Effects of Beetroot Juice Ingestion on Physical Performance in Highly Competitive Tennis Players.
Beetroot juice (BJ) contains high levels of inorganic nitrate (NO3-) and its intake has good evidence in increasing blood nitrate/nitrite concentrations. The ingestion of BJ has been associated with improvements in physical performance of endurance sports, however the literature in intermittent sports is scarce. The aim of this study was to investigate whether BJ could improve physical performance in tennis players. Thirteen well-trained tennis players (25.4 ± 5.1 years) participated in the study during their preparatory period for the tennis season. Subjects were randomly divided into two groups and performed a neuromuscular test battery after either BJ or placebo (PLA) consumption. Both trials were executed on two separate days, in randomized order, with one week of wash out period. The test battery consisted of serve velocity test (SVT), countermovement jump (CMJ), isometric handgrip strength (IHS), 5-0-5 agility test (5-0-5), and 10 m sprint (10-m). No significant differences were found in SVT (1.19%; p = 0.536), CMJ (0.96%; p = 0.327), IHS (4.06%; p = 0.069), 5-0-5 dominant and nondominant side (1.11-2.02%; p = 0.071-0.191) and 10-m (1.05%; p = 0.277) when comparing BJ and PLA ingestion. Thus, our data suggest that low doses of BJ (70 mL) consumption do not enhance tennis physical performance.


Dorsal column stimulation. Its effect on the somatosensory evoked response.
Several authors have shown that dorsal column stimulation (DCS) modifies appreciation of pain. We studied the effects of DCS on the somatosensory evoked response (SER) in six subjects. Somatosensory evoked responses to stimulation of the tibial nerve and effects of varying frequencies and intensities of DCS on SER components were recorded. During DCS there was attenuation of late SER components with little effect on early components. Stimulus intensities greater than necessary to relieve pain suppressed all SER components. Our findings suggest that the minimal effective DCS variables to relieve pain are those that produce selective suppression of late SER components.


Application of Mesoporous Silica Nanoparticle-Chitosan-Loaded BMP-2 in the Repair of Bone Defect in Chronic Osteomyelitis.
In order to test the effectiveness of nanoparticle- (NP-) loaded bone morphogenetic protein 2 (BMP-2) in chronic osteomyelitis (CO) complicated with bone defect, a new nanodrug delivery system composed of mesoporous silica NP (MSN) and chitosan were used to load BMP-2 and transfer it to the target region. Bone marrow mesenchymal stem cells (BMSCs) were purchased and cultivated to detect the osteogenesis of chitosan-MSN (Chi-MSN) and polylactic acid glycolic acid (PLGA) delivery system. In addition, the osteogenesis of Chi-MSN was further determined by constructing a bone defect mouse model. In physicochemical property test, we found Chi-MSN NPs could effectively maintain stability in vivo and had pH response characteristics. As a result, the release efficiency of dexamethasone (Dex) and BMP-2 in the environment with pH 7.4 was less, while it increased significantly in pH 6, so as to reduce the BMP-2 and Dex loss during transportation in vivo. Otherwise, we found that the permeation efficiency of Chi-MSN was significantly higher than that of PLGA delivery system, so as to effectively transport BMP-2 and Dex to action target. In the BMSC test, we found that Chi-MSN could better promote their activity and osteogenesis, and the expression of osteogenesis-related genes (runt-related transcription factor 2 (RUNX-2), osteopontine (OPN), alkaline phosphatase (ALP), and osteopontine (OCN)) in the Chi-MSN group was higher. In the bone defect mouse model test, we also found obviously increased bone trabecula number and thickness by Chi-MSN, contributing to better repair of bone defects. Therefore, BMP-2@Chi-MSN may be a better choice for the therapy of CO complicated with bone defect in the future.


Gene therapy for gastrointestinal tract cancer: a review.
Carcinomas of the gastrointestinal tract count as one of the most common causes of cancer-related death in the world. Despite improvement of conventional treatment modalities, the prognosis of patients with gastrointestinal tract cancer remains poor. Progress in understanding the molecular mechanism of gastrointestinal carcinogenesis may facilitate development of gene therapy strategies for the treatment of gastrointestinal tumors. This review describes new developments in vectors (tools for gene transfer) for gene therapy, possible therapeutic genes and the early clinical results of gastrointestinal tract cancer gene therapy. Results of current preclinical studies are promising for the future clinical application of gene therapy for gastrointestinal cancer. The first clinical trials have been initiated recently, the preliminary results reflecting low toxicity and clinical responses. Further clinical studies will be required to confirm the feasibility of gene therapy in the treatment of gastrointestinal cancer. In future, the greatest potential will probably lie in the field of combination strategies of gene therapy and existing treatment modalities, such as surgery combined with molecular chemotherapy.


Evaluation of mucoadhesive property and the effect of Boswellia carteri gum on intranasal vaccination against small ruminant morbillivirus infection (PPR).
A study was conducted to evaluate mucoadhesive property and immunomodulatory effect of phytogenic gums from Boswellia frereana, Boswellia carteri andCommiphora myrrha on intranasal Peste des petits ruminants (PPR) vaccination in goats and sheep in an ex-vivo and in-vivo situations. Plant gums were purified, dried and compressed into 500gm tablets. Modified shear stress measurement technique was used on freshly excised trachea and intestine tissues of goat to measure peak adhesion time. Forty eight animals (24 goats and 24 sheep) were divided into eight groups (of 3 goats and 3 sheep) and immunized intranasally with gum-vaccine combinations in two ratios (1:1, 1:2). Antibody against PPR virus was measured on day 14, 28, 42 and 56 post vaccination using H-based PPR bELISA. The peak adhesion time of the different gums was transient. PPR virus antibodies were detected in all immunized goats and sheep but not in unvaccinated control. The best percentage inhibition was recorded for Boswellia carteri-vaccine combination group at a ratio of 1:1. Administration of Boswellia carteri-PPR vaccine combination through intranasal or subcutaneous route, elicited similar antibody titre, implying that the intranasal route may be used as a non-invasive alternative delivery in PPR vaccination of small ruminants.


Natural genetic variation in selected populations of Arabidopsis thaliana is associated with ionomic differences.
Controlling elemental composition is critical for plant growth and development as well as the nutrition of humans who utilize plants for food. Uncovering the genetic architecture underlying mineral ion homeostasis in plants is a critical first step towards understanding the biochemical networks that regulate a plant's elemental composition (ionome). Natural accessions of Arabidopsis thaliana provide a rich source of genetic diversity that leads to phenotypic differences. We analyzed the concentrations of 17 different elements in 12 A. thaliana accessions and three recombinant inbred line (RIL) populations grown in several different environments using high-throughput inductively coupled plasma- mass spectroscopy (ICP-MS). Significant differences were detected between the accessions for most elements and we identified over a hundred QTLs for elemental accumulation in the RIL populations. Altering the environment the plants were grown in had a strong effect on the correlations between different elements and the QTLs controlling elemental accumulation. All ionomic data presented is publicly available at www.ionomicshub.org.


A parsimony approach to analysis of human segmental duplications.
Segmental duplications are abundant in the human genome, but their evolutionary history is not well-understood. The mystery surrounding them is due in part to their complex organization; many segmental duplications are mosaic patterns of smaller repeated segments, or duplicons. A two-step model of duplication has been proposed to explain these mosaic patterns. In this model, duplicons are copied and aggregated into primary duplication blocks that subsequently seed secondary duplications. Here, we formalize the problem of computing a duplication scenario that is consistent with the two-step model. We first describe a dynamic programming algorithm to compute the duplication distance between two strings. We then use this distance as the cost function in an integer linear program to obtain the most parsimonious duplication scenario. We apply our method to derive putative ancestral relationships between segmental duplications in the human genome.


Association of complementary and alternative medicines with HIV clinical disease among a cohort of women living with HIV/AIDS.
To assess the association between the use of complementary and alternative medicine (CAM) and HIV clinical disease indicators, CD4+ T-cell counts, viral load, number of HIV-related infections, Centers for Disease Control and Prevention categories, and Karnofsky scores. Data were collected from 391 HIV-positive women aged 18 to 50 years in Alabama and Georgia. A survey examining CAM use and other sociodemographic variables was used. Multiple logistic regression analyses were used to identify predictors of CAM use. Approximately 60% of study participants used 1 or more type of CAM. Predictors of CAM use included higher educational level (odds ratio [OR] = 2.4; P = 0.0008), absence of health insurance (OR = 0.49; P = 0.0055), longer disease duration (OR = 2.21; P = 0.0006), and higher number of infections (OR = 0.58; P = 0.017). Vitamins were the most commonly used CAM ( approximately 36%). Sociodemographic variables associated with vitamin use included higher educational level (OR = 2.34; P = 0.0055), longer disease duration (OR = 1.87; P = 0.026), and higher use among white women than among African-American women (OR = 0.41; P = 0.017). The use of CAM is prevalent among HIV-positive women, and vitamins are the most commonly used CAM among our study population. Several sociodemographic and clinical factors predicted CAM use. These findings have implications for improvement of care for HIV-positive women.


[Contribution to knowledge about the permanence and circulation of poliovirus vaccine in the environment].
The erradication of poliomyelitis in the world is a goal that requires the adoption of effective and safe strategies for its attainment. Knowing how long the strains of poliovirus derived from the oral attenuated virus vaccine may circulate and remain in the environment was essential to define the measures to be taken and was also the objective of our paper. Specimens of stools and sewage water, which were weekly obtained at the end of the National Polio Vaccination Campaign, in 1998, were analyzed. Viruses were isolated and identified by culture and neutralization tests for the identification of poliovirus. In the particular case of the sewage water, it was also used the polymerase chain reaction. The curves of elimination in both media were drawn and it was concluded that the permanence of viruses in the environment did not exceed the 12 weeks after the immunization with the oral attenuated virus vaccine.


