Inactivation of foodborne microorganisms using engineered water nanostructures (EWNS).
Foodborne diseases caused by the consumption of food contaminated with pathogenic microorganisms or their toxins have very serious economic and public health consequences. Here, we explored the effectiveness of a recently developed intervention method for inactivation of microorganisms on fresh produce, and food production surfaces. This method utilizes Engineered Water Nanostructures (EWNS) produced by electrospraying of water vapor. EWNS possess unique properties; they are 25 nm in diameter, remain airborne in indoor conditions for hours, contain Reactive Oxygen Species (ROS) and have very strong surface charge (on average 10 e/structure). Here, their efficacy in inactivating representative foodborne bacteria such as Escherichia coli, Salmonella enterica, and Listeria innocua, on stainless steel surfaces and on organic tomatoes, was assessed. The inactivation was facilitated using two different exposure approaches in order to optimize the delivery of EWNS to bacteria: (1) EWNS were delivered on the surfaces by diffusion and (2) a "draw through" Electrostatic Precipitator Exposure System (EPES) was developed and characterized for EWNS delivery to surfaces. Using the diffusion approach and an EWNS concentration of 24,000 #/cm3, the bacterial concentrations on the surfaces were reduced, depending on the bacterium and the surface type, by values ranging between 0.7 to 1.8 logs. Using the EPES approach and for an aerosol concentration of 50,000 #/cm3 at 90 min of exposure, results show a 1.4 log reduction for E. coli on organic tomato surfaces, as compared to the control (same conditions in regards to temperature and Relative Humidity). Furthermore, for L. innocua, the dose-response relationship was demonstrated and found to be a 0.7 and 1.2 logs removal at 12,000 and 23,000 #/cm3, respectively. The results presented here indicate that this novel, chemical-free, and environmentally friendly intervention method holds potential for development and application in the food industry, as a "green" alternative to existing disinfection methods.


Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration.
Infusion of atrial natriuretic peptide (ANP) increases the glomerular filtration rate (GFR), and ANP is released from cardiac myocytes in response to extracellular fluid volume expansion. Since diabetes mellitus is associated with glomerular hyperfiltration and volume expansion, we investigated the relationship between ANP and GFR in diabetic rats given insulin to achieve stable moderate hyperglycemia or normoglycemia. At 2 wk after induction of diabetes, moderately hyperglycemic diabetic rats exhibited elevations of plasma ANP levels averaging 281 +/- 28 pg/ml vs. 158 +/- 15 pg/ml in normoglycemic diabetic rats. In hyperglycemic rats, the GFR was also elevated on average to 2.24 +/- 0.28 ml/min as compared with 1.71 +/- 0.13 ml/min in normoglycemic diabetic rats. To test further the relationship between ANP and GFR in diabetes, moderately hyperglycemic diabetic rats were infused either with a specific ANP antiserum or with nonimmune serum. The infusion of specific ANP antiserum uniformly reduced the GFR on average from 2.38 +/- 0.1 ml/min to 1.60 +/- 0.1 ml/min, whereas the infusion of nonimmune serum was without effect. It is concluded that elevated endogenous ANP levels contribute to the hyperfiltration observed in early diabetes in the rat.


Dermabrasion of large congenital melanocytic naevi in neonates.
We describe our findings in a series of 12 patients with large congenital melanocytic naevi treated with dermabrasion between the first and fourteenth week of life. Postoperative follow-up ranged from 1-16 years. In all but two cases dermabrasion resulted in an appreciable and stable reduction of the hyperpigmentation, possibly by reducing the number of pigmented cells in the epidermis. In six of our 12 patients, reconstruction using grafts and flaps was done to improve the aesthetic result. Seven years after dermabrasion, one patient developed a minimal deviation melanoma in the treated area, but his subsequent clinical course has been uneventful.


The Walking Egg non-profit organisation.
The Walking Egg non-profit organisation (npo) was founded in 2010 by scientists and an artist to realise the Arusha Project which strives to implement accessible infertility programmes in resource-poor countries. Right from the start The Walking Egg has opted for a multidisciplinary and global approach towards the problem of infertility and in cooperation with the Special Task Force (STF) on "Developing countries and infertility" of the European Society of Human reproduction and Embryology (ESHRE) and the WHO, it gathers medical, social and economical scientists and experts along with artists to discuss and work together towards its goal. The project aims to raise awareness -surrounding childlessness in resource-poor countries and to make infertility care in all its aspects, including assisted reproductive technologies, available and accessible for a much larger part of the population.


Reducing the silent burden of impaired mental health.
Mental and behavioural disorders account for about one-third of the world's disability due to all ill health amongst adults, with unipolar depressive disorders set to be the world's number one cause of ill health and premature death in 2030, affecting high- and low-income countries alike. There is a range of evidence-based cost-effective interventions that can be implemented in parenting, at schools, at the workplace and in older age that can promote health and well-being, reduce mental disorders, lead to improved productivity and increase resilience to cope with many of the stressors that are facing the world. These facts need to be better communicated to policy makers to ensure that the silent burden of impaired mental health is adequately heard and reduced.


Ultraviolet-B- and ozone-induced biochemical changes in antioxidant enzymes of Arabidopsis thaliana.
Earlier studies with Arabidopsis thaliana exposed to ultraviolet B (UV-B) and ozone (O3) have indicated the differential responses of superoxide dismutase and glutathione reductase. In this study, we have investigated whether A. thaliana genotype Landsberg erecta and its flavonoid-deficient mutant transparent testa (tt5) is capable of metabolizing UV-B- and O3-induced activated oxygen species by invoking similar antioxidant enzymes. UV-B exposure preferentially enhanced guaiacol-peroxidases, ascorbate peroxidase, and peroxidases specific to coniferyl alcohol and modified the substrate affinity of ascorbate peroxidase. O3 exposure enhanced superoxide dismutase, peroxidases, glutathione reductase, and ascorbate peroxidase to a similar degree and modified the substrate affinity of both glutathione reductase and ascorbate peroxidase. Both UV-B and O3 exposure enhanced similar Cu,Zn-superoxide dismutase isoforms. New isoforms of peroxidases and ascorbate peroxidase were synthesized in tt5 plants irradiated with UV-B. UV-B radiation, in contrast to O3, enhanced the activated oxygen species by increasing membrane-localized NADPH-oxidase activity and decreasing catalase activities. These results collectively suggest that (a) UV-B exposure preferentially induces peroxidase-related enzymes, whereas O3 exposure invokes the enzymes of superoxide dismutase/ascorbate-glutathione cycle, and (b) in contrast to O3, UV-B exposure generated activated oxygen species by increasing NADPH-oxidase activity.


Flexible modelling of spatial variation in agricultural field trials with the R package INLA.
Established spatial models improve the analysis of agricultural field trials with or without genomic data and can be fitted with the open-source R package INLA. The objective of this paper was to fit different established spatial models for analysing agricultural field trials using the open-source R package INLA. Spatial variation is common in field trials, and accounting for it increases the accuracy of estimated genetic effects. However, this is still hindered by the lack of available software implementations. We compare some established spatial models and show possibilities for flexible modelling with respect to field trial design and joint modelling over multiple years and locations. We use a Bayesian framework and for statistical inference the integrated nested Laplace approximations (INLA) implemented in the R package INLA. The spatial models we use are the well-known independent row and column effects, separable first-order autoregressive ([Formula: see text]) models and a Gaussian random field (Matérn) model that is approximated via the stochastic partial differential equation approach. The Matérn model can accommodate flexible field trial designs and yields interpretable parameters. We test the models in a simulation study imitating a wheat breeding programme with different levels of spatial variation, with and without genome-wide markers and with combining data over two locations, modelling spatial and genetic effects jointly. The results show comparable predictive performance for both the [Formula: see text] and the Matérn models. We also present an example of fitting the models to a real wheat breeding data and simulated tree breeding data with the Nelder wheel design to show the flexibility of the Matérn model and the R package INLA.


[Morphometry of the non-villous placental cytotrophoblast in the interrupted pregnancy].
Relative volumes and functional activity of the non-villous cytotrophoblast in the main structural components of 40 placentas at various stages of normal pregnancy as well as in 38 placentas in the interrupted pregnancy are characterized. High morphofunctional activity of this trophoblast was found for 23-27 weeks and its relative decrease to the end of normal pregnancy. The decrease of both the relative volume and activity in the cell islands, septal and basal lamina was observed in two groups of interrupted pregnancy (28-32 and 33-37 weeks). Tendency to the increase of intervillous fibrinoid and "pseudo-infarctions" is connected mainly with the gestational changes and not with the pregnancy interruption.


Life history of the Glanville fritillary butterfly in fragmented versus continuous landscapes.
Habitat loss and fragmentation threaten the long-term viability of innumerable species of plants and animals. At the same time, habitat fragmentation may impose strong natural selection and lead to evolution of life histories with possible consequences for demographic dynamics. The Baltic populations of the Glanville fritillary butterfly (Melitaea cinxia) inhabit regions with highly fragmented habitat (networks of small dry meadows) as well as regions with extensive continuous habitat (calcareous alvar grasslands). Here, we report the results of common garden studies on butterflies originating from two highly fragmented landscapes (FL) in Finland and Sweden and from two continuous landscapes (CL) in Sweden and Estonia, conducted in a large outdoor cage (32 by 26 m) and in the laboratory. We investigated a comprehensive set of 51 life-history traits, including measures of larval growth and development, flight performance, and adult reproductive behavior. Seventeen of the 51 traits showed a significant difference between fragmented versus CL. Most notably, the growth rate of postdiapause larvae and several measures of flight capacity, including flight metabolic rate, were higher in butterflies from fragmented than CL. Females from CL had shorter intervals between consecutive egg clutches and somewhat higher life-time egg production, but shorter longevity, than females from FL. These results are likely to reflect the constant opportunities for oviposition in females living in continuous habitats, while the more dispersive females from FL allocate more resources to dispersal capacity at the cost of egg maturation rate. This study supports theoretical predictions about small population sizes and high rate of population turnover in fragmented habitats selecting for increased rate of dispersal, but the results also indicate that many other life-history traits apart from dispersal are affected by the degree of habitat fragmentation.


