Does Physical Activity Increase After Total Hip or Knee Arthroplasty for Osteoarthritis? A Systematic Review.
Study Design Systematic review. Background Despite improvements in self-reported symptoms and perceived functional ability after total hip arthroplasty (THA) and total knee arthroplasty (TKA), it is unclear whether changes in objectively measured physical activity (PA) occur after surgery. Objective To determine if objectively measured PA increases after THA and TKA in adults with osteoarthritis. Methods Five electronic databases were searched from inception to March 3, 2015. All study designs objectively measuring PA before and after THA or TKA were eligible, including randomized controlled trials, cohort studies, and case-control studies. Two reviewers independently screened abstracts and full texts and extracted study demographic, PA, and clinical outcome data. Standardized mean differences (SMDs) and 95% confidence intervals were calculated for accelerometer- and pedometer-derived estimates of PA. Risk of methodological bias was assessed with Critical Appraisal Skills Programme checklists. Results Eight studies with a total of 373 participants (238 TKA, 135 THA) were included. Findings were mixed regarding improvement in objectively measured PA at 6 months after THA (SMDs, -0.20 to 1.80) and TKA (SMDs, -0.36 to 0.63). Larger improvements from 2 studies at 1 year postsurgery were generally observed after THA (SMDs, 0.39 to 0.79) and TKA (SMDs, 0.10 to 0.85). However, at 1 year, PA levels were still considerably lower than those of healthy controls (THA SMDs, -0.25 to -0.77; TKA SMDs, -1.46 to -1.80). Risk-of-bias scores ranged from 3 to 9 out of 11 (27%-82%) for cohort studies, and from 3 to 8 out of 10 (30%-80%) for case-control studies. Conclusion The best available evidence indicates negligible changes in PA at 6 months after THA or TKA, with limited evidence for larger changes at 1 year after surgery. In the 4 studies that reported control-group data, postoperative PA levels were still considerably less than those of healthy controls. Improved perioperative strategies to instill behavioral change are required to narrow the gap between patient-perceived functional improvement and the actual amount of PA undertaken after THA and TKA. Registered with PROSPERO (registration number CRD42014010155). Level of Evidence Therapy, level 2a. J Orthop Sports Phys Ther 2016;46(6):431-442. Epub 26 Apr 2016. doi:10.2519/jospt.2016.6449.


X-ray detection of ingested non-metallic foreign bodies.
To determine the utility of X-ray in identifying non-metallic foreign body (FB) and assess inter-radiologist agreement in identifying non-metal FB. Focus groups of nurses, fellows, and attending physicians were conducted to determine commonly ingested objects suitable for inclusion. Twelve potentially ingested objects (clay, plastic bead, crayon, plastic ring, plastic army figure, glass bead, paperclip, drywall anchor, eraser, Lego™, plastic triangle toy, and barrette) were embedded in a gelatin slab placed on top of a water-equivalent phantom to simulate density of a child's abdomen. The items were selected due to wide availability and appropriate size for accidental pediatric ingestion. Plain radiography of the embedded FBs was obtained. Five experienced radiologists blinded to number and types of objects were asked to identify the FBs. The radiologist was first asked to count the number of items that were visible then to identify the shape of each item and describe it to a study investigator who recorded all responses. Overall inter-rater reliability was analyzed using percent agreement and κ coefficient. We calculated P value to assess the probability of error involved in accepting the κ value. Fourteen objects were radiographed including 12 original objects and 2 duplicates. The model's validity was supported by clear identification of a radiolucent paperclip as a positive control, and lack of identification of plastic beads (negative control) despite repeated inclusion. Each radiologist identified 7-9 of the 14 objects (mean 8, 67%). Six unique objects (50%) were identified by all radiologists and four unique objects (33%) were not identified by any radiologist (plastic bead, Lego™, plastic triangle toy, and barrette). Identification of objects that were not present, false-positives, occurred 1-2 times per radiologist (mean 1.4). An additional 17% of unique objects were identified by less than half of the radiologists. Agreement between radiologists was considered almost perfect (kappa 0.86 ± 0.08, P < 0.0001). We demonstrate potential non-identification of commonly ingested non-metal FBs in children. A registry for radiographic visibility of ingested objects should be created to improve clinical decision-making.


[Causes of obesity].
The aetiology and treatment of obesity requires a knowledge of the mechanisms that control the homeostasis of the fuel substrates and adiposity. The processes of regulation adjust the supply of macronutrients and energy demands with the aim of maintaining a stable body mass. In the light of the most recent research, the hypothesis can be advanced that the control of body weight and its composition depends on an axis integrated by three self-regulated components: appetite, stores thermogenesis and fat deposits. The most important factors involved in obesity seem to be dietary habits diet and physical activity, which are affected by genes, which in their turn affect energy expenditure, the metabolism of energy substrates and food consumption. However, the growing rates of obesity cannot be explained exclusively by genetic causes, since they are in some cases associated with the consumption of diets with a high energy density or rich in fat, and by a growing sedentary life style in society, both in developed and developing countries. The study of genetics and life style involved in the increase of body weight and obesity can facilitate the implementation of preventive actions.


The binding of plakoglobin to desmosomal cadherins: patterns of binding sites and topogenic potential.
Plakoglobin is the only protein that occurs in the cytoplasmic plaques of all known adhering junctions and has been shown to be crucially involved in the formation and maintenance of desmosomes anchoring intermediate-sized filaments (IFs) by its interaction with the desmosomal cadherins, desmoglein (Dsg), and desmocollin (Dsc). This topogenic importance of plakoglobin is now directly shown in living cells as well as in binding assays in vitro. We show that, in transfected human A-431 carcinoma cells, a chimeric protein combining the vesicle-forming transmembrane glycoprotein synaptophysin, with the complete human plakoglobin sequence, is sorted to small vesicles many of which associate with desmosomal plaques and their attached IFs. Immunoprecipitation experiments have further revealed that the chimeric plakoglobin-containing transmembrane molecules of these vesicles are tightly bound to Dsg and Dsc but not to endogenous plakoglobin, thus demonstrating that the binding of plakoglobin to desmosomal cadherins does not require its soluble state and is strong enough to attach large structures such as vesicles to desmosomes. To identify the binding domains and the mechanisms involved in the interaction of plakoglobin with desmosomal cadherins, we have developed direct binding assays in vitro in which plakoglobin or parts thereof, produced by recombinant DNA technology in E. coli, are exposed to molecules containing the "C-domains" of several cadherins. These assays have shown that plakoglobin associates most tightly with the C-domain of Dsg, to a lesser degree with that of Dsc and only weakly with the C-domain of E-cadherin. Three separate segments of plakoglobin containing various numbers of the so-called arm repeats exhibit distinct binding to the desmosomal cadherins comparable in strength to that of the entire molecule. The binding pattern of plakoglobin segments in vitro is compared with that in vivo. Paradoxically, in vitro some internal plakoglobin fragments bind even better to the C-domain of E-cadherin than the entire molecule, indicating that elements exist in native plakoglobin that interfere with the interaction of this protein with its various cadherin partners.


Pedipalps and venom vesicle anomalies in two families of scorpions (Scorpiones: Hemiscorpiidae, Buthidae) from Iran.
The developmental anomalies are reported in this study. The first and second abnormally are presented in right pedipalps of Paraorthochirus and Orthochirus (Buthidae) while Paraorthochirus pedipalp just includes coxa, trochanter and without other parts (femur, patella, movable and fixed finger). The right pedipalp of Orthochirus specimen has abnormally too; it has all parts ofpedipalp except complete fixed finger. In both of scorpions, the left pedipalp is normal. Another case is present in venom vesicle of Hemiscourpius (Hemiscorpiidae). Pictures and morphometric measurements for three specimens are given.


Blood lymphocyte subpopulations, neutrophil phagocytosis and proteinogram during late pregnancy and postpartum in mares.
The aim of this study was to evaluate peripheral blood lymphocyte subpopulations, neutrophil phagocytic capacity and proteinogram characteristics in mares, during the last trimester of pregnancy and in postpartum. Measurement of phagocytosis and quantification of T-lymphocyte subsets were done by flow cytometry. Quantification of T-lymphocyte subsets was performed with monoclonal antibodies specific for CD2, CD3, CD4 and CD8 cell markers. Natural killer and B-cell counts were estimated mathematically. Serum proteinogram was obtained by electrophoresis. No significant differences were observed between gestation and postpartum on CD4(+), CD8(+) and NK(+) lymphocyte subsets, CD4 : CD8 ratio and phagocytosis. The percentage of cells expressing CD3 (64.2 +/- 1.8) and CD2 (68.4 +/- 1.7) (Mean +/- SEM) was reduced during gestation vs postpartum (69.7 +/- 1.5 and 73.8 +/- 1.4 respectively) (p < 0.05). During pregnancy, CD19(+) (31.6 +/- 1.7) was higher than in postpartum (26.2 +/- 1.4) (p < 0.05). Total T cells (2911 +/- 227 cells/mul), T helper cells (2144 +/- 169 cells/mul) and T-cytotoxic cells (767 +/- 68 cells/mul) were depressed in pregnancy, when compared with postpartum (4093 +/- 337 cells/mul; 3004 +/- 276 cells/mul; 1089 +/- 94 cells/mul respectively) (p < 0.01). Total white blood cell count was reduced during pregnancy (8815 +/- 427 cells/mul) with respect to postpartum (10742 +/- 446 cells/mul) (p < 0.01), while neutrophil count did not change. Total proteins, albumin, alpha(1),alpha(2),beta(1), beta(2), gamma globulins and albumin : globulin did not differ. Our results suggest that the physiological immune depression occurring in mares, during gestation might be due to T-helper and T-cytotoxic lymphocytes reduction.


