Latex-coated polymeric monolithic ion-exchange stationary phases. 1. Anion-exchange capillary electrochromatography and in-line sample preconcentration in capillary electrophoresis.
A sulfonated methacrylate monolithic polymer has been synthesized inside fused-silica capillaries of diameters 50-533-microm i.d. and coated with 65-nm-diameter fully functionalized quaternary ammonium latex particles (AS18, Dionex Corp.) to form an anion-exchange stationary phase. This stationary phase was used for ion-exchange capillary electrochromatography of inorganic anions in a 75-microm-i.d. capillary with Tris/perchlorate electrolyte and direct UV detection at 195 nm. Seven inorganic anions (bromide, nitrate, iodide, iodate, bromate, thiocyanate, chromate) could be separated over a period of 90 s, and the elution order indicated that both ion exchange and electrophoresis contributed to the separation mechanism. Separation efficiencies of up to 1.66 x 10(5) plates m(-1) were achieved, and the monoliths were stable under pressures of up to 62 MPa. Another latex-coated monolith in a 250-microm-i.d. capillary was used for in-line preconcentration by coupling it to a separation capillary in which the EOF had been reversed using a coating of either a cationic polymer or cationic latex particles. Several capillary volumes of sample were loaded onto the preconcentration monolith, and the analytes (inorganic anions) were then eluted from the monolith with a transient isotachophoretic gradient before being separated by electrophoresis in the separation capillary. Linear calibration curves were obtained for aqueous mixtures of bromide, nitrite, nitrate, and iodide. Recoveries of all analytes except iodide were reduced significantly when the sample matrix contained high levels of chloride. The preconcentration method was applied to the determination of iodide in open ocean water and provided a limit of detection of 75 pM (9.5 ng/L) calculated at a signal-to-noise ratio of 3. The relative standard deviation for migration time and peak area for iodide were 1.1 and 2.7%, respectively (n = 6). Iodide was eluted as an efficient peak, yielding a separation efficiency of 5.13 x 10(7) plates m(-1). This focusing was reproducible for repeated analyses of seawater.


A candidate taste receptor gene near a sweet taste locus.
The mechanisms underlying sweet taste in mammals have been elusive. Although numerous studies have implicated G proteins in sweet taste detection, the expected G protein-coupled receptors have not been found. Here we describe a candidate taste receptor gene, T1r3, that is located at or near the mouse Sac locus, a genetic locus that controls the detection of certain sweet tastants. T1R3 differs in amino acid sequence in mouse strains with different Sac phenotypes ('tasters' versus 'nontasters'). In addition, a perfect correlation exists between two different T1r3 alleles and Sac phenotypes in recombinant inbred mouse strains. The T1r3 gene is expressed in a subset of taste cells in circumvallate, foliate and fungiform taste papillae. In circumvallate and foliate papillae, most T1r3-expressing cells also express a gene encoding a related receptor, T1R2, raising the possibility that these cells recognize more than one ligand, or that the two receptors function as heterodimers.


Empowering Personalized Medicine with Big Data and Semantic Web Technology: Promises, Challenges, and Use Cases.
In healthcare, big data tools and technologies have the potential to create significant value by improving outcomes while lowering costs for each individual patient. Diagnostic images, genetic test results and biometric information are increasingly generated and stored in electronic health records presenting us with challenges in data that is by nature high volume, variety and velocity, thereby necessitating novel ways to store, manage and process big data. This presents an urgent need to develop new, scalable and expandable big data infrastructure and analytical methods that can enable healthcare providers access knowledge for the individual patient, yielding better decisions and outcomes. In this paper, we briefly discuss the nature of big data and the role of semantic web and data analysis for generating "smart data" which offer actionable information that supports better decision for personalized medicine. In our view, the biggest challenge is to create a system that makes big data robust and smart for healthcare providers and patients that can lead to more effective clinical decision-making, improved health outcomes, and ultimately, managing the healthcare costs. We highlight some of the challenges in using big data and propose the need for a semantic data-driven environment to address them. We illustrate our vision with practical use cases, and discuss a path for empowering personalized medicine using big data and semantic web technology.


The incidence of severe complications of preeclampsia.
To examine the incidence of life-threatening (near-miss) complications, including hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome occurring in women with preeclampsia in the Grampian region of Scotland between 1981 and 2000. All women who were resident in a geographically determined region (the Grampian region of Scotland) and who developed moderate to severe preeclampsia in the time period 1981 to 2000 were identified from the Aberdeen Maternity and Neonatal Databank. All complications occurring antepartum, intrapartum, or postpartum in these pregnancies were listed as International Classification of Diseases (ICD) codes and significant complications were identified from these. The cases of HELLP syndrome were identified by case note review. Data were analyzed using Statistical Package for Social Scientists (SPSS). A total of 4188 cases of preeclampsia were identified over the 20-year period. Six percent (approx. 1 in 16) of preeclamptics developed one or more major systemic complications. The incidence of placental abruption and eclampsia was 2.8% and 1.65%, respectively. Hematological complications were most common, with reduced platelets accounting for about half of these cases; although, a definite diagnosis of HELLP syndrome could only be made in 13 cases over 20 years. After adjusting for gestational age, a woman was 1.14 times more likely to have a caesarean delivery (95% C.I. 1.08, 1.20) if she had complicated preeclampsia. She was also more likely to have a stillbirth [Odds Ratio (O.R.) = 1.45 (95% C.I. (confidence interval) 1.02, 2.29)] or a neonatal death [O.R. = 2.25 (95% C.I. 1.12, 4.260]. There has been a gradual decline in the rate of preeclampsia in the Grampian region of Scotland over the time period 1986 to 2000; although, the percentage of pre-eclamptics who developed one or more complications has not decreased appreciably. In fact, the incidence of eclampsia and placental abruption has increased in the most recent five years. The presence of complications in preeclampsia is associated with a poor neonatal outcome.


Pitfalls of HbA1c in the Diagnosis of Diabetes.
Many health care providers screen high-risk individuals exclusively with an HbA1c despite its insensitivity for detecting dysglycemia. The 2 cases presented describe the inherent caveats of interpreting HbA1c without performing an oral glucose tolerance test (OGTT). The first case reflects the risk of overdiagnosing type 2 diabetes (T2D) in an older African American male in whom HbA1c levels, although variable, were primarily in the mid-prediabetes range (5.7-6.4% [39-46 mmol/mol]) for many years although the initial OGTT demonstrated borderline impaired fasting glucose with a fasting plasma glucose of 102 mg/dL [5.7 mmol/L]) without evidence for impaired glucose tolerance (2-hour glucose ≥140-199 mg/dl ([7.8-11.1 mmol/L]). Because subsequent HbA1c levels were diagnostic of T2D (6.5%-6.6% [48-49 mmol/mol]), a second OGTT performed was normal. The second case illustrates the risk of underdiagnosing T2D in a male with HIV having normal HbA1c levels over many years who underwent an OGTT when mild prediabetes (HbA1c = 5.7% [39 mmol/mol]) developed that was diagnostic of T2D. To avoid inadvertent mistreatment, it is therefore essential to perform an OGTT, despite its limitations, in high-risk individuals, particularly when glucose or fructosamine and HbA1c values are discordant. Innate differences in the relationship between fructosamine or fasting glucose to HbA1c are demonstrated by the glycation gap or hemoglobin glycation index.


Ricinus communis intoxications in human and veterinary medicine-a summary of real cases.
Accidental and intended Ricinus communis intoxications in humans and animals have been known for centuries but the causative agent remained elusive until 1888 when Stillmark attributed the toxicity to the lectin ricin. Ricinus communis is grown worldwide on an industrial scale for the production of castor oil. As by-product in castor oil production ricin is mass produced above 1 million tons per year. On the basis of its availability, toxicity, ease of preparation and the current lack of medical countermeasures, ricin has gained attention as potential biological warfare agent. The seeds also contain the less toxic, but highly homologous Ricinus communis agglutinin and the alkaloid ricinine, and especially the latter can be used to track intoxications. After oil extraction and detoxification, the defatted press cake is used as organic fertilizer and as low-value feed. In this context there have been sporadic reports from different countries describing animal intoxications after uptake of obviously insufficiently detoxified fertilizer. Observations in Germany over several years, however, have led us to speculate that the detoxification process is not always performed thoroughly and controlled, calling for international regulations which clearly state a ricin threshold in fertilizer. In this review we summarize knowledge on intended and unintended poisoning with ricin or castor seeds both in humans and animals, with a particular emphasis on intoxications due to improperly detoxified castor bean meal and forensic analysis.


Improved early muscle recovery using FK506 in a rat nerve-repair model.
The authors hypothesized that FK506 improves maximal muscle force (P (0)) recovery during early muscle reinnervation. Rat peroneal nerve was unilaterally cut and repaired. Rats received subcutaneous injections of vehicle (controls) or FK506 at 1 mg/kg (FK506-1MG) or 5 mg/kg (FK506-5MG) for 3 weeks. Extensor digitorum longus (EDL) isometric muscle P (0) was measured bilaterally 4 weeks postoperatively. FK506 treatment adversely affected body mass. With body mass as a covariate, the P (0) for denervated-reinnervated muscle in the FK506-5MG group was statistically significantly higher by 34 percent and 32 percent, compared with controls and FK506-1MG groups. There was no group difference for the contralateral, nerve-intact EDL muscle P (0), when loss of body mass was considered. NCAM immunohistologic data showed significantly better reinnervation of the denervated muscle in a dose-dependent fashion. Thus, FK506 treatment at high dose improves early recovery of force in denervated-reinnervated muscle, following nerve repair, when loss of body mass is considered.