[Local Application of Tranexamic Acid in Total Hip Arthroplasty Decreases Blood Loss and Consumption of Blood Transfusion].
PURPOSE OF THE STUDY The primary aim of our study was to identify the effects of local application of tranexamic acid (TXA, Exacyl) on the amount of postoperative blood loss and blood transfusion requirement in primary total hip arthroplasty. We also recorded the levels of postoperative haemoglobin and its drop in early period after surgery. In each patient, we monitored in detail the incidence of early complications (haematoma, wound exudate). Lastly, the economic aspect of TXA administration was also taken into account. MATERIAL AND METHODS The prospective study included a total of 312 patients (122 men and 190 women) undergoing primary total hip arthroplasty (THA) at our department between January 2012 and November 2015. The patients enrolled in the study were divided into the intervention group with local (intra-articular) application of TXA and the control group without using TXA. Each group had 156 patients. The mean age of patients in the group with TXA was 65.6 years and the most frequent indication for THA surgery was primary osteoarthritis (59.0 %). The groups did not show any differences in basic characteristics, which was statistically verified. In each patient the volume of postoperative drainage, total blood loss, including the hidden loss, was recorded. In postoperative period, we monitored the haemoglobin levels and haematocrit. On discharge of each patient from the hospital, the size and site of a haematoma, wound exudate if still present even after postoperative day 4 and early surgical revision were evaluated. RESULTS In the group with TXA the blood losses from drains were significantly lower compared to the control group (493.4 ± 357.1 ml vs. 777.3 ± 382.5 ml; p < 0.0001). The median value for total blood loss (i.e. drainage volume and hidden loss) in the group with TXA was by 29.5 % lower than the median in the group without TXA (689.2 vs. 977.1 ml). The mean total blood loss (intraoperative + postoperative) was 783.8 ± 478.6 ml (mean ± standard deviation) in the patients with TXA and 1079.7 ± 487.1 ml in the second group without TXA. The difference in the total blood loss volume was significant (p < 0.0001). In the group with TXA the consumption of blood transfusion was significantly lower by 50 % (20 vs. 40 units), (p = 0.0004). The patients with TXA also reported a significantly lower consumption of allogeneic blood (p = 0.004), a higher level of postoperative haemoglobin (p < 0.0001) and a lower mean drop of haemoglobin (p < 0.0001). We did not observe any significant differences in the incidence of haematomas (p = 0.644). No higher volume of wound drainage and joint swelling after postoperative day 4 in patients with TXA was found (p = 0.565; p = 0.242). The TXA group did not show a higher rate of surgical revision (p = 1.000). The total economic costs of blood transfusion requirements were significantly lower in the TXA group than in the control group (p = 0.004), including consumption of autologous transfusions and blood salvage (p < 0.0001). DISCUSSION The main effect of the local application of TXA is to reduce bleeding which should result in lower postoperative blood loss and consumption of allogenic blood transfusion. The advantage of the local application of TXA is its easy application and maximum concentration of TXA at the surgical site. In addition, a potential harm associated with a systemic administration of a higher TXA dose is reduced because of only minimal TXA resorption into the circulation. According to a number of recent studies, the local application of TXA achieves comparable results to its intravenous application. The economic benefit of TXA intervention is also worth considering. CONCLUSIONS The local application of TXA is an effective and, simultaneously, safe method to reduce perioperative blood loss and consumption of blood transfusions and also to decrease the costs of hospital stay in the patients after THA. Another advantage of the local application is the need to administer one dose only, whereas at least two doses need to be administered intravenously in order to achieve the same effect. No significant complications were observed in the patients with TXA. According to the recent literature, it is therefore appropriate to include the local application of TXA among the recommended procedures for THA, as is the case in total knee arthroplasty. Key words: tranexamic acid, local application, blood loss, hidden blood loss, THA, total hip arthroplasty, complications.


Aperture size effect on ultrasonic wavefront distortion correction.
The influences of aperture size on wavefront distortion correction are investigated both theoretically and numerically. A multilayer, phase-screen model is assumed to be the underlying, distorting medium. Numerical simulations were performed using three wavefront distortion correction methods: time-shift compensation (TSC), backpropagation followed by time-shift compensation (BP+TSC), and the previously proposed, multilayer, phase-screen compensation (MPSC) method. The distorted wavefronts were generated by propagating a planar wavefront through a multilayer, phase-screen model constructed with a two-dimensional (2-D) scanned map of a real abdominal slice. Performances were evaluated by L2 errors between the corrected wavefronts and the undistorted planar wavefront. Point spread functions also were calculated to evaluate the relative image quality. Theoretical analysis shows L2 error will decrease as aperture size grows when exact phase compensation (EPC) is applied, although finite errors will always exist along the edges of the corrected wavefront. Three different aperture sizes, 14.24 mm (64 elements), 28.48 mm (128 elements), and 56.96 mm (256 elements) are considered in this study. Numerical results show that the quality of wavefront with EPC is essentially limited by the aperture size, and the correction methods considered are relatively robust against the aperture size. It also shows that, for low aberration, results with MPSC and EPC are comparable. However, for high aberration, MPSC significantly outperforms EPC in suppression of L2 error and sidelobes. This study suggests that, for most medical ultrasound imaging systems, the exact structure of the distorting medium may not be necessary to be known a priori for optimal distortion correction because of the limitation imposed by finite aperture size.


A phase III, randomized, two-armed, double-blind, parallel, active controlled, and non-inferiority clinical trial to compare efficacy and safety of biosimilar adalimumab (CinnoRA®) to the reference product (Humira®) in patients with active rheumatoid arthritis.
This study aimed to compare efficacy and safety of test-adalimumab (CinnoRA®, CinnaGen, Iran) to the innovator product (Humira®, AbbVie, USA) in adult patients with active rheumatoid arthritis (RA). In this randomized, double-blind, active-controlled, non-inferiority trial, a total of 136 patients with active RA were randomized to receive 40 mg subcutaneous injections of either CinnoRA® or Humira® every other week, while receiving methotrexate (15 mg/week), folic acid (1 mg/day), and prednisolone (7.5 mg/day) over a period of 24 weeks. Physical examinations, vital sign evaluations, and laboratory tests were conducted in patients at baseline and at 12-week and 24-week visits. The primary endpoint in this study was the proportion of patients achieving moderate and good disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR)-based European League Against Rheumatism (EULAR) response. The secondary endpoints were the proportion of patients achieving American College of Rheumatology (ACR) criteria for 20% (ACR20), 50% (ACR50), and 70% (ACR70) responses along with the disability index of health assessment questionnaire (HAQ), and safety. Patients who were randomized to CinnoRA® or Humira® arms had comparable demographic information, laboratory results, and disease characteristics at baseline. The proportion of patients achieving good and moderate EULAR responses in the CinnoRA® group was non-inferior to the Humira® group at 12 and 24 weeks based on both intention-to-treat (ITT) and per-protocol (PP) populations (all p values >0.05). No significant difference was noted in the proportion of patients attaining ACR20, ACR50, and ACR70 responses in the CinnoRA® and Humira® groups (all p values >0.05). Further, the difference in HAQ scores and safety outcome measures between treatment arms was not statistically significant. CinnoRA® was shown to be non-inferior to Humira® in terms of efficacy at week 24 with a comparable safety profile to the reference product. IRCT.ir, IRCT2015030321315N1 . Registered on 5 April 2015.


[Profile of Primary Health Care managers in small municipalities in the north of the state of Paraná, Brazil].
The scope of this article was to establish the profile of Primary Health Care (PHC) managers in 49 small municipalities (up to 20,000 inhabitants) in the north of the state of Paraná. A semi-structured questionnaire was applied to 90 managers in a quantitative-based study. For statistical analysis the EpiInfo 3.5.1. program was used. The results of the manager profile showed that 91.1% were women, 83.3% nurses, 50% aged 21 to 30 years and 75.6% with specialization. Concerning the entry into employment, 70% were through public exam/selective test. Regarding professional experience, 40% had worked professionally for more than 5 years, 43.4% had been involved in PHC up to 5 years and 32.2% had been in the current primary health care unit for less than 1 year. Regarding specific training for performing a managerial role, 71.1% had not taken any courses; only 23.3% reported having taken a management course, though 37.7% had already acted as managers. The conclusion reached is that there is a lack of professionalism, training and institutionalization of the position for the performance of this function.


Postnatal Gut Immunity and Microbiota Development Is Minimally Affected by Prenatal Inflammation in Preterm Pigs.
Chorioamnionitis (CA), resulting from intra-amniotic inflammation, is a frequent cause of preterm birth and exposes the immature intestine to bacterial toxins and/or inflammatory mediators before birth via fetal swallowing. This may affect intestinal immune development, interacting with the effects of enteral feeding and gut microbiota colonization just after birth. Using preterm pigs as model for preterm infants, we hypothesized that prenatal exposure to gram-negative endotoxin influences postnatal bacterial colonization and gut immune development. Pig fetuses were given intra-amniotic lipopolysaccharide (LPS) 3 days before preterm delivery by cesarean section and were compared with littermate controls (CON) at birth and after 5 days of formula feeding and spontaneous bacterial colonization. Amniotic fluid was collected for analysis of leukocyte counts and cytokines, and the distal small intestine was analyzed for endotoxin level, morphology, and immune cell counts. Intestinal gene expression and microbiota were analyzed by transcriptomics and metagenomics, respectively. At birth, LPS-exposed pigs showed higher intestinal endotoxin, neutrophil/macrophage density, and shorter villi. About 1.0% of intestinal genes were affected at birth, and DMBT1, a regulator of mucosal immune defense, was identified as the hub gene in the co-expression network. Genes related to innate immune response (TLR2, LBP, CD14, C3, SFTPD), neutrophil chemotaxis (C5AR1, CSF3R, CCL5), and antigen processing (MHC II genes and CD4) were also affected, and expression levels correlated with intestinal neutrophil/macrophage density and amniotic fluid cytokine levels. On day 5, LPS and CON pigs showed similar sensitivity to necrotizing enterocolitis, endotoxin levels, morphology, immune cell counts, gene expressions, and microbiota composition (except for difference in some low-abundant species). Our results show that CA markedly affects intestinal genes at preterm birth, including genes related to immune cell infiltration. However, a few days later, following the physiological adaptations to preterm birth, CA had limited effects on intestinal structure, function, gene expression, bacterial colonization, and necrotizing enterocolitis sensitivity. We conclude that short-term, prenatal intra-amniotic inflammation is unlikely to exert marked effects on intestinal immune development in preterm neonates beyond the immediate neonatal period.


