Lung Cancer in Nonelderly Patients: Facility and Patient Characteristics Associated With Not Receiving Treatment.
In elderly patients with lung cancer, race/ethnicity is associated with not receiving treatment; however, little attention has been given to nonelderly patients (aged ≤65 years) with a range of disease stages and histologies. Nonelderly patients with lung cancer have superior survival at NCI-designated Comprehensive Cancer Centers (CCCs), although the reasons remain unknown. A retrospective cohort study was conducted in 9,877 patients newly diagnosed with small cell or non-small cell lung cancer (all stages) between ages 22 and 65 years and reported to the Los Angeles County Cancer Surveillance Program registry between 1998 and 2008. Multivariable logistic regression examined factors associated with nontreatment. In multivariable analysis, race/ethnicity was associated with not receiving cancer treatment (black: odds ratio [OR], 1.22; P=.004; Hispanic: OR, 1.17; P=.04), adjusting for patient age, sex, disease stage, histology, diagnosis year, distance to treatment facility, type of facility (CCC vs non-CCC), and insurance status. With inclusion of socioeconomic status (SES) in the model, the effect of race/ethnicity was no longer significant (black: OR, 1.02; P=.80; Hispanic: OR, 1.00; P=1.00). Factors independently associated with nontreatment included low SES (OR range, 1.37-2.15; P<.001), lack of private insurance (public: OR, 1.71; P<.001; uninsured: OR, 1.30; P<.001), and treatment facility (non-CCC: OR, 3.22; P<.001). In nonelderly patients with lung cancer, SES was associated with nontreatment, mitigating the effect of race/ethnicity. Patients were also at higher odds of nontreatment if they did not have private insurance or received cancer care at a non-CCC facility. These findings highlight the importance of understanding how both patient-level factors (eg, SES, insurance status) and facility-level factors (eg, treatment facility) serve as barriers to treatment of nonelderly patients with lung cancer.


Oral Spindle Cell Lipoma in a Rare Location: A Differential Diagnosis.
Spindle cell lipoma (SCL) is an uncommon and histologically distinct variant of lipoma. It usually occurs as a solitary, subcutaneous, and well-circumscribed lesion in the posterior neck, shoulders, and back of older men. SCL of the oral cavity is rare. We present the clinical-pathologic features of the third case of SCL located on the hard palate and discuss the histological differential diagnosis with other fusiform neoplasms. A 56-year-old man was evaluated for an asymptomatic swelling on the right side of the hard palate. The intraoral examination showed a 25×20 mm sessile and circumscribed tumor, underlying an apparently healthy mucosa of normal color. The lesion revealed a floating consistency during palpation. Excisional biopsy was carried out based on a clinical diagnosis of lipoma or a benign minor salivary gland tumor. The histopathology demonstrated a well-circumscribed but unencapsulated proliferation of bland spindle cells admixed with mature adipocytes in a collagenous/myxoid stroma. The spindle cells were uniform, exhibiting elongated nuclei and narrow cytoplasmic processes without atypia. They were positive to CD34 and negative to factor VIII, alpha-smooth muscle actin, S100, cytokeratin, and actin. Mitotic activity was low, as confirmed by Ki-67 immunostaining. No lipoblastic activity was found. The diagnosis of SCL was therefore established. Oral spindle cell lipoma is a rare benign lipomatous tumor. The histologic picture shows a range of variations and the observation of morphological features is important to distinguish this lesion from other fusiform tumors. Immunohistochemistry should be helpful in this differentiation.


A ban on menthol cigarettes: impact on public opinion and smokers' intention to quit.
We assessed support for a ban by the Food and Drug Administration on menthol in cigarettes and behavioral intentions among menthol smokers in the event of such a ban. We surveyed 2649 never, former, and current smokers and used ordinal logistic regression to calculate weighted point estimates and predictors of support for a menthol ban among the adult population and menthol smokers only. For menthol smokers, we also calculated weighted point estimates and predictors of behavioral intentions. Overall, 28.2% of adults opposed, 20.0% supported, and 51.9% lacked a strong opinion about a menthol ban. Support was highest among Hispanics (36.4%), African Americans (29.0%), never smokers (26.8%), and respondents with less than a high school education (28.8%). Nearly 40% of menthol smokers said they would quit if menthol cigarettes were no longer available, 12.5% would switch to a nonmenthol brand, and 25.2% would both switch and try to quit. Support for a menthol ban is strongest among populations with the highest prevalence of menthol cigarette use. A menthol ban might motivate many menthol smokers to quit.


Medical Students' and Trainees' Country-By-Gender Profiles: Hofstede's Cultural Dimensions Across Sixteen Diverse Countries.
The global mobility of medical student and trainee populations has drawn researchers' attention to consider internationalization in medical education. Recently, researchers have focused on cultural diversity, predominately drawing on Hofstede's cross-cultural analysis of cultural dimensions from general population data to explain their findings. However, to date no research has been specifically undertaken to examine cultural dimensions within a medical student or trainee population. This is problematic as within-country differences between gender and professional groups have been identified within these dimensions. We address this gap by drawing on the theoretical concept of national context effects: specifically Hofstede's six-dimensional perspective. In doing so we examine medical students' and trainees' country profiles across dimensions, country-by-gender clustering, and differences between our data and Hofstede's general population data. We undertook a cross-cultural online questionnaire study (eight languages) containing Hofstede's 2013 Values Survey. Our questionnaire was live between 1st March to 19th Aug 2018, and December 2018 to mitigate country holiday periods. We recruited undergraduate medical students and trainees with at least 6-months' clinical training using school-specific methods including emails, announcements, and snowballing. We received 2,529 responses. Sixteen countries were retained for analyses (n = 2,307, 91%): Australia, Chile, China, Hong Kong, India, Indonesia, Ireland, Israel, Japan, Malaysia, New Zealand, Pakistan, South Africa, South Korea, Sri-Lanka, Taiwan. Power distance and masculinity are homogenous across countries. Uncertainty avoidance shows the greatest diversity. We identified four country clusters. Masculinity and uncertainty are uncorrelated with Hofstede's general population data. Our medical student and trainee data provides medical education researchers with more appropriate cultural dimension profiles than those from general population data. Country cluster profiles stimulate useful hypotheses for further research, especially as patterning between clusters cuts across traditional Eastern-Western divides with national culture being stronger than gendered influences. The Uncertainty dimension with its complex pattern across clusters is a particularly fruitful avenue for further investigation.


The Micronutrient Genomics Project: a community-driven knowledge base for micronutrient research.
Micronutrients influence multiple metabolic pathways including oxidative and inflammatory processes. Optimum micronutrient supply is important for the maintenance of homeostasis in metabolism and, ultimately, for maintaining good health. With advances in systems biology and genomics technologies, it is becoming feasible to assess the activity of single and multiple micronutrients in their complete biological context. Existing research collects fragments of information, which are not stored systematically and are thus not optimally disseminated. The Micronutrient Genomics Project (MGP) was established as a community-driven project to facilitate the development of systematic capture, storage, management, analyses, and dissemination of data and knowledge generated by biological studies focused on micronutrient-genome interactions. Specifically, the MGP creates a public portal and open-source bioinformatics toolbox for all "omics" information and evaluation of micronutrient and health studies. The core of the project focuses on access to, and visualization of, genetic/genomic, transcriptomic, proteomic and metabolomic information related to micronutrients. For each micronutrient, an expert group is or will be established combining the various relevant areas (including genetics, nutrition, biochemistry, and epidemiology). Each expert group will (1) collect all available knowledge, (2) collaborate with bioinformatics teams towards constructing the pathways and biological networks, and (3) publish their findings on a regular basis. The project is coordinated in a transparent manner, regular meetings are organized and dissemination is arranged through tools, a toolbox web portal, a communications website and dedicated publications.


[A case of gastric cancer with rhabdoid features showing better prognosis through S-1/CDDP chemotherapy].
Although gastric cancers(GCs)with rhabdoid features are rare, they are known to show a poorer prognosis compared with conventional GCs. Indeed, more than half of reported GCs with rhabdoid features died within 6 months after receiving any kind of initial treatment. Obviously, no effective chemotherapy has been reported. In this study, we present a case of GC with rhabdoid features which showed a better response to a chemotherapy, S-1/CDDP, and lived for over 12 months after the initial chemotherapy. A 75-year-old man was seen in our hospital for epigastralgia. Detailed examinations revealed that he had GC at Stage IV. Consequently, he underwent S-1/CDDP treatment. This treatment produced a good response for 6 months, minimizing the size of the primary tumor and eradicating distant metastases. Re-growth of the primary tumor without uprising distant metastasis was confirmed 8 months after the initialS -1/CDDP treatment, and the patient went through a gastrectomy for curative care. After surgery, a precise pathological examination revealed that the primary tumor possessed a poorly differentiated adenocarcinoma that contained tumor cells with typical rhabdoid features. In the end, the patient died of liver metastasis 13 months after the initial S-1/CDDP chemotherapy.


Proline dehydrogenase is essential for proline protection against hydrogen peroxide-induced cell death.
Proline metabolism has an underlying role in apoptotic signaling that influences tumorigenesis. Proline is oxidized to glutamate in the mitochondria, with the rate-limiting step catalyzed by proline dehydrogenase (PRODH). PRODH expression is inducible by p53, leading to increased proline oxidation, reactive oxygen species formation, and induction of apoptosis. Paradoxical to its role in apoptosis, proline also protects cells against oxidative stress. Here we explore the mechanism of proline protection against hydrogen peroxide stress in melanoma WM35 cells. Treatment of WM35 cells with proline significantly increased cell viability, diminished oxidative damage of cellular lipids and proteins, and maintained ATP and NADPH levels after exposure to hydrogen peroxide. Inhibition or siRNA-mediated knockdown of PRODH abolished proline protection against oxidative stress, whereas knockdown of Δ(1)-pyrroline-5-carboxylate reductase, a key enzyme in proline biosynthesis, had no impact on proline protection. Potential linkages between proline metabolism and signaling pathways were explored. The combined inhibition of the mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 eliminated proline protection. A significant increase in Akt activation was observed in proline-treated cells after hydrogen peroxide stress along with a corresponding increase in the phosphorylation of the forkhead transcription factor class O3a (FoxO3a). The role of PRODH in proline-mediated protection was validated in the prostate carcinoma cell line PC3. Knockdown of PRODH in PC3 cells attenuated phosphorylated levels of Akt and FoxO3a and decreased cell survival during hydrogen peroxide stress. The results provide evidence that PRODH is essential in proline protection against hydrogen peroxide-mediated cell death and that proline/PRODH helps activate Akt in cancer cells.


