Purification and characterization of the active precursor of a human sperm motility inhibitor secreted by the seminal vesicles: identity with semenogelin.
Human seminal plasma contains a sperm motility inhibitor that originates from seminal vesicles as a precursor form. This precursor is degraded into smaller peptides by prostatic proteases shortly after ejaculation. The seminal plasma sperm motility inhibitor (SPMI) precursor was purified by a combination of cation-exchange chromatography on S-Sepharose followed by C4 reverse-phase high-performance liquid chromatography directly from seminal vesicle fluid or washed seminal coagulum. The purification procedure yielded a protein of apparent homogeneity, with a molecular mass of 52 kDa by SDS-PAGE. It migrated as a 105-kDa protein by molecular sieving under denaturing conditions. The purified SPMI precursor was digested by the prostatic protease prostate-specific antigen (PSA), causing a 76 +/- 4% drop in biological activity and transformation into low molecular mass SPMI polypeptides (5-20 kDa) similar to those observed in liquefied semen. The N-terminal amino acid sequences of three degradation peptides were obtained by Edman degradation and found to correspond to residues 45-50, 85-90, and 137-143 of semenogelin, a protein characterized as the major structural component of semen coagulum. The amino acid composition of SPMI precursor was found to be almost identical to that of semenogelin. Moreover, the mass of the precursor was estimated at 49,620 daltons by electrospray-ionization mass spectrometry, a value in close agreement with the expected mass of semenogelin according to its cDNA sequence. The SPMI precursor was found to inhibit sperm motility in a dose-dependent manner, with complete immobilization at 500 U/ml of SPMI. The motility of completely immobilized spermatozoa was partially recovered after washing of the cells. The results suggest that SPMI precursor is the major component of the seminal vesicle secretions and seminal coagulum. It can be degraded by PSA in a manner reminiscent of its processing in whole semen. Taken together these results indicate that the SPMI precursor is semenogelin and that intact semenogelin can immobilize spermatozoa.


Ventricular remodeling in a mouse model of myocardial infarction.
We investigated the suitability of studying ventricular remodeling in a mouse model of myocardial infarction (MI). We performed left coronary ligation (n = 22) or a sham procedure (n = 21) on normal C57BL/6J mice. Six weeks later, animals underwent echocardiography and hemodynamic evaluation. Left ventricular (LV) volume at a common distending pressure was calculated from passive pressure-volume curves. The MI group exhibited lower systolic blood pressure (P < 0.05), higher LV end-diastolic pressure (P < 0.05), and lower peak first derivative of LV pressure (dP/dt, P < 0.05) than the sham group. Mice with moderate (< 40%, n = 11) and large (> or = 40%, n = 11) MIs displayed increased LV mass-to-body weight ratio (P < 0.02 and P < 0.01, respectively, vs. sham group), whereas only the large-MI group exhibited increased right ventricular mass-to-body weight ratio (P < 0.01). LV volumes were increased in the moderate-MI group (P = 0.059 vs. sham group) and to a much greater extent in the large-MI group (P < 0.0001 vs. sham group). The moderate- and large-MI groups also exhibited increases in LV end-diastolic diameter (P < 0.03 and P < 0.0001, respectively, vs. sham group) and LV end-systolic diameter (P < 0.01 and P < 0.0001, respectively, vs. sham group) with decreased fractional shortening (P < 0.01 for both). These data demonstrate ventricular remodeling in a mouse model of MI and confirm the feasibility of quantifying indexes of remodeling in vivo and postmortem. This model will be of particular usefulness when applied to transgenic strains.


Irreversible inactivation of red cell chloride exchange with phenylglyoxal, and arginine-specific reagent.
Chloride exchange in resealed human erythrocyte ghosts can be irreversibly inhibited with phenylglyoxal, a reagent specific for the modification of arginyl residues in proteins. Phenylglyoxal inhibits anion transport in two distinct ways. At 0 degrees C, inhibition is instantaneous and fully reversible, whereas at higher temperature in an alkaline extracellular medium, covalent binding of phenylglyoxal leads to an irreversible inhibition of the transport membranes system. Indiscriminate modification of membrane arginyl residues was prevented by reacting the with phenylglyoxal in an alkaline extracellular medium while maintaining intracellular pH near neutrality. The rate of modification of anion transport depends on phenylglyoxal concentration, pH, temperature, and the presence of anions and reversible inhibitors of the anion transport system in fashions that are fully compatible with the conclusion that phenylglyoxal modifies arginyl residues that are essential for anion binding and translocation. Phenylglyoxal reacts rapidly with the deprotonated form of the reactive groups. It is proposed that the effects of anions and of negatively charged transport inhibitors on the rate of irreversible binding of phenylglyoxal are related to the effects of the anions on a positive interfacial potential. This potential determines the local pH, and thereby the concentration of deprotonated groups, in an exofacial region of the anion transport protein.


Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa.
The development of antimicrobial resistance among gram-negative pathogens has been progressive and relentless. Pathogens of particular concern include extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Classic agents used to treat these pathogens have become outdated. Of the few new drugs available, many have already become targets for bacterial mechanisms of resistance. This review describes the current approach to infections due to these resistant organisms and elaborates on the available treatment options.


Relation between patient satisfaction, compliance and the clinical benefit of a teletreatment application for chronic pain.
We investigated the ease of use and usefulness as a measure of patient satisfaction, compliance, clinical benefit and its mutual relationships concerning a teletreatment application for chronic pain. Fifty-two subjects with neck and shoulder pain received and completed a four-week myofeedback-based teletreatment intervention. Prior to the onset of the intervention (at baseline) and immediately after the intervention they were asked to fill in questionnaires to measure discrepancies (gap scores) between expectations and experiences with the ease of use and usefulness of the treatment, as well as pain intensity and pain disability. In addition, the actual use of the system (i.e. the volume of muscle activity data available on the server) was logged. The subjects reported a significantly higher score on ease of use after the intervention compared to baseline, suggesting that the equipment was easier to use than they expected. Compliance was associated with clinical benefit. There was no significant relation between patient satisfaction and compliance. Patient satisfaction is a key indicator of how well the telemedicine treatment met expectations and compliance is important because of its association with clinical outcomes.


Molecular pathogenesis of myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorders characterized by inefficient hematopoiesis, hypercellular bone marrow, dysplasia of blood cells and cytopenias. Most patients are diagnosed in their late 60s to early 70s. MDS is a risk factor for the development of acute myeloid leukemia which can occur in 10-15% of patients with MDS. A variety of pathophysiologic mechanisms contributes to the genesis and persistence of MDS including immunologic, epigenetic, cytogenetic and genetic factors. The only potential curative option for MDS is hematopoietic cell transplantation which is suitable for only a few patients. Currently approved therapeutic options for MDS, including lenalidomide, decitabine, and 5-azacytidine, are targeted to improve transfusion requirements and quality of life. Moreover, 5-azacytidine has also been demonstrated to improve survival in some patients with higher risk MDS. New ways to predict which patients will better gain benefit from currently available therapeutic agents are the primary challenges in MDS. In the last 10 years, chromosome scanning and high throughput technologies (single nucleotide polymorphism array genotyping, comparative genomic hybridization, and whole genome/ exome sequencing) have tremendously increased our knowledge of MDS pathogenesis. Indeed, the molecular heterogeneity of MDS supports the idea of different therapeutic approaches which will take into account the diverse morphologic and clinical presentations of MDS patients rather than a restricted therapeutic strategy. This review will summarize the molecular abnormalities in key relevant components of the biology and pathogenesis of MDS and will provide an update on the clinical impact and therapeutic response in MDS patients.


Demographics, smoking status, and systemic health factors associated with apical periodontitis in a Brazilian rural population: a cross-sectional study.
To determine whether the systemic diseases diabetes mellitus (DM) and arterial hypertension (AH), and smoking status are associated with apical periodontitis (AP) in a representative rural population. Cross-sectional study using a representative sample of individuals obtained from a population-based epidemiological survey carried out in the rural area of the city of Rosário do Sul, RS, Brazil, from March 2015 to May 2016. Data were collected through structured questionnaires and clinical examination. Binary logistic regression analysis was performed to identify variables independently associated with AP. Of the 584 individuals included in the study, 353 (60.4%) had AP. The presence of AP was independently associated with age ≥ 40 years (odds ratio [OR] = 1.867, 95% confidence interval [CI]: 1.193-2.923, p = 0.006), non-white ethnicity (OR = 1.509, 95% CI: 1.029-2.115, p = 0.035), active or former smoker (OR = 2.087, 95% CI: 1.241-3.510, p = 0.006) and DM or prediabetes (OR = 1.676, 95% CI: 1.150-2.443, p = 0.007). The study identified significant associations between AP and demographics, smoking status, and systemic disease in a Brazilian rural population. The study emphasized the significance of comprehending and managing associated factors in preventing and treating AP.


Effects of Treatment with Adalimumab on Blood Lipid Levels and Atherosclerosis in Patients with Rheumatoid Arthritis.
Treatment with tumor necrosis factor inhibitors for rheumatoid arthritis has been associated with a decreased risk of cardiovascular disease in observational studies. There are conflicting data on the influence of tumor necrosis factor inhibitors on lipid levels. To evaluate the effect of treatment with adalimumab on blood lipid levels, lipoproteins, and atherosclerosis of the carotid artery. Fourteen patients with active rheumatoid arthritis (11 women and 3 men; mean age 63.7 years; median disease duration 9.0 years; and 78% rheumatoid factor positive) were treated with adalimumab 40 mg subcutaneously every 2 weeks and followed for 3 months. The patients had not been treated with adalimumab previously and had not received other tumor necrosis factor inhibitors within the past 3 months or moderate/high dose corticosteroids within the past 2 weeks. The intima-media thickness of the common carotid artery was assessed using B mode ultrasonography. Triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol levels were analyzed in fresh fasting blood samples, whereas apolipoprotein B and apolipoprotein A1 (apoA1) levels were determined in thawed plasma samples using standard turbidimetric immunoassays. Total cholesterol (mean = 5.36 vs 5.96 mmol/L; P = 0.005), LDL cholesterol (mean = 3.33 vs 3.77 mmol/L; P = .005), HDL cholesterol (mean = 1.43 vs 1.55 mmol/L; P = 0.048), apolipoprotein B (mean = 1.04 vs 1.13 g/L; P = .012), and apoA1 (mean = 1.42 vs 1.58 g/L; P = 0.005) all increased, but there were no major changes in the LDL to HDL cholesterol ratio (median = 2.56 vs 2.35; P = 0.27) or the apolipoprotein B to apoA1 ratio (mean = 0.76 vs 0.74; P = 0.46). There was no change in triglyceride levels (P = 0.55). Disease activity decreased significantly from baseline to the 3-month evaluation (disease activity score based on 28 joints mean = 5.6 vs 4.1; P = 0.007). An increase in apoA1 correlated with decreases in the patient global assessment of disease severity (r = 0.79; P = 0.001) and C-reactive protein level (r = 0.74; P = 0.003). Changes in the apoliprotein B to apoA1 ratio correlated with changes in erythrocyte sedimentation rate (r = 0.54; P = 0.046). There was no major change in the common carotid artery intima-media thickness (mean = 0.78 vs 0.80 mm; P = 0.48). Although these results suggest that control of inflammation could have a beneficial effect on the lipid profile through an increase in HDL cholesterol levels, the observed protective effect on cardiovascular disease events by tumor necrosis factor blockers is likely to be explained by other mechanisms than changes in lipid levels or short-term effects on atherosclerosis of the carotid artery.


