Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial.
Trastuzumab (Herceptin(R)) improves disease-free survival (DFS) and overall survival for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess the magnitude of its clinical benefit for subpopulations defined by nodal and steroid hormone receptor status using data from the Herceptin Adjuvant (HERA) study. HERA is an international multicenter randomized trial comparing 1 or 2 years of trastuzumab treatment with observation after standard chemotherapy in women with HER2-positive breast cancer. In total, 1703 women randomized to 1-year trastuzumab and 1698 women randomized to observation were included in these analyses. Median follow-up was 23.5 months. The primary endpoint was DFS. The overall hazard ratio (HR) for trastuzumab versus observation was 0.64 [95% confidence interval (CI) 0.54-0.76; P < 0.0001], ranging from 0.46 to 0.82 for subgroups. Estimated improvement in 3-year DFS in subgroups ranged from +11.3% to +0.6%. Patients with the best prognosis (those with node-negative disease and tumors 1.1-2.0 cm) had benefit similar to the overall cohort (HR 0.53, 95% CI 0.26-1.07; 3-year DFS improvement +4.6%, 95% CI -4.0% to 13.2%). Adjuvant trastuzumab therapy reduces the risk of relapse similarly across subgroups defined by nodal status and steroid hormone receptor status, even those at relatively low risk for relapse.


Relationships between the arteries and veins and the connective tissue system in the human orbit.
The arteries and veins in the apical region of the orbit occupy different areas. Furthermore, there is a difference in their relationships to the connective tissue system. In this part of the orbit, where only a few connective tissue septa are present, the arteries are mainly concentrated in the inner-space. The veins, on the other hand, are predominantly found peripherally, outside the muscle cone. The arteries are surrounded by adipose tissue. They are only in contact with connective tissue fibres when perforating the septa on their way to the outer regions of the inner-space. A small number of vessels, the posterior ciliary arteries and the central artery of the retina, keep their central position, grouped around the optic nerve. The conduct of this group of arteries in respect to the connective tissue is somewhat different than that of the other arteries. The ciliary arteries and the central retinal artery have varying contacts with the optic sheath. In contrast to the arteries, which in general lack firm connections with fibrous connective tissue, the major veins are encased in the tight connective tissue of the orbital fissures, or enveloped in connective tissue septa. For the smaller veins, these fibrous relationships are usually less intimate and occasionally disrupted. More extensive discussion and conclusions will be given in the following article. This will deal with the rest of the retrobulbar part of the orbit.


Pre-existing cardiovascular diseases and glycemic control in patients with type 2 diabetes mellitus in Europe: a matched cohort study.
Although there is a growing body of evidence showing that patients with type 2 diabetes mellitus (T2DM) have poor glycemic control in general, it is not clear whether T2DM patients with pre-existing cardiovascular diseases (CVD) are more or less likely to have good glycemic control than patients without pre-existing CVD. Our aim was to examine the degree of glycemic control among T2DM patients in Europe with and without pre-existing CVD. This is a matched cohort study based on a multi-center, observational study with retrospective medical chart reviews of T2DM patients in Spain, France, United Kingdom, Norway, Finland, Germany, and Poland. Included patients were aged >= 30 years at time of diagnosis of T2DM, had added a SU or a PPARgamma agonist to failing metformin monotherapy (index date) and had pre-existing CVD (cases). A control cohort with T2DM without pre-existing CVD was identified using 1:1 propensity score matching. With difference-in-difference approach, logistic and linear regression analyses were applied to identify differences in glycemic control by CVD during the follow up period, after controlling for baseline demographics, clinical information, and concurrent anti-hyperglycemic medication use. The percentage of case patients with adequate glycemic control relative to control patients during the 1st, 2nd, 3rd, and 4th years after the index date was 19.9 vs. 26.5, 16.8 vs. 26.5, 18.8 vs. 28.3, and 16.8 vs. 23.5 respectively. Cases were significantly less likely to have adequate glycemic control (odds ratio: 0.62; 95% confidence interval: 0.46-0.82) than controls after adjusting for baseline differences, secular trend, and other potential confounding covariates. T2DM patients with pre-existing CVD tended to have poorer glycemic control than those without pre-existing CVD, all other factors being equal. It suggests that clinicians may need to pay more attention to glycemic control among T2DM patients with CVD.


Women's health and behavioral health issues in health care reform.
As health care reform promises to change the landscape of health care delivery, its potential impact on women's health looms large. Whereas health and mental health systems have historically been fragmented, the Affordable Care Act (ACA) mandates integrated health care as the strategy for reform. Current systems fragment women's health not only in their primary care, mental health, obstetrical, and gynecological needs, but also in their roles as the primary caregivers for parents, spouses, and children. Changes in reimbursement, and in restructuring financing and care coordination systems through accountable care organizations and medical homes, will potentially improve women's health care.


A portable magnet for radiation biology and dosimetry studies in magnetic fields.
In the current and rapidly evolving era of real-time MRI-guided radiotherapy, our radiation biology and dosimetry knowledge is being tested in a novel way. This paper presents the successful design and implementation of a portable device used to generate strong localized magnetic fields. These are ideally suited for small-scale experiments that mimic the magnetic field environment inside an MRI-linac system, or more broadly MRI-guided particle therapy as well. A portable permanent magnet-based device employing an adjustable steel yoke and magnetic field focusing cones has been designed, constructed, and tested. The apparatus utilizes two banks of Nd 2 $_{2}$ Fe 14 $_{14}$ B permanent magnets totaling around 50 kg in mass to generate a strong magnetic field throughout a small volume between two pole tips. The yoke design allows adjustment of the pole tip gap and exchanging of the focusing cones. Further to this, beam portal holes are present in the yoke and focusing cones, allowing for radiation beams of up to 5 × $\times$ 5 cm 2 $^{2}$ to pass through the region of high magnetic field between the focusing cone tips. Finite element magnetic modeling was performed to design and characterize the performance of the device. Automated physical measurements of the magnetic field components at various locations were measured to confirm the performance. The adjustable pole gap and interchangeable cones allows rapid changing of the experimental set-up to allow different styles of measurements to be performed. A mostly uniform magnetic field of 1.2 T can be achieved over a volume of at least 3 × $\times$ 3 × $\times$ 3 cm 3 $^{3}$ . This can be reduced in strength to 0.3 T but increased in volume to 10 × $\times$ 10 × $\times$ 10 cm 3 $^{3}$ via removal of the cone tips and/or adjustment of the steel yoke. Although small, these volumes are sufficient to house radiation detectors, cell culture dishes, and various phantom arrangements targeted at examining small radiation field dosimetry inside magnetic field strengths that can be changed with ease. Most important is the ability to align the magnetic field both perpendicular to, or inline with, the radiation beam. To date, the system has been successfully used to conduct published research in the areas of radiation detector performance, lung phantom dosimetry, and how small clinical electron beams behave in these strong magnetic fields. A portable, relatively inexpensive, and simple to operate device has successfully been constructed and used for performing radiation oncology studies around the theme of MRI-guided radiotherapy. This can be in either inline and perpendicular magnetic fields of up to 1.2 T with x-ray and particle beams.


Effects of L-carnitine supplementation on respiratory distress syndrome development and prognosis in premature infants: A single blind randomized controlled trial.
The aim of the present study was to investigate the efficacy of L-carnitine therapy on the occurrence and prognosis of respiratory distress syndrome (RDS). A single blind, randomized controlled trial study was conducted on 130 infants with gestational ages of 28-36 weeks. Infants were assigned to experimental groups (groups 1 and 2) and control groups (groups 3 and 4). Groups 1 and 3 consisted of infants with RDS, and groups 2 and 4 groups were composed of infants without RDS. The experimental groups were treated with carnitine. No statistically significant differences in serum carnitine levels were detected between the study and the control groups on day 1 of treatment (P=0.06). However, on day 7 of treatment, serum carnitine levels in the experimental groups were significantly increased (P=0.02), as compared with the control groups. The surfactant requirement value, which is how many rounds of surfactant therapy were required, was 1.56±0.97 in group 1, and 2.12±0.99 in group 3 (P<0.001). The mean duration of mechanical ventilation required was 3.04±3.60 days in group 1, and 4.73±5.63 days in group 3 (P<0.001). The present results indicate that carnitine supplementation in premature infants with RDS may help to increase carnitine levels, thus decreasing the duration of mechanical ventilation and surfactant requirement.


Erythropoietin requirement for the maintenance of normal levels of erythropoiesis in the normal adult mouse.
Erythropoietin (EPO) is a glycoprotein which appears as the primary regulator of erythropoiesis under either normal or most of the pathologic conditions. In the rat with experimentally-reduced erythropoiesis, daily administration of 1.3 IRP units can restore the function and maintain steady-state conditions of red cell formation. This important information for the programming of both physiologic and pharmacologic studies is lacking for the mouse, in spite of the fact that most of the experiments performed on the regulation of erythropoiesis have been conducted in this species. In the present study, designed to determine EPO requirement for maintenance of steady-state erythropoiesis in the adult mouse under standard laboratory conditions, adult females of the CF#1 strain were exposed to hypobaria (18 h/day) during a 3-week period for induction of polycythemia (P). At the end of the hypoxic period. P mice were maintained at sea level conditions, as were normocythemic (N) mice during the entire experimental period. P mice were daily injected with 0, 0.5, 1.0, 1.5, or 2.0 IRP units of rHu-EPO during the 4-day period that followed the hypoxic one. The rate of erythropoiesis in N and P mice were measured by RBC-59Fe uptake. The plasma 59Fe half-clearance time was also measured in other groups of N and P mice similarly treated. One-way ANOVA showed that the only non-significant difference (P > 0.05) between N and EPO-injected P mice was established for the 1.0 unit dose group. It is thus suggested that approximately 1.0 unit of EPO should be synthesized daily in an adult mice to maintain a normal rate of erythropoiesis.


