The incremental cost of switching from Option B to Option B+ for the prevention of mother-to-child transmission of HIV.
To estimate the incremental cost over 5 years of a policy switch from the Option B to the Option B+ protocol for the prevention of mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV). Data from cost studies and other published sources were used to determine the cost, per woman and per cohort (1000 breastfeeding and 1000 non-breastfeeding women), of switching from Option B (maternal triple antiretroviral [ARV] regimen during pregnancy and breastfeeding plus daily nevirapine for the infant for 6 weeks) to Option B+ (maternal triple ARV regimen initiated during pregnancy and continued for life). The variables used to model the different scenarios were maternal CD4+ T lymphocyte (CD4+ cell) count (350-500 versus > 500 cells/µl), rate of decline in CD4+ cells (average, rapid, slow), breastfeeding status (yes, no) and breastfeeding duration (12, 18 or 24 months). For women with CD4+ cell counts of 350-500 cells/µl, the incremental cost per 1000 women was 157,345 United States dollars (US$) for breastfeeding women and US$ 92,813 for non-breastfeeding women. For women with CD4+ cell counts > 500 cells/µl, the incremental cost per 1000 women ranged from US$ 363,443 to US$ 484,591 for breastfeeding women and was US$ 605,739 for non-breastfeeding women. From a cost perspective, a policy switch from Option B to Option B+ is feasible in PMTCT programme settings where resources are currently being allocated to Option B.


Experiments on second- and third-harmonic generation from magnetic metamaterials.
Photonic metamaterials could provide optical nonlinearities far exceeding those of natural substances due to the combined action of (magnetic) resonances and local-field enhancements. Here, we present our experiments on second- and third-harmonic generation from magnetic metamaterials composed of nanoscale gold split-ring resonators and from control samples for excitation with 170-fs pulses centered at 1.5-microm wavelength. The strongest nonlinear signals are found for resonances with magnetic-dipole character.


Particulate matter (PM(2.5), PM(10-2.5), and PM(10)) and children's hospital admissions for asthma and respiratory diseases: a bidirectional case-crossover study.
Epidemiological studies reported adverse effects of air pollution on the prevalence of respiratory diseases in children. The purpose of this study was to examine the association between air pollution and admissions for asthma and other respiratory diseases among children who were younger than 15 yr of age. The study used data on respiratory hospital admissions and air pollutant concentrations, including thoracic particulate matter (PM(10)), fine (PM(2.5)), and coarse (PM(10-2.5)) particulate matter in Zonguldak, Turkey. A bidirectional case-crossover design was used to calculate odds ratios for the admissions adjusted for daily meteorological parameters. Significant increases were observed for hospital admissions in children for asthma, allergic rhinitis (AR), and upper (UPRD) and lower (LWRD) respiratory diseases. All fraction of PM in children showed significant positive associations with asthma admissions. The highest association noted was 18% rise in asthma admissions correlated with a 10-microg/m(3) increase in PM(10-2.5) on the same day of admissions. The adjusted odds ratios for exposure to PM(2.5) with an increment of 10 microg/m(3) were 1.15 and 1.21 for asthma and allergic rhinitis with asthma, respectively. PM(10) exerted significant effects on hospital admissions for all outcomes, including asthma, AR, UPRD, and LWRD. Our study suggested a greater effect of fine and coarse PM on asthma hospital admissions compared with PM(10) in children.


Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons.
Extracellular vesicles are highly transmissible and play critical roles in the propagation of tau pathology, although the underlying mechanism remains elusive. Here, for the first time, we comprehensively characterized the physicochemical structure and pathogenic function of human brain-derived extracellular vesicles isolated from Alzheimer's disease, prodromal Alzheimer's disease, and non-demented control cases. Alzheimer's disease extracellular vesicles were significantly enriched in epitope-specific tau oligomers in comparison to prodromal Alzheimer's disease or control extracellular vesicles as determined by dot blot and atomic force microscopy. Alzheimer's disease extracellular vesicles were more efficiently internalized by murine cortical neurons, as well as more efficient in transferring and misfolding tau, than prodromal Alzheimer's disease and control extracellular vesicles in vitro. Strikingly, the inoculation of Alzheimer's disease or prodromal Alzheimer's disease extracellular vesicles containing only 300 pg of tau into the outer molecular layer of the dentate gyrus of 18-month-old C57BL/6 mice resulted in the accumulation of abnormally phosphorylated tau throughout the hippocampus by 4.5 months, whereas inoculation of an equal amount of tau from control extracellular vesicles, isolated tau oligomers, or fibrils from the same Alzheimer's disease donor showed little tau pathology. Furthermore, Alzheimer's disease extracellular vesicles induced misfolding of endogenous tau in both oligomeric and sarkosyl-insoluble forms in the hippocampal region. Unexpectedly, phosphorylated tau was primarily accumulated in glutamic acid decarboxylase 67 (GAD67) GABAergic interneurons and, to a lesser extent, glutamate receptor 2/3-positive excitatory mossy cells, showing preferential extracellular vesicle-mediated GABAergic interneuronal tau propagation. Whole-cell patch clamp recordings of CA1 pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+ neurons and GAD67+ neuronal puncta surrounding pyramidal neurons in the CA1 region, confirming reduced GABAergic transmission in this region. Our study posits a novel mechanism for the spread of tau in hippocampal GABAergic interneurons via brain-derived extracellular vesicles and their subsequent neuronal dysfunction.


Direct extraction of Raman line-shapes from congested CARS spectra.
We show that Raman line-shapes can be extracted directly from congested coherent anti-Stokes Raman scattering (CARS) spectra, by using a numerical method to retrieve the phase-information hidden in measured CARS spectra. The proposed method utilizes the maximum entropy (ME) model to fit the CARS spectra and to further extract the imaginary part of the Raman susceptibility providing the Raman line-shape similar to the spontaneous Raman scattering spectrum. It circumvents the challenges arising with experimentally determining the real and imaginary parts of the susceptibility independently. Another important advantage of this method is that no a priori information regarding the vibrational resonances is required in the analysis. This permits, for the first time, the quantitative analysis of CARS spectra and microscopy images without any knowledge of e.g. sample composition or Raman response.


Services provided by volunteer psychiatrists after 9/11 at the New York City family assistance center: September 12-November 20, 2001.
To characterize the experience of volunteer disaster psychiatrists who provided pro bono psychiatric services to 9/11 survivors in New York City, from September 12, 2001 to November 20, 2001. Disaster Psychiatry Outreach (DPO) is a non-profit organization founded in 1998 to provide volunteer psychiatric care to people affected by disasters and to promote education and research in support of this mission. Data for this study were collected from one-page clinical encounter forms completed by 268 DPO psychiatrists for 2 months after 9/11 concerning 848 patients served by the DPO 9/11 response program at the New York City Family Assistance Center. In this endeavor, 268 psychiatrist volunteers evaluated 848 individuals and provided appropriate interventions. The most commonly recorded clinical impressions indicated stress-related and adjustment disorders, but other conditions such as bereavement, major depression, and substance abuse/dependence were also observed. Free samples were available for one sedative and one anxiolytic agent; not surprisingly, these were the most commonly prescribed medications. Nearly half of those evaluated received psychotropic medications. In the acute aftermath of the attacks of September 11, 2001, volunteer psychiatrists were able to provide services in a disaster response setting, in which they were co-located with other disaster responders. These services included psychiatric assessment, provision of medication, psychological first aid, and referrals for ongoing care. Although systematic diagnoses could not be confirmed, the fact that most patients were perceived to have a psychiatric diagnosis and a substantial proportion received psychotropic medication suggests potential specific roles for psychiatrists that are unique and different from roles of other mental health professionals in the early post-disaster setting. In addition to further characterizing post-disaster mental health needs and patterns of service provision, future research should focus on the short- and long-term effects of psychiatric interventions, such as providing acute psychotropic medication services and assessing the effectiveness of traditional acute post-disaster interventions including crisis counseling and psychological first aid.


Magnetic properties with multiwavelets and DFT: the complete basis set limit achieved.
Multiwavelets are emerging as an attractive alternative to traditional basis sets such as Gaussian-type orbitals and plane waves. One of their distinctive properties is the ability to reach the basis set limit (often a chimera for traditional approaches) reliably and consistently by fixing the desired precision ε. We present our multiwavelet implementation of the linear response formalism, applied to static magnetic properties, at the self-consistent field level of theory (both for Hartree-Fock and density functional theories). We demonstrate that the multiwavelets consistently improve the accuracy of the results when increasing the desired precision, yielding results that have four to five digits precision, thus providing a very useful benchmark which could otherwise only be estimated by extrapolation methods. Our results show that magnetizabilities obtained with the augmented quadruple-ζ basis (aug-cc-pCVQZ) are practically at the basis set limit, whereas absolute nuclear magnetic resonance shielding tensors are more challenging: even by making use of a standard extrapolation method, the accuracy is not substantially improved. In contrast, our results provide a benchmark that: (1) confirms the validity of the extrapolation ansatz; (2) can be used as a reference to achieve a property-specific extrapolation scheme, thus providing a means to obtain much better extrapolated results; (3) allows us to separate functional-specific errors from basis-set ones and thus to assess the level of cancellation between basis set and functional errors often exploited in density functional theory.