Destruction of microbial collections in response to select agent and toxin list regulations.
In this study we have followed up on anecdotal and hearsay evidence that microbial collections were destroyed in the United States following the imposition of the regulations associated with the Select Agents and Toxins List, to validate or refute that information. Using a questionnaire, we documented 13 episodes of microbial collection destruction involving viral, bacterial, and fungal strains, which we believe is almost certainly an underestimate of the number of collections destroyed. In every case, the motivation for the destruction of the collection was a desire to avoid the perceived burdens of the regulatory environment associated with operating under the Select Agent Regulations. Some institutions that destroyed isolates considered, and in some cases tried, transferring their collections to registered institutions prior to collection destruction but desisted when confronted with transport regulations. Destruction of microbial collections represents a loss of strains and biological diversity available for biomedical research and future mechanistic, forensic, and epidemiologic investigations. Given the rapid evolution of microbial strains, the destruction of archival collections is a potentially irretrievable loss that was an unintended consequence of regulations to protect society against the nefarious use of biological agents. Furthermore, unregistered institutions continue to destroy newly acquired clinical isolates, thus preventing the establishment of new repository collections. We recommend that government agencies develop plans to ensure that microbial collections are preserved when considering future additions to microbial threat lists under which the possession of certain microbes is criminalized.


Subcellular localization of dinoflagellate polyketide synthases and fatty acid synthase activity.
Dinoflagellates are prolific producers of polyketide secondary metabolites. Dinoflagellate polyketide synthases (PKSs) have sequence similarity to Type I PKSs, megasynthases that encode all catalytic domains on a single polypeptide. However, in dinoflagellate PKSs identified to date, each catalytic domain resides on a separate transcript, suggesting multiprotein complexes similar to Type II PKSs. Here, we provide evidence through coimmunoprecipitation that single-domain ketosynthase and ketoreductase proteins interact, suggesting a predicted multiprotein complex. In Karenia brevis (C.C. Davis) Gert Hansen & Ø. Moestrup, previously observed chloroplast localization of PKSs suggested that brevetoxin biosynthesis may take place in the chloroplast. Here, we report that PKSs are present in both cytosol and chloroplast. Furthermore, brevetoxin is not present in isolated chloroplasts, raising the question of what chloroplast-localized PKS enzymes might be doing. Antibodies to K. brevis PKSs recognize cytosolic and chloroplast proteins in Ostreopsis cf. ovata Fukuyo, and Coolia monotis Meunier, which produce different suites of polyketide toxins, suggesting that these PKSs may share common pathways. Since PKSs are closely related to fatty acid synthases (FAS), we sought to determine if fatty acid biosynthesis colocalizes with either chloroplast or cytosolic PKSs. [(3) H]acetate labeling showed fatty acids are synthesized in the cytosol, with little incorporation in chloroplasts, consistent with a Type I FAS system. However, although 29 sequences in a K. brevis expressed sequence tag database have similarity (BLASTx e-value <10(-10) ) to PKSs, no transcripts for either Type I (cytosolic) or Type II (chloroplast) FAS are present. Further characterization of the FAS complexes may help to elucidate the functions of the PKS enzymes identified in dinoflagellates.


Molecular imprinting inside dendrimers.
Synthetic hosts capable of binding porphyrins have been produced by a mixed-covalent-noncovalent imprinting process wherein a single binding site is created within cross-linked dendrimers. Two synthetic hosts were prepared, using as templates 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin and 5,10,15,20-tetrakis(3,5-dihydroxyphenyl)porphyrin. These two templates were esterified with, respectively, fourth- and third-generation Fréchet-type dendrons containing homoallyl end-groups. The resulting tetra- and octadendron macromolecules underwent the ring-closing metathesis reaction using Grubbs' Type I catalyst, RuCl(2)(P(C(6)H(5))(3))(2)(CHCH(2)C(6)H(5)), to give extensive interdendron cross-linking. Hydrolytic removal of the porphyrin cores afforded imprinted hosts whose ability to bind porphyrins with various peripheral substituents was investigated by UV-visible spectrophotometric titrations and size exclusion chromatography. The results indicate a high yield of imprinted sites that show high selectivity for binding of porphyrins capable of making at least four hydrogen bonds, but only a moderate degree of shape selectivity.


Alterations of the 70 kDa heat shock protein (HSP70) and sequestosome-1 (p62) in women with breast cancer.
Peripheral blood mononuclear cells (PBMCs) respond to altered physiological conditions to alleviate the threat. Production of the 70 kDa heat shock protein (HSP70) is up-regulated to protect proteins from degradation. Sequestosome-1 (p62) binds to altered proteins and the p62-protein complex is degraded by autophagy. P62 is also a regulator of intracellular kinase activity and cell differentiation. We hypothesized that the PBMC response to a malignant breast mass involves elevated production of HSP70 and a decrease in intracellular p62. In this study 46 women had their breast mass excised. PBMCs were isolated and intracellular levels of HSP70 and p62 were quantitated by ELISA. Differences between women with a benign or malignant breast mass were determined. A breast malignancy was diagnosed in 38 women (82.6%) while 8 had a benign lesion. Mean intracellular HSP70 levels were 79.3 ng/ml in PBMCs from women with a malignant lesion as opposed to 44.2 ng/ml in controls (p = 0.04). The mean PBMC p62 level was 2.3 ng/ml in women with a benign breast lesion as opposed to 0.6 ng/ml in those with breast cancer (p < 0.001). Mean p62 levels were lowest in women with invasive carcinoma and a positive lymph node biopsy when compared to those with in-situ carcinoma or absence of lymphadenopathy, respectively. Intracellular HSP70 and p62 levels in PBMCs differ between women with a malignant or benign breast lesion. These measurements may be of value in the preoperative triage of women with a breast mass.


Effect of the dwell time deviation constraint on brachytherapy treatment planning for cervical cancer.
This study aimed to quantify the effect of the dwell time deviation constraint (DTDC) on brachytherapy treatment for cervical cancer. A retrospective study was carried out on 20 patients with radical cervical cancer. The DTDC values changed from 0.0 to 1.0 by a step size of 0.2. We adjusted the optimization objectives to ensure that all plans were optimized to a high-risk clinical target volume (HRCTV) D90 (the dose to 90% of the HRCTV) = 6 Gy, while keeping the dose to the organs at risk as low as possible. The dose-volume histogram parameters and the dwell time data were compared between plans with different DTDC values. The HRCTV volume covered by 150% of the prescription dose gradually increased with increasing DTDC values. As the DTDC value increased from 0.0 to 1.0, the effective dwell point proportion increased from 61.78% to 90.30%. The mean dwell time initially decreased with an increase in the DTDC value, reached the minimum value at DTDC = 0.8, then slightly increased at DTDC = 1.0. When using inverse planning simulated annealing optimization for radical cervical cancer cases, the recommended DTDC value is approximately 0.6 if the organ dose needs to be limited.


In vitro evaluation of anticancer drugs against ovarian cancer at concentrations achievable by intraperitoneal administration.
High-dose intraperitoneal chemotherapy is a current developmental approach in the treatment of advanced ovarian cancer. Considerable pharmacologic data have been obtained on the intraperitoneal X time product for a number of agents administered by this route. We used the human tumor cloning assay (HTCA) to compare the activities of both standard and experimental agents used for intraperitoneal treatment. In vitro dose-survival curves were constructed for each drug over a two-log range of concentrations using fresh ovarian cancers from more than 50 patients. The mean concentration X time product (CXT) achievable in the intraperitoneal space after high-dose intraperitoneal drug administration was divided by the corresponding ID50 value (concentration of drug in vitro associated with 50% survival of tumor colonies) for each agent to calculate in vivo CXT: in vitro ID50 ratios. Using this approach, the standard agents, melphalan, cisplatin, and 5-FU were predicted to have similar efficacies by intraperitoneal administration, but doxorubicin and mitomycin were significantly inferior. Of the drugs tested, the new agent mitoxantrone was associated with the most favorable CXT to ID50 ratio and is, therefore, predicted to be particularly promising for intraperitoneal administration.


[Transposition of the phage D3112 genome in Escherichia coli cells].
It has been demonstrated that the genome of phage D3112 of Preudomonas aeruginosa can be transposed into Escherichia coli chromosome as a component of the hybrid plasmid RP4 TcrKms::D3112. Also, transposition of D3112 from E. coli (D3112) chromosome into RP4 plasmid occurs. The phage stimulates the chromosome mobilizing activity of RP4 plasmid, similar to other transposons. E. coli (RP4::D3112) cells were previously shown to form no colonies at 30 degrees C. Auxotrophic mutants and mutants incapable of utilizing different carbohydrates were found among E. coli clones survived after a long incubation at 30 degrees C (at frequencies approximately 10(-3) - 10(-4). These mutants inherited stably the capability to produce D3112 phage. E. coli auxotrophic mutants have arisen indeed as a consequence of phage integration into the E. coli chromosome, since prototrophic transductants derived from these mutants after their treatment with generalized transducing P1 phage have lost the ability to produce D3112 phage. Clones with mutations in Km or Tc genes of RP4 plasmid, occurring at high frequencies (about 3%) were found after introduction of RP4 into E. coli (D3112). These mutant RP4 plasmids carry insertions of D3112 genomes. Clones of E. coli which lost mutant plasmids still produce D3112 and retain their initial auxotrophic mutations.


Effect of an Educational Presentation about Extremely Preterm Infants on Knowledge and Attitudes of Health Care Providers.
Objective To determine healthcare providers' knowledge (HCP) about survival rates of extremely preterm infants (EPI) and attitudes toward resuscitation before and after an educational presentation and, to examine the relationship between knowledge and attitudes toward resuscitation. Study Design Participants completed a survey before and after attending a presentation detailing evidence-based estimates of survival rates and surrounding ethical issues. Respondents included neonatologists, obstetricians, pediatricians, maternal-fetal medicine specialists, trainees in pediatrics, obstetrics, neonatal-perinatal medicine and neonatal and obstetrical nurses. Results In total, 166 participants attended an educational presentation and 130 participants completed both pre- and postsurveys (response rate 78%). Prepresentation, for all gestations, ≤ 50% of respondents correctly identified survival/intact survival rates. Postpresentation, correct responses regarding survival/intact survival rates ranged from 49 to 86% (p < 0.001) and attitudes shifted toward being more likely to resuscitate at all gestations regardless of parental wishes. There was a weak-to-modest relationship (Spearman's coefficient 0.24-0.40, p < 0.001-0.004) between knowledge responses and attitudes. Conclusion Attendance at an educational presentation did improve HCP knowledge about survival and long term outcomes for EPI, but HCP still underestimated survival and were not always willing to resuscitate in accordance with parental wishes. These findings may represent barriers to some experts' recommendation to use shared decision-making with parents when considering the resuscitation options for their EPI.