Study of 8-year-old children with a history of respiratory syncytial virus bronchiolitis in infancy.
Thirty-five children known to have had respiratory syncytial virus bronchiolitis in infancy were examined at the age of 8 and their respiratory function tested. The results were compared with those in 35 controls matched for age, sex, and social class. Although 18 of the children who had had bronchiolitis in infancy had experienced subsequent episodes of wheezing, these were neither severe nor frequent in most cases and had apparently ceased by the age of 8. Nevertheless, the mean exercise bronchial lability of the children who had had bronchiolitis was significantly higher than that of the control children and the mean peak expiratory flow rate at rest significantly lower. Atopy, assessed by family and personal history alone, did not seem to be related to either bronchiolitis or wheezing episodes after bronchiolitis. The parents of the children who had had bronchiolitis smoked significantly more cigarettes during the infant's first year of life than those of the control children. The results suggest that bronchiolitis and childhood asthma are not closely related. Bronchial hyperreactivity might be inherited independently of atopy, but environmental factors seem the most likely link between severe respiratory infection in infancy and chronic or recurrent respiratory illness in adult life.


A validation study of depressive syndromes in Parkinson's disease.
The validity, sensitivity, and specificity of depressive symptoms for the diagnosis of major depression, minor depression, dysthymic disorder, and subsyndromal depression in Parkinson's disease (PD) were examined. A consecutive series of 173 patients with PD attending a Movement Disorders Clinic underwent a comprehensive psychiatric and neurological assessment. The symptoms of loss of interest/pleasure, changes in appetite or weight, changes in sleep, low energy, worthlessness or inappropriate guilt, psychomotor retardation/agitation, concentration deficits, and suicide ideation were all significantly associated with the presence of the DSM-IV depressed mood criterion for major depression. The symptoms of changes in appetite, changes in sleep, low energy, low self-esteem, poor concentration, and hopelessness were all significantly associated with the presence of the DSM-IV criterion of sad mood for dysthymic disorder. Thirty percent of our sample met DSM-IV diagnostic criteria for major depression, 20% met diagnostic criteria for dysthymic disorder, 10% met diagnostic criteria for minor depression, and 8% met clinical criteria for subsyndromal depression. Patients with either major or minor depression had significantly more severe deficits in activities of daily living, more severe cognitive impairments, and more severe Parkinsonism than patients with either dysthymic disorder or no depression. This study provides validation to the DSM-IV diagnostic criteria for major depression and dysthymic disorder for use in PD. The categories of minor and subsyndromal depression may need further validation.


Mumps epidemic in orthodox religious low-vaccination communities in the Netherlands and Canada, 2007 to 2009.
We assessed the epidemiological characteristics of a mumps virus epidemic (genotype D) that occurred in the Netherlands between August 2007 and May 2009 and its association with a subsequent mumps outbreak in Canada. In the Netherlands, five data sources were used: notifications (only mandatory since the end of 2008) (56 cases), laboratory confirmation data (177 cases), a sentinel general practitioner (GP) database (275 cases), hospitalisation data (29 cases) and weekly virological reports (96 cases). The median age of cases in the notification, laboratory and GP databases ranged from 13 to 15 years. The proportion of cases that were unvaccinated ranged from 65% to 85% in the notification, laboratory and GP databases. Having orthodox Protestant beliefs was the main reason for not being vaccinated. In Canada, a mumps virus strain indistinguishable from the Dutch epidemic strain was detected between February and October 2008 in an orthodox Protestant community with historical and family links to the affected community in the Netherlands, suggesting that spread to Canada had occurred. Prevention and control of vaccine-preventable diseases among population subgroups with low vaccination coverage remains a priority.


Characteristics and outcome among patients suffering from out-of-hospital cardiac arrest with the emphasis on availability for intervention trials.
To describe all patients treated for out-of-hospital cardiac arrest (OHCA) according to the Utstein criteria and their characteristics and outcome with emphasis on whether they were available for early intervention trials. Retrospective analysis of a study where data were collected prospectively. The Municipality of Göteborg/Mölndal in Sweden. All patients suffering from out-of-hospital cardiac arrest in the Municipality of Göteborg/Mölndal in whom cardiopulmonary resuscitation (CPR) was attempted between May 2003 and May 2005. Part of the study cohort, i.e. patients with a witnessed, non-traumatic, out-of-hospital cardiac arrest were distributed (cluster) to mechanical (LUCAS) or manual chest compression. The overall survival to discharge from hospital among the 508 patients was 8.5%. The corresponding value for non-cardiac cases was 5.1% and for cardiac cases if crew witnessed 16.1%, bystander witnessed 12.7% and non-witnessed 1.4%. Fifty-nine percent of the patients fulfilled the inclusion criteria for the trial and had no exclusion criteria and 9.7% of these survived to discharge. Ten percent of patients fulfilled the inclusion criteria but were excluded and 20.4% survived to discharge. Thirty-one percent of patients did not fulfil the inclusion criteria and 2.5% survived. Among patients included in the LUCAS group, many of the survivors, 10/13 (77%), experienced a rapid return of spontaneous circulation (ROSC) before the application of the device. Among patients with OHCA in whom CPR was started 8.5% survived to hospital discharge and 59% were theoretically available for an early intervention trial. These patients have a different outcome compared with patients not available. However, among those available, the majority of survivors had a rapid ROSC before the application of the intervention (LUCAS). This raises concerns about the potential for early intervention trials to improve outcome after OHCA.


Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes.
The accumulation of excess fat in the liver (hepatic steatosis) in the absence of heavy alcohol consumption causes nonalcoholic fatty liver disease (NAFLD), which has become a global epidemic. Identifying metabolic risk factors that interact with the genetic risk of NAFLD is important for reducing disease burden. We tested whether serum glucose, insulin, insulin resistance, triglyceride (TG), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index (BMI), and waist-to-hip ratio adjusted for BMI interact with genetic variants in or near the patatin-like phospholipase domain containing 3 (PNPLA3) gene, the glucokinase regulatory protein (GCKR) gene, the neurocan/transmembrane 6 superfamily member 2 (NCAN/TM6SF2) gene, and the lysophospholipase-like 1 (LYPLAL1) gene to exacerbate hepatic steatosis, estimated by liver attenuation. We performed association analyses in 10 population-based cohorts separately and then meta-analyzed results in up to 14,751 individuals (11,870 of European ancestry and 2,881 of African ancestry). We found that PNPLA3-rs738409 significantly interacted with insulin, insulin resistance, BMI, glucose, and TG to increase hepatic steatosis in nondiabetic individuals carrying the G allele. Additionally, GCKR-rs780094 significantly interacted with insulin, insulin resistance, and TG. Conditional analyses using the two largest European ancestry cohorts in the study showed that insulin levels accounted for most of the interaction of PNPLA3-rs738409 with BMI, glucose, and TG in nondiabetic individuals. Insulin, PNPLA3-rs738409, and their interaction accounted for at least 8% of the variance in hepatic steatosis in these two cohorts. Conclusion: Insulin resistance, either directly or through the resultant elevated insulin levels, more than other metabolic traits, appears to amplify the PNPLA3-rs738409-G genetic risk for hepatic steatosis. Improving insulin resistance in nondiabetic individuals carrying PNPLA3-rs738409-G may preferentially decrease hepatic steatosis.


Interphase cytogenetics and pathology: a tool for diagnosis and research.
Karyotypic analysis by direct demonstration of DNA sequences in interphase nuclei has been termed interphase cytogenetics and can be applied to a wide variety of cellular material, including paraffin-embedded tissue, allowing detection of both numerical and structural chromosome aberrations. The principal established method in the fluorescence in situ hybridization (FISH) technique, but more recently primed in situ labelling (PRINS) has been employed, as illustrated in an accompanying paper in this issue of the Journal. Where there are defining cytogenetic abnormalities, as is the case for the detection of fetal numerical chromosome abnormalities and in some paediatric and soft tissue tumours, this approach has clear diagnostic applicability. In other circumstances, such as the investigation of most solid tumours, this technique is largely of research interest but, particularly with application to paraffin sections, in providing valuable information on the morphological distribution of molecular changes in both invasive and 'pre-invasive' lesions. Continued technical refinement and research application of this methodology will lead not only to greater clinical applicability but also to improved understanding of the pathobiology of tumours.


Immunogenicity of attenuated vesicular stomatitis virus vectors expressing HIV type 1 Env and SIV Gag proteins: comparison of intranasal and intramuscular vaccination routes.
An experimental AIDS vaccine based on attenuated, recombinant vesicular stomatitis virus (rVSV), when administered by a combination of parenteral and mucosal routes, has proven effective at preventing AIDS in a rhesus macaque model (Rose NF, et al.: Cell 2001;106:539-549). In an effort to determine the optimal route of vaccine administration we evaluated the ability of rVSV-based vaccine vectors expressing HIV-1 Env and SIV Gag proteins, when given either intramuscularly (i.m.) or intranasally (i.n.), to elicit antigen-specific cellular and humoral immune responses, and to protect from a subsequent vaginal challenge with simian-human immunodeficiency virus (SHIV89.6P). Our results demonstrate that macaques vaccinated by the i.n. route developed significantly higher antigen-specific cellular immune responses as determined by MHC class I tetramer staining, IFN-gamma ELISPOT, and cytotoxic T cell assays. However, systemic and mucosal humoral immune responses did not vary significantly with the route of vaccine administration. Given the importance of cell-mediated immune responses in slowing AIDS progression, intranasal delivery of a VSV-based AIDS vaccine may be an optimal as well as practical route for vaccination and should be considered in design of clinical trials.