C. L. Oakley Lecture (1991). Cell adhesion and epithelial differentiation.
The differentiated function of epithelial tissues is dependent on the molecules which mediate the cohesion and polarization of the epithelium. Separate molecular families are responsible for the adhesion between adjacent cells and the adhesion between cells and the substratum. Using the kidney as a model of epithelial differentiation it has been shown that the assembly of a basal lamina containing the glycoprotein laminin and cadherin mediated intercellular adhesion are key events. The Wilms' tumour anti-oncogene plays a regulatory role in renal epithelial differentiation. Tissue modeling and tumour formation are both accompanied by reduced cell adhesion molecule function.


[Mutagenic effect of combined exposure to 8-methoxypsoralen or angelicin and long-wave ultraviolet light in uvs-strains of Aspergillus nidulans].
Combined mutagenic effect of near ultraviolet irradiation (NUV, lambda > 320 nm) and angelicin, which forms monoadducts, or 8-methoxypsoralen (8-MOP), which forms monoadducts and cross-links in DNA, were studied in uvs and uvs+ strains of Aspergillus nidulans. Mutations were induced intensively by both kinds of furocumarins. The induction of mutations by angelicin testifies the significance of psoralen-pyrimidine monoadducts in mutagenesis. Using the method of fractionating NUV-irradiation and studying the influence of monoadducts repair to the mutation frequency, it is found the interstrand crosslinks of DNA induced by 8-MOP plus NUV are also nighly mutagenic. The products of genes uvs 12, uvs 20b and uvs 26, acting in DNA excision repair, do not participate in forming the mutations induced by furocumarins plus NUV in Aspergillus nidulans. The products of genes uvs 19, uvs 20a, participating in DNA post-replicative repair, are important for repair of premutational damages induced by furocumarins plus NUV.


Functional expression and subcellular localization of the taurine transporter TauT in murine neural precursors.
Taurine addition to cultured embryonic neural precursor cells (NPC) significantly increased cell proliferation [Hernández-Benítez et al., 2010]. The medium used for NPC growing and proliferation is a fetal serum-free medium, and therefore, NPC become taurine depleted. Addition of taurine to the cultured medium fully replenished the cell taurine pool, suggesting the functional expression of a taurine transporter (TauT) in these cells. In the present study, TauT in NPC was functionally characterized and its protein expression and the subcellular distribution of immunoreactivity were determined. ³H-taurine uptake in NPC could be separated into a non-saturable component and a Na(+)/Cl⁻-dependent, saturable component. The saturable component showed an apparent 2:1:1 Na(+)/Cl⁻/taurine stoichiometry, a V(max) of 0.39 ± 0.04 nmol/mg protein/min, and a K(m) of 21.7 ± 2.6 μM. TauT in NPC was strongly inhibited by hypotaurine and β-alanine (92 and 79%, respectively) and reduced (71%) by γ-aminobutyric acid. TauT protein is expressed in NPC as a single band of about 70 kDa. Essentially all (98.8%) of the neurosphere-forming cells were positive to TauT immunoreactivity. Immunolocalization visualized by confocal microscopy localized TauT predominantly at the cell membrane. TauT was also found at the cytosol and only occasionally at the nuclear membrane. This study represents the first characterization of TauT in NPC.


Long-term follow-up of Thoratec ventricular assist device bridge-to-recovery patients successfully removed from support after recovery of ventricular function.
In certain forms of severe heart failure there is sufficient improvement in cardiac function during ventricular assist device (VAD) support to allow removal of the device. However, it is critical to know whether there is sustained recovery of the heart and long-term patient survival if VAD bridging to recovery is to be considered over the option of transplantation. To determine long-term outcome of survivors of VAD bridge-to-recovery procedures, we retrospectively evaluated 22 patients with non-ischemic heart failure successfully weaned from the Thoratec left ventricular assist device (LVAD) or biventricular assist device (BVAD) after recovery of ventricular function at 14 medical centers. All patients were in imminent risk of dying and were selected for VAD support using standard bridge-to-transplant requirements. There were 12 females and 10 males with an average age of 32 (range, 12-49). The etiologies were 12 with myocarditis, 7 with cardiomyopathies (4 post-partum [PPCM], 1 viral [VCM], and 2 idiopathic [IDCM]), and 3 with a combination of myocarditis and cardiomyopathy. BVADs were used in 13 patients and isolated LVADs in 9 patients, for an average duration of 57 days (range, 11-190 days), before return of ventricular function and successful weaning from the device. Post-VAD survival was compared with 43 VAD bridge-to-transplant patients with the same etiologies who underwent cardiac transplantation instead of device weaning. Nineteen of the 22 patients are currently alive. Three patients required heart transplantation, 1 within 1 day, 2 at 12 and 13 months post-weaning, and 2 died at 2.5 and 6 months. The remaining 17 patients are alive with their native hearts after an average of 3.2 years (range, 1.2-10 years). The actuarial survival of native hearts (transplant-free survival) post-VAD support is 86% at 1 year and 77% at 5 years, which was not significantly different (p = 0.94) from that of post-VAD transplanted patients, also at 86% and 77%, respectively. Long-term survival for bridge-to-recovery with VADs for acute cardiomyopathies and myocarditis is equivalent to that for cardiac transplantation. Recovery of the native heart, which can take weeks to months of VAD support, is the most desirable clinical outcome and should be actively sought, with transplantation used only after recovery of ventricular function has been ruled out.


Nocturnal polysomnography with and without continuous pharyngeal and esophageal pressure measurements.
PSG with simultaneous pharyngeal and esophageal pressure measurements of the upper airway may interfere with sleep architecture and cause a bias. The aim of this study was to evaluate the degree of disturbance to sleep caused by inclusion of pressure measurements of the airway, and whether this would reduce the validity of the PSG. Thirty-two consecutive patients referred for PSG for possible obstructive sleep apnea syndrome (OSAS) were included. For pressure recordings, a 6-F silicone tube, 1.9 mm in diameter, containing six pressure transducers, was introduced through one nostril into the pharynx and esophagus. Each patient had two nocturnal PSGs, one of which included airway pressure measurements. There were no statistically significant differences between PSGs performed with and without simultaneous pressure recordings for the following sleep quality parameters: total sleep time, number of sleep-stage shifts, sleep efficiency, arousal during sleep (= intrasleep wakefulness), percent REM sleep, and number of microarousals. We did not find any statistically significant differences for respiratory parameters such as type, duration, and index of different respiratory events and snoring. However, there was a slight tendency for reduced sleep quality and oxygen saturation when pressure measurements were included. The only significant change seen was in the duration of non-REM sleep with oxygen saturation below 90%. The multisensor airway pressure probe demonstrated that proximal obstructions were more common than distal obstructions, and obstruction in one or two segments was far more frequent than obstruction in more than two.


Sources of variability in cytosolic calcium transients triggered by stimulation of homogeneous uro-epithelial cell monolayers.
Epithelial tissue structure is the emergent outcome of the interactions between large numbers of individual cells. Experimental cell biology offers an important tool to unravel these complex interactions, but current methods of analysis tend to be limited to mean field approaches or representation by selected subsets of cells. This may result in bias towards cells that respond in a particular way and/or neglect local, context-specific cell responses. Here, an automated algorithm was applied to examine in detail the individual calcium transients evoked in genetically homogeneous, but asynchronous populations of cultured non-immortalized normal human urothelial cells when subjected to either the global application of an external agonist or a localized scratch wound. The recorded calcium transients were classified automatically according to a set of defined metrics and distinct sub-populations of cells that responded in qualitatively different ways were observed. The nature of this variability in the homogeneous cell population was apportioned to two sources: intrinsic variation in individual cell responses and extrinsic variability due to context-specific factors of the environment, such as spatial heterogeneity. Statistically significant variation in the features of the calcium transients evoked by scratch wounding according to proximity to the wound edge was identified. The manifestation of distinct sub-populations of cells is considered central to the coordination of population-level response resulting in wound closure.


Metastasis to the forearm skeletal muscle from an adenocarcinoma of the colon: report of a case.
While the liver and lung are primary targets for distant metastasis from colorectal carcinoma, metastasis in other distant sites is rarely found. We report herein an unusual case of metastasis to the skeletal muscle of the right forearm from an adenocarcinoma of the transverse colon. A 60-year-old man was originally admitted to our hospital for surgical treatment of an intestinal obstruction caused by a transverse colon carcinoma. Transverse colon resection along with lymph node dissection was performed and no evidence of distant metastatic foci was found. Angiography-enhanced computed tomography scanning done 14 months after the first operation revealed multiple hepatic metastases which were resected. A metastasis was subsequently detected in the right extensor carpi ulnaris muscle 2 years after the primary resection, and a major part of the right extensor carpi ulnaris and the extensor digiti minimi muscle were resected, warranting a sufficient margin of 5 cm of normal tissue from the tumor. Reattachment of the residual muscles into the ulna was performed. Metastases to bone and/or soft tissues from colorectal carcinomas are extremely rare and to our knowledge, only eight other cases have been reported in the world literature. This low incidence may be related to the anatomical characteristics and/or the biochemical environment of the skeletal muscle, but it is also possible that the true incidence is underestimated. Recent improvements in interventional radiological procedures may facilitate a diagnosis of skeletal muscle metastasis being made more frequently.


Inference for environmental intervention studies using principal stratification.
Previous research has found evidence of an association between indoor air pollution and asthma morbidity in children. Environmental intervention studies have been performed to examine the role of household environmental interventions in altering indoor air pollution concentrations and improving health. Previous environmental intervention studies have found only modest effects on health outcomes and it is unclear if the health benefits provided by environmental modification are comparable with those provided by medication. Traditionally, the statistical analysis of environmental intervention studies has involved performing two intention-to-treat analyses that separately estimate the effect of the environmental intervention on health and the effect of the environmental intervention on indoor air pollution concentrations. We propose a principal stratification approach to examine the extent to which an environmental intervention's effect on health outcomes coincides with its effect on indoor air pollution. We apply this approach to data from a randomized air cleaner intervention trial conducted in a population of asthmatic children living in Baltimore, Maryland, USA. We find that among children for whom the air cleaner reduced indoor particulate matter concentrations, the intervention resulted in a meaningful improvement of asthma symptoms with an effect generally larger than previous studies have shown. A key benefit of using principal stratification in environmental intervention studies is that it allows investigators to estimate causal effects of the intervention for sub-groups defined by changes in the indoor air pollution concentration.


