in the preconceptional counseling of anti-Ro/SS-A positive women. Furthermore mild electrocardiographic abnormalities may be found in their healthy newborns.


A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma.
Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease >100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5-5.6), and the median overall survival was 11.9 months (95% CI 9.0-16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release.


[Detection of a paramagnetic product developing during oxidative phosphorylation in mitochondria].
It was shown by ESR technique using flow system combined with ESR-spectrometer that paramagnetic product appearing in the course of oxidative phosphorylation was directly associated with mitochondrial ATPase operation. A decrease of ESR signal intensity and the changes of its form observed on mitochondria uncoupled by 2,4-dinitrophenol as compared with those inhibited by olygomicin suggest that in the case of olygomycin block a free radical ATPase linked intermediate can be recorded, the ESR signal of which seems to be partly due to flavin semiquinone of ATPsynthetase itself.


Structures and IR spectra of the Gramicidin S peptide: pushing the quest for low-energy conformations.
An extensive molecular modeling study was carried out on the doubly protonated cyclic decapeptide Gramicidin S following several recent gas-phase experiments. Our computational strategy includes replica-exchange molecular dynamics simulations with the new generation force field AMOEBA for exploration and density functional calculations using several functionals for refinement of structures and computation of IR spectra. This procedure yields low-energy structures of which three are proposed to correspond to the three conformers detected in low-temperature IR experiments. The most stable structure has C(2) symmetry and four strong β-sheet interactions between Orn and Val residues. Furthermore, all the other peptidic N-H bonds are involved in seven-membered C(7) motifs. The computed IR spectra of the three conformers are in good agreement with the experimental ones in the 1400-2000 cm(-1) range. In the 3000-3600 cm(-1) region, the computed spectrum is also in good agreement with experiment for the main conformer, and predictions are made of structure-specific signatures for the other two conformers. The accuracy of several density functionals is discussed in detail. These results point out that efficient potential energy surface explorations coupled to appropriate density functional theory (DFT) calculations are able to reveal the structures of molecules as large and flexible as decapeptides.


Electrophysiological effects of cholecystokinin: central dopaminergic systems.
The coexisting cholecystokinin (CCK)/dopamine (DA) neurons are located predominantly in the ventral tegmental area of the rat and project to the medial part of the nucleus accumbens (NAc). Iontophoretically applied CCK consistently activated presumed CCK/DA cells as well as those cells receiving CCK/DA projections in the medial NAc. Unsulfated CCK had little or no effect. The putative CCK antagonist proglumide selectively blocked the activation produced by CCK but not glutamate. DA also reversed CCK-induced excitation, presumably by its hyperpolarizing actions. These results suggest that CCK and DA may interact to influence the CCK/DA system.


Uncovering cell biology in the third dimension.
Developmental biology has long benefited from studies of classic model organisms. These model systems have provided the fundamental understanding of general principles of development, as well as insight into genes and signaling pathways that control unique aspects of cell fate specification and tissue morphogenesis. Because human brain development cannot be studied in vivo, scientists have relied on these model systems to study basic principles underlying the development of this complex organ as many of these genes and signaling pathways play conserved roles in human development. However, recent studies have shown species-specific signatures in neurodevelopment such as the transcriptome of outer-radial glia, suggesting use of a human-derived model remains imperative. Over the past decade, human stem cell-derived brain organoids have emerged as a biologically relevant model system to study normal human brain development and neurological diseases. Here, we provide a historical perspective of this emerging model system, discuss current systems and limitations, and propose that new mechanistic insight into cell biology can be revealed using these three-dimensional brain structures.


The development and impact of an app for a smart drug interaction reminder system.
Improved access to media and medical knowledge has elicited stronger public health awareness. This study developed a smart drug interaction reminder system for patients to increase knowledge and reduce nurse workload. This study used a single-group pre-test/post-test design and applied mining techniques to analyze the weight and probability of interaction among various medicines. Data were collected from 258 participants at a teaching hospital in northern Taiwan using convenience sampling. An app was used to give patients real-time feedback to obtain access to information and remind them of their health issues. In addition to guiding the patients on medications, this app measured the nurses' work satisfaction and patients' knowledge of drug interaction. The results indicate that using information technology products to assist the app's real-time feedback system promoted nurses' work satisfaction, improved their health education skills, and helped patients to better understand drug interactions. Using information technology to provide patients with real-time inquiring functions has a significant effect on nurses' load reduction. Thus, smart drug interaction reminder system apps can be considered suitable nursing health education tools and the SDINRS app can be integrated into quantitative structure-activity relationship intelligence in the future.


Protein abundance of AKT and ERK pathway components governs cell type-specific regulation of proliferation.
Signaling through the AKT and ERK pathways controls cell proliferation. However, the integrated regulation of this multistep process, involving signal processing, cell growth and cell cycle progression, is poorly understood. Here, we study different hematopoietic cell types, in which AKT and ERK signaling is triggered by erythropoietin (Epo). Although these cell types share the molecular network topology for pro-proliferative Epo signaling, they exhibit distinct proliferative responses. Iterating quantitative experiments and mathematical modeling, we identify two molecular sources for cell type-specific proliferation. First, cell type-specific protein abundance patterns cause differential signal flow along the AKT and ERK pathways. Second, downstream regulators of both pathways have differential effects on proliferation, suggesting that protein synthesis is rate-limiting for faster cycling cells while slower cell cycles are controlled at the G1-S progression. The integrated mathematical model of Epo-driven proliferation explains cell type-specific effects of targeted AKT and ERK inhibitors and faithfully predicts, based on the protein abundance, anti-proliferative effects of inhibitors in primary human erythroid progenitor cells. Our findings suggest that the effectiveness of targeted cancer therapy might become predictable from protein abundance.


Activities of daily living retraining and goal attainment during posttraumatic amnesia.
It is uncertain whether therapy delivered during posttraumatic amnesia (PTA) following traumatic brain injury can be effective due to risk of agitation and poor learning capacity. This study used goal attainment scaling (GAS) to assess gains in activities of daily living (ADL) retraining during PTA. Occupational therapists' perspectives on goal setting and therapy delivery were also explored qualitatively. Forty-nine rehabilitation inpatients were provided with manualised ADL retraining following errorless and procedural learning principles during PTA. From 104 GAS goals, 90% were achieved at PTA emergence. GAS T-scores changed significantly (p < .001) from baseline (M = 26.94, SD = 4.90) to post-intervention (M = 61.44, SD = 11.45). Mean post-intervention T-scores correlated significantly (p < .001) with change in Functional Independence Measure scores. The four therapists reported that GAS was unfamiliar and time-consuming initially, although it aided goal-directed therapy and measurement of patient performance. Application of manualised skill retraining using errorless and procedural learning techniques was described as novel and challenging, but providing valuable structure. The intervention reportedly promoted therapeutic alliance, skill-building and meaningful time-use without elevating agitation, but fatigue impeded therapy. Overall, GAS captured positive individual change following ADL retraining during PTA and therapists indicated that the intervention and use of GAS was generally beneficial and feasible within clinical practice.


