Physical activity level and sedentary behavior in patients with bronchiectasis: A systematic review of outcome measures and determinants.
Changes in respiratory functions negatively affect the physical activity (PA) levels of patients with bronchiectasis. Therefore, detecting the most frequently used assessments of PA is essential as determining related factors and improving PA. This review study aimed to investigate the PA levels, compare levels with the recommended PA guidelines, determine the outcome measurements of PA and examine the determinants related to PA in patients with bronchiectasis. This review was conducted using databases of MEDLINE, Web of Science, and PEDro. The searched terms were the variations of the words "bronchiectasis" and "physical activity". Full texts of cross-sectional studies and clinical trials were included. Two authors independently screened the studies for inclusion. The initial search identified 494 studies. A hundred articles were selected for full-text review. Following the application of the eligibility process, 15 articles were included. Twelve studies used activity monitors and five studies used questionnaires. The studies that used activity monitors presented daily step counts. The mean number of steps ranged between 4657 and 9164 for adult patients. It was approximately 5350 steps/day in older patients. One study investigated children's PA level reported 8229 steps/day. The functional exercise capacity, dyspnea, FEV1 and, quality of life as related determinants with PA have been reported in the studies. PA levels of patients with non-cystic fibrosis bronchiectasis were lower than the recommended levels. The objective measurements were frequently used in PA assessment. In further studies, it is needed to investigate the related determinants of PA in patients.


CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.
Methylation of CpG islands is increasingly recognized as an important event in colorectal carcinogenesis. We evaluated the extent of CpG island methylation in 426 sporadic colorectal cancers to define its relationship to microsatellite instability and to describe its clinicopathologic and genetic features. Fresh cancer tissue was obtained from 417 consecutive individuals undergoing curative surgery for sporadic colorectal cancer. Methylation of p16 and hMLH1 promoters was determined by methylation-specific polymerase chain reaction (PCR), whereas methylation at MINT 1, 2, 12, and 31 loci was assessed by bisulfite PCR. Microsatellite instability and K-ras and p53 status were determined using microsatellite PCR, restriction enzyme-mediated PCR, and immunohistochemistry, respectively. Individual loci were commonly methylated, but locus-specific phenotypic changes were not seen. CpG island methylation was associated with right-sided location, female sex, and older age, as well as high tumor grade, mucinous type, wild-type P53, microsatellite instability, and K-ras mutations. More than half of tumors showing CpG island methylation were microsatellite stable. Compared with microsatellite unstable cancers, they were more commonly left-sided, had fewer intraepithelial lymphocytes, presented later, and had a worse outcome. Colorectal cancers with CpG island methylation have distinct clinicopathologic features and in some cases lead to sporadic microsatellite unstable cancers.


A multiinstitutional study of the effects of medical therapy for lower urinary symptoms on the perioperative outcomes of holmium laser enucleation of the prostate.
The purpose of this research was to examine the influence of 5ARI and other benign prostatic hyperplasia medical therapies on the perioperative outcomes after holmium laser enucleation of the prostate (HoLEP). During HoLEP, the identification of the planes between the transitional and peripheral zones of the prostate is paramount to the success of the procedure. It has been proposed that delineating the prostate capsule may be more difficult after the use of 5-alpha reductase inhibitor (5ARI) medications. A retrospective review of patients who underwent HoLEP was performed. Patients were stratified according to their preoperative medication usage. Patient characteristics, pretreatment prostate characteristics and symptom scores, perioperative parameters and complications, and posttreatment symptoms scores were evaluated. There were 176 patients analyzed; 52 (29%) were on no medications, 54 (31%) were on an alpha-blocker (AB) alone, 13 (8%) were on a 5ARI alone, and 57 (32%) were on both a 5ARI and an AB. Enucleation rate (resected volume/resection time) was significantly faster in the combination group. The preoperative prostate-specific antigen value was significantly higher in the 5ARI group. A trend in the lower hemoglobin change was seen favoring the 5ARI group, but this did not reach statistical significance. Evaluating the groups based on the use of 5ARIs either alone or in combination vs no 5ARI confirmed that 5ARI was associated with a significantly faster enucleation rate. Preoperative 5ARI use does not appear to adversely alter the outcomes during HoLEP.


Spontaneous carotid-cavernous fistula in osteogenesis imperfecta.
A case of spontaneous carotid-cavernous fistula is presented in a patient suffering from osteogenesis imperfecta tarda type I. The patient was operated on under local anesthesia by intraluminal occlusion of the cavernous carotid artery with a Fogarty catheter, in accordance with Prolo's technique, with total remission except for homolateral loss of vision due to postglaucoma atrophy. the pathogenetic phenomena described in the literature are reviewed, with the suggestion that osteogenesis imperfecta be included with Ehlers-Danlos disease, Marfan's syndrome, and pseudoxanthoma elasticum, as a connective tissue disease with increased weakness of vessel walls that can produce a spontaneous carotid-cavernous fistula. Reports of cases operated on by intraluminal occlusion with various types of balloon-tipped catheters are also reviewed. The good results obtained place this technique among the elective ones for the treatment of carotid-cavernous fistula.


Balance Measures Over 12 Months in Individuals With Chronic Obstructive Pulmonary Disease.
To describe balance for 12 mo in people with chronic obstructive pulmonary disease (COPD). Individuals with COPD completed the Berg Balance Scale (BBS), the Balance Evaluation Systems Test (BEST), and the Activities-Specific Balance Confidence (ABC) scale before pulmonary rehabilitation (PR), post-PR and at 3, 6, and 12 mo. If an acute exacerbation of COPD (AECOPD) occurred, balance measures were repeated after 7 d and 1 mo. Descriptive data are displayed for balance measures at 5 time-points (pre-PR, post-PR, 3 mo, 6 mo, and 12 mo) in those without exacerbations. The outcome score at 7 d and 1 mo post-AECOPD was compared with the assessment closest to the AECOPD. A total of 42 patients were recruited and 32 patients (17 male; mean age ± standard deviation = 68.5 ± 9.9 yr; FEV1 % predicted =38 ± 15%) completed balance measures post-PR. Seventeen, 11, and 6 patients, who did not exacerbate, completed balance measures at 3, 6, and 12 mo, respectively, with no overall change in balance measures over time. Of 32 patients, 15 experienced an AECOPD and of these, 8 and 11 completed measures at 7 d and 1 mo, respectively. Balance declined from baseline to 7 d (BBS, P = .010; BEST, P = .002) and to 1 mo post-AECOPD (BBS, P = .035). Balance recovered from 7 d to 1 mo post-AECOPD but did not return to baseline levels (BBS, P = .045; BEST, P = .006). There were no changes in balance confidence post-AECOPD. Balance remained stable over 12 mo after completion of PR in those who remained exacerbation-free. The impact of an AECOPD on measures of balance persisted after 1 mo.


Lesions in nucleus basalis magnocellularis and medial septal area of rats produce qualitatively similar memory impairments.
The functional contribution of nucleus basalis magnocellularis (NBM) and the medial septal area (MSA) to memory was evaluated in two different spatial discriminations. Preoperatively, rats were trained to a criterion level of performance in a simultaneous left/right discrimination on the stem of a T-maze (a trial-independent memory) and a discrete-trial, rewarded alternation discrimination on the arms of the T-maze (a trial-dependent memory). Bilateral lesions were made by injecting ibotenic acid (IBO) into the NBM, MSA, both NBM and MSA, or dorsal globus pallidus (DGP), and by radiofrequency current (RF) in the NBM and MSA. Control rats received operations in which either no current was passed or no neurotoxin was injected. Lesions in the NBM, MSA, or both the NBM and MSA produced a similar pattern of behavioral changes relative to the performance of controls; postoperative reacquisition of the arm discrimination was initially impaired but showed recovery to normal levels, whereas postoperative reacquisition and reversal of the stem discrimination was not impaired (except following the combined NBM and MSA lesion). Lesions of the DGP had no effect on choice accuracy in any discrimination. When the discrimination on the arms was made more difficult by increasing the delay interval during which the information had to be remembered, rats with combined NBM and MSA lesions were again impaired relative to controls and showed no signs of recovery of function. These results provide information about the behavioral functions of the basal forebrain cholinergic system and suggest that pathological changes in certain components of this system can cause disorders of memory.


Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors.
Somatostatin receptor imaging with [(111)In-DTPA(0))octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors. Treatment with radiolabeled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized, well-differentiated neuroendocrine tumors. Symptomatic improvement may occur with all (111)In, (90)Y, or (177)Lu-labeled somatostatin analogues that have been used for peptide receptor radionuclide therapy. The results that were obtained with [(90)Y-DOTA(0), Tyr(3)]octreotide and [(177)Lu-DOTA(0), Tyr(3)]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months, respectively. The patients' self-assessed quality of life increases significantly after treatment with [(177)Lu-DOTA(0), Tyr(3)]octreotate. Finally, compared with historical controls, there is a benefit in overall survival of several years from time of diagnosis in patients treated with [(177)Lu-DOTA(0), Tyr(3)]octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of peptide receptor radionuclide therapy can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable gastroenteropancreatic neuroendocrine tumors.


Health systems strengthening for noncommunicable disease control and healthy aging: integrated actions in Aruba and Curaçao.
Caribbean countries are experiencing social, epidemiological, and demographic transitions shaped by the growing elderly population and the rise of noncommunicable diseases (NCDs)-now responsible for 78% of all deaths. These circumstances demand rethinking the model of care to improve health outcomes and build more sustainable health systems with new orientations in policy, service delivery, organization, training, technology, and financing. Policy must be aimed towards healthy living, leveraging interventions that ensure healthy aging. The health system must proactively structure interventions to reduce the incidence of new NCD cases and to prevent related complications. Interventions should be focused on optimizing the individual's capacity, functional ability, and autonomy within adapted environments, as well as with the necessary preventive, long-term care, self-care, community care, and health system support.


VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers.
Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.


Weaver granule neurons are rescued by calcium channel antagonists and antibodies against a neurite outgrowth domain of the B2 chain of laminin.
The weaver mutation impairs migration of the cerebellar granular neurons and induces neuronal death during the first two weeks of postnatal life. To elucidate the molecular mechanisms for the impaired neuronal migration, we investigated the rescue mechanisms of the weaver (wv/wv) granule neurons in vitro. We found that Fab2 fragments of antibodies against a neurite outgrowth domain of the B2 chain of laminin enhanced neurite outgrowth and neuronal migration of the weaver granule neurons on a laminin substratum and in the established cable culture system. The rescue of the weaver granule neurons by antibodies against the B2 chain of laminin may result from the neutralizing effect of these antibodies against the elevated B2 chain levels of the weaver brain. The L-type calcium channel blocker, verapamil (1-5 microM), also rescued the weaver granule neurons. High concentrations of MK-801 (10-20 microM), a glutamate receptor antagonist and voltage-gated calcium channel blocker, rescued the weaver granule neurons similar to verapamil, but low concentrations of MK-801 (1 microM) had no rescue effect. Simultaneous patch-clamp studies indicated that the weaver granule neurons did not express functional N-methyl-D-aspartate receptors further indicating that the rescue of the weaver granule neurons by MK-801 resulted from its known inhibition of voltage-gated calcium channels. The present results indicate that antibodies against the B2 chain of laminin, verapamil, and high concentrations of MK-801 protect the weaver granule neurons from the otherwise destructive action of the weaver gene. Thus, both the laminin system and calcium channel function contribute to the migration deficiency of the weaver granule neurons.


Structural Analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 Interactions for Its Implications in RecovER-phagy in Plasmodium falciparum.
Autophagy is a degradative pathway associated with many pathological and physiological processes crucial for cell survival. During ER stress, while selective autophagy occurs via ER-phagy, the re-establishment of physiologic ER homeostasis upon resolution of a transient ER stress is mediated by recovER-phagy. Recent studies demonstrated that recovER-phagy is governed via association of Sec62 as an ER-resident autophagy receptor through its autophagy interacting motifs (AIM)/LC3-interacting region (LIR) toAtg8/LC3. Atg8 is an autophagy protein, which is central to autophagosome formation and maturation. Plasmodium falciparum Atg8 (PfAtg8) has both autophagic and non-autophagic functions critical for parasite survival. Since Plasmodium also has Sec62 in the ER membrane and is prone to ER stress due to drastic transformation during their complex intraerythrocytic cycle; hence, we initiated the studies to check whether recovER-phagy occurs in the parasite. To achieve this, a comprehensive study based on the computational approaches was carried out. This study embarks upon identification of AIM sequences in PfSec62 by carrying out peptide-protein docking simulations and comparing the interactions of these AIMs with PfAtg8, based on the molecular dynamic simulations. Detailed analysis is based on electrostatic surface complementarity, peptide-protein interaction strength, mapping of non-covalent bond interactions and rupture force calculated from steered MD simulations. Potential mean forces and unbinding free energies (ΔGdissociation) using Jarzynski's equality were also computed for the AIM/LIR motif complexes with PfAtg8/HsLC3 autophagy proteins to understand their dissociation free energy profiles and thereby their binding affinities and stability of the peptide-protein complexes. Through this study, we predict Sec62 mediated recovER-phagy in Plasmodium falciparum, which might open new avenues to explore novel drug targets for antimalarial drug discovery.


Pre-T cell receptor localization and trafficking are independent of its signaling.
Expression of the pre-T cell receptor (preTCR) is an important checkpoint during the development of T cells, an essential cell type of our adaptive immune system. The preTCR complex is only transiently expressed and rapidly internalized in developing T cells and is thought to signal in a ligand-independent manner. However, identifying a mechanistic basis for these unique features of the preTCR compared with the final TCR complex has been confounded by the concomitant signaling that is normally present. Thus, we have reconstituted preTCR expression in non-immune cells to uncouple receptor trafficking dynamics from its associated signaling. We find that all the defining features of the preTCR are intrinsic properties of the receptor itself, driven by exposure of an extracellular hydrophobic region, and are not the consequence of receptor activation. Finally, we show that transitory preTCR cell surface expression can sustain tonic signaling in the absence of ligand binding, suggesting how the preTCR can nonetheless drive αβTCR lineage commitment.


Vitamin D deficiency, supplementation and testing: have we got it right in New Zealand?
Severe prolonged vitamin D deficiency can cause rickets or osteomalacia. Both can be prevented by sunshine exposure or vitamin D supplementation. Although New Zealand guidance does not recommend vitamin D supplementation for the general population, it can be considered for individuals at risk of vitamin D deficiency. Routine measurement of 25-hydroxyvitamin D (25OHD) is also considered unnecessary. We investigated the rates of vitamin D supplementation, rickets and osteomalacia in New Zealand, and of 25OHD results in Auckland, over the last two decades. Vitamin D prescriptions increased 14-fold, from 86,295/year to 1,215,507/year, between 2003 and 2019, with medication costs alone in 2019 being >$1 million. Despite these changes, the annual prevalence of hospital admissions for rickets, osteomalacia and unspecified vitamin D deficiency remained low and stable (10-20/year). 25OHD concentrations increased between 2002 and 2003 and between 2009 and 2019, and in the later time-period, 25OHD tests mainly identified individuals without vitamin D deficiency (40-50% >75nmol/L, 65-70% >50nmol/L and only 7-12.5% <25nmol/L). Osteomalacia and rickets persist at low rates despite widespread, increasingly costly vitamin D supplementation and testing, which largely identifies individuals without vitamin D deficiency. These results suggest that vitamin D guidance and practice in New Zealand should change.


Update on Misrepresentation of Research Publications Among Orthopaedic Surgery Residency Applicants.
Our 2 previous studies (1999, 2007) examining misrepresentation of research publications among orthopaedic residency applicants revealed rates of misrepresentation of 18.0% and 20.6%, respectively. As the residency selection process has become more competitive, the number of applicants who list publications has increased. The purpose of this study was to determine current rates of research misrepresentation by orthopaedic surgery applicants. We reviewed the publication listings and research section of the Common Application Form from the Electronic Residency Application Service (ERAS) for all applicants applying to 1 orthopaedic residency program. The PubMed-MEDLINE database was principally used to search for citations. The PubMed Identifier (PMID) number was used; if no PMID number was listed, a combination of authors or the title of the work was used. If the citations were not found through PubMed, a previously developed algorithm was followed to determine misrepresentation. Misrepresentation was defined as (1) nonauthorship of a published article in which authorship was claimed, (2) claimed authorship of a nonexistent article, or (3) self-promotion to a higher authorship status within a published article. Five hundred and seventy-three applicants applied to our institution for residency in 2016 to 2017: 250 (43.6%) of 573 applicants did not list a publication, whereas 323 (56.4%) of 573 applicants listed ≥1 publication. We found 13 cases of misrepresentation among a total of 1,100 citations (1.18% in 2017 versus 18.0% in 1999 and 20.6% in 2007, p < 0.001). Ten cases of misrepresentation were self-promotion to a higher authorship status. There were 2 cases of claimed authorship of an article that could not be found. Only 1 applicant misrepresented more than once. Based on our findings, orthopaedic surgery residency applicants are accurately representing their publication information. The incorporation of the PMID number on the ERAS application has streamlined the process for finding publications, and has possibly encouraged veracity on residency applications. Faculty involved in the resident selection process should be aware of the significant decline in the rate of misrepresentation by medical students applying for orthopaedic surgery residency versus the rate in our prior studies.


Infectious animal disease and its control.
The control of infectious diseases in the main food-producing animals is considered and the main factors involved in the epizootiology of disease are presented. The properties of infectious agents and their natural history together with factors that influence the spread and development of disease are summarized. The factors in intensive animal husbandry that affect the occurrence of infectious disease and its control are considered. These include population density, population movement, management, hygiene and genetic constitution of the host. They encourage the appearance of new diseases, changes in the character of established diseases and the development of pathogenicity in infectious agents that were previously of no importance. Intensive animal husbandry has also increased the importance of multifactorial disease, which includes diseases that require more than one infectious agent or one or more infectious agents plus other factors for their cause. The methods of control of infectious disease currently available are described and the success and difficulties of their control on a global, national and local (farm or enterprise) basis are considered. Examples of diseases of global importance where national and world programmes of control and eradication have been of varying success are described. Examples of diseases that are enzootic throughout the world and the procedures used for their control are also described. The technological opportunities for the improvement of the control of infectious disease in the future are discussed. It is considered that developments in molecular biology and immunology will provide improvements in diagnostic tools and will revolutionize the development of animal resistance to disease and the production and use of vaccines.


Strategies for screening young stock for antibodies - optimising numbers to test, cut-points, & predictive values for bovine viral diarrhoea virus.
The antibody seroprevalence of young stock can be a useful indicator of recent or current infection in a herd. We examine the factors that contribute to the assessment of herd exposure to disease, via spot testing for antibody, using bovine viral diarrhoea virus (BVDv) as an example. A statistical distribution of seroprevalences for BVDv in beef herds identified three groups of herds: low, intermediate and high within-herd BVDv antibody seroprevalence. We tested two assumptions -the intermediate seroprevalence group of herds is assumed to be negative for BVDv at the herd level and alternatively if this group is assumed to be positive. We found that: The herd-level sensitivity and specificity are sensitive to the assumption regarding the herds with intermediate seroprevalence. If an appropriate cut-point is chosen, reducing the sample size from ten to five does not produce a large drop in herd-level test performance. Increasing the cut-point may be valuable at the outset of an eradication programme. Increasing the sample size and decreasing the cut-point is advantageous towards the end of an eradication programme, to minimise the risk of positive herds being misclassified. The framework presented here illustrates how seroprevalence screening may be understood and assessed.


