Non-invasive detection of fatty liver in dairy cows by digital analyses of hepatic ultrasonograms.
During early lactation, many dairy cows develop fatty liver, which is associated with decreased health and reproductive performance. Currently, fatty liver can be detected reliably only by using liver biopsy followed by chemical or histological analysis, which is not practical in most on-farm situations. We tested whether digital analyses of hepatic ultrasonograms can be used to detect non-invasively fatty liver and estimate liver triacylglycerol content. A total of 49 liver biopsies and ultrasonograms were taken from 29 dairy cows within 2 weeks postpartum. The usefulness of 17 first- or second-order parameters from digital analysis of B-mode ultrasonograms were evaluated by discriminant, correlation, and regression analyses. A group of linear combinations of the 17 parameters correctly classified 40 of 49 samples into normal liver as well as mild, moderate and severe fatty liver when cut-off values were 1%, 5% and 10% and correctly classified 45 of 49 samples when cut-off values were 5% and 10% triacylglycerol of wet weight. A linear combination of 16 image parameters estimated triacylglycerol concentrations of 38 of the 39 liver samples below the cut-off value of 10% within 2.5% of liver wet weight, and a linear combination of 3 parameters estimated triacylglycerol concentrations of the 10 liver samples above the cut-off value of 10% within 2% of liver wet weight. Therefore, ultrasound imaging followed by digital analysis of sonograms has potential to non-invasively detect fatty liver and estimate liver triacylglycerol content.


Antibody response to common viruses and human leukocyte antigen-DRB1 in pediatric multiple sclerosis.
As remote infections with common herpes viruses are associated with modulation of the risk of multiple sclerosis (MS), we hypothesized that antibody concentrations against these viruses may further modify risk. As many common viruses are first encountered during childhood, pediatric MS offer a unique opportunity to investigate more closely their influence on susceptibility. Our aim was to determine if MS patients who were positive for these viruses had higher levels of antibodies to these viruses. We also assessed whether human leukocyte antigen (HLA)-DRB1*1501 genotype influenced viral antibody levels. Antibody response levels toward Epstein Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV)-1, and HLA-DRB1*1501 status were determined in pediatric MS patients (n=189) and controls (n=38). Multivariate analyses were used, adjusted for age, gender, race, ethnicity and use of disease-modifying therapies. The antibody concentrations against EBV (Epstein-Barr nuclear antigen 1 (EBNA-1), viral capsid antigen (VCA) and early antigen (EA)), CMV and HSV-1 were similar between pediatric MS patients and controls positive for seroconversion against the virus of interest. EBNA-1 humoral responses were higher in HLA-DRB1 positive individuals (p=0.005) whereas other viral humoral responses were similar in HLA-DRB1 positive and negative individuals. Among those positive for EBNA-1, MS patients did not have higher levels of antibody response to EBNA-1: however, titers for EBNA-1 were higher in those who were HLA-DRB1 positive. This suggests that genotype might influence the humoral response to EBV. Whether other genotypes influence antibody response to other viruses remains to be determined.


Why does Russia have such high cardiovascular mortality rates? Comparisons of blood-based biomarkers with Norway implicate non-ischaemic cardiac damage.
Russia has one of the highest rates of mortality from cardiovascular disease (CVD). At age 35-69 years, they are eight times higher than in neighbouring Norway. Comparing profiles of blood-based CVD biomarkers between these two populations can help identify reasons for this substantial difference in risk. We compared age-standardised mean levels of CVD biomarkers for men and women aged 40-69 years measured in two cross-sectional population-based studies: Know Your Heart (KYH) (Russia, 2015-2018; n=4046) and the seventh wave of the Tromsø Study (Tromsø 7) (Norway, 2015-2018; n=17 646). A laboratory calibration study was performed to account for inter-laboratory differences. Levels of total, low-density lipoprotein-, high-density lipoprotein-cholesterol and triglycerides were comparable in KYH and Tromsø 7 studies. N-terminal pro-b-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT) and high-sensitivity C-reactive protein (hsCRP) were higher in KYH compared with Tromsø 7 (NT-proBNP was higher by 54.1% (95% CI 41.5% to 67.8%) in men and by 30.8% (95% CI 22.9% to 39.2%) in women; hs-cTnT-by 42.4% (95% CI 36.1% to 49.0%) in men and by 68.1% (95% CI 62.4% to 73.9%) in women; hsCRP-by 33.3% (95% CI 26.1% to 40.8%) in men and by 35.6% (95% CI 29.0% to 42.6%) in women). Exclusion of participants with pre-existing coronary heart disease (279 men and 282 women) had no substantive effect. Differences in cholesterol fractions cannot explain the difference in CVD mortality rate between Russia and Norway. A non-ischemic pathway to the cardiac damage reflected by raised NT-proBNP and hs-cTnT is likely to contribute to high CVD mortality in Russia.


Disaster Ergonomics: Human Factors in COVID-19 Pandemic Emergency Management.
We aimed to identify opportunities for application of human factors knowledge base to mitigate disaster management (DM) challenges associated with the unique characteristics of the COVID-19 pandemic. The role of DM is to minimize and prevent further spread of the contagion over an extended period of time. This requires addressing large-scale logistics, coordination, and specialized training needs. However, DM-related challenges during the pandemic response and recovery are significantly different than with other kinds of disasters. An expert review was conducted to document issues relevant to human factors and ergonomics (HFE) in DM. The response to the COVID-19 crisis has presented complex and unique challenges to DM and public health practitioners. Compared to other disasters and previous pandemics, the COVID-19 outbreak has had an unprecedented scale, magnitude, and propagation rate. The high technical complexity of response and DM coupled with lack of mental model and expertise to respond to such a unique disaster has seriously challenged the response work systems. Recent research has investigated the role of HFE in modeling DM systems' characteristics to improve resilience, accelerating emergency management expertise, developing agile training methods to facilitate dynamically changing response, improving communication and coordination among system elements, mitigating occupational hazards including guidelines for the design of personal protective equipment, and improving procedures to enhance efficiency and effectiveness of response efforts. This short review highlights the potential for the field's contribution to proactive and resilient DM for the ongoing and future pandemics.


Downregulation of the tyrosine degradation pathway extends Drosophila lifespan.
Aging is characterized by extensive metabolic reprogramming. To identify metabolic pathways associated with aging, we analyzed age-dependent changes in the metabolomes of long-lived Drosophila melanogaster. Among the metabolites that changed, levels of tyrosine were increased with age in long-lived flies. We demonstrate that the levels of enzymes in the tyrosine degradation pathway increase with age in wild-type flies. Whole-body and neuronal-specific downregulation of enzymes in the tyrosine degradation pathway significantly extends Drosophila lifespan, causes alterations of metabolites associated with increased lifespan, and upregulates the levels of tyrosine-derived neuromediators. Moreover, feeding wild-type flies with tyrosine increased their lifespan. Mechanistically, we show that suppression of ETC complex I drives the upregulation of enzymes in the tyrosine degradation pathway, an effect that can be rescued by tigecycline, an FDA-approved drug that specifically suppresses mitochondrial translation. In addition, tyrosine supplementation partially rescued lifespan of flies with ETC complex I suppression. Altogether, our study highlights the tyrosine degradation pathway as a regulator of longevity.


Infiltrative cardiovascular diseases: cardiomyopathies that look alike.
Infiltrative cardiomyopathies are characterized by the deposition of abnormal substances that cause the ventricular walls to become progressively rigid, thereby impeding ventricular filling. Some infiltrative cardiac diseases increase ventricular wall thickness, while others cause chamber enlargement with secondary wall thinning. Increased wall thickness, small ventricular volume, and occasional dynamic left ventricular outflow obstruction (e.g., amyloidosis) can outwardly appear similar to conditions with true myocyte hypertrophy (e.g., hypertrophic cardiomyopathy, hypertensive heart disease). Likewise, infiltrative disease that presents with a dilated left ventricle with global or regional wall motion abnormalities and aneurysm formation (e.g., sarcoidosis) may mimic ischemic cardiomyopathy. Low-voltage QRS complex was the sine qua non of infiltrative cardiomyopathy (i.e., cardiac amyloid). However, low-voltage QRS complex is not a uniform finding with the infiltrative cardiomyopathies. The clinical presentation, along with functional and morphologic features, often provides enough insight to establish a working diagnosis. In most circumstances, however, tissue or serologic evaluation is needed to validate or clarify the cardiac diagnosis and institute appropriate therapy.