Simplified design of thin-film polarizing beam splitter using embedded symmetric trilayer stack.
An analytically tractable design procedure is presented for a polarizing beam splitter (PBS) that uses frustrated total internal reflection and optical tunneling by a symmetric LHL trilayer thin-film stack embedded in a high-index prism. Considerable simplification arises when the refractive index of the high-index center layer H matches the refractive index of the prism and its thickness is quarter-wave. This leads to a cube design in which zero reflection for the p polarization is achieved at a 45° angle of incidence independent of the thicknesses of the identical symmetric low-index tunnel layers L and L. Arbitrarily high reflectance for the s polarization is obtained at subwavelength thicknesses of the tunnel layers. This is illustrated by an IR Si-cube PBS that uses an embedded ZnS-Si-ZnS trilayer stack.


Comparison of Ammonia Emission Estimation between Passive Sampler and Chamber System in Paddy Soil after Fertilizer Application.
Ammonia (NH3) is an important precursor for particulate secondary aerosol formation. This study was conducted to evaluate the applicability of a passive sampler (PAS) for estimating the NH3 emission from chemical fertilizer application (85 kg-N·ha-1) at field scale and to compare the results with a chamber system for the calculation of NH3 emission flux at lab scale. The application of chemical fertilizer increased the ambient NH3 concentration from 7.11 to 16.87 μg·m-3. Also, the ambient NH3 concentration measured by the PAS was found to be highly influenced by not only the chemical fertilizer application but also the weather (temperature and rainfall). Wind rose diagram data can be useful for understanding the distribution of ambient NH3 concentration. In the case of a chamber with few environmental variables, NH3 was emitted very quickly in the early stages and gradually decreased, whereas it was delayed at intervals of about one week at the site. It was found that daily temperature range, atmospheric disturbance by wind and rainfall, changes in soil moisture, and the presence of a flooded water table were the main influencing factors. The PAS data and the chamber system data were observed to have significant differences in spatial-temporal scale. In order to reduce the gap, it seems to be necessary to further develop a chamber system, in order to improve the precision of field analysis and to strengthen the connection between experimental results.


"Something of an adventure": postwar NIH research ethos and the Guatemala STD experiments.
The STD experiments in Guatemala from 1946-1948 have earned a place of infamy in the history of medical ethics. But if the Guatemala STD experiments were so "ethically impossible," how did the U.S. government approve their funding? Although much of the literature has targeted the failings of Dr. John Cutler, we focus on the institutional context and research ethos that shaped the outcome of the research. After the end of WWII, Dr. Cassius Van Slyke reconstructed the federal research contracts process into a grant program. The inaugural NIH study section recommended approval of the Guatemala STD experiments at its first meeting. The funding and oversight process of the Guatemala research was marked with serious conflicts of interest and a lack of oversight, and it was this structure, as opposed to merely a maleficent individual, that allowed the Guatemala STD experiments to proceed. We conclude that while current research regulations are designed to prevent the abuses perpetrated on the subjects of the Guatemala STD experiments, it takes a comprehensive understanding of research ethics through professional education to achieve the longstanding ideal of the responsible investigator, and ensure ethical research under any regulatory scheme.


Enhanced Safety Surveillance of Seasonal Quadrivalent Influenza Vaccines in English Primary Care: Interim Analysis.
The European Medicines Agency (EMA) requires vaccine manufacturers to conduct enhanced safety surveillance (ESS) of seasonal influenza vaccines including a near real-time evaluation of collected data. The objective was to identify whether the use of passive surveillance or active surveillance provides different results of reported adverse events of interest (AEIs) by specified age strata and AEI type. We report the weekly incidence rates of AEIs within 7 days following seasonal influenza vaccination using passive and active surveillance. AEIs were collected within 7 days of vaccination from ten general practices predominantly administering inactivated quadrivalent influenza vaccine (IIV4, Fluarix Tetra, GSK). Vaccinees completed an adverse drug reaction (ADR) card. ADR card and medically attended AEIs data were recorded in practice electronic health records. We report the outcome of the first 5 weeks of safety surveillance (September 12, 2016-October 16, 2016); in an exploratory analysis, rates of AEI for IIV4 are compared to those passively reported through a sentinel network. Practices vaccinated 13.1% (12,864/98,091) of their registered population; 5.6% (95% CI 5.20-6.00) of them reported AEIs, none serious. The most frequent were respiratory 2.60% (95% CI 2.33-2.88), musculoskeletal 1.82% (95% CI 1.59-2.05) and neurological 1.05% (95% CI 0.88-1.23). AEIs were more frequently reported for adults than for children; 5.91% (95% CI 5.49-6.34) compared to 1.49% (95% CI 0.69-2.29); 47.18% of the adults reported AEI using the ADR card, none were returned for subjects < 18 years old. The frequency of AEIs reporting was higher, 6.88% (95% CI 6.35-7.42) vs. 3.30% (95% CI 2.68-3.96, 100/3028, p < 0.000), through ESS than passive surveillance. The ESS did not reveal any safety signal and we demonstrated the feasibility of conducting ESS following EMA recommendations. The use of a customised ADR card led to a doubling of AEIs reports over passive surveillance in adults. GlaxoSmithKline Biologicals SA, Wavre, Belgium.


Anemia and patient blood management in hip and knee surgery: a systematic review of the literature.
A systematic search was conducted to determine the characteristics of perioperative anemia, its association with clinical outcomes, and the effects of patient blood management interventions on these outcomes in patients undergoing major orthopedic surgery. In patients undergoing total hip or knee arthroplasty and hip fracture surgery, preoperative anemia was highly prevalent, ranging from 24 +/- 9% to 44 +/- 9%, respectively. Postoperative anemia was even more prevalent (51% and 87 +/- 10%, respectively). Perioperative anemia was associated with a blood transfusion rate of 45 +/- 25% and 44 +/- 15%, postoperative infections, poorer physical functioning and recovery, and increased length of hospital stay and mortality. Treatment of preoperative anemia with iron, with or without erythropoietin, and perioperative cell salvage decreased the need for blood transfusion and may contribute to improved patient outcomes. High-impact prospective studies are necessary to confirm these findings and establish firm clinical guidelines.


Mobile lidar system for environmental probing.
A fully mobile remote-sensing system based on the lidar principle is described. With this system, atmospheric probing using Mie scattering, differential absorption, or Raman techniques can be performed yielding information on atmospheric pollutants or general atmospheric parameters. The system incorporates a powerful Nd:YAG laser pumping a dye laser and is equipped with a fixed Newtonian telescope used in conjunction with a flat steering mirror. The lidar signals are electrically recorded using a fast-transient digitizer and are processed by a minicomputer, which also controls the laser, the chosen measuring direction, and the output media. Examples of measurements on atmospheric NO(2) and SO(2) are given.


Emergent Optoelectronic Properties of Mixed-Dimensional Heterojunctions.
ConspectusThe electronic dimensionality of a material is defined by the number of spatial degrees of confinement of its electronic wave function. Low-dimensional semiconductor nanomaterials with at least one degree of spatial confinement have optoelectronic properties that are tunable with size and environment (dielectric and chemical) and are of particular interest for optoelectronic applications such as light detection, light harvesting, and photocatalysis. By combining nanomaterials of differing dimensionalities, mixed-dimensional heterojunctions (MDHJs) exploit the desirable characteristics of their components. For example, the strong optical absorption of zero-dimensional (0D) materials combined with the high charge carrier mobilities of two-dimensional (2D) materials widens the spectral response and enhances the responsivity of mixed-dimensional photodetectors, which has implications for ultrathin, flexible optoelectronic devices. MDHJs are highly sensitive to (i) interfacial chemistry because of large surface area-to-volume ratios and (ii) electric fields, which are incompletely screened because of the ultrathin nature of MDHJs. This sensitivity presents opportunities for control of physical phenomena in MDHJs through chemical modification, optical excitation, externally applied electric fields, and other environmental parameters. Since this fast-moving research area is beginning to pose and answer fundamental questions that underlie the fundamental optoelectronic behavior of MDHJs, it is an opportune time to assess progress and suggest future directions in this field.In this Account, we first outline the characteristic properties, advantages, and challenges for low-dimensional materials, many of which arise as a result of quantum confinement effects. The optoelectronic properties and performance of MDHJs are primarily determined by dynamics of excitons and charge carriers at their interfaces, where these particles tunnel, trap, scatter, and/or recombine on the time scales of tens of femtoseconds to hundreds of nanoseconds. We discuss several photophysical phenomena that deviate from those observed in bulk heterojunctions, as well as factors that can be used to vary, probe, and ultimately control the behavior of excitons and charge carriers in MDHJ systems. We then discuss optoelectronic applications of MDHJs, namely, photodetectors, photovoltaics, and photocatalysts, and identify current performance limits compared to state-of-the-art benchmarks. Finally, we suggest strategies to extend the current understanding of dynamics in MDHJs toward the realization of stimuli-driven responses, particularly with respect to exciton delocalization, quantum emission, interfacial morphology, responsivity to external stimuli, spin selectivity, and usage of chemically reactive materials.


Comparison of umbo velocity in air- and bone-conduction.
This study investigates the ossicular motion produced by bone-conducted (BC) sound in live human ears. Laser Doppler vibrometry was used to measure air conduction (AC)- and BC-induced umbo velocity (V(U)) in both ears of 10 subjects, 20 ears total. Sound pressure in the ear canal (P(EC)) was measured simultaneously. For air conduction, V(U) at standard hearing threshold level was calculated. For BC, ΔV was defined as the difference between V(U) and the tympanic ring velocity (an estimate of the skull velocity measured in the ear canal). ΔV and P(EC) at BC standard hearing threshold were calculated. ΔV at standard BC threshold was significantly smaller than V(U) at standard AC threshold between 500 Hz and 2000 Hz. Ear canal pressure at BC threshold tended to be smaller than for AC below 3000 Hz (with significant differences at 1000 Hz and 2000 Hz). Our results are most consistent with inertia of the ossicles and cochlear fluid driving BC hearing below 500 Hz, but with other mechanisms playing a significant role at higher frequencies. Sound radiated into the external ear canal might contribute to BC hearing at 3000 Hz and above.


