Genetic diversity and antimicrobial susceptibility of Campylobacter jejuni isolates associated with sheep abortion in the United States and Great Britain.
Campylobacter infection is a leading cause of ovine abortion worldwide. Historically, genetically diverse Campylobacter fetus and Campylobacter jejuni strains have been implicated in such infections, but since 2003 a highly pathogenic, tetracycline-resistant C. jejuni clone (named SA) has become the predominant cause of sheep abortions in the United States. Whether clone SA was present in earlier U.S. abortion isolates (before 2000) and is associated with sheep abortions outside the United States are unknown. Here, we analyzed 54 C. jejuni isolates collected from U.S. sheep abortions at different time periods and compared them with 42 C. jejuni isolates associated with sheep abortion during 2002 to 2008 in Great Britain, using multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and array-based comparative genomic hybridization (CGH). Although clone SA (ST-8) was present in the early U.S. isolates, it was not as tetracycline resistant (19% versus 100%) or predominant (66% versus 91%) as it was in the late U.S isolates. In contrast, C. jejuni isolates from Great Britain were genetically diverse, comprising 19 STs and lacking ST-8. PFGE and CGH analyses of representative strains further confirmed the population structure of the abortion isolates. Notably, the Great Britain isolates were essentially susceptible to most tested antibiotics, including tetracycline, while the late U.S. isolates were universally resistant to this antibiotic, which could be explained by the common use of tetracyclines for control of sheep abortions in the United States but not in Great Britain. These results suggest that the dominance of clone SA in sheep abortions is unique to the United States, and the use of tetracyclines may have facilitated selection of this highly pathogenic clone.


Development of HPTLC method for determination of cefpodoxime proxetil and ambroxol hydrochloride in human plasma by liquid-liquid extraction.
To develop a simple, sensitive, rapid, and economic high performance thin layer chromatographic method for determination of cefpodoxime proxetil (CEFPO) and ambroxol hydrochloride (AMBRO) in human plasma by liquid-liquid extraction using paracetamol as an internal standard. The plasma sample was extracted by a mixture of methanol and acetonitrile. A concentration range from 500 to 3500 ng/spot for CEFPO and 1000 to 7000 ng/spot for AMBRO were used for the calibration curve, respectively. This recovery was found to be 74.40 and 94.50 for CEFPO and AMBRO, respectively. The mobile phase used consists of chloroform: methanol (9:1v/v). Densitometric analysis was carried out at a wavelength of 240 nm. The Rf values for CEFPO, AMBRO, and paracetamol were found to be 0.69 ± 0.005, 0.49 ± 0.0057, and 0.31 ± 0.0054, respectively. The stability of CEFPO and AMBRO in plasma was confirmed during three freeze-thaw cycles (-20°C), on bench during 24 h and post preparative during 48 h. The proposed method was validated statistically and by performing a recovery study for determination of CEFPO and AMBRO in human plasma.


The Still Bay and Howiesons Poort at Sibudu and Blombos: Understanding Middle Stone Age Technologies.
The classification of archaeological assemblages in the Middle Stone Age of South Africa in terms of diversity and temporal continuity has significant implications with respect to recent cultural evolutionary models which propose either gradual accumulation or discontinuous, episodic processes for the emergence and diffusion of cultural traits. We present the results of a systematic technological and typological analysis of the Still Bay assemblages from Sibudu and Blombos. A similar approach is used in the analysis of the Howiesons Poort (HP) assemblages from Sibudu seen in comparison with broadly contemporaneous assemblages from Rose Cottage and Klasies River Cave 1A. Using our own and published data from other sites we report on the diversity between stone artifact assemblages and discuss to what extent they can be grouped into homogeneous lithic sets. The gradual evolution of debitage techniques within the Howiesons Poort sequence with a progressive abandonment of the HP technological style argues against the saltational model for its disappearance while the technological differences between the Sibudu and Blombos Still Bay artifacts considerably weaken an interpretation of similarities between the assemblages and their grouping into the same cultural unit. Limited sampling of a fragmented record may explain why simple models of cultural evolution do not seem to apply to a complex reality.


D-dimer relates positively with increased blood pressure in black South Africans: the SABPA study.
Hypertension is highly prevalent in black South Africans in which morbidity and mortality from stroke are on the increase. Elevated blood pressure and haemostatic markers can induce changes in blood rheology and endothelial function which could result in a procoagulant state that increases the risk for cerebrovascular disease. Information about the coagulation and fibrinolytic systems of people from African descent are limited. We therefore, investigated the haemostatic profile and its relationships with blood pressure in black South Africans. We measured ambulatory blood pressure and haemostatic markers of 201 black and 208 white school teachers. The haemostatic markers included measurements representing coagulation and fibrinolysis (von Willebrand factor, fibrinogen, plasminogen activator inhibitor-1, fibrin D-dimer and clot lysis time). Black participants displayed significantly higher blood pressure, von Willebrand factor, fibrinogen, plasminogen activator inhibitor-1 and D-dimer levels and longer clot lysis times (p≤0.001). Single, partial and multiple regression analyses showed that systolic (p≤0.011) and diastolic blood pressure (p=0.010) correlated positively with D-dimer in black participants, while systolic (p≤0.001) and daytime diastolic blood pressure (p=0.011) correlated negatively with clot lysis time in white participants. The black population had a more prothrombotic profile, with higher levels of coagulation markers and inhibited fibrinolysis, than the white study participants. The positive association between blood pressure and elevated D-dimer in the blacks may contribute to the high prevalence of hypertension and related increased cardiovascular and cerebrovascular risk in this group.


Dynamics of liquid plugs in prewetted capillary tubes: from acceleration and rupture to deceleration and airway obstruction.
The dynamics of individual liquid plugs pushed at a constant pressure head inside prewetted cylindrical capillary tubes is investigated experimentally and theoretically. It is shown that, depending on the thickness of the prewetting film and the magnitude of the pressure head, the plugs can either experience a continuous acceleration leading to a dramatic decrease of their size and eventually their rupture or conversely, a progressive deceleration associated with their growth and an exacerbation of the airway obstruction. These behaviors are quantitatively reproduced using a simple nonlinear model [Baudoin et al., Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 859] adapted here for cylindrical channels. Furthermore, an analytical criterion for the transition between these two regimes is derived and successfully compared with extensive experimental data. The potential implications of this work for pulmonary obstructive diseases are discussed.


The role of ultrasound in the diagnosis and management of carpal tunnel syndrome: a new paradigm.
Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy, affecting 9% of women, and it is responsible for significant morbidity and occupational absence. Clinical assessment is used for initial diagnosis and nerve conduction (NC) studies are currently the principal test used to confirm the diagnosis. Sensitivity of NC studies is >85% and specificity is >95%. There is now good evidence that US can be used as an alternative to NC studies to diagnose CTS. US can assess the anatomy of the median nerve and also identify pathology of the surrounding structures that may compress the nerve. Median nerve enlargement (cross-sectional area ≥10 mm(2) at the level of the pisiform bone or tunnel inlet) is the most commonly used parameter to diagnose CTS on US, and sensitivity has been reported to be as high as 97.9% using this parameter. US may also be used to guide therapeutic corticosteroid injection into the carpal tunnel--thus avoiding median nerve injury--and to objectively monitor the response to treatment. There is now sufficient evidence to propose a new paradigm for the diagnosis of CTS that incorporates US. US is proposed as the initial diagnostic test in CTS based on similar sensitivity and specificity to NC studies but higher patient acceptability, lower cost and additional capability to assess carpal tunnel anatomy and guide injection.


Correlation of Minimum Inhibitory Concentration Breakpoints and Methicillin Resistance Gene Carriage in Clinical Isolates of Staphylococcus epidermidis.
Staphylococcus epidermidis is the most important member of coagulase negative staphylococci responsible for community and hospital acquired infections. Most clinical isolates of S. epidermidis are resistant to methicillin making these infections difficult to treat. In this study, correlation of methicillin resistance phenotype was compared with methicillin resistance (mecA) gene carriage in 55 clinical isolates of S. epidermidis. Susceptibility was measured by disc diffusion using methicillin discs, and minimum inhibitory concentrations (MIC) were measured using broth microdilution. Methicillin resistance gene (MecA gene) carriage was detected by specific primers and PCR. Disc susceptibility results showed 90.9% resistance to methicillin. Considering a MIC of 4 µg/ml, 78.1% of the isolates were methicillin resistant, 76.36% of which carried the mecA gene. On the other hand, when a breakpoint of 0.5 µg/ml was used, 89.09% were methicillin resistant, of which 93.75% were mecA positive. There was a better correlation between MIC of 0.5 µg/ml with disc diffusion results and mecA gene carriage. The findings suggest that despite the usefulness of molecular methods for rapid diagnosis of virulence genes, gene carriage does not necessarily account for virulence phenotype. Ultimately, gene expression, which is controlled by the environment, would determine the outcome.


Iterative learning control with unknown control direction: a novel data-based approach.
Iterative learning control (ILC) is considered for both deterministic and stochastic systems with unknown control direction. To deal with the unknown control direction, a novel switching mechanism, based only on available system tracking error data, is first proposed. Then two ILC algorithms combined with the novel switching mechanism are designed for both deterministic and stochastic systems. It is proved that the ILC algorithms would switch to the right control direction and stick to it after a finite number of cycles. Moreover, the input sequence converges to the desired one under the deterministic case. The input sequence converges to the optimal one with probability 1 under stochastic case and the resulting tracking error tends to its minimal value.


Diabetic Mario: Designing and Evaluating Mobile Games for Diabetes Education.
Traditionally, diabetes education has relied on written materials, with limited resources available for children with diabetes. Mobile games can be effective and motivating tools for the promotion of children's health. In our earlier work, we proposed a novel approach for designing computer games aimed at educating children with diabetes. In this article, we apply our game design to a mobile Android game (Mario Brothers). We also introduce four heuristics that are specifically designed for evaluating the mobile game, by adapting traditional usability heuristics. Results of a pilot study (n = 12) to evaluate gameplay over 1-week showed that the children found the game engaging and improved their knowledge of healthy diet and lifestyle.