Tunneling Controls the Reaction Pathway in the Deformylation of Aldehydes by a Nonheme Iron(III)-Hydroperoxo Complex: Hydrogen Atom Abstraction versus Nucleophilic Addition.
Mononuclear nonheme iron(III)-hydroperoxo intermediates play key roles in biological oxidation reactions. In the present study, we report the highly intriguing reactivity of a nonheme iron(III)-hydroperoxo complex, [(TMC)FeIII(OOH)]2+ (1), in the deformylation of aldehydes, such as 2-phenylpropionaldehyde (2-PPA) and its derivatives; that is, the reaction pathway of the aldehyde deformylation by 1 varies depending on reaction conditions, such as temperature and substrate. At temperature above 248 K, the aldehyde deformylation occurs predominantly via a nucleophilic addition (NA) pathway. However, as the reaction temperature is lowered, the reaction pathway changes to a hydrogen atom transfer (HAT) pathway. Interestingly, the reaction rate becomes independent of temperature below 233 K with a huge kinetic isotope effect (KIE) value of 93 at 203 K, suggesting that the HAT reaction results from tunneling. In contrast, reactions with a deuterated 2-PPA at the α-position and 2-methyl-2-phenylpropionaldehyde proceed exclusively via a NA pathway irrespective of the reaction temperature. We conclude that the bifurcation pathways between NA and HAT result from the tunneling effect in the HAT reaction by 1. To the best of our knowledge, this study reports the first example showing that tunneling plays a significant role in the activation of substrate C-H bonds by a mononuclear nonheme iron(III)-hydroperoxo complex.


Obstructive uropathy and vesicovaginal fistula secondary to a retained sex toy in the vagina.
Vaginal foreign bodies (FBs) are a rare cause of vesicovaginal, rectovaginal, or urethrovaginal fistulae. The aim of this study was to describe a rare case of vesicovaginal fistula (VVF) and obstructive uropathy and to review the literature. A case is presented. A comprehensive review of the literature was performed (1948-2013). A 38-year-old woman presenting with sepsis, obstructive uropathy, and severe emaciation was found to have a sex toy retained in her vagina for 10 years. This had caused a VVF and bilateral hydroureteronephrosis. Bilateral nephrostomies were inserted and she underwent cystoscopy and examination under anesthesia (EUA) with retrieval of FB. A left ureteric stricture was demonstrated. Transabdominal VVF repair with omental flap and left ureteric re-implantation was performed. The VVF recurred, which was successfully re-repaired transvaginally. Seventy-six full text articles were reviewed. There were no previously published cases of VVF following vaginal sex toy insertion. There are four cases of obstructive uropathy secondary to a vaginal FB in the literature: three pessaries and one plastic cap. There are 44 cases of VVF secondary to FB: 22 plastic caps (typically from aerosol bottles, inserted for masturbation or contraception) and 5 pessaries. At least nine were in girls aged ≤18 years. Average presentation is 15 months (range 2 months to 35 years) after FB insertion. Most cases were managed with surgical repair; predominantly transvaginal. This case describes an extremely rare but potentially life-threatening case of obstructive uropathy caused by a chronically retained sex toy, and adds to the list of potentially rare causes of a VVF and obstructive uropathy. We advocate urinary diversion, staged removal of FB, upper urinary tract imaging, and EUA with VVF repair and/or ureteric reimplantation if required. Transvaginal is the preferred access for FB-associated VVF repair without concomitant ureteric reimplantation.


A better way to define and describe Morlet wavelets for time-frequency analysis.
Complex Morlet wavelets are frequently used for time-frequency analysis of non-stationary time series data, such as neuroelectrical signals recorded from the brain. The crucial parameter of Morlet wavelets is the width of the Gaussian that tapers the sine wave. This width parameter controls the trade-off between temporal precision and spectral precision. It is typically defined as the "number of cycles," but this parameter is opaque, and often leads to uncertainty and suboptimal analysis choices, as well as being difficult to interpret and evaluate. The purpose of this paper is to present alternative formulations of Morlet wavelets in time and in frequency that allow parameterizing the wavelets directly in terms of the desired temporal and spectral smoothing (expressed as full-width at half-maximum). This formulation provides clarity on an important data analysis parameter, and can facilitate proper analyses, reporting, and interpretation of results. MATLAB code and sample data are provided.


True three-dimensional nuclear magnetic resonance neuro-imaging in ischemic stroke: correlation of NMR, X-ray CT and pathology.
True three-dimensional proton nuclear magnetic resonance (NMR) imaging was performed on an 84-year-old man following a recent cerebral embolic infarction. NMR data obtained using different pulse sequences were inter-correlated, stressing the significance of image appearance in terms of the NMR tissue parameters. Planes selected for display from the three-dimensional data set allowed optimal visualization of the pathology. Accurate correlations of the NMR data with X-ray computerized tomography scans and with subsequent autopsy findings indicate that NMR may play an important role in the detection and diagnosis of ischemic stroke.


Novel CT-based three-dimensional software improves the characterization of cam morphology.
Incomplete correction of femoral offset and sphericity remains the leading cause for revision surgery for symptomatic femoroacetabular impingement (FAI). Because arthroscopic exploration is technically difficult, a detailed preoperative understanding of morphology is of paramount importance for preoperative decision-making. The purposes of this study were to (1) characterize the size and location of peak cam deformity with a prototype CT-based software program; (2) compare software alpha angles with those obtained by plain radiograph and CT images; and (3) assess whether differences can be explained by variable measurement locations. We retrospectively reviewed the preoperative plain radiographs and CT scans of 100 symptomatic cam lesions treated by arthroscopy; recorded alpha angle and clockface measurement location with a novel prototype CT-based software program, CT, and Dunn lateral plain radiographs; and used ordinary least squares regressions to assess the relationship between alpha angle and measurement location. The software determined a mean alpha angle of 70.8° at 1:23 o'clock and identified 60% of maximum alpha angles between 12:45 and 1:45. The CT and plain radiographs underestimated by 5.7° and 8.2°, respectively. The software-based location was anterosuperior to the mean CT and plain radiograph measurement locations by 41 and 97 minutes, respectively. Regression analysis confirmed a correlation between alpha angle differences and variable measurement locations. Software-based three-dimensional (3-D) imaging generated alpha angles larger than those found by plain radiograph and CT, and these differences were the result of location of measurement. An automated 3-D assessment that accurately describes the location and topography of FAI may be needed to adequately characterize preoperative deformity.


Septic abortion caused by Salmonella enteritidis.
Septic abortion caused by salmonella infection is rare. Here we report a case of septic abortion due to Salmonella enteritidis. The route of infection was probably transplacental.


Metabolomics profiles of premenopausal women are different based on O-desmethylangolensin metabotype.
Urinary O-desmethylangolensin (ODMA) concentrations provide a functional gut microbiome marker of dietary isoflavone daidzein metabolism to ODMA. Individuals who do not have gut microbial environments that produce ODMA have less favourable cardiometabolic and cancer risk profiles. Urinary metabolomics profiles were evaluated in relation to ODMA metabotypes within and between individuals over time. Secondary analysis of data was conducted from the BEAN2 trial, which was a cross-over study of premenopausal women consuming 6 months on a high and a low soya diet, each separated by a 1-month washout period. In all of the 672 samples in the study, sixty-six of the eighty-four women had the same ODMA metabotype at seven or all eight time points. Two or four urine samples per woman were selected based on temporal metabotypes in order to compare within and across individuals. Metabolomics assays for primary metabolism and biogenic amines were conducted in sixty urine samples from twenty women. Partial least-squares discriminant analysis was used to compare metabolomics profiles. For the same ODMA metabotype across different time points, no profile differences were detected. For changes in metabotype within individuals and across individuals with different metabotypes, distinct metabolomes emerged. Influential metabolites (variables importance in projection score > 2) included several phenolic compounds, carnitine and derivatives, fatty acid and amino acid metabolites and some medications. Based on the distinct metabolomes of producers v. non-producers, the ODMA metabotype may be a marker of gut microbiome functionality broadly involved in nutrient and bioactive metabolism and should be evaluated for relevance to precision nutrition initiatives.