Pharmacokinetic interactions between herbal medicines and prescribed drugs: focus on drug metabolic enzymes and transporters.
Herbal medicines have been widely used for thousands of years, and now are gaining continued popularity worldwide as a complementary or alternative treatment for a variety of diseases, rehabilitation and health care. Since herbal medicines contain more than one pharmacologically active ingredient and are commonly used with many prescribed drugs, there are potential herb-drug interactions. A variety of reported herb-drug interactions are of pharmacokinetic origin, arising from the effects of herbal medicines on metabolic enzymes and/or transporters. Such an alteration in metabolism or transport can result in changes in absorption, distribution, metabolism, and excretion (e.g., induction or inhibition of metabolic enzymes, and modulation of uptake and efflux transporters), leading to changed pharmacokinetics of the concomitantly prescribed drugs. Pharmacokinetic herb-drug interactions have more clinical significance as pharmacokinetic parameters such as the area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax) or the elimination half-life (t1/2) of the concomitant drug alter. This review summarizes the mechanism underlying herb-drug interactions and the approaches to identify the interactions, and discusses pharmacokinetic interactions of eight widely used herbal medicines (Ginkgo biloba, ginseng, garlic, black cohosh, Echinacea, milk thistle, kava, and St. John's wort) with conventional drugs, using various in vitro, animal in vivo, and clinical studies. The increasing understanding of pharmacokinetic herb-drug interactions will make health care professionals and patients pay more attention to the potential interactions.


Enhanced thrombin generation and platelet binding on herpes simplex virus-infected endothelium.
Atherosclerotic lesions have been reported to contain herpes simplex virus 1 (HSV-1) genomic material. This, and other previous evidence, suggests that latent viral infection may be an atherogenic trigger. Moreover, active HSV-1 lesions manifest marked fibrin deposition in microvessels. In this report we show that very early infection of human endothelial cells with HSV-1 appears to alter surface conformation as detected by merocyanine 540 staining. Concomitantly, the efficiency of prothrombinase complex assembly increases, resulting in a 2- to 3-fold accelerated rate of thrombin generation on the cell surface. Increased thrombin generation is probably doubly procoagulant, since we also demonstrate that thrombin-induced platelet accumulation on HSV-infected endothelium (50.7 +/- 9.3%) is increased compared to uninfected endothelium (9.5 +/- 2.1%; P less than 0.002). Associated with HSV infection, prostacyclin secretion in response to thrombin is diminished by a factor of 20, probably explaining the enhanced platelet attachment. We conclude that HSV infection shifts endothelial cell properties from anticoagulant to procoagulant, both by promoting prothrombinase complex formation and function and by increasing platelet binding, well before cell disruption takes place. Virus-induced changes in the endothelial plasma membrane and diminished prostacyclin secretion are suggested as the pathways for this pathophysiologic mechanism, which may be germane to atherosclerotic thrombosis as well as HSV-mediated tissue necrosis.


Semi-parametric differential expression analysis via partial mixture estimation.
We develop an approach for microarray differential expression analysis, i.e. identifying genes whose expression levels differ between two or more groups. Current approaches to inference rely either on full parametric assumptions or on permutation-based techniques for sampling under the null distribution. In some situations, however, a full parametric model cannot be justified, or the sample size per group is too small for permutation methods to be valid. We propose a semi-parametric framework based on partial mixture estimation which only requires a parametric assumption for the null (equally expressed) distribution and can handle small sample sizes where permutation methods break down. We develop two novel improvements of Scott's minimum integrated square error criterion for partial mixture estimation [Scott, 2004a,b]. As a side benefit, we obtain interpretable and closed-form estimates for the proportion of EE genes. Pseudo-Bayesian and frequentist procedures for controlling the false discovery rate are given. Results from simulations and real datasets indicate that our approach can provide substantial advantages for small sample sizes over the SAM method of Tusher et al. [2001], the empirical Bayes procedure of Efron and Tibshirani [2002], the mixture of normals of Pan et al. [2003] and a t-test with p-value adjustment [Dudoit et al., 2003] to control the FDR [Benjamini and Hochberg, 1995].


Severe kidney dysfunction in sialidosis mice reveals an essential role for neuraminidase 1 in reabsorption.
Sialidosis is an ultra-rare multisystemic lysosomal disease caused by mutations in the neuraminidase 1 (NEU1) gene. The severe type II form of the disease manifests with a prenatal/infantile or juvenile onset, bone abnormalities, severe neuropathology, and visceromegaly. A subset of these patients present with nephrosialidosis, characterized by abrupt onset of fulminant glomerular nephropathy. We studied the pathophysiological mechanism of the disease in 2 NEU1-deficient mouse models, a constitutive Neu1-knockout, Neu1ΔEx3, and a conditional phagocyte-specific knockout, Neu1Cx3cr1ΔEx3. Mice of both strains exhibited terminal urinary retention and severe kidney damage with elevated urinary albumin levels, loss of nephrons, renal fibrosis, presence of storage vacuoles, and dysmorphic mitochondria in the intraglomerular and tubular cells. Glycoprotein sialylation in glomeruli, proximal distal tubules, and distal tubules was drastically increased, including that of an endocytic reabsorption receptor megalin. The pool of megalin bearing O-linked glycans with terminal galactose residues, essential for protein targeting and activity, was reduced to below detection levels. Megalin levels were severely reduced, and the protein was directed to lysosomes instead of the apical membrane. Together, our results demonstrated that desialylation by NEU1 plays a crucial role in processing and cellular trafficking of megalin and that NEU1 deficiency in sialidosis impairs megalin-mediated protein reabsorption.


Effects of transit signal priority on traffic safety: Interrupted time series analysis of Portland, Oregon, implementations.
Transit signal priority (TSP) has been implemented to transit systems in many cities of the United States. In evaluating TSP systems, more attention has been given to its operational effects than to its safety effects. Existing studies assessing TSP's safety effects reported mixed results, indicating that the safety effects of TSP vary in different contexts. In this study, TSP implementations in Portland, Oregon, were assessed using interrupted time series analysis (ITSA) on month-to-month changes in number of crashes from January 1995 to December 2010. Single-group and controlled ITSA were conducted for all crashes, property-damage-only crashes, fatal and injury crashes, pedestrian-involved crashes, and bike-involved crashes. Evaluation of the post-intervention period (2003-2010) showed a reduction in all crashes on street sections with TSP (-4.5%), comparing with the counterfactual estimations based on the control group data. The reduction in property-damage-only crashes (-10.0%) contributed the most to the overall reduction. Fatal and injury crashes leveled out after TSP implementation but did not change significantly comparing with the control group. Pedestrian and bike-involved crashes were found to increase in the post-intervention period with TSP, comparing with the control group. Potential reasons to these TSP effects on traffic safety were discussed.


Reference centiles for intrinsic capacity throughout adulthood and their association with clinical outcomes: a cross-sectional analysis from the INSPIRE-T cohort.
Intrinsic capacity (IC), a function-centered construct, is defined as the composite of all physical and mental capacities of an individual. IC and surrounding environmental factors determine an individual's functional ability to do what they want or feel valued. Current literature lacks evidence on how IC varies throughout adulthood. In this study, we demonstrated a method to establish age-specific and sex-specific reference centiles for IC using the Human Translational Research Cohort of the INSPIRE Platform (975 adults, aged 20-102 years, living in the southwest France, Toulouse area). IC was operationalized as the mean score of the five key domains (cognition, locomotion, psychology, sensory and vitality) and the factor score from a bifactor model, respectively. Both IC operationalizations showed higher IC levels in young and middle age and markedly lower levels after age 65 years, with greater inter-individual variation in old age than in youth. Individuals with IC ≤10th percentile tended to have high comorbidity, prefrailty/frailty, difficulties in basic and instrumental activities of daily living and falls than individuals with IC >90th percentile. These findings suggest that IC reference centiles can help monitor the functional capacity of individuals during aging, similar to tracking children's development with growth charts.


C-Kit/c-Kit ligand interaction of bone marrow endothelial progenitor cells is influenced in a cigarette smoke extract-induced emphysema model.
Smoking causes lung endothelial cell apoptosis and emphysema. Derived from bone marrow, circulating endothelial progenitor cells (EPCs) maintain vascular integrity by replacing and repairing damaged endothelial cells. Smoking influences the number of circulating EPCs. Recruitment of EPCs from bone marrow to peripheral blood depends on the interaction of c-Kit/soluble c-Kit ligand (sKitL). We hypothesized that smoking might influence c-Kit(+) EPCs/sKitL interaction in bone marrow in the development of smoking-related emphysema. In this study, we used a cigarette smoke extract (CSE)-induced emphysema model. Mice were injected intraperitoneally with PBS/CSE and sacrificed at day 28. Lung function and pathology of lung tissue were measured to characterize the model. Expressions of c-Kit in the lung tissue were assayed. Bone marrow cells were isolated by red blood cell lysis. EPCs/c-Kit(+) EPCs in nonred blood cells were analyzed by flow cytometry. Expressions of KitL and MMP-9, and activity MMP-9 in bone marrow were measured. Our data demonstrated that gene and protein expressions of c-Kit were decreased in the lung tissue in this model. Compared with the control group, the number of bone marrow nonred blood cells was unchanged following CSE treatment, while the depletion of bone marrow EPCs/c-Kit(+) EPCs was significant. The level of sKitL was reduced in the bone marrow in the model. The reduction of sKitL was associated with deregulated KitL expression and decreased MMP-9 activity. The interaction between c-Kit and sKitL in bone marrow EPCs, a critical step in endothelial repair, is negatively affected in a CSE-induced emphysema model.


