Involvement of the N-terminal polypeptide of vimentin in the formation of intermediate filaments.
The potential to form intermediate filaments of a 54 X 10(3) molecular weight (Mr) polypeptide derived from vimentin by cleavage by the intermediate filament-specific, Ca2+-activated proteinase was investigated. Under physiological conditions of assembly, the breakdown product did not form intermediate filaments. Electron microscopy revealed short, rod-like structures similar to those described by Geisler et al. for a 38 X 10(3) Mr alpha-helical core particle derived from desmin. Since the specific, Ca2+-activated proteinase degrades vimentin preferentially from its N terminus, this result suggests the involvement of the basic, N-terminal polypeptide of vimentin in the assembly of intermediate filaments. This was supported by the observation that arginine inhibits the formation of intermediate filaments from intact vimentin. Whereas lysine had very little effect on the assembly process, guanidinium hydrochloride was effective at the same concentration as arginine. On the basis of these findings, an affinity chromatography method for the identification and isolation of intermediate filament subunit proteins was developed. Beside vimentin, desmin, the 68 X 10(3) Mr neurofilament triplet protein, the glial fibrillary acidic protein and cytokeratins also bound to arginine methylester Sepharose 4B in a salt-stable manner and could be eluted with arginine. The 145 X 10(3) Mr neurofilament triplet protein exhibited reduced binding activity, whereas the 210 X 10(3) Mr subunit did not bind to the affinity matrix. Among the degradation products of vimentin produced by the specific, Ca2+-activated proteinase, only those with molecular weights higher than 40 X 10(3) bound to arginine methylester Sepharose 4B. The same applied to the high molecular weight degradation products of desmin with a protein-resistant 37 X 10(3) Mr polypeptide as the major component. The results suggest that arginine residues of the non-alpha-helical, N-terminal polypeptides of intermediate filament subunit proteins play an important role in filament assembly.


Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging.
Aging causes a general decline in cellular metabolic activity, and function in different tissues and whole body homeostasis. However, the understanding about the metabolomic and autophagy changes in skeletal muscle and heart during aging is still limited. We thus examined markers for macroautophagy, chaperone-mediated autophagy (CMA), mitochondrial quality control, as well as cellular metabolites in skeletal and cardiac muscle from young (5 months old) and aged (27 months old) mice. We found decreased autophagic degradation of p62 and increased ubiquitinated proteins in both tissues from aged mice, suggesting a decline in macroautophagy during aging. In skeletal muscle from aged mice, there also was a decline in LC3B-I conjugation to phosphatidylethanolamine (PE) possibly due to decreased protein levels of ATG3 and ATG12-ATG5. The CMA markers, LAMP-2A and Hsc70, and mitochondrial turnover markers, Drp1, PINK1 and PGC1α also were decreased. Metabolomics analysis showed impaired β-oxidation in heart of aged mice, whereas increased branched-chain amino acids (BCAAs) and ceramide levels were found in skeletal muscle of aged mice that in turn, may contribute to insulin resistance in muscle. Taken together, our studies showed similar declines in macroautophagy but distinct effects on CMA, mitochondrial turnover, and metabolic dysfunction in muscle vs. heart during aging.


Spirituality and recovery from cardiac surgery: a review.
A large research literature attests to the positive influence of spirituality on a range of health outcomes. Recently, a growing literature links spirituality to improved recovery from cardiac surgery. Cardiac surgery has become an increasingly common procedure in the United States, so these results may provide a promising indication for improved treatment of patients undergoing surgery. To our knowledge, a comprehensive review of the literature in this area does not exist. Therefore, this paper reviews the literature relevant to the influence of spirituality on recovery from cardiac surgery. In addition, it proposes a conceptual model that attempts to explicate relationships among the variables studied in the research on this topic. Finally, it discusses limitations, suggests directions for future research, and discusses implications for the treatment of patients undergoing cardiac surgery.


Differences in diagnostic activity in general practice and findings for individuals invited to the danish screening programme for colorectal cancer: a population-based cohort study.
To investigate the diagnostic activity in general practice and the cumulative incidence of colorectal cancer (CRC) in individuals invited to the Danish national screening programme for CRC. A historical population-based cohort study. The Danish CRC screening programme and general practice. The 376,198 individuals invited to the Danish CRC screening programme from 1 March to 31 December 2014. The diagnostic activity (consultations and haemoglobin measures) in general practice in the year preceding the screening invitation and the cumulated incidence of CRC in the year following the screening invitation. Screening participants had significantly higher diagnostic activity than non-participants. Individuals with a positive faecal immunochemical test (FIT) had higher diagnostic activity compared to individuals with a negative FIT, and a small increase in the months leading up to the invitation. Individuals with a screen-detected CRC had lower diagnostic activity than individuals with no CRC. In total, 308 (25.3%) of CRCs diagnosed in the invited population were diagnosed outside the screening programme. Non-participants with CRC more often had low socio-economic status, high comorbidity and stage IV CRC than participants with CRC. There was a tendency that participants and those with a positive FIT had a higher diagnostic activity the year before the screening. This was not seen for those with CRC detected through screening. CRC must still be diagnosed in general practice in the invited population and non-participants are of special interest as they have higher risk of late stage CRC. Key Points Current awareness:Individuals with colorectal cancer (CRC) in screening may be symptomatic and CRC may still occur outside screening in the invited population. Most important points:The majority of individuals with CRC in screening cannot be expected to be diagnosed on symptomatic presentation in general practice GPs have to be aware that CRC still occurs outside screening in the invited population Non-participants with CRC are often deprived and have late stage CRC.


Management of infections related to totally implantable venous-access ports: challenges and perspectives.
Use of totally implantable venous-access ports (TIVAPs) is standard practice for patients with diseases such as solid-tumour cancers, haematological malignancies, and chronic digestive diseases. Use of TIVAPs allows long-term administration of venotoxic compounds, improves patients' quality of life, and reduces the risk of infection. Microbial contamination, formation of pathogenic biofilms, and infection, however, are associated with morbidity, mortality, and increased health-care costs. Local and systemic complications or infections related to specific pathogens might lead to device removal. Alternatively, conservative treatment with combined systemic antibiotics and antibiotic lock therapy might be useful. We discuss in-vitro and in-vivo basic and clinical research findings on the epidemiology, diagnosis, and prevention of TIVAP-related infections, the current challenges to management, promising strategies, and some treatments in development that are likely to improve outcomes of TIVAP-related infections, with a particular focus on antibiotic lock therapy.


Young, Bullying, and Connected. Common Pathways to Cyberbullying and Problematic Internet Use in Adolescence.
Cyberbullying perpetration (CBP) and problematic Internet use (PIU) are the most studied risky online activities for adolescents in the current generation. However, few studies have investigated the relationship between CBP and PIU. Still lacking is a clear understanding of common or differentiated risk and protective pathways for adolescents interacting in the cyber world. The aim of this study was to understand the role of individual (emotional symptoms) and environmental variables (parental monitoring) underpinning both CBP and PIU, with time spent online as a mediator of these factors. Furthermore, we investigated gender and school level differences in these dynamics. A questionnaire was filled in by 3,602 students from Italian Lower Secondary Schools and Upper Secondary Schools. Structural equation modeling was used to test the effects of emotional symptoms and parental monitoring on CBP and PIU mediated by time spent online, controlling for school level. In addition, the model was implemented for girls and boys, respectively. Negative emotional symptoms and low levels of parental monitoring were risk factors for both CBP and PIU, and their effect was mediated by the time spent online. In addition, parental monitoring highlighted the strongest total effect on both CBP and PIU. Risk and protective pathways were similar in girls and boys across Lower Secondary and Upper Secondary Schools, although there were some slight differences. CBP and PIU are the outcomes of an interplay between risk factors in the individual and environmental systems. The results highlight the need to design interventions to reduce emotional symptoms among adolescents, to support parental monitoring, and to regulate the time spent online by adolescents in order to prevent risky online activities.


Aggregating single patient (n-of-1) trials in populations where recruitment and retention was difficult: the case of palliative care.
Randomized controlled trials (RCTs) are the gold standard for evaluating new interventions. Different RCT designs apply depending on the patient population, clinical setting, and intervention being evaluated. A design that may help to generate evidence in some clinical areas where recruitment is a challenge is aggregated n-of-1 trials. N-of-1 trials are randomized, double-blind, and multiple crossover comparisons of an intervention and a control treatment. Methodologically robust n-of-1 trials provide an objective means of testing the effectiveness of treatments within individual participants. Aggregation of multiple cycle identically conducted n-of-1 trials yield a population estimate of effect, which potentially commensurate with that derived from other RCT designs. Trial participants contribute data for both intervention and control treatments creating matched data sets while using generally smaller sample sizes than conventional RCT trials. Careful choice of symptoms and medications are required for n-of-1 trials to be feasible. A validated and reliable outcome measure sensitive to change is still required. This article reviews the utility and limitations of aggregated n-of-1 trials to gather evidence in populations where conducting formal RCTs is difficult because of the low prevalence of the underlying condition or the clinical condition making recruitment and retention difficult. The article examines a proposed palliative care trial as a test case.


The effects of breaks on low back pain, discomfort, and work productivity in office workers: A systematic review of randomized and non-randomized controlled trials.
The purpose of this study was to evaluate the effectiveness of breaks on low back pain, discomfort, and work productivity in office workers. Publications were systematically searched in several databases from 1980 to December 2016. Relevant randomized and non-randomized controlled trials were retrieved and assessed for methodological quality by two independent reviewers. Quality of evidence was assessed and rated according to GRADE guidelines. Eight randomized controlled trials and three non-randomized controlled trials were included in this review, of which 10 were rated as high-quality studies. The break programs were highly heterogeneous with work duration ranging from 5 min to 2 h and break duration ranging from 20 s to 30 min. The results showed low-quality evidence for the conflicting effect of breaks on pain and low-quality evidence for the positive effect of breaks on discomfort. When stratified by type of breaks, moderate-quality evidence was found for the positive effect of active breaks with postural change for pain and discomfort. Moderate-quality evidence indicated that the use of breaks had no detrimental effect on work productivity. More high-quality studies are needed before recommendations can be given. Within a number of methodological limitations that are present in the published studies, active breaks with postural change may be effective in reducing pain in workers with acute low back pain and to prevent discomfort in healthy subjects.