The effects of visual context and individual differences on perception and evaluation of modern art and graffiti art.
Traditionally, artworks are seen as autonomous objects that stand (or should stand) on their own. However, at least since the emergence of Conceptual Art in the 1920s and Pop Art in the 1960s, art lacks any distinctive perceptual features that define it as such. Art, therefore, cannot be defined without reference to its context. Some studies have shown that context affects the evaluation of artworks, and that specific contexts (street for graffiti art, museum for modern art) elicit specific effects (Gartus & Leder, 2014). However, it is yet unclear how context changes perception and appreciation processes. In our study we measured eye-movements while participants (64 psychology undergraduates, 48% women) perceived and evaluated beauty, interest, emotional valence, as well as perceived style for modern art and graffiti art embedded into either museum or street contexts. For modern art, beauty and interest ratings were higher in a museum than in a street context, but context made no difference for the ratings of graffiti art. Importantly, we also found an interaction of context and individual interest in graffiti for beauty and interest ratings, as well as for number of fixations. Analyses of eye-movements also revealed that viewing times were in general significantly longer in museum than in street contexts. We conclude that context can have an important influence on aesthetic appreciation. However, some effects depend also on the style of the artworks and the individual art interests of the viewers.


Decomposing multilocus linkage disequilibrium.
We present a mathematically precise formulation of total linkage disequilibrium between multiple loci as the deviation from probabilistic independence and provide explicit formulas for all higher-order terms of linkage disequilibrium, thereby combining J. Dausset et al.'s 1978 definition of linkage disequilibrium with H. Geiringer's 1944 approach. We recursively decompose higher-order linkage disequilibrium terms into lower-order ones. Our greatest simplification comes from defining linkage disequilibrium at a single locus as allele frequency at that locus. At each level, decomposition of linkage disequilibrium is mathematically equivalent to number theoretic compositions of positive integers; i.e., we have converted a genetic decomposition into a mathematical decomposition.


Derivation of stretched exponential tap density equations of granular powders.
The tap density of granular powders was found to be better fitted with the stretched exponential law. In our previous work, the stretched exponential tap density equations were derived with the rate process theory and free volume concept, under the assumption that the particle packing rate during the tapping process obeys the stretched Arrhenius equation, which, however, has an empirical origin. In this article, the above assumption is eliminated and attempts are made to obtain the stretched exponential tap density equations from very fundamental bases. In a vertical tapping process, the probability of particles attaining certain energy states is assumed to obey the Boltzmann distribution and particles traveling from one site to another are assumed to follow a very common memoryless random exponential law. The stretched exponential tap density equations are thus derived and all parameters acquire clear physical meanings. The most important parameter, the stretched exponential, is demonstrated to correlate with the interparticle forces: a small value may indicate a strong adhesive or cohesive interaction. Therefore, the stretched exponential could be a better indicator for powder flowability correlated with particle interactions as well.


Characterization of mucus glycoconjugates in normal human conjunctiva by lectins in light microscopy, transmission and scanning electron microscopy.
Maintenance of tear film in normal conditions is dependent on mucus layer integrity and the presence and distribution of conjunctival epithelial cell microvilli. In the present work a new methodology has been developed to gain correlative information about microprojection assessment and mucus composition, from the same specimen, by Light Microscopy (LM), Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM). We have characterized the glycosidic residues secreted by goblet cells in normal human conjunctiva, by means of four lectins (WGA, ConA, PNA and SBA), conjugated with FITC for LM and with colloidal gold for TEM and SEM. The cytochemical reactions were performed on histological sections of paraffin-embedded material and on semithin and ultrathin sections of both Epon embedded material directly processed for TEM and of blocks recovered from SEM and reprocessed for TEM. WGA, ConA, PNA and SBA receptors were found to be constituents of the mucus produced by goblet cells in human conjunctiva. The granules of the so-called "second mucus system" (SMS) cells were labelled mainly by WGA. A difference in the quality of glycoconjugates between goblet cells and SMS cells has been also demonstrated. Our results provide an improved method to evaluate alterations of tear film that occur in many conjunctival diseases.


[Efficiency of using the anxiolytic adaptol in the combination therapy of arterial hypertension in women].
To evaluate the effect of the anxiolytic adaptol on blood pressure (BP) level in its concurrent use with a fixed dose angiotensin-converting enzyme (ACE) inhibitor/diuretic combination on quality of life and on the correction of psychoautonomic disorders. The trial included women aged 40-60 years with the verified diagnosis of Stage 2B arterial hypertension (AH), risk 2, and a disease history of at least 5 years. A study group received a fixed dose ACE inhibitor/diuretic combination once daily and adaptol 500 mg twice daily for 2 months. A comparison group had only the fixed dose ACE inhibitor/diuretic combination once daily without adaptol. By the end of one-month therapy, a more pronounced statistically significant BP reduction was achieved in the study group receiving the ACE inhibitor/diuretic combination and adaptol than in the comparison group. The quality of life was improved in 6 of the 8 items in the study group and in 3 items in the comparison group. The total scores of psychoautonomic disorders decreased from 48.7 to 25.8 in the study group and from 47.8 to 38 in the comparison one. It is expedient to combine antihypertensive therapy and anxiolytics in female hypertensive patients with autonomic dystonic disorders.


Self-emulsification of alkaline-dissolved clove bud oil by whey protein, gum arabic, lecithin, and their combinations.
Low-cost emulsification technologies using food ingredients are critical to various applications. In the present study, a novel self-emulsification technique was studied to prepare clove bud oil (CBO) emulsions, without specialized equipment or organic solvents. CBO was first dissolved in hot alkaline solutions, added at 1% v/v into neutral solutions with 1% w/v emulsifier composed of whey protein concentrate (WPC), gum arabic, lecithin, or their equal mass mixtures, and adjusted to pH 7.0. The self-emulsification process did not affect UV-vis absorption spectrum, reversed-phase HPLC chromatogram, or antimicrobial activity of CBO against Escherichia coli O157:H7, Listeria monocytogenes Scott A, and Salmonella Enteritidis. The entrapment efficiency after extraction by petroleum ether was determined to be about 80%. Most emulsions were stable during 7 days of storage. Emulsions prepared with WPC had smaller particles, whereas emulsions prepared with emulsifier mixtures had more stable particle dimensions. The studied self-emulsification technique may find numerous applications in the preparation of low-cost food emulsions.


Harm reduction strategies for androgen users: providing appropriate support and improving engagement with healthcare.
As evidence continues to emerge of the harms associated with nonmedical androgen use, this review explores the implications from recent studies for designing strategies to reduce harm and support good health amongst androgen users. Studies have predominantly come from researchers in the UK and Australia. Major themes include questioning the scope and content of harm reduction strategies and identifying approaches to improve engagement between the androgen using community and healthcare providers. Findings suggest that a broader range of interventions and forms of advice are needed than are commonly provided. This must be supported by efforts to increase opportunities to deliver harm reduction through new engagement approaches, better relationships with health professionals and more guidance on identifying and managing associated adverse health impacts. A fully developed harm reduction-based response to nonmedical androgen use will be one that not only seeks to reduce risk of bloodborne virus transmission and injecting-related harms, but that considers the range of needs amongst the diverse community of androgen users and respects their decisions and rights. Co-producing interventions with members of this community will help develop effective and engaging approaches. Rigorous studies are needed to evaluate new harm reduction interventions as well as those already delivered.


The contribution of on-road studies of road user behaviour to improving road safety.
For over 40 years transport safety researchers have been using methods of vehicle instrumentation to gain greater insights into the factors that contribute to road user crash risk and the associated crash factors. In the previous decade in particular the widespread availability of lower cost and more advanced methods of vehicle instrumentation and recording technologies are supporting the increasing number of on-road research studies worldwide. The design of these studies ranges from multi-method studies using instrumented test vehicles and defined driving routes, to field operational tests, through to much larger and more naturalistic studies. It is timely to assess the utility of these methods for studying the influences of driver characteristics and states, the design and operation of the road system, and the influences of in-vehicle technologies on behaviour and safety for various road user groups. This special issue considers the extent to which on-road studies using vehicle instrumentation have been used to advance knowledge across these areas of road safety research. The papers included in this issue illustrate how research using instrumented test vehicles continues to generate new knowledge, and how the larger scale United States and European naturalistic and field operational test studies are providing a wealth of data about road user behaviour in real traffic. This is balanced with a number of studies that present methodological developments in data collection and analysis methods that, while promising, need further validation. The use of on-road methods to accurately describe the behaviours occurring in everyday real-world conditions, to quantify risks for safety critical events, and an improved understanding of the factors that contribute to risk, clearly has huge potential to promote further road trauma reductions.