Jamming of soft particles: geometry, mechanics, scaling and isostaticity.
Amorphous materials as diverse as foams, emulsions, colloidal suspensions and granular media can jam into a rigid, disordered state where they withstand finite shear stresses before yielding. Here we review the current understanding of the transition to jamming and the nature of the jammed state for disordered packings of particles that act through repulsive contact interactions and are at zero temperature and zero shear stress. We first discuss the breakdown of affine assumptions that underlies the rich mechanics near jamming. We then extensively discuss jamming of frictionless soft spheres. At the jamming point, these systems are marginally stable (isostatic) in the sense of constraint counting, and many geometric and mechanical properties scale with distance to this jamming point. Finally, we discuss current explorations of jamming of frictional and non-spherical (ellipsoidal) particles. Both friction and asphericity tune the contact number at jamming away from the isostatic limit, but in opposite directions. This allows one to disentangle the distance to jamming and the distance to isostaticity. The picture that emerges is that most quantities are governed by the contact number and scale with the distance to isostaticity, while the contact number itself scales with the distance to jamming.


Perfusion-related changes in intestinal diffusion detected by NMR-MOUSE® monitoring in minipigs.
The aim was to investigate perfusion-related changes in the intestinal diffusion assessed by NMR-MOUSE monitoring in minipigs. This was a follow-up study of previous experiments on landrace pigs demonstrating the feasibility of NMR-MOUSE monitoring in large animals. 5 mature female minipigs (mean body weight 50 ± 2 kg) underwent laparotomy with exposition of several small intestinal loops and their feeding vessels. The loops were examined consecutively using NMR-MOUSE monitoring for assessment of intestinal proton diffusion (fast diffusion component [FC] and slow diffusion component [SC]) and oxygen to see monitoring (O2C, LEA Medizintechnik GmbH, Giessen, Germany) for microcirculatory evaluation. Following a baseline measurement on each loop under physiological perfusion, measurements were continued as one of the following main treatments were performed per loop: method 1 - ischemia; method 2 - flow reduction; method 3 - intraluminal glucose followed by ischemia; method 4 - intraluminal glucose followed by flow reduction. Perioperative monitoring was supplemented by blood gas analyses and histopathological assessment of H.E. stained intestinal biopsies. The NMR-MOUSE measurement showed a significant difference in the change to baseline values in the FC during flow reduction compared to the other treatments according to the unadjusted (pM2 vs. M1 < 0.0001, pM2 vs. M3 = 0.0005, pM2 vs. M4 = 0.0005) and the adjusted p-values (pM2 vs. M1 < 0.0001, pM2 vs. M3 = 0.0030, pM2 vs. M4 = 0.0030). In the SC, the difference between ischemia and flow reduction was significant according to the unadjusted p-values (pM2 vs. M1 = 0.0397). Whereas the FC showed a trend towards ongoing increase during ischemia but towards ongoing decrease during flow reduction, the SC showed contrary trends. These effects seemed to be attenuated by prior glucose application. According to the results of O2C monitoring, ischemia as well as flow reduction caused a significant decrease of microcirculatory oxygen saturation (inner probe: methods 1-4 and outer probe methods 1, 2: p < 0.0001; outer probe: pM2 = 0.0001), velocity (inner probe: pM1 < 0.0001, pM2 = 0.0155, pM3 = 0.0027; outer probe: pM1 < 0.0001, pM2 = 0.0045, pM3 = 0.0047, pM4 = 0.0037) and serosal flow (outer probe, methods 1 and 2: p < 0.0001; pM3 = 0.0009, pM4 = 0.0008). The histopathological analysis showed a significant association with time (p = 0.003) but not with the experimental method (p = 0.1386). Intestinal diffusion is affected significantly by perfusion changes in mature minipigs. As shown by NMR-MOUSE monitoring, ischemia and flow reduction have contrary effects on intestinal diffusion and, additionally, the fast and slow diffusion components show opposite trends during each of those pathological perfusion states. Prior intraluminal glucose application seems to attenuate the effects of malperfusion on intestinal diffusion.


Long-term safety and efficacy of treatment with subcutaneous abatacept in Japanese patients with rheumatoid arthritis who are methotrexate inadequate responders.
To assess the long-term safety, immunogenicity, and efficacy of subcutaneous (SC) abatacept in combination with methotrexate (MTX) in Japanese patients with rheumatoid arthritis who were MTX inadequate responders, in a long-term extension (LTE) to a double-dummy, double-blind study (NCT01001832). Patients, who had previously received SC or intravenous (IV) abatacept with MTX (6-8 mg/week) for 24 weeks, received SC abatacept (125 mg/week) with MTX for an additional 52 weeks. Safety, immunogenicity, and efficacy were assessed. The LTE included 112 patients. SC abatacept was generally well tolerated in the LTE, with no new safety signals. American College of Rheumatology 20, 50, and 70 response rates, disease activity score 28 (C-reactive protein) remission rates (< 2.6), and Health Assessment Questionnaire-Disability Index response rates (≥ 0.3 improvement from baseline) achieved at the end of the double-blind period were maintained over the LTE and were comparable in patients who received SC or IV abatacept in the double-blind period. Seropositivity for immunogenicity occurred in 4 (3.6%) patients. Self-injection of SC abatacept was well controlled and not associated with additional safety events. SC abatacept had acceptable safety and was well tolerated and effective over the LTE (76 weeks in total), with low rates of immunogenicity in Japanese patients.


Evidence that different cation chloride cotransporters in retinal neurons allow opposite responses to GABA.
GABA gating an anion channel primarily permeable to chloride can hyperpolarize or depolarize, depending on whether the chloride equilibrium potential (E(Cl)) is negative or positive, respectively, to the resting membrane potential (E(rest)). If the transmembrane Cl(-) gradient is set by active transport, those neurons or neuronal regions that exhibit opposite responses to GABA should express different chloride transporters. To test this, we immunostained retina for the K-Cl cotransporter (KCC2) that normally extrudes chloride and for the Na-K-Cl cotransporter (NKCC) that normally accumulates chloride. KCC2 was expressed wherever E(Cl) is either known or predicted to be negative to E(rest) (ganglion cells, bipolar axons, and OFF bipolar dendrites), whereas NKCC was expressed wherever E(Cl) is either known or predicted to be positive to E(rest) (horizontal cells and ON bipolar dendrites). Thus, in the retina, the opposite effects of GABA on different cell types and on different cellular regions are probably primarily determined by the differential targeting of these two chloride transporters.


Nonclonal Chromosome Aberrations and Genome Chaos in Somatic and Germ Cells from Patients and Survivors of Hodgkin Lymphoma.
Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. However, some of these treatments do not have a specific cell target, damaging both cancerous and normal cells. Thus, HL survivors have a high risk of developing new primary cancers, both hematologic and solid tumors, which have been related to treatment. Several studies have shown that after treatment, HL patients and survivors present persistent chromosomal instability, including nonclonal chromosomal aberrations. The frequency and type of chromosomal abnormalities appear to depend on the type of therapy and the cell type examined. For example, MOPP chemotherapy affects hematopoietic and germ stem cells leading to long-term genotoxic effects and azoospermia, while ABVD chemotherapy affects transiently sperm cells, with most of the patients showing recovery of spermatogenesis. Both regimens have long-term effects in somatic cells, presenting nonclonal chromosomal aberrations and genomic chaos in a fraction of noncancerous cells. This is a source of karyotypic heterogeneity that could eventually generate a more stable population acquiring clonal chromosomal aberrations and leading towards the development of a new cancer.


Haemodynamic and humoral responses to chronic ketanserin treatment in essential hypertension.
Ketanserin (120 mg/day) or placebo was given orally to 14 patients with mild to moderate essential hypertension according to a double blind crossover protocol, each treatment period lasting six weeks. Resting intra-arterial pressure in the recumbent position was reduced from 150/84 to 141/77 mm Hg; the hypotensive effect persisted throughout an uninterrupted graded exercise test to the point of exhaustion. The haemodynamic effects were similar at rest and during exercise. Overall, systemic vascular resistance decreased by 14%, heart rate fell by 5%, but stroke volume and cardiac output increased. Mean pulmonary arterial pressure and capillary wedge pressure were not significantly affected, but pulmonary vascular resistance decreased by 15%. The pressor response to methoxamine was significantly reduced by ketanserin. Both plasma noradrenaline and adrenaline concentrations increased, plasma renin activity and angiotensin II concentration decreased, and plasma aldosterone concentration was unchanged. The data indicate that ketanserin induces arteriolar dilatation, possibly related to an alpha-1-antagonistic action and to a reduced circulating angiotensin II concentration. The haemodynamic response is complex, and an increase in cardiac output limits the hypotensive effect. There is no firm evidence of an effect on venous tone as cardiac filling pressures do not change.


Hyperprogressive disease in patients with non-small cell lung cancer on immunotherapy.
Immunotherapy agents in metastatic non-small cell lung cancer (NSCLC) can result in improved quality of life and survival when compared with platinum-based chemotherapy. Novel response patterns such as pseudoprogression and hyperprogression, however, have been described and pose a challenge to treating physicians. Predictors of hyperprogressive disease (HPD) have not yet been identified. Evaluation and management by a multidisciplinary team involving medical and radiation oncologists, thoracic radiologists, and proceduralists is necessary to identify this subset of patients in a timely manner. Repeat biopsy distinguishes HPD from pseudoprogression and may eventually elucidate predictive biomarkers. We describe the epidemiology of these two phenomena, their diagnostic criteria, and their relevance for interventional pulmonologists.


