Femoroacetabular impingement: defining the condition and its role in the pathophysiology of osteoarthritis.
Femoroacetabular impingement (FAI) is an increasingly recognized cause of hip pain. It is best defined as a pathologic mechanical process by which morphologic abnormalities of the acetabulum and/or femur combined with vigorous hip motion lead to repetitive collisions that damage the soft-tissue structures within the joint itself. Based on cross-sectional studies in which FAI morphology was studied before the presence of radiographic osteoarthritis (OA), and on prevalence studies in younger, asymptomatic persons, it is clear that FAI and its morphologic risk factors are common in young adult hips and predispose to the later development of OA in certain patients. Longitudinal studies also support the assertion that, in middle-aged adults, the presence of cam deformities at baseline substantially increases the risk of developing OA and the need for total hip arthroplasty. More long-term data are needed to better define the natural history of pincer deformities as well as FAI in younger cohorts.


Unraveling Steric Effects on Ultrafast Bond-Dissociation Processes of Photochromic Radical Complexes.
Photochromic reactions of the phenoxyl-imidazolyl radical complex (PIC), which is one of the rate-tunable fast T-type photoswitches, dramatically change by the introduction of bulky substituents around the photochromic units. While these substituents are expected to affect the initial bond dissociation processes, they have not been elucidated yet. Here, we revealed the ultrafast bond dissociation processes of PIC derivatives with different bulky substituents by subpicosecond to nanosecond transient absorption spectroscopy. We revealed that the bulky substituents around the photochromic units decelerate the bond dissociation processes, whereas they largely accelerate the thermal back reactions of the photogenerated open-ring isomer. Moreover, we found clear correlations between the formation kinetics of the open-ring isomer and molecular structural changes. The initial bond-dissociation process dictates the products and the efficiency of photochromic reactions. Therefore, revealing these processes is important not only for fundamental photochemistry but also for optimizing photochromic properties for advanced functional materials.


Stress and the dopaminergic reward system.
Dopamine regulates reward-related behavior through the mesolimbic dopaminergic pathway. Stress affects dopamine levels and dopaminergic neuronal activity in the mesolimbic dopamine system. Changes in mesolimbic dopaminergic neurotransmission are important for coping with stress, as they allow adaption to behavioral responses to various environmental stimuli. Upon stress exposure, modulation of the dopaminergic reward system is necessary for monitoring and selecting the optimal process for coping with stressful situations. Aversive stressful events may negatively regulate the dopaminergic reward system, perturbing reward sensitivity, which is closely associated with chronic stress-induced depression. The mesolimbic dopamine system is excited not only by reward but also by aversive stressful stimuli, which adds further intriguing complexity to the relationship between stress and the reward system. This review focuses on lines of evidence related to how stress, especially chronic stress, affects the mesolimbic dopamine system, and discusses the role of the dopaminergic reward system in chronic stress-induced depression.


Evidence-based medicine: a survey of American Urological Association members.
We investigated the attitudes and opinions of urologists toward evidence-based medicine. In April of 2005 we contacted members of the American Urological Association listed with an e-mail address to participate in a web based survey. Participants were asked to characterize their level of agreement with statements referring to the role of evidence-based medicine in urology, to indicate their level of understanding of 15 evidence-based medicine related terms and to report their familiarity with 6 evidence-based medicine related resources. Of 8,100 American Urological Association members 714 (8.8%) responded to this survey. There was widespread agreement (median score 9) with the concept that evidence-based medicine improves patient care and that every urologist should be familiar with critical appraisal techniques. Select terms such as median/mean, selection bias and type I error were well understood ("understand and could explain to others") by 86%, 57% and 17%, respectively. The American Urological Association Best Practice Guidelines were the single best known resource that 91% of respondents reviewed or used regularly. To our knowledge this survey represents the first evidence-based medicine survey of a large international group of urologists. Its results indicate that evidence-based medicine is viewed favorably and that the American Urological Association Best Practice Guidelines present a well accepted instrument for the dissemination of evidence-based medicine in urology. However, given the low response rate and the potential for selection bias, interpretation of these results must be performed with caution. Future efforts should be directed toward providing increased opportunities for urologists to learn the principles of critical appraisal, facilitating the application of evidence-based medicine in the community and promoting high quality research.


Out of sync? Demographic and other social science research on health conditions in developing countries.
In this paper, we present a framework for considering whether the marginal social benefits of demographic and social science research on various health conditions in developing countries are likely to be relatively high. Based on this framework, we argue that the relative current and future predicted prevalence of burdens of different health/disease conditions, as measured by disability-adjusted life years (DALYs), provide a fairly accurate reflection of some important factors related to the relative marginal social benefits of demographic and social science research on different health conditions. World Health Organization (WHO) DALYs projections for 2005-30 are compared with (a) demographic and other social science studies on health in developing countries during 1990-2005, and (b) presentations made at the Population Association of America annual meetings during the same time period. These comparisons suggest that recent demographic and social science research on health in developing countries has focused too much on HIV/AIDS, and too little on non-communicable diseases.


Effects of cage mesh on pointing: hand shapes in chimpanzees (Pan troglodytes).
It has been speculated that cage mesh exerts a shaping influence on reaching behavior by captive apes, which is then misconstrued as pointing by human observers. Although this notion is clearly falsified by the pointing of captive language-trained apes-who point in the absence of intervening cage mesh-nevertheless, the degree to which cage mesh might influence pointing hand shapes by captive great apes in other housing environments remains relatively unexplored. We examined 259 pointing gestures displayed in archival footage from over 18 h of observation by three nonlanguage-trained chimpanzees housed at a biomedical research center. We coded points in relation to how close to the boundaries of the diamond-shaped cage mesh their points were displayed. We found that points with the whole hand were significantly more likely to be displayed away from the mesh boundaries, relative to points with the index finger or other single-digit points. However, points of each hand shape were displayed at each location, demonstrating that these physical parameters do not fully account for the number of fingers extended while pointing by chimpanzees.


The comparative safety of analgesics in older adults with arthritis.
The safety of alternative analgesics is unclear. We examined the comparative safety of nonselective NSAIDs (nsNSAIDs), selective cyclooxygenase 2 inhibitors (coxibs), and opioids. Medicare beneficiaries from Pennsylvania and New Jersey who initiated therapy with an nsNSAID, a coxib, or an opioid from January 1, 1999, through December 31, 2005, were matched on propensity scores. We studied the risk of adverse events related to analgesics using incidence rates and adjusted hazard ratios (HRs) from Cox proportional hazards regression. The mean age of participants was 80.0 years, and almost 85% were female. After propensity score matching, the 3 analgesic cohorts were well balanced on baseline covariates. Compared with nsNSAIDs, coxibs (HR, 1.28; 95% confidence interval [CI], 1.01-1.62) and opioids (1.77; 1.39-2.24) exhibited elevated relative risk for cardiovascular events. Gastrointestinal tract bleeding risk was reduced for coxib users (HR, 0.60; 95% CI, 0.35-1.00) but was similar for opioid users. Use of coxibs and nsNSAIDs resulted in a similar risk for fracture; however, fracture risk was elevated with opioid use (HR, 4.47; 95% CI, 3.12-6.41). Use of opioids (HR, 1.68; 95% CI, 1.37-2.07) but not coxibs was associated with an increased risk for safety events requiring hospitalization compared with use of nsNSAIDs. In addition, use of opioids (HR, 1.87; 95 CI, 1.39-2.53) but not coxibs raised the risk of all-cause mortality compared with use of nsNSAIDs. The comparative safety of analgesics varies depending on the safety event studied. Opioid use exhibits an increased relative risk of many safety events compared with nsNSAIDs.


Nanoliposomal Trachyspermum ammi (L) sprague essential oil for effective control of malaria mosquito larvae, Anopheles stephensi Liston.
Controlling mosquito vectors at immature stages using larvicides is a practical strategy to stave off mosquito-borne diseases such as malaria. Developing nanoliposomes bearing essential oil is a promising approach to improving the efficacy and stability of EOs-derived larvicides. The main aim of this investigation was to assess the efficacy of nanoliposome containing Trachyspermum ammi L. EO (TAEO-NL) as a new potential formulation to control Anopheles stephensi Liston (Diptera, Culicidae) mosquito larvae. The chemical constituents of T. ammi L. essential oil (TAEO) were first investigated using gas chromatography-mass spectrometry (GC-MS) analysis; its dominant component (48.22%) was thymol. TAEO-NL with a particle size of 54.6 ± 5 nm and zeta potential of -18 ± 0.5 mV were then prepared using the ethanol injection method. Besides, the successful loading of TAEO was confirmed using Attenuated Total Reflection-Fourier Transform Infra-Red (ATR-FTIR) spectroscopy analysis. A significant difference (P < 0.05) was observed in the efficacy of TAEO-NL and TAEO with lethal concentration 50% (LC50) values of 14.09 and 59.47 μg/mL against An. stephensi larvae. However, free nanoliposomes show negligible larvicidal effects (<5%). This nano-formulation could thus be suggested as a green product against insects to impede transmission of deadly infectious diseases with possible field applicability scope.


Biogeographic variation in temperature sensitivity of decomposition in forest soils.
Determining soil carbon (C) responses to rising temperature is critical for projections of the feedbacks between terrestrial ecosystems, C cycle, and climate change. However, the direction and magnitude of this feedback remain highly uncertain due largely to our limited understanding of the spatial heterogeneity of soil C decomposition and its temperature sensitivity. Here we quantified C decomposition and its response to temperature change with an incubation study of soils from 203 sites across tropical to boreal forests in China spanning a wide range of latitudes (18°16' to 51°37'N) and longitudes (81°01' to 129°28'E). Mean annual temperature (MAT) and mean annual precipitation primarily explained the biogeographic variation in the decomposition rate and temperature sensitivity of soils: soil C decomposition rate decreased from warm and wet forests to cold and dry forests, while Q10-MAT (standardized to the MAT of each site) values displayed the opposite pattern. In contrast, biological factors (i.e. plant productivity and soil bacterial diversity) and soil factors (e.g. clay, pH, and C availability of microbial biomass C and dissolved organic C) played relatively small roles in the biogeographic patterns. Moreover, no significant relationship was found between Q10-MAT and soil C quality, challenging the current C quality-temperature hypothesis. Using a single, fixed Q10-MAT value (the mean across all forests), as is usually done in model predictions, would bias the estimated soil CO2 emissions at a temperature increase of 3.0°C. This would lead to overestimation of emissions in warm biomes, underestimation in cold biomes, and likely significant overestimation of overall C release from soil to the atmosphere. Our results highlight that climate-related biogeographic variation in soil C responses to temperature needs to be included in next-generation C cycle models to improve predictions of C-climate feedbacks.


