Fitness benefits of male dominance behaviours depend on the degree of individual inbreeding in a polyandrous lizard.
In polyandrous species, sexual selection extends beyond mating competition to selection for egg fertilization. As a result, the degree to which factors influencing mating success impact overall reproductive success becomes variable. Here, we used a longitudinal behavioural and genetic dataset for a population of eastern water dragons (Intellagama lesueurii) to investigate the degree to which male dominance, a pre-mating selection trait, influences overall reproductive success, measured as the number of surviving offspring. Moreover, we examine the interactive effects with a genetic trait, individual inbreeding, known to influence the reproductive success of males in this species. We found fitness benefits of male dominance, measured as body size and frequency of dominance behaviours displayed. However, individuals' propensity to display dominance behaviours had mixed effects, depending on the degree of inbreeding. While inbred males benefited from frequent displays, highly outbred males exhibited better reproductive outputs when displaying to a lesser extent. Given that outbred males have enhanced reproductive success in this species, the costs of displaying dominance behaviours may outweigh the benefits. Overall, our results demonstrate the fitness benefits of dominance in a polyandrous lizard, and suggest that these are modulated by an independent genetic trait. Our results may contribute to explaining the presence of alternative mating tactics in this species, owing to the variability in net fitness benefits of dominance. Our findings also reveal the challenges associated with investigating fitness traits in isolation, which may undermine the validity of results when important interactions are ignored.


Review: Preclinical studies on placenta-derived cells and amniotic membrane: an update.
Recent years have seen considerable advances in our knowledge of the biology and properties of stem/progenitor cells isolated from placental tissues. This has encouraged researchers to address the potential effects of these cells in animal models of different diseases, resulting in increasing expectations regarding their possible utility for cell-based therapeutic applications. This rapidly evolving research field is also enriched by studies aimed at expanding the use of the whole amniotic membrane (AM), a well-known surgical material, for pathological conditions other than those tested so far and for which clinical applications already exist. In this review, we provide an update on studies that have been performed with placenta-derived cells and fragments of the entire AM to validate their potential clinical applications in a variety of diseases, in particular those associated with degenerative processes induced by inflammatory and fibrotic mechanisms. We also offer, as far as possible, insight into the interpretation and suggested mechanisms to explain the most important outcomes achieved to date.


Echocardiographic predictors of intraoperative right ventricular dysfunction: a 2D and speckle tracking echocardiography study.
Intraoperative or post procedure right ventricular (RV) dysfunction confers a poor prognosis in the post-operative period. Conventional predictors for RV function are limited due the effect of cardiac surgery on traditional RV indices; novel echocardiographic techniques hold the promise to improve RV functional stratification. Comprehensive echocardiographic data were collected prospectively during elective cardiac surgery. Tricuspid annular plane systolic excursion (TAPSE), peak RV systolic velocity (S'), and RV fractional area change (FAC) were quantified on transesophageal echo (TEE). RV global and regional (septal and free wall) longitudinal strain was quantified using speckle-tracking echo in RV-focused views. Two intraoperative time points were used for comparison: pre-sternotomy (baseline) and after chest closure. The population was comprised of 53 patients undergoing cardiac surgery [15.1% coronary artery bypass graft (CABG) only, 28.3% valve only, 50.9% combination (e.g. valve/CABG, valve/aortic graft) surgeries], among whom 38% had impaired RV function at baseline defined as RV FAC < 35%. All conventional RV functional indices including TAPSE, S' and FAC declined immediately following CPB (1.5 ± 0.3 vs.1.1 ± 0.3 cm, 8.0 ± 2.1 vs. 6.2 ± 2.5 cm/s, 36.8 ± 9.3 vs. 29.3 ± 10.6%; p < 0.001 for all). However, left ventricular (LV) and RV hemodynamic parameters remained unchanged (LV ejection fraction (EF): 56.8 ± 13.0 vs. 55.8 ± 12.9%; p = 0.40, pulmonary artery systolic pressure (PASP): 26.5 ± 7.4 vs 27.3 ± 6.7 mmHg; p = 0.13). Speckle tracking echocardiographic data demonstrated a significant decline in RV global longitudinal strain (GLS) [19.0 ± 6.5 vs. 13.5 ± 6.9%, p < 0.001]. Pre-procedure FAC, GLS and free wall strain predicted RV dysfunction at chest closure (34.7 ± 9.1 vs. 41.6 ± 8.1%, p = 0.01, 17.7 ± 6.5 vs. 21.8 ± 5.4%; p = 0.03, 20.3 ± 6.4 vs. 24.2 ± 5.8%; p = 0.04), whereas traditional linear RV indices such as TAPSE and RV S' at baseline had no impact on intraoperative RV dysfunction (p = NS for both). Global and regional RV function, as measured by 2D indices and strain, acutely decline intraoperatively. Impaired RV strain is associated with intraoperative RV functional decline and provides incremental value to traditional RV indices in predicting those who will develop RV dysfunction.


Carbon Monoxide in the Earth's Atmosphere: Increasing Trend.
The results of an analysis of more than 60,000 atmospheric measurements of carbon monoxide taken over 3(1/2) years at Cape Meares, Oregon (45 degrees N, 125 degrees W), indicate that the background concentration of this gas is increasing. The rate of increase, although uncertain, is about 6 percent per year on average. Human activities are the likely cause of a substantial portion of this observed increase; however, because of the short atmospheric lifetime of carbon monoxide and the relatively few years of observations, fluctuations of sources and sinks related to the natural variability of climate may have affected the observed trend. Increased carbon monoxide may deplete tropospheric hydroxyl radicals, slowing down the removal of dozens of man-made and anthropogenic trace gases and thus indirectly affecting the earth's climate and possibly the stratospheric ozone layer.


Disseminated mycosis in veiled chameleons (Chamaeleo calyptratus) caused by Chamaeleomyces granulomatis, a new fungus related to Paecilomyces viridis.
An outbreak of disseminated granulomatous disease occurred in a group of veiled chameleons (Chamaeleo calyptratus) in a zoo collection. An adult female and six offspring developed large granulomas in multiple organs and were euthanized. At necropsy, roughly spherical yellow-to-white nodules 1 to 3 mm in diameter were grossly visible in the liver and other organs. Histopathology revealed fungal elements that were spherical to ovoid in shape, fragments of slender to irregularly swollen hyphae, and occasional conidia produced on phialides. Fungal isolates were initially suspected on the basis of morphology results to represent Paecilomyces viridis, a species known only from one outbreak of fatal mycosis in carpet chameleons (Furcifer lateralis). Data obtained from morphological studies and from phylogenetic analyses of nuclear ribosomal rRNA (rDNA) sequence data revealed the Danish chameleon isolates to be a related undescribed anamorphic species within the family Clavicipitaceae that includes many insect pathogens. Chamaeleomyces granulomatis gen. et sp. nov. is given as the name for the newly described fungus, and P. viridis is transferred to the new genus as Chamaeleomyces viridis comb. nov. Chamaeleomyces species are distinguished by having basally swollen phialides tapering to a narrow neck, conidia in fragile chains, and pale green to greenish-gray colonies. Both species are dimorphic, producing a transitory yeast stage characterized by ovoid-to-subglobose or subcylindrical yeast-like cells. Chamaeleomyces species appear to be rare but aggressive pathogens of chameleons.


Morbidity from urinary schistosomiasis in relation to intensity of infection in the Natal Province of South Africa.
Morbidity from urinary schistosomiasis was assessed on clinical, radiological, parasitologic and biochemical evidence in 510 schoolchildren living in a Schistosoma haematobium endemic area. The results were viewed against the background of the prevalence and intensity of infection in the subjects. Clinical morbidity correlated well with the intensity of infection, the latter in turn being influenced by factors such as water contact pattern, sex and water source. A surprisingly high prevalence (42%) of abnormalities was observed in the urinary tract of subjects, but no relationship could be demonstrated between the intensity of infection and structural damage to the urinary tract. Urographic changes were more severe in the 11-15 year age group than in the 6-10 year group. Significant rectal involvement (76%) in S. haematobium-infected subjects was regarded as a reflection of the heavy worm burdens borne by these children. The morbidity described in this study indicates a definite degree of pathology in the infected children but the impression was that they suffered only mild disability. However, given the structural lesions seen on urography and the limited sensitivity of the biochemical tests used for the assessment of renal function, renal pathology cannot be ruled out. Further studies on the renal status of these subjects are essential.


Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.
The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D. Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts. We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling. Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.


Frequent Occurrence of NRAS and BRAF Mutations in Human Acral Naevi.
Acral naevi are benign melanocytic tumors occurring at acral sites. Occasionally they can progress to become malignant tumors (melanomas). The genetics of acral naevi have not been assessed in larger studies. In our study, a large cohort of 130 acral naevi was screened for gene mutations known to be important in other naevi and melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with clinicopathological parameters. Frequent mutations in genes activating the MAP kinase pathway were identified, including n = 87 (67%) BRAF, n = 24 (18%) NRAS, and one (1%) MAP2K1 mutations. BRAF mutations were almost exclusively V600E (n = 86, 99%) and primarily found in junctional and compound naevi. NRAS mutations were either Q61K or Q61R and frequently identified in dermal naevi. Recurrent non-V600E BRAF, KIT, NF1, and TERT promoter mutations, present in acral melanoma, were not identified. Our study identifies BRAF and NRAS mutations as the primary pathogenic event in acral naevi, however, distributed differently to those in non-acral naevi. The mutational profile of acral naevi is distinct from acral melanoma, which may be of diagnostic value in distinguishing these entities.


