Tibia functionality and Division II female and male collegiate athletes from multiple sports.
Bone strength is developed through a combination of the size and shape (architecture) of a bone as well as the bone's material properties; and therefore, no one outcome variable can measure a positive or negative adaptation in bone. Skeletal robusticity (total area/ bone length) a measure of bones external size varies within the population and is independent of body size, but robusticity has been associated with bone strength. Athletes may have similar variability in robusticity values as the general population and thus have a wide range of bone strengths based on the robustness of their bones. Therefore, the purpose of this study was to determine if an athlete's bone strength and cortical area relative to body size was dependent on robusticity. The second aim was to determine if anthropometry or muscle function measurements were associated with bone robusticity. Bone variables contributing to bone strength were measured in collegiate athletes and a reference group using peripheral quantitative computed tomography (pQCT) at the 50% tibial site. Bone functionality was assessed by plotting bone strength and cortical area vs body size (body weight x tibial length) and robustness (total area/length) vs body size. Bone strength was measured using the polar strength-strain index (SSIp). Based on the residuals from the regression, an athlete's individual functionality was determined, and two groups were formed "weaker for size" (WS) and "stronger for size" (SS). Grip strength, leg extensor strength and lower body power were also measured. Division II athletes exhibited a natural variation in (SSIp) relative to robusticity consistent with previous studies. Bone strength (SSIp) was dependent on the robusticity of the tibia. The bone traits that comprise bone strength (SSIp) were significantly different between the SS and WS groups, yet there were minimal differences in the anthropometric data and muscle function measures between groups. A lower percentage of athletes from ball sports were "weaker for size" (WS group) and a higher percentage of swimmers were in the WS group. A range of strength values based on robusticity occurs in athletes similar to general populations. Bones with lower robusticity (slender) were constructed with less bone tissue and had less strength. The athletes with slender bones were from all sports including track and field and ball sports but the majority were swimmers. Athletes, even after optimal training for their sport, may have weaker bones based on robusticity. Slender bones may therefore be at a higher risk for fracture under extreme loading events but also yield benefits to some athletes (swimmers) due to their lower bone mass.


Novel WWP2 ubiquitin ligase isoforms as potential prognostic markers and molecular targets in cancer.
The WWP2 E3 ubiquitin ligase has previously been shown to regulate TGFβ/Smad signalling activity linked to epithelial-mesenchymal transition (EMT). Whilst inhibitory I-Smad7 was found to be the preferred substrate for full-length WWP2-FL and a WWP2-C isoform, WWP2-FL also formed a stable complex with an N-terminal WWP2 isoform (WWP2-N) in the absence of TGFβ, and rapidly stimulated activating Smad2/3 turnover. Here, using stable knockdown experiments we show that specific depletion of individual WWP2 isoforms impacts differentially on Smad protein levels, and in WWP2-N knockdown cells we unexpectedly find spontaneous expression of the EMT marker vimentin. Re-introduction of WWP2-N into WWP2-N knockout cells also repressed TGFβ-induced vimentin expression. In support of the unique role for WWP2-N in regulating TGFβ/Smad functional activity, we then show that a novel V717M-WWP2 mutant in the MZ7-mel melanoma cell line forms a stable complex with the WWP2-N isoform and promotes EMT by stabilizing Smad3 protein levels. Finally, we report the first analysis of WWP2 expression in cancer cDNA panel arrays using WWP2 isoform-specific probes and identify unique patterns of WWP2 isoform abundance associated with early/advanced disease stages. WWP2-N is significantly downregulated in stage IIIC melanoma and up-regulated in stage II/III prostate cancer, and we also find isolated examples of WWP2-FL and WWP2-C overexpression in early-stage breast cancer. Together, these data suggest that individual WWP2 isoforms, and particularly WWP2-N, could play central roles in tumourigenesis linked to aberrant TGFβ-dependent signalling function, and also have potential as both prognostic markers and molecular therapeutic targets.


Utility of supplemental screening with breast ultrasound in asymptomatic women with dense breast tissue who are not at high risk for breast cancer.
To assess the results of an initial round of supplemental screening with hand-held bilateral breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue who are not at high risk for breast cancer. A retrospective, Health Insurance Portability and Accountability Act compliant, Institutional Research Board approved study was performed at a single academic tertiary breast center. Informed consent was waived. A systematic review of the breast imaging center database was conducted to identify and retrieve data for all asymptomatic women, who were found to have heterogeneously dense or extremely dense breast tissue on screening bilateral mammograms performed from July 1, 2010 through June 30, 2012 and who received a mammographic final assessment American College of Radiology's (ACR) Breast Imaging Reporting and Data System (BI-RADS) category 1 or BI-RADS category 2. Hand-held screening ultrasound was performed initially by a technologist followed by a radiologist. Chi-square and t-test were used and statistical significance was considered at P < 0.05. A total of 1210 women were identified. Of these, 394 underwent the offered supplemental screening ultrasound. BI-RADS category 1 or 2 was assigned to 323 women (81.9%). BI-RADS category 3 was assigned to 50 women (12.9%). A total of 26 biopsies/aspirations were recommended and performed in 26 women (6.6%). The most common finding for which biopsy was recommended was a solid mass (88.5%) with an average size of 0.9 cm (0.5-1.7 cm). Most frequent pathology result was fibroadenoma (60.8%). No carcinoma was found. Our data support the reported occurrence of a relatively high number of false positives at supplemental screening with breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue, who are not at a high risk of developing breast cancer, and suggests that caution is necessary in establishing wide implementation of this type of supplemental screening for all women with dense breast tissue without considering other risk factors for breast cancer.


The perspective of siblings of children with chronic illness: a literature review.
This review gives an overview about the existing research concerning siblings' perspective within the familial experiences of childhood chronic illness. Besides attaining a conception of their world, it was intended to identify the unacknowledged issues concerning siblings' experience. Four databases were systematically searched. The analysis was concentrated on nine literature reviews. As a result, we identified a map of dimensions of experiences-well-elaborated as well as fragmentary. Many of the studies were conducted by a proxy and not from the sole siblings' perspective. Further research should concentrate on the sole siblings' perspective, in order to make siblings' voices audible.


Whole chromosome aneuploidy in the brain of Bub1bH/H and Ercc1-/Δ7 mice.
High levels of aneuploidy have been observed in disease-free tissues, including post-mitotic tissues such as the brain. Using a quantitative interphase-fluorescence in situ hybridization approach, we previously reported a chromosome-specific, age-related increase in aneuploidy in the mouse cerebral cortex. Increased aneuploidy has been associated with defects in DNA repair and the spindle assembly checkpoint, which in turn can lead to premature aging. Here, we quantified the frequency of aneuploidy of three autosomes in the cerebral cortex and cerebellum of adult and developing brain of Bub1b(H/H) mice, which have a faulty mitotic checkpoint, and Ercc1(-/Δ7) mice, defective in nucleotide excision repair and inter-strand cross-link repair. Surprisingly, the level of aneuploidy in the brain of these murine models of accelerated aging remains as low as in the young adult brains from control animals, i.e. <1% in the cerebral cortex and ∼0.1% in the cerebellum. Therefore, based on aneuploidy, these adult mice with reduced life span and accelerated progeroid features are indistinguishable from age-matched, normal controls. Yet, during embryonic development, we found that Bub1b(H/H), but not Ercc1(-/Δ7) mice, have a significantly higher frequency of aneuploid nuclei relative to wild-type controls in the cerebral cortex, reaching a frequency as high as 40.3% for each chromosome tested. Aneuploid cells in these mutant mice are likely eliminated early in development through apoptosis and/or immune-mediated clearance mechanisms, which would explain the low levels of aneuploidy during adulthood in the cerebral cortex of Bub1b(H/H) mice. These results shed light on the mechanisms of removal of aneuploidy cells in vivo.


Wheat Panache: A pangenome graph database representing presence-absence variation across sixteen bread wheat genomes.
Bread wheat (Triticum aestivum L.) is one of humanity's most important staple crops, characterized by a large and complex genome with a high level of gene presence-absence variation (PAV) between cultivars, hampering genomic approaches for crop improvement. With the growing global population and the increasing impact of climate change on crop yield, there is an urgent need to apply genomic approaches to accelerate wheat breeding. With recent advances in DNA sequencing technology, a growing number of high-quality reference genomes are becoming available, reflecting the genetic content of a diverse range of cultivars. However, information on the presence or absence of genomic regions has been hard to visualize and interrogate because of the size of these genomes and the lack of suitable bioinformatics tools. To address this limitation, we have produced a wheat pangenome graph maintained within an online database to facilitate interrogation and comparison of wheat cultivar genomes. The database allows users to visualize regions of the pangenome to assess PAV between bread wheat genomes.


Vaccination and 30-Day Mortality Risk in Children, Adolescents, and Young Adults.
This study evaluates the potential association of vaccination and death in the Vaccine Safety Datalink (VSD). The study cohort included individuals ages 9 to 26 years with deaths between January 1, 2005, and December 31, 2011. We implemented a case-centered method to estimate a relative risk (RR) for death in days 0 to 30 after vaccination.Deaths due to external causes (accidents, homicides, and suicides) were excluded from the primary analysis. In a secondary analysis, we included all deaths regardless of cause. A team of physicians reviewed available medical records and coroner's reports to confirm cause of death and assess the causal relationship between death and vaccination. Of the 1100 deaths identified during the study period, 76 (7%) occurred 0 to 30 days after vaccination. The relative risks for deaths after any vaccination and influenza vaccination were significantly lower for deaths due to nonexternal causes (RR 0.57, 95% confidence interval [CI] 0.38-0.83, and RR 0.44, 95% CI 0.24-0.80, respectively) and deaths due to all causes (RR 0.72, 95% CI 0.56-0.91, and RR 0.44, 95% CI 0.28-0.65). No other individual vaccines were significantly associated with death. Among deaths reviewed, 1 cause of death was unknown, 25 deaths were due to nonexternal causes, and 34 deaths were due to external causes. The causality assessment found no evidence of a causal association between vaccination and death. Risk of death was not increased during the 30 days after vaccination, and no deaths were found to be causally associated with vaccination.


