Bayesian Analysis of Air Emission Violations from Waste Incineration and Coincineration Plants.
Waste incineration and coincineration plants in most European countries have frequently updated their flue gas cleaning systems, surpassing in most cases E.U. air emission standards. At the same time, in most developing countries, cement and other coincineration facilities follow less stringent emission regulations and have a mixed record of protecting air quality. The European Union, the United States, and Canada have established penalties for air emission violations that account for the harm done to the environment and to human health and aiming to remove the economic benefit reaped as a result of noncompliance. Despite their legal completeness, these regulations do not adequately address the probabilistic nature of air pollution. This article recasts the issue of air pollution penalties in a Bayesian decision-making framework with the aspiration that the assessment of penalties on a rigorous mathematical framework can assist in alleviating the mistrust by sections of the public on the effectiveness of air pollution regulations. Integration of economic analyses into risk assessments of emission violations can help clarify to policymakers the effect of environmental policies. Our analysis indicates that the penalty structure of the United States appears to favor the update of emission systems more often than the corresponding European Commission's penalties. Our study advances the use of the loss function as a risk analysis tool that can be used as a public policy instrument to promote environmentally friendlier air emission choices. A parabolic, compared to a linear, loss function was seen to justify higher expenses in gas cleaning systems.


[Pharmacologic intolerance reaction after intravenous injection of pethidine].
We report on anaphylactoid reactions (urticae at the injection site and along the injection vein) after intravenous injections of pethidine in two patients. Skin tests with pethidine were negative, but intravenous challenge showed urticae. These results indicate that the reactions were due to a non-immunological mechanism resembling pharmacological intolerance. Retrospective analysis revealed a 5.6% incidence of pharmacological intolerance reactions to intravenous pethidine in 519 patients.


MytiBase: a knowledgebase of mussel (M. galloprovincialis) transcribed sequences.
Although bivalves are among the most studied marine organisms due to their ecological role, economic importance and use in pollution biomonitoring, very little information is available on the genome sequences of mussels. This study reports the functional analysis of a large-scale Expressed Sequence Tag (EST) sequencing from different tissues of Mytilus galloprovincialis (the Mediterranean mussel) challenged with toxic pollutants, temperature and potentially pathogenic bacteria. We have constructed and sequenced seventeen cDNA libraries from different Mediterranean mussel tissues: gills, digestive gland, foot, anterior and posterior adductor muscle, mantle and haemocytes. A total of 24,939 clones were sequenced from these libraries generating 18,788 high-quality ESTs which were assembled into 2,446 overlapping clusters and 4,666 singletons resulting in a total of 7,112 non-redundant sequences. In particular, a high-quality normalized cDNA library (Nor01) was constructed as determined by the high rate of gene discovery (65.6%). Bioinformatic screening of the non-redundant M. galloprovincialis sequences identified 159 microsatellite-containing ESTs. Clusters, consensuses, related similarities and gene ontology searches have been organized in a dedicated, searchable database http://mussel.cribi.unipd.it. We defined the first species-specific catalogue of M. galloprovincialis ESTs including 7,112 unique transcribed sequences. Putative microsatellite markers were identified. This annotated catalogue represents a valuable platform for expression studies, marker validation and genetic linkage analysis for investigations in the biology of Mediterranean mussels.


Protein interaction networks.
The study of protein interactions is playing an ever increasing role in our attempts to understand cells and diseases on a system-wide level. This article reviews several experimental approaches that are currently being used to measure protein-protein, protein-DNA and gene-gene interactions. These techniques have now been scaled up to produce extensive genome-wide data sets that are providing us with a first glimpse of global interaction networks. Complementing these experimental approaches, several computational methodologies to predict protein interactions are also reviewed. Existing databases that serve as repositories for protein interaction information and how such databases are used to analyze high-throughput data from a pathway perspective is also addressed. Finally, current efforts to combine multiple data types to obtain more accurate and comprehensive models of protein interactions are discussed. It is clear that the evolution of these experimental and computational approaches is rapidly changing our view of biology, and promises to provide us with an unprecedented ability to model cells and organisms at a system-wide level.


Carbimazole and the autoimmune response in Graves' disease.
Microsomal antibodies and antibodies directed toward the receptor for thyroid-stimulating hormone (TSH) decreased in parallel while patients with Graves' disease were taking carbimazole, whereas no significant changes were observed during treatment with placebo or propranolol. The changes in autoantibody levels during carbimazole treatment were independent of changes in serum thyroxine and could have been due to a direct effect of the drug on autoantibody synthesis. Evidence for this suggestion was provided when low doses of methimazole (the active metabolite of carbimazole) were found to inhibit thyroid-autoantibody production in cultured lymphocytes. Since thyroid lymphocytes are probably a major site of thyroid-antibody synthesis in Graves' disease and methimazole is concentrated in the thyroid during treatment, a local action of the drug on antibody production seems likely. This possibility could be important in the use of carbimazole to control hyperthyroidism.


Evaluation of the psychoneurotic tendencies risk using the woodworth mathews personality inventory in non-institutionalized persons.
Multiple factors of vulnerability may lead to development of abnormal social behaviour and to important psychiatric diseases. The psychopathological characteristics present at individual level can lead to a pattern of population groups that are subject to developing mental illness risks. Multidisciplinary study (2009-2011) to assessing the current situation of mental health and identifying population risk groups for developing psychiatric disorders in a non-institutionalised population. We used the Woodworth Mathews Inventory (76 items) to a randomly selected sample of 1,200 men and women, residents in urban and rural areas. The extreme scores for emotiveness had a frequency more than triple for women, and we found a similar situation for obsessive-neurasthenic and depressive tendencies. People aging over 35 years had a double score (limit and poignancy) for depression than younger people, meanwhile correlation between age under 35 years and instability and antisocial tendencies is highly statistically significant (p<0.001), the frequency of extreme scores being almost double than in the older people. Female gender has a vulnerability for develop depressive and emotional disorders and age over 35 is also significant correlated with depressive tendencies. Younger people (under 35 years) are predisposed for pathological antisocial behaviour, fact revealed by the high scores for instability and antisocial tendencies. It is necessary to develop a program focused on the two risk categories to prevent the possible occurrence of psychiatric disorders.


The fecal microbiome and serum concentrations of indoxyl sulfate and p-cresol sulfate in cats with chronic kidney disease.
Intestinal dysbiosis has been documented in humans with chronic kidney disease (CKD) and is thought to contribute to production of the uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (pCS). Characteristics of the fecal microbiome in cats with CKD and correlation to serum concentrations of uremic toxins are unknown. To characterize the fecal microbiome and measure serum IS and pCS concentrations of cats with CKD in comparison to healthy older cats. Thirty client-owned cats with CKD (International Renal Interest Society stages 2-4) and 11 older (≥8 years) healthy control cats. Prospective, cross-sectional study. Fecal samples were analyzed by sequencing of 16S rRNA genes and Escherichia coli quantitative PCR (qPCR). Serum concentrations of IS and pCS measured using liquid chromatography tandem mass spectrometry. Cats with CKD had significantly decreased fecal bacterial diversity and richness. Escherichia coli qPCR showed no significant difference in bacteria count between control and CKD cats. Cats with stage 2 (P = .01) and stages 3 and 4 (P = .0006) CKD had significantly higher serum IS concentrations compared to control cats. No significant difference found between stage 2 and stages 3 and 4 CKD. The pCS concentrations were not significantly different between CKD cats and control cats. Decreased fecal microbiome diversity and richness is associated with CKD in cats. Indoxyl sulfate concentration is significantly increased with CKD, and cats with stage 2 CKD may suffer from a similar uremic toxin burden as do cats with later stage disease.


Oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor/Ca2+ release channel (RyR1): sites and nature of oxidative modification.
In mammalian skeletal muscle, Ca(2+) release from the sarcoplasmic reticulum (SR) through the ryanodine receptor/Ca(2+)-release channel RyR1 can be enhanced by S-oxidation or S-nitrosylation of separate Cys residues, which are allosterically linked. S-Oxidation of RyR1 is coupled to muscle oxygen tension (pO2) through O2-dependent production of hydrogen peroxide by SR-resident NADPH oxidase 4. In isolated SR (SR vesicles), an average of six to eight Cys thiols/RyR1 monomer are reversibly oxidized at high (21% O2) versus low pO2 (1% O2), but their identity among the 100 Cys residues/RyR1 monomer is unknown. Here we use isotope-coded affinity tag labeling and mass spectrometry (yielding 93% coverage of RyR1 Cys residues) to identify 13 Cys residues subject to pO2-coupled S-oxidation in SR vesicles. Eight additional Cys residues are oxidized at high versus low pO2 only when NADPH levels are supplemented to enhance NADPH oxidase 4 activity. pO2-sensitive Cys residues were largely non-overlapping with those identified previously as hyperreactive by administration of exogenous reagents (three of 21) or as S-nitrosylated. Cys residues subject to pO2-coupled oxidation are distributed widely within the cytoplasmic domain of RyR1 in multiple functional domains implicated in RyR1 activity-regulating interactions with the L-type Ca(2+) channel (dihydropyridine receptor) and FK506-binding protein 12 as well as in "hot spot" regions containing sites of mutation implicated in malignant hyperthermia and central core disease. pO2-coupled disulfide formation was identified, whereas neither S-glutathionylated nor sulfenamide-modified Cys residues were observed. Thus, physiological redox regulation of RyR1 by endogenously generated hydrogen peroxide is exerted through dynamic disulfide formation involving multiple Cys residues.


Clinical evidence of the effect of bisphosphonates on pregnancy and the infant.
Bisphosphonates (BPs) are potent inhibitors of osteoclast mediated bone resorption. These drugs are widely used in the management of osteoporosis and other diseases, characterized by high bone turnover. The effect of BPs on gestation and lactation, when they are used as therapeutic agents in premenopausal women, is yet unknown. We conducted a detailed literature review and identified the cases of BPs use in young women, as well as, the effects of this therapy on the gestation and the embryo. The published data, regarding the use of BPs in premenopausal women and their effects on the pregnancy outcome, are limited. However, we could identify the outcomes of 40 pregnant women, who had received BPs prior to or during pregnancy, that have been documented in the literature. All women had valid indications to receive BPs for serious bone metabolism conditions. We could not identify any prospective trials, which focus on pregnancy outcomes following after the in-utero exposure to BPs. In total, no serious adverse effects were reported. Problems related to the offspring, such as hypocalcemia and a tendency for low body weight (LBW), were self-resolving. In addition, no serious adverse outcomes were reported for women having completed pregnancy. Nevertheless, follow-up was limited for both outcomes suggesting the necessity of national and international registries.