An Alternative to Mother and Infants Behind Bars: How One Prison Nursery Program Impacted Attachment and Nurturing for Mothers Who Gave Birth While Incarcerated.
The number of women in United States prisons has increased, with the most rapid growth among women of childbearing age. Detrimental effects on maternal-infant attachment have been shown to exist when mothers and infants are separated at birth. The purpose of this exploratory study was to examine the impact of an out-of-prison nursery program, Baby and Mother Bonding Initiative (BAMBI), on maternal-infant attachment and nurturing competencies among women who gave birth while incarcerated. A sample of 41 participants was recruited through a "Closed" BAMBI Alumni Facebook page and nonprobability snowball sampling. Participants were surveyed, and responses were submitted online or via mail. Data were analyzed using descriptive statistics, correlation coefficients, multiple regression, and logistic regression. Results indicated that the number of children living in the mother's household was a significant predictor of positive maternal nurturance. Inversely, the high number of children in the household was the most significant predictor of increased risk for infants to have insecure attachment to mothers. As the number of women giving birth in prisons continues to trend upward, the need for more programs to promote best outcomes for both mother and infants is crucial.


Hormonal therapy in the senescence: Prostatic microenvironment structure and adhesion molecules.
Hormonal replacement has been utilized to minimize the harmful effects of hormonal imbalance in elderly men. The development and progression of prostatic diseases and their relation to hormone therapy is still unclear. Thus, the aim herewith was to characterize the structure and dystroglycan molecule (DGs) reactivities in the ventral prostatic lobe from elderly rats submitted to steroid hormone replacement. Male rats (Sprague-Dawley) were divided into one Young group and six senile groups. The Young group (YNG) (4 months old) received peanut oil (5mL/kg, s.c.). The senile rats (10 months old) were submitted to the following treatments: Senile group (SEN) (5mL/kg peanut oil, s.c.); Testosterone group (TEST) (5mg/kg testosterone cipionate, s.c.); Estrogen group (EST) (25μg/kg 17β-estradiol, s.c.); Castrated group (CAS) (surgical castration); Castrated-Testosterone (CT) (surgical castration and treatment similar to TEST group); and Castrated-Estrogen (CE) (surgical castration and treatment similar to EST group). After 30 days treatment, blood samples were collected for hormonal analysis and ventral prostate samples were processed for light and transmission electron microscopies, morphometrical analysis, immunohistochemistry and Western Blotting. The results showed decreased serum testosterone levels in the senescence and increased testosterone and estrogen plasmatic levels after hormone administration in the TEST and EST groups, respectively, highlighting the therapy efficiency. Hypertrophied stroma and inflammatory cells were verified in the SEN group. After hormone replacement in the senescence or following castration, atrophic epithelium, epithelial cells with clear cytoplasmic halo around the nucleus, microacini and maintenance of hypertrophied stroma were seen. Decreased DG levels were verified in the senescence. After hormonal therapy, increased protein levels of these molecules were observed, especially in those groups which received estradiol. Thus, the occurrence of inflammatory cells, stromal hypertrophy and the presence of cells with clear halo around the nucleus after hormonal therapy probably indicated prostatic paracrine signaling imbalance, suggesting a stromal reactive microenvironment favorable to the development of glandular lesions. However, the increase of DG levels characterized positive effect of steroid hormone replacement on the prostate in the senescence. Thus, it could be concluded that despite having positive effects on important molecules involved in the maintenance of epithelial-stromal interaction and glandular cytoarchitecture, such as DGs, hormonal therapy enhanced structural changes associated with senescence, probably due to increased hormonal imbalance between androgens and estrogens in the prostatic tissue.


Modification of timolol release from silicone hydrogel model contact lens materials using hyaluronic acid.
The ability of hyaluronic acid (HA) to act as a functional additive in model silicone hydrogel contact lenses to alter the uptake and release characteristics of timolol was investigated. Model contact lenses were prepared using 2 primary formulations: 2-hydroxyethyl methacrylate (HEMA) with 3-methacryloxypropyltris (trimethylsiloxy) silane (TRIS) in a 9:1 (wt:wt) ratio or N,N-dimethylacrylamide (DMA) with TRIS in a 1:1 (wt:wt) ratio. Ethylene glycol dimethacrylate (EGDMA) was used as the cross-linker. Four different model lens compositions were explored: unmodified controls, lenses containing HA, lenses that were molecularly imprinted with timolol maleate, and those that were both imprinted and contained HA. Model lenses were then used in subsequent materials characterization, drug loading, and drug release studies. Hyaluronic acid was shown to have the ability to act as a functional additive in these model contact lenses, significantly increasing the drug loading and release mass. This ability seemed to be independent of molecular imprinting, but its efficacy was related to the concentration of HA contained within model lenses and the concentration of drug loading solution used to facilitate uptake. Timolol release was sustained for a duration of approximately 2 days, and the dose of drug was shown to be controlled by both HA-drug interactions and molecular imprinting within the silicone hydrogels. Hyaluronic acid, although different than typical functional monomers used in molecular imprinting, can be a useful additive to modify the mass of drug release from model silicone hydrogel lenses.


Experimental hydrophilic vinyl polysiloxane (VPS) impression materials incorporating a novel surfactant compared with commercial VPS.
To formulate experimental hydrophilic (Exp) VPS impression materials incorporating a novel surfactant (Rhodasurf CET-2), and to compare their contact angles (CAs) with commercial materials, before/after disinfection. CAs were measured immediately after setting and after disinfection (1% NaOCl; 30min and 24h), together with their change whilst a droplet remained on the materials surface (over 10, 20, 30 60 and 120s), on three commercial (Aquasil Ultra-Monophase [Aq M], Elite HD-Monophase [Elt M], Extrude Medium-bodied [Extr M]) and four experimental (Exp I-IV) materials, using the Drop Shape Analysis 100 technique. The results were compared statistically. CAs of all experimental materials were within the range of those obtained for the commercial materials, with the exception of Exp-IV, which presented with the lowest CAs at the three time points. The control Exp-I was hydrophobic at all three time points (CAs ∼100+), as was Elite. Immediately after setting, Aq M had low CAs but these increased significantly after 30min of disinfection. After twenty four hours' disinfection CAs of all Exp/commercial VPS increased significantly compared to immediately after setting. The CAs of droplets left on the material (120s) decreased with time, even after disinfection, except for Exp-I. The novel surfactant Rhodasurf CET-2 in Exp-III and IV, is an effective surfactant, retaining a low CA after disinfection, compared with Igepal CO-530 in Aq M. Disinfecting VPS impression materials for more than 30min increases their surface CAs, and therefore prolonged disinfection periods should be avoided.


Development and validation of stable ferroptosis- and pyroptosis-related signatures in predicting prognosis and immune status in breast cancer.
To develop and validate the predictive effects of stable ferroptosis- and pyroptosis-related features on the prognosis and immune status of breast cancer (BC). We retrieved as well as downloaded ferroptosis- and pyroptosis-related genes from the FerrDb and GeneCards databases. The minimum absolute contraction and selection operator (LASSO) algorithm in The Cancer Genome Atlas (TCGA) was used to construct a prognostic classifier combining the above two types of prognostic genes with differential expression, and the Integrated Gene Expression (GEO) dataset was used for validation. Seventeen genes presented a close association with BC prognosis. Thirteen key prognostic genes with prognostic value were considered to construct a new expression signature for classifying patients with BC into high- and low-risk groups. Kaplan-Meier analysis revealed a worse prognosis in the high-risk group. The receiver operating characteristic (ROC) curve and multivariate Cox regression analysis identified its predictive and independent features. Immune profile analysis showed that immunosuppressive cells were upregulated in the high-risk group, and this risk model was related to immunosuppressive molecules. We successfully constructed combined features of ferroptosis and pyroptosis in BC that are closely related to prognosis, clinicopathological and immune features, chemotherapy efficacy and immunosuppressive molecules. However, further experimental studies are required to verify these findings.


Widespread distribution of OH/H2O on the lunar surface inferred from spectral data.
Remote sensing data from lunar orbiters have revealed spectral features consistent with the presence of OH or H2O on the lunar surface. Analyses of data from the Moon Mineralogy Mapper spectrometer onboard the Chandryaan-1 spacecraft have suggested that OH/H2O is recycled on diurnal timescales and persists only at high latitudes. However, the spatial distribution and temporal variability of the OH/H2O, as well as its source, remain uncertain. Here we incorporate a physics-based thermal correction into analysis of reflectance spectra from the Moon Mineralogy Mapper and find that prominent absorption features consistent with OH/H2O can be present at all latitudes, local times, and surface types examined. This suggests the widespread presence of OH/H2O on the lunar surface without significant diurnal migration. We suggest that the spectra are consistent with the production of OH in space weathered materials by the solar wind implantation of H+ and formation of OH at crystal defect sites, as opposed to H2O sourced from the lunar interior. Regardless of the specific composition or formation mechanism, we conclude that OH/H2O can be present on the Moon under thermal conditions more wide-ranging than previously recognized.


Revealing the seed microbiome: Navigating sequencing tools, microbial assembly, and functions to amplify plant fitness.
Microbial communities within seeds play a vital role in transmitting themselves to the next generation of plants. These microorganisms significantly impact seed vigor and early seedling growth, for successful crop establishment. Previous studies reported on seed-associated microbial communities and their influence on processes like dormancy release, germination, and disease protection. Modern sequencing and conventional methods reveal microbial community structures and environmental impacts, these information helps in microbial selection and manipulation. These studies form the foundation for using seed microbiomes to enhance crop resilience and productivity. While existing research has primarily focused on characterizing microbiota in dried mature seeds, a significant gap exists in understanding how these microbial communities assemble during seed development. The review also discusses applying seed-associated microorganisms to improve crops in the context of climate change. However, limited knowledge is available about the microbial assembly pattern on seeds, and their impact on plant growth. The review provides insight into microbial composition, functions, and significance for plant health, particularly regarding growth promotion and pest control.