Genome-wide gene expression in response to parasitoid attack in Drosophila.
Parasitoids are insect parasites whose larvae develop in the bodies of other insects. The main immune defense against parasitoids is encapsulation of the foreign body by blood cells, which subsequently often melanize. The capsule sequesters and kills the parasite. The molecular processes involved are still poorly understood, especially compared with insect humoral immunity. We explored the transcriptional response to parasitoid attack in Drosophila larvae at nine time points following parasitism, hybridizing five biologic replicates per time point to whole-genome microarrays for both parasitized and control larvae. We found significantly different expression profiles for 159 probe sets (representing genes), and we classified them into 16 clusters based on patterns of co-expression. A series of functional annotations were nonrandomly associated with different clusters, including several involving immunity and related functions. We also identified nonrandom associations of transcription factor binding sites for three main regulators of innate immune responses (GATA/srp-like, NF-kappaB/Rel-like and Stat), as well as a novel putative binding site for an unknown transcription factor. The appearance or absence of candidate genes previously associated with insect immunity in our differentially expressed gene set was surveyed. Most genes that exhibited altered expression following parasitoid attack differed from those induced during antimicrobial immune responses, and had not previously been associated with defense. Applying bioinformatic techniques contributed toward a description of the encapsulation response as an integrated system, identifying putative regulators of co-expressed and functionally related genes. Genome-wide studies such as ours are a powerful first approach to investigating novel genes involved in invertebrate immunity.


Audiotactile temporal order judgments in sighted and blind individuals.
In the present study, we examined the potential modulatory effect of relative spatial position on audiotactile temporal order judgments (TOJs) in sighted, early, and late blind adults. Pairs of auditory and tactile stimuli were presented from the left and/or right of participants at varying stimulus onset asynchronies (SOAs) using the method of constant stimuli. The participants had to make unspeeded TOJs regarding which sensory modality had been presented first on each trial. Systematic differences between the participants emerged: While the performance of the sighted participants was unaffected by whether the two stimuli were presented from the same or different positions (replicating the results of several recent studies), the blind participants (regardless of the age of onset of blindness) were significantly more accurate when the auditory and tactile stimuli were presented from different positions rather than from the same position. These results provide the first empirical evidence to suggest a spatial modulation of audiotactile interactions in a temporal task performed by visually impaired humans. The fact that the performance of the blind participants was modulated by the relative spatial position of the stimuli is consistent with data showing that visual deprivation results in an improved ability to process spatial cues within the residual tactile and auditory modalities. These results support the hypothesis that the absence of visual cues results in the emergence of more pronounced audiotactile spatial interactions.


The analysis of placement values for evaluating discriminatory measures.
The idea of using measurements such as biomarkers, clinical data, or molecular biology assays for classification and prediction is popular in modern medicine. The scientific evaluation of such measures includes assessing the accuracy with which they predict the outcome of interest. Receiver operating characteristic curves are commonly used for evaluating the accuracy of diagnostic tests. They can be applied more broadly, indeed to any problem involving classification to two states or populations (D= 0 or 1). We show that the ROC curve can be interpreted as a cumulative distribution function for the discriminatory measure Y in the affected population (D= 1) after Y has been standardized to the distribution in the reference population (D= 0). The standardized values are called placement values. If the placement values have a uniform(0, 1) distribution, then Y is not discriminatory, because its distribution in the affected population is the same as that in the reference population. The degree to which the distribution of the standardized measure differs from uniform(0, 1) is a natural way to characterize the discriminatory capacity of Y and provides a nontraditional interpretation for the ROC curve. Statistical methods for making inference about distribution functions therefore motivate new approaches to making inference about ROC curves. We demonstrate this by considering the ROC-GLM regression model and observing that it is equivalent to a regression model for the distribution of placement values. The likelihood of the placement values provides a new approach to ROC parameter estimation that appears to be more efficient than previously proposed methods. The method is applied to evaluate a pulmonary function measure in cystic fibrosis patients as a predictor of future occurrence of severe acute pulmonary infection requiring hospitalization. Finally, we note the relationship between regression models for the mean placement value and recently proposed models for the area under the ROC curve which is the classic summary index of discrimination.


Use of wide-diameter and standard-diameter implants to replace single molars: two case presentations.
The ultimate goal in modern esthetic dentistry is the restoration of lost hard and soft tissues by imitating nature as closely as possible. With the increasing esthetic awareness of patients, surgical and technical developments, and dentists' enhanced skills and knowledge, optimal function and esthetics are achievable even with implant-supported restorations in molar regions. Anatomic and morphologic factors and poor bone quantity and quality might reduce success rates of dental implants in the posterior jaw. Today, there are two options to replace a single missing molar by an implant-supported crown: the single wide-diameter implant or two standard-diameter implants. These two approaches are described and their advantages and disadvantages discussed in two exemplary clinical cases. In one case, the edentulous ridge in the area of the mandibular right first molar (FDI tooth 46) provided sufficient mesiodistal space to restore tooth 46 with a porcelain-fused-to-metal crown on two standard-diameter implants, placed in a root-analog manner. In the other case, the manibular first molars (FDI teeth 36 and 46) were replaced by porcelain-fused-to-metal crowns on wide-diameter implants. It can be concluded that both options to replace a single molar provide more surface area and better biomechanical properties than one standard implant. Long-term data are needed before these treatment modalities can be recommended for the private practitioner.


Isolation of Cryptosporidium parvum and Cyclospora cayetanensis from vegetables collected in markets of an endemic region in Peru.
Cryptosporidium parvum and Cyclospora cayetanensis are protozoan pathogens that cause prolonged diarrhea in both immunocompetent and immunocompromised hosts. Cryptosporidium parvum can be transmitted via the fecal-oral route, while the exact mechanisms of transmission of Cyclospora cayetanensis have not been fully determined. Humans appear to be the sole host for the latter and a distinct seasonality has been observed in endemic areas around the world. Samples of vegetables were collected at several small markets in a periurban slum in Peru during the seasons of high and low incidence. The vegetables were washed, the supernatants were collected and centrifuged, and the pellets were resuspended in a solution of 2.5% potassium dichromate. Pellets were examined using direct microscopic observation, acid-fast staining, and immunofluorescent assays for C. parvum and Cyclospora cayetanensis oocysts. Samples were collected during three time periods: the season of low incidence, the beginning of the season of high incidence, and end of the season of high incidence. Of the total vegetables examined, 14.5% contained C. parvum oocysts and 1.8% had Cyclospora oocysts. Thus, market vegetables may provide a route by which Cryptosporidium and Cyclospora can be transmitted. Our study also suggests that washing vegetables does not completely remove Cryptosporidium and Cyclospora oocysts.


An integrated proteomic and transcriptomic analysis of perivitelline fluid proteins in a freshwater gastropod laying aerial eggs.
Proteins of the egg perivitelline fluid (PVF) that surrounds the embryo are critical for embryonic development in many animals, but little is known about their identities. Using an integrated proteomic and transcriptomic approach, we identified 64 proteins from the PVF of Pomacea maculata, a freshwater snail adopting aerial oviposition. Proteins were classified into eight functional groups: major multifunctional perivitellin subunits, immune response, energy metabolism, protein degradation, oxidation-reduction, signaling and binding, transcription and translation, and others. Comparison of gene expression levels between tissues showed that 22 PVF genes were exclusively expressed in albumen gland, the female organ that secretes PVF. Base substitution analysis of PVF and housekeeping genes between P. maculata and its closely related species Pomacea canaliculata showed that the reproductive proteins had a higher mean evolutionary rate. Predicted 3D structures of selected PVF proteins showed that some nonsynonymous substitutions are located at or near the binding regions that may affect protein function. The proteome and sequence divergence analysis revealed a substantial amount of maternal investment in embryonic nutrition and defense, and higher adaptive selective pressure on PVF protein-coding genes when compared with housekeeping genes, providing insight into the adaptations associated with the unusual reproductive strategy in these mollusks. There has been great interest in studying reproduction-related proteins as such studies may not only answer fundamental questions about speciation and evolution, but also solve practical problems of animal infertility and pest outbreak. Our study has demonstrated the effectiveness of an integrated proteomic and transcriptomic approach in understanding the heavy maternal investment of proteins in the eggs of a non-model snail, and how the reproductive proteins may have evolved during the transition from laying underwater eggs to aerial eggs.


Across space and time: infants learn from backward and forward visual statistics.
This study investigates whether infants are sensitive to backward and forward transitional probabilities within temporal and spatial visual streams. Two groups of 8-month-old infants were familiarized with an artificial grammar of shapes, comprising backward and forward base pairs (i.e. two shapes linked by strong backward or forward transitional probability) and part-pairs (i.e. two shapes with weak transitional probabilities in both directions). One group viewed the continuous visual stream as a temporal sequence, while the other group viewed the same stream as a spatial array. Following familiarization, infants looked longer at test trials containing part-pairs than base pairs, although they had appeared with equal frequency during familiarization. This pattern of looking time was evident for both forward and backward pairs, in both the temporal and spatial conditions. Further, differences in looking time to part-pairs that were consistent or inconsistent with the predictive direction of the base pairs (forward or backward) indicated that infants were indeed sensitive to direction when presented with temporal sequences, but not when presented with spatial arrays. These results suggest that visual statistical learning is flexible in infancy and depends on the nature of visual input.