A reversibly gated protein-transporting membrane channel made of DNA.
Controlled transport of biomolecules across lipid bilayer membranes is of profound significance in biological processes. In cells, cargo exchange is mediated by dedicated channels that respond to triggers, undergo a nanomechanical change to reversibly open, and thus regulate cargo flux. Replicating these processes with simple yet programmable chemical means is of fundamental scientific interest. Artificial systems that go beyond nature's remit in transport control and cargo are also of considerable interest for biotechnological applications but challenging to build. Here, we describe a synthetic channel that allows precisely timed, stimulus-controlled transport of folded and functional proteins across bilayer membranes. The channel is made via DNA nanotechnology design principles and features a 416 nm2 opening cross-section and a nanomechanical lid which can be controllably closed and re-opened via a lock-and-key mechanism. We envision that the functional DNA device may be used in highly sensitive biosensing, drug delivery of proteins, and the creation of artificial cell networks.


Confounding by Single Nucleotide Polymorphism rs117648444 (P70S) Affects the Association of Interferon Lambda Locus Variants with Response to Interferon-α-Ribavirin Therapy in Patients with Chronic Genotype 3 Hepatitis C Virus Infection.
Genome-wide association studies discovered interferon lambda (IFNL or IFN-λ) locus on chromosome 19 to be involved in clearance of chronic hepatitis C virus (HCV) infection in patients following interferon-α-ribavirin (IFN-RBV) therapy. Subsequent studies established a dinucleotide polymorphism rs368234815, as the prime causal variant behind this association. The ΔG allele of this variant gives rise to a new IFNL gene, IFNL4, coding for IFN-λ4 whose activity paradoxically associates with lesser viral clearance rates. A low-frequency, nonsynonymous single nucleotide polymorphism (SNP) rs117648444 within the 2nd exon of IFNL4 changes the 70th amino acid from proline to serine resulting in lower activity of the functional IFN-λ4 protein, thereby increasing HCV clearance rates. In the present study, we used a cohort of genotype 3 HCV-infected patients, drawn from different geographical regions of India who underwent IFN-RBV therapy, to examine the association of several important IFNL locus SNPs/variants with sustained virological response (SVR). Intriguingly, the causal variant rs368234815 did not show the best strength and significance of association with SVR, while further analysis revealed that a negative confounding effect of rs117648444 was responsible for this phenomenon. Our results indicate that IFNL locus SNPs are subject to either a positive or a negative confounding effect by rs117648444; the nature of confounding depends on the linkage of the IFNL SNPs with the low-activity IFN-λ4-generating minor allele of rs117648444. Thus, our work demonstrates that the linkage disequilibrium structure of the IFNL region may confound the results of association studies. These results have implications for the design and understanding of future case-control studies involving IFNL locus SNPs/variants.


BSA-caged metal clusters to exfoliate MoS2 nanosheets towards their hybridized functionalization.
Herein, we develop a facile exfoliation and in situ functionalization strategy to produce hybridized Au/MoS2 nanostructures comprised of size-controlled gold nanoparticles (Au NPs) and ultrathin MoS2 nanosheets by using bovine serum albumin (BSA)-caged Au25 clusters as both exfoliating and functionalizing agents. As revealed, BSA molecules are strongly adsorbed on MoS2via their hydrophobic interaction, and this drives the expansion of the BSA molecules that initially protect Au25 cores at pH 4, leading to the effective exfoliation of MoS2 nanosheets together with the epitaxial growth of Au25 cores into 5 nm-sized Au NPs on MoS2 nanosheets due to their reduced surface protection. Upon the addition of H2O2, the resulting Au NPs can further grow to achieve a controlled size from 5 to 30 nm with an increase of the reaction time. It is demonstrated that the hybridized Au/MoS2 nanosheets exhibit a better performance in the photocatalytic degradation of substrates compared to the individual components or their mixture. Moreover, the hybridized Ag/MoS2, Au/WO3 and Au/graphene nanosheets are further produced by the usage of BSA-caged Ag and Au clusters, respectively. Overall, this work reports the first utilization of protein-caged metal clusters for the exfoliation and hybridized functionalization of 2D materials, and this brings more opportunities to exploit unusual properties of hybridized 2D materials for novel applications.


Sodium migration pathways in multicomponent silicate glasses: Car-Parrinello molecular dynamics simulations.
The mechanism of sodium migration in low-silica alkali-alkaline earth silicate glasses is investigated through Car-Parrinello molecular dynamics (MD) simulations. The transport of sodium to the glass surface and its subsequent release is critical for the use of these glasses in biomedical applications. The analysis of the MD trajectory, mainly through a combination of space and time correlation functions, reveals a complex mechanism, with some common features to the migration in mixed-alkali silicate glasses and several important differences. The low site selectivity of Na cations in this glass allows them to use both Na and Ca sites in the migration process. The high fragmentation and the corresponding flexibility of the silicate network enable an additional mechanism for ion migration, not favorable in the more rigid network of common higher-silica glasses, involving the creation of empty transient sites through the correlated forward-backward motion of an Na or a Ca cation. We also show that because sodium migration must involve an undercoordinated intermediate, sharing of oxygen atoms in the initial and final coordination shells is a way to reduce the energetic cost of losing favorable Na-O interactions and Na migration proceeds between corner-sharing NaO(x) polyhedra, where x=5-7. For these low-silica compositions, the present simulations suggest that due to the participation of calcium in the Na migration, the latter will not be significantly hampered by extensive mixing with less mobile Ca ions, or, in any event, the effect will be less marked than for higher-silica glasses.


Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis.
Cholangiopathies are characterized by progressive dysregulation of the balance between proliferation and death of cholangiocytes. In the course of cholestasis, cholangiocytes undergo a neuroendocrine transdifferentiation and their biology is regulated by neuroendocrine hormones. Glucagon-like peptide-1 (GLP-1), secreted by neuroendocrine cells, sustains beta-cell survival in experimental diabetes and induces the neuroendocrine transdifferentiation of pancreatic ductal cells. GLP-1 receptor (GLP-1R) selective agonist exendin-4 is used in humans as a novel therapeutic tool for diabetes. The aim of this study was to define if GLP-1 modulates cholangiocyte biologic response to cholestasis. Expression of GLP-1R in cholangiocytes was determined. Effects on cholangiocyte proliferation of the in vitro and in vivo exposure to GLP-1 or exendin-4, together with the intracellular signals, were then studied. Synthesis of GLP-1 by cholangiocytes and the effects of GLP-1R blockage on their growth were also determined. Cholangiocytes express the GLP-1 receptor, which is up-regulated in the course of cholestasis. GLP-1 and exendin-4 increase cholangiocyte growth both in vitro and in vivo. The GLP-1R signal is mediated by the phosphatidyl-inositol-3-kinase, cAMP/Protein Kinase A, and Ca(2+)-CamKIIalpha but not by the ERK1/2 and PKCalpha pathways. Proliferating cholangiocytes synthesize GLP-1: neutralization of its action by GLP-1R antagonist blunts cholangiocyte response to cholestasis. GLP-1 is required for the cholangiocyte adaptive response to cholestasis. Cholangiocytes are susceptible to the activation of GLP-1R and respond with increased proliferation and functional activity. Exendin-4 availability for employment in humans and these data may open novel perspectives for the medical treatment of cholangiopathies.


On the accessibility and selection of the initiator site of mRNA in protein synthesis.
The specificity of the cell-free system of Escherichia coli for mRNA was examined, and the "accessibility" of some natural and synthetic RNAs to the ribosomes was determined by measurement of AcPhe-tRNA and fMet-tRNA binding, AcPhe-puromycin and fMet-puromycin formation, and polypeptide synthesis. The E. coli system effectively initiates the translation of various synthetic RNAs with AcPhe-tRNA or fMet-tRNA under conditions optimal for the translation of viral RNA. Poly(A,G,U) is accessible to the ribosomes according to all of the above criteria. Poly(A,C,G,U), 23 S rRNA, R17 RNA, and MS2 RNA, on the other hand, show limited accessibility when tested for initiator tRNA binding, or for AcPhe-puromycin and fMet-puromycin formation. MS2 and R17 RNA, but not poly(A,C,G,U) and 23 S rRNA, show accessibility when measured by polypeptide synthesis. The results suggest that, except at initiator sites of natural mRNA, an RNA containing about equal amounts of all four bases is inaccessible to E. coli ribosomes for polypeptide synthesis. Rate constants obtained for fMet-tRNA binding with MS2 RNA, poly(A,G,U), and poly(C,G,U) indicate that the ribosomes do not have any special affinity for the viral RNA. Thus, the selection of the initiator site in protein synthesis may be critically determined more by the accessibility of the initiator codon than by ribosomal recognition of the site.


Family structure and physicians' hours in large, multispecialty groups.
There is a consensus that male physicians work more hours than female physicians, but no consensus on how or why female physicians limit hours. Drawing on a new national survey of physicians in large, multispecialty groups, we conclude that much of the hours differential is due to differences in nonpractice incomes and is likely to be permanent. However, due to reductions in family responsibilities for women and increases in nonpractice incomes for men, the differential should narrow somewhat as the current cohort of physicians ages. We also infer that the link between hours and practice choices may well account for much of the diversity of the literature.


Exercising self-control increases approach motivation.
The present research tested the hypothesis that exercising self-control causes an increase in approach motivation. Study 1 found that exercising (vs. not exercising) self-control increases self-reported approach motivation. Study 2a identified a behavior--betting on low-stakes gambles--that is correlated with approach motivation but is relatively uncorrelated with self-control, and Study 2b observed that exercising self-control temporarily increases this behavior. Last, Study 3 found that exercising self-control facilitates the perception of a reward-relevant symbol (i.e., a dollar sign) but not a reward-irrelevant symbol (i.e., a percent sign). Altogether, these results support the hypothesis that exercising self-control temporarily increases approach motivation. Failures of self-control that follow from prior efforts at self-control (i.e., ego depletion) may be explained in part by increased approach motivation.