Gabapentin pretreatment for propofol and rocuronium injection pain: A randomized, double-blind, placebo-controlled study.
This prospectively-planned, randomized, double-blind and placebo-controlled study aims to evaluate the effect of 1200 mg gabapentin premedication on the incidence and severity of propofol and rocuronium injection pain. One hundred patients, between 18-60 years of age and ASA I-II for elective surgery planned under general anaesthetic, were randomized and divided into two groups. Two hours before the operation, the patients were given either a placebo tablet (Group P, n = 50) or 1200 mg gabapentin tablet (Group G, n = 50). On the back of the non-dominant hand, a vein was opened using a 20 G cannula , 0.9% NaCl was begun and preoxygenation was provided. For anaesthesia induction, 1% propofol at 800 ml/hr infusion rate was administered for 20 s. Propofol injection pain was evaluated up to the 20th second and recorded using a scale between 0 and 3 developed by McCrirrick and HunteR The remaining propofol dose (2.5 mg/kg), 5 ml saline and 0.6 mg/kg rocuronium were injected in that order over 10 seconds and rocuronium injection pain response was evaluated with a four point scale. Pain after propofol infusion average score (degree ≥ 1) (Group G = 0.5; Group P = 1.0) and incidence (Group G = 46%; Group P = 68%); and average withdrawal movements response score linked to rocuronium injection pain (≥ 1 response) (Group G = 0.3; Group P = 1.2) and incidence (Group G = 20%; Group P = 80%) were detected to be significantly lower in the gabapentin group compared to the placebo group (p < 0.001). Premedication with 1200 mg gabapentin 2 hours before propofol and rocuronium injection reduced the incidence and severity of injection pain.


Acoustic Radiation Force Impulse (ARFI) imaging-based needle visualization.
Ultrasound-guided needle placement is widely used in the clinical setting, particularly for central venous catheter placement, tissue biopsy and regional anesthesia. Difficulties with ultrasound guidance in these areas often result from steep needle insertion angles and spatial offsets between the imaging plane and the needle. Acoustic Radiation Force Impulse (ARFI) imaging leads to improved needle visualization because it uses a standard diagnostic scanner to perform radiation force based elasticity imaging, creating a displacement map that displays tissue stiffness variations. The needle visualization in ARFI images is independent of needle-insertion angle and also extends needle visibility out of plane. Although ARFI images portray needles well, they often do not contain the usual B-mode landmarks. Therefore, a three-step segmentation algorithm has been developed to identify a needle in an ARFI image and overlay the needle prediction on a coregistered B-mode image. The steps are: (1) contrast enhancement by median filtration and Laplacian operator filtration, (2) noise suppression through displacement estimate correlation coefficient thresholding and (3) smoothing by removal of outliers and best-fit line prediction. The algorithm was applied to data sets from horizontal 18, 21 and 25 gauge needles between 0-4 mm offset in elevation from the transducer imaging plane and to 18G needles on the transducer axis (in plane) between 10 degrees and 35 degrees from the horizontal. Needle tips were visualized within 2 mm of their actual position for both horizontal needle orientations up to 1.5 mm offset in elevation from the transducer imaging plane and on-axis angled needles between 10 degrees-35 degrees above the horizontal orientation. We conclude that segmented ARFI images overlaid on matched B-mode images hold promise for improved needle visibility in many clinical applications.


GenoLIB: a database of biological parts derived from a library of common plasmid features.
Synthetic biologists rely on databases of biological parts to design genetic devices and systems. The sequences and descriptions of genetic parts are often derived from features of previously described plasmids using ad hoc, error-prone and time-consuming curation processes because existing databases of plasmids and features are loosely organized. These databases often lack consistency in the way they identify and describe sequences. Furthermore, legacy bioinformatics file formats like GenBank do not provide enough information about the purpose of features. We have analyzed the annotations of a library of ∼2000 widely used plasmids to build a non-redundant database of plasmid features. We looked at the variability of plasmid features, their usage statistics and their distributions by feature type. We segmented the plasmid features by expression hosts. We derived a library of biological parts from the database of plasmid features. The library was formatted using the Synthetic Biology Open Language, an emerging standard developed to better organize libraries of genetic parts to facilitate synthetic biology workflows. As proof, the library was converted into GenoCAD grammar files to allow users to import and customize the library based on the needs of their research projects.


Development of a fidelity measure for research on the effectiveness of the Ayres Sensory Integration intervention.
We developed a reliable and valid fidelity measure for use in research on Ayres Sensory Integration (ASI) intervention. We designed a fidelity instrument to measure structural and process aspects of ASI intervention. Because scoring of process involves subjectivity, we conducted a series of reliability and validity studies on the process section. Raters were trained to score therapist strategies observed in video recordings of adult-child dyads. We examined content validity through expert ratings. Reliability of the process section was strong for total fidelity score (ICC = .99, Cronbach's alpha = .99) and acceptable for most items. Total score significantly differentiated ASI from four alternative interventions. Expert ratings indicated strong agreement that items in the structural and process sections represent ASI intervention. CONCLUSION. The Ayres Sensory Integration Fidelity Measure has strong content validity. The process section is reliable and valid when scored by trained raters with expertise in ASI.


Evidence against GB virus C infection in dromedary camels.
A recent publication described finding GB virus C (GBV-C) RNA in 4 of 22 dromedary camel sera, and sequence analysis found that these viruses were phylogenetically clustered within human GBV-C isolates. Since all other GB viruses to date form monophyletic groups according to their host species, the close relationship between the sequences generated from camel sera and human GBV-C isolates seemed implausible, leading us to conduct an independent analysis of the sequences. Our investigation found three lines of evidence arguing against GBV-C infection in dromedary camels. First, strong evidence of artifactual sequence generation was identified for some of the sequences. Secondly, the sequence diversity within individual camel sera was 10-152-fold greater than that described for GBV-C within a human host. Finally, GBV-C sequences generated from each camel shared near complete identity with human isolates previously described by the same laboratory. Taken together, these data strongly suggest laboratory contamination. We suggest that additional validation experiments are needed before it is possible to conclude that camels are permissive for GBV-C infection.


Changes in physical activity and sedentary behavior during the transition from elementary to secondary school.
The purpose of this study was to identify longitudinal changes in physical activity (PA) and sedentary behavior (SB) and to analyze its association with gender and weight status during the transition from elementary to secondary school. Flemish children were recruited in 6th grade of elementary school (age = 10.97 ± 0.41) and reassessed 2 years later (age = 12.96 ± .40). Children completed a questionnaire on moderate to vigorous PA and SB and wore pedometers to monitor habitual PA. Longitudinal data from 472 children were analyzed. A significant decrease was observed in self-reported moderate to vigorous PA (-12.2%), but not in pedometer-determined PA. With respect to SB, a pronounced increase in recreational computer use was found (+3.22 hours/week), particularly in overweight boys (+8.18 hours/week). Finally, a significant increase in time spent on homework was observed in girls (+3.57 hours/week) and normal weight children (+2.83 hours/week). No longitudinal change in pedometer-determined PA was observed. Nevertheless, the decline in self-reported moderate-to-vigorous PA suggests that the transition to secondary school induced a change in the contribution of different types of PA. Finally, time spent on homework and recreational computer use increased during the school transition.


Can social capital be intentionally generated? a randomized trial from rural South Africa.
While much descriptive research has documented positive associations between social capital and a range of economic, social and health outcomes, there have been few intervention studies to assess whether social capital can be intentionally generated. We conducted an intervention in rural South Africa that combined group-based microfinance with participatory gender and HIV training in an attempt to catalyze changes in solidarity, reciprocity and social group membership as a means to reduce women's vulnerability to intimate partner violence and HIV. A cluster randomized trial was used to assess intervention effects among eight study villages. In this paper, we examined effects on structural and cognitive social capital among 845 participants and age and wealth matched women from households in comparison villages. This was supported by a diverse portfolio of qualitative research. After two years, adjusted effect estimates indicated higher levels of structural and cognitive social capital in the intervention group than the comparison group, although confidence intervals were wide. Qualitative research illustrated the ways in which economic and social gains enhanced participation in social groups, and the positive and negative dynamics that emerged within the program. There were numerous instances where individuals and village loan centres worked to address community concerns, both working through existing social networks, and through the establishment of new partnerships with local leadership structures, police, the health sector and NGOs. This is among the first experimental trials suggesting that social capital can be exogenously strengthened. The implications for community interventions in public health are further explored.


An integrated assessment of sediment remediation in a midwestern U.S. stream using sediment chemistry, water quality, bioassessment, and fish biomarkers.
A comprehensive biological, sediment, and water quality study of the lower Little Scioto River near Marion, Ohio, USA, was undertaken to evaluate the changes or improvements in biotic measurements following the removal of creosote-contaminated sediment. The study area covered 7.5 river miles (RMs), including a remediated section between RMs 6.0 and 6.8. Fish and macroinvertebrate assemblages, fish biomarkers (i.e., polycyclic aromatic hydrocarbon [PAH] metabolite levels in white sucker [Castostomus commersoni] and common carp [Cyprinus carpio] bile and DNA damage), sediment chemistry, and water quality were assessed at five locations relative to the primary source of historical PAH contamination-upstream (RM 9.2), adjacent (RM 6.5), and downstream (RMs 5.7, 4.4, and 2.7). Overall, the biomarker results were consistent with the sediment PAH results, showing a pattern of low levels of PAH bile metabolites and DNA damage at the upstream (reference or background location), as well as the remediated section, high levels at the two immediate downstream sites, and somewhat lower levels at the furthest downstream site. Results show that remediation was effective in reducing sediment contaminant concentrations and exposure of fish to PAHs and in improving fish assemblages (60% increase in index of biotic integrity scores) in remediated river sections. Additional remedial investigation and potentially further remediation is needed to improve the downstream benthic fish community, which is still heavily exposed to PAH contaminants.