In vitro model for predicting bioavailability of subcutaneously injected monoclonal antibodies.
Monoclonal antibodies (mAbs), which are now more frequently administered by subcutaneous (SC) injection rather than intravenously, have become a tremendously successful drug format across a wide range of therapeutic areas. Preclinical evaluations of mAbs to be administered by SC injection are typically performed in species such as mice, rats, minipigs, and cynomolgus monkeys to obtain critical information regarding formulation performance and prediction of PK/PD outcomes needed to select clinical doses for first-in-human studies. Despite extensive efforts, no preclinical model has been identified to date that accurately predicts clinical outcomes for these SC injections. We have addressed this deficiency with a novel in vitro instrument, termed Scissor, to model events occurring at the SC injection site and now further validated this approach using a set of eight mAbs for which clinical PK/PD outcomes have been obtained. Diffusion of these mAbs from the Scissor system injection cartridge into a large volume physiological buffer, used to emulate mAb movement from the SC injection site into the systemic circulation, provided distinct profiles when monitored over a 6h period. Curve-fitting analysis of these profiles using the Hill equation identified parameters that were used, along with physicochemical properties for each mAb, in a partial least squares analysis to define a relationship between molecule and formulation properties with clinical PK outcomes. The results demonstrate that parameters of protein charge at neutral pH and isoelectric point (pI) along with combined formulation properties such as viscosity and mAb concentration can dictate the movement of the mAb from the injection cartridge to infinite sink compartment. Examination of profile characteristics of this movement provided a strong predictive correlation for these eight mAbs. Together, this approach demonstrates the feasibility of this in vitro modelling strategy as a tool to identify drug and formulation properties that can define the performance of SC injected medicines and provide the potential for predicting clinical outcomes that could be useful for formulation selection and a first-in-human clinical dosing strategy.


Modern treatment of tibial shaft fractures: Is there a role today for closed treatment?
The decision to attempt closed treatment on tibial shaft fractures can be challenging. At our institution, we attempt treatment of nearly all closed, isolated tibial shaft fractures. The purpose of this study was to report the results of 10 years of experience to develop a tool to identify patients for whom non-operative treatment of tibial shaft fractures may be a viable option METHOD: This was a retrospective review of patients with tibial shaft fracture seen at a level 1 trauma center over 10 years. Patients with closed, isolated injuries underwent sedation, closed reduction, long-leg casting, and outpatient follow-up. Patients were converted to surgery for inability to obtain or maintain acceptable alignment or patient intolerance. Radiographic characteristics and patient demographics were extracted. Logistic regression analysis was used to develop a model to predict which patient and injury characteristics determined success of nonoperative treatment. 334 patients were identified with isolated, closed tibial shaft fractures, who were reduced and treated in a long leg cast. 234 patients (70%) converted to surgical treatment due to inability to maintain alignment, patient intolerance, and nonunion. In a regression model, coronal/sagittal translation, sagittal angulation, fracture morphology, and smoking status were shown to be significant predictors of success of nonoperative treatment (p < 0.05). We developed a Tibial Operative Outcome Likelihood (TOOL) score designed to help predict success or failure of closed treatment. The TOOL score can be used to identify a subsegment of patients with injuries amenable to closed treatment (38% of injuries) with a nonoperative success rate over 60%. Non-operative treatment of tibial shaft fractures is feasible, although there is a relatively high conversion rate to operative treatment. However, it is possible to use injury characteristics to identify a cohort of patients with a higher chance of success with closed treatment, which is potentially useful in a resource-constrained setting or for patients who wish to avoid surgery. Prognostic Level 3.


Scalable, end-pumped, diode-laser-pumped laser.
A novel technique for scaling end-pumped lasers is demonstrated using three diode-laser arrays to pump a single Nd:YAG laser. Diffraction-limited output with a 58% slope efficiency was obtained. Simple arguments indicate that this method should allow at least an order of magnitude increase in pump power, compared with that from a single high-power diode array, to be focused into the same fixed-mode volume of the pumped laser. Such a scheme may be particularly useful with low-gain, quasi-three-level, or tunable lasers.


Developing a viva exam to assess clinical reasoning in pre-registration osteopathy students.
Clinical reasoning (CR) is a core capability for health practitioners. Assessing CR requires a suite of tools to encompass a wide scope of contexts and cognitive abilities. The aim of this project was to develop an oral examination and grading rubric for the assessment of CR in osteopathy, trial it with senior students in three accredited university programs in Australia and New Zealand, and to evaluate its content and face validity. Experienced osteopathic academics developed 20 cases and a grading rubric. Thirty senior students were recruited, 10 from each university. Twelve fourth year and 18 fifth year students participated. Three members of the research team were trained and examined students at an institution different from their own. Two cases were presented to each student participant in a series of vignettes. The rubric was constructed to follow a set of examiner questions that related to each attribute of CR. Data were analysed to explore differences in examiner marking, as well as relationships between cases, institutions, and different year levels. A non-examining member of the research team acted as an observer at each location. No statistical difference was found between the total and single question scores, nor for the total scores between examiners. Significant differences were found between 4th and 5th students on total score and a number of single questions. The rubric was found to be internally consistent. A viva examination of clinical reasoning, trialled with senior osteopathy students, showed face and content validity. Results suggested that the viva exam may also differentiate between 4th and 5th year students' capabilities in CR. Further work is required to establish the reliability of assessment, to further refine the rubric, and to train examiners before it is implemented as a high-stakes assessment in accredited osteopathy programs.


Increasing role of interventional cardiologists for peripheral vascular disease.
Improvements in the design of endovascular devices and technical skills of interventionalists have opened new possibilities for patients with a wide range of peripheral vascular diseases. In lower extremity peripheral artery disease, percutaneous treatments have become the predominant revascularization strategy for simple and complex lesions. Newer generations of stents and drug-coated balloons have demonstrated strong potential in the treatment of femoropopliteal and infrainguinal diseases. One of the most dramatic advances in the recent past has been endovascular repair of thoracic and abdominal aortic aneurysms, which has become the preferred approach in lieu of open surgical repair. Contemporary trials have established the safety and effectiveness of carotid stenting in selected patients with severe stenosis. Endovascular treatments for venous occlusive disease have long been underutilized, but their effectiveness is being increasingly recognized. This review covers new endovascular procedures performed by interventional cardiologists for peripheral vascular diseases.


Physician mothers' experience of workplace discrimination: a qualitative analysis.
To report woman physicians' experiences, in their own words, of discrimination based on their role as a mother. Qualitative analysis of physician mothers' free-text responses to the open question: "We want to hear your story and experience. Please share" included in questions about workplace discrimination. Three analysts iteratively formulated a structured codebook, then applied codes after inter-coder reliability scores indicated high concordance. The relationships among themes and sub-themes were organized into a conceptual model illustrated by exemplary quotes. Respondents to an anonymous, voluntary online survey about the health and wellbeing of physician mothers posted on a Facebook group, the Physician Moms Group, an online community of US physicians who identify as mothers. We analyzed 947 free-text responses. Participants provide diverse and vivid descriptions of experiences of maternal discrimination. Gendered job expectations, financial inequalities (including lower pay than equally qualified colleagues and more unpaid work), limited opportunities for advancement, lack of support during the pregnancy and postpartum period, and challenging work-life balance are some of the key themes identified. In addition, participants' quotes show several potential structural drivers of maternal discrimination and describe the downstream consequences of maternal discrimination on the physician herself, her career, family, and the healthcare system. These findings provide a view of maternal discrimination directly from the perspective of those who experience it. Women physicians report a range of previously uncharacterized ways in which they experience maternal discrimination. While certain aspects of these experiences are consistent with those reported by women across other professions, there are unique aspects of medical training and the medical profession that perpetuate maternal discrimination.


Toward a Rational and Mechanistic Account of Mental Effort.
In spite of its familiar phenomenology, the mechanistic basis for mental effort remains poorly understood. Although most researchers agree that mental effort is aversive and stems from limitations in our capacity to exercise cognitive control, it is unclear what gives rise to those limitations and why they result in an experience of control as costly. The presence of these control costs also raises further questions regarding how best to allocate mental effort to minimize those costs and maximize the attendant benefits. This review explores recent advances in computational modeling and empirical research aimed at addressing these questions at the level of psychological process and neural mechanism, examining both the limitations to mental effort exertion and how we manage those limited cognitive resources. We conclude by identifying remaining challenges for theoretical accounts of mental effort as well as possible applications of the available findings to understanding the causes of and potential solutions for apparent failures to exert the mental effort required of us.


Sodium and volume sensitivity of blood pressure. Age and pressure change over time.
Salt sensitivity has been implicated in the age-related increase in blood pressure. We studied the reproducibility of a rapid method for assessing sodium sensitivity and resistance of blood pressure as well as the effect of age on this phenomenon. Blood pressure after volume expansion with 2 l intravenous saline (0.9%) over 4 hours was compared with that after 1 day of 10 mmol sodium chloride intake and 3 and 40 mg oral doses of furosemide. Normal and hypertensive subjects (n = 28) were studied twice within a year. Cross-sectional observations of the effect of age were made from studies in 230 hypertensive and 430 normotensive subjects. Longitudinal observations of blood pressure change over time were made 10 or more years after categorization of sodium responsivity in 31 subjects. The blood pressure response was reproducible in 28 subjects studied twice (r = 0.56, p less than 0.002). Four subjects changed salt-responsiveness status and six were indeterminate on restudy. Sodium sensitivity of blood pressure increased significantly with increasing age in the entire population (n = 660, r = -0.38, p less than 0.001). The relation was more striking in hypertensive subjects (n = 230, r = -0.31, p less than 0.001) in whom a progressive increase in salt sensitivity with decades was seen than in the normotensive group (n = 430, r = -0.19, p less than 0.01) in whom salt sensitivity was not observed until the sixth decade. Salt-sensitive subjects had a significantly greater increase in systolic (p less than 0.001) and diastolic (p less than 0.01) pressure over time than those who were salt-resistant. Salt sensitivity is a reproducible phenomenon that is related to the age-associated increase in blood pressure characteristic of industrialized societies. In addition, salt sensitivity can be shown to be a predictor of subsequent, age-related blood pressure increase.


