Narrowband, high power light from diode lasers.
We have used a 100-mW cw laser diode array to amplify the light from a low power, single stripe diode laser (both lasers commercially available). The input light was spectrally narrowed and frequency stabilized to <300 kHz using optical feedback from a Fabry-Perot cavity, and the amplified beam had the same spectral characteristics. Also, the ~90-mW amplified beam had a single diffraction-limited spatial mode corresponding to the full 100-microm width of the array, indicating that all its stripes were coherent. When viewing the output of the free-running laser array, we observe that the input light causes its output spectrum and spatial distribution to be dramatically narrowed. We have tested a simple quantitative model of this process.


A readily retrievable pool of synaptic vesicles.
Although clathrin-mediated endocytosis is thought to be the predominant mechanism of synaptic vesicle recycling, it seems to be too slow for fast recycling. Therefore, it was suggested that a presorted and preassembled pool of synaptic vesicle proteins on the presynaptic membrane might support a first wave of fast clathrin-mediated endocytosis. In this study we monitored the temporal dynamics of such a 'readily retrievable pool' of synaptic vesicle proteins in rat hippocampal neurons using a new type of probe. By applying cypHer5E, a new cyanine dye-based pH-sensitive exogenous marker, coupled to antibodies to luminal domains of synaptic vesicle proteins, we could reliably monitor synaptic vesicle recycling and demonstrate the preferential recruitment of a surface pool of synaptic vesicle proteins upon stimulated endocytosis. By using fluorescence nanoscopy of surface-labeled synaptotagmin 1, we could resolve the spatial distribution of the surface pool at the periactive zone in hippocampal boutons, which represent putative sites of endocytosis.


Exact Gradients Improve Parameter Estimation in Nonlinear Mixed Effects Models with Stochastic Dynamics.
Nonlinear mixed effects (NLME) modeling based on stochastic differential equations (SDEs) have evolved into a promising approach for analysis of PK/PD data. SDE-NLME models go beyond the realm of standard population modeling as they consider stochastic dynamics, thereby introducing a probabilistic perspective on the state variables. This article presents a summary of the main contributions to SDE-NLME models found in the literature. The aims of this work were to develop an exact gradient version of the first-order conditional estimation (FOCE) method for SDE-NLME models and to investigate whether it enabled faster estimation and better gradient precision/accuracy compared to the use of gradients approximated by finite differences. A simulation-estimation study was set up whereby finite difference approximations of the gradients of each level were interchanged with the exact gradients. Following previous work, the uncertainty of the state variables was accounted for using the extended Kalman filter (EKF). The exact gradient FOCE method was implemented in Mathematica 11 and evaluated on SDE versions of three common PK/PD models. When finite difference gradients were replaced by exact gradients at both FOCE levels, relative runtimes improved between 6- and 32-fold, depending on model complexity. Additionally, gradient precision/accuracy was significantly better in the exact gradient case. We conclude that parameter estimation using FOCE with exact gradients can successfully be applied to SDE-NLME models.


Co-optimization of sponge-core bioreactors for removing total nitrogen and antibiotic resistance genes from domestic wastewater.
Inadequate sanitation can lead to the spread of infectious diseases and antimicrobial resistance (AMR) via contaminated water. Unfortunately, wastewater treatment is not universal in many developing and emerging countries, especially in rural and peri-urban locations that are remote from central sewers. As such, small-scale, more sustainable treatment options are needed, such as aerobic-Denitrifying Downflow Hanging Sponge (DDHS) bioreactors. In this study, DDHS reactors were assessed for such applications, and achieved over 79% and 84% removal of Chemical Oxygen Demand and Ammonium, respectively, and up to 71% removal of Total Nitrogen (TN) from domestic wastes. Elevated TN removals were achieved via bypassing a fraction of raw wastewater around the top layer of the DDHS system to promote denitrification. However, it was not known how this bypass impacts AMR gene (ARG) and mobile genetic element (MGE) levels in treated effluents. High-throughput qPCR was used to quantify ARG and MGE levels in DDHS bioreactors as a function of percent bypass (0, 10, 20 and 30% by volume). All systems obtained over 90% ARG reduction, although effluent ARG and TN levels differed among bypass regimes, with co-optimal reductions occurring at ~20% bypass. ARG removal paralleled bacterial removal rate, although effluent bacteria tended to have greater genetic plasticity based on higher apparent MGE levels per cell. Overall, TN removal increased and ARG removal decreased with increasing bypass, therefore co-optimization is needed in each DDHS application to achieve locally targeted TN and AMR effluent levels.


A 1-year follow-up study exploring the associations between perception of illness and health-related quality of life in persons with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease with an increasing prevalence worldwide. Its potential consequences, including reduced function and reduced social participation, are likely to be associated with decreased health-related quality of life (HRQoL). However, illness perceptions and self-efficacy beliefs may also play a part in determining HRQoL in persons with COPD. The aim of this study was to explore the relationships between illness perceptions, self-efficacy, and HRQoL in a sample of persons with COPD in a longitudinal perspective. The context of the study was a patient education course from which the participants were recruited. Data concerning sociodemographic variables, social support, physical activity, illness perceptions, general self-efficacy, and HRQoL were collected before the course started and 1 year after completion. Linear regression was used in the analyses. The results showed that less consequences and less symptoms (identity) were associated with higher physical HRQoL (PCS) at baseline and at 1-year follow-up. Less emotional response was similarly associated with higher mental HRQoL (MCS) at both time points. Lower self-efficacy showed a borderline significant association with higher PCS at baseline, but was unrelated to MCS at both time points. Self-efficacy showed no influence on the associations between illness perceptions and HRQoL. In conclusion, the study showed that specific illness perceptions had a stable ability to predict HRQoL in persons with COPD, whereas self-efficacy did not. The associations between illness perceptions and HRQoL were not mediated by self-efficacy.


The Influence of Single-level Versus Multilevel Decompression on the Outcome in Multisegmental Lumbar Spinal Stenosis: Analysis of the Lumbar Spinal Outcome Study (LSOS) Data.
This is prospective multicenter cohort study. To assess whether patients with confirmed multisegmental lumbar spinal stenosis benefit more from a single-level or a multilevel decompression. In multisegmental lumbar spinal stenotic cases, the decision as to how many levels of stenosis need to be operated to achieve the best possible clinical outcome is still unknown and remains a controversy between spine surgeons. Patients of the Swiss Lumbar Stenosis Outcome Study (LSOS) with confirmed multisegmental LSS undergoing first-time decompression without fusion were enrolled in this study. The main outcomes of this study were Spinal Stenosis Measure (SSM) symptoms and function over time, measured at baseline, 6, 12, and 24 months follow-up. Further outcomes of interest were changes in SSM, numeric rating scale, feeling thermometer, the EQ-5D-EL, and the Roland and Morris disability questionnaire from baseline to 6, 12, and 24 months. After 12 months, a total of 141 patients met the inclusion criteria; of these, 33 (23%) underwent a single-level and 108 (77%) a multilevel decompression. Multilevel decompression was associated with a significantly less favorable SSM symptoms and function score, respectively, as compared with single-level decompression. In all further outcomes of interest single-level as well as multilevel patients improved over time. Our study showed that in multisegmental stenotic cases a single-level decompression was associated with a significantly more favorable SSM symptoms and function score, respectively, as compared with multilevel decompression. This study provides evidence that in multisegmental stenotic cases a single-level decompression might be sufficient to improve patient's symptoms and function.


Physical activity, sedentary behavior and their correlates in children with Autism Spectrum Disorder: A systematic review.
Autism Spectrum Disorder affects up to 2.5% of children and is associated with harmful health outcomes (e.g. obesity). Low levels of physical activity and high levels of sedentary behaviors may contribute to harmful health outcomes. To systematically review the prevalence and correlates of physical activity and sedentary behaviors in children with Autism Spectrum Disorder, electronic databases (PsycINFO, SPORTDiscus, EMBASE, Medline) were searched from inception to November 2015. The review was registered with PROSPERO (CRD42014013849). Peer-reviewed, English language studies were included. Two reviewers screened potentially relevant articles. Outcomes of interest were physical activity and sedentary behaviour levels and their potential correlates. Data were collected and analysed in 2015. Of 35 included studies, 15 reported physical activity prevalence, 10 reported physical activity correlates, 18 reported sedentary behavior prevalence, and 10 reported sedentary behavior correlates. Estimates of children's physical activity (34-166 mins/day, average 86 mins/day) and sedentary behavior (126-558 mins/day in screen time, average 271 mins/day; 428-750 mins/day in total sedentary behavior, average 479 mins/day) varied across studies. Age was consistently inversely associated, and sex inconsistently associated with physical activity. Age and sex were inconsistently associated with sedentary behavior. Sample sizes were small. All but one of the studies were classified as having high risk of bias. Few correlates have been reported in sufficient studies to provide overall estimates of associations. Potential correlates in the physical environment remain largely unexamined. This review highlights varying levels of physical activity and sedentary behavior in children with Autism Spectrum Disorder. Research is needed to consistently identify the correlates of these behaviors. There is a critical need for interventions to support healthy levels of these behaviors.


Mirror neurons: functions, mechanisms and models.
Mirror neurons for manipulation fire both when the animal manipulates an object in a specific way and when it sees another animal (or the experimenter) perform an action that is more or less similar. Such neurons were originally found in macaque monkeys, in the ventral premotor cortex, area F5 and later also in the inferior parietal lobule. Recent neuroimaging data indicate that the adult human brain is endowed with a "mirror neuron system," putatively containing mirror neurons and other neurons, for matching the observation and execution of actions. Mirror neurons may serve action recognition in monkeys as well as humans, whereas their putative role in imitation and language may be realized in human but not in monkey. This article shows the important role of computational models in providing sufficient and causal explanations for the observed phenomena involving mirror systems and the learning processes which form them, and underlines the need for additional circuitry to lift up the monkey mirror neuron circuit to sustain the posited cognitive functions attributed to the human mirror neuron system.