Phosphorylation and stabilization of HURP by Aurora-A: implication of HURP as a transforming target of Aurora-A.
Aurora-A, a mitotic serine/threonine kinase with oncogene characteristics, has recently drawn intense attention because of its association with the development of human cancers and its relationship with mitotic progression. Using the gene expression profiles of Aurora-A as a template to search for and compare transcriptome expression profiles in publicly accessible microarray data sets, we identified HURP (encodes hepatoma upregulated protein) as one of the best Aurora-A-correlated genes. Empirical validation indicates that HURP has several characteristics in common with Aurora-A. These two genes have similar expression patterns in hepatocellular carcinoma, liver regeneration after partial hepatectomy, and cell cycle progression and across a variety of tissues and cell lines. Moreover, Aurora-A phosphorylated HURP in vitro and in vivo. Ectopic expression of either the catalytically inactive form of Aurora-A or the HURP-4P mutant, in which the Aurora-A phosphorylation sites were replaced with Ala, resulted in HURP instability and complex disassembly. In addition, HURP-wild-type stable transfectants were capable of growing in low-serum environments whereas HURP-4P grew poorly under low-serum conditions and failed to proliferate. These studies together support the view that the ability to integrate evidence derived from microarray studies into biochemical analyses may ultimately augment our predictive power when analyzing the potential role of poorly characterized proteins. While this combined approach was simply an initial attempt to answer a range of complex biological questions, our findings do suggest that HURP is a potential oncogenic target of Aurora-A.


Meanings of encounters for close relatives of people with a long-term illness within a primary healthcare setting.
Encounters play an important role in the relationship between healthcare personnel and the close relatives of people with a long-term illness.AimThe aim of this study was to elucidate the meanings of encounters for close relatives of people with a long-term illness within a primary healthcare setting. Interviews using a narrative approach were conducted with seven women and three men, and the phenomenological hermeneutic method was used to interpret the interview texts. The structural analysis revealed three major themes: being confirmed as a family, being informed of the care, and being respected as a valuable person. Close relatives stated that they wanted to be confirmed as a family and have a familiar and trusting relationship with healthcare personnel. They valued being informed concerning the care of the ill person so that they could give support at home. It was also important to be compassionately viewed as an important person in a welcoming atmosphere based on respect and dignity.


Atomic Force Microscopy: Single-Molecule Imaging and Force Spectroscopy in the Study of Flavoproteins Ligand Binding and Reaction Mechanisms.
Atomic force microscopy (AFM) is one of the most versatile tools currently used in nanoscience. AFM allows for performing nondestructive imaging of almost any sample in either air or liquid, regardless whether the specimen is insulating, conductive, transparent, or opaque. It also allows for measuring interaction forces between a sharp probe and a sample surface, therefore allowing to probe nanomechanical properties of the specimen by either applying a controlled force or pulling the sample. It can provide topography, mechanical, magnetic, and conductive maps for very different type of samples. Transferred to the field of biology, today, AFM is the only microscopy technique able to produce images from biomolecules to bacteria and cells with nanometric resolution in aqueous media. Here, we will focus on the biological applications of AFM to flavoproteins. Despite references in the literature are scarce in this particular field, here it is described how imaging with AFM can contribute to describe catalysis mechanisms of some flavoenzymes, how oxidation states or binding of relevant ligands influence the association state of molecules, the dynamics of functional quaternary assemblies, and even visualize structural differences of individual protein molecules. Furthermore, we will show how force spectroscopy can be used to obtain the kinetic parameters, the dissociation landscape and the mechanical forces that maintain flavoprotein complexes, including the possibility to specifically detect particular flavoproteins on a sample.


The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.
The increase in demand for renal replacement therapy makes it important to investigate the prognosis of the earlier stages of chronic kidney disease (CKD). We examined the change in glomerular filtration rate (GFR), and patient and renal survival in CKD stage 3 in the municipality of Tromsø, a well-defined European community with a population of 58,000. All patients with estimated GFR between 30 and 59 ml/min/1.73 m(2) for more than 3 months during a 10-year study period were identified from a complete database of all 248 560 measurements of serum creatinine made in the community in the study period. Change in GFR was estimated for each patient using a multilevel model. A complete follow-up with respect to patient and renal survival was obtained from hospital databases. A total of 3047 patients was included. The median number of measurements of creatinine for each patient was 9, and the median observation time was 44 months. Mean estimated change in GFR was--1.03 ml/min/1.73 m(2)/year. Seventy-three percent of the patients experienced a decline in GFR. The 10-year cumulative incidence of renal failure was 0.04 (95% CI 0.03-0.06) and mortality 0.51 (95% CI 0.48-0.55). Female gender was associated with slower decline in GFR and better patient and renal survival. In this population-based study, the decline in GFR in CKD was slower than in previously studied selected patient groups. A high mortality pre-empted the development of renal failure in many patients. The prognosis of CKD depended strongly on gender.


Antecedents of periventricular haemorrhage in infants weighing 1250 g or less at birth.
Fifty infants who weighed 1250 g or less at birth were studied with serial real time cerebral ultrasound to evaluate the temporal relation of various perinatal factors to the onset and progression of periventricular haemorrhage (PVH). The significant antecedents of PVH were severe bruising at birth, low birthweight, short gestation, ratio of arterial oxygen pressure (PaO2) to fractional inspired oxygen (FiO2), and haematocrit on admission, hyaline membrane disease, assisted ventilation, pneumothorax, administration of tubocurarine, hypercapnia, hypoxaemia, and hypotension. Case control studies, in which infants with PVH at 26 weeks' and 28 weeks' gestation were compared with matched infants without PVH, confirmed that the antecedents identified were independent of gestational influences. A multivariate discriminant analysis for the antecedents of PVH showed that hyaline membrane disease, hypercapnia, and short gestation correctly classified presence or absence of PVH in 78% of the study group. A similar analysis comparing infants with germinal layer haemorrhage or intraventricular haemorrhage with those who developed intracerebral extension of haemorrhage showed that three factors found on admission (hypothermia, a low PaO2:FiO2 ratio, and severe bruising) combined to classify correctly 90% of the haemorrhages. Our data suggest that prevention of perinatal trauma and asphyxia as well as respiratory illness, especially hyaline membrane disease, and stabilisation of blood gas tensions, blood pressure, and haematocrit within the physiological range, are likely to be the most effective ways of preventing PVH in extremely preterm infants.


An update on molecular biology and drug resistance mechanisms of multiple myeloma.
Multiple myeloma (MM), a neoplasm of plasma cells, is the second most common hematological malignancy. Incidance rates increase after age 40. MM is most commonly seen in men and African-American population. There are several factors to this, such as obesity, environmental factors, family history, genetic factors and monoclonal gammopathies of undetermined significance (MGUS) that have been implicated as potentially etiologic. Development of MM involves a series of complex molecular events, including chromosomal abnormalities, oncogene activation and growth factor dysregulation. Chemotherapy is the most commonly used treatment strategy in MM. However, MM is a difficult disease to treat because of its marked resistance to chemotherapy. MM has been shown to be commonly multidrug resistance (MDR)-negative at diagnosis and associated with a high incidence of MDR expression at relapse. This review deals with the molecular aspects of MM, drug resistance mechanisms during treatment and also possible new applications for overcoming drug resistance.


Protective cranial implant caps for macaques.
Neuroscience studies with macaque monkeys may require cranial implants to stabilize the head or gain access to the brain for scientific purposes. Wound management that promotes healing after the cranial implant surgery in non-human primates can be difficult as it is not necessarily possible to cover the wound margins. Here, we developed an easily modifiable head cap that protects the sutured skin margins after cranial implant surgery and contributes to wound healing. The protective head cap was developed in response to monkeys picking at sutured skin margins around an implant, complicating healing. The user-friendly protective cap, made from Klarity- R™ Sheet (3.2 mm thick with 36 % or 42 % perforation) is affixed to the implant post-surgically. Once secured and while the monkey is still anesthetized, the plastic sheeting is molded around the implant. The protective head cap restricts the monkey's finger access to its' wound margins while allowing air to circulate to promote wound healing. Across two UK primate facilities, the protective head cap promoted wound healing. In monkeys that did not wear the head cap, re-suturing was necessary in ∼30 % of cases. In contrast, none of the monkeys that wore the head cap required re-suturing. The monkeys wearing the head cap also had reduced numbers of days of prescribed antibiotics and analgesia. This bespoken, easily adaptable, protective head cap supports postoperative wound healing, and enhances the welfare of monkeys involved in neuroscience research.


Laboratory studies of carbon kinetic isotope effects on the production mechanism of particulate phenolic compounds formed by toluene photooxidation: a tool to constrain reaction pathways.
In this study, we examined compound-specific stable carbon isotope ratios for phenolic compounds in secondary organic aerosol (SOA) formed by photooxidation of isotope-label-free toluene. SOA generated by photooxidation of toluene using a continuous-flow reactor and an 8 m(3) indoor smog chamber was collected on filters, which were extracted with acetonitrile for compound-specific analysis. Eight phenolic compounds were identified in the extracts using a gas chromatograph coupled with a mass spectrometer, and their compound-specific stable carbon isotope ratios were determined using a gas chromatograph coupled with a combustion furnace followed by an isotope ratio mass spectrometer. The majority of products, including methylnitrophenols and methylnitrocatechols, were isotopically depleted by 5-6‰ compared to the initial isotope ratio of toluene, whereas the isotope ratio for 4-nitrophenol remained identical to that of toluene. On the basis of the reaction mechanisms proposed in previous reports, stable carbon isotope ratios of these products were calculated. By comparing the observed isotope ratios with the predicted isotope ratios, we explored possible production pathways for the particulate phenolic compounds.


Detection of the Presence of Gold Nanoparticles in Organs by Transmission Electron Microscopy.
Gold nanoparticles of 10 nm and 250 nm were intravenously injected in rats. At 24 h after administration, tissues were collected and prepared for transmission electron microscopy (TEM). In the liver and spleen of animals treated with 10 nm gold nanoparticles, groups of nanoparticles were observed that could be positively identified by Energy Dispersive X-ray (EDX) analysis to contain gold, while nanoparticles could not be detected in the heart, kidney and brain. The 10 nm gold nanoparticles were present in the phagocytic cells of the reticulo-endothelial system (RES). The 250 nm gold nanoparticles could not be detected in any of the organs investigated. Considering the number of 250 nm gold nanoparticles administered, calculations showed that it would indeed be almost impossible to detect the 250 nm gold nanoparticles in TEM preparations in view of the very low number of particles that would be theoretically present in one TEM tissue section. This shows that relatively high numbers of nanoparticles need to be administered to enable the detection of nanoparticles in organs by TEM. In a number of samples, several globular structures of approximately the expected size were found in liver cells and the endothelium of blood vessels in the brain. However, elemental analysis with EDX detection showed that these structures did not contain gold. Our studies thus indicate that the in vivo identification of nanoparticles cannot only depend on the detection of nanosized structures in cells. An additional identification of the composing elements of the nanomaterial is necessary for a positive identification of the nanomaterial.


