Hippocampal neural stem cells facilitate access from circulation via apical cytoplasmic processes.
Blood vessels (BVs) are considered an integral component of neural stem cells (NSCs) niches. NSCs in the dentate gyrus (DG(have enigmatic elaborated apical cellular processes that are associated with BVs. Whether this contact serves as a mechanism for delivering circulating molecules is not known. Here we uncovered a previously unrecognized communication route allowing exclusive direct access of blood-borne substances to hippocampal NSCs. BBB-impermeable fluorescent tracer injected transcardially to mice is selectively uptaken by DG NSCs within a minute, via the vessel-associated apical processes. These processes, measured >30 nm in diameter, establish direct membrane-to-membrane contact with endothelial cells in specialized areas of irregular endothelial basement membrane and enriched with vesicular activity. Doxorubicin, a brain-impermeable chemotherapeutic agent, is also readily and selectively uptaken by NSCs and reduces their proliferation, which might explain its problematic anti-neurogenic or cognitive side-effect. The newly-discovered NSC-BV communication route explains how circulatory neurogenic mediators are 'sensed' by NSCs.


Glucocorticoid and mineralocorticoid receptor-binding characteristics in obese (ob/ob) mice.
Adrenalectomy prevents development of obesity in genetically obese (ob/ob) mice. Replacement studies have shown that these mice exhibit hypersensitivity to corticosterone. This study was conducted to determine if this increased sensitivity was associated with alterations in corticoid receptor number or binding affinity. Cytosolic glucocorticoid receptor numbers were lower by 26% in liver, 23% in brain, and 26% in brown adipose tissue of 8-wk-old male ob/ob mice when compared with lean mice. Cytosolic glucocorticoid receptor numbers were similar in liver and brain of 4-wk-old lean and ob/ob mice is likely secondary to elevated plasma corticosterone concentrations in these older mice. Adrenalectomy increased cytosolic glucocorticoid receptor numbers in liver and brain of 8-wk-old ob/ob mice to values comparable to those in lean mice. Injection of dexamethasone (0.5 or 5 micrograms/g body wt) equally lowered cytosolic glucocorticoid receptor numbers in liver and brain of adrenalectomized ob/ob and lean mice. Brain mineralocorticoid receptor numbers and response to dexamethasone were similar in ob/ob and lean mice. These results suggest that the site responsible for increased sensitivity of ob/ob mice to corticosterone is postreceptor binding.


Lower dose of antithymocyte globulin does not increase graft-versus-host disease in patients undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell transplant.
The appropriate dose of antithymocyte globulin (ATG) to be utilized in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplant (alloHSCT) is as yet unknown. We retrospectively compared patients who received 7.5 mg/kg (R-ATG, 39 patients) and 6 mg/kg (r-ATG, 97 patients). The cumulative incidences of acute graft-versus-host disease (aGVHD) grade II-IV at 180 days were 46% and 41% and of aGVHD grade III-IV were 11% and 18% in r-ATG and R-ATG, respectively (p > 0.30). The respective estimated cumulative incidences at 24 months of cGVHD were 42% and 44% (p > 0.30). There was no significant difference in non-relapse mortality (p = 0.22), cumulative incidence of relapse (p = 0.53), progression-free survival (p = 0.69) or overall survival (p = 0.95). In conclusion, a decreased ATG dose of 6 mg/kg was associated with a similar proportion of GVHD to 7.5 mg/kg ATG. Given the increasing number of RIC HSCTs performed worldwide, the correct dose and preparation of ATG should be defined by prospective randomized trials.


The revised DCDQ: is it a suitable screening measure for motor difficulties in adolescents?
The parent-rated Developmental Coordination Disorder Questionnaire (DCDQ) has been revised to incorporate a wider age range, including adolescence. In this exploratory study, internal consistency and validity of the DCDQ-2007 was assessed using a community-based sample of 87 adolescents. Psychometric properties of the DCDQ-2007 were investigated and concurrent validity, sensitivity, and specificity were assessed with the MABC-2 as a criterion standard. The results demonstrated high internal consistency for the DCDQ-2007 and a relationship with the MABC-2 was found. The DCDQ-2007 met the recommended standard for sensitivity, although the confidence interval was large; however, it failed to meet the recommended standard for specificity. This has important implications concerning the suitability of the DCDQ-2007. Although promising psychometric properties were found within the current study, the applicability of the DCDQ-2007 as a screening measure for motor difficulties requires careful consideration.


Rho-ROCK signaling regulates tumor-microenvironment interactions.
Reciprocal biochemical and biophysical interactions between tumor cells, stromal cells and the extracellular matrix (ECM) result in a unique tumor microenvironment that determines disease outcome. The cellular component of the tumor microenvironment contributes to tumor growth by providing nutrients, assisting in the infiltration of immune cells and regulating the production and remodeling of the ECM. The ECM is a noncellular component of the tumor microenvironment and provides both physical and biochemical support to the tumor cells. Rho-ROCK signaling is a key regulator of actomyosin contractility and regulates cell shape, cytoskeletal arrangement and thereby cellular functions such as cell proliferation, differentiation, motility and adhesion. Rho-ROCK signaling has been shown to promote cancer cell growth, migration and invasion. However, it is becoming clear that this pathway also regulates key tumor-promoting properties of the cellular and noncellular components of the tumor microenvironment. There is accumulating evidence that Rho-ROCK signaling enhances ECM stiffness, modifies ECM composition, increases the motility of tumor-associated fibroblasts and lymphocytes and promotes trans-endothelial migration of tumor-associated lymphocytes. In this review, we briefly discuss the current state of knowledge on the role of Rho-ROCK signaling in regulating the tumor microenvironment and the implications of this knowledge for therapy, potentially via the development of selective inhibitors of the components of this pathway to permit the tuning of signaling flux, including one example with demonstrated utility in pre-clinical models.


Exosomal miR-16-5p as a target for malignant mesothelioma.
Malignant mesothelioma (MM) is an asbestos-induced cancer arising on the mesothelial surface of organ cavities. MM is essentially incurable without a means of early diagnosis and no successful standard of care. These facts indicate a deep chasm of knowledge that needs to be filled. Our group recently delved into MM tumor biology from the perspective of exosome-contained microRNAs (miRNAs). We discovered that the most abundant miRNAs in MM cancer exosomes were tumor suppressors, particularly miR-16-5p. This observation lead us to hypothesize that MM cells preferentially secreted tumor-suppressor miRNAs via exosomes. Through separate avenues of potential therapeutic advance, we embarked on an innovative strategy to kill MM tumor cells. We employed small molecule inhibitors to block exosome secretion, thereby reducing miR-16-5p exosome loss and replenishing cellular miR-16-5p leading to reduced tumorigenic capacity and miR-16-5p target oncoproteins CCND1 and BCL2. Additionally, we force-fed MM tumor exosomes back to MM tumor cells, which led to cell death, and a reduction in the same oncoproteins. We recapitulated these results with direct transfection of miR-16-5p, confirmed that this is a cancer-cell specific effect, and elucidated a part of the miR-16-5p mechanism of exosome loading.


Cystic fibrosis transmembrane conductance regulator mediates sulphonylurea block of the inwardly rectifying K+ channel Kir6.1.
1. Recombinant ATP-sensitive K+ channels (KATP channels) were heterologously expressed in the NIH3T3 mouse cell line, and the electrophysiological properties were studied using patch-clamp techniques. 2. The NIH3T3 cell lines transfected with the inwardly rectifying K+ channel Kir6.1 alone or with both Kir6.1 and cystic fibrosis transmembrane conductance regulator (CFTR) exhibited time-independent K+ currents with weak inward rectification. In contrast, no measurable K+ conductance was observed in mock-transfected cells or in cells transfected with CFTR alone. Regardless of co-transfection with Kir6.1, the transfection with CFTR produced a Cl- conductance that was activated by cell dialysis with cAMP (1 mM). The conductance was reversibly suppressed by glibenclamide (30 microM). 3. Whole-cell currents at +60 mV were blocked in a concentration-dependent manner by Ba2+ ions with similar IC50 values: 89.3 +/- 23.3 microM (Kir6.1 alone) and 67.3 +/- 24.9 microM (Kir6.1-CFTR). 4. The currents recorded from Kir6. 1-transfected cells were not affected by glibenclamide, whereas glibenclamide did inhibit the conductance expressed in cells co-transfected with CFTR (IC50 = 35.9 +/- 6.6 microM). 5. In the cell-attached mode with a 150 mM K+ pipette solution, both Kir6.1- and Kir6.1-CFTR-transfected cells displayed a class of K+ channels showing weak inward rectification and a slope conductance of 50.7 +/- 1.0 and 52.4 +/- 4.9 pS, respectively. 6. In the inside-out mode, the single-channel currents recorded from both types of cells were not inhibited by intracellular ATP (1 mM). However, glibenclamide was found to block the single-channel activities in the co-transfected cells.


Relationship between icam-1 serum levels and thymostimulin therapy in patients with liver-cirrhosis associated with hepatocellular-carcinoma.
Intercellular adhesion molecule-1 (ICAM-1), is a cell surface molecule involved in many immunological processes. Recently, ICAM-1 has also been detected as a soluble form in sera of patients affected by different pathologies and often associated with severity of the disease. However, all these studies were carried out in patients before drug treatment. Since in vitro experiments and recent evidence in humans has indicated the possibility that some cytokines may be responsible of ICAM-1 release, we have considered the possibility of quantitating ICAM-1 in sera of patients undergoing therapy with drugs influencing cytokine regulation. Thymostimulin, which seems to belong to this category, has been used in a pilot study by some of us in the treatment of patients with liver cirrhosis associated with hepatocellular carcinoma. By using an enzymatic sandwich assay, we found significantly high circulating ICAM-1 mean values in patients affected by liver cirrhosis alone or associated with hepatocellular carcinoma or non-Hodgkin lymphoma compared to control subjects (p<0.001), Moreover, in patients with hepatocellular carcinoma or liver cirrhosis who were treated with thymostimulin, serial detection of c-ICAM-1 was carried out and patients responsive to the drug showed significantly increased values of c-ICAM-1 (p=0.006), Our study suggests that an evaluation of c-ICAM-1 levels needs to be considered in the context of the therapeutic approach, with particular attention to those drugs which may affect the regulation of the cytokine pathway.