The Effect of Zataria multiflora and its Constituent, Carvacrol, on Tracheal Responsiveness and Lung Pathology in Guinea Pig Model of COPD.
The effects of Zataria multiflora (Z. multiflora) and its constituent, carvacrol, in guinea pigs model of chronic obstructive pulmonary disease (COPD) were examined. Animals were divided into control, COPD, COPD + drinking water containing three concentrations of extract of Z. multiflora (0.4, 0.8 and 1.6 mg/ml), COPD + drinking water containing three concentrations of carvacrol (60, 120 and 240 µg/ml) and COPD + dexamethasone (50 µg/ml). COPD was induced by exposing animals to cigarette smoke for 3 months. Emphysema as a pathological change of the lung and tracheal responsiveness were measured (n = 5 for control and COPD groups and n = 6 for another groups). Tracheal responsiveness (p < 0.05) and emphysema were significantly increased (p < 0.001) in COPD compared to the control group. Tracheal responsiveness in COPD groups treated with two higher concentrations of the Z. multiflora and three concentrations of carvacrol, and emphysema in treated with highest concentration of Z. multiflora and carvacrol were significantly improved compared to COPD group. Studied parameters were also significantly improved in the treated group with dexamethasone compared to COPD animals (p < 0.05 to p < 0.01). The results indicated a preventive effect of Z. multiflora extract and its constituent, carvacrol, on tracheal responsiveness and pathological changes of the lung.


Proposed mechanism for sensitization by hypochlorite treatment of Clostridium botulinum spores.
Hypochlorite-treated Clostridium botulinum 12885A spores, but not buffer-treated spores, could be germinated with lysozyme, indicating that their coats are made permeable to lysozyme by hypochlorite treatment so that the cortex is accessible. Hypochlorite-treated spores and spores extracted with 8 M urea-2-mercaptoethanol (pH 3.0) were sensitive to certain components of recovery media, but spores sensitized to lysozyme by other treatments were not. These data indicate that hypochlorite does more than increase coat permeability to lysozyme. Scanning electron microscopy revealed a more open-appearing surface of hypochlorite-treated spores, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that a greater amount of protein was removed from hypochlorite-treated and other lysozyme-sensitized spores than from buffer-treated spores. The data suggest that spore coat proteins may be removed by hypochlorite treatment, and this may be responsible for the sensitivity of spores and for their observed ability to germinate in lysozyme.


SMAD3 augments FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner.
Muscle-specific RING finger-1 (MuRF-1), a ubiquitin ligase and key regulator of proteasome-dependent protein degradation, is highly expressed during skeletal muscle atrophy. The transcription factor forkhead box O3 (FoxO3) induces MuRF-1 expression, but the direct role of other major atrophy-related transcription factors, such as SMAD3, is largely unknown. The goal of this study was to determine whether SMAD3 individually regulates, or with FoxO3 coordinately regulates, MuRF-1 expression. In cultured myotubes or human embryonic kidney cells, MuRF-1 mRNA content and promoter activity were increased by FoxO3 but not by SMAD3 overexpression. However, FoxO3 and SMAD3 coexpression synergistically increased MuRF-1 mRNA and promoter activity. Mutation of the SMAD-binding element (SBE) in the proximal MuRF-1 promoter or overexpression of a SMAD3 DNA-binding mutant attenuated FoxO3-dependent MuRF-1 promoter activation, showing that SMAD binding to DNA is required for optimal activation of FoxO3-induced transcription of MuRF-1. Using chromatin immunoprecipitation, SMAD3 DNA binding increased FoxO3 abundance and SBE mutation reduced FoxO3 abundance on the MuRF-1 promoter. Furthermore, SMAD3 overexpression dose-dependently increased FoxO3 protein content, and coexpression of FoxO3 and SMAD3 synergistically increased FoxO-dependent gene transcription [assessed with a FoxO response element (FRE)-driven reporter]. Collectively, these results show that SMAD3 regulates transcription of MuRF-1 by increasing FoxO3 binding at a conserved FRE-SBE motif within the proximal promoter region, and by increasing FoxO3 protein content and transcriptional activity. These data are the first to indicate that two major transcription factors regulating protein degradation, FoxO3 and SMAD3, converge to coordinately and directly regulate transcription of MuRF-1.


Supramolecular chiral host-guest nanoarchitecture induced by the selective assembly of barbituric acid derivative enantiomers.
Barbituric acid derivatives are prochiral molecules, i.e. they are chiral upon adsorption on surfaces. Scanning tunneling microscopy reveals that barbituric acid derivatives self-assemble into a chiral guest-host supramolecular architecture at the solid-liquid interface on graphite. The host nanoarchitecture has a sophisticated wavy shape pattern and paired guest molecules are nested insides the cavities of the host structure. Each unit cell of the host structure is composed of both enantiomers with a ratio of 1:1. Furthermore, the wavy patterns of the nanoarchitecture are formed from alternative appearance of left- and right-handed chiral building blocks, which makes the network heterochiral. The functional guest-host nanoarchitecture is the result of two-dimensional chiral amplification from single enantiomers to organizational heterochiral supramolecular self-assembly.


Dropwise additive manufacturing of pharmaceutical products for amorphous and self emulsifying drug delivery systems.
The improvements in healthcare systems and the advent of the precision medicine initiative have created the need to develop more innovative manufacturing methods for the delivery and production of individualized dosing and personalized treatments. In accordance with the changes observed in healthcare systems towards more innovative therapies, this paper presents dropwise additive manufacturing of pharmaceutical products (DAMPP) for small scale, distributed manufacturing of individualized dosing as an alternative to conventional manufacturing methods A dropwise additive manufacturing process for amorphous and self-emulsifying drug delivery systems is reported, which utilizes drop-on-demand printing technology for automated and controlled deposition of melt-based formulations onto inert tablets. The advantages of drop on demand technology include reproducible production of droplets with adjustable sizing and high placement accuracy, which enable production of individualized dosing even for low dose and high potency drugs. Flexible use of different formulations, such as lipid-based formulations, allows enhancement of the solubility of poorly water soluble and highly lipophilic drugs with DAMPP. Here, DAMPP is used to produce solid oral dosage forms from melts of an active pharmaceutical ingredient and a surfactant. The dosage forms are analyzed to show the amorphous nature, self-emulsifying drug delivery system characteristics and dissolution behavior of these formulations.


The feasibility of using mutation detection in ctDNA to assess tumor dynamics.
For many decades it has been known that tumor DNA is shed into the blood. As a consequence of technological limitations, researchers were unable to comprehensively characterize circulating DNA. The advent of ultrasensitive and highly specific molecular assays has provided a comprehensive profile of the molecular characteristics and dynamics of circulating DNA in healthy subjects and cancer patients. With these new tools in hand, significant interest has been provoked for an innovative type of tumor biopsy termed a "liquid biopsy". Liquid biopsies are obtained by minimal invasive blood draws from cancer patients. Circulating cancer cells, exosomes and a variety of molecules contained within the liquid biopsy including cell-free circulating tumor DNA (ctDNA) can serve as promising tools to track cancer evolution. Attractive features of ctDNA are that ctDNA isolation is straightforward, ctDNA levels increase or decrease in response to the degree of tumor burden and ctDNA contains DNA mutations found in both primary and metastatic lesions. Consequently, the analysis of circulating DNA for cancer-specific mutations might prove to be a valuable tool for cancer detection. Moreover, the capacity to screen for ctDNA in serial liquid biopsies offers the possibility to monitor tumor progression and responses to therapy and to influence treatment decisions that ultimately may improve patient survival. Here we focus on mutation detection in ctDNA and provide an overview of the characteristics of ctDNA, detection methods for ctDNA and the feasibility of ctDNA to monitor tumor dynamics. Current challenges associate with ctDNA will also be discussed.


Bottom-Up Construction of Complex Biomolecular Systems With Cell-Free Synthetic Biology.
Cell-free systems offer a promising approach to engineer biology since their open nature allows for well-controlled and characterized reaction conditions. In this review, we discuss the history and recent developments in engineering recombinant and crude extract systems, as well as breakthroughs in enabling technologies, that have facilitated increased throughput, compartmentalization, and spatial control of cell-free protein synthesis reactions. Combined with a deeper understanding of the cell-free systems themselves, these advances improve our ability to address a range of scientific questions. By mastering control of the cell-free platform, we will be in a position to construct increasingly complex biomolecular systems, and approach natural biological complexity in a bottom-up manner.


The ischemic etiology of heart failure in diabetics limits reverse left ventricular remodeling after cardiac resynchronization therapy.
The aim of this study was to evaluate reverse volumetric left ventricular (LV) remodeling after cardiac resynchronization therapy (CRT) in patients with heart failure (HF) with vs. without diabetes mellitus (DM). The study comprised 130 consecutive patients with HF (mean age, 61+/-12 years) who underwent CRT. Thirty patients (23%) had DM [mean glycated haemoglobin (HbA(1c)), 7.2+/-3.4%; 13 (43%) on insulin therapy]. Echocardiography, including tissue Doppler measurements, was performed before CRT and between 3 and 6 months after CRT. Echocardiographic response was defined as a >15% reduction in LV end-systolic volume (ESV). Patients with DM had more often hypertension (60% vs. 29%, P<.05) and ischemic HF etiology (87% vs. 51%, P<.05), but similar pre-CRT echocardiographic findings. After CRT, patients with DM had equal reductions in QRS duration and lateral-to-septal mechanical delay, but less improvement in LV ESV, mitral annular tissue velocity, the myocardial performance (or Tei) index and the E/E' ratio (ratio of early transmitral peak filling velocity to early mitral annular peak diastolic velocity, an indicator of LV filling pressure). Patients without reverse volumetric LV remodeling had more often DM [hazard ratio (HR), 1.897; P=.042] and an ischemic HF etiology (HR, 2.308; P=.006). An ischemic HF etiology (HR, 2.119; P=.018) was the only independent predictor of poor reverse volumetric LV remodeling. Ischemic etiology of HF is an independent predictor of poor echocardiographic response to CRT. Patients with DM and HF have a relatively poor echocardiographic response to CRT most probably due to a high incidence of ischemic etiology of HF.