DNA strand breaks are not induced in human cells exposed to 2.1425 GHz band CW and W-CDMA modulated radiofrequency fields allocated to mobile radio base stations.
We conducted a large-scale in vitro study focused on the effects of low level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system in order to test the hypothesis that modulated RF fields may act as a DNA damaging agent. First, we evaluated the responses of human cells to microwave exposure at a specific absorption rate (SAR) of 80 mW/kg, which corresponds to the limit of the average whole body SAR for general public exposure defined as a basic restriction in the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines. Second, we investigated whether continuous wave (CW) and Wideband Code Division Multiple Access (W-CDMA) modulated signal RF fields at 2.1425 GHz induced different levels of DNA damage. Human glioblastoma A172 cells and normal human IMR-90 fibroblasts from fetal lungs were exposed to mobile communication frequency radiation to investigate whether such exposure produced DNA strand breaks in cell culture. A172 cells were exposed to W-CDMA radiation at SARs of 80, 250, and 800 mW/kg and CW radiation at 80 mW/kg for 2 and 24 h, while IMR-90 cells were exposed to both W-CDMA and CW radiations at a SAR of 80 mW/kg for the same time periods. Under the same RF field exposure conditions, no significant differences in the DNA strand breaks were observed between the test groups exposed to W-CDMA or CW radiation and the sham exposed negative controls, as evaluated immediately after the exposure periods by alkaline comet assays. Our results confirm that low level exposures do not act as a genotoxicant up to a SAR of 800 mW/kg.


Evolution of a remedial CME course in professionalism: addressing learner needs, developing content, and evaluating outcomes.
Scant information is available about the nature of the professional violations resulting in referral of physicians for remedial continuing medical education (CME). The CME program at Case Western Reserve University (CWRU) School of Medicine has developed the Intensive Course in Medical Ethics, Boundaries, and Professionalism (medical ethics course) for physician referrals due to ethical breaches. In this report, the authors present 7 years of data regarding the type of behavior that resulted in course referral as well as information regarding course and outcome evaluation development and participant demographics. The medical ethics course has been designed in consultation with licensure agencies to address the learning needs of physicians with problems in the areas of boundary maintenance and ethics. Teaching methods and outcome evaluations include lectures, case discussions, multiple-choice question tests, skill practice sessions, and writing a reflective essay based on the participants' ethical lapse. Information is also gathered regarding participant demographics, training, and practice characteristics. Between September 2005 and February 2012, 358 learners participated in the course. The average age was 52 years and 73% were board certified. Of the 269 physicians who wrote a reflective essay, the reasons for referral included prescribing of controlled drugs, sexual boundary issues, providing services to family or friends, not maintaining proper medical records, and billing issues. This report outlines the strategies used by CWRU to develop remedial CME courses using the medical ethics course as an example for course and outcome evaluation development. This is the first report characterizing the type and frequency of the medical ethics violations that result in mandatory participation in remedial CME.


Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling.
Fisetin and hesperetin, naturally occurring flavonoids, have been reported as novel antioxidants with chemopreventive/chemotherapeutic potential against various types of cancer. However, their mechanism of action in CML is still unknown. This particular study aims to evaluate the therapeutic potentials of fisetin and hesperetin and their effects on cell proliferation, apoptosis, and cell cycle progression in human K562 CML cells. The results indicated that fisetin and hesperetin inhibited cell proliferation and triggered programmed cell death in these cells. The latter was confırmed by mitochondrial membrane depolarization and an increase in caspase-3 activation. In addition to that, we have detected S and G2/M cell cycle arrests and G0/G1 arrest upon fisetin and hesperetin treatment, respectively. To identify the altered genes and genetic networks in response to fisetin and hesperetin, whole-genome microarray analysis was performed. The microarray gene profiling analysis revealed some important signaling pathways including JAK/STAT pathway, KIT receptor signaling, and growth hormone receptor signaling that were altered upon fisetin and hesperetin treatment. Moreover, microarray data suggested potential candidate genes for targeted CML therapy. Fisetin and hesperetin significantly modulated the expression of genes involved in cell proliferation and division, apoptosis, cell cycle regulation, and other significant cellular processes such as replication, transcription, and translation. In conclusion, our results suggest that fisetin and hesperetin as potential natural agents for CML therapy.


Bronchoalveolar galactomannan in invasive pulmonary aspergillosis: a prospective study in pediatric patients.
Elevations in the number of immunocompromised patients in the past decade has lead to progressive increase in the incidence of Invasive Pulmonary Aspergillosis (IPA) among children; however, early diagnosis remains a challenge. Detection of galactomannan (GM) in the bronchoalveolar lavage (BAL) fluid appears to possess higher sensitivity and specificity than serum in immunocompromised adult patients but, it rarely has been investigated in pediatric patients. We performed a prospective case-control study to evaluate the efficacy of BAL GM in immunocompromised pediatric patients. Cases were subjects fulfilling the host factor criteria as defined by the EORTC/MSG and met established definitions for proven or probable IPA. Control group was patients with possible IPA in whom diagnoses other than IPA were confirmed and patients without risk factors of IPA who underwent bronchoscopy for other diagnostic purpose. Galactomannan testing was performed on BAL fluid samples using platelia Aspergillus seroassay. Sixteen cases of IPA (4 proven, 12 probable) and 54 controls (6 possible IPA and 48 no IPA) were documented according to EORTC/MSG definitions. The sensitivity and positive predictive values of BAL GM using an OD index of ≥0.5 were 87.5% and 93.33% respectively. We found seven cases of IPA with negative serum GM while their BAL GM was positive. We found high diagnostic value of BAL GM in immunocompromised pediatric patients with IPA. The lower OD index is necessary in children to avoid missing the cases of IPA in children.


Greater short-term weight loss in women 20-45 versus 55-65 years of age following bariatric surgery.
Whether and how sex and age affect bariatric-surgery outcome is poorly understood. Estrogens regulate body composition in women and animals, and increase weight loss in a rodent model of gastric bypass, suggesting that premenopausal women may lose more weight following bariatric surgery. One thousand three hundred fifty-six female gastric-bypass or gastric-banding patients were retrospectively grouped as 20-45 years old (presumptively premenopausal; n = 1,199) and 55-65 years old (presumptively postmenopausal; n = 157). Mixed-model ANCOVA followed by Bonferroni-corrected t tests were used to categorically test the effect of age on percent excess body weight loss (%EBWL) at 1 and 2 years post-surgery, controlling for preoperative EBW and surgery type. Age effects were also tested dimensionally in all women and in 289 male patients. Twenty- to forty-five-year-old women showed greater %EBWL 1 and 2 years post-surgery than 55-65-year-old women (p's < 0.0005). No age effect was detected in 20-25- vs. 30-35-, 30-35- vs. 40-45-, or 20-25- vs. 40-45-year-old women (p's > 0.2) This age effect was detected only after gastric banding, with 20-45-year-old women losing ∼7 kg more than 55-65-year-old women after 2 years. Dimensional analysis confirmed a significant inverse effect of age on bariatric surgery outcome in women, but did not detect any effect in men. Results indicate that 55-65-year-old women lose less weight than 20-45-year-old women in the initial 2 years after bariatric surgery, especially gastric banding; this may be mediated by age- or menopause-associated changes in physical activity, energy expenditure, or energy intake.


From Expectations to Experiences: Consumer Autonomy and Choice in Personal Genomic Testing.
Background: Personal genomic testing (PGT) offers individuals genetic information about relationships, wellness, sporting ability, and health. PGT is increasingly accessible online, including in emerging markets such as Australia. Little is known about what consumers expect from these tests and whether their reflections on testing resonate with bioethics concepts such as autonomy.Methods: We report findings from focus groups and semi-structured interviews that explored attitudes to and experiences of PGT. Focus group participants had little experience with PGT, while interview participants had undergone testing. Recordings were transcribed and analyzed using thematic analysis. Findings were critically interpreted with reference to bioethics scholarship on autonomy.Results: Fifty-six members of the public participated in seven focus groups, and 40 individuals were interviewed separately. Both groups valued the choice of PGT, and believed that it could motivate relevant actions. Focus group themes centered on the perceived value of choices, knowledge enabling action and knowledge about the self. Interview themes suggest that participants reflexively engage with their PGT information to make meaning, and that some appreciate its shortcomings. Critical interpretation of findings shows that while consumers of PGT are able to exercise a degree of autonomy in choosing, they may not be able to achieve a substantive conceptualization of autonomy, one that promotes alignment with higher-order desires.Conclusions: PGT consumers can critically reason about testing. However, they may uncritically accept test results, may not appreciate drawbacks of increased choice, or may overestimate the potential for information to motivate behavioral change. While consumers appear to be capable of substantive autonomy, they do so without ongoing support from companies. PGT companies promote a problematic ("default") account of autonomy, reliant on empowerment rhetoric. This leaves consumers vulnerable to making decisions inconsistent with their higher-order desires. As PGT expands, claims about its power and value need to be carefully drawn.


Career Preferences and Opinions on Animal Welfare and Ethics: A Survey of Veterinary Students in Australia and New Zealand.
Historically, the veterinary profession has understood animal welfare primarily in terms of animal health and productivity, with less recognition of animals' feelings and mental state. Veterinary students' career preferences and attitudes to animal welfare have been the focus of several international studies. As part of a survey in Australia and New Zealand, this study reports on whether veterinary students prioritize animal welfare topics or professional conduct on the first day of practice and examines links between students' career preferences and their institution, gender, and year of study. The questionnaire was designed to explore the importance that students assign to topics in animal welfare and ethics. Of the 3,320 students invited to participate in the online survey, a total of 851 students participated, representing a response rate of 25.5%. Students' preferences increased for companion-animal practice and decreased for production-animal practice as they progressed through their studies. Females ranked the importance of animal welfare topics higher than males, but the perceived importance declined for both genders in their senior years. In line with previous studies, this report highlighted two concerns: (1) the importance assigned to animal welfare declined as students progressed through their studies, and (2) males placed less importance overall on animal welfare than females. Given that veterinarians have a strong social influence on animal issues, there is an opportunity, through enhanced education in animal welfare, to improve student concern for animal welfare and in turn improve animal care and policy making by future veterinarians.