Sulcal and ventricular trajectories in stereotactic surgery.
The authors analyzed deep brain stimulation electrode trajectories on MR images to identify risks of cerebrovascular complications associated with the number of electrode insertions, traversal of a sulcus, and penetration of the ventricle. Pre- and postoperative MR volumes were fused to determine the proximity of electrodes to a sulcus or ventricle and whether there were cortical, subcortical, or intraventricular complications. Complications were further classified as hemorrhagic or nonhemorrhagic and symptomatic or asymptomatic. The authors examined 258 electrode implantation for deep brain stimulation. There were 4 symptomatic events (1.6% incidence): 3 hemorrhagic and 1 nonhemorrhagic, all within the cortex. Asymptomatic events included cortical hemorrhage in 1 patient, nonhemorrhagic cortical changes in 6, pallidal hemorrhage in 1, thalamic infarction in 1, and intraventricular hemorrhage (IVH) in 5 patients. Proximity to a sulcus was a significant risk factor for hemorrhagic and nonhemorrhagic cortical complications (p = 0.001). There was a complication rate of 10.1% within the trajectories penetrating or adjacent to a sulcus, and a 0.7% rate with trajectories clearly positioned within the gyrus. Asymptomatic IVH was observed in 5% of ventricular penetrations. A history of hypertension was a risk factor for cortical hemorrhage (p = 0.019), but not for cortical ischemic/edematous events (p = 0.605). The number of electrode penetrations did not differ between patients with and without complications (p = 0.868), and the sequence of electrode insertions was not a risk factor in bilateral surgeries. Symptomatic cortical complications occur when electrodes traverse close to a sulcus. Asymptomatic IVH occurs infrequently with ventricular penetration. Despite intraoperative efforts to avoid cortical sulci, a higher than expected incidence of electrode proximity to the sulci was identified on careful postoperative trajectory analysis. This finding emphasizes the importance of assiduously planning trajectories and reviewing cases with thorough MR analysis.


Bone thickness of the anterior palate for orthodontic miniscrews.
To determine the bone thickness in the anterior palate and to test whether there is any dependency between bone thickness and patient's age or gender and whether there is any difference between left and right sides. Cone beam computed tomographic (CBCT) evaluations (n = 431; 229 females, 202 males) of healthy orthodontic patients aged 9-30 years were selected from the database of the imaging center network Mesantis. In each CBCT image, palatal bone thickness was determined as the median and 2, 4, 6, and 8 mm paramedian bilaterally. Bone height was measured perpendicularly to the bony surface at 10, 12, 14, 16, 18, and 20 mm from the cementoenamel junction of the maxillary central incisor in the sagittal plane. The greatest bone thickness was found in the lateral anterior palate. Palatal bone thickness of male patients was on average 1.2 mm greater than that of females. Bone height of 9-13-year-olds was less than that of older patients. No difference could be determined between the left and right side. The lateral anterior palate offers the greatest bone thickness. Because there is considerable variation of bone thickness between individuals, a CBCT evaluation is recommended if maximum screw length is to be used.


Effects of anesthesia and species on the uptake or binding of radioligands in vivo in the Göttingen minipig.
Progress in neuroscience research often involves animals, as no adequate alternatives exist to animal models of living systems. However, both the physiological characteristics of the species used and the effects of anesthesia raise questions of common concern. Here, we demonstrate the confounding influences of these effects on tracer binding in positron emission tomography (PET). We determined the effects of two routinely used anesthetics (isoflurane and propofol) on the binding of two tracers of monoamine function, [(11)C]SCH23390, a tracer of the dopamine D1 and D5 receptors, and the alpha2-adrenoceptor antagonist, [(11)C]yohimbine, in Göttingen minipigs. The kinetics of SCH23390 in the pigs differed from those of our earlier studies in primates. With two different graphical analyses of uptake of SCH23390, the initial clearance values of this tracer were higher with isoflurane than with propofol anesthesia, indicative of differences in blood flow, whereas no significant differences were observed for the volumes of distribution of yohimbine. The study underscores the importance of differences of anesthesia and species when the properties of radioligands are evaluated under different circumstances that may affect blood flow and tracer uptake. These differences must be considered in the choice of a particular animal species and mode of anesthesia for a particular application.


Single-Cell Mass Spectrometry of Metabolites Extracted from Live Cells by Fluidic Force Microscopy.
Single-cell metabolite analysis provides valuable information on cellular function and response to external stimuli. While recent advances in mass spectrometry reached the sensitivity required to investigate metabolites in single cells, current methods commonly isolate and sacrifice cells, inflicting a perturbed state and preventing complementary analyses. Here, we propose a two-step approach that combines nondestructive and quantitative withdrawal of intracellular fluid with subpicoliter resolution using fluidic force microscopy, followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The developed method enabled the detection and identification of 20 metabolites recovered from the cytoplasm of individual HeLa cells. The approach was further validated in 13C-glucose feeding experiments, which showed incorporation of labeled carbon atoms into different metabolites. Metabolite sampling, followed by mass spectrometry measurements, enabled the preservation of the physiological context and the viability of the analyzed cell, providing opportunities for complementary analyses of the cell before, during, and after metabolite analysis.


Rust fungi causing galls, witches' brooms, and other abnormal plant growths in northwestern Argentina.
Conspicuous galls and witches' brooms frequently are symptoms of rust infections on plant hosts in the ecologically diverse northwestern region of Argentina. These symptoms are caused by systemic or locally systemic spermogonial-aecial infections, although uredinial and telial infections also might be involved. Sixteen species of rust fungi are treated in this paper, most of which cause a plant response that results in enlarged growth. Ypsilospora tucumanensis J.R. Hern. & J.F. Hennen on Inga edulis is described as a species new to science. Puccinia cordiae Arthur is cited as a new record for Argentina. These rusts also are included: Chaconia ingae, Gerwasia imperialis, Kuehneola loeseneriana, Prospodium appendiculatum, Prospodium elegans, Prospodium perornatum, Puccinia bougainvilleae, Puccinia pampeana, Ravenelia argentinica, Ravenelia hieronymi, Ravenelia papillosa, Ravenelia spegazziniana, Uromyces cestri and Uropyxis rickiana. For some of the scientific names, lectotype specimens have been designated.


Impact of toxic cyanobacteria on gastropods and microcystin accumulation in a eutrophic lake (Grand-Lieu, France) with special reference to Physa (= Physella) acuta.
Hepatotoxic microcystins (MCs) produced by cyanobacteria are known to accumulate in gastropods following grazing of toxic cyanobacteria and/or absorption of MCs dissolved in water, with adverse effects on life history traits demonstrated in the laboratory. In the field, such effects may vary depending on species, according to their relative sensitivity and ecology. The aims of this study were to i) establish how various intensities of MC-producing cyanobacteria proliferations alter the structure of gastropod community and ii) compare MC tissue concentration in gastropods in the field with those obtained in our previous laboratory experiments on the prosobranch Potamopyrgus antipodarum and the pulmonate Lymnaea stagnalis. We explored these questions through a one-year field study at three stations at Grand-Lieu Lake (France) affected by different intensities of cyanobacteria proliferations. A survey of the community structure and MC content of both cyanobacteria and gastropods was associated with a caging experiment involving P. antipodarum and L. stagnalis. In total, 2592 gastropods belonging to 7 prosobranch and 16 pulmonate species were collected. However, distribution among the stations was unequal with 62% vs 2% of gastropods sampled respectively at the stations with the lowest vs highest concentrations of MC. Irrespective of the station, pulmonates were always more diverse, more abundant and occurred at higher frequencies than prosobranchs. Only the pulmonate Physa acuta occurred at all stations, with abundance and MC tissue concentration (< or = 4.32 microg g DW(-1)) depending on the degrees of MC-producing cyanobacteria proliferations in the stations; therefore, P. acuta is proposed as a potential sentinel species. The caging experiment demonstrated a higher MC accumulation in L. stagnalis (< or = 0.36 microg g DW(-1) for 71% of individuals) than in P. antipodarum (< or = 0.02 microg g DW(-1) for 12%), corroborating previous laboratory observations. Results are discussed in terms of differential gastropod sensitivity and MC transfer through the food web.


The Imbalance Expression of DLX3 May Perform Critical Function in the Occurrence and Progression of Preeclampsia.
The present research focuses on preeclampsia (PE), a clinically relevant pregnancy disease. To date, the majority of research on PE was centered on placental insufficiency. However, the genes that regulate these processes, and the exact molecular mechanisms modulating these processes, are still unclear. We obtained placentae from a clinically well-specified group of patients with preeclampsia and gestationally matched control pregnancies in order to evaluate the expression of homeobox gene DLX3 by immunohistochemical staining, real-time PCR, and Western immunoblotting and determine the function of DLX3 utilizing lentivirus transfection in HTR-8/SVneo cells. In the present study, we detected DLX3 expression in a clinically well defined cohort of preeclampsia-affected and gestation-matched control pregnancies. As opposed to the controls, DLX3 was overexpressed in preeclampsia-affected placentae. Moreover, we found that the in vitro cell growth and invasive ability of HTR8/SVneo cells was enhanced by the exogenous overexpression of DLX3 (P < 0.05). It can be seen that DLX3 influences the cell cycle of HTR-8/SVneo cells in vitro. DLX3 has been shown to be strongly related to normal placental growth as well as the pathophysiology of preeclampsia. The imbalanced expression of DLX3 may perform an integral function in the occurrence and progression of preeclampsia.


The influence of preoperative mental health on clinical outcomes after laminectomy in patients with lumbar spinal stenosis.
The influence of preoperative mental health on health-related quality of life (HRQOL) in patients with lumbar spinal stenosis (LSS) remains unclear. This study aims to investigate the influence of preoperative mental health HRQOL after laminectomy in patients with LSS. We retrospectively reviewed 122 patients who had lumbar spinous process splitting laminectomy (LSPSL) for LSS. We assessed clinical information; Japanese Orthopedic Association (JOA) score; numerical rating scale (NRS) for low back pain, for leg pain, and for leg numbness; Zurich Claudication Questionnaire (ZCQ); JOA Back Pain Evaluation Questionnaire (JOABPEQ); Roland-Morris Disability Questionnaire (RMDQ); and Short Form 8 (SF-8) as patient reported outcomes. Patients were divided into two groups (Group L ≤ 36.2 points and Group NL > 36.2 points) based on the results of the preoperative mental health (MH) score in SF-8 to examine the influence of MH in LSS. We compared the HRQOL between the two groups postoperatively. The JOA score, NRS, and ZCQ score significantly improved after surgery. HRQOL outcomes including JOABPEQ, RMDQ, and SF-8 showed that the LSPSL improved not only the physical but also the mental function in patients with LSS. All HRQOL outcomes in Group L exhibited significantly worse scores preoperatively; however, no significant differences between two groups were found postoperatively. LSPSL greatly reduced low back pain, leg pain, and leg numbness. LSPSL resulted in a significant improvement based on HRQOL questionnaires even in patients with preoperative depressive mood. Not only the physical status but also the mental health may improve after LSPSL even in patients with LSS with a depressive mood preoperatively.