Prescribing antidepressants and benzodiazepines in the Netherlands: is chronic physical illness involved?
In this study we assessed differences in new and repeat prescriptions of psycho-tropics between patients receiving prescriptions for drugs to treat a common chronic disease and people without such prescriptions. The study used the databases of two Dutch health insurance companies (3 million people). We selected all Dutch men and women aged 45 and older who were registered for six consecutive years (1999-2004). Our analyses both found a consistent relation between psycho-tropics on the one hand and physical illness on the other. People with multi-morbidity were prescribed these drugs most often, especially men and those younger than 65. Epidemiological studies showed a prevalence of depression among people with multi-morbidity to be twice as high as among people without such conditions. According to recent guidelines non-drug treatment may be the first therapy option for patients with non severe depression. If prescribed for a long time, benzodiazepine prescriptions are especially known to be addictive. Our data raise the question to what extent patients with a chronic physical disease suffering from co-occurring mental problems are prescribed psycho-tropics in accord with the guidelines that also advise mental support in case of non severe mental problems. Further research can answer this important question.


Salivary cortisol levels in Parkinson's disease and its correlation to risk behaviour.
To investigate salivary cortisol samples in patients with Parkinson's disease (PD) with and without impulsive compulsive behaviours (ICB) during a risk task. Salivary cortisol levels were measured in 13 PD patients without ICB (PD-ICB) and in 15 PD patients with ICB (PD+ICB) before, after medication and throughout the day, and were compared with results with 14 healthy controls. All participants also performed a gambling task to assess risk taking behaviour. Significantly higher diurnal cortisol levels were found in the PD-ICB group compared with healthy controls but no differences were seen between the PD+ICB and the control group. Increased cortisol levels were significantly correlated with increased risk taking in PD+ICB patients but no interaction was found in the PD-ICB group. The findings are in keeping with previous studies which have linked low cortisol levels with antisocial behaviour. The higher cortisol levels during the risk task in the PD+ICB group are consistent with reports in pathological gamblers during gambling and addicts during drug abuse. The results support the hypothesis that cortisol plays an important role in risk taking in ICBs.


Mossbauer evidence for an exchange-coupled {[Fe4S4]1+ Nip1+} A-cluster in isolated alpha subunits of acetyl-coenzyme A synthase/carbon monoxide dehydrogenase.
The active site A-cluster in the alpha subunit of the title enzyme consists of an Fe4S4 cluster coordinated to a [Nip Nid] subcomponent. The cluster must be activated for catalysis using low-potential reductants such as Ti(III) citrate. Relative to the inactive {[Fe4S4]2+ Nip2+ Nid2+} state, the activated state appears to be 2-electrons more reduced, but the location of these electrons within the A-cluster is uncertain, with {[Fe4S4]2+ Nip0 Nid2+} and {[Fe4S4]1+ Nip1+ Nid2+} configurations proposed. Recombinant apo-alpha subunits oligomerize after activation with NiCl2. The dimer fraction, upon reduction with excess Ti(III)citrate, exhibited Mössbauer spectra consisting of two quadrupole doublets representing 51% and 21% of the Fe, with parameters indicating [Fe4S4]1+ states. Spectra recorded in strong magnetic fields were typical of diamagnetic systems, indicating an exchange-coupled S = 0 {[Fe4S4]1+ Nip1+} state. Additional treatment with CO altered the doublet Mössbauer parameters, suggesting an interaction with CO, but maintaining the cluster in the {[Fe4S4]1+ Nip1+} state. Reduction with substoichiometric equivalents of Ti(III) citrate afforded an EPR signal typical of Ni1+ ions, with g parallel = 2.10 and g perpendicular = 2.02. Addition of more Ti caused the signal intensity to decline, suggesting that it arises from the semireduced {[Fe4S4]2+ Nip1+} state.


Vascular nitric oxide-generating activities for organic nitrites and organic nitrates are distinct.
Like organic nitrates, the organic nitrites are assumed to undergo vascular metabolic activation to nitric oxide (NO) to produce vasodilating activity, but this assumption has never been examined. In this study, isobutyl nitrite and amyl nitrite were incubated with subcellular fractions of bovine coronary arterial smooth muscle at 37 degrees C, and NO generation was assessed by redox chemiluminescence assay of headspace NO. Bovine vascular subfractions exhibited substantial and significant catalytic activity for NO generation towards both organic nitrite substrates, and NO-generating activity could be inhibited by heating and irradiation. These observations suggest that organic nitrites are converted enzymatically to NO in vascular smooth muscle. Analysis of marker enzyme activities suggested that the primary NO-generating activity was associated with the cytosol, whereas a distinct, but relatively minor NO-generating activity was also identified in the microsomal fraction. The cytosolic and microsomal NO-generating activities exhibited different temperature dependencies for heat-induced inhibition of activity. The molecular weights of the NO-generating enzymes, determined by radiation inactivation target-size analysis, were 263 kDa (95% confidence interval: 236-298 kDa) for the cytosolic enzyme and 79 kDa (95% confidence interval: 54-148 kDa) for the microsomal enzyme. Previous studies in this laboratory have shown that the representative organic nitrate, nitroglycerin (NTG), is metabolized to NO by an enzyme associated with the plasma membrane of bovine vascular smooth muscle cells. Thus, the enzymes responsible for vascular bioconversion of organic nitrates and organic nitrites to NO are apparently different.(ABSTRACT TRUNCATED AT 250 WORDS)


Neferine prevents ultraviolet radiation-induced skin photoaging.
The aim of the present study was to evaluate the anti-photoaging effect of neferine upon exposure of mice to ultraviolet (UV) radiation. An in vivo photoaging model was established by repeatedly exposing mouse dorsal skin to UV-A and UV-B radiation for 12 weeks. Through skin photographs, hematoxylin and eosin staining, Masson's trichrome staining, and scanning and transmission electron microscopy, skin wrinkles, epidermal thickness and dermal collagen were analyzed in the UV-irradiated mouse skin. Furthermore, the levels of endogenous antioxidants, namely superoxide dismutase (SOD) and glutathione peroxidase (GPx), were measured to determine the extent of UV-induced oxidative stress that was associated with photoaging. The results demonstrated that the topical application of neferine following UV irradiation reduced oxidative stress by increasing SOD and GPx activities, and attenuated the photoaging process. Histological and ultrastructural examination revealed that neferine delayed skin wrinkle formation by inhibiting epidermal hypertrophy and collagen loss and degradation. In conclusion, the results of the present study indicated that neferine effectively prevents UV-induced skin photoaging and photodamage.


Program characteristics and organizational factors affecting the implementation of a school-based indicated prevention program.
Reconnecting Youth (RY) is a school-based drug prevention program designed to address academic, substance use and mood management goals among youth at risk of dropping out of high school. This paper presents the organizational factors and RY program characteristics that either promoted or hindered the implementation of the program during a randomized controlled effectiveness trial in 10 schools in two school districts in the United States. Data were collected using surveys and interviews from teachers and school and district staff who participated in the implementation of the RY program in these schools. Results suggest that certain RY program characteristics made it difficult to implement. Small class size, resource-intensive procedures for student selection and recruitment and special training, qualities and skills needed to be an effective RY teacher meant that schools had to significantly change their usual practices to implement the program. Organizational barriers included a lack of financial resources and leadership support for program implementation, and low priority for non-academic courses for high-risk students. Transient student populations, staff turnover and district-wide scheduling and curriculum changes all resulted in high levels of organizational turbulence at most schools, further hindering program implementation.


Smoldering multiple myeloma: the role of different scoring systems in identifying high-risk patients in real-life practice.
We explore the predictive role of 2014-updated International Myeloma Working Group (IMWG) diagnostic criteria and of some of currently available risk models for progression to symptomatic myeloma when applied in our unselected population of 75 smoldering multiple myeloma (SMM) patients observed between 2000 and 2015. Risk scores including routinely used clinical parameters such as bone marrow plasmacell infiltration rate, immunoparesis, serum monoclonal component (sMC) value, and altered free light chain ratio (FLCr), were clinically useful to identify SMM patients at higher risk of progression. Time to myeloma progression in our ultra-high risk SMM according to IMWG diagnostic update criteria was very short (12.4 months). Our analysis identified as independent reliable predictors of progression altered FLCr as well as increasing plasma cell infiltration which are part of most commonly applied risk models. Waiting for new scoring systems, bone marrow evaluation and complete laboratory screening are still milestones for SMM management.


Astaxanthin Alleviates Ochratoxin A-Induced Cecum Injury and Inflammation in Mice by Regulating the Diversity of Cecal Microbiota and TLR4/MyD88/NF-κB Signaling Pathway.
Ochratoxin A (OTA) is a common environmental pollutant found in a variety of foods and grains, and excessive OTA consumption causes serious global health effects on animals and humans. Astaxanthin (AST) is a natural carotenoid that has anti-inflammatory, antiapoptotic, immunomodulatory, antitumor, antidiabetes, and other biological activities. The present study is aimed at investigating the effects of AST on OTA-induced cecum injury and its mechanism of action. Eighty C57 mice were randomly divided into four groups, including the control group, OTA group (5 mg/kg body weight), AST group (100 mg/kg body weight), and AST intervention group (100 mg/kg body weight AST+5 mg/kg body weight OTA). It was found that AST decreased the endotoxin content, effectively prevented the shortening of mouse cecum villi, and increased the expression levels of tight junction (TJ) proteins, consisting of occludin, claudin-1, and zonula occludens-1 (ZO-1). AST increased the number of goblet cells, the contents of mucin-2 (MUC2), and defensins (Defa5 and β-pD2) significantly, while the expression of mucin-1 (MUC1) decreased significantly. The 16S rRNA sequencing showed that AST affected the richness and diversity of cecum flora, decreased the proportion of lactobacillus, and also decreased the contents of short-chain fatty acids (SCFAs) (acetate and butyrate). In addition, AST significantly decreased the expression of TLR4, MyD88, and p-p65, while increasing the expression of p65. Meanwhile, the expression of inflammatory factors including TNF-α and INF-γ decreased, while the expression of IL-10 increased. In conclusion, AST reduced OTA-induced cecum injury by regulating the cecum barrier function and TLR4/MyD88/NF-κB signaling pathway.


Maltotriose-based probes for fluorescence and photoacoustic imaging of bacterial infections.
Currently, there are no non-invasive tools to accurately diagnose wound and surgical site infections before they become systemic or cause significant anatomical damage. Fluorescence and photoacoustic imaging are cost-effective imaging modalities that can be used to noninvasively diagnose bacterial infections when paired with a molecularly targeted infection imaging agent. Here, we develop a fluorescent derivative of maltotriose (Cy7-1-maltotriose), which is shown to be taken up in a variety of gram-positive and gram-negative bacterial strains in vitro. In vivo fluorescence and photoacoustic imaging studies highlight the ability of this probe to detect infection, assess infection burden, and visualize the effectiveness of antibiotic treatment in E. coli-induced myositis and a clinically relevant S. aureus wound infection murine model. In addition, we show that maltotriose is an ideal scaffold for infection imaging agents encompassing better pharmacokinetic properties and in vivo stability than other maltodextrins (e.g. maltohexose).