The Mental Health of Transgender Youth: Advances in Understanding.
This review provides an update on the growing body of research related to the mental health of transgender youth that has emerged since the 2011 publication of the Institute of Medicine report on the health of lesbian, gay, bisexual, and transgender people. The databases PubMed and Ovid Medline were searched for studies that were published from January 2011 to March 2016 in English. The following search terms were used: transgender, gender nonconforming, gender minority, gender queer, and gender dysphoria. Age limits included the terms youth, child, children, teenager*, and adolescen*. The combined search produced 654 articles of potential relevance. The resulting abstracts went through a tiered elimination system, and the remaining 15 articles, which presented quantitative data related to the prevalence of transgender youth and their mental health, were included in the present review. In addition to providing new estimates of the number of young people who identify as transgender (.17%-1.3%), studies since 2011 have shown that transgender youth have higher rates of depression, suicidality and self-harm, and eating disorders when compared with their peers. Gender-affirming medical therapy and supported social transition in childhood have been shown to correlate with improved psychological functioning for gender-variant children and adolescents. Recent research has demonstrated increased rates of psychiatric morbidity among transgender youth compared to their peers. Future work is needed to understand those youth who identify as gender nonbinary, improve methods to capture and understand diverse gender identities and related health disparities, and delineate the social determinants of such disparities.


Dientamoeba fragilis masquerading as allergic colitis.
Dientamoeba fragilis is a rare cause of chronic infectious diarrhea and colitis in children. Review of the clinical manifestations, diagnostic methods, and clinical course of D. fragilis infection in our hospital. Eleven pediatric patients are discussed, seven of whom had a history of recent travel. Clinical manifestations of infectious diarrhea included anorexia, intermittent vomiting, abdominal pain, and diarrhea, ranging from 1 to 100 weeks in duration. Peripheral eosinophilia was present in seven patients. One patient with well-documented bovine protein allergy had intermittent episodes of diarrhea and abdominal pain, despite an appropriate elimination diet. Eosinophilic colitis documented by colonoscopy, was due to D. fragilis. Metronidazole was effective in treating five patients, and iodoquinol was effective in treating four others. D. fragilis should be included in the differential diagnosis of chronic diarrhea and eosinophilic colitis. The identification of this pathogen requires clinical awareness of epidemiologic risk factors and presenting complaints, as well as the laboratory staining procedures essential to its proper identification.


Fractional ridge regression: a fast, interpretable reparameterization of ridge regression.
Ridge regression is a regularization technique that penalizes the L2-norm of the coefficients in linear regression. One of the challenges of using ridge regression is the need to set a hyperparameter (α) that controls the amount of regularization. Cross-validation is typically used to select the best α from a set of candidates. However, efficient and appropriate selection of α can be challenging. This becomes prohibitive when large amounts of data are analyzed. Because the selected α depends on the scale of the data and correlations across predictors, it is also not straightforwardly interpretable. The present work addresses these challenges through a novel approach to ridge regression. We propose to reparameterize ridge regression in terms of the ratio γ between the L2-norms of the regularized and unregularized coefficients. We provide an algorithm that efficiently implements this approach, called fractional ridge regression, as well as open-source software implementations in Python and matlab (https://github.com/nrdg/fracridge). We show that the proposed method is fast and scalable for large-scale data problems. In brain imaging data, we demonstrate that this approach delivers results that are straightforward to interpret and compare across models and datasets. Fractional ridge regression has several benefits: the solutions obtained for different γ are guaranteed to vary, guarding against wasted calculations; and automatically span the relevant range of regularization, avoiding the need for arduous manual exploration. These properties make fractional ridge regression particularly suitable for analysis of large complex datasets.


'Atypical' and 'suspicious' diagnoses in breast aspiration cytology.
In 1996, the National Cancer Institute (NCI) recommended five categories for the diagnosis of breast aspiration cytology: benign, atypical, suspicious, malignant, and unsatisfactory. The authors evaluated the usefulness of separating inconclusive diagnoses into the aforementioned atypical and suspicious categories. The current study examined the correlation between cytologic and histologic findings made in breast aspiration cytology specimens that were categorized in accordance with these NCI guidelines. From 1992 to 2000, 7727 breast aspirations were performed at the University of Miami/Jackson Memorial Medical Center (Miami, FL). Aspirates were classified using criteria similar to the NCI recommendations. Four hundred eighty-nine aspirates (6%) were classified as being cytologically 'atypical' or 'suspicious'. Of those, 225 'atypical' aspirates and 162 'suspicious' aspirates had available histologic follow-up data and were included in the study. Among the 'atypical' aspirates, 118 (52%) yielded malignant findings on histologic evaluation. Infiltrating ductal carcinoma (n = 87; 74%) was the most common malignant diagnosis, followed by infiltrating lobular carcinoma (n = 12; 10%). Among 'suspicious' aspirates, 135 (83%) yielded malignant findings on histologic analysis. The most common benign diagnosis in both 'atypical' and 'suspicious' aspirates was proliferative fibrocystic changes with or without atypia, followed by fibroadenoma. Most aspirates that yielded suspicious findings on cytologic examination proved to be malignant, as did > 50% of aspirates that yielded atypical findings. Infiltrating lobular carcinoma commonly was underdiagnosed as being atypical on cytologic examination. Benign lesions with atypical or suspicious cytologic diagnoses included certain cases of atypical ductal hyperplasia. The authors concluded that the distinction between the atypical and suspicious categories, as recommended by the NCI, is not warranted. Therefore, they suggest the use of a single term, such as 'equivocal', to describe inconclusive diagnoses on breast fine-needle aspiration cytology.


Plasma fatty acid composition and 6-year incidence of hypertension in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study.
The association of baseline fatty acid composition in plasma cholesterol esters with 6-year incidence of hypertension was examined in middle-aged Minneapolis participants of the Atherosclerosis Risk in Communities (ARIC) Study (1987-1995). Compared with those who were never hypertensive (n = 1,975), incident hypertensives (n = 413) had statistically significantly higher baseline levels of palmitic (16:0) and palmitoleic (16:1n7) acids but lower levels of linoleic (18:2n6) acid and the polyunsaturated/saturated fatty acids ratio (P/S ratio). Among polyunsaturated fatty acids, levels of dihomo-gamma-linolenic (20:3n6) and arachidonic (20:4n6) acids were statistically significantly higher in incident hypertensives, compared with normotensives. After adjustment for age, sex, body mass index, waist/hip ratio, smoking status, ethanol intake, education level, physical activity, and baseline systolic blood pressure in separate models, the odds ratio estimates of incident hypertension for an interquartile increment of a fatty acid in cholesterol esters were 1.26 (95% confidence interval (CI): 1.05, 1.51) for 16:0, 1.11 (95% CI: 0.96, 1.28) for 16:1n7, 1.01 (95% CI: 0.85, 1.21) for 20:3n6, 1.14 (95% CI: 1.03, 1.27) for 20:5n3, 0.81 (95% CI: 0.68, 0.96) for 18:2n6, and 0.83 (95% CI: 0.70, 0.99) for the P/S ratio. The authors conclude that reduced levels of linoleic acid and the P/S ratio and elevated levels of palmitic and arachidonic acids are associated with a higher risk of hypertension.


Full practice authority and burnout among primary care nurse practitioners.
Full practice authority (FPA) improves clinical autonomy for nurse practitioners (NPs). Autonomy may reduce burnout. Estimate the effect of changing from reduced or restricted practice authority to FPA on NP burnout. In this quasi-experimental study, we compared NP burnout before (2016) and after (2018) a Veterans Health Administration (VHA) regulation authorized NP FPA. Burnout proportions were estimated for VHA facilities by aggregating responses to the VHA's All Employee Survey from 1,352 primary care NPs. Seventy-seven percent of facilities changed to FPA postregulation. Burnout was six points lower among NPs in facilities that changed to FPA compared to facilities that had FPA prior to the regulation; however, this association was not statistically significant. NPs are increasingly working under independent practice. While changing to FPA did not reduce NP burnout, this association may vary by health care setting or when burnout is measured for individuals or teams.


A novel coding-region RNA element modulates infectious dengue virus particle production in both mammalian and mosquito cells and regulates viral replication in Aedes aegypti mosquitoes.
Dengue virus (DENV) is an enveloped flavivirus with a positive-sense RNA genome transmitted by Aedes mosquitoes, causing the most important arthropod-borne viral disease affecting humans. Relatively few cis-acting RNA regulatory elements have been described in the DENV coding-region. Here, by introducing silent mutations into a DENV-2 infectious clone, we identify the conserved capsid-coding region 1 (CCR1), an RNA sequence element that regulates viral replication in mammalian cells and to a greater extent in Ae. albopictus mosquito cells. These defects were confirmed in vivo, resulting in decreased replication in Ae. aegypti mosquito bodies and dissemination to the salivary glands. Furthermore, CCR1 does not regulate translation, RNA synthesis or virion retention but likely modulates assembly, as mutations resulted in the release of non-infectious viral particles from both cell types. Understanding the role of CCR1 could help characterize the poorly-defined stage of assembly in the DENV life cycle and uncover novel anti-viral targets.