Applications of brain blood flow imaging in behavioral neurophysiology: cortical field activation hypothesis.
The 133xenon intracarotid method for rCBF measurements has been a very useful method for functional mapping and functional dissection of the cerebral cortex in humans. With this method it has been shown that different types of cortical information treatment activate different cortical areas and furthermore that sensory and motor functions of the cerebral cortex could be dissected into anatomical and informational subcomponents by behavioral manipulations. The brain organizes its own activity. One of the principles of organization was that the brain could recruit in advance cortical fields that were expected to participate in a certain type of information operation. During brain work in awake human beings the cerebral cortex was activated in fields that, projected on the cerebral surface, most often had a size greater than 3 cm2. Such activated fields appeared no matter which type of information processing was going on in the brain: during planning and execution of voluntary movements, during preparation for sensory information processing, and during sensory information processing, as well as during cognitive brain work and retrieval of specific memories. Therefore, it was hypothesized that cortical field activation was the physiological manifestation of normal brain work in awake humans.


Patient considerations in the treatment of cervical dystonia: focus on botulinum toxin type A.
Cervical dystonia is the most common form of focal dystonia characterized by involuntary muscle contractions causing abnormal movements and posturing of the head and neck and is associated with significant pain. Botulinum toxin is considered first-line therapy in the treatment of pain and abnormal head posturing associated with cervical dystonia. There are currently three botulinum toxin type A neurotoxins and one botulinum type B neurotoxin commercially available and US Food and Drug Administration (FDA) labeled for the treatment of cervical dystonia. This review will focus on the efficacy, safety, and therapeutic use of botulinum type A neurotoxins in the treatment of cervical dystonia. We conclude with a discussion of factors influencing toxin selection including therapeutic effect, duration of effect, side effect profile, cost, and physician preference.


Surface-assisted spin Hall effect in Au films with Pt impurities.
We show, both experimentally and theoretically, a novel route to obtain giant room temperature spin-Hall effect due to surface-assisted skew scattering. In the experiment, we report the spin-Hall effect in Pt-doped Au films with different thicknesses t(N). The giant spin-Hall angle γ(S)=0.12±0.04 is obtained for t(N)=10 nm at room temperature, while it is much smaller for the t(N)=20 nm sample. Combined ab initio and quantum Monte Carlo calculations for the skew scattering due to a Pt impurity show γ(S)≅0.1 on the Au (111) surface, while it is small in bulk Au. The quantum Monte Carlo results show that the spin-orbit interaction of the Pt impurity on the Au (111) surface is enhanced, because the Pt 5d levels are lifted to the Fermi level due to the valence fluctuation. In addition, there are two spin-orbit interaction channels on the Au (111) surface, while only one in bulk Au.


A caffeine-sensitive membrane electrode: previous misleading report and present approach.
Although a previous study [S.S.M. Hassan, M.A. Ahmed, M.M. Saoudi, Anal. Chem. 57 (1985) 1126] had shown that a caffeine-sensitive electrode made with picrylsulfonate and 1-octanol as a cation-exchanger and a solvent mediator, respectively, had a wide working pH range (5.5-9.5) and exhibited a Nernstian response, we could not find such response in this electrode. The present result was reasonable, because the pK(a) value of caffeinium ion was reported to be around 0.7 and the neutral form of caffeine was predominant in the pH range examined. Thus, we reinvestigated the response characteristics of a caffeine electrode, taking into consideration the pK(a) value, and constructed a new electrode with a combination of the lipophilic cation-exchanger, tetrakis[3,5-bis(2-methoxyhexafluoro-2-propyl)phenyl]borate (HFPB), and the solvent mediator with high degree of dielectric constant, 2-fluoro-2'-nitrodiphenyl ether (FNDPE). This electrode showed a pH-dependent response to caffeinium ion and gave a detection limit of 50muM with a slope of 55mV per concentration decade at pH 2. The use of other solvent mediators was less effective than that of FNDPE. The electrode was applied for the determination of caffeine in some central stimulants.


Comprehensive modeling of annulus fibrosus: from biphasic refined characterization to damage accumulation under viscous loading.
The annulus fibrosus (AF), a permeable, hydrated, and fiber-reinforced soft tissue, exhibits complex responses influenced by fluid pressure, osmotic pressure, and structural mechanics. Existing models struggle to comprehensively represent these intricate interactions and the heterogeneous solid responses within the AF. Additionally, the mechanisms driving differential damage accumulation between non-degenerative and degenerative intervertebral discs remain poorly understood. In this study, we introduce a biphasic-swelling damage model for the AF. We conceptually develop and rigorously validate this model through tissue-level tests employing various loading modes, consistently aligning model predictions with experimental data. Leveraging parametric geometric algorithms and custom Python scripts, we construct models simulating both non-degenerative and degenerative discs. Following calibration, we subject these models to viscous loading protocols. Our findings reveal the posterior AF's susceptibility to damage, contingent upon loading rate and water content. We elucidate the underlying mechanisms by examining the temporal evolution of fluid pressure, osmotic pressure, and the regionally dependent fiber network. This research presents a highly accurate model of the AF, providing valuable insights into disc damage. Future research endeavors should expand this model to incorporate ionic transport and diffusion, enabling a more profound exploration of intervertebral disc mechanobiology. This comprehensive model contributes to a better understanding of AF behavior and may inform therapeutic strategies for disc-related pathologies. STATEMENT OF SIGNIFICANCE: This research presents a comprehensive model of the annulus fibrosus (AF), a crucial component of the intervertebral disc that provides structural support and resists deformation. The study introduces a biphasic-swelling damage model for the AF and validates it through tissue-level tests. The model accounts for fluid pressure, osmotic pressure, and matrix mechanics, providing a more accurate representation of the AF's behavior. The study also investigates the differential damage accumulation between non-degenerative and degenerative discs, shedding light on the mechanisms driving disc degeneration. The findings have significant implications for medical treatments and interventions, as they highlight the posterior AF's susceptibility to damage. This research is of great interest to readers interested in biomechanics, tissue engineering, and medical treatments for disc degeneration.


Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1.
The activation of MAP kinase (MAPK) signal transduction pathways results in the phosphorylation of transcription factors by the terminal kinases in these cascades. Different pathways are activated by mitogenic and stress stimuli, which lead to the activation of distinct groups of target proteins. The ETS-domain transcription factor Elk-1 is a substrate for three distinct classes of MAPKs. Elk-1 contains a targeting domain, the D-domain, which is distinct from the phosphoacceptor motifs and is required for efficient phosphorylation and activation by the ERK MAPKs. In this study, we demonstrate that members of the JNK subfamily of MAPKs are also targeted to Elk-1 by this domain. Targeting via this domain is essential for the efficient and rapid phosphorylation and activation of Elk-1 both in vitro and in vivo. The ERK and JNK MAPKs use overlapping yet distinct determinants in the D-domain for targeting to Elk-1. In contrast, members of the p38 subfamily of MAPKs are not targeted to Elk-1 via this domain. Our data therefore demonstrate that different classes of MAPKs exhibit differential requirements for targeting to Elk-1.


Intraocular expression of endostatin reduces VEGF-induced retinal vascular permeability, neovascularization, and retinal detachment.
Endostatin, a proteolytic fragment of collagen XVIII, is an endogenous inhibitor of tumor angiogenesis that also inhibits choroidal neovascularization. In this study, we assessed the effects of increased intraocular expression of endostatin on vascular endothelial growth factor (VEGF)-induced changes in the retina. After subretinal injection of a pair of gutless adenoviral vectors (AGV) designed to provide tamoxifen-inducible expression of endostatin, diffuse endostatin immunoreactivity was induced thoroughout the retina by administration of tamoxifen. Induction of endostatin in double transgenic mice with doxycycline-induced expression of VEGF in the retina resulted in significant suppression of leakage of intravascular [3H]mannitol into the retina. The ability of endostatin to reduce VEGF-induced retinal vascular permeability was confirmed by using [3H]mannitol leakage and two other parameters, fluorescein leakage and retinal thickness, after subretinal injection of a bovine immunodeficiency lentiviral vector coding for endostatin (BIV-vectored endostatin, or BIVendostatin). Subretinal injection of BIVendostatin resulted in more discrete, less intense staining for endostatin in the retina than that seen with the inducible AGV system, which suggested lower levels and allowed visualization of sites where endostatin was concentrated. Endostatin staining outlined retinal blood vessels, which suggested endostatin binding to a component of vessel walls. More prolonged or higher level expression of VEGF in the retina resulted in neovascularization and retinal detachment, both of which were also significantly reduced by BIVendostatin. These data suggest that endostatin may be an endogenous inhibitor of vasopermeability as well as neovascularization. In patients with diabetic retinopathy, endostatin gene transfer may provide a way to decrease the risk of three causes of visual loss: macular edema, neovascularization, and retinal detachment.


Host cell reactivation of cisplatin-treated adenovirus is reduced in nucleotide excision repair deficient mammalian cells and several human tumour cells.
Cisplatin is widely used for chemotherapy of a variety of human cancers. Cisplatin exerts its toxic effect by covalently binding to DNA, resulting in monofunctional adducts, intrastrand crosslinks, and interstrand crosslinks. Several recent reports suggest that the cellular capacity for DNA repair, especially nucleotide excision repair (NER), is an important determinant in the sensitivity of cells to cisplatin. We have used a sensitive host cell reactivation (HCR) technique to examine the repair capacity for cisplatin-damaged DNA in several different mammalian cell types. HCR of cisplatin-damaged adenovirus (Ad) was reduced in all UV-sensitive NER deficient Chinese hamster ovary (CHO) cells examined (complementation groups 1 to 6) compared to NER proficient CHO cells. HCR of cisplatin-damaged Ad was also reduced in fibroblasts from patients with xeroderma pigmentosum (XP) complementation groups A, B, C, D, F, and G compared to that in normal human fibroblasts. Differences in the HCR of cisplatin-treated Ad were also detected among human cancer cell lines, suggesting some tumour cells may be deficient in the NER of cisplatin-DNA adducts.