Nutritional assessment and lipid profile in HIV-infected children and adolescents treated with highly active antiretroviral therapy.
HIV-infected children and adolescents treated with highly active antiretroviral therapy (HAART) regimens that include a protease inhibitor (PI) can show significant improvements in clinical outcomes, nutritional status and quality of life. The study aimed to report nutritional and metabolic alterations for pediatric patients continuously exposed to HAART and for healthy controls for up to 1 year. Clinical, anthropometric, lipid profile and food intake data were collected prospectively over approximately 12-months for each patient. Fifty-one individuals were studied, of these, 16 were healthy. After 12 months follow-up, HIV-positive individuals remained below the healthy control group parameters. No change was observed concerning food intake. Triglyceride serum levels were higher in patients using protease inhibitor at the onset of the study [PI groups: 114 (43 - 336), and 136 (63 - 271) versus control group: 54.5 (20 - 162); p = 0.003], but after twelve months follow-up, only the group using protease inhibitor for up to two months presented higher values [140 (73 - 273) versus 67.5 (33 - 117); p = 0.004]. HDL-cholesterol was lower in HIV-positive individuals [HIV-positive groups: 36 (27 - 58) and 36 (23 - 43); control 49.5 (34 - 69); p = 0.004]. HIV-infected children and adolescents treated with highly active antiretroviral therapy showed compromised nutritional parameters compared to a paired healthy control group. Individuals using protease inhibitor presented worse triglyceride serum levels compared to their healthy counterparts.


MicroRNA expression analysis: clinical advantage of propranolol reveals key microRNAs in myocardial infarction.
As playing important roles in gene regulation, microRNAs (miRNAs) are believed as indispensable involvers in the pathogenesis of myocardial infarction (MI) that causes significant morbidity and mortality. Working on a hypothesis that modulation of only some key members in the miRNA superfamily could benefit ischemic heart, we proposed a microarray based network biology approach to identify them with the recognized clinical effect of propranolol as a prompt. A long-term MI model of rat was established in this study. The microarray technology was applied to determine the global miRNA expression change intervened by propranolol. Multiple network analyses were sequentially applied to evaluate the regulatory capacity, efficiency and emphasis of the miRNAs which dysexpression in MI were significantly reversed by propranolol. Microarray data analysis indicated that long-term propranolol administration caused 18 of the 31 dysregulated miRNAs in MI undergoing reversed expression, implying that intentional modulation of miRNA expression might show favorable effects for ischemic heart. Our network analysis identified that, among these miRNAs, the prime players in MI were miR-1, miR-29b and miR-98. Further finding revealed that miR-1 focused on regulation of myocyte growth, yet miR-29b and miR-98 stressed on fibrosis and inflammation, respectively. Our study illustrates how a combination of microarray technology and functional protein network analysis can be used to identify disease-related key miRNAs.


Tigers and their prey: Predicting carnivore densities from prey abundance.
The goal of ecology is to understand interactions that determine the distribution and abundance of organisms. In principle, ecologists should be able to identify a small number of limiting resources for a species of interest, estimate densities of these resources at different locations across the landscape, and then use these estimates to predict the density of the focal species at these locations. In practice, however, development of functional relationships between abundances of species and their resources has proven extremely difficult, and examples of such predictive ability are very rare. Ecological studies of prey requirements of tigers Panthera tigris led us to develop a simple mechanistic model for predicting tiger density as a function of prey density. We tested our model using data from a landscape-scale long-term (1995-2003) field study that estimated tiger and prey densities in 11 ecologically diverse sites across India. We used field techniques and analytical methods that specifically addressed sampling and detectability, two issues that frequently present problems in macroecological studies of animal populations. Estimated densities of ungulate prey ranged between 5.3 and 63.8 animals per km2. Estimated tiger densities (3.2-16.8 tigers per 100 km2) were reasonably consistent with model predictions. The results provide evidence of a functional relationship between abundances of large carnivores and their prey under a wide range of ecological conditions. In addition to generating important insights into carnivore ecology and conservation, the study provides a potentially useful model for the rigorous conduct of macroecological science.


Long-Term Outcome of Amyotrophic Lateral Sclerosis in Korean Subjects.
To report the latest long-term outcome of amyotrophic lateral sclerosis (ALS) and to analyze the predictors of prognosis. Subjects who were diagnosed with ALS between January 2005 and December 2009 at a single institute were followed up until death or up to December 2014. Data regarding age, sex, date of onset, date of diagnosis, presence of bulbar symptoms on onset, date of initiation of non-invasive ventilation (NIV), and the date of tracheostomy were collected. Survival was assessed using Kaplan-Meier curves and multivariate analyses of the risk of death were performed using the Cox proportional hazards model. Among 212 suspicious subjects, definite ALS was diagnosed in 182 subjects. The survival rate at 3 and 5 years from onset was 61.5% and 40.1%, respectively, and the survival rate at 3 and 5 years post-diagnosis was 49.5% and 24.2%, respectively. Further, 134 patients (134/182, 73.6%) were initiated on NIV, and among them, 90 patients (90/182, 49.5%) underwent tracheostomy. Male gender and onset age of ≥65 years were independent predictors of adverse survival. The analysis of long term survival in ALS showed excellent outcomes considering the overall poor prognosis of this disease.


A central support system can facilitate implementation and sustainability of a Classroom-based Undergraduate Research Experience (CURE) in Genomics.
In their 2012 report, the President's Council of Advisors on Science and Technology advocated "replacing standard science laboratory courses with discovery-based research courses"-a challenging proposition that presents practical and pedagogical difficulties. In this paper, we describe our collective experiences working with the Genomics Education Partnership, a nationwide faculty consortium that aims to provide undergraduates with a research experience in genomics through a scheduled course (a classroom-based undergraduate research experience, or CURE). We examine the common barriers encountered in implementing a CURE, program elements of most value to faculty, ways in which a shared core support system can help, and the incentives for and rewards of establishing a CURE on our diverse campuses. While some of the barriers and rewards are specific to a research project utilizing a genomics approach, other lessons learned should be broadly applicable. We find that a central system that supports a shared investigation can mitigate some shortfalls in campus infrastructure (such as time for new curriculum development, availability of IT services) and provides collegial support for change. Our findings should be useful for designing similar supportive programs to facilitate change in the way we teach science for undergraduates.


How to approach aortic valve disease in the elderly: a 25-year retrospective study.
In the last decade, the number of elderly patients suffering from aortic valve disease has significantly increased. This study aimed to identify possible factors that could affect surgical and long-term outcomes in the light of a literature review regarding the management of aortic valve disease in the elderly. Between January 1990 and December 2012, a total of 114 patients (64 males, 50 females; mean age 76.6 ± 3.6 years; range 70-87 years) with aortic valve replacement (AVR) alone, or combined with coronary artery bypass grafting (CABG) or mitral surgery in our hospital, were retrospectively analysed. In-hospital mortality was seen in 19 patients. The major causes of in-hospital mortality were low-cardiac output syndrome in eight patients (42.1%), respiratory insufficiency or infection in six (31.5%), multi-organ failure in four (21%), and stroke in one patient (5.2%). The main postoperative complications included arrhythmia in 26 patients (22.8%), renal failure in 11 (9.6%), respiratory infection in nine (7.9%), and stroke in three patients (2.6%). The mean length of intensive care unit and hospital stays were 6.4 ± 4.3 and 18 ± 12.8 days, respectively. During follow up, late mortality was seen in 28 patients (29.4%). Possible risk factors for long-term mortality were type of prosthesis, EuroSCORE ≥ 15, postoperative pacemaker implantation, respiratory infection, and haemodialysis. Among 65 long-term survivors, their activity level was good in 53 (81.5%) and poor in two. Our study results demonstrated that an individually tailored approach including scheduled surgery increases short- and long-term outcomes of AVR in patients aged ≥ 70 years. In addition, shorter cardiopulmonary bypass time may be more beneficial in this high-risk patient population.


Emotion Regulation Failures Are Preceded by Local Increases in Sleep-like Activity.
Emotion self-regulation relies both on cognitive and behavioral strategies implemented to modulate the subjective experience and/or the behavioral expression of a given emotion. Although it is known that a network encompassing fronto-cingulate and parietal brain areas is engaged during successful emotion regulation, the functional mechanisms underlying failures in emotion suppression (ES) are still unclear. In order to investigate this issue, we analyzed video and high-density EEG recordings of 20 healthy adult participants during an ES and a free expression task performed on two consecutive days. Changes in facial expression during ES, but not free expression, were preceded by local increases in sleep-like activity (1-4 Hz) in brain areas responsible for emotional suppression, including bilateral anterior insula and anterior cingulate cortex, and in right middle/inferior frontal gyrus (p < .05, corrected). Moreover, shorter sleep duration the night before the ES experiment correlated with the number of behavioral errors (p = .03) and tended to be associated with higher frontal sleep-like activity during ES failures (p = .09). These results indicate that local sleep-like activity may represent the cause of ES failures in humans and may offer a functional explanation for previous observations linking lack of sleep, changes in frontal activity, and emotional dysregulation.


Geochemical evidence from the Sudbury structure for crustal redistribution by large bolide impacts.
Deformation and melting of the crust during the formation of large impact craters must have been important during the Earth's early evolution, but such processes remain poorly understood. The 1.8-billion-year-old Sudbury structure in Ontario, Canada, is greater than 200 km in diameter and preserves a complete impact section, including shocked basement rocks, an impact melt sheet and fallback material. It has generally been thought that the most voluminous impact melts represent the average composition of the continental crust, but here we show that the melt sheet now preserved as the Sudbury Igneous Complex is derived predominantly from the lower crust. We therefore infer that the hypervelocity impact caused a partial inversion of the compositional layering of the continental crust. Using geochemical data, including platinum-group-element abundances, we also show that the matrix of the overlying clast-laden Onaping Formation represents a mixture of the original surficial sedimentary strata, shock-melted lower crust and the impactor itself.


