The cerebellar GABAAR α6-R100Q polymorphism alters ligand binding in outbred Sprague-Dawley rats in a similar manner as in selectively bred AT and ANT rats.
The alcohol-tolerant AT and alcohol-nontolerant ANT rat lines have been selectively bred for innate sensitivity to ethanol-induced motor impairment. The cerebellar GABAA receptor (GABAAR) α6 subunit alleles α6-100R and α6-100Q are segregated in the AT and ANT rats, respectively. This α6 polymorphism might explain various differences in pharmacological properties and density of GABAARs between the rat lines. In the present study, we have used nonselected outbred Sprague-Dawley rats homozygous for the α6-100RR (RR) and α6-100QQ (QQ) genotypes to show that these RR and QQ rats display similar differences between genotypes as AT and ANT rat lines. The genotypes differed in their affinity for [3H]Ro 15-4513 and classic benzodiazepines (BZs) to cerebellar "diazepam-insensitive" (DZ-IS) binding sites, in density of cerebellar [3H]muscimol binding and in the antagonizing effect of furosemide on GABA-induced inhibition of [3H]EBOB binding. The results suggest the involvement of α6-R100Q polymorphism in these line differences and in the differences previously found between AT and ANT rats. In addition, the α6-R100Q polymorphism induces striking differences in [3H]Ro 15-4513 binding kinetics to recombinant α6β3γ2s receptors and cerebellar DZ-IS sites. Association of [3H]Ro 15-4513 binding was ∼10-fold faster and dissociation was ∼3-4-fold faster in DZ-IS α6βγ2 receptors containing the α6-100Q allele, with a resulting change of ∼2.5-fold in equilibrium dissociation constant (KD). The results indicate that in addition to the central role of the homologous α6-100R/Q (α1-101H) residue in BZ binding and efficacy, this critical BZ binding site residue has a major impact on BZ binding kinetics.


DPT vaccine-induced lipoatrophy: an observational study.
Diphtheria Pertussis Tetanus (DPT) vaccine is universally used in infants and children. It is generally safe and well tolerated. Local reactions such as erythema, induration, palpable nodules, and injection site abscess are well known. Injection site lipoatrophy has not been reported earlier. Retrospective review of all cases presenting with lipoatrophy developing at injection site following DPT administration between 2000-2005 in 3 hospitals in New Delhi, India was performed. In each case, the patients were extensively evaluated for other possible causes of lipoatrophy. 8 infants (2 boys & 6 girls), age range 4-12 months, had presented with injection site lipoatrophy following DPT vaccination. The duration between the last injection and lipoatrophy ranged from 4 to 8 weeks. All had been administered the vaccine in the buttock instead of the thigh, as generally recommended in infants. Majority (6/8) developed lipoatrophy after the second dose. No systemic causes were found. DPT vaccine may, in rare instances, lead to injection site lipoatrophy. Inadvertent administration into the subcutaneous fat of the buttock may have been causative. Other possible mechanisms are discussed. Paramedics and general practitioners need to be educated to administer intramuscular vaccines in the thigh in infants and young children.


A forensic dental determination of serial killings by three African lions.
Forensic dentistry's role in solving homicide cases is not limited to victim and other human identifications. This science also can apply to perpetrators, human as well as animal, and can clarify historical incidents that occurred many years ago. In two cases more than 90 years apart, three African lions were jointly responsible for the killing of 141 humans for food, replacing their normal animal prey. A thorough dental analysis identified pathologies that may have forced the cats to select slower and less troublesome prey (humans) over their traditional food sources. The uncanny ability of these lions to avoid traps, ambushes, and gunfire while they continued to prey on so many well-armed and forewarned men remains unexplained.


Detection and discrimination of sedative-hypnotics in spiked beverage dry residues using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy combined with chemometrics.
Drugs-facilitated crimes (DFCs) involve the incapacitation of victims under the influence of drugs. Conventionally, a drug administration act is often determined through the examination of biological samples; however, dry residues from any surface, such as drinking glass if related to a DFC could be a potential source of evidence. This study was aimed to establish an attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy coupled with chemometrics for the determination of spiked sedative-hypnotics from dry residues of a drug-spiked beverage. In this study, four sedative-hypnotics, namely diazepam, ketamine, nimetazepam, and xylazine were examined using ATR-FTIR spectroscopy. Subsequently, the ATR-FTIR profiles were compared and decomposed by principal component analysis (PCA) followed by linear discriminant analysis (LDA) for their detection and discrimination. Visual comparison of ATR-FTIR profiles revealed distinct spectra among the tested drugs. An initial unsupervised exploratory PCA model indicated the separation of four main sedative-hypnotics clusters, and the proposed PCA score-LDA model had allowed for a 100% accurate classification. Discrimination of sedative-hypnotics from a dry beverage previously spiked with these drugs was also possible upon an additional extraction procedure. In conclusion, ATR-FTIR coupled with PCA score-LDA model was useful in detecting and discriminating sedative-hypnotics, including those that had been previously spiked into a beverage.