An optical imaging chamber for viewing living plant cells and tissues at high resolution for extended periods.
Recent developments in both microscopy and fluorescent protein technologies have made live imaging a powerful tool for the study of plant cells. However, the complications of keeping plant material alive during a long duration experiment while maintaining maximum resolution has limited the use of these methods. Here, we describe an imaging chamber designed to overcome these limitations, which is flexible enough to support a range of sizes of plant materials. We were able use confocal microscopy to follow growth and development of plant cells and tissues over several days. The chamber design is based on a perfusion system, so that the addition of drugs and other experimental treatments are also possible. In this article we present a design of imaging chamber that makes it possible to image plant material with high resolution for extended periods of time.


The views of patients with severe chronic obstructive pulmonary disease on advance care planning: a qualitative study.
Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide and there are concerns that end-of-life care for these patients is inadequate. Advance care planning is encouraged, with the hope that it will improve communication and avoid unwanted interventions, which have been particular concerns; in practice, these discussions rarely occur. We have little knowledge of the views of patients with COPD on advance care planning. Understanding this could help integrate advance care planning into the routine management of patients with COPD. To explore the views of people with severe COPD about advance care planning. Qualitative design, with data collection incorporating audio recorded semi-structured interviews. Analysis followed a grounded theory approach. Patients with severe COPD (n =10, Gold Standards Framework criteria) were recruited from primary and secondary care settings. Participants felt they had not been given enough information about their diagnosis and prognosis, and were keen for more discussion with healthcare professionals. They wanted more involvement in decisions about their treatment when those decisions were required. Participants were happy to discuss their general views about future care, but felt uncomfortable with the traditional model of binding 'advance directives'. Considering advance care planning as a repeated process of discussion of prognosis, concerns and probable preferences for care would be more useful than encouraging binding advance decisions. Further research should assess the effectiveness of this approach. Local coordination of who is responsible for information provision is needed, and greater involvement of patients with COPD in management decisions as they arise.


Intramedullary spinal cord mass presumptively associated with leishmaniasis in a dog.
A 9-year-old male Miniature Poodle was evaluated because of progressive severe right hemiparesis, right forelimb lameness, and signs of cervical pain. A low body condition score (2/9) and popliteal lymphadenopathy were detected. Results of a CBC, serum biochemical analyses, urinalysis, cytologic examination of bone marrow and popliteal lymph node aspirates, and serum ELISA were consistent with systemic leishmaniasis. Magnetic resonance imaging of the cervical spinal cord revealed an intramedullary mass extending from the caudal aspect of the C5 vertebral body to the C5-6 intervertebral disk space with a contrast medium-enhanced pattern that had 3 zones (central contrast medium-enhanced core, intermediate isointense zone, and peripheral contrast medium-enhanced ring). Surgical biopsy of the mass was performed by means of a right C5-6 dorsal hemilaminectomy. Results of PCR assays for detection of Leishmania DNA in CSF and tissue biopsy samples were positive. Treatment for systemic leishmaniasis was initiated. Two months later, body condition, neurologic signs, and gait of the dog had substantially improved; the dog had mild right forelimb paresis at that time. Results of follow-up MRI indicated resolution of the cervical spinal cord lesion. Four months after diagnosis, the dog's neurologic condition was stable. To the authors' knowledge, this report is the first in which clinical findings, clinicopathologic data, and MRI characteristics of an intramedullary inflammatory spinal cord lesion presumptively attributable to leishmaniasis in a dog have been reported, and the first report of CNS leishmaniasis in a dog with MRI resolution and a successful clinical response to treatment.


Visualizing the ribonucleoprotein content of single bunyavirus virions reveals more efficient genome packaging in the arthropod host.
Bunyaviruses have a genome that is divided over multiple segments. Genome segmentation complicates the generation of progeny virus, since each newly formed virus particle should preferably contain a full set of genome segments in order to disseminate efficiently within and between hosts. Here, we combine immunofluorescence and fluorescence in situ hybridization techniques to simultaneously visualize bunyavirus progeny virions and their genomic content at single-molecule resolution in the context of singly infected cells. Using Rift Valley fever virus and Schmallenberg virus as prototype tri-segmented bunyaviruses, we show that bunyavirus genome packaging is influenced by the intracellular viral genome content of individual cells, which results in greatly variable packaging efficiencies within a cell population. We further show that bunyavirus genome packaging is more efficient in insect cells compared to mammalian cells and provide new insights on the possibility that incomplete particles may contribute to bunyavirus spread as well.


Association between Sirtuin 2 gene rs10410544 polymorphism and depression in Alzheimer's disease in two independent European samples.
Among the several genes associated with late-onset Alzheimer's disease (LOAD), recently, Sirtuin genes have roused a growing interest because of their involvement in metabolic homeostasis and in brain aging. Particularly SIRT2 gene has been associated with Alzheimer's disease (AD) as well as with mood disorders. The aim of this study is to investigate the possible associations between Sirtuin 2 gene (SIRT2) rs10410544 polymorphism and AD as well as depression in AD. In addition, we performed some exploratory analyses to investigate possible associations between the rs10410544 genotype and clinical features. We investigated these associations in two independent samples: the first one was composed of 275 Greek inhabitants and 117 patients; the second sample counted 181 Italian people and 43 patients. All patients were affected by LOAD. We failed to find any association between rs10410544 genotype and AD in the two samples. On the other hand, we found an association between the single nucleotide polymorphism (SNP) and depressive symptomatology (in the total sample p = 0.002), which was modulated by the tumor necrosis factor (TNF) values. Particularly, TT genotype seems to be protective versus depression. Finally, in the exploratory analyses, we found that the TT genotype was associated with earlier AD onset and a longer duration of the illness. In conclusion, we confirmed the association between SIRT2 gene and mood disturbances, although in AD patients. Further, we provided evidence that the TT genotype may be protective versus depressive symptoms, allowing an easier and thus earlier diagnosis of AD. This awareness may lead to a more detailed approach to these patients concerning diagnosis and therapy.


[Survey results of medical insurance reimbursement system for independent medical laboratories in Korea].
A questionnaire survey was performed to perceive the problem of the current medical insurance reimbursement system for laboratory tests referred to independent medical laboratories; then, we intended to find a way to improve the reimbursement system. Questionnaires were distributed to 220 independent medical laboratories and 700 laboratory physicians from July through October 2005. Frequency analysis was used to analyse the replies from 109 respondents to 25 questionnaire items regarding the current medical insurance reimbursement system for referral tests, problems with the system, and suggestions for the improvement of the system. Among the 109 respondents to this survey, 49 (45.8%) considered the current reimbursement system to be unsatisfactory, while only 16 (15.0%) answered satisfactory. The problem was that the referral clinics-not the laboratories that performed the tests--would first receive their reimbursement for the laboratory tests from Health Insurance Review Agency (HIRA) and then give a portion of the laboratory test fees to the independent medical laboratories after the deduction of administrative fees. They (62.5% of the respondents) would prefer a separated reimbursement system by which the referral clinic-as well as the independent medical laboratory-would receive their reimbursement directly from HIRA through an Electronic Data Interchange (EDI) system. In this new system, 34% of the respondents expected the quality of the laboratory tests to be improved; however, 41.6% answered that the income of the referral clinic is expected to decrease. For the improvement of the medical insurance reimbursement system, the administrative fee for the referral clinic and the test fee for the independent medical laboratory should be reimbursed directly to the respective organizations. These changes could be made possible with the proper analysis of medical costs and the development of an effective EDI reimbursement system.


Salience of spatiochromatic patterns.
We investigated the dependence of perceived contrast on cone-opponent stimulus content and its spatial distribution. Participants matched a comparison patch to a light gray standard of fixed contrast. The first experiment determined the point of iso-salience for gratings, Gabors and Gaussians along cardinal directions in cone-opponent color space for two-alternative forced choice (2AFC) and adjustment tasks. No difference was found between adjustment and 2AFC tasks, meaning that adjustment tasks provide a quick and robust way to measure perceived contrast, at least for relatively large suprathreshold stimuli. In line with the differences in contrast energy between Gaussians, Gabors, and gratings, Gaussians required less contrast to achieve equal perceived salience with a standard irrespective of color. More surprisingly, bluish Gaussians were found to have higher salience than yellowish Gaussians at equal levels of contrast. Although perceived contrast of grating and Gabor patterns likely depends on spatial frequency channels that at 1 cycle-per-degree are not too dissimilarly tuned for color and luminance, for Gaussians the contribution of single-opponent neurons would be greater for color than for luminance. In a follow-up experiment, we found that the bluish/yellowish asymmetry decreased as we reduced the proportion of the lowpass non-flat contrast distribution in the stimulus, with minimal asymmetry for the stimulus with a flat contrast distribution (i.e., uniform patch). Combined, this means that differential engagement of spatial frequency channels, single-opponent and double-opponent neurons impacts on perceived contrast of chromatic suprathreshold stimuli. Perceived contrast thus provides a window into neural computations enacted by low-level cone-opponent mechanisms.


Precise preoperative localization of prostate cancer employing 12-core needle biopsy with a tissue-marking method for effective surgical strategy.
Prostate needle biopsy plays a pivotal role not only in the diagnosis but also the management of patients with prostate cancer. Prostate cancer is often multifocal and diagnosis of the lesion could therefore be difficult with diagnostic imaging only; thus, multiple core biopsies are taken from several different regions of the prostate. In current practice, 10- or 12-core needle biopsy is considered the clinical standard. Several techniques have been reported to improve the orientation of the specimens, but tissue marking, which could theoretically provide important information on the location of the lesion in the prostate, has been rarely reported. Therefore, in this study, we evaluated the clinical significance of systematic 12-core needle biopsy with tissue marking for preoperative prediction of lesion sites and clinicopathological features of patients. We evaluated 93 patients who underwent 12-core prostate biopsy and subsequent radical prostatectomy. We correlated the biopsy results to the prostate sites in which biopsies were performed and prognostic factors of the patients, especially the degree of extraprostatic extension (EPE) obtained in surgical specimens. Among 253 cancer foci detected in 93 prostatectomy specimens, 168 (66.4%) foci were detected by biopsy. All patients had proven cancer. EPE-positive cancers were associated with a larger number of positive cores, larger tumor length, and higher percentage of cancer tissue in the corresponding cores. Systematic 12-core prostate biopsy with tissue marking is useful for preoperative detection of cancer foci and provides valuable information that enables effective surgical strategies.


