[A method for diagnosis of early-stage cataract].
The method is based on eye fundus photography using a fundus-camera with a digital camera being built in. With its use, the diagnosis of cataract is based on the instrumental determination of the extent of darkening of the eye fundus shown in the color photograph depending on the degree of opacity the lens through which the eye fundus is photographed. This diagnostic technique rules out visual (by eye) determination of lenticular opacity. Solution of the set technical problem makes it possible to diagnose optically significant cataract and hence to define indications for anticataract surgery.


[Hemostatic system function as affected by thromboplastic agents from higher plants].
It has been determined that the thromboplastic agents from the inflorescence of the birch Betula pendula Roth, blossoms of the willow Salix daphnoides Vill., seeds of the pea Pisum sativum L. provoke protective reaction of the animal's anticoagulation system, though weaker expressed than the reaction of thromboplastin from brain. The mechanisms of action of thromboplastic agents of plant origin is similar to the mechanism of action of tissue thromboplastin.


Mitochondrial dysfunction leads to telomere attrition and genomic instability.
Mitochondrial dysfunction and oxidative stress have been implicated in cellular senescence, apoptosis, aging and aging-associated pathologies. Telomere shortening and genomic instability have also been associated with replicative senescence, aging and cancer. Here we show that mitochondrial dysfunction leads to telomere attrition, telomere loss, and chromosome fusion and breakage, accompanied by apoptosis. An antioxidant prevented telomere loss and genomic instability in cells with dysfunctional mitochondria, suggesting that reactive oxygen species are mediators linking mitochondrial dysfunction and genomic instability. Further, nuclear transfer protected genomes from telomere dysfunction and promoted cell survival by reconstitution with functional mitochondria. This work links mitochondrial dysfunction and genomic instability and may provide new therapeutic strategies to combat certain mitochondrial and aging-associated pathologies.


Can time-resolved NIRS provide the sensitivity to detect brain activity during motor imagery consistently?
Previous functional magnetic resonance imaging (fMRI) studies have shown that a subgroup of patients diagnosed as being in a vegetative state are aware and able to communicate by performing a motor imagery task in response to commands. Due to the fMRI's cost and accessibility, there is a need for exploring different imaging modalities that can be used at the bedside. A promising technique is functional near infrared spectroscopy (fNIRS) that has been successfully applied to measure brain oxygenation in humans. Due to the limited depth sensitivity of continuous-wave NIRS, time-resolved (TR) detection has been proposed as a way of enhancing the sensitivity to the brain, since late arriving photons have a higher probability of reaching the brain. The goal of this study was to assess the feasibility and sensitivity of TR fNIRS in detecting brain activity during motor imagery. Fifteen healthy subjects were recruited in this study, and the fNIRS results were validated using fMRI. The change in the statistical moments of the distribution of times of flight (number of photons, mean time of flight and variance) were calculated for each channel to determine the presence of brain activity. The results indicate up to an 86% agreement between fMRI and TR-fNIRS and the sensitivity ranging from 64 to 93% with the highest value determined for the mean time of flight. These promising results highlight the potential of TR-fNIRS as a portable brain computer interface for patients with disorder of consciousness.


Effect of Low-Level Laser Therapy on Bone Regeneration During Osseointegration and Bone Graft.
The effect of low-level laser therapy (LLLT) on bone regeneration during osseointegration and bone graft is very controversial. Despite many positive reports of in vitro and in vivo studies and more than 50 randomized clinical trials claiming a positive effect of photobiomodulation (PBM), many reports found no significant effect of lasers. The aim of this study was to evaluate studies correlating PBM and bone regeneration and to assesses parameters that produce positive results based on dose and output power used. Four electronic databases were used: PubMed, Springer, Google Scholar, and Cochrane. The research yielded 230 articles. The full texts of all articles were evaluated and scored using eligibility criteria adapted from Cericato et al. After evaluation, only 19 articles met the inclusion criteria. A positive effect of low-level laser energy on bone regeneration within a certain relationship between dose and output power was found. LLLT stimulates cellular metabolism, increasing protein synthesis and subsequent bone regeneration. A high dose combined with low power or a low dose combined with high power appears to produce a positive effect.


Assessment of chk1 phosphorylation as a pharmacodynamic biomarker of chk1 inhibition.
Chk1 inhibitors, such as AZD7762, are in clinical development in combination with cytotoxic agents for the treatment of solid tumors, including pancreatic cancers. To maximize the likelihood of their clinical success, it is essential to optimize drug scheduling as well as pharmacodynamic biomarkers in preclinical models. We tested multiple schedules of administration of gemcitabine and AZD7762 on the survival of pancreatic cancer cells. Potential pharmacodynamic biomarkers including pChk1, pChk2, pHistone H3, and caspase-3 were evaluated in vitro, followed by assessment of promising candidate biomarkers in vivo. We then went on to determine the contributions of PP2A and DNA damage to the mechanism(s) of induction of the identified biomarker, pS345 Chk1. AZD7762 given during and after or after gemcitabine administration produced maximum chemosensitization. In vivo, AZD7762 significantly inhibited the growth of pancreatic tumor xenografts in response to gemcitabine. Of the biomarkers assessed, pS345 Chk1 was most consistently increased in response to gemcitabine and AZD7762 in tumors and normal tissues (hair follicles). pS345 Chk1 induction in response to gemcitabine and AZD7762 occurred in the presence of PP2A inhibition and in association with elevated γH2AX, suggesting that DNA damage is an underlying mechanism. AZD7762 sensitizes pancreatic cancer cells and tumors to gemcitabine in association with induction of pS345 Chk1. Together these data support the clinical investigation of AZD7762 with gemcitabine in pancreatic cancer under a dosing schedule in which gemcitabine is administered concurrent with or before AZD7762 and in conjunction with skin biopsies to measure pS345 Chk1.


Factors affecting pregnancy weight gain and relationships with maternal/fetal outcomes in Turkey.
To determine the effects of pre-pregnancy body mass index (BMI) and gestational weight gain on maternal and fetal complications, and to examine whether Turkish women achieve the recommended gestational weight gain. We also investigated the relationship between pregnancy weight gain and mode of delivery, with an examination of maternal anthropometry. Methods: A retrospective cross-sectional study was conducted on a population of 986 pregnant women between November 2011 and November 2015 at Atatürk Education and Research Hospital, Ankara, Turkey. Maternal age, BMI, monthly weight gain during pregnancy, infant birth weight, gender, and maternal and fetal adverse outcomes were evaluated. Results: The frequency of maternal complications was positively associated with elevated pre-pregnancy BMI (p less than 0.05), and weight gain during pregnancy was associated with parity and increased infant birth weight (p less than 0.05). However, no correlations were observed between mean pregnancy weight gain and maternal complications (p greater than 0.05). The percentage of women who gained the Institute of Medicine (IOM)-recommended amount of weight was the highest in the underweight BMI group (54.1%) and the lowest in the obese BMI group (24.3%). Pregnancy weight gain exceeded IOM recommendations in the overweight (56.3%) and obese (52.5%) groups. Conclusions: While maternal weight gain during pregnancy affects neonatal body weight, higher pre-pregnancy BMI has an adverse effect on recommended weight gain during pregnancy, with increased maternal complications.


STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression.
Metastasis is a life-threatening feature of cancer and is primarily responsible for cancer patient mortality. Cross talk between tumor cells and endothelium is important for tumor progression and metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to tumor cells, respond to the tumor cells during tumor progression and metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in tumor progression and metastasis. We found that the loss of STAT3 in ECs did not affect primary Lewis lung carcinoma (LLC) tumor growth, but it reduced in vivo LLC metastasis in experimental and spontaneous metastasis models. Mechanistically, STAT3 activation upregulated cell adhesion molecule expression, including E-selectin and P-selectin, in murine endothelial MS-1 cells treated with tumor cell-conditioned media in vitro and in pre-metastatic lungs of tumor-bearing mice in vivo. We also found that both E-selectin and P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However, tumor cell-conditioned media from B16F10 melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10 melanoma cell metastasis. In addition, various human cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis.


Immunohistochemical distinction of follicular thyroid adenomas and follicular carcinomas.
To use immunohistochemical (IHC) evaluation of proteins encoded by genes that were differentially expressed in follicular thyroid adenomas (FAs) vs follicular thyroid carcinomas (FTCs) to distinguish benign vs malignant follicular thyroid lesions. Multiple gene microarray studies suggest that benign and malignant follicular thyroid neoplasms have different gene expression profiles. Immunohistochemical analysis of thyroid neoplasms, including FA (n = 62), FTC (n = 62), and follicular variant of papillary thyroid carcinoma (n = 58), using tissue microarrays. We evaluated antibodies galectin-3, autotaxin, intestinal trefoil factor 3 (TFF3), extracellular matrix metalloproteinase inducer (EMMPRIN), and growth arrest and DNA damage-inducible protein 153 (GADD153). We analyzed data for quantitative differences in IHC intensity and the percentage of positive cells between FAs and combined follicular carcinomas. Sensitivity and specificity analysis are reported, along with a dual-protein clinical algorithm. Academic tertiary care center. Adults with known follicular and papillary thyroid lesions that were surgically resected during the past 15 years. Sensitivity and specificity of individual and combined antibodies for detecting benign from malignant lesions. Quantitative analysis showed IHC validation of the gene expression differences noted in previously published microarray reports. A significantly higher percentage of FTC cells stained with galectin-3, EMMPRIN, and GADD153. Galectin-3 and EMMPRIN also showed a significantly higher intensity of staining in FTC cells. Compared with malignant lesions, TFF3 stained a greater cell percentage in FAs. Galectin-3 (sensitivity, 0.72; specificity, 0.62) and EMMPRIN (sensitivity, 0.63; specificity, 0.49) had the most promising diagnostic potential with a dual-protein sensitivity of 0.80 and specificity of 0.70. Autotaxin and GADD153 had overall higher sensitivities (0.88 and 0.82, respectively) but very poor specificities (0.02 and 0.21, respectively). Protein expression data validate the pooled gene expression results that differentiate FTC from FA. Our results show promise for multiple-protein IHC analysis algorithms and their diagnostic ability. Future studies should focus on clinical translation of these molecular differences for the diagnosis of follicular thyroid neoplasms.