A novel homozygous missense mutation in the SH3-binding motif of STAMBP causing microcephaly-capillary malformation syndrome.
Microcephaly-capillary malformation syndrome is a congenital and neurodevelopmental disorder caused by biallelic mutations in the STAMBP gene. Here we identify the novel homozygous mutation located in the SH3 binding motif of STAMBP (NM_006463.4) (c.707C>T: p.Ser236Phe) through whole-exome sequencing. The case patient was a 2-year-old boy showing severe global developmental delay, progressive microcephaly, refractory seizures, dysmorphic facial features, and multiple capillary malformations. Immunoblot analysis of patient-derived lymphoblastoid cell lines (LCLs) revealed a severe reduction in STAMBP expression, indicating that Ser236Phe induces protein instability. STAMBP interacts with the SH3 domain of STAM and transduces downstream signals from the Jaks-STAM complex. The substitution of Ser236Phe found in the case patient was located in the SH3-binding motif, and we propose the mutation may block STAM binding and subsequently induce STAMBP degradation. Contrary to previously reported STAMBP mutations, the Ser236Phe mutation did not lead to constitutive activation of the PI3K-AKT-mTOR pathway in patient-derived LCLs, as indicated by the expression of phosphorylated S6 ribosomal protein, suggesting that it is not the major pathomechanism underlying the disorder in this patient.


Tensor decomposition for multiple-tissue gene expression experiments.
Genome-wide association studies of gene expression traits and other cellular phenotypes have successfully identified links between genetic variation and biological processes. The majority of discoveries have uncovered cis-expression quantitative trait locus (eQTL) effects via mass univariate testing of SNPs against gene expression in single tissues. Here we present a Bayesian method for multiple-tissue experiments focusing on uncovering gene networks linked to genetic variation. Our method decomposes the 3D array (or tensor) of gene expression measurements into a set of latent components. We identify sparse gene networks that can then be tested for association against genetic variation across the genome. We apply our method to a data set of 845 individuals from the TwinsUK cohort with gene expression measured via RNA-seq analysis in adipose, lymphoblastoid cell lines (LCLs) and skin. We uncover several gene networks with a genetic basis and clear biological and statistical significance. Extensions of this approach will allow integration of different omics, environmental and phenotypic data sets.


Well-ordered nanoparticle arrays for floating gate memory applications.
A non-volatile floating gate memory device containing well-ordered Au nanoparticles (NPs) is fabricated as a metal-oxide-semiconductor capacitor structure. With superior control on the size, shape and position of nanoparticles, the presented nano-floating gate memory (NFGM) device possesses almost perfect precision of device geometry. The well-ordered Au NPs embedded within the memory device exhibit large memory window at low operation voltages (8.8V @ ± 15V), fast operation time (<10-4 s) and good retention (up to 107 s). In this work, the structural properties of the NFGM device are correlated with the examined electrical properties. The current results are compared with the other studies in the literature to emphasis the advantages of the precise ordering and geometry of the NPs.


Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome.
Hemophagocytic syndrome (HPS) is characterized by an uncontrolled and poorly understood activation of T-helper 1 (Th-1) lymphocytes and macrophages. We studied 20 patients with HPS secondary to infections, autoimmune disease, lymphoma, or cancer and observed that the concentrations of serum interleukin 18 (IL-18), a strong inducer of Th-1 responses, interferon gamma (IFN-gamma) production, and stimulation of macrophages and natural killer (NK) cells were highly increased in HPS but not in control patients. In contrast, concentrations of its natural inhibitor, the IL-18 binding protein (IL-18BP), were only moderately elevated, resulting in a high level of biologically active free IL-18 in HPS (4.6-fold increase compared with controls; P < .001). Free IL-18 but not IL-12 concentrations significantly correlated with clinical status and the biologic markers of HPS such as anemia (P < .001), hypertriglyceridemia, and hyperferritinemia (P < .01) and also with markers of Th-1 lymphocyte or macrophage activation, such as elevated concentrations of IFN-gamma and soluble IL-2 and tumor necrosis factor alpha (TNF-alpha) receptor concentrations. Despite high IL-18 elevation, in vitro NK-cell cytotoxicity was severely impaired in HPS patients, in part due to NK-cell lymphopenia that was observed in a majority of patients but also secondary to an intrinsic NK-cell functional deficiency. We concluded that a severe IL-18/IL-18BP imbalance results in Th-1 lymphocyte and macrophage activation, which escapes control by NK-cell cytotoxicity and may allow for secondary HPS in patients with underlying diseases.


"We threw away the stones": a mixed method evaluation of a simple cookstove intervention in Malawi.
Background: Exposure to air pollution is responsible for a substantial burden of respiratory disease globally. Household air pollution from cooking using biomass is a major contributor to overall exposure in rural low-income settings. Previous research in Malawi has revealed how precarity and food insecurity shape individuals' daily experiences, contributing to perceptions of health. Aiming to avoid a mismatch between research intervention and local context, we introduced a simple cookstove intervention in rural Malawi, analysing change in fine particulate matter (PM 2.5) exposures, and community perceptions. Methods: Following a period of baseline ethnographic research, we distributed 'chitetezo mbaula', locally made clay cookstoves, to all households (n=300) in a rural Malawian village. Evaluation incorporated village-wide participant observation and concurrent exposure monitoring using portable PM 2.5 monitors at baseline and follow-up (three months post-intervention). Qualitative data were thematically analysed. Quantitative analysis of exposure data included pre-post intervention comparisons, with datapoints divided into cooking and non-cooking ('baseline') periods. Findings were integrated at the interpretation stage, using a convergent design mode of synthesis. Results: Individual exposure monitoring pre- and post-cookstove intervention involved a sample of 18 participants (15 female; mean age 43). Post-intervention PM 2.5 exposures (median 9.9μg/m 3 [interquartile range: 2.2-46.5]) were not significantly different to pre-intervention (11.8μg/m 3 [3.8-44.4]); p=0.71. On analysis by activity, 'baseline' exposures were found to be reduced post-intervention (from 8.2μg/m 3 [2.5-22.0] to 4.6μg/m 3 [1.0-12.6]; p=0.01). Stoves were well-liked and widely used by residents as substitutes for previous cooking methods (mainly three-stone fires). Most cited benefits related to fuel saving and shorter cooking times. Conclusions: The cookstove intervention had no impact on cooking-related PM 2.5 exposures. A significant reduction in baseline exposures may relate to reduced smouldering emissions. Uptake and continued use of the stoves was high amongst community members, who preferred using the stoves to cooking over open fires.


Translocation of protein kinase C isoforms is involved in propofol-induced endothelial nitric oxide synthase activation.
Previous studies have indicated that protein kinase C (PKC) may enhance endothelial nitric oxide synthase (eNOS) activation, although the detailed mechanism(s) remains unclear. In this study, we investigated the roles of PKC isoforms in regulating propofol-induced eNOS activation in human umbilical vein endothelial cells (HUVECs). We applied western blot (WB) analysis to investigate the effects of propofol on Ser(1177) phosphorylation-dependent eNOS activation in HUVECs. Nitrite (NO(2)(-)) accumulation was measured using the Griess assay. The phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway was examined by WB assay. Propofol-induced translocation of individual PKC isoforms in subcellular fractions in HUVECs was analysed using WB assay. In HUVECs, protocol treatment (1-100 microM) for 10 min induced a concentration-dependent increase in phosphorylation of eNOS at Ser(1177). The NO production was also increased accordingly. PKC inhibitors, bisindolylmaleimide I (0.1-1 microM), and staurosporine (20 and 100 nM), effectively blocked propofol-induced eNOS activation and NO production. Further analyses in fractionated endothelial lysate showed that short-term propofol treatment (50 microM) led to translocation of PKC-alpha, PKC-delta, PKC-zeta, PKC-eta, and PKC-epsilon from cytosolic to membrane fractions, which could also be inhibited by both PKC inhibitors. These data revealed that the differential redistribution of these isozymes is indispensable for propofol-induced eNOS activation. In addition, Akt was not phosphorylated in response to propofol at Ser(473) or Thr(308). Propofol induces the Ser(1177) phosphorylation-dependent eNOS activation through the drug-stimulated translocation of PKC isoforms to distinct intracellular sites in HUVECs, which is independent of PI3K/Akt-independent pathway.


Computed tomography angiography and perfusion to assess coronary artery stenosis causing perfusion defects by single photon emission computed tomography: the CORE320 study.
To evaluate the diagnostic power of integrating the results of computed tomography angiography (CTA) and CT myocardial perfusion (CTP) to identify coronary artery disease (CAD) defined as a flow limiting coronary artery stenosis causing a perfusion defect by single photon emission computed tomography (SPECT). We conducted a multicentre study to evaluate the accuracy of integrated CTA-CTP for the identification of patients with flow-limiting CAD defined by ≥50% stenosis by invasive coronary angiography (ICA) with a corresponding perfusion deficit on stress single photon emission computed tomography (SPECT/MPI). Sixteen centres enroled 381 patients who underwent combined CTA-CTP and SPECT/MPI prior to conventional coronary angiography. All four image modalities were analysed in blinded independent core laboratories. The prevalence of obstructive CAD defined by combined ICA-SPECT/MPI and ICA alone was 38 and 59%, respectively. The patient-based diagnostic accuracy defined by the area under the receiver operating characteristic curve (AUC) of integrated CTA-CTP for detecting or excluding flow-limiting CAD was 0.87 [95% confidence interval (CI): 0.84-0.91]. In patients without prior myocardial infarction, the AUC was 0.90 (95% CI: 0.87-0.94) and in patients without prior CAD the AUC for combined CTA-CTP was 0.93 (95% CI: 0.89-0.97). For the combination of a CTA stenosis ≥50% stenosis and a CTP perfusion deficit, the sensitivity, specificity, positive predictive, and negative predicative values (95% CI) were 80% (72-86), 74% (68-80), 65% (58-72), and 86% (80-90), respectively. For flow-limiting disease defined by ICA-SPECT/MPI, the accuracy of CTA was significantly increased by the addition of CTP at both the patient and vessel levels. The combination of CTA and perfusion correctly identifies patients with flow limiting CAD defined as ≥50 stenosis by ICA causing a perfusion defect by SPECT/MPI.