The novel ETS factor TEL2 cooperates with Myc in B lymphomagenesis.
The human ETS family gene TEL2/ETV7 is highly homologous to TEL1/ETV6, a frequent target of chromosome translocations in human leukemia and specific solid tumors. Here we report that TEL2 augments the proliferation and survival of normal mouse B cells and dramatically accelerates lymphoma development in Emu-Myc transgenic mice. Nonetheless, inactivation of the p53 pathway was a hallmark of all TEL2/Emu-Myc lymphomas, indicating that TEL2 expression alone is insufficient to bypass this apoptotic checkpoint. Although TEL2 is infrequently up-regulated in human sporadic Burkitt's lymphoma, analysis of pediatric B-cell acute lymphocytic leukemia (B-ALL) samples showed increased coexpression of TEL2 and MYC and/or MYCN in over one-third of B-ALL patients. Therefore, TEL2 and MYC also appear to cooperate in provoking a cadre of human B-cell malignancies.


Wherever I may roam: social viscosity and kin affiliation in a wild population despite natal dispersal.
Dispersal affects the social contexts individuals experience by redistributing individuals in space, and the nature of social interactions can have important fitness consequences. During the vagrancy stage of natal dispersal, after an individual has left its natal site and before it has settled to breed, social affiliations might be predicted by opportunities to associate (e.g., distance in space and time between natal points of origin) or kin preferences. We investigated the social structure of a population of juvenile great tits (Parus major) and asked whether social affiliations during vagrancy were predicted by 1) the distance between natal nest-boxes, 2) synchrony in fledge dates, and 3) accounting for spatial and temporal predictors, whether siblings tended to stay together. We show that association strength was affected predominantly by spatial proximity at fledging and, to a lesser extent, temporal proximity in birth dates. Independently of spatial and temporal effects, sibling pairs associated more often than expected by chance. Our results suggest that the structure of the winter population is shaped primarily by limits to dispersal through incomplete population mixing. In addition, our results reveal kin structure, and hence the scope for fitness-related interactions between particular classes of kin. Both spatial-mediated and socially mediated population structuring can have implications for our understanding of the evolution of sociality.


High-Throughput Image-Based Aggresome Quantification.
Aggresomes are subcellular perinuclear structures where misfolded proteins accumulate by retrograde transport on microtubules. Different methods are available to monitor aggresome formation, but they are often laborious, time-consuming, and not quantitative. Proteostat is a red fluorescent molecular rotor dye, which becomes brightly fluorescent when it binds to protein aggregates. As this reagent was previously validated to detect aggresomes, we have miniaturized its use in 384-well plates and developed a method for high-throughput imaging and quantification of aggresomes. Two different image analysis methods, including one with machine learning, were evaluated. They lead to similar robust data to quantify cells having aggresome, with satisfactory Z' factor values and reproducible EC50 values for compounds known to induce aggresome formation, like proteasome inhibitors. We demonstrated the relevance of this phenotypic assay by screening a chemical library of 1280 compounds to find aggresome modulators. We obtained hits that present similarities in their structural and physicochemical properties. Interestingly, some of them were previously described to modulate autophagy, which could explain their effect on aggresome structures. In summary, we have optimized and validated the Proteostat detection reagent to easily measure aggresome formation in a miniaturized, automated, quantitative, and high-content assay. This assay can be used at low, middle, or high throughput to quantify changes in aggresome formation that could help in the understanding of chemical compound activity in pathologies such as protein misfolding disorders or cancer.


Fiber-optic voltage sensor for SF6 gas-insulated high-voltage switchgear.
We present an optical-fiber voltage sensor for 170-kV gas-insulated high-voltage switchgear. The sensor is based on the converse piezoelectric effect of quartz. The full voltage is applied to a cylinder-shaped quartz crystal. The resulting alternating piezoelectric deformation of the crystal is sensed by an elliptical-core dual-mode fiber, which is wound onto the circumferential crystal surface. The fiber is interrogated by low-coherence interferometry. We address the dielectric design of the sensor and verify its dielectric reliability under ac overvoltages and lightning impulse voltages. We then investigate the sensor performance, including accuracy, dynamic range, bandwidth, and temperature dependence.


Tea and coffee and risk of endometrial cancer: cohort study and meta-analysis.
Previous reports, mostly from retrospective studies, suggested possible protective effects of both tea and coffee against endometrial cancer, but recent reports from prospective studies generally showed weaker or null associations. We investigated endometrial cancer risk in relation to tea and coffee consumption in a large prospective study and did a meta-analysis of published results. Daily consumption of tea and coffee was recorded in 560,356 participants (without a hysterectomy) in the UK Million Women Study of whom 4067 women developed endometrial cancer during 5.2 million person-years of follow up (average: 9.3 y per woman). With the use of Cox proportional hazards regression, we showed no significant association between endometrial cancer risk and consumption of either tea (multivariate adjusted RR per cup daily: 1.00; 95% CI: 0.98, 1.02) or coffee (RR per cup daily: 0.98; 95% CI: 0.96, 1.01). Our meta-analyses showed no significant association between endometrial cancer risk and tea consumption and a weak association for coffee consumption in prospective studies, but there may have been selective publication of only part of the evidence. There is little or no association between tea consumption and endometrial cancer risk. If there is any association with coffee consumption, it appears to be weak.


Towards Overhauser DNP in supercritical CO(2).
Overhauser Dynamic Nuclear Polarization (ODNP) is a well known technique to improve NMR sensitivity in the liquid state, where the large polarization of an electron spin is transferred to a nucleus of interest by cross-relaxation. The efficiency of the Overhauser mechanism for dipolar interactions depends critically on fast local translational dynamics at the timescale of the inverse electron Larmor frequency. The maximum polarization enhancement that can be achieved for (1)H at high magnetic fields benefits from a low viscosity solvent. In this paper we investigate the option to use supercritical CO2 as a solvent for Overhauser DNP. We have investigated the diffusion constants and longitudinal nuclear relaxation rates of toluene in high pressure CO2. The change in (1)H T1 by addition of TEMPO radical was analyzed to determine the Overhauser cross-relaxation in such a mixture, and is compared with calculations based on the Force Free Hard Sphere (FFHS) model. By analyzing the relaxation data within this model we find translational correlation times in the range of 2-4ps, depending on temperature, pressure and toluene concentration. Such short correlation times may be instrumental for future Overhauser DNP applications at high magnetic fields, as are commonly used in NMR. Preliminary DNP experiments have been performed at 3.4T on high pressure superheated water and model systems such as toluene in high pressure CO2.


Latin American Clinical Practice Guidelines on the Systemic Treatment of Psoriasis SOLAPSO - Sociedad Latinoamericana de Psoriasis (Latin American Psoriasis Society).
This Clinical Practice Guideline on the systemic treatment of Psoriasis includes the recommendations elaborated by a panel of experts from the Latin American Psoriasis Society SOLAPSO, who assessed the quality of the available evidence using the GRADE system and the PICO process to guide the literature search. To answer each question, the experts discussed the results of randomized controlled trials, observational studies and metanalysis evaluating the interventions identified (non-biologics, biologics and phototherapy) in different populations of patients with moderate to severe plaque-psoriasis, which was summarized in Tables ad-hoc. The main end-points considered to assess efficacy were PASI 50, 75, 90 and 100, PGA 0-1 and significant improvement of health-related quality of life. Specific adverse events, either severe or leading to treatment interruption, were also evaluated. The 31 recommendations included in this CPG follow the structure proposed by GRADE: direction (for or against) and strength (strong or weak). The goal of this CPG is to improve the management of patients with psoriasis by recommending interventions of proved benefit and providing a reference standard for the treating physician. Adhering to the contents of this CPG does not guarantee therapeutic success. The final decision on the specific treatment is the responsibility of the physician based on the individual circumstances and considering the values, the preferences and the opinions of the patient or caregivers.


Resistance artery tone is influenced independently by pressure and by flow.
The responses of rabbit resistance arteries to pressure and flow have been examined using two in vitro techniques--when mounted isometrically in a myograph and when perfused using a video system that automatically registers diameter. The latter approach allows pressure and flow to be independently controlled. Under such circumstances three responses were studied; myogenic contraction and flow-dependent constriction and dilation. All responses occurred after endothelium removal and were unaffected by indomethacin (10(-60 M). The pressure and flow effects can be elicited separately and have different ionic bases. The effective stimulus for the myogenic response is stretch and that for flow is presumably shear stress. The mechano-transducers for these effects are different and are located either in the vascular smooth muscle cells or their surrounding extracellular matrix.


IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium.
In the infarcted myocardium, activation of the inflammatory cascade clears the wound from dead cells, whereas stimulating matrix degradation and chamber dilation, thus contributing to the development of heart failure. IL-1 is critically involved in the postinfarction inflammatory reaction and mediates adverse dilative remodeling. We hypothesized that IL-1 may regulate postinfarction repair and remodeling through cell-specific actions on leukocytes and fibroblasts. Flow cytometry demonstrated that in mouse infarcts, early recruitment of proinflammatory Ly6C(hi) cells expressing IL-1R1, the signaling receptor for IL-1, was followed by infiltration with cells expressing the decoy receptor, IL-1R2. Increased expression of IL-1R2 may serve to terminate IL-1-driven inflammation after infarction. Loss of IL-1 signaling in IL-1R1 null mice globally attenuated leukocyte recruitment, reducing the number of infiltrating Ly6C(hi) and Ly6C(lo) cells. Nonmyeloid CD11b(-) cells harvested during the inflammatory phase of cardiac repair exhibited marked upregulation of chemokines and cytokines; their inflammatory activation was IL-1R1 dependent. Moreover, IL-1β attenuated TGF-β-induced contractile activity of fibroblasts populating collagen pads, attenuated α-smooth muscle actin expression, and stimulated matrix metalloproteinase synthesis in an IL-1R1-dependent manner. The effects of IL-1 on TGF-β responses in cardiac fibroblasts were not due to direct effects on Smad activation, but were associated with endoglin suppression and accentuated expression of bone morphogenetic protein and activin membrane-bound inhibitor, a negative regulator of TGF-β signaling. IL-1 may orchestrate fibroblast responses in the infarct; early stimulation of fibroblast IL-1R1 signaling during the inflammatory phase may prevent premature activation of a matrix-synthetic contractile phenotype until the wound is cleared, and the infarct microenvironment can support mesenchymal cell growth.