Data-based Reconstruction of Gene Regulatory Networks of Fungal Pathogens.
In the emerging field of systems biology of fungal infection, one of the central roles belongs to the modeling of gene regulatory networks (GRNs). Utilizing omics-data, GRNs can be predicted by mathematical modeling. Here, we review current advances of data-based reconstruction of both small-scale and large-scale GRNs for human pathogenic fungi. The advantage of large-scale genome-wide modeling is the possibility to predict central (hub) genes and thereby indicate potential biomarkers and drug targets. In contrast, small-scale GRN models provide hypotheses on the mode of gene regulatory interactions, which have to be validated experimentally. Due to the lack of sufficient quantity and quality of both experimental data and prior knowledge about regulator-target gene relations, the genome-wide modeling still remains problematic for fungal pathogens. While a first genome-wide GRN model has already been published for Candida albicans, the feasibility of such modeling for Aspergillus fumigatus is evaluated in the present article. Based on this evaluation, opinions are drawn on future directions of GRN modeling of fungal pathogens. The crucial point of genome-wide GRN modeling is the experimental evidence, both used for inferring the networks (omics 'first-hand' data as well as literature data used as prior knowledge) and for validation and evaluation of the inferred network models.


Artemether-lumefantrine for uncomplicated malaria: a systematic review.
The World Health Organization (WHO) is promoting artemether-lumefantrine for treating uncomplicated malaria. The objective of this review is to summarize available evidence of its effects compared with other antimalarial regimens. We sought randomized and quasi-randomized studies comparing artemether-lumefantrine with any other antimalarial drug regimen. Databases searched were MEDLINE (to February 2003), EMBASE (to February 2003), and the Cochrane Controlled Trials Register (issue 1, 2003). Conference proceedings and reference article lists were searched and malaria researchers and the drug manufacturer were contacted. Two reviewers independently applied inclusion criteria and extracted data. Six trials (1698 participants) studied the four-dose regimen. Fever and parasite clearance tended to be shorter with artemether-lumefantrine, but parasitological failure on day 28 was more common with artemether-lumefantrine in comparison with mefloquine (one trial, n = 233), halofantrine (one trial, n = 86) and mefloquine-artesunate (one trial, n = 537); but less common with chloroquine (two trials, n = 378). For the six-dose regimen, two studies compared artemether-lumefantrine with mefloquine-artesunate, but there was insufficient data to demonstrate any meaningful comparative effects for day 28 parasitaemia, and no difference in parasite or fever clearance time was detected. There were 11 parasitological failures with artemether-lumefantrine and none with mefloquine-artesunate. There is no evidence to demonstrate the four-dose regimen of artemether-lumefantrine results in a higher cure rate than other antimalarial regimens against which it has been tested, apart from chloroquine in areas with high chloroquine resistance. Artemether-lumefantrine has potential advantages over non-artemisinin regimens because of the faster clearance time and gametocyte clearance. There is insufficient evidence about the six-dose regimen to know whether it is less or more effective than current antimalarial drug regimens.


Strictly linear trinuclear Dy-Ca/Mg-Dy single-molecule magnets: the impact of long-range f-f ferromagnetic interactions on suppressing quantum tunnelling of magnetization leading to slow magnetic relaxation.
The synthesis, structural characterization and magnetic properties of four heterometallic complexes with formulas Ln2M(OQ)8 [Ln(iii) = Dy, M(ii) = Ca (1), Mg (2); Ln(iii) = Er, M(ii) = Ca (3), Mg (4); HOQ = 8-hydroxyquinoline] are reported. Complexes display a perfectly linear arrangement of three metal ions involving two terminal Ln(iii) ions and one central alkaline earth M(ii) ion, and they are bridged by three phenolato oxygen atoms from three 8-hydroxyquinoline ligands. Direct-current (dc) magnetic susceptibility studies show that there exists a long-range ferromagnetic (FM) interaction between two f-electronic centers in Dy-based complexes 1 and 2 albeit they are separated by diamagnetic alkaline earth ions, and the FM interaction has been successfully reproduced by ab initio calculations. Alternating current (ac) magnetic susceptibility measurements indicate that complexes 1 and 2 exhibit significant single-molecule magnet (SMM) behaviors. This is mostly attributed to the parallel magnetic axes of individual Dy(iii) sites aligning closely to the Dy-M-Dy direction, and the linearly extending magnetic susceptibility tensors of each ion lead to the FM interaction. The dc and ac susceptibility studies of the intramolecularly diluted complexes reveal that the f-f coupling suppresses the QTMs significantly in the absence of the external magnetic field.


Fracture of Jammed Colloidal Suspensions.
Concentrated colloidal suspensions display dramatic rises in viscosity, leading to jamming and granulation, with increasing shear rate. It has been proposed that these effects result from inter particle friction, as lubrication forces are overcome. This suggests the jamming of concentrated colloidal suspensions should exhibit some shared phenomenology with macroscopic granular systems where friction leads to two different types of jammed state. Here we show that transient rheological measurements can be used to probe the processes of granulation in concentrated colloidal suspensions. Our results support the idea that frictional contacts are created between jammed particles. The jamming behaviour displays two qualitatively different regimes separated by a critical strain rate with qualitatively different types of fracture/break up behaviour. In the lower strain rate regime, it is found that vibrations can be used to control jamming and granulation, resulting in a flowable fluid.


Assessing individual breast cancer risk within the U.K. National Health Service Breast Screening Program: a new paradigm for cancer prevention.
The aim of this study is to determine breast cancer risk at mammographic screening episodes and integrate standard risk factors with mammographic density and genetic data to assess changing the screening interval based on risk and offer women at high risk preventive strategies. We report our experience of assessing breast cancer risk within the U.K. National Health Service Breast Screening Program using results from the first 10,000 women entered into the "Predicting Risk Of breast Cancer At Screening" study. Of the first 28,849 women attending for screening at fifteen sites in Manchester 10,000 (35%) consented to study entry and completed the questionnaire. The median 10-year Tyrer-Cuzick breast cancer risk was 2.65% (interquartile range, 2.10-3.45). A total of 107 women (1.07%) had 10-year risks 8% or higher (high breast cancer risk), with a further 8.20% having moderately increased risk (5%-8%). Mammographic density (percent dense area) was 60% or more in 8.3% of women. We collected saliva samples from 478 women for genetic analysis and will extend this to 18% of participants. At time of consent to the study, 95.0% of women indicated they wished to know their risk. Women with a 10-year risk of 8% or more or 5% to 8% and mammographic density of 60% or higher were invited to attend or be telephoned to receive risk counseling; 81.9% of those wishing to know their risk have received risk counseling and 85.7% of these were found to be eligible for a risk-reducing intervention. These results confirm the feasibility of determining breast cancer risk and acting on the information in the context of population-based mammographic screening.


Components and Outcomes of Internet-Based Interventions for Caregivers of Older Adults: Systematic Review.
When trying to access interventions to improve their well-being and quality of life, family caregivers face many challenges. Internet-based interventions provide new and accessible opportunities to remotely support them and can contribute to reducing their burden. However, little is known about the link existing between the components, the use of behavior change techniques, and the outcomes of these Internet-based interventions. This study aimed to provide an update on the best available evidence about the efficacy of Internet-based interventions for caregivers of older adults. Specifically, the components and the use of behavior change techniques and how they impact on the efficacy of the intervention were sought. A systematic review searched primary source studies published between 2000 and 2015. Included studies were scored with a high level of evidence by independent raters using the GRADE criteria and reported caregiver-specific outcomes about interventions delivered through the Internet for caregivers of people aged 50 years and older. A narrative synthesis identified intervention components (eg, content, multimedia use, interactive online activities, and provision of support), behavior change techniques, and caregiver outcomes (eg, effects on stressors, mediators, and psychological health). The risk of bias within the included studies was assessed. A total of 2338 articles were screened and 12 studies describing 10 Internet-based interventions were identified. Seven of these interventions led to statistically significant improvements in caregiver outcomes (eg, reducing depression or anxiety, n=4). These efficacious interventions used interactive components, such as online exercises and homework (n=4) or questionnaires on health status (n=2) and five of them incorporated remote human support, either by professionals or peers. The most frequently used behavior change techniques included in efficacious interventions were provision of social support (n=6) and combinations of instructions to guide behavior change and barrier identification (n=5). The design and aim of the included studies did not permit determining exactly which component and/or behavior change technique was more efficacious in producing positive outcomes in caregivers. The risk for selection bias was low for all the studies, and low to high for performance, detection, and attrition biases. In sum, Internet-based interventions that incorporate professional and social support, and provide instructions to change behavior and problem solve in an interactive manner appear to lead to positive outcomes in caregivers. Studies isolating the specific effect of components are needed to improve our understanding of the underlying mechanism of action.


Oxidized LDL Is Associated With Metabolic Syndrome Traits Independently of Central Obesity and Insulin Resistance.
This study assesses whether oxidative stress, using oxidized LDL (ox-LDL) as a proxy, is associated with metabolic syndrome (MS), whether ox-LDL mediates the association between central obesity and MS, and whether insulin resistance mediates the association between ox-LDL and MS. We examined baseline data from 3,987 subjects without diabetes in the Progression of Early Subclinical Atherosclerosis (PESA) Study. For the second, third, and fourth ox-LDL quartiles versus the first, the odds ratios (95% CI) for MS were 0.84 (0.52, 1.36), 1.47 (0.95, 2.32), and 2.57 (1.66, 4.04) (P < 0.001 for trend) once adjusted for age, sex, smoking, LDL-cholesterol, BMI, waist circumference, and HOMA-insulin resistance (HOMA-IR). Results showing the same trend were found for all MS components except glucose concentration. Ox-LDL mediated 13.9% of the association of waist circumference with triglycerides and only 1-3% of the association with HDL-cholesterol, blood pressure, and insulin concentration. HOMA-IR did not mediate the association between ox-LDL and MS components. This study found higher ox-LDL concentrations were associated with MS and its components independently of central obesity and insulin resistance. Ox-LDL may reflect core mechanisms through which MS components develop and progress in parallel with insulin resistance and could be a clinically relevant predictor of MS development.


Bandwidth optimization of optical data links by use of error-control codes.
A design approach to optimizing the bandwidth of optical data links while simultaneously decreasing the bit-error rate is proposed. Mathematical analysis indicates that bandwidth gains by factors of 10-60 with power gains of as much as 8.9 dB are possible. To achieve these performance levels requires several innovations. First, conventional forward error-correcting codes cannot be used because of their excessive hardware cost. A reasonably powerful multidimensional parity-based error-control code is proposed and analyzed. These codes offer excellent error detection and moderate error-correction capabilities. Most importantly, they can operate at the fast clock rates that are required. Second, a hybrid automatic-repeat-request protocol is exploited to correct complex error patterns. In thermal-noise-limited systems this unique combination allows the optical clock rate to be increased significantly, thereby resulting in large bandwidth increases. The proposed design approach can be used in optical data links in which propagation delays are moderate and is applicable to fibers that exploit wavelength-division multiplexing or time-division multiplexing, one-dimensional parallel-fiber ribbons, and two-dimensional optical data links that use free space or guided waves. Several design examples are illustrated.


