Species-specific glucocorticoid and 1,25-dihydroxyvitamin D responsiveness in mouse MC3T3-E1 osteoblasts: dexamethasone inhibits osteoblast differentiation and vitamin D down-regulates osteocalcin gene expression.
The mouse MC3T3-E1 cell line is nontumorigenic and undergoes a typical program of osteoblast differentiation in vitro, producing a bone-like mineralized extracellular matrix. We report responses of these cells to dexamethasone (Dex) and 1,25-(OH)2D3 that are in contrast to findings from other osteoblast culture systems. First, chronic exposure of both early- and late-passaged MC3T3-E1 cells to 10(-7) M Dex, initiated during the proliferation period, blocked osteoblast differentiation, in contrast to the enhanced differentiation observed in cultures of fetal rat calvarial-derived cells. Secondly, 1,25-(OH)2D3 did not up-regulate expression (messenger RNA or protein synthesis) of the endogenous mouse osteocalcin (OC) gene. Several lines of evidence are presented that suggest this response is caused by sequence specific properties of the mouse OC vitamin D response element. We also observed both qualitative and quantitative differences in expression of cell growth (histone H2B) and phenotype-related genes (collagen, OC, osteopontin, glucocorticoid receptor, and 1, 25-(OH)2D3 receptor), between pre- and postmineralization stage osteoblasts, in response to 24 h steroid hormone treatment. Our findings in MC3T3-E1 cells are consistent with current concepts of selective influences of 1,25-(OH)2D3 and glucocorticoids as a function of osteoblast maturation. However, the inhibition of osteoblast differentiation by chronic Dex at 10(-7) M and the down-regulation of OC by 1,25-(OH)2D3 are novel observations relevant to species-specific responsiveness of mouse bone-expressed genes to steroid hormones during osteoblast differentiation.


A Prospective Observational Study of Technical Difficulty With GlideScope-Guided Tracheal Intubation in Children.
The GlideScope Cobalt is one of the most commonly used videolaryngoscopes in pediatric anesthesia. Although visualization of the airway may be superior to direct laryngoscopy, users need to learn a new indirect way to insert the tracheal tube. Learning this indirect approach requires focused practice and instruction. Identifying the specific points during tube placement, during which clinicians struggle, would help with targeted education. We conducted this prospective observational study to determine the incidence and location of technical difficulties using the GlideScope, the success rates of various corrective maneuvers used, and the impact of technical difficulty on success rate. We conducted this observational study at our quaternary pediatric hospital between February 2014 and August 2014. We observed 200 GlideScope-guided intubations and documented key intubation-related outcomes. Inclusion criteria for patients were <6 years of age and elective surgery requiring endotracheal intubation. We documented the number of advancement maneuvers required to intubate the trachea, the location where technical difficulty occurred, the types of maneuvers used to address difficulties, and the tracheal intubation success rate. We used a bias-corrected bootstrapping method with 300 replicates to determine the 95% confidence interval (CI) around the rate of difficulty with an intubation attempt. After excluding attempts by inexperienced clinicians, there were 225 attempts in 187 patients, 58% (131 of 225; bootstrap CI, 51.6%-64.6%]) of the attempts had technical difficulties. Technical difficulty was most likely to occur when inserting the tracheal tube between the plane of the arytenoid cartilages to just beyond the vocal cords: "zone 3." Clockwise rotation of the tube was the most common successful corrective maneuver in zone 3. The overall tracheal intubation success rate was 98% (CI, 95%-99%); however, the first attempt success rate was only 80% (CI, 74%-86%). Patients with technical difficulty had more attempts (median [interquartile range], 2 [1-3] than those without technical difficulty median (interquartile range, 1 [1-1; P value <.01]). A variety of clinicians experience technical difficulties with the GlideScope Cobalt videolaryngoscope in children. These difficulties result in more tracheal intubation attempts, an important risk factor for intubation-associated complications. Targeted education of clinicians may reduce the incidence of technical difficulties.


Neuropsychological executive functions and DSM-IV ADHD subtypes.
To evaluate and compare a focused set of component neuropsychological executive functions in the DSM-IV attention-deficit/hyperactivity disorder combined (ADHD-C) and inattentive (ADHD-I) subtypes. The Stop task, Tower of London, Stroop task, Trailmaking Test, and output speed measures were completed by 105 boys and girls aged 7-12 classified as either DSM-IV ADHD-C (n = 46), ADHD-I (n = 18), or community control (n = 41). Both subtypes had deficits on output speed. A group x gender interaction was observed on the Stop task: boys with ADHD-C were impaired versus boys with ADHD-I, whereas girls in the two subtypes did not differ. The ADHD-C type had a deficit in planning. Neither ADHD group had a deficit in interference control per se, although they were slower than controls on the Stroop tasks. ADHD-I shares neuropsychological deficits with ADHD-C in the domain of output speed; on most domains the subtypes did not differ. Neuropsychological distinctions between these ADHD subtypes may be few, depending on which domain of executive functioning is assessed, and these distinctions differ by gender. In the case of boys, the two subtypes may be distinguished by the specificity of motor inhibition deficits to ADHD-C.


Transgenic plants expressing HC-Pro show enhanced virus sensitivity while silencing of the transgene results in resistance.
Nicotiana benthamiana plants were engineered to express sequences of the helper component-proteinase (HC-Pro) of Cowpea aphid-borne mosaic potyvirus (CABMV). The sensitivity of the transgenic plants to infection with parental and heterologous viruses was studied. The lines expressing HC-Pro showed enhanced symptoms after infection with the parental CABMV isolate and also after infection with a heterologous potyvirus, Potato virus Y (PVY) and a comovirus, Cowpea mosaic virus (CPMV). On the other hand, transgenic lines expressing nontranslatable HC-Pro or translatable HC-Pro with a deletion of the central domain showed wild type symptoms after infection with the parental CABMV isolate and heterologous viruses. These results showed that CABMV HC-Pro is a pathogenicity determinant that conditions enhanced sensitivity to virus infection in plants, and that the central domain of the protein is essential for this. The severe symptoms in CABMV-infected HC-Pro expressing lines were remarkably followed by brief recovery and subsequent re-establishment of infection, possibly indicating counteracting effects of HC-Pro expression and a host defense response. One of the HC-Pro expressing lines (h48) was found to contain low levels of transgenic HC-Pro RNA and to be resistant to CABMV and to recombinant CPMV expressing HC-Pro. This indicated that h48 was (partially) posttranscriptionally silenced for the HC-Pro transgene inspite of the established role of HC-Pro as a suppressor of posttranscriptional gene silencing. Line h48 was not resistant to PVY, but instead showed enhanced symptoms compared to nontransgenic plants. This may be due to relief of silencing of the HC-Pro transgene by HC-Pro expressed by PVY.


Holographically aided iterative phase retrieval.
Fourier transform holography (FTH) is a noise-resistant imaging technique which allows for nanometer spatial resolution x-ray imaging, where the inclusion of a small reference scattering object provides the otherwise missing phase information. With FTH, one normally requires a considerable distance between the sample and the reference to ensure spatial separation of the reconstruction and its autocorrelation. We demonstrate however that this requirement can be omitted at the small cost of iteratively separating the reconstruction and autocorrelation. In doing so, the photon efficiency of FTH can be increased due to a smaller illumination area, and we show how the presence of the reference prevents the non-uniqueness problems often encountered with plane-wave iterative phase retrieval. The method was tested on a cobalt/platinum multilayer exhibiting out of plane magnetized domains, where the magnetic circular dichroism effect was used to image the magnetic domains at the cobalt L₃-edge at 780eV.


Electronic-dimensionality reduction of bulk MoS2 by hydrogen treatment.
A reduction in the electronic-dimensionality of materials is one method for achieving improvements in material properties. Here, a reduction in electronic-dimensionality is demonstrated using a simple hydrogen treatment technique. Quantum well states from hydrogen-treated bulk 2H-MoS2 are observed using angle resolved photoemission spectroscopy (ARPES). The electronic states are confined within a few MoS2 layers after the hydrogen treatment. A significant reduction in the band-gap can also be achieved after the hydrogen treatment, and both phenomena can be explained by the formation of sulfur vacancies generated by the chemical reaction between sulfur and hydrogen.


Confirmation of bean leaf beetle, Cerotoma trifurcata, feeding on cucurbits.
The objective of these studies was to assess the degree to which bean leaf beetle, Cerotoma trifurcata (Forster), will feed on cucurbits. In 2003, we documented an infestation of C. trifurcata in a commercial pumpkin field near Rosemount, MN, USA. To evaluate C. trifurcata feeding on cucurbits, we conducted laboratory no-choice and choice test feeding studies. In the laboratory, C. trifurcata fed most heavily on cotyledon-stage cucumber plants, followed by pumpkin and squash. With soybean plants present, C. trifurcata still fed on cucumber plants. However, C. trifurcata appeared to prefer soybeans until the quality of the soybean plants was diminished through feeding damage. This is the first known report of C. trifurcata feeding on cucurbits. The pest potential of C. trifurcata in cucurbit cropping systems should be further evaluated.


Mutation update: TGFBI pathogenic and likely pathogenic variants in corneal dystrophies.
Human transforming growth factor β-induced (TGFBI), is a gene responsible for various corneal dystrophies. TGFBI produces a protein called TGFBI, which is involved in cell adhesion and serves as a recognition sequence for integrins. An alteration in cell surface interactions could be the underlying cause for the progressive accumulation of extracellular deposits in different layers of the cornea with the resulting changes of refractive index and transparency. To this date, 69 different pathogenic or likely pathogenic variants in TGFBI have been identified in a heterozygous or homozygous state in various corneal dystrophies, including a novel variant reported here. All disease-associated variants were inherited as autosomal-dominant traits but one; this latter was inherited as an autosomal recessive trait. Most corneal dystrophy-associated variants are located at amino acids Arg124 and Arg555. To keep the list of corneal dystrophy-associated variant current, we generated a locus-specific database for TGFBI (http://databases.lovd.nl/shared/variants/TGFBI) containing all pathogenic and likely pathogenic variants reported so far. Non-disease-associated variants are described in specific databases, like gnomAD and ExAC but are not listed here. This article presents the most recent up-to-date list of disease-associated variants.