Pleural mesothelioma: epidemiological and public health issues. Report from the Second Italian Consensus Conference on Pleural Mesothelioma.
Malignant mesothelioma is closely connected to asbestos exposure, with epidemiological patterns closely reshaping the geography and history of asbestos exposure. Mechanisms of causation and of interaction of asbestos fibres with pleura are complex and currently not yet completely understood. Curative efforts so far provided little results. Italy shows one of the highest incidence of MM and developed a network of specialized cancer registries in order to monitor disease occurrence and describe its epidemiology in details. The second Italian Consensus Conference on Pleural Mesothelioma convened in Torino on November 24th-25th, 2011. Besides the main consensus report summarizing the contribution of the different expertises, that was published elsewhere, the participants in 'Public Health and Epidemiology' section decided to report in major details the evidence and the conclusions regarding epidemiology, causative mechanisms and the public health impact of the disease.


Temporal and spectral cues for musical timbre perception in electric hearing.
The purpose of this study was to investigate musical timbre perception in cochlear-implant (CI) listeners using a multidimensional scaling technique to derive a timbre space. Methods Sixteen stimuli that synthesized western musical instruments were used (McAdams, Winsberg, Donnadieu, De Soete, & Krimphoff, 1995). Eight CI listeners and 15 normal-hearing (NH) listeners participated. Each listener made judgments of dissimilarity between stimulus pairs. Acoustical analyses that characterized the temporal and spectral characteristics of each stimulus were performed to examine the psychophysical nature of each perceptual dimension. For NH listeners, the timbre space was best represented in three dimensions, one correlated with the temporal envelope (log-attack time) of the stimuli, one correlated with the spectral envelope (spectral centroid), and one correlated with the spectral fine structure (spectral irregularity) of the stimuli. The timbre space from CI listeners, however, was best represented by two dimensions, one correlated with temporal envelope features and the other weakly correlated with spectral envelope features of the stimuli. Temporal envelope was a dominant cue for timbre perception in CI listeners. Compared to NH listeners, CI listeners showed reduced reliance on both spectral envelope and spectral fine structure cues for timbre perception.


Biologically controlled synthesis and assembly of magnetite nanoparticles.
Magnetite nanoparticles have size- and shape-dependent magnetic properties. In addition, assemblies of magnetite nanoparticles forming one-dimensional nanostructures have magnetic properties distinct from zero-dimensional or non-organized materials due to strong uniaxial shape anisotropy. However, assemblies of free-standing magnetic nanoparticles tend to collapse and form closed-ring structures rather than chains in order to minimize their energy. Magnetotactic bacteria, ubiquitous microorganisms, have the capability to mineralize magnetite nanoparticles, the so-called magnetosomes, and to direct their assembly in stable chains via biological macromolecules. In this contribution, the synthesis and assembly of biological magnetite to obtain functional magnetic dipoles in magnetotactic bacteria are presented, with a focus on the assembly. We present tomographic reconstructions based on cryo-FIB sectioning and SEM imaging of a magnetotactic bacterium to exemplify that the magnetosome chain is indeed a paradigm of a 1D magnetic nanostructure, based on the assembly of several individual particles. We show that the biological forces are a major player in the formation of the magnetosome chain. Finally, we demonstrate by super resolution fluorescence microscopy that MamK, a protein of the actin family necessary to form the chain backbone in the bacteria, forms a bundle of filaments that are not only found in the vicinity of the magnetosome chain but are widespread within the cytoplasm, illustrating the dynamic localization of the protein within the cells. These very simple microorganisms have thus much to teach us with regards to controlling the design of functional 1D magnetic nanoassembly.


Atrioventricular septal defects among infants in Europe: a population-based study of prevalence, associated anomalies, and survival.
To describe the epidemiology of chromosomal and non-chromosomal cases of atrioventricular septal defects in Europe. Data were obtained from EUROCAT, a European network of population-based registries collecting data on congenital anomalies. Data from 13 registries for the period 2000-2008 were included. There was a total of 993 cases of atrioventricular septal defects, with a total prevalence of 5.3 per 10,000 births (95% confidence interval 4.1 to 6.5). Of the total cases, 250 were isolated cardiac lesions, 583 were chromosomal cases, 79 had multiple anomalies, 58 had heterotaxia sequence, and 23 had a monogenic syndrome. The total prevalence of chromosomal cases was 3.1 per 10,000 (95% confidence interval 1.9 to 4.3), with a large variation between registers. Of the 993 cases, 639 cases were live births, 45 were stillbirths, and 309 were terminations of pregnancy owing to foetal anomaly. Among the groups, additional associated cardiac anomalies were most frequent in heterotaxia cases (38%) and least frequent in chromosomal cases (8%). Coarctation of the aorta was the most common associated cardiac defect. The 1-week survival rate for live births was 94%. Of all cases, three-quarters were associated with other anomalies, both chromosomal and non-chromosomal. For infants with atrioventricular septal defects and no chromosomal anomalies, cardiac defects were often more complex compared with infants with atrioventricular septal defects and a chromosomal anomaly. Clinical outcomes for atrioventricular septal defects varied between regions. The proportion of termination of pregnancy for foetal anomaly was higher for cases with multiple anomalies, chromosomal anomalies, and heterotaxia sequence.


Curated genome annotation of Oryza sativa ssp. japonica and comparative genome analysis with Arabidopsis thaliana.
We present here the annotation of the complete genome of rice Oryza sativa L. ssp. japonica cultivar Nipponbare. All functional annotations for proteins and non-protein-coding RNA (npRNA) candidates were manually curated. Functions were identified or inferred in 19,969 (70%) of the proteins, and 131 possible npRNAs (including 58 antisense transcripts) were found. Almost 5000 annotated protein-coding genes were found to be disrupted in insertional mutant lines, which will accelerate future experimental validation of the annotations. The rice loci were determined by using cDNA sequences obtained from rice and other representative cereals. Our conservative estimate based on these loci and an extrapolation suggested that the gene number of rice is approximately 32,000, which is smaller than previous estimates. We conducted comparative analyses between rice and Arabidopsis thaliana and found that both genomes possessed several lineage-specific genes, which might account for the observed differences between these species, while they had similar sets of predicted functional domains among the protein sequences. A system to control translational efficiency seems to be conserved across large evolutionary distances. Moreover, the evolutionary process of protein-coding genes was examined. Our results suggest that natural selection may have played a role for duplicated genes in both species, so that duplication was suppressed or favored in a manner that depended on the function of a gene.


Testing vaccines in human experimental malaria: statistical analysis of parasitemia measured by a quantitative real-time polymerase chain reaction.
Clinical trials are an essential step in evaluation of safety and efficacy of malaria vaccines, and human experimental malaria infections have been used for evaluation of protective immunity of Plasmodium falciparum malaria. In this study, a quantitative real-time polymerase chain reaction was used to measure P. falciparum malaria parasitemia in non-immune volunteers who had been experimentally infected by mosquito bites. Based on a remarkably small variation in the kinetics of parasitemia, a statistical model was developed that provides detailed estimates of pre-patent periods and parasite multiplication of blood stages. Using this model, we could predict results on vaccine efficacy for 1) pre-erythrocytic vaccines in the asymptomatic incubation period and 2) asexual stage vaccines after a limited number of multiplication cycles. The model shows that stage-specific vaccines even with limited efficacy can be highly efficacious when used in combination. This P. falciparum challenge method significantly adds to the potential to evaluate efficacy of candidate malaria vaccines before going into field trials.


Reflected shadow method for the study of constrained zones in cracked plates.
An optical method was developed for the study of constrained zones around cracks in transparent specimens made of birefringent materials under conditions of plane stress. The absolute retardations of light rays impinging normally at the plate, partly reflected from the back face, and twice refracted at the front face create a caustic when emerged from the plate, which has the shape of a generalized epicycloid, when it is projected on a screen far from the plate. The caustic defines the constrained zone surrounding a crack tip. The characteristic properties of the caustic were studied in relation to the straining mode of the plate.


Assessment of the 2006 revised antiphospholipid syndrome classification criteria.
To analyse antiphospholipid (aPL) antibody-positive patients using the 2006 revised antiphospholipid syndrome (APS) classification criteria. A descriptive study of 200 aPL-positive patients identified in a local, hospital-based registry, analysing demographic, clinical and aPL characteristics. Patients were analysed for (1) fulfillment of the 1999 original (Sapporo) and 2006 revised APS classification criteria; (2) non-criteria aPL features (for all aPL-positive patients, based on the 2006 revised criteria definitions); and (3) non-aPL thrombosis risk factors at the time of the clinical events (for patients with APS, based on the 2006 revised criteria stratifications). Of the 200 patients, 183 patients had sufficient data for analysis. Of these, 39 (21%) patients did not meet the laboratory requirement of the original 1999 criteria. Of 81 patients with APS who met the 1999 classification criteria, 47 (58%) also met the 2006 revised criteria. Of 63 asymptomatic (no vascular or pregnancy events) aPL-positive patients who met the laboratory requirement of the 1999 classification criteria, 38 (60%) also met the laboratory requirement of the 2006 revised criteria. More than 50% of the patients with APS with vascular events had identifiable non-aPL thrombosis risk factors at the time of clinical events. Only 59% of the patients meeting the 1999 APS Sapporo classification criteria met the 2006 APS classification criteria. The revised criteria will have positive implications in APS research by way of limiting the inclusion of a heterogeneous group of patients and also by way of providing a risk-stratified approach.