Negative optical torque.
Light carries angular momentum, and as such it can exert torques on material objects. Applications of these opto-mechanical effects were limited initially due to their smallness in magnitude, but later becomes powerful and versatile after the invention of laser. Novel and practical approaches for harvesting light for particle rotation have since been demonstrated, where the structure is always subjected to a positive optical torque along a certain axis if the incident angular momentum has a positive projection on the same axis. We report here an interesting phenomenon of "negative optical torque", meaning that incoming photons carrying angular momentum rotate an object in the opposite sense. Surprisingly this can be realized quite straightforwardly in simple planar structures. Field retardation is a necessary condition and discrete rotational symmetry of material object plays an important role. The optimal conditions are explored and explained.


Antecedents of teenage pregnancy from a 14-year follow-up study using data linkage.
Many western nations continue to have high rates of teenage pregnancies and births, which can result in adverse outcomes for both mother and child. This study identified possible antecedents of teenage pregnancy using linked data from administrative sources to create a 14-year follow-up from a cross-sectional survey. Data were drawn from two sources - the 1993 Western Australian Child Health Survey (WACHS), a population-based representative sample of 2,736 children aged 4 to 16 years (1,374 girls); and administrative data relating to all their subsequent births and hospital admissions. We used weighted population estimates to examine differences between rates for teenage pregnancy, motherhood and abortion. We used Cox proportional hazards regression to model risk for teenage pregnancy. There were 155 girls aged less than 20 years at the time of their first recorded pregnancy. Teenage pregnancy was significantly associated with: family type; highest school year completed by primary carer; combined carer income; whether the primary carer was a smoker; and whether the girl herself displayed aggressive and delinquent behaviours. An age-interaction analysis on the association with aggressive and delinquent behaviours found that while girls with aggressive and delinquent behaviours who were older at the time of the survey were at highest risk of teenage pregnancy, there was elevated risk for future teenage pregnancy across all ages. Our findings suggest that interventions to reduce teenage pregnancy rates could be introduced during primary school years, including those that are focused on the prevention and management of aggressive and delinquent behaviour.


In vitro investigations of a novel wound dressing concept based on biodegradable polyurethane.
Non-healing and partially healing wounds are an important problem not only for the patient but also for the public health care system. Current treatment solutions are far from optimal regarding the chosen material properties as well as price and source. Biodegradable polyurethane (PUR) scaffolds have shown great promise for in vivo tissue engineering approaches, but accomplishment of the goal of scaffold degradation and new tissue formation developing in parallel has not been observed so far in skin wound repair. In this study, the mechanical properties and degradation behavior as well as the biocompatibility of a low-cost synthetic, pathogen-free, biocompatible and biodegradable extracellular matrix mimicking a PUR scaffold was evaluated in vitro. The novel PUR scaffolds were found to meet all the requirements for optimal scaffolds and wound dressings. These three-dimensional scaffolds are soft, highly porous, and form-stable and can be easily cut into any shape desired. All the material formulations investigated were found to be nontoxic. One formulation was able to be defined that supported both good fibroblast cell attachment and cell proliferation to colonize the scaffold. Tunable biodegradation velocity of the materials could be observed, and the results additionally indicated that calcium plays a crucial role in PUR degradation. Our results suggest that the PUR materials evaluated in this study are promising candidates for next-generation wound treatment systems and support the concept of using foam scaffolds for improved in vivo tissue engineering and regeneration.


Efficient storage and transmission of ladar imagery.
We develop novel methods for compressing volumetric imagery that has been generated by single-platform (mobile) range sensors. We exploit the correlation structure inherent in multiple views in order to improve compression efficiency. We show that, for lossless compression, three-dimensional volumes compress more efficiently than two-dimensional (2D) images by a factor of 60%. Furthermore, our error metric for lossy compression suggests that accumulating more than nine range images in one volume before compression yields as much as a 99% improvement in compression performance over 2D compression.


Study protocol for a type III hybrid effectiveness-implementation trial of strategies to implement firearm safety promotion as a universal suicide prevention strategy in pediatric primary care.
Insights from behavioral economics, or how individuals' decisions and behaviors are shaped by finite cognitive resources (e.g., time, attention) and mental heuristics, have been underutilized in efforts to increase the use of evidence-based practices in implementation science. Using the example of firearm safety promotion in pediatric primary care, which addresses an evidence-to-practice gap in universal suicide prevention, we aim to determine: is a less costly and more scalable behavioral economic-informed implementation strategy (i.e., "Nudge") powerful enough to change clinician behavior or is a more intensive and expensive facilitation strategy needed to overcome implementation barriers? The Adolescent and child Suicide Prevention in Routine clinical Encounters (ASPIRE) hybrid type III effectiveness-implementation trial uses a longitudinal cluster randomized design. We will test the comparative effectiveness of two implementation strategies to support clinicians' use of an evidence-based firearm safety practice, S.A.F.E. Firearm, in 32 pediatric practices across two health systems. All pediatric practices in the two health systems will receive S.A.F.E. Firearm materials, including training and cable locks. Half of the practices (k = 16) will be randomized to receive Nudge; the other half (k = 16) will be randomized to receive Nudge plus 1 year of facilitation to target additional practice and clinician implementation barriers (Nudge+). The primary implementation outcome is parent-reported clinician fidelity to the S.A.F.E Firearm program. Secondary implementation outcomes include reach and cost. To understand how the implementation strategies work, the primary mechanism to be tested is practice adaptive reserve, a self-report practice-level measure that includes relationship infrastructure, facilitative leadership, sense-making, teamwork, work environment, and culture of learning. The ASPIRE trial will integrate implementation science and behavioral economic approaches to advance our understanding of methods for implementing evidence-based firearm safety promotion practices in pediatric primary care. The study answers a question at the heart of many practice change efforts: which strategies are sufficient to support change, and why? Results of the trial will offer valuable insights into how best to implement evidence-based practices that address sensitive health matters in pediatric primary care. ClinicalTrials.gov, NCT04844021 . Registered 14 April 2021.


Expanded use of rituximab in the management of non-Hodgkin lymphoma.
Rituximab is a chimeric monoclonal antibody targeting the B cell antigen CD20. Since its first approval for clinical use in 1997, rituximab has become an inherent part of the treatment of CD20-positive lymphoma. In previously untreated non-Hodgkin lymphoma (NHL) conventional chemotherapy supplemented by rituximab (R-chemotherapy) was shown to be more effective than chemotherapy alone. This holds true for indolent as well as aggressive NHL. Rituximab was also shown to be beneficial when used as maintenance therapy or part of salvage and re-induction regimens in relapsed NHL. Administration of rituximab is generally well tolerated. The most common side effects including fever, urticaria and bronchospasm are mostly mild, treatable and restricted to the infusion period. Thus, rituximab can usually be administered in an outpatient setting. Due to its favorable effect/side effect ratio, clinical trials are currently evaluating a possible role for rituximab in several other diseases such as Hodgkin lymphoma (HL) and non-malignant autoimmune disorders. This review aims at giving an overview of the pharmacological properties of rituximab and summarizing key publications and recent literature on its use in NHL.


A Novel Mass Spectrometry Platform for Multiplexed N-Glycoprotein Biomarker Discovery from Patient Biofluids by Antibody Panel Based N-Glycan Imaging.
A new platform for N-glycoprotein analysis from serum that combines matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) workflows with antibody slide arrays is described. Antibody panel based (APB) N-glycan imaging allows for the specific capture of N-glycoproteins by antibodies on glass slides and N-glycan analysis in a protein-specific and multiplexed manner. Development of this technique has focused on characterizing two abundant and well-studied human serum glycoproteins, alpha-1-antitrypsin and immunoglobulin G. Using purified standard solutions and 1 μL samples of human serum, both glycoproteins can be immunocaptured and followed by enzymatic release of N-glycans. N-Glycans are detected with a MALDI FT-ICR mass spectrometer in a concentration-dependent manner while maintaining specificity of capture. Importantly, the N-glycans detected via slide-based antibody capture were identical to that of direct analysis of the spotted standards. As a proof of concept, this workflow was applied to patient serum samples from individuals with liver cirrhosis to accurately detect a characteristic increase in an IgG N-glycan. This novel approach to protein-specific N-glycan analysis from an antibody panel can be further expanded to include any glycoprotein for which a validated antibody exists. Additionally, this platform can be adapted for analysis of any biofluid or biological sample that can be analyzed by antibody arrays.


In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-beta1.
Down-regulation of CD4+CD25+ regulatory T (Treg) cell function might be beneficial to enhance the immunogenicity of viral and tumor vaccines or to induce breakdown of immunotolerance. Although the mechanism of suppression used by Treg cells remains controversial, it has been postulated that TGF-beta1 mediates their immunosuppressive activity. In this study, we show that P17, a short synthetic peptide that inhibits TGF-beta1 and TGF-beta2 developed in our laboratory, is able to inhibit Treg activity in vitro and in vivo. In vitro studies demonstrate that P17 inhibits murine and human Treg-induced unresponsiveness of effector T cells to anti-CD3 stimulation, in an MLR or to a specific Ag. Moreover, administration of P17 to mice immunized with peptide vaccines containing tumor or viral Ags enhanced anti-vaccine immune responses and improved protective immunogenicity against tumor growth or viral infection or replication. When CD4+ T cells purified from OT-II transgenic mice were transferred into C57BL/6 mice bearing s.c. EG.7-OVA tumors, administration of P17 improved their proliferation, reduced the number of CD4+Foxp3+ T cells, and inhibited tumor growth. Also, P17 prevented development of immunotolerance induced by oral administration of OVA by genetically modified Lactococcus lactis in DO11.10 transgenic mice sensitized by s.c. injection of OVA. These findings demonstrate that peptide inhibitors of TGF-beta may be a valuable tool to enhance vaccination efficacy and to break tolerance against pathogens or tumor Ags.