Electrorheological effect and electro-optical properties of side-on liquid crystalline polysiloxane in a nematic solvent.
The electrorheological (ER) effect and the electro-optical properties of a ''side-on'' liquid crystalline polysiloxane (PS) are investigated. A large ER effect is observed and the response to the shear stress of neat PS in the nematic phase is shown to be affected by the shear rate. PS is also mixed with a low-molar nematic liquid crystal (5CB) in order to improve the response behavior to the applied electric field. The rheological properties of such mixtures are highly dependent on the concentration of 5CB. The composites respond faster to the applied electric field and have improved electro-optical properties. This study offers a new perspective on the development of liquid crystal materials for the ER effect.


Hibiscus sabdariffa L.: A potent natural neuroprotective agent for the prevention of streptozotocin-induced Alzheimer's disease in mice.
Hibiscus sabdariffa L. (Malvaceae) is one of the well-known traditionally used remedy worldwide. It exhibited numerous pharmacological properties including antioxidant, antidepressant, sedative, anti-inflammatory, antiproliferative, antimicrobial and neuroprotective activities. The aim of this study is to highlight the mechanisms underlying the neuroprotective effects of anthocyanin-enriched extracts of two Hibiscus varieties (white and red calyces) in the management of Alzheimer's disease (AD) in addition to their metabolic profiling. The anthocyanin contents were determined quantitatively using the pH-differential technique and qualitatively by LC/MS/MS. The extracts were tested in vitro for their antioxidant potential as well as acetylcholinesterase inhibition activity and both showed promising activities. The LC/MS/MS analysis allowed the tentative identification of 26 and 24 metabolites in red and white calyces, respectively, represented by anthocyanins, flavonoids, aliphatic and phenolic acids. In vivo, streptozotocin induced AD in mice model was established and Hibiscus extracts were tested at a dose of 200 mg kg-1 compared to celecoxib (30 mg/kg). Histopathology of cerebral cortex and hippocampus, immunohistochemistry for tau- protein and caspase-3 with behavioral tests and measurement of several biochemical parameters were done. Hibiscus prevented memory impairment, and this could be attributed to the amelioration of STZ-induced neuroinflammation and amyloidogenesis. Consequently, Hibiscus represents a promising safe agent that can be repurposed for AD through exerting anti-inflammatory, anti-acetylcholinesterase, antioxidant, and anti-amyloidogenic activities.


Mechanical transmission of anaplasmosis by tabanids (Diptera: Tabanidae).
The role of tabanids in the mechanical transmission of anaplasmosis was further clarified by determining the number of horse fly bites needed to transmit the disease and the length of time that horse flies remain mechanically infective. Transmission of anaplasmosis from acutely infected calves to susceptible splenectomized calves was accomplished with as few as 10 horse fly bites. These flies were shown to remain mechanically infective for at least 2 hours after they had obtained a partial blood meal from an acutely infected calf. These data emphasize the efficiency of horse flies in the mechanical transmission of anaplasmosis and indicate that relatively short-distance barriers may not be adequate to prevent transmission between infected and noninfected herds.


Childhood emotional maltreatment severity is associated with dorsal medial prefrontal cortex responsivity to social exclusion in young adults.
Children who have experienced chronic parental rejection and exclusion during childhood, as is the case in childhood emotional maltreatment, may become especially sensitive to social exclusion. This study investigated the neural and emotional responses to social exclusion (with the Cyberball task) in young adults reporting childhood emotional maltreatment. Using functional magnetic resonance imaging, we investigated brain responses and self-reported distress to social exclusion in 46 young adult patients and healthy controls (mean age = 19.2±2.16) reporting low to extreme childhood emotional maltreatment. Consistent with prior studies, social exclusion was associated with activity in the ventral medial prefrontal cortex and posterior cingulate cortex. In addition, severity of childhood emotional maltreatment was positively associated with increased dorsal medial prefrontal cortex responsivity to social exclusion. The dorsal medial prefrontal cortex plays a crucial role in self-and other-referential processing, suggesting that the more individuals have been rejected and maltreated in childhood, the more self- and other- processing is elicited by social exclusion in adulthood. Negative self-referential thinking, in itself, enhances cognitive vulnerability for the development of psychiatric disorders. Therefore, our findings may underlie the emotional and behavioural difficulties that have been reported in adults reporting childhood emotional maltreatment.


Outbreak of Escherichia coli O157:H7 associated with raw milk consumption in the Pacific Northwest.
In late 2005, health officials in Clark County, Washington noted a higher than expected number of Escherichia coli cases among residents and sought to identify a possible common source for infection. In order to identify risk factors, health officials conducted a retrospective cohort study and an environmental site investigation using pulsed-field gel electrophoresis (PFGE) to identify and prevent future cases from occurring. Several lines of evidence supported raw milk as the cause of infections: 1) all ill persons drank raw milk from the same cow share; 2) illness was associated with an increasing amount of milk consumed; 3) E. coli O157:H7 was isolated from raw milk samples and environmental samples collected from the floor of the milking parlour; and 4) PFGE patterns were indistinguishable between case-patients, raw milk samples, and environmental samples. Together, these findings made clear the health risks associated with the consumption of raw milk. The high amount of media interest in this investigation empowered public health officials to work with state legislators to pass State Senate Bill 6377 in Washington State which clarified that state licensing requirements apply to all milk production facilities including cow-share programs.


Characterization of the abiotic drivers of abundance of nearshore Arctic fishes.
Fish are critical ecologically and socioeconomically for subsistence economies in the Arctic, an ecosystem undergoing unprecedented environmental change. Our understanding of the responses of nearshore Arctic fishes to environmental change is inadequate because of limited research on the physicochemical drivers of abundance occurring at a fine scale. Here, high-frequency in situ measurements of pH, temperature, salinity, and dissolved oxygen were paired with daily fish catches in nearshore Alaskan waters of the Beaufort Sea. Due to the threat that climate change poses to high-latitude marine ecosystems, our main objective was to characterize the abiotic drivers of abundance and elucidate how nearshore fish communities may change in the future. We used generalized additive models (GAMs) to describe responses to the nearshore environment for 18 fish species. Relationships between abundance and the physicochemical environment were variable between species and reflected life history. Each abiotic covariate was significant in at least one GAM, exhibiting both nonlinear and linear associations with abundance. Temperature was the most important predictor of abundance and was significant in GAMs for 11 species. Notably, pH was a significant predictor of abundance for six species: Arctic cod (Boreogadus saida), broad whitefish (Coregonus nasus), Dolly Varden (Salvelinus malma), ninespine stickleback (Pungitius pungitius), saffron cod (Eleginus gracilis), and whitespotted greenling (Hexagrammos stelleri). Broad whitefish and whitespotted greenling abundance was positively associated with pH, while Arctic cod and saffron cod abundance was negatively associated with pH. These results may be a bellwether for future nearshore Arctic fish community change by providing a foundational characterization of the relationships between abundance and the abiotic environment, particularly in regard to pH, and demonstrate the importance of including a wider range of physicochemical habitat covariates in future research.


Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population.
Activation of Akt is associated with enhanced cell cycling and cellular proliferation in nonmyocytes, but this effect of nuclear Akt accumulation has not been explored in the context of the myocardium. Cardiac-specific expression of nuclear-targeted Akt (Akt/nuc) in transgenics prolongs postnatal cell cycling as evidenced by increased numbers of Ki67+ cardiomyocytes at 2 to 3 weeks after birth. Similarly, nuclear-targeting of Akt promotes expansion of the presumptive cardiac progenitor cell population as assessed by immunolabeling for c-kit in combination with myocyte-specific markers Nkx 2.5 or MEF 2C. Increases in pro-proliferative cytokines, including tumor-necrosis superfamily 8, interleukin-17e, and hepatocyte growth factor, were found in nuclear-targeted Akt myocardial samples. Concurrent signaling mediated by paracrine factors downstream of Akt/nuc expression may be responsible for phenotypic effects of nuclear-targeted Akt in the myocardium, including enhanced cell proliferation and expansion of the stem cell population.


Human antigen R affects the migration and invasion of human lung cancer A549 cells via regulating E-cadherin suppressor Snail.
Recent studies demonstrated that the progression and metastasis of lung cancer were associated with human antigen R (HuR), a post-transcriptional RNA-binding protein that stabilize and regulate the expression of many tumor-related genes. Although HuR was shown to affect the expressions of epithelial cadherin (E-cadherin), a tumor migration suppressor, in airway epithelial cells, esophageal squamous and colon cancer cells, direct evaluation for the effect and mechanism of HuR on the migration and invasion of lung cancer cells is not documented. In this study, HuR was knocked down via RNA interference and overexpressed using recombinant plasmid in adenocarcinomic human alveolar basal epithelial A549 cells. No apparent inhibition of cell viability was observed. HuR knocked down significantly suppressed A549 migration and invasion in scratch wound healing and transwell assays, with an increase in E-cadherin expression, while the overexpression of HuR notably facilitated A549 migration and invasion, with a decrease in E-cadherin level. In addition, immunoprecipitation study showed that HuR directly interacted with Snail, a repressor of E-cadherin, and upregulated the expression of Snail in A549 cells. These combined results suggested that the effect of HuR on A549 migration and invasion was realized by stabilizing and increasing the expression of Snail, which in-turn interfered with the expression of E-cadherin. The finding of this study revealed direct evidence that HuR affected the migration and invasion of lung cancer cells via regulating E-cadherin and Snail, providing an additional reference and mechanistic clue for further researches and therapeutic strategies in treating lung cancer.


Chemical Approaches to Optimize the Properties of Organic Fluorophores for Imaging and Sensing.
Organic fluorophores are indispensable tools in cells, tissue and in vivo imaging, and have enabled much progress in the wide range of biological and biomedical fields. However, many available dyes suffer from insufficient performances, such as short absorption and emission wavelength, low brightness, poor stability, small Stokes shift, and unsuitable permeability, restricting their application in advanced imaging technology and complex imaging. Over the past two decades, many efforts have been made to improve these performances of fluorophores. Starting with the luminescence principle of fluorophores, this review clarifies the mechanisms of the insufficient performance for traditional fluorophores to a certain extent, systematically summarizes the modified approaches of optimizing properties, highlights the typical applications of the improved fluorophores in imaging and sensing, and indicates existing problems and challenges in this area. This progress not only proves the significance of improving fluorophores properties, but also provide a theoretical guidance for the development of high-performance fluorophores.