Life-style, aging and work ability among active Finnish workers in 1981-1992.
Life-style is an important factor in explaining the changes in health and well-being in old age. In this study life-style was defined according to Abel's definition as combining life chances and life conduct. The main question concerned the change in life-style components and work ability over a 11-year period. The study population comprised workers who responded to a questionnaire in both 1981 and 1992 and were still working in 1992 (N = 924). The changes in the dimensions of life-style (hobbies, living habits, life satisfaction) were tested with Pearson's chi-square test. The associations between life-style, work ability, and health were analyzed by correspondence analysis. Physical activity was the life-style factor that showed a major change; it increased among both genders. All other leisure-time activities decreased during the follow-up. The women's satisfaction with their life situation increased, but the men were less satisfied at the end of the study. Work ability, as measured with the work ability index, was a crucial factor in these changes. If the work ability remained good, the respondents were also more active and more satisfied with their life. This effect of work ability was strong, especially with respect to the men's satisfaction with their life situation. Life-style, work ability, and perceived health are highly associated, and studying them separately may give a simplistic view of the interaction between aging and work. In the future, more comprehensive approaches should be applied.


Brittle-to-ductile transition in a fiber bundle with strong heterogeneity.
We analyze the failure process of a two-component system with widely different fracture strength in the framework of a fiber bundle model with localized load sharing. A fraction 0≤α≤1 of the bundle is strong and it is represented by unbreakable fibers, while fibers of the weak component have randomly distributed failure strength. Computer simulations revealed that there exists a critical composition α(c) which separates two qualitatively different behaviors: Below the critical point, the failure of the bundle is brittle, characterized by an abrupt damage growth within the breakable part of the system. Above α(c), however, the macroscopic response becomes ductile, providing stability during the entire breaking process. The transition occurs at an astonishingly low fraction of strong fibers which can have importance for applications. We show that in the ductile phase, the size distribution of breaking bursts has a power law functional form with an exponent μ=2 followed by an exponential cutoff. In the brittle phase, the power law also prevails but with a higher exponent μ=9/2. The transition between the two phases shows analogies to continuous phase transitions. Analyzing the microstructure of the damage, it was found that at the beginning of the fracture process cracks nucleate randomly, while later on growth and coalescence of cracks dominate, which give rise to power law distributed crack sizes.


Analysis of human reticulocyte genes reveals altered erythropoiesis: potential use to detect recombinant human erythropoietin doping.
Enhancement of oxygen delivery to tissues is associated with improved sporting performance. One way of enhancing oxygen delivery is to take recombinant human erythropoietin (rHuEpo), which is an unethical and potentially dangerous practice. However, detection of the use of rHuEpo remains difficult in situations such as: i) several days after the end of treatment ii) when a treatment with low doses is conducted iii) if the rHuEpo effect is increased by other substances. In an attempt to detect rHuEpo abuse, we selected erythroid gene markers from a SAGE library and analyzed the effects of rHuEpo administration on expression of the HBB, FTL and OAZ genes. Ten athletes were assigned to the rHuEpo or placebo group. The rHuEpo group received subcutaneous injections of rHuEpo (50 UI/kg three times a week, 4 weeks; 20 UI/kg three times a week, 2 weeks). HBB, FTL and OAZ gene profiles were monitored by real time-polymerase chain reaction (PCR) quantification during and for 3 weeks after drug administration. The global analysis of these targeted genes detected in whole blood samples showed a characteristic profile of subjects misusing rHuEpo with a increase above the threshold levels. The individual analysis of OAZ mRNA seemed indicative of rHuEpo treatment. The performance-enhancing effect of rHuEpo treatment is greater than the duration of hematologic changes associated with rHuEpo misuse. Although direct electrophoretic methods to detect rHuEpo have been developed, recombinant isoforms of rHuEpo are not detectable some days after the last subcutaneous injection. To overcome these limitations indirect OFF models have been developed. Our data suggest that, in the near future, it will be possible to consolidate results achievable with the OFF models by analyzing selected erythroid gene markers as a supplement to indirect methods.


Adenosine is required for ethanol-induced heterologous desensitization.
Recent evidence suggests that ethanol initially causes an increase in receptor-dependent cAMP levels, followed by heterologous desensitization of receptors coupled to GS after chronic exposure. Here we investigated the role of adenosine in mediating these responses. We found that ethanol caused accumulation of extracellular adenosine in NG108-15 and S49 lymphoma cells. This adenosine activated adenosine receptors to increase intracellular cAMP levels. The addition of adenosine deaminase, to degrade accumulated extracellular adenosine, or isobutyl-methylxanthine, an adenosine receptor antagonist, completely blocked ethanol-induced increases in cAMP levels in NG108-15 cells. Chronic exposure of NG108-15 and S49 wild type cells to ethanol resulted in heterologous desensitization of adenosine receptor- and prostaglandin E1 receptor-dependent cAMP signal transduction. Coincubation of NG108-15 and S49 wild type cells with adenosine deaminase and ethanol for 48 hr prevented heterologous desensitization. Moreover, mutant S49 cells, which are unable to transport adenosine, did not accumulate extracellular adenosine after incubation with ethanol and did not develop ethanol-induced heterologous desensitization. Our results suggest that adenosine is an important mediator of both the acute and chronic effects of ethanol on cAMP signal transduction.


Chemomobilization: Overview of an Educational Quality Improvement Project for Recipients of Autologous Stem Cell Transplantation.
In preparation for an autologous stem cell transplantation, patients undergo chemomobilization; however, a dearth of standardized, evidence-based patient education on chemomobilization exists in the literature and in practice. . The purpose of this quality improvement educational initiative is to identify an evidence-based approach to appraise the educational needs of patients and their caregivers and to enhance chemomobilization education. . A review of the literature related to chemomobilization was conducted, as well as an informal survey of educational practices at five National Cancer Institute-designated comprehensive cancer centers. A 14-item survey was administered to 50 patients who underwent chemomobilization to assess their educational needs, experiences, and preferences. . Patients prefer written information to review. Receiving verbal education from reliable healthcare providers in a structured format may enhance effective comprehension and retention. Patients identified timing, process, side effects, and expectations about chemomobilization as the most important topics to include in education.


Health impact assessment of waste management facilities in three European countries.
Policies on waste disposal in Europe are heterogeneous and rapidly changing, with potential health implications that are largely unknown. We conducted a health impact assessment of landfilling and incineration in three European countries: Italy, Slovakia and England. A total of 49 (Italy), 2 (Slovakia), and 11 (England) incinerators were operating in 2001 while for landfills the figures were 619, 121 and 232, respectively. The study population consisted of residents living within 3 km of an incinerator and 2 km of a landfill. Excess risk estimates from epidemiological studies were used, combined with air pollution dispersion modelling for particulate matter (PM10) and nitrogen dioxide (NO2). For incinerators, we estimated attributable cancer incidence and years of life lost (YoLL), while for landfills we estimated attributable cases of congenital anomalies and low birth weight infants. About 1,000,000, 16,000, and 1,200,000 subjects lived close to incinerators in Italy, Slovakia and England, respectively. The additional contribution to NO2 levels within a 3 km radius was 0.23, 0.15, and 0.14 μg/m3, respectively. Lower values were found for PM10. Assuming that the incinerators continue to operate until 2020, we are moderately confident that the annual number of cancer cases due to exposure in 2001-2020 will reach 11, 0, and 7 in 2020 and then decline to 0 in the three countries in 2050. We are moderately confident that by 2050, the attributable impact on the 2001 cohort of residents will be 3,621 (Italy), 37 (Slovakia) and 3,966 (England) YoLL. The total exposed population to landfills was 1,350,000, 329,000, and 1,425,000 subjects, respectively. We are moderately confident that the annual additional cases of congenital anomalies up to 2030 will be approximately 2, 2, and 3 whereas there will be 42, 13, and 59 additional low-birth weight newborns, respectively. The current health impacts of landfilling and incineration can be characterized as moderate when compared to other sources of environmental pollution, e.g. traffic or industrial emissions, that have an impact on public health. There are several uncertainties and critical assumptions in the assessment model, but it provides insight into the relative health impact attributable to waste management.


Metabolic syndrome components and their response to lifestyle and metformin interventions are associated with differences in diabetes risk in persons with impaired glucose tolerance.
To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence. We used the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years. In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95% confidence interval) for diabetes in those with MetS (vs. no MetS) at baseline were 1.7 (1.3-2.3), 1.7 (1.2-2.3) and 2.0 (1.3-3.0) for placebo, metformin and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favourable changes in WC (placebo and lifestyle) and high-density lipoprotein cholesterol (placebo and metformin) contributed to reduced diabetes risk. MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycaemia, the most predictive factors for diabetes were baseline hypertriglyceridaemia and both baseline and lifestyle-associated changes in WC. Targeting these cardiometabolic risk factors may help to assess the benefits of interventions that reduce diabetes incidence.


Cataract surgery in camp patients: a study on visual outcomes.
To assess the complications and visual outcomes associated with cataract surgery in camp patients operated at a tertiary centre. In a retrospective study, 206 outreach camp patients had undergone cataract surgeries with posterior chamber intraocular lens implantation under peribulbar anesthesia over a period of 6 months. Post-operative complications on Day 1 were graded as per Oxford Cataract Treatment and Evaluation Team (OCTET) definitions. One month postoperative complications, best corrected visual acuity and refractive errors were assessed. 206 eyes underwent cataract extraction with PCIOL implantation. Small incision cataract surgery (SICS) was the commonest method (78.6%) used. The most common first post-operative day complication was mild iridocyclitis (26.2%). The complications were based on OCTET definitions, and showed that 33 % had Grade I and 3.4 % had Grade II complications. The major post-operative complication after 4 weeks of surgery was posterior capsular opacity. 89.8 % of the eyes had a 4 week-post-operative best corrected visual acuity of e± 6/24. The commonest refractive error was myopia with against the rule astigmatism, seen in 86 out of 150 cases. High quality cataract surgery with a low rate of intra-operative complications and good visual outcome can be attained in camp patients operated in the base hospitals, thus justifying more similar screening camps to clear the vast cataract backlog.