New genes that interact with lin-35 Rb to negatively regulate the let-60 ras pathway in Caenorhabditis elegans.
Previous studies have shown that a synthetic multivulva phenotype results from mutations in genes that antagonize the ras-mediated intercellular signaling system responsible for vulval induction in Caenorhabditis elegans. Synthetic multivulva mutations define two classes of genes, A and B, and a mutation in a gene of each class is required to produce the multivulva phenotype. The ectopic vulval tissue in multivulva animals is generated by vulval precursor cells that in the wild type do not generate vulval tissue. One of the class B synthetic multivulva genes, lin-35, encodes a protein similar to the retinoblastoma (Rb) protein. In this article, we describe the isolation and characterization of 50 synthetic multivulva mutations, the identification of new components of both the class A and class B lin-35 Rb pathways, and the cloning of lin-52, a class B gene that may have a conserved role in Rb-mediated signaling.


Environmental patterns in the origins of higher taxa: the post-paleozoic fossil record.
Of the 26 well-preserved orders of benthic marine invertebrates that have originated since the beginning of the Mesozoic, 20 first appear in onshore environments. This distribution differs significantly from that shown by well-preserved genera and families, and by the 16 poorly preserved orders. These discordances suggest that the pattern of preferential onshore origination is not an artifact of preservation or collection and that the origin of higher taxa cannot be regarded as a simple extrapolation of rates and patterns at lower levels. The onshore environment fosters production or enhances survivorship of species that initiate lineages tending to accumulate suites of derived characters and that thus are ultimately afforded high taxonomic rank.


Structural features that distinguish kinetically distinct biomineralization polypeptides.
AP7 and AP24 are mollusk shell proteins which are responsible for aragonite polymorph formation and stabilization within the nacre layer of the Pacific red abalone, Haliotis rufescens. It is known that the 30-AA N-terminal mineral modification domains of both proteins (AP7N, AP24N) possess identical multifunctional mineralization capabilities within in vitro assays but differ in terms of rate kinetics, with AP24N > AP7N. In this report, we identify previously unreported molecular features of AP24N and contrast the lowest energy polypeptide backbone structures of AP24N (planar configuration) with that of AP7N ("bent paper clip" configuration) using NMR data and simulated annealing molecular dynamics structure refinement. Like AP7N, we find that AP24N possesses an unfolded conformation, can sequester Ca(II) and other multivalent metal ions, can adsorb onto or within calcite crystals, and possesses anionic and cationic electrostatic "pocket" regions on its molecular surfaces. However, AP24N has some unique features: greater conformational responsiveness to Ca(II), the tendency to form a more planar backbone configuration, and longer anionic and hydrogen-bonding donor/acceptor sequence blocks. We conclude that the presence of unfolded polypeptide conformation, electrostatic surface pockets, and interactive sequence clustering endow both AP7N and AP24N with similar features that lead to comparable effects on crystal morphology and nucleation. However, AP24N possesses longer anionic and hydrogen-bonding sequence clusters and exhibits a tendency to adopt a more planar backbone configuration than AP7N does. We believe that these features facilitate peptide-mineral, peptide-ion, or water cluster interactions, thereby enhancing the mineralization kinetics of AP24N over AP7N.


Identification of inhibitory substances affecting bioleaching of heavy metals from anaerobically digested sewage sludge.
Significant inhibitory effects of the filtrate medium of anaerobically digested sewage sludge on iron oxidation by Acidithiobacillus ferrooxidans ANYL-1 were observed in our preliminary experiments, indicating the presence of inhibitory substances in anaerobically digested sewage sludge. The objectives of the present study were to identify the possible inhibitory substances and to evaluate their impacts on metal solubilization during bioleaching of sewage sludge. The results showed that the concentrations of total reducing sugars, all tested metal ions, and anions were too low to suppress iron oxidation, and only organic acids, especially acetic and propionic acids, were found at concentrations higher than their inhibitory levels. The presence of 10.8 mM acetic acid and 9.88 mM propionic acid in sewage sludge (sludge N) led to long lag periods of 6 and 7 days for solubilization of Cu and Cr, respectively, as compared to a lag period of only 1 day in the control and another sludge (sludge S) with a low level of organic acids. Meanwhile the leaching time for maximum solubilization of Zn also extended to 6 days in the presence of organic acids as compared to 3 days in the control. Acetic and propionic acids posed an unfavorable bioleaching condition for anaerobically digested sewage sludge; therefore, further studies are required to explore the means to remove the inhibitory effects to improve the heavy metal bioleaching efficiency.


The Year in Cardiology 2013: heart failure.
Heart failure has become a worldwide epidemic of the 21st century with increasing impact on healthcare systems. The 2012 ESC and 2013 ACCF/AHA guidelines have set the stage for current therapy to reduce mortality and morbidity. There is a dawn of hope for therapy of acute and diastolic heart failure; it has become clearer that patients benefit from mitral reconstruction and which patients benefit from heart failure management programmes; genetics and proteomics advance in great strides; competing concepts of cell therapy seem to spiral, hopefully upwards; and we can further nurture our hope for evidence-based individualized diagnostic and therapy.


Accretion of mudstone beds from migrating floccule ripples.
Mudstones make up the majority of the geological record. However, it is difficult to reconstruct the complex processes of mud deposition in the laboratory, such as the clumping of particles into floccules. Using flume experiments, we have investigated the bedload transport and deposition of clay floccules and find that this occurs at flow velocities that transport and deposit sand. Deposition-prone floccules form over a wide range of experimental conditions, which suggests an underlying universal process. Floccule ripples develop into low-angle foresets and mud beds that appear laminated after postdepositional compaction, but the layers retain signs of floccule ripple bedding that would be detectable in the rock record. Because mudstones were long thought to record low-energy conditions of offshore and deeper water environments, our results call for reevaluation of published interpretations of ancient mudstone successions and derived paleoceanographic conditions.


Target levels of functional C1-inhibitor in hereditary angioedema.
Hereditary angioedema (HAE) is a heterozygous deficiency of first component of complement-inhibitor (C1INH). Insufficient C1INH activity leads to uncontrolled activation of plasma cascade systems, which results in acute angioedema attacks in patients with HAE. Plasma-derived or recombinant C1INH products are approved for the treatment of such angioedema attacks. The target level of C1INH activity needed to achieve optimal efficacy, however, remains unknown. We determined the plasma level of C1INH associated with optimal clinical efficacy in the treatment of angioedema attacks. Efficacy and pharmacokinetic data were reviewed from recently published placebo-controlled randomized trials in the treatment of HAE with either plasma-derived or recombinant C1INH products, tested at various doses. A dose-dependent effect was observed on time to the beginning of relief of symptoms, on time to resolution of symptoms, and on the response rate within 4 h. Optimal efficacy of C1INH therapy is achieved at doses ≥50 U/kg. This dose increases plasma C1INH activity in almost all patients to values ≥0.7 U/ml (70% of normal), the lower limit of the normal range. The differences in half-lives of the various C1INH products do not have an obvious effect on clinical efficacy. A review of the efficacy and pharmacokinetic data from recently published controlled studies in the treatment of HAE attacks suggests that efficacy of C1INH therapy is optimal when C1INH activity levels are restored to the normal range.


Factors associated with meniscal body extrusion on knee MRI in overweight and obese women.
To determine factors associated with higher degree of meniscal body extrusion in overweight and obese women at high risk of knee osteoarthritis (OA). We used baseline data of the PRevention of knee Osteoarthritis in Overweight Females (PROOF) study, Netherlands, comprising overweight or obese women aged 50-60 years, free of clinical knee OA. All subjects completed a questionnaire on knee complaints and physical activity, underwent physical examination, radiography, and 1.5 T magnetic resonance imaging (MRI) of both knees. Using the mid-coronal MRI slice, one blinded observer measured tibial plateau width and meniscal body extrusion of both menisci in both knees. The association between baseline factors and meniscal extrusion, were analyzed with a random effects regression model. In addition, we used a fixed effect regression model for evaluation of knee-specific factors. Mean age of the included women (n = 395) was 55.7 years and mean body mass index (BMI) 32.4 kg/m2. Of all knees, 23% had an absolute medial meniscus body extrusion ≥3.0 mm and 4% had lateral meniscus body extrusion ≥3.0 mm. In the multivariable model, the medial meniscus extrusion was increased by 0.44 mm (95% confidence interval [CI] 0.11, 0.77) when a medial meniscus tear was present, by 0.20 mm per 5 kg/m2 (95% CI 0.05, 0.35) increase in BMI and by 0.25 in the presence of mild knee symptoms (95% CI 0.05 to 0.44). Kellgren-Lawrence (KL) grade ≥1 and tibia width were associated with increased both medial and lateral extrusion. In women, ipsilateral meniscus tear and high BMI are factors associated with medial meniscus body extrusion.


Chemical composition of the essential oils of serbian wild-growing Artemisia absinthium and Artemisia vulgaris.
The chemical composition of the aerial and root essential oils, hydrodistilled from Artemisia absinthium L. and Artemisia vulgaris L. (wild-growing populations from Serbia), were studied by gas chromatography, gas chromatography-mass spectrometry, and 13C nuclear magnetic resonance. During the storage of plant material under controlled conditions, a significant decrease of essential oil yields (isolated directly after drying and after 1 year of storage) and significant differences in their chemical compositions were observed. A possible mechanism for the observed oil component interconversion has been discussed. The noticeable differences in the chemical composition of the oils isolated from roots and aerial parts of A. absinthium and A. vulgaris were also correlated with the diverging biosynthetic pathways of volatiles in the respective plant organs. The antimicrobial activities against the common human pathogens of all of the isolated oils were tested according to National Committee on Clinical Laboratory Standards. The oils showed a broad spectrum of antimicrobial activity against the tested strains. Therefore, these oils can be used as flavor and fragrance ingredients.