Impact of Cerebral Small Vessel Disease on Functional Recovery After Intracerebral Hemorrhage.
Background and Purpose- In this study, we aim to investigate the association of computed tomography-based markers of cerebral small vessel disease with functional outcome and recovery after intracerebral hemorrhage. Methods- Computed tomographic scans of patients in the ERICH study (Ethnic and Racial Variations of Intracerebral Hemorrhage) were evaluated for the extent of leukoaraiosis and cerebral atrophy using visual rating scales. Poor functional outcome was defined as a modified Rankin Scale (mRS) of ≥3. Multivariable logistic and linear regression models were used to explore the associations of cerebral small vessel disease imaging markers with poor functional outcome at discharge and, as a measure of recovery, change in mRS from discharge to 90 days poststroke. Results- After excluding in-hospital deaths, data from 2344 patients, 583 (24.9%) with good functional outcome (mRS of 0-2) at discharge and 1761 (75.1%) with poor functional outcome (mRS of 3-5) at discharge, were included. Increasing extent of leukoaraiosis (P for trend, 0.01) and only severe (grade 4) global atrophy (odds ratio, 2.02; 95% CI, 1.22-3.39, P=0.007) were independently associated with poor functional outcome at discharge. Mean (SD) mRS change from discharge to 90-day follow-up was 0.57 (1.18). Increasing extent of leukoaraiosis (P for trend, 0.002) and severe global atrophy (β [SE], -0.23 [0.115]; P=0.045) were independently associated with less improvement in mRS from discharge to 90 days poststroke. Conclusions- In intracerebral hemorrhage survivors, the extent of cerebral small vessel disease at the time of intracerebral hemorrhage is associated with poor functional outcome at hospital discharge and impaired functional recovery from discharge to 90 days poststroke.


T6SS intraspecific competition orchestrates Vibrio cholerae genotypic diversity.
Vibrio cholerae is a diverse species that inhabits a wide range of environments from copepods in brackish water to the intestines of humans. In order to remain competitive, V. cholerae uses the versatile type-VI secretion system (T6SS) to secrete anti-prokaryotic and anti-eukaryotic effectors. In addition to competing with other bacterial species, V. cholerae strains also compete with one another. Some strains are able to coexist, and are referred to as belonging to the same compatibility group. Challenged by diverse competitors in various environments, different V. choleare strains secrete different combination of effectors - presumably to best suit their niche. Interestingly, all pandemic V. cholerae strains encode the same three effectors. In addition to the diversity displayed in the encoded effectors, the regulation of V. cholerae also differs between strains. Two main layers of regulation appear to exist. One strategy connects T6SS activity with behavior that is suited to fighting eukaryotic cells, while the other is linked with natural competence - the ability of the bacterium to acquire and incorporate extracellular DNA. This relationship between bacterial killing and natural competence is potentially a source of diversification for V. cholerae as it has been shown to incorporate the DNA of cells recently killed through T6SS activity. It is through this process that we hypothesize the transfer of virulence factors, including T6SS effector modules, to happen. Switching of T6SS effectors has the potential to change the range of competitors V. cholerae can kill and to newly define which strains V. cholerae can co-exist with, two important parameters for survival in diverse environments.


Quantification of loss of haemoglobin components from the circulating red blood cell in vivo.
Previous studies have shown that a considerable amount of haemoglobin is lost from the intact red cell during its lifespan. The aim of this study was to determine the relative contribution of all the haemoglobin components to this process. Therefore, the relative amount of haemoglobins A0, A2, F and the glycated haemoglobins were determined in 24 fractions of different cell age. These fractions were obtained by the combination of counterflow and density centrifugation. When the absolute amount of all haemoglobin components were calculated using the MCH-values of each fraction, it appeared that the mean red cell loss of haemoglobins A0, A2, F, an unknown X and "rest" comprised, respectively, 440, 23, 1, 4 and 1 amol per cell, while the mean gain of the glycated haemoglobins was 84 amol per cell. This resulted in a net loss of 385 amol of haemoglobin per cell. One of the glycated haemoglobins (HbA1e2) turned out to be the product of further carbamylation. It was concluded that in the first half of the red cell lifespan HbA0 and HbA2 decreased by glycation and carbamylation and that in the second half some of the HbA0 and HbA2 but also some of the glycated and carbamylated haemoglobin components leave the red cell. The total loss amounted to about 20%.


Redox potential inversion by ionic hydrogen bonding between phenylenediamines and pyridines.
In electrochemical oxidations, the second oxidation potential of phenylenediamines (PD) varies because of hydrogen-bonding formation for PD(+•) with pyridines. A linear relationship was obtained for the potential shift as a function of pK(a) of the protonated pyridines and potential inversion could be observed. The oxidized PD(+•) could also form hydrogen bonding with alcohols and the shift of potential exhibits a different pattern.


CaMKII activity is reduced in skeletal muscle during sepsis.
Exercise-induced muscle hypertrophy is associated with increased calcium/calmodulin-dependent protein kinase II (CaMKII) expression and activity. In contrast, the influence of muscle atrophy-related conditions on CaMKII is poorly understood. Here, we tested the hypothesis that sepsis-induced muscle wasting is associated with reduced CaMKII expression and activity. Sepsis, induced by cecal ligation and puncture in rats, and treatment of rats with TNFα, resulted in reduced total CaMKII activity in skeletal muscle whereas autonomous CaMKII activity was unaffected. The expression of CaMKIIδ, but not β and γ, was reduced in septic muscle. In additional experiments, treatment of cultured myotubes with TNFα resulted in reduced total CaMKII activity and decreased levels of phosphorylated glycogen synthase kinase (GSK)-3β, a downstream target of CaMKII. The present results suggest that sepsis-induced muscle wasting is associated with reduced CaMKII activity and that TNFα may be involved in the regulation of CaMKII activity in skeletal muscle. Decreased phosphorylation (consistent with activation) of GSK-3β may be a consequence of reduced CaMKII activity, indicating that inhibited CaMKII activity may be involved in the catabolic response to sepsis.


Analysis of enzyme-linked immunosorbent assay data for antigen quantitation using Lotus 1-2-3 software on a personal computer.
Absorbance data obtained in double-antibody sandwich enzyme-linked immunosorbent assay tests for quantitation of antigens are analyzed by a personal computer using the Lotus 1-2-3 software package. The sigmoid standard curve is processed by an iterative weighted regression analysis in the logit-log domain to obtain a linear dose-response relationship. A macro program is developed for quick calculation with easy operation, which is suited for routine laboratory tests in biomedical fields.


Bootstrap techniques for error estimation.
The design of a pattern recognition system requires careful attention to error estimation. The error rate is the most important descriptor of a classifier's performance. The commonly used estimates of error rate are based on the holdout method, the resubstitution method, and the leave-one-out method. All suffer either from large bias or large variance and their sample distributions are not known. Bootstrapping refers to a class of procedures that resample given data by computer. It permits determining the statistical properties of an estimator when very little is known about the underlying distribution and no additional samples are available. Since its publication in the last decade, the bootstrap technique has been successfully applied to many statistical estimations and inference problems. However, it has not been exploited in the design of pattern recognition systems. We report results on the application of several bootstrap techniques in estimating the error rate of 1-NN and quadratic classifiers. Our experiments show that, in most cases, the confidence interval of a bootstrap estimator of classification error is smaller than that of the leave-one-out estimator. The error of 1-NN, quadratic, and Fisher classifiers are estimated for several real data sets.


Pharmacology of a central nervous system delivered 2'-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates.
Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and nonhuman primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443-mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development.


Re-thinking recovery in post-conflict settings: Supporting the mental well-being of communities in Colombia.
Addressing mental health needs is a central focus of the Colombian Government's framework for socio-political reconstruction following over 60 years of conflict. Informed by WHO standards, country efforts utilise biopsychosocial models that prioritise individual psychological and psychiatric conditions. However, increasing scrutiny of the deployment of Western approaches to mental health and recovery in the global south suggests a need to explore the best route to improving mental health outcomes. Our research contributes to these debates through a qualitative study of local understandings of mental health recovery related concepts among internally displaced persons in Colombia. Analysis of focus groups with 40 internally displaced men and women established definitions for emotional distress and recovery as parallel processes linked to the fracture and rebuilding of social worlds and family life. Definitions were shaped heavily by cultural, political, economic and legal contexts of everyday survival, often linked to experiences of structural and symbolic forms of violence. We conclude that a locally informed mental health recovery model that stretches beyond individual experiences of mental ill-health to promote ideas of collective social change would be best suited to addressing mental health needs of internally displaced groups in Colombia. Implications for practice are discussed.


The first record of Centrocestus formosanus (Trematoda: Heterophyidae) in southern Brazil supported by molecular data.
Centrocestus formosanus is a digenean parasite first described from Asia, which parasitizes Melanoides tuberculata (Gastropoda: Thiaridae) at the first intermediate stage, and different fish species as second intermediate host. C. formosanus was previously recorded in Brazilian states, but never before in the southern region of this country. Recording and identification of digenean species through morphological identification is a taxonomic challenge. In light of this, we use an integrative taxonomic approach to report the occurrence of cercariae and metacercariae of C. formosanus in molluscs and fish, respectively, in an urban park located in southern Brazil. Specimens of M. tuberculata and the fishes Poecilia reticulata and Xiphophorus sp. (Poeciliidae) were collected for screening for parasites and molecular analyses using partial fragments of the 28S rDNA gene. The identification of C. formosanus obtained from molluscs and fish specimens permitted us to partially solve the life cycle of this parasite for the first time in the studied environment, demonstrating the necessity of monitoring and controlling molluscs populations. Nevertheless, our results will support future studies aiming to elucidate the life-cycle of C. formosanus in this region, since all sampled hosts' species are invasive in this environment.


Synthesis and anticancer mechanism investigation of dual Hsp27 and tubulin inhibitors.
Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development.