Performance of Disease-Specific Scoring Models in Intensive Care Patients with Severe Liver Diseases.
Egypt has the highest prevalence of Hepatitis C Virus (HCV) in the world, estimated nationally at 14.7%. HCV treatment consumes 20% ($80 million) of Egypt's annual health budget. Outcomes of cirrhotic patients admitted to the ICU may, in fact, largely depend on differences in the state of the disease, criteria and indications for admission, resource utilization, and intensity of treatment. The aim of the present study was to evaluate the efficacy of liver specific scoring models in predicting the outcome of critically ill cirrhotic patients in the ICU as it may help in prioritization of high risk patients and preservation of ICU resources. Over one year, a total of 777 patients with End Stage Liver Disease (ESLD) due to HCV infection were included in this retrospective non-randomized human study. All statistical analyses were performed by the statistical software SPSS version 22.0 (SPSS, Chicago, IL, USA). Child Turcotte Pugh (CTP) score, MELD score, MELD-Na, MESO, iMELD, Refit MELD and Refit MELD-Na were calculated on ICU admission. ICU admission was mainly due to Gastrointestinal (GI) bleeding and Hepatic Encephalopathy (HE). Overall mortality was 27%. Age and sex showed no statistical difference between survivors and non survivors. Significantly higher mean values were observed for all models among individuals who died compared to survivors. MELD-Na was the most specific compared to the other scores. MELD-Na was highly predictive of mortality at an optimized cut-off value of 20.4 (AURC=0.789±0.03-CI 95%=0.711-0.865) while original MELD was highly predictive of mortality at an optimized cut-off value of 17.4 (AURC=0.678±0.01-CI 95%=0.613-0.682) denoting the importance of adding serum sodium to the original MELD. INR, serum creatinine, bilirubin, white blood cells count and hyponatremia were significantly higher in non survivors compared to survivors, while hypoalbuminemia showed no statistical difference. The advent of Hepatorenal Syndrome (HRS) and Spontaneous Bacterial Peritonitis (SBP) carried worse prognosis. Hyponatremia and number of transfused blood bags were additional independent predictors of mortality. In cirrhosis of liver, due to HCV infection, patients who died during their ICU stay displayed significantly higher values on all prognostic scores at admission. The addition of sodium to MELD score greatly improves the predictive accuracy of mortality. MELD-Na showed the highest predictive value of all scores.


Changes in student attitudes toward interprofessional learning and collaboration arising from a case-based educational experience.
Working effectively with other disciplines is an important and necessary skill for healthcare practitioners. Academic institutions can provide educational experiences that can begin to foster the prerequisite competencies needed to collaborate successfully with other healthcare professionals. The purpose of this study was to examine changes in attitudes toward learning from and collaborating with other healthcare students and professionals arising from an interprofessional educational (IPE) experience. A total of 123 graduate students from clinical psychology (n = 35), education (n = 17), physical therapy (n = 36), and social work (n = 35) were enrolled in the study and participated in a 6-hour IPE experience designed to improve their understanding of the roles played by other healthcare professionals on teams and to teach the skills necessary to effectively collaborate. Attitudes toward learning from and collaborating with other disciplines were examined prior to and immediately after an IPE experience using the Interdisciplinary Education Preparation Scale (IEPS), the Readiness for Professional Learning Scale (RIPLS), and the Attitudes Toward Healthcare Teams Scales (ATHCTS). A 4 (discipline) 3 2 (pre- vs post-IPE) repeated measures ANOVA was used to investigate between- and within-group differences. Statistical significance was set at p ≤ 0.05 for all primary analyses, and post hoc differences for any statistically significant ANOVA findings were explored using a Bonferroni procedure. Statistically significant increases in post-IPE scores on the IEPS, RIPLS, and ATHCTS were found, indicating positive changes in attitudes toward learning from and collaborating with graduate students and other healthcare professionals. A well-structured educational experience, consisting of 6 hours of interprofessional interaction, can change student attitudes toward learning from and collaborating with peers in other healthcare disciplines prior to graduation and professional licensure. The current study provides evidence that a relatively short educational intervention implemented prior to graduation can positively change attitudes toward learning and collaboration.


Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood.
A previous study demonstrated that myelination of the superior medullary lamina along the surface of the parahippocampal gyrus is occurring in human brain during adolescence. To further investigate whether postnatal increases of myelination may continue during the second decade and possibly even longer, the extent of myelination in this region has been analyzed in 164 psychiatrically normal individuals aged newborn to 76 years. Cross sections of the hippocampal formation with adjoining hippocampal gyrus were analyzed on a blinded basis using either a global rating scale or measurements of the area of myelin staining. A curvilinear increase in the extent of myelination between the first and sixth decades of life (r = .71 and r = .67, respectively) was observed. When the area of myelination was expressed relative to brain weight, there was a twofold increase between the first and second decades and an additional increase of 60% between the fourth and sixth decades. Female subjects showed a significantly greater degree of myelin staining than did male subjects during the interval of ages 6 to 29 years; however, after the third decade, there were no gender differences in the area of myelin staining. The increased staining of myelin during the first and second decades principally occurred in the subicular region and adjacent portions of the presubiculum. During the fourth through sixth decades, however, it extended to progressively more lateral locations along the surface of the presubiculum. The precise origin(s) of the axons showing progressive myelination is unknown; however, the axons in the subiculum may include some perforant path fibers, while those found in the presubiculum may include cingulum bundle projections. Overall, our data are consistent with the idea that both early and late postnatal increases of myelination occur in a key corticolimbic relay area of the human brain and underscore the importance of applying a neurodevelopmental perspective to the study of psychopathology during childhood, adolescence, and even adulthood.


Interpreting change scores for pain and functional status in low back pain: towards international consensus regarding minimal important change.
Literature review, expert panel, and a workshop during the "VIII International Forum on Primary Care Research on Low Back Pain" (Amsterdam, June 2006). To develop practical guidance regarding the minimal important change (MIC) on frequently used measures of pain and functional status for low back pain. Empirical studies have tried to determine meaningful changes for back pain, using different methodologies. This has led to confusion about what change is clinically important for commonly used back pain outcome measures. This study covered the Visual Analogue Scale (0-100) and the Numerical Rating Scale (0-10) for pain and for function, the Roland Disability Questionnaire (0-24), the Oswestry Disability Index (0-100), and the Quebec Back Pain Disability Questionnaire (0-100). The literature was reviewed for empirical evidence. Additionally, experts and participants of the VIII International Forum on Primary Care Research on Low Back Pain were consulted to develop international consensus on clinical interpretation. There was wide variation in study design and the methods used to estimate MICs, and in values found for MIC, where MIC is the improvement in clinical status of an individual patient. However, after discussion among experts and workshop participants a reasonable consensus was achieved. Proposed MIC values are: 15 for the Visual Analogue Scale, 2 for the Numerical Rating Scale, 5 for the Roland Disability Questionnaire, 10 for the Oswestry Disability Index, and 20 for the QBDQ. When the baseline score is taken into account, a 30% improvement was considered a useful threshold for identifying clinically meaningful improvement on each of these measures. For a range of commonly used back pain outcome measures, a 30% change from baseline may be considered clinically meaningful improvement when comparing before and after measures for individual patients. It is hoped that these proposals facilitate the use of these measures in clinical practice and the comparability of future studies. The proposed MIC values are not the final answer but offer a common starting point for future research.


The experience of younger adults following myocardial infarction.
The aim of this study was to elucidate the meaning of the experience of younger people (< 55 years) during their first year following a myocardial infarction. We analyzed 17 interviews using a phenomenological-hermeneutic method. The core theme and central phenomenon was the everyday fight to redress the balance in life, which encompassed an existential, physical, and emotional battle to regain a foothold in daily life. The aftermath of a life-threatening event involved a process of transition while at the same time creating a new meaning in life. Lack of energy and its impact on the complex interplay of midlife combined with unreasonable demands from employers and health care professionals seemed to color the experience of the informants. The knowledge gained in this study can constitute a valuable contribution to overall quality assurance in nursing care and the development of nursing interventions for the cardiac rehabilitation of younger patients.


Adaptive supersensitivity and the Na+/K+ pump in the guinea pig vas deferens: time course of the decline in the alpha 2 subunit.
Adaptive supersensitivity in the guinea pig vas deferens has been shown previously to be associated with decreases in transmembrane potential, Na+/K+-ATPase activity, [3H]ouabain binding sites, and density of the alpha 2 subunit of the pump. One of several procedures that induce adaptive supersensitivity in the guinea pig vas deferens is neurotransmitter depletion by chronic administration of reserpine. Guinea pigs were treated with reserpine (1.0 mg/kg/day, intraperitoneally) for 2, 5, or 8 days. Tissues were homogenized and the concentration of the alpha 2 subunit was quantified by use of the selective antibody McB2, slot blot analysis, enhanced chemiluminescence, and densitometric analysis. As reported previously, the concentration of the alpha 2 protein was reduced 41% after 5 days of pretreatment. The reduction was maintained at 8 days (37%). However, there was no change from control after 2 days of pretreatment with reserpine. Thus, the time course of the decline in the alpha 2 subunit is similar to that of the appearance of supersensitivity, depolarization, and the declines in Na+/K+-ATPase and [3H]ouabain binding established earlier. Based upon results in the literature for several different tissues and species, membrane depolarization and decreases in Na+/K+ pump sites may represent widely occurring adaptive mechanisms.