Optimization of a pre-MEKC separation SPE procedure for steroid molecules in human urine samples.
Many steroid hormones can be considered as potential biomarkers and their determination in body fluids can create opportunities for the rapid diagnosis of many diseases and disorders of the human body. Most existing methods for the determination of steroids are usually time- and labor-consuming and quite costly. Therefore, the aim of analytical laboratories is to develop a new, relatively low-cost and rapid implementation methodology for their determination in biological samples. Due to the fact that there is little literature data on concentrations of steroid hormones in urine samples, we have made attempts at the electrophoretic determination of these compounds. For this purpose, an extraction procedure for the optimized separation and simultaneous determination of seven steroid hormones in urine samples has been investigated. The isolation of analytes from biological samples was performed by liquid-liquid extraction (LLE) with dichloromethane and compared to solid phase extraction (SPE) with C18 and hydrophilic-lipophilic balance (HLB) columns. To separate all the analytes a micellar electrokinetic capillary chromatography (MECK) technique was employed. For full separation of all the analytes a running buffer (pH 9.2), composed of 10 mM sodium tetraborate decahydrate (borax), 50 mM sodium dodecyl sulfate (SDS), and 10% methanol was selected. The methodology developed in this work for the determination of steroid hormones meets all the requirements of analytical methods. The applicability of the method has been confirmed for the analysis of urine samples collected from volunteers--both men and women (students, amateur bodybuilders, using and not applying steroid doping). The data obtained during this work can be successfully used for further research on the determination of steroid hormones in urine samples.


Enhancement of fluorescence molecular tomography with structural-prior-based diffuse optical tomography: combating optical background uncertainty.
The common approach in fluorescence molecular tomography (FMT) assumes homogeneous distributions of the optical properties and normally results in reconstructions of low sensitivity. A natural enhancement is to incorporate diffuse optical tomography (DOT) to FMT. However, the traditional voxel-based DOT has been a severely ill-posed inverse problem and cannot retrieve the optical property distributions accurately. We present a structural-prior-based DOT method to effectively acquire the heterogeneous optical background with the aid of some imperfect structural priors from x-ray computed tomography and/or magnetic resonance imaging anatomical imaging modalities, and quantitatively compare its hard- and soft-prior schemes for achieving an improved recovery of the fluorescence distribution. Numerical simulations are conducted on a region-labeled three-dimensional (3D) digital mouse model to investigate the performance of this method. Physical experiments on a cylindrical phantom are also conducted to assess this methodology. Our simulated and experimental reconstruction results indicate that the structural-prior-based DOT guided FMT approach can significantly improve the sensitivity of FMT reconstruction, as well as its imaging resolution and quantitative accuracy.


Measuring Uptake and Elimination of Nitrogen in Humans at Different Ambient Pressures.
To measure nitrogen (N2) wash-out and uptake requires elaborate set-ups, especially when doing the measurements at increased or decreased ambient pressure. Here we present a transportable device for quantifying N2 turnover in humans which can be used at different ambient pressures. A modified close-circuit electronic rebreather was used to assess N2 turnover. Changes in N2 volume within the rebreathing circuit, reflecting N2 uptake or washout, were derived from the continuously monitored total system volume and the calculated volumes of oxygen and water vapor. The calculation of continuous N2 volume curves was performed off-line using dedicated computer software. Four subjects participated in the proof-of-concept tests. At steady state, the drift in calculated N2 volume in the rebreathing circuit over a 1-h duration was minimal. Three of the subjects participated in additional N2 steady-state measurements where 1019 mL (BTPD) of N2 was injected into the rebreathing circuit over 20 min and the measured volume increase was 1006 ± 32 mL. Lastly, N2 elimination was assessed during decompression to 0.5 atm and while breathing hyperoxic gas. N2 uptake was measured during compression to 1.8 atm. The elimination and uptake curves were deemed to be realistic. A method for assessing N2 turnover in humans has been developed and a first evaluation has been performed. It is easy to work with operationally and can be used at different ambient pressures. More research is needed in order to further validate it as a method for assessing N2 turnover in humans.Sundblad P, Frånberg O, Siebenmann C, Gennser M. Measuring uptake and elimination of nitrogen in humans at different ambient pressures. Aerosp Med Hum Perform. 2016; 87(12):1045-1050.


Prescription Omega-3 Fatty Acid Products and Dietary Supplements Are Not Interchangeable.
To provide an overview of prescription and dietary supplement omega-3 fatty acid (OM3-FA) products and considerations for clinical use. Narrative review. The PubMed database was searched for cardiovascular-related investigations focused on eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) (limit: English-only articles). Additional regulatory information on prescription and dietary supplements was obtained from United States Food and Drug Administration online sources. Prescription QM3-FA products are supported by robust clinical development and safety monitoring programs, whereas dietary supplements are not required to demonstrate safety or efficacy prior to marketing. There are no over-the-counter OM3-FA products available in the United States. Investigations of OM3-FA dietary supplements show that quantities of EPA and DHA are highly variable within and between brands. Dietary supplements also may contain potentially harmful components, including oxidized OM3-FA, other lipids, cholesterol, and toxins. Prescription OM3-FA products may contain DHA and EPA or EPA alone. All prescription OM3-FA products have demonstrated statistically significant triglyceride reduction as monotherapy or in combination with statins in patients with hypertriglyceridemia. Differential effects between products containing EPA and DHA compared with a high-purity EPA product (icosapent ethyl) have clinical implications: Increases in low-density lipoprotein cholesterol associated with DHA have the potential to confound strategies for managing patients with dyslipidemia. Cardiovascular outcomes studies of prescription CM3-FA products are ongoing. OM3-FA dietary supplements should not be substituted for prescription products, and prescription OM3-FA products that contain DHA are not equivalent to or interchangeable with high-purity EPA (icosapent ethyl) and should not be substituted for it.


Pyrotag sequencing of the gut microbiota of the cockroach Shelfordella lateralis reveals a highly dynamic core but only limited effects of diet on community structure.
Although blattid cockroaches and termites share a common ancestor, their diets are distinctly different. While termites consume a highly specialized diet of lignocellulose, cockroaches are omnivorous and opportunistic feeders. The role of the termite gut microbiota has been studied intensively, but little is known about the cockroach gut microbiota and its function in digestion and nutrition, particularly the adaptation to different diets. Our analyses of the bacterial gut microbiota of the blattid cockroach Shelfordella lateralis combining terminal restriction fragment length polymorphism of their 16S rRNA genes with physiological parameters (microbial metabolites, hydrogen and methane emission) indicated substantial variation between individuals but failed to identify any diet-related response. Subsequent deep-sequencing of the 16S rRNA genes of the colonic gut microbiota of S. lateralis fed either a high- or a low-fiber diet confirmed the absence of bacterial taxa that responded to diet. Instead, we found a small number of abundant phylotypes that were consistently present in all samples and made up half of the community in both diet groups. They varied strongly in abundance between individual samples at the genus but not at the family level. The remaining phylotypes were inconsistently present among replicate batches. Our findings suggest that S. lateralis harbors a highly dynamic core gut microbiota that is maintained even after fundamental dietary shifts, and that any dietary effects on the gut community are likely to be masked by strong individual variations.


Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior.
A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF(Met/Met)) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNF(Met) was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNF(Met/Met) mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.


Comparing the Osteogenic Potentials and Bone Regeneration Capacities of Bone Marrow and Dental Pulp Mesenchymal Stem Cells in a Rabbit Calvarial Bone Defect Model.
The bone regeneration efficiency of bone marrow mesenchymal stem cells (BMSCs) and dental pulp mesenchymal stem cells (DPSCs) combined with xenografts in the craniofacial region remains unclear. Accordingly, this study commenced by comparing the cell morphology, cell proliferation, trilineage differentiation, mineral synthesis, and osteogenic gene expression of BMSCs and DPSCs in vitro. Four experimental groups (empty control, Bio-Oss only, Bio-Oss+BMSCs, and Bio-Oss+DPSCs) were then designed and implanted in rabbit calvarial defects. The BMSCs and DPSCs showed a similar morphology, proliferative ability, surface marker profile, and trilineage-differentiation potential in vitro. However, the BMSCs exhibited a higher mineral deposition and expression levels of osteogenic marker genes, including alkaline phosphatase (ALP), runt related transcription factor 2 (RUNX2), and osteocalcin (OCN). In the in vivo studies, the bone volume density in both MSC groups was significantly greater than that in the empty control or Bio-Oss only group. Moreover, the new bone formation and Collagen I / osteoprotegerin protein expressions of the scaffold+MSC groups were higher than those of the Bio-Oss only group. Finally, the Bio-Oss+BMSC and Bio-Oss+DPSC groups had a similar bone mineral density, new bone formation, and osteogenesis-related protein expression. Overall, the DPSCs seeded on Bio-Oss matched the bone regeneration efficacy of BMSCs in vivo and hence appear to be a promising strategy for craniofacial defect repair in future clinical applications.


[Interventional high frequency perforation and enlargement of the outflow tract of pulmonary atresia].
In 18 patients with pulmonary atresia interventional perforation of the atresia was attempted using radiofrequency. All patients were referred for palliative surgery. The age ranged from 4 days to 19 years. After angiographic delineation of the relations between the right ventricular outflow tract and main pulmonary artery the tip of a radiofrequency perforation catheter (Cerablate-catheter, 2F, Osypka) was brought into contact with the atresia. The radiofrequency was applied in the unipolar fashion (radiofrequency-generator HAT 200, Osypka). Radiofrequency perforation was successfully performed in 14/18 patients, subsequent balloon dilatation was performed in 12 of these patients. In six patients with muscular atresia a Palmaz-stent was implanted into the right ventricular outflow tract. An inadvertent perforation of the right ventricular outflow tract occurred in three patients, of the pulmonary artery in two patients. However, these were tolerated without sequelae or clinical symptoms. The arterial oxygen saturation increased by 21%; in none of the patients was cardiac failure or pulmonary edema observed. Using the Cerablate-catheter even muscular atresias could be perforated. Implantation of a stent into the newly created right ventricular outflow tract results in a predictable communication between the right ventricle and the pulmonary artery. Although this interventional right ventricular outflow tract creation seems to be a promising new technique, experience is limited and there are no long-term results.