First-Line Use of Vemurafenib to Enable Thyroidectomy and Radioactive Iodine Ablation for BRAF-Positive Metastatic Papillary Thyroid Carcinoma: A Case Report.
Background. Patients with metastatic or radioactive iodine refractory papillary thyroid carcinoma (PTC) have poor prognosis due to ineffective therapy for this condition beyond surgery and radioactive iodine (RAI or (131)I). BRAF mutation occurs in more than 44% of PCT. Tyrosine kinase inhibitors, the most commonly used agents for these patients, have weak BRAF inhibition activity. BRAF inhibitors have demonstrated promising efficacy in relapsed metastatic PCT after standard treatment, though they are not currently approved for this indication. Case Presentation. We present the case of a 48-year-old Hispanic male who initially presented with columnar-cell variant subtype of PTC and positive BRAFV600E mutation. The patient had widespread bulky metastases to lungs, chest wall, brain, and bone. Discussion. Initial use of vemurafenib demonstrated a 42% cytoreduction of targeted pulmonary metastases and facilitated thyroidectomy and RAI treatment. The patient achieved a durable response over 21 months in the setting of widely metastatic disease. Conclusion. Vemurafenib may be effectively used for cytoreduction in patients with bulky metastatic PTC to bridge them to thyroidectomy and RAI treatment.


Widening access to UK medical education for under-represented socioeconomic groups: modelling the impact of the UKCAT in the 2009 cohort.
To determine whether the use of the UK clinical aptitude test (UKCAT) in the medical schools admissions process reduces the relative disadvantage encountered by certain sociodemographic groups. Prospective cohort study. Applicants to 22 UK medical schools in 2009 that were members of the consortium of institutions utilising the UKCAT as a component of their admissions process. 8459 applicants (24,844 applications) to UKCAT consortium member medical schools where data were available on advanced qualifications and socioeconomic background. The probability of an application resulting in an offer of a place on a medicine course according to seven educational and sociodemographic variables depending on how the UKCAT was used by the medical school (in borderline cases, as a factor in admissions, or as a threshold). On univariate analysis all educational and sociodemographic variables were significantly associated with the relative odds of an application being successful. The multilevel multiple logistic regression models, however, varied between medical schools according to the way that the UKCAT was used. For example, a candidate from a non-professional background was much less likely to receive a conditional offer of a place compared with an applicant from a higher social class when applying to an institution using the test only in borderline cases (odds ratio 0.51, 95% confidence interval 0.45 to 0.60). No such effect was observed for such candidates applying to medical schools using the threshold approach (1.27, 0.84 to 1.91). These differences were generally reflected in the interactions observed when the analysis was repeated, pooling the data. Notably, candidates from several under-represented groups applying to medical schools that used a threshold approach to the UKCAT were less disadvantaged than those applying to the other institutions in the consortium. These effects were partially reflected in significant differences in the absolute proportion of such candidates finally taking up places in the different types of medical schools; stronger use of the test score (as a factor or threshold) was associated with a significantly increased odds of entrants being male (1.74, 1.25 to 2.41) and from a low socioeconomic background (3.57, 1.03 to 12.39). There was a non-significant trend towards entrants being from a state (non-grammar) school (1.60, 0.97 to 2.62) where a stronger use of the test was employed. Use of the test only in borderline cases was associated with increased odds of entrants having relatively low academic attainment (5.19, 2.02 to 13.33) and English as a second language (2.15, 1.03 to 4.48). The use of the UKCAT may lead to more equitable provision of offers to those applying to medical school from under-represented sociodemographic groups. This may translate into higher numbers of some, but not all, relatively disadvantaged students entering the UK medical profession.


Flow cytometry and FISH to measure the average length of telomeres (flow FISH).
Telomeres have emerged as crucial cellular elements in aging and various diseases including cancer. To measure the average length of telomere repeats in cells, we describe our protocols that use fluorescent in situ hybridization (FISH) with labeled peptide nucleic acid (PNA) probes specific for telomere repeats in combination with fluorescence measurements by flow cytometry (flow FISH). Flow FISH analysis can be performed using commercially available flow cytometers, and has the unique advantage over other methods for measuring telomere length of providing multi-parameter information on the length of telomere repeats in thousands of individual cells. The accuracy and reproducibility of the measurements is augmented by the automation of most pipetting (aspiration and dispensing) steps, and by including an internal standard (control cells) with a known telomere length in every tube. The basic protocol for the analysis of nucleated blood cells from 22 different individuals takes about 12 h spread over 2-3 days.


Slide tracheoplasty for congenital tracheal stenosis.
The aim of this study was to add to the experience of slide tracheoplasty in infants with congenital tracheal stenosis (CTS), to review the recent literature on this subject, and to evaluate the diagnostic workup in infants with CTS. A retrospective review of 3 infants with CTS treated with slide tracheoplasty was conducted at our institution. They all underwent bronchoscopy, tracheobronchography, and echocardiography. Therapy consisted of slide tracheoplasty and simultaneous correction of associated vascular malformations. A pulmonary artery sling was missed initially on esophagography in 2 patients. Stridor became worse in 2 patients after tracheobronchography. After surgical therapy, 2 patients survived and were discharged 12 days after surgery. Both are without symptoms at follow-up of 12 and 20 months. One patient had inoperable restenosis and died 27 days after the operation. Esophagography is not a reliable tool to depict associated vascular anomalies for patients with CTS. According to the literature, computer tomography has become more reliable to depict the tracheobronchial tree and is useful to elucidate associated vascular anomalies as well. Compared with other surgical techniques for infants with CTS reported in the literature, slide tracheoplasty has fewer postoperative complications and comparable survival rates.


Early intravenous nutrition for the prevention of neonatal jaundice.
The early institution of enteral feeding in the first few days of life is known to impact on the development of unconjugated hyperbilirubinaemia. However, the effect of early intravenous nutrition on neonatal jaundice remains unknown. To determine the effect of early intravenous nutrition on neonatal jaundice. The standard search strategy of the Cochrane Neonatal Review Group was used including searches of the Cochrane Controlled Trials Register (Cochrane Library: Issue 3, 2002), MEDLINE (1966-December 2002), and EMBASE (1974-December 2002). Randomised or quasi-randomised controlled trials evaluating the effect of early intravenous nutrition on unconjugated bilirubin. The search strategy identified no eligible studies, thus no data were collected. No studies were identified. Decisions regarding the institution of early intravenous nutrition must continue to be based upon factors others than its effect on neonatal jaundice.


Field Strains of Monilinia fructicola Resistant to Both MBC and DMI Fungicides Isolated from Stone Fruit Orchards in the Eastern United States.
In 2012, significant brown rot disease was observed on stone fruit in Pennsylvania, Maryland, and South Carolina despite preharvest application of methyl benzimidazole carbamate (MBC) and demethylase inhibitor (DMI) fungicides. In total, 140 Monilinia fructicola isolates were collected from diseased orchards and examined for fungicide sensitivity. In addition to isolates resistant to either the DMI propiconazole or the MBC thiophanate-methyl, 22 isolates were discovered that were resistant to both fungicides, including 4 isolates from peach in South Carolina, 12 isolates from peach and sweet cherry in Maryland, and 6 isolates from sweet cherry in Pennsylvania. Analysis of MBC resistance revealed that dual-resistant isolates from South Carolina carried the β-tubulin E198A mutation, whereas isolates from Maryland and Pennsylvania carried E198 mutations not previously described in the Monilinia genus, E198Q or F200Y. The genetic element Mona, associated with DMI fungicide resistance in M. fructicola, was detected in the dual-resistant isolates from South Carolina but not in the isolates from the two more northern states. An investigation into the molecular mechanism of DMI resistance in the latter isolates revealed that resistance was not based on increased expression or mutation of MfCYP51, which encodes the target of DMI fungicides. Label rates of formulated propiconazole or thiophanate-methyl were unable to control dual-resistant isolates on detached peach fruit, confirming field relevance of dual resistance. The same isolates were not affected by fitness penalties based on mycelial growth rate, ability to sporulate, and virulence on detached peach fruit. The emergence of M. fructicola strains resistant to both DMI and MBC fungicides in multiple states and multiple stone fruit crops is a significant development and needs to be considered when designing resistance management strategies in stone fruit orchards.


Isothermal Crystallization Kinetics and Time-Temperature-Transformation of the Conjugated Polymer: Poly(3-(2'-ethyl)hexylthiophene).
Thermal annealing strongly impacts the nano- and microstructure of conjugated polymers. Despite the fundamental importance for the resulting optoelectronic behavior of this class of materials, the underlying crystallization processes have not received the same attention that is encountered in other disciplines of materials science. The question arises whether classical treatment of nucleation and growth phenomena is truly applicable to conjugated polymers? Here, the isothermal crystallization behavior of the conjugated polymer poly(3-(2'-ethyl)hexylthiophene) (P3EHT) is monitored with differential scanning calorimetry (DSC). Avrami analysis reveals growth- and nucleation-limited temperature regimes that are separated by the maximum rate of crystallization. The molecular weight of the polymer is found to strongly influence the absolute rate of crystallization at the same degree of undercooling relative to the melting temperature. A combination of optical microscopy and grazing-incidence wide-angle X-ray scattering (GIWAXS) confirms that the resulting nano- and microstructure strongly correlate with the selected isothermal annealing temperature. Hence, this work establishes that classical nucleation and growth theory can be applied to describe the solidification behavior of the semicrystalline conjugated polymer P3EHT.


Biotransformation pathway maps in WikiPathways enable direct visualization of drug metabolism related expression changes.
In recent decades, our knowledge of the genetics and functional genomics of drug-metabolizing enzymes has increased and a wealth of data on drug-related 'omics' has become available. Despite the availability of large amounts of biological information on xenobiotic biotransformation, the number of available biotransformation pathway maps that can easily be used for visualization of multiple omics data is limited. Here, we created integrated biotransformation pathway maps suitable for multiple omics analysis using PathVisio. The ease of visualizing data on these maps was demonstrated by using published microarray data from human hepatocyte-like cell models, exemplifying - where a sufficient capacity for metabolizing chemicals is a prerequisite for a suited model - how the biotransformation pathway maps can be used for model selection.