The presenilins in Alzheimer's disease--proteolysis holds the key.
Alzheimer's disease (AD) research has shown that patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (the primary component of the amyloid deposits found in AD brains). However, it is not clear how the presenilins contribute to this increase. New findings now show that the presenilins affect APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is known that the presenilins are involved in the cleavage of the Notch receptor, hinting that they either directly regulate gamma-secretase activity or themselves are protease enzymes. These findings suggest that the presenilins may prove to be valuable molecular targets for the development of drugs to combat AD.


An evaluation of Bayesian designs for dose-escalation studies in healthy volunteers.
In this paper, Bayesian decision procedures previously proposed for dose-escalation studies in healthy volunteers are reviewed and evaluated. Modifications are made to the expression of the prior distribution in order to make the procedure simpler to implement and a more relevant criterion for optimality is introduced. The results of an extensive simulation exercise to establish the properties of the procedure and to aid choice between designs are summarized, and the way in which readers can use simulation to choose a design for their own trials is described. The influence of the value of the within-subject correlation on the procedure is investigated and the use of a simple prior to reflect uncertainty about the correlation is explored.


Breast cancer: factors associated with stage at diagnosis in black and white women. Black/White Cancer Survival Study Group.
Numerous studies have reported differences in cancer staging at diagnosis and in survival between Black and White patients with breast cancer. Utilizing data obtained from the National Cancer Institute's (NCI's) Black/White Cancer Survival Study for the period 1985-1986, a new study is presented here that systematically examines multiple explanatory factors (e.g., lack of mammograms) associated with these cancer-staging differences. We evaluated within a single study the relationship of selected demographic, lifestyle, antecedent medical experiences, and health care access factors to cancer staging at diagnosis in Black and White breast cancer patients. Data utilized in this population-based cohort study of 1222 eligible women (649 Black and 573 White) newly diagnosed for the period 1985-1986 with histologically confirmed primary breast cancer were obtained from the NCI's Black/White Cancer Survival Study. Sources of data included abstracts of hospital medical records, central review of histology slides by a study consultant pathologist, and patient interviews obtained from three metropolitan areas: Atlanta, New Orleans, and San Francisco-Oakland. Within each area, 70% of all Black incident cases were randomly selected, and a sample of White cases, frequency matched by age groups (20-49 years, 50-64 years, and 65-79 years), was selected for comparison. Stage of breast cancer at diagnosis was classified according to the international tumor-lymph node-metastases (TNM) system. Statistical models utilized in this study included the log-linear and polychotomous logistic regression with multiple predictor variables. Factors associated with cancer staging were differentially expressed in Blacks and Whites. Indicators of access to health care, a lack of mammograms, and an increased body mass index significantly (P < .02) contributed to stage differences in Blacks, whereas income was marginally associated (P = .06) with stage for Whites only. Nuclear grade, having a breast examination by a physician, and a history of patient delay explained approximately 50% of the excess risk for stage III-IV cancer versus stage I-IIN0 cancer among Blacks compared with Whites (odds ratio reduction from 2.19 to 1.68). These findings suggest that no single factor or group of factors can explain more than half of the race-stage differences noted in this study with respect to Black and White breast cancer patients.


Largest known Mesozoic multituberculate from Eurasia and implications for multituberculate evolution and biology.
A new multituberculate, Yubaartar zhongyuanensis gen. and sp. nov., is reported from the Upper Cretaceous of Luanchuan County, Henan Province, China. The holotype of the new taxon is a partial skeleton with nearly complete cranium and associated lower jaws with in situ dentitions. The new species is the southern-most record of a Late Cretaceous multituberculate from outside of the Mongolian Plateau in Asia and represents the largest known Mesozoic multituberculate from Eurasia. The new specimen displays some intriguing features previously unknown in multituberculates, such as the first evidence of replacement of the ultimate upper premolar and a unique paleopathological case in Mesozoic mammals in which the animal with a severely broken right tibia could heal and survive in natural condition. The phylogenetic analysis based on craniodental characters places Yubaartar as the immediate outgroup of Taeniolabidoidea, a group consisting of a North American clade and an Asian clade. This relationship indicates at least a faunal interchange of multituberculates before the K-Pg transition. The new evidence further supports the hypothesis that disparity in dental complexity, which relates to animal diets, increased with generic richness and disparity in body size, and that an adaptive shift towards increased herbivory across the K-Pg transitional interval.


Risk factors of postoperative ascites on hepatic resection for hepatocellular carcinoma.
The aim of this study was to identify the risk factors of the development of large amounts of ascites (LA) after hepatic resection for hepatocellular carcinoma (HCC). The medical records of 137 consecutive patients who underwent hepatic resection for HCC from January 2010 to December 2014 were retrospectively reviewed. Patients were divided into two groups: LA group, with ascites drainage >500 cc per day over 3 days (n=37) and control group (n=100). Preoperative and intraoperative clinical variables were compared between the two groups. Thirty-seven (27.0%) patients developed LA. Platelet counts of <100,000/mm3, ICG-R15 >10%, CTP scores of 6 or 7 points, major resection, the presence of cirrhosis, preoperative ascites, and portal hypertension were significantly more frequent in LA group. Multivariate analysis revealed that a higher CTP score (HR=4.1), the presence of portal hypertension (HR=26.7), and major resection (HR=18.5) were independent and significant risk factors of postoperative ascites development. Persistent refractory ascites developed in 6 (16.2%) patients who succumbed to hepatic failure during follow-up. Patients with a 6 or 7 point CTP score, major hepatic resection and/or portal hypertension were more likely to develop LA and experience deterioration of liver function after surgery. The selection of patients for hepatic resection should be based on a balanced assessment of the benefits of HCC treatment and risk of postoperative liver failure.


Recovery of visual field and acuity after removal of epiretinal and inner limiting membranes.
Visual acuity serves as only a rough gauge of macular function. The aim therefore was to ascertain whether central an assessment of the central visual field afforded a closer insight into visual function after removal of epiretinal membranes and Infracyanine-Green- or Trypan-Blue-assisted peeling of the inner limiting membrane. Fourty-three patients undergoing pars-plana vitrectomy for the removal of epimacular membranes and dye-assisted peeling of the inner limiting membrane using either Infracyanine Green (n = 29; group 1) or Trypan Blue (n = 14; group 2) were monitored prospectively for 12 months. Preoperatively, and 1, 6 and 12 months postoperatively, distance and reading visual acuities were evaluated; the central visual field was assessed by automated static perimetry. Twelve months after surgery, distance and reading visual acuities had improved in both groups, but to a significant degree only in Trypan-Blue-treated eyes. The difference between the two groups was not significant. Likewise at this juncture, the mean size of the visual-field defect remained unchanged in Trypan-Blue-treated eyes (preoperative: 4.3 (SD 2.1) dB; 12 months: 4.0 (2.1) dB (p = 0.15)), but had increased in Infracyanine-Green-treated ones (from 5.3 (3.7) dB to 8.0 (5.2) dB (p = 0.027)). Unlike visual acuity, the central visual field had deteriorated in Infracyanine-Green-treated eyes but not in Trypan-Blue-treated eyes 12 months after surgery. Hence, as a predictor of functional outcome, testing of the central visual field may be a more sensitive gauge than visual acuity. Furthermore, Infracyanine Green may have a chronic and potentially clinically relevant effect on the macula which is not reflected in the visual acuity.


MRI Assessment of Ischemic Lesion Evolution within White and Gray Matter.
In acute ischemic stroke (AIS), gray matter (GM) and white matter (WM) have different vulnerabilities to ischemia. Thus, we compared the evolution of ischemic lesions within WM and GM using MRI. From a European multicenter prospective database (I-KNOW), available T1-weighted images were identified for 50 patients presenting with an anterior AIS and a perfusion weighted imaging (PWI)/diffusion weighted imaging (DWI) mismatch ratio of 1.2 or more. Six lesion compartments were outlined: initial DWI (b = 1,000 s/mm2) lesion, initial PWI-DWI mismatch (Tmax >4 s and DWI-negative), final infarct mapped on 1-month fluid-attenuated inversion recovery (FLAIR) imaging, lesion growth between acute DWI and 1-month FLAIR, DWI lesion reversal at 1 month and salvaged mismatch. The WM and GM were segmented on T1-weighted images, and all images were co-registered within subjects to the baseline MRI. WM and GM proportions were calculated for each compartment. Fifty patients were eligible for the study. Median delay between symptom onset and baseline MRI was 140 min. The percentage of WM was significantly greater in the following compartments: initial mismatch (52.5 vs. 47.5%, p = 0.003), final infarct (56.7 vs. 43.3%, p < 0.001) and lesion growth (58.9 vs. 41.2%, p < 0.001). No significant difference was found between GM and WM percentages within the initial DWI lesion, DWI reversal and salvaged mismatch compartments. Ischemic lesions may extend preferentially within the WM. Specific therapeutic strategies targeting WM ischemic processes may deserve further investigation.


Whole Genome Amplification by T7-Based Linear Amplification of DNA (TLAD): I. CIP Treatment of Samples and Tailing Reaction with Terminal Transferase.
INTRODUCTIONT7-based linear amplification of DNA (TLAD) uses a linear amplification approach based on in vitro transcription (IVT) of template DNA by RNA polymerase from T7 phage. TLAD was designed for use with the ChIP-chip method (whereby DNA recovered from chromatin immunoprecipitation [ChIP] of cell lysate is used for subsequent analysis on DNA microarrays) and requires nanogram quantities of dsDNA to generate microgram amounts of amplified RNA. In Part I of the method, described here, a 3' conserved end is added to the template dsDNA, using terminal deoxynucleotidyl transferase (TdT) tailing. The initial treatment with calf intestinal phosphatase (CIP) is optional but strongly recommended for removing 3' phosphate groups, because most genomic DNA fragmentation methods (i.e., sonication, micrococcal nuclease digestion, and certain restriction digests) produce a significant proportion of 3' phosphate groups within the mixture of fragmented genomic DNA. This protocol is compatible with the presence of RNase A and can be carried out immediately after digestion of RNA carried over from ChIP, without any intermediate clean-up step. The tailing reaction involves the addition of a short (20-40 nucleotide [nt]) poly(dT) tail to the template DNA. The included dideoxynucleotide acts as a tail terminator in the reaction mixture and is necessary to maintain a tight size distribution. This poly(dT) tail provides a conserved 3' element that permits the addition of a T7 promoter sequence in the subsequent second-strand synthesis step. IVT can then use this newly appended T7 promoter and linearly amplify the template dsDNA, producing amplified RNA product.