Controlled trial of repeated halothane anaesthetics in patients with carcinoma of the uterine cervix treated with radium.
39 patients with carcinoma of the uterine cervix who were treated with radium and required repeated general anaesthetics were randomised to halothane and control groups. Their serum-alanine-aminotransferase (S.G.P.T.) levels were measured before each general anaesthetic, and those patients whose S.G.P.T. levels rose above 100 I.U. per litre were freed from the restriction determined by the initial allocation and treated as indicated clinically. None of the 21 patients in the control group had S.G.P.T. levels rising above 100 I.U. per litre. 4 out of 18 patients in the halothane group developed S.G.P.T. levels above 100 i.u. per litre before their third radium treatment. None of these had any symptoms or alteration in other liver-function tests, but liver biopsies in 2 of these patients showed changes characteristic of Hepatitis. Arbitrary selection of 18 out of the 39 patients would only give rise to the degree of abnormality observed in the halothane-treated group with a probability of about 0-02. In the patients studied who required repeated general anaesthetics at short time intervals, the monitoring of S.G.P.T. levels before each operation was useful screen for liver damage and may have reduced postoperative hepatic necrosis by preventing further anaesthetics with halothane when the liver was already damaged.


Disparities in breast cancer characteristics and outcomes by race/ethnicity.
Disparities in breast cancer stage and mortality by race/ethnicity in the United States are persistent and well known. However, few studies have assessed differences across racial/ethnic subgroups of women broadly defined as Hispanic, Asian, or Pacific Islander, particularly using more recent data. Using data from 17 population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) program, we evaluated the relationships between race/ethnicity and breast cancer stage, hormone receptor status, treatment, and mortality. The cohort consisted of 229,594 women 40-79 years of age diagnosed with invasive breast carcinoma between January 2000 and December 2006, including 176,094 non-Hispanic whites, 20,486 Blacks, 15,835 Hispanic whites, 14,951 Asians, 1,224 Pacific Islanders, and 1,004 American Indians/Alaska Natives. With respect to statistically significant findings, American Indian/Alaska Native, Asian Indian/Pakistani, Black, Filipino, Hawaiian, Mexican, Puerto Rican, and Samoan women had 1.3-7.1-fold higher odds of presenting with stage IV breast cancer compared to non-Hispanic white women. Almost all groups were more likely to be diagnosed with estrogen receptor-negative/progesterone receptor-negative (ER-/PR-) disease with Black and Puerto Rican women having the highest odds ratios (2.4 and 1.9-fold increases, respectively) compared to non-Hispanic whites. Lastly, Black, Hawaiian, Puerto Rican, and Samoan patients had 1.5-1.8-fold elevated risks of breast cancer-specific mortality. Breast cancer disparities persist by race/ethnicity, though there is substantial variation within subgroups of women broadly defined as Hispanic or Asian. Targeted, multi-pronged interventions that are culturally appropriate may be important means of reducing the magnitudes of these disparities.


Analysis of Wide-Neck Aneurysms in the Barrow Ruptured Aneurysm Trial.
Ruptured wide-neck aneurysms (WNAs) are difficult to treat and few publications have compared clipping to coiling. To determine, using Barrow Ruptured Aneurysm Trial (BRAT) data: (1) How many aneurysms had a wide neck? (2) Did wide-neck status influence treatment? (3) How did clipping compare to coiling for WNAs? A post hoc analysis was conducted of saccular WNAs in the BRAT. A WNA was defined as maximum neck width ≥ 4 mm or maximum aneurysm dome-diameter-to-neck-width ratio < 2. Both intent-to-treat and as-treated analyses were performed. Of the 327 patients analyzed, 177 (54.1%) had a WNA. WNAs were more likely to occur in older patients (P = .03) with worse presenting clinical grade (P = .02), were more likely to arise from the middle cerebral artery, basilar tip, or internal carotid artery other than the junction with the posterior communicating artery (P = .001) and were associated with worse clinical outcomes at all time points (P ≤ .01). WNAs were equally distributed in assigned treatment groups (clip 56.6% vs coil 51.8%; P = .38), but were overrepresented in the actual clipping group (clip 62.4% vs coil 37.6%, P < .001). Most patients (76.7%) in the coil-to-clip crossover group had a WNA. Comparing clipping to coiling, there was no difference in clinical outcomes at any time point in either analysis (P ≥ .33). The aneurysm obliteration rate was lower (P < .001) and the retreatment rate higher (P < .001) in the actual coiling group. Wide-neck status significantly impacted treatment strategy in the BRAT, favoring clipping. Clipping and coiling of ruptured WNAs resulted in statistically similar long-term clinical outcomes. 10.1093/neuros/nyy439 Video Abstract 10.1093.neuros.nyy439 5850292551001.


Is adrenal suppression in asthmatic children reversible? A case series.
Six hypocortisolaemic asthmatic children on steroids given at physiological doses were identified during a previous study. To establish whether hypothalamic-pituitary-adrenal axis suppression (HPAS) could be reversed in hypocortisolaemic asthmatic children treated with steroids without sacrificing asthma control. In this case series, treatment of six hypocortisolaemic patients was modified by introducing steroid-sparing asthma medications. Serum cortisol and repeat overnight metyrapone tests (ONMTPTs) were done until HPAS was reversed in all patients. A retrospective folder review was performed and the following data were extracted: body mass index standard deviation score (BMI SDS), adherence, daily steroid type and dose, treatment modification, serum cortisol, final ONMTPT result and time taken to achieve normalisation. The median serum cortisol level recovered to 311 nmol/L after 0.9 years (median). The ONMTPT normalised within 3.3 years (median). Steroid load decreased from 9.2 to 5.0 hydrocortisone equivalent mg/m2/d (medians), while asthma score improved from 1.42 to 0.85 (medians). Poor adherence was noted in two children before and four after treatment modification. BMI SDS decreased from -0.08 to -0.16 (medians). Hypocortisolaemia and HPAS could be reversed in asthmatic children treated with physiological doses of steroids by reducing steroid load by 40% and supplementing therapy with steroid-sparing medication. Poor adherence may have either contributed to or retarded HPA recovery. Simultaneously, asthma control improved. Confirmation by a prospective study would be ideal, but may not be feasible.


Variations in the efficiency of lineage marking and ablation confound distinctions between myogenic cell populations.
The myogenic regulatory genes Myf5, Mrf4, Myod, and Myogenin likely arose by gene duplications during evolution, presumably to address the more demanding requirements of the vertebrate body plan. Two cell lineages were proposed to be regulated independently by Myf5 and Myod to safeguard against tissue failure. Here we report severe muscle loss following ablation of Myf5-expressing cells. Using both lineage-specific and ubiquitous reporter alleles, we show that the remaining muscles in Myf5(Cre)-DTA embryos arise mainly from Myf5(+) escaper cells. Elimination of Myf5(Cre)-DTA cells on a Myod null background did not result in the total absence of skeletal muscles, as would be expected if a Myod(+)/Myf5-independent cell population played a major role in this scenario. Therefore, these observations are incompatible with a previously proposed functional two-lineage model. These findings will have an impact on the interpretation of phenotypes obtained using similar strategies in other tissues.


Postdeposition treatment of IBS coatings for UV applications with optimized thin-film stress properties.
Ion-beam-sputtering (IBS) single-layer and multilayer coating designs for UV applications were examined after the deposition process as well as after a defined postdeposition treatment. High internal compressive film stress as well as moderate absorption losses in the UV spectral range were measured at the as-deposited thin films. Due to a controlled postdeposition treatment process, the absorption losses and the high compressive stress can be reduced significantly. We show that the remaining thin-film stress of SiO2 and HfO2 multilayer designs can be specifically manipulated by the parameters of the postdeposition treatment. Even zero and tensile stress can be achieved for complex multilayer coatings.


A model of sensitivity: 1,3-butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene.
The specific role that polymorphisms in xenobiotic metabolizing enzymes play in modulating sensitivity to 1,3-butadiene (BD) genotoxicity has been relatively unexplored. The enzyme microsomal epoxide hydrolase (mEH) is important in detoxifying the mutagenic epoxides of BD (butadiene monoepoxide [BDO], butadiene diepoxide [BDO(2)]). Polymorphisms in the human mEH gene appear to affect the function of the enzyme. We exposed mice with normal mEH activity (WT) and knockout mice without mEH activity (KO) to 20 ppm BD (inhalation) or 30 mg/kg BDO(2) (intraperitoneal [IP] injection). We then compared Hprt mutant frequencies (MFs) among these groups. KO mice exposed to BD exhibited a significant (P < 0.05) 12.4-fold increase in MF over controls and a significant 5.4-fold increase in MF over exposed WT mice. Additionally, KO mice exposed to BDO(2) exhibited a significant 4.5-fold increase in MF over controls and a significant 1.7-fold increase in MF over exposed WT mice. We also compared genomic damage in WT and KO mice (comet tail moment) following IP exposure to 3 mg/kg and 30 mg/kg BDO(2). KO mice exposed to 3 mg/kg exhibited significantly more DNA damage than controls (7.5-12.1-fold increase) and exposed WT mice (3 mg/kg; 4.8-fold increase). KO mice exposed to 30 mg/kg BDO(2) exhibited significantly more DNA damage than all other groups (2.3-27.9-fold increase). Correlation analysis indicated that a significant, positive relationship (r(2) = 0.92) exists between comet-measured damage and Hprt MFs. The lack of mEH activity increases the genetic sensitivity of mice exposed to BD and BDO(2). This model should facilitate a mechanistic understanding of the observed variation in human genetic sensitivity following exposure to BD.