Unilateral groin surgery in children: will the addition of an ultrasound-guided ilioinguinal nerve block enhance the duration of analgesia of a single-shot caudal block?
Inguinal hernia repair, hydrocelectomy, and orchidopexy are commonly performed surgical procedures in children. Postoperative pain control is usually provided with a single-shot caudal block. Blockade of the ilioinguinal nerve may lead to additional analgesia. The aim of this double-blind, randomized controlled trial was to evaluate the efficacy of an adjuvant blockade of the ilioinguinal nerve using ultrasound (US) guidance at the end of the procedure with local anesthetic vs normal saline and to explore the potential for prolongation of analgesia with decreased need for postoperative pain medication. Fifty children ages 1-6 years scheduled for unilateral inguinal hernia repair, hydrocelectomy, orchidopexy, or orchiectomy were prospectively randomized into one of two groups: Group S that received an US-guided ilioinguinal nerve block with 0.1 ml x kg(-1) of preservative-free normal saline and Group B that received an US-guided nerve block with 0.1 ml x kg(-1) of 0.25% bupivacaine with 1 : 200,000 epinephrine at the conclusion of the surgery. After induction of anesthesia but prior to surgical incision, all patients received caudal anesthesia with 0.7 ml x kg(-1) of 0.125% bupivacaine with 1 : 200,000 epinephrine. Patients were observed by a blinded observer for (i) pain scores using the Children and Infants Postoperative Pain Scale, (ii) need for rescue medication in the PACU, (iii) need for oral pain medications given by the parents at home. Forty-eight patients, consisting of 46 males and two females, with a mean age of 3.98 (SD +/- 1.88) were enrolled in the study. Two patients were excluded from the study because of study protocol violation and/or alteration in surgical procedure. The average pain scores reported for the entire duration spent in the recovery room for the caudal and caudal/ilioinguinal block groups were 1.92 (SD +/- 1.59) and 1.18 (SD +/- 1.31), respectively. The average pain score difference was 0.72 (SD +/- 0.58) and was statistically significant (P < 0.05). In addition, when examined by procedure type, it was found that the difference in the average pain scores between the caudal and caudal/ilioinguinal block groups was statistically significant for the inguinal hernia repair patients (P < 0.05) but not for the other groin surgery patients (P = 0.13). For all groin surgery patients, six of the 23 patients in the caudal group and eight of the 25 patients in the caudal/ilioinguinal block group required pain rescue medications throughout their entire hospital stay or at home (P = 0.76). Overall, the caudal group received an average of 0.54 (SD +/- 1.14) pain rescue medication doses, while the caudal/ilioinguinal block group received an average of 0.77 (SD +/- 1.70) pain rescue medication doses; this was, however, not statistically significant (P = 0.58). The addition of an US-guided ilioinguinal nerve block to a single-shot caudal block decreases the severity of pain experienced by pediatric groin surgery patients. The decrease in pain scores were particularly pronounced in inguinal hernia repair patients.


Hourglass-like constrictions of peripheral nerve in the upper extremity: a clinical review and pathological study.
The development of an hourglass-like constriction in the nerve is rare, and its origin is unknown. Its clinical manifestations are not well documented, and the treatment protocol has not been established. To identify the cause, presentation, and possible treatment for patients with nerve palsies secondary to an hourglass-like constriction in the affected nerves. Patients presenting with peripheral nerve palsy caused by an hourglass-like constriction of nerves were retrospectively investigated in 2 hand centers. The patients' presentation and neurological findings were reviewed, and the immunohistochemistry of excised specimens was studied. Forty-two patients who presented with 47 nerve palsies were examined. Forty-one patients experienced a sudden onset of pain in the upper limb, followed by flaccid paralysis in the affected muscles. Ten patients had multiple nerve involvement. Surgical exploration found 1 or more hourglass-like constrictions in the nerve. The treatments included internal neurolysis, neurorrhaphy, and nerve grafting. Thirty-one of 42 patients (36 nerves) were followed up for a mean of 48 months (range, 8-157 months). Fifteen of 16 nerves treated by neurolysis, 10 of 13 nerves treated by neurorrhaphy, and 4 of 7 nerves treated by nerve grafting had good recovery. CD8-positive T-lymphocyte infiltration was observed in all the excised specimens. The clinical presentation of patients with hourglass-like constrictions in their nerves is similar to that of patients with neuralgic amyotrophy. Histochemical analysis suggests that the pathogenesis may be immunological in origin. The role of surgery in this condition is uncertain.


Water security, global change and land-atmosphere feedbacks.
Understanding the competing pressures on water resources requires a detailed knowledge of the future water balance under uncertain environmental change. The need for a robust, scientifically rigorous evidence base for effective policy planning and practice has never been greater. Environmental change includes, but is not limited to, climate change; it also includes land-use and land-cover change, including deforestation for agriculture, and occurs alongside changes in anthropogenic interventions that are used in natural resource management such as the regulation of river flows using dams, which can have impacts that frequently exceed those arising in the natural system. In this paper, we examine the role that land surface models can play in providing a robust scientific basis for making resource management decisions against a background of environmental change. We provide some perspectives on recent developments in modelling in land surface hydrology. Among the range of current land surface and hydrology models, there is a large range of variability, which indicates that the specification and parametrization of several basic processes in the models can be improved. Key areas that require improvement in order to address hydrological applications include (i) the representation of groundwater in models, particularly at the scales relevant to land surface modelling, (ii) the representation of human interventions such as dams and irrigation in the hydrological system, (iii) the quantification and communication of uncertainty, and (iv) improved understanding of the impact on water resources availability of multiple use through treatment, recycling and return flows (and the balance of consumptive and conservative uses). Through a series of examples, we demonstrate that changes in water use could have important reciprocal impacts on climate over a wide area. The effects of water management decisions on climate feedbacks are only beginning to be investigated-they are still only rarely included in climate impact assessments-and the links between the hydrological system and climate are rarely acknowledged in studies of ecosystem services. Nevertheless, because water is essential not only for its direct uses but also for the indirect functions that it serves (including food production, fisheries and industry), it is vital that these connected systems are studied. Building on the examples above, we highlight recent research showing that assessment of these trade-offs is particularly complex in wetland areas, especially in situations where these trade-offs play to the advantage of different communities.


Electroluminescence from metal-insulator-semiconductor tunneling diodes using compressively strained Ge on Si0.5Ge0.5 virtual substrates.
Direct band gap optical transition in compressively strained Ge film is demonstrated for the first time under current injection through a metal-insulator-semiconductor diode structure. The compressively strained Ge layer is grown on the relaxed Si0.5Ge0.5 substrate by solid source molecular beam epitaxy. The electroluminescence of direct band gap emission from strained Ge film and TO phonon assisted transition in Si and SiGe from the virtual substrate is observed under different current injections. The signature of heavy hole and light hole splitting in valence band is observed in the electroluminescence spectra from strained Ge layer. The temperature dependent electroluminescence characteristics have been studied over a temperature range of 10-300 K. AC frequency modulation for the Ge direct band electroluminescence has been studied to improve the emission efficiency over the DC bias.


Parkour-Based Activities in the Athletic Development of Youth Basketball Players.
While ideas from long-term athlete development (LTAD) models have been adopted and integrated across different sports, issues related to early specialization, such as increased risk of injury and burnout, are still common. Although some benefits may be associated with early sport specialization, sports sampling is purported to be a more effective approach to the long-term health and wellbeing of children. Furthermore, the concept of developing what are commonly referred to as "fundamental movement skills" (FMS) is central to the rationale for delaying single sports specialization. However, in place of sports sampling, it appears that the practice of strength and conditioning (S&C) has become a driving force behind developmental models for youth athletes, highlighted by the growing body of literature regarding youth athletic development training. In this perspective piece, we explore how conventional S&C practice may insufficiently develop FMS because typically, it only emphasizes a narrow range of foundational exercises that serve a limited role toward the development of action capabilities in youth athletic populations. We further discuss how this approach may limit the transferability of physical qualities, such as muscular strength, to sports-specific tasks. Through an ecological dynamics lens, and using basketball as an example, we explore the potential for parkour-based activity within the LTAD of youth basketball players. We propose parkour as a training modality to not only encourage movement diversity and adaptability, but also as part of an advanced strength training strategy for the transfer of conventional S&C training.


Synthesis of transforming growth factor-beta 1 by megakaryocytes and its localization to megakaryocyte and platelet alpha-granules.
We have directly demonstrated that megakaryocytes are a major site of synthesis and storage of transforming growth factor-beta 1 (TGF/beta 1) by combined immunohistochemical, immunocytochemical, and in situ hybridization methods. The presence of TGF/beta 1 messenger RNA (mRNA) in mature megakaryocytes in adult rat spleen and bone marrow (BM) was established by in situ hybridization. Localization of TGF/beta 1 protein to intact alpha-granules of megakaryocytes, its putative storage site, was accomplished in glycol-methacrylate embedded porcine BM with an immunoperoxidase technique and light microscopy. The TGF/beta 1 was sequestered in intracytoplasmic granules in a pattern virtually identical to that of another alpha-granule marker protein, fibrinogen. This observation strongly suggests packaging of TGF/beta 1 into this organelle within megakaryocytes. That TGF/beta 1 mRNA was localized to megakaryocytes suggests that the TGF/beta 1 found in the alpha-granules in platelets originates with megakaryocyte synthesis. The alpha-granule localization of TGF/beta 1, as well as fibrinogen, was also demonstrated in isolated platelets at the ultrastructural level by electronmicroscopy (EM) and postembedding colloidal-gold immunocytochemistry, thus directly demonstrating that alpha-granules are the final storage site for TGF/beta 1 in mature platelets.


Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus.
The relation between diabetic microangiopathy and macroangiopathy was studied by analysing the relative mortality from cardiovascular disease in patients with insulin dependent diabetes mellitus with and without persistent proteinuria. The study group comprised 2890 diabetics diagnosed between 1933 and 1972 before the age of 31, and the study was conducted by using the linear logistic discrete failure time model. In patients with proteinuria the relative mortality from cardiovascular disease was 37 times that in the general population; in patients without proteinuria it was 4.2 times that in the general population. In both groups women had a relative mortality twice to 2.6 times that of men. In neither group was relative mortality correlated with duration of diabetes, suggesting that the association between diabetes and cardiovascular disease may be conferred by factors other than hyperglycaemia and hyperinsulinaemia. The high relative mortality from cardiovascular disease in diabetics with proteinuria indicates a strong association between diabetic microangiopathy and macroangiopathy, suggesting a common (pathogenetic?) mechanism for these two late diabetic complications.


Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses.
Cystic fibrosis (CF), the most common fatal monogenic disease in the United States, results from mutations in CF transmembrane conductance regulator (CFTR), a chloride channel. The mechanisms by which CFTR mutations cause lung disease in CF are not fully defined but may include altered ion and water transport across the airway epithelium and aberrant inflammatory and immune responses to pathogens within the airways. We have shown that Cftr(-/-) mice mount an exaggerated IgE response toward Aspergillus fumigatus, with higher levels of IL-13 and IL-4, mimicking both the T helper cell type 2-biased immune responses seen in patients with CF. Herein, we demonstrate that these aberrations are primarily due to Cftr deficiency in lymphocytes rather than in the epithelium. Adoptive transfer experiments with CF splenocytes confer a higher IgE response to Aspergillus fumigatus compared with hosts receiving wild-type splenocytes. The predilection of Cftr-deficient lymphocytes to mount T helper cell type 2 responses with high IL-13 and IL-4 was confirmed by in vitro antigen recall experiments. Conclusive data on this phenomenon were obtained with conditional Cftr knockout mice, where mice lacking Cftr in T cell lineages developed higher IgE than their wild-type control littermates. Further analysis of Cftr-deficient lymphocytes revealed an enhanced intracellular Ca(2+) flux in response to T cell receptor activation. This was accompanied by an increase in nuclear localization of the calcium-sensitive transcription factor, nuclear factor of activated T cell, which could drive the IL-13 response. In summary, our data identified that CFTR dysfunction in T cells can lead directly to aberrant immune responses. These findings implicate the lymphocyte population as a potentially important target for CF therapeutics.


A facile approach for preparing densely-packed individual p-NiO/n-Fe2O3 heterojunction nanowires for photoelectrochemical water splitting.
Innovative design of electrode materials is crucial for efficient conversion of solar energy into chemical fuel through photoelectrochemical (PEC) water splitting. Herein, we report the development of a p-n heterojunction nanowire (NW) based photoanode made of low cost earth-abundant materials. Densely-packed and freestanding individual p-NiO/n-Fe2O3 heterojunction NWs are fabricated through consecutive electrodeposition of Fe and Ni NWs inside the pores of the anodic alumina template followed by controlled oxidation. Heterojunction formation in individual NWs is confirmed through energy dispersive spectroscopy (EDS) and transmission electron microscopy (TEM), along with elemental mapping on individual NWs through electron energy loss spectroscopy (EELS). An inverted 'V' shape nature of the Mott-Schottky curve suggests p-n diode like characteristics of the heterojunction NWs. These p-n heterojunction NWs demonstrate a significantly enhanced photocurrent density (∼24 times at a potential of 1.23 V vs. RHE) and a cathodic shift (∼0.4 V) of the photocurrent onset potential compared to the pristine Fe2O3 NW electrode, which can be attributed to the synergistic combination of n-Fe2O3 with the co-catalyst p-NiO facilitating the generation and transfer of photogenerated holes into the electrolyte for water oxidation. This study validates the feasibility of developing Fe2O3 based heterojunction photoelectrodes for efficient PEC water splitting.


How U38, 39, and 40 of many tRNAs become the targets for pseudouridylation by TruA.
Translational accuracy and efficiency depend upon modification of uridines in the tRNA anticodon stem loop (ASL) by a highly conserved pseudouridine synthase TruA. TruA specifically modifies uridines at positions 38, 39, and/or 40 of tRNAs with highly divergent sequences and structures through a poorly characterized mechanism that differs from previously studied RNA-modifying enzymes. The molecular basis for the site and substrate "promiscuity" was studied by determining the crystal structures of E. coli TruA in complex with two different leucyl tRNAs in conjunction with functional assays and computer simulation. The structures capture three stages of the TruA*tRNA reaction, revealing the mechanism by which TruA selects the target site. We propose that TruA utilizes the intrinsic flexibility of the ASL for site promiscuity and also to select against intrinsically stable tRNAs to avoid their overstabilization through pseudouridylation, thereby maintaining the balance between the flexibility and stability required for its biological function.


Ozone-climate interactions and effects on solar ultraviolet radiation.
This report assesses the effects of stratospheric ozone depletion and anticipated ozone recovery on the intensity of ultraviolet (UV) radiation at the Earth's surface. Interactions between changes in ozone and changes in climate, as well as their effects on UV radiation, are also considered. These evaluations focus mainly on new knowledge gained from research conducted during the last four years. Furthermore, drivers of changes in UV radiation other than ozone are discussed and their relative importance is assessed. The most important of these factors, namely clouds, aerosols and surface reflectivity, are related to changes in climate, and some of their effects on short- and long-term variations of UV radiation have already been identified from measurements. Finally, projected future developments in stratospheric ozone, climate, and other factors affecting UV radiation have been used to estimate changes in solar UV radiation from the present to the end of the 21st century. New instruments and methods have been assessed with respect to their ability to provide useful and accurate information for monitoring solar UV radiation at the Earth's surface and for determining relevant exposures of humans. Evidence since the last assessment reconfirms that systematic and accurate long-term measurements of UV radiation and stratospheric ozone are essential for assessing the effectiveness of the Montreal Protocol and its Amendments and adjustments. Finally, we have assessed aspects of UV radiation related to biological effects and human health, as well as implications for UV radiation from possible solar radiation management (geoengineering) methods to mitigate climate change.


Motility response of Rhodobacter sphaeroides to chemotactic stimulation.
Tethered rotating cells of Rhodobacter sphaeroides varied widely in their stopping frequency; 45% of cells showed no stops of longer than 1 s, whereas others showed stops of up to several seconds. Individual cells alternated between stops and rotation at a fairly constant rate, without continuous variation. Addition of the chemoattractant propionate to free-swimming cells of R. sphaeroides increased the mean population swimming speed from 15 to 23 microns s-1. After correction for nonmotile cells, the percentage swimming at less than 5 microns s-1 dropped from approximately 22 to 8, whereas the percentage swimming at greater than 50 microns s-1 increased from 6 to 15. However, cells already swimming did not swim faster after propionate addition; the increase in the mean population speed after propionate addition was caused by an increase in the mean run length between stops from 25 to 101 microns. The increased run length was the result of a drop in both the stopping frequency and the length of a stop. Addition of propionate over the range of 10 microM to 1 mM decreased the stopping frequency; this decrease was almost entirely blocked by benzoate, a competitive inhibitor of propionate transport. The chemoattractants acetate and potassium had the same effect as propionate on the distribution of stopping frequency, which demonstrated that this is a general behavioral response to chemotactic stimulation. Adaptation to propionate stimulation was slow and very variable, cultures frequently showing little adaptation over 30 min. This characteristic may be the result of the lack of a highly specific chemosensory system in R. sphaeroides.


Plasmonic-heating-induced nanofabrication on glass substrates.
Fabricating nano-sized through-holes on a coverslip approximately 100 μm thick is challenging but rewarding when applied to ultrafine filters that separate proteins and DNA of various sizes and isolate viruses from cells. Toward this end, we developed an in situ etching-assisted laser processing technique exploiting gold nanoparticles. Plasmonic heating of a single gold nanoparticle through focused illumination of a continuous-wave laser beam enables structural modifications to be localized to the contact area on the glass surface. This results in the embedding of the particle forming nanocavities caused by chemical etching with aqueous tetrabutylammonium hydroxide. Depending on the shape of the nanoparticle, a highly flexible face geometry design such as a disk and triangle was achieved. The etching was monitored in situ through measurements of spectral red shifts in single-particle scattering, indicating an increasing medium refractive index consistent with embedding. The embedding process is unexpectedly fast, at 0.8 μm with 5 minutes of illumination. Besides nanoholes, we fabricated nanodomes around a single gold nanoparticle supported on a glass substrate through laser-heating-induced encapsulation. Overall, we were able to demonstrate true nano-laser processing free from diffraction-limited optics, with potential benefits of simple low-cost fabrication.


Noninflammatory flap edema after laser in situ keratomileusis associated with asymmetrical preoperative corneal pachymetry.
To report persistent unilateral flap edema following laser in situ keratomileusis (LASIK) in patients with asymmetrical central corneal thickness. Minnesota Eye Consultants, Minneapolis, Minnesota. Retrospective, noncomparative interventional case series. We examined 6 eyes of 3 patients with asymmetrical preoperative pachymetry who developed persistent unilateral flap edema after uneventful myopic LASIK in the eye with thicker preoperative pachymetry. All cases had asymmetrical preoperative pachymetry with flap edema developing in the eye with higher preoperative mean central corneal thickness (CCT) values, preoperative mean CCT subject eye 622 microm (range 556-664 microm) versus fellow eye 583 microm (range 510-621 microm). There was no associated ocular inflammation or rise in intraocular pressure. Significant flap edema resolved on a combination treatment of topical steroid and hypertonic saline. Laser in situ keratomileusis can cause temporary endothelial cell dysfunction or stress, which manifests as temporary flap edema and subclinical corneal thickening. The edema appears to be limited to the actual flap and there was no loss of epithelial integrity in these eyes and no clinically noticeable interface fluid. This new clinical entity appears to occur in patients with asymmetrical preoperative corneal pachymetry and is associated with postoperative specular microscopy abnormalities. In cases with unexplained asymmetrical corneal thickness, preoperative evaluation should include specular microscopy to evaluate for risk features that may increase the chances of a slower postoperative recovery.


Senescent stromal-derived osteopontin promotes preneoplastic cell growth.
Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies showing that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole-genome transcriptional profiling and compared senescent fibroblasts with their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNA interference did not affect senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, showing that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we show that OPN is expressed in senescent stroma within preneoplastic lesions that arise following 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatment of mice, suggesting that stromal-derived OPN-mediated signaling events affect neoplastic progression.