Diatom gliding is the result of an actin-myosin motility system.
Diatoms are a group of unicellular microalgae that are encased in a highly ornamented siliceous cell wall, or frustule. Pennate diatoms have bilateral symmetry and many genera possess an elongated slit in the frustule called the raphe, a feature synonymous with their ability to adhere and glide over a substratum, a process little understood. We have used cytoskeleton-disrupting drugs to investigate the roles of actin, myosin, and microtubules in diatom gliding or motility. No effect on diatom gliding was observed using the cytochalasins, known actin inhibitors, or the microtubule-inhibitors oryzalin and nocodazole. The latrunculins are a new group of anti-actin drugs, and we show here that they are potent inhibitors of diatom gliding, resulting in the complete disassociation of the raphe-associated actin cables. The recovery of actin staining and motility following latrunculin treatment was extremely fast. Cells exposed to latrunculin for 12 h recovered full function and actin staining within 5 sec of the drug being removed, demonstrating that the molecular components required for this motility system are immediately available. Butanedione monoxime (BDM), a known myosin inhibitor, also reversibly inhibited diatom gliding in a manner similar to the latrunculins. This work provides evidence that diatom gliding is based on an actin/myosin motility system.


CircGPRC5A enhances colorectal cancer progress by stabilizing PPP1CA and inducing YAP dephosphorylation.
With the advancements in bioinformatic technology, an increasing number of circular RNAs (circRNAs) have been discovered and their crucial roles in the development and progression of various malignancies have been confirmed through multiple pathways. However, the specific mechanisms involving protein-binding circRNAs in colorectal cancer (CRC) remain largely unexplored. Differential circRNA expression was assessed using a human circRNA microarray in five CRC tissue and paired normal samples. CircGPRC5A expression was then confirmed in the CRC tissues and paired normal samples using qRT-PCR. The biological function of circGPRC5A in CRC were studied in vitro and in vivo. Western blotting, fluorescence in situ hybridization, immunofluorescence, RNA pulldown, mass spectrometry, immunoprecipitation, quantitative phosphoproteomics, and RNA-binding protein immunoprecipitation assays were used to study circGPRC5A. Our analysis revealed that circGPRC5A expression was higher in CRC tissues compared to normal tissues and was associated with tumor size, tumor stage and lymph node status. CircGPRC5A promoted CRC cell proliferation, migration, and metastasis in vitro and in vivo. CircGPRC5A could stabilize PPP1CA protein by inhibiting the binding between UBA1 and PPP1CA, and increasing YAP dephosphorylation. Our study revealed that circGPRC5A plays an essential function in CRC progression by stabilizing PPP1CA protein and enhancing YAP dephosphorylation. CircGPRC5A could act as a novel and potential target for CRC.


The prevalence and effect of burnout on graduate healthcare students.
Burnout is a growing epidemic among professional healthcare students. Unaddressed burnout has been shown to have psychological and performance related detriments. The purpose of this scoping literature review was to investigate the prevalence of burnout and its effects on the psychological, professional, empathetic ability, and academic acuity of graduate healthcare students. Inclusion criteria included English language papers published within the last 10 years and subjects in graduate healthcare professional programs. This search encompassed 8,214 articles. After title and abstract screening, 127 articles remained and were sorted into five domains of interest: etiology, professionalism, mental health, empathy, and academic performance. After duplicates were removed, 27 articles remained for the scoping review. Graduate level healthcare students had higher levels of burnout than age matched peers and the general population. The high prevalence of burnout within graduate healthcare students can have an effect on their mental health, empathy, and professional conduct. Understanding the occurrence and effects of burnout within graduate healthcare programs allows faculty and administration to plan curriculum, and provide information to students to understand, recognize, and create opportunities to decrease burnout in order to create long lasting quality clinicians.


Clearing-factor lipase in muscle and adipose tissue of pigs.
1. Clearing-factor lipase was assayed in acetone-ether-dried powders of heart and adipose tissue of pigs. The enzyme activity in heart was higher than that in adipose tissue. The activity in the outer layer of subcutaneous fat was greater than that in the inner subcutaneous fat and the perirenal fat, which had similar activities. 2. Starvation for 48h, but not for 24h, decreased the activity of the heart enzyme. 3. Starvation for 24h caused a rapid decrease in the activity in all three adipose tissues, but even after 72h of starvation the activity was still highest in the outer subcutaneous fat. 4. Plasma fatty acid, glucose and insulin concentrations were determined in fed and starved pigs. Starvation decreased the plasma insulin concentration and increased the non-esterified fatty acid concentration.


Adaptations in human muscle sarcoplasmic reticulum to prolonged submaximal training.
In this study, we employed single-leg submaximal cycle training, conducted over a 10-wk period, to investigate adaptations in sarcoplasmic reticulum (SR) Ca(2+)-regulatory proteins and processes of the vastus lateralis. During the final weeks, the untrained volunteers (age 21.4 +/- 0.3 yr; means +/- SE, n = 10) were exercising 5 times/wk and for 60 min/session. Analyses were performed on tissue extracted by needle biopsy approximately 4 days after the last training session. Compared with the control leg, the trained leg displayed a 19% reduction (P < 0.05) in homogenate maximal Ca(2+)-ATPase activity (192 +/- 11 vs. 156 +/- 18 micromol. g protein(-1). min(-1)), a 4.3% increase (P < 0.05) in pCa(50), defined as the Ca(2+) concentration at half-maximal activity (6.01 +/- 0.05 vs. 6.26 +/- 0.07), and no change in the Hill coefficient (1.75 +/- 0.15 vs. 1.76 +/- 0.21). Western blot analysis using monoclonal antibodies (7E6 and A52) revealed a 13% lower (P < 0.05) sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) 1 in trained vs. control in the absence of differences in SERCA2a. Training also resulted in an 18% lower (P < 0.05) SR Ca(2+) uptake and a 26% lower (P < 0.05) Ca(2+) release. It is concluded that a downregulation in SR Ca(2+) cycling in vastus lateralis occurs with aerobic-based training, which at least in the case of Ca(2+) uptake can be explained by reduction in Ca(2+)-ATPase activity and SERCA1 protein levels.


OnabotulinumtoxinA for the treatment of overactive bladder.
OnabotulinumtoxinA injection is a safe and effective treatment for adults with refractory overactive bladder. There is sufficient level 1 evidence to support offering onabotulinumtoxinA injections as a second-line treatment to patients who have failed behavioral therapy and oral medications such as antimuscarinics and β3 agonists. An intradetrusor injection of 100 U of onabotulinumtoxinA is likely the optimal dose to balance risks and benefits, and this is the dose approved by the US Food and Drug Administration. Improvement in urgency urinary incontinence episodes, as well as symptom scores and quality of life, were seen in around 60%-65% of patients, and were significantly improved compared with those on placebo. Most studies have reported a duration of symptom relief ranging from 6 to 12 months, with repeat injections being safe and efficacious. Overall, the risk of urinary retention was around 6% across the study populations.


Family Instability and Pathways to Adulthood in Urban South Africa.
Social, political, epidemiological, and economic forces have produced family instability during childhood for many young people transitioning to adulthood in South Africa. This study identifies pathways to adulthood for youth in Cape Town that capture the timing and sequencing of role transitions across the life domains of school, work, and family formation. It then uses these pathways to investigate the relationship between childhood family instability and the way young people's lives unfold during the transition to adulthood. Results indicate that changes in co-residence with parents are associated with following less advantageous pathways into adulthood, independent of particular family structure or orphan status. Overall, the findings suggest that family instability influences not only single transitions for youth, but also combinations of transitions. They also indicate the value of a multi-dimensional conceptualization of the transition to adulthood in empirical work.


[Problem-oriented analysis of the medical-anthropologic identification in forensic medicine].
The paper deals with a detailed analysis of the key trends in the current forensic-medical anthropology. The attention is focused on diagnosis of group personality signs: presence of osseous substance, species diagnosis, attribution of remains to one or several cadavers, determination of a possible residence territory, group adherence of the osseous and tooth tissues, as well as determination of race, sex, age, stature, etc. Such topical issues as personality reconstruction by skull, establishment of kindred, and special identification tools are detailed. Finally, conditions affecting the objects of expertise, i.e. prescription of corpse burying, fragmentation, signs of cadaver extermination, are also elucidated.


Cultural experiences of student and new-graduate dietitians in the Gomeroi gaaynggal ArtsHealth program: a quality assurance project.
Issue addressed: Undergraduate dietetic students are required to demonstrate cultural awareness and culturally respectful communication to meet national competencies, but exposure to practical experiences may be limited. The Gomeroi gaaynggal ArtsHealth Centre was established in 2009 after community consultation with the Indigenous community in Tamworth, New South Wales. The Centre provides a safe and welcoming space where women can create art while discussing health issues with visiting health professionals and students. The present study aimed to evaluate the cultural experiences of student and new-graduate dietitians visiting an Aboriginal ArtsHealth centre through a quality assurance project.Methods: Six student and new-graduate dietitians were invited to provide feedback on their experiences for this report. A generic inductive approach was used for qualitative data analysis.Results: Key qualitative themes of 'building rapport' and 'developing cultural understanding' were identified. Four of the participants interviewed felt they gained a deeper understanding of the context around health disparity for Indigenous Australians through their experiences. Key ways to build rapport with community members were identified.Conclusions: Results suggest that first-hand experiences working in an Aboriginal ArtsHealth centre are effective in building cultural competency skills for student and new-graduate dietitians. These experiences could be better supported through improved preparation for the cultural setting, and ongoing monitoring of participant experiences is recommended.So what?: The authors encourage undergraduate dietetic programs and students to seek out opportunities for further development of cultural awareness through increased practical experiences working with Indigenous communities.