Parasitism as the main factor shaping peptide vocabularies in current organisms.
Self/non-self-discrimination by vertebrate immune systems is based on the recognition of the presence of peptides in proteins of a parasite that are not contained in the proteins of a host. Therefore, a reduction of the number of 'words' in its own peptide vocabulary could be an efficient evolutionary strategy of parasites for escaping recognition. Here, we compared peptide vocabularies of 30 endoparasitic and 17 free-living unicellular organisms and also eight multicellular parasitic and 16 multicellular free-living organisms. We found that both unicellular and multicellular parasites used a significantly lower number of different pentapeptides than free-living controls. Impoverished pentapeptide vocabularies in parasites were observed across all five clades that contain both the parasitic and free-living species. The effect of parasitism on a number of peptides used in an organism's proteins is larger than effects of all other studied factors, including the size of a proteome, the number of encoded proteins, etc. This decrease of pentapeptide diversity was partly compensated for by an increased number of hexapeptides. Our results support the hypothesis of parasitism-associated reduction of peptide vocabulary and suggest that T-cell receptors mostly recognize the five amino acids-long part of peptides that are presented in the groove of major histocompatibility complex molecules.


Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study.
Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters. A total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks, or best supportive care. Response was assessed using the International Working Group criteria and required that response criteria be met for at least 8 weeks. Patients who were treated with decitabine achieved a significantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (P < .001). An additional 12 patients who were treated with decitabine (13%) achieved hematologic improvement. Responses were durable (median, 10.3 mos) and were associated with transfusion independence. Patients treated with decitabine had a trend toward a longer median time to acute myelogenous leukemia (AML) progression or death compared with patients who received supportive care alone (all patients, 12.1 mos vs. 7.8 mos [P = 0.16]; those with International Prognostic Scoring System intermediate-2/high-risk disease, 12.0 mos vs. 6.8 mos [P = 0.03]; those with de novo disease, 12.6 mos vs. 9.4 mos [P = 0.04]; and treatment-naive patients, 12.3 mos vs. 7.3 mos [P = 0.08]). Decitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death. The duration of decitabine therapy may improve these results further.


Storing of qi gong energy in various materials and drugs (qi gongnization): its clinical application for treatment of pain, circulatory disturbance, bacterial or viral infections, heavy metal deposits, and related intractable medical problems by selectively enhancing circulation and drug uptake.
In the process of evaluating the effects of external Qi Gong on inanimate substances by the Bi-Digital O-Ring Test, Qi Gong energy was shown to have a polarity which the author designated for convenience sake (+) or (-), where (+) increases the strength of muscles and (-) weakens them. Depending upon how external Qi Gong is applied and from which part of the body it emanates, the polarity changes. In general, it was found that, when (+) polarity is applied to the painful area or spastic muscles or arteries in vaso-constriction it often reduced or eliminated the pain, spastic muscles or circulatory disturbances. The author succeeded in storing part of the Qi Gong energy in inanimate materials, such as papers, metals (such as a sheet of aluminum foil), glass, stone, band-aids, clothes, drugs, etc. in bi-polar (one end of the same material becomes (+) polarity and the other end of the same material becomes (-) polarity) form in one material or uni-polar, i.e., the entire material either has pure (+) polarity or (-) polarity. Water, EPA, vitamins, antibiotics and other drugs were also converted to (+) polarity. When the material has a bi-polar state, it becomes possible to eliminate one of the polarities by applying certain changing electrical fields. The effect of placing (+) polarity Qi Gong energy stored material was compared with direct application of the Qi Gong on pain, spastic muscle and spastic vertebral arteries. The therapeutic effects of these 2 methods were quite similar for the identical time duration but a more predictable effect was often obtained in the former. As our previous study indicates that acupuncture, electrical stimulation (1-3 pulses/sec.), as well as Qi Gong not only improved the microcirculatory disturbance and relaxed spastic muscles and vaso-constrictive arteries but also reduced or eliminated the pain and also selectively enhanced drug uptake to the area where drugs could not be delivered due to existing circulatory disturbances, by placing (+) Qi Gong stored material, such as a sheet of paper or aluminum foil, band-aid or clothes. Bi- Digital O-Ring Test evaluation indicated that not only did it produce all the beneficial effects of Qi Gong but also enhanced the drug uptake selectively in the area where it is necessary for the drug to be delivered for effective treatment, and reduced lead deposits in tissue.(ABSTRACT TRUNCATED AT 400 WORDS)


Recessive MECR pathogenic variants cause an LHON-like optic neuropathy.
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterised by complex I defect leading to sudden degeneration of retinal ganglion cells. Although typically associated with pathogenic variants in mitochondrial DNA, LHON was recently described in patients carrying biallelic variants in nuclear genes DNAJC30, NDUFS2 and MCAT. MCAT is part of mitochondrial fatty acid synthesis (mtFAS), as also MECR, the mitochondrial trans-2-enoyl-CoA reductase. MECR mutations lead to a recessive childhood-onset syndromic disorder with dystonia, optic atrophy and basal ganglia abnormalities. We studied through whole exome sequencing two sisters affected by sudden and painless visual loss at young age, with partial recovery and persistent central scotoma. We modelled the candidate variant in yeast and studied mitochondrial dysfunction in yeast and fibroblasts. We tested protein lipoylation and cell response to oxidative stress in yeast. Both sisters carried a homozygous pathogenic variant in MECR (p.Arg258Trp). In yeast, the MECR-R258W mutant showed an impaired oxidative growth, 30% reduction in oxygen consumption rate and 80% decrease in protein levels, pointing to structure destabilisation. Fibroblasts confirmed the reduced amount of MECR protein, but failed to reproduce the OXPHOS defect. Respiratory complexes assembly was normal. Finally, the yeast mutant lacked lipoylation of key metabolic enzymes and was more sensitive to H2O2 treatment. Lipoic Acid supplementation partially rescued the growth defect. We report the first family with homozygous MECR variant causing an LHON-like optic neuropathy, which pairs the recent MCAT findings, reinforcing the impairment of mtFAS as novel pathogenic mechanism in LHON.


Measurements of the airglow continuum with a birefringent filter photometer.
The airglow continuum in the immediate vicinity of the strong line emissions of the airglow is measured by introducing a second rotating polarizer to the birefringent filter. The results are compared with those obtained by other workers using different techniques. It is shown that the method would be useful for the study of the continuum in the immediate vicinity of the airglow.


Delivery of a very low birth weight infant and increased maternal risk of cancer and death: a population study with 16 years of follow-up.
Pregnancy complications represent sentinel events for women's future health. We investigated whether delivery of a very low birth weight (VLBW) infant is associated with increased maternal risk for future incidence of maternal cancer and death. This is a population-based cohort study of linked Israeli Ministry of Health datasets between 1995 and 2011. Women delivering a live singleton <1,500 g infant (VLBW group) were compared with women delivering a live singleton, 3,000-3,500 g (control). The first pregnancy eligible for entry into the study, the "index pregnancy," reflected exposure status for each participant. Primary outcomes were maternal cancer and death. Cancer diagnoses were further classified by primary site. Cox regression models adjusted for follow-up period and maternal characteristics at index pregnancy: Age at delivery, ethnicity, years of education, marital status, and previous cancer afforded calculation of hazard ratios (HR) and 95% confidence intervals (CI). During the study period, 982,091 mothers with 2,243,736 live births were identified; of these, 13,773 births were VLBW eligible for inclusion in the study and 448,743 births were controls. Groups differed significantly by average follow-up and all maternal characteristics evaluated. Overall rate of cancers and death was significantly increased for VLBW women compared to controls: 18.4 versus 15.7% and 7.3 versus 3.2%, both p < 0.0001. The Cox model adjusted for maternal characteristics showed significantly increased risk of cancer (all sites) in the VLBW women: HR 1.18 (95% CI 1.02-1.37) and for death: HR 2.13 (95% CI 1.68-2.71), and an increased combined risk of both outcomes: HR 1.4 (95% CI 1.23-1.59). The delivery of a VLBW newborn is an independent lifetime risk factor for subsequent maternal cancers and death. These women may benefit from targeted cancer screening and counseling.


Usual Blood Pressure and Risk of New-Onset Diabetes: Evidence From 4.1 Million Adults and a Meta-Analysis of Prospective Studies.
Reliable quantification of the association between blood pressure (BP) and risk of type 2 diabetes is lacking. This study sought to determine the association between usual BP and risk of diabetes, overall and by participant characteristics. A cohort of 4.1 million adults, free of diabetes and cardiovascular disease, was identified using validated linked electronic health records. Analyses were complemented by a meta-analysis of prospective studies that reported relative risks of new-onset diabetes per unit of systolic blood pressure (SBP). Among the overall cohort, 20 mm Hg higher SBP and 10 mm Hg higher diastolic BP were associated with a 58% and a 52% higher risk of new-onset diabetes (hazard ratio: 1.58; 95% confidence interval [CI]: 1.56 to 1.59; and hazard ratio: 1.52; 95% confidence interval: 1.51 to 1.54), respectively. There was no evidence of a nadir to a baseline BP of 110/70 mm Hg. The strength of the association per 20 mm Hg higher SBP declined with age and with increasing body mass index. Estimates were similar even after excluding individuals prescribed antihypertensive or lipid-lowering therapies. Systematic review identified 30 studies with 285,664 participants and 17,388 incident diabetes events. The pooled relative risk of diabetes for a 20 mm Hg higher usual SBP across these studies was 1.77 (1.53 to 2.05). People with elevated BP are at increased risk of diabetes. The strength of the association declined with increasing body mass index and age. Further research should determine if the observed risk is modifiable.