Comparative Exergy and Environmental Assessment of the Residual Biomass Gasification Routes for Hydrogen and Ammonia Production.
The need to reduce the dependency of chemicals on fossil fuels has recently motivated the adoption of renewable energies in those sectors. In addition, due to a growing population, the treatment and disposition of residual biomass from agricultural processes, such as sugar cane and orange bagasse, or even from human waste, such as sewage sludge, will be a challenge for the next generation. These residual biomasses can be an attractive alternative for the production of environmentally friendly fuels and make the economy more circular and efficient. However, these raw materials have been hitherto widely used as fuel for boilers or disposed of in sanitary landfills, losing their capacity to generate other by-products in addition to contributing to the emissions of gases that promote global warming. For this reason, this work analyzes and optimizes the biomass-based routes of biochemical production (namely, hydrogen and ammonia) using the gasification of residual biomasses. Moreover, the capture of biogenic CO2 aims to reduce the environmental burden, leading to negative emissions in the overall energy system. In this context, the chemical plants were designed, modeled, and simulated using Aspen plus™ software. The energy integration and optimization were performed using the OSMOSE Lua Platform. The exergy destruction, exergy efficiency, and general balance of the CO2 emissions were evaluated. As a result, the irreversibility generated by the gasification unit has a relevant influence on the exergy efficiency of the entire plant. On the other hand, an overall negative emission balance of -5.95 kgCO2/kgH2 in the hydrogen production route and -1.615 kgCO2/kgNH3 in the ammonia production route can be achieved, thus removing from the atmosphere 0.901 tCO2/tbiomass and 1.096 tCO2/tbiomass, respectively.


Traf6 and A20 differentially regulate TLR4-induced autophagy by affecting the ubiquitination of Beclin 1.
Toll-like receptor 4 (TLR4) signaling triggers autophagy, which has been linked to both adaptive and innate immunity. Engagement of TLR4 recruits to the receptor complex Beclin 1, a key component of a class III phosphatidylinositol 3-kinase complex (PI3KC3) that initiates autophagosome formation. Recently, we found that tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)-mediates Lys(63) (K63)- linked ubiquitination of Beclin 1 is crucial for TLR4-triggered autophagy in macrophages. We identified two TRAF6-binding motifs in Beclin 1 that facilitate the binding of TRAF6 and the ubiquitination of Beclin 1. A lysine located in the Bcl-2 homology 3 (BH3) domain of Beclin 1 serves as a major site for K63-linked ubiquitination. Opposing TRAF6, the deubiquitinating enzyme A20 reduces the extent of K63-linked ubiquitination of Beclin 1 and limits the induction of autophagy in response to TLR4 signaling. Furthermore, treatment of macrophages with either interferonγ or interleukin-1 triggers the K63-linked ubiquitination of Beclin 1 and the formation of autophagosomes. These results indicate that the status of K63-linked ubiquitination of Beclin 1 plays a key role in regulating autophagy during inflammatory responses.


Continuous personnel scheduling algorithms: a literature review.
Hospitals frequently use personnel scheduling options as recruiting and retention instruments. The successful application of these personnel scheduling tools, whether developed in-house or purchased from vendors, requires appreciation of the interrelationships of three basic manpower decisions--staffing, personnel scheduling, and allocation. This article introduces these basic relationships and their influence on the development of satisfactory personnel schedules. Next, it reviews published personnel scheduling algorithms, applicable to hospital operations, within the context of the three manpower decisions. It is proposed that scheduling algorithms be classified by type of schedule produced (cyclic or noncyclic); and technique used (heuristic, mathematical programming, or self-scheduling). The characteristics of each classification are discussed. Considerations for the development of new personnel scheduling algorithms are also presented.


Evaluation of postural stability in elderly with diabetic neuropathy.
The objective of this study was to compare clinical and biomechanical characteristics of balance in diabetic polyneuropathic elderly patients and normal age-matched subjects. Fifteen elderly with distal neuropathy (DNP) and 15 healthy age-matched subjects were evaluated with the biomechanical variable COP-COM, which represents the distance between the center of pressure (COP) and the center of mass (COM). Measurements were taken in the quiet position with a double-leg stance, in eyes-open (EO) and eyes-closed (EC) conditions. Subjects were also assessed with clinical balance evaluations. The COP-COM variable was statistically significantly larger in the DNP group than in the healthy group in anterior-posterior (A/P) and medial-lateral (M/L) directions. Furthermore, the DNP group showed statistically significantly larger amplitudes of the COP-COM variable without vision. The severity of the neuropathy, as quantified using the Valk scoring system, was correlated with COP-COM amplitude in both directions. Evaluation of the postural stability of an elderly diabetic population using the COP-COM variable can detect a very small change in postural stability and could be helpful in identifying elderly with DNP at risk of falling.


Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy.
Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces T regulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non-NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P = .05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P = .04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT.


Lipid-Coated Mesoporous Silica Nanoparticles for the Delivery of the ML336 Antiviral to Inhibit Encephalitic Alphavirus Infection.
Venezuelan equine encephalitis virus (VEEV) poses a major public health risk due to its amenability for use as a bioterrorism agent and its severe health consequences in humans. ML336 is a recently developed chemical inhibitor of VEEV, shown to effectively reduce VEEV infection in vitro and in vivo. However, its limited solubility and stability could hinder its clinical translation. To overcome these limitations, lipid-coated mesoporous silica nanoparticles (LC-MSNs) were employed. The large surface area of the MSN core promotes hydrophobic drug loading while the liposome coating retains the drug and enables enhanced circulation time and biocompatibility, providing an ideal ML336 delivery platform. LC-MSNs loaded 20 ± 3.4 μg ML336/mg LC-MSN and released 6.6 ± 1.3 μg/mg ML336 over 24 hours. ML336-loaded LC-MSNs significantly inhibited VEEV in vitro in a dose-dependent manner as compared to unloaded LC-MSNs controls. Moreover, cell-based studies suggested that additional release of ML336 occurs after endocytosis. In vivo safety studies were conducted in mice, and LC-MSNs were not toxic when dosed at 0.11 g LC-MSNs/kg/day for four days. ML336-loaded LC-MSNs showed significant reduction of brain viral titer in VEEV infected mice compared to PBS controls. Overall, these results highlight the utility of LC-MSNs as drug delivery vehicles to treat VEEV.


Pigment pattern formation in the medaka embryo.
For the study of development of pigmentation, compared with mammalian models, fish offer the advantage of multiple chromatophore types and ready access to the developing embryo for observation and experimental manipulation. Compared with zebrafish embryos, medaka embryos have an additional unique chromatophore-type and superb properties for conditional mutation studies. The rich resources of medaka mutants, combined with data obtainable from other species, potentially offer information not otherwise readily available regarding chromatophore lineage. Here we summarize the embryonic development of normal medaka pigment pattern, based on observations using embryos of a panel of wild type and mutant fish. A more detailed description of development is available in the appendix of the on-line version of this paper (see Supplementary Material). We make some comparisons with zebrafish development to emphasize the increased power of both systems when utilized together. These two models will, in combination, be a powerful system for studies of the embryogenesis and evolution of pigmentation.


Elasticity analysis and design for large metabolic responses produced by changes in enzyme activities.
Metabolic control analysis has been extensively used to describe how the sensitivity properties of the component enzymes in a metabolic pathway (represented by the elasticity coefficients) determine the way in which metabolic variables respond (described by the control coefficients). Similarly, metabolic control design addresses the inverse problem of obtaining the sensitivity properties of the component enzymes that are required for the system to show a pre-established pattern of responses. These formalisms, including what is called elasticity analysis and design, were developed for small, strictly speaking infinitesimal, changes. Here we extend them to large metabolic responses. The new approach can be applied to simple two-step pathways or to any arbitrary metabolic system divided into two groups linked by one intermediate. General expressions that relate control and elasticity coefficients for large changes are derived. Concentration and flux connectivity relationships are obtained. The relationships for large changes indicate that the pattern of responses is not necessarily the same as the one obtained with the traditional infinitesimal approach, in some cases the patterns being qualitatively different. The general analysis is used to study the control of ketogenesis in rat liver mitochondria, starting from data available in the literature. The control profile of the pathway subject to large changes shows both quantitative and qualitative differences from the one obtained from an analysis that is performed with infinitesimal coefficients. This exemplifies the type of errors that may be introduced when drawing conclusions about large metabolic responses from results obtained with an infinitesimal treatment.


Classification of estrogenic compounds by coupling high content analysis and machine learning algorithms.
Environmental toxicants affect human health in various ways. Of the thousands of chemicals present in the environment, those with adverse effects on the endocrine system are referred to as endocrine-disrupting chemicals (EDCs). Here, we focused on a subclass of EDCs that impacts the estrogen receptor (ER), a pivotal transcriptional regulator in health and disease. Estrogenic activity of compounds can be measured by many in vitro or cell-based high throughput assays that record various endpoints from large pools of cells, and increasingly at the single-cell level. To simultaneously capture multiple mechanistic ER endpoints in individual cells that are affected by EDCs, we previously developed a sensitive high throughput/high content imaging assay that is based upon a stable cell line harboring a visible multicopy ER responsive transcription unit and expressing a green fluorescent protein (GFP) fusion of ER. High content analysis generates voluminous multiplex data comprised of minable features that describe numerous mechanistic endpoints. In this study, we present a machine learning pipeline for rapid, accurate, and sensitive assessment of the endocrine-disrupting potential of benchmark chemicals based on data generated from high content analysis. The multidimensional imaging data was used to train a classification model to ultimately predict the impact of unknown compounds on the ER, either as agonists or antagonists. To this end, both linear logistic regression and nonlinear Random Forest classifiers were benchmarked and evaluated for predicting the estrogenic activity of unknown compounds. Furthermore, through feature selection, data visualization, and model discrimination, the most informative features were identified for the classification of ER agonists/antagonists. The results of this data-driven study showed that highly accurate and generalized classification models with a minimum number of features can be constructed without loss of generality, where these machine learning models serve as a means for rapid mechanistic/phenotypic evaluation of the estrogenic potential of many chemicals.