Uses of winery and distillery effluents in agriculture: characterisation of nutrient and hazardous components.
Twenty-one samples of winery and distillery effluents were collected from different Spanish winery and distillery industries. Electrical conductivity, pH, redox potential, density, organic charge (chemical oxygen demand, biological oxygen demand, total, volatile and suspended solids, oxidisable organic C and polyphenols) and contents of plant nutrients and heavy metals were analysed. The aim of this work was to study the composition of these effluents and to find relationships which would make it possible to use easily determined parameters to estimate their composition. The winery wastewater (WW) and vinasse (V) showed an acidic pH, a high organic load and notable polyphenol, macronutrient, micronutrient and heavy metal contents. Some of these properties are not compatible with agricultural requirements; therefore, conditioning treatment of these liquid wastes is necessary to produce a safe, stable and easily manageable end product. Generally, in both effluent types, significant correlations were found between easily analysable parameters, such as suspended, volatile and total solids, pH, electrical conductivity, density and redox potential, and most of the parameters studied. The linear regression equations obtained permitted an immediate characterisation of the WW and V samples using these parameters.


Integration and transcription of virus DNA in herpes simplex virus transformed cell lines.
The physical state of the HSV I DNA present in two biochemically transformed cell lines, a revertant line and a supertransformed cell line, was determined. These cells all contained fragments of the HSV genome and the transformed and supertransformed cell lines expressed virus thymidine kinase. It was found that the virus DNA in these cells was maintained in a complex state with approximately half of the HSV DNA present in a covalently integrated state and the other half in a non-integrated state. There was no major cell line difference in the distribution of integrated and non-integrated virus DNA. RNA transcripts representing 5% of the HSV I genome are present in each of these lines. This is more than is required to code for the virus thymidine kinase present in the transformed and supertransformed cell lines and suggests the presence of other virus proteins in these cells.


Differences in subtype distribution between screen-detected and symptomatic invasive breast cancer and their impact on survival.
Stage shift is considered a major reason for more favorable outcomes in patients with screen-detected breast cancer. However, even after adjusting for clinical stage, unresolved issues concerning the reasons for a survival benefit associated with screening programs remain. This study aims to evaluate differences in subtype distribution and outcomes among patients with screen-detected and symptomatic invasive breast cancer and assess whether variations in subtype distribution could explain differences in prognosis. Survival analysis was performed to estimate the likelihood of distant recurrence and death in 1132 patients. Subtypes were defined as luminal A [estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)-, and Ki67 low], luminal B (HER2-) (ER+ and/or PR+, HER2-, and Ki67 high), luminal B (HER2+) (ER+ and/or PR+ and HER2+), HER2 overexpressing (ER-, PR-, and HER2+), and triple negative (ER-, PR-, and HER2-). Screen-detected cancers had favorable clinicopathological characteristics, such as smaller tumor size and a lower frequency of lymph node involvement. Women with screen-detected cancers had a survival advantage. Subtype distribution differed significantly among women with screen-detected and symptomatic cancer. Screen-detected cancers were more likely to be luminal A and less likely to be HER2 overexpressing or triple negative cancer compared with symptomatic cancers (luminal A 61.3 vs. 44.2%, HER2 overexpressing 4.0 vs. 8.0%, triple negative 8.0 vs. 15.9%). Node status, mode of detection, and subtype were independent prognostic factors in the multivariate analysis. Differences in subtype distribution between screen-detected and symptomatic cancer could partially explain differences in outcomes.


Adaptor bypass mutations of Bacillus subtilis spx suggest a mechanism for YjbH-enhanced proteolysis of the regulator Spx by ClpXP.
The global regulator, Spx, is under proteolytic control exerted by the adaptor YjbH and ATP-dependent protease ClpXP in Bacillus subtilis. While YjbH is observed to bind the Spx C-terminus, YjbH shows little affinity for ClpXP, indicating adaptor activity that does not operate by tethering. Chimeric proteins derived from B. subtilis AbrB and the Spx C-terminus showed that a 28-residue C-terminal section of Spx (AbrB28), but not the last 12 or 16 residues (AbrB12, AbrB16), was required for YjbH interaction and for ClpXP proteolysis, although the rate of AbrB28 proteolysis was not affected by YjbH addition. The result suggested that the YjbH-targeted 28 residue segment of the Spx C-terminus bears a ClpXP-recognition element(s) that is hidden in the intact Spx protein. Residue substitutions in the conserved helix α6 of the C-terminal region generated Spx substrates that were degraded by ClpXP at accelerated rates compared to wild-type Spx, and showed reduced dependency on the YjbH activity. The residue substitutions also weakened the interaction between Spx and YjbH. The results suggest a model in which YjbH, through interaction with residues of helix α6, exposes the C-terminus of Spx for recognition and proteolysis by ClpXP.


Automated deep-phenotyping of the vertebrate brain.
Here, we describe an automated platform suitable for large-scale deep-phenotyping of zebrafish mutant lines, which uses optical projection tomography to rapidly image brain-specific gene expression patterns in 3D at cellular resolution. Registration algorithms and correlation analysis are then used to compare 3D expression patterns, to automatically detect all statistically significant alterations in mutants, and to map them onto a brain atlas. Automated deep-phenotyping of a mutation in the master transcriptional regulator fezf2 not only detects all known phenotypes but also uncovers important novel neural deficits that were overlooked in previous studies. In the telencephalon, we show for the first time that fezf2 mutant zebrafish have significant patterning deficits, particularly in glutamatergic populations. Our findings reveal unexpected parallels between fezf2 function in zebrafish and mice, where mutations cause deficits in glutamatergic neurons of the telencephalon-derived neocortex.


High-precision radiocarbon dating of political collapse and dynastic origins at the Maya site of Ceibal, Guatemala.
The lowland Maya site of Ceibal, Guatemala, had a long history of occupation, spanning from the Middle Preclassic Period through the Terminal Classic (1000 BC to AD 950). The Ceibal-Petexbatun Archaeological Project has been conducting archaeological investigations at this site since 2005 and has obtained 154 radiocarbon dates, which represent the largest collection of radiocarbon assays from a single Maya site. The Bayesian analysis of these dates, combined with a detailed study of ceramics, allowed us to develop a high-precision chronology for Ceibal. Through this chronology, we traced the trajectories of the Preclassic collapse around AD 150-300 and the Classic collapse around AD 800-950, revealing similar patterns in the two cases. Social instability started with the intensification of warfare around 75 BC and AD 735, respectively, followed by the fall of multiple centers across the Maya lowlands around AD 150 and 810. The population of Ceibal persisted for some time in both cases, but the center eventually experienced major decline around AD 300 and 900. Despite these similarities in their diachronic trajectories, the outcomes of these collapses were different, with the former associated with the development of dynasties centered on divine rulership and the latter leading to their downfalls. The Ceibal dynasty emerged during the period of low population after the Preclassic collapse, suggesting that this dynasty was placed under the influence from, or by the direct intervention of, an external power.


Acceptance and Commitment Therapy versus Cognitive Behavior Therapy for Children With Anxiety: Outcomes of a Randomized Controlled Trial.
Acceptance and Commitment Therapy (ACT) has a growing empirical base in the treatment of anxiety among adults and children with other concerns. This study reports on the main outcomes of a randomized controlled trial of ACT and traditional cognitive behavioral therapy (CBT) in children with a Diagnostic and Statistical Manual of Mental Disorders (4th ed.) anxiety disorder. Participants were 193 children from urban Sydney, Australia, who were block-randomized to a 10-week group-based program of ACT or CBT or a 10-week waitlist control (WLC). Completers included 157 children (ACT = 54, CBT = 57, WLC = 46; M = 11 years, SD = 2.76; 78% Caucasian, 58% female). Pretreatment, posttreatment, and 3 months posttreatment assessments included clinician/self/parent-reported measures of anxiety, quality of life (QOL; anxiety interference, psychosocial and physical health-related QOL), and acceptance/defusion outcomes. Completer and intention-to-treat analyses revealed that ACT and CBT were both superior to WLC across outcomes, reflecting statistically and clinically significant differences, with gains maintained at 3 months posttreatment. Both completer and intention-to-treat analyses found ACT and CBT to produce similar outcomes. There was some support for ACT having greater effect sizes for QOL outcomes but not for avoidance/fusion. Although this study does not suggest that ACT is equivalent to CBT or should be adopted in its place, it does provide evidence that ACT might be another empirically supported treatment option for anxious youth. Further research is needed to replicate these findings.


Effect of different protein sources on satiation and short-term satiety when consumed as a starter.
Because the source of protein may play a role in its satiating effect, we investigated the effect of different proteins on satiation and short-term satiety. Two randomized single-blind cross-over studies were completed. In the first study, we investigated the effect of a preload containing 20 g of casein, whey, pea protein, egg albumin or maltodextrin vs. water control on food intake 30 min later in 32 male volunteers (25 ± 4 yrs, BMI 24 ± 0.4 kg/m(2)). Subjective appetite was assessed using visual analogue scales at 10 min intervals after the preload. Capillary blood glucose was measured every 30 min during 2 hrs before and after the ad libitum meal. In the second study, we compared the effect of 20 g of casein, pea protein or whey vs. water control on satiation in 32 male volunteers (25 ± 0.6 yrs, BMI 24 ± 0.5 kg/m(2)). The preload was consumed as a starter during an ad libitum meal and food intake was measured. The preloads in both studies were in the form of a beverage. In the first study, food intake was significantly lower only after casein and pea protein compared to water control (P = 0.02; 0.04 respectively). Caloric compensation was 110, 103, 62, 56 and 51% after casein, pea protein, whey, albumin and maltodextrin, respectively. Feelings of satiety were significantly higher after casein and pea protein compared to other preloads (P < 0.05). Blood glucose response to the meal was significantly lower when whey protein was consumed as a preload compared to other groups (P < 0.001). In the second study, results showed no difference between preloads on ad libitum intake. Total intake was significantly higher after caloric preloads compared to water control (P < 0.05). Casein and pea protein showed a stronger effect on food intake compared to whey when consumed as a preload. However, consuming the protein preload as a starter of a meal decreased its impact on food intake as opposed to consuming it 30 min before the meal.