Beta-adrenergic agonists and bronchial hyperreactivity: role of beta2-adrenergic and tachykinin neurokinin-2 receptors.
beta(2)-Adrenergic agonists are the most widely used bronchodilators for the treatment of asthma. On the other hand, there is concern that excessive use of beta(2)-agonists may contribute to the exacerbation of asthma. However, the mechanism of such adverse effects of beta(2)-agonists is not completely clear. The aim of this study was to assess the direct influence of beta(2)-agonists on airways by analyzing the effect of a beta(2)-agonist, fenoterol, on airway sensitivity in an animal model and on tachykinin neurokinin-2 receptor expression in bovine tracheal smooth muscle. We performed an acetylcholine challenge test on ovalbumin sensitized guinea pigs that were exposed to daily inhalation of ovalbumin and fenoterol. We also investigated the effects of fenoterol on neurokinin-2 receptor messenger RNA and density with Northern blot analysis and receptor binding assay. The increase of airway responsiveness and the decrease of beta(2)-adrenergic receptors were found in guinea pigs that were treated with fenoterol. There were time- and dose-dependent increases of neurokinin-2 receptor mRNA and of density in tracheal smooth muscle that was treated with fenoterol. This increased airway responsiveness, increased neurokinin-2 receptor expression, and decreased beta(2)-adrenergic receptor density may be relevant to asthma exacerbation.


The development of pediatric fluid resuscitation: an interview with Dr. Frederic A. 'Fritz' Berry.
Dr. Frederic A. 'Fritz' Berry (1935), Professor Emeritus of Anesthesiology and Pediatrics at the University of Virginia, has played a pioneering role in the development of pediatric anesthesiology through training generations of anesthesiologists. He identifies his early advocacy of balanced electrolyte solution for perioperative fluid resuscitation as his defining contribution. Based on his clinical experiences, he pushed to extend the advances in adult fluid resuscitation into pediatric practice. He imparted these and other insights to his colleagues although textbooks, book chapters, original journal publications, and decades of Refresher Course Lectures at the American Society of Anesthesiologists' annual meetings. A model educator, clinician, and researcher, he shaped the careers of hundreds of physicians-in-training while advancing the field of pediatric anesthesiology.


Formation and manipulation of ferrofluid droplets with magnetic fields in a microdevice: a numerical parametric study.
We present a numerical model that describes the microfluidic generation and manipulation of ferrofluid droplets under an external magnetic field. We developed a numerical Computational Fluid Dynamics (CFD) analysis for predicting and optimizing continuous flow generation and processing of ferrofluid droplets with and without the presence of a permanent magnet. More specifically, we explore the dynamics of oil-based ferrofluid droplets within an aqueous continuous phase under an external inhomogeneous magnetic field. The developed model determines the effect of the magnetic field on the droplet generation, which is carried out in a flow-focusing geometry, and its sorting in T-junction channels. Three-channel depths (25 μm, 30 μm, and 40 μm) were investigated to study droplet deformation under magnetic forces. Among the three, the 30 μm channel depth showed the most consistent droplet production for the studied range of flow rates. Ferrofluids with different loadings of magnetic nanoparticles were used to observe the behavior for different ratios of magnetic and hydrodynamic forces. Our results show that the effect of these factors on droplet size and generation rate can be tuned and optimized to produce consistent droplet generation and sorting. This approach involves fully coupled magnetic-fluid mechanics models and can predict critical details of the process including droplet size, shape, trajectory, dispensing rate, and the perturbation of the fluid co-flow for different flow rates. The model enables better understanding of the physical phenomena involved in continuous droplet processing and allows efficient parametric analysis and optimization.


Effects of circuit exercise training on vascular health and blood pressure.
As the global burden of cardiovascular disease (CVD) rises, public health-related interventions aimed at prevention of heart disease have gained medical attention. Clinical research reports that exercise is a protective risk factor associated with CVD and that clinicians need to provide exercise recommendations to patients. Nevertheless, physical inactivity remains a public health problem. In certain populations, like firefighters (FF), increased risk of CVD is especially concerning. The workload FF face is extreme, 50% of line-of-duty deaths (LODD) in FF are cardiac-related, and research on the volunteer FF population is scarce. Government regulations do not require volunteer FF companies to have fitness testing or programming, so exercise intervention studies are necessary to improve the burden of CVD risk in this population. Therefore, this study examined the effects of a 4-week exercise circuit training (CT) intervention on vascular health and fitness in volunteer FF (N = 27) from the Philadelphia PA area compared to a control group of Non-FF (N = 25). Carotid artery intima-media thickness (IMT), brachial artery flow-mediated dilation (FMD), augmentation index, and pulse pressure (PP), brachial and central blood pressure (BP) and fitness were measured pre- and post- intervention. Overall, volunteer FF had more significant improvements (p < 0.05) in vascular health measures (FMD, IMT, and PP). In both groups, we also found that brachial and central BP decreased with exercise. We show that a 4 week CT program can improve vascular structure and function in the volunteer FF population, suggesting that clinicians may be able to reduce or prevent cardiac LODD by exercise.


ProSeal versus Classic laryngeal mask airway (LMA) for positive pressure ventilation in adults undergoing elective surgery.
The development of supraglottic airway devices has revolutionized airway management during general anaesthesia. Two devices are widely used in clinical practice to facilitate positive pressure ventilation: the ProSeal laryngeal mask airway (pLMA) and the Classic laryngeal mask airway (cLMA). It is not clear whether these devices have important clinical differences in terms of efficacy or complications. To compare the effectiveness of the ProSeal laryngeal mask airway (pLMA) and the Classic LMA (cLMA) for positive pressure ventilation in adults undergoing elective surgery. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 3) in the Cochrane Library; MEDLINE (Ovid SP, 1997 to April 2017); Embase (Ovid SP, 1997 to April 2017); the Institute for Scientific Information (ISI) Web of Science (1946 to April 2017); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO host, 1982 to April 2017).We searched trial registries for ongoing studies to April 2017.We did not impose language restrictions. We restricted our search to the time from 1997 to April 2017 because pLMA was introduced into clinical practice in the year 2000. We included randomized controlled trials (RCTs) that compared the effectiveness of pLMA and cLMA for positive pressure ventilation in adults undergoing elective surgery. We planned to include only data related to the first phase of cross-over RCTs. We used standard methodological procedures expected by the Cochrane Collaboration. We included eight RCTs that involved a total of 829 participants (416 and 413 participants in the pLMA and cLMA groups, respectively). We identified six cross-over studies that are awaiting classification; one is completed but has not been published, and data related to the first treatment period for the other five studies were not yet available. Seven included studies provided data related to the primary outcome, and eight studies provided data related to more than one secondary outcome.Our analysis was hampered by the fact that a large proportion of the included studies reported no events in either study arm. No studies reported significant differences between devices in relation to the primary review outcome: failure to adequately mechanically ventilate. We evaluated this outcome by assessing two variables: inadequate oxygenation (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.17 to 3.31; four studies, N = 617) and inadequate ventilation (not estimable; one study, N = 80).More time was required to establish an effective airway using pLMA (mean difference (MD) 10.12 seconds, 95% CI 5.04 to 15.21; P < 0.0001; I² = 73%; two studies, N = 434). Peak airway pressure during positive pressure ventilation was lower in cLMA participants (MD 0.84, 95% CI 0.02 to 1.67; P = 0.04; I² = 0%; four studies, N = 259). Mean oropharyngeal leak (OPL) pressure was higher in pLMA participants (MD 6.93, 95% CI 4.23 to 9.62; P < 0.00001; I² = 87%; six studies, N = 709).The quality of evidence for all outcomes, as assessed by GRADE score, is low mainly owing to issues related to blinding and imprecision.Data show no important differences between devices with regard to failure to insert the device, use of an alternate device, mucosal injury, sore throat, bronchospasm, gastric insufflation, regurgitation, coughing, and excessive leak. Data were insufficient to allow estimation of differences for obstruction related to the device. None of the studies reported postoperative nausea and vomiting as an outcome. We are uncertain about the effects of either of the airway devices in terms of failure of oxygenation or ventilation because there were very few events. Results were uncertain in terms of differences for several complications. Low-quality evidence suggests that the ProSeal laryngeal mask airway makes a better seal and therefore may be more suitable than the Classic laryngeal mask airway for positive pressure ventilation. The Classic laryngeal mask airway may be quicker to insert, but this is unlikely to be clinically meaningful.