Unravelling the metabolic impact of SBS-associated microbial dysbiosis: Insights from the piglet short bowel syndrome model.
Liver disease is a major source of morbidity and mortality in children with short bowel syndrome (SBS). SBS-associated microbial dysbiosis has recently been implicated in the development of SBS-associated liver disease (SBS-ALD), however the pathological implications of this association have not been explored. In this study high-throughput sequencing of colonic content from the well-validated piglet SBS-ALD model was examined to determine alterations in microbial communities, and concurrent metabolic alterations identified in urine samples via targeted mass spectrometry approaches (GC-MS, LC-MS, FIA-MS) further uncovered impacts of microbial disturbance on metabolic outcomes in SBS-ALD. Multi-variate analyses were performed to elucidate contributing SBS-ALD microbe and metabolite panels and to identify microbe-metabolite interactions. A unique SBS-ALD microbe panel was clearest at the genus level, with discriminating bacteria predominantly from the Firmicutes and Bacteroidetes phyla. The SBS-ALD metabolome included important alterations in the microbial metabolism of amino acids and the mitochondrial metabolism of branched chain amino acids. Correlation analysis defined microbe-metabolite clustering patterns unique to SBS-ALD and identified a metabolite panel that correlates with dysbiosis of the gut microbiome in SBS.


Biogenesis of the mitochondrial Tom40 channel in skeletal muscle from aged animals and its adaptability to chronic contractile activity.
Evidence exists that mitochondrial content and/or function is reduced in muscle of aging individuals. The purposes of this study were to investigate the contribution of outer membrane protein import and assembly processes to this decline and to determine whether the assembly process could adapt to chronic contractile activity (CCA). Tom40 assembly into the translocases of the outer membrane (TOM complex) was measured in subsarcolemmal mitochondria obtained from young (6 mo old) and aged (36 mo old) Fischer 344 x Brown Norway animals. While the initial import of Tom40 did not differ between young and aged animals, its subsequent assembly into the final approximately 380 kDa complex was 2.2-fold higher (P < 0.05) in mitochondria from aged compared with young animals. This was associated with a higher abundance of Tom22, a protein vital for the assembly process. CCA induced a greater initial import and subsequent assembly of Tom40 in mitochondria from young animals, resulting in a CCA-induced 75% increase (P < 0.05) in Tom40 within mitochondria. This effect of CCA was attenuated in mitochondria from old animals. These data suggest that the import and assembly of proteins into the outer membrane do not contribute to reduced mitochondrial content or function in aged animals. Indeed, the greater assembly rate in mitochondria from aged animals may be a compensatory mechanism attempting to offset any decrements in mitochondrial content or function within aged muscle. Our data also indicate the potential of CCA to contribute to increased mitochondrial biogenesis in muscle through changes in the outer membrane import and assembly pathway.


Anti-Inflammatory mechanisms of the proteinase-activated receptor 2-inhibiting peptide in human synovial cells.
Osteoarthritis (OA) is a degenerative joint disease which affects the entire joint structure, including the synovial membrane. Disease progression was shown to involve inflammatory changes mediated by proteinase-activated receptor (PAR)-2. Previous studies demonstrated that PAR-2 messenger (m)RNA and protein levels increased in OA synovial cells, suggesting that PAR-2 is a potential therapeutic target of the disease. We designed a PAR-2-inhibiting peptide (PAR2-IP) by changing an isoleucine residue in the PAR-2-activating peptide (PAR2-AP), SLIGKV, to alanine, generating the SLAGKV peptide. We used it to test PAR-2-mediated inflammatory responses, including the expressions of cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-1 and activation of nuclear factor (NF)-κB in human synovial cells. As a control, expressions of COX-2 and MMP-1 were induced by trypsin at both the mRNA and protein levels. The PAR2-AP increased the expression of COX-2 more dramatically than that of MMP-1. When we treated cells with the designed PAR2-IP, the trypsin-induced COX-2 level was completely inhibited at a moderate concentration of the PAR2-IP. With further examination of trypsin-induced NF-κB activation, we observed sufficient inhibitory effects of the PAR2-IP in synoviosarcoma cells and primary synovial cells from OA patients. Our study suggests that the PAR2-IP inhibits trypsin-induced NF-κB activation, resulting in a reduction in inflammatory COX-2 expression in synovial cells. Application of PAR2-IP is suggested as a potential therapeutic strategy for OA.


What Is COVID-19 Teaching Us About Community Health Systems? A Reflection From a Rapid Community-Led Mutual Aid Response in Cape Town, South Africa.
The coronavirus disease 2019 (COVID-19) pandemic has exposed the wide gaps in South Africa's formal social safety net, with the country's high levels of inequality, unemployment and poor public infrastructure combining to produce devastating consequences for a vast majority in the country living through lockdown. In Cape Town, a movement of self-organising, neighbourhood-level community action networks (CANs) has contributed significantly to the community-based response to COVID-19 and the ensuing epidemiological and social challenges it has wrought. This article describes and explains the organising principles that inform this community response, with the view to reflect on the possibilities and limits of such movements as they interface with the state and its top-down ways of working, often producing contradictions and complexities. This presents an opportunity for recognising and understanding the power of informal networks and collective action in community health systems in times of unprecedented crisis, and brings into focus the importance of finding ways to engage with the state and its formal health system response that do not jeopardise this potential.


Building expert agreement on the importance and feasibility of workplace health promotion interventions for nurses and midwives: A modified Delphi consultation.
To use a Delphi panel to determine the relative importance and feasibility of workplace health promotion interventions to promote and support the health of the Australian nursing and midwifery workforce. The nursing workforce experiences rates of ill health above that of other workforces, yet there is little investment in workplace health promotion. The study used a modified Delphi design conducted between September and November 2015. Eleven of 19 purposively selected expert panellists discussed, rated and provided feedback through two rounds of an electronic questionnaire about the relative importance and feasibility of 46 workplace health promotion interventions and processes for nurses and midwives. Scores for importance and feasibility were calculated and ranked and a composite score of importance multiplied by feasibility. Mental health strategies were prioritized as the most important and feasible of the intervention topics, followed closely by healthy eating and physical activity interventions; smoking cessation ranked lowest. The most highly ranked interventions targeted healthy eating, stress management and resilience training. Highest ranked processes to support development of a healthy work environment included intersectoral collaboration and employee wellness groups. Study findings prompt consideration of health promotion opportunities to support nurses' health and well-being. Findings identified key workplace health promotion priorities and provide direction for policy makers and managers to promote nursing and midwifery workforce health.


16-MDCT angiography in living kidney donors at various tube potentials: impact on image quality and radiation dose.
The objective of our study was to compare the performance of 16-MDCT angiography at various peak kilovoltage (kVp) settings and the impact of the different settings on image quality and on radiation dose in adult kidney donors. Sixty-two renal donors (32 men, 30 women) who underwent 16-MDCT were divided into three groups: 18 subjects were studied at 140 kVp (group A); 20, at 120 kVp (group B); and 24, at 100 kVp (group C). Other constant scanning parameters were as follows: detector collimation, 0.625 mm; table feed, 9.375 mm/rotation; gantry rotation time, 500 milliseconds; and automatic current tube modulation (ATCM) using a noise index of 15. A total of 135-140 mL of iodinated contrast material (300 mg I/mL) was administered at 5 mL/s via an 18-gauge cannula, and arterial phase scanning was initiated using a bolus-tracking technique. Two observers evaluated image quality of the axial and 3D images and the visibility of branch order in the superior mesenteric artery (SMA) and renal arteries. Attenuation (in Hounsfield units [H]) in the aorta, SMA, and main renal artery was also measured by placing a region of interest. Radiation dose measurements were based on the scanner-generated CT dose index volume (CTDI(vol)). Each parameter tested was compared among the three groups using a nonparametric analysis of variance test, and a p value of 0.05 was considered significant. Differences in the quality of the axial images existed between groups A and C (p < 0.001) and between groups B and C (p < 0.01); the image quality of the 3D images and the visibility of branch order in the SMA and renal arteries were comparable for all groups. The difference in mean attenuation of the aorta, SMA, and renal arteries was significant between groups A and C (p < 0.001) and between groups B and C (p < 0.01). All groups had 100% diagnostic accuracy in identifying the number of renal arteries on the side of nephrectomy. The mean radiation dose in CTDI(vol) was 25 +/- 3 mGy at 140 kVp, 17 +/- 4 mGy at 120 kVp, and 12 +/- 3 mGy at 100 kVp (p < 0.001). Our initial observations suggest that the image quality of 16-MDCT angiography performed at 120 kVp is similar to that of CT angiography (CTA) performed at 140 kVp in adult kidney donors but with a significant radiation dose reduction. CTA at 100 kVp results in higher image noise but provides diagnostically acceptable images with significant radiation dose reduction compared with CTA at 120 or 140 kVp.


Highlights from the 13th African Continental Meeting of the International Society of Paediatric Oncology (SIOP), 6-9 March 2019, Cairo, Egypt.
The 13th African continental meeting of the international society of paediatric oncology, held on 6-9 March 2019 in Cairo, was organised in collaboration with the Children Cancer Hospital (57357) in Egypt and the global parents' organisation (Childhood Cancer International) and supported by a large international faculty. With 629 delegates from 37 countries (24 African), this was the largest forum of healthcare professionals focused on children and young people with cancer in Africa to showcase advances and discuss further improvements. Three targeted workshops, on nursing care, pharmacy and nutrition, attracted large numbers and catalysed new collaborative initiatives in supportive care studies, extended roles for pharmacists in quality control and care delivery and addressed malnutrition concurrently with cancer treatment. The Collaborative Wilms Tumour Africa Project, open in seven sub-Saharan countries, and the trials in Burkitt's lymphoma reported encouraging outcomes with further initiatives in supportive care (the supportive care for children with cancer in Africa project). While acknowledging deficits in radiotherapy provision, available in only 23 of 52 African countries, centres with facilities reported their technical advances that benefit patients. Of great importance for children with brain tumours, who are underdiagnosed in Africa, was the first announcement of African paediatric neuro-oncology society, whose 63 current members aim to tackle the shortage of neurosurgeons through training fellowships, workshops and a dedicated conference. The congress provided the opportunity to discuss how African countries will work with the WHO global initiative aiming to improve childhood cancer survival to 60% in all countries by 2030. This conference report is dedicated to the three Kenyan delegates who died tragically on the Ethiopian Airlines flight ET302 on their way home, full of new ideas and pride in what they had achieved so far. All those who heard their presentations are determined to continue their excellent work to improve cancer care for children in Africa.