Systematic biases in disease forecasting - The role of behavior change.
In a simple susceptible-infected-recovered (SIR) model, the initial speed at which infected cases increase is indicative of the long-term trajectory of the outbreak. Yet during real-world outbreaks, individuals may modify their behavior and take preventative steps to reduce infection risk. As a consequence, the relationship between the initial rate of spread and the final case count may become tenuous. Here, we evaluate this hypothesis by comparing the dynamics arising from a simple SIR epidemic model with those from a modified SIR model in which individuals reduce contacts as a function of the current or cumulative number of cases. Dynamics with behavior change exhibit significantly reduced final case counts even though the initial speed of disease spread is nearly identical for both of the models. We show that this difference in final size projections depends critically in the behavior change of individuals. These results also provide a rationale for integrating behavior change into iterative forecast models. Hence, we propose to use a Kalman filter to update models with and without behavior change as part of iterative forecasts. When the ground truth outbreak includes behavior change, sequential predictions using a simple SIR model perform poorly despite repeated observations while predictions using the modified SIR model are able to correct for initial forecast errors. These findings highlight the value of incorporating behavior change into baseline epidemic and dynamic forecast models.


Evaluation of a chest radiograph reading and recording system for tuberculosis in a HIV-positive cohort.
To assess the impact of introducing a chest radiograph reading and recording system (CRRS) with a short training session, on the accuracy and inter-reader variability of tuberculosis (TB) interpretation of chest radiographs (CXRs) by a group of non-expert readers in a human immunodeficiency virus (HIV)-positive cohort. A set of 139 CXRs was reviewed by a group of eight physicians pre- and post-intervention at two clinics in Shan State, Myanmar, providing HIV/TB diagnosis and treatment services. The results were compared against the consensus of expert radiologists for accuracy. Overall accuracy was similar pre- and post-intervention for most physicians with an average area under the receiver operating characteristic curve difference of 0.02 (95% confidence interval: -0.03, 0.07). The overall agreement among physicians was poor pre- and post-intervention (Fleiss κ=0.35 and κ=0.29 respectively). The assessment of agreement for specific disease patterns associated with active TB in HIV-infected patients showed that for intrinsically subtle findings, the agreement was generally poor but better for the more intrinsically obvious disease patterns: pleural effusion (Cohen's kappa range = 0.37-0.67) and milliary nodular pattern (Cohen's kappa range = 0.25-0.52). This study demonstrated limited impact of the introduction of a CRRS on CXR accuracy and agreement amongst non-expert readers. The role in which CXRs are used for TB diagnosis in a HIV-positive cohort in similar clinical contexts should be reviewed.


Risk factors associated with pulmonary exacerbations in pediatric patients with cystic fibrosis.
Cystic fibrosis patients develop pulmonary exacerbations (PEs) that require intravenous treatment. The objective of this study was to determine the risk factors associated with PEs and establish the percentage of patients who failed to recover their lung function. Observational, retrospective, cohort study. The medical records of cystic fibrosis patients seen at Hospital de Niños Ricardo Gutiérrez in 2013 were reviewed. Patients were divided into group 1, with PE (Fuchs criteria), and group 2, without PE. Age, sex, p.F508del mutation, percentage of baseline forced expiratory volume in the first second, baseline body mass index Z-score, chronic Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and Burkholderia cepacia complex colonization (Leeds criteria), percentage of cystic fibrosis-related diabetes, and recovery of baseline forced expiratory volume in the first second were recorded. A total of 117 patients were included. Group 1: 50, group 2: 67 patients. PEs were associated with a lower body mass index Z-score (RR: 1.45; p = 0.002), p.F508del mutation (RR: 3.23; p = 0.05), and chronic Burkholderia cepacia complex (RR: 3.69; p = 0.002), Pseudomonas aeruginosa (RR: 1.89; p = 0.01) and methicillinresistant Staphylococcus aureus colonization (RR: 2.32; p = 0.002). Twenty-four percent of patients failed to recover their lung function. The presence of the p.F508del mutation, a poor nutritional status, and chronic colonization were the risk factors for exacerbation. A fourth of patients failed to recover their lung function.


Mn(II) oxidation is catalyzed by heme peroxidases in "Aurantimonas manganoxydans" strain SI85-9A1 and Erythrobacter sp. strain SD-21.
A new type of manganese-oxidizing enzyme has been identified in two alphaproteobacteria, "Aurantimonas manganoxydans" strain SI85-9A1 and Erythrobacter sp. strain SD-21. These proteins were identified by tandem mass spectrometry of manganese-oxidizing bands visualized by native polyacrylamide gel electrophoresis in-gel activity assays and fast protein liquid chromatography-purified proteins. Proteins of both alphaproteobacteria contain animal heme peroxidase and hemolysin-type calcium binding domains, with the 350-kDa active Mn-oxidizing protein of A. manganoxydans containing stainable heme. The addition of both Ca(2+) ions and H(2)O(2) to the enriched protein from Aurantimonas increased manganese oxidation activity 5.9-fold, and the highest activity recorded was 700 microM min(-1) mg(-1). Mn(II) is oxidized to Mn(IV) via an Mn(III) intermediate, which is consistent with known manganese peroxidase activity in fungi. The Mn-oxidizing protein in Erythrobacter sp. strain SD-21 is 225 kDa and contains only one peroxidase domain with strong homology to the first 2,000 amino acids of the peroxidase protein from A. manganoxydans. The heme peroxidase has tentatively been named MopA (manganese-oxidizing peroxidase) and sheds new light on the molecular mechanism of Mn oxidation in prokaryotes.


Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures.
During vertebrate angiogenesis, Notch regulates the cell-fate decision between vascular tip cells versus stalk cells. Canonical Notch signaling depends on sequential proteolytic events, whereby interaction of Notch with membrane-anchored ligands triggers proteolytic processing, first by Adam10 and then presenilins. This liberates the Notch intracellular domain, allowing it to enter the nucleus and activate Notch-dependent genes. Here we report that conditional inactivation of Adam10 in endothelial cells (A10ΔEC) recapitulates the increased branching and density of the retinal vasculature that is also caused by interfering with Notch signaling. Moreover, A10ΔEC mice have additional vascular abnormalities, including aberrant subcapsular hepatic veins, enlarged glomeruli, intestinal polyps containing endothelial cell masses, abnormal endochondral ossification, leading to stunted long bone growth and increased pathologic neovascularization following oxygen-induced retinopathy. Our findings support a model in which Adam10 is a crucial regulator of endothelial cell-fate decisions, most likely because of its essential role in canonical Notch signaling.


Promoting Earth-Based Radar Astronomical Observations of the Moon.
Earth-based radar astronomical observations provide information on surface characteristics, orbits, and rotations for a wide variety of solar system objects. Based on compound radio telescopes, both the Chinese VLBI (Very Long Baseline Interferometry) network (CVN) and the Russian VLBI network (Quasar), in cooperation with the Chinese radar transmitters, we present the current ground radar astronomical observations of the moon. The spectrum of the reflected radio signals was obtained and the Doppler frequency shift in bi-static radar mode was measured. Radar albedo of the observed region and power ratios of the reflected signals with left- and right-hand circular polarizations were determined, allowing us to study the radar reflectivity and near-surface wavelength-scale roughness of the moon. Future developments on radar astronomy are also discussed in the paper.


Impact of initial therapy with upadacitinib or adalimumab on achievement of 48-week treatment goals in patients with rheumatoid arthritis: post hoc analysis of SELECT-COMPARE.
Evaluate the importance of treatment sequencing in SELECT-COMPARE, assessing potential differences between starting upadacitinib or adalimumab therapy following inadequate MTX response. Patients from SELECT-COMPARE were randomized to upadacitinib 15 mg once daily, placebo or adalimumab 40 mg. Per protocol, patients with <20% improvement in tender or swollen joint counts (weeks 14, 18, 22) or failure to achieve Clinical Disease Activity Index (CDAI) low disease activity (LDA) at week 26 were blindly switched from upadacitinib to adalimumab or vice versa. Treatment outcomes, including clinical remission/LDA, physical function, pain and a novel combined endpoint for deep response, were evaluated through 48 weeks and corresponding time-averaged response rates determined. Data were analysed by initial randomized group regardless of any subsequent switch in therapy. This post hoc analysis included 651 patients initially randomized to upadacitinib (of whom 252 switched to adalimumab) and 327 patients initially randomized to adalimumab (of whom 159 switched to upadacitinib). At week 48, patients randomized to either therapy demonstrated similar achievement of most treatment endpoints. Greater improvements in the total time spent in a lower disease state were observed for initial upadacitinib vs initial adalimumab therapy across most clinical and patient-reported outcomes through 48 weeks, and the median time to DAS28(CRP) <2.6/≤3.2 occurred 6-8 weeks earlier among those randomized to upadacitinib. Following a modified treat-to-target strategy, rates of CDAI remission/LDA and DAS28(CRP) <2.6/≤3.2 at 48 weeks were similar, regardless of starting therapy. However, patients initially receiving upadacitinib reached treatment targets more quickly and spent more time in clinical targets over the initial 48 weeks of treatment. ClinicalTrials.gov, https://clinicaltrials.gov, NCT02629159.


Cardiomyocyte DNA synthesis and binucleation during murine development.
Cardiomyocyte DNA synthesis and binucleation indexes were determined during murine development. Cardiomyocyte DNA synthesis occurred in two temporally distinct phases. The first phase occurred during fetal life and was associated exclusively with cardiomyocyte proliferation. The second phase occurred during early neonatal life and was associated with binucleation. Collectively, these results suggest that cardiomyocyte reduplication ceases during late fetal life. Northern and Western blot analyses identified several candidate genes that were differentially expressed during the reduplicative and binucleation phases of cardiomyocyte growth.