Identification and cell cycle control of a novel pilus system in Caulobacter crescentus.
Pilus assembly in CAULOBACTER: crescentus occurs during a short period of the cell cycle and pili are only present at the flagellar pole of the swarmer cell. Here we report a novel assay to visualize pili by light microscopy that led to the purification of CAULOBACTER: pili and the isolation of a cluster of seven genes, including the major pilin subunit gene pilA. This gene cluster encodes a novel group of pilus assembly proteins. We have shown that the pilA promoter is activated late in the cell cycle and that transcription of the pilin subunit plays an important role in the timing of pilus assembly. pilA transcription is regulated by the global two-component response regulator CtrA, which is essential for the expression of multiple cell cycle events, providing a direct link between assembly of the pilus organelle and bacterial cell cycle control.


Epidemiology and treatment utilization for Canadian patients with migraine: a literature review.
The objective of this narrative review was to identify real-world evidence regarding the burden of migraine in Canada. We conducted a literature search in MEDLINE, Embase, and the Cochrane Database of Systematic Reviews for studies published between August 2010 and August 2020. Of the 3269 publications identified, 29 studies were included. Prevalence estimates varied widely across Canada, and mental health comorbidities were common. Individuals with migraine have a lower quality of life, detrimental impact on workforce productivity, and higher rates of health care resource utilization (HCRU), with HCRU and costs highest among those with chronic migraine. We found inconsistencies in care, including underutilization of medications such as triptans, and varied utilization of over-the-counter and prescription medications. Increased medication use was identified among those with chronic migraine, and only a small number of patients used migraine preventive medications. The burden of migraine in Canada is substantial. Reduced quality of life and workforce productivity, increased HCRU and costs, and underutilization of triptans and migraine preventive medications highlight an important need for more effective management of individuals with migraine.


An 18-year follow-up of patients admitted to methadone treatment for the first time.
An 18-year addiction career, 1985-2003, for 157 heroin dependent subjects (73% men; 49% human immunodeficiency virus seropositive) admitted for the first time to Stockholm's Methadone Maintenance Treatment program during 1989 to 1991 was analyzed with data from seven official registers and patient records. Regression analyses and incidence rates for various outcomes were calculated for subjects in first methadone maintenance treatment at the end of the observation period, discharged from first methadone maintenance treatment, in second methadone maintenance treatment, and discharged from second methadone maintenance treatment. Being human immunodeficiency virus positive (HR = 3.8), lodging (HR = 1.9) and prison sentence (HR = 1.7) predicted mortality for the 45% deceased. Approximately 70% of living subjects participated in methadone maintenance treatment at some period each year. Subjects in first or second methadone maintenance treatment had less criminality and had spent more time in methadone maintenance treatment (70% to 100%) than those discharged from first or from second methadone maintenance treatment (50%). Efforts and interventions should be intensified to increase time in treatment also for those with high problem severity.


Association between MEFV Mutations M694V and M680I and Behçet's Disease: A Meta-Analysis.
Several studies have identified an association between Behçet's disease (BD) and mutations in the Mediterranean fever (MEFV) gene, which was originally linked to the autosomal recessive disease, Familial Mediterranean fever. However, no consensus has been reached. Here, a meta-analysis was conducted on published data to comprehensively evaluate this relationship. Literature searches were performed in Pubmed, Embase, the Web of Science, and HuGE Navigator databases, in order to identify studies pertaining to the association between MEFV mutations and BD. Two investigators independently extracted and evaluated the data from eligible studies. The association between MEFV mutations (M694V, M680I, and E148Q) and BD was estimated overall by the odds ratio (OR) and 95% confidence intervals (95% CI). Further analysis was conducted with STATA 12.0 software (Stata Corp.; College Station, TX). Eligible studies (n=8) included genotyping data obtained from 2538 BD patients and 2792 healthy controls. Of the three mutations, M694V (pooled OR: 2.60, 95% CI: 2.02-3.34) and M680I (pooled OR: 1.74, 95% CI: 1.23-2.46) were found to be associated with BD in the overall analysis. The third mutation, E148Q, however, was not found to be linked with BD (pooled OR: 1.26, 95% CI: 0.69-2.31). Subgroup analysis furthermore revealed that M694V and M680I were risk loci for BD specifically in Turkish patients. The meta-analysis confirmed that MEFV mutations M694V and M680I were associated with BD. Additional studies from other ethnic populations and functional experiments are necessary to determine the extent to which the MEFV gene underlies the development of BD.


Endothelin-1 and interleukin-8 in high altitude pulmonary oedema.
We present a case of high altitude pulmonary oedema (HAPE) with pulmonary hypertension and polymorphonuclear leucocyte (PMN) accumulation in bronchoalveolar lavage fluid (BALF), which occurred in a 21 year old man. Plasma endothelin-1 (ET-1) and interleukin-8 (IL-8) concentration in BALF were elevated on admission, and returned to normal level at recovery, when the pulmonary artery pressure and the PMN counts in BALF were normal. In addition, E-selectin and intercellular adhesion molecule-1 (ICAM-1) in BALF were also slightly increased on admission. These findings suggest that endothelin-1 is a vasoconstrictor which contributes to the pulmonary hypertension in high altitude pulmonary oedema, and that some of the inflammatory mediators play an important role in chemotaxis and accumulation of polymorphonuclear leucocytes in the development of high altitude pulmonary oedema.