The PPAR-γ agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-β treated pancreatic cancer cells.
We have previously shown that cancer cells can protect themselves from apoptosis induced by type I interferons (IFNs) through a ras→MAPK-mediated pathway. In addition, since IFN-mediated signalling components STATs are controlled by PPAR gamma we studied the pharmacological interaction between recombinant IFN-β and the PPAR-γ agonist troglitazone (TGZ). This combination induced a synergistic effect on the growth inhibition of BxPC-3, a pancreatic cancer cell line, through the counteraction of the IFN-β-induced activation of STAT-3, MAPK and AKT and the increase in the binding of both STAT-1 related complexes and PPAR-γ with specific DNA responsive elements. The synergism on cell growth inhibition correlated with a cell cycle arrest in G0/G1 phase, secondary to a long-lasting increase of both p21 and p27 expressions. Blockade of MAPK activation and the effect on p21 and p27 expressions, induced by IFN-β and TGZ combination, were due to the decreased activation of STAT-3 secondary to TGZ. IFN-β alone also increased p21 and p27 expression through STAT-1 phosphorylation and this effect was attenuated by the concomitant activation of IFNbeta-induced STAT-3-activation. The combination induced also an increase in autophagy and a decrease in anti-autophagic bcl-2/beclin-1 complex formation. This effect was mediated by the inactivation of the AKT→mTOR-dependent pathway. To the best of our knowledge this is the first evidence that PPAR-γ activation can counteract STAT-3-dependent escape pathways to IFN-β-induced growth inhibition through cell cycle perturbation and increased autophagic death in pancreatic cancer cells.


Simultaneous attainment of high electron and ion temperatures in discharges with internal transport barriers in ASDEX upgrade
Internal transport barriers have been demonstrated to exist also under conditions with T(e) approximately T(i) approximately 10 keV and predominant electron heating of the tokamak core region. Central electron cyclotron heating was added to neutral beam injection-heated ASDEX Upgrade discharges with a preexisting internal transport barrier, established through programmed current ramping leading to shear reversal. Compared to a reference internal transport barrier discharge without electron cyclotron resonance heating, the electron heat conductivity in the barrier region was found not to increase, in spite of a fivefold increase in electron heat flux, and also angular momentum and ion energy transport did not deteriorate.


Repair of DNA following incorporation of 1-beta-D-arabinofuranosylcytosine into herpes simplex virus type 1.
The nucleoside analogue 1-beta-D-arabinofuranosylcytosine (ara-C) is incorporated into herpes simplex virus type 1 (HSV-1) DNA, and this correlates with inhibition of virus replication. The technique of Weigle-type reactivation (WR) was used to compare the ability of induced cellular DNA repair pathways to recognize or repair ara-C incorporated into HSV-1 DNA and ultraviolet (UV)-irradiated virus DNA (254 nm). Pretreatment of monkey cells with low-fluence UV irradiation, growth in cis-dichlorodiammineplatinum(II), or growth in ara-C followed by infection after a 24-hr incubation period resulted in enhanced survival of UV-irradiated HSV-1. Under the same experimental conditions, no reactivation of HSV-1 inactivated by growth in ara-C is observed. Comparisons between uninfected Vero cells exposed to UV irradiation (30 J/m2) or grown in 10(-6) M ara-C demonstrated repair replication in irradiated cells, whereas there was no evidence for DNA repair at various time intervals following removal of the nucleoside analogue. These observations suggest that, once ara-C is incorporated into HSV-1 or eukaryotic DNA, it is not recognized as a repairable lesion within the limits of the DNA repair assays used in these studies.


Association between Influenza A Virus Infection and Pigs Subpopulations in Endemically Infected Breeding Herds.
Influenza A viruses (IAVs) are distributed worldwide in birds, pigs and humans, and cause important endemic disease affecting hosts in all countries. Although pigs play a key role in the ecology of IAVs, the epidemiology of IAVs within swine herds is poorly understood. In this longitudinal study we describe the prevalence of IAVs infection in three subpopulations of pigs in 5 breeding herds in the Midwestern USA. Each herd was sampled monthly for a year and, at each visit, 30 individual nasal swabs were collected from the three subpopulations, namely, a) replacement females, resident on-farm for less than 4 weeks (new gilts), b) replacement females, resident on-farm for more than 4 weeks (gilts), and c) neonatal pigs less than 21 days of age (piglets). Real time reverse transcriptase polymerase chain reaction (RRT-PCR) was used to detect IAVs, and the association between IAVs infection and pig subpopulation was measured using a mixed logistic regression model. Nasal swabs (n = 4,190) were collected from 141 groups of pigs. At least, one IAV-positive nasal swab was found in 19.9% (n = 28) of the sampled groups, and 7.7% (n = 324) of all nasal swabs tested positive. After adjusting by annual quarter and sampling event, the odds of testing IAV positive were 7.9 (95% CI 1.4, 43.9) and 4.4 (95% CI 1.1, 17.1) times higher in groups of new gilts and piglets compared to groups of gilts, respectively. Results indicate that new gilts and piglets had higher odds of testing IAV positive than gilts in swine breeding herds and that season influences IAV infection in pigs. Based on these findings, we recommend that IAV control strategies be aimed at preventing infection before gilts are introduced into the farm, and in pigs prior to weaning.


Retrospective analysis of Cryptosporidium species in Western Australian human populations (2015-2018), and emergence of the C. hominis IfA12G1R5 subtype.
Cryptosporidium species are a major cause of diarrhoea worldwide. In the present study, a retrospective analysis of 109 microscopically Cryptosporidium-positive faecal specimens from Western Australian patients, collected between 2015 and 2018 was conducted. Sequence analysis of the 18S rRNA and the 60 kDa glycoprotein (gp60) gene loci identified four Cryptosporidium species: C. hominis (86.2%, 94/109), C. parvum (11.0%, 12/109), C. meleagridis (1.8%, 2/109) and C. viatorum (0.9%, 1/109). Subtyping at the gp60 locus identified a total of 11 subtypes including the emergence of the previously rare C. hominis IfA12G1R5 subtype in 2017 as the dominant subtype (46.7%, 21/45). This subtype has also recently emerged as the dominant subtype in the United States but the reasons for its emergence are unknown. This is also the first report of C. viatorum in humans in Australia and a novel subtype (XVaA3g) was identified in the one positive patient.


Cyclooxygenase inhibition abolishes age-related differences in cerebral vasodilator responses to hypercapnia.
Blood flow and vasodilatory responses are altered by age in a number of vascular beds, including the cerebral circulation. To test the role of prostaglandins as regulators of cerebral vascular function, we examined cerebral vasodilator responses to CO(2) (cerebrovascular reactivity) in young (26 ± 5 yr; 6 males/6 females) and older (65 ± 6 yr, 5 males/5 females) healthy humans before and after cyclooxygenase inhibition (using indomethacin). Middle cerebral artery velocity (MCAv) responses to stepped hypercapnia were measured before and 90 min after indomethacin. Changes in MCAv during the recovery from hypercapnia (vasoconstrictor responses) were also evaluated before and after indomethacin. Cerebrovascular reactivity was calculated using linear regression between MCAv and end-tidal CO(2). Young adults demonstrated greater MCAv (55 ± 6 vs. 39 ± 5 cm/s: P < 0.05) and MCAv reactivity (1.67 ± 0.20 vs. 1.09 ± 0.19 cm·s(-1)·mmHg(-1); P < 0.05) to hypercapnia compared with older adults (P < 0.05). In both groups MCAv and MCAv reactivity decreased between control and indomethacin. Furthermore, the age-related differences in these cerebrovascular variables were abolished by indomethacin. During the recovery from hypercapnia, there were no age-related differences in MCAv reactivity; however, indomethacin significantly reduced the MCAv reactivity in both groups. Taken together, these results suggest that cerebral blood flow velocity and cerebrovascular reactivity are attenuated in aging humans, and may be due to a loss of prostaglandin-mediated vasodilation.


Legitimising fatigue after breast-cancer treatment.
This study aimed to explore the experience of women living with fatigue following chemotherapy for breast cancer. Six focus groups were conducted (n=40); all participants had taken part in a multi-site acupuncture trial. There were three to seven people per focus group. Additionally, two people attended one-to-one interviews and four people provided written responses to the trigger questions. The audiotapes from these sessions were transcribed and analysed using a thematic approach. Participants raised concerns about fatigue possibly being a symptom of the cancer coming back or a sign of senility. Respondents described the effects of fatigue on relationships, sexuality, social life, home life and returning to work. The Coping with Fatigue booklet ( Macmillan Cancer Support, 2011 ) was discussed in terms of legitimising the experience of cancer-related fatigue and explaining symptoms to family and work colleagues. More research work is required to evaluate non-pharmaceutical interventions and advice to support women living with fatigue after chemotherapy for breast cancer.


Distinct sets of acute phase plasma proteins are stimulated by separate human hepatocyte-stimulating factors and monokines in rat hepatoma cells.
A subline of the rat hepatoma (H-35) cells has been identified which responds to hepatocyte-stimulating factors (HSFs) of human squamous carcinoma cells by increased synthesis of all major rat acute phase plasma proteins. The regulation occurs at the level of mRNA. Two HSFs (HSF-I and HSF-II) have been purified from conditioned medium of the squamous carcinoma cells. HSF-I is a protein with an Mr = 18,000 and pI 5.5, and HSF-II is a glycoprotein with an Mr = 34,000 and a broad, neutral to basic charge. In H-35 cells, HSF-I predominantly stimulates the synthesis of complement C3 and haptoglobin and acts synergistically with dexamethasone to stimulate alpha 1-acid glycoprotein. HSF-II stimulates cysteine protease inhibitor, alpha 1-antichymotrypsin, alpha 1-antitrypsin, fibrinogen, and hemopexin, and acts synergistically with dexamethasone to stimulate alpha 2-macroglobulin. Each HSF is between 10 and 100 times less effective in regulating proteins of the other set. Human tumor necrosis factor and interleukin-1 increase complement C3, haptoglobin, and alpha 1-acid glycoprotein, as does HSF-I, but are unable to modulate any of the other acute phase proteins. The monokines differ from HSF-I is their low activity in HepG2 cells and rat hepatocytes.