[Accident with biological material at the prehospital mobile care: reality for health and non-healthcare workers].
Analytical transversal study that was conducted with the objectives of identifying the prevalence and characterizing the accidents with biological material among professionals in pre-hospital service (PHS) and comparing the risk behaviors adopted by healthcare and non-healthcare groups that can affect the occurrence and seriousness of such accidents. Data were obtained by questionnaire applied to all PHS workers in Goiânia-GO. The study revealed a high prevalence of accidents involving biological material which, although higher for the healthcare group, also affected the non-healthcare group. There were significant (p < 0.05) risk behaviors for these accidents in both groups: not using gloves, masks or eye protectors; inappropriate disposal of sharps; inadequate dress; re-capping of needles; and a lack of immunization against hepatitis B. The results underscore the importance of both groups in adhering to preventive measures, and further point to the need to structure and implement vigilance and control system for this type of accident.


Multimodal Behavior Analysis Towards Detecting Mild Cognitive Impairment: Preliminary Results on Gait and Speech.
Behavioral analysis for identifying changes in cognitive and physical functioning is expected to help detect dementia such as mild cognitive impairment (MCI) at an early stage. Speech and gait features have been especially recognized as behavioral biomarkers for dementia that possibly occur early in its course, including MCI. However, there are no studies investigating whether exploiting the combination of multimodal behavioral data could improve detection accuracy. In this study, we collected speech and gait behavioral data from Japanese seniors consisting of cognitively healthy adults and patients with MCI. Comparing the models using single modality behavioral data, we showed that the model using multimodal behavioral data could improve detection by up to 5.9%, achieving 82.4% accuracy (chance 55.9%). Our results suggest that the combination of multimodal behavioral features capturing different functional changes resulting from dementia might improve accuracy and help timely diagnosis at an early stage.


Biological variation estimates of thyroid related measurands - meta-analysis of BIVAC compliant studies.
Testing for thyroid disease constitutes a high proportion of the workloads of clinical laboratories worldwide. The setting of analytical performance specifications (APS) for testing methods and aiding clinical interpretation of test results requires biological variation (BV) data. A critical review of published BV studies of thyroid disease related measurands has therefore been undertaken and meta-analysis applied to deliver robust BV estimates. A systematic literature search was conducted for BV studies of thyroid related analytes. BV data from studies compliant with the Biological Variation Data Critical Appraisal Checklist (BIVAC) were subjected to meta-analysis. Global estimates of within subject variation (CVI) enabled determination of APS (imprecision and bias), indices of individuality, and indicative estimates of reference change values. The systematic review identified 17 relevant BV studies. Only one study (EuBIVAS) achieved a BIVAC grade of A. Methodological and statistical issues were the reason for B and C scores. The meta-analysis derived CVI generally delivered lower APS for imprecision than the mean CVA of the studies included in this systematic review. Systematic review and meta-analysis of studies of BV of thyroid disease biomarkers have enabled delivery of well characterized estimates of BV for some, but not all measurands. The newly derived APS for imprecision for both free thyroxine and triiodothyronine may be considered challenging. The high degree of individuality identified for thyroid related measurands reinforces the importance of RCVs. Generation of BV data applicable to multiple scenarios may require definition using "big data" instead of the demanding experimental approach.


Possible dissociation of the heparin-binding and mitogenic activities of heparin-binding (acidic fibroblast) growth factor-1 from its receptor-binding activities by site-directed mutagenesis of a single lysine residue.
The fibroblast or heparin-binding growth factors (HBGFs) are thought to be modulators of cell growth and migration, angiogenesis, wound repair, neurite extension, and mesoderm induction. A better understanding of the structural basis for the different activities of these proteins should facilitate the development of agonists and antagonists of specific HBGF activities and identification of the signal transduction pathways involved in the mechanisms of action of these growth factors. Chemical modification studies of Harper and Lobb (Harper, J. W., and R. R. Lobb. 1988. Biochemistry. 27:671-678) implicated lysine 132 in HBGF-1 (acidic fibroblast growth factor) as being important to the heparin-binding, receptor-binding, and mitogenic activities of the protein. We changed lysine 132 to a glutamic acid residue by site-directed mutagenesis of the human cDNA and expressed the mutant protein in Escherichia coli to obtain sufficient quantities for functional studies. Replacement of this lysine with glutamic acid reduces the apparent affinity of HBGF-1 for immobilized heparin (elutes at 0.45 M NaCl vs. 1.1 M NaCl for wild-type). Mitogenic assays established two points: (a) human recombinant HBGF-1 is highly dependent on the presence of heparin for optimal mitogenic activity, and (b) the change of lysine 132 to glutamic acid drastically reduces the specific mitogenic activity of HBGF-1. The poor mitogenic activity of the mutant protein does not appear to be due to a reduced affinity for the HBGF receptor. Similarly, the mutant HBGF-1 can stimulate tyrosine kinase activity and induce protooncogene expression. Differences in the biological properties of the wild-type and mutant proteins were observed in transfection studies. Mutant HBGF-1 expression in transfected NIH 3T3 cells did not induce the same transformed phenotype characteristic of cells expressing wild-type HBGF-1. Together these data indicate that different functional properties of HBGF-1 may be dissociated at the structural level.


Visuomotor performance based on peripheral vision is impaired in the visual form agnostic patient DF.
The perception-action model states that visual information is processed in different cortical areas depending on the purpose for which the information is acquired. Specifically, it was suggested that the ventral stream mediates visual perception, whereas the dorsal stream primarily processes visual information for the guidance of actions (Goodale & Milner, 1992). Evidence for the model comes from patient studies showing that patients with ventral stream damage (visual form agnosia) and patients with dorsal stream damage (optic ataxia) show divergent performance in action and perception tasks. Whereas DF, a patient suffering from visual form agnosia, was found to perform well in visuomotor tasks despite her inability to use vision for perceptual tasks, patients with optic ataxia show usually the opposite pattern, i.e. good perception but impaired visuomotor control. The finding that both disorders seem to provoke a mirror-reversed pattern of spared and impaired visual functions, led to the belief that optic ataxia and visual form agnosia can be considered as complementary disorders. However, the visuomotor performance of patients with optic ataxia is typically only impaired when they are tested in visual periphery while being often preserved when tested in central vision. Here, we show that DF's visuomotor performance is also only preserved when the target is presented centrally. Her reaching and grasping movements to targets in peripheral vision are abnormal. Our findings indicate that DF's visuomotor performance is quite similar to the visuomotor performance of patients with optic ataxia which undermines previous suggestions that the two disorders form a double-dissociation.


Effects of riboflavin supplementation on performance, nutrient digestion, rumen microbiota composition and activities of Holstein bulls.
To investigate the influences of dietary riboflavin (RF) addition on nutrient digestion and rumen fermentation, eight rumen cannulated Holstein bulls were randomly allocated into four treatments in a repeated 4 × 4 Latin square design. Daily addition level of RF for each bull in control, low RF, medium RF and high RF was 0, 300, 600 and 900 mg, respectively. Increasing the addition level of RF, DM intake was not affected, average daily gain tended to be increased linearly and feed conversion ratio decreased linearly. Total tract digestibilities of DM, organic matter, crude protein (CP) and neutral-detergent fibre (NDF) increased linearly. Rumen pH decreased quadratically, and total volatile fatty acids (VFA) increased quadratically. Acetate molar percentage and acetate:propionate ratio increased linearly, but propionate molar percentage and ammonia-N content decreased linearly. Rumen effective degradability of DM increased linearly, NDF increased quadratically but CP was unaltered. Activity of cellulase and populations of total bacteria, protozoa, fungi, dominant cellulolytic bacteria, Prevotella ruminicola and Ruminobacter amylophilus increased linearly. Linear increase was observed for urinary total purine derivatives excretion. The data suggested that dietary RF addition was essential for rumen microbial growth, and no further increase in performance and rumen total VFA concentration was observed when increasing RF level from 600 to 900 mg/d in dairy bulls.


A Trihelix Family Transcription Factor Is Associated with Key Genes in Mixed-Linkage Glucan Accumulation.
Mixed-linkage glucan (MLG) is a polysaccharide that is highly abundant in grass endosperm cell walls and present at lower amounts in other tissues. Cellulose synthase-like F (CSLF) and cellulose synthase-like H genes synthesize MLG, but it is unknown if other genes participate in the production and restructuring of MLG. Using Brachypodium distachyon transcriptional profiling data, we identified a B distachyon trihelix family transcription factor (BdTHX1) that is highly coexpressed with the B distachyon CSLF6 gene (BdCSLF6), which suggests that BdTHX1 is involved in the regulation of MLG biosynthesis. To determine the genes regulated by this transcription factor, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) experiments using immature B distachyon seeds and an anti-BdTHX1 polyclonal antibody. The ChIP-seq experiment identified the second intron of BdCSLF6 as one of the most enriched sequences. The binding of BdTHX1 to the BdCSLF6 intron sequence was confirmed using electrophoretic mobility shift assays (EMSA). ChIP-seq also showed that a gene encoding a grass-specific glycoside hydrolase family 16 endotransglucosylase/hydrolase (BdXTH8) is bound by BdTHX1, and the binding was confirmed by EMSA. Radiochemical transglucanase assays showed that BdXTH8 exhibits predominantly MLG:xyloglucan endotransglucosylase activity, a hetero-transglycosylation reaction, and can thus produce MLG-xyloglucan covalent bonds; it also has a lower xyloglucan:xyloglucan endotransglucosylase activity. B distachyon shoots regenerated from transformed calli overexpressing BdTHX1 showed an abnormal arrangement of vascular tissue and seedling-lethal phenotypes. These results indicate that the transcription factor BdTHX1 likely plays an important role in MLG biosynthesis and restructuring by regulating the expression of BdCSLF6 and BdXTH8.