The Sport Concussion Education Project. A brief report on an educational initiative: from concept to curriculum.
Current research on concussion is primarily focused on injury identification and treatment. Prevention initiatives are, however, important for reducing the incidence of brain injury. This report examines the development and implementation of an interactive electronic teaching program (an e-module) that is designed specifically for concussion education within an adolescent population. This learning tool and the accompanying consolidation rubric demonstrate that significant engagement occurs in addition to the knowledge gained among participants when it is used in a school curriculum setting.


Herpesvirus saimiri-induced proteins in lytically infected cells. I. Time-ordered synthesis.
The addition of TPA (phorbol-12-myristate-13-acetate) to cultures during the lytic infection with herpesvirus saimiri led to an enhanced and accelerated production of polypeptides induced by H. saimiri and to a rapid shut-down of host cell protein synthesis and allowed a detailed analysis of the protein patterns. Analysis of sequential protein synthesis in owl monkey kidney cells lytically infected with H. saimiri 11 permitted the identification of 31 virus-induced polypeptides. The use of the amino acid analogues canavanine (for arginine) and azetidine (for proline) in parallel allowed experiments on the identification of proteins synthesized early and late during lytic infection.


Prognostic Potential of the Expression of Podoplanin (D2-40) Within Cells of Squamous Cell Carcinoma of the Larynx and Hypopharynx.
Podoplanin (D2-20) stains immunohistochemically lymphatic vessels, regular mesothelium and tumor cells of different tumors, e.g. malignant mesothelioma or seminoma. In squamous cell carcinoma (SCC), the marker has been described as variously expressed. This study has investigated the value of the immunohistochemical analysis for the prognostic relevance of the expression in 119 SCCs of the larynx and hypopharynx. The clinical data and documentation of follow-up for at least 5 years were available. The collective showed the expected distribution of patient age with accentuation of the male sex and a balanced spread of tumor stages including nodal status. The immunohistochemical stain intensity (negative, weak or strong) and the distribution (equal versus focal) were evaluated. In addition, the accentuation of the staining reaction was separately examined at the border of invasion. SCCs with a strong expression of podoplanin were associated with an unfavorable prognosis. A comparison of grouped cases showed a trend emerging with borderline results (negative to weakly positive, P = 0.51; negative to strongly positive, P = 0.054; weakly positive to strongly positive, P = 0.17). The staining at the border of invasion had no statistical effect on overall survival. Multivariate survival statistics however showed that lymphonodal metastasis and a reaction with podoplanin in tumor cells are associated with significant worse prognosis. In summary, regardless of the exact function of podoplanin in the process of cell migration and tumor progression, an immunohistochemical identification of expression in tumor cells of SCC of the larynx and hypopharynx can give additional information about the expectable prognosis.


Graft Diameter as a Predictor for Revision Anterior Cruciate Ligament Reconstruction and KOOS and EQ-5D Values: A Cohort Study From the Swedish National Knee Ligament Register Based on 2240 Patients.
Anterior cruciate ligament (ACL) reconstruction (ACLR) using a hamstring tendon (HT) autograft is an effective and widespread method. Recent studies have identified a relationship between the graft diameter and revision ACLR. To evaluate the influence of the graft diameter on revision ACLR and patient-reported outcomes in patients undergoing primary ACLR using HT autografts. Cohort study; Level of evidence, 2. A prospective cohort study was conducted using the Swedish National Knee Ligament Register (SNKLR) involving all patients undergoing primary ACLR using HT autografts. Patients with graft failure who needed revision surgery (cases) were compared with patients not undergoing revision surgery (controls). The control group was matched for sex, age, and graft fixation method in a 3:1 ratio. Conditional logistic regression was performed to produce odds ratios and 95% CIs. Univariate linear regression analyses were performed for patient-related outcomes. The Knee injury and Osteoarthritis Outcome Score (KOOS) and EuroQol 5 dimensions questionnaire (EQ-5D) values were obtained. A total of 2240 patients were included in which there were 560 cases and 1680 controls. No significant differences between the cases and controls were found for sex (52.9% male), mean age (21.7 years), and femoral and tibial fixation. The mean graft diameter for the cases was 8.0 ± 0.74 mm and for the controls was 8.1 ± 0.76 mm. In the present cohort, the likelihood of revision surgery for every 0.5-mm increase in the HT autograft diameter between 7.0 and 10.0 mm was 0.86 (95% CI, 0.75-0.99; P = .03). Univariate linear regression analysis found no significant regression coefficient for the change in KOOS or EQ-5D values. In a large cohort of patients after primary ACLR with HT autografts, an increase in the graft diameter between 7.0 and 10.0 mm resulted in a 0.86 times lower likelihood of revision surgery with every 0.5-mm increase. This study provides further evidence of the importance of the HT autograft size in intraoperative decision making.


Reversibly Manipulating the Surface Chemistry of Polymeric Nanostructures via a "Grafting To" Approach Mediated by Nucleobase Interactions.
"Grafting to" polymeric nanostructures or surfaces is a simple and versatile approach to achieve functionalization. Herein, we describe the formation of mixed polymer-grafted nanoparticles through a supramolecular "grafting to" method that exploits multiple hydrogen-bonding interactions between the thymine (T)-containing cores of preformed micelles and the complementary nucleobase adenine (A) of added diblock copolymers. To demonstrate this new "grafting to" approach, mixed-corona polymeric nanoparticles with different sizes were prepared by the addition of a series of complementary diblock copolymers containing thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) to a preformed micelle with a different coronal forming block, poly(4-acryloylmorpholine) (PNAM). PNIPAM chains were distributed throughout the corona and facilitated a fast and fully reversible size change of the resulting mixed-corona micelles upon heating. Through the introduction of an environmentally sensitive fluorophore, the reversible changes in nanoparticle size and coronal composition could be easily probed. Furthermore, preparation of mixed-corona micelles also enabled ligands, such as d-mannose, to be concealed and displayed on the micelle surface. This supramolecular "grafting to" approach provides a straightforward route to fabricate highly functionalized mixed polymeric nanostructures or surfaces with potential applications in targeted diagnosis or therapy and responsive surfaces.


Limitations of randomized clinical trials. Proposed alternative designs.
The classical two-period crossover and two-parallel-groups designs for clinical drug trials are unable to answer many current scientific questions, and are sometimes ethically or financially difficult. For example, the classical designs do not allow the study of the effects of combined treatments and their interactions. Also, the generation of parallel data that are no more than a repetition of previous research is ethically debatable and in a sense a waste of money. Objectives are to identify what a classical clinical trial cannot manage, to summarize and discuss alternative trial designs that are helpful for such purposes. A classical clinical trial cannot: (i) assess combined therapies, (ii) take historical data into account, (iii) safeguard ethics and efficacy during the course of long-term trials, (iv) study drugs, before well-established toxicity information is available, (v) account for the possibility of therapeutic equivalence between test and reference treatment, (vi) study multiple treatments in one trial, and (vii) adjust change scores for baseline levels. Alternative designs helpful for such purposes are respectively: (i) factorial designs, (ii) historical controls designs, (iii) group-sequential interim analysis designs, (iv) sequential designs for continuous monitoring, (v) therapeutic equivalence designs, (vi) multiple crossover-periods/multiple parallel-groups design, and (vii) increased precision designs through multivariate adjustment. Main problems include the increased risks of type I and type II errors and the loss of validity criteria. Non-classical trial designs are reviewed. They offer relevant scientific, ethical, and financial advantages. The increased risks of type I and type II errors should be accounted for in the design stage of the trial.


Fasciola hepatica vaccine: we may not be there yet but we're on the right road.
Major advances have been made in identifying potential vaccine molecules for the control of fasciolosis in livestock but we have yet to reach the level of efficacy required for commercialisation. The pathogenesis of fasciolosis is associated with liver damage that is inflicted by migrating and feeding immature flukes as well as host inflammatory immune responses to parasite-secreted molecules and tissue damage alarm signals. Immune suppression/modulation by the parasites prevents the development of protective immune responses as evidenced by the lack of immunity observed in naturally and experimentally infected animals. In our opinion, future efforts need to focus on understanding how parasites invade and penetrate the tissues of their hosts and how they potentiate and control the ensuing immune responses, particularly in the first days of infection. Emerging 'omics' data employed in an unbiased approach are helping us understand liver fluke biology and, in parallel with new immunological data, to identify molecules that are essential to parasite development and accessible to vaccine-induced immune responses.


[De-professionalization or 'para-professionalization'?. The professional development of the midwife and her place in the obstetrics of the 19th century].
The present article deals with the standing and the tasks of midwives in 19th century Württemberg. After outlining the legal framework of obstetrics, special emphasis was given to the education and activities of contemporary midwives, and to their numbers. At the beginning of the 18th century, obstetrics was almost exclusively in the hands of women. After 1800, a growing number of barber-surgeons and physicians began to practise obstetrics. At the same time, vocational training and qualification of women-obstetricians increased considerably. Schools for midwives and lying-in hospitals were founded. In these schools a limited number of midwives were trained by physicians. Finally a hierarchy of different groups of obstetricians developed: first physicians, then barber-surgeons, midwives and folk healers. Although midwives were more or less excluded from operative obstetrics and high-risk-pregnancies, care and supervision of uncomplicated pregnancies, and of women in childbed remained their responsibility. It could be shown that in 19th century Württemberg more than 90 percent of pregnancies ran a safe course, and neither physicians nor barber-surgeons took a special interest in the care of normal births. Thus there was no dramatic transfer of obstetric care from the hands of the midwives to those of academically trained men. The high social status of the university-bred physicians separated them from most of the patients, as did the doctors' high fees. A certain indolence, and a remarkable sense of shame on the part of the pregnant women prevented much demand for academic obstetricians.