Natural history and morphology of the hoverfly Pseudomicrodon biluminiferus and its parasitic relationship with ants nesting in bromeliads.
The syrphid subfamily Microdontinae is characterized by myrmecophily of their immature stages, i.e., they develop in ant nests. Data on natural history of microdontines are scarce, especially in the Neotropics. Based on fieldwork in southern Brazil, this study provided new data on development and ecology of the hoverfly Pseudomicrodon biluminiferus (Hull) (Diptera: Syrphidae) as well as the first morphological descriptions of male genitalia, larvae, and pupa. Immature specimens were specifically found in colonies of the ant species Crematogaster limata Smith (Hymenoptera: Formicidae) found in rosettes of the bromeliad species Aechmea lindenii (E. Morren) Baker (Poales: Bromeliaceae) and A. nudicaulis (L.) Grisebach. Third instar larvae were observed preying on ant larvae, revealing the parasitic nature of P. biluminiferus. In this and several other aspects, the natural history of P. biluminiferus is similar to that of Holarctic microdontine species. Exceptions include: (i) indications that adults of P. biluminiferus outlast the winter months (in contrast to 3(rd)instar larvae in Holarctic species) and (ii) P. biluminiferus' relationship with bromeliads. The importance of bromeliads for this host-parasite system is evaluated in this paper. The single occurrence of another, unidentified microdontine species' pupae in a nest of the ant species Camponotus melanoticus Emery (Hymenoptera: Formicidae) is reported.


The Alcohol Use Disorders Identification Test and the risk of metachronous cancer after endoscopic resection of esophageal cancer.
Follow-up studies of Japanese patients who had undergone endoscopic resection (ER) for early esophageal squamous cell carcinoma (ESCC) have reported a high prevalence of metachronous SCC in the upper aerodigestive tract (UAT). This prospective multicenter cohort study followed up 330 Japanese patients after ER of ESCC for a median of 49.4 months. The Alcohol Use Disorders Identification Test (AUDIT) for the 12-month period prior to study registration revealed high frequencies of high-risk drinking behaviors: 84 (25.4%) subjects had AUDIT scores of ≥15 points (suspected alcohol dependence) and 121 (36.7%) subjects had AUDIT scores of 8-14 points (hazardous drinking). Seventy-four subjects were metachronously diagnosed with ESCC, and 20 subjects with head and neck SCC (HNSCC). AUDIT scores ≥15 were associated with increases in the total number of HNSCCs per 100 person-years (0.4 for 0-7, 1.2 for 8-14 and 7.1 for ≥15; P < 0.0001). AUDIT scores were progressively associated with the grade of esophageal Lugol-voiding lesions (LVLs), a predictor of field cancerization in the UAT. Both an AUDIT score of ≥15 points and the presence of multiple LVLs were independent predictors of metachronous HNSCC [multivariate hazard ratio (95% confidence interval) = 6.98 (1.31-37.09) and 3.19 (1.19-8.54), respectively]. However, a high AUDIT score was not a predictor of metachronous ESCC. In conclusion, high AUDIT scores were markedly frequent in this population and increased the risk of metachronous HNSCC. The assessment of drinking behavior using the AUDIT and the completion of interventions for alcohol problems should be incorporated into the treatment strategy of ESCC. The name of the clinical trial register and the clinical trial registration number: Japan Esophageal Cohort Study, UMIN000001676.


Distributed controller clustering in software defined networks.
Software Defined Networking (SDN) is an emerging promising paradigm for network management because of its centralized network intelligence. However, the centralized control architecture of the software-defined networks (SDNs) brings novel challenges of reliability, scalability, fault tolerance and interoperability. In this paper, we proposed a novel clustered distributed controller architecture in the real setting of SDNs. The distributed cluster implementation comprises of multiple popular SDN controllers. The proposed mechanism is evaluated using a real world network topology running on top of an emulated SDN environment. The result shows that the proposed distributed controller clustering mechanism is able to significantly reduce the average latency from 8.1% to 1.6%, the packet loss from 5.22% to 4.15%, compared to distributed controller without clustering running on HP Virtual Application Network (VAN) SDN and Open Network Operating System (ONOS) controllers respectively. Moreover, proposed method also shows reasonable CPU utilization results. Furthermore, the proposed mechanism makes possible to handle unexpected load fluctuations while maintaining a continuous network operation, even when there is a controller failure. The paper is a potential contribution stepping towards addressing the issues of reliability, scalability, fault tolerance, and inter-operability.


Molecular cloning and characterization of an adherence-related operon of Mycoplasma genitalium.
Adhesins and adhesin-related accessory proteins of pathogenic mycoplasmas are required for cytadherence and the subsequent development of disease pathology. The classic example has been Mycoplasma pneumoniae, which causes primary atypical pneumonia in humans. Mutants of M. pneumoniae defective in adhesins (P1 and P30) or in adherence-accessory proteins (HMW1 through HMW4) are unable to colonize host tissues and are avirulent. Mycoplasma genitalium, implicated in nongonococcal, nonchlamydial urethritis, pneumonia, arthritis, and AIDS progression, was found to encode a 140-kDa adhesin that shared both DNA and protein sequence similarities with P1, a major adhesin of M. pneumoniae. In this report, we show that M. genitalium possesses additional homolog sequences to well-characterized adherence-related genes and proteins of M. pneumoniae. The M. genitalium homologs are designated P32 and P69 and correspond to P30 and HMW3 of M. pneumoniae, respectively (J. B. Baseman, p. 243-259, in S. Rottem and I. Kahane, ed., Subcellular biochemistry, vol. 20. Mycoplasma cell membranes, 1993, and D. C. Krause, D. K. Leith, R. M. Wilson, and J. B. Baseman, Infect. Immun. 35:809-817, 1982). Interestingly, the operon-like organizations of P32 and P69 in the M. genitalium genome are similar to the organizations of P30 and HMW3 genes of M. pneumoniae, suggesting that the conservation of these adherence-related genes and proteins might have occurred through horizontal gene transfer events originating from an ancestral gene family.


Strategies to prevent HIV transmission among heterosexual African-American men.
As part of qualitative research for developing a culturally sensitive and developmentally appropriate videotape-based HIV prevention intervention for heterosexual African- American men, six focus groups were conducted with thirty African-American men to determine their perceptions of AIDS as a threat to the African-American community, characteristics of past situations that have placed African Americans at risk for HIV infection, their personal high risk behaviors, and suggestions on how HIV intervention videotapes could be produced to achieve maximum levels of interest among African-American men in HIV training programs. The groups took place at a low-income housing project in Houston, Texas, a major epicenter for HIV/AIDS. Each group was audiotaped, transcribed, and analyzed using theme and domain analysis. The results revealed that low-income African-American men perceive HIV/AIDS as a threat to their community and they have placed themselves at risk of HIV infection based on unsafe sex practices, substance abuse, and lack of knowledge. They also cite lack of income to purchase condoms as a barrier to safe sex practice. They believe that HIV training programs should address these risk factors and that videotapes developed for prevention should offer a sensationalized look at the effects of HIV/AIDS on affected persons. They further believe that programs should be held in African-American communities and should include condoms to facilitate reduction of risk behaviors. The results indicate that the respondents taking part in this study believe that HIV and AIDS are continued threats to the African-American community because of sexual risk taking behavior, that is, failure to use condoms. Further, African-American men are having sex without condoms when having sex with women often when they are under the influence of alcohol or other mind-altering substances and they are having sex with men while incarcerated and become infected and once released resume unprotected sexual relations with women. According to the men, substance abuse is an important part of the problem of HIV in the African-American community. This is in keeping with research that shows that drug use, especially crack cocaine, is linked to sexual risk taking among African Americans and to increased likelihood of becoming infected with other sexually transmitted diseases (STDs) including HIV. Thus, interventions for men should address condom use, condom availability, skills for using condoms, eroticizing condoms and substance abuse prevention. Men in the present study also strongly recommended that HIV/AIDS videotaped messages should include footage of the sensational effects of the disease.


Alternative reproductive tactics in female striped mice: Solitary breeders have lower corticosterone levels than communal breeders.
Alternative reproductive tactics (ARTs), where members of the same sex and population show distinct reproductive phenotypes governed by decision-rules, have been well-documented in males of many species, but are less well understood in females. The relative plasticity hypothesis (RPH) predicts that switches between plastic ARTs are mediated by changes in steroid hormones. This has received much support in males, but little is known about the endocrine control of female ARTs. Here, using a free-living population of African striped mice (Rhabdomys pumilio) over five breeding seasons, we tested whether females following different tactics differed in corticosterone and testosterone levels, as reported for male striped mice using ARTs, and in progesterone and oestrogen, which are important in female reproduction. Female striped mice employ three ARTs: communal breeders give birth in a shared nest and provide alloparental care, returners leave the group temporarily to give birth, and solitary breeders leave to give birth and do not return. We expected communal breeders and returners to have higher corticosterone, owing to the social stress of group-living, and lower testosterone than solitary breeders, which must defend territories alone. Solitary breeders had lower corticosterone than returners and communal breeders, as predicted, but testosterone and progesterone did not differ between ARTs. Oestrogen levels were higher in returners (measured before leaving the group) than in communal and solitary breeders, consistent with a modulatory role. Our study demonstrates hormonal differences between females following (or about to follow) different tactics, and provides the first support for the RPH in females.