FoxA proteins regulate H19 endoderm enhancer E1 and exhibit developmental changes in enhancer binding in vivo.
Multiple enhancers govern developmental and tissue-specific expression of the H19-Igf2 locus, but factors that bind these elements have not been identified. Using chromatin immunoprecipitation, we have found two FoxA binding sites in the H19 E1 enhancer. Mutating these sites diminishes E1 activity in hepatoma cells. Additional chromatin immunoprecipitations show that FoxA binds to E1 in fetal liver, where H19 is abundantly expressed, but that binding decreases in adult liver, where H19 is no longer transcribed, even though FoxA proteins are present at both times. FoxA proteins are induced when F9 embryonal carcinoma cells differentiate into visceral endoderm (VE) and parietal endoderm (PE). We show that FoxA binds E1 in VE cells, where H19 is expressed, but not in PE cells, where H19 is silent. This correlation between FoxA binding and H19 expression indicates a role for FoxA in regulating H19, including developmental activation in the yolk sac and liver and postnatal repression in the liver. This is the first demonstration of a tissue-specific factor involved in developmental control of H19 expression. These data also indicate that the presence of FoxA proteins is not sufficient for binding but that additional mechanisms must govern the accessibility of FoxA proteins to their cognate binding sites within the H19 E1 enhancer.


Stress management--holistic approach.
Trying to survive in the changing times of competition, productivity and quality issues, economic constraints, increasing healthcare costs and consumer satisfaction hospital administrator requires intellectual skills blended with emotional maturity. Challenge successfully dealt with is satisfying. Only when it cannot be met, when pressures become too great, does it become stressful. Coping with stress depends on holistic approach to health. Equally, Managers should ensure that their part of organisation provides an environment in which individuals can flourish to the benefit of the organisation and the individuals involved. The study explores the main causes of stress and various strategies to cope with it.


Irreversible Electroporation to Treat Unresectable Colorectal Liver Metastases (COLDFIRE-2): A Phase II, Two-Center, Single-Arm Clinical Trial.
Background Irreversible electroporation (IRE), an ablative technique that uses high-voltage electrical pulses, has shown promise for eradicating tumors near critical structures, including blood vessels and bile ducts. Purpose To investigate the efficacy and safety of IRE for colorectal liver metastases (CRLMs) unsuitable for resection or thermal ablation because of proximity to critical structures and for further systemically administered treatments. Materials and Methods Between June 2014 and November 2018, participants with fluorine 18 (18F) fluorodeoxyglucose (FDG) PET-avid CRLMs measuring 5.0 cm or smaller, unsuitable for partial hepatectomy and thermal ablation, underwent percutaneous or open IRE (ClinicalTrials.gov identifier: NCT02082782). Follow-up included tumor marker assessment and 18F-FDG PET/CT imaging. For the primary end point to be met, at least 50% of treated participants had to be alive without local tumor progression (LTP) at 12 months, defined as LTP-free survival. Secondary aims were safety, technical success, local control allowing for repeat procedures, disease-free status, and overall survival. Results A total of 51 participants (median age, 67 years [interquartile range, 62-75 years]; 37 men) underwent IRE. Of these 51 participants, 50 with a total of 76 CRLMs (median tumor size, 2.2 cm; range, 0.5-5.4 cm) were successfully treated in 62 procedures; in one participant, treatment was stopped prematurely because of pulse-induced cardiac arrhythmia. With a per-participant 1-year LTP-free survival of 68% (95% CI: 59, 84) according to competing risk analysis, the primary end point was met. Local control following repeat procedures was achieved in 74% of participants (37 of 50). Median overall survival from first IRE was 2.7 years (95% CI: 1.6, 3.8). Twenty-three participants experienced a total of 34 adverse events in 25 of the 62 procedures (overall complication rate, 40%). One participant (2%), who had an infected biloma after IRE, died fewer than 90 days after the procedure (grade 5 adverse event). Conclusion Irreversible electroporation was effective and relatively safe for colorectal liver metastases 5.0 cm or smaller that were unsuitable for partial hepatectomy, thermal ablation, or further systemic treatment. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Goldberg in this issue.


The role of ant nests in European ground squirrel's (Spermophilus citellus) post-reintroduction adaptation in two Bulgarian mountains.
The European ground squirrel (Spermophilus citellus) is a vulnerable species, whose populations are declining throughout its entire range in Central and South-Eastern Europe. To a great extent, its conservation depends on habitat restoration, maintenance and protection. In order to improve the conservation status of the species, reintroductions are increasingly applied. Therefore, researchers focus their attention on factors that facilitate these activities and contribute to their success. In addition to the well-known factors like grass height and exposition, others, related to the underground characteristics, are more difficult to evaluate. The presence of other digging species could help this evaluation. Here, we present two reintroduced ground squirrel colonies, where the vast majority of the burrows are located in the base of anthills, mainly of yellow meadow ant (Lasius flavus). This interspecies relationship offers numerous advantages for the ground squirrel and is mostly neutral for the ants. The benefits for the ground squirrel, including reduced energy demand for digging, as well as additional surveillance and hiding places available, could greatly enhance the post-reintroduction adaptation process.


Divergent patterns of matrix metalloproteinase activity during wound healing in ileum and colon of rats.
Uncontrolled and increased extracellular matrix degradation during early anastomotic repair in the intestine may reduce wound strength increasing the risk of anastomotic dehiscence. To characterise the metalloproteinases present in intact and anastomosed ileum and colon to study their role in matrix degradation after surgery. Tissue extracts of uninjured, and of anastomosed rat ileum and colon at postoperative days 1, 2, 3, 7, and 90, were used. Metalloproteinases were identified by gelatin and casein zymography. Aminophenylmercuric acetate (APMA) treatment was used to activate latent metalloproteinases. Both uninjured ileum and colon contained a 60 and 67 kDa activity, but a 54 and 72 kDa gelatinase was present in ileum only, and a 51 kDa activity in colon only. APMA treatment converted the 60 kDa protease to 54 and 51 kDa forms and the 72 kDa protease to the 67 kDa form. These gelatinases may correspond to latent and active forms of MMP 1 and MMP 2, respectively. Additional metalloproteinases were observed after anastomotic construction. Both ileum and colon contained 95 and 230 kDa gelatinases, which were converted to 83 and 76 kDa forms by APMA. They may be the latent and active forms of MMP 9, respectively. Gelatinolytic activities of 25 and 28 kDa were only found in anastomosed ileum. Caseinolytic activities were only found in ileum extracts and those were most prominent at day 1, 2, and 3 after surgery. The metalloproteinase pattern in ileum and colon differ considerably suggesting that matrix degradation after anastomotic construction may also vary.


Carbon dioxide induced plasticity of branchial acid-base pathways in an estuarine teleost.
Anthropogenic CO2 is expected to drive ocean pCO2 above 1,000 μatm by 2100 - inducing respiratory acidosis in fish that must be corrected through branchial ion transport. This study examined the time course and plasticity of branchial metabolic compensation in response to varying levels of CO2 in an estuarine fish, the red drum, which regularly encounters elevated CO2 and may therefore have intrinsic resilience. Under control conditions fish exhibited net base excretion; however, CO2 exposure resulted in a dose dependent increase in acid excretion during the initial 2 h. This returned to baseline levels during the second 2 h interval for exposures up to 5,000 μatm, but remained elevated for exposures above 15,000 μatm. Plasticity was assessed via gene expression in three CO2 treatments: environmentally realistic 1,000 and 6,000 μatm exposures, and a proof-of-principle 30,000 μatm exposure. Few differences were observed at 1,000 or 6,000 μatm; however, 30,000 μatm stimulated widespread up-regulation. Translocation of V-type ATPase after 1 h of exposure to 30,000 μatm was also assessed; however, no evidence of translocation was found. These results indicate that red drum can quickly compensate to environmentally relevant acid-base disturbances using baseline cellular machinery, yet are capable of plasticity in response to extreme acid-base challenges.


Arthritis mutilans: a report from the GRAPPA 2012 annual meeting.
Arthritis mutilans is often described as the most severe form of psoriatic arthritis. However, a widely agreed on definition of the disease has not been developed. At the 2012 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members hoped to agree on a definition of arthritis mutilans and thus facilitate clinical and molecular epidemiological research into the disease. Members discussed the clinical features of arthritis mutilans and definitions used by researchers to date; reviewed data from the ClASsification for Psoriatic ARthritis study, the Nordic psoriatic arthritis mutilans study, and the results of a premeeting survey; and participated in breakout group discussions. Through this exercise, GRAPPA members developed a broad consensus on the features of arthritis mutilans, which will help us develop a GRAPPA-endorsed definition of arthritis mutilans.


Assessment of Diesse Ves-matic automated system for measuring erythrocyte sedimentation rate.
Measurement of the erythrocyte sedimentation rate (ESR) using a closed tube system reduces the biohazard risk to laboratory staff. The Diesse Ves-matic system offers manual or vacuum collection of blood into plastic tubes, automated mixing of the sample, and automated reading of the end point after 20 minutes of sedimentation. This system was compared with the 1977 Westergren ESR method of the International Council for Standardization in Haematology (ICSH) and with the 1988 ICSH undiluted ESR method. Manually collected Ves-matic samples showed good agreement with ICSH values, although there was a tendency to false low results at low ESR values which may represent dilution of plasma protein with excess citrate. Vacuum collected Ves-matic samples also showed good agreement with ICSH values, although there was a tendency to false high results which may reflect a change in the blood: citrate ratio caused by loss of anticoagulant diluent or vacuum from plastic tubes during storage. The Diesse Ves-matic system incorporates several improvements over previous technology and offers a safer, quicker, and more standardised ESR.


Expression of C-type natriuretic peptide during development of rat lung.
C-type natriuretic peptide (CNP), recently found to be secreted from vascular endothelial cells, is now viewed as a novel endothelium-derived relaxing peptide. However, the distribution and expression of CNP during cardiopulmonary development is unclear. To follow changes in the expression of CNP during lung development, we examined rat embryos and neonates using Northern blot analysis and in situ hybridization for CNP mRNA and radioimmunoassay and immunohistochemistry for CNP protein. A substantial expression of CNP mRNA was first detected on postnatal day 2, and it thereafter remained fairly steady. The level of CNP protein also increased rapidly after postnatal day 1, reaching a settled level on postnatal day 4. CNP protein and mRNA were detected in the endothelium and smooth muscle cells of blood vessels and in bronchial airway and alveolar epithelia. Immunoreactivity for CNP protein in the endothelium of blood vessels increased to an intense level after the saccular stage. These results suggest that the changes in CNP levels may be related to the occurrence of pulmonary vasodilation after birth.