Toward a qualitative understanding of binge-watching behaviors: A focus group approach.
Background and aims Binge-watching (i.e., seeing multiple episodes of the same TV series in a row) now constitutes a widespread phenomenon. However, little is known about the psychological factors underlying this behavior, as reflected by the paucity of available studies, most merely focusing on its potential harmfulness by applying the classic criteria used for other addictive disorders without exploring the uniqueness of binge-watching. This study thus aimed to take the opposite approach as a first step toward a genuine understanding of binge-watching behaviors through a qualitative analysis of the phenomenological characteristics of TV series watching. Methods A focus group of regular TV series viewers (N = 7) was established to explore a wide range of aspects related to TV series watching (e.g., motives, viewing practices, and related behaviors). Results A content analysis identified binge-watching features across three dimensions: TV series watching motivations, TV series watching engagement, and structural characteristics of TV shows. Most participants acknowledged that TV series watching can become addictive, but they all agreed having trouble recognizing themselves as truly being an "addict." Although obvious connections could be established with substance addiction criteria and symptoms, such parallelism appeared to be insufficient, as several distinctive facets emerged (e.g., positive view, transient overinvolvement, context dependency, and low everyday life impact). Discussion and conclusion The research should go beyond the classic biomedical and psychological models of addictive behaviors to account for binge-watching in order to explore its specificities and generate the first steps toward an adequate theoretical rationale for these emerging problematic behaviors.


Emerging infections with community-associated methicillin-resistant Staphylococcus aureus in outpatients at an Army Community Hospital.
Methicillin-resistant Staphylococcus aureus (MRSA) infection typically occurs in chronically ill patients requiring long-term antimicrobial therapy or hospitalization. However, community-associated MRSA (CA-MRSA) necrotizing soft tissue infections seem to be increasing in incidence. Our aim was to describe the incidence and microbiologic characteristics of CA-MRSA isolates collected at an army community hospital. We report a retrospective review of MRSA isolates identified during 1998-2003 at the microbiology laboratory of Moncrief Army Community Hospital that serves a community of approximately 40,000 transient residents yearly in Fort Jackson, South Carolina. We evaluated the incidence of MRSA in our laboratory during 1998-2003. For MRSA isolates from 2003, we evaluated antimicrobial susceptibility patterns. Six selected isolates were evaluated by molecular typing, resistance gene analysis, and toxin analysis. During 1998-2003, 241 (23%) of 1041 S. aureus isolates identified at the hospital microbiology laboratory were resistant to methicillin. Of these 241 MRSA isolates, 223 were cultured from outpatients. The incidence of MRSA in our population increased from 12% of S. aureus isolates in 1998 to 43% in 2003. In 2003, MRSA was cultured from 76 different patients. Isolates of MRSA were often resistant to erythromycin (91%), although resistance to other agents was less common: Ciprofloxacin (14%), levofloxacin (14%), clindamycin (3%), tetracycline (3%), and trimethoprim sulfamethoxazole (1%). No isolates were resistant to vancomycin, gentamicin, nitrofurantoin, or rifampin. Six CA-MRSA isolates were compared by pulsed-field gel electrophoresis (PFGE). Five were PFGE type USA300, and one was PFGE type USA100, based on the U.S. Centers for Disease Control and Prevention (CDC) classification scheme. The five USA300 isolates carried SCCmec type IV, and the USA100 carried SCCmec II. None of the isolates were positive by PCR for genes encoding enterotoxins A-E and H, or toxic shock syndrome toxin (TSST-1), but the five USA300 isolates carried the gene coding for Panton-Valentine leukocidin toxin. The incidence of MRSA at our institution is increasing. Isolates of MRSA show resistance patterns and microbiologic characteristics consistent with CA-MRSA isolates from the United States. Clinicians should consider the possibility of CA-MRSA in patients with soft-tissue infections who do not respond to initial therapy with beta-lactam antimicrobial agents.


Long-living terahertz magnons in ultrathin metallic ferromagnets.
The main idea behind magnonics is to use the elementary magnetic excitations (magnons) for information transfer and processing. One of the main challenges, hindering the application of ultrafast terahertz magnons in magnonics, has been the short lifetime of these excitations in metallic ferromagnets. Here, we demonstrate that the engineering of the electronic structure of a ferromagnetic metal, by reducing its dimensionality and changing its chemical composition, opens a possibility to strongly suppress the relaxation channels of terahertz magnons and thereby enhance the magnons' lifetime. For the first time, we report on the long-lived terahertz magnons excited in ultrathin metallic alloy films. On the basis of the first-principles calculations, we explain the microscopic nature of the long lifetime being a consequence of the peculiar electronic hybridizations of the species. We further demonstrate a way of tailoring magnon energies (frequencies) by varying the chemical composition of the film.


Demonstration of coexisting catecholamine (dopamine), amino acid (GABA), and peptide (NPY) involved in inhibition of melanotrope cell activity in Xenopus laevis: a quantitative ultrastructural, freeze-substitution immunocytochemical study.
This quantitative ultrastructural immunocytochemical study demonstrates the coexistence of a catecholamine [dopamine (DA)], an amino acid (GABA), and a neuropeptide [neuropeptide Y (NPY)] in axon varicosities innervating the pars intermedia of Xenopus laevis. The varicosities are assumed to control the pars intermedia melanotrope cells, which regulate skin color during the physiological process of background adaptation. Varicosity profiles appear to abut melanotrope cells and folliculostellate cells, star-shaped cells that intimately contact the melanotropes. All varicosity profiles contain two morphological types of vesicle. Monolabeling studies on routinely fixed and freeze-substituted tissues showed that the small, electron-lucent vesicles store GABA, whereas DA and NPY occur in larger, electron-dense ones. Double and triple labeling experiments, in which the degree of immunoreactivity was quantified per varicosity profile and per vesicle, led to the conclusion that (1) DA, GABA, and NPY coexist within almost all varicosity profiles and (2) DA and NPY are costored within electron-dense vesicles. Varicosity profiles that about melanotrope cells show a much higher ratio between the numbers of electron-lucent and electron-dense vesicles than varicosities contacting folliculostellate cells (15.8 and 3.3, respectively). This differential distribution is in line with the previous demonstration that, in contrast to GABA, NPY does not act directly on the melanotrope cells but indirectly, by controlling the activity of the folliculostellate cells.


Comparison of Bayesian clustering and edge detection methods for inferring boundaries in landscape genetics.
Recently, techniques available for identifying clusters of individuals or boundaries between clusters using genetic data from natural populations have expanded rapidly. Consequently, there is a need to evaluate these different techniques. We used spatially-explicit simulation models to compare three spatial Bayesian clustering programs and two edge detection methods. Spatially-structured populations were simulated where a continuous population was subdivided by barriers. We evaluated the ability of each method to correctly identify boundary locations while varying: (i) time after divergence, (ii) strength of isolation by distance, (iii) level of genetic diversity, and (iv) amount of gene flow across barriers. To further evaluate the methods' effectiveness to detect genetic clusters in natural populations, we used previously published data on North American pumas and a European shrub. Our results show that with simulated and empirical data, the Bayesian spatial clustering algorithms outperformed direct edge detection methods. All methods incorrectly detected boundaries in the presence of strong patterns of isolation by distance. Based on this finding, we support the application of Bayesian spatial clustering algorithms for boundary detection in empirical datasets, with necessary tests for the influence of isolation by distance.


The Balanced Scorecard: a tool to monitor IPL curriculum implementation: January 2020.
This article was migrated. The article was marked as recommended. Introduction: Implementing interprofessional learning (IPL) in health profession curriculum is difficult despite widespread acknowledgement of the importance of interprofessional collaborative health care practice. The aim of this study was to develop a balanced scorecard using a Delphi technique to document and monitor implementation of IPL in a faculty of health and medical sciences. Methods/Results: Twenty-four academic teachers and health service clinical supervisors completed two electronic questionnaires as part of a two stage Delphi survey. Consensus (70% agreement/disagreement) was achieved for 27/36 items in round one and for all 10 items in round two. Ten performance metrics were subsequently identified. Discussion: The Delphi was an efficient and effective method for identifying performance metrics for monitoring faculty IPL implementation. With a strong focus on learning outcomes and assessment, the scorecard will enable the faculty to formally monitor implementation of our IPL strategy over time. A follow up process of identifying data sources for reporting against each of the scorecard items has already highlighted gaps in our current practices, predominantly in staff professional development and assessment.


Percutaneous ultrasonic debridement of equine tendinopathy and desmopathy: A report of 10 cases.
Tendinopathy and desmopathy are significant causes of morbidity in horses. To evaluate the use of percutaneous ultrasonic debridement (PUD) as a treatment for chronic tendinopathy and desmopathy in the horse. Eight adult horses with 10 affected limbs presented for lameness, ranging from 60-700 days postinjury. Diagnostic ultrasound identified the following: suspensory branch desmitis (n = 1), suspensory body desmitis (n = 2), Achilles tendinopathy (n = 1), desmitis of the accessory ligament of the deep digital flexor (DDF) tendon (n = 1), DDF tendinopathy (n = 2), and superficial digital flexor tendinopathy (n = 3). All horses had demonstrated lameness ranging from grade 1 to 4 [American Association of Equine Practitioners (AAEP) scale], with a mean pretreatment grade of 2.7. All horses underwent PUD using the Tenex Health TX® System. Follow-up results were available from 6 to 41 months (mean, 23.2 months). Follow-up ultrasound imaging demonstrated improvement in fiber alignment and architectural change in all cases. All horses had a reduction in lameness from the treated tendon or ligament (AAEP grade 0-1; mean AAEP grade, 0.2) following a single treatment; lameness completely resolved in 8 of 10 treated limbs. No adverse events occurred in any case. No horses in this study developed a recurrence of their original lesion. Horses in this study demonstrated improvement following the PUD procedure. The procedure was well-tolerated and safe. Removal of tendinopathic scar tissue with PUD resulted in a return to function and without recurrence of the original lesion in all horses.