Flexible weighting of body-related effects in action production.
A previous study on ideomotor action control showed that predictable action effects in the agent's environment influenced how an action is carried out. If participants were required to perform a forceful keypress, they exerted more force when these actions would produce a quiet compared to a loud tone, and this observation suggests that anticipated proprioceptive and auditory action effects are integrated with each other during action planning and control. In light of the typically weak influence of body-related effect found in recent work, we aimed to extend this pattern of results to the intra-modal case of integrating proprioceptive/tactile feedback of a movement and following vibro-tactile effects. Our results suggest that the same weighted integration process as for the cross-modal case applies to the intra-modal case. These observations support the idea of a common mechanism which binds all action-related features in an integrated action representation, irrespective of whether these features relate to exafferent or reafferent signals.


Recommendations for Healthy Nutrition in Female Endurance Runners: An Update.
The purpose of this review is to present the basic principles of a healthy nutrition in female endurance runner enriched by the latest scientific recommendations. Female endurance runners are a specific population of athletes who need to take specifically care of daily nutrition due to the high load of training and the necessity to keep a rather low body mass. This paradoxical situation can create some nutritional imbalances and deficiencies. Female endurance athletes should pay attention to their total energy intake, which is often lower than their energy requirement. The minimal energy requirement has been set to 45 kcal/kg fat free mass/day plus the amount of energy needed for physical activity. The usual recommended amount of 1.2-1.4 g protein/kg/day has recently been questioned by new findings suggesting that 1.6 g/kg/day would be more appropriate for female athletes. Although a bit less sensitive to carbohydrate loading than their male counterparts, female athletes can benefit from this nutritional strategy before a race if the amount of carbohydrates reaches 8 g/kg/day and if their daily total energy intake is sufficient. A poor iron status is a common issue in female endurance runners but iron-enriched food as well as iron supplementation may help to counterbalance this poor status. Finally, they should also be aware that they may be at risk for low calcium and vitamin D levels.


Metal-mediated post-Ugi transformations for the construction of diverse heterocyclic scaffolds.
The Ugi-4CR is by far one of the most successful multicomponent reactions leading to high structural diversity and molecular complexity. However, the reaction mostly affords a linear peptide backbone, enabling post-Ugi transformations as the only solution to rigidify the Ugi-adduct into more drug like species. Not surprisingly, the development of these transformations, leading to new structural frameworks, has expanded rapidly over the last few years. As expected, palladium-catalyzed reactions have received the foremost attention, yet other metals, particularly gold complexes, are fast catching up. This tutorial review outlines the developments achieved in the past decade, highlighting the modifications that are performed in a sequential or domino fashion with emphasis on major concepts, synthetic applications of the derived products as well as mechanistic aspects.


Aperture synthesis in phase retrieval using a volume-speckle field.
The resolution of the reconstructed wave by a phase-retrieval method using a volume-speckle field depends on the aperture defined by the size of the CCD array. The use of a larger aperture is introduced by measuring the speckle field at two different positions in the transverse plane and stitching the measurements together. Improvements in the quality of reconstructions are demonstrated experimentally and by computer simulations. Undesirable effects of camera tilt on the quality of reconstructions from synthetic aperture intensity measurements are experimentally observed and corrected.


Preferential flow paths shape the structure of bacterial communities in a clayey till depth profile.
Preferential flow paths in subsurface soils serve as transport routes for water, dissolved organic matter and oxygen. Little is known about bacterial communities in flow paths or in subsoils below ∼4 m. We compared communities from preferential flow paths (biopores, fractures and sand lenses) with those in adjacent matrix sediments of clayey till from the plough layer to a depth of 6 m. 16S rRNA gene-targeted community analysis showed bacterial communities of greater abundance and diversity in flow paths than in matrix sediments at all depths. Deep fracture communities contained a higher relative abundance of aerobes and plant material decomposers like Nitrospirae, Acidobacteria and Planctomycetes than adjacent matrix sediments. Similarly, analyses of the relative abundances of archaeal amoA, nirK and dsrB genes indicated transition from aerobic to anaerobic nitrogen and sulphur cycling at greater depth in preferential flow paths than in matrix sediments. Preferential flow paths in the top 260 cm contained more indicator operational taxonomic units from the plough layer community than the matrix sediments. This study indicates that the availability of oxygen and organic matter and downward transport of bacteria shape bacterial communities in preferential flow paths, and suggests that their lifestyles differ from those of bacteria in matrix communities.


Inhibitors of Bcl-2 protein family deplete ER Ca2+ stores in pancreatic acinar cells.
Physiological stimulation of pancreatic acinar cells by cholecystokinin and acetylcholine activate a spatial-temporal pattern of cytosolic [Ca(+2)] changes that are regulated by a coordinated response of inositol 1,4,5-trisphosphate receptors (IP(3)Rs), ryanodine receptors (RyRs) and calcium-induced calcium release (CICR). For the present study, we designed experiments to determine the potential role of Bcl-2 proteins in these patterns of cytosolic [Ca(+2)] responses. We used small molecule inhibitors that disrupt the interactions between prosurvival Bcl-2 proteins (i.e. Bcl-2 and Bcl-xl) and proapoptotic Bcl-2 proteins (i.e. Bax) and fluorescence microfluorimetry techniques to measure both cytosolic [Ca(+2)] and endoplasmic reticulum [Ca(+2)]. We found that the inhibitors of Bcl-2 protein interactions caused a slow and complete release of intracellular agonist-sensitive stores of calcium. The release was attenuated by inhibitors of IP(3)Rs and RyRs and substantially reduced by strong [Ca(2+)] buffering. Inhibition of IP(3)Rs and RyRs also dramatically reduced activation of apoptosis by BH3I-2'. CICR induced by different doses of BH3I-2' in Bcl-2 overexpressing cells was markedly decreased compared with control. The results suggest that Bcl-2 proteins regulate calcium release from the intracellular stores and suggest that the spatial-temporal patterns of agonist-stimulated cytosolic [Ca(+2)] changes are regulated by differential cellular distribution of interacting pairs of prosurvival and proapoptotic Bcl-2 proteins.


Comparative efficacy of estazolam, flurazepam, and placebo in outpatients with insomnia.
The efficacy and safety of estazolam, an investigational triazolobenzodiazepine, and flurazepam were compared in 65 insomniac outpatients. Patients completed sleep questionnaires each morning. Global evaluations demonstrated that both treatments were significantly superior to placebo. However, estazolam was preferred over flurazepam in a global rating that reflected how well rested and refreshed the subjects felt on arising. Improvement in complaints of difficulty in going to sleep showed only a trend toward significance favoring estazolam and flurazepam over placebo. Residual daytime drowsiness and fatigue accounted for approximately 70% of all side effects with both active treatments. Significantly more side effects occurred with flurazepam than with estazolam. Flurazepam-treated patients had a significantly more severe rating of adverse reactions than did placebo-treated patients.


Stress-induced cell surface expression and antigenic alteration of the Ro/SSA autoantigen.
Recent studies have shown that Ro/SSA autoantigen is heterogeneous. There are two isoform families; the 60 kD forms (Ro60) and the 52 kD forms (Ro52). Recently we have found that autoantibodies to the Ro/SSA proteins are conformation dependent. Anti-Ro60 antibodies are mainly directed to the native protein and conversely anti-Ro52 antibodies are directed only to the denatured protein. It has been known that UV irradiation to cultured keratinocytes induces cell surface expression of Ro/SSA and this phenomenon has been thought to be related with photosensitivity in patients with anti-Ro/SSA antibodies. We studied the quantitative and qualitative changes of the Ro/SSA protein induced by stress, such as with heat shock and UV irradiation, and found that only Ro52 could be expressed on the cell surface of human peripheral lymphocytes by either heat shock or UV irradiation. Moreover, flow cytometric analysis revealed that HS-treated and UV-treated lymphocytes could be stained with patient sera, and by using a technique which combined immunoprecipitation and Western immunoblotting, it has been confirmed that Ro52 expressed on the cell surface can be recognized by anti-Ro/SSA antibodies in native form while cytoplasmic Ro52 cannot be recognized. These data suggest that Ro52 can be antigenic in vivo when expressed on the cell surface and may explain the mechanism of direct tissue damage by anti-Ro/SSA antibodies.


Alternating block copolymer-based nanoparticles as tools to modulate the loading of multiple chemotherapeutics and imaging probes.
Cancer therapy often relies on the combined action of different molecules to overcome drug resistance and enhance patient outcome. Combined strategies relying on molecules with different pharmacokinetics often fail due to the lack of concomitant tumor accumulation and, thus, to the loss of synergistic effect. Due to their ability to enhance treatment efficiency, improve drug pharmacokinetics, and reduce adverse effects, polymer nanoparticles (PNPs) have been widely investigated as co-delivery vehicles for cancer therapies. However, co-encapsulation of different drugs and probes in PNPs requires a flexible polymer platform and a tailored particle design, in which both the bulk and surface properties of the carriers are carefully controlled. In this work, we propose a core-shell PNP design based on a polyurethane (PUR) core and a phospholipid external surface. The modulation of the hydrophilic/hydrophobic balance of the PUR core enhanced the encapsulation of two chemotherapeutics with dramatically different water solubility (Doxorubicin hydrochloride, DOXO and Docetaxel, DCTXL) and of Iron Oxide Nanoparticles for MRI imaging. The outer shell remained unchanged among the platforms, resulting in un-modified cellular uptake and in vivo biodistribution. We demonstrate that the choice of PUR core allowed a high entrapment efficiency of all drugs, superior or comparable to previously reported results, and that higher core hydrophilicity enhances the loading efficiency of the hydrophilic DOXO and the MRI contrast effect. Moreover, we show that changing the PUR core did not alter the surface properties of the carriers, since all particles showed a similar behavior in terms of cell internalization and in vivo biodistribution. We also show that PUR PNPs have high passive tumor accumulation and that they can efficient co-deliver the two drugs to the tumor, reaching an 11-fold higher DOXO/DCTXL ratio in tumor as compared to free drugs. STATEMENT OF SIGNIFICANCE: Exploiting the synergistic action of multiple chemotherapeutics is a promising strategy to improve the outcome of cancer patients, as different agents can simultaneously engage different features of tumor cells and/or their microenvironment. Unfortunately, the choice is limited to drugs with similar pharmacokinetics that can concomitantly accumulate in tumors. To expand the spectrum of agents that can be delivered in combination, we propose a multi-compartmental core-shell nanoparticles approach, in which the core is made of biomaterials with high affinity for drugs of different physical properties. We successfully co-encapsulated Doxorubicin Hydrochloride, Docetaxel, and contrast agents and achieved a significantly higher concomitant accumulation in tumor versus free drugs, demonstrating that nanoparticles can improve synergistic cancer chemotherapy.