Regulation of expression of type C virion DNA polymerase (reverse transcriptase) in human x mouse and human x rat hybrid cells.
Human cells from 13 different individuals were fused to mouse and rat cells producing abundant type C viral particles. The results demonstrate that incorporation of active DNA polymerase (reverse transcriptase) into mature type C particles is suppressed in many of the hybrid clones but not in the parental mouse cell clones. This low particle-associated DNA polymerase phenotype was a heritable trait for over 100 cell generations but reversion to a high particle-associated DNA polymerase phenotype was possible. In contrast, no evidence for suppression of viral p30 antigen was found. These results suggest that human cells contain a factor(s) capable of interfering with the normal maturation of the mouse retrovirus DNA polymerase protein; however, it was not possible to assign this function to any of 20 different human chromosomes tested. It is suggested that these somatic cell hybrids may be useful in examining individual events in retrovirus packaging and release.


The persistence of cone photoreceptors within the dorsal retina of aged retinally degenerate mice (rd/rd): implications for circadian organization.
Rod- and cone-opsin specific antibodies were used in an attempt to immunolabel remaining photoreceptor cells in the mutant rd (retinal degeneration) mouse retina. We identified a region-specific distribution in the pattern of photoreceptor degeneration, with the dorsal retina showing markedly less photoreceptor degeneration than the ventral retina. All rod and cone immunoreactive cells disappeared in the ventral retina by 100-120 days of age. By contrast, both cone and a small number of rod immunopositive cells were identified in the dorsal retina at this time. By 200 days all rod immunoreactive cells had disappeared. At 360 days numerous cone immunoreactive cells remained within a restricted region of the dorsal retina. As rd mice show unattenuated circadian responses to light, these remaining photoreceptor cells within the dorsal retina become candidates for the regulation of circadian physiology by light.


Effect of balloon size and stepwise inflation technique on the acute results of Inoue mitral commissurotomy. Inoue Balloon Catheter Investigators.
Currently percutaneous transvenous mitral commissurotomy (PTMC) is performed by most operators using stepwise inflation of the Inoue balloon beginning at a small diameter and increasing size by a sequence of inflations to nominal diameter. The effect of balloon size on procedure results using the Inoue balloon has not been evaluated. In 260 patients final balloon inflation was to nominal size in 42% of pts, larger than nominal size (overinflated) in 10%, and less than nominal size (underinflated) in 48% of pts. The average number of inflations was 3 (range 1-9). Pressure gradient and Doppler mitral regurgitation (MR) were assessed after each inflation. When MR increased, further inflations were not done. Patients in whom the balloon was overinflated underwent more balloon inflations than those in whom it was inflated to nominal size (5.0 +/- 2.1 vs. 2.9 +/- 1.4, p < 0.01). Those with balloon underinflation had fewer balloon inflations (2.4 +/- 1.2 vs. 2.9 +/- 1.4, p < 0.01). The post PTMC valve area in patients with overinflation was slightly less than those with nominal inflations (1.6 +/- 0.4 vs. 1.8 +/- 0.7), and with underinflation the valve area was no different compared to nominal inflation. Using a stepwise procedure, if mitral regurgitation was noted to increase after a balloon inflation, the procedure would be stopped even if less than an ideal result was achieved. Fewer inflations were done in patients in whom the balloon was inflated to less than nominal size because of the appearance of mitral regurgitation.(ABSTRACT TRUNCATED AT 250 WORDS)


Exposure to cyclic oxygen sufficient for development of oxygen-induced retinopathy does not induce bronchopulmonary dysplasia in rats.
Bronchopulmonary dysplasia and retinopathy of prematurity affect premature infants exposed to supplemental oxygen. Susceptibility to oxygen-induced retinopathy in the rat is heritable, with inbred Dark Agouti (DA) rats being more susceptible than Fischer 344 (F344) rats. To establish if hyperoxic exposure sufficient to induce florid retinopathy would induce strain-specific lung changes, newborn DA and F344 rats were exposed to cyclic hyperoxia or room air for up to 18 days. Lung function was assessed at 18 days, and standardized morphometry and immunohistochemistry were performed at intervals. No differences in arterial blood gases or protein concentration of bronchoalveolar lavage fluid were observed amongst groups at 18 days, although lung wet-to-dry weights were significantly lower for F344 than for DA rats. Pulmonary vascularity increased in all oxygen-exposed animals compared with room air-exposed controls, but there was no significant difference between strains. The lung surface area of oxygen-exposed F344 rats was significantly increased at day 10 compared with F344 controls and oxygen-treated DA rats, but at 14 and 17 days the oxygen-exposed DA rats showed increased lung surface area compared with oxygen-exposed F344 rats. The minor morphological differences found in the lung did not affect pulmonary function, suggesting that mechanisms inducing oxygen-induced retinopathy and bronchopulmonary dysplasia are fundamentally different, and that susceptibility to bronchopulmonary dysplasia is not heritable in the rat.


Development of 41Ca-based pharmacokinetic model for the study of bone remodelling in humans.
Initial studies show that 41Ca may be employed as a useful diagnostic bioassay for monitoring metabolic bone disease and its treatment management. The 41Ca-based pharmacokinetic model is developed to assess its feasibility in monitoring bone disease and clinical responsiveness to therapeutic regimens. A four-compartment calcium kinetic model is developed to interpret the results of clinically measured 41Ca tracer kinetics for oral and intravenous dose. This model is extended to simulate changes in bone turnover due to osteoporosis by using Gompertzian function with and without cellular accommodation. The rate constants obtained by fitting to the experimental data on drug intervention are used to simulate the impact of strategic treatment intervention. The present model fits well with the available experimental data on 41Ca tracer kinetics. In the simulated osteoporotic model, the negative bone balance (i.e. bone loss) reflected by 41Ca/Ca urine ratio is used to demonstrate slow/fast increase over time compared to the normal state. The cellular accommodation impact is reflected by a recovery from perturbed balance. The model's predictive ability on the impact of therapeutic intervention is verified using published experimental data. The effect of bisphosphonate intervention results in positive bone balance (i.e. bone gain). The four-compartment 41Ca tracer kinetic model can be flexibly used in the interpretation of results obtained from ongoing clinical studies.


Identification of a locus required for the regulation of bvg-repressed genes in Bordetella pertussis.
In Bordetella pertussis, the coordinate regulation of virulence factor expression is controlled by the products of the bvgAS locus. In the presence of modulating signals such as MgSO4, nicotinic acid, or reduced temperature, the expression of bvg-activated genes is reduced while the expression of bvg-repressed genes is induced. One model for the regulation of bvg-repressed genes predicts the existence of a repressor protein encoded by a bvg-activated gene. Once activated, the product of this bvg-activated gene would bind to and repress transcription from the bvg-repressed genes. We isolated five genetically independent transposon insertion mutants of B. pertussis that have a phenotype consistent with the knockout of a putative bvg-regulated repressor. These mutants constitutively expressed a vrg6-phoA transcriptional fusion but demonstrated normal bvgAS function. Genomic mapping and DNA sequence analysis of the sites of transposon insertion demonstrated that these mutants define a locus downstream of bvgAS. Introduction of an in-frame, 12-bp insertion within this locus also conferred the mutant phenotype, confirming that the phenotype seen in the transposon mutants is the result of disruption of a distinct gene, which we have designated bvgR, and is not a consequence of polar effects on bvgAS.


Jarid2 and PRC2, partners in regulating gene expression.
The Polycomb group proteins foster gene repression profiles required for proper development and unimpaired adulthood, and comprise the components of the Polycomb-Repressive Complex 2 (PRC2) including the histone H3 Lys 27 (H3K27) methyltransferase Ezh2. How mammalian PRC2 accesses chromatin is unclear. We found that Jarid2 associates with PRC2 and stimulates its enzymatic activity in vitro. Jarid2 contains a Jumonji C domain, but is devoid of detectable histone demethylase activity. Instead, its artificial recruitment to a promoter in vivo resulted in corecruitment of PRC2 with resultant increased levels of di- and trimethylation of H3K27 (H3K27me2/3). Jarid2 colocalizes with Ezh2 and MTF2, a homolog of Drosophila Pcl, at endogenous genes in embryonic stem (ES) cells. Jarid2 can bind DNA and its recruitment in ES cells is interdependent with that of PRC2, as Jarid2 knockdown reduced PRC2 at its target promoters, and ES cells devoid of the PRC2 component EED are deficient in Jarid2 promoter access. In addition to the well-documented defects in embryonic viability upon down-regulation of Jarid2, ES cell differentiation is impaired, as is Oct4 silencing.


Effects of a Brief Transdiagnostic Cognitive Behavioural Group Therapy on Disorder Specific Symptoms.
In recent years, cognitive behavioural group therapies (CBGT) have been increasingly deployed as a strategy to increase the efficiency and cost-effectiveness in treatment of common mental health problems. The vast majority of these therapies are disorder specific, but in the last few years there has been growing interest in transdiagnostic CBGT. The aim of this study was twofold: to evaluate the treatment effects of transdiagnostic CBGT on disorder specific symptoms and what (if any) differences would be observed in the treatment effects with regard to general as opposed to disorder specific symptoms measured pre- and post-treatment. The participants were 233 adult patients diagnosed with depression and/or anxiety disorders. They underwent a 6-week transdiagnostic CBGT. To compare treatment effects on general and disorder specific symptoms, raw scores on all measures were converted to standardized scores. Pre-post differences were significant and there was no evidence that treatment was differentially effective for general and disorder specific symptoms. Effect sizes ranged from medium to large. The 6-week transdiagnostic CBGT is feasible for a wide range of mood and anxiety disorders. The results indicate that low-intensity transdiagnostic group therapies may have similar effects on both general and disorder specific symptoms.