Prevalence of various respiratory viruses in the middle ear during acute otitis media.
Vaccines against respiratory viruses may be able to reduce the frequency of acute otitis media. Although the role of respiratory viruses in the pathogenesis of acute otitis media is well established, the relative importance of various viruses is unknown. We determined the prevalence of various respiratory viruses in the middle-ear fluid in 456 children (age, two months to seven years) with acute otitis media. At enrollment and after two to five days of antibiotic therapy, specimens of middle-ear fluid and nasal-wash specimens were obtained for viral and bacterial cultures and the detection of viral antigens. The viral cause of the infections was also assessed by serologic studies of serum samples obtained during the acute illness and convalescence. A specific viral cause of the respiratory tract infections was identified in 186 of the 456 children (41 percent). Respiratory syncytial virus was the most common virus identified in middle-ear fluid: it was detected in the middle-ear fluid of 48 of the 65 children (74 percent) infected by this virus (P< or =0.04 for the comparison with any other virus). Parainfluenza viruses (15 of 29 children [52 percent]) and influenzaviruses (10 of 24 children [42 percent]) were detected in the middle-ear fluid significantly more often than enteroviruses (3 of 27 children [11 percent]) or adenoviruses (1 of 23 children [4 percent]) (P< or =0.01 for all comparisons). Respiratory syncytial virus is the principal virus invading the middle ear during acute otitis media. An effective vaccine against upper respiratory tract infections caused by respiratory syncytial virus may reduce the incidence of acute otitis media in children.


Secretory granules are recaptured largely intact after stimulated exocytosis in cultured endocrine cells.
Classical cell biology teaches that exocytosis causes the membrane of exocytic vesicles to disperse into the cell surface and that a cell must later retrieve by molecular sorting whatever membrane components it wishes to keep inside. We have tested whether this view applies to secretory granules in intact PC-12 cells. Three granule proteins were labeled with fluorescent proteins in different colors, and two-color evanescent-field microscopy was used to view single granules during and after exocytosis. Whereas neuro-peptide Y was lost from granules in seconds, tissue plasminogen activator (tPA) and the membrane protein phogrin remained at the granule site for over 1 min, thus providing markers for postexocytic granules. When tPA was imaged simultaneously with cyan fluorescent protein (CFP) as a cytosolic marker, the volume occupied by the granule appeared as a dark spot where it excluded CFP. The spot remained even after tPA reported exocytosis, indicating that granules failed to flatten into the cell surface. Phogrin was labeled with GFP at its luminal end and used to sense the pH in granules. When exocytosis caused the acidic granule interior to neutralize, GFP-phogrin at first brightened and later dimmed again as the interior separated from the extracellular space and reacidified. Reacidification and dimming could be reversed by application of NH(4)Cl. We conclude that most granules reseal in <10 s after releasing cargo, and that these empty or partially empty granules are recaptured otherwise intact.


Social Integration and Reduced Risk of Coronary Heart Disease in Women: The Role of Lifestyle Behaviors.
Higher social integration is associated with lower cardiovascular mortality; however, whether it is associated with incident coronary heart disease (CHD), especially in women, and whether associations differ by case fatality are unclear. This study sought to examine the associations between social integration and risk of incident CHD in a large female prospective cohort. Seventy-six thousand three hundred and sixty-two women in the Nurses' Health Study, free of CHD and stroke at baseline (1992), were followed until 2014. Social integration was assessed by a simplified Berkman-Syme Social Network Index every 4 years. End points included nonfatal myocardial infarction and fatal CHD. Two thousand three hundred and seventy-two incident CHD events occurred throughout follow-up. Adjusting for demographic, health/medical risk factors, and depressive symptoms, being socially integrated was significantly associated with lower CHD risk, particularly fatal CHD. The most socially integrated women had a hazard ratio of 0.55 (95% confidence interval, 0.41-0.73) of developing fatal CHD compared with those least socially integrated (P for trend <0.0001). When additionally adjusting for lifestyle behaviors, findings for fatal CHD were maintained but attenuated (P for trend =0.02), whereas the significant associations no longer remained for nonfatal myocardial infarction. The inverse associations between social integration and nonfatal myocardial infarction risk were largely explained by health-promoting behaviors, particularly through differences in cigarette smoking; however, the association with fatal CHD risk remained after accounting for these behaviors and, thus, may involve more direct biological mechanisms. Social integration is inversely associated with CHD incidence in women, but is largely explained by lifestyle/behavioral pathways.


Predicting MSSA in Acute Hematogenous Osteomyelitis in a Setting With MRSA Prevalence.
Increased severity of illness in patient with acute hematogenous osteomyelitis (AHO) with methicillin-resistant Staphylococcus aureus (MRSA) necessitates prompt intervention, but overtreatment of methicillin-sensitive S. aureus (MSSA) may contribute to antibiotic resistance. Therefore, predicting methicillin sensitivity in suspected AHO is desirable. A previously published prediction algorithm has not performed well in settings with high prevalence of MRSA. We sought to develop a predictive equation using presenting factors to predict MRSA in our patient population with a predominance of MRSA. A retrospective chart review was performed. Consecutive cases of AHO with positive blood or bone cultures were identified at a single children's hospital. Presenting features were recorded including duration of symptoms, weight-bearing, prior antibiotic use, vital signs, complete blood count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Univariate comparison was made between the groups with MRSA and MSSA. Continuous variables were compared with t tests and discrete variables were compared using the Fischer exact test. Logistic regression was performed using a forward stepwise regression to develop a model to predict MRSA. A total of 68 patients formed the study group, and 60% had MRSA (41 MRSA, 27 MSSA). Temperature, respiratory rate, heart rate, white blood cell count, absolute neutrophil count (ANC), ESR), and CRP were significantly higher in MRSA cases, whereas platelets were lower. Logistic regression resulted in a model utilizing temperature, ANC, and CRP. This model correctly predicted 87% of cases (92% of MRSA and 79% of MSSA) with an area under the curve of 0.919±0.035 with a 95% confidence interval of 0.851, 0.987. A logistic regression model incorporating temperature, ANC, and CRP correctly predicts methicillin resistance of S. aureus in 87% of cases. The model differs from one developed at an institution with a low rate of MRSA. Prediction of MRSA could help direct antibiotic management, whereas prediction of MSSA could help prevent overuse of antibiotics directed against MRSA. Diagnostic study level IV.


Melatonin potentiates chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor cells.
Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant action. Thus, melatonin has proven useful in the treatment of tumors in association with chemotherapeutic drugs. This study was performed to evaluate the effect of melatonin on the cytotoxicity and apoptosis induced by three different chemotherapeutic agents, namely 5-fluorouracil (5-FU), cisplatin, and doxorubicin in the rat pancreatic tumor cell line AR42J. We found that both melatonin and the three chemotherapeutic drugs induce a time-dependent decrease in AR42J cell viability, reaching the highest cytotoxic effect after 48 hr of incubation. Furthermore, melatonin significantly augmented the cytotoxicity of the chemotherapeutic agents. Consistently, cotreatment of AR42J cells with each of the chemotherapeutic agents in the presence of melatonin increased the population of apoptotic cells, elevated mitochondrial membrane depolarization, and augmented intracellular reactive oxygen species (ROS) production compared to treatment with each chemotherapeutic agent alone. These results provide evidence that in vitro melatonin enhances chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor AR42J cells and, therefore, melatonin may be potentially applied to pancreatic tumor treatment as a powerful synergistic agent in combination with chemotherapeutic drugs.


The role of Xenopus dickkopf1 in prechordal plate specification and neural patterning.
Dickkopf1 (dkk1) encodes a secreted WNT inhibitor expressed in Spemann's organizer, which has been implicated in head induction in Xenopus. Here we have analyzed the role of dkk1 in endomesoderm specification and neural patterning by gain- and loss-of-function approaches. We find that dkk1, unlike other WNT inhibitors, is able to induce functional prechordal plate, which explains its ability to induce secondary heads with bilateral eyes. This may be due to differential WNT inhibition since dkk1, unlike frzb, inhibits Wnt3a signalling. Injection of inhibitory antiDkk1 antibodies reveals that dkk1 is not only sufficient but also required for prechordal plate formation but not for notochord formation. In the neural plate dkk1 is required for anteroposterior and dorsoventral patterning between mes- and telencephalon, where dkk1 promotes anterior and ventral fates. Both the requirement of anterior explants for dkk1 function and their ability to respond to dkk1 terminate at late gastrula stage. Xenopus embryos posteriorized with bFGF, BMP4 and Smads are rescued by dkk1. dkk1 does not interfere with the ability of bFGF to induce its immediate early target gene Xbra, indicating that its effect is indirect. In contrast, there is cross-talk between BMP and WNT signalling, since induction of BMP target genes is sensitive to WNT inhibitors until the early gastrula stage. Embryos treated with retinoic acid (RA) are not rescued by dkk1 and RA affects the central nervous system (CNS) more posterior than dkk1, suggesting that WNTs and retinoids may act to pattern anterior and posterior CNS, respectively, during gastrulation.