Improving selectivity of dopamine D3 receptor ligands.
The seminal human dopamine D3 receptor (hD3R) ligand BP 897 has shown interesting properties during clinical trials. However, its lack of selectivity towards human adrenergic receptor impedes further development. Two approaches were followed to increase hD3R selectivity. The lead optimisation succeeded, we disclose here ligands with subnanomolar potency for D3R, combined with a good selectivity for the closely related human dopamine D2 and human adrenergic alpha-1 receptors.


Hemothorax after oocyte retrieval in a patient with a history of COVID-19: a case report.
Spontaneous hemothorax is a rare disorder characterized by pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit without natural or iatrogenic trauma to the lungs or pleural space. Since the first case of COVID-19, more than 85 million cases have been confirmed and most patients have sustained symptoms after more than six months of acute infection. This paper reports the case of a 38-year-old woman without signs of endometriosis and a history of COVID-19 infection who developed spontaneous hemothorax after oocyte retrieval. Three months before undergoing assisted reproductive technology (ART) treatment, the patient had a symptomatic COVID-19 infection with a negative PCR test and a positive IgG test four weeks after the onset of symptoms. Controlled ovarian stimulation and oocyte retrieval were conducted uneventfully. Two hours after oocyte retrieval, the patient developed nausea and mild hypogastric pain. Ten hours after the procedure, the patient went to the emergency department with abdominal pain. Chest computed tomography scans revealed moderate right pleural effusion and laminar left pleural effusion. Since the patient had respiratory symptoms, the choice was made to drain the pleural fluid. Fluid analysis confirmed the patient had right hemothorax (400 mL). After drainage, the patient's clinical and imaging signs improved gradually without complications. The patient was asymptomatic one week after the procedure.


Reproductive isolation caused by visual predation on migrants between divergent environments.
In theory, natural selection can drive adaptation within species while simultaneously promoting the formation of new species by causing the evolution of reproductive isolation. Cryptic coloration is widespread in nature and is generally considered to be a clear visual example of adaptation. I provide evidence that population divergence in cryptic coloration can also cause reproductive isolation. First, a manipulative field experiment using walking-stick insects demonstrates that the relative survival of different colour-pattern morphs depends on the host-plant species on which they are resting, but only in the presence of avian predation. Second, natural populations adapted to different host plants have diverged in colour-pattern-morph frequencies such that between-host migrants are more likely to be the locally less-cryptic morph than are residents. Collectively, these data indicate that high rates of visual predation on less-cryptic migrants are likely to reduce encounters, and thus interbreeding, between host-associated populations. Comparison with previous estimates of sexual isolation reveals that the contribution of selection against between-host migrants to total premating isolation is as strong as, or stronger than, that of sexual isolation. These findings highlight the potential role of natural selection against migrants between divergent environments in the formation of new species.


Medicaid managed care: problems and promise.
Medicaid spending is an increasing burden on already stressed state budgets. The states find themselves trapped between these growing costs and mounting pressure to ensure access of the underserved to health care services. States are hopeful that managed care is the answer to meeting the seemingly diametric needs of reducing costs while increasing access. However, evidence of performance measured in cost, access, and quality, and financial viability is inconclusive. Nevertheless, there have been some successes and, clearly, Medicaid managed care has potential. The unanswered question is the extent to which states can meet the diverse challenges of both Medicaid and managed care and tap that potential.


Evidence, interpretation, and qualification from multiple reports of long-term outcomes in the Multimodal Treatment study of Children With ADHD (MTA): part I: executive summary.
To review the primary and secondary findings from the Multimodal Treatment study of ADHD (MTA) published over the past decade as three sets of articles. In a two-part article-Part I: Executive Summary (without distracting details) and Part II: Supporting Details (with additional background and detail required by the complexity of the MTA)-we address confusion and controversy about the findings. We discuss the basic features of the gold standard used to produce scientific evidence, the randomized clinical trial, for which was used to contrast four treatment conditions: medication management alone (MedMgt), behavior therapy alone (Beh), the combination of these two (Comb), and a community comparison of treatment "as usual" (CC). For each of the three assessment points we review three areas that we believe are important for appreciation of the findings: definition of evidence from the MTA, interpretation of the serial presentations of findings at each assessment point with a different definition of long-term, and qualification of the interim conclusions about long-term effects of treatments for ADHD. We discuss the possible clinical relevance of the MTA and present some practical suggestions based on current knowledge and uncertainties facing families, clinicians, and investigators regarding the long-term use of stimulant medication and behavioral therapy in the treatment of children with ADHD.


Impacts of Priming with Silicon on the Growth and Tolerance of Maize Plants to Alkaline Stress.
Silicon (Si) has been known to augment plant defense against biotic and abiotic pressures. Maize (Zea maize L.) is classified as a Si accumulator and is relatively susceptible to alkaline stress. In this study, seeds of maize were grown in pots and exposed to various concentrations of Na2CO3 (0, 25, 50, and 75 mM) with or without 1.5 mM Si in the form of sodium metasilicate Na2O3Si.5H2O for 25 days. Alkaline-stressed plants showed a decrease in growth parameters, leaf relative water content (LRWC), and the contents of photosynthetic pigments, soluble sugars, total phenols and potassium ion (K(+)), as well as potassium/sodium ion (K(+)/Na(+)) ratio. By contrast, alkaline stress increased the contents of soluble proteins, total free amino acids, proline, Na(+) and malondialdehyde (MDA), as well as the activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) in stressed plants. On the other hand, application of Si by seed-priming improved growth of stressed plants, which was accompanied by the enhancement in LRWC, and levels of photosynthetic pigments, soluble sugars, soluble proteins, total free amino acids and K(+), as well as activities of SOD, CAT, and POD enzymes. Furthermore, Si supplement resulted in a decrease in the contents of proline, MDA and Na(+), which together with enhanced K(+) level led to a favorable adjustment of K(+)/Na(+) ratio, in stressed plants relative to plants treated with alkaline stress alone. Taken together, these results indicate that Si plays a pivotal role in alleviating the negative effects of alkaline stress on maize growth by improving water status, enhancing photosynthetic pigments, accumulating osmoprotectants rather than proline, activating the antioxidant machinery, and maintaining the balance of K(+)/Na(+) ratio. Thus, our findings demonstrate that seed-priming with Si is an efficient strategy that can be used to boost tolerance of maize plants to alkaline stress.


Survival of neonates in rural Southern Tanzania: does place of delivery or continuum of care matter?
The concept of continuum of care has recently been highlighted as a core principle of maternal, newborn and child health initiatives, and as a means to save lives. However, evidence has consistently revealed that access to care during and post delivery (intra and postpartum) remains a challenge in the continuum of care framework. In places where skilled delivery assistance is exclusively available in health facilities, access to health facilities is critical to the survival of the mother and her newborn. However, little is known about the association of place of delivery and survival of neonates. This paper uses longitudinal data generated in a Health and Demographic Surveillance System in rural Southern Tanzania to assess associations of neonatal mortality and place of delivery. Three cohorts of singleton births (born 2005, 2006 and 2007) were each followed up from birth to 28 days. Place of birth was classified as either "health facility" or "community". Neonatal mortality rates were produced for each year and by place of birth. Poisson regression was used to estimate crude relative risks of neonatal death by place of birth. Adjusted ratios were derived by controlling for maternal age, birth order, maternal schooling, sex of the child and wealth status of the maternal household. Neonatal mortality for health facility singleton deliveries in 2005 was 32.3 per 1000 live births while for those born in the community it was 29.7 per 1000 live births. In 2006, neonatal mortality rates were 28.9 and 26.9 per 1,000 live births for deliveries in health facilities and in the community respectively. In 2007 neonatal mortality rates were 33.2 and 27.0 per 1,000 live births for those born in health facilities and in the community respectively. Neonates born in a health facility had similar chances of dying as those born in the community in all the three years of study. Adjusted relative risks (ARR) for neonatal death born in a health facility in 2005, 2006 and 2007 were 0.99 (95% CI: 0.58 - 1.70), 0.98 (95% CI: 0.62 - 1.54) and 1.18 (95% CI: 0.76 - 1.85) respectively. We found no evidence to suggest that delivery in health facilities was associated with better survival chances of the neonates.


SmgGDS-607 Regulation of RhoA GTPase Prenylation Is Nucleotide-Dependent.
Protein prenylation involves the attachment of a hydrophobic isoprenoid moiety to the C-terminus of proteins. Several small GTPases, including members of the Ras and Rho subfamilies, require prenylation for their normal and pathological functions. Recent work has suggested that SmgGDS proteins regulate the prenylation of small GTPases in vivo. Using RhoA as a representative small GTPase, we directly test this hypothesis using biochemical assays and present a mechanism describing the mode of prenylation regulation. SmgGDS-607 completely inhibits RhoA prenylation catalyzed by protein geranylgeranyltransferase I (GGTase-I) in an in vitro radiolabel incorporation assay. SmgGDS-607 inhibits prenylation by binding to and blocking access to the C-terminal tail of the small GTPase (substrate sequestration mechanism) rather than via inhibition of the prenyltransferase activity. The reactivity of GGTase-I with RhoA is unaffected by addition of nucleotides. In contrast, the affinity of SmgGDS-607 for RhoA varies with the nucleotide bound to RhoA; SmgGDS-607 has a higher affinity for RhoA-GDP compared to RhoA-GTP. Consequently, the prenylation blocking function of SmgGDS-607 is regulated by the bound nucleotide. This work provides mechanistic insight into a novel pathway for the regulation of small GTPase protein prenylation by SmgGDS-607 and demonstrates that peptides are a good mimic for full-length proteins when measuring GGTase-I activity.


QT variability during initial exposure to sotalol: experience based on a large electronic medical record.
A prolonged QT interval is associated with increased risk of Torsades de pointes (TdP) and may be fatal. We sought to investigate the extent to which clinical covariates affect the change in QT interval among 'real-world' patients treated with sotalol and followed in an electronic medical record (EMR) system. We used clinical alerts in our EMR system to identify all patients in whom a new prescription for sotalol was written (2001-11). Rate-corrected QT (QTc) was calculated by Bazett's formula. Correlates of sotalol-induced change in the QTc interval and sotalol discontinuation were examined using linear and logistic regression, respectively. Overall, 541 sotalol-exposed patients were identified (n = 200 women, 37%). The mean first sotalol dose was 86 ± 39 mg, age 64 ± 13 years, and BMI 30 ± 7 kg/m(2). Atrial fibrillation/flutter was the predominant indication (92.2%). After initial exposure, the change in the QTc interval from baseline was highly variable: ΔQTc after 2 h = 3 ± 42 ms (P = 0.17) and 11 ± 37 ms after ≥48 h (P < 0.001). Multivariable linear regression analysis identified female gender and age, reduced left ventricular ejection fraction, high sotalol dose, hypertrophic cardiomyopathy, and loop diuretic co-administration as correlates of increased ΔQTc at ≥48 h (P < 0.05 for all). Within 3 days of initiation, 12% discontinued sotalol of which 31% were because of exaggerated QTc prolongation. One percent developed TdP. In this EMR-based cohort, the increase in QTc with sotalol initiation was highly variable, and multiple clinical factors contributed. These data represent an important step in ongoing work to identify real-world patients likely to tolerate long-term therapy and reinforces the utility of EMR-based cohorts as research tools.