Beta-lipotropin is the major component of the plasma opioid response to surgical stress in humans.
There is growing experimental evidence that beta-endorphin immunoreactivity is raised by surgical stress in patients undergoing general anesthesia. As the assay methods employed to date did not allow to fully discriminate between beta-endorphin and its immediate precursor, beta-lipotropin, we have investigated in the present study plasma levels of these two peptides by separating them by chromatography on plasma extracts prior to radioimmunoassay in eighteen surgical patients under general anesthesia and eight under spinal anesthesia. Beta-lipotropin, but not beta-endorphin, plasma levels were found to be significantly elevated during surgery in the general anesthesia group, while no change was found in either peptide concentration in the spinal one. Cortisol plasma levels also increased significantly 90 minutes after the beginning of surgery, when they were positively correlated to beta-lipotropin ones. Although the sampling time we adopted may have prevented us from detecting an early peak of beta-endorphin during the first 30 minutes of surgery, the major component of the pituitary opioid response to surgical stress appears to be related to beta-lipotropin. This is in agreement with results of experimental work on various kinds of stress in animals and humans and seems to rule out a role for plasma beta-endorphin in post-operative analgesia.


Varicella zoster virus (VZV) infects and establishes latency in enteric neurons.
Case reports have linked varicella-zoster virus (VZV) to gastrointestinal disorders, including severe abdominal pain preceding fatal varicella and acute colonic pseudoobstruction (Ogilvie's syndrome). Because we had previously detected DNA and transcripts encoding latency-associated VZV gene products in the human gut, we sought to determine whether latent VZV is present in the human enteric nervous system (ENS) and, if so, to identify the cells in which it is located and its route to the bowel. Neither DNA, nor transcripts encoding VZV gene products, could be detected in resected gut from any of seven control children (<1 year old) who had not received the varicella vaccine or experienced varicella; however, VZV DNA and transcripts were each found to be present in resected bowel from 6/6 of children with a past history of varicella and in that of 6/7 of children who received the varicella vaccine. Both wild-type (WT) and vaccine-type (vOka) VZV thus establish latent infection in human gut. To determine routes by which VZV might gain access to the bowel, we injected guinea pigs with human or guinea pig lymphocytes expressing green fluorescent protein (GFP) under the control of the VZV ORF66 gene (VZV(OKA66.GFP)). GFP-expressing enteric neurons were found throughout the bowel within 2 days and continued to be present for greater than 6 weeks. DNA encoding VZV gene products also appeared in enteric and dorsal root ganglion (DRG) neurons following intradermal administration of WT-VZV and in enteric neurons after intradermal injection of VZV(OKA66.GFP); moreover, a small number of guinea pig DRG neurons were found to project both to the skin and the intraperitoneal viscera. Viremia, in which lymphocytes carry VZV, or axonal transport from DRG neurons infected through their epidermal projections are thus each potential routes that enable VZV to gain access to the ENS.


Surveying knowledge, practice and attitudes towards intervention fidelity within trials of complex healthcare interventions.
Intervention fidelity is the degree to which interventions have been implemented as intended by their developers. Assessing fidelity is crucial for accurate interpretation of intervention effectiveness, but fidelity is often poorly addressed within trials of complex healthcare interventions. The reasons for this are unclear, and information on the use of methods to enhance and assess fidelity in trials of complex interventions remains insufficient. This study aimed to explore the knowledge, practice and attitudes towards intervention fidelity amongst researchers, triallists and healthcare professionals involved with the design and conduct of trials of complex healthcare interventions. An online survey consisting of closed and open-ended questions exploring four sections (Demographics, Fidelity knowledge, Practice and Attitudes) was conducted. This was an opportunistic sample of individuals with experience of direct involvement in trials of complex healthcare interventions (e.g. design/development, conduct, evaluation). Data from 264 participants representing 15 countries were analysed. The majority (65.9%, n = 174) of participants identified themselves as 'Researchers'. The majority of participants were familiar with the term "intervention fidelity" (69.7%, n = 184) and indicated that fidelity is important (89.7%, n = 236). Mean self-reported understanding of fidelity was moderate. Although 68% (n = 182) had previously used strategies to assess (e.g. audio/video-recording sessions) and enhance (e.g. training manual) fidelity in trials of complex interventions, only a limited proportion of participants indicated always reporting these strategies in subsequent publications (30.9%, n = 56). Poor knowledge or understanding was the most commonly cited barrier to addressing intervention fidelity in trials (77.4%, n = 202). Over half of respondents (52.1%, n = 137) had never completed specific fidelity training or research, and the vast majority (89.7%, n = 236) would welcome specific training in this area. Despite good awareness of intervention fidelity and its importance, poor knowledge and understanding appears to be a key factor limiting how intervention fidelity is addressed in trials of complex interventions. Participants identified a need for further training and education in this area. Additionally, clarification of the terminology, definition and components of intervention fidelity would facilitate better understanding of the concept. A discrepancy between participants' use of fidelity strategies and subsequent reporting raises concerns around inadequate fidelity reporting in the trials literature.


[The effectiveness and safety of the balneotherapeutic treatment of the mechanical transport drivers suffering heart rhythm disorders].
To estimate the effectiveness and safety of the balneotherapeutic treatment of the of mechanical transport drivers (MTD) suffering heart rhythm and cardiac conduction (HR&CC) disorders with concomitant arterial hypertension (AH) treated based at a Nalchik health resort. A total of 42 MTD (all men) presenting with HR&CC disorders and I-II grade AH were admitted for the balneotherapeutic treatment at a Nalchik health resort using two main approaches, viz. (a) thermal nitrogen mineral baths 36-37 degrees C in the form of 22 courses consisting of 8-10 sessions each (10-15 min every other day) and (b) bromine-iodine mineral baths 36-37 degrees C in the form of 20 courses consistingof 8-10 sessions each (10-15 min every other day). The outcomes of the treatment were estimated based on the results of general clinical examination and laboratory analyses supplemented by round-the-clock monitoring of arterial pressure and ECG, psychological and psychophysiological testing (PPT). The results of clinical and instrumental investigations into dynamics of the general health status, peripheral and coronary hemodynamics in the drivers with HR&CC disorders and AH give evidence of the improvement of their psychosomatic status following the treatment with the use ofthermal nitrogen and bromine-iodine mineral baths in 86.4 and 80.0% of the cases, respectively. In the subjects of the former group, significant changes in the dynamic response system were documented. 75% of MTD included in the latter group were characterized by the absence of improvement of professionally significant functions and skills that were found to deteriorate in the remaining 25%. The balneotherapeutic treatment of MTD presenting with HR&CC disorders and I-II grade AH with the use of thermal nitrogen mineral baths proved to be a highly effective, specific, and safe method in 86.4% of the cases. The use of bromine-iodine mineral baths resulted in clinical and hemodynamic changes of the psychosomatic status in 80.0% of the drivers concomitant with the deterioration of their professional activities. It is concluded that PPT is mandatory for the mechanical transport drivers presenting with HR&CC disorders and I-II grade AH before they resume their professional activities after the balneotherapeutic treatment.


The modulatory effects of mu and kappa opioid agonists on 5-HT release from hippocampal and hypothalamic slices of euthermic and hibernating ground squirrels.
To elucidate the role of opioids in regulating hibernation, the modulatory effects of different opioids on 35 mM K(+)-stimulated [3H]-5-HT release from brain slices were examined in the Richardson's ground squirrels. DAGO ([D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin), a specific mu agonist, evoked a significant dose-dependent (10(-7)-10(-5) M) inhibition of K(+)-stimulated 5-HT release from hippocampal slices of the non-hibernating squirrels. The inhibitory effect of DAGO was attenuated by either the opioid antagonist naloxone (10(-6) M) or the voltage dependent sodium channel blocker tetrodotoxin (TTX, 10(-6) M). The inhibitory effect of DAGO persisted in the hibernating squirrels; however, a ten fold higher concentration of DAGO (10(-6)-10(-5) M) was required to elicit a significant inhibition. In contrast, kappa agonist U50488 (10(-5) M) exerted a significant enhancement of K(+)-stimulated 5-HT release from hippocampal slices of the non-hibernating squirrels. This enhancement was blocked by either the specific kappa antagonist nor-binaltorphimine (10(-6) M) or TTX (10(-6) M). However, in the hibernating squirrels, the stimulatory effect of U50488 (10(-5) M) on 5-HT release was absent. DAGO and U50488 had no modulatory effects on K(+)-stimulated 5-HT release from the hypothalamic slices of either the non-hibernating or hibernating squirrels. These results demonstrate that the modulatory effects of opioids on 5-HT release are receptor-specific and state-dependent, indicating the complex nature of the roles of different opioids in regulating hibernation.


Expression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells.
Human papillomavirus (HPV) infection represents the most important risk factor for developing cervical cancer. In this study, we examine the potential of full-length E7-pulsed autologous dendritic cells (DCs) to induce antigen-specific CTL responses from the peripheral blood of healthy individuals against HLA-A2-matched HPV-16 and HPV-18-positive tumor target cells in vitro. We show that DCs pulsed with E7 oncoprotein can consistently stimulate antigen-specific CTL responses that recognize and lyse HPV-16 or HPV-18-positive naturally infected cervical cancer cell lines. HPV-negative, EBV-transformed lymphoblastoid cell lines (LCLs) sharing the HLA haplotype of the target tumor cells, as well as autologous donor LCLs, were not significantly killed by E7-specific CTLs. Cytotoxicity against HLA-A2-matched HPV-16 and HPV-18 tumor target cells could be significantly inhibited by anti-HLA class I and by anti-HLA-A2 monoclonal antibodies. CD8+ CTLs expressed variable levels of CD56 and showed a strongly polarized Type 1 cytokine profile. Sorting of the CD8+ T cells on the basis of CD56 expression demonstrated that the most highly cytotoxic CTLs were CD56+ and expressed higher levels of perforin and IFN-gamma, compared with the CD8+/CD56- population. Taken together, these data demonstrate that full-length, E7-pulsed DCs can consistently induce E7-specific CD8+ CTL responses in healthy individuals that are able to kill naturally HPV-16 and HPV-18-infected cancer cells, and that CD56 expression defines a subset of CD8+ CTLs with high cytolytic activity against tumor cells.