Evaluation of effectiveness of hydrocolloid dressing vs ceramide containing dressing against pressure ulcers.
Pressure Ulcers (PUs) often is an indication of quality of nursing care as it remains as severe manifestation of the integrity of impaired skin. Our study designed to evaluate the effectiveness of hydrocolloid dressings and ceramide dressings in healing of PU. The study was done at Chinese hospital between Feb 2014-November 2014. 72 study group patients and 25 control group patients were included in the study. The study group patients were divided into Group A with 24 patients received only ordinary hydrocolloid dressings, Group B with 24 patients who ceramide containing hydrocolloid dressings and Group C with 24 patients received both hydrocolloid and ceramide dressings. Dressings were applied for 4 weeks. The dressings were changed every 10 days and skin conditions such as pH of the skin, hydration are measured by capacitive method. Among 72 study population 48 (66.7%) were male and 24 (33.3%) were females. Group A with 18 (75%) males and 6 (25%) females, group B with 20 (83.3%) males and 4 (16.7%) females, and group C with 10 (41.7%) males and 14 (58.3%) females. 25 Control group patients with 8 (32%) males and 16 (68%) females. Erythema seen in 4/24 (16.67%) group A patients, group B and C patients had 1/24 (4.17%) erythema. In control group patients 6/25(24%) developed erythema. In our study, we evaluated the effectiveness of the hydrocolloid dressings and ceramide containing dressings in which ceramide containing dressings showed effective prevention and water holding capacity. Our study highlights that ceramide containing dressings found to be more effective in reducing erythema and improving the healing of PU.


A German-Wide Systematic Study on Mobilization and Collection of Hematopoietic Stem Cells in Poor Mobilizer Patients with Multiple Myeloma prior to Autologous Stem Cell Transplantation.
In patients with a clinical indication for autologous hematopoietic stem cell transplantation (ASCT), sufficient mobilization of CD34+ precursor cells into peripheral blood is essential to ensure adequate hematopoietic stem cell (HSC) collection prior to intensive therapy. However, with standard granulocyte-colony stimulating factor (G-CSF)-based mobilization schemes, an important minority of patients fail to mobilize sufficient (e.g., >10/µL) CD34+ cell counts into the peripheral blood and are considered as poor mobilizers (PM). Because failure to achieve sufficient CD34+ cell mobilization can negatively affect important clinical treatment endpoints, the use of plerixafor (PLX) was approved to increase CD34+ mobilization in PM patients. The German non-interventional, multicenter, open-label, prospective OPTIMOB study evaluated HSC mobilization strategies prior to planned ASCT in adult patients with hematologic malignancies (lymphomas or multiple myeloma [MM]) focusing on PM patients. PM patients were defined as follows: (1) never achieving ≥20 CD34+ cells/µL before 1st apheresis, (2) receiving PLX at any timepoint of mobilization, (3) their initially planned stem cell yield had to be reduced, or (4) they had not received apheresis due to low CD34+ count in peripheral blood. 168 of 475 MM patients (35%) participating in the OPTIMOB study were classified as PM, and 155 of them (92%) received PLX (PM+PLX) during the study. PM patients were 40-78 years old, slightly more often male (n = 97, 58%), mostly newly diagnosed (n = 146, 87%) and received highly individualized previous treatments. Ninety-four of the PMs underwent chemotherapy mobilization (65%), and 51 patients (35%) received steady-state mobilization with G-CSF only during 1st mobilization attempt. 92% of the total PM population (n = 155) underwent apheresis, 78% of them (n = 117) achieved >2.0 × 106 CD34+ cells/kg body weight on the 1st day of apheresis. PM+PLX had a higher median total collection result than those PM patients without PLX support (7.2 vs. 5.7 × 106 CD34+ cells/kg body weight). In total, ASCT was performed in 136 PM+PLX (88%) versus 8 PM-PLX patients (62%). The OPTIMOB study showed that a considerable proportion of adult MM patients in Germany are PMs. Even though most of PMs were supported with PLX in the OPTIMOB study, PM-PLX also successfully mobilized HSCs, allowing ASCT in majority of all PMs. However, further analyses are required for treatment optimization in PMs.


Genetic and antigenic polymorphism of P. vivax apical membrane antigen-1 (pvama1I-II) from Nicaragua was examined. Infected blood samples from patients were obtained during 2012-2013. A gene fragment comprising domains I-II was amplified and sequenced, and the genetic parameters, haplotype relationships, genetic structure, and amino acid variation in predicted B cell epitopes were analyzed. 65 sequences of pvama1III had 19 nonsynonymous and five synonymous nucleotide changes. Nicaraguan parasites had low diversity, high linkage disequilibrium, and few recombination events. Neutrality tests indicate a positive and divergent selection, and three genetic clusters with loss of haplotypes were demonstrated. Amino acid variation predominated in predicted B cell epitopes and was closely related to that in Latin American parasites. Nicaraguan P. vivax is a moderately differentiated population under contraction and focalization processes, and the antigenic diversity resembles that of Latin American parasites. This information is relevant for vaccine development and epidemiological surveillance.


Comparison of blood pressure between Indiana AMA and NMA members.
1) To determine whether African-American physicians, compared to caucasian physicians, were at increased risk to develop hypertension; and 2) to determine whether physicians' knowledge of cardiovascular risk factors influenced their pattern of exercise. A mailed survey of members of the American Medical Association (AMA) and the National Medical Association (NMA) was completed to assess health status and plans for retirement. High-normal blood pressure was defined as systolic blood pressure of 85-89 mmHg. Mild (stage-1) hypertension was defined as systolic blood pressure of 140-159 mmHg and diastolic blood pressure of 90-99 mmHg. Gender (male), age, and body mass index (BMI) were significantly correlated with elevated levels of selected blood pressure measures. Using regression analysis to control for gender, age, and BMI, ethnicity was identified as a fourth factor accounting for elevated blood pressure. NMA physicians had 3.25 times the risk of having systolic blood pressure in the mild (stage-1) hypertension range, 5.78 times the risk for blood pressure in the high-normal diastolic hypertension range, and 5.19 times the risk for blood pressure in the mild (stage-1) diastolic hypertension range. Medical specialty and type of psychological support were not significant predictors of elevated blood pressure. These data suggest that African-American physicians may be at an increased risk to develop abnormal blood pressure, compared to caucasian physicians, potentially affecting the number of physicians available to minority communities.


Vectorial analytical description of the polarized light of a high-power laser diode.
A mathematical model to describe the far-field of a high-power laser diode (LD) beam is presented. The laser beam propagation is studied by the vector Rayleigh-Sommerfeld far-field diffraction integral formula The far-field distribution of the LD beam is studied in detail; the light polarized parallel and perpendicular to the junction plane are all considered. This model is employed to predict the light intensity of high-power LDs. The computed intensity distributions are in a good agreement with the corresponding measurements. This model can be easily used to analyze the propagation properties of the high-power LD beam.


Inhibition of the p50 (NKkappaB1) subunit of NF-kappaB by phosphorothioate-modified antisense oligodeoxynucleotides reduces NF-kappaB expression and immunoglobulin synthesis in murine B cells.
NF-kappaB is a regulatory protein of immune response genes and a candidate for targeting in immunosuppressive therapy. NF-kappaB proteins are formed from components of which p50 (NFkappaB1) is a subunit. By targeting p50 gene expression with specific antisense 3' phosphorothioate-oligodeoxynucleotides (3' PS-ODNs), an effect upon NF-kappaB regulation and immunoglobulin synthesis in murine B cells was achieved. A 49% decrease in p50 protein was induced by treatment of WEHI 231 B cells with p50 antisense 3' PS-ODNs and not by control 3' PS-ODNs. p50 antisense specifically reduced the expression of NF-kappaB by 51%, but not the transcription factor, Oct-1. In the BXSB murine model of autoimmunity, p50 antisense inhibited NF-kappaB expression and total IgM and IgG synthesis, but, more importantly, dsDNA antibodies were reduced 90%. These results validate the use of p50 antisense to reduce NF-kappaB expression and, by downregulating the immune response, has application in the treatment of autoimmune disorders.


Reconsidering the benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer.
Colorectal cancer is one of the most frequent solid tumors in the western world, with low survival rates in patients with metastatic disease. Doublet chemotherapy regimens such as FOLFOX or FOLFIRI are the mainstay of standard first-line chemotherapy in the metastatic setting. The conventional treatment as a first-line approach is continuous application until progression or intolerable toxicities. However, only one third of patients are treated until progression mainly due to the side effects of chemotherapy. Notably, oxaliplatin-containing regimens such as FOLFOX/CapOx or FOLFOXIRI are associated with oxaliplatin-induced neuropathy, which is the main reason for treatment discontinuation or treatment de-escalation. On this basis, recent studies have investigated the clinical benefits of bevacizumab-based intermittent and continuous treatment regimens in the metastatic colorectal setting, together with various strategies to optimize maintenance therapy including regimens with targeted therapies, such as cetuximab, ziv-aflibercept and regorafenib. Recent studies have also investigated when maintenance therapy should be initiated as well individualizing treatment based on patient, tumor and treatment characteristics, as well as molecular biomarkers. This article reviews the current evidence for the clinical benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer, and also evaluates the effect of RAS and BRAF mutational status on maintenance strategies.