Antibacterial Low Molecular Weight Cationic Polymers: Dissecting the Contribution of Hydrophobicity, Chain Length and Charge to Activity.
The balance of cationicity and hydrophobicity can profoundly affect the performance of antimicrobial polymers. To this end a library of 24 cationic polymers with uniquely low degrees of polymerization was synthesized via Cu(0)-mediated polymerization, using three different cationic monomers and two initiators: providing two different hydrocarbon chain tail lengths (C2 and C12). The polymers exhibited structure-dependent antibacterial activity when tested against a selection of bacteria, viz, Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae ATCC 13883, Acinetobacter baumannii ATCC 19606, and Pseudomonas aeruginosa ATCC 27853 as a representative palette of Gram-positive and Gram-negative ESKAPE pathogens. The five best-performing polymers were identified for additional testing against the polymyxin-resistant A. baumannii ATCC 19606R strain. Polymers having the lowest DP and a C12 hydrophobic tail were shown to provide the broadest antimicrobial activity against the bacteria panel studied as evidenced by lower minimum inhibitory concentrations (MICs). An optimal polymer composition was identified, and its mechanism of action investigated via membrane permeability testing against Escherichia coli. Membrane disruption was identified as the most probable mechanism for bacteria cell killing.


Entrectinib Response to ROS1-Fusion-Positive Non-Small-Cell Lung Cancer That Progressed on Crizotinib with Leptomeningeal Metastasis: A Case Report.
C-ros oncogene 1 (ROS1) translocation is an oncogenic driver-mutation identified in 1-2% of non-small-cell lung cancer (NSCLC) cases. Although crizotinib, a tyrosine kinase inhibitor (TKI) against ALK/ROS1, is known to be effective against ROS1-fusion-positive NSCLC, such cases sometimes progress with brain metastases. The most frequently reported crizotinib-resistance mutation is ROS1 G2032R, and some studies have found that even newly developed ROS1 TKIs, such as entrectinib and lorlatinib, show a decreased efficacy against it. The optimal therapies for ROS1-fusion-positive NSCLC and how such cases can be sequenced have not yet been established. We herein report a patient with ROS1-fusion-positive NSCLC diagnosed at 34 years old. Crizotinib was started at the diagnosis and switched after 25 months to cisplatin/pemetrexed/bevacizumab once the disease progressed with multiple brain metastases that were resistant to stereotactic radiation therapy. The cytotoxic chemotherapy stabilized the patient's condition for 17 months until he developed leptomeningeal metastasis (LM). He underwent lumboperitoneal shunting and whole-brain radiotherapy, followed by crizotinib re-administration. Despite crizotinib treatment, his neurological symptoms, such as double vision, headache, weakness in the legs, and walking difficulties, progressed. Eventually, subsequent entrectinib treatment was initiated, which resolved all of the symptoms mentioned above. Regrettably, liquid next-generation sequencing had failed to detect the resistance mechanism due to minimal ctDNA in this case. These findings imply that sequential entrectinib administration may be effective in patients with disease progression limited to central nervous system metastases during crizotinib administration.


[Morphologic MR imaging with T1-weighted sequences for radiotherapy goal volume definition of intracranial tumors. Comparison with FLASH-Turbo-FLASH and SE sequences].
The goal of this study was to compare contrast-enhanced T1-weighted Flash and Turbo-Flash sequences with conventional spin-echo sequences as a basis for planning high-precision radiotherapy. A total of 25 consecutive patients with different intracranial tumors and a disrupted blood-brain barrier were studied. T1-weighted Flash, Turbo-Flash and conventional spin-echo images were evaluated after controlled 30-s infusion of 0.1 mmol/kg body weight of Gd-DTPA. The evaluation of the three sequences included the measurement of the spinal- and contrast-to-noise ratios, the visual inspection of the tumors and artifacts, and the measurement of tumor size. The signal- and contrast-to-noise ratios were significantly (P < 0.05-0.01) lower for Flash and Turbo-Flash than for conventional spin-echo sequences. However, visual inspection of the contrast-enhancing tumors revealed in 23 and 24 of 25 lesions on Flash and Turbo-Flash images, respectively, good or very good tumor visibility when compared with conventional spin-echo images with a reduction of imaging time by a factor of 7-8. Flash and Turbo-Flash sequences were more prone to susceptibility artifacts, conventional spin-echo sequences more to pulsation artifacts in the posterior fossa. Tumor sizes were comparable in all three techniques. At present, conventional spin-echo images are superior to fast Flash and ultrafast Turbo-Flash sequences as a basis for accurate target volume definition in high-precision radiotherapy. However, fast Flash and Turbo-Flash images may be a practicable alternative to conventional spin-echo images for tumors in the posterior fossa or in patients unable to tolerate a stereotactic fixation device. Despite some limitations, Turbo-Flash sequences enable fast dynamic MR imaging combined with an acceptable morphology, which may be sufficient to target volume planning in high-precision radiotherapy.


Cost of treatment of bleeding esophageal varices.
We examined the cost of four methods of treatment of bleeding esophageal varices--medical treatment, sclerotherapy, variceal ligation operations, and portal systemic shunts--in 49 consecutive patients from 1977 to 1979, and correlated the two-year outcome with cost. We found that, despite bias imposed by selection, the cost per patient and cost per survivor at two years was lowest in patients who received sclerotherapy, even though they were more seriously ill than patients who received other treatments. Patients treated with sclerotherapy also had the lowest mortality during primary hospitalization and the lowest readmission rate during a two-year period.


Value of reference tracings in diagnosis and assessment of constrictive epi- and pericarditis.
Reference tracings are of great value in the diagnosis and assessment of constrictive pericarditis. The Q-h interval in the jugular venous pulse tracing is strongly correlated with the mean right atrial pressure (r=0.91). The left ventricular ejection time, the Q-A2 interval, and the Q-h interval are independent during atrial fibrillation from the preceding diastolic filling interval. This differentiates constrictive pericarditis from valvular heart disease. Cases with haemodynamically significant constrictive epicarditis are characterized by a rapid evolution, absence of pericardial calcification and absence of an early diastolic filling sound, a dominant a wave in the jugular venous pulse tracing, and a high early diastolic ventricular pressure. The haemodynamic behaviour is similar to that found in cases with myocardial fibrosis.


Emulsifying activities of purified Alasan proteins from Acinetobacter radioresistens KA53.
The bioemulsifier of Acinetobacter radioresistens KA53, referred to as alasan, is a high-molecular-weight complex of polysaccharide and protein. The emulsifying activity of the purified polysaccharide (apo-alasan) is very low. Three of the alasan proteins were purified by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis and had apparent molecular masses of 16, 31, and 45 kDa. Emulsification assays using the isolated alasan proteins demonstrated that the active components of the alasan complex are the proteins. The 45-kDa protein had the highest specific emulsifying activity, 11% higher than the intact alasan complex. The 16- and 31-kDa proteins gave relatively low emulsifying activities, but they were significantly higher than that of apo-alasan. The addition of the purified 16- and 31-kDa proteins to the 45-kDa protein resulted in a 1.8-fold increase in the specific emulsifying activity and increased stability of the oil-in-water emulsion. Fast-performance liquid chromatography analysis indicated that the 45-kDa protein forms a dimer in nondenaturing conditions and interacts with the 16- and 31-kDa proteins to form a high-molecular-mass complex. The 45-kDa protein and the three-protein complex had substrate specificities for emulsification and a range of pH activities similar to that of alasan. The fact that the purified proteins are active emulsifiers should simplify structure-function studies and advance our understanding of their biological roles.


[Rhabdomyoma of the right ventricle associated with Behcet disease simulating the presence of a malignant tumor].
To present the clinical case of a patient suffering from a rhabdomyoma associated to Behçet's disease. A 35-year-old man with a history of high fever associated to oral ulcers, sinus tachycardia, leukocytosis and a high erythrocyte sedimentation rate. Physical examination, chest x-ray, blood chemistry, serology and rheumatic tests were normal. Seriate sputum cultures, urocultures and blood cultures were negative. The echocardiogram showed a non-obstructive mass in the right ventricle, which was confirmed by magnetic resonance imaging. Resection of the tumor under cardiopulmonary bypass. After the post-operative recurrence of the fever and the appearance of genital ulcers, the diagnosis of Behçet's disease was made. Two and a half years after the operation the patient remains asymptomatic under treatment with colchicine. The clinical setting suggested a malignant tumor of the right ventricle but the pathological findings showed an adult rhabdomyoma. The rarity of finding a rhabdomyoma in an adult is stressed, as well as its association with Behçet's disease.


Hepatic resection for metastatic colon and rectal cancer. An evaluation of preoperative and postoperative factors.
Hepatic resection for metastatic colorectal cancer has been reported in over 700 patients. However, approximately 5000 patients each year are candidates for surgical excision. Since 1972, 25 patients have undergone hepatic resection for colorectal metastases at New York University. Potentially curable synchronous lesions were detected by preoperative liver chemistries and operative palpation. Patients were screened for metachronous lesions by serial liver chemistries and carcinoembryonic antigen (CEA) determinations; when clinical findings or laboratory findings were either positive or equivocal, then scanning techniques were used. Most patients had solitary lesions (20). Thirteen of 25 lesions were synchronous; 12 were metachronous. Anatomic lobectomy was performed in 13 patients (6 extended resections); and wedge resection was performed in 12. The operative mortality rate was four per cent; the 2-year survival rate, 65%; the 5-year survival rate, 25%. Hypertonic dextrose solutions were administered during and after operation. Post-operative albumin requirements ranged from 200 to 300 grams/day. Coagulation factors II, V, VII, and fibrinogen decreased after surgery to 30 to 50% of their preoperative levels. Subsequent elevation of these factors correlated with increased bile production and improvement in liver chemistries 10 to 14 days after operation. At present, hepatic resection for colorectal metastases provides the only potential method of salvage, offering a 20 to 25% long-term survival rate.


Systematic identification and characterization of Aedes aegypti long noncoding RNAs (lncRNAs).
Long noncoding RNAs (lncRNAs) play diverse roles in biological processes. Aedes aegypti (Ae. aegypti), a blood-sucking mosquito, is the principal vector responsible for replication and transmission of arboviruses including dengue, Zika, and Chikungunya virus. Systematic identification and developmental characterisation of Ae. aegypti lncRNAs are still limited. We performed genome-wide identification of lncRNAs, followed by developmental profiling of lncRNA in Ae. aegypti. We identified a total of 4,689 novel lncRNA transcripts, of which 2,064, 2,076, and 549 were intergenic, intronic, and antisense respectively. Ae. aegypti lncRNAs share many characteristics with other species including low expression, low GC content, short in length, and low conservation. Besides, the expression of Ae. aegypti lncRNAs tend to be correlated with neighbouring and antisense protein-coding genes. A subset of lncRNAs shows evidence of maternal inheritance; hence, suggesting potential role of lncRNAs in early-stage embryos. Additionally, lncRNAs show higher tendency to be expressed in developmental and temporal specific manner. The results from this study provide foundation for future investigation on the function of Ae. aegypti lncRNAs.