Two-year course of cognitive function and mood in adults with congestive heart failure and coronary artery disease: the Heart-Mind Study.
Congestive heart failure (CHF) has been associated with impaired cognitive function, but it is unclear if these changes are specific to CHF and if they get worse with time. We designed this study to determine if adults with CHF show evidence of cognitive decline compared with adults with and without coronary artery disease (CAD). A longitudinal study was carried out of 77 adults with CHF (ejection fraction, EF < 0.4), 73 adults with a clinical history of CAD and EF > 0.6, and 81 controls with no history of CAD. The Cambridge Cognitive Examination of the Elderly (CAMCOG) was the primary outcome measure. Secondary measures included the California Verbal Learning Test (CVLT), digit coding and copying, Hospital Anxiety and Depression Scale (HADS), and the short form health survey (SF36). Endpoints were collected at baseline and after 12 and 24 months. The adjusted CAMCOG scores of CHF participants declined 0.9 points over two years (p = 0.022) compared with controls without CAD. There were no differences between the groups on other cognitive measures. Participants with CHF and with CAD experienced similar changes in cognitive function over two years. Left ventricular EF and six-minute walk test results could not explain the observed associations. The changes in cognitive function and mood associated with CHF over two years are subtle and not specific to CHF.


Neural losses correlated with visual losses in clinical perimetry.
The validity of clinical perimetry for evaluation of the pathology of glaucoma is based on correlated losses in retinal ganglion cells and visual sensitivity, but procedures to quantify neural losses from visual field defects have not been developed. The purpose of the present study was to investigate the neural and sensitivity losses from experimental glaucoma to establish the framework for a quantitative model for the structure-function relationships of standard clinical perimetry. Perimetry, by behavioral testing, and retinal histology data were obtained from rhesus monkeys with significant visual field defects caused by experimental glaucoma. Ganglion cell densities were obtained from sections of retina that corresponded to 16 perimetry test locations. Perimetry sensitivity as a function of ganglion cell density at corresponding retina/visual field locations was analyzed. The structure-function relationships were linear on log-log coordinates, with parameters that varied systematically with eccentricity. The slope value varied from 1.25 dB/dB at 4.2 degrees from fixation to a value of 2.32 dB/dB at 24 degrees from fixation, whereas the intercept value varied from -25.2 dB to -55.7 dB over the same range of eccentricities. The structure-function relationships produced a model to predict the ganglion cell density underlying a given level of visual sensitivity and location in the visual field. The model, with no free parameters, produced an accurate and relatively precise quantification of retinal ganglion cell losses caused by experimental glaucoma in monkeys. However, because the early detection of glaucoma is limited by intersubject variability, ganglion cell losses of 40% to 50% were necessary before visual sensitivity losses exceeded the normal 95% confidence limits. With retinal eccentricity as a factor, the neural losses from glaucoma are predictable from visual sensitivity measurements by clinical perimetry. The relationships derived from experimental glaucoma in monkeys also accurately predict the rate of age-related losses of retinal ganglion cells in humans, based on the normative perimetry data for age-related reductions in visual sensitivity. The success of the model in this study suggested that it is potentially applicable to the clinical interpretation of the state of glaucomatous optic neuropathy.


Leaf miner and plant galler species richness on Acacia: relative importance of plant traits and climate.
Diversity patterns of herbivores have been related to climate, host plant traits, host plant distribution and evolutionary relationships individually. However, few studies have assessed the relative contributions of a range of variables to explain these diversity patterns across large geographical and host plant species gradients. Here we assess the relative influence that climate and host plant traits have on endophagous species (leaf miners and plant gallers) diversity across a suite of host species from a genus that is widely distributed and morphologically variable. Forty-six species of Acacia were sampled to encapsulate the diversity of species across four taxonomic sections and a range of habitats along a 950 km climatic gradient: from subtropical forest habitats to semi-arid habitats. Plant traits, climatic variables, leaf miner and plant galler diversity were all quantified on each plant species. In total, 97 leaf mining species and 84 plant galling species were recorded from all host plants. Factors that best explained leaf miner richness across the climatic gradient (using AIC model selection) included specific leaf area (SLA), foliage thickness and mean annual rainfall. The factor that best explained plant galler richness across the climatic gradient was C:N ratio. In terms of the influence of plant and climatic traits on species composition, leaf miner assemblages were best explained by SLA, foliage thickness, mean minimum temperature and mean annual rainfall, whilst plant gall assemblages were explained by C:N ratio, %P, foliage thickness, mean minimum temperature and mean annual rainfall. This work is the first to assess diversity and structure across a broad environmental gradient and a wide range of potential key climatic and plant trait determinants simultaneously. Such methods provide key insights into endophage diversity and provide a solid basis for assessing their responses to a changing climate.


Molecular dissection of mammalian RNA polymerase II transcriptional termination.
Transcriptional termination of mammalian RNA polymerase II (Pol II) is an essential but little-understood step in protein-coding gene expression. Mechanistically, termination by all DNA-dependent RNA polymerases can be reduced to two steps, namely release of the RNA transcript and release of the DNA template. Using a simple nuclear fractionation procedure, we have monitored transcript and template release in the context of both natural and artificial Pol II terminator sequences. We describe the timing and relationship between these events and in so doing establish the roles of the poly(A) signal, cotranscriptional RNA cleavage events, and 5'-3' exonucleolytic RNA degradation in the mammalian Pol II termination process.


The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats.
To examine the influence of the sex hormones on mechanical properties and biochemistry of the adult heart, we studied left ventricular function and cardiac contractile proteins in hearts from 20-week-old male and female rats that had been gonadectomized at 18 days of age, compared with hearts from sham-operated animals. Testosterone and estradiol were not detectable in serum from male and female gonadectomized rats, respectively. The male rats had lower body and heart weights than male sham operated rats, whereas these values were higher in female gonadectomized than in female sham-operated rats. Left ventricular function was studied in a working heart apparatus at similar heart rate and at controlled levels of aortic diastolic pressure and left atrial pressure. At moderate left atrial pressure, end-diastolic pressure and volume per gram dry left ventricle were the same in all groups, but at high left atrial pressure, end-diastolic pressure, and volume per gram dry left ventricle were lower in male and female gonadectomized than in the respective sham-operated rats. Further increases in left atrial pressure were associated with mechanical alternans in male and female gonadectomized rats. Significantly (P less than 0.05) lower values for cardiac output, peak systolic pressure, ejection fraction, and myocardial oxygen consumption occurred in male gonadectomized compared with sham-operated rats at moderate and high left atrial pressure at higher levels of aortic diastolic pressure. Decreases in these values for female gonadectomized compared with sham-operated rats occurred only at high left atrial pressure. A significant downward shift in the mean force-velocity relationship was observed in all gonadectomized rats at both moderate and high left atrial pressure. In a follow-up study, when end-diastolic pressure was kept the same at both moderate and high left atrial pressure in female sham-operated and gonadectomized rats by reducing heart rate, decreases in contractile function in gonadectomized rats were observed at all preloads. Ca++-myosin ATPase activity was significantly reduced by 34% in male and by 19% in female gonadectomized rats when compared to respective sham-operated control hearts. These alterations in myosin ATPase activity were associated with a reduction in the V1 myosin isoenzyme and an increase in the V3 isoenzyme. Thus, left ventricular filling and left ventricular function were impaired in hearts of gonadectomized rats. Alterations in function were associated with depressed cardiac myosin ATPase activity in male and female gonadectomized rats.(ABSTRACT TRUNCATED AT 400 WORDS)


Development and evaluation of PCR assays for the detection of Paenibacillus larvae in honey samples: comparison with isolation and biochemical characterization.
PCR assays were developed for the direct detection of Paenibacillus larvae in honey samples and compared with isolation and biochemical characterization procedures. Different primer pairs, designed from the 16S rRNA and the metalloproteinase precursor gene regions, and different DNA extraction methods were tested and compared. The sensitivity of the reactions was evaluated by serial dilutions of DNA extracts obtained from P. larvae cultures. The specificity of the primers was assessed by analyzing related Paenibacillus and Bacillus strains isolated from honey. The PCR assays also amplified these related bacteria, but at lower sensitivity. In the next step, the PCR assays were applied to contaminated honey and other bee products originating from 15 countries. Lysozyme treatment followed by proteinase K digestion was determined to be the best DNA extraction method for P. larvae spores. The most sensitive primer pair detected P. larvae in 18 of 23 contaminated honey samples, as well as in pollen, wax, and brood. Honey specimens containing saprophyte bacilli and paenibacilli, but not P. larvae, were PCR negative. Although the isolation and biochemical identification method (BioLog) showed higher sensitivity and specificity, PCR proved to be a valuable technique for large-scale screening of honey samples for American foulbrood, especially considering its rapidity and moderate costs.


Investigation of the role of ENPP1 and TNAP genes in chondrocalcinosis.
Extracellular inorganic pyrophosphate (ePPi) inhibits certain forms of pathological mineralization while promoting others. Three molecules involved in ePPi regulation are important candidates for the development of calcium pyrophosphate dihydrate chondrocalcinosis (CPPD CC). These include ANKH, ectonucleotide pyrophosphatase (ENPP1) and TNAP. We have previously showed that genetic variation in ANKH is a cause of autosomal dominant familial CC and also some sporadic cases of CPPD CC. We now investigate the possible role of ENPP1 and TNAP in CPPD CC. Exons, untranslated regions (UTR) and exon-intron boundaries of ENPP1 and TNAP were sequenced using ABI Big Dye chemistry on automated sequencers. Sixteen variants were identified (3 in ENPP1 and 13 in TNAP) and were subsequently genotyped in 128 sporadic Caucasian CPPD CC patients and 600 healthy controls using a combination of polymerase chain reaction/restriction fragment-length polymorphism analysis or using Taqman. Allele and genotype frequencies were compared between cases and controls using the chi(2) test. Linkage disequilibrium, haplotype and the single nucleotide polymorphism-specific analyses were also performed. This study had 80% power to detect an odds ratio of 2.2 or more at these loci. No difference was observed in the allele or genotype frequencies between patients and controls at either ENPP1 or TNAP. Polymorphisms of ENPP1 and TNAP are not major determinants of susceptibility to CC in the population studied. Further studies of the aetiology of sporadic CPPD CC are required to determine its causes.


Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia.
Cytoarchitectural changes in the hippocampal formation have been prominent among the various neuropathological abnormalities reported in schizophrenia. Replicated positive findings include decreased neuronal size and alterations in presynaptic and dendritic markers. These findings, in the absence of neurodegenerative changes, suggest that there are alterations in the neural circuitry in schizophrenia. These may represent the anatomical correlate of the aberrant functional connectivity described in neuroimaging studies, which in turn contributes to the psychotic and cognitive symptomatology of the disorder. The identity of the affected hippocampal circuits remains unclear; there is evidence for both glutamatergic and GABAergic involvement, and perhaps for a gradient of pathology in which changes are most apparent in CA4 and the subiculum, and least in CA1. The data, their interpretation, and their limitations are discussed, with particular emphasis upon molecular and immunological studies of synaptic protein gene expression.


Nonsteroidal anti-inflammatory drugs and other analgesic use and bladder cancer in northern New England.
A few epidemiologic studies have found that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of bladder cancer. However, the effects of specific NSAID use and individual variability in risk have not been well studied. We examined the association between NSAIDs use and bladder cancer risk, and its modification by 39 candidate genes related to NSAID metabolism. A population-based case-control study was conducted in northern New England, enrolling 1,171 newly diagnosed cases and 1,418 controls. Regular use of nonaspirin, nonselective NSAIDs was associated with reduced bladder cancer risk, with a statistically significant inverse trend in risk with duration of use (ORs of 1.0, 0.8, 0.6 and 0.6 for <5, 5-9, 10-19 and 20+ years, respectively; p(trend) = 0.015). This association was driven mainly by ibuprofen; significant inverse trends in risk with increasing duration and dose of ibuprofen were observed (p(trend) = 0.009 and 0.054, respectively). The reduced risk from ibuprofen use was limited to individuals carrying the T allele of a single nucleotide polymorphism (rs4646450) compared to those who did not use ibuprofen and did not carry the T allele in the CYP3A locus, providing new evidence that this association might be modified by polymorphisms in genes that metabolize ibuprofen. Significant positive trends in risk with increasing duration and cumulative dose of selective cyclooxygenase (COX-2) inhibitors were observed. Our results are consistent with those from previous studies linking use of NSAIDs, particularly ibuprofen, with reduced risk. We observed a previously unrecognized risk associated with use of COX-2 inhibitors, which merits further evaluation.


Non-Invasive Targeted Peripheral Nerve Ablation Using 3D MR Neurography and MRI-Guided High-Intensity Focused Ultrasound (MR-HIFU): Pilot Study in a Swine Model.
Ultrasound (US)-guided high intensity focused ultrasound (HIFU) has been proposed for noninvasive treatment of neuropathic pain and has been investigated in in-vivo studies. However, ultrasound has important limitations regarding treatment guidance and temperature monitoring. Magnetic resonance (MR)-imaging guidance may overcome these limitations and MR-guided HIFU (MR-HIFU) has been used successfully for other clinical indications. The primary purpose of this study was to evaluate the feasibility of utilizing 3D MR neurography to identify and guide ablation of peripheral nerves using a clinical MR-HIFU system. Volumetric MR-HIFU was used to induce lesions in the peripheral nerves of the lower limbs in three pigs. Diffusion-prep MR neurography and T1-weighted images were utilized to identify the target, plan treatment and immediate post-treatment evaluation. For each treatment, one 8 or 12 mm diameter treatment cell was used (sonication duration 20 s and 36 s, power 160-300 W). Peripheral nerves were extracted < 3 hours after treatment. Ablation dimensions were calculated from thermal maps, post-contrast MRI and macroscopy. Histological analysis included standard H&E staining, Masson's trichrome and toluidine blue staining. All targeted peripheral nerves were identifiable on MR neurography and T1-weighted images and could be accurately ablated with a single exposure of focused ultrasound, with peak temperatures of 60.3 to 85.7°C. The lesion dimensions as measured on MR neurography were similar to the lesion dimensions as measured on CE-T1, thermal dose maps, and macroscopy. Histology indicated major hyperacute peripheral nerve damage, mostly confined to the location targeted for ablation. Our preliminary results indicate that targeted peripheral nerve ablation is feasible with MR-HIFU. Diffusion-prep 3D MR neurography has potential for guiding therapy procedures where either nerve targeting or avoidance is desired, and may also have potential for post-treatment verification of thermal lesions without contrast injection.


Signal processing of heart signals for the quantification of non-deterministic events.
Heart signals represent an important way to evaluate cardiovascular function and often what is desired is to quantify the level of some signal of interest against the louder backdrop of the beating of the heart itself. An example of this type of application is the quantification of cavitation in mechanical heart valve patients. An algorithm is presented for the quantification of high-frequency, non-deterministic events such as cavitation from recorded signals. A closed-form mathematical analysis of the algorithm investigates its capabilities. The algorithm is implemented on real heart signals to investigate usability and implementation issues. Improvements are suggested to the base algorithm including aligning heart sounds, and the implementation of the Short-Time Fourier Transform to study the time evolution of the energy in the signal. The improvements result in better heart beat alignment and better detection and measurement of the random events in the heart signals, so that they may provide a method to quantify nondeterministic events in heart signals. The use of the Short-Time Fourier Transform allows the examination of the random events in both time and frequency allowing for further investigation and interpretation of the signal. The presented algorithm does allow for the quantification of nondeterministic events but proper care in signal acquisition and processing must be taken to obtain meaningful results.


Within-treatment change in antisocial attitudes and reoffending in a large sample of custodial and community offenders.
This study tested evidence for antisocial attitudes as a mechanism of change in offender treatment by examining whether the Measures of Antisocial Attitudes and Associates (MCAA) and within-treatment change in scores on this scale have predictive validity for risk of reoffending. Pretreatment and posttreatment scores on the MCAA were obtained from a large sample of 1,858 offenders who had completed offender treatment programs while in custody (n = 854) or in the community (n = 1,004). Individual within-treatment change was calculated with simple difference scores as well as categorizations of clinically significant change. Results showed that discrete scores on a number of MCAA measures were associated with reoffending hazard at pretreatment and at posttreatment. Change over treatment was also highly significant at the group level whereas a modest proportion of offenders achieved clinically significant change. None of the measures of within-treatment change were significantly associated with reoffending, however. The results suggest that self-reported antisocial attitudes may not be a valid indicator of causal mechanisms of treatment or change in offenders' risk of reoffending as a result of completing treatment. (PsycINFO Database Record


Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study.
Previous studies have shown that major depression is frequently accompanied by hypercortisolemia. There is some evidence suggesting that an increase in the glucocorticoid levels may make hippocampal cells more vulnerable to insults caused by hypoxia, hypoglycemia, or excitatory neurotransmitters. Using magnetic resonance imaging (MRI), the hippocampi of patients with major depression were measured and compared with values observed in control subjects. Thirty-eight patients with primary unipolar major depression were recruited. Twenty control subjects were matched for age, gender, and years of education. The hippocampal volume was measured from coronal MRI scans in all of the subjects. Patients were also grouped and compared as responders and nonresponders to treatment with fluoxetine of 20 mg/day, for 8 weeks. Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depression. No significant differences were observed between the hippocampal volumes of patients with major depression and control subjects; however, a significant correlation was observed between the left hippocampal volume of men and their HDRS baseline values. In addition, female responders had a statistically significant higher mean right hippocampal volume than nonresponders. The results of our study indicate no reduction in the volume of the hippocampus in patients with major depression. Nonetheless, the results do suggest that the effects of disease severity, gender, and treatment response may influence hippocampal volume.


Intellectual property rights and innovation: Evidence from the human genome.
Do intellectual property (IP) rights on existing technologies hinder subsequent innovation? Using newly-collected data on the sequencing of the human genome by the public Human Genome Project and the private firm Celera, this paper estimates the impact of Celera's gene-level IP on subsequent scientific research and product development. Genes initially sequenced by Celera were held with IP for up to two years, but moved into the public domain once re-sequenced by the public effort. Across a range of empirical specifications, I find evidence that Celera's IP led to reductions in subsequent scientific research and product development on the order of 20 to 30 percent. Taken together, these results suggest that Celera's short-term IP had persistent negative effects on subsequent innovation relative to a counterfactual of Celera genes having always been in the public domain.


Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study.
Rifaximin has been reported to be effective for the treatment of hepatic encephalopathy (HE) in Europe. However, it is unknown whether Rifaximin is effective for the treatment of HE in Koreans, therefore we conducted a open-label prospective randomized study to evaluate the efficacy of rifaximin versus lactulose in Korean patients. Fifty-four patients with liver cirrhosis and hepatic encephalopathy were enrolled. Thirty-two patients were randomized to receive rifaximin and 22 to receive lactulose both over a 7-day periods. Before and at the end of treatment, gradation of blood ammonia, flapping tremor, mental status, number connection test (NCT) were performed and estimation of HE indexes determined. Both rifaximin and lactulose were effective in the majority of patients (84.4% and 95.4%, respectively, p = 0.315). Blood NH3, flapping tremor, mental status, and NCT was significantly improved by rifaximin and lactulose, and the post- treatment levels of these measures were similar for the rifaximin and lactulose-treated groups, as was the HE index (rifaximin group (10.0 --> 4.2, p = 0.000); lactulose group (11.3 --> 5.0, p = 0.000)). One patient treated with rifaximin complained of abdominal pain, which was easily controlled. There was no episode of renal function impairment in either treatment group. Rifaximin proved to be as safe and as effective as lactulose for the treatment of Korean patients with hepatic encephalopathy.