The involvement of noradrenaline in rapid eye movement sleep mentation.
Noradrenaline, one of the main brain monoamines, has powerful central influences on forebrain neurobiological processes which support the mental activities occurring during the sleep-waking cycle. Noradrenergic neurons are activated during waking, decrease their firing rate during slow wave sleep, and become silent during rapid eye movement (REM) sleep. Although a low level of noradrenaline is still maintained during REM sleep because of diffuse extrasynaptic release without rapid withdrawal, the decrease observed during REM sleep contributes to the mentation disturbances that occur during dreaming, which principally resemble symptoms of schizophrenia but seemingly also of attention deficit hyperactivity disorder.


m-Diethynylbenzene macrocycles: syntheses and self-association behavior in solution.
m-Diethynylbenzene macrocycles (DBMs), buta-1,3-diyne-bridged [4(n)]metacyclophanes, have been synthesized and their self-association behaviors in solution were investigated. Cyclic tetramers, hexamers, and octamers of DBMs having exo-annular octyl, hexadecyl, and 3,6,9-trioxadecyl ester groups were prepared by intermolecular oxidative coupling of dimer units or intramolecular cyclization of the corresponding open-chain oligomers. The aggregation properties were investigated by two methods, the (1)H NMR spectra and the vapor pressure osmometry (VPO). Although some discrepancies were observed between the association constants obtained from the two methods, the qualitative view was consistent with each other. The analysis of self-aggregation by VPO revealed unique aggregation behavior of DBMs in acetone and toluene, which was not elucidated by the NMR method. Namely, the association constants for infinite association are several times larger than the dimerization constant, suggesting that the aggregation is enhanced by the formation of dimers (a nucleation mechanism). In polar solvents, DBMs aggregate more strongly than in chloroform due to the solvophobic interactions between the macrocyclic framework and the solvents. Moreover, DBMs self-associate in aromatic solvents such as toluene and o-xylene more readily than in chloroform. In particular, the hexameric DBM having a large macrocyclic cavity exhibits extremely large association constants in aromatic solvents. By comparing the aggregation properties of DBMs with the corresponding acyclic oligomers, the effect of the macrocyclic structure on the aggregation propensity was clarified. Finally, it turned out that DBMs tend to aggregate more readily than the corresponding phenylacetylene macrocycles, acetylene-bridged [2(n)]metacyclophanes, owing to the withdrawal of the electron density from the aromatic rings by the butadiyne linkages which facilitates pi-pi stacking interactions.


The influence of vibratory courtship on female mating behaviour in orb-web spiders (Argiope keyserlingi, Karsch 1878).
Web-building spiders are important models for sexual selection. While our understanding of post-copulatory mechanisms including sperm competition and cryptic female choice is considerable, our knowledge of courtship and how it influences male and female mating decisions is still extremely poor. Here, we provide the first comprehensive description of male courtship behaviour and vibrations generated in the web by the orb-web spider, Argiope keyserlingi - a recognised model species. We identified three main elements of male courtship: shudders, abdominal wags and mating thread dances (including both plucks and bounces). The vibrations generated by these behaviours are described in detail. Male shuddering behaviour appears to have a strong influence on female latency to mate acceptance, with males that shudder at high rates without compromising shudder duration being preferred. Shuddering behaviour may also mediate female aggressive behaviour, with males that generate long shudders less likely to be cannibalised after copulation. Male abdominal wagging behaviour, however, appears to have only limited influence on female mating decisions. This study provides avenues for future work that synthesises pre- and post-copulatory mechanisms in web-building spiders to generate an all-encompassing model of how sexual selection operates.


General protocol for the synthesis of functionalized magnetic nanoparticles for magnetic resonance imaging from protected metal-organic precursors.
The development of magnetic nanoparticles (MNPs) with functional groups has been intensively pursued in recent years. Herein, a simple, versatile, and cost-effective strategy to synthesize water-soluble and amino-functionalized MNPs, based on the thermal decomposition of phthalimide-protected metal-organic precursors followed by deprotection, was developed. The resulting amino-functionalized Fe3O4, MnFe2O4, and Mn3O4 MNPs with particle sizes of about 14.3, 7.5, and 6.6 nm, respectively, had narrow size distributions and good dispersibility in water. These MNPs also exhibited high magnetism and relaxivities of r2 = 107.25 mM(-1) s(-1) for Fe3O4, r2 = 245.75 mM(-1) s(-1) for MnFe2O4, and r1 = 2.74 mM(-1) s(-1) for Mn3O4. The amino-functionalized MNPs were further conjugated with a fluorescent dye (rhodamine B) and a targeting ligand (folic acid: FA) and used as multifunctional probes. Magnetic resonance imaging and flow-cytometric studies showed that these probes could specifically target cancer cells overexpressing FA receptors. This new protocol opens a new way for the synthesis and design of water-soluble and amino-functionalized MNPs by an easy and versatile route.


Heterosis breeding in rice (Oryza sativa L.).
Studies conducted at the International Rice Research Institute (IRRI) during 1980 and 1981 have shown up to 73% heterosis, 59% heterobeltiosis and 34% standard heterosis for yield in rice. The latter was estimated in comparison to commercial varieties: IR36 and IR42 (yield 4-5 t/ha in wet season trials and 7-8 t/ha in dry season trials). Generally speaking, absolute yield was lower and extent of standard heterosis was higher in wet season than in dry season with some exception. Yields up to 5.9 t/ha (22% standard heterosis) in the wet season and 10.4 t/ha (34% standard heterosis) in the dry season were obtained. Most of the hybrids performed better in some season while some performed better in both seasons. Hybrids showed better lodging resistance although they were 5-10 cm taller. F1 hybrids had significant positive correlations with the parental traits viz., yield (r = 0.446), tillering (r = 0.746), height (r = 0.810) and flowering (r = 0.843). Selection of parents among elite breeding lines on the basis of their per se yield performance, diverse origin and resistance to insects and diseases should give heterotic combination. Yield advantage of hybrids was due primarily to increase in number of spikelets per unit area even though tiller number was reduced. Grain weight was either the same or slightly higher. High yielding hybrids also showed significant heterosis and heterobeltiosis for total dry matter and harvest index. For commercial utilization of heterosis in rice, effective male sterility and fertility restoration systems are available and up to 45% natural outcrossing on male sterile lines has been observed. Consequently, F1 rice hybrid have been successfully developed and used in China. Prospects of developing hybrid rice varieties elsewhere appear bright especially in countries that have organized seed production, certification and distribution programs and where hybrid seed can be produced at a reasonable cost.


Relating circular dichroism to atomic structure by means of MD simulations and computed CD spectra with α-peptoids as an example.
Classical molecular dynamics simulations have been combined with quantum calculations of CD spectra in order to fruitfully relate the experimental CD spectra, not only to the overall conformation of chiral α-peptoids, but also to their structure at the atomic scale, including the dihedral feature of the backbone (ψ,φ) and the orientation of the chiral side-chain (χ1). These simulations have been performed up to the hexamer Ac-(stbe)6-CO2tBu. We have shown that the number of states has a significant impact on the shape of the spectrum below 215 nm. The number of states computed is also critical to simulate the spectra of long oligomers. While 10 to 20 states are sufficient to simulate the CD spectra of short oligomers, 100 states or more are mandatory to converge the CD spectral shape for longer oligomers. The conformational sampling and the analysis of the intramolecular interactions responsible for the specific folding of the objects have been jointly explored by means of Replica Exchange MD and DFT calculations.


Could donor multipotent mesenchymal stromal cells prevent or delay the onset of diabetic retinopathy?
Diabetes mellitus is a complex metabolic disease that has become a global epidemic with more than 285 million cases worldwide. Major medical advances over the past decades have substantially improved its management, extending patients' survival. The latter is accompanied by an increased risk of developing chronic macro- and microvascular complications. Amongst them, diabetic retinopathy (DR) is the most common and frightening. Furthermore, during the past two decades, it has become the leading cause of visual loss. Irrespective of the type of diabetes, DR follows a well-known clinical and temporal course characterized by pericytes and neuronal cell loss, formation of acellular-occluded capillaries, occasional microaneurysms, increased leucostasis and thickening of the vascular basement membrane. These alterations progressively affect the integrity of retinal microvessels, leading to the breakdown of the blood-retinal barrier, widespread haemorrhage and neovascularization. Finally, tractional retinal detachment occurs leading to blindness. Nowadays, there is growing evidence that local inflammation and oxidative stress play pivotal roles in the pathogenesis of DR. Both processes have been associated with pericytes and neuronal degeneration observed early during DR progression. They may also be linked to sustained retinal vasculature damage that results in abnormal neovascularization. Currently, DR therapeutic options depend on highly invasive surgical procedures performed only at advanced stages of the disease, and which have proved to be ineffective to restore visual acuity. Therefore, the availability of less invasive and more effective strategies aimed to prevent or delay the onset of DR is highly desirable. Multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs), are promising healing agents as they contribute to tissue regeneration by pleiotropic mechanisms, with no evidence of significant adverse events. Here, we revise the pathophysiology of DR to identify therapeutic targets for donor MSCs. Also, we discuss whether an MSC-based therapy could prevent or delay the onset of DR.


Environment and evolutionary history shape phylogenetic turnover in European tetrapods.
Phylogenetic turnover quantifies the evolutionary distance among species assemblages and is central to understanding the main drivers shaping biodiversity. It is affected both by geographic and environmental distance between sites. Therefore, analyzing phylogenetic turnover in environmental space requires removing the effect of geographic distance. Here, we apply a novel approach by deciphering phylogenetic turnover of European tetrapods in environmental space after removing geographic land distance effects. We demonstrate that phylogenetic turnover is strongly structured in environmental space, particularly in ectothermic tetrapods, and is well explained by macroecological characteristics such as niche size, species richness and relative phylogenetic diversity. In ectotherms, rather recent evolutionary processes were important in structuring phylogenetic turnover along environmental gradients. In contrast, early evolutionary processes had already shaped the current structure of phylogenetic turnover in endotherms. Our approach enables the disentangling of the idiosyncrasies of evolutionary processes such as the degree of niche conservatism and diversification rates in structuring biodiversity.


School Climate and the Impact of Neighborhood Crime on Test Scores.
Does school climate ameliorate or exacerbate the impact of neighborhood violent crime on test scores? Using administrative data from the New York City Department of Education and the New York City Police Department, we find that exposure to violence in the residential neighborhood and an unsafe climate at school lead to substantial test score losses in English language arts (ELA). Middle school students exposed to neighborhood violent crime before the ELA exam who attend schools perceived to be less safe or to have a weak sense of community score 0.06 and 0.03 standard deviations lower, respectively. We find the largest negative effects for boys and Hispanic students in the least safe schools, and no effect of neighborhood crime for students attending schools with better climates.