Facile synthesis of 14 C-nitrofurazone from 14 C-urea.
The veterinary drug nitrofurazone (5-nitro-2-furaldehyde semicarbazone) exhibits excellent antimicrobial properties but its application in food-producing animals is prohibited. The illegal use of nitrofurazone is regularly monitored by food regulatory agencies. Currently, semicarbazide (SEM) is used as a marker of nitrofurazone exposure. However, the use of SEM as a marker of nitrofurazone is under scrutiny after evidence of a high incidence of false positive tests. To overcome the current dilemma, it is necessary to identify a nitrofurazone-specific marker analyte which requires conducting nitrofurazone metabolism studies in food-producing animals. The use of carbon-14 labeled nitrofurazone would facilitate metabolism studies and structural elucidation of nitrofurazone metabolites of possible utility as a marker compound. In the present work, a synthetic method is described to procure radiolabeled nitrofurazone that incorporates 14 C- carbon at the semicarbazide moiety. The method incorporates 14 C-carbon via employing readily available and more economically affordable [14 C]-urea compared with [14 C]-semicarbazide. To the best of our knowledge, there is no report on the synthesis of 5-nitro-2-furaldehyde [14 C]-semicarbazone from 14 C-urea. The developed method involves monoamination of [14 C]-urea followed by a condensation reaction with 5-nitro-2-furaldehyde to produce 5-nitro-2-furaldehyde [14 C]-semicarbazone in 85% yield with greater than 98% radiochemical purity.


Endogenous voltage-gated potassium channels in human embryonic kidney (HEK293) cells.
Endogenous voltage-gated potassium currents were investigated in human embryonic kidney (HEK293) and Chinese hamster ovary (CHO) cells using whole-cell voltage clamp recording. Depolarizing voltage steps from -70 mV triggered an outwardly rectified current in nontransfected HEK293 cells. This current had an amplitude of 296 pA at +40 mV and a current density of 19.2 pA/pF. The outward current was eliminated by replacing internal K+ with Cs+ and suppressed by the K+ channel blockers tetraethylammonium and 4-aminopyridine. Raising external K+ attenuated the outward current and shifted the reversal potential towards positive potentials as predicted by the Nernst equation. The current had a fast activation phase but inactivated slowly. These features implicate delayed rectifier (I(K))-like channels as mediators of the observed current, which was comparable in size to I(K) currents in many other cells. A small native inward rectifier current but no transient outward current I(A), the M current I(M), or Ca2+-dependent K+ currents were detected in HEK293 cells. In contrast to these findings in HEK293 cells, little or no I(K)-like current was detected in CHO cells. The difference in endogenous voltage-activated currents in HEK293 and CHO cells suggest that CHO cell lines are a preferred system for exogenous K+ channel expression.


Tuberculosis and travel.
Tuberculosis is increasing worldwide with most countries having a high prevalence. Protection against tuberculosis, the risks of acquiring tuberculosis during air travel, and the evidence for clinical tuberculosis acquired on extended visits to such countries are all reviewed in this article.


Expression of a cloned Staphylococcus aureus alpha-hemolysin determinant in Bacillus subtilis and Staphylococcus aureus.
A DNA sequence encoding Staphylococcus aureus alpha-hemolysin, which had been previously cloned and mapped in Escherichia coli K-12, was introduced into Bacillus subtilis BD170 and several strains of S. aureus by using plasmid vectors, some of which could replicate in all three organisms. The determinant was cloned on a 3.3-kilobase pair DNA fragment into B. subtilis by using the vector plasmid pXZ105 to form the hybrid plasmid pXZ111. B. subtilis cells harboring pXZ111 produced large zones of alpha-hemolysis after 18 h of growth at 37 degrees C on rabbit blood agar plates, and alpha-hemolysin activity was detected in supernatants prepared from growing cultures of this strain. The alpha-hemolysin was apparently secreted across the B. subtilis cell envelope. Polypeptides of molecular weights 34,000 and 33,000 were precipitated with anti-alpha-hemolysin serum from lysates prepared from BD170 cells harboring pXZ111. A hybrid replicon which could replicate in both E. coli and S. aureus was constructed in E. coli by ligating a HindIII fragment encoding the replication functions and chloramphenicol resistance genes of S. aureus plasmid pCW59 to the pBR322 alpha-hemolysin hybrid plasmid pDU1150. The DNA of this plasmid, pDU1212, was prepared in E. coli and used to transform protoplasts prepared from a non-alpha-hemolytic, nonrestricting strain of S. aureus RN4220. Some of the transformants contained plasmids which had suffered extensive deletions. Some plasmids, however, were transformed intact into RN4220. Such plasmids were subsequently maintained in a stable manner. pDU1212 DNA was prepared from RN4220 and transformed into alpha-hemolytic S. aureus 8325-4 and two mutant derivatives defective in alpha-hemolysin synthesis. All three strains expressed alpha-hemolysin when harboring pDU1212.


Impact and recognition of cognitive impairment among hospitalized elders.
Older adults are predisposed to developing cognitive deficits. This increases their vulnerability for adverse health outcomes when hospitalized. To determine the prevalence and impact of cognitive impairment (CI) among hospitalized elders based on recognition by lCD-coding versus screening done on admission. Observational cohort study. Urban public hospital in Indianapolis. 997 patients age 65 and older admitted to medical services between July 2006 and March 2008. Impact of CI in terms of length of stay, survival, quality of care and prescribing practices. Cognition was assessed by the Short Portable Mental Status Questionnaire (SPMSQ). 424 patients (43%) were cognitively impaired. Of those 424 patients with CI, 61% had not been recognized by ICD-9 coding. Those unrecognized were younger (mean age 76.1 vs. 79.1, P <0.001); had more comorbidity (mean Charlson index of 2.3 vs.1.9, P = 0.03), had less cognitive deficit (mean SPMSQ 6.3 vs. 3.4, P < 0.001). Among elders with CI, 163 (38%) had at least one day of delirium during their hospital course. Patients with delirium stayed longer in the hospital (9.2 days vs. 5.9, P < 0.001); were more likely to be discharged into institutional settings (75% vs. 31%, P < 0.001) and more likely to receive tethers during their care (89% vs. 69%, P < 0.001), and had higher mortality (9% vs. 4%, P = 0.09). Cognitive impairment, while common in hospitalized elders, is under-recognized, impacts care, and increases risk for adverse health outcomes.


Utility of routinely acquired primary care data for paediatric disease epidemiology and pharmacoepidemiology.
The majority of medicines prescribed for children are prescribed in primary care for common acute and chronic conditions. This is in contrast to prescribing in secondary care where the population of children admitted is small but where a large number of different medicines are prescribed to treat more serious and less common conditions. Data on prescribing was extracted from the General Practice Administration System for Scotland (GPASS) for the year November 1999 to October 2000 and prescribing patterns for children aged 0-16 years expressed as percentages. A comparison of age specific consultations for asthma, as an example of a common paediatric condition, was also made between two separate general practice data sets, the General Practice Research Database (GRPD) and the continuous morbidity recording (CMR) subset of GPASS. Of 214 medicines investigated for unlicensed and off-label prescribing no unlicensed prescribing was identified. Off-label prescribing due to age was most common among younger and older children. The most common reasons for off-label prescriptions were, in order of frequency, lower than recommended dose, higher than recommended dose, below the recommended age, and unlicensed formulation. Age and gender specific consultations for asthma were similar in the two representative databases, GPRD and CMR, both showing disappearance of the male predominance in the teenage years. Large primary care data sets available within a unified health care system such as the UK National Health Service (NHS) are likely to be broadly compatible and produce similar results. The prescribing of off-label medicines to children is common in primary care, most commonly due to prescribing out with the recommended dosage regimen.