Experimental infection of human nasal mucosal explants with Neisseria meningitidis.
The interaction of Neisseria meningitidis with rhinopharyngeal epithelium was studied by experimental infection of explants of human nasal turbinate mucosa with two wild strains: a fully capsulate case isolate, and an epidemiologically related non-capsulate nasopharyngeal isolate. After incubation for 4 h, epithelial cells of infected explants changed conformation from tall columnar morphology towards cuboidal, and there was increased discharge of mucus globules from goblet cells. By 24 h there was significant damage to infected epithelia, including projection of cells out of the surface, cytoplasmic blebbing and mitochondrial abnormalities. Meningococci were associated with surface non-ciliated cells by 4 h after infection. By 24 h after infection they were associated extensively with all cell types exhibiting damage. There was little association with secreted mucus. In areas of cell damage, penetration between surface cells was observed. Endocytosis into non-ciliated cells was observed in only a minority of explants studied and only in those infected for 24 h. From this intracellular site there was apparent migration to adjacent cells and to intercellular locations. No organisms were observed within or beneath basement membrane collagen in any explants but internalisation into mononuclear phagocytes was observed occasionally.


Unaffected siblings of adolescents and adults with fragile X syndrome: Effects on maternal well-being.
The present study investigated the effects of children without disabilities on maternal physical and mental health in families with adolescents or adults with fragile X syndrome. Mothers with the FMR1 premutation (N = 87) reported on behavior problems and functional limitations of their adolescent or adult child with fragile X syndrome and their own physical and mental health. Mothers also provided a blood sample to determine FMR1 CGG repeat length. The proportion of unaffected children in the family significantly buffered the effect of both child behavior problems and functional limitations on maternal self-rated health, such that having a higher proportion of unaffected children in the family had a protective effect on maternal health when the target child had more severe behavior problems and functional limitations. There was a similar buffering process for maternal depressive symptoms but at a trend level. Additionally, maternal CGG repeat length had a significant curvilinear association with self-rated health, indicating that mothers with midrange repeat lengths reported the poorest health, whereas mothers with lower and higher repeat lengths in the premutation range reported better health. The data suggest that unaffected children in the family may be an important resource for premutation carrier mothers. Findings are consistent with previous research indicating that mothers with varying levels of genetic liability have variable risk for health problems. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Association Between Depressive Symptoms and Incident Cardiovascular Diseases.
It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVDs). To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood. A pooled analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 162 036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and the UK Biobank (401 219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline. Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Center for Epidemiological Studies Depression (CES-D) scale (range, 0-60; ≥16 indicates possible depressive disorder). The UK Biobank recorded the 2-item Patient Health Questionnaire 2 (PHQ-2; range, 0-6; ≥3 indicates possible depressive disorder). Primary outcomes were incident fatal or nonfatal coronary heart disease (CHD), stroke, and CVD (composite of the 2). Hazard ratios (HRs) per 1-SD higher log CES-D or PHQ-2 adjusted for age, sex, smoking, and diabetes were reported. Among 162 036 participants from the ERFC (73%, women; mean age at baseline, 63 years [SD, 9 years]), 5078 CHD and 3932 stroke events were recorded (median follow-up, 9.5 years). Associations with CHD, stroke, and CVD were log linear. The HR per 1-SD higher depression score for CHD was 1.07 (95% CI, 1.03-1.11); stroke, 1.05 (95% CI, 1.01-1.10); and CVD, 1.06 (95% CI, 1.04-1.08). The corresponding incidence rates per 10 000 person-years of follow-up in the highest vs the lowest quintile of CES-D score (geometric mean CES-D score, 19 vs 1) were 36.3 vs 29.0 for CHD events, 28.0 vs 24.7 for stroke events, and 62.8 vs 53.5 for CVD events. Among 401 219 participants from the UK Biobank (55% were women, mean age at baseline, 56 years [SD, 8 years]), 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1 years). The HR per 1-SD higher depression score for CHD was 1.11 (95% CI, 1.08-1.14); stroke, 1.10 (95% CI, 1.06-1.14); and CVD, 1.10 (95% CI, 1.08-1.13). The corresponding incidence rates per 10 000 person-years of follow-up among individuals with PHQ-2 scores of 4 or higher vs 0 were 20.9 vs 14.2 for CHD events, 15.3 vs 10.2 for stroke events, and 36.2 vs 24.5 for CVD events. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors. In a pooled analysis of 563 255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels lower than the threshold indicative of a depressive disorder. However, the magnitude of associations was modest.


On-farm Campylobacter and Escherichia coli in commercial broiler chickens: Re-used bedding does not influence Campylobacter emergence and levels across sequential farming cycles.
Limitations in quality bedding material have resulted in the growing need to re-use litter during broiler farming in some countries, which can be of concern from a food-safety perspective. The aim of this study was to compare the Campylobacter levels in ceca and litter across three litter treatments under commercial farming conditions. The litter treatments were (a) the use of new litter after each farming cycle; (b) an Australian partial litter re-use practice; and (c) a full litter re-use practice. The study was carried out on two farms over two years (Farm 1, from 2009-2010 and Farm 2, from 2010-2011), across three sheds (35,000 to 40,000 chickens/shed) on each farm, adopting three different litter treatments across six commercial cycles. A random sampling design was adopted to test litter and ceca for Campylobacter and Escherichia coli, prior to commercial first thin-out and final pick-up. Campylobacter levels varied little across litter practices and farming cycles on each farm and were in the range of log 8.0-9.0 CFU/g in ceca and log 4.0-6.0 MPN/g for litter. Similarly the E. coli in ceca were ∼log 7.0 CFU/g. At first thin-out and final pick-up, the statistical analysis for both litter and ceca showed that the three-way interaction (treatments by farms by times) was highly significant (P<0.01), indicating that the patterns of Campylobacter emergence/presence across time vary between the farms, cycles and pickups. The emergence and levels of both organisms were not influenced by litter treatments across the six farming cycles on both farms. Either C. jejuni or C. coli could be the dominant species across litter and ceca, and this phenomenon could not be attributed to specific litter treatments. Irrespective of the litter treatments in place, cycle 2 on Farm 2 remained Campylobacter-free. These outcomes suggest that litter treatments did not directly influence the time of emergence and levels of Campylobacter and E. coli during commercial farming.


A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists.
CXCR4 is a G protein-coupled receptor for stromal-derived factor 1 (SDF-1) that plays a critical role in leukocyte trafficking, metastasis of mammary carcinoma, and human immunodeficiency virus type-1 infection. To elucidate the mechanism for CXCR4 activation, a constitutively active mutant (CAM) was derived by coupling the receptor to the pheromone response pathway in yeast. Conversion of Asn-119 to Ser or Ala, but not Asp or Lys, conferred autonomous CXCR4 signaling in yeast and mammalian cells. SDF-1 induced signaling in variants with substitution of Asn-119 to Ser, Ala, or Asp, but not Lys. These variants had similar cell surface expression and binding affinity for SDF-1. CXCR4-CAMs were constitutively phosphorylated and present in cytosolic inclusions. Analysis of antagonists revealed that exposure to AMD3100 or ALX40-4C induced G protein activation by CXCR4 wild type, which was greater in the CAM, whereas T140 decreased autonomous signaling. The affinity of AMD3100 and ALX40-4C binding to CAMs was less than to wild type, providing evidence of a conformational shift. These results illustrate the importance of transmembrane helix 3 in CXCR4 signaling. Insight into the mechanism for CXCR4 antagonists will allow for the development of a new generation of agents that lack partial agonist activity that may induce toxicities, as observed for AMD3100.


Hereditary angioedema: a clinical review for the otolaryngologist.
Hereditary angioedema (HAE) is a relatively rare genetic disorder that is usually characterized by either low levels of C1 esterase inhibitor (C1-INH) or the presence of dysfunctional C1-INH. It can present with relatively mild and self-limiting symptoms, but it is also potentially fatal; the most common cause of death is asphyxiation secondary to edema of the upper airway. The diagnosis of HAE, especially in the emergency situation, is not straightforward. HAE must be distinguished from several other types of angioedema that require different management approaches. Management approaches include trigger avoidance and pharmacologic therapy; the latter has traditionally involved the administration of attenuated androgens and antifibrinolytics. Recently, a new class of agent-C1-INH-has been introduced in the United States. This article provides an update on the pathophysiology, clinical picture, diagnosis, prophylaxis, and acute treatment of HAE. We must keep HAE in mind as a possible diagnosis whenever we are faced with a case of unexplained angioedema if we are to take advantage of the effective and more specific therapies that are becoming available.


Experiences of liver health related uncertainty and self-reported stress among people who inject drugs living with hepatitis C virus: a qualitative study.
People who inject drugs (PWID) are most at risk of hepatitis C virus infection in Australia. The introduction of transient elastography (TE) (measuring hepatitis fibrosis) and direct acting antiviral medications will likely alter the experience of living with hepatitis C. We aimed to explore positive and negative influences on wellbeing and stress among PWID with hepatitis C. The Treatment and Prevention (TAP) study examines the feasibility of treating hepatitis C mono-infected PWID in community settings. Semi-structured interviews were conducted with 16 purposively recruited TAP participants. Participants were aware of their hepatitis C seropositive status and had received fibrosis assessment (measured by TE) prior to interview. Questions were open-ended, focusing on the impact of health status on wellbeing and self-reported stress. Interviews were voice recorded, transcribed verbatim and thematically analysed, guided by Mishel's (1988) theory of Uncertainty in Illness. In line with Mishel's theory of Uncertainty in Illness all participants reported hepatitis C-related uncertainty, particularly mis-information or a lack of knowledge surrounding liver health and the meaning of TE results. Those with greater fibrosis experienced an extra layer of prognostic uncertainty. Experiences of uncertainty were a key motivation to seek treatment, which was seen as a way to regain some stability in life. Treatment completion alleviated hepatitis C-related stress, and promoted feelings of empowerment and confidence in addressing other life challenges. TE scores seemingly provide some certainty. However, when paired with limited knowledge, particularly among people with severe fibrosis, TE may be a source of uncertainty and increased personal stress. This suggests the need for simple education programs and resources on liver health to minimise stress.