Validation of the Japanese Version of the Fremantle Back Awareness Questionnaire in Patients with Low Back Pain.
There is a growing interest in the role of disturbed body perception in people with persistent pain problems such as chronic low back pain (CLBP). A questionnaire, the Fremantle Back Awareness Questionnaire (FreBAQ), was recently developed as a simple and quick way of assessing disturbed perceptual awareness of the back in people with CLBP and appears to have acceptable psychometric properties. The aim of the present study was to develop a Japanese version of the FreBAQ (FreBAQ-J) and evaluate its psychometric properties in a sample of Japanese people with low back pain (LBP). Translation of the FreBAQ into Japanese was conducted using a forward-backward method. One hundred participants with LBP completed the resultant FreBAQ-J. A subset of the participants completed the FreBAQ-J again 2 weeks later. Validity was investigated by examining the relationship between the FreBAQ-J and clinical valuables. Rasch analysis was used to assess targeting, category ordering, unidimensionality, person fit, internal consistency, and differential item functioning. The FreBAQ-J was significantly correlated with pain in motion, disability, pain-related catastrophizing, fear of movement, and anxiety symptomatology. The FreBAQ-J had acceptable internal consistency, a minor departure from unidimensionality, and good test-retest reliability, and was functional on the category rating scale. The FreBAQ-J has acceptable psychometric properties and is suitable for use in people with LBP. Participants with high levels of disturbed body perception are well targeted by the scale. The functioning of one item (item 8) was poor. Further study is warranted to confirm if this item should be excluded.


Melioidosis: the great mimicker presenting as spondylodiscitis.
Melioidosis, a syndrome with protean clinical manifestations, is caused by Gram-negative soil saprophyte Burkholderiapseudomallei Among its diverse clinical presentations, the involvement of spine is a rare phenomenon and can mimic tuberculosis on presentation. A 65-year-old female with a known case of diabetes presented with fever with lower back pain. Blood culture grew Staphylococcus aureus, and as per sensitivity report, clindamycin and cefazolin were started. X-ray and MRI lumbosacral spine showed spondylodiscitis (likely Koch's). Decompression and biopsy were done, and a sample was sent for microbiological investigations that showed no growth of any significant pathogen; furthermore, all tests for tuberculosis diagnosis also remained negative. Active Melioidosis Detect Lateral Flow Assay was used on the tissue sample, which was positive for B. pseudomallei Capsular Polysaccharide (CPS) antigen; the case was confirmed by typethree secretion system 1 PCR for melioidosis. Antibiotics were changed to parenteral ceftazidime for 2 weeks followed by oral cotrimoxazole. A dedicated team of microbiologists and physicians is required to identify and treat the disease.


Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment.
Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29-14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni.


Ethics education for clinician-researchers in genetics: The combined approach.
Advancements in genomic technology and genetic research have uncovered new and unforeseen ethical and legal issues that must now be faced by clinician-researchers. However, lack of adequate ethical training places clinician-researchers in a position where they might be unable to effectively assess and resolve the issues presented to them. The literature demonstrates that ethics education is relevant and engaging where it is targeted to the level and context of the learners, and it includes real-world based cases approached in innovative ways. In order to test the feasibility of a combined approach to ethics education, a conference was held in 2012 to raise awareness and familiarize participants with the ethical and legal issues surrounding medical technology in genetics and then to have them apply this to reality-based case studies. The conference included participants from a variety of backgrounds and was divided into three sections: (i) informative presentations by experts in the field; (ii) mock REB deliberations; and (iii) a second mock-REB, conducted by a panel of experts. Feedback from participants was positive and indicated that they felt the learning objectives had been met and that the material was presented in a clear and organized fashion. Although only an example of the combined approach in a particular setting, the success of this conference suggests that combining small group learning, practical cases, role-play and interdisciplinary learning provides a positive experience and is an effective approach to ethics education.


Salvage video-assisted thoracoscopic lobectomy for isolated local relapse after stereotactic body radiotherapy for early stage non-small cell lung cancer: technical aspects and perioperative management.
Limited data is available on salvage surgery for local relapse (LR) after stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC). We aimed to characterize treatment options and clarify long-term outcomes of isolated LR after SBRT for patients with clinical stage I NSCLC. Herein, we discuss technical aspects, perioperative management, and postoperative follow-up of two patients of the 12 patients undergoing salvage surgery for LR after SBRT at Kyoto University between 1999 and 2013. A 76-year-old male, 15 months after SBRT, underwent a salvage right upper lobectomy combined with adjacent right lower lobe wedge resection via video-assisted thoracoscopic surgery (VATS) for a 5.0-cm mass. Local recurrence was found 5 years after salvage surgery and treated with repeat SBRT, however he died from multiple distant metastases. An 85-year-old male, 14 months after SBRT, underwent a salvage left upper lobectomy via VATS for a 3.5-cm mass. Moderate intrapleural adhesion was noted and required careful dissection on the mediastinum. He is alive with no recurrence at 2 years from salvage surgery. Salvage VATS lobectomy was feasible after SBRT in two patients. Long-term follow-up and continued discussions at multidisciplinary conferences are required.


Functional characterization of the rice UDP-glucose 4-epimerase 1, OsUGE1: a potential role in cell wall carbohydrate partitioning during limiting nitrogen conditions.
Plants grown under inadequate mineralized nitrogen (N) levels undergo N and carbon (C) metabolic re-programming which leads to significant changes in both soluble and insoluble carbohydrate profiles. However, relatively little information is available on the genetic factors controlling carbohydrate partitioning during adaptation to N-limitation conditions in plants. A gene encoding a uridine-diphospho-(UDP)-glucose 4-epimerase (OsUGE-1) from rice (Oryza sativa) was found to be N-responsive. We developed transgenic rice plants to constitutively over-express the OsUGE-1 gene (OsUGE1-OX1-2). The transgenic rice lines were similar in size to wild-type plants at the vegetative stage and at maturity regardless of the N-level tested. However, OsUGE1-OX lines maintained 18-24% more sucrose and 12-22% less cellulose in shoots compared to wild-type when subjected to sub-optimal N-levels. Interestingly, OsUGE1-OX lines maintained proportionally more galactose and glucose in the hemicellulosic polysaccharide profile of plants compared to wild-type plants when grown under low N. The altered cell wall C-partitioning during N-limitation in the OsUGE1-OX lines appears to be mediated by OsUGE1 via the repression of the cellulose synthesis associated genes, OsSus1, OsCesA4, 7, and 9. This relationship may implicate a novel control point for the deposition of UDP-glucose to the complex polysaccharide profiles of rice cell walls. However, a direct relationship between OsUGE1 and cell wall C-partitioning during N-limitation requires further investigation.


The functional role of interhemispheric synchronization in the control of bimanual timing tasks.
The aim of the present study was to investigate whether synchronized activity between the right and left primary sensorimotor cortices has a functional role in the organization of bimanual in-phase and anti-phase movement patterns, performed at different cycling frequencies. To this end we evaluated the cortical dynamics by means of task-related EEG. Both behavioral performance and coupling between the primary sensorimotor cortices in the beta frequency band were reduced with increasing movement speed, and this effect was far more powerful in the anti-phase than in-phase mode. Thus, a progressive degradation of interhemispheric connectivity with cycling rate was associated with a deteriorating behavioral output. Overall, these results support a significant role for interhemispheric synchronization in the control of bimanual movements.


Disclosing information about the self is intrinsically rewarding.
Humans devote 30-40% of speech output solely to informing others of their own subjective experiences. What drives this propensity for disclosure? Here, we test recent theories that individuals place high subjective value on opportunities to communicate their thoughts and feelings to others and that doing so engages neural and cognitive mechanisms associated with reward. Five studies provided support for this hypothesis. Self-disclosure was strongly associated with increased activation in brain regions that form the mesolimbic dopamine system, including the nucleus accumbens and ventral tegmental area. Moreover, individuals were willing to forgo money to disclose about the self. Two additional studies demonstrated that these effects stemmed from the independent value that individuals placed on self-referential thought and on simply sharing information with others. Together, these findings suggest that the human tendency to convey information about personal experience may arise from the intrinsic value associated with self-disclosure.