Preparing the community health nursing workforce: internal and external enablers and challenges influencing undergraduate nursing programs in Canada.
The Canadian Schools of Nursing (CASN) task force on public health was mandated to facilitate Schools of Nursing to provide students with the foundation required to meet the Canadian Community Health Nursing Standards of Practice. This paper reports on an environmental scan that explored barriers and enablers influencing the integration of community health nursing content in baccalaureate education in Canada. Data was collected over three phases including: 1) a pan-Canadian survey of nursing schools, 2) completion of open-ended workbook questions by educators, policy makers, administrators, and community health nursing managers attending a pan-Canadian symposium on community health nursing, and 3) recorded notes from the symposium. The response rate for the survey was 72.5% (n = 61 schools) and approximately 125 stakeholders participated in symposium activities. Internal and external enablers and challenges as well as recommendations for practice and education are presented.


What is the value of adding Medicare data in estimating VA hospital readmission rates?
To determine the effects of including diagnostic and utilization data from a secondary payer on readmission rates and hospital profiles. Veterans Health Administration (VA) and Medicare inpatient and outpatient administrative data for veterans discharged from 153 VA hospitals during FY 2008-2010 with a principal diagnosis of acute myocardial infarction, heart failure, or pneumonia. We estimated hospital-level risk-standardized readmission rates derived using VA data only. We then used data from both VA and Medicare to reestimate readmission rates and compared hospital profiles using two methods: Hospital Compare and the CMS implementation of the Hospital Readmissions Reduction Program (HRRP). Retrospective data analysis using VA hospital discharge and outpatient data matched with Medicare fee-for-service claims by scrambled Social Security numbers. Less than 2 percent of hospitals in any cohort were classified discordantly by the Hospital Compare method when using VA-only compared with VA/Medicare data. In contrast, using the HRRP method, 13 percent of hospitals had differences in whether they were flagged as having excessive readmission rates in at least one cohort. Inclusion of secondary payer data may cause changes in hospital profiles, depending on the methodology used. An assessment of readmission rates should include, to the extent possible, all available information about patients' utilization of care.


Impact of the work environment on glycemic control and adaptation to diabetes.
To evaluate quantitatively whether the work environments of adults with diabetes relate to the adequacy of metabolic control and/or to the individual's adaptation to diabetes and to explore qualitatively the interactions between an individual's life at work and ways of coping with diabetes. A total of 129 insulin-requiring adults who were employed outside of the home were assessed on a single occasion. They completed two work system measures (The Work Environment Scale and The Work Apgar Scale) and two quality-of-life measures (The Diabetes Quality of Life Scale and The Appraisal of Diabetes Scale). Subjects also participated in a semi-structured interview concerning the interaction of work and diabetes. Glycemic control was assessed by using HbAlc results. Demographic data (age, sex, diabetes type, duration of diabetes, number of diabetes-related medical complications) were gathered from the charts. Concerning glycemic control, neither of the work system measures was a significant predictor of HbAlc. Concerning psychosocial adaptation, supervisor support was found to be a significant predictor of positive appraisal and diabetes-related satisfaction. Involvement and coworker cohesion also predicted aspects of diabetes-related quality of life. Interview themes showed that for a minority (18%), diabetes affected choice of work and that for a majority (60%), diabetes affected relationships at work and raised financial/job concerns (49%). Most adjust their diet, blood glucose testing, and exercise regimen through work-related modifications. For insulin-treated adults with diabetes, work system variables do not directly relate to glycemic control, but they do relate to psychosocial adaptation. Future work should examine further the specific aspects of the workplace that might affect adaptation, with the goal being to develop worksite interventions that target not only the employee with diabetes but also their supervisors and coworkers.


An addressable packing parameter approach for reversibly tuning the assembly of oligo(aniline)-based supra-amphiphiles.
We present a newly developed approach to non-covalently address the packing parameter of an electroactive amphiphile. The pH-responsive reversible switching of a tetra(aniline)-based cationic amphiphile, TANI-pentyl trimethylammonium bromide (TANI-PTAB), between self-assembled vesicles and nanowires by acid/base chemistry in aqueous solution is used to exemplify this approach. Trifluoroacetic acid (TFA) was selected as a prototypical acid to form emeraldine salt (ES) state (TANI(TFA)2-PTAB) vesicles for this new class of small-molecule supramolecular amphiphiles. UV-vis-NIR spectroscopy, transmission electron microscopy (TEM), tapping-mode atomic force microscopy (AFM), and fluorescence spectroscopy were used to investigate the reversible structural transformation from vesicles to nanowires. We show that utilising different protonic acid-dopants for TANI-PTAB can regulate the packing parameter, and thus the final self-assembled structures, in a predictable fashion. We envisage potential application of this concept as smart and switchable delivery systems.


Impact of nutrients on circadian rhythmicity.
The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock.


A Comparative Structure/Function Analysis of Two Type IV Pilin DNA Receptors Defines a Novel Mode of DNA Binding.
DNA transformation is a widespread process allowing bacteria to capture free DNA by using filamentous nano-machines composed of type IV pilins. These proteins can act as DNA receptors as demonstrated by the finding that Neisseria meningitidis ComP minor pilin has intrinsic DNA-binding ability. ComP binds DNA better when it contains the DNA-uptake sequence (DUS) motif abundant in this species genome, playing a role in its trademark ability to selectively take up its own DNA. Here, we report high-resolution structures for meningococcal ComP and Neisseria subflava ComPsub, which recognize different DUS motifs. We show that they are structurally identical type IV pilins that pack readily into filament models and display a unique DD region delimited by two disulfide bonds. Functional analysis of ComPsub defines a new mode of DNA binding involving the DD region, adapted for exported DNA receptors.


Implementing person-centred key performance indicators to strengthen leadership in community nursing: A feasibility study.
To explore the utility and feasibility of implementing eight person-centred nursing key performance indicators in supporting community nurses to lead the development of person-centred practice. Policy advocates person-centred health care, but few quality indicators exist that explicitly focus on evaluating person-centred practice in community nursing. Current quality measurement frameworks in the community focus on incidences of poor or missed opportunities for care, with few mechanisms to measure how clients perceive the care they receive. An evaluation approach derived from work of the Medical Research Council was used, and the study was underpinned by the Person-centred Practice Framework. Participatory methods were used, consistent with person-centred research. Data were thematically analysed, revealing five themes: giving voice to experience; talking the language of person-centredness; leading for cultural change; proud to be a nurse; and facilitating engagement. The findings suggest that implementing the eight person-centred nursing key performance indicators (KPIs) and the measurement framework is feasible and offers a means of evidencing person-centredness in community nursing. Person-centred KPI data, used alongside existing quality indicators, will enable nurse managers to evidence a high standard of care delivery and assist in the development of person-centred practice.


[Sexually transmitted infections (STI)].
Towards the end of the last century some sexually transmitted infections (STI), which had been held to be almost extinct, have seen an unexpected resurgence. They mainly present as urethritis, genital ulcers or genital warts and must always be diagnosed and treated so as to prevent further transmission. The main causes of urethritis are gonorrhea and chlamydia, the latter can also cause only minor symptoms. The pathogen should always be diagnosed with direct microscopy of a urethral smear as well as culture or PCR. Antibiotic treatment is usually straightforward. Genital ulcer disease can be caused by a wide spectrum of bacteria and viruses as well as non-infectious causes. It is significant as it can facilitate the transmission of HIV. The most frequent cause is herpes simplex virus which usually presents itself with painful ulcers and a recurrent course. Syphilis occurs in different clinical stages. The first stage is usually a painless ulcer, it can be difficult to diagnose and is often missed. In the second stage, characterised by a rash and a variety of classical symptoms such as condylomata lata, the diagnosis can be made with various serologic tests. Long-acting penicillin remains the treatment of choice. Genital warts are a consequence of HPV infection and can usually easily be diagnosed based on the clinical picture. Some high-risk HPV types can lead to malignant transformation, especially in immunocompromised patients. Besides different destructive therapeutic modalities, some effective treatments can be applied locally by patients themselves.


LUCAS: a theoretically informed instrument to assess clinical communication in objective structured clinical examinations.
We reviewed papers describing the development of instruments for assessing clinical communication in undergraduate medical students. The instruments had important limitations: most lacked a theoretical basis, and their psychometric properties were often poor or inadequately investigated and reported. We therefore describe the development of a new instrument, the Liverpool Undergraduate Communication Assessment Scale (LUCAS), which is intended to overcome some of these limitations. We designed LUCAS to reflect the theory that communication is contextually dependent, inherently creative and cannot be fully described within a conceptual framework of discrete skills. We investigated the preliminary psychometric properties of LUCAS in two studies. To assess construct and external validity, we examined correlations between examiners' LUCAS ratings and simulated patients' ratings of their relationships with students in Year 1 formative (n = 384) and summative (n = 347) objective structured clinical examination (OSCE) samples. Item-total correlations and item difficulty analyses were also performed. The dimensionality of LUCAS was examined by confirmatory factor analysis. We also assessed inter-rater reliability; four raters used LUCAS to rate 40 video-recorded encounters between Year 1 students and simulated patients. Simulated patient ratings correlated with examiner ratings across two OSCE datasets. All items correlated with the total score. Item difficulty showed LUCAS was able to discriminate between student performances. LUCAS had a two-dimensional factor structure: we labelled Factor 1 creative communication and Factor 2 procedural communication. The intraclass correlation coefficient was 0.73 (95% confidence interval 0.54-0.85), indicating acceptable reliability. We designed LUCAS to move the primary focus of examiners away from an assessment of students' enactment of behavioural skills to a judgement of how well students' communication met patients' needs. LUCAS demonstrated adequate reliability and validity. The instrument can be administered easily and efficiently and is therefore suitable for use in medical school examinations.