Control of colloidal placement by modulated molecular orientation in nematic cells.
Colloids self-assemble into various organized superstructures determined by particle interactions. There is tremendous progress in both the scientific understanding and the applications of self-assemblies of single-type identical particles. Forming superstructures in which the colloidal particles occupy predesigned sites and remain in these sites despite thermal fluctuations represents a major challenge of the current state of the art. We propose a versatile approach to directing placement of colloids using nematic liquid crystals with spatially varying molecular orientation preimposed by substrate photoalignment. Colloidal particles in a nematic environment are subject to the long-range elastic forces originating in the orientational order of the nematic. Gradients of the orientational order create an elastic energy landscape that drives the colloids into locations with preferred type of deformations. As an example, we demonstrate that colloidal spheres with perpendicular surface anchoring are driven into the regions of maximum splay, whereas spheres with tangential surface anchoring settle into the regions of bend. Elastic forces responsible for preferential placement are measured by exploring overdamped dynamics of the colloids. Control of colloidal self-assembly through patterned molecular orientation opens new opportunities for designing materials and devices in which particles should be placed in predesigned locations.


Neural and psychological characteristics of college students with alcoholic parents differ depending on current alcohol use.
A significant proportion of college students are adult children of an alcoholic parent (ACoA), which can confer greater risk of depression, poor self-esteem, alcohol and drug problems, and greater levels of college attrition. However, some ACoA are resilient to these negative outcomes. The goal of this study was to better understand the psychobiological factors that distinguish resilient and vulnerable college-aged ACoAs. To do so, scholastic performance and psychological health were measured in ACoA college students not engaged in hazardous alcohol use (resilient) and those currently engaged in hazardous alcohol use (vulnerable). Neural activity (as measured by functional magnetic resonance imaging) in response to performing working memory and emotion-based tasks were assessed. Furthermore, the frequency of polymorphisms in candidate genes associated with substance use, risk taking and stress reactivity were compared between the two ACoA groups. College ACoAs currently engaged in hazardous alcohol use reported more anxiety, depression and posttraumatic stress symptoms, and increased risky nicotine and marijuana use as compared to ACoAs resistant to problem alcohol use. ACoA college students with current problem alcohol showed greater activity of the middle frontal gyrus and reduced activation of the posterior cingulate in response to visual working memory and emotional processing tasks, which may relate to increased anxiety and problem alcohol and drug behaviors. Furthermore, polymorphisms of cholinergic receptor and the serotonin transporter genes also appear to contribute a role in problem alcohol use in ACoAs. Overall, findings point to several important psychobiological variables that distinguish ACoAs based on their current alcohol use that may be used in the future for early intervention.


Cytometry by time of flight identifies distinct signatures in patients with systemic sclerosis, systemic lupus erythematosus and Sjögrens syndrome.
Systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and primary Sjögrens syndrome (pSS) are clinically distinct systemic autoimmune diseases (SADs) that share molecular pathways. We quantified the frequency of circulating immune-cells in 169 patients with these SADs and 44 healty controls (HC) using mass-cytometry and assessed the diagnostic value of these results. Alterations in the frequency of immune-cell subsets were present in all SADs compared to HC. Most alterations, including a decrease of CD56hi NK-cells in SSc and IgM+ Bcells in pSS, were disease specific; only a reduced frequency of plasmacytoid dendritic cells was common between all SADs Strikingly, hierarchical clustering of SSc patients identified 4 clusters associated with different clinical phenotypes, and 9 of the 12 cell subset-alterations in SSc were also present during the preclinical-phase of the disease. Additionally, we found a strong association between the use of prednisone and alterations in B-cell subsets. Although differences in immune-cell frequencies between these SADs are apparent, the discriminative value thereof is too low for diagnostic purposes. Within each disease, mass cytometry analyses revealed distinct patterns between endophenotypes. Given the lack of tools enabling early diagnosis of SSc, our results justify further research into the value of cellular phenotyping as a diagnostic aid.


Handgrip Strength Is Related to Hippocampal and Lobar Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden.
Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). To model the relationships between handgrip strength, mobility, and MRI volumetry. We selected 38 participants with Alzheimer's disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.


Associations of reproductive time events and intervals with breast cancer risk: a report from the Shanghai Breast Cancer Study.
While there is clear evidence for an association between later age at first live birth and increased breast cancer risk, associations with the timing of other reproductive events are less clear. As breast tissues undergo major structural and cellular changes during pregnancy, we examined associations between reproductive time events and intervals with breast cancer risk among parous women from the population-based Shanghai Breast Cancer Study (SBCS). Unconditional logistic regression was used to evaluate associations with breast cancer risk for 3,269 cases and 3,341 controls. In addition to later age at first live birth, later ages at first pregnancy and last pregnancy were significantly associated with increased breast cancer risk (p-trend = 0.002, 0.015, 0.008, respectively); longer intervals from menarche to first or last live birth were also associated with increased risk (p-trend < 0.001, =0.018, respectively). Analyses stratified by menopausal status and estrogen receptor (ER)/progesterone receptor (PR) status revealed that associations for later age at first pregnancy or live birth and longer intervals from menarche to first or last live birth occurred among premenopausal women and ER+/PR+ breast cancers, whereas the association for later age at last pregnancy occurred among postmenopausal women and women with ER+/PR- or ER-/PR+ breast cancers. Because of the high correlation with other reproductive variables, models did not include adjustment for age at first live birth; when included, the significance of all associations was attenuated. These findings suggest that while reproductive time events and intervals play an important role in breast cancer etiology, contributions may differ by menopausal status and hormone receptor status of breast cancers.


Neuronal calcium signaling: function and dysfunction.
Calcium (Ca(2+)) is an universal second messenger that regulates the most important activities of all eukaryotic cells. It is of critical importance to neurons as it participates in the transmission of the depolarizing signal and contributes to synaptic activity. Neurons have thus developed extensive and intricate Ca(2+) signaling pathways to couple the Ca(2+) signal to their biochemical machinery. Ca(2+) influx into neurons occurs through plasma membrane receptors and voltage-dependent ion channels. The release of Ca(2+) from the intracellular stores, such as the endoplasmic reticulum, by intracellular channels also contributes to the elevation of cytosolic Ca(2+). Inside the cell, Ca(2+) is controlled by the buffering action of cytosolic Ca(2+)-binding proteins and by its uptake and release by mitochondria. The uptake of Ca(2+) in the mitochondrial matrix stimulates the citric acid cycle, thus enhancing ATP production and the removal of Ca(2+) from the cytosol by the ATP-driven pumps in the endoplasmic reticulum and the plasma membrane. A Na(+)/Ca(2+) exchanger in the plasma membrane also participates in the control of neuronal Ca(2+). The impaired ability of neurons to maintain an adequate energy level may impact Ca(2+) signaling: this occurs during aging and in neurodegenerative disease processes. The focus of this review is on neuronal Ca(2+) signaling and its involvement in synaptic signaling processes, neuronal energy metabolism, and neurotransmission. The contribution of altered Ca(2+) signaling in the most important neurological disorders will then be considered.


Symptoms related to sleep-disordered breathing in white and Hispanic children: the Tucson Children's Assessment of Sleep Apnea Study.
The Tucson Children's Assessment of Sleep Apnea (TuCASA) study is designed to investigate the prevalence and correlates of objectively measured sleep-disordered breathing (SDB) in preadolescent children. This article describes the parental report of sleep symptoms associated with SDB in Hispanic and white children. A 13-question sleep habits screening questionnaire designed to assess the severity of sleep-related symptoms associated with SDB in children 4 to 11 years of age. Questionnaires were completed by the parents of children attending elementary school in the Tucson Unified School District, Tucson, AZ. There were 1,494 questionnaires returned, which comprised a sample of whites (38%), Hispanics (45%), and other races (17%). Of these questionnaires, 1,214 were returned for the children of white (45.8%; 556 children) or Hispanic (54.2%; 658 children) ethnicity only. The primary analysis was completed on these 613 boys (50.5%) and 601 girls (49.5%). In the total sample of 1,494 children, parents were more likely to report excessive daytime sleepiness (EDS) in female children than in male children (p <.01), however, this association did not achieve significance in the sample of only white and Hispanic children (p <.07). Composite variables for EDS and witnessed apnea (WITAP) show that parents of Hispanic children were more likely to report EDS (p <.01) and WITAP (p <.007). Hispanic children were also more likely to have learning problems (LPs) [p <.03] and to snore frequently (SN) [p <.02] than were white children. There were no significant differences between boys and girls for SN or WITAP. Hispanic boys were more likely to have reports of EDS (p <.02) and LPs (p <.04) than white boys, however, there were no other significant differences in gender or ethnicity in reports of EDS or LPs for white or Hispanic boys and girls. Those children with frequent LPs were significantly more likely to have SN (p <.001), EDS (p <.001), and WITAP (p <.001). A logistic regression model predicting LP resulted in significant adjusted odds ratios (ORs) of 2.4 for SN, 2.5 for EDS, and 2.1 for children aged 8 to 11 years. A similar model for EDS resulted in significant adjusted ORs of 3.2 for SN, 5.7 for WITAP, and 1.6 for female gender. Ethnicity was not significant in either model. Hispanic children in the population-based TuCASA study experienced more frequent symptoms associated with SDB, such as SN, EDS, WITAP, and LPs, than did white children. Children with LPs are 2.4 times more likely to have SN, 2.5 times more likely to have EDS, and were 2.1 times more likely to be between the ages of 8 and 11 years. Children with EDS were 3.2 times more likely to have SN, 5.7 times more likely to have WITAP, and were 1.6 times more likely to be a girl.