Plant Extracts Rich in Polyphenols as Potent Modulators in the Growth of Probiotic and Pathogenic Intestinal Microorganisms.
Medicinal plants and their extracts contain substantial quantities of polyphenols. As metabolically active plant metabolites, polyphenols are food components with a wide range of biological activities. Given their poor absorbability in the digestive tract their activity toward the human host is typically mediated through interaction with intestinal microbes. As a result, polyphenols comprise a novel group of prebiotics. In this study, we tested the effect of five polyphenol-rich extracts from four medicinal herbs on the growth of probiotic and pathogenic microbes. The studied medicinal herbs were Gentiana asclepiadea L. (willow gentian), Hypericum perforatum L. (St. John's wort), Satureja montana L. (winter savory), and Achillea millefolium L. (yarrow). All these plants are traditionally used for the treatment of digestive problems. Extracts were prepared using safe solvent combinations. We tested the impact of addition of plant extracts on the growth of three probiotic lactobacilli and probiotic yeast Saccharomyces boulardii. The effect of addition of plant extracts to liquid media (concentration range 0.25-10 mg/mL) on the growth of probiotics, was tested in vitro. The antimicrobial activity of the extracts was tested against several opportunistic bacteria and yeast. St. John's wort, winter savory, and willow gentian extracts showed a stimulative effect on probiotic yeast growth, while the highest growth-stimulating effect was achieved when microwave-assisted yarrow extract was used in the concentration of 0.5 mg/mL. Under these conditions growth of S. boulardii was increased 130-fold. In addition, the yarrow extract stimulated the growth of Lactiplantibacillus plantarum 299v. The growth of two Lacticasibacillus rhamnosus strains was not stimulated by the addition of any extracts. Our results show that plant polyphenol-rich extracts can influence the growth of microorganisms that are typical members of the intestinal microbiota. For the first time we demonstrate that probiotic yeast growth can be stimulated by extracts of medicinal herbs, which when accompanied by suppression of Candida yeasts suggests a potential benefit of the treatment in diseases that are associated with fungal dysbiosis.


Template-particle stabilized bicontinuous emulsion yielding controlled assembly of hierarchical high-flux filtration membranes.
A novel solvent-evaporation-based process that exploits template-particle stabilized bicontinuous emulsions for the formation of previously unreached membrane morphologies is reported in this article. Porous membranes have a wide range of applications spanning from water filtration, pharmaceutical purification, and battery separators to scaffolds for tissue engineering. Different situations require different membrane morphologies including various pore sizes and pore gradients. However, most of the previously reported membrane preparation procedures are restricted to specific morphologies and morphology alterations require an extensive optimization process. The tertiary system presented in this article, which consists of a poly(ether sulfone)/dimethylacetamide (PES/DMAc) solution, glycerol, and ZnO-nanoparticles, allows simple and exact tuning of pore diameters ranging from sub-20 nm, up to 100 nm. At the same time, the pore size gradient is controlled from 0 up to 840%/μm yielding extreme asymmetry. In addition to structural analysis, water flux rates of over 5600 L m(-2) h(-1) are measured for membranes retaining 45 nm silica beads.


Cooperative dyads for two-photon uncaging.
A series of dyads that combine a photolabile protecting group (PPG) 4,5-dimethoxy-2-nitrobenzyl and different bis-donor or bis-acceptor dissymmetric chromophores acting as two-photon (2P) absorbers were synthesized. Even for low energy transfer efficiency from the 2PA subunit to the uncaging one, improvement of the 2P uncaging sensitivity in the NIR is achieved as compared to isolated PPG. Moreover enhancement of the 2PA response is achieved by tuning the electronic dissymmetry of the 2PA subunit and the arrangement of the complementary subunits in the dyads.