Blunted natriuretic response to a high-sodium meal in obese dogs. Role of renal nerves.
Although the relation between body weight and arterial pressure is well established, the mechanisms involved in the pathogenesis of obesity-related hypertension are unclear. However, recent studies suggest that abnormalities in renal function may be involved. The purpose of this study was to test the hypothesis that obese animals have a reduced ability to excrete a sodium load as a result of abnormal renal nerve function. To quantify the role of renal nerves, we examined changes in renal hemodynamics and sodium excretion in response to a high-sodium meal (200 mmol Na) in separate innervated and denervated kidneys simultaneously within the same conscious dog. Two surgically designed hemibladders with indwelling catheters were used to collect urine from innervated and denervated kidneys of the same dog. Body weight averaged 19.9 +/- 1.0 kg in the control lean dogs and 25.1 +/- 1.1 kg in the obese dogs. Arterial pressure averaged 101 +/- 4 mm Hg in the obese dogs and 90 +/- 4 mm Hg in the lean dogs. In response to the high-sodium meal in lean dogs, urinary sodium excretion increased from 20.8 +/- 4.2 to 189.7 +/- 21.2 mumol/min in the innervated kidneys and from 25.3 +/- 5.9 to 194.8 +/- 26.9 mumol/min in the denervated kidneys. In contrast, urinary sodium excretion in obese dogs increased from 9.6 +/- 1.4 to 129.9 +/- 34.3 mumol/min in the innervated kidneys and from 18.4 +/- 3.7 to 125.2 +/- 30.5 mumol/min in the denervated kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)


Essential and nonessential amino acids in appropriate and small for gestational age fetuses with congenital cytomegalovirus infection.
The aim of the study was to evaluate the correlation between valine and glycine, representatives of essential and nonessential amino acids, in appropriate and small fetuses for gestational age with congenital cytomegalovirus (CMV) infection. Umbilical venous cord blood was obtained by cordocentesis at 22 to 29 weeks' gestation from 18 women (11 in appropriate for gestational age (AGA) -A, and 7 in small for gestational age (SGA) -B) fetuses with CMV infection. Plasma amino acids were measured with a Beckman M 121 amino acid analyzer. Maternal valine level was 136.0 mmol/l; fetal valine in AGA and SGA fetuses: 219 and 189 mmol/l, respectively. Fetomaternal valine ratio was significantly lower in the SGA group (1.39 mmol/l-SGA, 1.61 mmol/l AGA, t = 6.9 p < 0.001). The glycine level in maternal blood was 139.0 mmol/l; fetal in SGA and AGA fetuses 137 mmol/l, and 176 mmol/l, respectively. The fetomaternal glycine ratio was also significantly lower in the SGA group than in AGA. 1.01 and 1.27, respectively (t = -2.96, p < 0.001). Valine/glycine maternal and fetal ratio did not show any difference between groups. In the congenital CMV infected fetuses with intrauterine growth retardation there were decreased valine and glycine levels compared to the congenitally CMV infected fetuses with normal intrauterine growth. There was a lower fetal concentration of these amino acids compared to the maternal level in SGA fetuses. A decreased glycine level compared to the valine level has also been found in congenitally CMV infected fetuses with intrauterine growth retardation.


Secondary patenting of branded pharmaceuticals: a case study of how patents on two HIV drugs could be extended for decades.
Pharmaceutical manufacturers rely on patents to protect their intellectual property and often seek to extend market exclusivity for their products to maximize their return on investment. One method is by obtaining patents on features other than the original active drug ingredient, including secondary patents on alternate formulations of the drug or on methods of administration. This article examines how secondary patents can extend market exclusivity and thus delay generic competition, using as an example two key antiretroviral drugs for the management of HIV: ritonavir (Norvir) and lopinavir/ritonavir (Kaletra). We identified 108 patents, which together could delay generic competition until at least 2028--twelve years after the expiration of the patents on the drugs' base compounds and thirty-nine years after the first patents on ritonavir were filed. Some of the secondary patents that were reviewed were found to be of questionable inventiveness. We argue that increased transparency for existing patents, stricter patentability standards, and increased opportunities to challenge patent applications and patents could reduce inappropriate market exclusivity extensions on brand-name drugs and open the door to lower-cost generics.


Home endotoxin exposure and wheeze in infants: correction for bias due to exposure measurement error.
Exposure to elevated levels of endotoxin in family-room dust was previously observed to be significantly associated with increased wheeze in the first year of life among a cohort of 404 children in the Boston, Massachusetts, metropolitan area. However, it is likely that family-room dust endotoxin was a surrogate for airborne endotoxin exposure. Therefore, a related substudy characterized the relationship between levels of airborne household endotoxin and the level of endotoxin present in house dust, in addition to identifying other significant predictors of airborne endotoxin in the home. We now reexamine the relationship between endotoxin exposure and wheeze under the assumption that the level of airborne endotoxin in the home is the exposure of interest and that the amount of endotoxin in household dust is a surrogate for this exposure. We applied a measurement error correction technique, using all available data to estimate the effect of endotoxin exposure in terms of airborne concentration and accounting for the measurement error induced by using house-dust endotoxin as a surrogate measure in the portion of the data in which airborne endotoxin could not be directly measured. After adjusting for confounding by lower respiratory infection status and race/ethnicity, endotoxin exposure was found to be significantly associated with a nearly 6-fold increase in prevalence of wheeze for a one interquartile range increase in airborne endotoxin (95% confidence interval, 1.2-26) among the 360 children in households with dust endotoxin levels between the 5th and 95th percentiles.


Neural migration. Structures of netrin-1 bound to two receptors provide insight into its axon guidance mechanism.
Netrins are secreted proteins that regulate axon guidance and neuronal migration. Deleted in colorectal cancer (DCC) is a well-established netrin-1 receptor mediating attractive responses. We provide evidence that its close relative neogenin is also a functional netrin-1 receptor that acts with DCC to mediate guidance in vivo. We determined the structures of a functional netrin-1 region, alone and in complexes with neogenin or DCC. Netrin-1 has a rigid elongated structure containing two receptor-binding sites at opposite ends through which it brings together receptor molecules. The ligand/receptor complexes reveal two distinct architectures: a 2:2 heterotetramer and a continuous ligand/receptor assembly. The differences result from different lengths of the linker connecting receptor domains fibronectin type III domain 4 (FN4) and FN5, which differs among DCC and neogenin splice variants, providing a basis for diverse signaling outcomes.


American Society of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards.
Standardization of care can reduce the risk of errors, increase efficiency, and provide a framework for best practice. In 2008, the American Society of Clinical Oncology (ASCO) and the Oncology Nursing Society (ONS) invited a broad range of stakeholders to create a set of standards for the administration of chemotherapy to adult patients in the outpatient setting. At the close of a full-day structured workshop, 64 draft standards were proposed. After a formal process of electronic voting and conference calls, 29 draft standards were eliminated, resulting in a final list of 35 draft measures. The proposed set of standards was posted for 6 weeks of open public comment. Three hundred twenty-two comments were reviewed by the Steering Group and used as the basis for final editing to a final set of standards. The final list includes 31 standards encompassing seven domains, which include the following: review of clinical information and selection of a treatment regimen; treatment planning and informed consent; ordering of treatment; drug preparation; assessment of treatment compliance; administration and monitoring; assessment of response and toxicity monitoring. Adherence to ASCO and ONS standards for safe chemotherapy administration should be a goal of all providers of adult cancer care.


Long-term Kidney Transplant Outcomes in Primary Glomerulonephritis: Analysis From the ERA-EDTA Registry.
We evaluated the 15-year kidney allograft survival in patients with primary glomerulonephritis and determined if the risk of graft loss varied with donor source within each glomerulonephritis group. Using data from the European Renal Association-European Dialysis and Transplant Association Registry, Kaplan-Meier, competing risk, and Cox regression analyses were performed on adult, first kidney transplant recipients during 1991 to 2010 (n = 14 383). Follow-up was set to December 31, 2011. Adjustments for pretransplant dialysis duration, sex, country, and transplant era were made. "Death-adjusted graft survival" was assessed in patients with glomerulonephritis and compared with those with autosomal dominant polycystic kidney disease (ADPKD), in which the native kidney disease cannot recur. Additionally, death-adjusted graft survival was compared between living and deceased donor transplants within each glomerulonephritis group. All glomerulonephritides had a 15-year death-adjusted graft survival probability above 55%. The 15-year risk of death-adjusted graft failure compared to ADPKD ranged from 1.17 (95% confidence interval [95% CI], 1.05-1.31) for immunoglobulin A nephropathy to 2.09 (95% CI, 1.56-2.78) for membranoproliferative glomerulonephritis type II. The expected survival benefits of living over deceased donor transplants were not present in membranoproliferative glomerulonephritis type I (adjusted hazard ratios [HRa], 1.08; 95% CI, 0.73-1.60) or type II (HRa, 0.90; 95% CI, 0.32-2.52) but present in immunoglobulin A nephropathy (HRa, 0.74; 95% CI, 0.59-0.92), membranous nephropathy (HRa, 0.47; 95% CI, 0.29-0.75), and focal segmental glomerulosclerosis (HRa, 0.69; 95% CI, 0.45-1.06). This large European study shows favorable long-term kidney graft survival in all primary glomerulonephritides, although this remains lower than graft survival in ADPKD, and confirms that the reluctance to use living donors in some primary glomerulonephritides remains unfounded. These data will further inform prospective renal transplant recipients and donors during pretransplant counselling.


Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study.
Glutathione plays crucial roles in the detoxification and antioxidant systems of cells and has been used to treat acute poisoning and chronic liver diseases by intravenous injection. This is a first study examining the therapeutic effects of oral administration of glutathione in patients with nonalcoholic fatty liver disease (NAFLD). The study was an open label, single arm, multicenter, pilot trial. Thirty-four NAFLD patients diagnosed using ultrasonography were prospectively evaluated. All patients first underwent intervention to improve their lifestyle habits (diet and exercise) for 3 months, followed by treatment with glutathione (300 mg/day) for 4 months. We evaluated their clinical parameters before and after glutathione treatment. We also quantified liver fat and fibrosis using vibration-controlled transient elastography. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels. Twenty-nine patients finished the protocol. ALT levels significantly decreased following treatment with glutathione for 4 months. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased with glutathione treatment. Following dichotomization of ALT responders based on a median 12.9% decrease from baseline, we found that ALT responders were younger in age and did not have severe diabetes compared with ALT non-responders. The controlled attenuation parameter also decreased in ALT responders. This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy. UMIN000011118 (date of registration: July 4, 2013).