Copy number variants in German patients with schizophrenia.
Large rare copy number variants (CNVs) have been recognized as significant genetic risk factors for the development of schizophrenia (SCZ). However, due to their low frequency (1∶150 to 1∶1000) among patients, large sample sizes are needed to detect an association between specific CNVs and SCZ. So far, the majority of genome-wide CNV analyses have focused on reporting only CNVs that reached a significant P-value within the study cohort and merely confirmed the frequency of already-established risk-carrying CNVs. As a result, CNVs with a very low frequency that might be relevant for SCZ susceptibility are lost for secondary analyses. In this study, we provide a concise collection of high-quality CNVs in a large German sample consisting of 1,637 patients with SCZ or schizoaffective disorder and 1,627 controls. All individuals were genotyped on Illumina's BeadChips and putative CNVs were identified using QuantiSNP and PennCNV. Only those CNVs that were detected by both programs and spanned ≥30 consecutive SNPs were included in the data collection and downstream analyses (2,366 CNVs, 0.73 CNVs per individual). The genome-wide analysis did not reveal a specific association between a previously unknown CNV and SCZ. However, the group of CNVs previously reported to be associated with SCZ was more frequent in our patients than in the controls. The publication of our dataset will serve as a unique, easily accessible, high-quality CNV data collection for other research groups. The dataset could be useful for the identification of new disease-relevant CNVs that are currently overlooked due to their very low frequency and lack of power for their detection in individual studies.


Adenosine triphosphate and arachidonic acid stimulate glycogenolysis in primary cultures of mouse cerebral cortical astrocytes.
Adenosine triphosphate (ATP) promotes glycogenolysis in primary cultures of mouse cerebral cortical astrocytes with an EC50 of 1.5 microM. A pharmacological analysis indicates an involvement of purinergic P2Y receptors in this action of ATP. Application of either arachidonic acid (AA), or certain unsaturated fatty acids, also results in glycogen breakdown. The EC50 of AA is approximately 50 microM. Thus ATP and AA can be added to the list of neuroactive agents that control glycogen levels in astrocytes, which includes noradrenaline, vasoactive intestinal peptide (VIP), adenosine and histamine.


Direct introduction of neomycin phosphotransferase II protein into apple leaves to confer kanamycin resistance.
The recent developments of transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) have expanded plant breeding technology. One technical issue related to the current genome editing process is residual transgenes for TALEN and CRISPR/Cas9 left in plant genomes after the editing process. Here, we aim to add transient kanamycin resistance into apple leaf cells by introducing neomycin phosphotransferase II (NPTII) into apple leaf cells using the fusion peptide system. At 75 mg/L of kanamycin for 2 days, apple JM1 leaf cells infiltrated with NPTII could be selected. Thus, we successfully demonstrated the first transient selection system of plant cells using a fusion peptide-mediated protein delivery system.


Resource-Aware Distributed Epilepsy Monitoring Using Self-Awareness From Edge to Cloud.
The integration of wearable devices in humans' daily lives has grown significantly in recent years and still continues to affect different aspects of high-quality life. Thus, ensuring the reliability of the decisions becomes essential in biomedical applications, while representing a major challenge considering battery-powered wearable technologies. Transferring the complex and energy-consuming computations to fogs or clouds can significantly reduce the energy consumption of wearable devices and result in a longer lifetime of these systems with a single battery charge. In this work, we aim to distribute the complex and energy-consuming machine-learning computations between the edge, fog, and cloud, based on the notion of self-awareness that takes into account the complexity and reliability of the algorithm. We also model and analyze the trade-offs in terms of energy consumption, latency, and performance of different Internet of Things (IoT) solutions. We consider the epileptic seizure detection problem as our real-world case study to demonstrate the importance of our proposed self-aware methodology.


Optical scattering and absorption by branched chains of aerosols.
We utilize the Volume Integral Equation Formulation (VIEF) and the method of moments to calculate the electromagnetic scattering and absorption of aerosol particles with branched-chain structures. Two kinds of polarization of the incident electromagnetic wave were considered: the cross- and end-fire polarizations. The numerical results of internal electric field distribution, absorbed power, and extinction and scattering cross sections, obtained from the VIEF, show excellent agreement with the Mie theory for the special case of spherical particles. Comparison between the results of the VIEF and Iterative Extended Boundary Condition Method for very long oriented (elongated) chains of particles also showed good agreement. After validating the accuracy of the VIEF, the absorption characteristics of three branched-chain structuressimulated from microscopic pictures of coagulated smoke aerosol particles were calculated. Results showed that the ratio of absorption in the two polarization cases, P(cross-fire)/P(end-fire), for very long oriented chain structures is as high as a factor of 4 at lower frequencies (lambda =10microm). While in the higher frequency (lambda = 0.5-microm) case, the ratio Of P(cross-fire)/P(end-fire) is reduced to 2.0. For branched-chain structures, the ratio Of P(cross-fire)/P(end-fire) decreased with the increase in the number of the side branches. These observations show that the frequency, polarization, and structure factors play important roles in determining the optical characteristics of branched chains of aerosol particles.


Continuous hemodynamic monitoring in acute stroke: an exploratory analysis.
Non-invasive, continuous hemodynamic monitoring is entering the clinical arena. The primary objective of this study was to test the feasibility of such monitoring in a pilot sample of Emergency Department (ED) stroke patients. Secondary objectives included analysis of hemodynamic variability and correlation of continuous blood pressure measurements with standard measurements. This study was a secondary analysis of 7 stroke patients from a prospectively collected data set of patients that received 2 hours of hemodynamic monitoring in the ED. Stroke patients were included if hemorrhagic or ischemic stroke was confirmed by neuroimaging, and symptom onset was within 24 hours. They were excluded for the presence of a stroke mimic or transient ischemic attack. Monitoring was performed using the Nexfin device (Edwards Lifesciences, Irvine CA). The mean age of the cohort was 71 ± 17 years, 43% were male, and the mean National Institute of Health Stroke Scale (NIHSS) was 6.9 ± 5.5. Two patients had hemorrhagic stroke. We obtained 42,456 hemodynamic data points, including beat-to-beat blood pressure measurements with variability of 18 mmHg and cardiac indices ranging from 1.8 to 3.6 l/min/m2. The correlation coefficient between continuous blood pressure measurements with the Nexfin device and standard ED readings was 0.83. This exploratory investigation revealed that continuous, noninvasive monitoring in the ED is feasible in acute stroke. Further research is currently underway to determine how such monitoring may impact outcomes in stroke or replace the need for invasive monitoring.


Cohesin rings devoid of Scc3 and Pds5 maintain their stable association with the DNA.
Cohesin is a protein complex that forms a ring around sister chromatids thus holding them together. The ring is composed of three proteins: Smc1, Smc3 and Scc1. The roles of three additional proteins that associate with the ring, Scc3, Pds5 and Wpl1, are not well understood. It has been proposed that these three factors form a complex that stabilizes the ring and prevents it from opening. This activity promotes sister chromatid cohesion but at the same time poses an obstacle for the initial entrapment of sister DNAs. This hindrance to cohesion establishment is overcome during DNA replication via acetylation of the Smc3 subunit by the Eco1 acetyltransferase. However, the full mechanistic consequences of Smc3 acetylation remain unknown. In the current work, we test the requirement of Scc3 and Pds5 for the stable association of cohesin with DNA. We investigated the consequences of Scc3 and Pds5 depletion in vivo using degron tagging in budding yeast. The previously described DHFR-based N-terminal degron as well as a novel Eco1-derived C-terminal degron were employed in our study. Scc3 and Pds5 associate with cohesin complexes independently of each other and require the Scc1 "core" subunit for their association with chromosomes. Contrary to previous data for Scc1 downregulation, depletion of either Scc3 or Pds5 had a strong effect on sister chromatid cohesion but not on cohesin binding to DNA. Quantity, stability and genome-wide distribution of cohesin complexes remained mostly unchanged after the depletion of Scc3 and Pds5. Our findings are inconsistent with a previously proposed model that Scc3 and Pds5 are cohesin maintenance factors required for cohesin ring stability or for maintaining its association with DNA. We propose that Scc3 and Pds5 specifically function during cohesion establishment in S phase.


Super-condenser enables labelfree nanoscopy.
Labelfree nanoscopy encompasses optical imaging with resolution in the 100 nm range using visible wavelengths. Here, we present a labelfree nanoscopy method that combines coherent imaging techniques with waveguide microscopy to realize a super-condenser featuring maximally inclined coherent darkfield illumination with artificially stretched wave vectors due to large refractive indices of the employed Si3N4 waveguide material. We produce the required coherent plane wave illumination for Fourier ptychography over imaging areas 400 μm2 in size via adiabatically tapered single-mode waveguides and tackle the overlap constraints of the Fourier ptychography phase retrieval algorithm two-fold: firstly, the directionality of the illumination wave vector is changed sequentially via a multiplexed input structure of the waveguide chip layout and secondly, the wave vector modulus is shortend via step-wise increases of the illumination light wavelength over the visible spectrum. We test the method in simulations and in experiments and provide details on the underlying image formation theory as well as the reconstruction algorithm. While the generated Fourier ptychography reconstructions are found to be prone to image artefacts, an alternative coherent imaging method, rotating coherent scattering microscopy (ROCS), is found to be more robust against artefacts but with less achievable resolution.