Rivaroxaban versus fondaparinux for thromboprophylaxis after endovenous laser ablation.
Endovenous heat-induced thrombosis (EHIT) and deep venous thrombosis (DVT) are well-known complications after superficial endovenous thermoablation. We investigated the efficacy of rivaroxaban in preventing EHIT and DVT after endovenous laser ablation (EVLA). We retrospectively analyzed a consecutive series of patients presenting with truncal varicosis class C2 to C6 undergoing EVLA. After EVLA, all patients received oral rivaroxaban (10 mg) or subcutaneous fondaparinux (2.5 mg) once daily for 3 consecutive days. The primary end point was the composite of EHIT or DVT assessed by duplex ultrasound imaging after 1 and 4 weeks. EHIT class 1 was defined as the thrombus extending to the saphenofemoral junction. Extension into the deep venous system with a cross-sectional area obstruction <50% was considered EHIT class 2. EHIT class 3 was defined as >50% cross-sectional area obstruction. EHIT class 4 was total occlusion of the femoral vein. The secondary end points were minor or major bleeding, paresthesia, and skin burns. Between February 2009 and December 2015, 391 patients (473 limbs) were treated with EVLA of the truncal saphenous vein. The primary end point occurred in 13 of 166 (7.8%) and 14 of 225 (6.2%) after 1 week and in 13 of 166 (7.8%) and 15 of 225 (6.7%) after 4 weeks comparing the rivaroxaban and fondaparinux groups (P = .659). EHIT class 1 was observed in 20 patients (5.1%) and EHIT class 2 in five (1.3%). No patients had EHIT class 3 or 4. The incidence of DVT was one of 166 (0.6%) in the rivaroxaban group and two of 225 (0.9%) in the fondaparinux group (P = .750). Minor bleeding events occurred in 17 of 166 patients (10.2%) and in 20 of 225 patients (8.9%), respectively (P = .652). No major bleeding events were observed. Paresthesia was observed in 12.5% in the rivaroxaban group and in 17.8% in the fondaparinux group. No skin burns were observed. Rivaroxaban offers an oral medication approach showing no difference in preventing EHIT and DVT compared with fondaparinux, without increased bleeding risk.


Lhermitte's Sign Developing after IMRT for Head and Neck Cancer.
Background. Lhermitte's sign (LS) is a benign form of myelopathy with neck flexion producing an unpleasant electric-shock sensation radiating down the extremities. Although rare, it can occur after head and neck radiotherapy. Results. We report a case of Lhermitte's developing after curative intensity-modulated radiotherapy (IMRT) for a patient with locoregionally advanced oropharyngeal cancer. IMRT delivers a conformal dose of radiation in head and neck cancer resulting in a gradient of radiation dose throughout the spinal cord. Using IMRT, more dose is delivered to the anterior spinal cord than the posterior cord. Conclusions. Lhermitte's sign can develop after IMRT for head and neck cancer. We propose an anterior spinal cord structure, the spinothalamic tract to be the target of IMRT-caused LS.


Circadian rhythmicity of antioxidant markers in rats exposed to 1.8 GHz radiofrequency fields.
The potential health risks of exposure to Radiofrequency Fields (RF) emitted by mobile phones are currently of considerable public interest, such as the adverse effects on the circadian rhythmicities of biological systems. To determine whether circadian rhythms of the plasma antioxidants (Mel, GSH-Px and SOD) are affected by RF, we performed a study on male Sprague Dawley rats exposed to the 1.8 GHz RF. All animals were divided into seven groups. The animals in six groups were exposed to 1.8 GHz RF (201.7 μW/cm² power density, 0.05653 W/kg specific absorption rate) at a specific period of the day (3, 7, 11, 15, 19 and 23 h GMT, respectively), for 2 h/day for 32 consecutive days. The rats in the seventh group were used as sham-exposed controls. At the end of last RF exposure, blood samples were collected from each rat every 4 h (total period of 24 h) and also at similar times from sham-exposed animals. The concentrations of three antioxidants (Mel, GSH-Px and SOD) were determined. The data in RF-exposed rats were compared with those in sham-exposed animals. circadian rhythms in the synthesis of Mel and antioxidant enzymes, GSH-Px and SOD, were shifted in RF-exposed rats compared to sham-exposed animals: the Mel, GSH-Px and SOD levels were significantly decreased when RF exposure was given at 23 and 3 h GMT. The overall results indicate that there may be adverse effects of RF exposure on antioxidant function, in terms of both the daily antioxidative levels, as well as the circadian rhythmicity.


Modification of the actions of ethanol by centrally active peptides.
Ethanol (2.0-5.0 g/kg, IP) caused a dose-related impairment of the aerial righting reflex of mice 60 min after injection. Ethanol (3.5 g/kg, IP) given simultaneously with neurotensin (30 micrograms, IC), bombesin (30 micrograms, IC) or beta-endorphin (20 micrograms, IC) caused a greater impairment of the reflex than ethanol alone. Simultaneous treatment with ethanol (4.0 g/kg, IP) and thyrotropin-releasing hormone (TRH, 3.0-30 micrograms, IC) caused less impairment of this measure than ethanol alone. None of the peptides altered the height of aerial righting when administered alone, or when administered with ethanol no peptide altered blood or brain ethanol content. Unexpectedly, TRH (20 and 40 mg/kg, IP) potentiated the action of ethanol by increasing punished licking in water-deprived rats, rather than antagonizing this acute action of ethanol. Like ethanol (1.0 and 2.0 g/kg, IP), beta-endorphin (100 micrograms, IC) suppressed ethanol-withdrawal tremor and audiogenic-seizure susceptibility in ethanol-dependent rats. beta-Endorphin (1 microgram) and bombesin (10 and 30 micrograms, IC) reduced only audiogenic-seizure susceptibility. TRH (10-100 micrograms, IC, or 1-40 mg/kg, IV) and neurotensin (10-100 micrograms, IC) had no effect on these ethanol-withdrawal signs. These findings suggest that centrally active peptides may play a role in certain acute and chronic actions of ethanol. Because TRH, neurotensin, bombesin and beta-endorphin do not alter all actions of ethanol in the same way, an interaction of ethanol with many functionally independent neuronal circuits is suggested.


ELISpot displays a better detection over ELISA of T helper (Th) 2-type cytokine-production by ex vivo-stimulated antigen-specific T cells from human peripheral blood.
Detection of cytokines secreted by ex vivo antigen-stimulated peripheral blood mononuclear cells (PBMC) by ELISA is hampered by low frequencies of specific T cells and cellular receptor consumption. We investigated if ELISpot, measuring cytokine production at the single cell level, facilitated a better detection of the Th2 cytokines IL-4 and IL-5. PBMC from nickel-allergic (n = 31) and non-allergic subjects (n = 10) were stimulated with nickel or tetanus toxoid (TT) and cytokine production assessed by ELISpot and ELISA. By IL-4 ELISpot, 74% of the allergic and 0% control subjects responded to nickel and 56% of all subjects to TT. ELISA detected IL-4 after nickel stimulation only in 13% of the allergic subjects. Also detection of TT-induced IL-5 was improved by ELISpot with 54% subjects responding versus 24% in ELISA. In contrast, detection of nickel-induced IL-5 was more comparable between methods, most likely due to the 7-fold higher IL-5 production per cell in response to nickel versus TT. The low IL-5 response to TT was associated with a higher induction of the down-regulatory cytokine IL-10 by TT as compared to nickel (p < 0.001). Overall, ELISpot displayed a better detection of IL-4 as well as low intensity IL-5 responses thus emphasizing the importance of selecting suitable methods for the measurement of cytokine production ex vivo.


Flavour aversion produced by running and attenuated by prior exposure to wheels.
In two experiments hungry rats were given access to running wheels. When given the novel flavour, almond, prior to novel access to the wheels, a conditioned aversion to almond was revealed by a subsequent two-bottle test. No such aversion was found in rats with previous experience of wheel running, whether this prior running occurred in the absence of any novel flavour, as in Experiment 1, or following access to saccharin, as in Experiment 2. These results suggest that the failure of rats with prior experience of the running wheels to develop a flavour aversion (unconditioned stimulus, US, preexposure effect) is unlikely to be due to associative blocking. Instead it seems that increasing exposure to a wheel produces habituation of its nausea-inducing properties.


Involvement of histone H2B monoubiquitination in the regulation of mouse preimplantation development.
Histone H2B monoubiquitination (H2Bub1) plays an important role in developmental regulation in various vertebrate species. However, the role of H2Bub1 in mammalian preimplantation development remains unclear. In the present study, we examined the role of H2Bub1 in the regulation of mouse preimplantation development. Based on immunocytochemical analysis using an anti-H2Bub1 antibody, no H2Bub1 signal was detected in the metaphase chromosomes of unfertilized oocytes or the pronuclei of early 1-cell stage embryos, but a weak signal was observed in late 1-cell stage embryos. The signal increased after cleavage into the 2-cell stage, and thereafter a strong signal was observed until the blastocyst stage. To assess the significance of H2Bub1 in the regulation of preimplantation development, RNF20 (an H2B-specific ubiquitin E3 ligase) was knocked down using small interfering RNA (siRNAs). In embryos treated with siRNA, the levels of Rnf20 mRNA and H2Bub1 decreased at the 4-cell and morula stages. Although these embryos developed normally until the morula stage, only one-third developed into the blastocyst stage. These results suggested that H2Bub1 is involved in the regulation of preimplantation development.


Sensitive red protein calcium indicators for imaging neural activity.
Genetically encoded calcium indicators (GECIs) allow measurement of activity in large populations of neurons and in small neuronal compartments, over times of milliseconds to months. Although GFP-based GECIs are widely used for in vivo neurophysiology, GECIs with red-shifted excitation and emission spectra have advantages for in vivo imaging because of reduced scattering and absorption in tissue, and a consequent reduction in phototoxicity. However, current red GECIs are inferior to the state-of-the-art GFP-based GCaMP6 indicators for detecting and quantifying neural activity. Here we present improved red GECIs based on mRuby (jRCaMP1a, b) and mApple (jRGECO1a), with sensitivity comparable to GCaMP6. We characterized the performance of the new red GECIs in cultured neurons and in mouse, Drosophila, zebrafish and C. elegans in vivo. Red GECIs facilitate deep-tissue imaging, dual-color imaging together with GFP-based reporters, and the use of optogenetics in combination with calcium imaging.