Durably Antibacterial and Bacterially Antiadhesive Cotton Fabrics Coated by Cationic Fluorinated Polymers.
Considerable attention has been devoted to producing antibacterial fabrics due to their very wide applications in medicine, hygiene, hospital, etc. However, the poor antibacterial durability and bad bacterial antiadhesion capacity of most existing antibacterial fabrics limit their applications. In this work, a series of antibacterial and polymeric quaternary ammonium monomers with different alkyl chain length were successfully synthesized to copolymerize with fluorine-containing and other acrylic monomers to generate cationic fluorinated polymer emulsions and durably antibacterial and bacterially antiadhesive cotton fabrics. The relation between antibacterial constituent and its antibacterial activity was investigated. The study indicated that the alkyl chain length and contents of the antibacterial monomers, as well as the add-on percentage of polymer greatly influenced the antibacterial activities of the fabrics. In addition, it was found that incorporation of fluorine component into the polymer greatly enhanced the antibacterial activity and bacterial antiadhesion of the treated fabrics due to the low surface energy induced hydrophobicity. Finally, antibacterial and antiadhesive models of action of the obtained fabrics were illustrated.


Mimicking the Martian Hydrological Cycle: A Set-Up to Introduce Liquid Water in Vacuum.
Liquid water is well known as the life ingredient as a solvent. However, so far, it has only been found in liquid state on this planetary surface. The aim of this experiment and technological development was to test if a moss sample is capable of surviving in Martian conditions. We built a system that simulates the environmental conditions of the red planet including its hydrological cycle. This laboratory facility enables us to control the water cycle in its three phases through temperature, relative humidity, hydration, and pressure with a system that injects water droplets into a vacuum chamber. We successfully simulated the daytime and nighttime of Mars by recreating water condensation and created a layer of superficial ice that protects the sample against external radiation and minimizes the loss of humidity due to evaporation to maintain a moss sample in survival conditions in this extreme environment. We performed the simulations with the design and development of different tools that recreate Martian weather in the MARTE simulation chamber.


Low-loss terahertz waveguide Bragg grating using a two-wire waveguide and a paper grating.
We propose a low-loss terahertz waveguide Bragg grating (TWBG) fabricated using a plasmonic two-wire waveguide and a micromachined paper grating for potential applications in terahertz (THz) communications. Two TWBGs were fabricated with different periods and lengths. Transmission spectra of these TWBGs show 16 dB loss and 14 dB loss in the middle of their respective stop bands at 0.637 and 0.369 THz, with Q factors of 142 and 105, respectively. Insertion loss of 1-4 dB in the whole 0.1-0.7 THz region was also measured. Finally, TWBG modal dispersion relations, modal loss, and field distributions were studied numerically, and low-loss, high-coupling-efficiency operation of TWBGs was confirmed.


Examining the Protein Interactome and Subcellular Localization of RNase J2 Complexes in Streptococcus mutans.
Regulated RNA turnover is vital for the control of gene expression in all cellular life. In Escherichia coli, this process is largely controlled by a stable degradosome complex containing RNase E and a variety of additional enzymes. In the Firmicutes phylum, species lack RNase E and often encode the paralogous enzymes RNase J1 and RNase J2. Unlike RNase J1, surprisingly little is known about the regulatory function and protein interactions of RNase J2, despite being a central pleiotropic regulator for the streptococci and other closely related organisms. Using crosslink coimmunoprecipitation in Streptococcus mutans, we have identified the major proteins found within RNase J2 protein complexes located in the cytoplasm and at the cell membrane. In both subcellular fractions, RNase J2 exhibited the most robust interactions with RNase J1, while additional transient and/or weaker "degradosome-like" interactions were also detected. In addition, RNase J2 exhibits multiple novel interactions that have not been previously reported for any RNase J proteins, some of which were highly biased for either the cytoplasmic or membrane fractions. We also determined that the RNase J2 C-terminal domain (CTD) encodes a structure that is likely conserved among RNase J enzymes and may have an analogous function to the C-terminal portion of RNase E. While we did observe a number of parallels between the RNase J2 interactome and the E. coli degradosome paradigm, our results suggest that S. mutans degradosomes are either unlikely to exist or are quite distinct from those of E. coli.


Growth patterns of craniopharyngiomas: clinical analysis of 226 patients.
OBJECT Craniopharyngiomas (CPs) are rare epithelial tumors that are often associated with an enigmatic and unpredictable growth pattern. Understanding the growth patterns of these tumors has a direct impact on surgical planning and may enhance the safety of radical tumor removal. The aim of this study was to analyze the growth patterns and surgical treatment of CPs with a focus on the involvement of the hypothalamopituitary axis and the relationship of the tumor to the arachnoid membrane and surrounding structures. METHODS Clinical data from 226 consecutive patients with primary CP were retrospectively reviewed. Tumor location and the relationship of the tumor to the third ventricle floor and the pituitary stalk were evaluated using preoperative MRI and intraoperative findings. A topographic classification scheme was proposed based on the site of tumor origin and tumor development. The clinical relevance of this classification on patient presentation and outcomes was also analyzed. RESULTS The growth of CPs can be broadly divided into 3 groups based on the site of tumor origin and on tumor-meningeal relationships: Group I, infrasellar/infradiaphragmatic CPs (Id-CPs), which mainly occurred in children; Group II, suprasellar subarachnoid extraventricular CPs (Sa-CPs), which were mainly observed in adults and rarely occurred in children; and Group III, suprasellar subpial ventricular CPs (Sp-CPs), which commonly occurred in both adults and children. Tumors in each group may develop complex growth patterns during vertical expansion along the pituitary stalk. Tumor growth patterns were closely related to both clinical presentation and outcomes. Patients with Sp-CPs had more prevalent weight gain than patients with Id-CPs or Sa-CPs; the rates of significant weight gain were 41.7% for children and 16.7% for adults with Sp-CPs, 2.2% and 7.1% for those with Id-CPs, and 12.5% and 2.6% for those with Sa-CPs (p < 0.001). Moreover, patients with Sp-CPs had increased hypothalamic dysfunction after radical removal; 39% of patients with Sp-CPs, 14.5% with Id-CPs, and 17.4% with Sa-CPs had high-grade hypothalamic dysfunction in the first 2 postoperative years (p < 0.001). CONCLUSIONS The classification of CPs based on growth pattern may elucidate the best course of treatment for this formidable tumor. More tailored, individualized surgical strategies based on tumor growth patterns are mandatory to provide long-term tumor control and to minimize damage to hypothalamic structures. Differences in the distribution of growth patterns between children and adults imply that hierarchical comparison is necessary when investigating outcomes and survival across treatment paradigms in patients with CP.


Ang-(1-7) is an endogenous β-arrestin-biased agonist of the AT1 receptor with protective action in cardiac hypertrophy.
The renin-angiotensin system (RAS) plays a key role in the control of vasoconstriction as well as sodium and fluid retention mediated mainly by angiotensin (Ang) II acting at the AT1 receptor (AT1R). Ang-(1-7) is another RAS peptide, identified as the endogenous ligand of the Mas receptor and known to counterbalance many of the deleterious effects of AngII. AT1R signaling triggered by β-arrestin-biased agonists has been associated to cardioprotection. Because position 8 in AngII is important for G protein activation, we hypothesized that Ang-(1-7) could be an endogenous β-arrestin-biased agonist of the AT1R. Here we show that Ang-(1-7) binds to the AT1R without activating Gq, but triggering β-arrestins 1 and 2 recruitment and activation. Using an in vivo model of cardiac hypertrophy, we show that Ang-(1-7) significantly attenuates heart hypertrophy by reducing both heart weight and ventricular wall thickness and the increased end-diastolic pressure. Whereas neither the single blockade of AT1 or Mas receptors with their respective antagonists prevented the cardioprotective action of Ang1-7, combination of the two antagonists partially impaired the effect of Ang-(1-7). Taken together, these data indicate that Ang-(1-7) mediates at least part of its cardioprotective effects by acting as an endogenous β-arrestin-biased agonist at the AT1R.


The rapid in vivo evolution of Pseudomonas aeruginosa in ventilator-associated pneumonia patients leads to attenuated virulence.
Pseudomonas aeruginosa is an opportunistic pathogen that causes severe airway infections in humans. These infections are usually difficult to treat and associated with high mortality rates. While colonizing the human airways, P. aeruginosa could accumulate genetic mutations that often lead to its better adaptability to the host environment. Understanding these evolutionary traits may provide important clues for the development of effective therapies to treat P. aeruginosa infections. In this study, 25 P. aeruginosa isolates were longitudinally sampled from the airways of four ventilator-associated pneumonia (VAP) patients. Pacbio and Illumina sequencing were used to analyse the in vivo evolutionary trajectories of these isolates. Our analysis showed that positive selection dominantly shaped P. aeruginosa genomes during VAP infections and led to three convergent evolution events, including loss-of-function mutations of lasR and mpl, and a pyoverdine-deficient phenotype. Specifically, lasR encodes one of the major transcriptional regulators in quorum sensing, whereas mpl encodes an enzyme responsible for recycling cell wall peptidoglycan. We also found that P. aeruginosa isolated at late stages of VAP infections produce less elastase and are less virulent in vivo than their earlier isolated counterparts, suggesting the short-term in vivo evolution of P. aeruginosa leads to attenuated virulence.