Inferior Vena Cava Filter Malpractice Litigation: Damned if You Do, Damned if You Don't.
The aim of this study was to analyze malpractice litigation trends and to better understand the causes and outcomes of suits involving inferior vena cava filters (IVCF) to prevent future litigation and improve physician education. Jury verdict reviews from the Westlaw database from January 1, 2000, to December 31, 2015, were reviewed. The search term "inferior vena cava filter" was used to compile data on the demographics of the defendant, plaintiff, allegation, complication, and verdict. A total of 156 cases were identified. Duplicates and cases in which the IVCF was incidentally included were excluded from the analysis. Forty-nine cases involving either failure to place or a complication of IVCF placement were identified. Throughout the last 15 years, there has been increased number of jury verdicts toward IVCF. The most frequent defendants were internal medicine physicians (38%), vascular surgeons (19%), and cardiothoracic surgeons (12%). The most frequent claims were denied treatment or delay in treatment (in 35% of cases), negligent surgery (in 24% of cases), and failure to diagnose and treat complications (in 24% of cases). Of these, the most frequent specific claims were failure to place IVC filter (41%), implantation failure such as misplacement and/or misaligned implant (24%), erosion of IVC/retroperitoneal bleed (6%), and discontinuation of anticoagulation prematurely (6%). Seventeen cases (35%) were found for the plaintiff, with median awards worth of $1,092,500. In the 21 cases where pulmonary embolism (PE) was involved (43% of cases), 19 were fatal (90%). Of the fatal PE cases, 8 cases ended with verdicts in favor of the plaintiff (42%). Both nonfatal PE cases were won by the defense. IVCF placement with subsequent PE and death results in verdicts that favor the plaintiffs. This study emphasizes that adequate and transparent communication regarding preoperative planning, decision for IVCF placement, and informed consent may reduce the frequency of litigation. Public awareness of complications related to the placement of IVCF is increasing largely and spurned by aggressive advertising and marketing by plaintiff attorneys. Conditions for which IVCF placement is contemplated carry significant risk of malpractice litigation.


Adherence challenges in the management of type 1 diabetes in adolescents: prevention and intervention.
Despite the availability of effective therapies, adolescents with type 1 diabetes demonstrate poorer adherence to treatment regimens compared with other pediatric age groups. Nonadherence is tightly linked to suboptimal glycemic control, increasing morbidity, and risk for premature mortality. This article will review barriers to adherence and discuss interventions that have shown promise in improving outcomes for this population. Adolescents face numerous obstacles to adherence, including developmental behaviors, flux in family dynamics, and perceived social pressures, which compound the relative insulin resistance brought on by pubertal physiology. Some successful interventions have relied on encouraging nonjudgmental family support in the daily tasks of blood glucose monitoring and insulin administration. Other interventions overcome these barriers through the use of motivational interviewing and problem-solving techniques, flexibility in dietary recommendations, and extending provider outreach and support with technology. Effective interventions build on teens' internal and external supports (family, technology, and internal motivation) in order to simplify their management of diabetes and provide opportunities for the teens to share the burdens of care. Although such strategies help to minimize the demands placed upon teens with diabetes, suboptimal glycemic control will likely persist for the majority of adolescents until technological breakthroughs allow for automated insulin delivery in closed loop systems.


Examining Factors that Influence the Existence of Heinrich's Safety Triangle Using Site-Specific H&S Data from More than 25,000 Establishments.
In the 1930s, Heinrich established one of the most prominent and enduring accident prevention theories when he concluded that high severity occupational safety and health (OSH) incidents are preceded by numerous lower severity incidents and near misses. Seventy-five years of theory expansion/interpretation includes two fundamental tenets: (1) the ratio of lower to higher severity incidents exists in the form of a "safety-triangle" and (2) similar causes underlie both high and low severity events. Although used extensively to inform public policy and establishment-level health and safety priorities, recent research challenges the validity of the two tenets. This study explored the validity of the first tenet, the existence of the safety triangle. The advantage of the current study is the use of a detailed, establishment-specific data set that evaluated over 25,000 establishments over a 13-year time period, allowing three specific questions to be explored: (1) Are an increased number of lower severity incidents at an establishment significantly associated with the probability of a fatal event over time? (2) At the establishment level, do the effects of OSH incidents on the probability of a fatality over time decrease as the degree of severity decreases-thereby taking the form of a triangle? and (3) Do distinct methods for delineating incidents by severity affect the existence of the safety triangle form? The answer to all three questions was yes with the triangle form being dependent upon how severity was delineated. The implications of these findings in regard to Heinrich's theory and OSH policy and management are discussed.


Exposure to Acute and Chronic Fluoxetine has Differential Effects on Sociability and Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus of Juvenile Male BALB/c Mice.
Although the neurobiological mechanisms underlying autism spectrum disorder (ASD) are still unknown, dysregulation of serotonergic systems has been implicated in the etiology of ASD, and serotonergic antidepressant drugs are often prescribed to treat some symptoms of ASD. The BALB/c strain of mice express a dysregulated serotonergic system and a phenotype that is relevant to ASD. In this study, juvenile male BALB/c mice were exposed to the selective serotonin reuptake inhibitor fluoxetine either chronically (18 mg/kg/day in drinking water, post-natal day (PND) 28-39) or acutely (18 mg/kg, i.p.; PND40), or to vehicle control conditions (0.9% sterile saline, i.p.; PND40), prior to being exposed to the three-chambered sociability test (SAT; PND40). One cohort of mice then received an injection of the aromatic amino acid decarboxylase inhibitor, NSD-1015, and one hour later brain tissue was collected for quantification of 5-hydroxytryptophan accumulation in the dorsal raphe nucleus (DR) as a measure of TPH2 activity. For the second cohort, brain tissue was collected ninety minutes after the onset of the social phase of the SAT and prepared for immunohistochemical staining for c-Fos and TPH2 to measure the activation of serotonergic neurons within subregions of the DR. Acute fluoxetine decreased social behavior, while chronic fluoxetine increased social behavior compared with vehicle-treated controls. Furthermore, acute and chronic fluoxetine treatments were without effect on TPH2 activity but differentially affected populations of serotonergic neurons in the DR. These data are consistent with the hypothesis that serotonergic systems are implicated in social behavior that is relevant for ASD.


High-power tunable low-noise coherent source at 1.06 μm based on a surface-emitting semiconductor laser.
Exploiting III-V semiconductor technologies, vertical external-cavity surface-emitting laser (VECSEL) technology has been identified for years as a good candidate to develop lasers with high power, large coherence, and broad tunability. Combined with fiber amplification technology, tunable single-frequency lasers can be flexibly boosted to a power level of several tens of watts. Here, we demonstrate a high-power, single-frequency, and broadly tunable laser based on VECSEL technology. This device emits in the near-infrared around 1.06 µm and exhibits high output power (>100 mW) with a low-divergence diffraction-limited TEM00 beam. It also features a narrow free-running linewidth of <400 kHz with high spectral purity (side mode suppression ratio >55 dB) and continuous broadband tunability greater than 250 GHz (<15 V piezo voltage, 6 kHz cutoff frequency) with a total tunable range up to 3 THz. In addition, a compact design without any movable intracavity elements offers a robust single-frequency regime. Through fiber amplification, a tunable single-frequency laser is achieved at an output power of 50 W covering the wavelength range from 1057 to 1066 nm. Excess intensity noise brought on by the amplification stage is in good agreement with a theoretical model. A low relative intensity noise value of -145 dBc/Hz is obtained at 1 MHz, and we reach the shot-noise limit above 200 MHz.


Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications.
Focal cerebral ischaemia and post-ischaemic reperfusion cause cerebral capillary dysfunction, resulting in oedema formation and haemorrhagic conversion. There are substantial gaps in understanding the pathophysiology, especially regarding early molecular participants. Here, we review physiological and molecular mechanisms involved. We reaffirm the central role of Starling's principle, which states that oedema formation is determined by the driving force and the capillary "permeability pore". We emphasise that the movement of fluids is largely driven without new expenditure of energy by the ischaemic brain. We organise the progressive changes in osmotic and hydrostatic conductivity of abnormal capillaries into three phases: formation of ionic oedema, formation of vasogenic oedema, and catastrophic failure with haemorrhagic conversion. We suggest a new theory suggesting that ischaemia-induced capillary dysfunction can be attributed to de novo synthesis of a specific ensemble of proteins that determine osmotic and hydraulic conductivity in Starling's equation, and whose expression is driven by a distinct transcriptional program.


Minimal effect on energy intake by additional evening meal for frail elderly service flat residents--a pilot study.
Nutritional problems are common in frail elderly individuals receiving municipal care. To evaluate if an additional evening meal could improve total daily food intake, nutritional status, and health-related quality of life (HRQOL) in frail elderly service flat (SF) residents. Out of 122 residents in two SF complexes, 60 subjects agreed to participate, of which 49 subjects (median 84 (79-90) years, (25th-75th percentile)) completed the study. For six months 23 residents in one SF complex were served 530 kcal in addition to their regular meals, i.e. intervention group (I-group). Twenty-six residents in the other SF building were controls (C-group). Nutritional status, energy and nutrient intake, length of night time fast, cognitive function and HRQOL was assessed before and after the intervention. At the start, the Mini Nutritional Assessment classified 27% as malnourished and 63% as at risk for malnutrition, with no difference between the groups. After six months the median body weight was unchanged in the I-group, +0.6 (-1.7-+1.6) kg (p=0.72) and the C-group -0.6 (-2.0-+0.5) kg (p=0.15). Weight change ranged from -13% to +15%. The evening meal improved the protein and carbohydrate intake (p<0.01) but the energy intake increased by only 180 kcal/day (p=0.15). The night time fast decreased in the I-group from 15.0 (13.0-16.0) to 13.0 (12.0-14.0) hours (p<0.05). There was no significant difference in cognitive function or HRQOL between the groups. Nine out of ten frail elderly SF residents had nutritional problems. Serving an additional evening meal increased the protein and carbohydrate intake, but the meal had no significant effect on energy intake, body weight or HRQOL. The variation in outcome within each study group was large.