Numerical simulation of speckle noise in laser vibrometry.
The fundamental mechanism by which speckle noise is generated in laser vibrometry before describing a new numerical simulation for prediction of speckle noise level in a real measurement is considered. Factors within the simulation include rate of change of phase within individual speckle transitions, low-pass filtering to match the frequency range of experimental data with which comparison is to be made, a track-and-hold facility for periods of low signal amplitude, and wavefront curvature effects. The simulation data provide real insight into the phase and amplitude modulation of the Doppler signal, and good agreement is found in the final comparison with experimental data from a measurement on a rotating target.


Vascular Contributions to Neurodegeneration: Protocol of the COMPASS-ND Study.
To describe the neuroimaging and other methods for assessing vascular contributions to neurodegeneration in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study, a Canadian multi-center, prospective longitudinal cohort study, including reliability and feasibility in the first 200 participants. COMPASS-ND includes persons with Alzheimer's disease (AD; n = 150), Parkinson's disease (PD) and Lewy body dementias (LBDs) (200), mixed dementia (200), mild cognitive impairment (MCI; 400), subcortical ischemic vascular MCI (V-MCI; 200), subjective cognitive impairment (SCI; 300), and cognitively intact elderly controls (660). Magnetic resonance imaging (MRI) was acquired according to the validated Canadian Dementia Imaging Protocol and visually reviewed by either of two experienced readers blinded to clinical characteristics. Other relevant assessments include history of vascular disease and risk factors, blood pressure, height and weight, cholesterol, glucose, and hemoglobin A1c. Analyzable data were obtained in 197/200 of whom 18 of whom were clinically diagnosed with V-MCI or mixed dementia. The overall prevalence of infarcts was 24.9%, microbleeds was 24.6%, and high white matter hyperintensity (WMH) was 31.0%. MRI evidence of a potential vascular contribution to neurodegeneration was seen in 12.9%-40.0% of participants clinically diagnosed with another condition such as AD. Inter-rater reliability was good to excellent. COMPASS-ND will be a useful platform to study vascular brain injury and its association with risk factors, biomarkers, and cognitive and functional decline across multiple age-related neurodegenerative diseases. Initial findings show that MRI-defined vascular brain injury is common in all cognitive syndromes and is under-recognized clinically.


Is it my cancer or am i just getting older?: Impact of cancer on age-related health conditions of older cancer survivors.
The extent to which cancer exacerbates or creates new health conditions is a long-standing, unanswered question. The current prospective study examined the short-term impact of cancer on the functioning, development of, and worsening of age-related health conditions among older adults who develop cancer compared with age-matched controls. Surveillance, Epidemiology, and End Results registry data were linked with Medicare Health Outcomes Survey (MHOS) data. A total of 921 eligible cases were Medicare beneficiaries with diagnosis of breast, colorectal, lung, or prostate cancer made between their baseline and follow-up MHOS. Using propensity score matching, 4605 controls without cancer were matched from the MHOS. Analysis of covariance and logistic regression were used to examine changes in physical functioning, activities of daily living, age-related conditions, and exacerbation of preexisting conditions for cases compared with controls. Cancer groups demonstrated greater declines in activities of daily living and physical function compared with controls (mean, -1.53 [standard error, 0.14]), with the greatest change noted for patients with lung cancer (mean, -6.72 [standard error, 0.94]). Having a cancer diagnosis increased the risk of depression but did not increase the odds of developing arthritis in the hand and/or hip, urinary incontinence (except for prostate cancer), or vision and/or hearing problems. Having a cancer diagnosis also did not exacerbate the severity of arthritis or foot neuropathy. The findings of the current study suggest that cancer is a stronger driver for declines in physical functioning and an increased risk of depression in older adults. Interventions are needed to decrease these risks. Clinicians need to prepare patients and families for changes in functioning levels and interventions that limit the declines for older patients with cancer are needed. Cancer 2016;122:1946-53. © 2016 American Cancer Society.


A high speed wavefront determination method based on spatial frequency modulations for focusing light through random scattering media.
A large number of degrees of freedom are required to produce a high quality focus through random scattering media. Previous demonstrations based on spatial phase modulations suffer from either a slow speed or a small number of degrees of freedom. In this work, a high speed wavefront determination technique based on spatial frequency domain wavefront modulations is proposed and experimentally demonstrated, which is capable of providing both a high operation speed and a large number of degrees of freedom. The technique was employed to focus light through a strongly scattering medium and the entire wavefront was determined in 400 milliseconds, ~three orders of magnitude faster than the previous report.


Effect of cinnamon oil on icaA expression and biofilm formation by Staphylococcus epidermidis.
Staphylococcus epidermidis is notorious for its biofilm formation on medical devices, and novel approaches to prevent and kill S. epidermidis biofilms are desired. In this study, the effect of cinnamon oil on planktonic and biofilm cultures of clinical S. epidermidis isolates was evaluated. Initially, susceptibility to cinnamon oil in planktonic cultures was compared to the commonly used antimicrobial agents chlorhexidine, triclosan, and gentamicin. The MIC of cinnamon oil, defined as the lowest concentration able to inhibit visible microbial growth, and the minimal bactericidal concentration, the lowest concentration required to kill 99.9% of the bacteria, were determined using the broth microdilution method and plating on agar. A checkerboard assay was used to evaluate the possible synergy between cinnamon oil and the other antimicrobial agents. The effect of cinnamon oil on biofilm growth was studied in 96-well plates and with confocal laser-scanning microscopy (CLSM). Biofilm susceptibility was determined using a metabolic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Real-time PCR analysis was performed to determine the effect of sub-MIC concentrations of cinnamon oil on expression of the biofilm-related gene, icaA. Cinnamon oil showed antimicrobial activity against both planktonic and biofilm cultures of clinical S. epidermidis strains. There was only a small difference between planktonic and biofilm MICs, ranging from 0.5 to 1% and 1 to 2%, respectively. CLSM images indicated that cinnamon oil is able to detach and kill existing biofilms. Thus, cinnamon oil is an effective antimicrobial agent to combat S. epidermidis biofilms.


Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments.
Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation into oligomers and tangles is considered an important pathological event in tauopathies, such as frontotemporal dementia (FTD) and Alzheimer's disease (AD). Tauopathies are also associated with deficits in synaptic plasticity such as long-term potentiation (LTP), but the specific role of tau in the manifestation of these deficiencies is not well-understood. We examined long lasting forms of synaptic plasticity in JNPL3 (BL6) mice expressing mutant tau that is identified in some inherited FTDs. We found that aged (>12 months) JNPL3 (BL6) mice exhibit enhanced hippocampal late-phase (L-LTP), while young JNPL3 (BL6) mice (age 6 months) displayed normal L-LTP. This enhanced L-LTP in aged JNPL3 (BL6) mice was rescued with the GABAAR agonist, zolpidem, suggesting a loss of GABAergic function. Indeed, we found that mutant mice displayed a reduction in hippocampal GABAergic interneurons. Finally, we also found that expression of mutant tau led to severe sensorimotor-gating and hippocampus-dependent memory deficits in the aged JNPL3 (BL6) mice. We show for the first time that hippocampal GABAergic function is impaired by pathological tau protein, leading to altered synaptic plasticity and severe memory deficits. Increased understanding of the molecular mechanisms underlying the synaptic failure in AD and FTD is critical to identifying targets for therapies to restore cognitive deficiencies associated with tauopathies.


A prospective observational study of the main features of nocturnal leg cramps in primary care.
There are few data available regarding the characteristics of nocturnal leg cramps in primary care. However, this condition is particularly common among older adults and often causes sleep disturbances, which can seriously affect quality of life. We aimed to investigate the main characteristics of nocturnal leg cramps occurring over a two-week period in patients visiting primary care physicians. This prospective observational study was conducted in western Switzerland from January 2015 until June 2016. Twenty primary care physicians were asked to recruit up to 20 consecutive patients over the age of 50 who had suffered from cramps in the previous three months. Patients completed a daily log during a two-week period, reporting the number and duration (in minutes) of their cramps. They also reported the severity of the cramps and their level of cramp-related sleep disturbance on a scale from 0 to 10. Crude and adjusted associations between the number of cramps and patient characteristics were computed using a generalised mixed effects model (Poisson). Of 550 consecutive patients, 233 agreed to be contacted for participation. Of these, 129 signed the consent to participation form and all completed the questionnaire and the daily log (men: 67%; mean age: 71 years; follow-up rate: 100%). Overall, 41% of patients were suffering from hypertension, 20% from dyslipidaemia, 19% from sleep disturbances and depression, and 6% from diabetes. Half the patients reported having already used a treatment against nocturnal leg cramps in the past, and 25% were currently using magnesium. Most of them also used medication for other health problems (mean number 3.7 per patient; psychotropic drugs: 36%). Patients had a median of two cramps per week, which were generally mild (median rating of 0.7 on a 10-point scale) and short (median: 0.4 min), leading to mild sleep disturbances (median rating of 0.8 on a 10-point scale). Multivariate analysis showed that older age and previous cramp treatment were associated with more cramps per day, while the use of magnesium and/or psychotropic drugs was associated with fewer cramps per day. Although nocturnal leg cramps are common among older patients in primary care, the disease burden of nocturnal leg cramps only appears to be severe in a minority of patients.