Safety and efficacy of posaconazole in the long-term treatment of azole-refractory oropharyngeal and esophageal candidiasis in patients with HIV infection.
To evaluate safety and efficacy of long-term posaconazole in HIV-infected patients with azole-refractory oropharyngeal candidiasis and/or esophageal candidiasis. In this noncomparative, open-label study, participants received oral posaconazole 400 mg twice daily (bid) for 3 months. Enrolled patients (N = 100) included 60 from a previous 1-month acute study of posaconazole and 40 posaconazole-naïve participants. Participants with a clinical response could be followed untreated for up to 1 month afterwards. Participants who relapsed during follow-up, showed improvement at the end of 3 months of treatment (EOT), or were cured but likely to benefit from further therapy could continue on posaconazole 400 mg bid for up to 12 months. In the modified intent-to-treat population, clinical response (cure or improvement) occurred in 85.6% (77/90) at EOT. The results were similar in the previously treated participants and the posaconazole-naïve participants, 88.1% (52/59) and 80.6% (25/31), respectively. Posaconazole was well-tolerated, showing a similar safety profile during the 3-month study period and during suppressive therapy. The most frequently reported treatment-related adverse event was vomiting (4/100, 4%) during the early follow-up period (on or before day 105) and elevated hepatic enzymes (3/51, 6%) during the long-term follow-up (after day 105). Oral posaconazole 400 mg bid demonstrated long-term safety, tolerability, and efficacy, offering a long-term, suppressive treatment option for HIV-infected participants with azole-refractory mucosal candidiasis.


Induction of aP2 gene expression by nonmetabolized long-chain fatty acids.
Long-chain fatty acids (FA) have been shown to regulate expression of the gene for the adipocyte FA-binding protein aP2. We examined whether this effect was exerted by FA themselves or by a FA metabolite. The alpha-bromo derivative of palmitate, an inhibitor of FA oxidation, was synthesized in the radioactive form, and its metabolism was investigated and correlated with its ability to induce aP2 in Ob1771 preadipocytes. alpha-Bromopalmitate was not utilized by preadipocytes. It was not cleared from the medium over a 24-hr period and was not incorporated into cellular lipids. Short incubations indicated that alpha-bromopalmitate exchanged across the preadipocyte membrane but remained in the free form inside the cell. In line with this, preadipocyte homogenates did not activate alpha-bromopalmitate to the acyl form. However, although it was not metabolized, bromopalmitate was much more potent than native FA in inducing aP2 gene expression. Induction exhibited the characteristics previously described for native FA, indicating that a similar if not identical mechanism was involved. The data indicated that induction of aP2 was exerted by unprocessed FA. Finally, in contrast to preadipocytes, adipocytes metabolized bromopalmitate. This reflected increased activity with cell differentiation of a palmitoyl-CoA synthase that could activate palmitate and bromopalmitate at about one-fifth the rate for palmitate. In preadipocytes, the predominant fatty-acyl-CoA synthase, arachidonyl-CoA synthase, had very low affinity for both FA. Increased activity of the palmitoyl-CoA synthase, which has a wider substrate range, is likely to be important for initiation of lipid deposition.


Personalizing Risk Stratification for Sudden Death in Dilated Cardiomyopathy: The Past, Present, and Future.
Results from the DANISH Study (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heat Failure on Mortality) suggest that for many patients with dilated cardiomyopathy (DCM), implantable cardioverter-defibrillators do not increase longevity. Accurate identification of patients who are more likely to die of an arrhythmia and less likely to die of other causes is required to ensure improvement in outcomes and wise use of resources. Until now, left ventricular ejection fraction has been used as a key criterion for selecting patients with DCM for an implantable cardioverter-defibrillator for primary prevention purposes. However, registry data suggest that many patients with DCM and an out-of-hospital cardiac arrest do not have a markedly reduced left ventricular ejection fraction. In addition, many patients with reduced left ventricular ejection fraction die of nonsudden causes of death. Methods to predict a higher or lower risk of sudden death include the detection of myocardial fibrosis (a substrate for ventricular arrhythmia), microvolt T-wave alternans (a marker of electrophysiological vulnerability), and genetic testing. Midwall fibrosis is identified by late gadolinium enhancement cardiovascular magnetic resonance imaging in ≈30% of patients and provides incremental value in addition to left ventricular ejection fraction for the prediction of sudden cardiac death events. Microvolt T-wave alternans represents another promising predictor, supported by large meta-analyses that have highlighted the negative predictive value of this test. However, neither of these strategies have been routinely adopted for risk stratification in clinical practice. More convincing data from randomized trials are required to inform the management of patients with these features. Understanding of the genetics of DCM and how specific mutations affect arrhythmic risk is also rapidly increasing. The finding of a mutation in lamin A/C, the cause of ≈6% of idiopathic DCM, commonly underpins more aggressive management because of the malignant nature of the associated phenotype. With the expansion of genetic sequencing, the identification of further high-risk mutations appears likely, leading to better-informed clinical decision making and providing insight into disease mechanisms. Over the next 5 to 10 years, we expect these techniques to be integrated into the existing algorithm to form a more sensitive, specific, and cost-effective approach to the selection of patients with DCM for implantable cardioverter-defibrillator implantation.


Intramedullary stabilization of distal-third femur fractures in octogenarians.
Management of distal-third femoral fractures is challenging, especially in the elderly population, where the associated complication rate has been reported to be as high as 40%. This study reviews the techniques and safety of intramedullary stabilization for displaced and unstable fractures involving the distal third of the femur in patients who were at least 80 years old, with the use of Ender nails. A retrospective study of 12 patients with 14 femur fractures underwent closed fixation of their fracture(s) with Ender nails performed within 24 hours of the injury. There were 10 females and 2 males, whose average age was 88 years (range, 82-103 years). The average length of follow-up was 3 years. Twelve fractures (86%) healed uneventfully. There were two nonunions (14%) with no other major or minor complications. No patients were lost to follow-up evaluation. All patients eventually returned to their preinjury level of function. This technique is particularly applicable to elderly patients with severe osteopenia and preexisting medical problems, as it minimizes blood loss and other associated complications, while providing stability for immediate mobilization.


Brachial artery catheterization: an assessment of use patterns and associated complications.
Although studies have compared safety and outcomes of radial artery cannulation with other arterial catheterization locations, there is insufficient information describing brachial artery catheterization. In this study, we characterized the perioperative use patterns and the complication rates associated with brachial arterial catheterization and compared these outcomes with radial artery catheterization. We performed a retrospective analysis of adult patients (age ≥18 years) undergoing surgical procedures at an academic medical center from January 1, 2008, to December 31, 2011. An institutional database containing information on anesthetic care was queried to identify all brachial artery catheterizations. Baseline characteristics, details relating to the surgical and catheterization procedures, and catheter-related complications were collected and compared with a random sample of patients receiving radial artery catheterization. We identified 858 patients receiving brachial catheterization perioperatively. An additional 3432 patients receiving radial catheterization were identified. Patients receiving brachial catheterization were more often women, had a lower body mass index, had more comorbidities, and had longer anesthetic and catheterization durations. Three vascular complications were identified in the cohort receiving brachial artery catheterization compared with 1 patient with a peripheral neuropathy in the radial artery catheterization cohort (unadjusted complication incidence [95% confidence intervals] brachial artery catheterization, 0.35% [0.12%-1.02%] vs radial artery catheterization, 0.03% [0.005%-0.16%], respectively; P = 0.030; relative risk [95% confidence interval] = 12.0 [1.7-83.4]). There were no catheter-related bloodstream infections. We found that brachial artery catheterization is used in more medically complex patients and for longer duration than radial artery catheterizations. Although the limited number of adverse outcomes precluded statistical adjustments in this investigation, the observed differences in complication rates between cannulation methods suggest that brachial artery catheterization may be a suitable alternative to radial artery catheterization in patients with complex medical comorbidities.


Tempol protects against oxidative damage and delays epithelial tumor onset in Fanconi anemia mice.
Fanconi anemia (FA) is a genetic disorder characterized by congenital abnormalities, bone marrow failure, and marked cancer susceptibility. FA patients have an elevated risk of developing hematologic malignancies and solid tumors. Using Fancd2(-/-) knockout mice as a model of FA, we examined the potential of tempol, a nitroxide antioxidant and a superoxide dismutase mimetic, as a tumor-delaying agent for solid tumors. Dietary tempol increased the mean tumor-free survival time of Fancd2(-/-) Trp53(+/-) mice by 27% (P < 0.01), from 308 to 390 days, without changing the overall tumor spectrum. More strikingly, tempol delayed the onset of epithelial tumors and increased the mean epithelial tumor-free survival time by 38% (P < 0.0001), from 312 to 432 days, in Fancd2(-/-) Trp53(+/-) mice. These results show that tempol can significantly delay tumor formation in Fancd2(-/-) Trp53(+/-) mice. Furthermore, tempol treatment did not adversely affect the repopulating ability of FA hematopoietic stem cells. The reduction in oxidative DNA damage in tempol-treated FA fibroblasts and mice suggests that its tumor-delaying function may be attributed to its antioxidant activity.