A patch-graft technique for correction of pulmonic stenosis in dogs.
Pulmonic stenosis in 6 dogs were corrected surgically by means of a patch-graft technique, without using cardiac bypass or venous occlusion. Five of the 6 dogs have remained clinically normal for 4 to 40 months following surgery. The stenosis in 1 dog was inadequately repaired. The technique resulted in minimal blood loss, no mortality, and was easily adapted to the minimal size of several of the affected dogs. When performed correctly, the technique relieved the stenosis wherever it occurred (viz, supravalvular, valvular, subvalvular, infundibular, or any combination). The success of the procedure was determined, in part, by pre- and postoperative pressure measurements at the time of surgery, and by periodic physical, radiographic, and electrocardiographic examinations after surgery.


Application of the privacy principles to general practice.
There are escalating requirements for general practitioners to comply with recognised privacy principles. With amendments to the Commonwealth Privacy Act (1988) imminent, there is an urgent need to formulate methods for applying these principles to general practice. The article provides an explanation of the origins of the privacy principles and a simple self audit which general practitioners can use to assess the extent to which their usual practices conform with them. A careful review of the principles indicates that new measures will be needed before most general practices will be able to approach required standards of conduct. Practical strategies for achieving best practice are discussed and challenges confronting general practices in applying the principles are canvassed. Ethics committees should be used more often to provide independent review of practice policies and proposals to use patient information in new ways. General practitioners can expect increasing scrutiny and debate concerning confidentiality. In order to maintain patient trust in GPs as responsible data custodians, the privacy principles can be seen as a quality improvement tool.


Biotransformation of American Ginseng Stems and Leaves by an Endophytic Fungus Umbelopsis sp. and Its Effect on Alzheimer's Disease Control.
Common ginsenosides can be transformed into rare ginsenosides through microbial fermentation, and some rare ginsenosides can prevent Alzheimer's disease (AD). This study aimed to transform common ginsenosides into rare ginsenosides through solid-state fermentation of American ginseng stems and leaves (AGSL) by an endophytic fungus and to explore whether fermented saponin extracts prevent AD. The powders of AGSL were fermented in a solid state by endophytic fungus. Total saponins were extracted from fermentation products using the methanol extraction method. The types of saponins were analyzed by liquid chromatography mass spectrometry (LC/MS). The Aβ42 concentration and β-secretase activity were measured by ELISA for the prevention of AD. After AGSL was fermented by an endophytic fungus NSJG, the total saponin concentration of the fermented extract G-SL was higher than the unfermented CK-SL. Rare ginsenoside Rh1 was newly produced and the yield of compound K (561.79%), Rh2 (77.48%), and F2 (40.89%) was increased in G-SL. G-SL had a higher inhibition rate on Aβ42 concentration (42.75%) and β-secretase activity (42.22%) than CK-SL, possibly because the rare ginsenoside Rh1, Rh2, F2, and compound K included in it have a strong inhibitory effect on AD. The fermented saponin extracts of AGSL show more inhibition effects on AD and may be promising therapeutic drugs or nutrients for AD.


Evaluation of the stable fly (Stomoxys calcitrans) as a vector of enzootic bovine leukosis.
Experiments reported here were directed at 2 questions: (1) Can the stable fly (Stomoxys calcitrans) transmit enzootic bovine leukosis? (2) Could early viremia augment the probability of transmission by this insect? In one vector experiment, calves and bovine leukemia virus (BLV)-infected cows were housed with and without stable flies. The calves were monitored serologically during a 3-month postexposure period, using the agar gel immunodiffusion test. All fly-infested and fly-free calves remained BLV-seronegative. For a second vector experiment, donor calves, newly injected with blood from BLV-infected cows with high virus expression, were tethered alternately between uninoculated, weaned BLV-seronegative calves. These groups were housed with or without flies in 2 replicate trials. The inoculated calves from the first replicate seroconverted at 16 and 23 days after inoculation; the inoculated calves from the second replicate seroconverted at 11, 16, 16, and 37 days after inoculation. All uninoculated calves remained BLV-seronegative. In a manual transmission experiment, 50 unfed stable flies were allowed to complete a meal on each of 3 BLV-seronegative calves after feeding on a BLV-seropositive cow with high (42%) virus expression. One control calf was injected with blood from the cow. Seroconversion occurred in the control calf and 1 calf on which flies were given access. A scanning electron microscopic study was made of the everted and closed mouth parts of the stable fly. Given the lymphocyte count in blood from the cow used in the manual vector transmission experiment, it was calculated that 3,950 mouth part volumes would be necessary to transmit BLV.(ABSTRACT TRUNCATED AT 250 WORDS)


Genetic liability for schizophrenia predicts risk of immune disorders.
Schizophrenia patients and their parents have an increased risk of immune disorders compared to population controls and their parents. This may be explained by genetic overlap in the pathogenesis of both types of disorders. The purpose of this study was to investigate the genetic overlap between schizophrenia and three immune disorders and to compare with the overlap between schizophrenia and two disorders not primarily characterized by immune dysregulation: bipolar disorder and type 2 diabetes. We performed a polygenic risk score analysis using results from the schizophrenia Psychiatric GWAS consortium (PGC) (8922 cases and 9528 controls) and five Wellcome Trust Case Control Consortium (WTCCC) case samples as target cases: bipolar disorder (n=1998), type 1 diabetes (n=2000), Crohn's diseases (n=2005), rheumatoid arthritis (n=1999), and type 2 diabetes (n=1999). The WTCCC British Birth Cohort and National Blood Service samples (n=3004) were used as target controls. Additionally, we tested whether schizophrenia polygenic risk scores significantly differed between patients with immune disorder, bipolar disorder, and type 2 diabetes respectively. Polygenic risk scores for schizophrenia significantly predicted disease status in all three immune disorder samples (Nagelkerke-R(2) 1.1%-1.3%; p<0.05). The polygenic risk of schizophrenia in patients with immune disorders was significantly lower than in patients with bipolar disorder (Nagelkerke-R(2) 6.0%; p<0.05), but higher than in type 2 diabetes patients (Nagelkerke-R(2) 0.5%; p<0.05). Our results suggest that genetic factors are shared between schizophrenia and immune disorders. This contributes to an accumulating body of evidence that immune processes may play a role in the etiology of schizophrenia.


Child Sexual Abuse and Situational Context: Children's Experiences in Post-Conflict Northern Uganda.
Although substantial literature exists on child sexual abuse (CSA), little is known about abuses children encounter in northern Uganda, a post-conflict area. Media reports have indicated a high incidence for CSA. The study, firstly, explored boys' and girls' experiences of sexual abuse by adults in this post-conflict region and secondly, interventions directed at improving the current situation of children at risk of child abuse and the survivors were investigated as well. The study was guided by radical feminism and nested ecological framework theories. Semi-structured interviews were conducted involving 43 sexually abused children. Narrative responses were audio recorded and transcribed. Content qualitative analysis was used to understand sexual offenses from children's perspectives. Participants mentioned the following as the most perilous situations; laxity in parental roles, cultural norms, and practices, patriarchal attitudes, child sexual desires and attitudes, family breakdown and alcoholism. The study found many reported cases of CSA in the region. The results imply the exigent need of separate units specifically for reporting and handling child sexual offenses, need for personnel training on gender issues and filing system in child protection agencies and family programs for both fathers and mothers on child protection strategies for prevention and mitigation of CSA.


Diagnostic and prognostic value of plasma brain natriuretic peptide in non-dialysis-dependent CRF.
Brain natriuretic peptide (BNP) is useful for the evaluation of ventricular dysfunction in patients with various cardiac diseases. However, its diagnostic value has been considered to be limited in patients with chronic renal failure (CRF) because renal dysfunction itself may affect BNP levels. This study is designed to clarify the diagnostic and prognostic value of plasma BNP level in patients with CRF. In 103 non-dialysis-dependent patients with CRF without heart failure and 60 hypertensive patients with normal renal function, echocardiographic examinations and BNP measurements were performed. Plasma BNP level was much greater in patients with CRF than in hypertensive controls; however, multiple regression analysis showed that left ventricular (LV) end-diastolic volume (EDV) index (LVEDVI) and the difference in mitral and pulmonary venous atrial wave duration (Ad-PVad), a marker of LV end-diastolic pressure, were independent determinants of plasma BNP levels in patients with CRF. The influence of LV overload (LVEDVI > or = 75 mL/m 2 and/or Ad-PVad < 0 milliseconds) on plasma BNP levels in subjects with CRF was independent of the severity of renal dysfunction. From Kaplan-Meier event-free curves (mean follow-up, 13 months), the incidence of heart failure was much greater in patients with a plasma BNP level of 150 pg/mL or greater ( P < 0.001). By means of multivariate Cox regression analysis, high plasma BNP level was the strongest predictor for heart failure events (hazard ratio, 6.31; P < 0.001). These findings support plasma BNP level as a reliable marker of LV overload, even in nondialysis patients with CRF. Also, a high BNP level (> or =150 pg/mL) may have powerful predictive potential for heart failure in these patients.


Depletion of oxidative and endoplasmic reticulum stress regulators in Pick disease.
Both oxidative and endoplasmic reticulum (ER) stress is associated with multiple neurodegenerative, age-related diseases. The rare disorder Pick disease (PiD) shares some pathological hallmarks of other neurodegenerative diseases that may be related to oxidative stress. Importantly, activation of an ER stress response, which is also involved in aging, has not yet been investigated in PiD. In this study, we assessed the implication of ER stress associated with oxidative stress in PiD as a potential mechanism involved in its pathogenesis. Samples from morphologically affected frontal cortex and apparently pathologically preserved occipital cortex showed region-dependent increases in different protein oxidative damage pathways. The oxidative modifications targeted antioxidant enzymes, proteases, heat shock proteins, and synaptic proteins. These effects were associated with compromised proteasomal function and ER stress in frontal cortex samples. In addition, we observed a depletion in ER chaperones (glucose-regulated proteins Grp78/BiP and glucose-regulated protein 94) and differences in tissue content and distribution of nuclear factor-erythroid 2 p45-related respiratory 2, required for cell survival during the unfolded protein response. These results demonstrate increased region-specific protein oxidative damage in PiD, with proteasomal alteration and dysfunctional ER stress response. We suggest this was caused by complete and specific depletion of Grp78/BiP, contributing to the pathophysiology of this neurodegenerative disease.