Standardization of the diagnostic criteria for canine ehrlichiosis. Towards a universal case definition.
Canine ehrlichiosis is a highly variable syndrome presenting a significant differential diagnostic difficulty. It imitates many metabolic and infectious diseases and lacks standardized diagnostic criteria, common reagents, and database resources. A clinical diagnosis of canine ehrlichiosis may be based on the manifestation of fever, thrombocytopenia, anorexia, nasolacrimal discharge, epistaxis, and exclusion of autoimmune and common canine vector borne diseases. These parameters are not invariably observed especially in the atypical form of the disease often caused by species other than Ehrlichia canis. A definitive diagnosis is based on the presence of specific antibodies to ehrlichial agent(s), the demonstration of the etiologic agent(s) itself, or specific amplicons by a strigently quality controlled PCR protocol. The relationship of the various clinical and laboratory parameters, the status of the currently available tests, and their real or presumed predictive value are discussed in the context of stimulating an effort to formulate an international standard for the diagnosis of this and related diseases of man and animals.


Revisiting heme mechanisms. A perspective on the mechanisms of nitric oxide synthase (NOS), Heme oxygenase (HO), and cytochrome P450s (CYP450s).
Despite the essential biological importance of reactions that involve heme, mechanisms of heme reactions in enzymes like nitric oxide synthase (NOS), heme oxygenase (HO), and cytochrome P450s (CYP450s) are still not well-understood. This Perspective on NOS, HO, and CYP450 mechanisms is written from the point of view of the heme chemistry. Steps in the classical heme catalytic cycle are discussed based on the specific environment within each of these enzymes. Elucidation of the mechanisms of NOS inactivation by some substrate analogues provides important mechanistic clues to the NOS catalytic mechanism. On the basis of mechanistic studies of NOS inactivation by amidine analogues of l-arginine and other previous mechanistic results, a new mechanism for NOS-catalyzed l-arginine NG-hydroxylation (the first half of the catalytic reaction) is proposed in this Perspective. The key step in the second half of the NOS catalytic reaction, the internal electron transfer between the substrate and heme, is discussed on the basis of mechanistic results of NOS inactivation by NG-allyl-l-arginine and the structures of the substrate intermediates. Elucidation of the mechanism of NOS inactivation by amidines, which leads to heme degradation, also provides important mechanistic implications for heme oxygenase-catalyzed heme catabolism. Focusing on the meso-hydroxylation step during inactivation of NOS by amidines as well as the HO-catalyzed reaction, the essential nature of the heme-oxygen species responsible for porphyrin meso-hydroxylation is discussed. Finally, on the basis of the proposed heme degradation mechanism during NOS inactivation and the HO-catalyzed reaction, the mechanism for the formation of the monooxygenated heme species in P450-catalyzed reactions is discussed.


Left Motor δ Oscillations Reflect Asynchrony Detection in Multisensory Speech Perception.
During multisensory speech perception, slow δ oscillations (∼1-3 Hz) in the listener's brain synchronize with the speech signal, likely engaging in speech signal decomposition. Notable fluctuations in the speech amplitude envelope, resounding speaker prosody, temporally align with articulatory and body gestures and both provide complementary sensations that temporally structure speech. Further, δ oscillations in the left motor cortex seem to align with speech and musical beats, suggesting their possible role in the temporal structuring of (quasi)-rhythmic stimulation. We extended the role of δ oscillations to audiovisual asynchrony detection as a test case of the temporal analysis of multisensory prosody fluctuations in speech. We recorded Electroencephalograph (EEG) responses in an audiovisual asynchrony detection task while participants watched videos of a speaker. We filtered the speech signal to remove verbal content and examined how visual and auditory prosodic features temporally (mis-)align. Results confirm (1) that participants accurately detected audiovisual asynchrony, and (2) increased δ power in the left motor cortex in response to audiovisual asynchrony. The difference of δ power between asynchronous and synchronous conditions predicted behavioral performance, and (3) decreased δ-β coupling in the left motor cortex when listeners could not accurately map visual and auditory prosodies. Finally, both behavioral and neurophysiological evidence was altered when a speaker's face was degraded by a visual mask. Together, these findings suggest that motor δ oscillations support asynchrony detection of multisensory prosodic fluctuation in speech.SIGNIFICANCE STATEMENT Speech perception is facilitated by regular prosodic fluctuations that temporally structure the auditory signal. Auditory speech processing involves the left motor cortex and associated δ oscillations. However, visual prosody (i.e., a speaker's body movements) complements auditory prosody, and it is unclear how the brain temporally analyses different prosodic features in multisensory speech perception. We combined an audiovisual asynchrony detection task with electroencephalographic (EEG) recordings to investigate how δ oscillations support the temporal analysis of multisensory speech. Results confirmed that asynchrony detection of visual and auditory prosodies leads to increased δ power in left motor cortex and correlates with performance. We conclude that δ oscillations are invoked in an effort to resolve denoted temporal asynchrony in multisensory speech perception.


Cortical Thickness and Natural Scene Recognition in the Child's Brain.
Visual scenes are processed in terms of spatial frequencies. Low spatial frequencies (LSF) carry coarse information, whereas high spatial frequencies (HSF) subsequently carry information about fine details. The present magnetic resonance imaging study investigated how cortical thickness covaried with LSF/HSF processing abilities in ten-year-old children and adults. Participants indicated whether natural scenes that were filtered in either LSF or HSF represented outdoor or indoor scenes, while reaction times (RTs) and accuracy measures were recorded. In adults, faster RTs for LSF and HSF images were consistently associated with a thicker cortex (parahippocampal cortex, middle frontal gyrus, and precentral and insula regions for LSF; parahippocampal cortex and fronto-marginal and supramarginal gyri for HSF). On the other hand, in children, faster RTs for HSF were associated with a thicker cortex (posterior cingulate, supramarginal and calcarine cortical regions), whereas faster RTs for LSF were associated with a thinner cortex (subcallosal and insula regions). Increased cortical thickness in adults and children could correspond to an expansion mechanism linked to visual scene processing efficiency. In contrast, lower cortical thickness associated with LSF efficiency in children could correspond to a pruning mechanism reflecting an ongoing maturational process, in agreement with the view that LSF efficiency continues to be refined during childhood. This differing pattern between children and adults appeared to be particularly significant in anterior regions of the brain, in line with the proposed existence of a postero-anterior gradient of brain development. Taken together, our results highlight the dynamic brain processes that allow children and adults to perceive a visual natural scene in a coherent way.


EGF receptor attenuates Dpp signaling and helps to distinguish the wing and leg cell fates in Drosophila.
Wing and leg precursors of Drosophila are recruited from a common pool of ectodermal cells expressing the homeobox gene Dll. Induction by Dpp promotes this cell fate decision toward the wing and proximal leg. We report here that the receptor tyrosine kinase EGFR antagonizes the wing-promoting function of Dpp and allows recruitment of leg precursor cells from uncommitted ectodermal cells. By monitoring the spatial distribution of cells responding to Dpp and EGFR, we show that nuclear transduction of the two signals peaks at different position along the dorsoventral axis when the fates of wing and leg discs are specified and that the balance of the two signals assessed within the nucleus determines the number of cells recruited to the wing. Differential activation of the two signals and the cross talk between them critically affect this cell fate choice.


Improvement of exploratory eye movements in schizophrenic patients during recovery period.
In the present paper exploratory eye movements were examined as biologic markers in both acute schizophrenic patients (acute patients discharged after approximately 3 months and treated as outpatients, n = 8; acute patients who were still in hospital after 6 months, n = 8) and chronic schizophrenic patients (hospital stay >5 years, n = 15) in comparison with age-matched healthy subjects (n = 30). Using an eye-mark recorder, exploratory eye movements were analyzed for mean gazing time (MGT), and total eye scanning length (TESL) as subjects viewed six simple pictures in preparation for copying them. In acute schizophrenic patients discharged after 6 months (DP), MGT became significantly shorter and TESL became longer after 3 or 6 months treatment. In acute schizophrenic patients during admission after 6 months, TESL became longer after 3 or 6 months of treatment. However, no significant changes were observed in chronic patients in these measures. In schizophrenic patients, negative symptom scores were positively correlated with MGT (r = 0.43; P < 0.001), and negatively correlated with TESL (r = -45; P < 0.001). These findings suggest that exploratory eye movements are a biologic state and trait marker useful for evaluation of schizophrenia.


Separation of megakaryocytes from mouse bone marrow by density gradient centrifugation.
The density profile of mouse bone marrow megakaryocytes, as determined by discontinuous albumin density gradient centrifugation, was characterized by a single density population (1.088 to 1.119 g/ml) with a peak density of 1.10 g/ml and a maximum enrichment of 15.5. This single population comprised both mature and immature megakaryocytes. The density profile of small, acetylcholinesterase-positive cells, a class of potential megakaryocyte precursors, was almost identical to that of morphologically recognizable megakaryocytes.


Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.
Anti-tumor necrosis factor (TNF) agents are effective in treating patients with rheumatoid arthritis (RA), but they are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared with continuation of the standard dose. To evaluate the benefits and harms of down-titration (dose reduction, discontinuation or disease activity guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) on disease activity, functioning, costs, safety and radiographic damage compared with usual care in patients with RA and low disease activity. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 8, 2013; Ovid MEDLINE (1946 to 8 September 2013); EMBASE (1947 to 8 September 2013); Science Citation Index (Web of Science); and conference proceedings of the American College of Rheumatology (2005 to 2012) and European League against Rheumatism (2005 to 2013). We contacted authors of the seven included studies to ask for additional information on their study; five responded. Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down-titration (dose reduction, discontinuation, disease activity-guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) to usual care/no down-titration in patients with RA and a low disease activity state. Two review authors independently selected studies, assessed risk of bias and extracted data. Six RCTs and one CCT (total 1203 participants), reporting anti-TNF down-titration, were included. Three studies (559 participants) reported anti-TNF dose reduction compared with anti-TNF continuation. Five studies (732 participants) reported anti-TNF discontinuation compared with anti-TNF continuation (two studies assessed both anti-TNF discontinuation and dose reduction), and one study assessed disease activity-guided anti-TNF dose tapering (137 participants). These studies include only adalimumab and etanercept; controlled data on other anti-TNF agents are absent. Two studies were available in full text; one was assessed as having low risk of bias and the other high risk. Five studies were available only as one or more abstracts. Because data provided in these abstracts were limited, risk of bias was unclear. Clinical heterogeneity between the trials was high.Dose reduction of anti-TNF (etanercept data only) showed no statistically significant or clinical relevant difference in disease activity score in 28 joints (DAS28) (mean difference (MD) 0.10, 95% confidence interval (CI) -0.11 to 0.31) (scale 0.9 to 8; higher score indicates worse disease activity). The proportion of participants who maintained low disease activity was slightly lower among participants given reduced doses of the anti-TNF agent (risk ratio (RR) 0.87, 95% CI 0.78 to 0.98, absolute risk difference (ARD) 9%). Radiographic outcome was slightly worse, but this was not clinically meaningful, compared with continuation of anti-TNF (MD 0.11, 95% CI 0.08 to 0.14) (scale 0 to 448; higher score indicates greater joint damage). Function was not statistically different between anti-TNF dose reduction and continuation (MD 0.10, 95% CI 0.00 to 0.20) (scale 0 to 3; higher score indicates worse functioning). Reinstalment of anti-TNF after failure of dose reduction showed a 5% risk of persistent flare. Data on numbers of serious adverse events (SAEs) (RR 0.58, 95% CI 0.23 to 1.45, ARD -2%) and withdrawals due to adverse events (AEs) (RR 0.57, 95% CI 0.17 to 1,92, ARD -1%) were inconclusive. Most outcomes were based on moderate quality evidence.Participants who discontinued anti-TNF (adalimumab and etanercept data) had higher mean DAS28 (DAS28-erythrocyte sedimentation rate (ESR): MD 1.10, 95% CI 0.86 to 1.34) and DAS28-C-reactive protein (CRP): MD 0.57 95% CI -0.09 to 1.23) and were less likely to maintain a low disease activity state (RR 0.43, 95% CI 0.27 to 0.68, ARD 40%). Also, radiographic and functional outcomes are worse after anti-TNF discontinuation (MD 0.66, 95% CI 0.63 to 0.69, and MD 0.30, 95% CI 0.19 to 0.41, respectively). Data on numbers of SAEs (RR 1.26, 95% CI 0.61 to 2.63, ARD 2%) and withdrawals due to AEs (RR 0.72, 95% CI 0.23 to 2.24, ARD -1%) were inconclusive. Most outcomes were based on moderate quality evidence.The one study comparing disease activity-guided anti-TNF dose tapering (adalimumab and etanercept data) reported no statistically significant differences in functional outcomes (MD 0.20, 95% CI -0.02 to 0.42). Significantly higher mean disease activity was found among participants with tapered anti-TNF at study end (MD 0.50, 95% CI 0.11 to 0.89). No full text of this trial was available for this review. No other major outcomes were reported. All outcomes were based on low quality evidence. We can conclude, mostly based on moderate quality evidence, that non-disease activity guided dose reduction of etanercept 50 mg weekly to 25 mg weekly, after at least three to 12 months of low disease activity, seems as effective as continuing the standard dose with respect to disease activity and functional outcomes, although dose reduction significantly induces minimal and not clinically meaningful differences in radiological progression. Discontinuation (also without disease activity-guided adaptation) of adalimumab and etanercept is inferior to continuation of treatment with respect to disease activity and radiological outcomes and function. Disease activity-guided dose tapering of adalimumab and etanercept seems slightly inferior to continuation of treatment with respect to disease activity, with no difference in function. However the only study investigating this comparison included lower than projected numbers of participants.Caveats of this review are that available data are limited. Also, the heterogeneity between studies and the suboptimal design choices (including absence of disease activity-guided dose reduction and discontinuation and use of superiority designs) limit definitive conclusions. None of the included studies assessed long-term safety and costs, although these factors are specific reasons why clinicians consider lowering the dose or stopping the administration of anti-TNF agents.Future research should include other anti-TNF agents; assessment of disease activity, function and radiographic outcomes after longer follow-up; and assessment of long-term safety, cost-effectiveness and predictors for successful down-titration. Also use of a validated flare criterion, non-inferiority designs and disease activity-guided instead of fixed-dose tapering or stopping would allow researchers to better interpret study findings and generalise the information to clinical practice.


Case for diagnosis. Localized scleroderma or morphea.
Localized scleroderma or morphea is a chronic disease of the connective tissue. Its etiology may be autoimmune and the condition results from a disturbance in collagen synthesis and deposition, clinically represented by sclerotic skin lesions. Some plaques may be yellowish, which can be misleading at diagnosis. This article reports the case of an adolescent girl who concomitantly presented erythematous lesions and yellowish lesions, both of which constitute clinical manifestations of the disease.


A Single Conserved Residue Mediates Binding of the Ribonucleotide Reductase Catalytic Subunit RRM1 to RRM2 and Is Essential for Mouse Development.
The ribonucleotide reductase (RNR) complex, composed of a catalytic subunit (RRM1) and a regulatory subunit (RRM2), is thought to be a rate-limiting enzymatic complex for the production of nucleotides. In humans, the Rrm1 gene lies at 11p15.5, a tumor suppressor region, and RRM1 expression in cancer has been shown to predict responses to chemotherapy. Nevertheless, whether RRM1 is essential in mammalian cells and what the effects of its haploinsufficiency are remain unknown. To model RNR function in mice we used a mutation previously described in Saccharomyces cerevisiae (Rnr1-W688G) which, despite being viable, leads to increased interaction of the RNR complex with its allosteric inhibitor Sml1. In contrast to yeast, homozygous mutant mice carrying the Rrm1 mutation (Rrm1(WG/WG)) are not viable, even at the earliest embryonic stages. Proteomic analyses failed to identify proteins that specifically bind to the mutant RRM1 but revealed that, in mammals, the mutation prevents RRM1 binding to RRM2. Despite the impact of the mutation, Rrm1(WG/+) mice and cells presented no obvious phenotype, suggesting that the RRM1 protein exists in excess. Our work reveals that binding of RRM1 to RRM2 is essential for mammalian cells and provides the first loss-of-function model of the RNR complex for genetic studies.


Joint modeling of progression-free survival and overall survival by a Bayesian normal induced copula estimation model.
In cancer clinical trials, in addition to time to death (i.e., overall survival), progression-related measurements such as progression-free survival and time to progression are also commonly used to evaluate treatment efficacy. It is of scientific interest and importance to understand the correlations among these measurements. In this paper, we propose a Bayesian semi-competing risks approach to jointly model progression-related measurements and overall survival. This new model is referred to as the NICE model, which stands for the normal induced copula estimation model. Correlation among these variables can be directly derived from the joint model. In addition, when correlation exists, simulation shows that the joint model is able to borrow strength from correlated measurements, and as a consequence the NICE model improves inference on both variables. The proposed model is in a Bayesian framework that enables us to use it in various Bayesian contexts, such as Bayesian adaptive design and using posterior predictive samples to simulate future trials. We conducted simulation studies to demonstrate properties of the NICE model and applied this method to a data set from chemotherapy-naive patients with extensive-stage small-cell lung cancer.


Organogenic nodule development in hop (Humulus lupulus L.): transcript and metabolic responses.
Hop (Humulus lupulus L.) is an economically important plant forming organogenic nodules which can be used for genetic transformation and micropropagation. We are interested in the mechanisms underlying reprogramming of cells through stress and hormone treatments. An integrated molecular and metabolomic approach was used to investigate global gene expression and metabolic responses during development of hop's organogenic nodules. Transcript profiling using a 3,324-cDNA clone array revealed differential regulation of 133 unigenes, classified into 11 functional categories. Several pathways seem to be determinant in organogenic nodule formation, namely defense and stress response, sugar and lipid metabolism, synthesis of secondary metabolites and hormone signaling. Metabolic profiling using 1H NMR spectroscopy associated to two-dimensional techniques showed the importance of metabolites related to oxidative stress response, lipid and sugar metabolism and secondary metabolism in organogenic nodule formation. The expression profile of genes pivotal for energy metabolism, together with metabolites profile, suggested that these morphogenic structures gain energy through a heterotrophic, transport-dependent and sugar-degrading anaerobic metabolism. Polyamines and auxins are likely to be involved in the regulation of expression of many genes related to organogenic nodule formation. These results represent substantial progress toward a better understanding of this complex developmental program and reveal novel information regarding morphogenesis in plants.


High prevalence of modifiable stroke risk factors identified in a pharmacy-based screening programme.
Population-based screening for atrial fibrillation (AF) is a promising public health strategy to prevent stroke. However, none of the published reports have evaluated comprehensive screening for additional stroke risk factors such as hypertension and diabetes in a pharmacy setting. The Program for the Identification of 'Actionable' Atrial Fibrillation in the Pharmacy Setting (PIAAF-Pharmacy) screened individuals aged ≥65 years, attending community pharmacies in Canada, who were not receiving oral anticoagulation (OAC). Participants were screened for AF using a hand-held ECG device, had blood pressure (BP) measured, and diabetes risk estimated using the Canadian Diabetes Risk Assessment Questionnaire (CANRISK) questionnaire. 'Actionable' AF was defined as unrecognised or undertreated AF. A 6-week follow-up visit with the family physician was suggested for participants with 'actionable' AF and a scheduled 3-month visit occurred at an AF clinic. During 6 months, 1145 participants were screened at 30 pharmacies. 'Actionable' AF was identified in 2.5% (95% CI 1.7 to 3.6; n=29); of these, 96% were newly diagnosed. Participants with 'actionable AF' had a mean age of 77.2±6.8 years, 58.6% were male and 93.1% had a CHA2DS2-VASc score ≥2. A BP>140/90 was found in 54.9% (616/1122) of participants and 44.4% (214/492) were found to be at high risk of diabetes. At 3 months, only 17% of participants were started on OAC, 50% had improved BP and 71% had confirmatory diabetes testing. Integrated stroke screening identifies a high prevalence of individuals who could benefit from stroke prevention therapies but must be coupled with a defined care pathway.