[Stature of Chilean parents and children of different ethnicity and social vulnerability].
To analyze and compare the heights of first-year school children and their parents, according to ethnic background and socioeconomic status. This is a cross-sectional study of indigenous and non-indigenous school children and their parents, belonging to three levels of social vulnerability: very high (poverty), medium, and very low. An indigenous school child was defined as any child having all four parental surnames of Mapuche origin; non-indigenous were those having Hispanic parental surname. Height was compared using Z scores, using WHO nutritional change reference values. Statistical analysis consisted in comparing differences of mean heights between parents and their children. Differences were assessed using Scheffe's method. Improvement in socioeconomic conditions was associated with increasing mean parental height (p < 0.001), except for indigenous mothers, who showed no height increase. Fathers from highly impoverished counties were 4 cm shorter than those living in very low vulnerability areas; height differences reached 2 cm among mothers (p < 0.001). Indigenous school children showed a positive height gradient with improving socioeconomic conditions (p < 0.001). This was not observed among non-indigenous children. When comparing parental height with children's height, children had a better height/age ratio than their parents (p < 0.01). This was specially evident among indigenous school children, who had on average 1.4 Z scores more than their parents. The upward height gradient related to improved social conditions, and the better height/age ratio seen in children in comparison to their parents, regardless their ethnic background and level of social vulnerability, is encouraging and suggests that interventions directed to the poorest groups, including the indigenous population, must be carried out.


Laryngeal Dysfunction: Assessment and Management for the Clinician.
The larynx is one of the most highly innervated organs in humans and serves a number of vitally important, complex, and highly evolved biological functions. On a day-to-day basis, the larynx functions autonomously, addressing several roles including airway protection, swallowing, and phonation. In some situations the larynx appears to adopt a functional state that could be considered maladaptive or "dysfunctional." This laryngeal dysfunction can underpin and account for a number of respiratory symptoms that otherwise appear incongruous with a clinical disease state and/or contribute to the development of symptoms that appear "refractory" to treatment. These include conditions associated with a heightened tendency for inappropriate laryngeal closure (e.g., inducible laryngeal obstruction), voice disturbance, and chronic cough. Recognition of laryngeal dysfunction is important to deliver targeted treatment and failure to recognize the condition can lead to repeated use of inappropriate treatment. Diagnosis is not straightforward, however, and many patients appear to present with symptoms attributable to laryngeal dysfunction, but in whom the diagnosis has been overlooked in clinical work-up for some time. This review provides an overview of the current state of knowledge in the field of laryngeal dysfunction, with a focus on pragmatic clinical assessment and management.


Herpes Simplex Virus Type 1 Neuronal Infection Triggers the Disassembly of Key Structural Components of Dendritic Spines.
Herpes simplex virus type 1 (HSV-1) is a widespread neurotropic virus. Primary infection of HSV-1 in facial epithelium leads to retrograde axonal transport to the central nervous system (CNS) where it establishes latency. Under stressful conditions, the virus reactivates, and new progeny are transported anterogradely to the primary site of infection. During the late stages of neuronal infection, axonal damage can occur, however, the impact of HSV-1 infection on the morphology and functional integrity of neuronal dendrites during the early stages of infection is unknown. We previously demonstrated that acute HSV-1 infection in neuronal cell lines selectively enhances Arc protein expression - a major regulator of long-term synaptic plasticity and memory consolidation, known for being a protein-interaction hub in the postsynaptic dendritic compartment. Thus, HSV-1 induced Arc expression may alter the functionality of infected neurons and negatively impact dendritic spine dynamics. In this study we demonstrated that HSV-1 infection induces structural disassembly and functional deregulation in cultured cortical neurons, an altered glutamate response, Arc accumulation within the somata, and decreased expression of spine scaffolding-like proteins such as PSD-95, Drebrin and CaMKIIβ. However, whether these alterations are specific to the HSV-1 infection mechanism or reflect a secondary neurodegenerative process remains to be determined.


Cas6 specificity and CRISPR RNA loading in a complex CRISPR-Cas system.
CRISPR-Cas is an adaptive prokaryotic immune system, providing protection against viruses and other mobile genetic elements. In type I and type III CRISPR-Cas systems, CRISPR RNA (crRNA) is generated by cleavage of a primary transcript by the Cas6 endonuclease and loaded into multisubunit surveillance/effector complexes, allowing homology-directed detection and cleavage of invading elements. Highly studied CRISPR-Cas systems such as those in Escherichia coli and Pseudomonas aeruginosa have a single Cas6 enzyme that is an integral subunit of the surveillance complex. By contrast, Sulfolobus solfataricus has a complex CRISPR-Cas system with three types of surveillance complexes (Cascade/type I-A, CSM/type III-A and CMR/type III-B), five Cas6 paralogues and two different CRISPR-repeat families (AB and CD). Here, we investigate the kinetic properties of two different Cas6 paralogues from S. solfataricus. The Cas6-1 subtype is specific for CD-family CRISPR repeats, generating crRNA by multiple turnover catalysis whilst Cas6-3 has a broader specificity and also processes a non-coding RNA with a CRISPR repeat-related sequence. Deep sequencing of crRNA in surveillance complexes reveals a biased distribution of spacers derived from AB and CD loci, suggesting functional coupling between Cas6 paralogues and their downstream effector complexes.


[Prevention of functional impairments of cardiac muscle mitochondria in emotional-painful stress].
In experiments with 216 male rats emotional-painful stress impaired distinctly the oxidative phosphorylation and Ca2+ transport in heart muscle mitochondria. When gamma-hydroxybutyric acid, inderal, antioxidants ionol and isoptin were used as selective inhibitors of definite steps in the pathogenetic chain of stress heart impairments, these impairments of the mitochondrial functions were effectively prevented at the step of regulatory mechanisms responsible for the stress reactions.


Three-reaction high-resolution melting assay for rapid differentiation of Mycobacterium tuberculosis complex members.
The possibility of introducing a reliable assay for a quick identification and differentiation of the main species of Mycobacterium tuberculosis complex (MTBC) supports the improvement of efficient tuberculosis combating strategies worldwide. Commercially available assays are often based on cultured samples; however, due to the long cultivation time of mycobacteria, results are delayed. Developed PCR approaches have been published previously, though, when testing intricate veterinary samples, the complex composition of multiplex qPCRs frequently leads to assay failure. In order to overcome those limits, a paradigm of a three-reaction high-resolution melting (HRM) assay for the simultaneous identification and differentiation of the main members of MTBC was established. The assay is based on single nucleotide polymorphisms within gyrB and gyrA, which have been used as target for the establishment of two highly specific HRM assays (HRM assays 1 and 2) discriminating M. tuberculosis/ Mycobacterium canetti, Mycobacterium bovis/M. bovis BCG, Mycobacterium caprae/rare M. caprae/M. bovis ecotypes, Mycobacterium africanum/Mycobacterium orygis/ Mycobacterium pinnipedii/Clade A1, Mycobacterium microti, and a rare subtype of M. canettii followed by a third HRM assay (HRM assay 3) allowing a further differentiation of M. bovis, M. bovis BCG, and a rare subtype of M. caprae/M. bovis, which is considered to be a novel ecotype. High-resolution melting assay 1 is described in a previously published report. High-resolution melting assay 2 showed 100% correlation of all 39 examined isolates with the results of a commercial identification kit. 96% of the clinical samples tested demonstrated concordant results. High-resolution melting assay 3 showed an accordance of 100% with the results of the commercially available identification kit of all 22 samples analyzed. The proposed strategy of the three-reaction HRM assay can be used for an accurate differentiation of up to seven groups of MTBC and potentially to identify a rare subtype of M. canettii either on isolates or on clinical samples.


First worldwide proficiency study on variable-number tandem-repeat typing of Mycobacterium tuberculosis complex strains.
Although variable-number tandem-repeat (VNTR) typing has gained recognition as the new standard for the DNA fingerprinting of Mycobacterium tuberculosis complex (MTBC) isolates, external quality control programs have not yet been developed. Therefore, we organized the first multicenter proficiency study on 24-locus VNTR typing. Sets of 30 DNAs of MTBC strains, including 10 duplicate DNA samples, were distributed among 37 participating laboratories in 30 different countries worldwide. Twenty-four laboratories used an in-house-adapted method with fragment sizing by gel electrophoresis or an automated DNA analyzer, nine laboratories used a commercially available kit, and four laboratories used other methods. The intra- and interlaboratory reproducibilities of VNTR typing varied from 0% to 100%, with averages of 72% and 60%, respectively. Twenty of the 37 laboratories failed to amplify particular VNTR loci; if these missing results were ignored, the number of laboratories with 100% interlaboratory reproducibility increased from 1 to 5. The average interlaboratory reproducibility of VNTR typing using a commercial kit was better (88%) than that of in-house-adapted methods using a DNA analyzer (70%) or gel electrophoresis (50%). Eleven laboratories using in-house-adapted manual typing or automated typing scored inter- and intralaboratory reproducibilities of 80% or higher, which suggests that these approaches can be used in a reliable way. In conclusion, this first multicenter study has documented the worldwide quality of VNTR typing of MTBC strains and highlights the importance of international quality control to improve genotyping in the future.


Purification and characterization of Clostridium perfringens delta-toxin.
Delta-toxin, an extracellular hemolysin released by Clostridium perfringens type C, was purified from culture supernatant fluid by sequential ammonium sulfate precipitation, thiol-Sepharose gel chromatography, isoelectric focusing, and Sephadex G-75 gel filtration. The purified preparation had a specific activity of 320,000 hemolytic units per mg of protein and was homogeneous, as determined by immunochemical and electrophoretic tests. This toxin was characterized as a single polypeptide chain composed of 391 amino acid residues, 30% of which were hydrophobic. The molecular weight was found to be 42,000, and the isoelectric point was pH 9.1. Delta-toxin appeared to be amphiphilic by charge shift electrophoresis in a three-detergent system. It was immunogenic in rabbits and lethal to mice at a dose of 0.12 micrograms. The lytic activity of delta-toxin was restricted to erythrocytes of even-toed ungulates (sheep, goats, and pigs). This activity was inhibited by GM2 ganglioside but not by other gangliosides, cholesterol, lecithin, or sphingomyelin.