Effects of simvastatin on the development of osteopenia caused by ovariectomy in rats.
Simvastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-determining enzyme for cholesterol synthesis which is used in the treatment of hypercholesterolemias, particularly in type IIa and IIb hyperlipoproteinemias, frequently in postmenopausal women. Inhibition of cholesterol synthesis by simvastatin may cause disorders of bone remodelling. The aim of the present study was to investigate the effects of simvastatin (3 mg and 6 mg/kg/day per os) administered for 4 weeks on the development of ovariectomy-induced osteopenia in 3-month-old female Wistar rats. The experiments were carried out on six groups of animals: I (C)--sham operated rats, II (S-3)--sham operated rats + simvastatin 3 mg/kg/day p.o., III (S-6)--sham operated rats + simvastatin 6 mg/kg/day p.o., IV (OVX)--ovariectomized rats, V (OVX + S-3)--ovariectomized rats + simvastatin 3 mg/kg/day p.o., VI (OVX + S-6)--ovariectomized rats + simvastatin 6 mg/kg/day p.o. In all the groups, we examined body weight gain, and macrometrical, histomorphometrical and mechanical parameters. Bilateral ovariectomy induced osteopenic skeletal changes in mature female rats. In cortical bone, ovariectomy intensified resorption processes at the marrow cavity, as indicated by a decrease in endosteal transverse growth and an increase in transverse cross-section surface area of the marrow cavity in the tibia. Intensification of resorption processes was observed in cancellous bone (a statistically significant decrease in the width of trabeculae in the epiphysis and metaphysis of the femur). Structural changes in the long bones resulting from bilateral ovariectomy were manifested by deterioration of mechanical properties of the shaft and neck of the femur. The force needed to fracture the neck and shaft of the femur was significantly smaller than that in sham operated rats. Simvastatin (3 and 6 mg/kg/day p.o.) slightly influenced bone remodelling in sham operated rats. Simvastatin (3 and 6 mg/kg p.o. daily) administered to ovariectomized rats intensified bone formation processes and decreased bone resorption processes induced by bilateral ovariectomy, showing stronger activity at 6 mg/kg.


DNA variation in a 13-Mb region including the F9 gene: inferring the genealogical history and causal role of a hemophilia B mutation (IVS 5+13 A-->G).
About 5.5% of all UK hemophilia B patients have the base substitution IVS 5+13 A-->G as the only change in their factor (F)IX gene (F9). This generates a novel donor splice site which fits the consensus better than the normal intron 5 donor splice. Use of the novel splice site should result in a missense mutation followed by the abnormal addition of four amino acids to the patients' FIX. In order to explain the prevalence of this mutation, its genealogical history is examined. Analysis of restriction fragment length polymorphism in the 21 reference UK individuals (from different families) with the above mutation showed identical haplotypes in 19 while two differed from the rest and from each other. In order to investigate the history of the mutation and to verify that it had occurred independently more than once, the sequence variation in 1.5-kb segments scattered over a 13-Mb region including F9 was examined in 18 patients and 15 controls. This variation was then analyzed with a recently developed Bayesian approach that reconstructs the genealogy of the gene investigated while providing evidence of independent mutations that contribute disconnected branches to the genealogical tree. The method also provides minimum estimates of the age of the mutation inherited by the members of coherent trees. This revealed that 17 or 18 mutant genes descend from a founder who probably lived 450 years ago, while one patient carries an independent mutation. The independent recurrence of the IVS5+13 A-->G mutation strongly supports the conclusion that it is the cause of these patients' mild hemophilia.


Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o)
The most characteristic change in progressive dementia of Alzheimer's type is a tissue deposit of amyloid beta/A4 protein, which is derived from its precursor protein APP (ref.2). Structural alterations of APP are implicated in the pathogenesis of Alzheimer's disease, but it is not known how they cause the disease. Although APP has a receptor-like architecture, is located on the neuronal surface, and has a conserved cytoplasmic domain, no receptor function has been demonstrated for APP. Here we report that APP forms a complex with G(o), a major GTP-binding protein in brain. The cytoplasmic APP sequence His 657-Lys 676 shows a specific G(o)-activating function and is necessary for complex formation. G(o) protein treated with GTP-gamma S lost the ability to associate with APP. This suggests that APP is a receptor coupled to G(o) and that abnormal APP-G(o) signalling is involved in the Alzheimer's disease process.


Anti-Nogo on the go: from animal models to a clinical trial.
Small lesions of the adult central nervous system (CNS) often have a good prognosis with extensive functional recovery based in part on spontaneous neuritic sprouting and rearrangements of projections. This is well documented for the cortex, but these changes can also occur in the spinal cord. Nogo-A is a protein present in CNS myelin that inhibits neurite growth. Models of spinal cord injury (SCI) in rats and macaque monkeys demonstrate that treatment with function-blocking antibodies of Nogo-A results in an upregulation of growth-specific proteins, enhanced regenerative and compensatory sprouting of fibers, and the formation of new functional connections in the spinal cord. In animals with unilateral sensorimotor cortex lesions followed by Nogo-A antibody treatment, fibers from the intact corticofugal system crossed the midline, supplying innervation to the denervated brain stem or spinal cord. Behavioral tests showed marked improvements of functional recovery in the Nogo-A antibody treated spinal cord- or brain-injured animals. A Phase I clinical trial applying anti-Nogo-A antibody to subjects with acute SCI has been successfully conducted and a multicentric, multinational Phase II trial is currently in preparation.


Learning more and spending less with neglected laboratory parameters: the paradigmatic case of red blood cell distribution width.
Due to increasing shortage of public healthcare resources in many countries around the globe, the use of simple, rapid and inexpensive laboratory parameters may be seen as a valuable aid for preliminary and cost-effective risk stratification of patients. Anisocytosis, conventionally measured by hematologic analyzers as the red blood cell distribution width (RDW), is an index of the heterogeneity of erythrocytes volumes. Several lines of evidence now attest that increased RDW values are commonplace in patients with many disorders, especially in those with the most prevalent conditions such as cardiovascular disease, diabetes, cancer and infections. Although the nature of this association remains to be definitely disclosed, what is strongly emerging from the recent scientific research is that the RDW should now be regarded as a "non" innocent bystander, wherein anisocytosis may be an active player in the pathogenesis of many pathologies. Therefore, major attention should be placed on this inexpensive but clinically meaningful parameter. The recent finding that dynamic changes of RDW are strongly predictors of mortality also suggests that continuous monitoring of anisocytosis may be an ancillary useful tool for establishing the effectiveness of managed care, as well as for deciding whether or not the overall clinical status is improving.


Heterosynaptic cross-talk of pre- and postsynaptic strengths along segments of dendrites.
Dendrites are crucial for integrating incoming synaptic information. Individual dendritic branches are thought to constitute a signal processing unit, yet how neighboring synapses shape the boundaries of functional dendritic units is not well understood. Here, we address the cellular basis underlying the organization of the strengths of neighboring Schaffer collateral-CA1 synapses by optical quantal analysis and spine size measurements. Inducing potentiation at clusters of spines produces NMDA-receptor-dependent heterosynaptic plasticity. The direction of postsynaptic strength change shows distance dependency to the stimulated synapses where proximal synapses predominantly depress, whereas distal synapses potentiate; potentiation and depression are regulated by CaMKII and calcineurin, respectively. In contrast, heterosynaptic presynaptic plasticity is confined to weakening of presynaptic strength of nearby synapses, which requires CaMKII and the retrograde messenger nitric oxide. Our findings highlight the parallel engagement of multiple signaling pathways, each with characteristic spatial dynamics in shaping the local pattern of synaptic strengths.


Baseline observations from the POSSIBLE EU® study: characteristics of postmenopausal women receiving bone loss medications.
SUMMARY: Prospective Observational Scientific Study Investigating Bone Loss Experience in Europe (POSSIBLE EU®) is an ongoing longitudinal cohort study that utilises physician- and patient-reported measures to describe the characteristics and management of postmenopausal women on bone loss therapies. We report the study design and baseline characteristics of 3,402 women recruited from general practice across five European countries. PURPOSE: The POSSIBLE EU® is a study describing the characteristics and management of postmenopausal women receiving bone loss medications. METHODS: Between 2005 and 2008, general practitioners enrolled postmenopausal women initiating, switching or continuing treatment with bone loss treatment in France, Germany, Italy, Spain and the UK. Patients and physicians completed questionnaires at study entry and at 3-month intervals, for 1 year. RESULTS: Of 3,402 women enrolled (mean age 68.2 years [SD] 9.83), 96% were diagnosed with low bone mass; 55% of these using dual energy X-ray absorptiometry. Most women (92%) had comorbidities. Mean minimum T score (hip or spine) at diagnosis was -2.7 (SD 0.89; median -2.7 [interquartile range, -3.2, -2.2]) indicating low bone mineral density. Almost 40% of the women had prior fractures in adulthood, mostly non-vertebral, non-hip in nature, 30% of whom had at least two fractures and more than half experienced moderate/severe pain or fatigue. Bisphosphonates were the most common type of bone loss treatment prescribed in the 12 months preceding the study. CONCLUSIONS: POSSIBLE EU® characterises postmenopausal women with low bone mass, exhibiting a high rate of prevalent fracture, substantial bone fragility and overall comorbidity burden. Clinical strategies for managing osteoporosis in this population varied across the five participating European countries, reflecting their different guidelines, regulations and standards of care.


Reiki for Pain During Hemodialysis: A Feasibility and Instrument Evaluation Study.
Pain is a problem for individuals undergoing hemodialysis. Renal disease, comorbidities, concurrent symptoms, and dialysis procedures pose barriers to adequate pain management. The purpose of this study was to evaluate feasibility, examine construct validity of The Patient-Reported Outcomes Measurement Information System (PROMIS) computerized adaptive testing (CAT) instruments, and explore pain benefits of Reiki sessions conducted during hemodialysis. A one group, repeated-measures design was used. Fifteen participants received Reiki for 20 minutes, twice a week for 4 weeks. Pain, fatigue, and depression were evaluated using established symptom scales and PROMIS CAT instruments. Participants reported general relaxation feelings with Reiki and acceptability of using a touch-screen device to respond to web-based measures. Although staff were initially reluctant to engage patients for Reiki, they reported Reiki did not interfere with workflow and thought Reiki could be integrated into the practice setting. Significant, strong correlations with established symptom scales support construct validity of PROMIS CAT instruments. There was a significant decrease in mean symptom scores after four weeks of Reiki. Effect size values suggest a range of practical significance. Findings suggest Reiki provides symptom relief for individuals receiving hemodialysis, and randomized clinical trials to establish Reiki's pain benefits in this population are warranted.