Investigating the Mechanical Properties of ZrO2-Impregnated PMMA Nanocomposite for Denture-Based Applications.
Acrylic resin PMMA (poly-methyl methacrylate) is used in the manufacture of denture bases but its mechanical properties can be deficient in this role. This study investigated the mechanical properties (flexural strength, fracture toughness, impact strength, and hardness) and fracture behavior of a commercial, high impact (HI), heat-cured denture base acrylic resin impregnated with different concentrations of yttria-stabilized zirconia (ZrO2) nanoparticles. Six groups were prepared having different wt% concentrations of ZrO2 nanoparticles: 0% (control), 1.5%, 3%, 5%, 7%, and 10%, respectively. Flexural strength and flexural modulus were measured using a three-point bending test and surface hardness was evaluated using the Vickers hardness test. Fracture toughness and impact strength were evaluated using a single edge bending test and Charpy impact instrument. The fractured surfaces of impact test specimens were also observed using a scanning electron microscope (SEM). Statistical analyses were conducted on the data obtained from the experiments. The mean flexural strength of ZrO2/PMMA nanocomposites (84 ± 6 MPa) at 3 wt% zirconia was significantly greater than that of the control group (72 ± 9 MPa) (p < 0.05). The mean flexural modulus was also significantly improved with different concentrations of zirconia when compared to the control group, with 5 wt% zirconia demonstrating the largest (23%) improvement. The mean fracture toughness increased in the group containing 5 wt% zirconia compared to the control group, but it was not significant. However, the median impact strength for all groups containing zirconia generally decreased when compared to the control group. Vickers hardness (HV) values significantly increased with an increase in ZrO2 content, with the highest values obtained at 10 wt%, at 0 day (22.9 HV0.05) in dry conditions when compared to the values obtained after immersing the specimens for seven days (18.4 HV0.05) and 45 days (16.3 HV0.05) in distilled water. Incorporation of ZrO2 nanoparticles into high impact PMMA resin significantly improved flexural strength, flexural modulus, fracture toughness and surface hardness, with an optimum concentration of 3-5 wt% zirconia. However, the impact strength of the nanocomposites decreased, apart from the 5 wt% zirconia group.


Equilibrium binding of spin-labeled fatty acids to bovine serum albumin: suitability as surrogate ligands for natural fatty acids.
Electron paramagnetic resonance (EPR) and saturation transfer EPR (ST-EPR) spectroscopies were used to characterize the binding of spin-labeled fatty acid (SLFA) to bovine serum albumin (BSA). Association constants of three stearic acid derivatives labeled with a nitroxyl radical at C-5, C-12, or C-16 were estimated by EPR spectroscopy as the ratio of SLFA to BSA was increased from about 0 to 9. The values were compared to those for unmodified stearate. With all three SLFA, it was apparent that the nitroxyl residue modified the binding pattern. For SLFA:BSA ratios up to 1, which probably involves the site(s) on BSA most specific for long-chain FA, the C-16 derivative bound with an affinity similar to that of the natural FA. At higher ratios, the association constants for this SLFA were lower than those for stearate. The C-12 and C-5 derivatives showed only low-affinity binding relative to stearate. The spectral parameter, W, was constant for SLFA:BSA ratios between 0 and 1 in the case of C-16 compound, indicating physical homogeneity of the high-affinity binding site. At higher ratios, the spectra changed progressively, indicating inhomogeneity of the lower affinity binding sites although parallel changes in association constants were not observed. Changes in W due to Heisenberg spin exchange were ruled out. By examining the mobility profile of the bound SLFA by both EPR and ST-EPR techniques, it was shown that the nitroxyl group was maximally immobilized when attached near the center of the carbon chain of the bound SLFA.


Transphyseal reconstruction of the anterior cruciate ligament in prepubescent children.
We present the results of 17 children of Tanner stage 1 or 2 who underwent reconstruction of the anterior cruciate ligament between 1999 and 2006 using a transphyseal procedure, employing an ipsilateral four-strand hamstring graft. The mean age of the children was 12.1 years (9.5 to 14). The mean follow-up was 44 months (25 to 100). Survival of the graft, the functional outcome and complications were recorded. There was one re-rupture following another injury. Of the remaining patients, all had good or excellent results and a normal International Knee Documentation Committee score. The mean post-operative Lysholm score was 97.5 (SD 2.6) and the mean Tegner activity scale was 7.9 (SD 1.4). One patient had a mild valgus deformity which caused no functional disturbance. No other abnormality or discrepancy of leg length was seen. Measurements with a KT1000 arthrometer showed no significant difference between the normal and the operated legs. In this small series, transphyseal reconstruction of the anterior cruciate ligament appeared to be safe in these young children.


Toward a Three-Dimensional Chromosome Shape Alphabet.
The study of the three-dimensional (3D) structure of chromosomes-the largest macromolecules in biology-is one of the most challenging to date in structural biology. Here, we develop a novel representation of 3D chromosome structures, as sequences of shape letters from a finite shape alphabet, which provides a compact and efficient way to analyze ensembles of chromosome shape data, akin to the analysis of texts in a language by using letters. We construct a Chromosome Shape Alphabet from an ensemble of chromosome 3D structures inferred from Hi-C data-via SIMBA3D or other methods-by segmenting curves based on topologically associating domains (TADs) boundaries, and by clustering all TADs' 3D structures into groups of similar shapes. The median shapes of these groups, with some pruning and processing, form the Chromosome Shape Letters (CSLs) of the alphabet. We provide a proof of concept for these CSLs by reconstructing independent test curves by using only CSLs (and corresponding transformations) and comparing these reconstructions with the original curves. Finally, we demonstrate how CSLs can be used to summarize shapes in an ensemble of chromosome 3D structures by using generalized sequence logos.


Effect of high FFA on glycogenolysis in oxidative rat hindlimb muscles during twitch stimulation.
The effect of elevated free fatty acids (FFA) on carbohydrate (CHO) utilization in the oxidative muscles of the isolated hindlimb was determined using twitch contraction paradigms evoking a wide range of O2 uptakes and glycogenolysis. The hindlimb was perfused with either 0 or 1.8 mM FFA for 10 min at rest and then subjected to 20 min of stimulation at 0.4, 0.7, 1, 2, 3, or 4 Hz. Soleus (Sol), plantaris (Pl), and red gastrocnemius (RG) were sampled after rest perfusion or stimulation. FFA had little effect on glycogenolysis during stimulation, although glycogen sparing occurred with one of the lesser intensity protocols in each muscle (Sol, 0.4 Hz; RG, 0.7 Hz; Pl, 1 Hz). Muscle citrate and acetyl-CoA were elevated in Sol during several stimulation protocols with high FFA, but this effect was inconsistent in Pl and RG. The sparing of glycogen, when it did occur, was generally unrelated to increases in either citrate or acetyl-CoA content. Furthermore, protocols in which citrate or acetyl-CoA were elevated in the presence of elevated FFA did not demonstrate glycogen sparing. Hindlimb lactate efflux at rest was reduced with FFA but unaffected during stimulation. Glucose uptake was unaffected by FFA at rest and during stimulation protocols, except 3 Hz. The present study does not support the classically proposed roles of citrate and acetyl-CoA in the FFA-induced downregulation of CHO utilization in electrically stimulated rat skeletal muscle.


GC-MS fingerprints for discrimination of Ligusticum chuanxiong from Angelica.
A GC-MS fingerprinting technique based on the essential oil components has been developed for the discrimination of chuanxiong against Chinese Angelica (Angelica sinensis (Oliv.) Diels) or other herbs with similar compositions. The analytical performance of four different extraction methods for the separation of essential oil components have been compared and these include: ultrasound-assisted extraction (UAE), supercritical fluid extraction (SFE), Soxhlet extraction (SHE) and hydro-distillation extraction (HDE). The results showed that UAE was the most effective extraction method, and the operational parameters of UAE were optimized. 3-Butylphthalide, Z-butylidenephthalide, senkyunolide I, senkyunolide H, E-butylidenephthalide, senkyunolide A, neocnidilide, Z-ligustilide and E-ligustilide were tentatively identified in chromatograms of chuanxiong based on their GC-EI-MS data. Similarity coefficient calculations based on correlation methods have been performed on the GC-MS fingerprints. Using an authentic standard Chuanxiong as the reference, the similarity coefficients between the standard and all other chuanxiong samples ranged from 0.90 to 1.0 (with 1.0 being the perfect match), which as a group can be readily separated from the Angelica samples for which the similarity index against the chuanxiong standard ranged from 0.75 to 0.77. Conversely, when an authentic Angelica standard was used as the reference, the respective similarity coefficients fall in the range of 0.70-0.75 and 0.98-1.00 for the chuanxiong and Angelica sample groups. Our results thus demonstrate that the fingerprinting technique developed in the study can indeed discriminate the two herbs with high reliability.


Patient and physician perspectives vary on atopic dermatitis.
We compared the written responses of physicians (n=303) and patients (n=961) from a nationwide US survey concerning atopic dermatitis (AD). Physicians, primarily dermatologists, responded to 32 questions, and patients responded to 44 questions about AD and its management. Most physicians and patients were in agreement regarding disease severity, the relative lack of effectiveness of over-the-counter products, concerns about drug adverse effects, and the need for more patient support groups. However, physicians were more concerned about long-term adverse effects than were patients. Additionally, 91% of physicians versus 46% of patients rated prescription medications as "moderately" or "very" effective. Patients were generally pleased with their overall AD-related medical care: 42% were "a lot" or "very" satisfied, while only 8% were dissatisfied. Although physician and patient perceptions sometimes differed, both groups preferred treatments offering greater effectiveness, fewer adverse effects, and greater applicability to the pediatric population.


Functional profiling of circulating tumor cells with an integrated vortex capture and single-cell protease activity assay.
Tumor cells are hypothesized to use proteolytic enzymes to facilitate invasion. Whether circulating tumor cells (CTCs) secrete these enzymes to aid metastasis is unknown. A quantitative and high-throughput approach to assay CTC secretion is needed to address this question. We developed an integrated microfluidic system that concentrates rare cancer cells >100,000-fold from 1 mL of whole blood into ∼50,000 2-nL drops composed of assay reagents within 15 min. The system isolates CTCs by size, exchanges fluid around CTCs to remove contaminants, introduces a matrix metalloprotease (MMP) substrate, and encapsulates CTCs into microdroplets. We found CTCs from prostate cancer patients possessed above baseline levels of MMP activity (1.7- to 200-fold). Activity of CTCs was generally higher than leukocytes from the same patient (average CTC/leukocyte MMP activity ratio, 2.6 ± 1.5). Higher MMP activity of CTCs suggests active proteolytic processes that may facilitate invasion or immune evasion and be relevant phenotypic biomarkers enabling companion diagnostics for anti-MMP therapies.