Between-hand difference in ipsilateral deactivation is associated with hand lateralization: fMRI mapping of 284 volunteers balanced for handedness.
In right-handers (RH), an increase in the pace of dominant hand movement results in increased ipsilateral deactivation of the primary motor cortex (M1). By contrast, an increase in non-dominant hand movement frequency is associated with reduced ipsilateral deactivation. This pattern suggests that inhibitory processes support right hand dominance in right-handers and raises the issues of whether this phenomenon also supports left hand preference in left-handers (LH), and/or whether it relates to asymmetry of manual ability in either group. Thanks to the BIL&GIN, a database dedicated to the investigation of hemispheric specialization (HS), we studied the variation in M1 activity during right and left finger tapping tasks (FTT) in a sample of 284 healthy participants balanced for handedness. An M1 fMRI localizer was defined for each participant as an 8 mm diameter sphere centered on the motor activation peak. RH exhibited significantly larger deactivation of the ipsilateral M1 when moving their dominant hand than their non-dominant hand. In contrast, LH exhibited comparable ipsilateral M1 deactivation during either hand movement, reflecting a bilateral cortical specialization. This pattern is likely related to left-handers' good performances with their right hand and consequent lower asymmetry in manual ability compared with RH. Finally, inter-individual analyses over the whole sample demonstrated that the larger the difference in manual skill across hands, the larger the difference in ipsilateral deactivation. Overall, we propose that difference in ipsilateral deactivation is a marker of difference in manual ability asymmetry reflecting differences in the strength of transcallosal inhibition when a given hand is moving.


Epithelial-specific and stage-specific functions of insulin-like growth factor-I during postnatal mammary development.
Postnatal development of the mammary gland requires interactions between the epithelial and stromal compartments, which regulate actions of hormones and growth factors. IGF-I is expressed in both epithelial and stromal compartments during postnatal development of the mammary gland. However, little is known about how local expression of IGF-I in epithelium or stroma regulates mammary growth and differentiation during puberty and pregnancy-induced alveolar development. The goal of this study was to investigate the mechanisms of IGF-I actions in the postnatal mammary gland and test the hypothesis that IGF-I expressed in stromal and epithelial compartments has distinct functions. We established mouse lines with inactivation of the igf1 gene in mammary epithelium by crossing igf1/loxP mice with mouse lines expressing Cre recombinase under the control of either the mouse mammary tumor virus long-terminal repeat or the whey acidic protein gene promoter. Epithelial-specific loss of IGF-I during pubertal growth resulted in deficits in ductal branching. In contrast, heterozygous reduction of IGF-I throughout the gland decreased expression of cyclins A2 and B1 during pubertal growth and resulted in alterations in proliferation of the alveolar epithelium and milk protein levels during pregnancy-induced differentiation. Reduction in epithelial IGF-I at either of these stages had no effect on these indices. Taken together, our results support distinct roles for IGF-I expressed in epithelial and stromal compartments in mediating growth of the postnatal mammary gland.


[Hyperacidification-induced, clear appearance of venules caused by the swelling of erythrocytes in microcirculation].
In the mesenterium of rats it was found that an overacidity of the blood flowing in the area of microcirculation and caused by irrigation with acid media may be objectively represented in the clearing of venols measurable by means of video technique. The cause of this clearing process is the swelling of erythrocytes setting in at lower pH-values. According to in-vitro findings this swelling of erythrocytes will lead to an increase of the apparent viscosity of the blood fluid or blood cell suspension respectively in conformity with the increase of hematocrit connected with it.


The synergistic effect of κ-carrageenan and l-lysine on the 3D printability of yellow flesh peach gels: The importance of material elasticity in the printing process.
This study investigated the effect of κ-carrageenan and l-lysine on the physical, chemical and textural properties of yellow flesh peaches and their suitability for 3D printing. The addition of κ-carrageenan and l-lysine was found to improve the apparent viscosity, elasticity, gel strength, and Young's modulus of the yellow flesh peach with κ-carrageenan and l-lysine gels (PCLG) and increase the minimum piston pressure required for 3D printing, thereby improving the printing performance. Optimum levels of κ-carrageenan and l-lysine (0.1 mmol/mL and 3.42 × 10-2 mmol/mL, respectively) were found to enhance mechanical strength, viscoelasticity and print fidelity. On the other hand, when the addition of κ-carrageenan is 0.1 mmol/mL, the addition of l-lysine causes an increase in the G0 value and a decrease in the η0 value of the PCLG according to Burger's model, indicating a transition from viscosity to elasticity and an increase in maximum extrusion force, while the apparent viscosity does not change significantly. The results of 3D printing showed that when the addition of κ-carrageenan and l-lysine reached 0.1 mmol/mL and 6.84 × 10-2 mmol/mL, respectively, the PCLG could not be smoothly extruded, indicating that elasticity also plays an important role during the extrusion process of the mixed gel.


Opportunity for HiAP through a Healthy Cities initiative in Taiwan: a multiple streams analysis.
Health in All Policies (HiAP) is an effective approach to promote population health through addressing comprehensive social determinants of health. In 1997, the World Health Organization designed a 20-step protocol for developing a Healthy Cities (HC) project to build healthy public policies. Taiwan adopted the concept of HC in 2002 and established the first demonstration project in Tainan City in 2003. This study explores the impact of the HC initiative on the development of HiAP, as well as how a window of opportunities for HiAP was opened through the HC movement, using Tainan City as an example. Tainan was selected as the case for this study because of its relative maturity in the development of an HC initiative. A theory-driven thematic analysis was conducted in the study with archived documents between 2003 and 2010. We first adopted a Multiple Streams Approach to examine how the city government opened a window for HiAP through the HC initiative and then drew on the Maturity Model to evaluate the stage of HiAP in the Tainan HC project. After analyzing all related documents, we concluded that HiAP in the Tainan HC project had reached Stage V Institutionalization after 7 years. Key contexts, factors, challenges and strategies were identified. This study suggests that the HC initiative can indeed contribute to the development of HiAP and that the window was opened for HiAP through a concurrence of the three streams of problem, policy and politics along with the HC movement process.


Evaluation of Natural Additives to Enhance the Persistence of Spodoptera littoralis (Lepidoptera: Noctuidae) Nucleopolyhedrovirus (SpliMNPV) Under Field Conditions in Saudi Arabia.
Nucleopolyhedrovirus is an effective biocontrol agent but for its biggest disadvantage of short persistence under sunlight conditions. In this study, 10 plant extracts were evaluated as ultraviolet (UV) protectants to improve the persistence of Spodoptera littoralis multiple-embedded nucleopolyhedrovirus (SpliMNPV) against cotton leafworm (Spodoptera littoralis Boisduval). In the primary lab screening test, 5 out of 10 additives (cloves, henna, green tea, pomegranate, and grape extracts) presented a high rate of virus protection with original activity remaining (OAR) percentage of 100%, 97%, 91%, 90.6%, and 77%, respectively, when used at a concentration of 1% and exposed to UVB for a period of 1 h. A secondary screening was then performed with these best five extracts at a concentration of 0.5% and for an exposure timing of 5 h to UVB. Among these, clove and henna that showed highest protection with OAR values of 96.6% and 76.5%, respectively, were selected for the field trials. When applied on cabbage in the field during sunny summer conditions, clove and henna extracts enhanced the persistence of SpliMNPV by twofold. These findings are encouraging to be applied in the field studies.


Effects of pH on salicylic acid toxicity in terms of biomarkers determined in the marine gastropod Gibbula umbilicalis.
Alterations of the physical-chemical properties of the oceans due to anthropogenic activities are, at present, one of the most concerning environmental issues studied by researchers. One of these issues is ocean acidification, mainly caused by overproduction and release of carbon dioxide (CO2) from anthropogenic sources. Another component of environmental degradation is related to the production and release of potential toxic compounds, namely active pharmaceutical ingredients, into the aquatic environment that, combined with oceanic acidification, can cause unpredictable and never before considered deleterious effects on non-target marine organisms. Regarding this issue, the hereby study used predictions of future ocean acidification to simulate realistic scenarios of environmental exposure to a common therapeutic drug, salicylic acid (SA), in the marine gastropod Gibbula umbilicalis under different pH values. This species was exposed to a range of pH values (8.2, 7.9 and 7.6), and to already reported environmentally realistic concentrations (5, 25 and 125 μg/L) of SA. To evaluate the effects of these environmental stressors, key physiological biomarkers (GSTs, CAT, TBARS, AChE and COX) and shell hardness (SH) were quantified. Results from the present study showed that CAT and GSTs activities were enhanced by SA under water acidification; increased lipid peroxidation was also observed in organisms exposed to SA in more acidic media. In addition, the hereby study demonstrated the neurotoxic effects of SA through the inhibition of AChE. Effects were also observed in terms of COX activity, showing that SA absorption may be affected by water acidification. In terms of SH, the obtained data suggest that SA may alter the physical integrity of shells of exposed organisms. It is possible to conclude that the combination of seawater acidification and exposure to toxic xenobiotics (namely to the drug SA) may be strenuous to marine communities, making aquatic biota more susceptible to xenobiotics, and consequently endangering marine life in an unpredictable extent.