Bottom-up proteomics of Escherichia coli using dynamic pH junction preconcentration and capillary zone electrophoresis-electrospray ionization-tandem mass spectrometry.
We report the use of the dynamic pH junction based capillary zone electrophoresis-electrospray ionization-tandem mass spectrometry (CZE-ESI-MS/MS) for bottom-up proteomics with an electrokinetically pumped sheath-flow nanospray capillary electrophoresis-mass spectrometry (CE-MS) interface and both LTQ-XL and LTQ-Orbitrap-Velos mass spectrometers. Conventional injection of 20 nL of a 1 mg/mL BSA digest identified 37 peptides and produced 66% sequence coverage. In contrast, pH junction injection of 130 nL (or larger) of a 0.05 mg/mL BSA digest identified 40 peptides and produced 70% coverage using a pH 6.5 sample buffer and the LTQ. A 20 nL conventional injection of a 1 mg/mL Escherichia coli digest identified 508 peptides and 199 proteins with the LTQ. A 400 nL pH junction injection of a 0.1 mg/mL E. coli digest identified 527 peptides and 179 proteins with the LTQ. Triplicate technical replicates of a 0.01 mg/mL sample with 400-nL injection volume using a pH junction identified 288 ± 9 peptides and 121 ± 5 proteins with the LTQ. There was outstanding concordance in migration time between the pH junction and normal injection. The pH junction produced narrower peaks and significant concentration for all but the most acidic components in the sample. Compared with the conventional stacking method, the pH junction method can generate comparable performance for small injection volume (20 nL) and significantly better concentration performance for a large injection volume (200 nL). We also applied the pH junction to three intact standard proteins and observed a >10× increase in peak intensity compared to conventional injection.


Anisotropy of the in-plane resistivity of underdoped Ba(Fe(1-x)Co(x))2As2 superconductors induced by impurity scattering in the antiferromagnetic orthorhombic phase.
We investigated the in-plane resistivity anisotropy for underdoped Ba(Fe(1-x)Co(x))(2)As(2) single crystals with improved quality. We demonstrate that the anisotropy in resistivity in the magnetostructural ordered phase arises from the anisotropy in the residual component which increases in proportion to the Co concentration x. This gives evidence that the anisotropy originates from the impurity scattering by Co atoms substituted for the Fe sites, rather than the so far proposed mechanisms such as the anisotropy of Fermi velocities of reconstructed Fermi surface pockets. As doping proceeds to the paramagnetic-tetragonal phase, a Co impurity transforms to a weak and isotropic scattering center.


Polluted-site killifish (Fundulus heteroclitus) embryos are resistant to organic pollutant-mediated induction of CYP1A activity, reactive oxygen species, and heart deformities.
Exposure to coplanar polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) can adversely affect fish embryonic development, induce expression of cytochrome P4501A (CYP1A), and increase reactive oxygen species (ROS) production, effects believed to be mediated by the aryl hydrocarbon receptor (AHR). Killifish (Fundulus heteroclitus) populations in New Bedford Harbor, Massachusetts, USA (NBH) and Newark Bay, New Jersey, USA (NB) are generationally exposed to coplanar PCBs and PAHs and have developed resistance to PCB mediated induction of CYP1A. We hypothesized that fish resistant to CYP1A induction would also exhibit resistance to PCB and PAH induced ROS production and teratogenesis. Killifish embryos from two contaminated (NB, NBH) and two reference-site populations were exposed to vehicle or 3,3'4,4'5-pentachlorobiphenyl (PCB126) or 3-methylcholanthrene (3-MC) and evaluated for in ovo CYP1A activity, heart deformities, and ROS production. Both chemicals significantly increased in ovo ethoxyresorufin-O-deethylase (EROD) and ROS production in reference-site embryos. These chemicals provoked only moderate induction of in ovo EROD in NBH and NB embryos, and neither PCB126 nor 3-MC induced ROS production in these populations. Similarly, heart deformities were significantly induced by PCB126 in reference-site embryos, but had no significant effects on NB and NBH animals. These results indicate that fish resistant to CYP1A induction also exhibit decreased sensitivity to PCB126 and 3-MC-induced ROS production and teratogenesis. These findings further our understanding of toxicant resistance by demonstrating that reduced response to coplanar PCBs and PAHs extends beyond resistance to CYP1A induction to resistance to the physiological and teratogenic effects of these toxicants, responses that undoubtedly contribute to the increased survival of killifish inhabiting contaminated sites.


In situ observation of structural transformation of gold nanorods under pulsed laser irradiation in an HVEM.
A pulsed laser light illumination system was attached to a high-voltage electron microscope (HVEM) for in situ observation of light-induced behaviors of nano objects. The wavelength λ of emitted laser pulses was 1064, 532 or 266 nm, and the pulse duration was 6-8 ns. Using this combined HVEM system, we observed the deformation behavior of gold nanorods irradiated by a pulsed laser (λ = 1064 nm) at an intensity of 310 J m(-2) pulse or higher. A single shot of pulsed laser reduced the aspect ratio of the gold nanorods from 5 to a much smaller value. The extent of the reduction increased at higher laser intensities. However, at 310 J m(-2) pulse(-1), additional pulsed shots induced limited further deformation. The mean aspect ratio approximated to 2.5 even after irradiation with 7 pulses (total fluence exceeding 2 MJ m(-2)). In situ high resolution transmission electron microscopy (HRTEM) observation revealed that deformation was accompanied by total atomic restructuring of the nanorod interiors.


Coenzyme Q10: is there a clinical role and a case for measurement?
Coenzyme Q(10) (CoQ(10)) is an essential cofactor in the mitochondrial electron transport pathway, and is also a lipid-soluble antioxidant. It is endogenously synthesised via the mevalonate pathway, and some is obtained from the diet. CoQ(10) supplements are available over the counter from health food shops and pharmacies. CoQ(10) deficiency has been implicated in several clinical disorders, including but not confined to heart failure, hypertension, Parkinson's disease and malignancy. Statin, 3-hydroxy-3- methyl-glutaryl (HMG)-CoA reductase inhibitor therapy inhibits conversion of HMG-CoA to mevalonate and lowers plasma CoQ(10) concentrations. The case for measurement of plasma CoQ(10) is based on the relationship between levels and outcomes, as in chronic heart failure, where it may identify individuals most likely to benefit from supplementation therapy. During CoQ(10) supplementation plasma CoQ(10) levels should be monitored to ensure efficacy, given that there is variable bioavailability between commercial formulations, and known inter-individual variation in CoQ(10) absorption. Knowledge of biological variation and reference change values is important to determine whether a significant change in plasma CoQ(10) has occurred, whether a reduction for example following statin therapy or an increase following supplementation. Emerging evidence will determine whether CoQ(10) does indeed have an important clinical role and in particular, whether there is a case for measurement.


Delayed tezampanel and caramiphen treatment but not midazolam protects against long-term neuropathology after soman exposure.
Prolonged status epilepticus (SE) can cause brain damage; therefore, treatment must be administered promptly after seizure onset to limit SE duration and prevent neuropathology. Timely treatment of SE is not always feasible; this would be particularly true in a mass exposure to an SE-inducing agent such as a nerve agent. Therefore, the availability of anticonvulsant treatments that have neuroprotective efficacy even if administered with a delay after SE onset is an imperative. Here, we compared the long-term neuropathology resulting from acutely exposing 21-day-old male and female rats to the nerve agent soman, and treating them with midazolam (3 mg/kg) or co-administration of tezampanel (10 mg/kg) and caramiphen (50 mg/kg), at 1 h postexposure (~50 min after SE onset). Midazolam-treated rats had significant neuronal degeneration in limbic structures, mainly at one month postexposure, followed by neuronal loss in the basolateral amygdala and the CA1 hippocampal area. Neuronal loss resulted in significant amygdala and hippocampal atrophy, deteriorating from one to six months postexposure. Rats treated with tezampanel-caramiphen had no evidence of neuropathology, except for neuronal loss in the basolateral amygdala at the six-month timepoint. Anxiety was increased only in the midazolam-treated rats, at one, three, and six months postexposure. Spontaneous recurrent seizures appeared only in midazolam-treated rats, at three and six months postexposure in males and only at six months in females. These findings suggest that delayed treatment of nerve agent-induced SE with midazolam may result in long-lasting or permanent brain damage, while antiglutamatergic anticonvulsant treatment consisting of tezampanel and caramiphen may provide full neuroprotection.


[The Cancer Registry of the Jules Bordet Institute, a new tool for the institution and its researchers. Description of cases incident in 2000-2001].
A hospital Cancer Registry has recently been initiated at the Jules Bordet Institute. The collected information allows to report pathology items such as incidence date, site, morphology and stage. It permits to describe the therapeutic choices, which, broken down by organ and stage, can be compared to guidelines in a process assessment. The objectives of this registry are institutional (statistical and organisational finalities as well as quality control ones), extra-institutional (participation to the public network of cancer registration), and scientific (providing the researchers a common database that can be queried using multiple criteria to be completed by further detailed data). This paper reports on 3,587 incident cancer cases in 2000 and 2001 which were managed at the Jules Bordet Institute for the primary episode. Cancers in women represent 64.3% of all records, for only 35.7% of men, while in the Belgian National Cancer Registry, the proportion is reversed to 46.7% of women and 53.3% of men. The distribution of cancer by site is also quite different in our hospital registry where breast cancer in women, melanoma in both sexes, lung cancer and head and neck cancers in men are over-represented compared to the general population, while colorectal cancer is underrepresented in both sexes.