Comparison of Acoustic and Stroboscopic Findings and Voice Handicap Index between Allergic Rhinitis Patients and Controls.
In our experience Allergic Rhinitis (AR) patients suffer from voice problems more than health subjects. To investigate the acoustic analysis of voice, stroscopic findings of larynx and Voice Handicap Index scores in allergic rhinitis patients compared with healthy controls. Case-control study. Thirty adult patients diagnosed with perennial allergic rhinitis were compared with 30 age- and sex-matched healthy controls without allergy. All assessments were performed in the speech physiology laboratory and the testing sequence was as follows: 1. Voice Handicap Index (VHI) questionnaire, 2. Laryngovideostroboscopy, 3. Acoustic analyses. No difference was observed between the allergic rhinitis and control groups regarding mean Maximum Phonation Time (MPT) values, Fo values, and stroboscopic assessment (p>0.05). On the other hand, mean VHI score (p=0.001) and s/z ratio (p=0.011) were significantly higher in the allergic rhinitis group than in controls. Our findings suggest that the presence of allergies could have effects on laryngeal dysfunction and voice-related quality of life.


Plant uptake of depleted uranium from manure-amended and citrate treated soil.
Six plant species were tested for their ability to accumulate depleted uranium in their above-ground biomass from deployed munitions contaminated soil in New Mexico. In greenhouse experiments, Kochia (Kochia scoparia L. Schrad.) and pigweed (Amaranthus retroflexus L) were grown with steer manure added at rates of 22.4, 44.8, and 89.6 Mg ha(-1). Citric acid and glyphosate (N-(phosphonomethyl) glycine) applied at the end of the growing season increased DU concentrations from 2.5 to 17 times. Leaf and stem DU concentrations in kochia increased from 17.0 to 41.9 mg kg(-1) and from 3.5 to 18.0 mg kg(-1), respectively. In pigweed, leaf and stem DU concentrations increased from 1.0 to 17.3 and from 1.0 to 4.7 mg kg(-1), respectively. Manure generally decreased or had no effect on DU uptake. The effect of citric acid and ammonium citrate on DU uptake by kochia, sunflower (Helianthus annuus L), and sweet corn (Zea mays L) was also studied. Ammonium citrate was just as effective in enhancing DU uptake as citric acid. This implies that the citrate ion is more important in DU uptake and translocation than the solubilization of DU through acidification. In both experiments, leaves had higher DU concentrations than stems.


MicroRNA-106a Inhibits Autophagy Process and Antimicrobial Responses by Targeting ULK1, ATG7, and ATG16L1 During Mycobacterial Infection.
Autophagy is a key element of innate immune response against invading pathogens including Mycobacterium tuberculosis (M. tuberculosis). The emerging roles of microRNAs in regulating host antimicrobial responses against M. tuberculosis have gained widespread attention. However, the process by which miRNAs specifically influence antibacterial autophagy during mycobacterial infection is largely uncharacterized. In this study, we demonstrate a novel role of miR-106a in regulating macrophage autophagy against M. tuberculosis. H37Ra infection leads to downregulation of miR-106a in a time- and dose-dependent manner and concomitant upregulation of its three targets (ULK1, ATG7, and ATG16L1) in THP-1 macrophages. MiR-106a could inhibit autophagy activation and antimicrobial responses to M. tuberculosis by targeting ULK1, ATG7, and ATG16L1. Overexpression of miR-106a dramatically inhibited H37Ra-induced activation of autophagy in human THP-1 macrophages, whereas inhibitors of miR-106a remarkably promoted H37Ra-induced autophagy. The inhibitory effect of miR-106a on autophagy process during mycobacterial infection was also confirmed by Transmission Electron Microscope (TEM) observation. More importantly, forced expression of miR-106a increased mycobacterial survival, while transfection with miR-106a inhibitors attenuated the survival of intracellular mycobacteria. Taken together, these data demonstrated that miR-106a functioned as a negative regulator in autophagy and antimicrobial effects by targeting ULK1, ATG7, and ATG16L1 during M. tuberculosis infection, which may provide a potential target for developing diagnostic reagents or antibacterials against tuberculosis.


Molecular characterization of ESBL- producing uropathogenic Escherichia coli recovered from urine samples of patients attending a University Teaching hospital in Nigeria.
Infection of the urinary tract ranks as one of the most common infections affecting people worldwide and its treatment is made complicated by the rising incidence of antibiotic resistance. This study aimed to detect extended spectrum beta-lactamase (ESBL) genes and antibiotic resistance profile of uropathogenic Escherichia coli (E. coli) recovered from patients attending a University Teaching hospital in Nigeria. Uropathogenic E. coli isolates were obtained from the culture collection of Department of Microbiology and Parasitology of the University Teaching hospital for a period of four months (October 2019-January, 2020). Antibiotic susceptibility testing was done using the disc diffusion method while phenotypic ESBL production was detected using double disc synergy test (DDST). Detection of β-lactamase genes was done using Real-Time PCR. Forty-nine E. coli isolates were recovered from 120 urine samples, with 24 (49%) being ESBL positive. The resistance to antibiotics in the ESBL producers was: ciprofloxacin (100%), cefotaxime (100%), cefpodoxime (100%), tetracycline (95.7%), ceftazidime (56.7%), amoxicillin-clavulanate (50%), gentamicin (33.3%), and imipenem (0%). All the ESBL producers carried blaTEM, blaCTX-M-1 and blaCTX-M-9, 75% (18/24) carried blaSHV, while blaCTX-M-2, blaCTX-M-8 and blaCTX-M-25 groups were detected in 20.8% (5/24) of the isolates. There was co-occurrence of CTX-M, SHV and TEM β-lactamases in 79.2% (19/24) isolates, while five isolates (20.8%) co-harbored blaCTX-M and blaTEM. This study showed a high level of multidrug resistance and ESBL gene carriage in uropathogenic E. coli obtained in this study, suggesting a likely review of therapeutic options in the treatment of UTI to clamp down on the rising cases of antibiotic resistance.


Effect of melatonin on the regulation of proenkephalin and prodynorphin mRNA levels induced by kainic acid in the rat hippocampus.
The in vivo short-term effect of melatonin on kainic acid (KA)-induced proenkephalin (proENK) or prodynorphin (proDYN) mRNA, and on AP-1 protein levels in the rat hippocampus, were studied. Melatonin (5 mg/kg) or saline was administered intraperitoneally (i.p.) to rats 30 min prior to and immediately after i.p. injection of KA (10 mg/kg). Rats were sacrificed 1 and 3 h after KA injection. The proENK and proDYN mRNA levels were significantly increased 3 h after KA administration. The elevations of both proENK and proDYN mRNA levels induced by KA were significantly inhibited by the preadministration with melatonin. The increases of proENK and proDYN mRNA levels induced by KA were well-correlated with the increases of c-Fos, Fra-2, FosB, c-Jun, and JunB protein levels, which were significantly increased 3 h after KA administration and effectively inhibited by administration with melatonin. In an electrophoretic mobility shift assay, both AP-1 and ENKCRE-2 DNA binding activities were increased by KA, which were also attenuated by the administration of melatonin. In addition, cross-competition studies revealed that AP-1 or ENKCRE-2 DNA binding activity was effectively reduced by the 50x unlabeled cross-competitor. Therefore, these data suggest that melatonin has an inhibitory role in KA-induced gene expression, such as proENK and proDYN mRNA expression, and this may be due to a reduction of KA-induced AP-1 or ENKCRE-2 DNA binding activity.


Caffeine levels following treatment of obstructive sleep apnoea.
Randomised trials show that treatment of obstructive sleep apnoea (OSA) with nasal continuous positive airway pressure (CPAP) greatly improves sleepiness and also lowers diurnal systemic blood pressures (BP). Such patients consume more coffee than controls (presumably to combat their sleepiness) and might reduce their consumption following effective treatment, thus lowering BP by this mechanism rather than via a direct effect of alleviating OSA. Plasma caffeine levels before and after treatment with either therapeutic (n=52) or subtherapeutic (control, n=49) CPAP were measured in stored blood samples from a previous randomised controlled trial of CPAP for 4 weeks in patients with OSA. There was a small significant rise in caffeine levels when the two groups were analysed as a whole (p=0.02), but not individually. Despite the fall in sleepiness measured objectively in the therapeutic CPAP group, there was no difference in absolute (or change in) caffeine levels between the two groups (mean (SE) micro mol/l; therapeutic CPAP 9.2 (1.2), 10.2 (1.0), subtherapeutic 6.7 (0.9), 8.6 (0.9) before and after treatment, respectively). Reduced coffee consumption is unlikely to be the explanation for the falls in BP following treatment of OSA.


Evaluation of the sustainability of contrasted pig farming systems: breeding programmes.
The sustainability of breeding activities in 15 pig farming systems in five European countries was evaluated. One conventional and two differentiated systems per country were studied. The Conventional systems were the standard systems in their countries. The differentiated systems were of three categories: Adapted Conventional with focus on animal welfare, meat quality or environment (five systems); Traditional with local breeds in small-scale production (three systems) and Organic (two systems). Data were collected with a questionnaire from nine breeding organisations providing animals and semen to the studied farming systems and from, on average, five farmers per farming system. The sustainability assessment of breeding activities was performed in four dimensions. The first dimension described whether the market for the product was well defined, and whether the breeding goal reflected the farming system and the farmers' demands. The second dimension described recording and selection procedures, together with genetic change in traits that were important in the system. The third dimension described genetic variation, both within and between pig breeds. The fourth dimension described the management of the breeding organisation, including communication, transparency, and technical and human resources. The results show substantial differences in the sustainability of breeding activities, both between farming systems within the same category and between different categories of farming systems. The breeding activities are assessed to be more sustainable for conventional systems than for differentiated systems in three of the four dimensions. In most differentiated farming systems, breeding goals are not related to the system, as these systems use the same genetic material as conventional systems. The breeds used in Traditional farming systems are important for genetic biodiversity, but the small scale of these systems renders them vulnerable. It is hoped that, by reflecting on different aspects of sustainability, this study will encourage sustainable developments in pig production.


Hormonal regulation of DNA polymerase beta activity and expression in rat adrenal glands and testes.
We investigated whether DNA polymerase beta activity and expression in rat adrenal glands and testes are controlled by the cAMP dependent protein kinase (A-kinase) phosphorylation system in addition to anterior pituitary hormones. DNA polymerase beta mRNA expression in rat testes was decreased by hypophysectomy and recovered with administration of gonadotropic hormone, suggesting that this enzyme is controlled at the mRNA level by this pituitary hormone. In addition, DNA polymerase beta activity in the adrenal glands and testes and the amount of mRNA in the testes increased when cAMP was administered to the normal rat. This activity was decreased by administration of the cyclic AMP-dependent protein kinase inhibitor, H(8). Moreover, when alkaline phosphatase was added to the assay system in vitro, a decrease in DNA polymerase beta activity was observed. These findings indicate that changes in the activity and expression of DNA polymerase beta are mediated via cAMP and the A-kinase system, and that phosphorylation of this enzyme is also involved in this expression.