Magnetic field modulated SERS enhancement of CoPt hollow nanoparticles with sizes below 10 nm.
It is well known that Pt shows much weaker plasmonic effects in the visible spectrum when compared to Au, Ag and Cu. Therefore, the realization of efficient optical absorption by Pt nanoparticles with sizes below 10 nm in the visible spectrum remains a challenge. One possible way to enhance the optical absorption is to prepare Pt-based bimetallic magnetic nanoparticles. Furthermore, if an external magnetic field is applied, the synergistic effect of both electric and magnetic fields may provide sufficient SERS enhancement. In this paper, CoPt hollow nanoparticles (NPs) with sizes below 10 nm and ultrathin shells (∼2 nm) were synthesized in solution, at room temperature. The NPs have high surface-to-volume ratios and excellent structural stability. The hollow NPs exhibited enhanced light absorption characterized by surface-enhanced Raman scattering (SERS) with 4-mercaptobenzoic acid (4-MBA) as tip molecules. It is noted that the SERS enhancement of these alloyed NPs can be tuned by using an external magnetic field. A synergistic optical effect between these hollow NPs and the Ag film substrate is obtained. Hence, CoPt hollow NPs show promise as SERS substrates and potential for other applications in optical enhancement.


A novel 50-kilodalton fragment of host cell factor 1 (C1) in G(0) cells.
Host cell factor 1 (HCF-1; also called C1) is a 230-kDa protein which is cleaved posttranslationally into separate but associated N- and C-terminal polypeptides. These polypeptides are components of the C1 complex, along with Oct-1 and the viral protein VP16. The C1 complex is formed when herpes simplex virus (HSV) infects a cell and is responsible for transcription of the HSV immediate-early genes. A temperature-sensitive mutation in the N-terminal kelch domain of HCF-1 reversibly arrests cells in a G(0)-like state when grown at the nonpermissive temperature, and the same domain interacts with VP16 in the formation of the C1 complex. The form of HCF-1 in primary G(0) cells was investigated by using peripheral blood mononucleocytes and serum-arrested human primary fibroblasts. A novel 50-kDa N-terminal fragment of HCF-1 encompassing the kelch domain was identified in the cytoplasm of these cells. This fragment arises by proteolysis of the full-length HCF-1 protein and is able to associate with VP16.


Caspase regulation of genotoxin-induced neural precursor cell death.
Neural precursor cells (NPCs) critically regulate brain morphogenesis and recent studies have revealed an unexpectedly high frequency of NPC chromosomal abnormalities and apoptosis in the developing brain. We have shown previously that the apoptotic response of NPCs to genotoxic agents is dependent on p53 and caspase-9, but not Bax or caspase-3 expression. In this study, we found that NPCs deficient in Apaf-1, or both the pro-apoptotic multidomain Bcl-2 family members Bax and Bak, were resistant to cytosine arabinoside and gamma-irradiation-induced apoptosis. Inhibitors of gene transcription, protein translation, and caspase activity also blocked genotoxin-induced NPC apoptosis. Although caspase-3 and caspase-6 were both cleaved in response to DNA damage, neither of these effector caspases was critical for apoptosis. Genotoxin-induced NPC death was accompanied by the generation of reactive oxygen species and could be inhibited by several known antioxidants. Conversely, DNA damage-induced reactive oxygen species generation was inhibited significantly by gene disruption of p53, Apaf-1, or caspase-9, and combined deficiency of Bax and Bak, but not by caspase-3 or caspase-6 deficiency. These studies suggest that caspase-9 activation is both necessary and sufficient for genotoxin-induced neural precursor cell reactive oxygen species generation and death.


Tritiated thymidine incorporation does not measure DNA synthesis in ribavirin-treated human cells.
When the incorporation of tritiated thymidine into acid insoluble material was measured, ribavirin appeared to be a potent inhibitor of DNA synthesis in KB cells and human lymphocytes. Inhibition was nearly 100-fold less, however, when DNA synthesis was measured by incorporation of phosphorus-32-labeled phosphate or by DNA fluorescence. The potent inhibition detected by incorporation of tritiated thymidine into DNA actually was the result of a potent effect on the labeling of deoxythymidine triphosphate, not on the synthesis of DNA.


Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma.
Next generation sequencing and large-scale analysis of patient specimens has created a more complete picture of multiple myeloma (MM) revealing that epigenetic deregulation is a prominent factor in MM pathogenesis. Over half of MM patients have mutations in genes encoding epigenetic modifier enzymes. The DNA methylation profile of MM is related to the stage of the disease and certain classes of mutations in epigenetic modifiers are more prevalent upon disease relapse, suggesting a role in disease progression. Many small molecules targeting regulators of epigenetic machinery have been developed and clinical trials are underway for some of these in MM. Recent findings suggest that epigenetic targeting drugs could be an important strategy to cure MM. Combining these agents along with other strategies to affect the MM cell such as immunomodulatory drugs and proteasome inhibitors may enhance efficacy of combination regimens in MM.


Current knowledge on the use of ultrasound measurements of fetal soft tissues for the assessment of pregnancy development.
Ultrasonography, with its detailed imaging of the fetus, is very widely used in obstetrics. The primary aim of ultrasound scanning in pregnancy is to limit the risk of obstetric complications by early detection of abnormalities, such as intrauterine growth restriction and macrosomia. Currently, morphometric formulae are used for estimating fetal weight. They utilize basic biometric parameters. However, Hadlock formula, used for fetal weight estimation, has an error rate of 20%. For this reason, researchers all over the world have been looking for other sonographic parameters correlating with fetal weight, with a higher predictive value. The current scientific reports indicate that new sonographic parameters, such as soft tissue thickness values, are useful for fetal weight assessment. The measurements can be conducted in various parts of the fetus's body, e.g. thigh, upper arm, abdomen or the subscapular area. Different types of measurements are characterized by different levels of correlation with other sonographic and anthropometric parameters as well as body mass and gestational age. Based on the reports, numerous studies proposing new fetal weight calculation formulae have been produced. Apart from soft tissue, some more advanced and detailed measurements are taken, such as those involving adipose and lean tissue or using three-dimensional ultrasound (3D), for determining fetal weight. Ultrasound measurement of subcutaneous tissue thickness in various parts of the body may prove to be a strong predictor of fetal weight, which is useful for sonographic assessment of pregnancy.


Estrogen Modulates Specific Life and Death Signals Induced by LH and hCG in Human Primary Granulosa Cells In Vitro.
Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are glycoprotein hormones used for assisted reproduction acting on the same receptor (LHCGR) and mediating different intracellular signaling. We evaluated the pro- and anti-apoptotic effect of 100 pM LH or hCG, in the presence or in the absence of 200 pg/mL 17β-estradiol, in long-term, serum-starved human primary granulosa cells (hGLC) and a transfected granulosa cell line overexpressing LHCGR (hGL5/LHCGR). To this purpose, phospho-extracellular-regulated kinase 1/2 (pERK1/2), protein kinase B (pAKT), cAMP-responsive element binding protein (pCREB) activation and procaspase 3 cleavage were evaluated over three days by Western blotting, along with the expression of target genes by real-time PCR and cell viability by colorimetric assay. We found that LH induced predominant pERK1/2 and pAKT activation STARD1, CCND2 and anti-apoptotic XIAP gene expression, while hCG mediated more potent CREB phosphorylation, expression of CYP19A1 and procaspase 3 cleavage than LH. Cell treatment by LH is accompanied by increased (serum-starved) cell viability, while hCG decreased the number of viable cells. The hCG-specific, pro-apoptotic effect was blocked by a physiological dose of 17β-estradiol, resulting in pAKT activation, lack of procaspase 3 cleavage and increased cell viability. These results confirm that relatively high levels of steroidogenic pathway activation are linked to pro-apoptotic signals in vitro, which may be counteracted by other factors, i.e., estrogens.