Dietary intake of flavonoids and asthma in adults.
Epidemiological studies have suggested that a high consumption of apples may protect against asthma and chronic obstructive pulmonary disease. This effect has been attributed to their high flavonoid content, but few studies have investigated the relationship between flavonoid intake and obstructive lung disease directly. In a population-based, case-control study of 1,471 adults aged 16-50 yrs in London (UK), the present study examined whether dietary intake of catechins, flavonols and flavones was negatively associated with asthma, asthma severity and chronic sputum production. Asthma was defined by positive responses to a standard screening questionnaire in 1996 and information about usual diet was obtained by a food frequency questionnaire in 1997. After controlling for potential confounders, dietary intake of these three flavonoid subclasses was not significantly associated with asthma, (odds ratio per quintile (95% confidence interval) = 0.94 (0.86-1.02); 1.00 (0.92-1.09); 0.98 (0.88 -1.08) for flavones, flavonols and total catechins, respectively) nor was it associated with asthma severity, or chronic sputum production. In conclusion, no evidence was found for a protective effect of three major subclasses of dietary flavonoids on asthma. It is possible that other flavonoids or polyphenols present in apples may explain the protective effect of apples on obstructive lung disease.


Mutualist-Provisioned Resources Impact Vector Competency.
Many symbionts supplement their host's diet with essential nutrients. However, whether these nutrients also enhance parasitism is unknown. In this study, we investigated whether folate (vitamin B9) production by the tsetse fly (Glossina spp.) essential mutualist, Wigglesworthia, aids auxotrophic African trypanosomes in completing their life cycle within this obligate vector. We show that the expression of Wigglesworthia folate biosynthesis genes changes with the progression of trypanosome infection within tsetse. The disruption of Wigglesworthia folate production caused a reduction in the percentage of flies that housed midgut (MG) trypanosome infections. However, decreased folate did not prevent MG trypanosomes from migrating to and establishing an infection in the fly's salivary glands, thus suggesting that nutrient requirements vary throughout the trypanosome life cycle. We further substantiated that trypanosomes rely on symbiont-generated folate by feeding this vitamin to Glossina brevipalpis, which exhibits low trypanosome vector competency and houses Wigglesworthia incapable of producing folate. Folate-supplemented G. brevipalpis flies were significantly more susceptible to trypanosome infection, further demonstrating that this vitamin facilitates parasite infection establishment. Our cumulative results provide evidence that Wigglesworthia provides a key metabolite (folate) that is "hijacked" by trypanosomes to enhance their infectivity, thus indirectly impacting tsetse species vector competency. Parasite dependence on symbiont-derived micronutrients, which likely also occurs in other arthropod vectors, represents a relationship that may be exploited to reduce disease transmission.IMPORTANCE Parasites elicit several physiological changes in their host to enhance transmission. Little is known about the functional association between parasitism and microbiota-provisioned resources typically dedicated to animal hosts and how these goods may be rerouted to optimize parasite development. This study is the first to identify a specific symbiont-generated metabolite that impacts insect vector competence by facilitating parasite establishment and, thus, eventual transmission. Specifically, we demonstrate that the tsetse fly obligate mutualist Wigglesworthia provisions folate (vitamin B9) that pathogenic African trypanosomes exploit in an effort to successfully establish an infection in the vector's MG. This process is essential for the parasite to complete its life cycle and be transmitted to a new vertebrate host. Disrupting metabolic contributions provided by the microbiota of arthropod disease vectors may fuel future innovative control strategies while also offering minimal nontarget effects.


Molecular genetic and biochemical characterization of the vaccinia virus I3 protein, the replicative single-stranded DNA binding protein.
Vaccinia virus, the prototypic poxvirus, efficiently and faithfully replicates its ∼200-kb DNA genome within the cytoplasm of infected cells. This intracellular localization dictates that vaccinia virus encodes most, if not all, of its own DNA replication machinery. Included in the repertoire of viral replication proteins is the I3 protein, which binds to single-stranded DNA (ssDNA) with great specificity and stability and has been presumed to be the replicative ssDNA binding protein (SSB). We substantiate here that I3 colocalizes with bromodeoxyuridine (BrdU)-labeled nascent viral genomes and that these genomes accumulate in cytoplasmic factories that are delimited by membranes derived from the endoplasmic reticulum. Moreover, we report on a structure/function analysis of I3 involving the isolation and characterization of 10 clustered charge-to-alanine mutants. These mutants were analyzed for their biochemical properties (self-interaction and DNA binding) and biological competence. Three of the mutant proteins, encoded by the I3 alleles I3-4, -5, and -7, were deficient in self-interaction and unable to support virus viability, strongly suggesting that the multimerization of I3 is biologically significant. Mutant I3-5 was also deficient in DNA binding. Additionally, we demonstrate that small interfering RNA (siRNA)-mediated depletion of I3 causes a significant decrease in the accumulation of progeny genomes and that this reduction diminishes the yield of infectious virus.


Utility of DXA screening for diagnosis of osteoporosis in US veterans aged 70 years and older.
Dual energy X-ray absorptiometry (DXA) is recommended for osteoporosis screening in men aged 70 years and older but supportive data is limited. The aim of this study was to determine the efficacy of DXA for the diagnosis of increased fragility in this group of subjects. We retrospectively identified men aged 70 years and older without prior history of fracture and/or conditions predisposing to low bone mineral density (BMD) who attended the VA endocrinology clinic and performed DXA for osteoporosis screening. We analyzed the relationship between BMD and demographic, anthropometric data and biochemical parameters using linear regression models. Out of 55 subjects identified, 13 (24%) men had normal BMD, 30 (54%) had osteopenia and 12 (22%) had a diagnosis of osteoporosis based on the femoral neck (FN) T-score. Lumbar spine T-scores were normal in all three groups. Weight and body mass index (BMI) were significantly higher in the normal BMD group compared with the osteopenia and osteoporosis groups (p<0.001). After adjustments for age, weight, BMI, vitamin D concentrations, and diabetes status, differences in the FN BMD among the groups remained significant (p<0.001). Based on the Fracture Risk Assessment Tool (FRAX) score calculations in 43 non-osteoporotic patients, 15 patients with osteopenia had a 10-year hip fracture probability ≥3%. Screening with DXA in male US veterans aged 70 years and older without known osteoporosis risk factors revealed that up to 50% of men may qualify for diagnostic workup to determine the etiology of low BMD and/or to meet criteria to initiate pharmacological therapy to reduce future fracture risk.


Decreased neuronal inhibition in vitro after long-term administration of ethanol.
The pathophysiology of brain dysfunction was studied with an animal model of chronic alcoholism. Rats were fed a liquid diet with or without ethanol for 20 weeks and then the diet without ethanol for three more weeks. Hippocampal slices were prepared and intracellular recordings were obtained from dentate granule and CA1 cells. Significant depression of orthodromically elicited inhibitory postsynaptic potentials and postspike afterhyperpolarizations was observed in neurons from ethanol-exposed animals. No differences were observed in other active or passive membrane characteristics. These results suggest that a loss of neuronal inhibition could contribute to brain dysfunction in chronic alcoholism.


Prostaglandin E2 reduces swine myocardial ischemia reperfusion injury via increased endothelial nitric oxide synthase and vascular endothelial growth factor expression levels.
Prostaglandin E2 (PGE2) has been demonstrated to attenuate cardiac ischemia-reperfusion (I/R) injury. However, the underlying mechanism of PGE2 in cardiac I/R injury remains unknown. Upregulated expression levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were reported in acute myocardial infarction (AMI), and were demonstrated to diminish I/R injury. In the current study the involvement of VEGF and eNOS in the myocardial protective effect of PGE2 were investigated in a catheter-based porcine model of AMI. Twenty-two Chinese miniature pigs were randomized into sham-surgery (n=6), control (n=8) and PGE2 (n=8) groups. PGE2 (1 µg/kg) was injected from 10 min prior to left anterior descending occlusion up to 1 h after reperfusion in the PGE2 group. Subsequently, the hemodynamic parameters were evaluated. Thioflavin-S and Evans Blue double staining were performed to evaluate the extent of the myocardial reperfusion area (RA) and no-reflow area (NRA). Immunohistochemical and western blot analysis were used to evaluate protein expression levels of VEGF and eNOS. Left ventricular (LV) systolic pressure significantly improved and LV end-diastolic pressure significantly decreased in the PGE2 group when compared with the control group 2 h after occlusion and 3 h after reperfusion (P<0.05, respectively). The RA and NRA were smaller in the PGE2 group than in the control group (P<0.05, respectively). Furthermore, PGE2 treatment increased the myocardial content of VEGF and eNOS when compared with the control group (P<0.05, respectively). Thus, the results of the present study demonstrate the cardio-protective mechanisms of PGE2, which may protect the heart from I/R injury via enhancement of VEGF and eNOS expression levels.


Selective Antibacterial Activity and Lipid Membrane Interactions of Arginine-Rich Amphiphilic Peptides.
The self-assembly behavior and antimicrobial activity of two designed amphiphilic peptides, R3F3 and R4F4, containing short hydrophobic phenylalanine (F) and cationic arginine (R) sequences, are investigated. The conformation of the peptides was examined using circular dichroism and FTIR spectroscopy, which show that they have a disordered secondary structure. Concentration-dependent fluorescence assays show the presence of a critical aggregation concentration (cac) for each peptide. Above the cac, small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) reveal a population of twisted tapes for R3F3 and nanosheets for R4F4. The interaction of the peptides with model bacterial membranes comprising mixtures of the lipids DPPG [1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol] and DPPE [1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine], was studied using SAXS and cryogenic-TEM. Analysis of the SAXS structure factor indicates that R3F3 interacts with lipid bilayers by inducing correlation between bilayers, whereas R4F4 interacts with the bilayers causing an increase in polydispersity of the vesicle wall thickness. Both peptides break vesicles with a 1:3 DPPG:DPPE composition, which is close to the ratio of PG and PE lipids observed in the lipid membrane of Pseudomonas aeruginosa, a pathogen responsible for serious infections and which has developed antimicrobial resistant strains. Both peptides show activity against this bacterium in planktonic form. Peptide R4F4 shows particularly strong bioactivity against this microbe, with a minimum inhibitory concentration (MIC) value in the range of concentrations where the peptide is cytocompatible. It was further shown to have activity against other Pseudomonas species including the common plant pathogen Pseudomonas syringae. Finally, we show that R4F4 inhibits the development of P. aeruginosa biofilms. This was examined in detail and a proposed mechanism involving binding of the signaling molecule c-di-GMP is suggested, based on circular dichroism spectroscopy studies and Congo red assays of extracellular polysaccharides produced by the stressed bacteria. Thus, R4F4 is a promising candidate antimicrobial peptide with activity against Pseudomonas species.