Apomine, an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo.
Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphosphonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM murine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease.


Responses in early visual areas to contour integration are context dependent.
It has been shown that early visual areas are involved in contour processing. However, it is not clear how local and global context interact to influence responses in those areas, nor has the interarea coordination that yields coherent structural percepts been fully studied, especially in human observers. In this study, we used functional magnetic resonance imaging (fMRI) to measure activity in early visual cortex while observers performed a contour detection task in which alignment of Gabor elements and background clutter were manipulated. Six regions of interest (two regions, containing either the cortex representing the target or the background clutter, in each of areas V1, V2, and V3) were predefined using separate target versus background functional localizer scans. The first analysis using a general linear model showed that in the presence of background clutter, responses in V1 and V2 target regions of interest were significantly stronger to aligned than unaligned contours, whereas when background clutter was absent, no significant difference was observed. The second analysis using interarea correlations showed that with background clutter, there was an increase in V1-V2 coordination within the target regions when perceiving aligned versus unaligned contours; without clutter, however, correlations between V1 and V2 were similar no matter whether aligned contours were present or not. Both the average response magnitude and the connectivity analysis suggest different mechanisms support contour processing with or without background distractors. Coordination between V1 and V2 may play a major role in coherent structure perception, especially with complex scene organization.


Acute Lymphoblastic Leukemia with Malignant Hypercalcemia: A Case Report.
BACKGROUND Malignant hypercalcemia is a rare finding in the pediatric population, even more rare in hematological malignancies, such as leukemia. CASE REPORT We present a case of a 6-year-old female patient who was diagnosed with acute lymphoblastic leukemia, with secondary hypercalcemia. She started chemotherapy following the IC-BFM ALL2002 protocol with simultaneous calcitonin, diuretics and aggressive hydration for hypercalcemia, and went into complete remission after the induction therapy. After 4 months of chemotherapy, she was diagnosed with relapse associated again with malignant hypercalcemia, and underwent chemotherapy with the relapse protocol. There was no response after the first 2 cycles, so we decided to start her on clofarabine. Due to the severe hypercalcemia and consecutive osteolysis, she developed several bone fractures and needed gypsum immobilization. We started her again on calcitonin, but she developed severe adverse reactions, so we found it necessary to start bisphosphonates, first zoledronic acid intravenously, and afterwards clodronate orally. Consolidation of bone fractures was achieved, but due to prolonged immobilization she developed bedsores, superinfected with Lichtheimia corymbifera. We started posaconazole orally, but she rapidly went into severe sepsis with multiple organ failure. The leukemia showed no response to chemotherapy, progressed rapidly, and the patient died. CONCLUSIONS Malignant hypercalcemia is associated with a poor prognosis in leukemia, and might need a more aggressive therapy.


Emerging issues in the evolution of animal nuptial gifts.
Uniquely positioned at the intersection of sexual selection, nutritional ecology and life-history theory, nuptial gifts are widespread and diverse. Despite extensive empirical study, we still have only a rudimentary understanding of gift evolution because we lack a unified conceptual framework for considering these traits. In this opinion piece, we tackle several issues that we believe have substantively hindered progress in this area. Here, we: (i) present a comprehensive definition and classification scheme for nuptial gifts (including those transferred by simultaneous hermaphrodites), (ii) outline evolutionary predictions for different gift types, and (iii) highlight some research directions to help facilitate progress in this field.


The ubiquitin-conjugating enzyme CDC34 is essential for cytokinesis in contrast to putative subunits of a SCF complex in Trypanosoma brucei.
The ubiquitin-proteasome system is a post-translational regulatory pathway for controlling protein stability and activity that underlies many fundamental cellular processes, including cell cycle progression. Target proteins are tagged with ubiquitin molecules through the action of an enzymatic cascade composed of E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, and E3 ubiquitin ligases. One of the E3 ligases known to be responsible for the ubiquitination of cell cycle regulators in eukaryotes is the SKP1-CUL1-F-box complex (SCFC). In this work, we identified and studied the function of homologue proteins of the SCFC in the life cycle of Trypanosoma brucei, the causal agent of the African sleeping sickness. Depletion of trypanosomal SCFC components TbRBX1, TbSKP1, and TbCDC34 by RNAi resulted in decreased growth rate and contrasting cell cycle abnormalities for both procyclic (PCF) and bloodstream (BSF) forms. Depletion of TbRBX1 in PCF cells interfered with kinetoplast replication, whilst depletion of TbSKP1 arrested PCF and BSF cells in the G1/S transition. Silencing of TbCDC34 in BSF cells resulted in a block in cytokinesis and caused rapid clearance of parasites from infected mice. We also show that TbCDC34 is able to conjugate ubiquitin in vitro and in vivo, and that its activity is necessary for T. brucei infection progression in mice. This study reveals that different components of a putative SCFC have contrasting phenotypes once depleted from the cells, and that TbCDC34 is essential for trypanosome replication, making it a potential target for therapeutic intervention.


Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion.
We report the clinical features in 27 Australasian patients with Angelman syndrome (AS), all with a DNA deletion involving chromosome 15(q11-13), spanning markers from D15S9 to D15S12, about 3 center dot 5 Mb of DNA. There were nine males and 18 females. All cases were sporadic. The mean age at last review (end of 1994) was 11 center dot 2 years (range 3 to 34 years). All patients were ataxic, severely retarded, and lacking recognisable speech. In all patients, head circumference (HC) at birth was normal but skewed in distribution, with 62 center dot 5% at the 10th centile. At last review HC was around the 50th centile in three patients (12 center dot 5%) while 15 had poor postnatal head growth. Short stature was not invariable, 5/26 (19%) were on or above the 50th centile. Hypotonia at birth was recorded in 15/24 (63%) and neonatal feeding difficulties were recorded in 20/26 (77%). Epilepsy was present in 26/27 (96%) with onset by the third year of life in 20 patients (83%). Improvement in epilepsy was reported in 11/16 patients (69%) with age. An abnormal EEG was reported in 25/25 patients. Hypopigmentation was present in 19/26 (73%). One patient had oculocutaneous albinism. Five patients could not walk independently. Of the remaining 22 who could walk, age of onset of walking ranged from 2 to 8 years. Disrupted sleep patterns were present in 18/21 patients (86%), with improvement in 9/12 patients (75%) over 10 years of age. The clinical features in this group of deletional AS patients were similar to previous reports, but these have not separated patients into subgroups based on DNA studies. In our group of deletional cases, 100% showed severe mental retardation, ataxic movements, absent language, abnormal EEG, happy disposition (noted in infancy in 95%), normal birth weight and head circumference at birth, and a large, wide mouth. These features occurred with a higher frequency than in AS patients as a whole. Our study also provided information on the evolution of the phenotype. The data can act as a benchmark for comparisons of AS resulting from other genetic mechanisms.


Effect of Ocimum sanctum, ascorbic acid, and verapamil on macrophage function and oxidative stress in mice exposed to cocaine.
To investigate the effect of Ocimum sanctum, ascorbic acid, and verapamil on macrophage function and oxidative stress in experimental animals exposed to cocaine. Mice were used in this study and were divided randomly into different groups of six animals each. They were either treated with intraperitoneal injection of saline or cocaine hydrochloride or an oral feeding of oil of Ocimum sanctum, ascorbic acid or verapamil, or both (ascorbic acid and verapamil), and were evaluated for a respiratory burst of macrophages, superoxide and nitric oxide (NO) production, estimation of TNF-alpha in the serum and supernatant of cultured macrophages, estimation of lipid peroxidation (malondialdehyde- MDA) in the serum, and superoxide dismutase activity in the erythrocytes. Unstimulated respiratory burst as well as superoxide production was enhanced on treatment with cocaine and all the three drugs were found to attenuate this enhancement. The bactericidal capacity of macrophages decreased significantly on chronic cocaine exposure, as it was associated with decreased respiratory burst and superoxide production. There was a significant decrease in NO production by macrophages on chronic cocaine exposure and all the test drugs were found to restore nitrite formation to a normal level. There was an increase in the malonylodialdehyde (MDA) level and decrease in the superoxide dismutase level on chronic cocaine exposure, and all the three drugs effectively decreased the MDA level and increased superoxide dismutase level. There was an increase in serum TNF-alpha on chronic cocaine exposure, which was decreased significantly by ascorbic acid and verapamil. O. sanctum, ascorbic acid, and verapamil were equally effective in improving the macrophage function and reducing oxidative stress. These findings suggested that O. sanctum, ascorbic acid, and verapamil attenuated acute and chronic cocaine-mediated effects.


A comparative resonance Raman analysis of heme-binding PAS domains: heme iron coordination structures of the BjFixL, AxPDEA1, EcDos, and MtDos proteins.
The heme-PAS is a specialized domain with which a broad class of signal-transducing heme proteins detect physiological heme ligands. Such domains exhibit a wide range of ligand binding parameters, yet they are all expected to feature an alpha-beta heme binding fold and a predominantly hydrophobic heme distal pocket without a distal histidine. We have compared, for the first time, the resonance Raman spectra of several heme-PASs: the heme-binding domains of Bradyrhizobium japonicum FixL, Escherichia coli Dos, Acetobacter xylinum PDEA1, and Methanobacterium thermoautotrophicum Dos. In all cases, the nu(Fe)-(CO) and nu(C-O) values of the carbonmonoxy forms were consistent with coordination of the heme iron to histidine on the proximal side and binding of the CO without electrostatic interaction with the heme distal pocket. EcDos was unusual in having predominantly hexacoordinate heme iron in the deoxy and met forms. Despite an evident lack of CO interaction with the EcDos heme pocket, relatively low Fe-O(2) (562 cm(-1)) and N-O (1576 cm(-1)) stretching frequencies indicated that strong polar interactions with that heme distal pocket are possible for highly bent ligands such as O(2) or NO. None of the newly studied NO adducts exhibited evidence of the Fe-His rupture and pentacoordination previously noted for Sinorhizobium meliloti FixL. A low Fe-His stretching frequency, formerly interpreted as a strained Fe-His bond, and the slow association of O(2) with S. meliloti FixL failed to correlate with the newly studied proteins having low association rate or low equilibrium association constants for binding of O(2). We conclude that although heme-PASs share some features, they represent distinct signal transduction mechanisms.


Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.


Degree of polarization as a criterion to obtain the nine bilinear constraints between the Mueller-Jones matrix elements.
The degree of polarization is employed as a criterion to find the nine independent relations among the elements of the Mueller-Jones matrix. This procedure is applied by considering a previously determined, physically realizable Mueller matrix. On the other hand, the nine bilinear constrains are obtained by directly measuring the degree of polarization from an outgoing beam of light from an optical system by considering nine incident states of light taken from the Poincaré sphere. For practical purposes, all the incident polarization states must be scanned from the Poincaré sphere in order to satisfy the over-polarization and the over-gain conditions, respectively, for the physical realizability of the Mueller matrix.


Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
A study was undertaken to record exacerbations and health resource use in patients with COPD during 6 months of treatment with tiotropium, salmeterol, or matching placebos. Patients with COPD were enrolled in two 6-month randomised, placebo controlled, double blind, double dummy studies of tiotropium 18 micro g once daily via HandiHaler or salmeterol 50 micro g twice daily via a metered dose inhaler. The two trials were combined for analysis of heath outcomes consisting of exacerbations, health resource use, dyspnoea (assessed by the transitional dyspnoea index, TDI), health related quality of life (assessed by St George's Respiratory Questionnaire, SGRQ), and spirometry. 1207 patients participated in the study (tiotropium 402, salmeterol 405, placebo 400). Compared with placebo, tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation. Fewer COPD exacerbations/patient year occurred in the tiotropium group (1.07) than in the placebo group (1.49, p<0.05); the salmeterol group (1.23 events/year) did not differ from placebo. The tiotropium group had 0.10 hospital admissions per patient year for COPD exacerbations compared with 0.17 for salmeterol and 0.15 for placebo (not statistically different). For all causes (respiratory and non-respiratory) tiotropium, but not salmeterol, was associated with fewer hospital admissions while both groups had fewer days in hospital than the placebo group. The number of days during which patients were unable to perform their usual daily activities was lowest in the tiotropium group (tiotropium 8.3 (0.8), salmeterol 11.1 (0.8), placebo 10.9 (0.8), p<0.05). SGRQ total score improved by 4.2 (0.7), 2.8 (0.7) and 1.5 (0.7) units during the 6 month trial for the tiotropium, salmeterol and placebo groups, respectively (p<0.01 tiotropium v placebo). Compared with placebo, TDI focal score improved in both the tiotropium group (1.1 (0.3) units, p<0.001) and the salmeterol group (0.7 (0.3) units, p<0.05). Evaluation of morning pre-dose FEV(1), peak FEV(1) and mean FEV(1) (0-3 hours) showed that tiotropium was superior to salmeterol while both active drugs were more effective than placebo. Exacerbations of COPD and health resource usage were positively affected by daily treatment with tiotropium. With the exception of the number of hospital days associated with all causes, salmeterol twice daily resulted in no significant changes compared with placebo. Tiotropium also improved health related quality of life, dyspnoea, and lung function in patients with COPD.


Surface area measurement utilizing an acoustic bridge
A new method is proposed for measuring the surface area of an object. The acoustic conductance of a cavity is proportional to the surface area of the cavity inner wall. The surface area of an object thus can be known from the measurement of the acoustic impedance of a chamber in which the object is placed. In order to measure the acoustic impedance accurately; the proposed method employs the acoustic bridge technique. The experimental device is composed of the following elements so arranged that their electric equivalents form a bridge circuit: a measuring chamber in which an object under test is placed and whose volume can be adjusted; a reference chamber whose inner surface area can be varied; a loudspeaker (the signal source) mounted between the two chambers; and a bypass channel at the midpoint of which a microphone (the null detector) is installed. This bridge balances when the volume and the inner surface area of each chamber become equal. The surface area of the object can then be known from the inner surface area of the reference chamber. Several experiments were performed with this device and the success of the proposed method was verified.


Lower regulatory frequency for postural control in patients with fibromyalgia and chronic fatigue syndrome.
As many similar symptoms are reported in fibromyalgia (FM) and chronic fatigue syndrome (CFS), underlying defcits may potentially also be similar. Postural disequilibrium reported in both conditions may thus be explained by similar deviations in postural control strategies. 75 females (25/group FM, CFS and control, age 19-49 years) performed 60 s of quiet standing on a force platform in each of three conditions: 1) firm surface with vision, 2) firm surface without vision and, 3) compliant surface with vision. Migration of center of pressure was decomposed into a slow and a fast component denoting postural sway and lateral forces controlling postural sway, analyzed in the time and frequency domains. Main effects of group for the antero-posterior (AP) and medio-lateral (ML) directions showed that patients displayed larger amplitudes (AP, p = 0.002; ML, p = 0.021) and lower frequencies (AP, p < 0.001; ML, p < 0.001) for the slow component, as well as for the fast component (amplitudes: AP, p = 0.010; ML, p = 0.001 and frequencies: AP, p = 0.001; ML, p = 0.029) compared to controls. Post hoc analyses showed no significant differences between patient groups. In conclusion, both the CFS- and the FM-group differed from the control group. Larger postural sway and insufficient control was found in patients compared to controls, with no significant differences between the two patient groups.


Characteristics of adults with serious psychological distress as measured by the K6 scale: United States, 2001-04.
This report estimates the prevalence of serious psychological distress (SPD) in the noninstitutionalized adult population of the United States, as measured by the K6 scale of nonspecific psychological distress, and describes the characteristics of adults with and without SPD. These findings are compared with results from previous studies of the characteristics of adults with serious mental illnesses that cause significant disability, such as severe major depression, bipolar disorder, and schizophrenia. The estimates in this report were derived from the Family Core and Sample Adult components of the 2001-04 National Health Interview Survey, conducted by the Centers for Disease Control and Prevention's National Center for Health Statistics (NCHS). Estimates were calculated using the SUDAAN statistical package to account for the complex survey design. The prevalence of SPD was higher among adults 45-64 years old than younger adults 18-44 years or older adults 65 years and over. Adults with SPD were more likely to be female, have less than a high school diploma, and live in poverty, and less likely to be married than adults without SPD. Moreover, those with SPD were more likely to be obese and to be current smokers. They have a higher prevalence of ever being diagnosed with heart disease, diabetes, arthritis, and stroke than persons without SPD. Adults with SPD were more likely to report needing help with activities of daily living (ADLs) and instrumental activities of daily living (IADLs). They also used more medical care services such as doctor visits and visits to mental health professionals than adults without SPD. The associations between SPD and sociodemographic characteristics, health status, and health care utilization are similar to the relationships found between serious mental illnesses (for example, major depression or schizophrenia) and these same variables. Persons with SPD demonstrate disadvantage in both socioeconomic status and health outcomes.


Dental plaque microbial profiles of children from Khartoum, Sudan, with congenital heart defects.
Few studies have focused on the bacterial species associated with the deterioration of the dental and gingival health of children with congenital heart defects (CHD). The aims of this study were (1) to examine the dental plaque of children with CHD in order to quantify bacterial load and altered bacterial composition compared with children without CHD; and (2) to investigate the correlation between the level of caries and gingivitis and dental biofilm bacteria among those children. In this cross-sectional study, participants were children (3-12 years) recruited in Khartoum State, Sudan. A total of 80 CHD cases from the Ahmed Gasim Cardiac Centre and 80 healthy controls from randomly selected schools and kindergartens were included. Participants underwent clinical oral examinations for caries (decayed, missing, and filled teeth indices [DMFT] for primary dentition, and DMFT for permanent dentition), and gingivitis (simplified gingival index [GI]). Pooled dental biofilm samples were obtained from four posterior teeth using paper points. Real-time quantitative polymerase chain reaction was used for the detection and quantification of Streptococcus mutans, Streptococcussanguinis, and Lactobacillus acidophilus. Checkerboard DNA-DNA hybridization was used for the detection of 40 additional bacterial species. CHD cases had a significantly higher caries experience (DMFT = 4.1 vs. 2.3, p < 0.05; DMFT = 1.4 vs. 0.7, p < 0.05) and a higher mean number of examined teeth with gingivitis (4.2 vs. 2.0; p < 0.05) compared with controls. S. mutans counts were significantly higher among the CHD cases (p < 0.05). Checkerboard results revealed that 18/40 bacterial species exhibited significantly higher mean counts among CHD cases (p < 0.01). Correlation analyses revealed that among CHD cases, the detection levels of Tannerella forsythia, Campylobacter rectus, Fusobacterium nucleatum subsp. vincentii, F. nucleatum subsp. nucleatum, and F. nucleatum subsp. polymorphum were highly positively correlated with GI. CHD cases harbor more cariogenic and periodontopathogenic bacterial species in their dental plaque, which correlated with higher levels of caries and gingivitis.