Evaluation of a long-chain polyunsaturated fatty acid supplemented formula on growth, tolerance, and plasma lipids in preterm infants up to 48 weeks postconceptional age.
The last trimester of pregnancy is a period of rapid accretion of long-chain polyunsaturated fatty acids, both in the central nervous system and the body as a whole. Human milk contains these fatty acids, whereas some preterm infant formulas do not. Infants fed formulas without these fatty acids have lower plasma and erythrocyte concentrations than infants fed human milk. Preclinical and clinical studies have demonstrated that single-cell sources (algal and fungal) of long-chain polyunsaturated fatty acids are bioavailable. A balanced addition of fatty acids from these oils to preterm formula results in blood fatty acid concentrations in low birth weight infants comparable to those of infants fed human milk. In the present study the growth, acceptance (overall incidence of discontinuation, reasons for discontinuation, overall incidence and type of individual adverse events), and plasma fatty acid concentrations were compared in three groups of infants fed a long-chain polyunsaturated fatty acid-supplemented preterm infant formula, an unsupplemented control formula, or human milk. The study was prospective, double-blind (formula groups only), and randomized (formula groups only). Two hundred eighty-eight infants were enrolled (supplemented formula group, n = 77; control formula group, n = 78; human milk group, n = 133). Anthropometric measurements at enrollment, at first day of full oral feeding, and at both 40 and 48 weeks postconceptional age did not differ between the formula groups, whereas the human milk-fed group initially grew at a lower rate. The incidence of severe adverse events was rare and not significantly different between formula groups. The groups fed either human milk or supplemented formula had long-chain polyunsaturated fatty acid concentrations higher than those in the control formula group. The results of this study demonstrate the safety and efficacy of a preterm formula supplemented with long-chain polyunsaturated fatty acids from single-cell oils.


Replacing dichromate with hydrogen peroxide in the chemical oxygen demand (COD) test.
The widely used standard method for chemical oxygen demand (COD) involves hazardous chromium species, and its two-hour heating protocol entails a substantial amount of energy expenditure. In the present work we report a proof of concept for a major modification of this method in the range 10-800 mgCOD/L, whereby H2O2 is proposed as a replacement oxidizer. This modification not only reduces the use of unsafe chromium species but also allows for the use of milder conditions that decrease the total energy outlay. The results are comparable with those obtained either with the standard method or with a commercial Hach® kit.


Evaluation of the effect of energy drink consumption on retina and choroid: an optical coherence tomography and optical coherence tomography angiography study.
Evaluation of retinal and choroidal changes after energy drink consumption by optical coherence tomography and optical coherence tomography angiography. Forty-two healthy volunteers with neither systemic nor ocular diseases were enrolled in the study. The energy drink (250 mL Red Bull energy drink) was provided to all volunteers. The vascular density of superficial (SCP) and deep capillary plexus (DCP), vascular density in FAZ region, its circumference (PERIM) and vascular density around 300 micron (FD-300), and blood flow in outer retinal and choriocapillaris were measured by OCT-A (AngioVue RTVue XR Avanti, Optovue, Fremont, CA) before and 30 min after consumption of energy drink, in an interval of 1, 2, 3, 6, and 24 h. Central macular thickness (CMT) was measured by OCT (Heidelberg Engineering, Inc., Heidelberg, Germany), whereas choroid thickness (CT) and retinal nerve fibre layer (RNFL) measurements of the optic nerve were measured by enhanced depth imaging OCT. For control comparison, the same measurements were made after drinking 250 mL of water in the same healthy group. The obtained data were statistically analysed. Among 42 volunteers enrolled in the study, 25 (59,5%) were males and 17 (40,5%) were females, with an average age of 20,58 ± 0,71. The vascular density measurements of parafoveal and perifoveal deep capillary plexus obtained after energy drink consumption were statistically significant. This increase in vascular density of the deep capillary plexus after energy drink consumption seemed to start after half an hour and continued until measurement at 24th hour. On the other hand, the changes in measurements of vascular density from other regions, the blood flows, FAZ, CMT, CT and RNFL values were not statistically significant. In water consumption measurements; despite a statistically significant increase in choroidal thickness at 30 min and 1 h (p = 0.027, p = 0.045, respectively), no significant difference was found in other parameters between consecutive measurements. The consumption of energy drinks acutely leads to changes in retinal vascular density parameters.


Comparison of Corticosteroids by 3 Approaches to the Treatment of Chronic Rhinosinusitis With Nasal Polyps.
Corticosteroids are regarded as the mainstay of medical treatment of eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP). To date, a head-to-head comparison of the efficacy and safety of glucocorticoid preparations administered via different routes for the treatment of chronic rhinosinusitis with nasal polyps has not been reported. To compare the efficacy and safety of steroids administered via the oral, intranasal spray and transnasal nebulization routes in the management of ECRSwNP over a short course. Overall, 91 patients with ECRSwNP were recruited prospectively and randomized to receive either oral methylprednisolone, budesonide inhalation suspension (BIS) via transnasal nebulization, or budesonide nasal spray (BNS) for 2 weeks. Nasal symptoms and polyp sizes were assessed before and after the treatment. Similarly, nasal polyp samples were evaluated for immunological and tissue remodeling markers. Serum cortisol levels were assessed as a safety outcome. Oral methylprednisolone and BIS decreased symptoms and polyp sizes to a significantly greater extent from baseline (P < 0.05) than BNS. Similarly, BIS and oral methylprednisolone significantly reduced eosinophils, T helper 2 cells, eosinophil cationic protein, interleukin (IL)-5, and expression of matrix metalloproteinases 2 and 9, and significantly increased type 1 regulatory T cells, IL-10, transforming growth factor-β, and tissue inhibitor of metalloproteinases 1 and 2 in nasal polyps to a greater extent than BNS. Post-treatment serum cortisol levels were significantly decreased by oral methylprednisolone compared to BIS or BNS, which did not significantly alter the cortisol levels. A short course of BIS transnasal nebulization is more efficacious compared to BNS in the management of ECRSwNP and is safer than oral methylprednisolone with respect to hypothalamic-pituitary-adrenal axis function.