Targeting the Nef induced increase of HIV infectivity.
Nef is a regulatory protein expressed exclusively by HIV-1/2 and SIV. It is critical for the optimal viral infectivity and for the destruction of the host immune system. This renders Nef a rather attractive therapeutic target. The most affordable point(s) of attack for effective anti-Nef therapeutic strategies can be individuated on the basis of a detailed knowledge of the mechanisms underlying the Nef induced enhancement of infectivity. However, the emerging picture still appears rather complex and not always coherent, so that additional, intensive endeavours in basic research are required for an effective exploitation of the Nef induced increase of infectivity as a therapeutic target.


Gammadelta T cells enhance the expression of experimental autoimmune encephalomyelitis by promoting antigen presentation and IL-12 production.
Using an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP)-reactive lymph node cells (LNC), we have shown that depletion of gammadelta T cells from LNC resulted in diminished severity of EAE in recipient mice, both clinically and histopathologically. The reduced potency of gammadelta T cell-depleted LNC to induce EAE correlated with decreased cell proliferation in response to MBP. The gammadelta T cell effect upon the threshold of MBP-induced LNC proliferation and EAE transfer was restored by reconstitution of gammadelta T cells derived from either MBP-immunized or naive mice, indicating that this effect was not Ag specific. The enhancing effect of gammadelta T cells on MBP-induced proliferation and EAE transfer required direct cell-to-cell contact with LNC. The gammadelta T cell effect upon the LNC response to MBP did not involve a change in expression of the costimulatory molecules CD28, CD40L, and CTLA-4 on TCRalphabeta(+) cells, and CD40, CD80, and CD86 on CD19(+) and CD11b(+) cells. However, depletion of gammadelta T cells resulted in significant reduction in IL-12 production by LNC. That gammadelta T cells enhanced the MBP response and severity of adoptive EAE by stimulating IL-12 production was supported by experiments showing that reconstitution of the gammadelta T cell population restored IL-12 production, and that gammadelta T cell depletion-induced effects were reversed by the addition of IL-12. These results suggest a role for gammadelta T cells in the early effector phase of the immune response in EAE.


Relationship between cognitive activity and adjustment in four spinal-cord-injured individuals: a longitudinal investigation.
Although most of the stress one faces in life occurs in anticipation of a stressful period, very little research has been done on what anticipatory cognitive activities are related to subsequent adjustment. The present study investigated the relationship between measures of anticipatory cognitive activity and subsequent adjustment in four spinal-cord-injured individuals. Measures of anticipatory cognitive activity, which were assessed before subjects left the rehabilitation center, were related to measures of adjustment, which were assessed when subjects returned to the rehabilitation center for a medical checkup anywhere from 7 to 13 1/2 weeks following discharge. Seven-month follow-ups were conducted with two of the subjects. Although the small sample size precluded any statistical analysis of the data, the rank orderings of subjects across the variables of interest revealed a number of interesting trends. The most striking trend was that the best adjusted subject predominantly employed rationalization and denial in anticipating going home. A theory to explain why these strategies may be effective for spinal-cord-injured individuals is proposed. Other trends revealed that individuals who avoid catastrophizing and worrying about what their life will be like, who think more about the various goals they may have once they leave the rehabilitation center, and who employ internal forms of mental rehearsal in anticipating going home tend to be better adjusted. Although any conclusions that can be drawn from this study are only suggestive, given the small sample size, the fruitfulness of conducting this type of research is demonstrated.


Stenting of unprotected left main coronary artery stenoses: immediate and late outcomes.
We examined the immediate and long-term outcomes after stenting of unprotected left main coronary artery (LMCA) stenoses in patients with normal left ventricular (LV) function. Left main coronary artery disease is regarded as an absolute contraindication for coronary angioplasty. Recently, several reports on protected or unprotected LMCA stenting, or both, suggested the possibility of percutaneous intervention for this prohibited area. Forty-two consecutive patients with unprotected LMCA stenoses and normal LV function were treated with stents. The post-stent antithrombotic regimens were aspirin and ticlopidine; 14 patients also received warfarin. Patients were followed very closely with monthly telephone interviews and follow-up angiography at 6 months. The procedural success rate was 100%, with no episodes of subacute thrombosis regardless of anticoagulation regimen. Six-month follow-up angiography was performed in 32 of 34 eligible patients. Angiographic restenosis occurred in seven patients (22%, 95% confidence interval 7% to 37%); five patients subsequently underwent elective coronary artery bypass graft surgery (CABG), and two patients were treated with rotational atherectomy plus adjunct balloon angioplasty. The only death occurred 2 days after elective CABG for treatment of in-stent restenosis. The other patients (without angiographic follow-up) remain asymptomatic. Stenting of unprotected LMCA stenoses may be a safe and effective alternative to CABG in carefully selected patients with normal LV function. Further studies in larger patient populations are needed to assess late outcome.


Study on lockout procedures for the safety of workers intervening on equipment in the municipal sector in Québec.
In Québec, workers intervening in hazardous zones of machines, equipment and processes during maintenance, repairs and unjamming activities have to apply lockout procedures. Lockout procedures involve shutting down the equipment, isolating it, applying individual locks, releasing residual energies and verifying the absence of energies. Lockout has mostly been linked to industrial sectors. However, the municipal sector also faces challenges when it comes to controlling hazardous energies. The objectives of this research are to study serious accidents linked to our subject, study the application of lockout in different municipalities in Québec, identify the specificities for the municipal sector and propose some means to support the application of lockout. We will show that lockout procedures are required in different locations in municipalities and that they are currently being implemented in the municipal sector in Québec. Moreover, we propose a model which aims at facilitating the implementation of lockout procedures in the municipal sector.


Glycosylated hemoglobin and risk of colorectal cancer and adenoma (United States).
The consistently observed epidemiologic associations of obesity and physical activity with colorectal cancer and precursor adenoma risk suggest that insulin and glucose control may be contributory. We evaluated the association of glycosylated hemoglobin (HbA1c), a clinical indicator of average glycemia over the previous 2 months, and possibly, indirectly, a marker of average blood insulin level, with colorectal carcinogenesis. Among women in the Nurses' Health Study, who provided blood in 1989-90 and were diagnosed subsequently in 1989-94, we included 79 colorectal cancer cases and 156 matched controls, and 201 distal colorectal adenoma cases and 201 matched controls. HbA1c concentrations in red blood cells were determined blindly by turbidometric immunoinhibition. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression models. HbA1c level did not significantly differ between colorectal cancer cases (median 5.5%) and controls (5.5%, p = 0.5), although a small difference between adenoma cases (5.6%) and controls (5.5%, p = 0.06) was noted. Compared to the lowest tertile of HbA1c (median 5.2%), women in the middle (median 5.5%, OR = 1.2, CI = 0.6-2.5) and upper (5.8%, OR = 1.2, CI = 0.6-2.7) tertiles were not at an increased risk for colorectal cancer. A modestly elevated risk of distal colorectal adenoma in the upper (median 5.8%, OR = 1.4, CI = 0.9-2.3) versus lower (median 5.3%) tertile could not be excluded. These associations were not appreciably altered after adjusting for known and suspected colorectal cancer risk factors. Over the range of levels observed in this relatively small sample of middle-aged women, prediagnostic HbA1c does not clearly predict colorectal cancer and adenoma risk.


Quality of care emerges as a determinant of creditworthiness.
Sophisticated profiles of the quality of care provided in hospitals are prompting investors and bond rating agencies to ask questions about debt capitalization: What elements of the quality of care--measured by illness outcome, length of stay, morbidity, and mortality--will improve as a result of a proposed capital financing? Can the hospital demonstrate that cost benefits will result from a proposed financing by correlating costs with measurable improvements in patient outcomes? Can the hospital show, through financial feasibility analyses that reflect quality assessments, that its market share will remain stable? Hospitals' ability to gain access to credit markets will be influenced materially by their answers to these questions.


Application of RNAi inducible TNFRI knockdown cells to the analysis of TNFalpha-induced cytotoxicity.
RNA interference (RNAi) has become a popular tool for downregulating in many species including mammalian cells. Therefore, suppression of target genes in mammalian cultured cells using RNAi may represent an ideal alternative to knockout studies for understanding the molecular mechanisms of chemical toxicity. Here, we assessed the potential of RNAi mediated gene knockdown in HeLa and HepG2 cells to cytotoxicity studies. Tumor necrosis factor receptor I (TNFRI) was chosen as a target gene because its signaling has been implicated in xenobiotic-induced toxicity. We optimized the design and performance of a vector-based RNAi experiment and then investigated viability of both HeLa and HepG2 cells exposed to TNFalpha. In addition, we examined gene expression profile of TNFRI knockdown HeLa cells after TNFalpha treatment, and then protein expression levels for several apoptosis-related genes of the cells. In both HeLa and HepG2 cells, TNFalpha exposure resulted in significantly reduced susceptibility of the knockdown cells to the cytotoxicity as compared with those of mock-transfected cells. Furthermore, the gene expression profiling and western blotting revealed that several genes including apoptosis and/or NF-kappaB pathway were downregulated in the knockdown HeLa cells. These results suggest that downregulation of the TNFRI gene in both HeLa and HepG2 cells by RNAi participates in resistance to TNFalpha-induced cytotoxicity. Therefore, this study raises the possibility that RNAi-based gene silencing in mammalian cells may be a valuable tool for elucidating the relationships between phenotypic changes and target gene functions in response to xenobiotic-induced cytotoxicity. Further exposure study using xenobiotics needs to be done to validate the potential utility of RNAi technology.