Rethinking Theta/Beta Ratio in ADHD through Functional Data Analysis.
ADHD is a neurodevelopmental disorder largely diffused among children and adolescents. The current method of diagnosis is based on agreed clinical literature such as DSM-5, by identifying and evaluating signs of hyperactivity and inattention. Multiple reviews have assessed that EEG is not sufficiently reliable for the diagnosis of ADHD. Theta-Beta Ratio is now the sole EEG parameter considered for analysis, although it is not robust enough to be utilized as a confirmatory technique for diagnosis. In this setting, new objective approaches for reliably classifying neurotypical and ADHD subjects are required. As a result, we suggest a new methodology based on Functional Data Analysis, a statistical class of methods for dealing with curves and functions. The initial stage in our method is to separate frequency bands from the EEG signal using a wavelet decomposition. We next compute the Power Spectral Densities of each of these bands and represent them as mathematical functions via spline interpolation. Finally, the relevance of the collected features is assessed using the Permutation ANOVA test. Using this method, we can detect different patterns in the PSDs of the groups and identify statistically significant features, confirming prior findings in the literature. We validate the features using classification techniques such as Bagging trees, Random Forest, and AdaBoost. The latter reaches the highest accuracy score of 76.65%, confirming the relevance of the extracted features.


[Diagnosis and treatment of primary osteosarcoma in 2009].
Curative treatment for high-grade osteosarcoma consists in surgery of the primary tumor and chemotherapy, in order to achieve a limb salvage surgery and increase the disease-free survival rate. Patients with suggestive diagnosis of osteosarcoma should be sent to a reference center before biopsy. Confirmation of diagnosis by a pathologist with particular expertise in bone tumors is recommended. Multimodal treatment is often given within the framework of prospective collaborative studies. Currently, doxorubicin, cisplatinum, high-dose methotrexate and ifosfamide are considered the most active agents against osteosarcoma. High-dose methotrexate with leucovorin rescue always takes part of first-line regimen in children and adolescents, alternative regimens are proposed for adults because of excessive toxicity despite appropriate management by skilled teams. Compared with surgery alone, multimodal treatment of localized high-grade osteosarcoma improves outcome for patients from 20% to more than 60% of them been alive 5-year after diagnosis.


Systemic Bevacizumab for Recurrent Respiratory Papillomatosis: A Single Center Experience of Two Cases.
BACKGROUND Recurrent respiratory papillomatosis (RRP), caused by human papillomavirus (HPV), is the most common benign neoplasm of the larynx and central airways. RRP has a significant impact on quality life and high annual costs to healthcare. Currently, there is no cure for RRP, leading to repeated debulking operations for symptomatic palliation. Various local adjuvant therapies have also been studied with mixed efficacy. HPV oncogene products increase expression of vascular endothelial growth factor (VEGF) providing a potential target for treatment of RRP. Bevacizumab, a recombinant monoclonal antibody that inhibits VEGF, has shown efficacy in patients with localized disease. CASE REPORT We present two cases of extensive airway and parenchymal RRP successfully managed with systemically administered bevacizumab, a recombinant monoclonal antibody that inhibits VEGF. CONCLUSIONS Bevacizumab has shown efficacy in patients with localized disease, but here we illustrate the potential of bevacizumab for patients with extensive parenchymal burden as well as provide a brief review of the literature.


Stroke survivors' perceptions of their sedentary behaviours three months after stroke.
Sedentary behaviour is any waking behaviour in sitting, lying or reclining postures with low energy expenditure. High sedentary behaviour levels, common after stroke, are associated with poor health and higher levels of mobility disability. The aim of this study was to undertake a behavioural diagnosis of sedentary behaviour in the early phase after stroke to inform interventions that may reduce sedentary behaviour and associated disability. Independently mobile stroke survivors were interviewed three months after stroke. The topic guide was informed by the central layer of the Behaviour Change Wheel to explore three components: capability, opportunity and motivation. This model recognises that behaviour is the consequence of an interacting system of these components. Interviews were transcribed verbatim and analysed using The Framework Method. Thirty one people were interviewed (66.7 years; 16 male). The perception of diminished capability to reduce sedentary behaviour due to physical tiredness/fatigue, and pain/discomfort acting as both a motivator and inhibitor to movement, were discussed. Environmental barriers and the importance of social interaction were highlighted. Perceived motivation to reduce sedentary behaviour was influenced by enjoyment of sedentary behaviours, fear of falling and habitual nature of sedentary behaviours. This information will inform evidence-based sedentary behaviour interventions after stroke.Implications for rehabilitationHigher levels of sedentary behaviours are associated with poor health and stroke survivors are highly sedentary.Stroke survivors have complex reasons for spending time in sedentary behaviours including fatigue, pain, fear of falling and environmental barriers.Future interventions should educate stroke survivors on the health consequences of sedentary behaviours and encourage an increased awareness of time spent sedentary.Supporting stroke survivors to identify enjoyable and achievable activities that involve standing and movement, and ideally social interaction, is recommended.


Subcellular distribution and some properties of N-ethylmaleimide-sensitive and-insensitive forms of glycerol phosphate acyltransferase in rat adipocytes.
1. Glycerol phosphate acyltransferase (GPAT) activities were measured in subcellular fractions obtained from rat epididymal adipocytes. These contained both N-ethylmaleimide-sensitive and N-ethylmaleimide-insensitive forms of the enzyme. 2. As shown by parallel measurements of marker enzymes, N-ethylmaleimide-insensitive GPAT is most probably a mitochondrial activity, whereas N-ethylmaleimide-sensitive GPAT is the microsomal enzyme. 3. Subcellular distributions are also reported for dihydroxyacetone phosphate acyltransferase (DHAPAT) (assayed with and without N-ethylmaleimide), monoacylglycerol phosphate acyltransferase (MGPAT) and Mg2+-dependent and Mg2+-independent forms of phosphatidate phosphohydrolase (PPH).


Pregnancy-induced insulin resistance in liver and skeletal muscles of the conscious rabbit.
Insulin sensitivity of maternal nonuterine tissues (liver and skeletal muscles) has been investigated in the conscious rabbit during late gestation (24 and 30 days). The specific effect of insulin on glucose production and utilization was evaluated with the hyperinsulinemic euglycemic clamp technique. The net balance of glucose across the hindlimb muscles was studied by means of the Fick principle in basal and insulin stimulated conditions (clamp study). Our results show that an insulin-resistant state develops between days 24 and 30 of gestation in the rabbit and involves both glucose producing (liver) and utilizing (muscles) tissues. On day 30 of gestation, muscle glucose uptake was not significantly stimulated at a plasma insulin concentration of 700 microU/ml, whereas it was stimulated by 30-40% in nonpregnant and 24 day pregnant rabbits. At similar plasma insulin concentration, endogenous glucose production was suppressed by 85% in both nonpregnant and 24 day pregnant rabbits, whereas it was decreased by only 30% in 30 day pregnant rabbits. The present data suggest that hindlimb muscles of late pregnant rabbits are able to reduce their insulin-induced glucose utilization. This could contribute to meet the glucose requirements of pregnant uterus in late gestation.


[A case of multiple malignant schwannoma as the only disease in a 40-year-old patient: is this a new type of neurofibromatosis?].
We present the case of a 40-year-old man that presented a fast growing tumour on the external side of the left elbow. The tumour was extirpated by means of marginal exerectomy. The microscopic study corresponded to epithelioid malignant schwannoma, and the patient received radiotherapy and adjuvant chemotherapy. During the following years two local recidives and two new malignant schwannomas, one in the left sciatic common trunk and another paraspinal one, appeared and were extirpated. Radiotherapy and chemotherapy were again administered. In the last year, four new tumours have appeared: in the supraclavicular space, right posterior costofrenic, left costovertebral, and in the inferior abdominal wall, none of them has been extirpated or has hystologic diagnosis at the moment, however radiologic findings suggest malignant schwannomas. In this moment there is no neurologic deficiency except for the secondary ones to surgical procedures, and no neurofibromatosis types I to VII signs have been observed. So, the possibility of a new neurofibromatosis type is appointed.


Phytostimulatory effect of silver nanoparticles (AgNPs) on rice seedling growth: An insight from antioxidative enzyme activities and gene expression patterns.
The knowledge on the mode of action, biocompatibility and ecological tolerance of silver nanoparticles (AgNPs) is gradually accumulating over the years with contradictory findings. Most of the studies indicated the toxic impact of AgNPs on plant growth and development, where induction of oxidative stress was considered to be one of the causal factors. The present study demonstrates the phytostimulatory effect of bio-synthesized silver nanoparticles (AgNPs) during seed germination and seedling growth of rice (Oryza sativa L., cv. Swarna) under in vitro condition. All the tested concentrations of AgNPs (10, 20, 40 ppm) promote both the shoot and root growth which was evident from the increased length and biomass of the seedlings. Exposure to AgNPs also significantly increased the chlorophyll a and carotenoid contents. The content and the pattern of distribution of phenolic metabolites among the different treatments are indicative of non-toxic impact of AgNP mimicking mild or no stress to the seedlings. Growth stimulation of rice seedlings by AgNPs was further supported by a low level of reactive oxygen species (ROS) concomitant with decreased amount of lipid peroxidation and H2O2 content, compared to control. In order to unravel the stimulatory impact of AgNPs on rice seedling growth, the present study also describes the AgNPs induced changes in antioxidative enzyme activity and related gene expression levels. Elevated levels of catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR) activities were recorded in all the AgNPs treated seedlings with improved growth. The activity of superoxide dismutase (SOD) was not significantly altered at low concentration of AgNPs. It appears that enzymes of ascorbate cycle, APX and GR are more active in ensuring protection against oxidative damage than SOD. There was significant up-regulation of CAT and APX gene expressions in seedlings exposed to AgNPs, whereas the expression level of CuZnSOD gene was decreased gradually with an increase in the concentration of AgNPs. The antioxidant enzyme activities and gene expression patterns coupled with the levels of H2O2 and lipid peroxidation indicates that the efficiency of redox reactions was increased in the presence of AgNPs and that accelerates the seedling growth.