Copy, edit, and paste: natural product approaches to biomaterials and neuroengineering.
Progress in the chemical sciences has formed the world we live in, both on a macroscopic and on a nanoscopic scale. The last century witnessed the development of high performance materials that interact with humans on many layers, from clothing to construction, from media to medical devices. On a molecular level, natural products and their derivatives influence many biological processes, and these compounds have enormously contributed to the health and quality of living of humans. Although coatings of stone materials with oils or resins (containing natural products) have led to improved tools already millennia ago, in contrast today, natural product approaches to designer materials, that is, combining the best of both worlds, remain scarce. In this Account, we will summarize our recent research efforts directed to the generation of natural product functionalized materials, exploiting the strategy of "copy, edit, and paste with natural products". Natural products embody the wisdom of evolution, and only total synthesis is able to unlock the secrets enshrined in their molecular structure. We employ total synthesis ("copy") as a scientific approach to address problems related to molecular structure, the biosynthesis of natural products, and their bioactivity. Additionally, the fundamental desire to investigate the mechanism of action of natural products constitutes a key driver for scientific inquiry. In an emerging area of relevance to society, we have prepared natural products such as militarinone D that can stimulate neurite outgrowth and facilitate nerve regeneration. This knowledge obtained by synthetic organic chemistry on complex natural products can then be used to design structurally simplified compounds that retain the biological power of the parent natural product ("edit"). This process, sometimes referred to as function-oriented synthesis, allows obtaining derivatives with better properties, improving their chemical tractability and reducing the step count of the synthesis. Along these lines, we have demonstrated that militarinone D can be truncated to yield structurally simplified analogs with improved activity. Finally, with the goal of designing bioactive materials, we have immobilized functionally optimized, neuritogenic natural products ("paste"). These materials could facilitate nerve regeneration, act as nerve guidance conduits, or lead to new approaches in neuroengineering. Based on the surface-adhesive properties of electron-deficient catecholates and the knowledge gathered on neuritogenic natural product derivatives, two mechanistically different design principles have been applied to generate neuritogenic materials. In conclusion, natural products, and their functionally optimized analogs, present a large, mostly untapped reservoir of powerful modulators of biological systems, and their hybridization with materials can lead to new approaches in various fields, from biofilm prevention to neuroengineering.


The pH dependence of polymerization and bundling by the essential bacterial cytoskeletal protein FtsZ.
There is a growing body of evidence that bacterial cell division is an intricate coordinated process of comparable complexity to that seen in eukaryotic cells. The dynamic assembly of Escherichia coli FtsZ in the presence of GTP is fundamental to its activity. FtsZ polymerization is a very attractive target for novel antibiotics given its fundamental and universal function. In this study our aim was to understand further the GTP-dependent FtsZ polymerization mechanism and our main focus is on the pH dependence of its behaviour. A key feature of this work is the use of linear dichroism (LD) to follow the polymerization of FtsZ monomers into polymeric structures. LD is the differential absorption of light polarized parallel and perpendicular to an orientation direction (in this case that provided by shear flow). It thus readily distinguishes between FtsZ polymers and monomers. It also distinguishes FtsZ polymers and less well-defined aggregates, which light scattering methodologies do not. The polymerization of FtsZ over a range of pHs was studied by right-angled light scattering to probe mass of FtsZ structures, LD to probe real-time formation of linear polymeric fibres, a specially developed phosphate release assay to relate guanosine triphosphate (GTP) hydrolysis to polymer formation, and electron microscopy (EM) imaging of reaction products as a function of time and pH. We have found that lowering the pH from neutral to 6.5 does not change the nature of the FtsZ polymers in solution--it simply facilitates the polymerization so the fibres present are longer and more abundant. Conversely, lowering the pH to 6.0 has much the same effect as introducing divalent cations or the FtsZ-associated protein YgfE (a putative ZapA orthologue in E. coli)--it stabilizes associations of protofilaments.


Variations in habitat, season, flower traits and pollinators in dimorphic Narcissus tazetta L. (Amaryllidaceae) in Israel.
Narcissus tazetta shows a genetically-based discrete polymorphism for style length similar to that well known in heterostylous plants. Plants are either short- (S) or long-styled (1). In Israel, marsh populations are dominated by S plants and hill populations by L plants. Populations differ in size, flowering time and duration, flower orientation, inflorescence display, vegetative reproduction, and pollinators. The main visitors to flowers in marshes are hawkmoths, whereas in the hills they are visited by short-tongued insects: solitary bees and hoverflies. The pollination efficiency of these insects was investigated by studying foraging behaviour, visit rate, and pollen deposition on stigmas. Our findings are consistent with the hypothesis of lower efficiency of pollination of S flowers by short-tongued insects, resulting in the exclusion of this morph from the hills. Additionally, we considered the possibility that there might be pollination ecotypes corresponding to the two habitats (marsh and hill) and examined variation in a set of continuous flower traits related to pollination biology. Flower tube length was the only trait showing a distinct difference between the two habitat types. Although the concentration of nectar was not different between habitats, L flowers presented more concentrated nectar than S flowers. Such a difference in nectar concentration may he of adaptive value for the pollination of the L flowers by short-tongued pollinators in the hills.


Signal recognition particle receptor is important for cell growth and protein secretion in Saccharomyces cerevisiae.
In mammalian cells, the signal recognition particle (SRP) receptor is required for the targeting of nascent secretory proteins to the endoplasmic reticulum (ER) membrane. We have identified the Saccharomyces cerevisiae homologue of the alpha-subunit of the SRP receptor (SR alpha) and characterized its function in vivo. S. cerevisiae SR alpha is a 69-kDa peripheral membrane protein that is 32% identical (54% chemically similar) to its mammalian homologue and, like mammalian SR alpha, is predicted to contain a GTP binding domain. Yeast cells that contain the SR alpha gene (SRP101) under control of the GAL1 promoter show impaired translocation of soluble and membrane proteins across the ER membrane after depletion of SR alpha. The degree of the translocation defect varies for different proteins. The defects are similar to those observed in SRP deficient cells. Disruption of the SRP101 gene results in an approximately sixfold reduction in the growth rate of the cells. Disruption of the gene encoding SRP RNA (SCR1) or both SCR1 and SRP101 resulted in an indistinguishable growth phenotype, indicating that SRP receptor and SRP function in the same pathway. Taken together, these results suggest that the components and the mechanism of the SRP-dependent protein targeting pathway are evolutionarily conserved yet not essential for cell growth. Surprisingly, cells that are grown for a prolonged time in the absence of SRP or SRP receptor no longer show pronounced protein translocation defects. This adaptation is a physiological process and is not due to the accumulation of a suppressor mutation. The degree of this adaptation is strain dependent.


Is there a place for pediatric valvotomy in the autograft era?
Valvotomy and the autograft procedure are the most common surgical treatment options for children with valvular aortic stenosis. We evaluated the results of these surgical procedures in our institution. Retrospective analysis was done of all patients presenting with aortic stenosis and operated upon before the age of 18. In 11 patients a valvotomy was performed and in 36 an autograft procedure. There was no hospital mortality. Mean follow-up in the valvotomy group was 4.8 years (SD 3.3), in the autograft group 4.5 years (SD 3.3). During follow-up one patient died suddenly 2 months after valvotomy. Two patients in the autograft group died (not valve-related). After valvotomy three patients underwent a balloon valvotomy, in one followed by an autograft procedure and one patient had a repeat valvotomy. In the autograft group one patient was reoperated for severe aortic regurgitation and moderate pulmonary stenosis. At last echocardiography after valvotomy (eight remaining patients) in only two patients (25%) no aortic stenosis or regurgitation was present. In the remaining six patients aortic stenosis is mild in two and moderate in three, including one with moderate aortic regurgitation. In one patient without stenosis, moderate aortic regurgitation was seen. No pulmonary stenosis or regurgitation is present. Echocardiography after autografting (33 remaining patients) showed no aortic stenosis. Aortic regurgitation was mild in seven patients, moderate in two, severe in one. Pulmonary stenosis was present in two patients (16%). Pulmonary regurgitation was mild in three patients and moderate in one. In selected patients with valvular aortic stenosis who are beyond infancy, valvotomy may be adequate and may postpone further surgery for a significant length of time. After valvotomy the main problem is residual aortic stenosis while after autografting a shift occurs to aortic regurgitation and problems related to the pulmonary valve. Careful clinical and echocardiographic follow-up is therefore warranted in young patients after the autograft procedure.


Detection of 'Candidatus Neoehrlichia mikurensis' and other Anaplasmataceae and Rickettsiaceae in Canidae in Switzerland and Mediterranean countries.
'Candidatus Neoehrlichia mikurensis' is an emerging tick-borne zoonotic agent that primarily affects immunocompromised human patients. Dogs and foxes are frequently exposed to ticks, and both species are in close proximity to humans. This is the first study to systematically investigate the occurrence of 'Candidatus Neoehrlichia mikurensis' in Canidae in Europa. We analyzed 1'739 blood samples from dogs in Switzerland, Italy, Spain and Portugal and 162 blood samples from free-ranging red foxes (Vulpes vulpes) in Switzerland. All samples were tested using a previously described multiplex real-time PCR for the Anaplasmataceae family, the 'Candidatus Neoehrlichia' genus and the 'Candidatus Neoehrlichia mikurensis' species. All Anaplasmataceae positive samples were subsequently tested using specific real-time PCRs for Anaplasma phagocytophilum, Anaplasma platys, Ehrlichia canis and Rickettsia helvetica. Among the tested animals, one dog from Zurich tested positive for 'Candidatus Neoehrlichia mikurensis'. The 12-year old West Highland white terrier had been splenectomized 3 months prior to the blood collection and presented with polyuria/polydipsia. Fanconi syndrome was diagnosed based on glucosuria with normoglycemia and hyperaminoaciduria. A. platys and E. canis were detected in 14/249 dogs from Sicily and Portugal; two of the dogs were coinfected with both agents. Four Swiss foxes tested positive for A. phagocytophilium. R. helvetica was detected for the first time in a red fox. In conclusion, 'Candidatus Neoehrlichia mikurensis' infection should be considered in sick dogs, particularly when immunocompromised. The pathogen seems not to be widespread in Canidae in the investigated countries. Conversely, other Anaplasmataceae were more readily detected in dogs and foxes.


Antiviral strategies against influenza virus: towards new therapeutic approaches.
Influenza viruses are major human pathogens responsible for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need annual updating and give limited protection. Only two classes of drugs are currently approved for the treatment of influenza: M2 ion channel blockers and neuraminidase inhibitors. However, they are often associated with limited efficacy and adverse side effects. In addition, the currently available drugs suffer from rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Several new classes of antiviral agents targeting viral replication mechanisms or cellular proteins/processes are under development. This review gives an overview of novel strategies targeting the virus and/or the host cell for counteracting influenza virus infection.