Drug induced pancreatitis: A systematic review of case reports to determine potential drug associations.
A current assessment of case reports of possible drug-induced pancreatitis is needed. We systematically reviewed the case report literature to identify drugs with potential associations with acute pancreatitis and the burden of evidence supporting these associations. A protocol was developed a priori (PROSPERO CRD42017060473). We searched MEDLINE, Embase, the Cochrane Library, and additional sources to identify cases of drug-induced pancreatitis that met accepted diagnostic criteria of acute pancreatitis. Cases caused by multiple drugs or combination therapy were excluded. Established systematic review methods were used for screening and data extraction. A classification system for associated drugs was developed a priori based upon the number of cases, re-challenge, exclusion of non-drug causes of acute pancreatitis, and consistency of latency. Seven-hundred and thirteen cases of potential drug-induced pancreatitis were identified, implicating 213 unique drugs. The evidence base was poor: exclusion of non-drug causes of acute pancreatitis was incomplete or poorly reported in all cases, 47% had at least one underlying condition predisposing to acute pancreatitis, and causality assessment was not conducted in 81%. Forty-five drugs (21%) were classified as having the highest level of evidence regarding their association with acute pancreatitis; causality was deemed to be probable or definite for 19 of these drugs (42%). Fifty-seven drugs (27%) had the lowest level of evidence regarding an association with acute pancreatitis, being implicated in single case reports, without exclusion of other causes of acute pancreatitis. Much of the case report evidence upon which drug-induced pancreatitis associations are based is tenuous. A greater emphasis on exclusion of all non-drug causes of acute pancreatitis and on quality reporting would improve the evidence base. It should be recognized that reviews of case reports, are valuable scoping tools but have limited strength to establish drug-induced pancreatitis associations. CRD42017060473.


Loss of TP53 in sarcomas with 17p12 to approximately p11 gain. A fine-resolution oligonucleotide array comparative genomic hybridization study.
The amplification or gain of the p-arm of chromosome 17 is common in sarcomas, suggesting its role in carcinogenesis. Here, we report the architectural structure and targets of 17p aberrations commonly shared by osteosarcoma (OS), leiomyosarcoma (LMS) and malignant fibrous histiocytoma (MFH) of soft tissue. Two low-grade and two high-grade soft tissue LMS, three OS, and two MFH samples were studied using fine-resolution oligonucleotide-based microarray comparative genomic hybridization. Eight of the nine samples showed a loss of 17pter-->p13, the locus of tumor suppressor TP53 preceding the amplified area 17p12-->p11.2. The size and detailed architecture of the amplified region of 17p differed between the studied sarcoma entities. OS and high-grade LMS showed similar complex patterns of discontinuous amplifications with regions of gain in between. MFH and low-grade LMS showed continuous regions of gains and amplifications. Precise boundaries of the lost or gained regions were determined, and in addition to the previously suggested targets of the region, ELAC and FLCN were amplified in all the sarcoma entities.


Towards graphene bromide: bromination of graphite oxide.
Halogenated graphene derivatives are interesting for their outstanding physical and chemical properties. In this paper, we present various methods for the synthesis of brominated graphene derivatives by the bromination of graphite oxides. Graphite oxides, prepared according to either the Hummers or Hofmann method, were brominated using bromine or hydrobromic acid under reflux or in an autoclave at elevated temperatures and pressures. The influence of both graphite oxide precursors on the resulting brominated graphenes was investigated by characterization of the graphenes, which was carried out using various techniques, including SEM, SEM-EDS, high-resolution XPS, FTIR, STA and Raman spectroscopy. In addition, the resistivity of the brominated graphenes was measured and the electrochemical properties were investigated by cyclic voltammetry. Although the brominated graphenes were structurally similar, they had remarkably different bromine concentrations. The most highly brominated graphene (bromine concentration above 26 wt%) exhibited a C/O ratio above 44 and partial hydrogenation. Brominated graphenes with such properties could be used for reversible bromine storage or as a starting material for further chemical modifications.


Care Delivery in Community Health Centers Before, During, and After the COVID-19 Pandemic (2019-2022).
Health centers provide primary and behavioral health care to the nation's safety net population. Many health centers served on the frontlines of the COVID-19 pandemic, which brought major changes to health center care delivery. To elucidate primary care and behavioral health service delivery patterns in health centers before and during the COVID-19 public health emergency (PHE). We compared annual and monthly patients from 2019 to 2022 for new and established patients by visit type (primary care, behavioral health) and encounter visits by modality (in-person, telehealth) across 218 health centers in 13 states. There were 1581,744 unique patients in the sample, most from health disparate populations. Review of primary care data over 4 years show that health centers served fewer pediatric patients over time, while retaining the capacity to provide to patients 65+. Monthly data on encounters highlights that the initial shift in March/April 2020 to telehealth was not sustained and that in-person visits rose steadily after November/December 2020 to return as the predominant care delivery mode. With regards to behavioral health, health centers continued to provide care to established patients throughout the PHE, while serving fewer new patients over time. In contrast to primary care, after initial uptake of telehealth in March/April 2020, telehealth encounters remained the predominant care delivery mode through 2022. Four years of data demonstrate how COVID-19 impacted delivery of primary care and behavioral health care for patients, highlighting gaps in pediatric care delivery and trends in telehealth over time.


[The path from science to the practicing surgeon. Engagement of documentation of the Swiss Academy of Medical Sciences for providing evidence-based medicine].
The flood of information that comes along with the rise of electronic media has changed the expectations towards the Documentation Service of the Swiss Academy of Medical Sciences (DOKDI): Evidence Based Medicine (EMB) in particular not only demands procurement of information, but also a selection regarding quality and relevance: The question arising out of the clinical situation requires an answer correct in its content and helpful in the specific situation. Getting an idea of what evidence exists about the correctness of a certain procedure through critical lecture is an ideal often obstructed by lack of time and methodical problems in the practice; therefore, one often has to rely on evidence acquired through others and consult e.g. the Cochrane Library. DOKDI commits itself to the development of systematic reviews as well as to the dissemination of evidence found by using its experience in the documentation with electronic media and by providing the corresponding infrastructure. In addition to these activities, the Academy has spoken a grant for the training of EBM-Tutors. During a weekly workshop held in Oxford, clinicians will be trained as EBM-Tutors. This will allow an increasing number of EBM-Workshops held in Switzerland in the future.


High-level association of bovine digital dermatitis Treponema spp. with contagious ovine digital dermatitis lesions and presence of Fusobacterium necrophorum and Dichelobacter nodosus.
Contagious ovine digital dermatitis (CODD) is an important foot disease in sheep, with significant animal welfare and economic implications. It is thought that CODD emerged from bovine digital dermatitis (BDD) via treponemal bacteria. With wildlife species such as elk now suffering a CODD-like disease, it is imperative to clarify these disease etiologies. A large investigation into treponemal association with CODD is warranted. CODD lesions (n = 58) and healthy sheep foot tissues (n = 56) were analyzed by PCR for the three BDD-associated Treponema phylogroups and two other lameness-associated bacteria, Dichelobacter nodosus and Fusobacterium necrophorum. Spirochete culture was also attempted on CODD lesions. "Treponema medium/Treponema vincentii-like," "Treponema phagedenis-like," and Treponema pedis spirochetes were identified in 39/58 (67%), 49/58 (85%), and 41/58 (71%) of CODD lesions, respectively. One or more BDD-associated Treponema phylogroups were detected in 100% of CODD lesions. Healthy foot tissues did not amplify BDD-associated Treponema phylogroup DNA. D. nodosus and F. necrophorum were present in 34/58 (59%) and 41/58 (71%) of CODD lesions and 22/56 (39%) and 5/56 (9%) of healthy foot tissues, respectively. Thirty-two spirochetes were isolated from CODD lesions, with representatives clustering with, and indistinguishable from, each of the three BDD-associated Treponema phylogroups based on 16S rRNA gene comparisons. This study for the first time demonstrates a high-level association for BDD treponeme phylogroups in CODD and their absence from healthy tissues, supporting the hypothesis that BDD treponemes play a primary causative role in CODD and confirming that the specific PCR assays are an effective differential diagnostic tool for CODD.


Climate anomalies, land degradation and rural out-migration in Uganda.
Globally, rural livelihoods are increasingly challenged by the dual threats of land degradation and climate change. These issues are of particular concern in sub-Saharan Africa, where land degradation is believed to be severe and where climate change will bring higher temperatures and shifts in rainfall. To date, however, we know little about the relative effects of these various potential environmental stressors on migration. To examine these processes, we link longitudinal data from 850 Ugandan households with environmental data on soils, forests, and climate, and then analyze these data using approaches that account for potential spatial and temporal confounders. Our findings reveal that climate anomalies, rather than land degradation, are the primary contributor to environmental migration in Uganda, with heat stress of particular importance. Short hot spells increase temporary migration, an element of a diversified household livelihood strategy, while long-term heat stress induces permanent migration through an agricultural livelihoods pathway.


Effect of acute posttrauma propranolol on PTSD outcome and physiological responses during script-driven imagery.
Animal and human research suggests that the development of posttraumatic stress disorder (PTSD) may involve the overconsolidation of memories of a traumatic experience. Previous studies have attempted to use pharmaceutical agents, especially the β-adrenergic blocker propranolol, to reduce this overconsolidation. In this randomized, placebo-controlled study of the efficacy of propranolol in reducing the development of PTSD, we optimized dosages and conducted both psychophysiological and clinical assessments 1 and 3 months after the traumatic event. Forty-one emergency department patients who had experienced a qualifying acute psychological trauma were randomized to receive up to 240 mg/day of propranolol or placebo for 19 days. At 4 and 12 weeks post-trauma, PTSD symptoms were assessed. One week later, participants engaged in script-driven imagery of their traumatic event while psychophysiological responses were measured. Physiological reactivity during script-driven traumatic imagery, severity of PTSD symptoms, and the rate of the PTSD diagnostic outcome were not significantly different between the two groups. However, post hoc subgroup analyses showed that in participants with high drug adherence, at the 5-week posttrauma assessment, physiological reactivity was significantly lower during script-driven imagery in the propranolol than in the placebo subjects. The physiological results provide some limited support for a model of PTSD in which a traumatic conditioned response is reduced by posttrauma propranolol. However, the clinical results from this study do not support the preventive use of propranolol in the acute aftermath of a traumatic event.