Novel and emerging drugs for chronic lymphocytic leukemia.
During the last decades advanced treatment options for chronic lymphocytic leukemia have enabled the shift from rather ineffective palliative treatment to therapies that are aiming for long lasting complete remission and prolongation of survival. This remarkable progress was achieved by combining conventional chemotherapy with monoclonal antibodies such as rituximab and alemtuzumab. Despite this improvement, CLL remains an incurable disease and all patients will eventually relapse and become refractory to treatment. Allogeneic stem cell transplantation is the only curative option but is feasible only in a minority of patients due to the comorbidity and impaired physical fitness of many patients, since the mean age at first diagnosis lies between 70 and 75 years. Therefore, novel less-toxic therapeutic agents are needed, particularly for patients with comorbidities or high-risk cytogenetic abnormalities. Research in the field of CLL and growing understanding of the pathogenesis of B-cell lymphomas has produced a wide variety of new substances for different targets, e.g. different novel monoclonal antibodies, immunomodulatory agents and inhibitors targeting different kinases of B-cell receptor signalling cascade, such as Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K). This article reviews novel drugs that were recently developed for the use in CLL. The agents discussed in this article were selected for having already shown preliminary evidence of clinical activity.


Genetic analysis of 63 mutations affecting maize kernel development isolated from Mutator stocks.
Sixty-three mutations affecting development of the maize kernel were isolated from active Robertson's Mutator (Mu) stocks. At least 14 previously undescribed maize gene loci were defined by mutations in this collection. Genetic mapping located 53 of these defective kernel (dek) mutations to particular chromosome arms, and more precise map determinations were made for 21 of the mutations. Genetic analyses identified 20 instances of allelism between one of the novel mutations and a previously described dek mutation, or between new dek mutations identified in this study; phenotypic variability was observed in three of the allelic series. Viability testing of homozygous mutant kernels identified numerous dek mutations with various pleiotropic effects on seedling and plant development. The mutations described here presumably arose by insertion of a Mu transposon within a dek gene; thus, many of the affected loci are expected to be accessible to molecular cloning via transposon-tagging.


Postnatal iron overload destroys NA-DA functional interactions.
C57/BL6 mice were administered either postnatal iron (Fe(2+) 7.5 mg/kg, on postnatal days 10-12) or vehicle, followed by administration of either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 mg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, iron/vehicle treated, DSP4/vehicle treated mice were injected with either a low dose of MPTP (2 x 20 mg/kg, with a 24-hr interval between injections) or vehicle. Behaviour testing took place a further three weeks (spontaneous behaviour and L-Dopa induced) and two weeks (clonidine-L-Dopa induced) later. Postnatal iron administration exacerbated the bradykinesia induced by MPTP and virtually abolished all spontaneous motor activity in NA-denervated mice that were MPTP-treated. Postnatal iron administration reduced markedly the restoration of motor activity by suprathreshold L-Dopa (20 mg/kg) following a 60-min habituation to the test chambers. Pretreatment with DSP4 effectively eliminated the restorative effect of L-Dopa in the MPTP mice. The synergistic effects of co-administration of clinidine (1 mg/kg) with a subthreshold dose of L-Dopa (5 mg/kg) in elevating the motor activity of MPTP mice were reduced markedly by postnatal iron administration, as well as by pretreatment with DSP4. NA-denervation by DSP4, after postnatal iron treatment, totally abolished the activity-elevating effects of the alpha-adrenoceptor agonist + DA-precursor combination in MPTP mice, and virtually eliminated these effects in saline (non-MPTP) mice. Postnatal iron administration caused enduring higher levels of total iron content in all the groups with an increased level in mice treated with DSP4 followed by MPTP. These divergent findings confirm the direct influence of NA innervation upon dopaminergic functional expression and indicate a permanent vulnerability both in the noradrenergic and dopaminergic pathways following the postnatal infliction of an iron overload.


Application of computer-aided diagnosis for Lung-RADS categorization in CT screening for lung cancer: effect on inter-reader agreement.
To evaluate the effects of computer-aided diagnosis (CAD) on inter-reader agreement in Lung Imaging Reporting and Data System (Lung-RADS) categorization. Two hundred baseline CT scans covering all Lung-RADS categories were randomly selected from the National Lung Cancer Screening Trial. Five radiologists independently reviewed the CT scans and assigned Lung-RADS categories without CAD and with CAD. The CAD system presented up to five of the most risk-dominant nodules with measurements and predicted Lung-RADS category. Inter-reader agreement was analyzed using multirater Fleiss κ statistics. The five readers reported 139-151 negative screening results without CAD and 126-142 with CAD. With CAD, readers tended to upstage (average, 12.3%) rather than downstage Lung-RADS category (average, 4.4%). Inter-reader agreement of five readers for Lung-RADS categorization was moderate (Fleiss kappa, 0.60 [95% confidence interval, 0.57, 0.63]) without CAD, and slightly improved to substantial (Fleiss kappa, 0.65 [95% CI, 0.63, 0.68]) with CAD. The major cause for disagreement was assignment of different risk-dominant nodules in the reading sessions without and with CAD (54.2% [201/371] vs. 63.6% [232/365]). The proportion of disagreement in nodule size measurement was reduced from 5.1% (102/2000) to 3.1% (62/2000) with the use of CAD (p < 0.001). In 31 cancer-positive cases, substantial management discrepancies (category 1/2 vs. 4A/B) between reader pairs decreased with application of CAD (pooled sensitivity, 85.2% vs. 91.6%; p = 0.004). Application of CAD demonstrated a minor improvement in inter-reader agreement of Lung-RADS category, while showing the potential to reduce measurement variability and substantial management change in cancer-positive cases. • Inter-reader agreement of five readers for Lung-RADS categorization was minimally improved by application of CAD, with a Fleiss kappa value of 0.60 to 0.65. • The major cause for disagreement was assignment of different risk-dominant nodules in the reading sessions without and with CAD (54.2% vs. 63.6%). • In 31 cancer-positive cases, substantial management discrepancies between reader pairs, referring to a difference in follow-up interval of at least 9 months (category 1/2 vs. 4A/B), were reduced in half by application of CAD (32/310 to 16/310) (pooled sensitivity, 85.2% vs. 91.6%; p = 0.004).


Enhanced target-specific delivery of docetaxel-loaded nanoparticles using engineered T cell receptors.
For effective targeted therapy of cancer with chemotherapy-loaded nanoparticles (NPs), antigens that are selective for cancer cells should be targeted to minimise off-tumour toxicity. Human leukocyte antigens (HLAs) are attractive cancer targets as they can present peptides from tumour-selective proteins on the cell surface, which can be recognised by T cells via T cell receptors (TCRs). In this study, docetaxel-loaded polymeric NPs were conjugated to recombinant affinity-enhanced TCRs to target breast cancer cells presenting a tumour-selective peptide-HLA complex. The TCR-conjugated nanoparticles enabled enhanced delivery of docetaxel and induced cell death through tumour-specific peptide-HLA targeting. These in vitro data demonstrate the potential of targeting tumour-restricted peptide-HLA epitopes using high affinity TCR-conjugated nanoparticles, representing a novel treatment strategy to deliver therapeutic drugs specifically to cancer cells.


MicroRNA-7a2 Regulates Prolactin in Developing Lactotrophs and Prolactinoma Cells.
Prolactin production is controlled by a complex and temporally dynamic network of factors. Despite this tightly coordinated system, pathological hyperprolactinemia is a common endocrine disorder that is often not understood, thereby highlighting the need to expand our molecular understanding of lactotroph cell regulation. MicroRNA-7 (miR-7) is the most highly expressed miRNA family in the pituitary gland and the loss of the miR-7 family member, miR-7a2, is sufficient to reduce prolactin gene expression in mice. Here, we used conditional loss-of-function and gain-of-function mouse models to characterize the function of miR-7a2 in lactotroph cells. We found that pituitary miR-7a2 expression undergoes developmental and sex hormone-dependent regulation. Unexpectedly, the loss of mir-7a2 induces a premature increase in prolactin expression and lactotroph abundance during embryonic development, followed by a gradual loss of prolactin into adulthood. On the other hand, lactotroph development is delayed in mice overexpressing miR-7a2. This regulation of lactotroph function by miR-7a2 involves complementary mechanisms in multiple cell populations. In mouse pituitary and rat prolactinoma cells, miR-7a2 represses its target Raf1, which promotes prolactin gene expression. These findings shed light on the complex regulation of prolactin production and may have implications for the physiological and pathological mechanisms underlying hyperprolactinemia.


Dual Color Sensors for Simultaneous Analysis of Calcium Signal Dynamics in the Nuclear and Cytoplasmic Compartments of Plant Cells.
Spatiotemporal changes in cellular calcium (Ca2+) concentrations are essential for signal transduction in a wide range of plant cellular processes. In legumes, nuclear and perinuclear-localized Ca2+ oscillations have emerged as key signatures preceding downstream symbiotic signaling responses. Förster resonance energy transfer (FRET) yellow-based Ca2+ cameleon probes have been successfully exploited to measure the spatiotemporal dynamics of symbiotic Ca2+ signaling in legumes. Although providing cellular resolution, these sensors were restricted to measuring Ca2+ changes in single subcellular compartments. In this study, we have explored the potential of single fluorescent protein-based Ca2+ sensors, the GECOs, for multicolor and simultaneous imaging of the spatiotemporal dynamics of cytoplasmic and nuclear Ca2+ signaling in root cells. Single and dual fluorescence nuclear and cytoplasmic-localized GECOs expressed in transgenic Medicago truncatula roots and Arabidopsis thaliana were used to successfully monitor Ca2+ responses to microbial biotic and abiotic elicitors. In M. truncatula, we demonstrate that GECOs detect symbiosis-related Ca2+ spiking variations with higher sensitivity than the yellow FRET-based sensors previously used. Additionally, in both M. truncatula and A. thaliana, the dual sensor is now able to resolve in a single root cell the coordinated spatiotemporal dynamics of nuclear and cytoplasmic Ca2+ signaling in vivo. The GECO-based sensors presented here therefore represent powerful tools to monitor Ca2+ signaling dynamics in vivo in response to different stimuli in multi-subcellular compartments of plant cells.