Machinability of Rene 65 Superalloy.
Nickel-based superalloys are heavily used in the aerospace and power industries due to their excellent material and mechanical properties. They offer high strength at elevated temperatures, high hardness, corrosion resistance, thermal stability and improved fatigue properties. These superalloys were developed to address the demand for materials with the enhanced heat and stress capabilities needed to increase operational temperatures and speeds in jet and turbine engines. However, most of these properties come with machining difficulty, high wear rate, increased force and poor surface finish. Rene 65 is one of the next generation wrought nickel superalloys that addresses these demands at a reduced cost versus powder metallurgy superalloys. It is strengthened by the presence of gamma prime precipitates in its microstructure, which enhance its strength at high temperatures. Notwithstanding its advantages, Rene 65 must also deal with the reality of the poor workability and machinability generally associated with Ni-based superalloys. This study examines the machinability-using drilling tests-of Rene 65 and seeks to establish the influence of hardness (with varying microstructure) and cutting conditions on machinability indicators (surface finish, forces and chip formation). The experimental setup is based on a set of experimental drilling tests using three different heat-treated samples of varying hardness. The results indicate a negligible effect from material hardness, ranging from 41 HRC to 52 HRC, on generated cutting forces and a similarly low effect from cutting speeds. The feed rate was identified as the main factor of relevance in cutting force and chip morphology during the machining of this new superalloy.


Computed tomography of hereditary multifocal renal cystadenocarcinomas in German shepherd dogs.
The purpose of the study was to characterize the renal lesions of hereditary renal cystadenocarcinomas in the German shepherd dog using computed tomography (CT). Fourteen dogs with renal cystadenocarcinomas and nodular dermatofibrosis, and two unaffected dogs were studied. There were nine dogs with spontaneous disease and seven dogs from a test mating. The characteristic renal CT findings of renal cystadenocarcinomas were bilateral multiple cysts and tumor masses of various sizes. The earliest changes were detected between 4 and 5 years of age and the smallest cysts measured 2-3 mm in diameter. Abdominal CT examination gives a wide field view and excellent anatomic images of the kidneys. It is easy to differentiate between cysts and solid tumors. CT examination is useful for the early detection of renal cystadenocarcinomas and for screening suspected carrier dogs before breeding.


Tumor suppressor function of the interferon-induced double-stranded RNA-activated protein kinase.
RNA-dependent protein kinase is a M(r) 68,000 protein in human cells (p68 kinase) or a M(r) 65,000 protein in murine cells (p65 kinase). p65/p68 is a serine/threonine kinase induced by interferon treatment and generally activated by double-stranded RNAs. Once activated, the known function of this kinase is inhibition of protein synthesis through phosphorylation of the eukaryotic initiation factor 2. Here we have investigated the potential for tumorigenicity in mice of murine NIH 3T3 clones expressing human p68 kinase, either the wild-type or a mutant inactive kinase with a single amino acid substitution in the invariant lysine-296 in the catalytic domain II. Expression of the mutant p68 kinase was correlated with a malignant transformation phenotype, giving rise to the production of large tumors of at least 1 cm in diameter within 7-12 days in all inoculated mice. In contrast, no tumor growth was observed for several weeks in mice inoculated with NIH 3T3 cell clones expressing either the wild-type recombinant p68 kinase or only the endogenous p65 kinase, the murine analogue of the p68 kinase. These results suggest that functional p65/p68 kinase (recently called PKR), by a still undefined mechanism, may also act as a tumor suppressor. Consequently, one of the pathways by which interferon inhibits tumor growth might be through its capacity to induce the enhanced expression of this kinase.


Increased energy expenditure but decreased stress responsiveness during molt.
Baseline and stress-induced corticosterone (CORT), heart rate (fH), and energy expenditure were measured in eight captive European starlings Sturnus vulgaris during and following a prebasic molt. The fH and oxygen consumption (V O2 ) were measured simultaneously across a range of heart rates, and energy expenditure (kJ/d) was then calculated from data. Energy expenditure and fH were strongly and positively correlated in each individual. Baseline fH and energy expenditure were significantly higher during molt. Molting starlings expended 32% more energy over 24 h than nonmolting birds, with the most significant increase (60%) occurring at night, indicating a substantial energetic cost to molt. Furthermore, the cardiac and metabolic responses to stress during molt were different than during nonmolt. Birds were subjected to four different 30-min acute stressors. The fH and CORT responses to these stressors were generally lower during molt. Although restraint caused a 64% increase in daily energy expenditure during nonmolt, no other stressor caused a significant increase in energy expenditure. Overall, our data suggest that molt is not only energetically expensive but that it also alters multiple stress response pathways. Furthermore, most acute stressors do not appear to require a significant increase in energy expenditure.


Field trial of a new aeration system for enhancing biodegradation in a biopile.
The influence of a new aeration system on the biopile performance was investigated. The purpose was to increase biodegradation efficiency by optimising airflow through the pile. During a 1-month field trial, the performance of a new system using two perforated vertical pipes with wind-driven turbines was compared with that of a standard pile configuration with two horizontal perforated pipes. Both piles were composed of a similar mix of diesel-contaminated soils, woodchips, compost and NPK fertiliser. Hydrocarbons were recovered using solvent extraction, and determined both gravimetrically and by gas chromatography. Total heterotrophs, pH and moisture content were also assessed. Air pressure measurements were made to compare the efficiency of suction in the pipes. Results at the end of the experiment showed that there was no significant difference between the two piles in the total amount of hydrocarbon biodegradation. The normalised degradation rate was, however, considerably higher in the new system than in the standard one, suggesting that the vertical venting method may have improved the efficiency of the biological reactions in the pile. The pressure measurements showed a significant improvement in the suction produced by the new aeration system. However, many factors other than the airflow (oxygen supply) may influence and limit the biodegradation rates, including moisture content, age of contaminants and the climatic conditions. Additional experiments and modelling need to be carried out to explore further the new aeration method and to develop criteria and guidelines for engineering design of optimal aeration schemes in order to achieve maximum biodegradation in biopiles.


Pre-exposure Prophylaxis Awareness and Use Among Cisgender Men Who Have Sex With Men and Use Methamphetamine in 3 Western US Cities.
In the United States, cisgender men who have sex with men (MSM) who use methamphetamine are at substantial risk for HIV and can benefit from pre-exposure prophylaxis (PrEP). We used data from the National HIV Behavioral Surveillance 2017 survey from Seattle, WA; Portland, OR; and Denver, CO, to estimate PrEP awareness and use in the past 12 months among MSM who use methamphetamine. We then compared these estimates with participants who do not use methamphetamine but meet other criteria for PrEP use (i.e., condomless anal sex or a bacterial sexually transmitted infection). We explored reasons for not using PrEP and challenges using PrEP. Of the 1602 MSM who participated in the 2017 National HIV Behavioral Surveillance survey in Seattle, WA; Portland, OR; and Denver, CO, 881 met the inclusion criteria for this study, of whom 88 (10%) reported methamphetamine use in the past 12 months. Most (95%) participants had heard of PrEP, and 35% had used it in the past 12 months. Pre-exposure prophylaxis awareness was lower among MSM who used methamphetamine (P = 0.01), but use was not different (P = 0.26). Among those who had not used PrEP, the most common reason for not using it was not thinking one's HIV risk was high enough (51%). Men who have sex with men who used methamphetamine were more likely to report that they were not sure PrEP would prevent them from getting HIV (38% vs. 19%, P = 0.002). These results highlight the need for continued efforts to educate and promote PrEP uptake among MSM, particularly those who use methamphetamine.


Preventing type 2 diabetes: systematic review of studies of cost-effectiveness of lifestyle programmes and metformin, with and without screening, for pre-diabetes.
Explore the cost-effectiveness of lifestyle interventions and metformin in reducing subsequent incidence of type 2 diabetes, both alone and in combination with a screening programme to identify high-risk individuals. Systematic review of economic evaluations. Database searches (Embase, Medline, PreMedline, NHS EED) and citation tracking identified economic evaluations of lifestyle interventions or metformin alone or in combination with screening programmes in people at high risk of developing diabetes. The International Society for Pharmaco-economics and Outcomes Research's Questionnaire to Assess Relevance and Credibility of Modelling Studies for Informing Healthcare Decision Making was used to assess study quality. 27 studies were included; all had evaluated lifestyle interventions and 12 also evaluated metformin. Primary studies exhibited considerable heterogeneity in definitions of pre-diabetes and intensity and duration of lifestyle programmes. Lifestyle programmes and metformin appeared to be cost effective in preventing diabetes in high-risk individuals (median incremental cost-effectiveness ratios of £7490/quality-adjusted life-year (QALY) and £8428/QALY, respectively) but economic estimates varied widely between studies. Intervention-only programmes were in general more cost effective than programmes that also included a screening component. The longer the period evaluated, the more cost-effective interventions appeared. In the few studies that evaluated other economic considerations, budget impact of prevention programmes was moderate (0.13%-0.2% of total healthcare budget), financial payoffs were delayed (by 9-14 years) and impact on incident cases of diabetes was limited (0.1%-1.6% reduction). There was insufficient evidence to answer the question of (1) whether lifestyle programmes are more cost effective than metformin or (2) whether low-intensity lifestyle interventions are more cost effective than the more intensive lifestyle programmes that were tested in trials. The economics of preventing diabetes are complex. There is some evidence that diabetes prevention programmes are cost effective, but the evidence base to date provides few clear answers regarding design of prevention programmes because of differences in denominator populations, definitions, interventions and modelling assumptions.


Distinct types of IgG and IgA anti-intercellular autoantibodies from patients with pemphigus and vesiculopustular dermatosis.
The pattern of binding of two different types of IgA class pemphigus-like antibodies was compared with that of the true IgG class pemphigus antibody. The IgG antibodies from pemphigus vulgaris (PV) and pemphigus foliaceus (PF) sera bound to the intercellular spaces in normal human epidermis, whereas only the PV antibody reacted with monolayers of keratinocytes derived from human foreskin. Both IgG and IgA antibodies from a patient with PF were found in the intercellular spaces of the epidermis and only the IgA antibody reacted with the cultured keratinocytes. The IgA antibody from a patient with a vesiculopustular eruption and whose serum contained IgA intercellular space antibody alone, bound to the upper epidermis but not to the monolayers of keratinocytes. These findings indicate that PV but not PF antigens can be expressed by monolayers of cultured human keratinocytes and that there are at least two distinct types of IgA intercellular antibodies.