Plasticization of a protein-based film by glycerol: a spectroscopic, mechanical, and thermal study.
Kafirin, the seed storage protein of the cereal sorghum, is highly homologous with the maize storage protein zein. The effects of plasticisation of a kafirin film by glycerol in the absence of water were examined by a combination of spectroscopic (NMR and infrared), rheological, and calorimetric methods. The results suggest that at low glycerol levels the glycerol is absorbed onto and possibly into the protein. Increasing the level of glycerol increases the motion of the protein and changes the protein conformation. There are corresponding changes of the mechanical properties of protein films. At 40% (w/w) of glycerol, two glass transition temperatures were observed, one of which corresponded to the glass transition temperature of pure glycerol. This result indicates that at this level of plasticizer there are sufficient glycerol/glycerol interactions occurring to allow a separate glass formation process for glycerol.


Postprandial glycaemic, lipaemic and haemostatic responses to ingestion of rapidly and slowly digested starches in healthy young women.
The objective of the present study was to investigate the postprandial metabolism of two starches with contrasting rates of hydrolysis in vitro. Characterized using the Englyst method of in vitro starch classification, C*Set 06 598 contained predominantly rapidly digestible starch and C*Gel 04 201 contained predominantly slowly digestible starch. Each test starch, naturally enriched with 13C, was fed to ten healthy female volunteers as part of a moderate fat test meal (containing 75 g test starch and 21 g fat), in a double-blind randomized crossover design. The metabolic response to each starch was measured after an overnight fast, in an acute 6 h study, before and after 14 d of daily consumption of 75 g test starch. During each acute study, blood samples were taken at 15 min intervals for the first 2 h and at 30 min intervals for the remaining 4 h. Breath 13CO2 enrichment was measured at the same time points and indirect calorimetry was performed for 20 min every 40 min immediately before and throughout the study. Significantly more rapid, greater changes in postprandial plasma glucose, NEFA and serum insulin concentrations were observed after consumption of the rapidly digestible starch. Breath 13CO2 output over the first 3-4 h rose rapidly then began to decline following consumption of the rapidly digestible starch, but plateaued for the slowly digestible starch. The 14 d adaptation period did not affect any of the glycaemic or lipaemic variables but there was a reduction in postprandial plasminogen activator inhibitor-1 concentrations. These data confirm that starches characterized as predominantly rapidly digestible versus slowly digestible by the Englyst procedure provoke distinctly different patterns of metabolism postprandially.


Variability of gene expression profiles in human blood and lymphoblastoid cell lines.
Readily accessible samples such as peripheral blood or cell lines are increasingly being used in large cohorts to characterise gene expression differences between a patient group and healthy controls. However, cell and RNA isolation procedures and the variety of cell types that make up whole blood can affect gene expression measurements. We therefore systematically investigated global gene expression profiles in peripheral blood from six individuals collected during two visits by comparing five of the following cell and RNA isolation methods: whole blood (PAXgene), peripheral blood mononuclear cells (PBMCs), lymphoblastoid cell lines (LCLs), CD19 and CD20 specific B-cell subsets. Gene expression measurements were clearly discriminated by isolation method although the reproducibility was high for all methods (range rho = 0.90-1.00). The PAXgene samples showed a decrease in the number of expressed genes (P < 1*10(-16)) with higher variability (P < 1*10(-16)) compared to the other methods. Differentially expressed probes between PAXgene and PBMCs were correlated with the number of monocytes, lymphocytes, neutrophils or erythrocytes. The correlations (rho = 0.83; rho = 0.79) of the expression levels of detected probes between LCLs and B-cell subsets were much lower compared to the two B-cell isolation methods (rho = 0.98). Gene ontology analysis of detected genes showed that genes involved in inflammatory responses are enriched in B-cells CD19 and CD20 whereas genes involved in alcohol metabolic process and the cell cycle were enriched in LCLs. Gene expression profiles in blood-based samples are strongly dependent on the predominant constituent cell type(s) and RNA isolation method. It is crucial to understand the differences and variability of gene expression measurements between cell and RNA isolation procedures, and their relevance to disease processes, before application in large clinical studies.


Ecological implications of single and mixed nitrogen nutrition in Arabidopsis thaliana.
Ecologists recognize that plants capture nitrogen in many chemical forms that include amino acids. Access to multiple nitrogen types in plant communities has been argued to enhance plant performance, access to nitrogen and alter ecological interactions in ways that may promote species coexistence. However, data supporting these arguments have been limited. While it is known that plants uptake amino acids from soil, long term studies that link amino acid uptake to measures of plant performance and potential reproductive effort are not typically performed. Here, a series of experiments that link uptake of nitrate, glutamine or asparagine with lifetime reproductive effort in Arabidopsis thaliana are reported. Nitrogen was offered either singly or in mixture and at a variety of combinations. Traits related to reproductive output were measured, as was the preference for each type of nitrogen. When plants were supplied with a single nitrogen type at concentrations from 0.1-0.9 mM, the ranking of nitrogen types was nitrate > glutamine > asparagine in terms of the relative performance of plants. When plants were supplied with two types of nitrogen in mixture at ratios between 0.1:0.9-0.9:0.1 mM, again plants performed best when nitrate was present, and poorly when amino acids were mixed. Additionally, stable isotopes revealed that plants preferentially captured nitrogen types matching the hierarchy of nitrate > glutamine > asparagine. Comparing between the two experiments revealed that mixed nitrogen nutrition was a net cost to the plants. Plant performance on mixed nitrogen was less than half the performance on equal amounts of any single nitrogen type. We asked: why did A. thaliana capture amino acids when doing so resulted in a net cost? We argue that available data cannot yet answer this question, but hypothesize that access to lower quality forms of nitrogen may become important when plants compete.


Observational analytic studies in multiple sclerosis: controlling bias through study design and conduct. The Australian Multicentre Study of Environment and Immune Function.
Rising multiple sclerosis incidence over the last 50 years and geographic patterns of occurrence suggest an environmental role in the causation of this multifactorial disease. Design options for epidemiological studies of environmental causes of multiple sclerosis are limited by the low incidence of the disease, possible diagnostic delay and budgetary constraints. We describe scientific and methodological issues considered in the development of the Australian Multicentre Study of Environment and Immune Function (the Ausimmune Study), which seeks, in particular, to better understand the causes of the well-known MS positive latitudinal gradient. A multicentre, case-control design down the eastern seaboard of Australia allows the recruitment of sufficient cases for adequate study power and provides data on environmental exposures that vary by latitude. Cases are persons with an incident first demyelinating event (rather than prevalent multiple sclerosis), sourced from a population base using a two tier notification system. Controls, matched on sex, age (within two years) and region of residence, are recruited from the general population. Biases common in case-control studies, eg, prevalence-incidence bias, admission-rate bias, non-respondent bias, observer bias and recall bias, as well as confounding have been carefully considered in the study design and conduct of the Ausimmune Study.


Effect of physical activity, social support, and skills training on late-life emotional health: a systematic literature review and implications for public health research.
Given that emotional health is a critical component of healthy aging, we undertook a systematic literature review to assess whether current interventions can positively affect older adults' emotional health. A national panel of health services and mental health researchers guided the review. Eligibility criteria included community-dwelling older adult (aged ≥ 50 years) samples, reproducible interventions, and emotional health outcomes, which included multiple domains and both positive (well-being) and illness-related (anxiety) dimensions. This review focused on three types of interventions - physical activity, social support, and skills training - given their public health significance and large number of studies identified. Panel members evaluated the strength of evidence (quality and effectiveness). In all, 292 articles met inclusion criteria. These included 83 exercise/physical activity, 25 social support, and 40 skills training interventions. For evidence rating, these 148 interventions were categorized into 64 pairings by intervention type and emotional health outcome, e.g., strength training targeting loneliness or social support to address mood. 83% of these pairings were rated at least fair quality. Expert panelists found sufficient evidence of effectiveness only for skills training interventions with health outcomes of decreasing anxiety and improving quality of life and self-efficacy. Due to limitations in reviewed studies, many intervention-outcome pairings yielded insufficient evidence. Skills training interventions improved several aspects of emotional health in community-dwelling older adults, while the effects for other outcomes and interventions lacked clear evidence. We discuss the implications and challenges in moving forward in this important area.


FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis.
FOXA1, estrogen receptor alpha (ERalpha) and GATA3 independently predict favorable outcome in breast cancer patients, and their expression correlates with a differentiated, luminal tumor subtype. As transcription factors, each functions in the morphogenesis of various organs, with ERalpha and GATA3 being established regulators of mammary gland development. Interdependency between these three factors in breast cancer and normal mammary development has been suggested, but the specific role for FOXA1 is not known. Herein, we report that Foxa1 deficiency causes a defect in hormone-induced mammary ductal invasion associated with a loss of terminal end bud formation and ERalpha expression. By contrast, Foxa1 null glands maintain GATA3 expression. Unlike ERalpha and GATA3 deficiency, Foxa1 null glands form milk-producing alveoli, indicating that the defect is restricted to expansion of the ductal epithelium, further emphasizing the novel role for FOXA1 in mammary morphogenesis. Using breast cancer cell lines, we also demonstrate that FOXA1 regulates ERalpha expression, but not GATA3. These data reveal that FOXA1 is necessary for hormonal responsiveness in the developing mammary gland and ERalpha-positive breast cancers, at least in part, through its control of ERalpha expression.