Steroid-induced myopathy in patients intubated due to exacerbation of chronic obstructive pulmonary disease.
To determine incidence, risk factors and impact on various outcome parameters of the development of acute quadriplegic myopathy in a selected population of critically ill patients. A prospective cohort study carried out in the intensive care unit of a tertiary-level university hospital. All patients admitted due to acute exacerbation of chronic obstructive pulmonary disease who required intubation and mechanical ventilation, and received high doses of intravenous corticosteroids. A neurophysiological study was performed in all cases at the onset of weaning. Muscular biopsy was taken when the neurophysiological study revealed a myopathic pattern. Twenty-six patients were enrolled in the study. Nine patients (34.6%) developed myopathy. Only seven patients were treated with muscle relaxants. Histology confirmed the diagnosis in the three patients who underwent muscle biopsy. APACHE II score at admission, the rate of sepsis and the total doses of corticosteroids were significantly higher in patients with myopathy compared with those patients that did not develop it. Myopathy is associated with an increase in the duration of mechanical ventilation [15.4 (9.2) versus 5.7 (3.9) days; p<0.006], the length of ICU stay [23.6 (10.7) versus 11.4 (7.05) days; p<0.003] and hospital stay [33.3 (19.2) versus 21.2 (16.1) days; p<0.034)]. Myopathy was not associated with increased mortality. In the population under study, severity of illness at admission, the development of sepsis and the total dose of corticosteroids are factors associated with the occurrence of myopathy after the administration of corticosteroids. Myopathy was associated with prolonged mechanical ventilation and in-hospital stay.


Acupuncture for gender differences and similarities in cerebral activity of health volunteers: A pilot fMRI study.
This study aimed to explore the feasible gender differences and similarities in cerebral activity response to the acupuncture at local acupoints around knee.Fifteen male and 15 female healthy adults were recruited and included in this study. Functional magnetic resonance imaging (fMRI) was applied to measure cerebral activity response to acupuncture at Liangqiu (ST34), Xuehai (SP-10), Neixiyan (EX-LE4), and Dubi (ST-35).Acupuncture activated the postcentral gyrus, precuneus, temporal, posterior lobe, and occipital lobe in both males and females. When compared with females, males showed brain activation in the right middle frontal gyrus, inferior frontal gyrus, right precuneus, right superior parietal lobule, left cerebellum anterior lobe; and brain deactivation in the right frontal. When compared with males, females were observed brain activation in the right frontal lobe, right parietal lobe, and right middle temporal gyrus; and brain deactivation in the left and right medial frontal gyrus.The results of this study demonstrated that the neural effects of local acupoints around knee might be different between male and female subjects. Further clinical trials should take this gender effect into account in their design of studies.


Efflux Pump Mediated Antimicrobial Resistance by Staphylococci in Health-Related Environments: Challenges and the Quest for Inhibition.
The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with increased use of sanitisers and disinfectants due to the ongoing COVID-19 pandemic can further aggravate the problem of antimicrobial resistance. Staphylococci utilise multiple mechanisms to circumvent the effects of antimicrobials. One of these resistance mechanisms is the export of antimicrobial agents through the activity of membrane-embedded multidrug efflux pump proteins. The use of efflux pump inhibitors in combination with currently approved antimicrobials is a promising strategy to potentiate their clinical efficacy against resistant strains of staphylococci, and simultaneously reduce the selection of resistant mutants. This review presents an overview of the current knowledge of staphylococcal efflux pumps, discusses their clinical impact, and summarises compounds found in the last decade from plant and synthetic origin that have the potential to be used as adjuvants to antibiotic therapy against multidrug resistant staphylococci. Critically, future high-resolution structures of staphylococcal efflux pumps could aid in design and development of safer, more target-specific and highly potent efflux pump inhibitors to progress into clinical use.


Research, ethics and the data protection legislation.
As nursing research becomes more common, so does the issue of whether or not patients should be involved and, if so, to what extent. This article examines how the data protection legislation helps to protect patients, and whether they have the capability to decide to participate, or not.


Can primordial magnetic fields be the origin of the BICEP2 data?
If the B-mode signal in the cosmic microwave background polarization seen by the BICEP2 experiment is confirmed, it has dramatic implications for models of inflation. The result is also in tension with Planck limits on standard inflationary models. It is, therefore, important to investigate whether this signal can arise from alternative sources. If so, this could lessen the pressure on inflationary models and the tension with Planck data. We investigate whether vector and tensor modes from primordial magnetic fields can explain the signal. We find that, in principle, magnetic fields generated during inflation can indeed produce the required B mode, for a suitable range of energy scales of inflation. In this case, the primordial gravitational wave amplitude is negligible, so that there is no tension with Planck and no problems posed for current inflationary models. However, the simplest magnetic model is in tension with Planck limits on non-Gaussianity in the trispectrum. It may be possible to fine tune the magnetogenesis model so that this non-Gaussianity is suppressed. Alternatively, a weaker magnetic field can pass the non-Gaussianity constraints and allow the primordial tensor mode to be reduced to r ≃ 0.09, thus removing the tension with Planck data and alleviating the problems with simple inflationary models.


Objective intraoperative method to record averaged electromyographic stapedius muscle reflexes in cochlear implant patients.
We have developed a procedure to measure the averaged stapedius muscle reflex in response to electrical stimulation (AESR) with a cochlear implant. The AESR, as activated by ipsilateral stimulation with a cochlear implant, was investigated intra-operatively in a series of 12 children. After the cochlear implant was placed into the cochlea and secured by the surgeon, an electromyographic (EMG) needle electrode was gently placed into the stapedius muscle. During stimulation of the cochlear implant, the stapedius reflex was monitored visually (VESR) and as an averaged EMG response (AESR). Consistent AESRs were obtained in 7 of the 12 children. These measures provide a method to obtain stapedius muscle responses that may be helpful in the programming of young children with cochlear implants. Comparative post-operative measures were also obtained, including behavioral threshold levels, behavioral comfort levels, and the contralateral stapedius reflex threshold (ESR) on selected electrodes.


Fibro-osseous lesions of the oral and maxillo-facial region: Retrospective analysis for 20 years.
Fibro-osseous lesions (FOLs) are one of the commonest entities reported in the head and neck region. However, studies on these groups of lesions on Indian population were not carried out before. So this motivated us to analyze the clinico-pathologic correlation of fibro-osseous lesions reported at our hospital. A retrospective review was made of all the lesions surgically treated in our hospital. A total of 6,175 biopsies were performed during the study period. All the cases which were histopathologically diagnosed as FOLs were included in the study. The demographic data, radiographic features, and histopathologic findings were analyzed and compared with similar studies on other races. We could find 80 cases diagnosed as fibro-osseous lesions and information about them was documented. The most common FOL reported in the region was cemento-ossifying fibroma (COF) (75%) than fibrous dysplasia (FD) (25%). These were commonly occurring in 2(nd) decade without any sex or site predilection. However, COF was showing a slight female predominance and FD with a definite male predominance. COF was commonly seen in mandible (posterior region) whereas FD mainly confined to the maxilla (as a whole bone). Radiographically, most of COF showed well-defined mixed opaque and lucent areas whereas FD showed diffuse borders. Cortical plate expansion and resorption of associated teeth was a frequent finding in COF when compared with FD. Histopathologically, stroma was fibrocellular in many cases of COF, whereas most FDs showed fibrous stroma, interspersed with mainly woven bone.


Valve-in-Valve Transcatheter Implantation Versus Redo Surgical Aortic Valve Replacement.
Valve-in-valve (ViV) transcatheter aortic valve implantation (TAVI) for a failing prosthesis is an appealing alternative to redo surgical AVR. We utilized data from the US National Inpatient Sample for the period 2012 to 2016 to identify hospitalizations for either ViV-TAVI or redo-SAVR. The primary outcomes of interest were in-hospital adverse events composite outcome (comprising of mortality, myocardial infarction, stroke, or acute kidney injury) and all-cause mortality. We used propensity score matching to adjust for the baseline differences between ViV-TAVI and redo-SAVR cohorts. Survey techniques were employed to compare the 2 groups. Over 5 years, there has been a considerable increase in both interventions for prosthetic aortic valve failure, with significantly higher utilization of ViV-TAVI compared to redo-SAVR (p <0.01). Out of the 3,305 hospitalizations for prosthetic aortic valve failure, 1,420 in matched pairs underwent either ViV-TAVI (n = 710) or redo-SAVR (n = 710). ViV-TAVI was associated with lower in-hospital composite adverse outcomes (14.1% vs 25.4%, p = 0.018), and numerically lower but statistically insignificant mortality (<1.0% vs 5.2%; p = 0.06). ViV-TAVI was associated with a decreased length of hospitalization (mean 6.6 vs 9.7 days; p <0.01). In the matched cohort, postoperative bleeding and transfusions were significantly lower for ViV-TAVI compared with redo-SAVR (17.6% vs 31.0% and 12% vs 31% respectively, p <0.01 for both). Acute kidney injury, sepsis, permanent pacemaker implantation, and vascular complications, although numerically better, did not differ between 2 strategies. In conclusion, ViV-TAVI is associated with lower in-hospital MACE rates and reduced length of hospitalization compared with redo-SAVR.


The ketogenic diet as a potential treatment and prevention strategy for Alzheimer's disease.
The prevalence of Alzheimer's disease, a chronic neurodegenerative condition, is increasing as is the need for effective treatments and preventions. The underlying pathology of Alzheimer's is not yet fully understood, so existing research has focused on understanding the prominent features of the disease. These include amyloid plaques, which accumulate in the brains of those with Alzheimer's disease; impaired glucose metabolism; and neuronal cell death. Emerging evidence suggests that a low-carbohydrate, high-fat ketogenic diet may help to mitigate the damage associated with these pathologies. The ketogenic diet could alleviate the effects of impaired glucose metabolism by providing ketones as a supplementary energy source. In addition, this diet may help to reduce the accumulation of amyloid plaques while reversing amyloid β toxicity. Research has begun to identify early underlying mechanisms in Alzheimer's disease that could be targeted by new prevention strategies. Glycation of the ApoE protein leads to impaired transportation of important lipids, including cholesterol, to the brain, resulting in lipid deficiencies that could explain progression to the later pathologies of the disease. In this review, we hypothesize that the ketogenic diet could be an effective treatment and prevention for Alzheimer's disease, but both ketone production and carbohydrate restriction may be needed to achieve this.


Verification of the Saccharina japonica Translocon Tic20 and its Localization in the Chloroplast Membrane in Diatoms.
Tic20 is an important translocon protein that plays a role in protein transport in the chloroplast. The sequence of Tic20 was determined in the lower brown alga Saccharina japonica. Structural analysis of SjTic20 revealed a noncanonical structure consisting of an N-terminal non-cyanobacterium-originated EF-hand domain (a helix-loop-helix structural domain) and a C-terminal cyanobacterium-originated Tic20 domain. Subcellular localization and transmembrane analysis indicated that SjTic20 featured an "M"-type Nin-Cin-terminal orientation, with four transmembrane domains in the innermost membrane of the chloroplast in the microalga Phaeodactylum tricornutum, and the EF-hand domain was entirely extruded into the chloroplast stroma. Our study provides information on the structure, localization, and topological features of SjTic20, and further functional analysis of SjTic20 in S. japonica is needed.