One year mirror-image study using paliperidone palmitate for relapse prevention of schizophrenia in four university hospitals in Canada.
Superiority of long acting injectable antipsychotics (LAI) over oral antipsychotics remains controversial and dependent on study design and inclusion criteria. Meta-analysis of 21 RCTs demonstrated no difference in their effectiveness, but meta-analysis of 25 mirror-image studies did. None of these included paliperidone palmitate (PP). We challenged efficiency of PP in a multicentric mirror-image study. Primary outcome was total hospitalization days. Mirror periods were 365days either side of the first injection in model-1, and either side of index admission in model-2. Inclusion criteria were: 18 to 65years, schizophrenia spectrum disorder, ≥3 injections received, and oral antipsychotic prescriptions before PP trial. Exclusion criteria were: prior clozapine or LAI trial. Cost-effectiveness was calculated from a public payer's perspective. 114 patients were recruited (77% males, mean 37years, mean disease duration 10years). Oral antipsychotics adherence was 43%. Mean PP treatment lasted 297days (adherence 81%). Mean annual hospitalization days weren't significantly different in model-1 (45.8days vs 38.5days, p=0.058), but were significantly lower in model-2, (14.4days vs 24.2days, p=0.003). 1.9 admissions per patient-year fell to 0.64 on PP (p<0.0001). PP was approximately cost-neutral: differences were -$326 and $1788 for model-1 and model-2. PP as a first LAI improved adherence, decreased hospital visits and duration was cost neutral. Drawbacks are the retrospective design and lack of comparator and safety data. Strengths are naturalistic design and adherence calculation. A subset of patients responds well to LAI, leading to meaningful reductions in hospital services requirements.


Salt loading increases urinary excretion of linoleic acid diols and triols in healthy human subjects.
Increased dietary linoleic acid has been associated with reduced blood pressure in clinical and animal studies possibly mediated by prostaglandins. Urinary linoleate and prostaglandin metabolite excretion were investigated in subjects exposed to a salt-loading/salt-depletion regimen. Twelve healthy subjects were recruited from the New Orleans population (before Hurricaine Katrina) and admitted to the Tulane-Louisiana State University-Charity Hospital General Clinical Research Center after a 5-day outpatient lead-in phase on a 160-mmol sodium diet. On inpatient day 1, the subjects were maintained on the 160-mmol sodium diet, and a 24-hour urine specimen was collected. On day 2, the subjects received 2 L of IV normal saline over 4 hours and continued on a 160-mmol Na(+) diet (total: 460 mmol of sodium). Two 12-hour urine collections were obtained. On day 3, the subjects received three 40-mg oral doses of furosemide, two 12-hour urine collections were obtained, and the subjects were given a 10-mmol sodium diet. Urinary oxidized lipids were measured by high-performance liquid chromatography-tandem quadrupole mass spectroscopy. The excretion of the urinary linoleate metabolites, dihydroxyoctadecamonoenoic acids, and trihydroxyoctadecamonoenoic acids increased significantly during intravenous salt loading as compared with day 1 and the salt-depleted periods. The urinary excretion of 6-keto- prostaglandin F1alpha was unaffected by salt loading but was dramatically increased 7- to 10-fold by salt depletion. Prostaglandin E2 excretion was positively correlated with sodium excretion. The salt-stimulated production of linoleic acid diols and triols may inhibit tubular sodium reabsorption, thereby assisting in the excretion of the sodium load.


Label-free peptide profiling of Orbitrap™ full mass spectra.
We developed a new version of the open source software package Peptrix that can yet compare large numbers of Orbitrap™ LC-MS data. The peptide profiling results for Peptrix on MS1 spectra were compared with those obtained from a small selection of open source and commercial software packages: msInspect, Sieve™ and Progenesis™. The properties compared in these packages were speed, total number of detected masses, redundancy of masses, reproducibility in numbers and CV of intensity, overlap of masses, and differences in peptide peak intensities. Reproducibility measurements were taken for the different MS1 software applications by measuring in triplicate a complex peptide mixture of immunoglobulin on the Orbitrap™ mass spectrometer. Values of peptide masses detected from the high intensity peaks of the MS1 spectra by peptide profiling were verified with values of the MS2 fragmented and sequenced masses that resulted in protein identifications with a significant score. Peptrix finds about the same number of peptide features as the other packages, but peptide masses are in some cases approximately 5 to 10 times less redundant present in the peptide profile matrix. The Peptrix profile matrix displays the largest overlap when comparing the number of masses in a pair between two software applications. The overlap of peptide masses between software packages of low intensity peaks in the spectra is remarkably low with about 50% of the detected masses in the individual packages. Peptrix does not differ from the other packages in detecting 96% of the masses that relate to highly abundant sequenced proteins. MS1 peak intensities vary between the applications in a non linear way as they are not processed using the same method. Peptrix is capable of peptide profiling using Orbitrap™ files and finding differential expressed peptides in body fluid and tissue samples. The number of peptide masses detected in Orbitrap™ files can be increased by using more MS1 peptide profiling applications, including Peptrix, since it appears from the comparison of Peptrix with the other applications that all software packages have likely a high false negative rate of low intensity peptide peaks (missing peptides).


The nitric oxide-responsive regulator NsrR controls ResDE-dependent gene expression.
The ResD-ResE signal transduction system is essential for aerobic and anaerobic respiration in Bacillus subtilis. ResDE-dependent gene expression is induced by oxygen limitation, but full induction under anaerobic conditions requires nitrite or nitric oxide (NO). Here we report that NsrR (formerly YhdE) is responsible for the NO-dependent up-regulation of the ResDE regulon. The null mutation of nsrR led to aerobic derepression of hmp (flavohemoglobin gene) partly in a ResDE-independent manner. In addition to its negative role in aerobic hmp expression, NsrR plays an important role under anaerobic conditions for regulation of ResDE-controlled genes, including hmp. ResDE-dependent gene expression was increased by the nsrR mutation in the absence of NO, but the expression was decreased by the mutation when NO was present. Consequently, B. subtilis cells lacking NsrR no longer sense and respond to NO (and nitrite) to up-regulate the ResDE regulon. Exposure to NO did not significantly change the cellular concentration of NsrR, suggesting that NO likely modulates the activity of NsrR. NsrR is similar to the recently described nitrite- or NO-sensitive transcription repressors present in various bacteria. NsrR likely has an Fe-S cluster, and interaction of NO with the Fe-S center is proposed to modulate NsrR activity.


Fresh Israeli Jaffa blond (Shamouti) orange and Israeli Jaffa red Star Ruby (Sunrise) grapefruit juices affect plasma lipid metabolism and antioxidant capacity in rats fed added cholesterol.
The bioactivity of Israeli Jaffa blond (Shamouti) fresh orange and Israeli Jaffa red Star Ruby (Sunrise) grapefruit juices was investigated in vitro and in vivo. The contents of bioactive compounds of these juices were determined. The influence of bioactive compounds on plasma lipids and plasma antioxidant activity in rats fed cholesterol-containing and cholesterol-free diets was assessed. Significant differences in the contents of dietary fibers were not found. The contents of total polyphenols, flavonoids, and anthocyanins in fresh orange and grapefruit juices were 962.1 +/- 27.2 and 906.9 +/- 27.1; 50.1 +/- 3.3 and 44.8 +/- 3.2; and 69.9 +/- 5.6 and 68.7 +/- 5.5 microg/mL, respectively. The antioxidant potential measured by the scavenging activity against nitric oxide, the beta-carotene-linoleate model system (beta-carotene), and the 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) diamonium salt assays was higher in orange juice but not significantly. A high level of correlation between contents of total polyphenols and flavonoids and antioxidant potential values of both juices was found. Diets supplemented with orange and to a lesser degree with grapefruit juices improved plasma lipid metabolism only in rats fed added cholesterol. However, an increase in the plasma antioxidant activity was observed in both groups. In conclusion, fresh orange and grapefruit juices contain high quantities of bioactive compounds, which guarantee their high antioxidant potential, and the positive influence on plasma lipid metabolism and plasma antioxidant activity could make fresh orange and grapefruit juices a valuable supplement for disease-preventing diets.


Onabotulinum toxin-A injections for sleep bruxism: A double-blind, placebo-controlled study.
To test the safety and efficacy of onabotulinum toxin-A (BoNT-A) injections into the masseter and temporalis muscles in patients with symptomatic sleep bruxism. Participants 18 to 85 years old with clinically diagnosed sleep bruxism confirmed by polysomnography were enrolled in this randomized, placebo-controlled, 1:1, parallel-design trial with open-label extension. Participants were injected with BoNT-A 200 units (60 into each masseter and 40 into each temporalis) or placebo and were evaluated at 4 to 8 weeks after the initial treatment visit. The primary efficacy endpoint was clinical global impression (CGI), and the secondary efficacy endpoint was a visual analog scale (VAS) of change in bruxism and in pain at 4 to 8 weeks after injection. Exploratory endpoints included modified Montreal Bruxism Questionnaire, Headache Impact Test-6, total Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Self-Rated Anxiety Scale, and polysomnography data, including EMG recordings of the masseter and temporalis muscle bruxing events. Adverse events were recorded. Thirty-one participants were recruited and 23 were randomized (19 female, age 47.4 ± 16.9 years). All 13 randomized to BoNT-A and 9 of 10 randomized to placebo completed the study. CGI (p < 0.05) and VAS of change (p < 0.05) favored the BoNT-A group. None of the exploratory endpoints changed significantly, but total sleep time and number/duration of bruxing episodes favored the BoNT-A group. Two participants randomized to BoNT-A reported a cosmetic change in their smile. No dysphagia or masticatory adverse events were reported. BoNT-A effectively and safely improved sleep bruxism in this placebo-controlled pilot trial. A large multicenter trial is needed to confirm these encouraging data. NTC00908050. This study provides Class II evidence that botulinum injections into the masseter and temporalis muscles improve subjective bruxism and painful symptoms associated with sleep bruxism.