Functional network reconstruction reveals somatic stemness genetic maps and dedifferentiation-like transcriptome reprogramming induced by GATA2.
Somatic stem cell transplantation holds great promise in regenerative medicine. The best-characterized adult stem cells are mesenchymal stem cells (MSCs), neural stem cells (NSCs), and CD133(+) hematopoietic stem cells (HSCs). The applications of HSCs are hampered since these cells are difficult to maintain in an undifferentiated state in vitro. Understanding genes responsible for stem cell properties and their interactions will help on this issue. The construction of stem cell genetic networks will also help to develop rational strategies to revert somatic cells back to a stem-like state. We performed a systemic study on human CD133(+) HSCs, NSCs, MSCs, and embryonic stem cells and two different progenies of CD133(+) HSCs, microvascular endothelial cells (MVECs) and peripheral blood mononuclear cells. Genes abundant in each or in all three somatic stem cells were identified. We also observed complex genetic networks functioning in postnatal stem cells, in which several genes, such as PTPN11 and DHFR, acted as hubs to maintain the stability and connectivity of the whole genetic network. Eighty-seven HSC genes, including ANGPT1 and GATA2, were independently identified by comparing CD34(+)CD33(-)CD38(-) hematopoietic stem cells with CD34(+) precursors and various matured progenies. Introducing GATA2 into MVECs resulted in dedifferentiation-like transcriptome reprogramming, with HSC genes (such as ANGPT1) being up and endothelial genes (such as EPHB2) being down. This study provides a foundation for a more detailed understanding of human somatic stem cells. Expressing the newly discovered stem cell genes in matured cells might lead to a global reversion of somatic transcriptome to a stem-like status.


The use of amnion-derived cellular cytokine solution to improve healing in acute and chronic wound models.
Growth factors demonstrate mixed results improving wound healing. Amnion-derived multipotent cells release physiologic levels of growth factors and tissue inhibitors of metalloproteinases. This solution was tested in models of acute and chronic wound healing. Acute model: Sprague-Dawley rats underwent laparotomy incisions. The midline fascia was primed with phosphate-buffered saline, unconditioned media, or amnion-derived cellular cytokine suspension prior to incision. Breaking strength of laparotomy wounds was tested with an Instron tensiometer. Incisional hernia formation was measured after 28 days. Chronic model: Chronic, infected granulating wounds were produced in rats by excising full thickness burn eschars inoculated with Escherica coli. Granulating wounds were treated with unconditioned media or amnion-derived cellular cytokine suspension. Treatments were applied either on day 0 and day 7 or day 0 and then every other day. Wounds were traced every 72 hours and biopsied for quantitative bacteriology. Acute model: Priming with amnion-derived cellular cytokine suspension increased the breaking strength of laparotomy incisions in comparison with phosphate-buffered saline or unconditioned media (P < .05). Acute wound failure and incisional hernia formation was 100% in the phosphate-buffered saline and unconditioned media groups and 18% in the amnion-derived cellular cytokine suspension-treated group (P <.05). Chronic model: The rate of wound closure was accelerated in amnion-derived cellular cytokine suspension-treated chronic wounds (P < .05). Multidosing improved the effect. A physiologic solution of cytokines and tissue inhibitors of metalloproteinases improves healing in models of acute and chronic wounds. Such a cocktail can be produced from amnion-derived multipotent progenitor cells.


Central compartment atopic disease.
Isolated polypoid changes of the middle turbinate were recently reported as having a high association with inhalant allergy. A more advanced manifestation of this association may present as polypoid changes of the entire central sinonasal compartment (i.e., the middle and superior turbinates, and the posterosuperior nasal septum), while the lateral sinus mucosa remains relatively normal. To introduce and describe this newly recognized variant of chronic rhinosinusitis (CRS), termed central compartment atopic disease (CCAD). A case series of 15 patients from two institutions who presented with sinonasal symptoms and demonstrated central compartment polypoid mucosal changes on computed tomography (CT). The endoscopic appearance of central compartment edema was assessed. Allergy status was determined by skin or serum in vitro testing. The mean ± standard deviation patient age was 42.4 ± 14.8 years, and 47% of the patients were women. All 15 patients had a diagnosis of allergic rhinitis symptomatically, and those who underwent allergy assessment (14/15) tested positive. All the patients had central compartment polypoid edema on endoscopy and central nasal soft-tissue thickening with peripheral clearing on CT. Even with more severe sinus disease, a central focus of inflammatory change existed. CCAD may represent a local inhalant allergy process that affects the central nasal structures of ethmoid origin. Although inhalant allergy changes mainly appear within the nasal cavity, medial-to-lateral progression to involve the sinuses can occur as a simple obstructive phenomenon. This is a pattern of CRS distinct from the more diffuse sinonasal inflammatory disease and likely requires allergy management as a core component.


Insights into apolipoprotein C metabolism from transgenic and gene-targeted mice.
Studies in humans on the in vivo metabolism of apolipoprotein (apo) Cs have been hampered by the highly complex nature of lipoprotein metabolism, which can be influenced by multiple genetic and environmental factors. In order to gain new insights into the function of the individual apoCs in lipoprotein metabolism, several laboratories have created mouse models lacking or overexpressing the respective APOC genes through the technologies of gene targeting and transgenesis. Until now, the only well-established in vivo metabolic function of apoC-I has been its inhibitory action on the uptake of very low-density lipoprotein (VLDL) via hepatic receptors, particularly the low-density lipoprotein (LDL) receptor-related protein. Consequently, the presence of apoC-I on the lipoprotein particle may prolong its residence time in the circulation and subsequently facilitate its conversion to LDL. ApoC-II, on the other hand, is a major activator of lipoprotein lipase, which is required for an efficient processing of triglyceride-rich lipoproteins in the circulation. However, an excess of apoC-II on the lipoprotein particle has been suggested to inhibit the lipoprotein-lipase-mediated hydrolysis of triglycerides. From studies with APOC3 transgenic and ApoC3-knockout mice, it appears that apoC-III inhibits the lipolysis of triglyceride-rich lipoproteins by hampering the interaction of these lipoproteins with the heparan sulfate proteoglycan-lipoprotein lipase complex. Subsequently, the poorly lipolyzed apoC-III-containing lipoprotein particles may accumulate in plasma because of their lower binding affinity towards hepatic receptors due to a change in lipid composition, particle size or the presence of apoC-III on the particle itself. From these data it can thus be concluded that all C apolipoproteins specifically modulate the metabolism of triglyceride-rich lipoproteins, which may contribute to the development of hyperlipidemia and other lipoprotein abnormalities in humans.


Surface multi-gap vector solitons.
We analyze nonlinear collective effects near surfaces of semi-infinite periodic systems with multi-gap transmission spectra and introduce a novel concept of multi-gap surface solitons as mutually trapped surface states with the components associated with different spectral gaps. We find numerically discrete surface modes in semi-infinite binary waveguide arrays which can support simultaneously two types of discrete solitons, and analyze different multi-gap states including the soliton-induced waveguides with the guided modes from different gaps and composite vector solitons.


Symptom Dimension Response in Children and Adolescents with Obsessive-Compulsive Disorder.
This report examined the nature of obsessive-compulsive disorder (OCD) symptoms nominated for treatment and investigate improvement in OCD symptom dimensions. Youth with OCD (N = 71) participated in a clinical trial that compared exposure-based cognitive behavior therapy (CBT) to psychoeducation plus relaxation training (PRT). Participants completed a baseline assessment to characterize OCD severity. Next, parents and youth collaboratively developed an OCD symptom treatment hierarchy. Afterward, these symptoms were independently reassessed at each session by youth and parents. After 12 sessions, a posttreatment assessment was completed by independent evaluators. A greater incidence of baseline aggressive/checking symptoms predicted a positive CBT treatment response. For parent ratings of youth distress, CBT outperformed PRT across symptom dimensions, but hoarding symptoms exhibited a slower rate of improvement relative to other dimensions across treatments. For youth distress ratings, CBT outperformed PRT across most symptom dimensions. Although symmetry/ordering symptoms exhibited a slower rate of improvement relative to other dimensions across treatments, post hoc tests found no difference in the average distress rating for symmetry/ordering symptoms between treatment groups. Finally, across symptom dimensions, parents reported a linear reduction in youth distress, whereas youth experienced a nonlinear reduction in distress that diminished over treatment. Exposure-based CBT is beneficial for OCD symptoms and remains the principle treatment for pediatric OCD. However, as symmetry/ordering symptoms exhibited improvement from CBT and PRT, there is some shared treatment mechanisms that improves these symptoms. Finally, as youth perceive diminishing distress reduction over time, clinicians are encouraged to employ appropriate reinforcement strategies in treatment.


Trehalose conserves expression of bullous pemphigoid antigen 180 during desiccation and freezing.
Bullous pemphigoid antigen 180 (BP180) is targeted by autoantibodies in a variety of subepidermal blistering skin diseases. We have recently developed a simple, highly specific and sensitive immunofluorescence (IF) assay for the detection of circulating antibodies against BP180. This novel assay involves the expression of full-length (FL) BP180 in Sf21 insect cells that are then examined under IF microscopy after staining with anti-BP180 antibodies. Application of this assay as a routine diagnostic tool requires long-term storage of FL-BP180, which can result in substantial loss of expression. Here, we show that the disaccharide trehalose, a natural cryo- and lyoprotectant, is capable of preserving the FL-BP180 antigen expressed in Sf21 insect cells under various (dry) storage conditions including 40 degrees C, room temperature (RT), 4-8, -20, and -80 degrees C. The protective effect was dose-dependent reaching a maximum at about 200 mM trehalose. Trehalose was superior to other sugars or conventional cryoprotective agents (e.g. sucrose, myo-inositol, DMSO) in preventing greatly reduced antigen expression. Trehalose conserved the expression of both extra- and intracellular epitopes of FL-BP180. Interestingly, protection of the intracellular domain was only observed when trehalose was introduced into the cytosol. Trehalose significantly prolonged the storage time of FL-BP180 expressed in Sf21 insect cells, thus permitting the routine use of the IF assay in clinics for the detection of serum antibodies. The method described here has potential applications for the preservation of other transmembrane proteins.


[The first member of a novel family of eukaryotic transcription factors detected by the heterospecific complementation].
The cDNA of a previously uncharacterized gene fet5 (factor of eukaryotic transcription, clone no. 5) of the fission yeast Schizosaccharomyces pombe was cloned by the heterospecific complementation of a conditional mutant of Saccharomyces cerevisiae defective in the function of the RNA polymerases I-III common subunit ABC10 beta. The gene encodes a new factor of eukaryotic transcription, Fet5, the first member of a superfamily of proteins for which the area of functioning is determined. The Fet5-superfamily consists of three distinct families of proteins highly evolutionarily conserved and widely spread among eukaryotes. Features of the Fet5 amino acid sequence suggest that it belongs to ATP/GTP-binding proteins.