Conversion of a phosphoseryl/threonyl phosphatase into a phosphotyrosyl phosphatase.
By use of the autophosphorylated epidermal-growth-factor receptor and the synthetic peptide RRLIE-DAEY(P)AARG, representing an autophosphorylation site of the transforming protein of Rous-sarcoma virus, it is demonstrated that the phosphotyrosyl phosphatase activity of the polycation-stimulated phosphatases is substantially increased by an enzyme-directed effect of ATP or PPi. Concomitant with this increase in phosphotyrosyl phosphatase activity, the phosphorylase phosphatase activity is decreased, thus dramatically changing the substrate specificity of these enzymes. The dephosphorylation of four different phosphotyrosyl sites of the epidermal-growth-factor receptor is neither consecutive nor at random, but a preferred dephosphorylation of the P1 site over the P3 greater than P2 greater than P4 sites is observed. This phosphatase activity represents a substantial fraction of the total phosphotyrosyl phosphatase activity in the post-mitochondrial supernatant of Xenopus laevis oocytes.


Potential parasite transmission in multi-host networks based on parasite sharing.
Epidemiological networks are commonly used to explore dynamics of parasite transmission among individuals in a population of a given host species. However, many parasites infect multiple host species, and thus multi-host networks may offer a better framework for investigating parasite dynamics. We investigated the factors that influence parasite sharing--and thus potential transmission pathways--among rodent hosts in Southeast Asia. We focused on differences between networks of a single host species and networks that involve multiple host species. In host-parasite networks, modularity (the extent to which the network is divided into subgroups of rodents that interact with similar parasites) was higher in the multi-species than in the single-species networks. This suggests that phylogeny affects patterns of parasite sharing, which was confirmed in analyses showing that it predicted affiliation of individuals to modules. We then constructed "potential transmission networks" based on the host-parasite networks, in which edges depict the similarity between a pair of individuals in the parasites they share. The centrality of individuals in these networks differed between multi- and single-species networks, with species identity and individual characteristics influencing their position in the networks. Simulations further revealed that parasite dynamics differed between multi- and single-species networks. We conclude that multi-host networks based on parasite sharing can provide new insights into the potential for transmission among hosts in an ecological community. In addition, the factors that determine the nature of parasite sharing (i.e. structure of the host-parasite network) may impact transmission patterns.


Transfer of Cd, Cu, Ni, Pb, and Zn in a soil-plant-invertebrate food chain: a microcosm study.
The transfer of Cd, Cu, Ni, Pb, and Zn was evaluated in a soil-plant (lettuce, Lactuca sativa)-invertebrate (snail, Helix aspersa) food chain during a microcosm experiment. Two agricultural soils, polluted and unpolluted, were studied. Lettuce was cultivated for eight weeks before introduction of snails into the microcosms (M-snails). In a parallel experiment, snails were exposed to lettuce only (i.e., without soil) in simpler exposure devices called containers (C-snails). Snail exposure duration was eight weeks for both M- and C-snails. No effects on snail survival were found. Both M- and C-snails exposed to polluted soil showed a growth reduction, but only after two weeks of exposure. Time-dependent accumulation in M-snails exposed to the polluted environment showed a regular increase of Cd and Zn concentrations over time and a rapid increase of Pb concentrations within the first two weeks, which then remained stable. Copper and Ni concentrations did not increase during any of the experiments. Concentrations in M- and C-snails were compared to estimate the relative contribution of soil and plant to the total bioaccumulation. The results suggest that the soil contribution may be higher than 80% for Pb, from 30 to 60% for Zn, and from 2 to 40% for Cd.


From Constitutional Protections to Medical Ethics: The Future of Pregnant Patients' Medical Self-Determination Rights After Dobbs.
This article argues that the Supreme Court's decision in Dobbs is likely to impact medical decision-making by pregnant patients in a variety of contexts. Of particular concern are situations where a patient declines treatment recommended for its potential benefit to the fetus and situations where treatment is withheld due to potential risk to the fetus. The Court's elevation of fetal interests, combined with a history of courts using abortion jurisprudence to guide their reasoning in compelled treatment cases, means that Dobbs has the potential to limit patient autonomy in a wide array of clinical settings. The article calls on professional medical associations to issue ethical guidance affirming the duty to respect the medical self-determination of pregnant patients.


Early regional cuprizone-induced demyelination in a rat model revealed with MRI.
The cuprizone model of demyelination is well established in the mouse as a tool for the study of the mechanisms of both demyelination and remyelination. It is often desirable, however, to have a larger model, such as the rat, especially for imaging-based studies, yet initial work has failed to show demyelination in cuprizone-fed rats. Several recent studies have demonstrated demyelination in the rat, but only in the corpus callosum. In this study, we acquired high-resolution, three-dimensional images of the whole brain every 2 weeks, using a T1 -weighted magnetization-prepared rapid acquisition gradient echo imaging sequence, optimized for myelin contrast, in order to assess myelination across the entire rat brain over a period of 8 weeks on a 1% cuprizone diet. We observed a consistent pattern of demyelination, beginning in the cerebellum by 4 weeks and involving more rostral regions of the brain by 8 weeks on the cuprizone diet, with validation using Luxol fast blue histology. This imaging technique permits the effects of cuprizone-induced demyelination to be followed longitudinally in a single animal, over the entire brain. In turn, this may facilitate the establishment of the cuprizone model of demyelination in the rat.


Residues of organochlorine pesticides and polychloribiphenyls in starlings (Sturnus vulgaris), from the continental United States, 1982.
Starlings were collected from 129 sites throughout the contiguous United States in the fall of 1982 and analyzed for organochlorine compounds as part of a nationwide monitoring program. Residues of 14 organochlorine compounds were found. Only DDE, polychlorobiphenyls (PCB), dieldrin, and heptachlor epoxide occurred in more than 50% of the 10-starling pools. Geographical variation in the occurrence of seven organochlorine compounds was noted. Mean DDE levels were higher in the southwestern United States. Mean PCB levels were higher in the eastern United States. The occurrence frequency of most organochlorines in 1982 was similar to that which was reported in the previous nationwide study in 1979. A slight increase in occurrence was noted for trans-nonachlor. Mean DDE level in 1982 was similar to that of 1979. Mean PCB level in 1982 was lower than the 1979 mean, but this change may not reflect a decrease in environmental PCB levels.


Usefulness of prebiopsy multifunctional and morphologic MRI combined with free-to-total prostate-specific antigen ratio in the detection of prostate cancer.
The purpose of the study was to assess the predictive value for prostate cancer of MRI using morphologic (T2-weighted imaging [T2WI]) and functional (MR spectroscopy [MRS], diffusion-weighted imaging [DWI], and dynamic contrast-enhanced [DCE] MRI) sequences and the free-to-total prostate-specific antigen (PSA) ratio, alone and combined. This retrospective study included 70 patients (PSA level, > 4 ng/mL; free-to-total PSA ratio, < 20%) who underwent endorectal 1.5-T MRI before biopsy. We graded the likelihood of cancer on a 5-point scale. Imaging data were compared with histologic results on biopsy or prostatectomy. Accuracies were estimated from the area under receiver operating characteristic using the hemiprostate as the unit of analysis. A p value less than 0.05 denoted statistical significance. The model combining all variables was more accurate than each variable alone (95.2% vs 73.5% for T2WI, 76.0% for MRS, 81.8% for DWI, 75.6% for DCE-MRI, and 78.8% for free-to-total PSA ratio). The complete model had accuracy similar to that of combining two imaging variables with free-to-total PSA ratio, especially free-to-total PSA ratio, T2WI, and DWI (94.0%); and free-to-total PSA ratio, DWI, and MRS (93.8%); with negative predictive values of 91.0% and 89.5%, respectively. The best models combining two imaging variables (MRS and DWI, 85.8%; T2WI and DWI, 84.8%) had accuracy that was similar to that of the combination of all imaging variables (87.3%) and higher than that of the best individual imaging variable (DWI, 81.8%), but lower than that of the complete model. The combination of at least one functional technique with free-to-total PSA ratio is more accurate than combining only imaging variables in cancer detection. The use of more than two imaging variables does not increase the detection rate. Functional MRI has the potential to help avoid a large number of negative biopsies.


Hip abductor weakness and lower extremity kinematics during running.
To determine if females with hip abductor weakness are more likely to demonstrate greater knee abduction during the stance phase of running than a strong hip abductor group. Observational prospective study design. University biomechanics laboratory. 15 females with weak hip abductors and 15 females with strong hip abductors. Group differences in lower extremity kinematics were analyzed using repeated measures ANOVA with one between factor of group and one within factor of position with a significance value of P < .05. The subjects with weak hip abductors demonstrated greater knee abduction during the stance phase of treadmill running than the strong group (P < .05). No other significant differences were found in the sagittal or frontal plane measurements of the hip, knee, or pelvis. Hip abductor weakness may influence knee abduction during the stance phase of running.


Perceived vs Actual Shared Decision-Making Behavior Among Urologists: A Convergent, Parallel, Mixed-Methods Study of Self-Reported Practice.
To evaluate the association between self-perceived use of shared decision-making among urologists with use of validated prediction tools and self-described surgical decision-making. This is a convergent mixed methods study of these parallel data from two modules (Shared Decision Making and Validated Prediction tools) within the 2019 American Urological Association (AUA) Annual Census. The shared decision-making (SDM) module queried aspects of SDM that urologists regularly used. The validated prediction tools module queried whether urologists regularly used, trusted, and found prediction tools helpful. Selected respondents to the 2019 AUA Annual Census underwent qualitative interviews on their surgical decision-making. In the weight sampled of 12,312 practicing urologists, most (77%) reported routine use of SDM, whereas only 30% noted regular use of validated prediction tools. On multivariable analysis, users of prediction tools were not associated with regular SDM use (31% vs 28%, P = .006) though was associated with use of decision aids f (32% vs 26%, P < .001). Shared decision-making emerged thematically with respect to matching treatment options, prioritizing goals, and navigating challenging decisions. However, the six specific components of shared decision-making ranged in their mentions within qualitative interviews. Most urologists report performing SDM as supported by its thematic presence in surgical decision-making. However, only a minority use validated prediction tools and urologists infrequently mention specific SDM components. This discrepancy provides an opportunity to explore how urologists perform SDM and can be used to support integrated strategies to implement SDM more effectively in clinical practice.