Enabling independence: restorative approaches to home care provision for frail older adults.
This study reviews the 'real world' potential (i.e. efficacy and effectiveness) of restorative approaches towards home care for frail older adults. Such approaches aim to go beyond traditional home care goals of 'maintenance' and 'support' towards improvements in functional status and quality of life. Our review of the literature included searches of health and gerontology databases as well as 'grey literature' across Australia, the UK and the USA. We provide an initial overview of the efficacy of a range of single component restorative interventions, including occupational therapy, physical therapy, health education and social rehabilitation. In order to answer questions about the overall efficacy and cost-effectiveness of restorative home care provision, we also review the nature of in-house programmes across the three nations as well as the evidence base for such programmes, particularly when they have been compared to home care 'as usual'. A range of positive outcomes has emerged, including improved quality of life and functional status and reduced costs associated with a reduction in the ongoing use of home care services postintervention. Questions remain about which components are most beneficial, which clients are likely to receive the greatest benefit, and the appropriate intensity and duration of such interventions.


Republished: Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime.
The heritability of most common, multifactorial diseases is rather modest and known genetic effects account for a small part of it. The remaining portion of disease aetiology has been conventionally ascribed to environmental effects, with an unknown part being stochastic. This review focuses on recent studies highlighting stochastic events of potentially great importance in human disease-the accumulation of post-zygotic structural aberrations with age in phenotypically normal humans. These findings are in agreement with a substantial mutational load predicted to occur during lifetime within the human soma. A major consequence of these results is that the genetic profile of a single tissue collected at one time point should be used with caution as a faithful portrait of other tissues from the same subject or the same tissue throughout life. Thus, the design of studies in human genetics interrogating a single sample per subject or applying lymphoblastoid cell lines may come into question. Sporadic disorders are common in medicine. We wish to stress the non-heritable genetic variation as a potentially important factor behind the development of sporadic diseases. Moreover, associations between post-zygotic mutations, clonal cell expansions and their relation to cancer predisposition are central in this context. Post-zygotic mutations are amenable to robust examination and are likely to explain a sizable part of non-heritable disease causality, which has routinely been thought of as synonymous with environmental factors. In view of the widespread accumulation of genetic aberrations with age and strong predictions of disease risk from such analyses, studies of post-zygotic mutations may be a fruitful approach for delineation of variants that are causative for common human disorders.


Proteome analysis of serum from type 2 diabetics with nephropathy.
Diabetic nephropathy (DN) is a renal disease which develops as a consequence of diabetes mellitus. Microalbuminuria is the earliest clinical sign of DN. There are no specific diagnostic biomarkers for type 2 diabetics with nephropathy other than microalbuminuria and macroalbuminuria. However, microalbuminuria does not constitute a sole independent indicator for type 2 diabetics with nephropathy, and thus, another screening method, such as a biomarker assay, is required in order to diagnose it more correctly. Therefore, we have utilized two-dimensional electrophoresis (2-DE) to identify human serum protein markers for the more specific and accurate prediction of progressive nephropathy in type 2 diabetes patients, via comparisons of the serum proteome in three experimental groups: type 2 diabetes patients without microalbuminuria (DM, n = 30), with microalbuminuria (MA, n = 29), and with chronic renal failure (CRF, n = 31). As a result, proteins which were differentially expressed with statistical significance (p < 0.05) in MA and CRF groups as compared to those in DM group were selected and identified by ESI-Q-TOF MS/MS. Among these identified proteins, two proteins which might be useful as diagnostic biomarkers of type 2 diabetics with nephropathy were verified by Western blotting: extracellular glutathione peroxidase (eGPx) and apolipoprotein (ApoE) were found to exhibit a progressive reduction in MA and CRF groups. Notably, eGPx was further verified by ELISA using DM (n = 100) and MA (n = 96) patient samples. Collectively, our results show that the two proteins identified in this study may constitute potential biomarkers for the diagnosis of type 2 diabetics with nephropathy.


Novel Analysis Software for Detecting and Classifying Ca2+ Transient Abnormalities in Stem Cell-Derived Cardiomyocytes.
Comprehensive functioning of Ca2+ cycling is crucial for excitation-contraction coupling of cardiomyocytes (CMs). Abnormal Ca2+ cycling is linked to arrhythmogenesis, which is associated with cardiac disorders and heart failure. Accordingly, we have generated spontaneously beating CMs from induced pluripotent stem cells (iPSC) derived from patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), which is an inherited and severe cardiac disease. Ca2+ cycling studies have revealed substantial abnormalities in these CMs. Ca2+ transient analysis performed manually lacks accepted analysis criteria, and has both low throughput and high variability. To overcome these issues, we have developed a software tool, AnomalyExplorer based on interactive visualization, to assist in the classification of Ca2+ transient patterns detected in CMs. Here, we demonstrate the usability and capability of the software, and we also compare the analysis efficiency to manual analysis. We show that AnomalyExplorer is suitable for detecting normal and abnormal Ca2+ transients; furthermore, this method provides more defined and consistent information regarding the Ca2+ abnormality patterns and cell line specific differences when compared to manual analysis. This tool will facilitate and speed up the analysis of CM Ca2+ transients, making it both more accurate and user-independent. AnomalyExplorer can be exploited in Ca2+ cycling analysis to study basic disease pathology and the effects of different drugs.


Genotype and animal infectivity of a human isolate of Cryptosporidium parvum in the Republic of Korea.
Cryptosporidium parvum oocysts were isolated from a child suffering from acute gastroenteritis and successfully passaged in a calf and mice (designated hereafter SNU-H1) in the Republic of Korea; its molecular genotype has been analyzed. The GAG microsatellite region was amplified by a polymerase chain reaction (PCR), with a 238 base pair product, which is commonly displayed in C. parvum. The isolate was shown to be a mixture of the genotypes 1 (anthroponotic) and 2 (zoonotic). To study its infectivity in animals, 2 calves and 3 strains of mice were infected with the SNU-H1; in these animals, the propagation of both genotypes was successful. In immunosuppressed (ImSP) BALB/c and C57BL/6 mice the number of oocysts decreased after day 10 post-infection (PI); but in ImSP ICR mice, they remained constant until day 27 PI. The results show that both the C. parvum genotypes 1 and 2 can be propagated in calves and ImSP mice.


A neuropsychological instrument measuring age-related cerebral decline in older drivers: development, reliability, and validity of MedDrive.
When facing age-related cerebral decline, older adults are unequally affected by cognitive impairment without us knowing why. To explore underlying mechanisms and find possible solutions to maintain life-space mobility, there is a need for a standardized behavioral test that relates to behaviors in natural environments. The aim of the project described in this paper was therefore to provide a free, reliable, transparent, computer-based instrument capable of detecting age-related changes on visual processing and cortical functions for the purposes of research into human behavior in computational transportation science. After obtaining content validity, exploring psychometric properties of the developed tasks, we derived (Study 1) the scoring method for measuring cerebral decline on 106 older drivers aged ≥70 years attending a driving refresher course organized by the Swiss Automobile Association to test the instrument's validity against on-road driving performance (106 older drivers). We then validated the derived method on a new sample of 182 drivers (Study 2). We then measured the instrument's reliability having 17 healthy, young volunteers repeat all tests included in the instrument five times (Study 3) and explored the instrument's psychophysical underlying functions on 47 older drivers (Study 4). Finally, we tested the instrument's responsiveness to alcohol and effects on performance on a driving simulator in a randomized, double-blinded, placebo, crossover, dose-response, validation trial including 20 healthy, young volunteers (Study 5). The developed instrument revealed good psychometric properties related to processing speed. It was reliable (ICC = 0.853) and showed reasonable association to driving performance (R (2) = 0.053), and responded to blood alcohol concentrations of 0.5 g/L (p = 0.008). Our results suggest that MedDrive is capable of detecting age-related changes that affect processing speed. These changes nevertheless do not necessarily affect driving behavior.


Spatial frequency, phase, and the contrast of natural images.
We examined contrast sensitivity and suprathreshold apparent contrast with natural images. The spatial-frequency components within single octaves of the images were removed (notch filtered), their phases were randomized, or the polarity of the images was inverted. Of Michelson contrast, root-mean-square (RMS) contrast, and band-limited contrast, RMS contrast was the best index of detectability. Negative images had lower apparent contrast than their positives. Contrast detection thresholds showed spatial-frequency-dependent elevation following both notch filtering and phase randomization. The peak of the spatial-frequency tuning function was approximately 0.5-2 cycles per degree (c/deg). Suprathreshold contrast matching functions also showed spatial-frequency-dependent contrast loss for both notch-filtered and phase-randomized images. The peak of the spatial-frequency tuning function was approximately 1-3 c/deg. There was no detectable difference between the effects of phase randomization and notch filtering on contrast sensitivity. We argue that these observations are consistent with changes in the activity within spatial-frequency channels caused by the higher-order phase structure of natural images that is responsible for the presence of edges and specularities.


Economic evaluation of influenza vaccination and economic modelling. Can results be pooled?
Scientific reviewing methods were applied to economic studies of influenza vaccination, and an economic model of influenza vaccination was developed from these primary sources. Issues arising from the secondary literature review include the quality of evidence on the effectiveness of the vaccines, the absence of a traditional population-based approach to reviewing economic data, confusion in terminology, and how to generalise from resource data contained in primary evaluations. Data from the literature review were summarised in terms of resource units used in the prevention and treatment of influenza. An economic model was constructed using local unit costs (from the Emilia region of Italy) and applying the data to a notional population. The model was sensitive to length of stay in hospital but not to variation in incidence of influenza, days off work or number of medical consultations. The model was predicated on and is sensitive to an estimate of 80% vaccine effectiveness. The approach is constrained by the available data, but could be more generally useful in that it allows variations in the quantity of inputs to be considered separately from variations in their values. The model may be used locally as a decision-making tool, although the method needs further development.