Disc size markedly influences concentration profiles of intravenously administered solutes in the intervertebral disc: a computational study on glucosamine as a model solute.
Tests on animals of different species with large differences in intervertebral disc size are commonly used to investigate the therapeutic efficacy of intravenously injected solutes in the disc. We hypothesize that disc size markedly affects outcome. Here, using a small non-metabolized molecule, glucosamine (GL) as a model solute, we calculate the influence of disc size on transport of GL into rat, rabbit, dog and human discs for 10 h post intravenous-injection. We used transient finite element models and considered an identical GL supply for all animals. Huge effects of disc size on GL concentration profiles were found. Post-injection GL concentration in the rat disc reached 70% blood concentration within 15 min but remained below 10% in the human disc nucleus throughout. The GL rapidly penetrated post-injection into smaller discs resulting in homogeneous concentrations. In contrast, GL concentration, albeit at much lower levels, increased with time in the human disc with a small outward flux at the annulus periphery at longer periods. Changes in the disc size hugely influenced GL concentrations throughout the disc at all regions and times. Increases in administered dose can neither remedy the very low concentration levels in the disc center in larger human disc at early post-injection hours nor alter the substantial differences in concentration profiles estimated among various species. The size effect will only be exacerbated as molecular weight of the solute increases and as the endplate calcifies. Extrapolation of findings from animal to human discs on the efficacy of intravenously administered solutes must proceed with great caution.


Impact of Falls on Physical Activity in People with Parkinson's Disease.
A complex relationship exists between motor impairment, physical activity (sedentary behavior, standing and ambulatory activity) and falls in people with Parkinson's disease (PD). To explore associations between recent fall history and the ability to retain an active lifestyle as determined by the volume, pattern and variability of physical activity in people with PD. Forty-eight participants with PD were recruited from the Norwegian ParkWest study. Body posture and ambulatory activity were monitored objectively over 7 days using the activPAL3 accelerometer. Clinical assessments included the Hoehn and Yahr stage, Unified Parkinson's Disease Rating Scale motor section and Falls Efficacy Scale-International. Structured interviews were performed to obtain information about demographics, fall history last 6 months, mobility and dementia. Participants with a fall history (n = 20) spent more time sedentary and less time standing than non-falling participants (n = 28). There were no significant differences regarding pattern or variability of sedentary behavior, standing or ambulatory activity in falling versus non-falling participants. Confidence in being able to get up from floor contributed significantly to time spent in sedentary behavior and ambulatory activity in participants with fall history, whereas motor impairment was significantly associated with time spent in all facets of physical activity for non-falling participants. Fall history in our PD cohort was associated with a more sedentary lifestyle, but not less ambulatory activity. More emphasis on improving the capacity to safely complete activities of daily living and increase confidence in getting up from floor may reduce sedentary behavior in people with PD.


Treatment of hind limb ischemia using angiogenic peptide nanofibers.
For a proangiogenic therapy to be successful, it must promote the development of mature vasculature for rapid reperfusion of ischemic tissue. Whole growth factor, stem cell, and gene therapies have yet to achieve the clinical success needed to become FDA-approved revascularization therapies. Herein, we characterize a biodegradable peptide-based scaffold engineered to mimic VEGF and self-assemble into a nanofibrous, thixotropic hydrogel, SLanc. We found that this injectable hydrogel was rapidly infiltrated by host cells and could be degraded while promoting the generation of neovessels. In mice with induced hind limb ischemia, this synthetic peptide scaffold promoted angiogenesis and ischemic tissue recovery, as shown by Doppler-quantified limb perfusion and a treadmill endurance test. Thirteen-month-old mice showed significant recovery within 7 days of treatment. Biodistribution studies in healthy mice showed that the hydrogel is safe when administered intramuscularly, subcutaneously, or intravenously. These preclinical studies help establish the efficacy of this treatment for peripheral artery disease due to diminished microvascular perfusion, a necessary step before clinical translation. This peptide-based approach eliminates the need for cell transplantation or viral gene transfection (therapies currently being assessed in clinical trials) and could be a more effective regenerative medicine approach to microvascular tissue engineering.


Emergency Medicine Palliative Care Access (EMPallA): protocol for a multicentre randomised controlled trial comparing the effectiveness of specialty outpatient versus nurse-led telephonic palliative care of older adults with advanced illness.
Emergency department (ED)-initiated palliative care has been shown to improve patient-centred outcomes in older adults with serious, life-limiting illnesses. However, the optimal modality for providing such interventions is unknown. This study aims to compare nurse-led telephonic case management to specialty outpatient palliative care for older adults with serious, life-limiting illness on: (1) quality of life in patients; (2) healthcare utilisation; (3) loneliness and symptom burden and (4) caregiver strain, caregiver quality of life and bereavement. This is a protocol for a pragmatic, multicentre, parallel, two-arm randomised controlled trial in ED patients comparing two established models of palliative care: nurse-led telephonic case management and specialty, outpatient palliative care. We will enrol 1350 patients aged 50+ years and 675 of their caregivers across nine EDs. Eligible patients: (1) have advanced cancer (metastatic solid tumour) or end-stage organ failure (New York Heart Association class III or IV heart failure, end-stage renal disease with glomerular filtration rate <15 mL/min/m2, or global initiative for chronic obstructive lung disease stage III, IV or oxygen-dependent chronic obstructive pulmonary disease); (2) speak English; (3) are scheduled for ED discharge or observation status; (4) reside locally; (5) have a working telephone and (6) are insured. Patients will be excluded if they: (1) have dementia; (2) have received hospice care or two or more palliative care visits in the last 6 months or (3) reside in a long-term care facility. We will use patient-level block randomisation, stratified by ED site and disease. Effectiveness will be compared by measuring the impact of each intervention on the specified outcomes. The primary outcome will measure change in patient quality of life. Institutional Review Board approval was obtained at all study sites. Trial results will be submitted for publication in a peer-reviewed journal. NCT03325985; Pre-results.


Effect of Ivacaftor on Objective and Subjective Measures of Cough in Patients with Cystic Fibrosis.
Cough is a major symptom in cystic fibrosis. Ivacaftor is a novel drug which targets the G551D mutation and has been demonstrated to improve lung function and weight in the long term. It also improves symptoms of extra-oesophageal reflux. We wanted to evaluate the effect of ivacaftor on cough in cystic fibrosis. In two patients with cystic fibrosis the Hull Airway Reflux Questionnaire (HARQ) was completed and objective cough counts were measured prior to and within 4 weeks after initiation of treatment with ivacaftor. Spirometry was also undertaken and weight checked at these time frames. In the first patient the HARQ score decreased from 29 to 11 and objective cough counts from 29 to 9 cough events per hour. Similarly in the second patient the HARQ score decreased from 13 to 9 and objective cough count from 76 to 5 cough events per hour. There was no significant change in spirometric parameters or weight. We have observed early subjective and objective improvement in cough measures on treatment with ivacaftor. We suggest that this improvement could be attributed to improvement of gastro-intestinal function and that cough metrics could be used as early and accurate end points of drug efficacy.


Between the Reasonable and the Particular: Deflating Autonomy in the Legal Regulation of Informed Consent to Medical Treatment.
The law of informed consent to medical treatment has recently been extensively overhauled in England. The 2015 Montgomery judgment has done away with the long-held position that the information to be disclosed by doctors when obtaining valid consent from patients should be determined on the basis of what a reasonable body of medical opinion agree ought to be disclosed in the circumstances. The UK Supreme Court concluded that the information that is material to a patient's decision should instead be judged by reference to a new two-limbed test founded on the notions of the 'reasonable person' and the 'particular patient'. The rationale outlined in Montgomery for this new test of materiality, and academic comment on the ruling's significance, has focused on the central ethical importance that the law now (rightfully) accords to respect for patient autonomy in the process of obtaining consent from patients. In this paper, we dispute the claim that the new test of materiality articulated in Montgomery equates with respect for autonomy being given primacy in re-shaping the development of the law in this area. We also defend this position, arguing that our revised interpretation of Montgomery's significance does not equate with a failure by the courts to give due legal consideration to what is owed to patients as autonomous decision-makers in the consent process. Instead, Montgomery correctly implies that doctors are ethically (and legally) obliged to attend to a number of relevant ethical considerations in framing decisions about consent to treatment, which include subtle interpretations of the values of autonomy and well-being. Doctors should give appropriate consideration to how these values are fleshed out and balanced in context in order to specify precisely what information ought to be disclosed to a patient as a requirement of obtaining consent, and as a core component of shared decision-making within medical encounters more generally.


Factors influencing the uptake of neonatal bereavement support services - Findings from two tertiary neonatal centres in the UK.
Research on perinatal bereavement services is limited. The aim of the study was to compare the uptake of bereavement support services between two tertiary neonatal units (NNU), and to investigate influencing factors. The medical and bereavement records of all neonatal deaths were studied from January 2006 to December 2011. Data collected included parent and baby characteristics, mode of death, consent for autopsy and bereavement follow-up. The categorical data were compared by chi-square or Fisher's exact test and continuous data by Wilcoxon signed-rank test; a multivariable regression analysis was performed using STATA 12.0. The neonatal deaths of 297 babies (182 in NNU1 and 115 in NNU2) with full datasets were analysed. Baby characteristics were similar between units except for lower median gestational age in NNU1 (p = 0.03). Significantly more NNU1 parents were non-Caucasian (p < 0.01), from lower socio-economic status (p = 0.01) and had previous stillbirth/miscarriage (p = 0.03). More babies had care withdrawn in NNU2 (p < 0.01). A significantly higher proportion of parents from NNU1 (61 %) attended bereavement follow-up compared to NNU2 (34 %; p < 0.01). On multivariable analysis, significantly more parents who were married or co-habiting (p = 0.02) and consented for an autopsy (p = 0.01) attended bereavement services. Uptake of bereavement services varied between the two NNUs, which could be due to differences in the ethnic and socio-economic mix of the population. Significantly more parents who were married or co-habiting, or consented for autopsy, attended bereavement follow up services.