The effect of physical training on patients with rheumatoid arthritis: changes in disease activity, muscle strength and aerobic capacity. A clinically controlled minimized cross-over study.
For decades, physical training of rheumatoid arthritis (RA)-patients has been controversial, especially for patients with active disease. The aim of this study was to investigate whether RA-patients could receive graduated training without increasing the activity of the disease. In a controlled cross-over study the effect of graduated progressive training has been evaluated in 18 RA-patients with moderately active disease. The training was performed twice weekly with aerobic conditioning and strength exercises progressing to strenuous exercises over an 8-week period. The design was a crossover project with two groups obtained by minimisation. After training the patients had significantly fewer swollen joints than before. Training of the muscles acting over the swollen joints resulted in more than a 35% decrease in the number of swollen joints. The hemoglobin level increased significantly after the training period. The erythrocyte sedimentation rate, the complement factor C3d, and the number of sore joints remained unchanged. A decrease in the need for medicine was non-significant. From this study it appears that RA-patients with some activity are trainable without aggravating the disease, even in the chronically swollen joints. The rheumatoid arthritis activity decreased with fewer swollen joints and higher hemoglobin level after training.


Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties.
The v-abl protein of Abelson murine leukemia virus is a tyrosine-specific kinase. Its normal cellular homolog, murine c-abl, does not possess detectable tyrosine kinase activity in vitro. Previously, we have detected tyrosine kinase activity in vitro for an altered c-abl gene product (c-abl P210) in the K562 human chronic myelogenous leukemia cell line. The expression of this variant c-abl gene product correlates with chromosomal translocation and amplification of the c-abl gene in K562 cells. Like v-abl, c-abl P210 is a fusion protein containing non-abl sequences near the amino terminus of c-abl. We compared the in vitro tyrosine kinase activity of c-abl P210 with that of wild-type murine v-abl. The remarkable similarities of these two proteins with respect to cis-acting autophosphorylation, trans-acting phosphorylation of exogenous substrates, and kinase inhibition, using site-directed abl-specific antisera, suggested that c-abl P210 could function similarly to v-abl in vivo. In addition, c-abl P210 possessed an associated serine kinase activity in immunoprecipitates. The serine kinase activity was not inhibited by site-directed, abl-specific antisera that inhibit the tyrosine kinase activity, suggesting that the serine kinase activity is not an intrinsic property of c-abl P210. Thus, the activation of the c-abl gene in a human leukemia cell line may have functional consequences analogous to activation of the c-abl gene in Abelson murine leukemia virus.


Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer's disease.
Alzheimer's disease is a progressive neurodegenerative disorder of the central nervous system. One pathological characteristic is excessive neuronal loss in specific regions of the brain. Among the areas most severely affected are the basal forebrain cholinergic neurons and their projection regions, the hippocampus and cortex. Neurotrophic factors, particularly the neurotrophins nerve growth factor and brain-derived neurotrophic factor, play an important role in the development, regulation and survival of basal forebrain cholinergic neurons. Furthermore, brain-derived neurotrophic factor regulates the function of hippocampal and cortical neurons. Neurotrophins are synthesized in hippocampus and cortex and retrogradely transported to the basal forebrain. Decreased levels of neurotrophic factors are suspected to be involved in the neurodegenerative changes observed in Alzheimer's disease. We examined autopsied parietal cortex samples from age- and gender-matched Alzheimer's diseased and neurologically non-impaired individuals using the quantitative technique of competitive RT-PCR. We demonstrate a 3.4-fold decrease in brain-derived neurotrophic factor mRNA levels in the parietal cortex of patients with Alzheimer's disease compared to controls (p<0.004). A decrease in brain-derived neurotrophic factor synthesis could have detrimental effects on hippocampal, cortical and basal forebrain cholinergic neurons and may account for their selective vulnerability in Alzheimer's disease.


Understanding the Impact of Rainfall on Diarrhea: Testing the Concentration-Dilution Hypothesis Using a Systematic Review and Meta-Analysis.
Projected increases in extreme weather may change relationships between rain-related climate exposures and diarrheal disease. Whether rainfall increases or decreases diarrhea rates is unclear based on prior literature. The concentration-dilution hypothesis suggests that these conflicting results are explained by the background level of rain: Rainfall following dry periods can flush pathogens into surface water, increasing diarrhea incidence, whereas rainfall following wet periods can dilute pathogen concentrations in surface water, thereby decreasing diarrhea incidence. In this analysis, we explored the extent to which the concentration-dilution hypothesis is supported by published literature. To this end, we conducted a systematic search for articles assessing the relationship between rain, extreme rain, flood, drought, and season (rainy vs. dry) and diarrheal illness. A total of 111 articles met our inclusion criteria. Overall, the literature largely supports the concentration-dilution hypothesis. In particular, extreme rain was associated with increased diarrhea when it followed a dry period [incidence rate ratio (IRR)=1.26; 95% confidence interval (CI): 1.05, 1.51], with a tendency toward an inverse association for extreme rain following wet periods, albeit nonsignificant, with one of four relevant studies showing a significant inverse association (IRR=0.911; 95% CI: 0.771, 1.08). Incidences of bacterial and parasitic diarrhea were more common during rainy seasons, providing pathogen-specific support for a concentration mechanism, but rotavirus diarrhea showed the opposite association. Information on timing of cases within the rainy season (e.g., early vs. late) was lacking, limiting further analysis. We did not find a linear association between nonextreme rain exposures and diarrheal disease, but several studies found a nonlinear association with low and high rain both being associated with diarrhea. Our meta-analysis suggests that the effect of rainfall depends on the antecedent conditions. Future studies should use standard, clearly defined exposure variables to strengthen understanding of the relationship between rainfall and diarrheal illness. https://doi.org/10.1289/EHP6181.


Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells.
Retinoids, which are derivatives of vitamin A, induce differentiation of acute promyelocytic leukemia (APL) cells in vitro and in patients. However, APL cells develop resistance to retinoic acid treatment. Arsenic trioxide (As2O3) can induce clinical remission in patients with APL, including those who have relapsed after retinoic acid treatment, by inducing apoptosis (programmed cell death) of the leukemia cells. In this study, we investigated the molecular mechanisms by which As2O3 induces apoptosis in retinoic acid-sensitive NB4 APL cells, in retinoic acid-resistant derivatives of these cells, and in fresh leukemia cells from patients. Apoptosis was assessed by means of DNA fragmentation analyses, TUNEL assays (i.e., deoxyuridine triphosphate labeling of DNA nicks with terminal deoxynucleotidyl transferase), and flow cytometry. Expression of the PML/RAR alpha fusion protein in leukemia cells was assessed by means of western blotting, ligand binding, and immunohistochemistry. Northern blotting and ribonuclease protection assays were used to evaluate changes in gene expression in response to retinoic acid and As2O3 treatment. As2O3 induces apoptosis without differentiation in retinoic acid-sensitive and retinoic acid-resistant APL cells at concentrations that are achievable in patients. As2O3 induces loss of the PML/RAR alpha fusion protein in NB4 cells, in retinoic-acid resistant cells derived from them, in fresh APL cells from patients, and in non-APL cells transfected to express this protein. As2O3 and retinoic acid induce different patterns of gene regulation, and they inhibit the phenotypes induced by each other. Understanding the molecular basis of these differences in the effects of As2O3 and retinoic acid may guide the clinical use of arsenic compounds and provide insights into the management of leukemias that do not respond to retinoic acid.


Circadian regulation of pulmonary disease: the importance of timing.
Circadian regulation causes the activity of biological processes to vary over a 24-h cycle. The pathological effects of this variation are predominantly studied using two different approaches: pre-clinical models or observational clinical studies. Both these approaches have provided useful insights into how underlying circadian mechanisms operate and specifically which are regulated by the molecular oscillator, a key time-keeping mechanism in the body. This review compares and contrasts findings from these two approaches in the context of four common respiratory diseases (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and respiratory infection). Potential methods used to identify and measure human circadian oscillations are also discussed as these will be useful outcome measures in future interventional human trials that target circadian mechanisms.


Planar polarity in the ciliated epidermis of Xenopus embryos.
The coordinated orientation of ciliary beat in the larval epidermis of amphibians, evident in an organized streamline pattern, suggests a planar polarity of the epithelium, i.e., a polarity within the plane of the cell sheet. It has been proposed that the direction of ciliary beat is determined at mid gastrula by a gradient of a diffusible factor produced by the mesoderm. To analyze whether ectoderm in isolation can establish a uniform direction of ciliary beat, and at what stage its polarity is specified in the embryo, ectoderm of Xenopus laevis embryos of different stages was cultured in vitro on substrates. On concanavalin A, ectoderm isolated at early gastrula stages, i.e., prior to any contact with mesoderm, can autonomously coordinate the direction of ciliary beat, at least in small regions. A uniform planar polarity is expressed by ectoderm explanted from the early mid gastrula onward. On fibronectin, which promotes migration, the direction of movement correlates well with the direction of ciliary beat, and directional migration can even override the inherent polarity specified prior to explantation. Embryos which lack dorsal mesoderm nevertheless develop a highly organized streamline pattern, excluding a strict requirement for dorsal mesoderm for the determination of planar polarity. However, in spite of the early specification of planar polarity found for isolated tissue, rotated ectodermal transplants in situ can readjust their polarity in accordance with that of the host.