A new approach to understanding the impact of circadian disruption on human health.
Light and dark patterns are the major synchronizer of circadian rhythms to the 24-hour solar day. Disruption of circadian rhythms has been associated with a variety of maladies. Ecological studies of human exposures to light are virtually nonexistent, however, making it difficult to determine if, in fact, light-induced circadian disruption directly affects human health. A newly developed field measurement device recorded circadian light exposures and activity from day-shift and rotating-shift nurses. Circadian disruption defined in terms of behavioral entrainment was quantified for these two groups using phasor analyses of the circular cross-correlations between light exposure and activity. Circadian disruption also was determined for rats subjected to a consistent 12-hour light/12-hour dark pattern (12L:12D) and ones subjected to a "jet-lagged" schedule. Day-shift nurses and rats exposed to the consistent light-dark pattern exhibited pronounced similarities in their circular cross-correlation functions and 24-hour phasor representations except for an approximate 12-hour phase difference between species. The phase difference reflects the diurnal versus nocturnal behavior of humans versus rodents. Phase differences within species likely reflect chronotype differences among individuals. Rotating-shift nurses and rats subjected to the "jet-lagged" schedule exhibited significant reductions in phasor magnitudes compared to the day-shift nurses and the 12L:12D rats. The reductions in the 24-hour phasor magnitudes indicate a loss of behavioral entrainment compared to the nurses and the rats with regular light-dark exposure patterns. This paper provides a quantitative foundation for systematically studying the impact of light-induced circadian disruption in humans and in animal models. Ecological light and activity data are needed to develop the essential insights into circadian entrainment/disruption actually experienced by modern people. These data can now be obtained and analyzed to reveal the interrelationship between actual light exposures and markers of circadian rhythm such as rest-activity patterns, core body temperature, and melatonin synthesis. Moreover, it should now be possible to bridge ecological studies of circadian disruption in humans to parametric studies of the relationships between circadian disruption and health outcomes using animal models.


Long-term results of brentuximab vedotin in relapsed and refractory Hodgkin lymphoma: multi-center real-life experience.
Classical Hodgkin lymphoma (cHL) is considered a curable disease; however, approximately one-third of responders experience disease relapse following first-line therapy. Several studies have shown the efficacy of brentuximab vedotin (BV) in patients with relapsed/refractory HL. We present a retrospective analysis of 58 patients with relapsed/refractory HL treated with BV in a named patient program from 11 centers. The median follow-up duration was 20 (range, 4-84) months. The best overall response rate was 64% (complete response [CR], 31%; partial response [PR], 33%). The 5-year progression-free survival (PFS) and overall survival (OS) rates were 12% (95% confidence interval [CI], 0.05-0.22) and 26% (95% CI, 0.16-0.38), respectively. Among patients who achieved CR, the estimated 5-year PFS and OS rates were 32% (95% CI, 0.13-0.54) and 60% (95% CI, 0.33-0.78), respectively. A total of 26 patients underwent subsequent stem cell transplantation. The 5-year PFS and OS rates for 10 patients who had consolidative stem cell transplantation were 28% and 30%, respectively. Twenty-seven patients required further therapy following BV. At the time of the analysis, 12 patients (21%) were alive. Five patients (9%) had long-term remission after achieving CR with BV monotherapy, with a median PFS of 76 months. Three of them (5%) did not receive any other treatment following BV and their median PFS was 75 months. Our long-term results showed that a small subset of patients with relapsed/refractory cHL may benefit from and even be cured with BV monotherapy.


Opioidergic System and Functional Architecture of Intrinsic Brain Activity: Implications for Psychiatric Disorders.
The opioidergic system and intrinsic brain activity, as organized in large-scale networks such as the salience network (SN), sensorimotor network (SMN), and default-mode network (DMN), play core roles in healthy behavior and psychiatric disorders. This work aimed to investigate how opioidergic signaling affects intrinsic brain activity in healthy individuals by reviewing relevant neuroanatomical, molecular, functional, and pharmacological magnetic resonance imaging studies in order to clarify their physiological links and changes in psychiatric disorders. The SN shows dense opioidergic innervations of subcortical structures and high expression levels of opioid receptors in subcortical-cortical areas, with enhanced or reduced activity with low or very high doses of opioids, respectively. The SMN shows high levels of opioid receptors in subcortical areas and functional disconnection caused by opioids. The DMN shows low levels of opioid receptors in cortical areas and inhibited or enhanced activity with low or high doses of opioids, respectively. Finally, we proposed a working model. Opioidergic signaling enhances SN and suppresses SMN (and DMN) activity, resulting in affective excitation with psychomotor inhibition; stronger increases in opioidergic signaling attenuate the SN and SMN while disinhibiting the DMN, dissociating affective and psychomotor functions from the internal states; the opposite occurs with a deficit of opioidergic signaling.


Microsecond light-induced proton transfer to flavin in the blue light sensor plant cryptochrome.
Plant cryptochromes are blue light photoreceptors that regulate key responses in growth and daily rhythm of plants and might be involved in magnetoreception. They show structural homology to the DNA repair enzyme photolyase and bind flavin adenine dinucleotide as chromophore. Blue light absorption initiates the photoreduction from the oxidized dark state of flavin to the flavin neutral radical, which is the signaling state of the sensor. Previous time-resolved studies of the photoreduction process have been limited to observation of the decay of the radical in the millisecond time domain. We monitored faster, light-induced changes in absorption of an algal cryptochrome covering a spectral range of 375-750 nm with a streak camera setup. Electron transfer from tryptophan to flavin is completed before 100 ns under formation of the flavin anion radical. Proton transfer takes place with a time constant of 1.7 micros leading to the flavin neutral radical. Finally, the flavin radical and a tryptophan neutral radical decay with a time constant >200 micros in the millisecond and second time domain. The microsecond proton transfer has not been observed in animal cryptochromes from insects or photolyases. Furthermore, the strict separation in time of electron and proton transfer is novel in the field of flavin-containing photoreceptors. The reaction rate implies that the proton donor is not in hydrogen bonding distance to the flavin N5. Potential candidates for the proton donor and the involvement of the tryptophan triad are discussed.


Effects of hydrocortisone administration on leptin and adiponectin synthesis in dogs.
To determine effects of hydrocortisone administration on serum leptin and adiponectin concentrations, abdominal fat distribution, and mRNA expression of leptin and adiponectin in abdominal adipose tissue of dogs. 12 healthy dogs. Dogs received hydrocortisone (8.5 mg/kg; n = 6) or a placebo (6) orally every 12 hours for 90 days. Serum leptin and adiponectin concentrations were measured with a canine-specific ELISA on the day before (day 0; baseline) and during (days 1, 3, 7, 30, 60, and 90) administration. On days 0, 30, 60, and 90, abdominal fat mass was quantified with CT, and mRNA expression of leptin and adiponectin in abdominal fat was analyzed by use of a PCR assay. Hydrocortisone administration resulted in an increase in visceral fat mass on days 60 and 90, compared with the mass at baseline. Visceral fat mass at the level of L3 increased during hydrocortisone administration. Serum leptin concentration began to increase on day 1 and was significantly higher than the baseline concentration on days 30 and 60. Serum adiponectin concentration on days 30, 60, and 90 was significantly lower than the baseline concentration. Leptin and adiponectin mRNA expression in abdominal fat was greater on day 30, compared with expression at baseline, but lower on days 60 and 90, compared with expression on day 30. Serum leptin concentration and visceral fat mass were correlated. Hydrocortisone administration affected abdominal fat distribution and serum leptin and adiponectin concentrations through dysregulation of leptin and adiponectin expression.


ARMC5 variants in PRKAR1A-mutated patients modify cortisol levels and Cushing's syndrome.
Mutations in the protein kinase A (PKA) regulatory subunit type 1A (PRKAR1A) and armadillo repeat-containing 5 (ARMC5) genes cause Cushing's syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD) and primary bilateral macronodular adrenocortical hyperplasia (PBMAH), respectively. Between the two genes, ARMC5 is highly polymorphic with several variants in the population, whereas PRKAR1A has very little, if any, non-pathogenic variation in its coding sequence. We tested the hypothesis that ARMC5 variants may affect the clinical presentation of PPNAD and CS among patients with PRKAR1A mutations. In this study, 91 patients with PPNAD due to PRKAR1A mutations were tested for abnormal cortisol secretion or CS and for ARMC5 sequence variants. Abnormal cortisol secretion was present in 71 of 74 patients with ARMC5 variants, whereas 11 of 17 patients negative for ARMC5 variants did not have hypercortisolemia. The presence of ARMC5 variants was a statistically strong predictor of CS among patients with PRKAR1A mutations (P < 0.001). Among patients with CS due to PPNAD, ARMC5 variants were associated with lower cortisol levels at baseline (P = 0.04) and after high dose dexamethasone administration (P = 0.02). The ARMC5 p.I170V variant increased ARMC5 protein accumulation in vitro and decreased viability of NCI-H295 cells (but not HEK 293T cells). PPNAD tissues with ARMC5 variants showed stronger ARMC5 protein expression than those that carried a normal ARMC5 sequence. Taken together, our results suggest that ARMC5 variants among patients with PPNAD due to PRKAR1A defects may play the role of a genetic modifier for the presence and severity of hypercortisolemia.


Angiotensin II upregulates RAGE expression on podocytes: role of AT2 receptors.
Advanced glycation end products (AGEs) play an important role in diabetic nephropathy. The receptor for AGEs, called RAGE, is present on podocytes. We investigated whether angiotensin II (ANG II) modulates RAGE expression on cultured differentiated podocytes. Cultured podocytes expressed AT1 and AT2 receptors. Surprisingly, ANG II induced RAGE mRNA and protein expression through AT2 receptors. ANG II had no influence on proliferation or protein content of podocytes. The increase in RAGE expression depended on stimulated transcriptional activity. Using various mutant reporter constructs of the RAGE promoter region, it was shown that a NF-kappaB binding site at -1519 was essential for ANG II-induced transcriptional activity. Preincubation with ANG II increased the expression of tumor necrosis factor-alpha mRNA and protein expression induced by AGE, indicating that the ANG II-mediated upregulation of RAGE has functional consequences. AGE-BSA was incorporated into cells as measured by Western blots for N epsilon-carboxymethyllysine, but ANG II did not influence this process. ANG II in the absence or presence of AGE-BSA did not induce apoptosis of podocytes. Our study revealed aninteraction between the renin-angiotensin system and the AGE/RAGE axis in podocytes. Since intraglomerular ANG II levels are increased in diabetic nephropathy, this interaction may have pathophysiological consequences for podocyte injury and inflammation associated with the development of diabetic nephropathy.