HIV type 1 A/J recombinant with a pronounced pol gene mosaicism.
A nearly full-length genome sequence of a novel HIV-1 A/J recombinant with a complex structure of the pol gene has been analyzed. This virus was isolated in 1998 from a 35-year-old female from Botswana. The virus demonstrated a dual pattern for CXCR4/CCR5 coreceptor utilization. Using short-term enrichment of the donor's PBMCs, the 98BW21 isolate was long-range amplified, cloned, and sequenced. The sequence of the clone 98BW21.17 spanned 9103 bp from the PBS site to the U5 region of the 3' LTR. The phylogenetic relationship of the 98BW21.17 clone to HIV-1 sequences represented by M, N, and O groups and A-K subtypes of the M group was examined across the entire viral genome. The 98BW21.17 clone demonstrated a unique phylogenetic topology clustering within subtype A or subtype J reference sequences. However, the subtype origin of two regions within the pol gene (p51 RT and integrase) could not be identified. Recombination patterns of the 98BW21.17 clone were different from known AGJ/AGIJ-type viruses such as isolates BFP90 and 95ML84. This study demonstrated the existence and replication competence of a new dual-tropic X4/R5 recombinant form of HIV-1 on the subtype J backbone. The nucleotide sequence of the 98BW21.17 clone was submitted to GenBank under accession number AF192135.


Comparison of vaginal flora after treatment with a clotrimazole 500 mg vaginal pessary or a fluconazole 150 mg capsule for vaginal candidosis.
The effect of antifungal therapy on the vaginal microbial flora was studied in 23 patients suffering from culture-positive, symptomatic vaginal candidosis. They were randomly allocated to receive either a 500 mg clotrimazole vaginal pessary or a 150 mg fluconazole capsule. Quantitative microbiological examination was carried out on samples of vaginal secretions obtained prior, and at intervals up to 10 days after, treatment. No significant difference was found in the vaginal flora before or after therapy in individual patients or between the treatment groups. In patients with C glabrata or C krusei, the yeasts persisted longer in the vagina with poorer response to either of the medications.


Assessment of Virus Interference in a Test-negative Study of Influenza Vaccine Effectiveness.
The observational test-negative study design is used to estimate vaccine effectiveness against influenza virus infection. An important assumption of the test-negative design is that vaccination does not affect the risk of infection with another virus. If such virus interference occurred, detection of other respiratory viruses would be more common among influenza vaccine recipients and vaccine effectiveness estimates could differ. We evaluated the potential for virus interference using data from the Influenza Incidence Surveillance Project. From 2010 to 2013, outpatients presenting to clinics in 13 US jurisdictions with acute respiratory infections were tested for influenza and other respiratory viruses. We investigated whether virus interference might affect vaccine effectiveness estimates by first evaluating the sensitivity of estimates using alternative control groups that include or exclude patients with other respiratory virus detections by age group and early/middle/late stage of influenza seasons. Second, we evaluated the association between influenza vaccination receipt and other respiratory virus detection among influenza test-negative patients. Influenza was detected in 3,743/10,650 patients (35%), and overall vaccine effectiveness was 47% (95% CI: 42%, 52%). Estimates using each control group were consistent overall or when stratified by age groups, and there were no differences among early, middle, or late phase during influenza season. We found no associations between detection of other respiratory viruses and receipt of influenza vaccination. In this 3-year test-negative design study in an outpatient setting in the United States, we found no evidence of virus interference or impact on influenza vaccine effectiveness estimation.


An effective technique to correct anterior mitral leaflet prolapse.
Up to one-third of the patients with degenerative mitral valve disease and severe mitral regurgitation have anterior mitral valve prolapse due to chordal rupture or elongation. Surgical treatment of such a condition is often technically demanding and not infrequently associated with suboptimal results. Techniques used to treat anterior leaflet prolapse include chordal transfer, chordal shortening, artificial chordae, and anterior leaflet resection or plication. Each of these strategies has potential shortcomings, and there is considerable controversy concerning the durability of anterior leaflet prolapse repairs using these techniques. The "edge-to-edge" technique, a simple and effective method of correcting anterior mitral leaflet prolapse is described.


The ERC1 scaffold protein implicated in cell motility drives the assembly of a liquid phase.
Several cellular processes depend on networks of proteins assembled at specific sites near the plasma membrane. Scaffold proteins assemble these networks by recruiting relevant molecules. The scaffold protein ERC1/ELKS and its partners promote cell migration and invasion, and assemble into dynamic networks at the protruding edge of cells. Here by electron microscopy and single molecule analysis we identify ERC1 as an extended flexible dimer. We found that ERC1 scaffolds form cytoplasmic condensates with a behavior that is consistent with liquid phases that are modulated by a predicted disordered region of ERC1. These condensates specifically host partners of a network relevant to cell motility, including liprin-α1, which was unnecessary for the formation of condensates, but influenced their dynamic behavior. Phase separation at specific sites of the cell periphery may represent an elegant mechanism to control the assembly and turnover of dynamic scaffolds needed for the spatial localization and processing of molecules.


Dosimetry for treatment with radiolabelled somatostatin analogues. A review.
Peptide Receptor Radionuclide Therapy (PRRT) has proven its efficacy in the treatment of neuroendocrine and other somatostatin receptor expressing tumours (SR-tumours). Several clinical trials have confirmed that adverse effects are represented by possible renal impairment, which is the major concern, and low but not absent hematological toxicity. High kidney irradiation is a constant, despite the sparing of dose obtained by renal protectors. Hematological toxicity, although low, needs to be monitored. The clinical and dosimetry results collected in more than a decade have recognized weak points to unravel, increased knowledge, offering new views. When planning therapy with radiopeptides, the large patients' variability as for biodistribution and tumour uptake must be taken into account in order to tailor the therapy, or at least to avoid foreseeable gross treatments. Reliable and personalized dosimetry is more and more requested. This paper reviews through the literature the methods to study the biokinetics, the dosimetry outcomes, some clue information and correlations obtained once applying the radiobiological models. Special focus is given on recent improvements and indications for critical organ protection that light up challenging perspectives for PRRT.


Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.
Fifty consecutive patients with thrombocythemia (35 men and 15 women) were diagnosed as primary thrombocythemia (PT) in 30 and thrombocythemia associated with polycythemia vera (PV) in 20. The symptoms were platelet-mediated erythromelalgia in 16 PT and 15 PV, coronary artery disease in 3 PT and 2 PV, atypical cerebral ischemic attacks in 8 PT and 3 PV, paradoxical thrombosis and bleeding in 3 PT and 2 PV and hemorrhages alone in 6 PT and 2 PV patients. Erythromelalgia was localized in the forefoot sole and toes in 28, the fingertips in 9, the handpalm in 2. Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases. Painful red, warm and indurated erythromelalgic hot spots in the skin of the upper legs were misdiagnosed as superficial thrombophelebitis in 5 PT and 2 PV patients. Erythromelalgia in thrombocythemia already occurred at slightly increased platelet counts above 400 x 10(9)/l. The curative effect of aspirin on erythromelalgia in thrombocythemia was consistently accompanied by a significant increase of platelet counts. Erythromelalgia and bleeding paradoxically occurred in 5 patients at platelet counts between 1000 and 2000 x 10(9)/l. In this situation aspirin prevents erythromelalgic and microcirculatory circulation disturbances, but further increases the risk of serious bleeding complications. Presenting hemorrhagic manifestations in thrombocythemia were observed at platelet counts in excess of 1000 x 10(9)/l in 9 PT and 4 PV patients as severe epistaxis in 5, atypical ecchymoses in 3, gastrointestinal bleeding in 2 and secondary bleeding in 3. The concept of platelet-mediated erythromelalgia, thrombosis and hemorrhages in thrombocythemia is discussed.


Cauliflower-like CeO2-TiO2 hybrid nanostructures with extreme photocatalytic and self-cleaning properties.
In recent years, heterogeneous photocatalysis has gained enormous interest due to increasing concerns about environmental pollution. Here we propose a facile approach to synthesize cauliflower-like CeO2-TiO2 hybrid structures by magnetron reactive sputtering, exhibiting an extremely high photocatalytic activity. While heating and air-quenching of the sputter deposited TiO2 thin film (first layer) triggered the formation of a nanocrack network, the second heat-treatment led to transformation of the CeO2 film (second layer) into CeO2 nanoclusters (NCs). We attribute the resulting high photocatalytic activity to the confined structure of the CeO2 NCs and the CeO2-TiO2 interface, which allows Ce3+/Ce4+ dynamic shifting. In addition to high photocatalytic activity in an aqueous medium, the prepared CeO2-TiO2 hybrid structures exhibited significant self-cleaning properties in air (non-aqueous).


The Effects of Knee Orthosis with Two Degrees of Freedom Joint Design on Gait and Sit-to-Stand Task in Patients with Medial Knee Osteoarthritis.
Knee bracing as a conservative treatment option for patients with medial knee osteoarthritis (KOA) is of great interest to health practitioners and patients alike. Optimal orthotic knee joint structure is essential to achieve biomechanical and clinical effectiveness. Therefore, this study aimed to identify the effects of a knee orthosis with a new two-degrees-of-freedom (DOF) joint design on selected gait parameters and in a sit-to-stand task in patients with mild-to-moderate medial KOA. This study was conducted both at the Physical Medicine and Rehabilitation Clinic in Shahid Modarres Academic Hospital and the Biomechanical Laboratory of Rehabilitation Faculty of Iran University of medical Sciences in Tehran, Iran from September 2015 to October 2017. The gait performance of 16 patients was assessed without an orthosis, using a common one-DOF (DOF) knee orthosis and using the same knee orthosis with a two-DOF orthotic joint design. The interactive shearing force between limb and brace in the shell area during a sit-to-stand test was also identified. Repeated measures analysis of variance was used to analyse the data. Compared with walking with no orthosis, both orthosis conditions reduced the external knee adduction moment significantly (P ≤0.05). A significant increase between the one-DOF and two-DOF conditions in terms of walking speed (P = 0.041 and P = 0.009, respectively) and stride length (P = 0.028 and P = 0.038, respectively) was observed. In a sit-to-stand test, wearing the orthosis significantly decreased knee transverse plane range of motion (P ≤0.05). There was a 41.31 ± 8.34 Newtons reduction in knee flexion constraint force. The two-DOF knee orthosis was more comfortable compared to the one-DOF knee orthosis during deep knee flexion. Otherwise, the one-DOF- and two-DOF-braces performed similarly.