Possible association of urinary incontinence with post-COVID-19: a report of three cases.
The disorder denominated urinary incontinence (UI) has been diagnosed amongst 25-45% of women worldwide. Muscle weakness is one of the more notable symptoms, which is exhibited in the acute form of coronavirus disease 2019 (COVID-19) that compromises the respiratory musculature. Accordingly, this report aims to delineate three cases in women with UI possibly associated with post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Three elderly Brazilian women expressed UI symptomology post-COVID-19 recovery. In the investigation reports, there was no documented acute impairment or hospitalization post-COVID-19. Nevertheless, some form of UI derived from muscle weakness was detected and treated by physiotherapy in these patients. The patient 1 (P1) was classified as mixed urinary incontinence (MUI) based on the presented symptomology during the filling phase and urinary leakage on exertion. Intravaginal probing suggested neural integrity. The P2 and P3 were classified as stress urinary incontinence (SUI), related to increased abdominal pressure. In all the three cases, there were benefits from physical therapy treatment. This case report is relevant in improving our understanding and lead to future research about the possibility of clinical variations as UI after infection by SARS COV 2 contributing to greater awareness in the diagnostic workup and allowing for earlier treatment and management. It is concluded that the surveillance of the distinct symptomologies associated with the SARS-CoV-2 infection is fundamental, because there is no adequate corroboratory evidence in the scientific literature, for the cases of pelvic floor muscles weakness that causes UI.


Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability.
The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of the mSWI/SNF (BAF) complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the ability of SS18-SSX to occupy H2AK119ub1-rich regions is an intrinsic property of its SSX C terminus, which can be exploited by fusion to transcriptional regulators beyond SS18. Accordingly, SS18-SSX recruitment occurs in a manner that is independent of the core components and catalytic activity of BAF. Alternative SSX fusions are also recruited to H2AK119ub1-rich chromatin and reproduce the expression signatures of SS18-SSX by engaging with transcriptional activators. Variant Polycomb repressive complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C terminus not only depends on H2AK119ub1 for localization, but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition.


Tungstate promotes β-cell survival in Irs2-/- mice.
Pancreatic β-cells play a central role in type 2 diabetes (T2D) development, which is characterized by the progressive decline of the functional β-cell mass that is associated mainly with increased β-cell apoptosis. Thus, understanding how to enhance survival of β-cells is key for the management of T2D. The insulin receptor substrate-2 (IRS-2) protein is pivotal in mediating the insulin/IGF signaling pathway in β-cells. In fact, IRS-2 is critically required for β-cell compensation in conditions of increased insulin demand and for β-cell survival. Tungstate is a powerful antidiabetic agent that has been shown to promote β-cell recovery in toxin-induced diabetic rodent models. In this study, we investigated whether tungstate could prevent the onset of diabetes in a scenario of dysregulated insulin/IGF signaling and massive β-cell death. To this end, we treated mice deficient in IRS2 (Irs2(-/-)), which exhibit severe β-cell loss, with tungstate for 3 wk. Tungstate normalized glucose tolerance in Irs2(-/-) mice in correlation with increased β-cell mass, increased β-cell replication, and a striking threefold reduction in β-cell apoptosis. Islets from treated Irs2(-/-) exhibited increased phosphorylated Erk1/2. Interestingly, tungstate repressed apoptosis-related genes in Irs2(-/-) islets in vitro, and ERK1/2 blockade abolished some of these effects. Gene expression profiling showed evidence of a broad impact of tungstate on cell death pathways in islets from Irs2(-/-) mice, consistent with reduced apoptotic rates. Our results support the finding that β-cell death can be arrested in the absence of IRS2 and that therapies aimed at reversing β-cell mass decline are potential strategies to prevent the progression to T2D.


Laboratory testing of anticoagulants: the present and the future.
This review provides an update on laboratory testing and monitoring for existing and emerging anticoagulants, starting with an overview of haemostasis and the routine coagulation tests currently employed within most haemostasis laboratories, including the prothrombin time (PT)/international normalised ratio (INR) and the activated partial thromboplastin time (APTT). Current anticoagulant therapy and laboratory monitoring is then discussed in terms of benefits and limitations, followed by a similar brief discussion of the new and emerging anticoagulants. The main focus, however, is laboratory testing related to vitamin K antagonists, heparin, lepirudin and the new agents dabigatran etexilate and rivaroxaban. Although the newer agents do not require laboratory monitoring, laboratory testing will occasionally be required, and pathology laboratories should become proactive in developing appropriate strategies. The tests most likely to fulfill this role are the ecarin clotting time (or chromogenic alternatives), and the chromogenic anti-Xa assay. Nevertheless, the dilute Russell viper venom time (dRVVT) assay may provide another alternative, and existing routine tests are also likely to be utilised for the foreseeable future, potentially also for laboratory testing of the new anticoagulants, albeit perhaps in modified form.


Large-scale grid-enabled lattice Boltzmann simulations of complex fluid flow in porous media and under shear.
Well-designed lattice Boltzmann codes exploit the essentially embarrassingly parallel features of the algorithm and so can be run with considerable efficiency on modern supercomputers. Such scalable codes permit us to simulate the behaviour of increasingly large quantities of complex condensed matter systems. In the present paper, we present some preliminary results on the large-scale three-dimensional lattice Boltzmann simulation of binary immiscible fluid flows through a porous medium, derived from digitized X-ray micro-tomographic data of Bentheimer sandstone, and from the study of the same fluids under shear. Simulations on such scales can benefit considerably from the use of computational steering, and we describe our implementation of steering within the lattice Boltzmann code, called LB3D, making use of the RealityGrid steering library. Our large-scale simulations benefit from the new concept of capability computing, designed to prioritize the execution of big jobs on major supercomputing resources. The advent of persistent computational grids promises to provide an optimal environment in which to deploy these mesoscale simulation methods, which can exploit the distributed nature of computer, visualization and storage resources to reach scientific results rapidly; we discuss our work on the grid-enablement of lattice Boltzmann methods in this context.


Endothelial Adenosine Monophosphate-Activated Protein Kinase-Alpha1 Deficiency Potentiates Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension.
Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) α1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPKα1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPKα1 knockdown decreases angiogenesis in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPKα1-sufficient and -deficient mice exposed to 21% O2 (normoxia) or 70% O2 (hyperoxia) from P1-P14. We also performed tubule formation assays on control- or AMPKα1-siRNA transfected HPMECs, exposed to 21% O2 or 70% O2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPKα1-deficient mice. AMPKα1 siRNA knocked down AMPKα1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPKα1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPKα1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury.


Neurocysticercosis control for primary epilepsy prevention: a systematic review.
Neurocysticercosis (NCC) is a leading cause of preventable epilepsy in lower- and upper- middle-income countries (LMICs/UMICs). NCC is a human-to-human transmitted disease caused by ingestion of Taenia solium eggs from a Taenia carrier. T. solium infection control is the key to reduce NCC incidence. This systematic review aims to identify T. solium control programs that can provide frameworks for endemic areas to prevent NCC-related epilepsy. A systematic search was conducted in PubMed/Medline, Embase, Web of Science, and Cochrane Library databases in March 2021. After title and abstract review, full texts were screened for qualitative analysis. Additional articles were identified via citation search. Of 1322 total results, 34 unique studies were included. Six major intervention types were identified: national policy (8.8%), community sanitation improvement (8.8%), health education (8.8%), mass drug administration (29.4%), pig vaccination and treatment (32.4%), and combined human and pig treatment (11.8%). Overall, 28 (82.4%) studies reported decreased cysticercosis prevalence following the intervention. Only health education and combined human and pig treatment were effective in all selected studies. NCC causes preventable epilepsy in LMICs/UMICs and its incidence can be reduced through T. solium control. Most interventions that disrupt the T. solium transmission cycle are effective. Long-term sustained results require comprehensive programs, ongoing surveillance, and collaborative effort among multisectoral agencies.


Fitness for work in health care workers: state of the art and possible operational recommendations for its formulation and management in relationship to alcohol and drug addiction.
Both chronic and acute alcohol or drug consumption have severe health consequences, alter the subject's cognitive functions and work performance and increase the risk of work-related accidents, for the worker and for third parties (e.g., co-workers and other people subject to negative impact of worker's actions). Limited scientific evidence has suggested that some working conditions present in the health care sector (e.g., high levels of responsibility, competitiveness, burnout, shiftwork, work-related stress) may favour alcohol and drug abuse. The aim of the present report is to describe the problem of alcohol and drug consumption among health care professionals and to evaluate the problem of related fitness for work. The magnitude of this problem remains unclear; recent estimates have reported alcohol abuse and addiction problems in 1-14% and psychotropic, illicit and non-illicit, substance abuse in 6-15% of health care workers. The prevalence of tranquilizer and sedative/hypnotic drug use is high, particularly among physicians. However, it remains unclear whether the incidence of workplace accidents and injuries is higher among drug abusers, and whether the statutory introduction of prevention programmes has led to actual control of this problem in the workplace. Italian legislation identifies the occupational physician as a key figure to prevent psychotropic substance abuse in some work activities, but some difficulties in its application remain. Legislators should issue simple norms that clearly define the responsibilities and skills of each actor involved in safeguarding workplace health and safety, as well as clearly outlining workplace monitoring procedures.


Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice.
Previously, we reported that the stress associated with chronic isolation was associated with increased beta-amyloid (Abeta) plaque deposition and memory deficits in the Tg2576 transgenic animal model of Alzheimer's disease (AD) [Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Effects of isolation stress on hippocampal neurogenesis, memory, and amyloid plaque deposition in APP (Tg2576) mutant mice. Neuroscience 127:601-609]. In this study, we investigated the potential mechanisms of stress-accelerated Abeta plaque deposition in this Tg2576 mice by examining the relationship between plasma corticosterone levels, expression of glucocorticoid receptor (GR) and corticotropin-releasing factor receptor-1 (CRFR1) in the brain, brain tissue Abeta levels and Abeta plaque deposition during isolation or group housing from weaning (i.e. 3 weeks of age) until 27 weeks of age. We found that isolation housing significantly increased plasma corticosterone levels as compared with group-housing in both Tg+ mice (which contain and overexpress human amyloid precursor protein (hAPP) gene) and Tg- mice (which do not contain hAPP gene as control). Also, isolated, but not group-housed animals showed increases in the expression of GR in the cortex. Furthermore, the expression of CRFR1 was increased in isolated Tg+ mice, but decreased in isolated Tg- mice in both cortex and hippocampus. Changes in the components of hypothalamic-pituitary-adrenal (HPA) axis were accompanied by increases in brain tissue Abeta levels and Abeta plaque deposition in the hippocampus and overlying cortex in isolated Tg+ mice. These results suggest that isolation stress increases corticosterone levels and GR and CRFR1 expression in conjunction with increases in brain tissue Abeta levels and Abeta plaque deposition in the Tg2576 mouse model of AD.


Technology-Facilitated Abuse Prevalence and Associations Among a Nationally Representative Sample of Young Men.
We undertook a study to determine the prevalence and associations of technology-facilitated abuse (TFA)-insults, harassment, coercion, or threats carried out using digital tools such as smartphones and computers-among a US nationally representative sample of young men. Analyses were based on 1,079 men aged 18 to 35 years who completed questionnaires during August and September of 2014 and reported ever having been in a romantic relationship. We used validated measures to assess demographics, health service use, mental health and substance use, and TFA delivered to and received from partners in the past year. We calculated survey-weighted descriptive statistics and conducted multinomial logistic regression analysis. Overall, 4.1% of men reported delivering TFA only, 8.0% receiving TFA only, and 25.6% both delivering and receiving TFA. Men were more likely to report only delivering TFA if they identified as Hispanic (adjusted odds ratio [AOR] = 2.72; 95% CI, 1.13 to 6.57), used marijuana (AOR = 1.31; 95% CI, 1.02 to 1.68), and used prescription opioids for nonmedical reasons (AOR 2.86; 95% CI, 1.48 to 5.54). Men were more likely to report only receiving TFA if they identified as Hispanic (AOR = 2.55; 95% CI, 1.01 to 6.43) and used prescription opioids for nonmedical reasons (AOR = 2.43; 95% CI, 1.34 to 4.39), whereas a primary care connection appeared protective (AOR = 0.43; 95% CI, 0.22 to 0.86). Men were more likely to report both delivering and receiving TFA if they identified as non-Hispanic Black (AOR = 2.83; 95% CI, 1.44 to 5.58), owned a smartphone (AOR = 1.80; 95% CI, 1.05 to 3.09), had ever had mental health care visits (AOR = 1.86; 95% CI, 1.16 to 2.98), misused alcohol (AOR = 1.10; 95% CI, 1.04 to 1.17), and used prescription opioids for nonmedical reasons (AOR = 1.79; 95% CI, 1.04 to 3.08). We found that TFA was prevalent among young men, with 1 in 25 reporting delivery only, 1 in 12 reporting receipt only, and 1 in 4 reporting both. Primary care physicians can consider assessing TFA among male patients and developing interventions to mitigate this behavior.VISUAL ABSTRACT.


Central control of fever and female body temperature by RANKL/RANK.
Receptor-activator of NF-kappaB ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland. RANKL and RANK are also expressed in the central nervous system. However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1beta and TNFalpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.


Paroxysmal motor disorders: expanding phenotypes lead to coalescing genotypes.
Paroxysmal movement disorders encompass varied motor phenomena. Less recognized features and wide phenotypic and genotypic heterogeneity are impediments to straightforward molecular diagnosis. We describe a family with episodic ataxia type 1, initially mis-characterized as paroxysmal dystonia to illustrate this diagnostic challenge. We summarize clinical features in affected individuals to highlight underappreciated aspects and provide comprehensive phenotypic description of the rare familial KCNA1 mutation. Delayed diagnosis in this family is emblematic of the broader challenge of diagnosing other paroxysmal motor disorders. We summarize genotypic and phenotypic overlap and provide a suggested diagnostic algorithm for approaching patients with these conditions.


GelMA/TCP nanocomposite scaffold for vital pulp therapy.
Pulp capping is a necessary procedure for preserving the vitality and health of the dental pulp, playing a crucial role in preventing the need for root canal treatment or tooth extraction. Here, we developed an electrospun gelatin methacryloyl (GelMA) fibrous scaffold incorporating beta-tricalcium phosphate (TCP) particles for pulp capping. A comprehensive morphological, physical-chemical, and mechanical characterization of the engineered fibrous scaffolds was performed. In vitro bioactivity, cell compatibility, and odontogenic differentiation potential of the scaffolds in dental pulp stem cells (DPSCs) were also evaluated. A pre-clinical in vivo model was used to determine the therapeutic role of the GelMA/TCP scaffolds in promoting hard tissue formation. Morphological, chemical, and thermal analyses confirmed effective TCP incorporation in the GelMA nanofibers. The GelMA+20%TCP nanofibrous scaffold exhibited bead-free morphology and suitable mechanical and degradation properties. In vitro, GelMA+20%TCP scaffolds supported apatite-like formation, improved cell spreading, and increased deposition of mineralization nodules. Gene expression analysis revealed upregulation of ALPL, RUNX2, COL1A1, and DMP1 in the presence of TCP-laden scaffolds. In vivo, analyses showed mild inflammatory reaction upon scaffolds' contact while supporting mineralized tissue formation. Although the levels of Nestin and DMP1 proteins did not exceed those associated with the clinical reference treatment (i.e., mineral trioxide aggregate), the GelMA+20%TCP scaffold exhibited comparable levels, thus suggesting the emergence of differentiated odontoblast-like cells capable of dentin matrix secretion. Our innovative GelMA/TCP scaffold represents a simplified and efficient alternative to conventional pulp-capping biomaterials. STATEMENT OF SIGNIFICANCE: Vital pulp therapy (VPT) aims to preserve dental pulp vitality and avoid root canal treatment. Biomaterials that bolster mineralized tissue regeneration with ease of use are still lacking. We successfully engineered gelatin methacryloyl (GelMA) electrospun scaffolds incorporated with beta-tricalcium phosphate (TCP) for VPT. Notably, electrospun GelMA-based scaffolds containing 20% (w/v) of TCP exhibited favorable mechanical properties and degradation, cytocompatibility, and mineralization potential indicated by apatite-like structures in vitro and mineralized tissue deposition in vivo, although not surpassing those associated with the standard of care. Collectively, our innovative GelMA/TCP scaffold represents a simplified alternative to conventional pulp capping materials such as MTA and Biodentine™ since it is a ready-to-use biomaterial, requires no setting time, and is therapeutically effective.


Design and synthesis of a new class of membrane-permeable triazaborolopyridinium fluorescent probes.
A new class of fluorescent triazaborolopyridinium compounds was synthesized from hydrazones of 2-hydrazinylpyridine (HPY) and evaluated as potential dyes for live-cell imaging applications. The HPY dyes are small, their absorption/emission properties are tunable through variation of pyridyl or hydrazone substituents, and they offer favorable photophysical characteristics featuring large Stokes shifts and general insensitivity to solvent or pH. The stability, neutral charge, cell membrane permeability, and favorable relative influences on the water solubility of HPY conjugates are complementary to existing fluorescent dyes and offer advantages for the development of receptor-targeted small-molecule probes. This potential was assessed through the development of a new class of cysteine-derived HPY-conjugate imaging agents for the kinesin spindle protein (KSP) that is expressed in the cytoplasm during mitosis and is a promising chemotherapeutic target. Conjugates possessing the neutral HPY or charged Alexa Fluor dyes that function as potent, selective allosteric inhibitors of the KSP motor were compared using biochemical and cell-based phenotypic assays and live-cell imaging. These results demonstrate the effectiveness of the HPY dye moiety as a component of probes for an intracellular protein target and highlight the importance of dye structure in determining the pathway of cell entry and the overall performance of small-molecule conjugates as imaging agents.


Locating landmarks on high-dimensional free energy surfaces.
Coarse graining of complex systems possessing many degrees of freedom can often be a useful approach for analyzing and understanding key features of these systems in terms of just a few variables. The relevant energy landscape in a coarse-grained description is the free energy surface as a function of the coarse-grained variables, which, despite the dimensional reduction, can still be an object of high dimension. Consequently, navigating and exploring this high-dimensional free energy surface is a nontrivial task. In this paper, we use techniques from multiscale modeling, stochastic optimization, and machine learning to devise a strategy for locating minima and saddle points (termed "landmarks") on a high-dimensional free energy surface "on the fly" and without requiring prior knowledge of or an explicit form for the surface. In addition, we propose a compact graph representation of the landmarks and connections between them, and we show that the graph nodes can be subsequently analyzed and clustered based on key attributes that elucidate important properties of the system. Finally, we show that knowledge of landmark locations allows for the efficient determination of their relative free energies via enhanced sampling techniques.


Small-angle X-ray scattering study on nano-scale structures controlled by water content in a binary water/ionic liquid system.
We report the water-in-ionic-liquid microemulsions (ME) formed in a binary water/ionic liquid system, without organic solvents, using a surfactant ionic liquid (SAIL) based on 1-butyl-3-methylimidazolium (C4mIm+) as the cation and dioctyl sulfosuccinate (AOT-) as the anion. Small-angle X-ray scattering (SAXS) revealed that MEs were stably formed in the binary water/SAIL solutions in the low water content region (water volume fraction, φw < 0.1), and the ME size systematically increased with increasing φw. We further investigated the nanostructures of the high φw region using a combination of SAXS and rheological measurements and found that the MEs changed to a stacked lamellar structure comprising SAIL bilayers and water phases at φw > 0.12. At the largest water content, φw = 0.99, vesicle structures were obtained.