A global geometric framework for nonlinear dimensionality reduction.
Scientists working with large volumes of high-dimensional data, such as global climate patterns, stellar spectra, or human gene distributions, regularly confront the problem of dimensionality reduction: finding meaningful low-dimensional structures hidden in their high-dimensional observations. The human brain confronts the same problem in everyday perception, extracting from its high-dimensional sensory inputs-30,000 auditory nerve fibers or 10(6) optic nerve fibers-a manageably small number of perceptually relevant features. Here we describe an approach to solving dimensionality reduction problems that uses easily measured local metric information to learn the underlying global geometry of a data set. Unlike classical techniques such as principal component analysis (PCA) and multidimensional scaling (MDS), our approach is capable of discovering the nonlinear degrees of freedom that underlie complex natural observations, such as human handwriting or images of a face under different viewing conditions. In contrast to previous algorithms for nonlinear dimensionality reduction, ours efficiently computes a globally optimal solution, and, for an important class of data manifolds, is guaranteed to converge asymptotically to the true structure.


Molecular identification and chromosomal localization of new powdery mildew resistance gene Pm11 in oat.
The appropriate selection of various traits in valuable plants is very important for modern plant breeding. Effective resistance to fungal diseases, such as powdery mildew, is an example of such a trait in oats. Marker-assisted selection is an important tool that reduces the time and cost of selection. The aims of the present study were the identification of dominant DArTseq markers associated with a new resistance gene, annotated as Pm11 and derived from Avena sterilis genotype CN113536, and the subsequent conversion of these markers into a PCR-based assay. Among the obtained 30,620 silicoDArT markers, 202 markers were highly associated with resistance in the analysed population. Of these, 71 were selected for potential conversion: 42 specific to resistant and 29 to susceptible individuals. Finally, 40 silicoDArT markers were suitable for primer design. From this pool, five markers, 3 for resistant and 2 for susceptible plants, were selected for product amplification in the expected groups. The developed method, based on 2 selection markers, provides certain identification of resistant and susceptible homozygotes. Also, the use of these markers allowed the determination of heterozygotes in the analysed population. Selected silicoDArT markers were also used for chromosomal localization of new resistance genes. Five out of 71 segregating silicoDArT markers for the Pm11 gene were found on the available consensus genetic map of oat. Five markers were placed on linkage groups corresponding to Mrg12 on the Avena sativa consensus map.


RNA extraction from mammalian tissues.
Purification of intact RNA is the primary step of many molecular biology techniques, including Northern blotting, RNase protection, quantitative polymerase chain reaction, and microarray assays. RNA extraction is typically conducted using either a phenol-chloroform or a solid phase method. This article concentrates primarily on the former approach, which is highly versatile, and is easily adapted to different tissues ranging from whole organs down to submillimeter biopsy punches. The major problem with RNA extraction is the ubiquitous nature of RNases, enzymes that rapidly degrade RNA. RNases may be difficult to eliminate, although with care and appropriate countermeasures, reproducible extraction of high-quality RNA from important biological samples should be attainable. This article focuses on the isolation of RNA from the tissue collection step, homogenization all the way through to the quantification of the purified nucleic acid, providing guidelines for the prevention of the problems associated with RNAse contamination.


Effective integration of serially presented stochastic cues.
This study examines how people deal with inherently stochastic cues when estimating a latent environmental property. Seven cues to a hidden location were presented one at a time in rapid succession. The seven cues were sampled from seven different Gaussian distributions that shared a common mean but differed in precision (the reciprocal of variance). The experimental task was to estimate the common mean of the Gaussians from which the cues were drawn. Observers ran in two conditions on separate days. In the "decreasing precision" condition the seven cues were ordered from most precise to least precise. In the "increasing precision" condition this ordering was reversed. For each condition, we estimated the weight that each cue in the sequence had on observers' estimates and compared human performance to that of an ideal observer who maximizes expected gain. We found that observers integrated information from more than one cue, and that they adaptively gave more weight to more precise cues and less weight to less precise cues. However, they did not assign weights that would maximize their expected gain, even over the course of several hundred trials with corrective feedback. The cost to observers of their suboptimal performance was on average 16% of their maximum possible winnings.


Signaling activities of the Drosophila wingless gene are separately mutable and appear to be transduced at the cell surface.
The Drosophila segment polarity gene wingless encodes an intercellular signaling molecule that transmits positional information during development of the embryonic epidermis. We have explored the mechanism of wg signal transduction by perturbing cellular processes genetically and by performing structure/function analysis of the Wg protein. We present evidence that Wingless protein may transduce signal at the cell surface and that Wg may bind to its cell surface receptor without necessarily activating it. We demonstrate that two specific signaling activities of the Wg molecule can be disrupted independently by mutation. Sequence analysis indicates that these different signaling activities are not promoted by discrete functional domains, but rather than the overall conformation of the molecule may control distinct signaling functions. We conclude that wg signaling may involve complex interactions between the Wg ligand and its cell surface receptor molecule(s) and that some of this complexity resides within the Wg ligand itself.


Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial.
The relationships between long-term intensive control of glycemia and indicators of skin collagen glycation (furosine), glycoxidation (pentosidine and N(epsilon)-[carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 diabetes from the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30-32% lower furosine, 9% lower pentosidine, 9-13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P < 0.006-0.001) and also of the secondary intervention cohort (P < 0.015-0.001) with the exception of CML and acid-soluble collagen. Age- and duration-adjusted collagen variables were significantly associated with the HbA1c value nearest the biopsy and with cumulative prior HbA1c values. Multiple logistic regression analyses with six nonredundant collagen parameters as independent variables and various expressions of retinopathy, nephropathy, and neuropathy outcomes as dependent variables showed that the complications were significantly associated with the full set of collagen variables. Surprisingly, the percentage of total variance (R2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and from 14 to 51% with conventional treatment. These associations generally remained significant even after adjustment for HbA1c, and, most unexpectedly, in conventionally treated subjects, glycated collagen was the parameter most consistently associated with diabetic complications. Continued monitoring of these subjects may determine whether glycation products in the skin, and especially the early Amadori product (furosine), have the potential to be predictors of the future risk of developing complications, and perhaps be even better predictors than glycated hemoglobin (HbA1c).


Association of HLA-DPA1, HLA-DPB1, and HLA-DQB1 Alleles With the Long-Term and Booster Immune Responses of Young Adults Vaccinated Against the Hepatitis B Virus as Neonates.
The neonatal hepatitis B vaccination (HBVac) was implemented 35 years ago in Taiwan, but many vaccinees exhibit inadequate long-term vaccine-induced seroprotective hepatitis B surface antibody (anti-HBs) levels. We investigated the association of the human leukocyte antigen (HLA) alleles (DPA1, DPB1, DQA1, and DQB1) with the long-term immunological response to the neonatal HBVac and adolescent booster HBVac in a Taiwanese cohort. We divided 281 Han students (median age 22, age range 17-29 years) into the following groups: (1) Group A (n = 61): anti-HBs titer ≥ 10 mIU/mL at the beginning of the study; (2) Group B (n = 75): anti-HBs level > 1000 mIU/mL after the first booster; (3) Group C (n = 37): anti-HBs level < 10 mIU/mL after the first booster; and (4) Group D (n = 5): anti-HBs level < 10 mIU/mL after three boosters. DQA1, DQB1, DPA1, and DPB1 typing of the participants was performed using sequence-specific oligonucleotides. Associations of HLA alleles and haplotypes with effects on neonatal HBVac and booster HBVac were examined through logistic regression analysis and Fisher's exact test. A false discovery rate-based measure of significance, the q-value, was used for multiple comparisons, and an association was considered significant if the corresponding q-value was < 0.1. DPA1 alleles were associated with the long-term immunological response to the neonatal HBVac. The estimated odds ratio (OR) of the lack of HBV protective immunity when carrying an additional DPA1*01 and DPA1*02 was 0.36 [95% confidence interval (CI) = 0.17-0.76, p = 0.0076] and 2.39 (95% CI = 1.17-4.87, p = 0.016), respectively. DPB1 and DQB1 alleles were associated with a response to the adolescent booster vaccination. The estimated ORs of being nonresponsive to the first booster when carrying an additional DPB1*05 and DQB1*02 were 2.11 (95% CI = 1.13-3.93, p = 0.019) and 3.73 (95% CI = 1.43-9.71, p = 0.0070), respectively. All DPB1*03 carriers responded to the first booster (p of Fisher's exact test = 0.0045). In our study, we discovered that HLA-DPA1 was primarily associated with the long-term response of primary infantile HBVac, and HLA-DPB1 and HLA-DQB1 exhibited associations with the HBV booster vaccination.


Conserved CDC20 cell cycle functions are carried out by two of the five isoforms in Arabidopsis thaliana.
The CDC20 and Cdh1/CCS52 proteins are substrate determinants and activators of the Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligase and as such they control the mitotic cell cycle by targeting the degradation of various cell cycle regulators. In yeasts and animals the main CDC20 function is the destruction of securin and mitotic cyclins. Plants have multiple CDC20 gene copies whose functions have not been explored yet. In Arabidopsis thaliana there are five CDC20 isoforms and here we aimed at defining their contribution to cell cycle regulation, substrate selectivity and plant development. Studying the gene structure and phylogeny of plant CDC20s, the expression of the five AtCDC20 gene copies and their interactions with the APC/C subunit APC10, the CCS52 proteins, components of the mitotic checkpoint complex (MCC) and mitotic cyclin substrates, conserved CDC20 functions could be assigned for AtCDC20.1 and AtCDC20.2. The other three intron-less genes were silent and specific for Arabidopsis. We show that AtCDC20.1 and AtCDC20.2 are components of the MCC and interact with mitotic cyclins with unexpected specificity. AtCDC20.1 and AtCDC20.2 are expressed in meristems, organ primordia and AtCDC20.1 also in pollen grains and developing seeds. Knocking down both genes simultaneously by RNAi resulted in severe delay in plant development and male sterility. In these lines, the meristem size was reduced while the cell size and ploidy levels were unaffected indicating that the lower cell number and likely slowdown of the cell cycle are the cause of reduced plant growth. The intron-containing CDC20 gene copies provide conserved and redundant functions for cell cycle progression in plants and are required for meristem maintenance, plant growth and male gametophyte formation. The Arabidopsis-specific intron-less genes are possibly "retrogenes" and have hitherto undefined functions or are pseudogenes.