Comparison between a new ultrasound probe with a capacitive micromachined transducer (CMUT) and a traditional one in musculoskeletal pathology.
The capacitive micromachined ultrasound transducer (CMUT) is a new ultrasound (US) probe manufactured by state-of-the-art cutting-edge semi-conductor micromachined electro-mechanical systems (MEMS) technology. To demonstrate the peculiar characteristics of each probe and the limitations that should be improved. This study was performed from March to April 2018. The only inclusion criterion was the presence of disease, so all patients with musculoskeletal, skin, and subcutaneous pathology were included. A total of 66 patients entered this study. The exams of each patient, with both probes, were evaluated retrospectively and independently by three radiologists. Panoramicity of the images, the definition of superficial structures (<2 cm of depth), the definition of deep structures (>2 cm), and Doppler signal were assessed. A 5-point scale was used for each parameter. A total of 89 pathologies were detected. The mean of score for 4G-CMUT was higher than L64 for the panoramicity of the images and the definition of the deep structures. Instead, the mean score for L64 was higher than for 4G-CMUT in the evaluation of superficial structures and Doppler signal. A statistically significant difference was found (P < 0.05). CMUT is a breakthrough in US technology. It allows the use of a single probe for different US examinations. The musculoskeletal, skin, and subcutaneous US can be evaluated with a piezoelectric linear transducer or CMUT. In the present study, the overall diagnostic performance was similar. Improvements in CMUT will provide even more dynamic and flexible imaging capabilities by a transducer, with a wider bandwidth.


Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury.
The inhibitor of NF-kappaB (I-kappaB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-kappaB essential modulator (NEMO), and is involved in the activation of NF-kappaB by various stimuli. IKK2 or NEMO constitutive knockout mice die during embryogenesis as a result of massive hepatic apoptosis. Therefore, we examined the role of IKK2 in TNF-induced apoptosis and ischemia/reperfusion (I/R) injury in the liver by using conditional knockout mice. Hepatocyte-specific ablation of IKK2 did not lead to impaired activation of NF-kappaB or increased apoptosis after TNF-alpha stimulation whereas conditional NEMO knockout resulted in complete block of NF-kappaB activation and massive hepatocyte apoptosis. In a model of partial hepatic I/R injury, mice lacking IKK2 in hepatocytes displayed significantly reduced liver necrosis and inflammation than wild-type mice. AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.


Molecular modeling applied to anti-cancer drug development.
In the past, anti-cancer drugs were identified and developed without focusing on a particular macromolecular target. Currently, the fields of molecular biochemistry, molecular biology, genetics and pharmacology, among other disciplines, have grown considerably in their ability to identify biological targets. These disciplines are now searching for specific targets to treat cancer. These targets exist in different cellular compartments (membrane, cytoplasm, nucleus) as proteins, glycoproteins, nucleic acids, etc. Computational tools have recently been used to explore such targets and to corroborate previously obtained experimental data. These methods have also been used to design new drugs with the aim of decreasing illness and the economic resources needed to discover drug candidates. Some of these computational methods include quantum mechanics (ab initio and density functional theories) and molecular mechanics (docking, molecular dynamics, and protein folding). Docking and molecular dynamics are the most commonly used computational tools for elucidating cancer targets. Using these tools, one can identify the recognition processes between ligands and targets at the atomic level. In addition, one can identify the affinity and conformational changes of these molecular complexes. In conclusion, we propose that the use of such tools is necessary in order to identify new anti-cancer drugs.


The addition of Cytosorb in patients on VA-ECMO improves urinary output and ICU survival.
The aim of this study was to analyze the efficiency of CytoSorb adsorber in patients presenting with cardiogenic shock and treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO). Sixteen patients put on VA ECMO due to cardiogenic shock were included, stratified according to the use of Cytosorb adsorber in the first 24 h and compared across different clinical outcomes. Significantly lower vasopressor doses were required among patients treated with Cytosorb at the initiation and before weaning from ECMO. Furthermore, these patients showed significantly higher urine output before weaning and lower lactate levels during the extracorporeal support. Finally, the mortality rate was lower among the Cytosorb therapy group (22.2% vs 57.1%). While a decrease in vasopressor doses was already associated with CytoSorb use, this is the first study showing an increase in urinary output and a trend towards better survival among patients on VA ECMO treated with CytoSorb.


Guidelines for the use of long-term central venous catheter in children with hemato-oncological disorders. On behalf of supportive therapy working group of Italian Association of Pediatric Hematology and Oncology (AIEOP).
In the last 30 years, the use of long-term central venous catheters (CVC) is increased especially for children with hemato-oncological disorders. However, the use of CVC is associated to complications, as mechanical accidents, thrombosis, and infections that can determine a prolongation of hospital stay, an increase of costs, and sometimes life-threatening conditions that require urgent systemic treatment or CVC removal. CVC removal may be troublesome especially in neonates, infants, or any other "highly needed CVC patients"; in these selected cases, the prevention and treatment of CVC-related complications play a pivotal role and specific surveillance programs are crucial. While extensive literature is focused on CVC management in adults, no guidelines are available for children. To this aim, the first recommendations for the management of CVC infectious complication in pediatric age have been written after pediatric and adult literature review and collegial discussion among members of Supportive Therapy working group of Italian Association of Pediatric Hematology and Oncology. Compared to the adult age, the necessity of peripheral vein cultures for the diagnosis of CVC-related infection remains controversial in children because of the poorer venous asset and a conservative, pharmacologically focused management through CVC remains mandatory, with CVC removal to be performed only in selected cases.


Significant event analysis: a comparative study of knowledge, process and attitudes in primary care.
Significant event analysis (SEA) is now well established in UK primary care. Previously, considerable variation has been reported in the knowledge, skills and attitudes of general practitioners undertaking SEA. Little is known about the wider team's understanding, participation or perceptions. We therefore aimed to determine the awareness, degree of analysis and perceived risk of recurrence of a recent significant event, types of discussion forums, staff groups' participation and perceived barriers. Comparisons were made with a 2003 survey and significant changes described. A postal questionnaire survey was undertaken of a random selection of general practice team members in National Health Service Greater Glasgow in 2008/9. In total, 375/711 respondents (53%) from 111 practices participated. The vast majority was aware of a recent significant event, 29% reported not implementing a change and 23% perceived the risk of recurrence as moderate to high. Administrative and community-based staff were infrequently involved in meetings. Dedicated significant event meetings remain uncommon (P = 0.06). Perceptions improved since 2003, but lack of time remained a concern. This survey was the first known attempt to include all members of the primary care team while studying SEA. Awareness and analysis levels were high, but only lead to sustainable improvement of care quality and clinical safety if teams implement change. Greater use should be made of dedicated SEA meetings and participation of all staff groups increased to gain full benefits. Lack of time can be managed pragmatically by prioritizing events based on their perceived severity, potential for change and potential team involvement.


[Equipment for endolaryngeal microsurgery].
A special set of endolaryngeal instruments has been designed with aim of facilitating the early diagnosis of laryngeal neoplasms, their radical treatment, as well as rendering more effective therapeutic assistance to patients with disturbances of the vocal function. This set comprises instruments with rod-shaped holders (lancets, crescent-shaped knives, trapezoidal scraper knives, hooks, a scoop), end-pieces and laryngeal needles, hinged slider instruments (6 kinds of scoop- and frame-shaped nippers scissors and forceps) and an operating laryngoscope with the breast support and combined illumination.


Fabrication of vertical van der Waals gap array using single-and multi-layer graphene.
Arrays of van der Waals gaps were manufactured by synthesizing the vertically aligned graphene layer stacked between two copper (Cu) catalytic films. The Cu-graphene-Cu laminated structure was obtained by directly synthesizing graphene on a patterned Cu film followed by depositing a second copper layer for optical measurements. The synthesis of graphene on the Cu surface was optimized by adjusting the synthesis temperatures and pre-annealing time using plasma enhanced chemical vapor deposition (PECVD). Resonant Raman spectroscopy measurements reveal that graphene can be synthesized on both bulk Cu foil and relatively thin Cu film under the same growth mechanism using PECVD. Structural and optical characterizations of the array of graphene van der Waals gaps were implemented by the transmission electron microscope and terahertz-time domain spectroscopy (THz-TDS). In THz-TDS, the measured THz amplitude transmitted through the graphene van der Waals gap slit array was constant regardless of the gap width determined by the number of graphene layers between the Cu thin films in a single slit. These results imply that the optical dielectric constant of graphene at THz frequencies in the out-of-plane direction is linearly proportional to the gap width. Our results of the manufacturing method can be adopted to investigate mechanical, electrical, and optical properties of other 2D materials such as h-BN, MoS2, and others. Furthermore, metal-graphene-metal structures with vertical orientations can be used in many electronic, optic, and optoelectronic applications.


Efficacy and safety of Kanglaite plus EGFR-TKI in the treatment of advanced non-small cell lung cancer: A meta-analysis of 13 RCTs.
Kanglaite (KLT) is a Chinese medicine antitumor drug independently developed in China, which has been widely used in the treatment of advanced non-small cell lung cancer (NSCLC). The purpose of this study was to systematically evaluate the efficacy and safety of KLT plus epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in the treatment of advanced NSCLC. Up to September 1, 2022, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, Chinese Biomedical Literature, China Science and Technology Journal, and Wanfang were searched, and the randomized controlled clinical trials (RCTs) of KLT plus EGFR-TKI in the treatment of advanced NSCLC were included. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Revman5.4 software was used for meta-analysis. A total of 1057 patients were included in 13 RCTs. The results of meta-analysis showed that KLT plus EGFR-TKI could improve the objective response rate (ORR) (risk ratio (RR) confidence interval (CI) [RR = 1.54, 95% CI: 1.27-1.86, P < .00001]), the disease control rate (DCR) (RR = 1.23, 95% CI: 1.14-1.32, P < .00001), and quality of life (QOL) (RR = 1.79, 95% CI: 1.36-2.36, P < .0001) in patients with advanced NSCLC. The percentages of CD3+T cells (standardized mean difference [SMD = 2.37, 95% CI: 0.80-3.93, P = .003]), CD4+T cells (SMD = 1.39, 95% CI: 0.85-1.93, P < .00001), NK cells (SMD = 1.59, 95% CI: 0.88-2.30, P < .0001), and CD4+/CD8+ratio (SMD = 0.37, 95% CI: 0.19-0.55, P < .0001) were also increased. However, the results of subgroup analysis showed that in patients with EGFR mutation NSCLC, compared with EGFR-TKI alone, KLT plus EGFR-TKI did not significantly increase ORR and DCR (RR = 1.43, 95% CI: 0.88-2.32, P = .15; RR = 1.07, 95% CI: 0.96-1.20, P = .21). In terms of adverse events of drugs, the incidence of diarrhea, rash, anorexia, nausea and vomiting, liver and renal function damage of KLT plus EGFR-TKI was similar to that of EGFR-TKI alone (P > .05). KLT plus EGFR-TKI has some clinical benefits and good safety compared with EGFR-TKI alone in the treatment of advanced NSCLC. However, it seems that patients with EGFR mutations do not get significant clinical benefits, and more high-quality RCTs are needed to prove the efficacy of the combined regimen.