Observing the devastating coffee berry borer (Hypothenemus hampei) inside the coffee berry using micro-computed tomography.
The coffee berry borer is the most devastating insect pest of coffee throughout the world. The insect spends most of its life cycle inside the coffee berry, which makes it quite difficult to observe its behaviour. Micro-computed tomography (micro-CT) was used to observe all developmental stages of the coffee berry borer inside coffee berries (Coffea canephora). An interesting oviposition pattern involving a sequential placement of eggs starting in the periphery of the seed and moving inwards was observed. Micro-CT should be useful in elucidating unknown life history aspects of other seed-feeding bark beetles as well as of bark and ambrosia beetles in general.


Mapping of resection margins of oral cancer for p53 overexpression and chromosome instability to detect residual (pre)malignant cells.
Oral squamous cell cancers (OSCCs) have a high local recurrence rate, partly due to problems in the recognition of minimal residual disease. The use of molecular markers is shown to increase the sensitivity of detection of residual malignant cells in tumour margins of OSCC. p53 immunohistochemistry was combined with in situ hybridization for chromosomes 1 and 7 to determine the presence of genetically unstable cells in resection specimens of OSCC containing invasive cancer. An increased frequency of genetically aberrant cells was observed, as detected by p53 overexpression and/or aneusomy, with histological progression of normal mucosa via hyperplasia to dysplasia. Of clinical importance was the finding that 11 of 20 resection margins, all of which were initially diagnosed as being tumour-free, were found to contain genetically aberrant (pre)malignant cells. In these areas, closer histological examination of the genetically aberrant compartment within these margins often also revealed small dysplastic areas that were missed in the initial diagnosis, showing that this genetic approach can assist in diagnosis.


Induction of serum- and glucocorticoid-induced kinase-1 (SGK1) by cAMP regulates increases in alpha-ENaC.
Alpha-ENaC expression and activity is regulated by a variety of hormones including beta-adrenergic agonists via the second messenger cAMP. We evaluated the early intermediate pathways involved in the up-regulation of SGK1 by DbcAMP and whether SGK1 is a prerequisite for induction of alpha-ENaC expression. Submandibular gland epithelial (SMG-C6) cells treated with DbcAMP (1 mM) induced both SGK1 mRNA and protein expression. DbcAMP-stimulated SGK1 mRNA expression was decreased by actinomycin D and mRNA and protein expressions were attenuated by PKA inhibitors (H-89 and KT5720). Inhibition of PI3-K with either LY294002 or dominant negative PI3-K reduced DbcAMP-stimulated SGK1 protein and mRNA levels, attenuated the phosphorylation of CREB (a cAMP-activated transcription factor) and decreased alpha-ENaC protein levels and Na(+) transport. In addition, the combination of PKA inhibitors with dominant negative PI3-K synergistically inhibited DbcAMP-induced Na(+) transport. Inhibition of SGK1 expression by siRNA decreased but did not obliterate DbcAMP-induced alpha-ENaC expression. Thus, in a cell line which endogenously exhibits minimal alpha-ENaC expression, induction of SGK1 by DbcAMP occurs via the PI3-K and PKA pathways. Increased alpha-ENaC levels and function are partly dependent upon the early induction of SGK1 expression.


Ankle paresis in incomplete spinal cord injury: relation to corticospinal conductivity and ambulatory capacity.
There is limited data on the relation of corticospinal tract conductivity to clinical measures in incomplete spinal cord injury. This study examined the relationship of muscle strength to corticospinal tract input assessed by motor evoked potentials (MEPs) during static and dynamic conditions and to gait. Dorsiflexor strength was established by manual muscle test, maximal voluntary contraction, and maximal movement velocity, the latter being acquired during auditory-paced ankle movements. MEPs were elicited during isometric contractions with constant or continuously increasing ankle joint torque. Gait was assessed by quantifying its speed and independence. Linear regression analyses showed that maximal movement velocity was related to the MEP latencies and amplitudes in the dynamic condition (R(2)(adj.) = 0.62) and to the MEP latencies in the static condition (R(2)(adj.) = 0.45). Maximal voluntary contraction was only related to the MEP latencies in the static (R(2)(adj.) = 0.45) and the dynamic condition (R(2)(adj.) = 0.21), whereas manual muscle test did not show any relationship to the MEPs. In incomplete spinal cord injury patients, the dynamic measure maximal movement velocity might be a useful clinical assessment of corticospinal tract function. Clinical studies on recovery and repair of corticospinal tract function in spinal lesions could substantially benefit from implementing dynamic measures in the clinical assessment protocol.


Cytokine gene polymorphisms in type I and type II reactions in Hansen's disease.
Leprosy or Hansen's disease is a chronic debilitating disease caused by Mycobacterium leprae. Host genetics are believed to strongly influence the course of the disease. It is known that cytokines play an important role in leprosy and cytokine gene polymorphisms probably influence the course of the disease. In the present study, we evaluated 70 patients with leprosy and 243 controls. DNA was extracted from the peripheral blood and genotyping was done for the following polymorphisms: IL-1 RA intron 2, IL-1β-511 C/T and TNF-α A/G. A strong association of TNF-α-308 G/A polymorphism with Hansen's disease with both genotypes and alleles was found. However, no correlation was identified between the other two polymorphisms and Hansen's disease. A strong association between the IL-1β gene polymorphisms and the type of reactions seen in leprosy was found. In contrast, the other two polymorphisms did not show any such association. Genetic polymorphisms are association studies. They are not a direct reflection of the transcriptome or proteome and this is a major limitation of this study. In conclusion, cytokine gene polymorphisms appear to influence the susceptibility and course of Hansen's disease. An evaluation of the cytokine levels in the skin during lepra reactions would confirm this observation. Possibly, in future, this would be a guide to therapeutic decisions in cases of lepra reactions.


The effect of back squat depth on the EMG activity of 4 superficial hip and thigh muscles.
The purpose of this study was to measure the relative contributions of 4 hip and thigh muscles while performing squats at 3 depths. Ten experienced lifters performed randomized trials of squats at partial, parallel, and full depths, using 100-125% of body weight as resistance. Electromyographic (EMG) surface electrodes were placed on the vastus medialis (VMO), the vastus lateralis, (VL), the biceps femoris (BF), and the gluteus maximus (GM). EMG data were quantified by integration and expressed as a percentage of the total electrical activity of the 4 muscles. Analysis of variance (ANOVA) and Tukey post hoc tests indicated a significant difference (p < 0.001*, p = 0.056**) in the relative contribution of the GM during the concentric phases among the partial- (16.9%*), parallel- (28.0%**), and full-depth (35.4%*) squats. There were no significant differences between the relative contributions of the BF, the VMO, and the VL at different squatting depths during this phase. The results suggest that the GM, rather than the BF, the VMO, or the VL, becomes more active in concentric contraction as squat depth increases.


Onyx embolization of carotid-cavernous fistulas.
The authors conducted a study to determine the safety and efficacy of embolization of carotid-cavernous fistulas (CCFs) with the ethylene vinyl alcohol copolymer, Onyx. They prospectively collected data in all patients with CCFs who underwent Onyx-based embolization at their institution over a 3-year period. The type of fistula, route of embolization, viscosity of Onyx, additional use of coils, extent of embolization, procedural complications, and clinical follow-up were recorded. A total of 12 patients (5 men and 7 women who were age 24-88 years) underwent embolization in which Onyx was used. There were 1 Barrow Type A, 1 Type B, 3 Type C, and 7 Type D fistulas. Embolization was performed via a transvenous route in 8 cases and a transarterial route in 4 cases. Onyx 34 was used in all but 2 cases: a direct Type A fistula embolized with Onyx 500 and an indirect Type C fistula embolized with Onyx 18. Adjuvant embolization with framing coils was performed in 7 cases. All procedures were completed in a single session. Immediate fistula obliteration was achieved in all cases. Clinical resolution of presenting symptoms occurred in 100% of the patients by 2 months. Neurological complications occurred in 3 patients. One patient developed a complete cranial nerve (CN) VII palsy that has not resolved. Two patients developed transient neuropathies--1 a Horner syndrome and partial CN VI palsy, and 1 a complete CN III and partial CN V palsy. Radiographic follow-up (mean 16 months, range 4-35 months) was available in 6 patients with complete resolution of the lesion in all. Onyx is a liquid embolic agent that is effective in the treatment of CCFs but not without hazards. Postembolization cavernous sinus thrombosis and swelling may result in transient compressive cranial neuropathies. The inherent gradual polymerization properties of Onyx allow for casting of the cavernous sinus but may potentially result in deep penetration within arterial collaterals that can cause CN ischemia/infarction. Although not proven, the angiotoxic effects of dimethyl sulfoxide may also play a role in postembolization CN deficits.


Former patients' experiences of recovery from self-harm as an individual, prolonged learning process: a phenomenological hermeneutical study.
To explore, describe and understand former patients' experiences of recovery from self-harm. Previous research shows that a person's development towards a more secure self-image, mastery of their emotions, an understanding of what triggers self-harm and mastery of new ways to cope with problems are central to recovery. Recovery from self-harm is still a relatively new field of research. A phenomenological hermeneutical approach. Eight participants were interviewed in 2013. Inclusion criteria were as follows: to have committed no self-harm during the past 2 years, to have experienced recovery and to be 18 or older. We analysed data using a phenomenological hermeneutical method. The findings resulted in three themes with subthemes. The first theme, the turning point, occurred at the start of the recovery process. Participants learned to choose life, verbally express their inner pain and reconcile with their life histories. In the second theme, coping with everyday life, participants learned how to choose alternative actions instead of self-harm and attend to their basic, physical needs. In the third theme, valuing close relationships and relationships with mental health nurses, participants learned to receive support from close relationships with others and mental health nurses. A tentative model illustrates the comprehensive understanding of the recovery process, described as an individual, prolonged learning process. To achieve recovery, persons who self-harm need guidance and knowledge of how to realize a personal learning process. More research is needed on how mental health nurses can support individual transition processes and thereby facilitate recovery.