Microgravity effect on testicular functions.
In mammals spaceflight influences spermatogenesis since spermatogonial germ cell proliferation, compared to synchronous controls, is lightly decreased in irradiated or flown rats. Moreover, changes of the plasmatic testosterone production was described either in flight rats, or in rats maintained in simulated microgravity conditions. The hormonal levels of the astronauts change as it has been previously described, including hormones involved in the regulation of spermatogenesis such as testosterone and luteinizing hormone (LH). In microgravity conditions, human testosterone levels decreased whereas circulating LH levels increased. To study the effect of simulated microgravity on mammalian spermatogenesis we have utilized the Rotary Cell Culture System (RCCS) and we have cultured testicular fragments isolated from prepuberal rats in a chemically defined medium for three days under microgravity conditions. As control we have cultured the same amount of fragments at unit gravity. The morphology of the samples has been studied and the number of proliferating cells has been counted in control samples and in samples maintained in RCCS. The results indicate that the number of duplicating cells in the tubules was significantly increased in the microgravity-cultured fragments. The amount of testosterone secreted in the culture medium has been also evaluated and in RCCS samples the amount of the hormone was higher respect to the control samples.


ADAM12: a potential target for the treatment of chronic wounds.
Wound healing is a complex process involving multiple cellular events, including cell proliferation, migration, and tissue remodeling. A disintegrin and metalloprotease 12 (ADAM12) is a membrane-anchored metalloprotease, which has been implicated in activation-inactivation of growth factors that play an important role in wound healing, including heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and insulin growth factor (IGF) binding proteins. Here, we report that expression of ADAM12 is fivefold upregulated in the nonhealing edge of chronic ulcers compared to healthy skin, based on microarrays of biopsies taken from five patients and from healthy controls (p = 0.013). The increase in ADAM12 expression in chronic ulcers was confirmed by quantitative real-time polymerase chain reaction (RT-PCR). Moreover, immunohistochemical analysis demonstrated a pronounced increase in the membranous and intracellular signal for ADAM12 in the epidermis of chronic wounds compared to healthy skin. These findings, coupled with our previous observations that lack of keratinocyte migration contributes to the pathogenesis of chronic ulcers, prompted us to evaluate how the absence of ADAM12 affects the migration of mouse keratinocytes. Skin explants from newborn ADAM12-/- or wild-type (WT) mice were used to quantify keratinocyte migration out of the explants over a period of 7 days. We found a statistically significant increase in the migration of ADAM12-/- keratinocytes compared to WT control (p = 0.0014) samples. Taken together, the upregulation of ADAM12 in chronic wounds and the increased migration of keratinocytes in the absence of ADAM12 suggest that ADAM12 is an important mediator of wound healing. We hypothesize that increased expression of ADAM12 in chronic wounds impairs wound healing through the inhibition of keratinocyte migration and that topical ADAM12 inhibitors may therefore prove useful for the treatment of chronic wounds.


Analytic continuation of Wolynes theory into the Marcus inverted regime.
The Wolynes theory of electronically nonadiabatic reaction rates [P. G. Wolynes, J. Chem. Phys. 87, 6559 (1987)] is based on a saddle point approximation to the time integral of a reactive flux autocorrelation function in the nonadiabatic (golden rule) limit. The dominant saddle point is on the imaginary time axis at tsp=iλspℏ, and provided λsp lies in the range -β/2≤λsp≤β/2, it is straightforward to evaluate the rate constant using information obtained from an imaginary time path integral calculation. However, if λsp lies outside this range, as it does in the Marcus inverted regime, the path integral diverges. This has led to claims in the literature that Wolynes theory cannot describe the correct behaviour in the inverted regime. Here we show how the imaginary time correlation function obtained from a path integral calculation can be analytically continued to λsp<-β/2, and the continuation used to evaluate the rate in the inverted regime. Comparison with exact golden rule results for a spin-boson model and a more demanding (asymmetric and anharmonic) model of electronic predissociation shows that the theory is just as accurate in the inverted regime as it is in the normal regime.