Work and disability status of persons with fibromyalgia.
To determine the prevalence and determinants of self-reported work disability in persons with fibromyalgia (FM). A longitudinal, multicenter survey of 1604 patients with FM from 6 centers with diverse socioeconomic characteristics was begun in 1988. Assessments were by self-report questionnaire and telephone contact, and included work and disability events that occurred before and after 1988. Comparative analyses were performed on the entire data set and, separately, on the Wichita data set. More than 16% of patients reported receiving US Social Security disability (SSD) payments (highest center rate 35.7%; lowest center rate 6.3%) compared to 2.2% of the US population (US Social Security Administration data) and 28.9% of patients with rheumatoid arthritis seen at the Wichita outpatient rheumatology clinic. Overall, 26.5% reported receiving at least one form of disability payment when SSD and other sources of disability payments were considered. In Wichita, less than 25% of SSD awards were made specifically for FM, but after 1988 that figure increased to 46.4%. Work disability was greatest at the San Antonio and Los Angeles centers. Multivariate predictors (correlates) included pain, Health Assessment Questionnaire disability, and unmarried status. In addition, more than 70% of patients reporting being disabled did receive disability payments. On the other hand, 64% reported being able to work all or most days, and more than 70% were employed or were homemakers. Although most patients (64%) report being able to work, we found high rates of self-reported work disability awards among persons with FM followed in 6 rheumatology centers. But we also found great variability among centers as to awards and as to self-reported work ability. Center differences in work disability might reflect clinic referral patterns, physician beliefs, or socioeconomic status.


In vitro and in vivo nonlinear optical imaging of silicon nanowires.
Understanding of cellular interactions with a nanostructure requires tracking directly the nanostructure. Current investigation is challenged by the lack of a strong, intrinsic signal from the nanostructure. We demonstrate intensive four-wave mixing and third-harmonic generation signals from dimension-controllable silicon nanowires as small as 5 nm in diameter. The nonlinear optical signals observed from the nanowires are highly photostable with an intensity level of 10 times larger than that observed from silver nanoparticles of comparable sizes. This intrinsic optical signal enabled intravital imaging of nanowires circulating in the peripheral blood of a mouse and mapping of nanowires accumulated in the liver and spleen, opening up further opportunities to investigate in vivo cellular response to nanomaterials as a function of size, aspect ratio, and surface chemistry.


A factor model to analyze heterogeneity in gene expression.
Microarray technology allows the simultaneous analysis of thousands of genes within a single experiment. Significance analyses of transcriptomic data ignore the gene dependence structure. This leads to correlation among test statistics which affects a strong control of the false discovery proportion. A recent method called FAMT allows capturing the gene dependence into factors in order to improve high-dimensional multiple testing procedures. In the subsequent analyses aiming at a functional characterization of the differentially expressed genes, our study shows how these factors can be used both to identify the components of expression heterogeneity and to give more insight into the underlying biological processes. The use of factors to characterize simple patterns of heterogeneity is first demonstrated on illustrative gene expression data sets. An expression data set primarily generated to map QTL for fatness in chickens is then analyzed. Contrarily to the analysis based on the raw data, a relevant functional information about a QTL region is revealed by factor-adjustment of the gene expressions. Additionally, the interpretation of the independent factors regarding known information about both experimental design and genes shows that some factors may have different and complex origins. As biological information and technological biases are identified in what was before simply considered as statistical noise, analyzing heterogeneity in gene expression yields a new point of view on transcriptomic data.


Randomized effectiveness trial of a brief course of acupuncture for posttraumatic stress disorder.
Initial posttraumatic stress disorder (PTSD) care is often delayed and many with PTSD go untreated. Acupuncture appears to be a safe, potentially nonstigmatizing treatment that reduces symptoms of anxiety, depression, and chronic pain, but little is known about its effect on PTSD. Fifty-five service members meeting research diagnostic criteria for PTSD were randomized to usual PTSD care (UPC) plus eight 60-minute sessions of acupuncture conducted twice weekly or to UPC alone. Outcomes were assessed at baseline and 4, 8, and 12 weeks postrandomization. The primary study outcomes were difference in PTSD symptom improvement on the PTSD Checklist (PCL) and the Clinician-administered PTSD Scale (CAPS) from baseline to 12-week follow-up between the 2 treatment groups. Secondary outcomes were depression, pain severity, and mental and physical health functioning. Mixed model regression and t test analyses were applied to the data. Mean improvement in PTSD severity was significantly greater among those receiving acupuncture than in those receiving UPC (PCLΔ=19.8±13.3 vs. 9.7±12.9, P<0.001; CAPSΔ=35.0±20.26 vs. 10.9±20.8, P<0.0001). Acupuncture was also associated with significantly greater improvements in depression, pain, and physical and mental health functioning. Pre-post effect-sizes for these outcomes were large and robust. Acupuncture was effective for reducing PTSD symptoms. Limitations included small sample size and inability to parse specific treatment mechanisms. Larger multisite trials with longer follow-up, comparisons to standard PTSD treatments, and assessments of treatment acceptability are needed. Acupuncture is a novel therapeutic option that may help to improve population reach of PTSD treatment.


Within-family obesity associations: evaluation of parent, child, and sibling relationships.
How parent and sibling obesity status comparatively shape a child's obesity is unknown. To investigate how the obesity status of different children within the same family is related to a parent or sibling's obesity. A national sample of adults in 10,244 American households was surveyed during 2011; data were analyzed in 2012-2013. Of these households, 1,948 adults had one or two children; provided sociodemographic information; and reported on adult and child height and weight, physical activity, and food environment. Logistic regression models were estimated in which the outcome of interest was child obesity status, with parent and sibling obesity as key predictors, adjusting for a range of both adult and child social and demographic confounders. In one-child households, it was 2.2 times more likely (SE=0.5) that the child would be obese if a parent was obese. In households with two children, having an obese younger sibling was more strongly associated with elder-child obesity (OR=5.4, SE=1.9) than parent's obesity status (OR=2.3, SE=0.8). Having an obese elder sibling was associated with younger-child obesity (OR=5.6, SE=1.9), and parent obesity status was no longer significant. Within-family sibling obesity was more strongly patterned between siblings of the same gender than between different genders, and child physical activity was significantly associated with obesity status. Considering offspring composition and sibling gender may be beneficial in childhood obesity prevention and intervention.


Identification of a DNA methylation marker that detects the presence of lymph node metastases of gastric cancers.
The accurate detection of the presence of lymph node metastases (LNM) of gastric cancers (GCs) is useful for the implementation of necessary and sufficient treatment, but current methods of detection are unsatisfactory. In the present study, we focused on DNA methylation markers since they have several advantages, including biological and chemical stability and informativeness even in the presence of contaminating cells. Using three metastatic lymph nodes and three primary GCs without LNM, methylation bead array analyses were performed, which enabled the interrogation of 485,577 CpG sites. A total of 31 CpG sites that were hypermethylated in the metastatic lymph nodes, compared with the GCs without LNM, were isolated. Using primary GCs with and without LNM (28 GCs with LNM and 10 without), their methylation levels were measured using quantitative PCR following treatment with sodium bisulfite or a methylation-sensitive restriction enzyme. Of the genomic regions around the 31 CpG sites, 10 regions demonstrated higher methylation levels in the GCs with LNM compared with the GCs without LNM (P<0.05). Finally, the hypermethylation of the 10 regions was validated using another set of samples (129 GCs with LNM and 20 without). Hypermethylation of the region around the cg06436185 CpG site predicted the presence of LNM at a sensitivity of 43% and specificity of 85%. Additionally, the hypermethylation of the region was associated with a poor survival rate among GC patients with LNM. The results of the present study indicated that the methylation status of the region was a promising candidate marker to detect the presence of LNM of GCs and may reflect the malignant potential of GCs.


Factors associated with visual acuity outcomes after vitrectomy for diabetic macular edema: diabetic retinopathy clinical research network.
To evaluate factors ¶associated with favorable outcomes after vitrectomy for diabetic macular edema. Data were collected prospectively on 241 eyes undergoing vitrectomy for diabetic macular edema. Multivariate models were used to evaluate associations of 20 preoperative and intraoperative factors with 6-month outcomes of visual acuity and retinal thickness. Median central subfield thickness decreased from 412 μm to 278 μm at 6 months, but median visual acuity remained unchanged (20/80, Snellen equivalent). Greater visual acuity improvement occurred in eyes with worse baseline acuity (P < 0.001) and in eyes in which an epiretinal membrane was removed (P = 0.006). Greater reduction in central subfield thickness occurred with worse baseline visual acuity (P < 0.001), greater preoperative retinal thickness (P = 0.001), removal of internal limiting membrane (P = 0.003), and optical coherence tomography evidence of vitreoretinal abnormalities (P = 0.006). No associations with clinician's preoperative assessments of the posterior vitreous were identified. These results suggest that the removal of epiretinal membranes may favorably affect visual outcome after vitrectomy. Preoperative presence of vitreoretinal abnormalities appeared to be associated with somewhat greater reductions in retinal thickness but not with visual acuity outcome. These results may be useful for future studies evaluating vitrectomy for diabetic macular edema.


An Elevated Glycemic Gap is Associated with Adverse Outcomes in Diabetic Patients with Acute Myocardial Infarction.
Acute hyperglycemia is a frequent finding in patients presenting to the emergency department (ED) with acute myocardial infarction (AMI). The prognostic role of hyperglycemia in diabetic patients with AMI remains controversial. We retrospectively reviewed patients' medical records to obtain demographic data, clinical presentation, major adverse cardiac events (MACEs), several clinical scores and laboratory data, including the plasma glucose level at initial presentation and HbA1c levels. The glycemic gap, which represents changes in serum glucose levels during the index event, was calculated from the glucose level upon ED admission minus the HbA1c-derived average glucose (ADAG). We enrolled 331 patients after the review of medical records. An elevated glycemic gap between admission serum glucose levels and ADAG were associated with an increased risk of mortality in patients. The glycemic gap showed superior discriminative power regarding the development of MACEs when compared with the admission glucose level. The calculation of the glycemic gap may increase the discriminative powers of established clinical scoring systems in diabetic patients presenting to the ED with AMI. In conclusion, the glycemic gap could be used as an adjunct parameter to assess the severity and prognosis of diabetic patients presenting with AMI. However, the usefulness of the glycemic gap should be further explored in prospective longitudinal studies.