Regional hyperthermia of the abdomen, a pilot study towards the treatment of peritoneal carcinomatosis.
Peritoneal carcinomatosis occurs in different cancer subtypes and is associated with a dismal prognosis. Some doubts remain whether the whole abdomen can be treated by regional hyperthermia, therefore we analyzed feasibility conducting a pilot study. A simulation of the abdominopelvic heat distribution in 11 patients with peritoneal carcinomatosis was done using the HyperPlan software and the SIGMA-60 and SIGMA-Eye applicators. Tissue-specific region-related electrical and thermal parameters were used to solve the Maxwell's equations and the bioheat-transfer equation. Three-dimensional specific absorption rate (SAR) distributions and, additionally, estimated region-related perfusion rates were used to solve the bioheat-transfer equation. The predicted SAR and temperature distributions were compared with minimally invasive measurements in pelvic reference points. In 11 patients (7 of them treated in the SIGMA-60 and 4 in the SIGMA-Eye applicator) the measured treatment variables (SAR, temperatures in the pelvic reference points) indicated that the heated volumes were higher for the SIGMA-Eye applicator. The mean computed abdominal SARs were less for the SIGMA-Eye (33 versus 44 W/kg). Nevertheless, the temperature distributions in the abdomen (peritoneal cavity) were more homogeneous in the SIGMA-Eye applicator as compared to the SIGMA-60 as indicated by higher values of T90 (mean 40.2 versus 38.2 °C) and T50 (mean 41.1 versus 40.2 °C), while the maximum temperatures were similar (in the range 41 to 43 °C). Even though the mean abdominal SAR was lower in the SIGMA-Eye, the heat distribution covered a larger volume of the abdomen (in particular the upper abdomen). For the SIGMA-60 applicator the achieved T90 appeared to be limited between 41 and 42 °C, for the SIGMA Eye applicator more effective T90 in the range 42 to 43 °C were obtained. Our results suggest that an adequate heating of the abdomen and therefore abdominal regional hyperthermia in PC patients appears feasible. The SIGMA-Eye applicator appears to be superior compared to the SIGMA-60 applicator for abdominal hyperthermia.


Do extraverts get more bang for the buck? Refining the affective-reactivity hypothesis of extraversion.
One of the most robust observations in personality and emotion research is the finding that extraverts are happier than introverts. Some theorists have attributed this to differential reactivity of the brain reward system, which is central to many biologically inspired models of extraversion. This affective-reactivity hypothesis, which suggests that extraverts should be more susceptible to the induction of positive affect, has so far received very mixed empirical support. In this article, we consider a more biologically plausible account of extraverts' affective-reactivity. Over 5 experiments, we demonstrate that extraverts show greater affective-reactivity only in response to clearly appetitive stimuli and situations (e.g., where rewards are being pursued). Conversely, after merely pleasant stimuli and situations (without any reward-approach element), extraverts and introverts respond similarly. We also show that it is specifically activated affect (e.g., feelings of alertness), rather than pleasantly valenced affect (e.g., feelings of contentment), that characterizes the affective-reactivity of extraverts. Such reactions may potentially facilitate the reward-seeking behavior associated with extraversion, but they seem unlikely to explain the broadly happy disposition of extraverts.


Selective estrogen receptor modulators--a new age of estrogens in cardiovascular disease?
A large body of evidence suggests hormone replacement therapy (HRT) reduces cardiovascular risk in postmenopausal women. It is, however, associated with serious side effects, such as increased risk of breast and endometrial cancer. This has likely caused uneasiness among both women and health care providers. A new class of compounds, called selective estrogen receptor modulators (SERMs), have emerged. Through their interactions at the estrogen receptor level they have become a class of compounds distinct from estrogen. While they share similar effects with estrogen on such factors as lipid profile and bone density, they affect other tissues differently. Specifically, they do not induce endometrial hyperplasia and are therefore not associated with endometrial cancer. In vitro studies have also shown that they inhibit lipoprotein oxidation and vascular smooth muscle cell proliferation. The cumulative effects of these compounds may prove quite beneficial in reducing cardiovascular risk in postmenopausal women while avoiding serious side effects. This may, in turn, ease much of the anxiety surrounding the issue of HRT. Clinical trials are presently being conducted to evaluate the effectiveness of raloxifene, a SERM, on cardiovascular risk reduction in postmenopausal women.


Outreach and Inreach Organized Service Screening Programs for Colorectal Cancer.
Outreach (i.e., to invite those who do not use, or who under use screening services) and inreach (i.e., to invite an existing population who have already accessed the medical system) approaches may influence people to increase their use of screening test; however, whether their outcomes would be equivalent remains unclear. A total of 3,363,896 subjects, 50-69 years of age, participated in a colorectal cancer (CRC) screening program using biennial fecal immunochemical tests; 34.5% participated during 2004-2009 when the outreach approach alone was used, and 65.5% participated from 2010-2013 when outreach was integrated with an inreach approach. We compared the outcomes of the two approaches in delivery of screening services. Coverage rates increased from 21.4% to 36.9% and the positivity rate increased from 4.0% to 7.9%, while referral for confirmatory diagnostic examinations declined from 80.0% to 53.3%. The first period detected CRC in 0.20% of subjects screened, with a positive predictive value (PPV) of 6.1%, and the second detected CRC in 0.34% of subjects, with a PPV of 8.0%. After adjusting for confounders, differences were observed in the PPV for CRC (adjusted relative risk, 1.50; 95% confidence interval [CI], 1.41-1.60), cancer detection rate (1.20; 95% CI, 1.13-1.27), and interval cancer rate (0.72; 95% CI, 0.65-0.80). When we focused on the comparison between two approaches during the same study period of 2010-2013, the positivity rate of fecal testing (8.2% vs. 7.6%) and the PPV for CRC detection remained higher (1.07; 95% CI, 1.01-1.12) in subjects who were recruited from the inreach approach. Outcomes of screening were equivalent or better after integration of outreach and inreach approaches. The results will encourage makers of health-care policy to adopt the integration approach to deliver screening services.


Sixty-minute infusion rituximab protocol allows for safe and efficient workflow.
Rituximab is a chimeric monoclonal antibody approved to treat B cell non-Hodgkin's lymphoma (NHL). Infusion reactions among NHL patients are common during the first exposure but decrease with subsequent infusions. We sought to assess the safety and feasibility of a rituximab rapid infusion protocol in the outpatient treatment area of a comprehensive cancer center. Patients with indolent and intermediate B cell NHL were invited to enroll in this prospective, single-institution study if they had received the first dose of rituximab according to the manufacturer-labeled standard titration schedule without grade >2 infusion reaction. The subsequent infusion proceeded without the use of steroid premedication at 100 mg/h administered over 15 min, with the remaining dose given over 45 min. Time savings between rapid infusion and standard titration were calculated. Fifty patients received 60-min rituximab infusions during the second drug administration. No infusion-related reactions of any grade were observed with the rapid infusion protocol (0%, one-sided 97.5% CI 0-7.1%). The mean time for the rapid rituximab infusion was 62.4 min (95% CI 61.2-63.6). When compared to the standard second dose infusion recommendation, a mean time of 94.2 min (95% 90-98.4) was saved with rapid infusion. Nursing surveys demonstrated 100% satisfaction with the rapid infusion protocol. Subsequent rituximab infusions can be safely administered over 60 min and without steroid premedication in an experienced outpatient infusion center when patients are appropriately screened. The faster infusions can reduce resource utilization and increase nursing satisfaction. NCT01206777.


Estimate of DMFT index using teeth most affected by dental caries in twelve-year-old children.
The objective of the study was to develop regression models to describe the epidemiological profile of dental caries in 12-year-old children in an area of low prevalence of caries. Two distinct random probabilistic samples of schoolchildren (n=1,763) attending public and private schools in Piracicaba, Southeastern Brazil, were studied. Regression models were estimated as a function of the most affected teeth using data collected in 2005 and were validated using a 2001 database. The mean (SD) DMFT index was 1.7 (2.08) in 2001 and the regression equations estimated a DMFT index of 1.67 (1.98), which corresponds to 98.2% of the DMFT index in 2001. The study provided detailed data on the caries profile in 12-year-old children by using an updated analytical approach. Regression models can be an accurate and feasible method that can provide valuable information for the planning and evaluation of oral health services.


High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources.
Extracellular vesicles (EVs), including exosomes and microvesicles (MVs), are explored for use in diagnostics, therapeutics and drug delivery. However, little is known about the relationship of protein and lipid composition of EVs and their source cells. Here, we report high-resolution lipidomic and proteomic analyses of exosomes and MVs derived by differential ultracentrifugation from 3 different cell types: U87 glioblastoma cells, Huh7 hepatocellular carcinoma cells and human bone marrow-derived mesenchymal stem cells (MSCs). We identified 3,532 proteins and 1,961 lipid species in the screen. Exosomes differed from MVs in several different areas: (a) The protein patterns of exosomes were more likely different from their cells of origin than were the protein patterns of MVs; (b) The proteomes of U87 and Huh7 exosomes were similar to each other but different from the proteomes of MSC exosomes, whereas the lipidomes of Huh7 and MSC exosomes were similar to each other but different from the lipidomes of U87 exosomes; (c) exosomes exhibited proteins of extracellular matrix, heparin-binding, receptors, immune response and cell adhesion functions, whereas MVs were enriched in endoplasmic reticulum, proteasome and mitochondrial proteins. Exosomes and MVs also differed in their types of lipid contents. Enrichment in glycolipids and free fatty acids characterized exosomes, whereas enrichment in ceramides and sphingomyelins characterized MVs. Furthermore, Huh7 and MSC exosomes were specifically enriched in cardiolipins; U87 exosomes were enriched in sphingomyelins. This study comprehensively analyses the protein and lipid composition of exosomes, MVs and source cells in 3 different cell types.


[Application of cognitive behavioral therapy to early phase of psychosis].
Attempts to apply cognitive-behavioral therapy (CBT) to treat patients in the early stage of psychosis, including those with First-Episode Psychosis (FEP) and those with an At-Risk Mental State (ARMS), have recently attracted considerable attention. Such CBT for FEP focuses on promoting the recovery process and relapse prevention, although evidence on its efficacy is currently limited. Further, studies on CBT for ARMS have not consistently demonstrated its effectiveness. Some reports affirm the effectiveness of CBT in FEP prevention, while others claim that the treatment leads to no compelling difference in comparison to nonspecific treatment such as supportive therapy and treatment as usual. It is evident that psychosocial interventions play a fundamental role in the treatment of early stages of psychosis. Therapeutic approaches based on CBT have been applied to various cases: however, further research is necessary in order to produce more concrete results and obtain the evidence needed to approve this method.