Harassment Patterns and Risk Profile in Spanish Trans Persons.
This article describes the harassment patterns and the risk profile in trans people living in Spain. A sample of 212 trans persons, aged 10-62, participated in this cross-sectional study. Results showed a high percentage of harassment (59.9%) and frequency of daily harassment (12.6%), especially verbal attacks (59%) that occurred in public spaces (49.1%) and within educational contexts (46.2%). Harassment is more prevalent in trans women than men. Those who disclose their gender identities at a younger age experience higher percentages and frequency of harassment than those who disclose at an older age. They also suffer more harassment of different types. The risk profile of harassment indicates that older trans women are more likely to suffer harassment than younger ones, and the risk decreases each year they delay their gender identity disclosure. The elimination of transphobic attitudes and the promotion of gender justice should be priority strategies in Spain.


Interplay between MexAB-OprM and MexEF-OprN in clinical isolates of Pseudomonas aeruginosa.
MexAB-OprM and MexEF-OprN are Pseudomonas aeruginosa efflux pumps involved in the development of antibiotic resistance. Several studies developed with laboratory strains or using a few clinical isolates have reported that the regulation system of MexEF-OprN is involved in the final levels of MexAB-OprM expression. Therefore, this study was aimed to determine the interplay between MexAB-OprM and MexEF-OprN in 90 out of 190 P. aeruginosa clinical isolates with an efflux pump overexpression phenotype. Regarding oprD, 33% (30/90) of isolates displayed relevant modifications (RM) defined as frameshift or premature stop, both related to carbapenem resistance. On the other hand, 33% of the isolates displayed RM in nalC, nalD or mexR, which were significantly associated with multidrug resistance (MDR), non-susceptibility to carbapenems, OprD alterations and strong biofilm production. Meanwhile, the RM in MexS were associated with presence of pigment (p = 0.004). Otherwise, when all the regulators were analysed together, the association between RM in MexAB-OprM regulators and MDR was only significant (p = 0.039) when mexS was the wild type. These data show the modulatory effect of MexEF-OprN on MexAB-OprM in a clinical population of P. aeruginosa. Further studies may contribute to design of novel molecules acting on this interplay to fight against antimicrobial resistance.


Interventions using electronic medical records improve follow up of infants born to hepatitis C virus infected mothers.
The American Academy of Pediatrics recommends hepatitis C virus (HCV) antibody testing for all HCV- exposed infants at age ≥ 18 months. However, many of these infants are not appropriately tested. In 2006, the pediatric infectious disease service (PIDS) at our institution implemented interventions using electronic medical records (EMR) to improve appropriate HCV testing for HCV-exposed infants. Two-part study: During the first period (January 1, 1993, to December 31, 2005), medical records of all infants born to mothers with HCV were retrospectively reviewed for patient's demographics and infant's HCV testing. PIDS interventions included contacting the primary care physician through EMR requesting HCV testing for children without proper testing. During the second period (January 1, 2006, to December 31, 2011), interventions using EMR were implemented prospectively, including PIDS consultations during birth hospitalization for all HCV-exposed infants, addition of HCV exposure to the EMR problem list and communication with PCPs via the EMR to assure appropriate HCV testing. About 67,112 infants were born during the study period; 280 had maternal HCV infection and 193 continued to receive medical care at our institution. PIDS interventions using EMR resulted in a significant improvement of appropriate HCV testing among HCV-exposed infants from 8% (10/121) to 50% (36/72); P <0.0001. It also resulted in the identification of 5 new HCV-infected children; 3 of them were born before 2006 and previously undiagnosed. Interventions using EMR improved the identification and appropriate HCV follow up of infants born to HCV-infected mothers.


Influence of phomopsin and ivalin on steroid-hormone binding and growth of MCF-7 human breast cancer cells.
Ivalin is a plant alkaloid that inhibits the induction of tumors in animals. Phomopsin is a mycotoxin known to be carcinogenic. To determine if these compounds influence endocrine responsiveness, their effect on steroid receptors was measured. Neither of these toxins had a direct effect on either the binding capacity or the rate of steroid association of [3H]estradiol-17 beta, [3H]R5020, or [3H]dexamethasone to their respective receptors in cytosol of human breast cancer and rat liver. However, steroid receptor levels of MCF-7 cells, grown in tissue culture, were altered by ivalin and phomopsin. Ivalin at 10(-6) M depressed estrogen receptor levels, while glucocorticoid receptor levels were increased. At 10(-6) M, phomopsin was inhibitory of both progestin and glucocorticoid binding capacities. Data obtained from the proliferation of MCF-7 cells indicated that ivalin and phomopsin at 10(-6) M decreased the number of cells grown in tissue culture. Phomopsin exhibited an inhibitory effect on both [3H]thymidine and [3H]glycine incorporation, while ivalin stimulated [3H]glycine incorporation.


Mechanism of enteroviral inactivation by ozone.
The mechanism of enteroviral inactivation by ozone was investigated with poliovirus 1 (Mahoney) as the model virus. Ozone was observed to alter two of the four polypeptide chains present in the viral protein coat of poliovirus 1. However, the alteration of the protein coat did not significantly impair virus adsorption or alter the integrity of the virus particle. Damage to the viral RNA after exposure to ozone was demonstrated by velocity sedimentation analysis. It was concluded that the damage to the viral nucleic acid is the major cause of poliovirus 1 inactivation by ozone.


Olfactory foraging in temperate waters: sensitivity to dimethylsulphide of shearwaters in the Atlantic Ocean and Mediterranean Sea.
Many procellariiforms use olfactory cues to locate food patches over the seemingly featureless ocean surface. In particular, some of them are able to detect and are attracted by dimethylsulphide (DMS), a volatile compound naturally occurring over worldwide oceans in correspondence with productive feeding areas. However, current knowledge is restricted to sub-Antarctic species and to only one study realized under natural conditions at sea. Here, for the first time, we investigated the response to DMS in parallel in two different environments in temperate waters, the Atlantic Ocean and the Mediterranean Sea, employing Cory's (Calonectris borealis) and Scopoli's (Calonectris diomedea) shearwaters as models. To test whether these birds can detect and respond to DMS, we presented them with this substance in a Y-maze. Then, to determine whether they use this molecule in natural conditions, we tested the response to DMS at sea. The number of birds that chose DMS in the Y-maze and that were recruited at DMS-scented slicks at sea suggests that these shearwaters are attracted to DMS in both non-foraging and natural contexts. Our findings show that the use of DMS as a foraging cue may be a strategy adopted by procellariiforms across oceans but that regional differences may exist, giving a worldwide perspective to previous hypotheses concerning the use of DMS as a chemical cue.


Extreme Risk Protection Orders in Older Adults in Six U.S. States: A Descriptive Study.
Extreme Risk Protection Orders (ERPOs) allow a court to restrict firearm access for individuals ("respondents") at imminent risk of harm to self/others. Little is known about ERPOs use for older adults, a population with higher rates of suicide and dementia. We abstracted ERPO cases through June 30, 2020, from California, Colorado, Connecticut, Florida, Maryland, and Washington. We restricted our analysis to petitions for older (≥65 years) respondents, stratified by documented cognitive impairment. Among 6,699 ERPO petitions, 672 (10.0%) were for older adults; 13.7% (n = 92) of these noted cognitive impairment. Most were white (75.7%) men (90.2%). Cognitively impaired (vs. non-impaired) respondents were older (mean age 78.2 vs 72.7 years) and more likely to have documented irrational/erratic behavior (30.4% vs 15.7%), but less likely to have documented suicidality (33.7% vs 55.0%). At the time of the petition, 56.2% of older adult respondents had documented firearm access (median accessible firearms = 3, range 1-160). Approximately 14% of ERPO petitions for older adults involved cognitive impairment; one-third of these noted suicide risk. Studies examining ERPO implementation across states may inform usage and awareness. ERPOs may reduce firearm access among older adults with cognitive impairment, suicidality, or risk of violence.


Laparoscopic Roux-en-Y gastric bypass in super obese Göttingen minipigs.
The specific mechanisms behind weight loss and comorbidity improvements in obese patients after Roux-en-Y gastric bypass (RYGBP) are still poorly understood. The aim of this study was to establish and evaluate the feasibility of a long-term survival RYGBP model in super obese Göttingen minipigs in order to improve the translational potential relative to current animal models. Eleven Göttingen minipigs with diet-induced obesity underwent laparoscopic RYGBP and were followed up to 9 months after surgery. Intra- and post-operative complications, body weight (BW), food intake and necropsy data were recorded. Five minipigs survived without complications to the end of the study. Four minipigs developed surgical related complications and were euthanized while two minipigs died due to central venous catheter related complications. BW and food intake is reported for the six minipigs surviving longer than 4.5 months post-surgery. Weight loss and reduced food intake was seen in all minipigs. After 2-3 months of weight loss, weight regain was evident in all but two minipigs which seemed to continue losing weight. Necropsy revealed some variation in the length of the alimentary, biliary and common limb between minipigs. The use of obese Göttingen minipigs as a translational RYGBP model is feasible and has potential for the study of RYGBP-related changes in gut function, type-2 diabetes and appetite regulation. Still, the surgical procedure is technically highly demanding in obese Göttingen minipigs and the peri-operative animal care and follow up requires close monitoring.


Changes in cerebrospinal fluid flow assessed using intraoperative MRI during posterior fossa decompression for Chiari malformation.
OBJECT The authors completed a prospective, institutional review board-approved study using intraoperative MRI (iMRI) in patients undergoing posterior fossa decompression (PFD) for Chiari I malformation. The purpose of the study was to examine the utility of iMRI in determining when an adequate decompression had been performed. METHODS Patients with symptomatic Chiari I malformations with imaging findings of obstruction of the CSF space at the foramen magnum, with or without syringomyelia, were considered candidates for surgery. All patients underwent complete T1, T2, and cine MRI studies in the supine position preoperatively as a baseline. After the patient was placed prone with the neck flexed in position for surgery, iMRI was performed. The patient then underwent a bone decompression of the foramen magnum and arch of C-1, and the MRI was repeated. If obstruction was still present, then in a stepwise fashion the patient underwent dural splitting, duraplasty, and coagulation of the tonsils, with an iMRI study performed after each step guiding the decision to proceed further. RESULTS Eighteen patients underwent PFD for Chiari I malformations between November 2011 and February 2013; 15 prone preincision iMRIs were performed. Fourteen of these patients (93%) demonstrated significant improvement of CSF flow through the foramen magnum dorsal to the tonsils with positioning only. This improvement was so notable that changes in CSF flow as a result of the bone decompression were difficult to discern. CONCLUSIONS The authors observed significant CSF flow changes when simply positioning the patient for surgery. These results put into question intraoperative flow assessments that suggest adequate decompression by PFD, whether by iMRI or intraoperative ultrasound. The use of intraoperative imaging during PFD for Chiari I malformation, whether by ultrasound or iMRI, is limited by CSF flow dynamics across the foramen magnum that change significantly when the patient is positioned for surgery.