An approach for particle sinking velocity measurements in the 3-400 μm size range and considerations on the effect of temperature on sinking rates.
The flux of organic particles below the mixed layer is one major pathway of carbon from the surface into the deep ocean. The magnitude of this export flux depends on two major processes-remineralization rates and sinking velocities. Here, we present an efficient method to measure sinking velocities of particles in the size range from approximately 3-400 μm by means of video microscopy (FlowCAM®). The method allows rapid measurement and automated analysis of mixed samples and was tested with polystyrene beads, different phytoplankton species, and sediment trap material. Sinking velocities of polystyrene beads were close to theoretical values calculated from Stokes' Law. Sinking velocities of the investigated phytoplankton species were in reasonable agreement with published literature values and sinking velocities of material collected in sediment trap increased with particle size. Temperature had a strong effect on sinking velocities due to its influence on seawater viscosity and density. An increase in 9 °C led to a measured increase in sinking velocities of ~40 %. According to this temperature effect, an average temperature increase in 2 °C as projected for the sea surface by the end of this century could increase sinking velocities by about 6 % which might have feedbacks on carbon export into the deep ocean.


The role of integrins in glioma biology and anti-glioma therapies.
The tumor environment is critical for tumor maintenance and progression. Integrins are a large family of cell surface receptors mediating the interaction of tumor cells with their microenvironment and play important roles in glioma biology, including migration, invasion, angiogenesis and tumor stem cell anchorage. Here, we review preclinical and clinical data on integrin inhibition in malignant gliomas. Various pharmacological approaches to the modulation of integrin signaling have been explored including antibodies and peptide-based agents. Cilengitide, a cyclic RGD-mimetic peptide of αvβ3 and αvβ5 integrins is in advanced clinical development in glioblastoma. Cilengitide had only limited activity as a single agent in glioblastoma, but, when added to standard radiochemotherapy, appeared to prolong progression-free and overall survival in patients with newly diagnosed glioblastomas and methylation of the promoter of the O⁶ methylguanine methyltransferase (MGMT) gene. MGMT gene promoter methylation in turn predicts benefit from alkylating chemotherapy. A phase III randomized clinical trial in conjunction with standard radiochemotherapy in newly diagnosed glioblastoma patients with MGMT gene promoter methylation has recently completed accrual (EORTC 26071-22072). A companion trial explores a dose-escalated regimen of cilengitide added to radiotherapy plus temozolomide in patients without MGMT gene promoter methylation. Promising results in these trials would probably result in a broader interest in integrins as targets for glioma therapy and hopefully the development of a broader panel of anti-integrin agents.


DreamTel; Diabetes risk evaluation and management tele-monitoring study protocol.
The rising prevalence of type 2 diabetes underlines the importance of secondary strategies for the prevention of target organ damage. While access to diabetes education centers and diabetes intensification management has been shown to improve blood glucose control, these services are not available to all that require them, particularly in rural and northern areas. The provision of these services through the Home Care team is an advance that can overcome these barriers. Transfer of blood glucose data electronically from the home to the health care provider may improve diabetes management. The study population will consist of patients with type 2 diabetes with uncontrolled A1c levels living on reserve in the Battlefords region of Saskatchewan, Canada. This pilot study will take place over three phases. In the first phase over three months the impact of the introduction of the Bluetooth enabled glucose monitor will be assessed. In the second phase over three months, the development of guidelines based treatment algorithms for diabetes intensification will be completed. In the third phase lasting 18 months, study subjects will have diabetes intensification according to the algorithms developed. The first phase will determine if the use of the Bluetooth enabled blood glucose devices which can transmit results electronically will lead to changes in A1c levels. It will also determine the feasibility of recruiting subjects to use this technology. The rest of the Diabetes Risk Evaluation and Management Tele-monitoring (DreamTel) study will determine if the delivery of a diabetes intensification management program by the Home Care team supported by the Bluetooth enabled glucose meters leads to improvements in diabetes management. Protocol NCT00325624.


Bevacizumab added to neoadjuvant chemotherapy for breast cancer.
Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response. We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy. The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects--specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis. The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.).


The effect of Wolbachia on gene expression in Drosophila paulistorum and its implications for symbiont-induced host speciation.
The Neotropical fruit fly Drosophila paulistorum (Diptera: Drosophilidae) is a species complex in statu nascendi comprising six reproductively isolated semispecies, each harboring mutualistic Wolbachia strains. Although wild type flies of each semispecies are isolated from the others by both pre- and postmating incompatibilities, mating between semispecies and successful offspring development can be achieved once flies are treated with antibiotics to reduce Wolbachia titer. Here we use RNA-seq to study the impact of Wolbachia on D. paulistorum and investigate the hypothesis that the symbiont may play a role in host speciation. For that goal, we analyze samples of heads and abdomens of both sexes of the Amazonian, Centro American and Orinocan semispecies of D. paulistorum. We identify between 175 and 1192 differentially expressed genes associated with a variety of biological processes that respond either globally or according to tissue, sex or condition in the three semispecies. Some of the functions associated with differentially expressed genes are known to be affected by Wolbachia in other species, such as metabolism and immunity, whereas others represent putative novel phenotypes involving muscular functions, pheromone signaling, and visual perception. Our results show that Wolbachia affect a large number of biological functions in D. paulistorum, particularly when present in high titer. We suggest that the significant metabolic impact of the infection on the host may cause several of the other putative and observed phenotypes. We also speculate that the observed differential expression of genes associated with chemical communication and reproduction may be associated with the emergence of pre- and postmating barriers between semispecies, which supports a role for Wolbachia in the speciation of D. paulistorum.


Embryotoxicity of mirtazapine: a study using Chick Embryotoxicity Screening Test.
Mirtazapine is a new antidepressant used in last years, however experience with it during pregnancy is unsatisfactory on the present. Its wide therapeutic range and only little proved side effects may be an advantage for treatment during pregnancy. Aim of our study was to contribute to the knowledge on possible risks. For embryotoxicity testing we used an alternative method - CHEST, that used chicken embryos as experimental model. Fertilized eggs of outbred Grey Leghorn stock (AVČR farm Koleč) were treated on embryonic day (ED) 4 by Mirtazapine, incubated till 9ED, when they were weighed and examined. Summing the proportions of dead and malformed embryos, the beginning of the embryotoxicity dose range was estimated. Mirtazapine solved in 15% DMSO in water revealed low embryotoxicity corresponding data from preclinical studies. If 100% DMSO was used as a solvent, the dose 0.05 μg/3 μL resulted in 57% mortality (LD50). Typical malformations were microphtalmia and malformation (shortening) of limbs on left side, which is a place of contact the embryonic body with maximal Mirtazapine concentration. Approximation of doses in chick embryos to mammals is complicated by low solubility of mirtazapine. If the embryotoxic dose was close to LD50, risk at therapeutical doses will be probably low. Mirtazapine according to results of testing and cases published in literature is relatively safe for pregnant women, only higher rate of abortions was demonstrated, however more information is needed to exclude all potential risks.


[Turkish Hypertension Consensus Report].
Hypertension is a common and important public health problem in Turkey and worldwide. Recommendations on the diagnosis and treatment of hypertension have been presented in many nationally and internationally agreed European and American guidelines. However, there are differences among these guidelines, and some of the recommendations are not consistent with clinical practice in our country. Consensus report preparation, with the participation of relevant associations, was considered necessary to merge recommendations by evaluating hypertension guidelines from the perspective of Turkey and to create a joint approach in the diagnosis and treatment of hypertension in adults. For this purpose, it was aimed to prepare a practical text in Turkey in which all physicians dealing with hypertensive patients, from family practitioners in primary care to specialists in tertiary care, could come to agreement on common concepts, and which would be used as a basic reference guideline. Considering health care practices and sociocultural structure in Turkey, this report aimed to enhance awareness on hypertension, provide a common basis for different definitions and values as well as therapeutic options in various guidelines, and establish a practical reference guide to improve clinical practices in Turkey. This report is not a document describing hypertension in every aspect, but a reference, including basic recommendations with outlines. Care was taken to ensure that recommendations were evidence-based and valid for a majority of patients in clinical practice. However, it should be kept in mind that an approach assessment should be made on an individual basis for each patient.


Measles associated with international travel in the region of the Americas, Australia and Europe, 2001-2013: a systematic review.
Travel volumes are still increasing resulting in a more interconnected world and fostering the spread of infectious diseases. We aimed to evaluate the relevance of travel-related measles, a highly transmissible and vaccine-preventable disease. Between 2001 and 2013, surveillance and travel-related measles data were systematically reviewed according to the PRISMA guidelines with extraction of relevant articles from Medline, Embase, GoogleScholar and from public health authorities in the Region of the Americas, Europe and Australia. From a total of 960 records 44 articles were included and they comprised 2128 imported measles cases between 2001 and 2011. The proportion of imported cases in Europe was low at 1-2%, which reflects the situation in a measles-endemic region. In contrast, imported and import-related measles accounted for up to 100% of all cases in regions with interrupted endemic measles transmission. Eleven air-travel related reports described 132 measles index cases leading to 47 secondary cases. Secondary transmission was significantly more likely to occur if the index case was younger or when there were multiple infectious cases on board. Further spread to health care settings was found. Measles cases associated with cruise ship travel or mass gatherings were sporadically observed. Within both, endemic and non-endemic home countries, pretravel health advice should assess MMR immunity routinely to avoid measles spread by nonimmune travelers. To identify measles spread as well as to increase and sustain high vaccination coverages joint efforts of public health specialists, health care practitioners and travel medicine providers are needed.