Novel approaches in the synthesis of batracylin and its analogs: rebirth of an old player?
Batracylin (8-aminoisoindol[1,2-b]-quinasolin-12(10H)-one, BAT), a heterocyclic amine, was isolated in 1978 (NCI, Bethesda, USA) in the course of search for the new anticancer drugs. It showed high in vitro and in vivo anticancer activities against murine leukemia P338 and colon adenocarcinoma 38. Mechanism of action of BAT is still not completely clear. It was reported, that BAT is a topoisomerase II inhibitor and induces unscheduled DNA synthesis (UDS) in non-proliferating cells. Low solubility of BAT in water, high toxicity and necessity of high drug dosing are major limitations of its use as a chemotherapeutic drug. As a result, new BAT analogs were synthesized to improve its pharmacological properties. The modifications of BAT chemical structure include various substituents introduced to isoindoloquinazoline moiety (Cl, Br, NO(2), CH(2), NH(2), Me, CO(2)Me, OMe). It has been shown that the desamino derivative and the 8-aza analog of BAT retained the ability to inhibit topoisomerase II but did not induce unscheduled DNA synthesis. While less active than BAT, these analogs were cytotoxic toward CCRF-CEM leukemia cells. The isoindolo [2,1-a]benzimidazole derivatives were inactive as topoisomerase II inhibitors and, in general, failed to exhibit comparable antitumor activity or to induce unscheduled DNA synthesis. Batracylin was acylated with aminoacids, dipeptides, tripeptides to increase its solubility in water. Other modifications include introduction of nitrogen atom to ring A or D, extension of polycyclic ring 4, reduction of ring B from six- to five-membered one, and obtaining of benzimidazole, indole or derivatives containing a fucose ring. A series of novel BAT analogs bearing sugar residues and thiocarbonyl aminoacids, which provided better solubility in water and high cytostatic activity have been designed. Also, new azabatracylines, where aniline ring was replaced by pyridine or other substituted quinazolines, have been obtained. This paper reviews the most important approaches in batracylin synthesis and its analogs and presents structure-reactivity relationships for these compounds.


A prospective study of the value of pre- and post-treatment magnetic resonance imaging examinations for advanced cervical cancer.
Cervical cancer has high incidence and mortality in developing countries. It is the only gynecological malignancy that is clinically staged. Staging at the time of diagnosis is crucial for treatment planning. After radiation therapy, clinical examination is limited because of radiation changes. An imaging method relatively unaffected by radiation changes would be useful for the assessment of therapy results and for management. We sought to demonstrate the value of magnetic resonance imaging (MRI) in the pre- and post-treatment assessment of cervical cancer. This was a prospective study, carried out between November 2012 and October 2014 on 18 subjects with advanced-stage cervical cancer diagnosed by colposcopy. The disease stage was determined clinically according to the International Federation of Gynecology and Obstetrics (FIGO) criteria. Only patients with disease stage ≥ IIB or IIA with one of the tumor dimensions > 4 cm were enrolled in the study. All patients underwent abdominal-pelvic contrast-enhanced MRI as part of the workup. Tumor size, local invasion, involved pelvic lymph nodes, and staging according to MRI criteria were evaluated. Clinical and MRI examinations were also performed after chemoradiotherapy. After chemoradiotherapy, 94% of the patients (17 of 18) were treated surgically. Eighteen patients aged 32-67 met the inclusion criteria and were enrolled: 10 stage IIB, 6 stage IIIA, 1 stage IIA and 1 stage IIIB, according to clinical staging. Using histopathological findings as a reference, MRI staging accuracy was 83.3%. The concordance of the clinical stage with MRI stage at the first examination was 56%. Parametrial involvement was assessed on pretreatment and post-treatment MRI, with post-treatment MRI compared with histology. There was no statistically significant difference between the pre- and post-therapy gynecological examinations (GYN) and the corresponding MRI assessments as to tumor size measurements (p>0.05). The post-therapy restoration of the cervical stroma ruled out tumor recurrence. For a detailed characterization of loco-regional extension, the calculation of tumor volume, and the evaluation of distant metastatic changes, clinical examination is insufficient. Magnetic resonance imaging is helpful aftertherapy.


Skull-base osteomyelitis: fungal vs. bacterial infection.
Skull-base osteomyelitis (SBO) occurs secondary to invasive bacterial and fungal infection. Distinguishing between fungal and bacterial aetiologies of SBO has significant therapeutic implications. An 18-year (1990-2007) retrospective review of patients with SBO presenting to Westmead Hospital was performed. Epidemiological, clinical, laboratory and radiology data were collated. Twenty-one patients (median age 58 years) with SBO were identified: ten (48%) had bacterial and 11 (52%) had fungal SBO. Diabetes mellitus (57%) and chronic otitis externa (33%) were the most frequent co-morbidities; immunosuppression was present in five cases (24%). Cranial nerve deficits occurred in ten (48%) patients. The commonest pathogens were Pseudomonas aeruginosa (50% bacterial SBO) and a zygomycete (55% fungal SBO). Compared to bacterial SBO, fungal SBO was more frequently associated with underlying chronic sinusitis, sinonasal pain, facial/periorbital swelling and nasal stuffiness or discharge and the absence of purulent ear discharge (all p <0.05). Bacterial SBO was more frequently associated with deafness, ear pain or ear discharge (all p <0.05). Median time to presentation was longer in patients with bacterial SBO (26.3 weeks vs. 8.1 weeks, p 0.08). Overall 6-month survival was 88% (14/18 patients). All four deaths occurred in patients with fungal SBO. Immunosuppression was a risk factor for death (p <0.05). Early diagnostic sampling is recommended in patients at increased risk of fungal SBO to enable optimal antimicrobial and surgical management.


An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology.
The circadian clock protein BMAL1 modulates glial activation and amyloid-beta deposition in mice. However, the effects of BMAL1 on other aspects of neurodegenerative pathology are unknown. Here, we show that global post-natal deletion of Bmal1 in mouse tauopathy or alpha-synucleinopathy models unexpectedly suppresses both tau and alpha-synuclein (αSyn) aggregation and related pathology. Astrocyte-specific Bmal1 deletion is sufficient to prevent both αSyn and tau pathology in vivo and induces astrocyte activation and the expression of Bag3, a chaperone critical for macroautophagy. Astrocyte Bmal1 deletion enhances phagocytosis of αSyn and tau in a Bag3-dependent manner, and astrocyte Bag3 overexpression is sufficient to mitigate αSyn spreading in vivo. In humans, BAG3 is increased in patients with AD and is highly expressed in disease-associated astrocytes (DAAs). Our results suggest that early activation of astrocytes via Bmal1 deletion induces Bag3 to protect against tau and αSyn pathologies, providing new insights into astrocyte-specific therapies for neurodegeneration.


Oxidative stress and inflammation in atrial fibrillation: role in pathogenesis and potential as a therapeutic target.
Atrial fibrillation (AF) is one of the most prevalent and vexing cardiovascular conditions. Available treatments for AF based on ion channel blockade are only poorly effective. The fundamental mechanisms that underlie AF are still not clearly understood, and likely vary depending on the etiology of AF. In older individuals with senile AF, likely mechanisms include abnormal calcium cycling, oxidant stress, and deleterious inflammatory responses. Clinical and experimental evidence is provided to support the role of oxidant and inflammatory mechanisms in AF. On the basis of these studies, the prospects of manipulating oxidant and inflammatory pathways as targets for therapeutic intervention are discussed.


Ejaculate investment and attractiveness in the stalk-eyed fly, Diasemopsis meigenii.
The phenotype-linked fertility hypothesis proposes that male fertility is advertised via phenotypic signals, explaining female preference for highly sexually ornamented males. An alternative view is that highly attractive males constrain their ejaculate allocation per mating so as to participate in a greater number of matings. Males are also expected to bias their ejaculate allocation to the most fecund females. We test these hypotheses in the African stalk-eyed fly, Diasemopsis meigenii. We ask how male ejaculate allocation strategy is influenced by male eyespan and female size. Despite large eyespan males having larger internal reproductive organs, we found no association between male eyespan and spermatophore size or sperm number, lending no support to the phenotype-linked fertility hypothesis. However, males mated for longer and transferred more sperm to large females. As female size was positively correlated with fecundity, this suggests that males gain a selective advantage by investing more in large females. Given these findings, we consider how female mate preference for large male eyespan can be adaptive despite the lack of obvious direct benefits.


Ultra-long-term subcutaneous home monitoring of epilepsy-490 days of EEG from nine patients.
To explore the feasibility of home monitoring of epilepsy patients with a novel subcutaneous electroencephalography (EEG) device, including clinical implications, safety, and compliance via the first real-life test. We implanted a beta-version of the 24/7 EEG SubQ (UNEEG Medical A/S, Denmark) subcutaneously in nine participants with temporal lobe epilepsy. Data on seizures, adverse events, compliance in using the device, and use of antiepileptic drugs (AEDs) were collected. EEG was recorded for up to 3 months, and all EEG data were reviewed visually to identify electrographic seizures. These were descriptively compared to seizure counts and AED changes reported in diaries from the same period. Four hundred ninety days of EEG and 338 electrographic seizures were collected. Eight participants completed at least 9 weeks of home monitoring, while one cancelled participation after 4 weeks due to postimplantation soreness. In total, 13 cases of device-related adverse events were registered, none of them serious. Recordings obtained from the device covered 73% of the time, on average (range 45%-91%). Descriptively, electrographic seizure counts were substantially different from diary seizure counts. We uncovered several cases of underreporting and revealed important information on AED response. Electrographic seizure counts revealed circadian distributions of seizures not visible from seizure diaries. The study shows that home monitoring for up to 3 months with a subcutaneous EEG device is feasible and well tolerated. No serious adverse device-related events were reported. An objective seizure count can be derived, which often differs substantially from self-reported seizure counts. Larger clinical trials quantifying the benefits of objective seizure counting should be a priority for future research as well as development of algorithms for automated review of data.