Improving the coordination of patients' medication management: a regional Finnish development project.
In this paper, we present an overview of activities and results from a regional development project in Finland. The aim in this project was to analyze how healthcare providers produce and receive information on a patient's medication, and to identify opportunities to improve the quality, effectiveness, availability and collaboration of social and healthcare services in relation to medication information. The project focused on the most important points in patients' medication management such as home care and care transitions. In a regional development project, data was gathered by interviews and a multi professional workshop. The study revealed that medication information reached only some professionals and lay caregivers despite electronic patient record (EPR) systems and tools. Differences in work processes related to medication reconciliation and information management were discussed in the group meeting and were regarded as a considerable risk for patient safety.


Operational Basin Larvicide Evaluations in Northern Cook County, Illinois During 2019 and 2020.
Over the course of 2019 and 2020, 7 larvicide formulations for use in catch basins were evaluated using a standardized pass/fail protocol. A comparison between 1- and 2-pouch doses of VectoLex® water-soluble pouches (WSP; 10 g per pouch) and 20 g of VectoLex FG (loose granules) suggests that the WSP formulation may have a shorter duration than the FG formulation. Results also suggest that 20 g doses of each of 2 larvicides, Duplex™-G and Sumilarv® 0.5G, may have a minimum effective duration in basins for approximately 40 days. A 20 g dose of Altosid® XR-G and a single briquet Altosid XR each had an observed minimum effective duration of 20 days. Sustain MBG had an observed duration of only 7 wk posttreatment. These observations provide evidence that, in some locations, 20 g granular applications may have a longer effective duration than a single briquet. This work highlights the utility of applying a standardized protocol for routine quality control assessments of the thousands of catch basin larvicide applications performed seasonally by mosquito abatement districts.


RAD51 mutants cause replication defects and chromosomal instability.
RAD51 is important for restarting stalled replication forks and for repairing DNA double-strand breaks (DSBs) through a pathway called homology-directed repair (HDR). However, analysis of the consequences of specific RAD51 mutants has been difficult since they are toxic. Here we report on the dominant effects of two human RAD51 mutants defective for ATP binding (K133A) or ATP hydrolysis (K133R) expressed in mouse embryonic stem (ES) cells that also expressed normal mouse RAD51 from the other chromosome. These cells were defective for restarting stalled replication forks and repairing breaks. They were also hypersensitive to camptothecin, a genotoxin that generates breaks specifically at the replication fork. In addition, these cells exhibited a wide range of structural chromosomal changes that included multiple breakpoints within the same chromosome. Thus, ATP binding and hydrolysis are essential for chromosomal maintenance. Fusion of RAD51 to a fluorescent tag (enhanced green fluorescent protein [eGFP]) allowed visualization of these proteins at sites of replication and repair. We found very low levels of mutant protein present at these sites compared to normal protein, suggesting that low levels of mutant protein were sufficient for disruption of RAD51 activity and generation of chromosomal rearrangements.


Fluorescent Dynamic Covalent Polymers for DNA Complexation and Templated Assembly.
Dynamic covalent polymers (DCPs) offer opportunities as adaptive materials of particular interest for targeting, sensing and delivery of biological molecules. In this view, combining cationic units and fluorescent units along DCP chains is attractive for achieving optical probes for the recognition and delivery of nucleic acids. Here, we report on the design of acylhydrazone-based DCPs combining cationic arginine units with π-conjugated fluorescent moieties based on thiophene-ethynyl-fluorene cores. Two types of fluorescent building blocks bearing neutral or cationic side groups on the fluorene moiety are considered in order to assess the role of the number of cationic units on complexation with DNA. The (chir)optical properties of the building blocks, the DCPs, and their complexes with several types of DNA are explored, providing details on the formation of supramolecular complexes and on their stability in aqueous solutions. The DNA-templated formation of DCPs is demonstrated, which provides new perspectives on the assembly of fluorescent DCP based on the nucleic acid structure.


Mercury in Hair Is Inversely Related to Disease Associated Damage in Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease, and environmental factors are proposed to exacerbate existing symptoms. One such environmental factor is mercury. The aim of this study was to investigate the relationship between exposure to mercury (Hg) and disease activity and disease associated damage in Total Hg concentrations in hair and urine were measured in 52 SLE patients. Dental amalgams were quantified. Disease activity was assessed using three indexes including the British Isles Lupus Assessment Group Index (BILAG). Disease associated damage was measured using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology SLICC/ACR Damage Index. Pearson's correlation identified a significant negative correlation between hair Hg and BILAG (r = -0.323, p = 0.029) and SLICC/ACR (r = -0.377, p = 0.038). Multiple regression analysis identified hair Hg as a significant predictor of disease associated damage as determined by SLICC/ACR (β = -0.366, 95% confidence interval (CI): -1.769, -0.155 p = 0.019). Urinary Hg was not related to disease activity or damage. Fish consumption is the primary route of MeHg exposure in humans and the inverse association of hair Hg with disease activity observed here might be explained by the anti-inflammatory effects of n-3 long chain polyunsaturated fatty acids also found in fish.


Relationship between limb movement speed and associated contraction of the trunk muscles.
Rapid shoulder movement is preceded by contraction of the abdominal muscles to prepare the body for the expected disturbance to postural equilibrium and spinal stability provoked by the reactive forces resulting from the movement. The magnitude of the reactive forces is proportional to the inertia of the limb. The aim of the study was to investigate if changes in the reaction time latency of the abdominal muscles was associated with variation in the magnitude of the reactive forces resulting from variation in limb speed. Fifteen participants performed shoulder flexion at three different speeds (fast, natural and slow). The onset of EMG of the abdominal muscles, erector spinae and anterior deltoid (AD) was recorded using a combination of fine-wire and surface electrodes. Mean and peak velocity was recorded for each limb movement speed for five participants. The onset of transversus abdominis (TrA) EMG preceded the onset of AD in only the fast movement condition. No significant difference in reaction time latency was recorded between the fast and natural speed conditions for all muscles. The reaction time of each of the abdominal muscles relative to AD was significantly delayed with the slow movement compared to the other two speeds. The results indicate that the reaction time latency of the trunk muscles is influenced by limb inertia only with limb movement below a threshold velocity.


Validity of self-reported varicella disease history in pregnant women attending prenatal clinics.
The purpose of this study was to assess the validity of self-reported history for varicella disease relative to serological evidence of varicella immunity in pregnant women attending antenatal care at clinics located in two diverse geographical locations in the U.S. (Antelope Valley, California, and Philadelphia) with high varicella vaccination coverage. Pregnant women attending prenatal care appointments who needed blood drawn as part of their routine care were eligible to participate. Self-reported varicella disease history was obtained via questionnaire. Varicella serostatus was determined using a whole-cell enzyme-linked immunosorbent assay to test for varicella zoster virus-specific immunoglobulin G (VZV IgG) antibodies. Of the 309 study participants from Antelope Valley and the 528 participants from Philadelphia who self-reported having had chickenpox disease, 308 (99.7%; 95% confidence interval [CI]: 98.2, 100) and 517 (97.9%; 95% CI: 96.3, 99.0), respectively, had serological evidence of immunity to varicella. Only 6.8% (95% CI: 3.9, 11.0) and 17.4% (95% CI: 13.1, 22.5) of women who self-reported having a negative or uncertain varicella disease history in Antelope Valley and Philadelphia, respectively, were seronegative for varicella antibodies. Despite the dramatic changes in the epidemiology of varicella that have occurred since 1995 due to the introduction and subsequent widespread use of the varicella vaccine, self-reported history of varicella continues to be a strong predictor of VZV IgG antibodies in pregnant women. Negative or uncertain history remains poorly predictive of negative serostatus.


Thromboembolic prophylaxis in moderate-risk patients undergoing elective abdominal surgery: decision and cost-effectiveness analyses.
We conducted a retrospective, literature-based decision analysis to compare the cost-effectiveness of conventional low-dose heparin, dalteparin, and intermittent pneumatic compression (IPC) as thromboembolic prophylaxis to a no-prophylaxis option in patients at moderate risk of developing thromboembolic complications after major elective abdominal surgery. The analysis was conducted through an institutional perspective. Probability and incidence rate data were summarized from the literature. Cost data were obtained from the Detroit Medical Center's cost accounting systems and from national diagnosis-related group estimates. Mortality and complications avoided were the main outcome measures on which cost-effectiveness was based. Overall costs associated with conventional low-dose heparin, dalteparin, intermittent pneumatic compression, and no prophylaxis were $84, $122, $102, and $112, respectively in the primary analysis, which included costs of labor. Corresponding cost-effectiveness ratios in terms of costs/complication-free patient were $86, $124, $103, and $118, respectively. Compared with no prophylaxis, incremental cost-effectiveness analysis in terms of cost/mortality avoided involved savings of $6087 and $3125 with conventional low-dose heparin and IPC, respectively, and expenses of $2857 with dalteparin. A secondary analysis excluding costs of labor showed similar results. The results of the study consistently showed conventional low-dose heparin to provide the most cost-effective thromboembolic prophylaxis of the methods considered in terms of reducing both morbidity and mortality in the patient population studied.