Effects of source of starch on net portal flux of glucose, lactate, volatile fatty acids and amino acids in the pig.
The ileal digestibilities of maize starch and native pea starch do not differ. However maize starch is digested faster than pea starch and the ileal amino acid digestibility of a diet containing pea starch is lower. In the present study, the net portal fluxes of glucose, lactate, volatile fatty acids (VFA) and amino acids were measured for diets including 650 g maize starch or pea starch/kg. The diets were fed at a level 870 kJ digestible energy/kg0.75 twice daily (06.00 and 18.00 hours) to four female pigs in a crossover design. Portal vein blood flow did not differ between maize and pea starches (1620 and 1484 ml/min respectively; SED 100; P = 0.23). For maize starch portal glucose flux was significantly higher during the first 6 h after feeding, was not different 8 h after feeding and was significantly lower thereafter. Net portal glucose flux was higher for maize starch than for pea starch (1759 and 1265 mmol/12 h respectively; SED 182; P = 0.054). Net portal lactate flux was not significantly different between maize and pea starches (36.5 and 67.2 mmol/12 h respectively; SED 24.1; P = 0.27) and net portal VFA flux was lower for maize starch than for pea starch (169 and 218 mmol/12 h respectively; SED 18; P = 0.054). Net portal fluxes of valine, isoleucine, phenylalanine, tryptophan, arginine, serine, cystine, tyrosine, lysine, histidine and the sum of essential amino acids tended to be or were higher (P < 0.1 or P < 0.05) and net portal flux of aspartic acid tended to be lower for pea starch (P < 0.1). It can be concluded that, although ileal digestibility of both starches is equal, the rate of appearance of glucose in the portal vein was higher for maize starch, influencing the net portal flux of amino acids.


Estimating premorbid functioning in huntington's disease: the relationship between disease progression and the wide range achievement test reading subtest.
The estimation of premorbid abilities is an essential part of a neuropsychological evaluation, especially in neurodegenerative conditions. Although word pronunciation tests are one standard method for estimating the premorbid level, research suggests that these tests may not be valid in neurodegenerative diseases. Therefore, the current study sought to examine two estimates of premorbid intellect, the Wide Range Achievement Test (WRAT) Reading subtest and the Barona formula, in 93 patients with mild to moderate Huntington's disease (HD) to determine their utility and to investigate how these measures relate to signs and symptoms of disease progression. In 89% of participants, WRAT estimates were below the Barona estimates. WRAT estimates were related to worsening memory and motor functioning, whereas the Barona estimates had weaker relationships. Neither estimate was related to depression or functional capacity. Irregular word reading tests appear to decline with HD progression, whereas estimation methods based on demographic factors may be more robust but overestimate premorbid functioning.


[The peregrination of pregnant women in Rio de Janeiro City: deaths and births profile].
This ecological study presented analyze of the birth pathways in the Rio de Janeiro City and identification of the relationship between the health services offer and pregnant flow between their households and the maternity. It was used the data available in the Mortality Information System (MIS) and Live Birth Information System (LBIS) in 2004. The TabWin program processed the data and drew the maps. The LBIS processed 99,042 declarations of live birth and MIS processed 1,318 declarations of deaths in less than one year old in the Rio Janeiro City. The conclusion was that the possibility of intervention in the infantile and maternal mortality profile has happened at the health services, and the access to the quality assistance has fundamental hole in the mortality determination. The existence of access inequalities to the services must be investigated.


Structural genomics on membrane proteins: mini review.
Structural genomics, structure-based analysis of gene products, has so far mainly concentrated on soluble proteins because of their less demanding requirements for overexpression, purification and crystallisation compared to membrane proteins. This so-called "low-hanging fruit" approach has generated more than 25,000 structures deposited in databases. In contrast, the substantially more complex membrane proteins, in relation to all steps from overexpression to high-resolution structure determination, represent less than 1% of available crystal structures. This is in sharp contrast to the importance of this type of proteins, particularly G protein-coupled receptors (GPCRs), as today 60-70% of the current drug targets are based on membrane proteins. The key to improved success with membrane protein structural elucidation is technology development. The most efficient approach constitutes parallel studies on a large number of targets and evaluation of various systems for expression. Next, high throughput format solubilisation and refolding screening methods for a wide range of detergents and additives in numerous concentrations should be established. Today, several networks dealing with structural genomics approaches of membrane proteins have been initiated, among them the Membrane Protein Network (MePNet) programme that deals with the pharmaceutically important mammalian GPCRs. In MePNet, three overexpression systems have been employed for the evaluation of 101 GPCRs, which has generated large quantities of numerous recombinant GPCRs, compatible for structural biology applications.


ICD-10 Coding of Musculoskeletal Conditions in the Veterans Health Administration.
We describe the most frequently used musculoskeletal diagnoses in Veterans Health Administration care. We report the number of visits and patients associated with common musculoskeletal International Classification of Diseases (ICD)-10 codes and compare trends across primary and specialty care settings. Secondary analysis of a longitudinal cohort study. Veterans included in the Musculoskeletal Diagnosis Cohort with a musculoskeletal diagnosis from October 1, 2015, through September 30, 2017. We obtained counts and proportions of all musculoskeletal diagnosis codes used and the number of unique patients with each musculoskeletal diagnosis. Diagnosis use was compared between primary and specialty care settings. Of more than 6,400 possible ICD-10 M-codes describing "Diseases of the Musculoskeletal System and Connective Tissue," 5,723 codes were used at least once. The most frequently used ICD-10 M-code was "Low Back Pain" (18.3%), followed by "Cervicalgia" (3.6%). Collectively, the 100 most frequently used codes accounted for 80% of M-coded visit diagnoses, and 95% of patients had at least one of these diagnoses. The most common diagnoses (spinal pain, joint pain, osteoarthritis) were used similarly in primary and specialty care settings. A diverse sample of all available musculoskeletal diagnosis codes were used; however, less than 2% of all possible codes accounted for 80% of the diagnoses used. This trend was consistent across primary and specialty care settings. The most frequently used diagnosis codes describe the types of musculoskeletal conditions, among a large pool of potential diagnoses, that prompt veterans to present to the Veterans Health Administration for musculoskeletal care.


Familial ring (18) mosaicism in a 23-year-old young adult with 46,XY,r(18) (::p11→q21::)/46,XY karyotype, intellectual disability, motor retardation and single maxillary incisor and in his phenotypically normal mother, karyotype 47,XX,+r(18)(::p11→q21::)/46,XX.
We report on a 23-year-old man with craniofacial findings of the holoprosencephaly spectrum disorder (microcephaly, hypotelorism, depressed nasal bridge, single median maxillary central incisor), fusion of C2-C3 vertebrae, intellectual disability, and severe sleep apnea. Chromosome analysis of blood lymphocytes showed 75% ring (18) cells and 25% normal cells, karyotype mos 46,XY,r(18)(::p11→q21::)[75]/46,XY[25]. His mother was phenotypically normal except for a double ureter and bifid renal pelvis as in his son. She had a supernumerary ring (18) in 10% of blood lymphocytes, karyotype mos 47,XX,+r(18)(::p11→q21::)[10]/46,XX[90]. Familial ring (18) is a rare cytogenetic abnormality. This is the first report of a mother with a supernumerary ring (18) and a son with ring (18) mosaicism. Interestingly, the son showed a true mosaicism (mixoploidy) of ring (18) and normal cells. The mother's 46,XX cells could be easily explained by mitotic instability and ring loss during cell division. However, the coexistence of ring (18) and normal cells in the son is unusual. Possibly, during early postzygotic divisions of a 47,XY,+r(18) zygote, two (possibly subsequent) genetic events could have occurred, one when one normal chromosome 18 was lost (resulting in a cell line with ring 18), and one when the ring 18 was lost (resulting in a cell line without ring, "escape to normal"). Alternatively, the zygote of the son could have been 46,XY,r(18), and postzygotic loss of the ring 18 could have resulted in monosomy 18 cells followed by duplication of chromosome 18 in these cells (a rare mechanism for cell survival previously described as "compensatory" isodisomy).