Mobile healthcare simulation units: a narrative review.
For healthcare professionals working and living in geographical isolation, there are few opportunities to maintain skills and knowledge, and to update themselves with recent advances in care compared to their citydwelling peers. It is known that within a short period and limited practice, clinical skills erode. A mobile healthcare simulation unit provides high-quality, technologicallyenhanced, convenient, and affordable training for healthcare professionals under expert supervision in any remote setting. The current narrative review was planned to summarise the outcomes and challenges related to developing and effectively utilising mobile healthcare simulation units as experienced globally. A literature search was performed on PubMed, Google Scholar and Cochrane databases for relevant articles published between 2000 and 2020, which resulted in 18 articles that were shortlisted and three major themes. The identification of common strengths, weaknesses and challenges will be a starting point for those engaged in planning and operating such a centre in any location.


Different suppression of Ph1 positive hemopoiesis induced by intensive chemotherapy in lymphoid and myeloid blast crisis of CML.
The suppression of Ph1-positive hemopoiesis is a major goal in the treatment of CML; in this context the CML patients in blast crisis obtaining a complete clinical remission represent a useful model to investigate the behavior of the Ph1-positive and negative clones during bone marrow repopulation after ablative therapy. Seven CML patients in blast crisis (four lymphoid and three myeloid) who obtained a complete clinical remission after an intensive polychemotherapy treatment were evaluated by cytogenetic and molecular analysis both in blast and remission phases. Standard cytogenetic and Southern techniques were employed; in addition, minimal residual disease status (MRD) was ascertained by amplification (PCR) of the specific bcr-abl chimeric transcripts. After a single cycle of induction, all lymphoid cases displayed a complete restoration of Ph1-negative hemopoiesis; by contrast, one myeloid blast crisis showed a partial suppression of Ph1-positive hemopoiesis only after two cycles of chemotherapy, and in the remaining two cases the hematological remission was indeed a reversion to the chronic phase. Ph1-positive chronic clones present in lymphoid blast crisis showed a higher degree of sensitivity to intensive chemotherapy than those present in the myeloid cases. This observation further suggests that the growth properties of the Ph1-positive clones are highly variable from case to case and probably tend to progress during the time-course of the disease.


HSATII RNA is induced via a noncanonical ATM-regulated DNA damage response pathway and promotes tumor cell proliferation and movement.
Pericentromeric human satellite II (HSATII) repeats are normally silent but can be actively transcribed in tumor cells, where increased HSATII copy number is associated with a poor prognosis in colon cancer, and in human cytomegalovirus (HCMV)-infected fibroblasts, where the RNA facilitates viral replication. Here, we report that HCMV infection or treatment of ARPE-19 diploid epithelial cells with DNA-damaging agents, etoposide or zeocin, induces HSATII RNA expression, and a kinase-independent function of ATM is required for the induction. Additionally, various breast cancer cell lines growing in adherent, two-dimensional cell culture express HSATII RNA at different levels, and levels are markedly increased when cells are infected with HCMV or treated with zeocin. High levels of HSATII RNA expression correlate with enhanced migration of breast cancer cells, and knockdown of HSATII RNA reduces cell migration and the rate of cell proliferation. Our investigation links high expression of HSATII RNA to the DNA damage response, centered on a noncanonical function of ATM, and demonstrates a role for the satellite RNA in tumor cell proliferation and movement.


A blinded, crossover study of the efficacy of the ketogenic diet.
Despite over 80 years of use, the ketogenic diet (KD) has never been tested in a blinded manner. Twenty children with intractable Lennox-Gastaut syndrome (LGS) were fasted 36 h and then randomized to receive the classic KD in conjunction with a solution containing either 60 g/day of glucose or saccharin. Parents and physicians were blinded to both the solution composition and level of ketosis. A crossover to the KD with the alternate solution occurred following the sixth day and a repeat fast. A 24-h electroencephalography (EEG) was obtained at baseline and after each arm. After administration of the solution, there was moderate evidence of a reduction in parent-reported seizures between the glucose and saccharin arms, with a median difference of 1.5 seizures per day (p = 0.07). There was no reduction in the number of EEG-identified events, with a median reduction of 7 events per day (p = 0.33). Ketosis was not completely eliminated in the glucose-added arm.


Halotropism is a response of plant roots to avoid a saline environment.
Tropisms represent fascinating examples of how plants respond to environmental signals by adapting their growth and development. Here, a novel tropism is reported, halotropism, allowing plant seedlings to reduce their exposure to salinity by circumventing a saline environment. In response to a salt gradient, Arabidopsis, tomato, and sorghum roots were found to actively prioritize growth away from salinity above following the gravity axis. Directionality of this response is established by an active redistribution of the plant hormone auxin in the root tip, which is mediated by the PIN-FORMED 2 (PIN2) auxin efflux carrier. We show that salt-induced phospholipase D activity stimulates clathrin-mediated endocytosis of PIN2 at the side of the root facing the higher salt concentration. The intracellular relocalization of PIN2 allows for auxin redistribution and for the directional bending of the root away from the higher salt concentration. Our results thus identify a cellular pathway essential for the integration of environmental cues with auxin-regulated root growth that likely plays a key role in plant adaptative responses to salt stress.


Saccharides in straw hydrolysate decrease cell membrane damage by phenolics by inducing the formation of extracellular matrix in yeast.
The bioconversion of rice straw into ethanol can alleviate the energy crisis and solve problems related to waste treatment. In this study, the effect of soluble polysaccharides (SPs) produced during rice straw saccharification on the formation of extracellular matrices (EMs) by the yeast Saccharomyces cerevisiae was investigated. SPs were characterized by high-performance liquid chromatography (HPLC) and fourier transform infrared spectroscopy (FT-IR). SPs reduced the inhibition of alcohol dehydrogenase activity by phenolic acids (PAs) and regulated the intracellular redox state, resulting in higher ethanol production. The results of flow cytometry, confocal laser scanning microscopy, and atomic force microscopy indicated that PAs changed microbial morphology and caused damage in microbial cell membranes. The protective effect of SPs against cell membrane damage could be attributed to the synthesis of polysaccharide-dependent extracellular matrix, which maintained cellular integrity even under phenolic acid stress. These findings provide new strategies to improve pretreatment and saccharification processes.


Evaluation of Stress Pattern Caused by Mini-Implant in Mandibular Alveolar Bone with Different Angulations and Retraction Forces: A Three-Dimensional Finite Element Study.
The objective of the study was to evaluate the stress pattern in cortical and cancellous bones, periodontal ligament, and in the implant itself when a mini-implant (MI) is inserted in the inter-radicular space between mandibular first molar and second premolar at various angulations and different retraction forces. Finite element study was conducted with MI insertion at 30°, 45°, 60°, 75°, and 90° angulations in the mandibular posterior region (between second premolar and first molar). At these angulations, horizontal forces of 150, 200, and 250 g were applied to the middle of the MI head. von Mises stress values were then evaluated using the ANSYS software. Highest von Mises stress values were detected in the MI itself, followed by cortical bone, cancellous bone, and periodontal ligament. The von Mises stress values in cortical bone were highest at 30° angulation and lowest at 90° angulation. In the cancellous bone, the stress value was found to be maximum at 90°. The von Mises stress values in the MI were lowest at 90°. In all four structures, as the load increased from 150 to 250 g, the von Mises stress values increased. The von Mises stress values in the cortical bone, MI, and periodontal ligament were found to be lowest at 90°. Placement of the MI at 90° appears to be an ideal angulation when applied with a horizontal load. Force range used is within clinically recommended levels; however, the increase in load causes an increase in the stress values.


Cross-species Blink Characterisation Tool for the Analysis of Emerging Interventions for Overcoming Facial Paralysis.
The loss of the ability to blink is considered the most severe consequence of facial nerve paralysis. Surgical techniques and implantable technologies continue to be developed to reanimate the eye; however, few analyse the full movement of blink when evaluating success. Here, we describe a method of taking high-quality, and high-speed video recordings of the eye, to non-invasively extract meaningful data about the dynamic movement of blinking. This can then be used to assess the effectiveness of a new technology in mimicking the natural movement. The tool was validated on humans (N=2, authors) before testing on an ovine recording (N=1), to confirm the cross-species utility of the tool, for use during preclinical development of technologies. It was found to be accurate and comprehensive, able to give insights on blinking in both human and ovine cases.


[Effect of electric stimulation of the caudate nucleus on the foci of epileptic activity in the cerebral cortex].
It was shown in the acute experiments on rats that caudate nucleus is one of the main structures of brain antiepileptic system. It was noted that reduction of the influence of activating cerebral structures is a tool for abolishing the proepileptic effects which occur in some cases under conditions of electrical stimulations of neostriatum. Results of the investigation confirm G. N. Kryzhanovsky theory of a role of system-antisystem interrelations in suppression of neuropathological syndromes as a result of system hyperactivity.


Synthesis and liquid crystalline properties of mono-, di- and tri-O-alkyl pentaerythritol derivatives bearing tri-, di- or monogalactosyl heads: the effects of curvature of molecular packing on mesophase formation.
Self-organisation and self-assembly are critical to the stability of synthetic and biological membranes. Of particular importance is consideration of the packing arrangements of the various molecular species. Both phospho- and glycolipids can pack in ways in which curvature can be introduced into self-organised or self-assembled systems. For instance, it is known that the degree of curvature can affect the structures of any condensed phases that are formed. In this article we report on a systematic study in which we have varied the shapes of glycolipids and examined the condensed phases that they form. In doing so, we have also unified the shape dependency of lyotropic liquid crystals with those of thermotropic liquid crystals. In order to undertake this systematic study a range of different pentaerythritol derivatives was synthesized, which covers combinations of one to three alkyl chains of different lengths (6,7,9,10,11,12,14,16 carbon atoms) and three to one galactosyl heads. Mono- and di-O-galactosyl derivatives were prepared directly by glycosylation of the corresponding alcohols using 2,3,4,6-tetra-O-benzoyl or acetyl-alpha-D-galactopyranosyl trichloroacetimidate or bromide as the donors; the tri-O-galactosyl derivatives were synthesized from O-alkyl-O-benzyl di-O-galactosyl pentaerythritol intermediates, followed by de-O-benzylation and glycosylation steps. All of the fully deprotected products were obtained by standard methods, and their self-organising and self-assembling properties examined.