Construction of a ceRNA-based lncRNA-mRNA network to identify functional lncRNAs in polycystic ovarian syndrome.
Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder in women of childbearing age. Recent studies suggest important roles for lncRNAs in PCOS development. Based on the hypothesis that lncRNAs are able to regulate mRNA functions by competitive binding to shared miRNAs, the present work sought to construct a PCOS-related lncRNA-mRNA network (PCLMN) to identify key lncRNAs with dysregulated expression and potential prognostic and therapeutic relevance. A global background network was constructed after retrieving lncRNA-miRNA and miRNA-mRNA pairs from the lncRNASNP2, miRTarBase and StarBase databases. Based on gene expression profiles from ovarian granulosa cells from PCOS patients and controls in the GEO's GSE95728 dataset, the PCLMN was then constructed by applying hypergeometric testing. Using topological analysis, we identified 3 lncRNAs (LINC00667, AC073172.1 and H19) ranking within the top-ten gene lists for all three centrality measures. We then explored their subcellular localization, performed functional module analyses, and identified 4 sex hormone-related transcription factors as potential regulators of their expression. Significant associations with inflammation, oxidative stress, and apoptosis-related processes and pathways were revealed for the key lncRNAs in our PCMLN. Further studies verifying the mRNA/lncRNA relationships identified herein are needed to clarify their clinical significance.


gamma-Aminobutyric acid receptor distribution in the mushroom bodies of a fly (Calliphora erythrocephala): a functional subdivision of Kenyon cells?
Antibodies against the Drosophila gamma-aminobutyric acid (GABA) receptor subunit RDL were used to investigate the significance of inhibitory inputs to the mushroom bodies in the blowfly (Calliphora erythrocephala) brain. The pedunculus and the lobes of the mushroom body, which mainly consist of Kenyon cell fibers, revealed strong immunoreactivity against RDL. Pedunculi, alpha- and beta-lobe show characteristic unstained core structures with concentric labeling along the neuropile axis. The gamma-lobes in contrast exhibit a compartmentalized RDL-immunoreactive pattern. These data suggest an important role of GABAergic inhibition in the pedunculus and the lobes of insect mushroom bodies. It is most likely that the RDL-immunoreactivity in the mushroom bodies is closely related to Kenyon cell fibers suggesting that Kenyon cells are an inhomogeneous class of neurons, only part of which receive inhibitory GABAergic input from extrinsic elements. GABAergic inhibition, therefore, may play a substantial role in the process of learning and memory formation in the insect mushroom bodies.


[Organization of therapeutic aid to pregnant women, delivering and delivered women].
An experience on the organization of therapeutic care for pregnant women, women-in-labour and puerperants is presented by the example of the city of Tolyatti. An organizational model related with rendering such care is defined; the model envisages the continuity of obstetrics, therapeutic and pediatric complexes, the general therapeutic practice, the practice of maternity welfare clinics, the practice of day-time inhospital policlinic facilities as well as the practice of somatic maternity hospitals. "Therapeutic consultations" and "Passport of extragenital pathology" came to be principally new technologies in Tolyatti.


Oblique split technique in septal reconstruction.
The septum is considered to be the most important anatomical structure in providing nasal support. Because of a variety of potential etiologies nasal septum could be severely deformed or even diminished. Autogenous cartilage has generally been considered the gold standard grafting material in reconstructive septal surgery for creating the infrastructure of the nose. In the restructuring of the nasal skeleton autogenous cartilage can be harvested from the auricle or the rib. For the major septal problems requiring a large volume of tissues with severe structural defects costal cartilage is considered the best graft material. Apart from its advantages, warping has been the main problem with costal cartilage grafting. Oblique split method, provides straight costal cartilage grafts of varying thicknesses without the risk of warping. Segmental reconstruction of the L-strut with oblique split method, composed of dorsal and caudal struts, enables fine adjustment of height of the reconstructed septum.


Spinal cord intramedullary cavernoma: A case report.
Spinal Cord Intramedullary Cavernoma is a rare disease. It is a vascular disorder composed of capillary-liked vessels without intervening neurons within a spinal lesion. It may only be discovered incidentally or may be diagnosed after a neurologic deficit. Patients may present with weakness which could mimic other neurologic pathology. A case of a 65 year old with history of hypertension and diabetes mellitus. He had previous microdissectomy of the lumbar L4-L5 disc. He presented with progressive lower leg paresis, urinary retention and obstipation. An MRI revealed a cavernous angioma at the T5 level. A multitude of neurologic deficits could lead to a patient presenting with a Spinal Cord Cavernoma. Prompt imaging is warranted in cases presenting with the symptoms to allow appropriate diagnoses and treatment. The clinician must be aware of this rare, but debilitating disease complex.


Trail running injury risk factors: a living systematic review.
To review and frequently update the available evidence on injury risk factors and epidemiology of injury in trail running. Living systematic review. Updated searches will be done every 6 months for a minimum period of 5 years. Eight electronic databases were searched from inception to 18 March 2021. Studies that investigated injury risk factors and/or reported the epidemiology of injury in trail running. Nineteen eligible studies were included, of which 10 studies investigated injury risk factors among 2 785 participants. Significant intrinsic factors associated with injury are: more running experience, level A runner and higher total propensity to sports accident questionnaire (PAD-22) score. Previous history of cramping and postrace biomarkers of muscle damage is associated with cramping. Younger age and low skin phototypes are associated with sunburn. Significant extrinsic factors associated with injury are neglecting warm-up, no specialised running plan, training on asphalt, double training sessions per day and physical labour occupations. A slower race finishing time is associated with cramping, while more than 3 hours of training per day, shade as the primary mode of sun protection and being single are associated with sunburn. An injury incidence range 0.7-61.2 injuries/1000 hours of running and prevalence range 1.3% to 90% were reported. The lower limb was the most reported region of injury, specifically involving blisters of the foot/toe. Limited studies investigated injury risk factors in trail running. Our review found eight intrinsic and nine extrinsic injury risk factors. This review highlighted areas for future research that may aid in designing injury risk management strategies for safer trail running participation.PROSPERO registration numberCRD42021240832.


Cell cycle control as a basis for cancer chemoprevention through dietary agents.
The development of cancer is associated with disorders in the regulation of the cell cycle. The purpose of this review is to briefly summarize the known sequence of events that regulate cell cycle progression with an emphasis on the checkpoints and the mechanisms cell employ to insure DNA stability in the face of genotoxic stress. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinases (CDK) molecules. The cyclins are CDK binding partners which are required for kinase activity and their protein levels are intimately linked to the cell cycle stage. CDK activity can be regulated by other mechanisms, such as phosphorylation events, that may contribute to deregulation of cell cycle and the development of cancer. While fruits and vegetables are recommended for prevention of cancer, their active ingredients and mechanisms of action are less well understood. Here, we briefly present evidence that dietary agents identified from fruits and vegetables can act to modulate the effects of deregulated cell cycle checkpoints, and that this may contribute to the prevention of cancer. The agents include apigenin (celery, parsley), curcumin (turmeric), (-)-epigallocatechin-3-gallate (green tea), resveratrol (red grape, peanuts and berries), genistein (soybean), and silymarin (milk thistle). The teachings of Hippocrates are still true "let food be thy medicine and medicine be thy food".


A longitudinal cohort study of the relationship between Thimerosal-containing hepatitis B vaccination and specific delays in development in the United States: Assessment of attributable risk and lifetime care costs.
Epidemiological evidence suggests a link between mercury (Hg) exposure from Thimerosal-containing vaccines and specific delays in development. A hypothesis-testing longitudinal cohort study (n=49,835) using medical records in the Vaccine Safety Datalink (VSD) was undertaken to evaluate the relationship between exposure to Hg from Thimerosal-containing hepatitis B vaccines (T-HBVs) administered at specific intervals in the first 6months of life and specific delays in development [International Classification of Disease, 9th revision (ICD-9): 315.xx] among children born between 1991 and 1994 and continuously enrolled from birth for at least 5.81years. Infants receiving increased Hg doses from T-HBVs administered within the first month, the first 2months, and the first 6months of life were significantly more likely to be diagnosed with specific delays in development than infants receiving no Hg doses from T-HBVs. During the decade in which T-HBVs were routinely recommended and administered to US infants (1991-2001), an estimated 0.5-1million additional US children were diagnosed with specific delays in development as a consequence of 25μg or 37.5μg organic Hg from T-HBVs administered within the first 6months of life. The resulting lifetime costs to the United States may exceed $1 trillion.


WI12Rhg1 interacts with DELLAs and mediates soybean cyst nematode resistance through hormone pathways.
The soybean cyst nematode (SCN) is one of the most important causes of soybean yield loss. The major source of genetic resistance to SCN is the Rhg1 repeat, a tandem copy number polymorphism of three genes. The roles of these genes are only partially understood. Moreover, nematode populations virulent on Rhg1-carrying soybeans are becoming more common, increasing the need to understand the most successful genetic resistance mechanism. Here, we show that a Rhg1-locus gene (Glyma.18G02270) encoding a wound-inducible protein (WI12Rhg1 ) is needed for SCN resistance. Furthermore, knockout of WI12Rhg1 reduces the expression of DELLA18, and the expression of WI12Rhg1 is itself induced by either JA, SA or GA. The content of the defence hormone SA is significantly lower whilst GA12 and GA53 are increased in WI12Rhg1 knockout roots compared with unedited hairy roots. We find that WI12Rhg1 directly interacts with DELLA18 (Glyma.18G040000) in yeast and plants and that double knockout of DELLA18 and its homeolog DELLA11 (Glyma.11G216500) significantly reduces SCN resistance and alters the root morphology. As DELLA proteins are implicated in hormone signalling, we explored the content of defence hormones (JA and SA) in DELLA knockout and unedited roots, finding reduced levels of JA and SA after the knockout of DELLA. Additionally, the treatment of DELLA-knockout roots with JA or SA rescues SCN resistance lost by the knockout. Meanwhile, the SCN resistance of unedited roots decreases after the treatment with GA, but increases with JA or SA. Our findings highlight the critical roles of WI12Rhg1 and DELLA proteins in SCN resistance through interconnection with hormone signalling.


[Evaluation of the quality of hospital care of prisoners (results of sociological interviews)].
Interregional hospital attached to administration of prisons renders specialized care to prisoners. Anonymous sociological questionnaires distributed among 815 patients treated at the hospital showed that the patients were satisfied with organization of medical care and communal provision and demonstrated serious problems in organization of hospital care rendered to prisoners.