A case of 'fat-free' pleomorphic lipoma occurring in the upper back and axilla simultaneously.
Pleomorphic lipoma is a rare neoplasm that predominantly occurs in the dermis or subcutis of the posterior neck, upper back, and shoulders. Although pleomorphic lipoma is a benign tumor, it may contain atypical cells. As a variant of spindle cell lipoma, pleomorphic lipoma clinically presents as a slow-growing and well-circumscribed subcutaneous mass. Rarely, some patients have multiple lesions. Histologically, pleomorphic lipoma is composed of mature fat, bland spindle-shaped mesenchymal cells, and coarse 'rope-like' collagen bands. In addition, lipoma contains multinucleated floret-like giant cells. Although spindle cell lipoma/pleomorphic lipoma with little fat was seen in the original series described by Enzinger and Harvey, cases with little to no fat remain diagnostically challenging. Herein, we report a case of 'fat-free' pleomorphic lipoma occurring in the upper back and axilla simultaneously. Although the lipoma was typically composed of bland spindle-shaped cells, rope-like collagen, scattered floret-like giant cells, and striking stromal myxoid change in the background, mature fat was absent. Immunohistochemical analyses showed positive staining for CD34, vimentin, and Bcl-2, and negative staining for S100, confirming the diagnosis of pleomorphic lipoma.


What is the most interesting part of the brain?
Creative ideas and rigorous analysis are the hallmarks of much impactful science. However, there is an oft-aired suspicion in the neuroscience community that some scientists start with an advantage, simply because of the brain region or behaviour they study. We tested this unstated hypothesis by regressing the journal impact factor against both the pattern of brain activity and the experimental keywords across thousands of brain imaging studies. We found the results to be illuminating.


Impact of pulmonary arterial endothelial cells on duroquinone redox status.
The study objective was to use pulmonary arterial endothelial cells to examine kinetics and mechanisms contributing to the disposition of the quinone 2,3,5,6-tetramethyl-1,4-benzoquinone (duroquinone, DQ) observed during passage through the pulmonary circulation. The approach was to add DQ, durohydroquinone (DQH2), or DQ with the cell membrane-impermeant oxidizing agent, ferricyanide (Fe(CN)6(3)-), to the cell medium, and to measure the medium concentrations of substrates and products over time. Studies were carried out under control conditions and with dicumarol, to inhibit NAD(P)H:quinone oxidoreductase 1 (NQO1), or cyanide, to inhibit mitochondrial electron transport. In control cells, DQH2 appears in the extracellular medium of cells incubated with DQ, and DQ appears when the cells are incubated with DQH2. Dicumarol blocked the appearance of DQH2 when DQ was added to the cell medium, and cyanide blocked the appearance of DQ when DQH2 was added to the cell medium, suggesting that the two electron reductase NQO1 dominates DQ reduction and mitochondrial electron transport complex III is the predominant route of DQH2 oxidation. In the presence of cyanide, the addition of DQ also resulted in an increased rate of appearance of DQH2 and stimulation of cyanide-insensitive oxygen consumption. As DQH2 does not autoxidize-comproportionate over the study time course, these observations suggest a cyanide-stimulated one-electron DQ reduction and durosemiquinone (DQ*-) autoxidation. The latter processes are apparently confined to the cell interior, as the cell membrane impermeant oxidant, ferricyanide, did not inhibit the DQ-stimulated cyanide-insensitive oxygen consumption. Thus, regardless of whether DQ is reduced via a one- or two-electron reduction pathway, the net effect in the extracellular medium is the appearance of DQH2. These endothelial redox functions and their apposition to the vessel lumen are consistent with the pulmonary endothelium being an important site of DQ reduction to DQH2 observed in the lungs.


A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.
Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).


Phosphate glasses via coacervation route containing CdFe2O4 nanoparticles: structural, optical and magnetic characterization.
CdFe2O4 nanoparticles of around 3.9 nm were synthesized using the coprecipitation method and protected by a silica layer. The nanoparticles were mixed with a coacervate and transformed into phosphate glasses with 1, 4 and 8% in mass of nanoparticles by the melt-quenching method. TEM images confirm that the nanoparticles were successfully incorporated into the matrix without inducing crystallization. 31P NMR and Raman spectral analyses show that new P-O-Si bonds are formed in the glasses containing nanoparticles. The glass transition increases as a function of the nanoparticle content due to an increase in the connectivity of the phosphate glass chains. The UV-Vis spectra show bands at 415 and 520 nm assigned to Fe3+ ions and at 1025 nm, characteristic of Fe2+ ions, indicating that some of the nanoparticles dissolve during the melting process. The sample with 8% CdFe2O4 presents a paramagnetic behavior. The glasses obtained are transparent, non-hygroscopic and possess enormous thermal stability which is important for the production of optical devices.


Anaerobic treatment of residual lemon pulp in digesters with semi-continuous feed.
Lemon growing areas in the north of Argentina have industries that produce concentrated juice, peel and essential oil and generate a significant amount of liquid and solid waste as lemon pulp. In Argentina, despite the potential applications that the pulp has as animal feed and human and industrial raw material, only 10% is used for these purposes and the rest is discarded into the environment causing many ecological and economic problems. There is little information in the literature on biotechnologies for the treatment of this industrial waste. This paper shows that lemon pulp is a suitable substrate to be treated by anaerobic digestion. We obtained 86 and 92% reduction of chemical oxygen demand in a digester with a semi-continuous feed and retention time of 10 and 20 days respectively and a productivity of 0.406 g CH(4)/g VS h. Comparative tests showed that pre-digesting the pulp improved the process of digestion and increased biogas generation by 20%.


Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy.
Ovarian cancer is the most frequent cause of cancer death among all gynecologic cancers. We demonstrate here that lysophosphatidic acid (LPA)-induced ectodomain shedding of heparin-binding EGF-like growth factor (HB-EGF) is a critical to tumor formation in ovarian cancer. We found that among the epidermal growth factor receptor (EGFR) family of growth factors, HB-EGF gene expression in cancerous tissues and HB-EGF protein levels in patients' ascites fluid were significantly elevated. The human ovarian cancer cell lines SKOV3 and RMG-1 form tumors in nude mice. Tumor formation of these cells was enhanced by exogenous expression of pro-HB-EGF and completely blocked by pro-HB-EGF gene RNA interference or by CRM197, a specific HB-EGF inhibitor. Transfection with mutant forms of HB-EGF indicated that the release of soluble HB-EGF is essential for tumor formation. LPA, which is constitutively produced by ovarian cancer cells, induced HB-EGF ectodomain shedding in SKOV3 and RMG-1 cells, resulting in the transactivation of EGFR and the downstream kinase extracellular signal-regulated kinase/mitogen-activated protein kinase. LPA-induced transactivation was abrogated by HB-EGF gene RNA interference or by CRM197. Introduction of lipid phosphate phosphohydrolase, which hydrolyzes LPA, decreased the constitutive shedding of HB-EGF, EGFR transactivation, and the tumorigenic potential of SKOV3 and RMG-1 cells. These results indicate that HB-EGF is the primary member of the EGFR family of growth factors expressed in ovarian cancer and that LPA-induced ectodomain shedding of this growth factor is a critical step in tumor formation, making HB-EGF a novel therapeutic target for ovarian cancer.


[Clinical outcome in cases of viral breakthrough during lamivudine therapy in chronic hepatitis B patients].
Long-term lamivudine therapy can induce the emergence of lamivudine resistant hepatitis B virus (HBV) mutants. Clinically emergence of the mutant is expressed by the reappearance of disappeared HBV DNA in serum. Continued lamivudine treatment has been usually recommended in cases of viral breakthrough. However, the clinical outcome in patients with viral breakthrough is not clear. The aim of this study was to investigate the clinical course of chronic hepatitis B patients after viral breakthrough during lamivudine therapy. A total of 74 patients with chronic hepatitis B who showed viral breakthrough after at least 6 months of lamivudine treatment were included in this study. They had positive HBeAg and HBV DNA before treatment. The median follow-up duration after breakthrough was 13 months. After viral breakthrough, only 8 patients (11%) maintained normal ALT levels and 66 patients (89%) showed elevation of ALT. 30 patients (41%) showed acute exacerbation of hepatitis (ALT increase over five-times upper normal limit). These acute exacerbations occurred within three months after breakthrough in 19 patients (63%). In the cases of acute exacerbation, 6 patients showed decompensated progression such as elevation of serum total bilirubin. One of them died of hepatic failure. A predictive factor for acute exacerbation was not found. HBeAg seroconversion occurred in 8 patients after viral breakthrough but their clinical course was highly variable. Chronic hepatitis B patients who had viral breakthrough during lamivudine therapy should be followed carefully and regularly in mind of potential clinical deterioration. New strategies are needed to manage the cases of acute exacerbation after viral breakthrough.


Evolutionary regulation of the blind subterranean mole rat, Spalax, revealed by genome-wide gene expression.
We applied genome-wide gene expression analysis to the evolutionary processes of adaptive speciation of the Israeli blind subterranean mole rats of the Spalax ehrenbergi superspecies. The four Israeli allospecies climatically and adaptively radiated into the cooler, mesic northern domain (N) and warmer, xeric southern domain (S). The kidney and brain mRNAs of two N and two S animals were examined through cross-species hybridizations with two types of Affymetrix arrays (mouse and rat) and muscle mRNA of six N and six S animals with spotted cDNA mouse arrays. The initial microarray analysis was hypothesis-free, i.e., conducted without reference to the origin of animals. Principal component analysis revealed that 20-30% of the expression signal variability could be explained by the differentiation of N-S species. Similar N-S effects were obtained for all tissues and types of arrays: two Affymetrix microarrays using probe oligomer signals and the spotted array. Likewise, ANOVA and t test statistics demonstrated significant N-S ecogeographic divergence and region-tissue specificity in gene expression. Analysis of differential gene expression between species corroborates previous results deduced by allozymes and DNA molecular polymorphisms. Functional categories show significant N-S ecologic putative adaptive divergent up-regulation of genes highlighting a higher metabolism in N, and potential adaptive brain activity and kidney urine cycle pathways in S. The present results confirm ecologic-genomic separation of blind mole rats into N and S. Gene expression regulation appears to be central to the evolution of blind mole rats.