Improvement of a national public health surveillance system through use of a quality circle.
Surveillance systems for infectious diseases build the basis for effective public health measures in the prevention and control of infectious diseases. Assessing and improving the quality of such national surveillance systems is a challenge, as many different administrations and professions contribute to a complex system in which sensitive information must be exchanged in a reliable and timely fashion. We conducted a multidisciplinary quality circle on the national public health surveillance system in Germany which included clinicians, laboratory physicians, and staff from local and state health departments as well as from the Robert Koch-Institut. The recommendations resulting from the quality circle included proposals to change the federal law for the control of infectious diseases as well as practical activities such as the change of notification forms and the mailing of faxed information letters to clinicians. A number of recommendations have since been implemented, and some have resulted in measurable improvements. This demonstrates that the applied method of quality circle is a useful tool to improve the quality of national public health surveillance systems.


Testosterone reactivity to provocation mediates the effect of early intervention on aggressive behavior.
We tested the hypotheses that the Fast Track intervention program for high-risk children would reduce adult aggressive behavior and that this effect would be mediated by decreased testosterone responses to social provocation. Participants were a subsample of males from the full trial sample, who during kindergarten had been randomly assigned to the 10-year Fast Track intervention or to a control group. The Fast Track program attempted to develop children's social competencies through child social-cognitive and emotional-coping skills training, peer-relations coaching, academic tutoring, and classroom management, as well as training for parents to manage their child's behavior. At a mean age of 26 years, participants responded to laboratory provocations. Results indicated that, relative to control participants, men assigned to the intervention demonstrated reduced aggression and testosterone reactivity to social provocations. Moreover, reduced testosterone reactivity mediated the effect of intervention on aggressive behavior, which provides evidence for an enduring biological mechanism underlying the effect of early psychosocial intervention on aggressive behavior in adulthood.


Adapting to a warmer ocean--seasonal shift of baleen whale movements over three decades.
Global warming poses particular challenges to migratory species, which face changes to the multiple environments occupied during migration. For many species, the timing of migration between summer and winter grounds and also within-season movements are crucial to maximise exploitation of temporarily abundant prey resources in feeding areas, themselves adapting to the warming planet. We investigated the temporal variation in the occurrence of fin (Balaenoptera physalus) and humpback whales (Megaptera novaeangliae) in a North Atlantic summer feeding ground, the Gulf of St. Lawrence (Canada), from 1984 to 2010 using a long-term study of individually identifiable animals. These two sympatric species both shifted their date of arrival at a previously undocumented rate of more than 1 day per year earlier over the study period thus maintaining the approximate 2-week difference in arrival of the two species and enabling the maintenance of temporal niche separation. However, the departure date of both species also shifted earlier but at different rates resulting in increasing temporal overlap over the study period indicating that this separation may be starting to erode. Our analysis revealed that the trend in arrival was strongly related to earlier ice break-up and rising sea surface temperature, likely triggering earlier primary production. The observed changes in phenology in response to ocean warming are a remarkable example of phenotypic plasticity and may partly explain how baleen whales were able to survive a number of changes in climate over the last several million years. However, it is questionable whether the observed rate of change in timing can be maintained. Substantial modification to the distribution or annual life cycle of these species might be required to keep up with the ongoing warming of the oceans.


Spirituality as compensation for low-quality social environments in childhood among young Kenyan men.
This study explores the role of spirituality as a coping mechanism for poor social conditions in childhood, asking whether spirituality moderates poor childhood social conditions and suicide ideation, self-rated health and collective self-esteem among young Kenyan men. Measured outcomes were worse among men who recalled fewer memories of relational warmth and safety in childhood, and better among men who reported higher spirituality. Consistent with the "religion as attachment" framework, spirituality significantly moderated associations between suicide ideation, self-rated health and childhood relational warmth and safety. Contrary to expectations, the association between low childhood warmth and safety and collective self-esteem was exacerbated, rather than compensated for, by higher spirituality. We consider whether "a safe harbor" may exist for people higher in spirituality to accept and critique social arrangements, and whether such a situation might illuminate another way spirituality compensates for poor social environments.


Early expression of glutamate transporter proteins in ramified microglia after controlled cortical impact injury in the rat.
Traumatic brain injury is followed by increased extracellular glutamate concentration. Uptake of glutamate is mainly mediated by the glial glutamate transporters GLAST and GLT-1. Extent and distribution of GLAST and GLT-1 were studied in a rat model of controlled cortical impact injury (CCII). Western Blot analysis revealed lowest levels of GLAST and GLT-1 with a decrease by 40%-54% and 42%-49% between 24 and 72 h posttrauma. By 8 h after CCII, CSF glutamate levels were increased (10.5 microM vs. 2.56 microM in controls; P < 0.001), reaching maximum values by 48 h. A significant increase in de novo GLAST and GLT-1 expressing ramified microglia was observed within 4 h, reached a stable level by 48 h, and remained high up to 72 h after CCII. Furthermore, ramified microglia de novo expressed the neuronal glutamate transporter EAAC1 after CCII. Following CCII, GLAST/GLT-1 and GFAP coexpressing astrocytes were immediately reduced, reaching minimum levels within 8 h. This reduction of expression could be either due to protein downregulation or loss of astrocytes. At 72 h, a marked population of GLAST- and GLT-1-positive reactive astrocytes appeared. These results support the hypothesis that reduced astrocytic GLAST and GLT-1 protein levels following CCII contribute to evolving secondary injury. Microglia are capable of de novo expressing glutamate transporter proteins, indicating that the expression of glial and neuronal glutamate transporters is not restricted to a specific glial or neuronal lineage. Ramified microglia may play an important compensatory role in the early regulation of extracellular glutamate after CCII.


Abundance and diversity of GI microbiota rather than IgG4 levels correlate with abdominal inconvenience and gut permeability in consumers claiming food intolerances.
Food intolerances are an increasing global health problem. Interactions between genetics and environmental changes such as microbial- and stress factors remain poorly understood. Whereas the analyses of IgE mediated allergic responses is based on solid concepts, the roles of microbiota, gut permeability, and IgG antibodies remain widely unclear and are under fierce discussion for scientific relevance. The present pilot study analyzes forty participants, under consultation of nutritional health professionals, for gastrointestinal discomfort and claimed food intolerances. Food frequency questionnaire addresses nutrition, lifestyle and present discomfort. Feces samples are analyzed for dominant microbiota using 16S rDNA based methods and the fecal marker Calprotectin. Blood samples are analyzed for IgG4 levels. The total microbial abundance significantly correlates with claimed discomfort (R=-0.37; p=0.02). The abundance and diversity of microbiota significantly correlates with low Calprotectin values (R=-0.35; p=0.01) and with higher abundance of Faecalibacterium prausnitzii (R=0.78; p<0.01) and Akkermansia (R=0.82; p<0.01). Participants with low discomfort show enhanced Clostridium Cluster XIVa (p=0.008). An increased diversity is also correlating with reduced antibodies against IgG4 of egg white (R=0.68; p<0.01). Data suggest an interaction of low gut permeability and reduced inflammation with an established microbial equilibrium. Self-reported abdominal inconvenience of participants relates mainly to characteristics of microbiota and gut permeability. Anti-inflammatory effects of Faecalibacterium prausnitzii or Lactobacilli and gut barrier functions of Akkermansia may have a key role in food intolerances. The role of IgG4 linking food immune responses with intolerances remains unclear.


Connectivity in fMRI: Blind Spots and Breakthroughs.
In recent years, driven by scientific and clinical concerns, there has been an increased interest in the analysis of functional brain networks. The goal of these analyses is to better understand how brain regions interact, how this depends upon experimental conditions and behavioral measures and how anomalies (disease) can be recognized. In this paper, we provide, first, a brief review of some of the main existing methods of functional brain network analysis. But rather than compare them, as a traditional review would do, instead, we draw attention to their significant limitations and blind spots. Then, second, relevant experts, sketch a number of emerging methods, which can break through these limitations. In particular we discuss five such methods. The first two, stochastic block models and exponential random graph models, provide an inferential basis for network analysis lacking in the exploratory graph analysis methods. The other three addresses: network comparison via persistent homology, time-varying connectivity that distinguishes sample fluctuations from neural fluctuations, and network system identification that draws inferential strength from temporal autocorrelation.


Bayesian integration of sensor information and a multivariate dynamic linear model for prediction of dairy cow mastitis.
Rapid detection of dairy cow mastitis is important so corrective action can be taken as soon as possible. Automatically collected sensor data used to monitor the performance and the health state of the cow could be useful for rapid detection of mastitis while reducing the labor needs for monitoring. The state of the art in combining sensor data to predict clinical mastitis still does not perform well enough to be applied in practice. Our objective was to combine a multivariate dynamic linear model (DLM) with a naïve Bayesian classifier (NBC) in a novel method using sensor and nonsensor data to detect clinical cases of mastitis. We also evaluated reductions in the number of sensors for detecting mastitis. With the DLM, we co-modeled 7 sources of sensor data (milk yield, fat, protein, lactose, conductivity, blood, body weight) collected at each milking for individual cows to produce one-step-ahead forecasts for each sensor. The observations were subsequently categorized according to the errors of the forecasted values and the estimated forecast variance. The categorized sensor data were combined with other data pertaining to the cow (week in milk, parity, mastitis history, somatic cell count category, and season) using Bayes' theorem, which produced a combined probability of the cow having clinical mastitis. If this probability was above a set threshold, the cow was classified as mastitis positive. To illustrate the performance of our method, we used sensor data from 1,003,207 milkings from the University of Florida Dairy Unit collected from 2008 to 2014. Of these, 2,907 milkings were associated with recorded cases of clinical mastitis. Using the DLM/NBC method, we reached an area under the receiver operating characteristic curve of 0.89, with a specificity of 0.81 when the sensitivity was set at 0.80. Specificities with omissions of sensor data ranged from 0.58 to 0.81. These results are comparable to other studies, but differences in data quality, definitions of clinical mastitis, and time windows make comparisons across studies difficult. We found the DLM/NBC method to be a flexible method for combining multiple sensor and nonsensor data sources to predict clinical mastitis and accommodate missing observations. Further research is needed before practical implementation is possible. In particular, the performance of our method needs to be improved in the first 2 wk of lactation. The DLM method produces forecasts that are based on continuously estimated multivariate normal distributions, which makes forecasts and forecast errors easy to interpret, and new sensors can easily be added.