Comparison between cortical distribution of I-123 iomazenil and Tc-99m HMPAO in patients with Alzheimer's disease using SPECT.
To compare brain perfusion and synaptic density in Alzheimer's disease assessed using I-123 iomazenil SPECT with brain perfusion assessed using Tc-99m HMPAO SPECT. Early and delayed I-123 iomazenil SPECT images acquired 20 and 180 minutes after injection were compared with Tc-99m HMPAO SPECT studies acquired 15 to 20 minutes after injection in five patients with Alzheimer's disease. Visual analysis of I-123 iomazenil images showed more severe (n = 4) and extensive (n = 3) defects than did Tc-99m HMPAO. Semiquantitative analysis was performed by normalizing the uptake of Tc-99m HMPAO and I-123 iomazenil in individual brain regions in the cerebellum and expressing these values as a ratio of the occipital regions. The analysis of brain regional ratios in Tc-99m HMPAO studies showed a low but significant correlation with ratios of delayed (r = 0.325, P < 0.05) images in the I-123 iomazenil studies. Furthermore, when compared with Tc-99m HMPAO, early (P < 0.01) and delayed mean ratios (P < 0.05) were significantly less in the frontal regions; early mean ratios were significantly less in the temporal regions (P < 0.05), and delayed (P < 0.05) mean ratios were significantly less in the parietal regions. Tc-99m HMPAO images were better correlated with I-123 iomazenil images, indicating cortical synaptic density (delayed images). I-123 iomazenil SPECT in patients with Alzheimer's disease provided more sensitive information than Tc-99m HMPAO, allowing evaluation of brain perfusion and synaptic density.


Spurious correlations and inference in landscape genetics.
Reliable interpretation of landscape genetic analyses depends on statistical methods that have high power to identify the correct process driving gene flow while rejecting incorrect alternative hypotheses. Little is known about statistical power and inference in individual-based landscape genetics. Our objective was to evaluate the power of causal-modelling with partial Mantel tests in individual-based landscape genetic analysis. We used a spatially explicit simulation model to generate genetic data across a spatially distributed population as functions of several alternative gene flow processes. This allowed us to stipulate the actual process that is in action, enabling formal evaluation of the strength of spurious correlations with incorrect models. We evaluated the degree to which naïve correlational approaches can lead to incorrect attribution of the driver of observed genetic structure. Second, we evaluated the power of causal modelling with partial Mantel tests on resistance gradients to correctly identify the explanatory model and reject incorrect alternative models. Third, we evaluated how rapidly after the landscape genetic process is initiated that we are able to reliably detect the effect of the correct model and reject the incorrect models. Our analyses suggest that simple correlational analyses between genetic data and proposed explanatory models produce strong spurious correlations, which lead to incorrect inferences. We found that causal modelling was extremely effective at rejecting incorrect explanations and correctly identifying the true causal process. We propose a generalized framework for landscape genetics based on analysis of the spatial genetic relationships among individual organisms relative to alternative hypotheses that define functional relationships between landscape features and spatial population processes.


Analyzing microbial evolution through gene and genome phylogenies.
Microbiome scientists critically need modern tools to explore and analyze microbial evolution. Often this involves studying the evolution of microbial genomes as a whole. However, different genes in a single genome can be subject to different evolutionary pressures, which can result in distinct gene-level evolutionary histories. To address this challenge, we propose to treat estimated gene-level phylogenies as data objects, and present an interactive method for the analysis of a collection of gene phylogenies. We use a local linear approximation of phylogenetic tree space to visualize estimated gene trees as points in low-dimensional Euclidean space, and address important practical limitations of existing related approaches, allowing an intuitive visualization of complex data objects. We demonstrate the utility of our proposed approach through microbial data analyses, including by identifying outlying gene histories in strains of Prevotella, and by contrasting Streptococcus phylogenies estimated using different gene sets. Our method is available as an open-source R package, and assists with estimating, visualizing, and interacting with a collection of bacterial gene phylogenies.


Culturable epiphytic bacteria isolated from Teleogryllus occipitalus crickets metabolize insecticides.
The development of insecticide resistance is attributed to evolutionary changes in pest insect genomes, such as alteration of drug target sites, upregulation of degrading enzymes, and enhancement of drug excretion. Beyond these well-known mechanisms, symbiotic bacteria may confer insecticide resistance to host crickets. The current study was designed to screen all possible culturable bacterial groups found living in and on the bodies of Teleogryllus occipitalis crickets. We recovered 263 visible bacterial colonies and cultured them individually. After identifying the colonies based on morphology and phylogenetic analysis, we shortlisted 55 bacterial strains belonging to 28 genera. Of these 55 bacterial strains, 18 degraded at least 50% of the original amount of 400 mg/L chlorpyrifos (CP) after 24 hr of coculture. Six of these strains degraded more than 70% of the original amount of 400 mg/L CP. Three strains had antagonistic effects on Bacillus thuringiensis growth. Additionally, the ability of the isolates to degrade glyphosate, phoxim, and esfenvalerate was assessed. We also detected extracellular hydrolase enzyme activities in these isolates. We propose that epiphytic bacterial strains play multiple roles in cricket biology, one of which contributes to chemical and biological pesticide resistance.


Organic light detectors: photodiodes and phototransistors.
While organic electronics is mostly dominated by light-emitting diodes, photovoltaic cells and transistors, optoelectronics properties peculiar to organic semiconductors make them interesting candidates for the development of innovative and disruptive applications also in the field of light signal detection. In fact, organic-based photoactive media combine effective light absorption in the region of the spectrum from ultraviolet to near-infrared with good photogeneration yield and low-temperature processability over large areas and on virtually every substrate, which might enable innovative optoelectronic systems to be targeted for instance in the field of imaging, optical communications or biomedical sensing. In this review, after a brief resume of photogeneration basics and of devices operation mechanisms, we offer a broad overview of recent progress in the field, focusing on photodiodes and phototransistors. As to the former device category, very interesting values for figures of merit such as photoconversion efficiency, speed and minimum detectable signal level have been attained, and even though the simultaneous optimization of all these relevant parameters is demonstrated in a limited number of papers, real applications are within reach for this technology, as it is testified by the increasing number of realizations going beyond the single-device level and tackling more complex optoelectronic systems. As to phototransistors, a more recent subject of study in the framework of organic electronics, despite a broad distribution in the reported performances, best photoresponsivities outperform amorphous silicon-based devices. This suggests that organic phototransistors have a large potential to be used in a variety of optoelectronic peculiar applications, such as a photo-sensor, opto-isolator, image sensor, optically controlled phase shifter, and opto-electronic switch and memory.


The Child Opportunity Index and asthma morbidity among children younger than 5 years old in Washington, DC.
Place-based social determinants of health are associated with pediatric asthma morbidity. However, there is little evidence on how social determinants of health correlate to the disproportionately high rates of asthma morbidity experienced by children <5 years old. This study sought to evaluate census tract associations between the Child Opportunity Index ±COI) and at-risk rates (ARRs) for pediatric asthma-related emergency department (ED) encounters and hospitalizations in Washington, DC. This was a cross-sectional study of children <5 years old with physician-diagnosed asthma included in the DC Asthma Registry between January 2018 and December 2019. Census tract COI score (1-100) and its 3 domains (social/economic, health/environmental, and educational) were the exposures (source: www.diversitydatakids.org). ED and hospitalization ARRs (outcomes) were created by dividing counts of ED encounters and hospitalizations by populations with asthma for each census tract and adjusted for population-level demographic (age, sex, insurance), clinical (asthma severity), and community (violent crime and limited English proficiency) covariates. Within a study population of 3806 children with a mean age of 2.4 ± 1.4 years, 2132 (56%) had 5852 ED encounters, and 821 (22%) had 1418 hospitalizations. Greater census tract overall COI, social/economic COI, and educational COI were associated with fewer ED ARRs. There were no associations between the health/environmental COI and ED ARRs or between the COI and hospitalization ARRs. Improving community-level social, economic, and educational opportunity within specific census tracts may reduce ED ARRs in this population.


Interpretation of diffuse scattering in the high-Tc superconductor HgBa2CuO4+δ.
Published diffuse X-ray scattering from the high-Tc superconductor HgBa2CuO4+δ has been reexamined with a view to developing a model that more satisfactorily accounts for the observed patterns. The present work agrees with the previous conclusion that the doping oxygen atoms form long and isolated interstitial chains that run in both tetragonal directions. However, a distinctly different model is proposed for the accompanying displacement patterns of the atoms surrounding these linear defects. In this new model it is proposed that it is the correlated shifts of the Ba atoms along the length of the defect chains that are the primary source of the observed scattering, and that the variations of intensity in the generated diffuse streaks of scattering originate from lateral shifts of both Hg and Ba atoms away from defects. The new model yields diffraction patterns that are in much more convincing agreement with the observations than the original model.


SSC-ILD mouse model induced by osmotic minipump delivered bleomycin: effect of Nintedanib.
Systemic sclerosis (SSc) is an autoimmune disease characterized by an excessive production and accumulation of collagen in the skin and internal organs often associated with interstitial lung disease (ILD). Its pathogenetic mechanisms are unknown and the lack of animal models mimicking the features of the human disease is creating a gap between the selection of anti-fibrotic drug candidates and effective therapies. In this work, we intended to pharmacologically validate a SSc-ILD model based on 1 week infusion of bleomycin (BLM) by osmotic minipumps in C57/BL6 mice, since it will serve as a tool for secondary drug screening. Nintedanib (NINT) has been used as a reference compound to investigate antifibrotic activity either for lung or skin fibrosis. Longitudinal Micro-CT analysis highlighted a significant slowdown in lung fibrosis progression after NINT treatment, which was confirmed by histology. However, no significant effect was observed on lung hydroxyproline content, inflammatory infiltrate and skin lipoatrophy. The modest pharmacological effect reported here could reflect the clinical outcome, highlighting the reliability of this model to better profile potential clinical drug candidates. The integrative approach presented herein, which combines longitudinal assessments with endpoint analyses, could be harnessed in drug discovery to generate more reliable, reproducible and robust readouts.