First Reports, Morphological, and Molecular Characterization of Longidorus caespiticola and Longidorus poessneckensis (Nematoda: Longidoridae) from Ukraine.
Seven needle nematode species of the genus Longidorus have been reported in Ukraine. Nematological surveys for needle nematodes were carried out in Ukraine between 2016 and 2017 and two nematode species of Longidorus (L. caespiticola and L. poessneckensis) were collected from natural and anthropogenically altered habitats on the territory of Opillia and Zakarpattia in Ukraine. Nematodes were extracted from 500 cm3 of soil by modified sieving and decanting method. Extracted specimens were processed to glycerol and mounted on permanent slides and subsequently identified morphologically and molecularly. Nematode DNA was extracted from single individuals and PCR assays were conducted as previously described for D2-D3 expansion segments of 28S rRNA. Sequence alignments for D2-D3 from L. caespiticola showed 97%-99% similarity to other sequences of L. caespiticola deposited in GenBank from Belgium, Bulgaria, Czech Republic, Russia, Slovenia, and Scotland. Similarly, D2-D3 sequence alignments from L. poessneckensis, showed 99% to other sequences of L. poessneckensis deposited in GenBank from Slovakia and Czech Republic. Morphology, morphometry, and molecular data obtained from these samples were consistent with L. caespiticola and L. poessneckensis identification. To our knowledge, these are the first reports of L. caespiticola and L. poessneckensis in Ukraine, extending the geographical distribution of these species.


Fourier space design of high-Q cavities in standard and compressed hexagonal lattice photonic crystals.
Building upon the results of recent work [1], we use momentum space design rules to investigate high quality factor (Q) optical cavities in standard and compressed hexagonal lattice photonic crystal (PC) slab waveguides. Beginning with the standard hexagonal lattice, the results of a symmetry analysis are used to determine a cavity geometry that produces a mode whose symmetry immediately leads to a reduction in vertical radiation loss from the PC slab. The Q is improved further by a tailoring of the defect geometry in Fourier space so as to limit coupling between the dominant Fourier components of the defect mode and those momentum components that radiate. Numerical investigations using the finite-difference time-domain (FDTD) method show significant improvement using these methods, with total Q values exceeding 10;5. We also consider defect cavities in a compressed hexagonal lattice, where the lattice compression is used to modify the in-plane bandstructure of the PC lattice, creating new (frequency) degeneracies and modifying the dominant Fourier components found in the defect modes. High Q cavities in this new lattice geometry are designed using the momentum space design techniques outlined above. FDTD simulations of these structures yield Q values in excess of 10;5 with mode volumes of approximately 0.35 cubic half-wavelengths in vacuum.


Ultrahigh-speed optical coherence tomography for three-dimensional and en face imaging of the retina and optic nerve head.
To demonstrate ultrahigh-speed optical coherence tomography (OCT) imaging of the retina and optic nerve head at 249,000 axial scans per second and a wavelength of 1060 nm. To investigate methods for visualization of the retina, choroid, and optic nerve using high-density sampling enabled by improved imaging speed. A swept-source OCT retinal imaging system operating at a speed of 249,000 axial scans per second was developed. Imaging of the retina, choroid, and optic nerve were performed. Display methods such as speckle reduction, slicing along arbitrary planes, en face visualization of reflectance from specific retinal layers, and image compounding were investigated. High-definition and three-dimensional (3D) imaging of the normal retina and optic nerve head were performed. Increased light penetration at 1060 nm enabled improved visualization of the choroid, lamina cribrosa, and sclera. OCT fundus images and 3D visualizations were generated with higher pixel density and less motion artifacts than standard spectral/Fourier domain OCT. En face images enabled visualization of the porous structure of the lamina cribrosa, nerve fiber layer, choroid, photoreceptors, RPE, and capillaries of the inner retina. Ultrahigh-speed OCT imaging of the retina and optic nerve head at 249,000 axial scans per second is possible. The improvement of approximately 5 to 10x in imaging speed over commercial spectral/Fourier domain OCT technology enables higher density raster scan protocols and improved performance of en face visualization methods. The combination of the longer wavelength and ultrahigh imaging speed enables excellent visualization of the choroid, sclera, and lamina cribrosa.


Stimulating numbers: signatures of finger counting in numerosity processing.
Finger counting is one of the first steps in the development of mature number concepts. With a one-to-one correspondence of fingers to numbers in Western finger counting, fingers hold two numerical meanings: one is based on the number of fingers raised and the second is based on their ordinal position within the habitual finger counting sequence. This study investigated how these two numerical meanings of fingers are intertwined with numerical cognition in adults. Participants received tactile stimulation on their fingertips of one hand and named either the number of fingers stimulated (2, 3, or 4 fingers; Experiment 1) or the number of stimulations on one fingertip (2, 3, or 4 stimulations; Experiment 2). Responses were faster and more accurate when the set of stimulated fingers corresponded to finger counting habits (Experiment 1) and when the number of stimulations matched the ordinal position of the stimulated finger (Experiment 2). These results show that tactile numerosity perception is affected by individual finger counting habits and that those habits give numerical meaning to single fingers.


Pedal claw curvature in birds, lizards and mesozoic dinosaurs--complicated categories and compensating for mass-specific and phylogenetic control.
Pedal claw geometry can be used to predict behaviour in extant tetrapods and has frequently been used as an indicator of lifestyle and ecology in Mesozoic birds and other fossil reptiles, sometimes without acknowledgement of the caveat that data from other aspects of morphology and proportions also need to be considered. Variation in styles of measurement (both inner and outer claw curvature angles) has made it difficult to compare results across studies, as have over-simplified ecological categories. We sought to increase sample size in a new analysis devised to test claw geometry against ecological niche. We found that taxa from different behavioural categories overlapped extensively in claw geometry. Whilst most taxa plotted as predicted, some fossil taxa were recovered in unexpected positions. Inner and outer claw curvatures were statistically correlated, and both correlated with relative claw robusticity (mid-point claw height). We corrected for mass and phylogeny, as both likely influence claw morphology. We conclude that there is no strong mass-specific effect on claw curvature; furthermore, correlations between claw geometry and behaviour are consistent across disparate clades. By using independent contrasts to correct for phylogeny, we found little significant relationship between claw geometry and behaviour. 'Ground-dweller' claws are less curved and relatively dorsoventrally deep relative to those of other behavioural categories; beyond this it is difficult to assign an explicit category to a claw based purely on geometry.


Increased cerebral cannabinoid-1 receptor availability is a stable feature of functional dyspepsia: a [F]MK-9470 PET study.
Functional dyspepsia (FD) is a prevalent functional gastrointestinal disorder (FGID) defined by chronic epigastric symptoms in the absence of organic abnormalities likely to explain them. Comorbidity with mood and anxiety disorders as well as with other FGIDs and functional somatic syndrome (FSS) is high. FD is characterized by abnormal regional cerebral activity in cognitive/affective pain modulatory circuits, but it is unknown which neurotransmitter systems are involved. The authors aimed to assess and compare in vivo cerebral cannabinoid-1 (CB1) receptor availability between FD patients and age-, gender- and BMI-matched healthy controls (HC). Twelve FD patients and 12 matched HC were investigated using positron emission tomography (PET) with the CB1 receptor radioligand [(18)F]MK-9470. Nine of the patients received a second PET scan after a naturalistic follow-up period of 36 ± 9.6 months (range: 25.2-50.4 months). FD patients had significantly higher CB1 receptor availability in the cerebral regions involved in (visceral) nociception (brainstem, insula, anterior cingulate cortex) as well as in the homeostatic and hedonic regulation of food intake [hypothalamus, (ventral) striatum] (p < 0.05 corrected for multiple testing, region of interest analysis), which persisted after a follow-up period of 36 ± 9.6 months. Although these findings need replication in larger samples, they suggest that the abnormal brain activity in several of these regions, previously demonstrated in FD, may be due to a sustained endocannabinoid system dysfunction, identifying it as a potential novel target for treatment and warranting further studies to elucidate whether it is also a feature of other FGIDs or FSSs.


Benefits of Family Meals for Children With Special Therapeutic and Behavioral Needs.
Frequency of family meals (FMs) is associated with favorable child outcomes; however, no study to date has examined the relationship between frequency of FMs and outcomes for children with disabilities. Data from the 2007 National Survey of Children's Health for children with disabilities (N = 4,336) were used. Logistic regression for each dependent variable was completed using frequency of FMs and covariates of age, gender, race, family structure, and poverty level. Each day per week increase in the frequency of FMs increased the likelihood for positive social skills (odds ratio [OR] = 1.09, 95% confidence interval [CI] [1.01, 1.19]) and engagement in school (OR = 1.09, 95% CI [1.02, 1.16]). Frequency of FMs was not associated with problematic social behaviors or parental aggravation with child. Our findings suggest that children with disabilities whose families participate in frequent FMs have a greater likelihood of positive social and family health outcomes.


What social media told us in the time of COVID-19: a scoping review.
With the onset of the COVID-19 pandemic, social media has rapidly become a crucial communication tool for information generation, dissemination, and consumption. In this scoping review, we selected and examined peer-reviewed empirical studies relating to COVID-19 and social media during the first outbreak from November, 2019, to November, 2020. From an analysis of 81 studies, we identified five overarching public health themes concerning the role of online social media platforms and COVID-19. These themes focused on: surveying public attitudes, identifying infodemics, assessing mental health, detecting or predicting COVID-19 cases, analysing government responses to the pandemic, and evaluating quality of health information in prevention education videos. Furthermore, our Review emphasises the paucity of studies on the application of machine learning on data from COVID-19-related social media and a scarcity of studies documenting real-time surveillance that was developed with data from social media on COVID-19. For COVID-19, social media can have a crucial role in disseminating health information and tackling infodemics and misinformation.