Extraordinary sensitivity for H2S and Fe(iii) sensing in aqueous medium by Al-MIL-53-N3 metal-organic framework: in vitro and in vivo applications of H2S sensing.
An Al(iii) metal-organic framework (MOF) called Al-MIL-53-N3 (1) was synthesized under solvothermal reaction conditions using Al(NO3)3·9H2O and H2BDC-N3 (H2BDC-N3 = 2-azido-1,4-benzenedicarboxylic acid) ligand in a DMF/water (DMF = N,N-dimethylformamide) mixture. Phase purity was checked by performing X-ray powder diffraction, infrared spectroscopy and thermogravimetric analysis. Thermogravimetric analysis suggests that 1 is highly stable up to 300 °C under air atmosphere. The activated 1 (called 1') showed a very fast fluorescence response to H2S (turn-on) and Fe(iii) ions (turn-off) in an aqueous medium with excellent sensitivity and selectivity even in the presence of other potentially intrusive analytes. In the presence of H2S, the conversion of the azide moiety to amine is responsible for the fluorescence turn-on properties. On the other hand, the partial replacement of framework Al(iii) ions by Fe(iii) can be assigned for the selective detection behavior to Fe(iii) ions. The detection limits (90.47 nM for H2S and 0.03 μM for Fe(iii) ions in water) of 1' are lower than those of the formerly reported MOF type of fluorescent sensors. The 1'-loaded J774A.1 macrophage cells are healthy and respond to intracellular H2S to exhibit strong blue fluorescence, confirming its suitability to detect H2S inside the cells. In addition, 1' can detect H2S in human blood plasma (HBP) and sulfide ions in real water samples. These features make 1' a very promising candidate for the on-site sensing of Fe(iii) ions and the detection of intracellular and extracellular H2S.


Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity.
The only reported role for the conjugation of the NEDD8 ubiquitin-like molecule is control of the activity of SCF ubiquitin ligase complexes. Here, we show that the Mdm2 RING finger E3 ubiquitin ligase can also promote NEDD8 modification of the p53 tumor suppressor protein. Mdm2 is itself modified with NEDD8 with very similar characteristics to the autoubiquitination activity of Mdm2. By using a cell line (TS-41) with a temperature-sensitive mutation in the NEDD8 conjugation pathway and a p53 mutant that cannot be NEDDylated (3NKR), we demonstrate that Mdm2-dependent NEDD8 modification of p53 inhibits its transcriptional activity. These findings expand the role for Mdm2 as an E3 ligase, providing evidence that Mdm2 is a common component of the ubiquitin and NEDD8 conjugation pathway and indicating the diverse mechanisms by which E3 ligases can control the function of substrate proteins.


MEMS segmented-based adaptive optics scanning laser ophthalmoscope.
The performance of a MEMS (micro-electro-mechanical-system) segmented deformable mirror was evaluated in an adaptive optics (AO) scanning laser ophthalmoscope. The tested AO mirror (Iris AO, Inc, Berkeley, CA) is composed of 37 hexagonal segments that allow piston/tip/tilt motion up to 5 μm stroke and ±5 mrad angle over a 3.5 mm optical aperture. The control system that implements the closed-loop operation employs a 1:1 matched 37-lenslet Shack-Hartmann wavefront sensor whose measurements are used to apply modal corrections to the deformable mirror. After a preliminary evaluation of the AO mirror optical performance, retinal images from 4 normal subjects over a 0.9°x0.9° field size were acquired through a 6.4 mm ocular pupil, showing resolved retinal features at the cellular level. Cone photoreceptors were observed as close as 0.25 degrees from the foveal center. In general, the quality of these images is comparable to that obtained using deformable mirrors based on different technologies.


Increased microparticle production and impaired microvascular endothelial function in aldosterone-salt-treated rats: protective effects of polyphenols.
We aimed to characterize circulating microparticles in association with arterial stiffness, inflammation and endothelial dysfunction in aldosterone-salt-induced hypertension in rats and to investigate the preventive effects of red wine polyphenols. Uninephrectomized male Sprague-Dawley rats were treated with aldosterone-salt (1 µg.h(-1)), with or without administration of either red wine polyphenols, Provinols™ (20 mg.kg(-1).day(-1)), or spironolactone (30 mg.kg(-1).day(-1)) for 4 weeks. Microparticles, arterial stiffness, nitric oxide (NO) spin trapping, and mesenteric arterial function were measured. Aldosterone-salt rats showed increased microparticle levels, including those originating from platelets, endothelium and erythrocytes. Hypertension resulted in enhanced aortic stiffness accompanied by increased circulating and aortic NO levels and an upregulation of aortic inducible NO-synthase, NFκB, superoxide anions and nitrotyrosine. Flow-induced dilatation was reduced in mesenteric arteries. These effects were prevented by spironolactone. Provinols™ did not reduce arterial stiffness or systolic hypertension but had effects similar to those of spironolactone on endothelial function assessed by flow-mediated vasodilatation, microparticle generation, aortic NO levels and oxidative stress and apoptosis in the vessel wall. Neither the contractile response nor endothelium-dependent relaxation in mesenteric arteries differed between groups. The in vivo effects of Provinols™ were not mediated by mineralocorticoid receptors or changes in shear stress. In conclusion, vascular remodelling and endothelial dysfunction in aldosterone-salt-mediated hypertension are associated with increased circulating microparticles. Polyphenols prevent the enhanced release of microparticles, macrovascular inflammation and oxidative stress, and microvascular endothelial dysfunction independently of blood pressure, shear stress and mineralocorticoid receptor activation in a model of hyperaldosteronism.


Feeding difficulty in older adults with dementia.
To use concept analysis to identify characteristics of feeding difficulty and its antecedents and consequences that provide direction for assessment and management. Feeding difficulty is often recognised as a common problem for older adults and is associated with weight loss, poor nutrition and risk for aspiration pneumonia. The cognitive impairment found in persons with dementia impairs the ability of these adults to complete motor and perceptual tasks required for eating and often prevent the older adult from accepting help with feeding from caregivers. Systematic review. In 2006, literature searches using keywords (feeding, eating, nutrition, malnutrition, feeding assessment, dementia, ageing and concept analysis, dementia and feeding and excluding enteral feeding, tube feedings, PEG and enteral nutrition) were done in Medline, CINHAL, AGELINE and Social Science Full Text. Seventy relevant articles in English were found. After a review of the relevant articles, concept analysis was used to develop a definition of feeding difficulty, its defining characteristics and to delineate feeding difficulty from its antecedents and consequences. Feeding difficulties arise at the interface between the caregiver strategies to assist the older adult with getting food into the mouth and chewing and swallowing food. A model of feeding difficulty delineates the antecedents and consequences of feeding difficulties. The conceptual model of feeding difficulties provides a strong and clear organising structure for research that can be used to developed evidence based guidelines for practice. The conceptual model provides directions for assessment of feeding difficulties and their antecedents. The model can be used to identify interventions that address antecedents of feeding difficulty (risk factors) and different types of feeding difficulties.


Targeted variant detection using unaligned RNA-Seq reads.
Mutations identified in acute myeloid leukemia patients are useful for prognosis and for selecting targeted therapies. Detection of such mutations using next-generation sequencing data requires a computationally intensive read mapping step followed by several variant calling methods. Targeted mutation identification drastically shifts the usual tradeoff between accuracy and performance by concentrating all computations over a small portion of sequence space. Here, we present km, an efficient approach leveraging k-mer decomposition of reads to identify targeted mutations. Our approach is versatile, as it can detect single-base mutations, several types of insertions and deletions, as well as fusions. We used two independent cohorts (The Cancer Genome Atlas and Leucegene) to show that mutation detection by km is fast, accurate, and mainly limited by sequencing depth. Therefore, km allows the establishment of fast diagnostics from next-generation sequencing data and could be suitable for clinical applications.


Total-internal-reflection mode in holographic polymer dispersed liquid crystals.
We have developed a holographic polymer dispersed liquid-crystal device based on total internal reflection (TIR). In the field-off state, the holographic planes are slanted such that the angle of the diffraction beam is beyond the TIR angle of the glass substrate. The beam is trapped in the sample and propagates to the edge. In the field-on state, the holographic grating is erased and the incident beam propagates directly through the sample. Contrast ratios of 10 dB, submillisecond response times, and an index modulation of 0.042 at 1550 nm are reported.


[An outbreak of parainfluenza 3 virus infection in the elderly in a ward].
In the D ward of Nagoyashi-Koseiin geriatric hospital (36-beds), upper respiratory illnesses were recognized in all the inpatients between July and August in 1995, and we studied 7 elderly subjects with parainfluenza 3 infection diagnosed by serology and viral culture. The outbreak of upper respiratory illnesses occurred in the ward during the 17 days from July 21 through August 6, 1996. Fifteen of the 18 elderly persons with upper respiratory illnesses were tested by serology; parainfluenza 3 infection was identified in 7. One of the 7 patients, parainfluenza 3 virus was isolated. Seven elderly subjects with parainfluenza 3 infection were 2 males and 5 females and five of them (71.4%) were bedridden. The most common complaint was fever and coughing in 7/7 (100%), followed by sputum in 5/7 (71.4%), wheezing in 4/7 (42.9%). The pyrexial period in the parainfluenza-infected group ranged from 1 to 4 days (average 3.1 days), and was significantly shorter than that of the influenza group. The maximum recorded temperature in the parainfluenza-infected group ranged from 37.0 to 39.2 degrees C (average 38.1 degrees C), and was significantly lower than that of the influenza group. Two of the 7 patients with parainfluenza 3 virus infection had pneumonia, but nobody died, and all 7 patients recovered without sequele. It is possible that parainfluenza 3 virus infection among elderly subjects cause secondary bacterial infection, so we think that prevention of nosocomial parainfluenza infection should be a high priority in the case of outbreak of such an infection in a ward.


Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative.
Patients with rare and complex diseases such as congenital adrenal hyperplasia (CAH) often receive fragmented and inadequate care unless efforts are coordinated among providers. Translating the concepts of the medical home and comprehensive health care for individuals with CAH offers many benefits for the affected individuals and their families. This manuscript represents the recommendations of a 1.5 day meeting held in September 2009 to discuss the ideal goals for comprehensive care centers for newborns, infants, children, adolescents, and adults with CAH. Participants included pediatric endocrinologists, internal medicine and reproductive endocrinologists, pediatric urologists, pediatric surgeons, psychologists, and pediatric endocrine nurse educators. One unique aspect of this meeting was the active participation of individuals personally affected by CAH as patients or parents of patients. Representatives of Health Research and Services Administration (HRSA), New York-Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), and National Newborn Screening and Genetics Resource Center (NNSGRC) also participated. Thus, this document should serve as a "roadmap" for the development phases of comprehensive care centers (CCC) for individuals and families affected by CAH.


Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth.
Arsenic trioxide exhibits antiproliferative, antiangiogenic and proapoptotic activity in cancer cells, and many genes associated with these responses are regulated by specificity protein (Sp) transcription factors. Treatment of cancer cells derived from urologic (bladder and prostate) and gastrointestinal (pancreas and colon) tumors with arsenic trioxide demonstrated that these cells exhibited differential responsiveness to the antiproliferative effects of this agent and this paralleled their differential repression of Sp1, Sp3 and Sp4 proteins in the same cell lines. Using arsenic trioxide-responsive KU7 and non-responsive 253JB-V bladder cancer cells as models, we show that in KU7 cells, < or =5 microM arsenic trioxide decreased Sp1, Sp3 and Sp4 and several Sp-dependent genes and responses including cyclin D1, epidermal growth factor receptor, bcl-2, survivin and vascular endothelial growth factor, whereas at concentrations up to 15 microM, minimal effects were observed in 253JB-V cells. Arsenic trioxide also inhibited tumor growth in athymic mice bearing KU7 cells as xenografts, and expression of Sp1, Sp3 and Sp4 was significantly decreased. Inhibitors of oxidative stress such as glutathione or dithiothreitol protected KU7 cells from arsenic trioxide-induced antiproliferative activity and Sp repression, whereas glutathione depletion sensitized 253JB-V cells to arsenic trioxide. Mechanistic studies suggested that arsenic trioxide-dependent downregulation of Sp and Sp-dependent genes was due to decreased mitochondrial membrane potential and induction of reactive oxygen species, and the role of peroxides in mediating these responses was confirmed using hydrogen peroxide.


Altered sensory processing and dendritic remodeling in hyperexcitable visual cortical networks.
Epilepsy is characterized by impaired circuit function and a propensity for spontaneous seizures, but how plastic rearrangements within the epileptic focus trigger cortical dysfunction and hyperexcitability is only partly understood. Here we have examined alterations in sensory processing and the underlying biochemical and neuroanatomical changes in tetanus neurotoxin (TeNT)-induced focal epilepsy in mouse visual cortex. We documented persistent epileptiform electrographic discharges and upregulation of GABAergic markers at the completion of TeNT effects. We also found a significant remodeling of the dendritic arbors of pyramidal neurons, with increased dendritic length and branching, and overall reduction in spine density but significant preservation of mushroom, mature spines. Functionally, spontaneous neuronal discharge was increased, visual responses were less reliable, and electrophysiological and behavioural visual acuity was consistently impaired in TeNT-injected mice. These data demonstrate robust, long-term remodeling of both inhibitory and excitatory circuitry associated with specific disturbances of network function in neocortical epilepsy.


Identifying inaccuracies on emergency medicine residency applications.
Previous trials have showed a 10-30% rate of inaccuracies on applications to individual residency programs. No studies have attempted to corroborate this on a national level. Attempts by residency programs to diminish the frequency of inaccuracies on applications have not been reported. We seek to clarify the national incidence of inaccuracies on applications to emergency medicine residency programs. This is a multi-center, single-blinded, randomized, cohort study of all applicants from LCME accredited schools to involved EM residency programs. Applications were randomly selected to investigate claims of AOA election, advanced degrees and publications. Errors were reported to applicants' deans and the NRMP. Nine residencies reviewed 493 applications (28.6% of all applicants who applied to any EM program). 56 applications (11.4%, 95%CI 8.6-14.2%) contained at least one error. Excluding "benign" errors, 9.8% (95% CI 7.2-12.4%), contained at least one error. 41% (95% CI 35.0-47.0%) of all publications contained an error. All AOA membership claims were verified, but 13.7% (95%CI 4.4-23.1%) of claimed advanced degrees were inaccurate. Inter-rater reliability of evaluations was good. Investigators were reluctant to notify applicants' dean's offices and the NRMP. This is the largest study to date of accuracy on application for residency and the first such multi-centered trial. High rates of incorrect data were found on applications. This data will serve as a baseline for future years of the project, with emphasis on reporting inaccuracies and warning applicants of the project's goals.


Workplace bullying: the effectiveness of a workplace program.
Workplace bullying can not only cost thousands of dollars to replace an affected nurse, but also have detrimental economic effects on health care organizations. Occupational health nurses can provide leadership in preventing or eliminating workplace bullying. This pilot study determined that attendance at a cognitive rehearsal program decreased workplace bullying. The study used an Internet-based survey administered 6 months after nurses completed the 2-hour cognitive rehearsal program. Half of the nurses reported witnessing bullying behaviors since attending the program; 70% of the nurses reported changing their own behaviors following the course; and 40% of the nurses reported a decrease in bullying behaviors during the past 6 months. Although 70% of the nurses believed they could intervene in bullying situations, only 16% reported they responded to bullying at the time of occurrence. This study illuminates the need to continue searching for other effective methods to prevent and manage workplace bullying.


Acupuncture gone awry: a case report of a patient who required surgical removal of two single-use filament needles following acupuncture treatment.
Background: Acupuncture and dry needling are increasingly popular treatment modalities used to treat pain around the world. This case report documents the clinical history of a patient who presented to an outpatient physical therapy clinic following surgical removal of two single-use filament needles that fractured in the patient's neck during acupuncture treatment. Case Description: The purpose of this case report was to highlight a rare adverse event following acupuncture treatment. The patient received the acupuncture treatment from a practitioner licensed in acupuncture, while on an international business trip. Following the acupuncture treatment, the practitioner realized that a needle had fractured and remained in the patient's neck. After failing to retrieve the needle, the patient was sent for imaging. Radiograph revealed that the patient had two needle fragments located in his cervical tissue. After determining that the needles did not pose an immediate threat, the patient boarded a flight home to the United States. Following his flight, the patient presented to an American hospital where it was discovered that the needle fragments had migrated during the flight, with one needle now located 2 mm from the patient's vertebral artery. Surgical intervention was required to retrieve the needles, resulting in the patient needing physical therapy to increase cervical range of motion and mediate pain relief. Outcomes: The patient suffered a setback in his treatment of chronic neck pain that resulted in decreased cervical range of motion and increased pain. Discussion: Clinicians utilizing single-use filiform needles in their practice, whether for acupuncture or dry needling, should be aware of the potential for this type of adverse event. Further, to minimize the risk of similar adverse events occurring in the future, clinicians should make sure that they are using high quality needles and make a habit of counting in and counting out the needles that they use to verify that all needles are accounted for.


Substrates for microsomal azoreductase. Hammett substituent effects, NMR studies, and response to inhibitors.
In previous studies on azoreduction by microsomal cytochrome P-450, we identified two classes of substrates structurally related to 4-dimethylaminoazobenzene. Both require polar electron-donating groups for binding to enzyme and are differentiated by their structure, their redox potentials, their rates of chemical and enzymic reduction, and the influence on their metabolism of inducing agents, CO and O2. Azo compounds whose reductions are insensitive to CO and O2 (I-substrates) contain electron-donating substituents on either ring. Azo compounds whose reductions are O2- and CO-sensitive (S-substrates) also contain electron-withdrawing groups on the opposite (prime) ring. For all dyes, NMR studies revealed minor differences in the chemical shifts of the protons attached to the phenyl ring substituted with electron-donating substituents (ring A). This is consistent with the narrow range of pKa's (basicity) and KM values for all substrates. However, there are significant differences in the chemical shifts of the aromatic protons of the prime ring (ring B). The difference in chemical shifts is most pronounced for aromatic protons adjacent to the prime ring substituents, showing a clear distinction between I and S substrates. Furthermore, the Hammett sigma substituent constants on the prime ring clearly distinguish between the two classes of dyes. I- and S-substrates have negative and positive sigma Hammett values, respectively. This implies that the mechanism of microsomal azoreduction is critically dependent on the charge and redox potentials of the dyes and is exclusively determined by the nature of the substituents on the prime ring.(ABSTRACT TRUNCATED AT 250 WORDS)


Attentional capture by task-irrelevant fearful faces is revealed by the N2pc component.
We measured the N2pc component as an electrophysiological indicator of attentional selection to investigate whether fearful faces can attract attention even when they are entirely task-irrelevant and attention is focused on another demanding visual monitoring task. Participants had to detect infrequent luminance changes of the fixation cross, while ignoring stimulus arrays containing a face singleton (a fearful face among neutral faces, or neutral face among fearful faces) to the left or right of fixation. On trials without a target luminance change, an N2pc was elicited by fearful faces presented next to fixation, irrespective of whether they were singletons or not, demonstrating that irrelevant fearful faces can bias the spatial distribution of attention. The N2pc to fearful faces was attenuated when face arrays were presented simultaneously with a target luminance change, suggesting that concurrent target processing reduces attentional capture by emotional salient events.