Array of polarization singularities in interference of three waves.
In this paper, we show that arrayed polarization singularities (PSs) can be generated by interference of three polarized waves. An experimental setup was proposed and used to produce one of the available types of array structures. We then analytically identified factors that control the structures of these arrays and classified all the structures into three types. Simulation results were used to assist this analysis.


Changes in mass and energy transfer between the canopy and the atmosphere: model development and testing with a free-air CO2 enrichment (FACE) experiment.
The rationale for this study is found in the probable higher temperatures and changes in rainfall patterns that are expected in the future as a result of increasing levels of CO2 in the atmosphere. In particular, higher air temperatures may cause an increase in evapotranspiration demand while a reduction in rainfall could increase the severity and duration of drought in arid and semi-arid regions. Representation of the water transfer scheme includes water uptake by roots and the interaction between evapotranspiration and CO2 enrichment. The predicted response of a spring wheat (Triticum aestivum L. cv. Yecora rojo) canopy in terms of energy exchange processes to elevated atmospheric CO2 level was tested against measurements collected at the FACE (Free Air Enrichment Experiment) site in 1994. Simulated and measured canopy conductances were reduced by about 30% under elevated [CO2] under optimum conditions of water supply. Reductions in latent heat fluxes under elevated instead of ambient [CO2] caused reductions in both simulated and measured seasonal water use of 6% under optimum and 2% under suboptimum irrigation. The soil-plant-atmosphere water transfer scheme proposed here offers several advances in the simulation of land surface interactions. First, the stomatal resistance model minimizes assumptions in existing land surface schemes about the effects of interactions among environmental conditions (radiation, temperature, CO2) upon stomatal behavior. These interactions are resolved in the calculation of CO2 in which processes are already well understood.


Papillary carcinoma arising in struma ovarii versus ovarian metastasis from primary thyroid carcinoma: a case report and review of the literature.
We present a case of a postmenopausal woman diagnosed with an ovarian mass containing thyroid follicles and foci of papillary thyroid carcinoma during pathological examination. This patient referred having had a metachronous thyroid malignancy 10 years before. The differential diagnosis between a thyroid malignancy arising from a struma ovarii and a metastatic ovarian tumor originating from thyroid-cancer is challenging. Struma ovarii should be considered when thyroid components are the predominant element or when thyroid malignant tissue is identified within an ovarian lesion. Thyroid carcinoma arising from a struma ovarii is reported to occur in a minority of cases. Of these, papillary carcinoma is the most frequent subtype encountered. Regarding primary thyroid carcinomas, papillary carcinomas have a lower metastatic potential when compared to follicular carcinomas, and most of the metastases occur in the cervical lymph nodes. Ovarian metastases are exceedingly rare and generally associated with widespread disease. However, they must be considered in the presence of previous history of malignant thyroid carcinoma. The authors review the main clinical, imaging and therapeutic aspects of both these entities and present the most likely diagnosis.


Pathogenesis of herpes simplex virus in congenitally athymic mice: the relative roles of cell-mediated and humoral immunity.
Athymic nude (nu/nu) mice were inoculated in the ear pinna with 10(4) p.f.u. herpes simplex virus type 1 (strain SC 16). Initially, the virus was observed to replicate in the pinna, spreading via a neurological route to the dorsal root ganglia, spinal cord, brain and adrenal glands. Following the transfer of lymphoid cells from day 7 herpesvirus-infected hairy immunocompetent donors into infected nude mice, virus was not isolated from the pinna and nervous system of the majority of the mice. The passive transfer of neutralizing polyclonal anti-herpesvirus serum or neutralizing monoclonal anti-gp D serum did not reduce infectivity in the pinna, but markedly reduced the amount of virus in the ganglia and spinal cord. These data suggest that neutralizing antibodies play an important role in restricting the movement of virus to the nervous system, whereas cell-mediated immune (CMI) mechanisms are essential for eliminating virus from the pinna.


Induction of Cellular Senescence in Rat Vaginal Fibroblasts and Treatment With Senolytics: An in Vitro Model for the Study of Pelvic Organ Prolapse.
The objective of this study was to develop an in vitro model of cellular senescence using rat vaginal fibroblasts and determine the effects of treatment with senolytics. Rat vaginal tissue biopsies were collected. Primary vaginal fibroblasts were isolated and characterized by immunofluorescence. To induce cellular senescence, fibroblasts were treated with etoposide at 3, 10, and 20 mM for 24 hours, followed by treatment with the senolytics dasatinib (1 mM) and/or quercetin (20 mM). After treatment, RNA was extracted and the expression of selected genes was quantified. Immunostaining of senescence markers was also performed. Fibroblasts were confirmed by positive immunostaining for α-smooth muscle actin and vimentin, and negative immunostaining for pan-cytokeratin. Treatment with etoposide resulted in a dose-dependent increase in expression of the senescence-associated secretory phenotype markers MMP-7, MMP-9, and IL-b1 (P < 0.05) compared with controls. Immunostaining showed increased expression of γ-H2A and p21 after treatment with etoposide. Cells treated with dasatinib and quercetin after etoposide treatment had decreased expression of p21, MMP-7, MMP-9, and IL-1b compared with cells treated only with etoposide (P < 0.05). Upregulation of senescence-associated factors provided evidence that senescence can be induced in vaginal fibroblasts in vitro. Furthermore, treatment with the senolytics dasatinib and quercetin abrogated the senescence phenotype induced by etoposide in rat vaginal fibroblasts. Our findings provide a novel model for the study and development of new therapies targeting the disordered extracellular matrix associated with pelvic organ prolapse.


Surgical Reconstruction following Wide Local Excision of Malignant Melanoma of the Scalp.
Scalp reconstruction in cases of melanoma excision can be challenging due to specific functional and aesthetic outcome requirements. Reconstructive techniques reported in the literature were reviewed to establish whether a surgical algorithm for the management of melanoma of the scalp may be deduced. A literature search was conducted to evaluate reconstructive strategies after melanoma wide local excision of the scalp according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Inclusion criteria were English language, diagnosis of melanoma of the scalp, and the presence of the following data: characteristics of the residual defect (width and depth), type of reconstruction, follow-up, and surgical outcome. Six hundred twenty-five records were identified after excluding the duplicates; 48 full-text articles were assessed for eligibility, and 17 records were selected for inclusion. A total of 39 patients were included in the review. The majority of patients (n = 20) underwent skin grafting subsequent to dermal regeneration template positioning. Local flaps (n = 10), free flaps (n = 7), skin grafting alone (n = 1), and dermal regeneration template positioning alone (n = 1) were less frequent. Numerous reconstructive strategies for the scalp are described in the literature. Melanoma patients present a greater variability in terms of general health conditions and social needs that must be taken into account while choosing the most suitable procedure.


Whole-Genome Re-sequencing and Transcriptome Reveal Candidate Genes and Pathways Associated with Hybrid Sterility in Hermaphroditic Argopecten Scallops.
The interspecific hybrid scallops generated from the hermaphroditic bay scallops (Argopecten irradians) and Peruvian scallops (Argopecten purpuratus) showed significant heterosis in growth. However, its sterility limits large-scale hybridization and hinders the development of the scallop breeding industry. Hybrid sterility is regulated by plenty of genes and involves a range of biochemical and physiological transformations. In this study, whole-genome re-sequencing and transcriptomic analysis were performed in sterile and fertile hybrid scallops. The potential genetic variations and abnormally expressed genes were detected to explore the mechanism underlying hybrid sterility in hermaphroditic Argopecten scallops. Compared with fertile hybrids, 24 differentially expressed genes (DEGs) with 246 variations were identified to be related to fertility regulation, which were mainly enriched in germarium-derived egg chamber formation, spermatogenesis, spermatid development, mismatch repair, mitotic and meiotic cell cycles, Wnt signaling pathway, MAPK signaling pathway, calcium modulating pathway, and notch signaling pathway. Specifically, variation and abnormal expression of these genes might inhibit the progress of mitosis and meiosis, promote cell apoptosis, and impede the genesis and maturation of gametes in sterile hybrid scallops. Eleven DEGs (XIAP, KAZN, CDC42, MEIS1, SETD1B, NOTCH2, TRPV5, M- EXO1, GGT1, SBDS, and TBCEL) were confirmed by qRT-PCR validation. Our findings may enrich the determination mechanism of hybrid sterility and provide new insights into the use of interspecific hybrids for extensive breeding.


Australian and New Zealand clinical practice guidelines for the treatment of panic disorder and agoraphobia.
The Royal Australian and New Zealand College of Psychiatrists is co-ordinating the development of clinical practice guidelines (CPGs) in psychiatry, funded under the National Mental Health Strategy (Australia) and the New Zealand Health Funding Authority. For these guidelines, the CPG team reviewed the treatment outcome literature, consulted with practitioners and patients and conducted a meta-analysis of recent outcome research. Education for the patient and significant others covering: (i) the nature and course of panic disorder and agoraphobia; (ii) an explanation of the psychopathology of anxiety, panic and agoraphobia; (iii) rationale for the treatment, likelihood of a positive response, and expected time frame. Cognitive behaviour therapy (CBT) is more effective and more cost-effective than medication. Tricyclic antidepressants (TCAs) and serotonin selective reuptake inhibitors are equal in efficacy and both are to be preferred to benzodiazepines. Treatment choice depends on the skill of the clinician and the patient's circumstances. Drug treatment should be complemented by behaviour therapy. If the response to an adequate trial of a first-line treatment is poor, another evidence-based treatment should be used. A second opinion can be useful. The presence of severe agoraphobia is a negative prognostic indicator, whereas comorbid depression, if properly treated, has no consistent effect on outcome.