454 Genome sequencing of Pseudoperonospora cubensis reveals effector proteins with a QXLR translocation motif.
Pseudoperonospora cubensis is a biotrophic oomycete pathogen that causes downy mildew of cucurbits, a devastating foliar disease threatening cucurbit production worldwide. We sequenced P. cubensis genomic DNA using 454 pyrosequencing and obtained random genomic sequences covering approximately 14% of the genome, thus providing the first set of useful genomic sequence information for P. cubensis. Using bioinformatics approaches, we identified 32 putative RXLR effector proteins. Interestingly, we also identified 29 secreted peptides with high similarity to RXLR effectors at the N-terminal translocation domain, yet containing an R-to-Q substitution in the first residue of the translocation motif. Among these, a family of QXLR-containing proteins, designated as PcQNE, was confirmed to have a functional signal peptide and was further characterized as being localized in the plant nucleus. Internalization of secreted PcQNE into plant cells requires the QXLR-EER motif. This family has a large number of near-identical copies within the P. cubensis genome, is under diversifying selection at the C-terminal domain, and is upregulated during infection of plants, all of which are common characteristics of characterized oomycete effectors. Taken together, the data suggest that PcQNE are bona fide effector proteins with a QXLR translocation motif, and QXLR effectors are prevalent in P. cubensis. Furthermore, the massive duplication of PcQNE suggests that they might play pivotal roles in pathogen fitness and pathogenicity.


Apoptosis-inducing effect of erlotinib is potentiated by 3,3'-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer.
Blockade of epidermal growth factor receptor (EGFR) by EGFR tyrosine kinase inhibitors is insufficient for effective antitumor activity because of independently activated survival pathways. A multitargeted approach may therefore improve the outcome of anti-EGFR therapies. In the present study, we determined the effects of 3,3'-diindolylmethane (Bioresponse BR-DIM referred to as B-DIM), a formulated DIM with greater bioavailability on cell viability and apoptosis with erlotinib in vitro and in vivo using an orthotopic animal tumor model. BxPC-3 and MIAPaCa cells with varying levels of EGFR and nuclear factor-kappaB (NF-kappaB) DNA-binding activity were treated with B-DIM (20 micromol/L), erlotinib (2 micromol/L), and the combination. Cell survival and apoptosis was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and histone-DNA ELISA. Electrophoretic mobility shift assay was used to evaluate NF-kappaB DNA-binding activity. We found significant reduction in cell viability by both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic assays, induction of apoptosis, down-regulation of EGFR phosphorylation, NF-kappaB DNA-binding activity, and expression of antiapoptotic genes in BxPC-3 cells when treated with the combination of erlotinib and B-DIM compared with either agent alone. In contrast, no such effect was observed in MIAPaCa cells by similar treatment. Most importantly, these in vitro results were recapitulated in animal model showing that B-DIM in combination with erlotinib was much more effective as an antitumor agent compared with either agent alone. These results suggest that the utilization of B-DIM could be a useful strategy for achieving better treatment outcome in patients with activated status of EGFR and NF-kappaB in their tumors.


Regulation of membrane protein function by lipid bilayer elasticity-a single molecule technology to measure the bilayer properties experienced by an embedded protein.
Membrane protein function is generally regulated by the molecular composition of the host lipid bilayer. The underlying mechanisms have long remained enigmatic. Some cases involve specific molecular interactions, but very often lipids and other amphiphiles, which are adsorbed to lipid bilayers, regulate a number of structurally unrelated proteins in an apparently non-specific manner. It is well known that changes in the physical properties of a lipid bilayer (e.g., thickness or monolayer spontaneous curvature) can affect the function of an embedded protein. However, the role of such changes, in the general regulation of membrane protein function, is unclear. This is to a large extent due to lack of a generally accepted framework in which to understand the many observations. The present review summarizes studies which have demonstrated that the hydrophobic interactions between a membrane protein and the host lipid bilayer provide an energetic coupling, whereby protein function can be regulated by the bilayer elasticity. The feasibility of this 'hydrophobic coupling mechanism' has been demonstrated using the gramicidin channel, a model membrane protein, in planar lipid bilayers. Using voltage-dependent sodium channels, N-type calcium channels and GABA(A) receptors, it has been shown that membrane protein function in living cells can be regulated by amphiphile induced changes in bilayer elasticity. Using the gramicidin channel as a molecular force transducer, a nanotechnology to measure the elastic properties experienced by an embedded protein has been developed. A theoretical and technological framework, to study the regulation of membrane protein function by lipid bilayer elasticity, has been established.


Multipolar and dark-mode plasmon resonances on drilled silver nano-triangles.
Dark-mode plasmon resonances can be excited by positioning a suitable nano-antenna above a nanostructure to couple a planar incident wave-front into a virtual point source. We explore this phenomenon using a prototypical nanostructure consisting of a silver nanotriangle into which a hole has been drilled and a rod-like nano-antenna of variable aspect ratio. Using numerical simulations, we establish the behavior of the basic drilled nanotriangle under plane wave illumination and electron beam irradiation to provide a baseline, and then add the nano-antenna to investigate the stimulation of additional dark-mode plasmon resonances. The introduction of a suitably tuned nano-antenna provides a new and general means of exciting dark-mode resonances using plane wave light. The resulting system exhibits a very rich variety of radiant and sub-radiant resonance modes.


Impact of Hunt-Hess grade on the glycemic status of aneurysmal subarachnoid hemorrhage patients.
This study has explored the impact of Hunt-Hess (H-H) grade of aneurysmal subarachnoid hemorrhage (aSAH) on the glycemic status of such patients during their intensive care unit (ICU) stay and has also analyzed whether H-H grade predicts their outcome independent of their glycemic status. This was a retrospective case record review of prospectively maintained database of 1090 previously non-diabetic aSAH patients admitted to Thomas Jefferson University Hospital, Philadelphia. H-H grade of SAH, serum and CSF glucose on admission, serum glucose on the day of surgery and 14 days post-surgery, as well as the extended Glasgow Outcome Score (GOS-E score) at discharge were noted. After univariate analysis, significant variables (P < 0.05) were entered into a logistic regression model to identify significant associations with admission H-H grade. Although admission serum glucose was significantly higher for H-H grades 4-5 than grades 1-3 (P < 0.001); after postoperative day 4, the difference between the H-H grades got blurred. Admission CSF glucose was also significantly higher for H-H grades 3-4 than for grades 1-3 and 5 (P < 0.001). H-H grades 4-5 were related with higher incidences of both hypoglycemia (serum glucose level < 80 mg/dl) and hyperglycemia (serum glucose level > 200 mg/dl) (P < 0.001) during the 14-day period of ICU stay. Also, the relationship between serum and CSF glucose levels at admission increased with HH grades 1 through 4, but became negative and more tightly bound at H-H grade 5. Admission H-H grades 4-5 contributed to poor outcome compared to lower H-H grades (P < 0.0001). Poor admission H-H grades lead to poor immediate glycemic status as well as poor short-term outcome, and it is dependent on serum glucose but independent of CSF glucose in predicting the outcome.


Conductometric monitoring of protein-protein interactions.
Conductometric monitoring of protein-protein and protein-sterol interactions is here proved feasible by coupling quartz crystal microbalance with dissipation monitoring (QCM_D) to nucleic acid programmable protein arrays (NAPPA). The conductance curves measured in NAPPA microarrays printed on quartz surface allowed the identification of binding events between the immobilized proteins and the query. NAPPA allows the immobilization on the quartz surface of a wide range of proteins and can be easily adapted to generate innumerous types of biosensors. Indeed multiple proteins on the same quartz crystal have been tested and envisaged proving the possibility of analyzing the same array for several distinct interactions. Two examples of NAPPA-based conductometer applications with clinical relevance are presented herein, the interaction between the transcription factors Jun and ATF2 and the interaction between Cytochrome P540scc and cholesterol.


The effects of lateral prefrontal transcranial magnetic stimulation on item memory encoding.
Previous neuroimaging research has established that the left ventrolateral prefrontal cortex (VLPFC) is involved in long-term memory (LTM) encoding for individual items. Dorsolateral prefrontal cortex (DLPFC) is implicated less frequently, and one theory that has gained support to explain this discrepancy is that DLPFC is involved in forming item-item relational but not item LTM. Given that neuroimaging results are correlational, complimentary methods such as repetitive transcranial magnetic stimulation (TMS) have been used to test causal hypotheses generated from imaging data. Most TMS studies of LTM encoding have found that disruption of lateral PFC activity impairs subsequent memory. However these studies have lacked methods to precisely localize and directly compare TMS effects from frontal subregions implicated by the neuroimaging literature. Here, we target specific subregions of lateral PFC with TMS to test the prediction from the item/relational framework that temporary disruption of VLPFC during encoding will impair subsequent memory whereas TMS to DLPFC during item encoding will not. Frontal TMS was administered prior to a LTM encoding task in which participants were presented with a list of individual nouns and asked to judge whether each noun was concrete or abstract. After a 40 min delay period, item recognition memory was tested. Results indicate that VLPFC and DLPFC TMS have differential effects on subsequent item memory. VLPFC TMS reliably disrupted subsequent item memory whereas DLPFC TMS led to numerical enhancement in item memory, relative to TMS to a control region.