Animal Models of Nonalcoholic Fatty Liver Disease-A Starter's Guide.
Nonalcoholic fatty liver disease (NAFLD) constitutes a major health concern with the increasing incidence of obesity and diabetes in many Western countries, reaching a prevalence of up to 30% in the general population. Animal models have played a vital role in elucidating the pathophysiological mechanisms of NAFLD and continue to do so. A myriad of different models exists, each with its advantages and disadvantages. This review presents a brief overview of these models with a particular focus on the basic mechanisms and physical, biochemical and histological phenotype. Both nutritional and chemically induced, as well as genetic models are examined, including models combining different approaches.


Molecular mechanisms of polyamine analogs in cancer cells.
The natural polyamines are aliphatic cations with multiple functions and are essential for cell growth. Soon after the critical requirement of polyamines for cell proliferation was recognized, the metabolism of polyamines was pursued as a target for antineoplastic therapy. Initially, much attention was focused on the development of inhibitors of polyamine biosynthesis as a means to inhibit tumor growth. The best-characterized inhibitor is alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. While compensatory mechanisms in polyamine metabolism reduce the effectiveness of DFMO as a single chemotherapeutic agent, it is currently undergoing extensive testing and clinical trials for chemoprevention and other diseases. There has been increasing interest over the last two decades in the cytotoxic response to agents that target the regulation of polyamine metabolism rather than directly inhibiting the metabolic enzymes in tumor cells. This interest resulted in the development of a number of polyamine analogs that exhibit effective cytotoxicity against tumor growth in preclinical models. The analogs enter cells through a selective polyamine transport system and can be either polyamine antimetabolites that deplete the intracellular polyamines or polyamine mimetics that displace the natural polyamines from binding sites, but do not substitute in terms of growth-promoting function. Synthesis of the first generation of symmetrically substituted bis(alkyl)polyamine analogs in the mid-1980s was based on the theory that polyamines may utilize feedback mechanisms to auto-regulate their synthesis. In the 1990s, unsymmetrically substituted bis(alkyl) polyamine analogs were developed. These compounds display structure-dependent and cell type-specific cellular effects and regulation on polyamine metabolism. More recently, a novel class of analogs has been synthesized, which include conformationally restricted, cyclic and long-chain oligoamine analogs. The development and use of these analogs have provided valuable information for understanding the molecular mechanisms of targeting the polyamine pathway as a means of cancer therapy.


A critical approach to clinical practice guidelines.
The rate of publication of clinical practice guidelines for the management of common medical illnesses continues to accelerate. The appropriate dissemination and uptake of high quality practice guidelines can synthesize evidence, improve patient outcomes and enhance the efficiency of health care delivery. However, the methodological rigour and relevance of the growing number of publications labelled 'clinical practice guidelines' vary widely. Health care payers, providers and advocates must learn to appraise and interpret guideline recommendations critically. A simple and practical nine-question approach to evaluating the quality, relevance and effectiveness of clinical practice guidelines is presented.


[Experience of proton stereotactic therapy for cerebral arteriovenous malformations in children].
The authors present the results of proton stereotactic therapy (using continuous double-axis pendulum irradiation) in 27 children with cerebral arteriovenous malformations (AVM). At the moment of therapy, the children's age was 6 to 15 years. The volume of AVM was 0.2 to 31.2 cm3. The absorbed doses in the maximum of a dose field were 40 to 80 Gy. Complete AVM obliteration (the mean volume in the group was 3.03 cm3) was obtained in 11 (41%) patients. A 50% or more reduction in AVM volume (mean volume, 10.6 cm3) was seen in 8 (30%) patients. There was a less than 50% reduction in AVM volumes (mean volume 9.6 cm3) in 2 (7%) patients and no effect could be achieved in 6 (22%) (mean AMV volume 19.7 cm3).


A hybrid wavelet de-noising and Rank-Set Pair Analysis approach for forecasting hydro-meteorological time series.
Accurate, fast forecasting of hydro-meteorological time series is presently a major challenge in drought and flood mitigation. This paper proposes a hybrid approach, wavelet de-noising (WD) and Rank-Set Pair Analysis (RSPA), that takes full advantage of a combination of the two approaches to improve forecasts of hydro-meteorological time series. WD allows decomposition and reconstruction of a time series by the wavelet transform, and hence separation of the noise from the original series. RSPA, a more reliable and efficient version of Set Pair Analysis, is integrated with WD to form the hybrid WD-RSPA approach. Two types of hydro-meteorological data sets with different characteristics and different levels of human influences at some representative stations are used to illustrate the WD-RSPA approach. The approach is also compared to three other generic methods: the conventional Auto Regressive Integrated Moving Average (ARIMA) method, Artificial Neural Networks (ANNs) (BP-error Back Propagation, MLP-Multilayer Perceptron and RBF-Radial Basis Function), and RSPA alone. Nine error metrics are used to evaluate the model performance. Compared to three other generic methods, the results generated by WD-REPA model presented invariably smaller error measures which means the forecasting capability of the WD-REPA model is better than other models. The results show that WD-RSPA is accurate, feasible, and effective. In particular, WD-RSPA is found to be the best among the various generic methods compared in this paper, even when the extreme events are included within a time series.


Exploring collaboration models between geneticists and intensivists for implementing rapid genome sequencing in critical care settings.
The availability of rapid genome sequencing (rGS) for children in a critical-care setting is increasing. This study explored the perspectives of geneticists and intensivists on optimal collaboration and division of roles when implementing rGS in neonatal and pediatric intensive care units (ICUs). We conducted an explanatory mixed methods study involving a survey embedded within an interview with 13 genetics and intensive care providers. Interviews were recorded, transcribed, and coded. Geneticists endorsed higher confidence in performing a physical exam and interpreting/communicating positive results. Intensivists endorsed highest confidence in determining whether genetic testing was appropriate, communicating negative results, and consenting. Major qualitative themes that emerged were: (1) concerns with both "genetics-led" and "intensivist-led" models with workflows and sustainability (2) shift the role of determining rGS eligibility to ICU medical professionals, (3) continued role of geneticists to assess phenotype, and (4) include genetic counselors (GCs) and neonatal nurse practitioners to enhance workflow and care. All geneticists supported shifting decisions regarding eligibility for rGS to the ICU team to minimize time cost for the genetics workforce. Exploring models of geneticist-led phenotyping, intensivist-led phenotyping for some indications, and/or inclusion of a dedicated inpatient GC may help offset the time burden of consenting and other tasks associated with rGS.


The Use of Soluble FMS-like Tyrosine Kinase 1/Placental Growth Factor Ratio in the Clinical Management of Pre-eclampsia.
Hypertensive disorders of pregnancy in particular the category preeclampsia (PE), remains a major cause of both maternal and fetal morbidity and mortality. Angiogenic growth factors (PlGF and VEGF) and their tyrosine kinase receptors -1 and 2 (Flt-1 and KDR) are involved in both fetal and placental development. Inadequate placentation and the consequent release of antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) is thus instrumental in the etiology of this disease. sFlt-1 binds to both angiogenic growth factors and neutralizes their effect thereby creating an angiogenic imbalance. This imbalance is frequently reported in women diagnosed with preeclampsia occurring before the clinical manifestation of the disease. The recent prognostic value of the sFlt-1/PlGF ratio has received considerable attention as a risk indicator of preeclampsia development. The aim of this review is to highlight the current advances in the diagnostic utility of the sFlt-1/PlGF ratio with regards to preeclampsia development.


Self-assembling doxorubicin-tocopherol succinate prodrug as a new drug delivery system: synthesis, characterization, and in vitro and in vivo anticancer activity.
Self-assembled prodrugs forming nanoaggregates are a promising approach to enhance the antitumor efficacy and to reduce the toxicity of anticancer drugs. To achieve this goal, doxorubicin was chemically conjugated to d-α-tocopherol succinate through an amide bond to form N-doxorubicin-α-d-tocopherol succinate (N-DOX-TOS). The prodrug self-assembled in water into 250 nm nanostructures when stabilized with d-α-tocopherol poly(ethylene glycol) 2000 succinate. Cryo-TEM analysis revealed the formation of nanoparticles with a highly ordered lamellar inner structure. NMR spectra of the N-DOX-TOS nanoparticles indicated that N-DOX-TOS is located in the core of the nanoparticles while PEG chains and part of the tocopherol are in the corona. High drug loading (34% w/w) and low in vitro drug release were achieved. In vitro biological assessment showed significant anticancer activity and temperature-dependent cellular uptake of N-DOX-TOS nanoparticles. In vivo, these nanoparticles showed a greater antitumor efficacy than free DOX. N-DOX-TOS nanoparticles might have the potential to improve DOX-based chemotherapy.


Immunoregulation through extracellular nucleotides.
Extracellular ATP (eATP), the most abundant among nucleotides, can act as a mediator during inflammatory responses by binding to plasmamembrane P2 purinergic receptors, which are widely expressed on cells of the immune system. eATP is generally considered as a classical danger signal, which stimulates immune responses in the presence of tissue damage. Converging evidence from several studies using murine models of chronic inflammation have supported this hypothesis; however, the role of eATP in the regulation of human immune function appears to be more complex. Chronic stimulation with micromolar eATP concentrations inhibits the proliferation of T and NK lymphocytes and enhances the capacity of dendritic cells to promote tolerance. The effect of eATP depends on multiple factors, such as the extent of stimulation, eATP concentration, presence/absence of other mediators in the microenvironment, and pattern of P2 receptor engagement. Small but significant differences in the pattern of P2 receptor expression in mice and humans confer the diverse capacities of ATP in regulating the immune response. Such diversity, which is often overlooked, should therefore be carefully considered when evaluating the role of eATP in human inflammatory and autoimmune diseases.