Drug use patterns and continuous enrollment in college: results from a longitudinal study.
Few longitudinal studies have examined the relationship between illicit drug use and academic outcomes among college students. This study characterized drug use patterns of a cohort of young adults who were originally enrolled as first-time, first-year college students in a longitudinal study. It evaluated the association between these drug use patterns and continuous enrollment during college, holding constant demographic characteristics, high school grade point average, fraternity/sorority involvement, personality/temperament characteristics, nicotine dependence, and alcohol use disorder. Participants (n = 1,133; 47% male) were purposively selected from one university and interviewed annually for 4 years, beginning with their first year of college, regardless of continued college attendance. Enrollment data were culled from administrative records. Group-based trajectory analyses characterized 4-year longitudinal drug use patterns. Two grouping variables were derived based on (a) marijuana use frequency and (b) number of illicit drugs used other than marijuana. Seventy-one percent of the sample was continuously enrolled in the home institution during the first 4 years of study. Multivariable logistic regression models demonstrated that infrequent, increasing, and chronic/heavy marijuana use patterns were significantly associated with discontinuous enrollment (adjusted odds ratio = 1.66, 1.74, and 1.99, respectively), compared with minimal use, holding constant covariates. In separate models, drug use other than marijuana also was significantly associated with discontinuous enrollment. Marijuana use and other illicit drug use are both associated with a decreased likelihood of continuous enrollment in college, independent of several other possible risk factors. These findings highlight the need for early intervention with illicit drug users to mitigate possible negative academic consequences.


The caBIG terminology review process.
The National Cancer Institute (NCI) is developing an integrated biomedical informatics infrastructure, the cancer Biomedical Informatics Grid (caBIG), to support collaboration within the cancer research community. A key part of the caBIG architecture is the establishment of terminology standards for representing data. In order to evaluate the suitability of existing controlled terminologies, the caBIG Vocabulary and Data Elements Workspace (VCDE WS) working group has developed a set of criteria that serve to assess a terminology's structure, content, documentation, and editorial process. This paper describes the evolution of these criteria and the results of their use in evaluating four standard terminologies: the Gene Ontology (GO), the NCI Thesaurus (NCIt), the Common Terminology for Adverse Events (known as CTCAE), and the laboratory portion of the Logical Objects, Identifiers, Names and Codes (LOINC). The resulting caBIG criteria are presented as a matrix that may be applicable to any terminology standardization effort.


Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control (UKPDS 70).
We examined the prevalence of islet autoantibodies and their relationship to glycaemic control over 10 years in patients diagnosed clinically with new-onset type 2 diabetes. Patient clinical characteristics and autoantibody status were determined at entry to the UK Prospective Diabetes Study (UKPDS) before randomisation to different glucose control policies. Patients were followed for 10 years. Data available on 4,545 of the 5,102 UKPDS patients showed that 11.6% had antibodies to at least one of three antigens: islet cell cytoplasm, glutamic acid decarboxylase and islet autoantibody 2A (IA-2A). Autoantibody-positive patients were younger, more often Caucasian and leaner, with lower beta cell function and higher insulin sensitivity than autoantibody-negative patients. They also had higher HbA1c, and HDL-cholesterol levels, and lower blood pressure, total cholesterol and plasma triglyceride levels. Despite relative hyperglycaemia, autoantibody-positive patients were less likely to have the metabolic syndrome (as defined by the National Cholesterol Education Program Adult Treatment Program III), reflecting a more beneficial overall risk factor profile. Of 3,867 patients with post-dietary run-in fasting plasma glucose (FPG) values between 6.0 and 14.9 mmol/l and no hyperglycaemic symptoms, 9.4% were autoantibody-positive, compared with 25.1% of 678 patients with FPG values of 15.0 mmol/l or higher, or hyperglycaemic symptoms. In both groups, no differences were seen between those with and without autoantibodies in changes to HbA1c over time, but autoantibody-positive patients required insulin treatment earlier, irrespective of the allocated therapy (p<0.0001). Autoantibody-positive patients can be treated initially with sulphonylurea, but are likely to require insulin earlier than autoantibody-negative patients.


Estimation of wavelength difference using scale adjustment in two-wavelength digital holographic interferometry.
We propose a method for an estimation of wavelength difference using scale adjustment in two-wavelength digital holographic interferometry. To estimate wavelength difference, two holograms recorded with different wavelengths are reconstructed on the basis of the Fresnel diffraction integral, and pixel sizes in the reconstruction plane, which depend on the wavelength in recording hologram, are analyzed. In the analysis, a zero-padding method and an intensity correlation function are used to adjust pixel sizes in the reconstruction plane and then obtain a wavelength difference given by a difference between the pixel sizes. Theoretical predictions and experimental results are shown to indicate the usefulness of the proposed method in this paper.


Human gnathostomiasis: infection with an immature male Gnathostoma spinigerum.
Gnathostomiasis, usually caused by larvae of Gnathostoma spinigerum, is a significant cause of morbidity in the Far East. We report a case of gnathostomiasis involving a male Thai residing in Kuwait who presented with acute pain in the right iliac fossa. A resection of the terminal ileum and cecum was performed. Microscopic examination showed a parasite in an eosinophilic abscess. The nematode was identified as an immature male G. spinigerum based on size, morphology, and distribution of cuticular spines.


Ten-year follow-up of anorexia nervosa: clinical course and outcome.
The clinical course and outcome of anorexia nervosa are presented in a 10-year follow-up study of 76 severely ill females with anorexia nervosa who met specific diagnostic criteria and had participated in a well-documented hospital treatment study. Information was obtained on 100% of the subjects. A comprehensive assessment was made in 93% of the living subjects in specific categories of weight, eating and weight control behaviours, menstrual function, anorexic attitudes, and psychological, sexual, social and vocational adjustment. Five subjects had died, which gives a crude mortality rate of 6.6%. Standardized mortality rates demonstrated an almost 13-fold increase in mortality in the anorexia nervosa subjects. Only eighteen (23.7%) were fully recovered. Sixty-four per cent developed binge-eating at some time during their illness, 57% at least weekly. Twenty-nine (41%) were still bulimic at follow-up. The high frequency and chronicity of the bulimic symptoms plus the high rate of weight relapse (42% during the first year after hospital treatment) suggest that intensive intervention is needed to help anorexics restore and maintain their weight within a normal range and to decrease abnormal eating and weight control behaviours.


Two remarkable events in the field of intraocular foreign body: (1) The reversal of siderosis bulbi. (2) The spontaneous extrusion of an intraocular copper foreign body.
Two unusual events concerning intraocular foreign bodies are presented. The first patient had an occult or unsuspected intraocular foreign body. He showed iridoplegia with mydriasis, siderosis iridis, and an intraocular piece of iron lying posteriorly near the retina. The foreign body was removed and the patient regained normal iris color and pupillary activity. His vision remains 20/15 six years postoperatively dispite ensuing retinal detachment one year after removal of the foreign body. The second patient was a young boy injured by a blasting cap explosion. He lost one eye from the injury and had a piece of intraocular brass in his left eye. In spite of the development of chalcosis and a mature cataract the lens gradually shrank in the pupillary space permitting a clear aphakic area and 20/25 vision. The brass fragment migrated forward and inferiorly and was finally extruded under the conjunctiva five years later, where it was removed and chemically analyzed by x-ray diffraction.


A manifesto for reproducible science.
Improving the reliability and efficiency of scientific research will increase the credibility of the published scientific literature and accelerate discovery. Here we argue for the adoption of measures to optimize key elements of the scientific process: methods, reporting and dissemination, reproducibility, evaluation and incentives. There is some evidence from both simulations and empirical studies supporting the likely effectiveness of these measures, but their broad adoption by researchers, institutions, funders and journals will require iterative evaluation and improvement. We discuss the goals of these measures, and how they can be implemented, in the hope that this will facilitate action toward improving the transparency, reproducibility and efficiency of scientific research.


Review of therapeutic options and the management of patients with myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are a poorly understood group of disorders caused by one or more genetic aberrations in the bone marrow-derived cell line responsible for hematopoiesis. Recent advances in genetic medicine have offered new insights into the epigenesis as well as the prognosis of MDS, but have not resulted in new or improved curative treatment options. Bone marrow transplantation, introduced before the advent of genetic medicine, is still the only potential cure. Advances in other medical and pharmaceutical areas have broadened the scope of supportive care and disease-modifying therapies, and treating physicians now have a broad range of disease management options depending on a patient's likely prognosis. There is now clear evidence that appropriate supportive care and therapeutic intervention can improve progression-free and overall survival of MDS patients.


Item by item analysis strategy of the relationship between symptoms and signs in early dry eye.
The present study aimed at analyzing the relationship between several particular symptoms, risk factors or global questionnaire scores and some tear clinical signs in early dry eye patients. A total of 77 volunteers were enrolled in the study without any prior classification, although patients with severe dry eye were excluded. Two questionnaires were used to assess ocular symptoms and risk factors, and clinical tear signs were evaluated with four tests (osmolarity, ferning, break-up time and the phenol red thread test). Multiple linear regression analysis was performed to determine the relative predictive value of each particular ocular symptom and risk factor, for each clinical sign. This analysis was repeated using symptoms and risk factors global scores. The symptom "eyes stuck shut in the morning" was the only predictor variable for the sign "ferning crystallization" (R = 0.228, p < 0.05) and "dryness" for "break-up time" (R = -0.315, p < 0.01). "Burning sensation" and "computer use for more than 3 h" were predictor variables for "tear osmolarity" (R = 0.342, p < 0.01), while "itching" and "female gender" were found to predict the outcomes of the "phenol red thread test" (R = -0.462, p < 0.05). Global questionnaire scores were not found to predict any tear clinical sign. The present findings support the informative value of exploring the associations between clinical signs, ocular symptoms and risk factors by following an item by item strategy rather than opting for global questionnaire scores.


Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements.
The negative impact of consuming sugar-sweetened beverages on weight and other health outcomes has been increasingly recognized; therefore, many people have turned to high-intensity sweeteners like aspartame, sucralose, and saccharin as a way to reduce the risk of these consequences. However, accumulating evidence suggests that frequent consumers of these sugar substitutes may also be at increased risk of excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. This paper discusses these findings and considers the hypothesis that consuming sweet-tasting but noncaloric or reduced-calorie food and beverages interferes with learned responses that normally contribute to glucose and energy homeostasis. Because of this interference, frequent consumption of high-intensity sweeteners may have the counterintuitive effect of inducing metabolic derangements.