Fruit Consumption by Youth in the United States.
To describe the contribution of whole fruit, including discrete types of fruit, to total fruit consumption and to investigate differences in consumption by sociodemographic characteristics. We analyzed data from 3129 youth aged 2 to 19 years from the National Health and Nutrition Examination Survey, 2011 to 2012. Using the Food Patterns Equivalents Database and the What We Eat in America 150 food groups, we calculated the contribution of whole fruit, 100% fruit juices, mixed fruit dishes, and 12 discrete fruit and fruit juices to total fruit consumption. We examined differences by age, gender, race and Hispanic origin, and poverty status. Nearly 90% of total fruit intake came from whole fruits (53%) and 100% fruit juices (34%) among youth aged 2 to 19 years. Apples, apple juice, citrus juice, and bananas were responsible for almost half of total fruit consumption. Apples accounted for 18.9% of fruit intake. Differences by age were predominately between youth aged 2 to 5 years and 6 to 11 years. For example, apples contributed a larger percentage of total fruit intake among youth 6 to 11 years old (22.4%) than among youth 2 to 5 years old (14.6%), but apple juice contributed a smaller percentage (8.8% vs 16.8%), P < .05. There were differences by race and Hispanic origin in intake of citrus fruits, berries, melons, dried fruit, and citrus juices and other fruit juices. These findings provide insight into what fruits US youth are consuming and sociodemographic factors that may influence consumption.


Expanding the chemistry of fluorescent protein biosensors through genetic incorporation of unnatural amino acids.
Fluorescent proteins are essential tools in biological research, ranging from the study of individual biological components to the interrogation of complex cellular systems. Fluorescent protein derived biosensors are increasingly applied to the study of biological molecules and events in living cells. The present review focuses on a specific class of fluorescent protein biosensors in which a genetically installed unnatural amino acid (UAA*) acts as the sensing element. Upon direct interaction with the analyte of interest, the chemical and/or physical properties of UAA* are altered, which triggers fluorescence property changes of the biosensor and generates readouts. In comparison to mutagenesis approaches within the standard genetic code, introduction of UAA*s with a unique functionality and chemical reactivity could broaden the scope of analytes and improve the specificity of biosensors. Nonconventional functional groups in fluorescent proteins enable sensor designs that are not readily accessible using the common twenty amino acids. Recent reports of UAA*-containing fluorescent protein sensors serve as excellent examples for the utility of such sensor design. We envisage that the integration of the two powerful chemical biology tools, fluorescent protein sensors and genetic incorporation of UAA*s, will lead to novel biosensors that can expand and deepen current understanding of cellular processes.


Behavioral and electroantennogram responses of plum curculio, Conotrachelus nenuphar, to selected noxious plant extracts and insecticides.
Behavioral and electroantennogram responses of plum curculio, Conotrachelus nenuphar (Herbst) (Coleoptera: Curculionidae), adults were tested for several methanolic plant extracts and organically approved insecticides. Plant extracts were evaluated for their potential as antifeedants or oviposition deterrents. These extract responses were also compared to those elicited by the non-neurotoxic, organic irritant-insecticide kaolin clay. Both sexes of plum curculio exhibited antennal response as measured by electroantennogram, which ranged from 0.2 to 1.1 mV, to plant extracts and the organic irritant/insecticide, with the greatest response to the extract of rough cocklebur, Xanthium strumarium L. (1.1 mV). No choice tests were conducted to compare feeding and oviposition by plum curculio on untreated apples or on apples treated with one of the extracts or the insecticide. The insecticide pyrethrum and extracts of X. strumarium and greater burdock, Arctium lappa L., significantly reduced feeding. Also, pyrethrum, A. lappa, Humulus lupulus L. (common hop), X. strumarium, and Verbascum songaricum Schrenk extracts completely inhibited egg deposition. In no-choice assays, the effects of kaolin clay with incorporated plant extracts on plum curculio feeding and oviposition were monitored as complementary tests. A. lappa-kaolin, H. lupulus-kaolin, and X. strumarium-kaolin mixtures significantly reduced the feeding of plum curculio compared to the control or kaolin clay alone. Each of the plant extract-kaolin mixtures evaluated, with the exception of Bifora radians Bieberstein (wild bishop), completely inhibited plum curculio oviposition as compared to controls.


Pinocembrin-Enriched Fractions of Elytranthe parasitica (L.) Danser Modulates Apoptotic and MAPK Cellular Signaling in HepG2 Cells.
Hepatocellular carcinoma (HCC) is the fifth leading cause of cáncer mortality. Elytranthe parasitica (L.) Danser (EP), a hemiparasitic plant (Loranthaceae) has potent anti-cancer properties. In the study, we investigated the effect of EP fractions on the expression of apoptosis and mitogenactivated protein kinase (MAPK) markers deregulated in HCC. Bioactivity fractionation was performed to isolate the phytochemical(s) exerting anti-tumor activity in HepG2 cells. Anti-proliferative, clonogenic and anti-metastatic effects of EP fractions were examined in hepatocellular carcinoma cell line, HepG2 by Sulphorhodamine B, colony formation and scratch wound assays respectively in hepatocellular cell line, HepG2. The effects of EP fractions on key markers of apoptosis and MAPK signaling pathways were explored. EP bioactive fractions showed significant anti-tumor potential, reduced clonogenicity and considerably inhibited cell migration in HepG2 cells in vitro. The fractions augmented annexin V binding and induced apoptosis by causing cell cycle arrest at G2/M and S phase checkpoints. The fractions increased expression levels of p53, bad, cleaved PARP (Poly ADP ribose polymerase) and cleaved Caspase-3. Expression levels of phosphorylated ERK1/2 (Extracellular signal-regulated kinase) were downregulated. Pinocembrin-7-O-ß-D-glucoside and chrysin were isolated and characterized for the first time from Elytranthe parasitica (L.) Danser. Our findings reveal that EP fractions induced cell cycle arrest and triggered apoptosis in HepG2 cells by upregulating apoptosis and deactivating MAPK pathway. It signifies that pinocembrin glycoside and chrysin are bioactive phytochemicals contributing to the potent anti-hepatocarcinoma effects on HepG2 cells. Hence, bioactive EP fractions could be used as a therapeutic agent for effective HCC therapy.


Electrostatic control of spin exchange between mobile spin-correlated radical pairs created in micellar solutions.
A series of photoinduced H-atom abstraction reactions between anthraquinone-2,6,-disulfonate, disodium salt (AQDS) and differently charged micellar substrates is presented. After a 248 nm excimer laser flash, the first excited triplet state of AQDS is rapidly formed and then quenched by abstraction of a hydrogen atom from the alkyl chain of the micelle surfactant, leading to a spin-correlated radical pair (SCRP). The SCRP is detected 500 ns after the laser flash using time-resolved (direct detection) electron paramagnetic resonance (TREPR) spectroscopy at X-band (9.5 GHz). By changing the charge on the surfactant headgroup from negative (sodium dodecyl sulfate, SDS) to positive (dodecyltrimethylammonium chloride, DTAC), TREPR spectra with different degrees of antiphase structure (APS) in their line shape were observed. The first derivative-like APS line shape is the signature of an SCRP experiencing an electron spin exchange interaction between the radical centers, which was clearly observable in DTAC micelles and absent in SDS micellar solutions. Solutions with surfactant concentrations well below the critical micelle concentration (cmc) or solutions where micellar formation had been disrupted (1:1 v/v CH(3)CN/H(2)O) also showed no APS line shapes in their TREPR spectra. These results support the conclusion that electrostatic forces between the sensitizer (AQDS) charge and the substrate (surfactant) headgroup charge are responsible for the observed effects. The results represent a new example of electrostatic control of a spin exchange interaction in mobile radical pairs.


A biomechanical analysis of muscle strength as a limiting factor in standing posture.
We developed a method for studying muscular coordination and strength in multijoint movements and have applied it to standing posture. The method is based on a musculoskeletal model of the human lower extremity in the sagittal plane and a technique to visualize, geometrically, how constraints internal and external to the body affect movement. We developed an algorithm to calculate the set of all feasible accelerations (i.e., the 'feasible acceleration set', or FAS) that muscles can induce. For the ankle, knee, and hip joints in the sagittal plane, this set is a polyhedron in three dimensions. Using the volume of the FAS as an indicator of overall mobility, we found that strengthening muscles on the posterior side (as opposed to the anterior) of the body would cause greater increases in mobility. Employing the experimental observations of others, we also found that acceleration constraints greatly reduce the range of feasible accelerations. We then defined a set of four basic acceleration vectors which, when used in various combinations, can produce the repertoire of postural movements. We used linear programming to find the maximum magnitudes of these vectors, and the sensitivity of these magnitudes to muscle strength, thereby delineating those muscles which, if strengthened, would cause the greatest increase in the body's ability to generate the basic acceleration vectors. For our particular model, those muscle groups were found to be hamstrings, tibialis anterior, rectus femoris, and gastrocnemius. These muscle groups would be of great importance in cases involving severely reduced muscle strength. This methodology may therefore be useful for purposes such as design of functional electrical stimulation controllers or exercises for persons at risk for falling.


Identification and characterization of ϕH111-1: A novel myovirus with broad activity against clinical isolates of Burkholderia cenocepacia.
Characterization of prophages in sequenced bacterial genomes is important for virulence assessment, evolutionary analysis, and phage application development. The objective of this study was to identify complete, inducible prophages in the cystic fibrosis (CF) clinical isolate Burkholderia cenocepacia H111. Using the prophage-finding program PHAge Search Tool (PHAST), we identified three putative intact prophages in the H111 sequence. Virions were readily isolated from H111 culture supernatants following extended incubation. Using shotgun cloning and sequencing, one of these virions (designated ϕH111-1 [vB_BceM_ϕH111-1]) was identified as the infective particle of a PHAST-detected intact prophage. ϕH111-1 has an extremely broad host range with respect to B. cenocepacia strains and is predicted to use lipopolysaccharide (LPS) as a receptor. Bioinformatics analysis indicates that the prophage is 42,972 base pairs in length, encodes 54 proteins, and shows relatedness to the virion morphogenesis modules of AcaML1 and "Vhmllikevirus" myoviruses. As ϕH111-1 is active against a broad panel of clinical strains and encodes no putative virulence factors, it may be therapeutically effective for Burkholderia infections.