Digital Health Skillsets and Digital Preparedness: Comparison of Veterans Health Administration Users and Other Veterans Nationally.
As health care systems shift to greater use of telemedicine and digital tools, an individual's digital health literacy has become an important skillset. The Veterans Health Administration (VA) has invested resources in providing digital health care; however, to date, no study has compared the digital health skills and preparedness of veterans receiving care in the VA to veterans receiving care outside the VA. The goal of the research was to describe digital health skills and preparedness among veterans who receive care within and outside the VA health care system and examine whether receiving care in the VA is associated with digital preparedness (reporting more than 2 digital health skills) after accounting for demographic and social risk factors. We used cross-sectional data from the 2016-2018 National Health Interview Survey to identify veterans (aged over 18 years) who obtain health care either within or outside the VA health care system. We used multivariable logistic regression models to examine the association of sociodemographic (age, sex, race, ethnicity), social risk factors (economic instability, disadvantaged neighborhood, low educational attainment, and social isolation), and health care delivery location (VA and non-VA) with digital preparedness. Those who received health care within the VA health care system (n=3188) were younger (age 18-49 years: 33.3% [95% CI 30.7-36.0] vs 24.2% [95% CI 21.9-26.5], P<.01), were more often female (34.7% [95% CI 32.0-37.3] vs 6.6% [95% CI 5.5-7.6], P<.01) and identified as Black (13.1% [95% CI 11.2-15.0] vs 10.2% [95% CI 8.7-11.8], P<.01), and reported greater economic instability (8.3% [95% CI 6.9-9.8] vs 5.5% [95% CI 4.6-6.5], P<.01) and social isolation (42.6% [95% CI 40.3-44.9] vs 35.4% [95% CI 33.4-37.5], P<.01) compared to veterans who received care outside the VA (n=3393). Veterans who obtained care within the VA reported more digital health skills than those who obtained care outside the VA, endorsing greater rates of looking up health information on the internet (51.8% [95% CI 49.2-54.4] vs 45.0% [95% CI 42.6-47.3], P<.01), filling a prescription using the internet (16.2% [95% CI 14.5-18.0] vs 11.3% [95% CI 9.6-13.0], P<.01), scheduling a health care appointment on the internet (14.1% [95% CI 12.4-15.8] vs 11.6% [95% CI 10.1-13.1], P=.02), and communicating with a health care provider by email (18.0% [95% CI 16.1-19.8] vs 13.3% [95% CI 11.6-14.9], P<.01). Following adjustment for sociodemographic and social risk factors, receiving health care from the VA was the only characteristic associated with higher odds (adjusted odds ratio [aOR] 1.36, 95% CI 1.12-1.65) of being digitally prepared. Despite these demographic disadvantages to digital uptake, veterans who receive care in the VA reported more digital health skills and appear more digitally prepared than veterans who do not receive care within the VA, suggesting a positive, system-level influence on this cohort.


Exploring the cognitive load of negative thinking: a novel dual-task experiment.
Females are more likely to engage in the preoccupation of past negative experiences than males, which might contribute to their greater tendency toward depression. However, there is limited understanding regarding the cognitive basis for the negative autobiographical information processing of females. In the present study, we assessed the cognitive resources required for negative thinking, by using a novel dual-task paradigm that combined think-aloud and time-estimation tasks. Fifty-three Japanese undergraduate students were asked to think aloud about personal past or future emotional episodes for a particular duration. In addition, they were asked to estimate the duration of their speech. Their estimates were compared to the actual time taken, and the errors were used as indices of cognitive burden during the speech task. As compared to males, females exhibited greater judgment errors, particularly when thinking about their past negative experiences. This suggests that females allocate more attentional resources toward thinking about the past. Participants could rehearse the task during the time reproduction phase, and the quality of the rehearsal and their memory capacity might have influenced the accuracy of their duration judgment. Females tend to allocate more attentional resources than males to thinking about past negative episodes, which in turn might be associated with reduced availability of resources for central cognitive control processes such as inhibition of and switching away from processing of negative autobiographical information.


Acquired immunodeficiencies and tuberculosis: focus on HIV/AIDS and diabetes mellitus.
The spread of human immunodeficiency virus (HIV) infection within Africa led to marked increases in numbers of cases of tuberculosis (TB), and although the epidemic peaked in 2006, there were still 1.8 million new cases in 2013, with 29.2 million prevalent cases. Half of all TB cases in Africa are in those with HIV co-infection. A brief review of the well-documented main immunological mechanisms of HIV-associated increased susceptibility to TB is presented. However, a new threat is facing TB control, which presents itself in the form of a rapid increase in the number of people living with type II diabetes mellitus (T2DM), particularly in areas that are already hardest hit by the TB epidemic. T2DM increases susceptibility to TB threefold, and the TB burden attributable to T2DM is 15%. This review addresses the much smaller body of research information available on T2DM-TB, compared to HIV-TB comorbidity. We discuss the altered clinical presentation of TB in the context of T2DM comorbidity, changes in innate and adaptive immune responses, including lymphocyte subsets and T-cell phenotypes, the effect of treatment of the different comorbidities, changes in biomarker expression and genetic predisposition to the respective morbidities, and other factors affecting the comorbidity. Although significant gains have been made in improving our understanding of the underlying mechanisms of T2DM-associated increased susceptibility, knowledge gaps still exist that require urgent attention.


Natural variation in preparation for nutrient depletion reveals a cost-benefit tradeoff.
Maximizing growth and survival in the face of a complex, time-varying environment is a common problem for single-celled organisms in the wild. When offered two different sugars as carbon sources, microorganisms first consume the preferred sugar, then undergo a transient growth delay, the "diauxic lag," while inducing genes to metabolize the less preferred sugar. This delay is commonly assumed to be an inevitable consequence of selection to maximize use of the preferred sugar. Contrary to this view, we found that many natural isolates of Saccharomyces cerevisiae display short or nonexistent diauxic lags when grown in mixtures of glucose (preferred) and galactose. These strains induce galactose utilization (GAL) genes hours before glucose exhaustion, thereby "preparing" for the transition from glucose to galactose metabolism. The extent of preparation varies across strains, and seems to be determined by the steady-state response of GAL genes to mixtures of glucose and galactose rather than by induction kinetics. Although early GAL gene induction gives strains a competitive advantage once glucose runs out, it comes at a cost while glucose is still present. Costs and benefits correlate with the degree of preparation: strains with higher expression of GAL genes prior to glucose exhaustion experience a larger upfront growth cost but also a shorter diauxic lag. Our results show that classical diauxic growth is only one extreme on a continuum of growth strategies constrained by a cost-benefit tradeoff. This type of continuum is likely to be common in nature, as similar tradeoffs can arise whenever cells evolve to use mixtures of nutrients.


Effects of oscillatory flow on fertilization in the green sea urchin Strongylocentrotus droebachiensis.
Broadcast spawning invertebrates that live in shallow, high-energy coastal habitats are subjected to oscillatory water motion that creates unsteady flow fields above the surface of animals. The frequency of the oscillatory fluctuations is driven by the wave period, which will influence the stability of local flow structures and may affect fertilization processes. Using an oscillatory water tunnel, we quantified the percentage of eggs fertilized on or near spawning green sea urchins, Strongylocentrotus droebachiensis. Eggs were sampled in the water column, wake eddy, substratum and aboral surface under a range of different periods (T = 4.5-12.7 s) and velocities of oscillatory flow. The root-mean-square wave velocity (rms(u(w))) was a good predictor of fertilization in oscillatory flow, although the root-mean-square of total velocity (rms(u)), which incorporates all the components of flow (current, wave and turbulence), also provided significant predictions. The percentage of eggs fertilized varied between 50-85% at low flows (rms(u(w)) <0.02 m s(-1)), depending on the location sampled, but declined to below 10% for most locations at higher rms(u(w)). The water column was an important location for fertilization with a relative contribution greater than that of the aboral surface, especially at medium and high rms(u(w)) categories. We conclude that gametes can be successfully fertilized on or near the parent under a range of oscillatory flow conditions.


Scoredist: a simple and robust protein sequence distance estimator.
Distance-based methods are popular for reconstructing evolutionary trees thanks to their speed and generality. A number of methods exist for estimating distances from sequence alignments, which often involves some sort of correction for multiple substitutions. The problem is to accurately estimate the number of true substitutions given an observed alignment. So far, the most accurate protein distance estimators have looked for the optimal matrix in a series of transition probability matrices, e.g. the Dayhoff series. The evolutionary distance between two aligned sequences is here estimated as the evolutionary distance of the optimal matrix. The optimal matrix can be found either by an iterative search for the Maximum Likelihood matrix, or by integration to find the Expected Distance. As a consequence, these methods are more complex to implement and computationally heavier than correction-based methods. Another problem is that the result may vary substantially depending on the evolutionary model used for the matrices. An ideal distance estimator should produce consistent and accurate distances independent of the evolutionary model used. We propose a correction-based protein sequence estimator called Scoredist. It uses a logarithmic correction of observed divergence based on the alignment score according to the BLOSUM62 score matrix. We evaluated Scoredist and a number of optimal matrix methods using three evolutionary models for both training and testing Dayhoff, Jones-Taylor-Thornton, and Muller-Vingron, as well as Whelan and Goldman solely for testing. Test alignments with known distances between 0.01 and 2 substitutions per position (1-200 PAM) were simulated using ROSE. Scoredist proved as accurate as the optimal matrix methods, yet substantially more robust. When trained on one model but tested on another one, Scoredist was nearly always more accurate. The Jukes-Cantor and Kimura correction methods were also tested, but were substantially less accurate. The Scoredist distance estimator is fast to implement and run, and combines robustness with accuracy. Scoredist has been incorporated into the Belvu alignment viewer, which is available at ftp://ftp.cgb.ki.se/pub/prog/belvu/.