Overexpression of an Arabidopsis thaliana high-affinity phosphate transporter gene in tobacco cultured cells enhances cell growth under phosphate-limited conditions.
A higher plant homologue to the high-affinity phosphate transporter gene of yeast (Saccharomyces cerevisiae) PHO84 was isolated from Arabidopsis thaliana. Expression of the Arabidopsis gene PHT1 at high levels in tobacco-cultured cells increased the rate of phosphate uptake. The uptake activity attributable to the transgene was inhibited by protonophores, suggesting an H+ cotransport mechanism of phosphate uptake, and had a Km of 3.1 microM which is within limits characteristic of high-affinity transport mechanisms. These results indicate that PHT1 encodes a high-affinity phosphate transporter. The transgenic cells exhibited increased biomass production when the supply of phosphate was limited, establishing gene engineering of phosphate transport as one approach toward enhancing plant cell growth.


An endoplasmic reticulum-targeting signal sequence enhances the immunogenicity of an immunorecessive simian virus 40 large T antigen cytotoxic T-lymphocyte epitope.
An immunological hierarchy among three H-2Db-restricted cytotoxic T lymphocyte (CTL) determinants in simian virus 40 (SV40) large T antigen (Tag) was described previously: determinants I and II/III are immunodominant, whereas determinant V is immunorecessive. To assess the immunogenicity of each determinant individually and define mechanisms that contribute to the immunorecessive nature of determinant V, we constructed a panel of recombinant vaccinia viruses (rVVs) expressing minigenes encoding these determinants in various polypeptide contexts. We found the following. (i) Immunization of mice with an rVV encoding full-length SV40 Tag resulted in priming for CTL responses to determinants I and II/III but not determinant V. (ii) rVVs encoding peptide I or II/III in the cytosol or targeted to the endoplasmic reticulum (ER) were highly antigenic and immunogenic. (iii) rVVs encoding peptide V minigenes were antigenic and immunogenic if the peptide was targeted to the ER, expressed in the cytosol with short flanking sequences, or expressed from within a self-protein, murine dihydrofolate reductase. (iv) Presentation of the nonflanked peptide V (preceded by a Met codon only) could be enhanced by using a potent inhibitor of the proteasome. (v) H-2Db-epitope V peptide complexes decayed more rapidly than complexes containing epitope I or II/III peptides. In brefeldin A blocking experiments, functional epitope V complexes were detected longer on targets expressing ER-targeted epitope V than on targets expressing forms of epitope V dependent on the transporter associated with antigen processing. Therefore, limited formation of relatively unstable cell surface H-2Db complexes most likely contributes to the immunorecessive nature of epitope V within SV40 Tag. Increasing the delivery of epitope V peptide to the major histocompatibility complex class I presentation pathway by ER targeting dramatically enhanced the immunogenicity of epitope V.


Cyclosporine induces endothelial cell release of complement-activating microparticles.
Defective control of the alternative pathway of complement is an important risk factor for several renal diseases, including atypical hemolytic uremic syndrome. Infections, drugs, pregnancy, and hemodynamic insults can trigger episodes of atypical hemolytic uremic syndrome in susceptible patients. Although the mechanisms linking these clinical events with disease flares are unknown, recent work has revealed that each of these clinical conditions causes cells to release microparticles. We hypothesized that microparticles released from injured endothelial cells promote intrarenal complement activation. Calcineurin inhibitors cause vascular and renal injury and can trigger hemolytic uremic syndrome. Here, we show that endothelial cells exposed to cyclosporine in vitro and in vivo release microparticles that activate the alternative pathway of complement. Cyclosporine-induced microparticles caused injury to bystander endothelial cells and are associated with complement-mediated injury of the kidneys and vasculature in cyclosporine-treated mice. Cyclosporine-induced microparticles did not bind factor H, an alternative pathway regulatory protein present in plasma, explaining their complement-activating phenotype. Finally, we found that in renal transplant patients, the number of endothelial microparticles in plasma increases 2 weeks after starting tacrolimus, and treatment with tacrolimus associated with increased C3 deposition on endothelial microparticles in the plasma of some patients. These results suggest that injury-associated release of endothelial microparticles is an important mechanism by which systemic insults trigger intravascular complement activation and complement-dependent renal diseases.


Assessment of midpalatal suture ossification using cone-beam computed tomography.
The degree of ossification of the midpalatal suture is an important factor in the selection of treatment procedure, especially in young individuals. Considering the discrepancies in the results of studies on the exact time of the closure of this suture, the present study was undertaken to evaluate ossification and morphology of the suture with the use of CBCT. In the present cross-sectional study, the CBCT images of the maxilla in 144 Iranian subjects (72 males, 72 females) with an age range of 10 to 70 years, referring to a private radiology center in Sari, Iran, were evaluated. The CBCT images were evaluated in the axial cross-sectional slice at 1 mm intervals to determine morphology and the maturation stage of the suture and its degree of ossification. The six developmental stages that were observed were as follows: stage A, a direct line without disturbances; stage B, a scalloped appearance in the suture; stage C, two parallel lines with a scalloped appearance that were connected at some points; stage CD, the anterior portion was similar to stage C, and the posterior region was similar to stage D; stage D, ossification only in the palatine bone; stage E, complete ossification of the suture. The degree of ossification of the suture was calculated with the use of the ratio of the length of the ossified segment to the entire length of the suture. Data were analyzed with Spearman's correlation test, Chi-squared test, t-test, ANOVA, Mann-Whitney U, and Kruskal-Wallis test. Intra-observer agreement was calculated with the use of weighted kappa coefficient. Data were analyzed with SPSS 17. There was a strong correlation between the age groups and the developmental stages of the midpalatal suture in both genders (r=0.681, p<0.001). The ossification process occurred in the posterior to anterior direction in 98% of the cases. There was a significant relationship between aging and the degree of ossification (p<0.001); however, the difference was not significant between the two genders (p=0.193). Although the rate of suture closure increased with aging, age was not a reliable factor alone to determine the developmental stage of the suture. Use of CBCT is necessary in all the patients to determine the degree of ossification and morphology of the midpalatal suture.


Clinical spectrum of Celiac Disease in adults at a tertiary care hospital in Karachi, Pakistan.
Celiac Disease (CD) is a disorder that impacts physical, social and emotional health. Requiring life-long treatment, it poses a major economic burden on the healthcare system. Our objective was to study CD in patients from initial presentation to diagnosis and to ascertain the effect of a low resource setting on improvement in disease process. This is a retrospective cross-sectional study conducted at a Aga Khan University Hospital (AKUH), a tertiary care center in Karachi, Pakistan. Medical records of patients (≥ 18 years) from 2008 to 2018 with a diagnosis of CD were reviewed. Data on demographics, presenting complaints, investigations, endoscopy results and follow up visits was collected. One hundred and twenty-six patients were included (61.6% females, mean age 35.5 years). The most common intestinal and extra-intestinal symptoms were abdominal pain (56.3%) and fatigue (24.6%) respectively. After microcytic anemia (36.5%), increased ALT (27.2%) was the most common laboratory derangement. On endoscopy, visible fissuring (29.4%) and atrophic mucosa (29.4%) were reported. Biopsy findings showed increased intraepithelial lymphocytes (92.9%) and villous atrophy (77.8%). Improvement in at least one of three parameters (symptoms, laboratory values or EGD) was reported by 42.0% of subjects, whereas 48.4% subjects were lost to follow-up. The most commonly reported symptoms by CD patients were abdominal pain, diarrhea and anemia. Thus, patients presenting with vague abdominal symptoms and anemia should be worked up for CD. A concerning majority of subjects was lost to follow up for reasons such as inability to afford advised GFD and a poor understanding of the disease process.


Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium falciparum-Parasitized Erythrocytes.
Although artemisinin-based combination therapies (ACTs) treat Plasmodium falciparum malaria effectively throughout most of the world, the recent expansion of ACT-resistant strains in some countries of the Greater Mekong Subregion (GMS) further increased the interest in improving the effectiveness of treatment and counteracting resistance. Recognizing that (1) partially denatured hemoglobin containing reactive iron (hemichromes) is generated in parasitized red blood cells (pRBC) by oxidative stress, (2) redox-active hemichromes have the potential to enhance oxidative stress triggered by the parasite and the activation of artemisinin to its pharmaceutically active form, and (3) Syk kinase inhibitors block the release of membrane microparticles containing hemichromes, we hypothesized that increasing hemichrome content in parasitized erythrocytes through the inhibition of Syk kinase might trigger a virtuous cycle involving the activation of artemisinin, the enhancement of oxidative stress elicited by activated artemisinin, and a further increase in hemichrome production. We demonstrate here that artemisinin indeed augments oxidative stress within parasitized RBCs and that Syk kinase inhibitors further increase iron-dependent oxidative stress, synergizing with artemisinin in killing the parasite. We then demonstrate that Syk kinase inhibitors achieve this oxidative enhancement by preventing parasite-induced release of erythrocyte-derived microparticles containing redox-active hemichromes. We also observe that Syk kinase inhibitors do not promote oxidative toxicity to healthy RBCs as they do not produce appreciable amounts of hemichromes. Since some Syk kinase inhibitors can be taken daily with minimal side effects, we propose that Syk kinase inhibitors could evidently contribute to the potentiation of ACTs.


The prawn Macrobrachium vollenhovenii in the Senegal River basin: towards sustainable restocking of all-male populations for biological control of schistosomiasis.
Early malacological literature suggests that the outbreak of schistosomiasis, a parasitic disease transmitted by aquatic snails, in the Senegal River basin occurred due to ecological changes resulting from the construction of the Diama dam. The common treatment, the drug praziquantel, does not protect from the high risk of re-infection due to human contact with infested water on a daily basis. The construction of the dam interfered with the life cycle of the prawn Macrobrachium vollenhovenii by blocking its access to breeding grounds in the estuary. These prawns were demonstrated to be potential biological control agents, being effective predators of Schistosoma-susceptible snails. Here, we propose a responsible restocking strategy using all-male prawn populations which could provide sustainable disease control. Male prawns reach a larger size and have a lower tendency to migrate than females. We, therefore, expect that periodic restocking of all-male juveniles will decrease the prevalence of schistosomiasis and increase villagers' welfare. In this interdisciplinary study, we examined current prawn abundance along the river basin, complemented with a retrospective questionnaire completed by local fishermen. We revealed the current absence of prawns upriver and thus demonstrated the need for restocking. Since male prawns are suggested to be preferable for bio-control, we laid the molecular foundation for production of all-male M. vollenhovenii through a complete sequencing of the insulin-like androgenic gland-encoding gene (IAG), which is responsible for sexual differentiation in crustaceans. We also conducted bioinformatics and immunohistochemistry analyses to demonstrate the similarity of this sequence to the IAG of another Macrobrachium species in which neo-females are produced and their progeny are 100% males. At least 100 million people at risk of schistosomiasis are residents of areas that experienced water management manipulations. Our suggested non-breeding sustainable model of control-if proven successful-could prevent re-infections and thus prove useful throughout the world.