Phagocytic efficiency of monocytes and macrophages obtained from Sydney blood bank cohort members infected with an attenuated strain of HIV-1.
Defective function of monocyte-derived macrophages contributes to HIV-1 pathogenesis. We found that phagocytosis of the opportunistic pathogens Mycobacterium avium complex and Toxoplasma gondii was impaired in monocytes obtained from individuals infected with wild-type strains of HIV-1 but generally not in monocytes collected over a 6-year period from Sydney Blood Bank Cohort (SBBC) members infected with nef/long terminal repeats (LTR) region-defective strains of HIV-1. However, longitudinal analysis of phagocytosis in 1 SBBC member, C54, showed the development of defective engulfment of opportunistic pathogens at the most recent time points, coincident with the development of further molecular deletions in the nef/LTR region. Another SBBC member, C98, underwent bronchoscopy, which provided material to examine phagocytic signaling in alveolar macrophages. In contrast to normal phagocytic efficiency of C98's monocytes (over a 6-year period), defective signaling events during FcgammaR-mediated phagocytosis by C98's alveolar macrophages were observed. High basal phosphorylation within HIV-infected macrophages correlated with colocalization of tyrosine-phosphorylated proteins with HIV-1 p24 antigen rather than around the phagocytic targets as observed in uninfected cells. Thus, although phagocytic efficiency appears to be generally unimpaired in monocytes from SBBC members, evidence of impairment in recent samples from 1 SBBC member, coincident with further genetic changes within the virus, and abnormal phagocytic signaling in alveolar macrophages from another SBBC member may herald loss of attenuation of those strains.


Avian VEGF-C: cloning, embryonic expression pattern and stimulation of the differentiation of VEGFR2-expressing endothelial cell precursors.
VEGF-C is a recently discovered secreted polypeptide related to the angiogenic mitogen VEGF. We have isolated the quail VEGF-C cDNA and shown that its protein product is secreted from transfected cells and interacts with the avian VEGFR3 and VEGFR2. In situ hybridization shows that quail VEGF-C mRNA is strongly expressed in regions destined to be rich in lymphatic vessels, particularly the mesenteries, mesocardium and myotome, in the region surrounding the jugular veins, and in the kidney. These expression sites are similar to those observed in the mouse embryo (E. Kukk, A. Lymboussaki, S. Taira, A. Kaipainen, M. Jeltsch, V. Joukov and K. Alitalo, 1996, Development 122, 3829-3837). We have observed VEGFR3-positive endothelial cells in proximity to most of the VEGF-C-expressing sites, suggesting functional relationships between this receptor-ligand couple. The comparison of the VEGF and VEGFR2 knockout phenotypes had suggested the existence of another ligand for VEGFR2. We therefore investigated the effect of VEGF-C on VEGFR2-positive cells isolated from the posterior mesoderm of gastrulating embryos. We have recently shown that VEGF binding triggers endothelial differentiation of these cells, whereas hemopoietic differentiation appears to be mediated by binding of a so far unidentified VEGFR2 ligand. We show here that VEGF-C also triggers endothelial differentiation of these cells, presumably via VEGFR2. These results indicate that VEGF and VEGF-C can act in a redundant manner via VEGFR2. In conclusion, VEGF-C appears to act during two different developmental phases, one early in posterior mesodermal VEGFR2-positive endothelial cell precursors which are negative for VEGFR3 and one later in regions rich in lymphatic vessels at a time when endothelial cells express both VEGFR2 and VEGFR3.


Changing predictors of statin initiation in US women over two decades.
To describe changing roles of predictors of statin initiation before and after incident coronary heart disease, and before and after publication of National Cholesterol Education Program Adult Treatment Panel-III (ATP-III) guidelines in a cohort of US women. We identified 34 382 women enrolled into the Women's Health Study from 1993 to 1995 and followed up until 2012. Proportions of previous nonusers initiating statins were described over time. We used multivariable linear regression models to estimate adjusted initiation proportion differences (IPDs) for initiation overall, separately before and after incident coronary heart disease, and separately for ATP-II and ATP-III time periods. Key predictors of initiation overall were self-reported total cholesterol, and previous incident coronary heart disease, cerebrovascular disease, and diabetes. Adjusted IPDs (percentage) for total cholesterol > 240 vs <200 mg/dL were 7.5 (95% confidence interval [CI], 7.0-8.0) and 9.3 (95% CI, 8.7-9.9) during ATP-II and ATP-III time periods, respectively. Adjusted IPDs in women with diabetes were 7.0 (95% CI, 6.3-7.8) and 11.9 (95% CI, 6.7-17.0) for primary and secondary prevention, respectively, and 3.1 (95% CI, 2.1-4.0) and 9.2 (95% CI 8.2-10.2) for before and after ATP-III, respectively. Secular trends reflected evolution toward risk factor-based treatment indications for statin initiation with increased initiation among diabetics and women with normal and borderline cholesterol. The role of serum cholesterol changed over time, though the character was scale (multiplicative vs additive) dependent. In pharmacoepidemiologic studies of statins, strength of confounding by important variables sometimes unmeasured in claims data, such as cholesterol level, may be calendar time dependent.


Episodic long-term memory in post-infectious SARS-CoV-2 patients.
Episodic long-term memory (LTM) difficulties/deficits are frequent in COVID-19-recovered patients and negatively impact on prognosis and outcome. However, little is known about their semiology and prevalence, also being still debated whether they arise from primary amnesic features or are secondary to dysexecutive/inattentive processes and disease-related/premorbid status. Hence, this study aimed at (1) assessing LTM functioning in post-infectious SARS-CoV-2 patients by accounting for premorbid and disease-related confounders and (2) exploring its cognitive etiology. Measures of global cognition (Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA)) and LTM (Babcock Memory Test (BMT)) of fifty-four COVID-19-recovered patients were retrospectively collected. Patients were subdivided into those being already at risk or not for cognitive decline (RCD + ; RCD -). Cognitive measures were converted into equivalent scores (ESs). LTM sub-clinical/clinical deficits (ESs = 0/1) were mildly-to-moderately prevalent in both RCD + (MoCA-Memory, 31.8%; BMT, 31.8%) and RCD - (MoCA-Memory, 28.6%; BMT, 39.3%) patients. MMSE and MoCA total scores, but not the MoCA-Attention subtest, were associated with the BMT. RCD + asymptomatic patients performed better on the BMT (p = .033) than those requiring O2 therapy (but not ventilation). COVID-19-recovered individuals might show LTM deficits of both primary and secondary etiology and should be thus screened for them, especially those having suffered mid-to-moderate COVID-19 and those already being at risk for cognitive decline. Both I- and II-level measures of verbal LTM can be adopted, although the former might be more sensitive.


Brief report: Emergency department utilization by individuals with autism.
To identify medical problems most commonly presenting to emergency departments among individuals with autism as compared to non-autistic persons across age groups. Data was obtained from the 2010 National Emergency Department database and was analyzed by age categories: 3-5, 6-11, 12-15, 16-18 and 19 years and older. Epilepsy emerged as the leading presenting diagnosis among those with Autism spectrum disorder (ASD), ages 16-19 years and 19 over. Psychiatric conditions were primary among ASD individuals aged 12-15 years, accounting for more than 11% of all visits. In this sample, age-related differences were noted in medical diagnoses among autistic individuals as compared to non-autistic persons.


Protein adsorption of ultrafine metal oxide and its influence on cytotoxicity toward cultured cells.
Many investigations about the cellular response by metal oxide nanoparticles in vitro have been reported. However, the influence of the adsorption ability of metal oxide nanoparticles toward cells is unknown. The aim of this study is to understand the influence of adsorption by metal oxide nanoparticles on the cell viability in vitro. The adsorption abilities of six kinds of metal oxide nanoparticles, namely, NiO, ZnO, TiO2, CeO2, SiO2, and Fe2O3, to Dulbecco's modified Eagle's medium supplemented with a 10% fetal bovine serum (DMEM-FBS) component such as serum proteins and Ca2) were estimated. All of the metal oxide nanoparticles adsorbed proteins and Ca2+ in the DMEM-FBS; in particular, TiO2, CeO2, and ZnO showed strong adsorption abilities. Furthermore, the influence of the depletion of medium components by adsorption to metal oxide nanoparticles on cell viability and proliferation was examined. The particles were removed from the dispersion by centrifugation, and the supernatant was applied to the cells. Both the cell viability and the proliferation of human keratinocyte HaCaT cells and human lung carcinoma A549 cells were affected by the supernatant. In particular, cell proliferation was strongly inhibited by the supernatant of TiO2 and CeO2 dispersions. The supernatant showed depletion of serum proteins and Ca2+ by adsorption to metal oxide nanoparticles. When the adsorption effect was blocked by the pretreatment of particles with FBS, the inhibitory effect was lost. However, in NiO and ZnO, which showed ion release, a decrease of inhibitory effect by pretreatment was not shown. Furthermore, the association of the primary particle size and adsorption ability was examined in TiO2. The adsorption ability of TiO2 depended on the primary particle size. The TiO2 nanoparticles were size dependently absorbed with proteins and Ca2+, thereby inducing cytotoxicity. In conclusion, the adsorption ability of metal oxide nanoparticles is an important factor for the estimation of cytotoxicity in vitro for low-toxicity materials.


A critical appraisal of radiographic scoring systems for assessment of juvenile idiopathic arthritis.
Assessing structural damage to joints over time is essential for evaluating the effectiveness of therapeutic interventions for patients with inflammatory arthritis. Although radiography is able to quantify joint damage, the changes found with conventional radiography early in the disease course are nonspecific, and late radiographic changes are often irreversible. Although many clinical trials on drug development for children still use radiographic scales as endpoints for the study, more specific therapies have been developed for juvenile idiopathic arthritis (JIA) that would enable imaging to "fine-tune" patients to placement into specific treatment algorithms. As a result, new imaging scales to identify early abnormalities are clearly needed. Many pediatric rheumatology centers around the world persistently apply adult-designed radiographic scoring systems to evaluate the progression of JIA. Few pediatric-targeted radiographic scales are available for assessment of progression of JIA in growing joints, and the clinimetric and psychometric properties of such scales have been poorly investigated. We present a critique to the evaluative, discriminative, and predictive roles of the van der Heijde modification of Sharp's radiographic method, a scale originally designed to assess damage to joints of adults with rheumatoid arthritis, when it is applied to a pediatric population. We discuss the advantages and drawbacks of this radiographic scoring system for assessing growing joints and the ability of MRI to overcome inadequacies of conventional radiography.