Three-dimensional optical phantom and its application in photodynamic therapy.
A technique to manufacture a stable, reproducible three-dimensional optical phantom is presented. This phantom reproduces the tissue's optical properties as well as the geometry and, to some extent, the mechanical properties of the organ concerned. Easy to make and to handle, this phantom is a useful tool for numerous medical applications involving light interaction with biological tissues. The phantom is based on a transparent two-component silicone, which is molded into the desired shape and cured at room temperature. Specific optical properties are obtained by adding scatterers (Al2O3 particles or polystyrene microspheres) and absorbers (dyes or pigments). A method to measure the radiant energy fluence rate in the phantom is described. This method is based on a small isotropic optical detector. A three-dimensional phantom of the bronchial tree is presented. This phantom is used for testing new light distributors designed for photodynamic therapy of the bronchi. The proposed technique allows one to produce a stable three-dimensional phantom with accurately predictable optical properties.


The Warwick Hip Trauma Evaluation One -an abridged protocol for the WHiTE One Study: An embedded randomised trial comparing the X-bolt with slidinghip screw fixation in extracapsular hip fractures.
Fractures of the proximal femur are one of the greatest challenges facing the medical community, constituting a heavy socioeconomic burden worldwide. Controversy exists regarding the optimal treatment for patients with unstable trochanteric proximal femoral fractures. The recognised treatment alternatives are extramedullary fixation usually with a sliding hip screw and intramedullary fixation with a cephalomedullary nail. Current evidence suggests that best results and lowest complication rates occur using a sliding hip screw. Complications in these difficult fractures are relatively common regardless of type of treatment. We believe that a novel device, the X-Bolt dynamic plating system, may offer superior fixation over a sliding hip screw with lower reoperation risk and better function. We therefore propose to investigate the clinical effectiveness of the X-bolt dynamic plating system compared with standard sliding hip screw fixation within the framework of a the larger WHiTE (Warwick Hip Trauma Evaluation) Comprehensive Cohort Study. Cite this article: Bone Joint Res 2013;2:206-9.


Factors associated with physicians' prescriptions for rheumatoid arthritis drugs not filled by patients.
This study estimated the extent and predictors of primary nonadherence (i.e., prescriptions made by physicians but not initiated by patients) to methotrexate and to biologics or tofacitinib in rheumatoid arthritis (RA) patients who were newly prescribed these medications. Using administrative claims linked with electronic health records (EHRs) from multiple healthcare provider organizations in the USA, RA patients who received a new prescription for methotrexate or biologics/tofacitinib were identified from EHRs. Claims data were used to ascertain filling or administration status. A logistic regression model for predicting primary nonadherence was developed and tested in training and test samples. Predictors were selected based on clinical judgment and LASSO logistic regression. A total of 36.8% of patients newly prescribed methotrexate failed to initiate methotrexate within 2 months; 40.6% of patients newly prescribed biologics/tofacitinib failed to initiate within 3 months. Factors associated with methotrexate primary nonadherence included age, race, region, body mass index, count of active drug ingredients, and certain previously diagnosed and treated conditions at baseline. Factors associated with biologics/tofacitinib primary nonadherence included age, insurance, and certain previously treated conditions at baseline. The area under the receiver operating characteristic curve of the logistic regression model estimated in the training sample and applied to the independent test sample was 0.86 and 0.78 for predicting primary nonadherence to methotrexate and to biologics/tofacitinib, respectively. This study confirmed that failure to initiate new prescriptions for methotrexate and biologics/tofacitinib was common in RA patients. It is feasible to predict patients at high risk of primary nonadherence to methotrexate and to biologics/tofacitinib and to target such patients for early interventions to promote adherence.


Rapid and efficient purification of native histidine-tagged protein expressed by recombinant vaccinia virus.
Vaccinia virus has been used as a vector to express foreign genes for the production of functional and posttranslationally modified proteins. A procedure is described here that allows the rapid native purification of vaccinia-expressed proteins fused to an amino-terminal tag of six histidines. Extracts from cells infected with recombinant vaccinia virus are loaded onto Ni2+.nitrilotriacetic acid (Ni2+.NTA)-agarose and histidine-tagged proteins are selectively eluted with imidazole-containing buffers. In the case of the human serum response factor (SRF), a transcription factor involved in the regulation of the c-fos protooncogene, the vaccinia-expressed histidine-tagged SRF (SRF-6His) could be purified solely by this step to greater than 95% purity. SRF-6His was shown to resemble authentic SRF by functional criteria: it was transported to the nucleus, bound specifically the c-fos serum response element, interacted with the p62TCF protein to form a ternary complex, and stimulated in vitro transcription from the serum response element. Thus, the combination of vaccinia virus expression and affinity purification by Ni2+.NTA chromatography promises to be useful for the production of proteins in a functional and posttranslationally modified form.


Molecular basis for interactions of G protein betagamma subunits with effectors.
Both the alpha and betagamma subunits of heterotrimeric guanine nucleotide-binding proteins (G proteins) communicate signals from receptors to effectors. Gbetagamma subunits can regulate a diverse array of effectors, including ion channels and enzymes. Galpha subunits bound to guanine diphosphate (Galpha-GDP) inhibit signal transduction through Gbetagamma subunits, suggesting a common interface on Gbetagamma subunits for Galpha binding and effector interaction. The molecular basis for interaction of Gbetagamma with effectors was characterized by mutational analysis of Gbeta residues that make contact with Galpha-GDP. Analysis of the ability of these mutants to regulate the activity of calcium and potassium channels, adenylyl cyclase 2, phospholipase C-beta2, and beta-adrenergic receptor kinase revealed the Gbeta residues required for activation of each effector and provides evidence for partially overlapping domains on Gbeta for regulation of these effectors. This organization of interaction regions on Gbeta for different effectors and Galpha explains why subunit dissociation is crucial for signal transmission through Gbetagamma subunits.


Measuring sleep quality in older adults: a comparison using subjective and objective methods.
Sleep quality decreases with aging and thus sleep complaints are prevalent in older adults, particularly for those with cognitive impairment and dementia. For older adults, emerging evidence suggests poor sleep quality increases risk of developing cognitive impairment and dementia. Given the aging population-and the impending economic burden associated with increasing numbers of dementia patients-there is pressing need to improve sleep quality among older adults. As such, research efforts have increased focus on investigating the association between age-related sleep changes and cognitive decline in older adults. Sleep quality is a complex construct to evaluate empirically, and yet the Pittsburg Sleep Quality Index (PSQI) is commonly used in studies as their only measure of sleep quality. Furthermore, the PSQI may not be the best sleep quality measure for older adults, due to its reliance on the cognitive capacity to reflect on the past month. Further study is needed to determine the PSQI's validity among older adults. Thus, the current study examined sleep quality for 78 community dwelling adults 55+ to determine the PSQI's predictive validity for objective sleep quality (as measured by actigraphy). We compared two subjective measures of sleep quality-the PSQI and Consensus Sleep Diary (CSD)-with actigraphy (MotionWatch 8©; camntech). Our results suggest perceived sleep quality is quite different from objective reality, at least for adults 55+. Importantly, we show this difference is unrelated to age, gender, education, or cognitive status (assessed using standard screens). Previous studies have shown the PSQI to be a valuable tool for assessing subjective sleep quality; however, our findings indicate for older adults the PSQI should not be used as a substitute for actigraphy, or vice versa. Hence, we conclude best practice is to include both subjective and objective measures when examining sleep quality in older adults (i.e., the PSQI, CSD, and actigraphy).


'First, do no harm': are disability assessments associated with adverse trends in mental health? A longitudinal ecological study.
In England between 2010 and 2013, just over one million recipients of the main out-of-work disability benefit had their eligibility reassessed using a new functional checklist-the Work Capability Assessment. Doctors and disability rights organisations have raised concerns that this has had an adverse effect on the mental health of claimants, but there are no population level studies exploring the health effects of this or similar policies. We used multivariable regression to investigate whether variation in the trend in reassessments in each of 149 local authorities in England was associated with differences in local trends in suicides, self-reported mental health problems and antidepressant prescribing rates, while adjusting for baseline conditions and trends in other factors known to influence mental ill-health. Each additional 10,000 people reassessed in each area was associated with an additional 6 suicides (95% CI 2 to 9), 2700 cases of reported mental health problems (95% CI 548 to 4840), and the prescribing of an additional 7020 antidepressant items (95% CI 3930 to 10100). The reassessment process was associated with the greatest increases in these adverse mental health outcomes in the most deprived areas of the country, widening health inequalities. The programme of reassessing people on disability benefits using the Work Capability Assessment was independently associated with an increase in suicides, self-reported mental health problems and antidepressant prescribing. This policy may have had serious adverse consequences for mental health in England, which could outweigh any benefits that arise from moving people off disability benefits.


TCF7L2 polymorphism, weight loss and proinsulin:insulin ratio in the diabetes prevention program.
TCF7L2 variants have been associated with type 2 diabetes, body mass index (BMI), and deficits in proinsulin processing and insulin secretion. Here we sought to test whether these effects were apparent in high-risk individuals and modify treatment responses. We examined the potential role of the TCF7L2 rs7903146 variant in predicting resistance to weight loss or a lack of improvement of proinsulin processing during 2.5-years of follow-up participants (N = 2,994) from the Diabetes Prevention Program (DPP), a randomized controlled trial designed to prevent or delay diabetes in high-risk adults. We observed no difference in the degree of weight loss by rs7903146 genotypes. However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline (P<0.001), higher baseline proinsulin:insulin ratio (p<0.0001) and increased proinsulin:insulin ratio over a median of 2.5 years of follow-up (P = 0.003). Effects were comparable across treatment arms. The combination of a lack of impact of the TCF7L2 genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin:insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production.