Remediating Residual Rhotic Errors With Traditional and Ultrasound-Enhanced Treatment: A Single-Case Experimental Study.
Purpose The aim of the study was to examine how ultrasound visual feedback (UVF) treatment impacts speech sound learning in children with residual speech errors affecting /ɹ/. Method Twelve children, ages 9-14 years, received treatment for vocalic /ɹ/ errors in a multiple-baseline across-subjects design comparing 8 sessions of UVF treatment and 8 sessions of traditional (no-biofeedback) treatment. All participants were exposed to both treatment conditions, with order counterbalanced across participants. To monitor progress, naïve listeners rated the accuracy of vocalic /ɹ/ in untreated words. Results After the first 8 sessions, children who received UVF were judged to produce more accurate vocalic /ɹ/ than those who received traditional treatment. After the second 8 sessions, within-participant comparisons revealed individual variation in treatment response. However, group-level comparisons revealed greater accuracy in children whose treatment order was UVF followed by traditional treatment versus children who received the reverse treatment order. Conclusion On average, 8 sessions of UVF were more effective than 8 sessions of traditional treatment for remediating vocalic /ɹ/ errors. Better outcomes were also observed when UVF was provided in the early rather than later stages of learning. However, there remains a significant individual variation in response to UVF and traditional treatment, and larger group-level studies are needed. Supplemental Material https://doi.org/10.23641/asha.8206640.


Compressed sensing MRI: a review of the clinical literature.
MRI is one of the most dynamic and safe imaging techniques available in the clinic today. However, MRI acquisitions tend to be slow, limiting patient throughput and limiting potential indications for use while driving up costs. Compressed sensing (CS) is a method for accelerating MRI acquisition by acquiring less data through undersampling of k-space. This has the potential to mitigate the time-intensiveness of MRI. The limited body of research evaluating the effects of CS on MR images has been mostly positive with regards to its potential as a clinical tool. Studies have successfully accelerated MRI with this technology, with varying degrees of success. However, more must be performed before its diagnostic efficacy and benefits are clear. Studies involving a greater number radiologists and images must be completed, rating CS based on its diagnostic efficacy. Also, standardized methods for determining optimal imaging parameters must be developed.


Pressure points in primary care: blood pressure and management of hypertension in 532 050 patients from 2005 to 2010.
Hypertension results in high morbidity and mortality. Its management is predominantly undertaken in the primary care setting. The aim of this study was to assess trends in blood pressure (BP) and hypertensive management in primary care in Australia. A retrospective analysis of patient-based electronic medical records was conducted. Antihypertensive therapy was determined by prescription data. We identified 532 050 patients (55% women, average age 54 ± 18 years) being managed by 733 general practitioners from 286 clinics Australia-wide who had at least one visit with BP recorded between 2005 and 2010. Average BP did not change and men had consistently higher levels than women (132/79 vs. 127/77 mmHg, P < 0.001). At least 25% of all individuals had a visit where elevated BP more than 140/90 mmHg was recorded. Up to 50% of patients on antihypertensive therapy had a BP more than 140/90 mmHg. In any year, the odds of elevated BP more than 140/90 mmHg were three-fold to four-fold higher in treated individuals (yearly range OR 3.0-3.97; 95% CI 2.93-3.83 to 3.08-4.10). Over annual contiguous visits in 51 721 patients with BP more than 140/90 mmHg, BP decreased after two visits and then remained stable (P < 0.001) irrespective of frequency of visits or antihypertensive treatment. Individuals with more frequent visits were more likely to attain target BP less than 140/90 mmHg [OR 1.08 (three visits) to 1.29 (five visits); 95% CI range 1.03-1.38]. In the absence of any significant gains in the community control of hypertension since 2005, a more intensive approach to BP management in primary care is required to ensure more patients achieve BP targets.


Platelet disorders in adolescents.
Acquired and inherited platelet disorders can present with bleeding symptoms during adolescence. Platelet disorders include disorders of platelet number and disorders of platelet function. In adolescent females with platelet disorders, menorrhagia is a common presenting bleeding symptom. Other associated bleeding symptoms are also primarily mucocutaneous, including epistaxis and bruising. Excessive bleeding may also occur after hemostatic challenges. Diagnosis of disorders of platelet function usually requires light transmission platelet aggregometry. Management of menorrhagia in the adolescent with platelet disorders requires both hematologic and gynecologic treatment.


Bayesian inference of agent-based models: a tool for studying kidney branching morphogenesis.
The adult mammalian kidney has a complex, highly-branched collecting duct epithelium that arises as a ureteric bud sidebranch from an epithelial tube known as the nephric duct. Subsequent branching of the ureteric bud to form the collecting duct tree is regulated by subcellular interactions between the epithelium and a population of mesenchymal cells that surround the tips of outgrowing branches. The mesenchymal cells produce glial cell-line derived neurotrophic factor (GDNF), that binds with RET receptors on the surface of the epithelial cells to stimulate several subcellular pathways in the epithelium. Such interactions are known to be a prerequisite for normal branching development, although competing theories exist for their role in morphogenesis. Here we introduce the first agent-based model of ex vivo kidney uretic branching. Through comparison with experimental data, we show that growth factor-regulated growth mechanisms can explain early epithelial cell branching, but only if epithelial cell division depends in a switch-like way on the local growth factor concentration; cell division occurring only if the driving growth factor level exceeds a threshold. We also show how a recently-developed method, "Approximate Approximate Bayesian Computation", can be used to infer key model parameters, and reveal the dependency between the parameters controlling a growth factor-dependent growth switch. These results are consistent with a requirement for signals controlling proliferation and chemotaxis, both of which are previously identified roles for GDNF.


Recent advances in mantle cell lymphoma: report of the 2012 Mantle Cell Lymphoma Consortium Workshop.
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by overexpression of cyclin D1 and the t(11;14)(q13;q32) chromosomal translocation. MCL is biologically and clinically heterogeneous and frequently disseminates to extranodal areas. While a subset of patients have an indolent clinical course, the overall outcome for patients with MCL remains poor. There is no proven curative therapy, and no standard of care has been established for initial or subsequent lines of therapy. Several regimens are highly active in previously untreated patients, and recent research has led to improvements in currently available therapy. Moreover, investigational agents have recently demonstrated promising activity in clinical trials. A workshop was held to review recent data on MCL pathogenesis, novel molecular targets and alternative approaches to immunotherapy, and to discuss recent and ongoing clinical trials in MCL. The presentations are summarized in this article, which is intended to highlight areas of active investigation and identify important avenues for future research.


The problem of defensive medicine.
Defensive medicine--the use of diagnostic and end-treatment measures explicitly for the purposes of averting malpractice suits--is frequently cited as one of the least desirable effects of the current rise in medical litigation. Many physicians and policy-makers claim that defensive medicine is responsible not only for the increasing costs of health care but the exposing of patients to significant risks of harm from unnecessary procedures. Very little solid information is available about defensive medicine. The studies that have been conducted have been fraught with statistical difficulties and are by no means definitive. Even more important than the issue of defensive medicine is the more basic problem of our system of compensation for medical injuries.


Comparison of DNA Damage and Oxidative Stress in Patients Anesthetized With Desflurane Associated or Not With Nitrous Oxide: A Prospective Randomized Clinical Trial.
Little is known about the effects of desflurane associated or not with nitrous oxide (N2O) on oxidative stress and patient genetic material. The aim of this study was to compare the effects of anesthesia maintained with desflurane associated or not with N2O on DNA damage (as a primary outcome) and oxidative stress (as a secondary outcome) in patients who underwent an elective minimally invasive surgery. This prospective randomized clinical trial analyzed 40 patients of both sexes with an American Society of Anesthesiologists physical status I who were 18-50 years of age and scheduled for septoplasty. The patients were randomly allocated into 2 groups according to anesthesia maintenance as follows: desflurane (n = 20) or desflurane/N2O (n = 20). Blood samples were collected before anesthesia (T1 = baseline), 1.5 hours after anesthesia induction (T2), and on the morning of the postoperative first day (T3). Basal and oxidative DNA damage (determined using formamidopyrimidine DNA glycosylase to detect oxidized purines and endonuclease III to detect oxidized pyrimidines) were evaluated using the comet assay. Oxidative stress markers were evaluated based on lipid peroxidation (by assessing 4-hydroxynonenal and 8-iso-prostaglandin F2α [8-isoprostane] using enzyme linked immunosorbent immunoassay), protein carbonyls (assessed by enzyme linked immunosorbent immunoassay), and antioxidant defense (ferric-reducing antioxidant power by spectrophotometry). The effect size was expressed as the mean differences between groups and the corresponding 95% confidence interval (CI). There was no significant mean difference between groups in relation to DNA damage (-1.7 [95% CI, -7.0 to 3.5]), oxidized DNA pyrimidines (-1.8 [95% CI, -12.5 to 8.9]) and purines (-1.9 [95% CI, -13.9 to 10.1]), 4-hydroxynonenal (-0.2 [95% CI, -2.8 to 2.4]), 8-isoprostane (549 [95% CI, -2378 to 3476]), protein carbonyls (0.2 [95% CI, -2.1 to 2.3]), or ferric-reducing antioxidant power (24 [95% CI, -52.0 to 117.2]). The coadministration of 60% N2O with desflurane did not seem to impair the effects on DNA or the redox status compared with desflurane anesthesia, suggesting that both studied anesthetic techniques can be suitable options for healthy individuals who undergo minimally invasive surgery lasting at least 1.5 hours. However, due to the low power of the study, more research is necessary to confirm our findings.


Effect of tea tree (Melaleuca alternifolia) oil as a natural antimicrobial agent in lipophilic formulations.
There has been increased interest surrounding the use of tea tree oil (TTO) as a natural antimicrobial. In this study, the antimicrobial activity of TTO and its components were investigated in vitro and in a predominantly lipid-based personal care formulation. In vitro, TTO showed minimal inhibitory concentrations of 0.2% (for Saccharomyces cerevisiae and Pythium sulcatum), 0.4% (for Escherichia coli, Bacillus subtilis, and Rhizopus stolonifer), and 0.8% (for Botrytis cinerea). TTO at 0.08%-0.8% was often as efficient as parabens. Comparison of the antimicrobial activities of TTO components showed that terpinen-4-ol and γ-terpinene were generally most effective in inhibiting microbial growth. TTO activity in a personal care product was evaluated through air and water exposure, artificial inoculation, and shelf life studies. While TTO did not increase shelf life of unopened products, it decreased microbial load in products exposed to water and air. Results from this study support that antimicrobial activity of TTO can be attributed to varying levels of its components and that low levels of TTO were effective in reducing microbial growth during the use of the product. This study showed that TTO can act as a suitable preservative system within an oil-based formulation.