Memory trace in feeding neural circuitry underlying conditioned taste aversion in Lymnaea.
The pond snail Lymnaea stagnalis can maintain a conditioned taste aversion (CTA) as a long-term memory. Previous studies have shown that the inhibitory postsynaptic potential (IPSP) evoked in the neuron 1 medial (N1M) cell by activation of the cerebral giant cell (CGC) in taste aversion-trained snails was larger and lasted longer than that in control snails. The N1M cell is one of the interneurons in the feeding central pattern generator (CPG), and the CGC is a key regulatory neuron for the feeding CPG. Previous studies have suggested that the neural circuit between the CGC and the N1M cell consists of two synaptic connections: (1) the excitatory connection from the CGC to the neuron 3 tonic (N3t) cell and (2) the inhibitory connection from the N3t cell to the N1M cell. However, because the N3t cell is too small to access consistently by electrophysiological methods, in the present study the synaptic inputs from the CGC to the N3t cell and those from the N3t cell to the N1M cell were monitored as the monosynaptic excitatory postsynaptic potential (EPSP) recorded in the large B1 and B3 motor neurons, respectively. The evoked monosynaptic EPSPs of the B1 motor neurons in the brains isolated from the taste aversion-trained snails were identical to those in the control snails, whereas the spontaneous monosynaptic EPSPs of the B3 motor neurons were significantly enlarged. These results suggest that, after taste aversion training, the monosynaptic inputs from the N3t cell to the following neurons including the N1M cell are specifically facilitated. That is, one of the memory traces for taste aversion remains as an increase in neurotransmitter released from the N3t cell. We thus conclude that the N3t cell suppresses the N1M cell in the feeding CPG, in response to the conditioned stimulus in Lymnaea CTA.


Effect of keyswitch design of desktop and notebook keyboards related to key stiffness and typing force.
This study aimed to compare and analyse rubber-dome desktop, spring-column desktop and notebook keyboards in terms of key stiffness and fingertip typing force. The spring-column keyboard resulted in the highest mean peak contact force (0.86N), followed by the rubber dome desktop (0.68N) and the notebook (0.59N). All these differences were statistically significant. Likewise, the spring-column keyboard registered the highest fingertip typing force and the notebook keyboard the lowest. A comparison of forces showed the notebook (rubber dome) keyboard had the highest fingertip-to-peak contact force ratio (overstrike force), and the spring-column generated the least excess force (as a ratio of peak contact force). The results of this study could aid in optimizing computer key design that could possibly reduce subject discomfort and fatigue.


Photosensitisation facilitates cross-priming of adjuvant-free protein vaccines and stimulation of tumour-suppressing CD8 T cells.
Cancer vaccines aim to induce CD8 T cells infiltrating the tumour. For protein-based vaccines, the main biological barrier to overcome is the default MHC class-II-pathway, with activation of CD4 T cells rather than CD8 T cells. The latter requires antigens to access the cytosol and MHC class I antigen presentation. We applied photosensitiser and light to trigger disruption of antigen-containing endosomes and thereby MHC class I cross-presentation of a model cancer vaccine. This "photochemical internalisation" resulted in activation, proliferation, and IFN-γ production of cytotoxic CD8 T cells, which suppressed tumour growth by infiltrating CD8 T cells and caspase-3-dependent apoptosis. The process was independent of MHC class II, MyD88, and TLR4 signalling, but dependent on trypsin- and caspase-like proteasome activity and partly also on chloroquine. This novel method of vaccination may find applications in cancer immunotherapy where the activation of CD8 T cells is important.


Two approaches to repetition suppression.
Repetition suppression refers to the phenomenon that prior processing of stimuli (or stimulus attributes) decreases activation elicited by processing subsequent stimuli with identical attributes. We present two complementary approaches to identify regions that show repetition suppression for subsequent sentences with either identical: (1) sentence forms or (2) speakers. The first categorical approach simply compares sentences that are presented in Same and Different blocks. The second factorial approach operationally defines repetition suppression as decreased activation for the subsequent Same stimulus relative to its preceding sentence. To account for nonspecific time confounds, this approach tests for a repetition x condition (Same or Different) interaction. Surprisingly, the two approaches revealed different results: Only the categorical analysis detected sentence repetition effects in multiple regions within a bilateral frontotemporal system that has previously been implicated in sentence processing. These discrepancies might be due to the different efficiencies with which the particular contrasts were estimated or spurious differences in stimuli or attentional set that could not be entirely controlled within a single subject. Finally, we combined the two approaches in a [global null] conjunction analysis.


Impact of Pretreatment Change on Mechanism of Behavior Change Research: An Applied Example Using Alcohol Abstinence Self-Efficacy.
With the growing recognition that, for some, significant changes in drinking occur before the first treatment session (i.e., pretreatment change), researchers have called for the careful assessment of when change occurs and its potential impact on mechanism of behavior change (MOBC) research. Using a commonly hypothesized MOBC variable, alcohol abstinence self-efficacy, the primary aim of this study was to examine the effect of pretreatment change on the study of MOBCs. Sixty-three individuals diagnosed with alcohol dependence were recruited to participate in a 12-week cognitive-behavioral treatment. Participants completed weekly assessments of self-efficacy and drinking behaviors. Multilevel time-lagged regression models indicated that pretreatment change significantly moderated the effect of self-efficacy on the number of drinking days, such that among those higher on pretreatment change, higher self-efficacy ratings predicted lower rates of drinking days in the week until the next treatment session. In contrast, pretreatment change did not moderate the effect of self-efficacy on the rate of heavy drinking days. Results from the current study add to a small but growing body of research highlighting the importance of pretreatment change when studying MOBCs. Further, these results provide important insights into the conditions in which self-efficacy may play an important role in treatment outcomes.


Medical waiting periods: imminence, emotions and coping.
The diagnosis and treatment of various medical conditions requires patients to wait for results that are potentially threatening to their wellbeing (e.g., breast biopsy results, pregnancy test results after fertility treatment and genetic screening outcomes). Little research has been carried out to document the psychological processes that unfold during such waiting periods. The aim of the present study was to document the course of anxiety, depression, positive affect and coping during the waiting period before a pregnancy test result in fertility treatment. Using a daily record-keeping chart designed for fertility treatment, 61 women undergoing IVF were monitored daily for emotional reactions (e.g., anxiety, depression and positive affect) and coping during 7 days of active treatment (stimulation), 7 days of waiting to find out whether a pregnancy was achieved (waiting) and 4 days of reacting to the pregnancy test results (outcome). The stimulation stage of treatment was characterized by positive affect with a lesser degree of anxiety, whereas the predominant emotions in the waiting stage were a combination of positive affect and anxiety symptoms versus depression. From the pregnancy test day onwards, the predominant emotion was depression. There was a significant increase in coping activity between the stimulation and waiting stages, with variable effects across coping strategies. It was concluded that whilst medical waiting periods have a clearly defined emotional trajectory, the coping pattern is less differentiated. This may explain why waiting for medical test results is so demanding. Healthcare professionals can assist their patients by facilitating coping strategies that better fit the demands of the waiting period and by offering support once outcomes are known.


Retention of Plasmodium falciparum ring-infected erythrocytes in the slow, open microcirculation of the human spleen.
The current paradigm in Plasmodium falciparum malaria pathogenesis states that young, ring-infected erythrocytes (rings) circulate in peripheral blood and that mature stages are sequestered in the vasculature, avoiding clearance by the spleen. Through ex vivo perfusion of human spleens, we examined the interaction of this unique blood-filtering organ with P falciparum-infected erythrocytes. As predicted, mature stages were retained. However, more than 50% of rings were also retained and accumulated upstream from endothelial sinus wall slits of the open, slow red pulp microcirculation. Ten percent of rings were retained at each spleen passage, a rate matching the proportion of blood flowing through the slow circulatory compartment established in parallel using spleen contrast-enhanced ultrasonography in healthy volunteers. Rings displayed a mildly but significantly reduced elongation index, consistent with a retention process, due to their altered mechanical properties. This raises the new paradigm of a heterogeneous ring population, the less deformable subset being retained in the spleen, thereby reducing the parasite biomass that will sequester in vital organs, influencing the risk of severe complications, such as cerebral malaria or severe anemia. Cryptic ring retention uncovers a new role for the spleen in the control of parasite density, opening novel intervention opportunities.


Suicide ideation and attempts in obsessive-compulsive disorder.
Obsessive-compulsive disorder (OCD) places individuals at risk for suicidality. Inconsistencies regarding the associated features of suicidality and OCD remain. Regression analysis determined the extent to which psychiatric comorbidity, illness severity, OCD symptom dimensions, childhood trauma history, and the Val66Met (rs6265) polymorphism of the brainderived neurotrophic factor (BDNF) gene predict lifetime suicidal ideation and attempts in adults with OCD. Among the 496 participants, 51.8% reported suicidal ideation and 16.5% reported ≥1 suicide attempts. Females and individuals with borderline personality disorder (BPD) were at higher risk of presenting with suicide attempts (female: odds ratio [OR] = 2.75; 95% confidence interval [CI], 1.28 to 5.94; BPD: OR = 7.35; 95% CI, 3.25 to 16.61). Major depressive disorder (MDD), BPD, and avoidant personality disorder (AVPD) were significant predictors of suicidal ideation (MDD: OR = 2.4; 95% CI, 1.5 to 3.86; BPD: OR = 2.8; 95% CI, 1.36 to 5.73; AVPD: OR = 1.96; 95% CI, 1.02 to 3.75). No significant association was observed between BDNF Val66Met and suicidality. Suicidality is common among patients with OCD. Several variables were associated with risk, including female sex, depression, and personality pathology. Further research into the underlying mechanisms is warranted. Emphasis is placed on assessment of suicidality risk and addressing modifiable features associated with suicidality to ensure better outcomes.


Generalized valence bond description of chalcogen-nitrogen compounds. II. NO, F(NO), and H(NO).
The electronic structure of the ground state of NO and those of F(NO) and H(NO), that is, the XNO and NOX isomers with X = F, H, were analyzed within the framework of generalized valence bond theory. In distinct contrast to the ground state of NS, it was found that the two-center, three-electron π interaction in NO(X(2)Π) is composed of a lone pair on O and a singly occupied orbital on N. Thus, F and H addition to NO preferentially leads to FNO and HNO. Somewhat surprisingly, the NOF and NOH isomers were found to be weakly bound, although for different reasons. The NOF state has a very unusual through-pair interaction with a NO-F bond length 0.444 Å longer than its covalent counterpart in OF(X(2)Π), while NOH arises from the N((2)D) + OH(X(2)Π) separated atom limit, similar to what we found for NSH.