Making distance education accessible for students who are deaf and hard-of-hearing.
Distance education is based on providing learning "anytime, anywhere." The design of many distance education courses, however, may actually erect barriers to the full participation of some students with disabilities, particularly those with hearing impairments. Without careful consideration, distance education could become learning anytime, anywhere, but not for anybody. It is not only unethical, but also illegal to ignore the special needs of these learners. The specific impact of such legislation on distance education for those students with hearing impairments will be addressed. Students with disabilities are often faced with a double digital divide that must be bridged. Universal design uses an excellent proactive approach to closing this digital divide caused by inaccessible courses. Each medium of transmission in distance education poses unique access barriers. Even within the same medium, what is best for one student or class may not be the most ideal accommodation in another situation. Individualized accommodation methods will be examined, and specific technologies and software will be discussed.


Financial interventions and movement restrictions for managing the movement of health workers between public and private organizations in low- and middle-income countries.
Health workers move between public and private organizations in both urban and rural areas during the course of their career. Depending on the proportion of the population served by public or private organizations in a particular setting, this movement may result in imbalances in the number of healthcare providers available relative to the population receiving care from that sector. However, both public and private organizations are needed as each sector has unique contributions to make to the effective delivery of health services. To assess the effects of financial incentives and movement restriction interventions to manage the movement of health workers between public and private organizations in low- and middle-income countries. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (10 November 2012); EMBASE (7 June 2011); LILACS (9 June 2011); MEDLINE (10 November 2012); CINAHL (13 August 2012); and the British Nursing Index (13 August 2012). Randomized controlled trials and non-randomized controlled trials; controlled before-and-after studies if pre- and post-intervention periods for study and control groups were the same and there were at least two units included in both the intervention and control groups; uncontrolled and controlled interrupted time series studies if the point in time when the intervention occurred was clearly defined and there were at least three or more data points before and after the intervention. Interventions included payment of special allowances, increasing salaries, bonding health workers, offering bursary schemes, scholarships or lucrative terminal benefits, and hiring people on contract basis. Two review authors independently applied the criteria for inclusion and exclusion of studies to the titles and abstracts of all articles obtained from the search. The same two review authors independently screened the full reports of the selected citations. At each stage, we compared the results and resolved discrepancies through discussion with a third review author. We found no studies that were eligible for inclusion in this review. We identified no rigorous studies on the effects of interventions to manage the movement of health workers between public and private organizations in low- and middle-income countries. Health worker availability is a key obstacle in delivery of health services. Interventions to make the health sector more responsive to the expectations of populations by having more health workers in the sector that serves most people would contribute to the more efficient use of the health workforce. More research is needed to assess the effect of increase in salaries, offering scholarships or bonding on movement of health workers in one sector compared with another.


Radiographic loss of contact between radial head fracture fragments is moderately reliable.
Loss of contact between radial head fracture fragments is strongly associated with other elbow or forearm injuries. If this finding has adequate interobserver reliability, it could help examiners identify and treat associated ligament injuries and fractures (eg, forearm interosseous ligament injury or elbow dislocation). (1) What is the interobserver agreement on radiographic loss of contact between radial head fracture fragments? (2) Are there factors associated with the observer such as location of practice or subspecialization that increase interobserver reliability? Fully trained practicing orthopaedic and trauma surgeons from around the world evaluated 27 anteroposterior and lateral radiographs of radial head fractures on a web-based platform for the following characteristics: (1) loss of contact between at least one radial head fracture fragment and the remaining radial head and neck; (2) a gap between fragments of 2 mm or greater; (3) anticipated fracture instability (mobility) on operative exposure; (4) anticipated associated ligament injuries; and (5) recommendation for treatment. Agreement among observers was measured using the multirater kappa measure. Kappas for various observer characteristics were compared using 95% confidence intervals. The overall interobserver agreement was moderate (range, 0.49-0.55) for each question except associated ligament injury, which was fair (0.33). Shoulder and elbow surgeons had substantial agreement (range, 0.51-0.61) in many areas, but kappas were generally in the moderate range (0.41-0.59) based on number of years in practice, radial head fractures treated per year, and trainee supervision. Radiographic signs of radial head fracture instability such as loss of contact have moderate reliability. This characteristic seems clinically useful, because loss of contact between at least one radial head fracture fragment and the remaining radial head and neck is strongly associated with associated ligament injury or other fractures. Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.


A novel, automated nutrition screening system as a predictor of nutritional risk in an oncology day treatment unit (ODTU).
Paper-based nutrition screening tools can be challenging to implement in the ambulatory oncology setting. The aim of this study was to determine the validity of the Malnutrition Screening Tool (MST) and a novel, automated nutrition screening system compared to a 'gold standard' full nutrition assessment using the Patient-Generated Subjective Global Assessment (PG-SGA). An observational, cross-sectional study was conducted in an outpatient oncology day treatment unit (ODTU) within an Australian tertiary health service. Eligibility criteria were as follows: ≥ 18 years, receiving outpatient anticancer treatment and English literate. Patients self-administered the MST. A dietitian assessed nutritional status using the PG-SGA, blinded to the MST score. Automated screening system data were extracted from an electronic oncology prescribing system. This system used weight loss over 3 to 6 weeks prior to the most recent weight record or age-categorised body mass index (BMI) to identify nutritional risk. Sensitivity and specificity against PG-SGA (malnutrition) were calculated using contingency tables and receiver operating curves. There were a total of 300 oncology outpatients (51.7% male, 58.6 ± 13.3 years). The area under the curve (AUC) for weight loss alone was 0.69 with a cut-off value of ≥ 1% weight loss yielding 63% sensitivity and 76.7% specificity. MST (score ≥ 2) resulted in 70.6% sensitivity and 69.5% specificity, AUC 0.77. Both the MST and the automated method fell short of the accepted professional standard for sensitivity (~≥ 80%) derived from the PG-SGA. Further investigation into other automated nutrition screening options and the most appropriate parameters available electronically is warranted to support targeted service provision.


Electrical Stimulation in the Bone Repair of Defects Created in Rabbit Skulls.
Electrical stimulation has been used in different conditions for tissue regeneration. The aim of this study was to analyze the tissue response of defects created in rabbit skulls to electrical stimulation. Two groups were formed, each with 9 New Zealand rabbits; two 5 mm defects were made, one in each parietal, with one being randomly filled with autogenous bone extracted as particles and the other maintained only with blood clotting. The rabbits were euthanized at 8 weeks and 15 weeks to then study the samples collected histologically. In the 8-week analysis bone formation was observed in the defects in the test and control filled with bone graft, whereas the defects with clotting presented a very early stage of bone formation with abundant connective tissue. At 15 weeks an advanced stage of bone regeneration was identified in the defects with bone graft, whereas no significant differences were found in the electrically stimulated defects. In conclusion, electrical stimulus does not alter the sequence of bone formation; new studies could help establish patterns and influences of the stimulus on bone regeneration.


miR-149 in Human Cancer: A Systemic Review.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate post-transcriptional gene expression via binding to the 3'-untranslated region (3'-UTR) of targeted mRNAs. They are reported to play important roles in tumorigenesis and progression of various cancers. Among them, miR-149 was confirmed to be aberrantly regulated in various tumors. In this review, we provide a complex overview of miR-149, particularly summarize the critical roles of it in cancers and expect to lay the foundation for future works on this important microRNA.


Inhibition of protein-protein interactions: the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening.
The interaction between beta-catenin and Tcf family members is crucial for the Wnt signal transduction pathway, which is commonly mutated in cancer. This interaction extends over a very large surface area (4800 A(2)), and inhibiting such interactions using low molecular weight inhibitors is a challenge. However, protein surfaces frequently contain "hot spots," small patches that are the main mediators of binding affinity. By making tight interactions with a hot spot, a small molecule can compete with a protein. The Tcf3/Tcf4-binding surface on beta-catenin contains a well-defined hot spot around residues K435 and R469. A 17,700 compounds subset of the Pharmacia corporate collection was docked to this hot spot with the QXP program; 22 of the best scoring compounds were put into a biophysical (NMR and ITC) screening funnel, where specific binding to beta-catenin, competition with Tcf4 and finally binding constants were determined. This process led to the discovery of three druglike, low molecular weight Tcf4-competitive compounds with the tightest binder having a K(D) of 450 nM. Our approach can be used in several situations (e.g., when selecting compounds from external collections, when no biochemical functional assay is available, or when no HTS is envisioned), and it may be generally applicable to the identification of inhibitors of protein-protein interactions.


Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease.
Achieving normal growth is one of the most challenging problems in the management of children with chronic kidney disease (CKD). Treatment with recombinant human growth hormone (GH) promotes longitudinal growth and likely enables children with CKD and short stature to reach normal adult height. Here, members of the European Society for Paediatric Nephrology (ESPN) CKD-Mineral and Bone Disorder (MBD), Dialysis and Transplantation working groups present clinical practice recommendations for the use of GH in children with CKD on dialysis and after renal transplantation. These recommendations have been developed with input from an external advisory group of paediatric endocrinologists, paediatric nephrologists and patient representatives. We recommend that children with stage 3-5 CKD or on dialysis should be candidates for GH therapy if they have persistent growth failure, defined as a height below the third percentile for age and sex and a height velocity below the twenty-fifth percentile, once other potentially treatable risk factors for growth failure have been adequately addressed and provided the child has growth potential. In children who have received a kidney transplant and fulfil the above growth criteria, we recommend initiation of GH therapy 1 year after transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not a feasible option. GH should be given at dosages of 0.045-0.05 mg/kg per day by daily subcutaneous injections until the patient has reached their final height or until renal transplantation. In addition to providing treatment recommendations, a cost-effectiveness analysis is provided that might help guide decision-making.