Fimbriae- and flagella-mediated association with and invasion of cultured epithelial cells by Salmonella enteritidis.
Salmonella enteritidis expresses flagella and several finely regulated fimbriae, including SEF14, SEF17 and SEF21 (type 1). A panel of mutants was prepared in three strains of S. enteritidis to elucidate the role of these surface appendages in the association with and invasion of cultured epithelial cells. In all assays, the naturally occurring regulatory-defective strain 27655R associated with tissue culture cells significantly more than wild-type progenitor strains LA5 and S1400/94. Compared with wild-type strains, SEF14 mutants had no effect on association and invasion, whereas SEF17, SEF21 and aflagellate mutants showed significant reductions in both processes. Histological examination suggested a role for SEF17 in localized, aggregative adherence, which could be specifically blocked by anti-SEF17 sera and purified SEF17 fimbriae. SEF21-mediated association was neutralized by mannose and a specific monoclonal antibody, although to observe enhanced association it was necessary for the bacteria to be in fimbriate phase prior to infection. Additionally, aflagellate mutants associated and invaded less than motile bacteria. This study demonstrated the potential for multifactorial association and invasion of epithelial cells which involved SEF17 and SEF21 fimbriae, and flagella-mediated motility.


Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors.
CA1 pyramidal neurons degenerate after transient forebrain ischemia, whereas neurons in other regions of the hippocampus remain intact. Here we show that in rat hippocampal CA1 neurons, forebrain ischemia induces the phosphorylation of the N-methyl-D-aspartate (NMDA) receptor 2A subunit at Ser1232 (phospho-Ser1232). Ser1232 phosphorylation is catalyzed by cyclin-dependent kinase 5 (Cdk5). Inhibiting endogenous Cdk5, or perturbing interactions between Cdk5 and NR2A subunits, abolished NR2A phosphorylation at Ser1232 and protected CA1 pyramidal neurons from ischemic insult. Thus, we conclude that modulation of NMDA receptors by Cdk5 is the primary intracellular event underlying the ischemic injury of CA1 pyramidal neurons.


Ayahuasca Exposure: Descriptive Analysis of Calls to US Poison Control Centers from 2005 to 2015.
Ayahuasca is a hallucinogenic plant preparation which usually contains the vine Banisteriopsis caapi and the shrub Psychotria viridis. This tea originates from the Amazon Basin where it is used in religious ceremonies. Because interest in these religious groups spreading as well as awareness of use of ayahuasca for therapeutic and recreational purposes, its use is increasing. Banisteriopsis caapi is rich in β-carbolines, especially harmine, tetrahydroharmine and harmaline, which have monoamine oxidase inhibiting (MAOI) activity. Psychotria viridis contains the 5HT2A/2C/1A receptor agonist hallucinogen N,N-dimethyltryptamine (DMT). Usual desired effects include hallucination, dissociation, mood alteration and perception change. Undesired findings previously reported are nausea, vomiting, hypertension, and tachycardia. All human exposure calls reported to the American Association of Poison Controls Centers' (AAPCC) National Poison Data System (NPDS) between September 1, 2005 and September 1, 2015 were reviewed. Cases were filtered for specific plant derived ayahuasca-related product codes. Abstracted data included the following: case age and gender, exposure reason, exposure route, clinical manifestations, treatments given, medical outcomes and fatality. Five hundred and thirty-eight exposures to ayahuasca botanical products were reported. The majority of the calls to poison control centers came from healthcare facilities (83%). The most common route of exposure was ingestion. Most cases were men (437, 81%, 95% CI 77.7% - 84.3%). The median age was 21 (IQR 18-29). Most exposures were acute. Three hundred thirty-seven (63%) were reported to have a major or moderate clinical effect. The most common clinical manifestations reported were hallucinations (35%), tachycardia (34%), agitation (34%), hypertension (16%), mydriasis (13%) and vomiting (6%). Benzodiazepines were commonly given (30%). There were 28 cases in the series who required endotracheal intubation (5%). Four cases were reported to have had a cardiac arrest and 7 a respiratory arrest. Twelve cases had a seizure. Reports of exposures called to poison centers appeared to increase during this period based on annual estimates. Three fatalities were reported. Ayahuasca use appears to be rising in the United States based on calls to poison control centers. While most use is reported to be safe and well tolerated, with possible beneficial effects, serious and life threatening adverse manifestations are possible. Most of the exposures reported to poison control centers were young people, more likely to be men and already in a healthcare facility. Further research, which includes comprehensive drug testing, will be needed to better identify the risks and effects of ayahuasca use.


Single-stage bilateral medial Oxford Unicompartmental Knee Arthroplasty: A case-control study of perioperative blood loss, complications and functional results.
The benefits and risks of a single-stage medial UKA remains a subject of debate because of the theoretically higher risk of complications and specifically blood loss. The aim of this study was to evaluate the perioperative blood loss, risks and the functional results of single-stage bilateral medial Oxford Unicompartmental Knee Arthroplasty (OUKA) compared to a standard unilateral medial OUKA procedure (control group). The blood loss observed during bilateral single-stage medial Oxford UKA is not different from that of the control group. In this case-control prospective study, fifty patients (100 knees) who underwent single-stage bilateral medial OUKA (study group) were compared to a hundred patients (100 knees) with unilateral medial OUKA (control group), performed by the same surgeon. The real blood loss (in mL of hematocrit at 100%), incidence of blood transfusions, and complication rates were compared. Clinical results were assessed at 6 month and at a two-year minimum follow-up (FU) using IKS, KOOS and OKS scores, in addition to a satisfaction questionnaire. Groups were deemed comparable. Concerning blood loss, no significant difference was observed compared to the control group (465mL±225 vs. 396±190; p=0.07). No difference was found, either, between groups regarding the complication rates (p=0.36), nor the clinical results (p=0.61) and patient satisfaction (p=0.23) at last FU. Single-stage bilateral procedure does not cause increased blood loss compared with controls. Moreover, clinical results were deemed good and excellent in spite of a slightly greater complication rate than those found in the literature but similar to controls. Case-control study, level III.


Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis.
Genetic determinants of the early steps of carcinogenesis on cirrhosis are still poorly understood. We aimed to evaluate the occurrence of telomerase reverse transcriptase (TERT) promoter mutations in the transformation of cirrhotic nodules into hepatocellular carcinoma (HCC). We analyzed a series of 268 liver samples, including 96 nodules developed in 58 patients with cirrhosis and 114 additional cirrhosis. All samples were screened for TERT promoter mutations, and in 31 nodules, for 10 genes recurrently mutated in HCC. Immunohistochemistry (IHC) analyses were performed for glypican 3, glutamine synthase, and heat shock protein 70. Six liver pathologists reviewed all the samples. Among The 96 nodules, 88 were firmly diagnosed as low-grade dysplastic nodules (LGDNs; 32 cases), high-grade dysplastic nodules (HGDNs; 16 cases), early HCC (eHCC; 23 cases), or small and progressed HCC in 17 cases. The agreement between the initial diagnosis from pathological report and the final expert consensus report was moderate for the diagnosis of benign versus malignant nodules (weighted kappa = 0.530). TERT promoter mutations were highly related to the step-wise hepatocarcinogenesis because mutations were identified in 6% of LGDNs, 19% of HGDNs, 61% of eHCCs, and 42% of small and progressed HCC. TERT promoter mutation is the most frequent molecular alteration in eHCC given that the IHC criteria for diagnosis of malignancy were found in only 39% of the cases. TERT promoter mutation was also the earliest genetic alteration because mutations in 10 other genes were only identified in 28% of the small and progressed HCC. Frequency of TERT promoter mutations rapidly increases during the different steps of the transformation of premalignant lesions into HCC on cirrhosis. Consequently, somatic TERT promoter mutation is a new biomarker predictive of transformation of premalignant lesions into HCC.


Damage in the anca-associated vasculitides: long-term data from the European vasculitis study group (EUVAS) therapeutic trials.
To describe short-term (up to 12 months) and long-term (up to 7 years) damage in patients with newly diagnosed antineutrophil-cytoplasm antibody-associated vasculitis (AAV). Data were combined from six European Vasculitis Study group trials (n=735). Long-term follow-up (LTFU) data available for patients from four trials (n=535). Damage accrued was quantified by the Vasculitis Damage Index (VDI). Sixteen damage items were defined a priori as being potentially treatment-related. VDI data were available for 629 of 735 patients (85.6%) at baseline, at which time 217/629 (34.5%) had ≥1 item of damage and 32 (5.1%) ≥5 items, reflecting disease manifestations prior to diagnosis and trial enrolment. LTFU data were available for 467/535 (87.3%) at a mean of 7.3 years postdiagnosis. 302/535 patients (56.4%) had VDI data at LTFU, with 104/302 (34.4%) having ≥5 items and only 24 (7.9%) no items of damage. At 6 months and LTFU, the most frequent items were proteinuria, impaired glomerular filtration rate, hypertension, nasal crusting, hearing loss and peripheral neuropathy. The frequency of damage, including potentially treatment-related damage, rose over time (p<0.01). At LTFU, the most commonly reported items of treatment-related damage were hypertension (41.5%; 95% CI 35.6 to 47.4%), osteoporosis (14.1%; 9.9 to 18.2%), malignancy (12.6%; 8.6 to 16.6%), and diabetes (10.4%; 6.7 to 14.0%). In AAV, renal, otolaryngological and treatment-related (cardiovascular, disease, diabetes, osteoporosis and malignancy) damage increases over time, with around one-third of patients having ≥5 items of damage at a mean of 7 years postdiagnosis.


A large T cell invagination with CD2 enrichment resets receptor engagement in the immunological synapse.
T cell activation is driven by the TCR and complemented by costimulation. We have studied the dynamics of ligand-engagement of the costimulatory receptor CD2 in T cell/APC couples. Thousands of ligand-engaged CD2 molecules were included in a large T cell invagination at the center of the cellular interface within 1 min of cell couple formation. The structure and regulation of this invagination shared numerous features with phagocytosis and macropinocytosis. Three observations further characterize the invagination and the inclusion of CD2: 1) numerous ligand-engaged receptors were enriched in and internalized through the T cell invagination, none as prominently as CD2; 2) dissolution of the T cell invagination and CD2 engagement were required for effective proximal T cell signaling; and 3) the T cell invagination was uniquely sensitive to the affinity of the TCR for peptide-MHC. Based on this characterization, we speculate that the T cell invagination, aided by CD2 enrichment, internalizes parts of the TCR signaling machinery to reset T cell signaling upon agonist-mediated, stable APC contact.