Suppression of microglial activation is neuroprotective in a mouse model of human retinitis pigmentosa.
Retinitis pigmentosa (RP) is a photoreceptor-degenerative disease caused by various mutations and is characterized by death of rod photoreceptor cell followed by gradual death of cone photoreceptors. The molecular mechanisms that lead to rod and cone death are not yet fully understood. Neuroinflammation contributes to the progression of many chronic neurodegenerative disorders. However, it remains to be determined how microglia contribute to photoreceptor disruption in RP. In this study, we explored the role of microglia as a contributor to photoreceptor degeneration in the rd10 mouse model of RP. First, we demonstrated that microglia activation was an early alteration in RP retinas. Inhibition of microglia activation by minocycline reduced photoreceptor apoptosis and significantly improved retinal structure and function and visual behavior in rd10 mice. Second, we identified that minocycline exerted its neuroprotective effects through both anti-inflammatory and anti-apoptotic mechanisms. Third, we found that Cx3cr1 deficiency dysregulated microglia activation and subsequently resulted in increased photoreceptor vulnerability in rd10 mice, suggesting that the Cx3cl1/Cx3cr1 signaling pathway might protect against microglia neurotoxicity. We concluded that suppression of neuroinflammatory responses could be a potential treatment strategy aimed at improving photoreceptor survival in human RP.


Reduction in cyclic 3',5'-adenosine monophosphate phosphodiesterase activity in exudate and cultured mouse peritoneal macrophages.
Cyclic nucleotides have been implicated in the normal function of macrophages, but the nature of the cyclic nucleotide catabolizing enzyme phosphodiesterase (PDE) and its role in regulation of macrophage function has not been previously reported. Cyclic adenosine monophosphate PDE activity was studied in mouse peritoneal macrophages and found to be similar to that reported in other tissues with regard to stability and divalent cation requirement. Exudate macrophages induced by injection of either endotoxin or proteose peptone broth were found to have reduced PDE activity and enhanced EAC phagocytic capacity and acid phosphatase (AP) activity. When resident peritoneal macrophages were cultured in vitro; AP activity increased over 24 hr and remained elevated for 96 hr. PDE activity declined steadily over 96 hr. This steady decline in PDE activity observed during culture was not altered by inclusion of endotoxin. These studies suggest that PDE activity is reduced in macrophages with maximally enhanced function but does not appear to be significantly altered during early phases of functional change in macrophages.


Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing.
Endothelin (ET)-1 is known for the most potent vasoconstrictive peptide that is released mainly from endothelial cells. Several studies have reported ET-1 signaling is involved in the process of wound healing or fibrosis as well as vasodilation. However, little is known about the role of ET-1 in these processes. To clarify its mechanism, we compared skin fibrogenesis and wound repair between vascular endothelial cell-specific ET-1 knockout mice and their wild-type littermates. Bleomycin-injected fibrotic skin of the knockout mice showed significantly decreased skin thickness and collagen content compared to that of wild-type mice, indicating that bleomycin-induced skin fibrosis is attenuated in the knockout mice. The mRNA levels of transforming growth factor (TGF)-β were decreased in the bleomycin-treated skin of ET-1 knockout mice. On the other hand, skin wound healing was accelerated in ET-1 knockout mice, which was indicated by earlier granulation tissue reduction and re-epithelialization in these mice. The mRNA levels of TGF-β, tumor necrosis factor (TNF)-α and connective tissue growth factor (CTGF) were reduced in the wound of ET-1 knockout mice. In endothelial ET-1 knockout mouse, the expression of TNF-α, CTGF and TGF-β was down-regulated. Bosentan, an antagonist of dual ET receptors, is known to attenuate skin fibrosis and accelerate wound healing in systemic sclerosis, and such contradictory effect may be mediated by above molecules. The endothelial cell-derived ET-1 is the potent therapeutic target in fibrosis or wound healing, and investigations of the overall regulatory mechanisms of these pathological conditions by ET-1 may lead to a new therapeutic approach.


Lactobacillus paracasei R3 Alleviates Tumor Progression in Mice with Colorectal Cancer.
Lactobacillus paracasei (L. paracasei), a common probiotic lactobacillus, has important functions in the food industry and human health. However, different strains of L. paracasei inevitably show differences in activity and colonization resistance, leading to differentiation in their functions, as well as their physical or chemical properties. The purpose of this study was to evaluate the characteristics of L. paracasei R3 (L.p R3) isolated from healthy human feces and determine whether the criteria for edible probiotics is met. The hemolysis type, biofilm-forming ability, antibiotic susceptibility, toxicity, and effective activity of L.p R3 were determined by establishing its probiotic activity traits in vitro and in vivo. The results showed that L.p R3 had a moderate biofilm formation ability, was sensitive to 11 antibiotics, was resistant to eight antibiotics, and was not hemolytic. The culture characteristics, morphology, and biochemical responses of the strain were consistent with the seed batch characteristics. In toxicity assays, L.p R3-fed mice showed no abnormalities in body weight, growth, or various organs. Additionally, L.p R3 was found to be effective in the prevention and treatment of colorectal cancer. In conclusion, our results revealed that L.p R3 has potential value as an edible probiotic without toxic side effects and alleviated the tumor progression of colorectal cancer in mice.


The interface between spoken and written language: developmental disorders.
We review current knowledge about reading development and the origins of difficulties in learning to read. We distinguish between the processes involved in learning to decode print, and the processes involved in reading for meaning (reading comprehension). At a cognitive level, difficulties in learning to read appear to be predominantly caused by deficits in underlying oral language skills. The development of decoding skills appears to depend critically upon phonological language skills, and variations in phoneme awareness, letter-sound knowledge and rapid automatized naming each appear to be causally related to problems in learning to read. Reading comprehension difficulties in contrast appear to be critically dependent on a range of oral language comprehension skills (including vocabulary knowledge and grammatical, morphological and pragmatic skills).


Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice.
We examined whether cells of the adaptive immune system retain the memory of psychosocial stress and thereby alter mood states and CNS function in the host. Lymphocytes from mice undergoing chronic social defeat stress or from unstressed control mice were isolated and adoptively transferred into naive lymphopenic Rag2(-/-) mice. Changes in affective behavior, hippocampal cell proliferation, microglial activation states, and blood cytokine levels were examined in reconstituted stress-naive mice. The mice receiving lymphocytes from defeated donors showed less anxiety, more social behavior, and increased hippocampal cell proliferation compared with those receiving no cells or cells from unstressed donors. Mice receiving stressed immune cells had reduced pro-inflammatory cytokine levels in the blood relative to the other groups, an effect opposite to the elevated donor pro-inflammatory cytokine profile. Furthermore, mice receiving stressed immune cells had microglia skewed toward an anti-inflammatory, neuroprotective M2-like phenotype, an effect opposite the stressed donors' M1-like pro-inflammatory profile. However, stress had no effect on lymphocyte surface marker profiles in both donor and recipient mice. The data suggest that chronic stress-induced changes in the adaptive immune system, contrary to conferring anxiety and depressive behavior, protect against the deleterious effects of stress. Improvement in affective behavior is potentially mediated by reduced peripheral pro-inflammatory cytokine load, protective microglial activity, and increased hippocampal cell proliferation. The data identify the peripheral adaptive immune system as putatively involved in the mechanisms underlying stress resilience and a potential basis for developing novel rapid-acting antidepressant therapies.


BRAF mutation status is an independent prognostic factor for resected stage IIIB and IIIC melanoma: implications for melanoma staging and adjuvant therapy.
5-year survival for melanoma metastasis to regional lymph nodes (American Joint Committee on Cancer stage III) is <50%. Knowledge of outcomes following therapeutic lymphadenectomy for stage III melanoma related to BRAF status may guide adjuvant use of BRAF/MEK inhibitors along with established and future therapies. To determine patterns of melanoma recurrence and survival following therapeutic lymph node dissection (TLND) associated with oncogenic mutations. DNA was obtained from patients who underwent TLND and had ⩾2 positive nodes, largest node >3cm or extracapsular invasion. Mutations were detected using an extended Sequenom MelaCARTA panel. Mutations were most commonly detected in BRAF (57/124 [46%] patients) and NRAS (26/124 [21%] patients). Patients with BRAF mutations had higher 3-year recurrence rate (77%) versus 54% for BRAF wild-type patients (hazard ratio (HR) 1.8, p=0.008). The only prognostically significant mutations occurred in BRAF: median recurrence-free (RFS) and disease-specific survival (DSS) for BRAF mutation patients was 7 months and 16 months, versus 19 months and not reached for BRAF wild-type patients, respectively. Multivariate analysis identified BRAF mutant status and number of positive lymph nodes as the only independent prognostic factors for RFS and DSS. Patients with BRAF mutations experienced rapid progression of metastatic disease with locoregional recurrence rarely seen in isolation, supporting incorporation of BRAF status into melanoma staging and use of BRAF/MEK inhibitors post-TLND.


Cavernous sinus aneurysms: risk of growth over time and risk factors.
Cavernous internal carotid artery (ICA) aneurysms are frequently diagnosed incidentally and the benign natural history of these lesions is well known, but there is limited information assessing the risk of growth in untreated patients. The authors sought to assess and analyze risk factors in patients with cavernous ICA aneurysms and compare them to those of patients with intracranial berry aneurysms in other locations. Data from consecutive patients who were diagnosed with a cavernous ICA aneurysm were retrospectively reviewed. The authors evaluated patients for the incidence of cavernous ICA aneurysm growth and rupture. In addition, the authors analyzed risk factors for cavernous ICA aneurysm growth and compared them to risk factors in a population of patients diagnosed with intracranial berry aneurysms in locations other than the cavernous ICA during the same period. In 194 patients with 208 cavernous ICA aneurysms, the authors found a high risk of aneurysm growth (19.2% per patient-year) in patients with large/giant aneurysms. Size was significantly associated with higher risk of growth. Compared to patients with intracranial berry aneurysms in other locations, patients with cavernous ICA aneurysms were significantly more likely to be female and have a lower incidence of hypertension. Aneurysms of the cavernous ICA are benign lesions with a negligible risk of rupture but a definite risk of growth. Aneurysm size was found to be associated with aneurysm growth, which can be associated with new onset of symptoms. Serial follow-up imaging of a cavernous ICA aneurysm might be indicated to monitor for asymptomatic growth, especially in patients with larger lesions.