[Tolerance of different cell types for hypotonic action].
The behavior of cells with different structure of cytoskeleton was studied in the hypotonic media: protoplasts, embryonal mouse fibroblasts and transformed mouse fibroblasts (L-line). Protoplasts were most sensitive to the hypotonic media. They began to disrupt in the hypotonic medium 4:1, and in the hypotonic medium 1:7 a complete lysis of cells was observed. Transformed mouse fibroblasts were disrupted in the medium diluted 1:15, while embryonal mouse fibroblasts were not disrupted in the medium diluted 1:31. Moreover, in the hypotonic conditions an essential difference was observed between the cells studied. Embryonal mouse fibroblasts are more tolerant to the hypotonic conditions than L-cells and protoplasts. It is suggested that the cytoskeleton may define the cell tolerance in hypotonic media.


A study comparing standard and transepithelial collagen cross-linking riboflavin solutions: epithelial findings and pain scores.
To evaluate epithelial signs and pain after epithelial-on corneal collagen cross-linking (Epi-on CCL) with new transepithelial riboflavin formulation and epithelial-off corneal collagen cross-linking (Epi-off CCL) with standard riboflavin formulation and to compare pain and duration of epithelial healing between both techniques. Thirty-nine eyes of 39 patients undergoing Epi-on CCL and 39 eyes of 39 patients undergoing Epi-off CCL were evaluated. Corneal epithelial signs and durations of corneal epithelial healing and subjective pain scores after the procedures were recorded and compared between 2 groups. Total epithelialization was observed after 2.7 ± 0.7 days in Epi-on CCL and 2.3 ± 0.4 days in Epi-off CCL (P = 0.006). The mean pain score on the first day was 3.1 ± 0.6 in Epi-on CCL and 2.3 ± 0.4 in Epi-off CCL with a significant difference (P = 0.0001). The epithelial damage was observed in both procedures; also, the epithelial healing time was longer in Epi-on CCL and it is of great importance that the patients should have therapeutic contact lenses until the epithelium heals in both procedures. The Epi-off CCL group had less pain scores than the Epi-on CCL group and more pain problems after Epi-on CCL still remains. The patient should be informed about pain, even if the Epi-on CCL procedure was performed.


Human tumor-infiltrating Th17 cells have the capacity to differentiate into IFN-γ+ and FOXP3+ T cells with potent suppressive function.
Accumulating evidence suggests that Th17 cells and Tregs may exhibit development plasticity and that CD4(+) Tregs can differentiate into IL-17-producing T cells; however, whether Th17 cells can reciprocally convert into Tregs has not been described. In this study, we generated Th17 clones from tumor-infiltrating T lymphocytes (TILs). We showed that Th17 clones generated from TILs can differentiate into IFN-γ-producing and FOXP3(+) cells after in vitro stimulation with OKT3 and allogeneic peripheral blood mononuclear cells. We further demonstrated that T-cell receptor (TCR) engagement was responsible for this conversion, and that this differentiation was due to the epigenetic modification and reprogramming of gene expression profiles, including lineage-specific transcriptional factor and cytokine genes. In addition to expressing IFN-γ and FOXP3, we showed that these differentiated Th17 clones mediated potent suppressive function after repetitive stimulation with OKT3, suggesting that these Th17 clones had differentiated into functional Tregs. We further demonstrated that the Th17-derived Tregs, unlike naturally occurring CD4(+) CD25(+) Tregs, did not reconvert back into Th17 cells even under Th17-biasing cytokine conditions. These results provide the critical evidence that human tumor-infiltrating Th17 cells can differentiate into Tregs and indicate a substantial developmental plasticity of Th17 cells.


Calcium-gated potassium channel blockade via membrane-facing fenestrations.
Quaternary ammonium blockers were previously shown to bind in the pore to block both open and closed conformations of large-conductance calcium-activated potassium (BK and MthK) channels. Because blocker entry was assumed through the intracellular entryway (bundle crossing), closed-pore access suggested that the gate was not at the bundle crossing. Structures of closed MthK, a Methanobacterium thermoautotrophicum homolog of BK channels, revealed a tightly constricted intracellular gate, leading us to investigate the membrane-facing fenestrations as alternative pathways for blocker access directly from the membrane. Atomistic free energy simulations showed that intracellular blockers indeed access the pore through the fenestrations, and a mutant channel with narrower fenestrations displayed no closed-state TPeA block at concentrations that blocked the wild-type channel. Apo BK channels display similar fenestrations, suggesting that blockers may use them as access paths into closed channels. Thus, membrane fenestrations represent a non-canonical pathway for selective targeting of specific channel conformations, opening novel ways to selectively drug BK channels.


Decrease of cocaine, but not heroin, self-administration and relapse by the tyrosine kinase inhibitor masitinib in male Sprague Dawley rats.
Accumulating evidence shows that cocaine, and also heroin, influence several tyrosine kinases, expressed in neurons and in non-neuronal populations such as microglia, astrocytes and mast-cells. Drug-induced activation of mast cells both triggers inflammatory processes in the brain mediated by the glial cells they activate, and facilitates histamine release which may directly influence the dopamine system. Thus, by triggering the activation and degranulation of mast cells dependent on the tyrosine kinase c-kit and Fyn, the latter being also involved in NMDA-dependent synaptic plasticity, cocaine and heroin may indirectly influence the neural mechanisms that mediate their reinforcing properties. Masitinib, a novel tyrosine kinase inhibitor with high selectivity for c-Kit, Fyn and Lyn, may alter the aberrant consequences of the activation of these tyrosine kinases by cocaine and heroin. We investigated in rats the effect of a chronic oral treatment with masitinib (20 mg/kg) on the reinforcing and motivational properties of self-administered cocaine (250 μg/infusion) and heroin (40 μg/infusion). Three different cohorts of rats were trained instrumentally to respond for cocaine, heroin or food under continuous reinforcement. In each group, we assessed the influence of chronic daily treatment with masitinib on the maintenance of instrumental responding and intake and the motivation for the reinforcer. Thus, masitinib and vehicle-treated rats were challenged to adapt to high behavioural demand, to respond under a progressive ratio schedule of reinforcement and to reinstate instrumental responding after extinction and/or abstinence. Masitinib selectively decreased cocaine intake, the motivation for cocaine and the subsequent propensity to respond for cocaine under extinction, while having no effect on instrumental responding for heroin or food. The present findings suggest masitinib, a drug with proven efficacy in CNS disorders, could represent a novel treatment for cocaine addiction provided its influence on the reinforcing and incentive properties of the drug is confirmed.


Assessment of dental fluorosis prevalence in Swiss populations.
In 1996 and 2006, recruits of the Swiss army participated in a dental survey. Similarly in 1995/96 and 2004/05, randomly selected schoolchildren from 16 rural communities of the Canton of Zurich participated in a dental survey. As part of these surveys, color slides were taken of the incisor teeth of all recruits, as well as of third and fourth grade schoolchildren. The slides (N = 2049) were examined for the presence of fluoride-associated enamel opacities (FOP), using the Thyl-strup-Fejerskov (TF) index. Two examiners (A and B) assessed all slides. The examiners were blind as to the year of survey. Examiner A recorded prevalences of FOP between 18% and 27% depending on population; examiner B recorded prevalences between 7% and 12%. The examiners' influence on the estimation of the prevalence was obvious. The prevalences reported should, therefore, be considered as rough estimates. FOP of TF score 2 were only observed in approximately 1% of the participants. One examiner recorded a TF score 3 in a single individual. FOP therefore are not a cosmetic problem and certainly not a public health concern. The prevalence of FOP decreased slightly during observation period I (recruits born 1975-77 vs 1985-87) and period II (school children born 1985-87 vs 1994-96). However, the decline was statistically supported in only one instance (Period I, Examiner B).


EEG characteristics of healthy adults living at higher elevations.
EEG data from 400 healthy adult volunteers in the Xining area (with an altitude of 2260 meters) are summarized to show changes in indices of waves, frequencies and amplitude. Analysis and observations were made for tests of eyes open-close, acoustic stimulation and hyperventilation. Differences in EEGs were compared between males and females of various age groups, and between adults living at the higher elevations in Xining and those living on the plains in the Beijing area (altitude 40 meters). Comparisons showed that EEG characteristics of healthy adults at the higher altitude were: an increase in the incidence of abnormality, a decrease of alpha indices, an increase in the number of slow waves, the appearance of spikes and sharp waves, and a reduction in the level of sensitivity to activation tests.


Overview of solidification techniques for self-emulsifying drug delivery systems from industrial perspective.
Self-emulsifying drug delivery systems (SEDDS) are lipid formulations that improve solubility and oral bioavailability of the incorporated drug with poor biopharmaceutical properties. As liquids they are traditionally filled into soft or hard capsules. Transformation of SEDDS into solid dosage form has been extensively investigated in the recent years because solid dosage forms improve stability, handling and patient compliance. By using different solidification techniques selfemulsifying powders, granules, pellets and tablets can be produced. Appropriate excipients, solid carriers and processing parameters must be selected for each solidification technique to enable processability and preserve the self-emulsifying ability of the system upon its transformation into the solid formulation. In the present review various industrially applicable solidification techniques and excipients used for transforming liquid SEDDS into solid dosage forms with high production yield and good perspectives for being produced in large scales are discussed.


Effect of permethrin treatment of cattle on Psorophora columbiae populations: preliminary field test of a host management concept.
The results of a field test conducted in cooperation with the Jefferson Davis Parish Mosquito Abatement District (JDPMAD) during 1988 in southwestern Louisiana suggested that the biweekly treatment of cattle with permethrin reduced the number of adult Psorophora columbiae in nearby areas. Routine mosquito control operations by JDPMAD were similar from 1987 to 1988 in the cattle-treated area but increased an average of 41% in control areas. In spite of this, during the year of cattle treatment, captures in New Jersey light traps averaged 86 and 26% of the previous 4-year average in control and treated areas, respectively. Similarly, the proportion of trap nights in 1988 when Ps. columbiae captures exceeded 500 averaged 73 and 30% of the previous 4-year average in control and treated areas, respectively. Simulation model projections that took into account differences in JDPMAD operations, weather, cattle density, agricultural practices and the presence of treated cattle were accurate within an average of 9% of observed values for the treated and control areas. The simulation studies indicated that the treatment of cattle with permethrin reduced Ps. columbiae populations by 83%. These results suggest that host management may be a viable method for suppressing populations of Ps. columbiae and that some form of host management be considered for inclusion in integrated control programs in this environment. Further evaluation of this concept is warranted.