The Epidemiology of Metatarsal Fractures Among Older Females With Bisphosphonate Exposure.
Bisphosphonates (BP) are used to treat osteoporosis, although rare atypical femur fractures have occurred with long-term exposure, especially among Asians. Metatarsal fractures have also been reported with atypical femur fracture. We examined the epidemiology of metatarsal fractures among 48,390 females aged ≥50 years who initiated oral BP and were followed for a median 7.7 years, including 68 females who experienced an atypical femur fracture. Incident metatarsal fractures after BP initiation were identified by clinical diagnoses and validated by record review. The association of BP, clinical risk factors, race/ethnicity, and metatarsal fracture was examined by using Cox proportional hazard analyses. Among 1123 females with incident metatarsal fracture, 61.0% had an isolated fifth metatarsal fracture. The incidence of metatarsal fracture was 312 per 100,000 person-years of follow-up and was substantially lower for Asians. The adjusted relative rate for metatarsal fractures was 0.5 (95% confidence interval 0.4 to 0.6) for Asians compared with whites. Younger age, prior fracture, other risk factors, and current BP were associated with an increased relative rate of metatarsal fracture, but BP duration was not. Females with atypical femur fracture were not more likely to experience metatarsal fracture (2.9% versus 2.3%, p = .7), but only 68 females had an atypical fracture and stress fracture of the metatarsals was not examined. Except for age, the demographic profile for metatarsal fracture after initiating BP was similar to that for osteoporotic fracture, with Asians at a much lower risk. Although metatarsal fractures were not associated with BP duration or atypical femur fracture, the subset of metatarsal stress fractures was not specifically examined.


Molecular dynamics of a short-range ordered smectic phase nanoconfined in porous silicon.
4-n-octyl-4-cyanobiphenyl has been recently shown to display an unusual sequence of phases when confined into porous silicon (PSi). The gradual increase of oriented short-range smectic (SRS) correlations in place of a phase transition has been interpreted as a consequence of the anisotropic quenched disorder induced by confinement in PSi. Combining two quasielastic neutron scattering experiments with complementary energy resolutions, the authors present the first investigation of the individual molecular dynamics of this system. A large reduction of the molecular dynamics is observed in the confined liquid phase, as a direct consequence of the boundary conditions imposed by the confinement. Temperature fixed window scans reveal a continuous glasslike reduction of the molecular dynamics of the confined liquid and SRS phases on cooling down to 250 K, where a solidlike behavior is finally reached by a two-step crystallization process.


Mesenchymal stem cells: application for solid-organ transplantation.
Mesenchymal stem or stromal cells (MSCs) are multipotent cells with immunomodulatory and regenerative capacities. These properties make MSCs interesting for use as a cell therapeutic agent in solid-organ transplantation (SOT). Their applicability in SOT has recently been evaluated in numerous preclinical and clinical studies, which are reviewed in this article. Animal transplant studies indicate that MSCs can improve the outcome of SOT. In-vitro research has resulted in new insights into the paracrine mechanism and cell-dependent mechanism of action, migratory behaviour and immunogenicity of MSCs that are relevant for application of MSCs in SOT. Currently, six trials are registered to evaluate MSCs in phase I/II studies in SOT. The first clinical data are now published describing MSC infusion in organ transplant recipients. The research to date confirms that MSCs are a promising cell therapeutic agent for application in SOT and the first clinical trials have been initiated. The exact mechanisms of MSC therapy have, however, not been elucidated. Further basic and clinical research is needed to develop effective MSC therapy in SOT patients.


Inactivation of the renal outer cortical brush-border membrane D-glucose transporter by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.
The inactivation of the renal outer cortical brush-border membrane D-glucose transporter by the covalent carboxyl reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is studied by monitoring its effects on sodium-dependent phlorizin binding to the active site of the carrier. In the presence of EEDQ, this component of phlorizin binding decreases exponentially and irreversibly with time. The order of this inactivation reaction is very close to 1, indicating that EEDQ modifies the transporter at a single essential site. This site can be partially protected by glucose and by other substrates of the transporter and completely protected by phlorizin, a nontransported competitive inhibitor. By contrast, sodium, a co-transported activator, has no protective effect. The concentration dependence of the protection provided by glucose and phlorizin indicates that the site of action of EEDQ is at or closely related to the substrate binding site on the carrier. The effects of EEDQ on the transporter are mimicked by another carboxyl specific reagent, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate. The rate of inactivation of the transporter by EEDQ increases dramatically with decreasing pH, consistent with the hypothesis that the rate-limiting step in the inactivation process is a reaction with an essential carboxyl group. The properties of this group indicate, however, that it is distinct from the carboxyl group proposed by others as forming (a part of) the sodium binding site of sodium-coupled sugar carriers.


Eosinophilia and resistance to Schistosoma haematobium in man.
We have measured the levels of infection with Schistosoma haematobium in children resident in an endemic area of The Gambia before and 3 months after successful chemotherapy and following reinfection. An exposure index was calculated from data collected on water contact, cercarial densities and infected snail densities at water contact sites. Peripheral blood eosinophil levels were recorded and the ability of serum (heat inactivated) from the children to allow killing of schistosomula of S. haematobium was examined. Of 50 children with a post-treatment egg count of less than 1 ovum/10 ml urine, 26 were classified as reinfected, acquiring greater than 1 ovum/10 ml urine over the transmission season. Twenty-four were classified as not reinfected, acquiring less than 1 ovum/10 ml of urine over the same period. These two groups did not differ with respect to their estimated age, weight or pretreatment egg counts. Children who were reinfected had significantly higher levels of exposure and significantly lower peripheral blood eosinophil counts than children who were not reinfected. At all levels of exposure children with high eosinophil counts were less likely to be reinfected than those with lower counts. But antibody-dependent, complement-independent killing of schistosomula of S. haematobium by eosinophils was barely detectable and did not differ between reinfected and non reinfected groups. These observations suggest that subjects with elevated counts are less susceptible to reinfection but the mechanisms involved are not apparent.


Paramedic Initiated Lisinopril For Acute Stroke Treatment (PIL-FAST): results from the pilot randomised controlled trial.
High blood pressure (BP) during acute stroke is associated with poorer stroke outcome. Trials of treatments to lower BP have not resulted in improved outcome, but this may be because treatment commenced too late. Emergency medical service staff (paramedics) are uniquely placed to administer early treatment; however, experience of prehospital randomised controlled trials (RCTs) is very limited. We conducted a pilot RCT to determine the feasibility of a definitive prehospital BP-lowering RCT in acute stroke. Paramedics were trained to identify, consent and deliver a first dose of lisinopril or placebo to adults with suspected stroke and hypertension while responding to the emergency call. Further treatment continued in hospital. Study eligibility, recruitment rate, completeness of receipt of study medication and clinical data (eg, BP) were collected to inform the design of a definitive RCT. In 14 months, 14 participants (median age=73 years, median National Institute of Health Stroke Scale=4) were recruited and received the prehospital dose of medication. Median time from stroke onset (as assessed by paramedic) to treatment was 70 min. Four participants completed 7 days of study treatment. Of ambulance transported suspected stroke patients, 1% were both study eligible and attended by a PIL-FAST paramedic. It is possible to conduct a paramedic initiated double-blind RCT of a treatment for acute stroke. However, to perform a definitive RCT in a reasonable timescale, a large number of trained paramedics across several ambulance services would be needed to recruit the number of patients likely to be required. http://www.clinicaltrials.gov. Unique identifier: NCT01066572.


Positive effects of intermittent fasting in ischemic stroke.
Intermittent fasting (IF) is a dietary protocol where energy restriction is induced by alternate periods of ad libitum feeding and fasting. Prophylactic intermittent fasting has been shown to extend lifespan and attenuate the progress and severity of age-related diseases such as cardiovascular (e.g. stroke and myocardial infarction), neurodegenerative (e.g. Alzheimer's disease and Parkinson's disease) and cancerous diseases in animal models. Stroke is the second leading cause of death, and lifestyle risk factors such as obesity and physical inactivity have been associated with elevated risks of stroke in humans. Recent studies have shown that prophylactic IF may mitigate tissue damage and neurological deficit following ischemic stroke by a mechanism(s) involving suppression of excitotoxicity, oxidative stress, inflammation and cell death pathways in animal stroke models. This review summarizes data supporting the potential hormesis mechanisms of prophylactic IF in animal models, and with a focus on findings from animal studies of prophylactic IF in stroke in our laboratory.


Hypokalemia: causes, consequences and correction.
Hypokalemia poses a common diagnostic challenge with many potential etiologies. Multiple factors may contribute to this electrolyte deficiency in any given patient. Gastrointestinal potassium wasting usually is identifiable by an associated increase in fluid losses via biliary tract or bowel. A urinary potassium excretion of 20 mEq or more per day in the presence of a low serum potassium (less than 3.5 mEq/L) suggests inappropriate potassium wasting. Although diuretic therapy (loop diuretics, thiazides) undoubtedly is the most common cause of a potassium deficit, one also must consider abnormalities of the pituitary-adrenal axis, renal disorders including tumors, other drugs, and a variety of less well-defined entities. Potassium deficiency may produce both functional and structural defects in the kidneys, myocardium, skeletal muscle, central nervous system, and gastrointestinal tract. Treatment is aimed at replacing potassium intravenously or orally or preventing further potassium loss (spironolactone, triamterene); when associated with a metabolic alkalosis (chloride deficiency), the replacement should be potassium chloride.


MALAT1 as a Diagnostic and Therapeutic Target in Diabetes-Related Complications: A Promising Long-Noncoding RNA.
Diabetes mellitus is a global issue with increasing incidence rate worldwide. In an uncontrolled case, it can advance to various organ-related complications leading to an increase in morbidity and mortality. Long non-coding RNA (lncRNA) Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) appears to be a fairly novel lncRNA that is relevant to diabetes and its role in diabetic-related diseases initiation and progression have long been a subject of attention to many scholars. The expression of MALAT1 is elevated in different diabetic-related diseases. In this review, we demonstrate the various functions of MALAT1 in the different diabetes-related complications including ischemic reperfusion injury, retinopathy, cataract, atherosclerosis, cardiomyopathy, non-alcoholic steatohepatitis, gastroparesis, kidney disease, and gestational diabetes. The emerging evidence showed that the role of MALAT1 in diabetic-related complications is both pro-inflammatory and apoptosis in different cell types. These results concluded that MALAT1 is a potential diagnostic and future targeted therapy for diabetes-associated complications.