High-Capacity Sample Multiplexing for Single Cell Chromatin Accessibility Profiling.
Single-cell chromatin accessibility has emerged as a powerful means of understanding the epigenetic landscape of diverse tissues and cell types, but profiling cells from many independent specimens is challenging and costly. Here we describe a novel approach, sciPlex-ATAC-seq, which uses unmodified DNA oligos as sample-specific nuclear labels, enabling the concurrent profiling of chromatin accessibility within single nuclei from virtually unlimited specimens or experimental conditions. We first demonstrate our method with a chemical epigenomics screen, in which we identify drug-altered distal regulatory sites predictive of compound- and dose-dependent effects on transcription. We then analyze cell type-specific chromatin changes in PBMCs from multiple donors responding to synthetic and allogeneic immune stimulation. We quantify stimulation-altered immune cell compositions and isolate the unique effects of allogeneic stimulation on chromatin accessibility specific to T-lymphocytes. Finally, we observe that impaired global chromatin decondensation often coincides with chemical inhibition of allogeneic T-cell activation.


Continuous measurement of rat gastric blood flow using Doppler flowmeter.
We describe the use of pulsed Doppler flowmetry to permit continuous measurement of gastric blood flow in the anesthetized rat. The aims of this study were: 1) to assess the stability of blood flow during Doppler flowmetry; 2) to assess the ability of Doppler flowmetry to record rapid, transient blood flow changes; and 3) to validate Doppler flowmetry against an established blood flow measurement technique using labeled microspheres. Measurements over 3-h periods with a Doppler probe placed on the left gastric artery showed that there was an initial 30-min stabilization period; after this the mean percentage coefficient of variation, indicating intraindividual variability for blood flow, was < 10% for the remaining 150 min. The infusion of norepinephrine produced rapid, transient blood flow changes, including the typical "autoregulatory escape" and "postinfusion hyperemia," both of which were detected by Doppler flowmetry. The accuracy of pulsed Doppler flowmetry in measuring gastric blood flow was established by the demonstration of a highly significant agreement between blood flow measured by the Doppler flowmetry and microsphere techniques. These data indicate that pulsed Doppler flowmetry is an accurate method for the continuous measurement of left gastric artery blood flow in the rat.


Preclinical animal models of multiple myeloma.
Multiple myeloma is an incurable plasma-cell malignancy characterized by osteolytic bone disease and immunosuppression. Murine models of multiple myeloma and myeloma bone disease are critical tools for an improved understanding of the pathogenesis of the disease and the development of novel therapeutic strategies. This review will cover commonly used immunocompetent and xenograft models of myeloma, describing the advantages and disadvantages of each model system. In addition, this review provides detailed protocols for establishing systemic and local models of myeloma using both murine and human myeloma cell lines.


Circulating angiopoietin-2 as a biomarker in ANCA-associated vasculitis.
The endothelial-specific Angiopoietin-Tie2 ligand-receptor system is an important regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to Tie2 receptor renders the endothelial barrier responsive to pro-inflammatory cytokines. We previously showed that circulating Ang-2 correlated with disease severity in a small cohort of critically ill patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The current study reassessed Ang-2 as a biomarker of disease activity and relapse in AAV. Circulating Ang-2 was measured in 162 patients with severe AAV (BVAS/WG≥3, with or without glomerulonephritis) in a clinical trial. Ang-2 levels during active AAV were compared to levels in the same patients during remission (BVAS/WG = 0). Levels in clinical subsets of AAV were compared, and association with future disease course was assessed. Ang-2 levels were elevated in severe disease (median 3.0 ng/ml, interquartile range 1.9-4.4) compared to healthy controls (1.2, 0.9-1.5). However, they did not reliably decline with successful treatment (median 2.6 ng/ml, interquartile range 1.9-3.8, median change -0.1). Ang-2 correlated weakly with BVAS/WG score (r = 0.17), moderately with markers of systemic inflammation (r = 0.25-0.41), and inversely with renal function (r = -0.36). Levels were higher in patients with glomerulonephritis, but levels adjusted for renal dysfunction were no different in patients with or without glomerulonephritis. Levels were higher in patients with newly diagnosed AAV and lower in patients in whom treatment had recently been started. Ang-2 levels during active disease did not predict response to treatment, and Ang-2 levels in remission did not predict time to flare. Thus, Ang-2 appears to have limited practical value in AAV as a biomarker of disease activity at time of measurement or for predicting future activity.


Superconductivity in topological insulator β-PdBi2 under pressure.
The topological insulator PdBi2 exhibits two different crystal phases at ambient pressure, i.e., 'α-PdBi2' and ' -PdBi2'. The pressure dependence of crystal structure and superconductivity of α-PdBi2 has been fully elucidated thus far. However, the physical properties of β-PdBi2 crystals under pressure have not been sufficiently investigated. In this study, we fully investigate the crystal structure and superconductivity of β-PdBi2 under pressure based on synchrotron x-ray diffraction (XRD) patterns. The temperature dependence of β-PdBi2 indicates its superconductivity with a superconducting transition temperature (T c) as high as 4.10 K, and its crystal structure is tetragonal [space group of I4/mmm (no. 139)]. The XRD patterns at 0-22.0 GPa indicate no structural phase transitions, and the unit cell volume shrinks monotonically with pressure, unlike the behavior of α-PdBi2. Furthermore, α-PdBi2 transformed to β-PdBi2 under pressure. This suggests that β-PdBi2 is stable under pressure. The superconductivity is clearly observed at 0-11.8 GPa, and the value of T c is almost constant at ∼4.4 K. The temperature dependence of the upper critical field at ambient pressure and 10.7 GPa indicates that the superconductivity is not attributed to a simple s-wave dirty limit but an s-wave clean or p-wave polar model. This is the first systematic study of superconductivity of topological insulator β-PdBi2 under pressure.


Targeting cardiovascular risk in patients with diabetes: management of dyslipidemia.
The management of dyslipidemia in patients with diabetes is a key component of cardiovascular risk reduction. In particular, the atherogenic dyslipidemia of diabetes often requires combination therapy to target aspects of the lipid profile beyond low-density lipoprotein cholesterol. This article will review the characteristics of dyslipidemia in diabetes, and discuss guidelines and strategies for treatment to reduce cardiovascular disease risk. A number of clinical outcomes trials supports the use of statins to reduce cardiovascular events in patients with type 2 diabetes mellitus. The disappointing results of clinical trials involving torcetrapib to increase high-density lipoprotein levels may lead to renewed interest and utilization of niacin for the management of atherogenic dyslipidemia. Long-term use of fibrate therapy in patients with atherogenic dyslipidemia has recently been associated with reduction in all-cause, cancer, and cardiovascular mortality rates. Ongoing trials are investigating whether addition of niacin or fibrate to statin therapy is superior to statin therapy alone in preventing cardiovascular events. Aggressive low-density lipoprotein control continues to be the primary goal of therapy in dyslipidemia management. Given the growing body of evidence showing the cardiovascular benefits of treating other lipid components, however, it is easy to anticipate that full normalization of the lipid profile may become the standard of care for diabetic dyslipidemia.


Schizophrenia gene expression profile reverted to normal levels by antipsychotics.
Despite the widespread use of antipsychotics, little is known of the molecular bases behind the action of antipsychotic drugs. A genome-wide study is needed to characterize the genes that affect the clinical response and their adverse effects. Here we show the analysis of the blood transcriptome of 22 schizophrenia patients before and after medication with atypical antipsychotics by next-generation sequencing. We found that 17 genes, among the 21 495 genes analyzed, have significantly-altered expression after medication (p-value adjusted [Padj] <0.05). Six genes (ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2, and UNC45B) out of the 17 are among the 200 genes that we characterized with differential expression in a previous study between antipsychotic-naïve schizophrenia patients and controls (Sainz et al., 2013). This number of schizophrenia-altered expression genes is significantly higher than expected by chance (Chi-test, Padj 1.19E-50), suggesting that at least part of the antipsychotic beneficial effects is exerted by modulating the expression of these genes. Interestingly, all six of these genes were overexpressed in patients and reverted to control levels of expression after treatment. We also found a significant enrichment of genes related to obesity and diabetes, known adverse affects of antipsychotics. These results may facilitate understanding of unknown molecular mechanisms behind schizophrenia symptoms and the molecular mechanisms of antipsychotic drugs.


Ethanol sensitivity in high drinking in the dark selectively bred mice.
Mouse lines are being selectively bred in replicate for high blood ethanol concentrations (BECs) achieved after a short period of ethanol (EtOH) drinking early in the circadian dark phase. High Drinking in the Dark-1 (HDID-1) mice were in selected generation S18, and the replicate HDID-2 line in generation S11. To determine other traits genetically correlated with high DID, we compared naïve animals from both lines with the unselected, segregating progenitor stock, HS/Npt. Differences between HDID-1 and HS would imply commonality of genetic influences on DID and these traits. HDID-1 mice showed less basal activity, greater EtOH stimulated activity, and greater sensitivity to EtOH-induced foot slips than HS. They showed lesser sensitivity to acute EtOH hypothermia and longer duration loss of righting reflex than HS. HDID-1 and control HS lines did not differ in sensitivity on 2 measures of intoxication, the balance beam and the accelerating rotarod. None of the acute response results could be explained by differences in EtOH metabolism. HDID-2 differed from HS on some, but not all, of the above responses. These results show that some EtOH responses share common genetic control with reaching high BECs after DID, a finding consistent with other data regarding genetic contributions to EtOH responses.