Wider Letter-Spacing Facilitates Word Processing but Impairs Reading Rates of Fast Readers.
Previous reports of improved oral reading performance for dyslexic children but not for regular readers when between-letter spacing was enlarged led to the proposal of a dyslexia-specific deficit in visual crowding. However, it is in this context also critical to understand how letter spacing affects visual word recognition and reading in unimpaired readers. Adopting an individual differences approach, the present study, accordingly, examined whether wider letter spacing improves reading performance also for non-impaired adults during silent reading and whether there is an association between letter spacing and crowding sensitivity. We report eye movement data of 24 German students who silently read texts presented either with normal or wider letter spacing. Foveal and parafoveal crowding sensitivity were estimated using two independent tests. Wider spacing reduced first fixation durations, gaze durations, and total fixation time for all participants, with slower readers showing stronger effects. However, wider letter spacing also reduced skipping probabilities and elicited more fixations, especially for faster readers. In terms of words read per minute, wider letter spacing did not provide a benefit, and faster readers in particular were slowed down. Neither foveal nor parafoveal crowding sensitivity correlated with the observed letter-spacing effects. In conclusion, wide letter spacing reduces single word processing time in typically developed readers during silent reading, but affects reading rates negatively since more words must be fixated. We tentatively propose that wider letter spacing reinforces serial letter processing in slower readers, but disrupts parallel processing of letter chunks in faster readers. These effects of letter spacing do not seem to be mediated by individual differences in crowding sensitivity.


[Digital roentgen analysis as a tool for kinematic studies of the shoulder--a study of radiation dosage].
The radiation exposure during biomechanical investigation of the shoulder joint done with a digital radiography system (Polytron 1000 VR - Siemens) was measured experimentally. Total radiation dose and surface dose were determined by phantom measurements. The radiation exposure per image is about 1/6 to 1/7 of that of a conventional study. The digital radiography system used is thus suitable for kinesiologic studies of large joints in healthy volunteers.


Feasibility and Acceptability of Computerised Cognitive Training of Everyday Cognition in Parkinson's Disease.
We piloted a computerised cognitive training battery in a group of participants with Parkinson's disease without dementia to investigate the relevance of the training to daily life and the feasibility and the acceptability of the tasks. Previous studies of CT have had limited success in the benefits of training, extending to improvements in everyday function. By taking a pragmatic approach and targeting training to the cognitive skills affected by Parkinson's disease (planning, attention, and recollection), whilst using tasks that emulated real-life scenarios, we sought to understand whether participants perceived the training to be effective and to identify the elements of the training that elicited beneficial effects. Four participants completed a cognitive training session comprising three distinct tasks 5 days a week over two weeks. Participants completed baseline questionnaires examining health-related quality of life, everyday cognition, and apathy before the training period, after the last session, and two weeks after the last session. An interview was held after participants had completed the training. The findings indicated that participants felt the training was acceptable, enhanced their awareness, and encouraged them to monitor their thinking abilities. The group interview indicated that the training was feasible; participants felt the tasks had potential to improve everyday performance, but more supporting information should be provided to facilitate this transfer. Responses to the questionnaires reflected these findings, indicating improvement for some participants' cognition and quality of life. Objective measures supported the subjective reports; there were improvements in some but not all domains. Performance on the planning and recollection tasks improved over the training period, and the evidence for improvement on the attention task was mixed. This study has found that pragmatic computer-based training with real-life outcomes is both feasible and acceptable and should be evaluated more extensively using controlled methods.


Realization of a Z-Classified Chiral-Symmetric Higher-Order Topological Insulator in a Coupling-Inverted Acoustic Crystal.
Higher-order topological band theory has transformed the landscape of topological phases in quantum and classical systems. Here, we experimentally demonstrate a two-dimensional higher-order topological phase, referred to as the multiple chiral topological phase, which is protected by a multipole chiral number (MCN). Our realization differs from previous higher-order topological phases in that it possesses a larger-than-unity MCN, which arises when the nearest-neighbor couplings are weaker than long-range couplings. Our phase has an MCN of 4, protecting the existence of 4 midgap topological corner modes at each corner. The multiple topological corner modes demonstrated here could lead to enhanced quantum-inspired devices for sensing and computing. Our study also highlights the rich and untapped potential of long-range coupling manipulation for future research in topological phases.


IGFBP-3 Is the Key Target of Sanguinarine in Promoting Apoptosis in Hepatocellular Carcinoma.
Chemotherapeutic treatment of hepatocellular carcinoma (HCC) has always been plagued by nonspecific and side effects. Plant extracts have potential anticancer capabilities with low cytotoxicity and few side effects, but their detailed mechanisms are still unclear, thus limiting their clinical applications. In this study, five plant extracts were chosen, their inhibition on HCC cell viability was compared by CCK-8 assay and sanguinarine (SAN) was selected. Then, wound healing assay, transwell assay, and apoptosis assay were carried out in Hep3B cells. Bioinformatics methods were performed and IGFBP-3 was predicted the targets of SAN in HCC. The mechanism of SAN regulating IGFBP-3 was explored using qRT-PCR, Western blotting, cell viability assay and apoptosis assay. Meanwhile, knockdown of IGFBP-3 were used by small interfering RNA (siRNA). In five plant extracts, SAN inhibited the proliferation of HCC cell lines most considerably. In addition, apoptosis was promoted, and invasion and migration were inhibited in the Hep3B cell line by treatment with SAN at 2 μM. Bioinformatics indicated that SAN could affect HCC apoptosis through the TP53/IGFBP-3 pathway, and further verification experiments showed that SAN upregulated the expression of insulin-like growth factor binding protein-3 (IGFBP-3) in the Hep3B cell line; SAN also inhibited the expression of Bcl-2 and promoted the expression of BAX and caspase-3. After using siRNA to inhibit the expression of IGFBP-3, the effect of SAN was blocked. Our study further reveals a novel mechanism that IGFBP-3 is an important target of SAN, by upregulating expression of IGFBP-3, SAN promotes apoptosis in HCC.


Host age and genotypic effects on enterotropic mouse hepatitis virus infection.
Intestinal lesions due to infection with an enterotropic strain of mouse hepatitis virus (MHV-Y) were found to be more severe and wide-spread in BALB/cByJ and Cr1:CD-1(ICR) mice than in SJL mice inoculated at 1 week of age, using nonparametric ranking analysis. Lesions and viral antigen were limited largely to the bowel, but also occurred in the liver and brain of some mice. BALB/cByJ mice developed a particularly high prevalence of brain infection, resulting in mortality after the enteric phase of infection had ceased. MHV-Y antigen was present in neurons, glia and vascular endothelium in a vascular distribution. Cr1:CD-1(ICR) pups inoculated with MHV-Y at 4 or 7 days of age developed severe typhlocolitis, enteritis and encephalitis with moderate mortality. Pups infected at 2 or 3 weeks of age had mild intestinal lesions with minimal alteration of mucosal architecture, no encephalitis and no mortality. These results demonstrate that host age and genotype influence the course of enterotropic mouse hepatitis virus, as has been shown previously with non-enterotropic, respiratory-type strains of mouse hepatitis virus.


Junctions in the meninges and marginal glia.
The meninges of various mammals were prepared for examination with the electronmicroscope by thin sectioning or freeze-fracturing. Particular attention was given to the distribution of tight junctions in order to determine the basis for the meningeal barrier between the blood circulating in dural vessels and the cerebrospinal fluid in the subarachnoid space. While some dural blood vessels are fenestrated, those in the subarachnoid space are not and their component endothelial cells are joined by an extensive system of tight junctions. An extensive and continuous system of tight junctions was also found in a layer of specialized cells at the border of the arachnoid with the dura. This arachnoid barrier layer is apparently the only basis of the meningeal barrier because often cellular layers in the dura and arachnoid lack tight junctions although they are linked by gap junctions and desmosomes. In particular, tight junctions are lacking at the border of the "subdural space" which is actually a fascial plane within the dura. Tight junctions are also lacking between astrocytes at the surface of the brain but these cells are linked by gap junctions and a new type of intercellular junction. The distribution of these junctions, as well as assemblies of intramembranous particles at the astrocytic border, raises the question whether this layer might have a role in the exchange of certain substances between the brain and cerebrospinal fluid.


Girls prone to urinary infections followed into adulthood. Indices of renal disease.
This study describes blood pressure and renal function, as well as indices of renal disease, in females with and without renal scarring followed from their first urinary tract infection (UTI) in childhood. Of the 111 patients with a median follow-up time of 15 years, 54 had renal scarring (reflux nephropathy) on urography, which was severe in 19 and moderate in 35. The glomerular filtration rate was lower in patients with severe renal scarring and correlated with renal area on urography. However, the filtration rate was decreased below the lower reference limit in only 7 patients, with a lowest value of 70 ml/min per 1.73 m2. The diastolic blood pressure was higher in women with severe scarring. Hypertension of at least 140/90 mmHg was diagnosed in 3 of 54 (5.5%) females with renal scarring, 2 before and 1 at the follow-up examination. The excretion of albumin in urine was low and not correlated to filtration rate. Tubular enzymes in urine were similar in all groups. Thus the renal function was well preserved and the incidence of hypertension low. Within this range of renal function, the level of albumin in urine did not predict the degree of renal scarring.


[Primary central nervous system lymphoma in a patient with systemic lupus erythematosus].
A 36 year-old woman with systemic lupus erythematosus was admitted to our hospital with headache, brachiocrural hemiparesis and hemianesthesia. She had been treated with prednisone and cyclophosphamide. CT scan and MRI revealed a 15 mm nodular mass enhanced with gadolinium in left frontal convexity. CNS biopsy was performed and a diffuse large B-cell lymphoma was diagnosed. She was treated with radiation therapy without response and died. There are few reports of erythematosus systemic lupus associated with primary central nervous system lymphoma.