Evaluating the effects between metal mixtures and serum vaccine antibody concentrations in children: a prospective birth cohort study.
Many populations are exposed to arsenic, lead, and manganese. These metals influence immune function. We evaluated the association between exposure to single and multiple metals, including arsenic, lead, and manganese, to humoral immunity as measured by antibody concentrations to diphtheria and tetanus toxoid among vaccinated Bangladeshi children. Additionally, we examined if this association was potentially mediated by nutritional status. Antibody concentrations to diphtheria and tetanus were measured in children's serum at age 5 (n = 502). Household drinking water was sampled to quantify arsenic (W-As) and manganese (W-Mn), whereas lead was measured in blood (B-Pb). Exposure samples were taken during pregnancy, toddlerhood, and early childhood. Multiple linear regression models (MLRs) with single or combined metal predictors were used to determine the association with antibody outcomes. MLR results were transformed to units of percent change in outcome per doubling of exposure to improve interpretability. Structural equation models (SEMs) were used to further assess exposure to metal mixtures. SEMs regressed a latent exposure variable (Metals), informed by all measured metal variables (W-As, W-Mn, and B-Pb), on a latent outcome variable (Antibody), informed by measured antibody variables (diphtheria and tetanus). Weight-for-age z-score (WFA) at age 5 was evaluated as a mediator. Diphtheria antibody was negatively associated with W-As during pregnancy in MLR, but associations were attenuated after adjusting for W-Mn and B-Pb (- 2.9% change in diphtheria antibody per doubling in W-As, 95% confidence interval [CI]: - 7%, 1.5%). Conversely, pregnancy levels of B-Pb were positively associated with tetanus antibody, even after adjusting for W-As and W-Mn (13.3%, 95% CI: 1.7%, 26.3%). Overall, null associations were observed between W-Mn and antibody outcomes. Analysis by SEMs showed that the latent Metals mixture was significantly associated with the latent Antibody outcome (β = - 0.16, 95% CI: - 0.26, - 0.05), but the Metals variable was characterized by positive and negative loadings of W-As and B-Pb, respectively. Sex-stratified MLR and SEM analyses showed W-As and B-Pb associations were exclusive to females. Mediation by WFA was null, indicating Metals only had direct effects on Antibody. We observed significant modulation of vaccine antibody concentrations among children with pregnancy and early life exposures to drinking water arsenic and blood lead. We found distinct differences by child sex, as only females were susceptible to metal-related modulations in antibody levels. Weight-for-age, a nutritional status proxy, did not mediate the association between the metal mixture and vaccine antibody.


A distinct neurogenomic response to a trade-off between social challenge and opportunity in male sticklebacks (Gasterosteus aculeatus).
Animals frequently make adaptive decisions about what to prioritize when faced with multiple, competing demands simultaneously. However, the proximate mechanisms of decision-making in the face of competing demands are not well understood. We explored this question using brain transcriptomics in a classic model system: threespined sticklebacks, where males face conflict between courtship and territorial defence. We characterized the behaviour and brain gene expression profiles of males confronted by a trade-off between courtship and territorial defence by comparing them to males not confronted by this trade-off. When faced with the trade-off, males behaviourally prioritized defence over courtship, and this decision was reflected in their brain gene expression profiles. A distinct set of genes and biological processes was recruited in the brain when males faced a trade-off and these responses were largely non-overlapping across two brain regions. Combined, these results raise new questions about the interplay between the neural and molecular mechanisms involved in decision-making.


Carotid artery intima-media thickness measured by ultrasonography in normal clinical practice correlates well with atherosclerosis risk factors.
The intima-media thickness (IMT) of extracranial carotid arteries determined by B-mode ultrasound is a measurable index of the presence of atherosclerosis. The ultrasonographic scan protocol and the scan reading techniques used until now to measure IMT are, however, time consuming and require the participation of specialized research centers. In this study we present a cross-sectional study of 963 patients attending the Enrica Grossi Paoletti Center in Milan, Italy, with the aim of assessing whether ultrasonographic measurements of carotid artery in routine clinical practice can yield the same results as those obtained with quantitative methods used until now in clinical trials. Maximum and mean maximum IMT of carotid arteries were assessed by B-mode ultrasound with the use of the electronic caliper of the machine in real time. The intraobserver and interobserver variability of IMT of carotid arteries performed with the electronic caliper in real time was similar to that of quantitative processing of frozen images (coefficients of variation of intraobserver and interobserver mean maximum IMT measurements were 4.2% and 7.3%, respectively). Carotid artery IMT thus measured correlated with most of the known atherosclerosis risk factors and discriminated between patients with and without previous history of cardiovascular events. IMT was linearly related to the total number of vascular risk factors both in the whole group and after stratification of patients into 3 age classes. These observations establish a strong correlation between B-mode imaging of carotid atherosclerosis evaluated in normal clinical practice and data provided by clinical trials and validate this simple reading technique as a means of identifying IMT as another possible risk factor in patients at high risk of vascular disease.


Patterns of MHC selection in African mole-rats, family Bathyergidae: the effects of sociality and habitat.
African mole-rats are a family of rodents exhibiting an eclectic range of social behaviour and occupying a variety of habitat types. These differences are likely to impact upon the risk of parasite transmission and virulence, with increasing sociality predicted to correspond to an increased risk of transmission. We investigate these factors by analysing the major histocompatibility complex (MHC), a set of genes responsible for encoding highly variable intermediaries of the vertebrate adaptive immune response. To this end we assessed selection at exons 2 and 3 of the MHC class II DQalpha1 gene of four African mole-rat species representing a range of social behaviours. We demonstrate that: (i) the overall pattern of selection at these exons differentiates according to the predicted function of different regions, with the presence of positive selection indicating the likely influence of host-parasite coevolution; and (ii) contrary to the often observed and predicted positive correspondence between sociality and the risk of parasite transmission, two highly social African mole-rat species in fact appear to have comparatively weak positive selection, suggesting diminished host immunity and thus a low overall risk of parasite transmission.


Differentiation of Entamoeba histolytica from E. dispar facilitated by monoclonal antibodies against a 150-kDa surface antigen.
Murine monoclonal antibodies (mAbs) were produced against an n-octyl-beta-D-glucopyranoside-extracted fraction of trophozoites of Entamoeba histolytica HM-1:IMSS. Four of the mAbs were reactive with a 150-kDa surface antigen characterized by Western-immunoblot analysis under nonreducing conditions. When the reactivity of the four mAbs with nine reference strains of E. histolytica was examined by an indirect fluorescence antibody test, two of the mAbs (EH3015 and EH3023) were found to react with all nine strains and the other two mAbs (EH3056 and EH3126) reacted with seven strains. The four mAbs did not react with any E. dispar reference strain or with other enteric protozoan parasites. The reactivity of EH3015 and EH3023 with numerous isolates of E. histolytica and E. dispar collected in our laboratories was also examined. The 2 mAbs reacted with all of the 37 E. histolytica isolates tested but did not react with any of the 33 isolates of E. dispar. These results indicate that common antigenic epitopes of E. histolytica are on the 150-kDa surface molecule and that mAbs can distinguish between E. histolytica and E. dispar.


Continuous Symmetry Breaking in 1D Long-Range Interacting Quantum Systems.
Continuous symmetry breaking (CSB) in low-dimensional systems, forbidden by the Mermin-Wagner theorem for short-range interactions, may take place in the presence of slowly decaying long-range interactions. Nevertheless, there is no stringent bound on how slowly interactions should decay to give rise to CSB in 1D quantum systems at zero temperature. Here, we study a long-range interacting spin chain with U(1) symmetry and power-law interactions V(r)∼1/r^{α}. Using a number of analytical and numerical techniques, we find CSB for α smaller than a critical exponent α_{c}(≤3) that depends on the microscopic parameters of the model. Furthermore, the transition from the gapless XY phase to the gapless CSB phase is mediated by the breaking of conformal and Lorentz symmetries due to long-range interactions, and is described by a universality class akin to, but distinct from, the Berezinskii-Kosterlitz-Thouless transition. Signatures of the CSB phase should be accessible in existing trapped-ion experiments.


Habitual physical activity in children and adolescents with cystic fibrosis.
This study was conducted to: 1) measure total physical activity levels, including the intensities of the various types of activities, in children and adolescents with CF compared with non-CF healthy control subjects; and 2) determine whether vigorous activity level was related to aerobic fitness and disease status in patients with CF. Thirty patients with CF (18 male, 12 female) and 30 control subjects (17 male, 13 female), 7-17 yr old, participated in this study. Habitual physical activity was measured using Kriska's Modifiable Activity Questionnaire (MAQ) and the past year's average of total hours, MET-hours, and vigorous (VIG) hours (>6 METs) of activity per week were determined. Aerobic fitness was determined from peak oxygen uptake (VO2peak) obtained via maximal exercise testing on a cycle ergometer. Standard spirometry was used to measure pulmonary function. Body mass index (BMI) was determined from height and weight measurements. The CF and control groups were similar in age and gender distribution, but the patients were smaller (BMI, 98 vs 112% of predicted) and less aerobically fit (36.5 vs 41.4 mL x kg(-1) x min(-1)). Total and MET-hours of physical activity did not differ between groups; however, the CF group participated in significantly fewer hours of vigorous activities than the control group (2 vs 3.7 h x wk(-1)). In patients with worse lung disease, VIG-h x wk(-1) were significantly related to VO2peak (r = 0.83). These results suggest that children with CF engage in less vigorous physical activities than their healthy non-CF peers, despite having good lung function. In view of the progressive nature of the disease, and the association between aerobic fitness and vigorous activity, patients should be encouraged to engage in more vigorous activities that promote aerobic fitness and may ultimately have an impact on survival.