Coronary MR angiography.
Coronary MR angiography is a new noninvasive diagnostic method in rapid evolution. It has the potential to combine structural information with functional assessment of coronary blood flow. Advances in technology will undoubtedly lead to enhanced resolution, improved accuracy, and shorter scan times. It is certain that coronary MR angiography will be a prominent diagnostic clinical tool in the years to come.


Coherent states formulation of polymer field theory.
We introduce a stable and efficient complex Langevin (CL) scheme to enable the first direct numerical simulations of the coherent-states (CS) formulation of polymer field theory. In contrast with Edwards' well-known auxiliary-field (AF) framework, the CS formulation does not contain an embedded nonlinear, non-local, implicit functional of the auxiliary fields, and the action of the field theory has a fully explicit, semi-local, and finite-order polynomial character. In the context of a polymer solution model, we demonstrate that the new CS-CL dynamical scheme for sampling fluctuations in the space of coherent states yields results in good agreement with now-standard AF-CL simulations. The formalism is potentially applicable to a broad range of polymer architectures and may facilitate systematic generation of trial actions for use in coarse-graining and numerical renormalization-group studies.


Free-floating thrombus and embolic risk in patients with angiographically confirmed proximal deep venous thrombosis. A prospective study.
A free-floating thrombus (FFT) is often considered to be a risk factor for pulmonary embolism (PE), despite adequate anticoagulation therapy, in patients with proximal deep venous thrombosis. Ninety-five patients underwent prospective assessment according to the presence (FFT group [n = 62]) or absence (occlusive thrombus group [n = 28]) of an FFT. On day 1, color venous duplex scanning, venography (reference method), perfusion lung scanning, and, if results of the lung scan were abnormal, pulmonary angiography were performed. On day 10 (range, days 9-11), the lung scan was repeated, as well as pulmonary angiography if the lung scan demonstrated impairment. A 3-month clinical follow-up visit was scheduled. Five patients were retrospectively excluded from analysis for uncertain diagnosis of FFT. Patients were treated with intravenous unfractionated heparin sodium adjusted for activated partial thromboplastin time (n = 1) or subcutaneous low-molecular-weight heparin (n = 89) (nadroparin calcium, 225 Institut Choay factor Xa inhibitory units per kilogram for 12 hours). Warfarin sodium therapy was initiated on day 3 (range, days 2-4). Both groups were well-matched according to age, sex, risk factors, and delay from onset of symptoms to treatment. Positive and negative predictive values of color venous duplex scanning for the diagnosis of an FFT were 91% and 55%, respectively. On admission, PE prevalence was 64% in the FFT group (40 of 62 patients) and 50% in the occlusive thrombus group (14 of 28 patients) (P = .19). Two patients were excluded on follow-up analysis (range, days 9-11) for preventive vena cava filtering (due to major bleeding in 1 and cholecystectomy in the other); the recurrent rate of PE was 3.3% in the FFT group (2 of 61 patients) and 3.7% in the occlusive thrombus group (1 of 27 patients). No symptomatic recurrent PE occurred between day 10 (range, days 9-11) and 3 months. Four patients died of evolutive neoplasm after hospital discharge. No higher risk for PE was observed in patients with free-floating proximal deep venous thrombosis; anticoagulant therapy should prevent recurrent PE in such patients.


Human interferon-gamma-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion.
Individuals with inherited disorders of interferon gamma (IFN-gamma)-mediated immunity appear to be specifically vulnerable to mycobacterial infections. The severity of clinical features of affected individuals differs between cases. Some patients die of mycobacterial infection in early childhood, whereas others have long asymptomatic periods in childhood and as adults. This rare syndrome also shows high allelic and non-allelic genetic heterogeneity. Mutations in IL12B, encoding the interleukin (IL)-12 p40 subunit, and in IL12RB1, encoding the beta1 chain of the IL-12 receptor, result in impaired IFN-gamma production. Mutations in IFNGR1 and IFNGR2, encoding the two IFN-gamma receptor chains, and mutations in STAT1, encoding an essential signaling component, result in impaired cellular responses to IFN gamma. Different types of mutation define two types of complete and two types of partial IFNgammaR1 deficiency. Complete and partial IFNgammaR2 deficiency have also been described. We herein compare the genotypes, cellular phenotypes, and clinical phenotypes of healthy individuals and patients with the seven known genetic disorders impairing cellular responses to IFN-gamma. Patients with defective IFN-gamma production were not considered in this study. The mutations and clinical features of patients with IFNgammaR1, IFNgammaR2, and STAT-1 deficiency are reviewed. Selected cell lines from each of the eight groups were tested for their response to IFN-gamma. We find that individuals may be classified into four broad groups based on genotype, cellular phenotype, and clinical phenotype (normal individuals and patients with mild, intermediate, or severe disease). This correlation suggests that IFN-gamma-mediated cell activation is a genetically controlled quantitative trait and that it determines the outcome of mycobacterial invasion in man.


Starving honeybees lose self-control.
Impulsivity, the widespread preference for a smaller and more immediate reward over a larger and more delayed reward, is known to vary across species, and the metabolic and social hypotheses present contrasting explanations for this variation. However, this presents a paradox for an animal such as the honeybee, which is highly social, yet has a high metabolic rate. We test between these two competing hypotheses by investigating the effect of hunger on impulsivity in bees isolated from their social environment. Using an olfactory conditioning assay, we trained individuals to associate a small and a large reward with or without a delay, and we tested their choice between the two rewards at different levels of starvation. We found an increase in impulsive behaviour and an associated increase in dopamine levels in the brain with increasing starvation. These results suggest that the energetic state of an individual, even in a eusocial group, is a critical driver of impulsivity, and that the social harmony of a group can be threatened when the energetic states of the group members are in conflict.


The effects of whole body vibration on humans: dangerous or advantageous?
The effects of whole body vibration (WBV) have been studied extensively in occupational medicine. In particular, it has been shown that when the body undergoes chronically to whole body vibrations spinal degeneration is likely to be one of the deleterious outcomes. Low back pain has been shown to be the leading major cause of industrial disability in the population under the age of 45 years and has been linked to whole body vibration exposure encountered in some industrial settings. Whole body vibration has been recently purposed as an exercise intervention suggesting its effectiveness in increasing force-generating capacity in lower limbs and low back. It has also been reported to be an effective non-pharmacological intervention for patients with low back pain. Relatively short exposure to whole body vibration has been also shown to increase the serum levels of testosterone and growth hormone. The combined effects on the neuromuscular system and endocrine system seem to suggest its effectiveness as a therapeutic approach for sarcopenia and possibly osteoporosis. Due to the danger of long-term exposure to whole body vibration, it is important to develop safe exercise protocols in order to determine exercise programs for different populations.


Clinical features and outcomes of hospitalised patients with COVID-19 and Parkinsonian disorders: A multicentre UK-based study.
Parkinson's disease has been identified as a risk factor for severe Coronavirus disease 2019 (COVID-19) outcomes. However, whether the significant high risk of death from COVID-19 in people with Parkinson's disease is specific to the disease itself or driven by other concomitant and known risk factors such as comorbidities, age, and frailty remains unclear. To investigate clinical profiles and outcomes of people with Parkinson's disease and atypical parkinsonian syndromes who tested positive for COVID-19 in the hospital setting in a multicentre UK-based study. A retrospective cohort study of Parkinson's disease patients with a positive SARS-CoV-2 test admitted to hospital between February 2020 and July 2021. An online survey was used to collect data from clinical care records, recording patient, Parkinson's disease and COVID-19 characteristics. Associations with time-to-mortality and severe outcomes were analysed using either the Cox proportional hazards model or logistic regression models, as appropriate. Data from 552 admissions were collected: 365 (66%) male; median (inter-quartile range) age 80 (74-85) years. The 34-day all-cause mortality rate was 38.4%; male sex, increased age and frailty, Parkinson's dementia syndrome, requirement for respiratory support and no vaccination were associated with increased mortality risk. Community-acquired COVID-19 and co-morbid chronic neurological disorder were associated with increased odds of requiring respiratory support. Hospital-acquired COVID-19 and delirium were associated with requiring an increase in care level post-discharge. This first, multicentre, UK-based study on people with Parkinson's disease or atypical parkinsonian syndromes, hospitalised with COVID-19, adds and expands previous findings on clinical profiles and outcomes in this population.


Cytokine expression during the outcome of canine experimental infection by Leishmania infantum.
In this study, the cytokines, interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-12 p40, IL-6 and IL-10, expressed by peripheral blood mononuclear cells of 13 beagle dogs inoculated with Leishmania infantum amastigotes, were analysed during a period of up to 23 months. The course of infection was monitored through clinical and parasitological examinations, haematological alterations and serum antileishmania antibody levels. Dogs developed symptomatic infections with haematological alterations, humoral immune response and reduced specific lymphoproliferative response. Parasite presence was detected in bone marrow, popliteal lymph node and skin. Specifically stimulated cytokine transcripts were generally observed in a low proportion of dogs, except at months 9, 10 and 11 post-infection where there was a considerable increase in the proportion of dogs expressing IFN-gamma and IL-2 mRNA. IL-12 p40 and IL-10 transcripts were sporadically detected in few animals. In non-infected animals, IFN-gamma mRNA was the only detectable cytokine but only in cells cultured in the presence of concanavalin A (ConA). The low proportion of animals expressing specific cytokines, during the first 8 months of infection associated with evidences of parasite dispersion without clinical signs of disease, suggests the occurrence of a relatively "silent establishment" of the parasite avoiding adverse host-cell-mediated immunological reactions. The humoral immune response displayed in these animals, the cell-mediated immunosuppression, nor the disease severity could be related with the expression of IL-10. The predominance of a Th1 type response for a relatively short period indicates that these cytokines are required to control the infection delaying the appearance of progressive disease.