A multilingual gold-standard corpus for biomedical concept recognition: the Mantra GSC.
To create a multilingual gold-standard corpus for biomedical concept recognition. We selected text units from different parallel corpora (Medline abstract titles, drug labels, biomedical patent claims) in English, French, German, Spanish, and Dutch. Three annotators per language independently annotated the biomedical concepts, based on a subset of the Unified Medical Language System and covering a wide range of semantic groups. To reduce the annotation workload, automatically generated preannotations were provided. Individual annotations were automatically harmonized and then adjudicated, and cross-language consistency checks were carried out to arrive at the final annotations. The number of final annotations was 5530. Inter-annotator agreement scores indicate good agreement (median F-score 0.79), and are similar to those between individual annotators and the gold standard. The automatically generated harmonized annotation set for each language performed equally well as the best annotator for that language. The use of automatic preannotations, harmonized annotations, and parallel corpora helped to keep the manual annotation efforts manageable. The inter-annotator agreement scores provide a reference standard for gauging the performance of automatic annotation techniques. To our knowledge, this is the first gold-standard corpus for biomedical concept recognition in languages other than English. Other distinguishing features are the wide variety of semantic groups that are being covered, and the diversity of text genres that were annotated.


Heart rate responses and training load during nonspecific and specific aerobic training in adolescent taekwondo athletes.
The efficacy of replacing generic running with Taekwondo (TKD) specific technical skills during interval training at an intensity corresponding to 90-95% of maximum heart rate (HRmax) has not yet been demonstrated. Therefore, the purpose of this study was to compare the HR responses and perceived exertion between controlled running and high-intensity TKD technical interval training in adolescent TKD athletes. Eighteen adolescent, male TKD athletes performed short-duration interval running and TKD specific technical skills (i.e. 10-20 [10-s of exercise interspersed with 20 s of passive recovery]) in a counterbalanced design. In both training methods, HR was measured and expressed as the percentage of HR reserve (%HRres). Rating of perceived exertion (RPE, Borg's category rating-10 scale), Banister's training impulse (TRIMP) and Edwards' training load (TL) were used to quantify the internal training load. Recorded cardiovascular responses expressed in %HRres in the two training methods were not significantly different (p > 0.05). Furthermore, the two training methods induced similar training loads as calculated by Banister and Edwards' methods. Perceived exertion ranged between "hard" and "very hard" during all interval training sessions. These findings showed that performing repeated TKD specific skills increased HR to the same level, and were perceived as producing the same training intensity as did short-duration interval running in adolescent TKD athletes. Therefore, using specific TKD kicking exercises in high-intensity interval training can be applied to bring more variety during training, mixing physical and technical aspects of the sport, while reaching the same intensity as interval running.


Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2.
The most common pathology associated with obesity is insulin resistance, which results in the onset of type 2 diabetes mellitus. Several studies have implicated the mammalian target of rapamycin (mTOR) signaling pathway in obesity. Eukaryotic translation initiation factor 4E-binding (eIF4E-binding) proteins (4E-BPs), which repress translation by binding to eIF4E, are downstream effectors of mTOR. We report that the combined disruption of 4E-BP1 and 4E-BP2 in mice increased their sensitivity to diet-induced obesity. Increased adiposity was explained at least in part by accelerated adipogenesis driven by increased expression of CCAAT/enhancer-binding protein delta (C/EBPdelta), C/EBPalpha, and PPARgamma coupled with reduced energy expenditure, reduced lipolysis, and greater fatty acid reesterification in the adipose tissue of 4E-BP1 and 4E-BP2 double KO mice. Increased insulin resistance in 4E-BP1 and 4E-BP2 double KO mice was associated with increased ribosomal protein S6 kinase (S6K) activity and impairment of Akt signaling in muscle, liver, and adipose tissue. These data clearly demonstrate the role of 4E-BPs as a metabolic brake in the development of obesity and reinforce the idea that deregulated mTOR signaling is associated with the development of the metabolic syndrome.


Nandrolone-induced nuclear accumulation of MyoD protein is mediated by Numb, a Notch inhibitor, in C2C12 myoblasts.
Signaling via the androgen receptor (AR) stimulates myogenic progenitor differentiation. In addition, myogenic differentiation factor D (MyoD) and Numb, a Notch inhibitor, play key roles in regulating myogenic differentiation. Nandrolone, an anabolic steroid, upregulates both MyoD and Numb expression in myogenic cells. However, the molecular mechanisms by which MyoD is upregulated by nandrolone are unclear. Moreover, the potential crosstalk between nandrolone, MyoD, and Numb is not well understood. With these considerations in mind, we examined the effects of nandrolone on the expression of MyoD mRNA and protein, and determined the interactions of MyoD and Numb in the presence or absence of nandrolone in differentiating C2C12 myoblasts. Nandrolone increased MyoD mRNA and protein expression and significantly enhanced nuclear translocation of MyoD protein. The later effect of nandrolone was blunted by siRNA against Numb. Immunoprecipitation (IP) studies confirmed that Numb forms complexes with MyoD. Chromatin IP revealed that in the presence of nandrolone, Numb is recruited to a region of the MyH7 promotor containing the E-box to which MyoD binds. These data indicate that nandrolone-regulated MyoD activation occurs mainly through a posttranslational mechanism which promotes MyoD nuclear accumulation, and suggest that this effect of nandrolone is, at least in part, mediated by Numb.


Modifications to the dNTP triphosphate moiety: from mechanistic probes for DNA polymerases to antiviral and anti-cancer drug design.
Abnormal replication of DNA is associated with many important human diseases, most notably viral infections and neoplasms. Existing approaches to chemotherapeutics for diseases associated with dysfunctional DNA replication classically involve nucleoside analogues that inhibit polymerase activity due to modification in the nucleobase and/or ribose moieties. These compounds must undergo multiple phosphorylation steps in vivo, converting them into triphosphosphates, in order to inhibit their targeted DNA polymerase. Nucleotide monophosphonates enable bypassing the initial phosphorylation step at the cost of decreased bioavailability. Relatively little attention has been paid to higher nucleotides (corresponding to the natural di- and triphosphate DNA polymerase substrates) as drug platforms due to their expected poor deliverability. However, a better understanding of DNA polymerase mechanism and fidelity dependence on the triphosphate moiety is beginning to emerge, aided by systematic incorporation into this group of substituted methylenebisphosphonate probes. Meanwhile, other bridging, as well as non-bridging, modifications have revealed intriguing possibilities for new drug design. We briefly survey some of this recent work, and argue that the potential of nucleotide-based drugs, and intriguing preliminary progress in this area, warrant acceptance of the challenges that they present with respect to bioavailability and metabolic stability.


Computer-Aided Decision Support for Melanoma Detection Applied on Melanocytic and Nonmelanocytic Skin Lesions: A Comparison of Two Systems Based on Automatic Analysis of Dermoscopic Images.
Commercially available clinical decision support systems (CDSSs) for skin cancer have been designed for the detection of melanoma only. Correct use of the systems requires expert knowledge, hampering their utility for nonexperts. Furthermore, there are no systems to detect other common skin cancer types, that is, nonmelanoma skin cancer (NMSC). As early diagnosis of skin cancer is essential, there is a need for a CDSS that is applicable to all types of skin lesions and is suitable for nonexperts. Nevus Doctor (ND) is a CDSS being developed by the authors. We here investigate ND's ability to detect both melanoma and NMSC and the opportunities for improvement. An independent test set of dermoscopic images of 870 skin lesions, including 44 melanomas and 101 NMSCs, were analysed by ND. Its sensitivity to melanoma and NMSC was compared to that of Mole Expert (ME), a commercially available CDSS, using the same set of lesions. ND and ME had similar sensitivity to melanoma. For ND at 95% melanoma sensitivity, the NMSC sensitivity was 100%, and the specificity was 12%. The melanomas misclassified by ND at 95% sensitivity were correctly classified by ME, and vice versa. ND is able to detect NMSC without sacrificing melanoma sensitivity.


Integrating routine lactation consultant support into a pediatric practice.
Although research shows that healthcare professionals' support improves breastfeeding duration, many physicians do not believe they have adequate time to address breastfeeding concerns during office visits. This study evaluated the impact of a pediatric practice's postnatal lactation consultant intervention. To improve breastfeeding support, the study practice changed policy and began using a lactation consultant overseen by a physician, to conduct the initial postpartum office visit for all breastfeeding infants. A retrospective chart review was performed on consecutive newborns before (n = 166) and after (n = 184) implementation of the program. Feeding method was assessed at each well child visit during the infant's first 9 months. χ² and logistic growth curve analyses were used to test the association between implementation status and non-formula feeding (NFF). Mothers and infants in 2007 and 2009 were similar with regard to type of insurance, parity, gestational age, multiple births, and cesarean sections. Overall, NFF improved after program implementation (odds ratio = 1.12, 95% confidence interval 1.02-1.23). In 2009, NFF rates at 2 months, 4 months, 6 months, and 9 months were greater than 2007 rates by 10%, 15%, 11%, and 9%, respectively. Logistic growth curve analysis indicated the difference across these time points was significant between 2007 and 2009. A routine post-discharge outpatient lactation visit coordinated within a primary care practice improved breastfeeding initiation and intensity. This effect was sustained for 9 months.


Babesia divergens-like infection, Washington State.
Most reported U.S. zoonotic cases of babesiosis have occurred in the Northeast and been caused by Babesia microti. In Washington State, three cases of babesiosis have been reported previously, which were caused by WA1 (for "Washington 1")-type parasites. We investigated a case of babesiosis in Washington in an 82-year-old man whose spleen had been removed and whose parasitemia level was 41.4%. The complete 18S ribosomal RNA gene of the parasite was amplified from specimens of his whole blood by polymerase chain reaction. Phylogenetic analysis showed the parasite is most closely related, but not identical, to B. divergens (similarity score, 99.5%), a bovine parasite in Europe. By indirect fluorescent-antibody testing, his serum reacted to B. divergens but not to B. microti or WA1 antigens. This case demonstrates that babesiosis can be caused by novel parasites detectable by manual examination of blood smears but not by serologic or molecular testing for B. microti or WA1-type parasites.