Cooperation of specific ICAM-3 grabbing nonintegrin-related 1 (SIGNR1) and complement receptor type 3 (CR3) in the uptake of oligomannose-coated liposomes by macrophages.
Resident peritoneal macrophages (PEMs) express SIGNR1 on the cell surface as a major mannose receptor. These cells also ingest oligomannose-coated liposomes (OMLs) in an oligomannose-dependent manner following intraperitoneal administration. Therefore, the current study was conducted to investigate the possible role of SIGNR1 in capture of OMLs. Transient expression of several SIGN-related lectins potentially expressed on PEMs in CHO cells revealed that only SIGNR1 contributed to capture of OMLs. When SIGNR1 was introduced into mouse macrophage-like RAW264.7 cells, SIGNR1-expressing RAW (RAW-SIGNR1) cells recognized OMLs under serum-free conditions. OML recognition by RAW-SIGNR1 cells as well as that by PEMs was partially inhibited by an anti-SIGNR1 antibody (ER-TR9) and by mannan, and completely inhibited by EDTA. Interestingly, OML recognition by RAW-SIGNR1 cells was accelerated in the presence of serum, partially inhibited by an anti-complement receptor 3 (CR3) antibody (M1/70), and almost completely inhibited by a combination of ER-TR9 and M1/70. Complete inhibition of OML ingestion by the combination of ER-TR9 and M1/70 was also observed under serum-free conditions, suggesting that SIGNR1 and CR3 cooperate in an additive way in capture of OMLs by macrophage-like RAW cells. Administration of ER-TR9 or M1/70 into the peritoneal cavity led to a significant decrease of OML uptake by PEMs. Therefore, SIGNR1 expressed on macrophages acts as a receptor for recognition of OMLs under physiological conditions.


Evaluation of carryover effects of dietary lysine intake by Cobb 500 broiler breeder hens.
Two experiments were conducted to examine the progeny performance of broiler breeder (BB) hens fed diets differing in digestible lysine (dLys). A total of 240 Cobb 500 BB pullets and 40 cockerels, 20 wk of age, were used for each of 2 experiments. In experiment 1, treatment diets were fed from 35 to 45 wk of age. Treatment 1 and 2 diets were formulated with common feed ingredients and BB had dLys daily intakes of 1,200 (IDL-1,200) and 1,010 mg/hen per d (ID-1,010), respectively. Treatments 3 and 4 were composed of semipurified diets formulated to dLys intakes of 1,010 (SPL-1,010) and 600 mg/hen per d (SP-600), respectively. In experiment 1, chick weight at hatch was lower (P < 0.05) for those that came from the SP-600 and SPL-1,010-fed hens, but 42 and 56 d BW was similar for all treatments. Improvements (P < 0.10) in feed conversion ratio were seen at 42 and 56 d for chicks from ID-1,010-fed hens compared with IDL-1,200 hens. For experiment 2, diets were fed to BB hens from 24 to 42 wk of age. Treatment 1 was composed of corn-soybean meal and formulated to a dLys intake of 1,000 mg/hen per d (CS-1,000). Treatments 2, 3, and 4 had inclusion of 25% distillers dried grains with solubles (DDGS) with dLys intake levels of 1,000 (DDGS-1,000), 800 (DDGS-800), and 600 (DDGS-600) mg/hen per d, respectively. Progeny performance was evaluated from eggs collected at wk 26, 31, and 36. Chick hatch weight was similar for all 3 hatches. Chicks from 26-wk-old BB hens and fed DDGS-600 diets resulted in lower (P < 0.05) BW, carcass weight, and breast weight, and higher (P < 0.05) back half (drumsticks and thighs) yield, at 42 d of age. Growout studies performed on eggs laid during wk 31 and 36 revealed no effect on growth or carcass parameters. In conclusion, the results from experiments 1 and 2 may not be comparable, and therefore, the impact on progeny performance needs to be further evaluated.


Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by oxycodone.
Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by xenobiotic receptors [XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of oxycodone administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats. Microarray, quantitative real-time polymerase chain reaction and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g., PXR, CAR, and AhR), 27 transporters (e.g., ABCB1 and SLC22A8), and 19 DMEs (e.g., CYP2B2 and CYP3A1) were regulated (P < 0.05) with fold changes ranging from -46.3 to 17.1. Using MetaCore (computational platform), we identified a unique gene-network of transporters and DMEs assembled around PXR, CAR, and AhR. Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of PXR, CAR, or AhR by oxycodone or its major metabolites (noroxycodone and oxymorphone). Neither oxycodone nor its metabolites activated PXR, CAR, or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated oxycodone administration in rats and demonstrate that oxycodone alters the expression of many transporters and DMEs (without direct activation of PXR, CAR, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with oxycodone.


On the Construction of Property Based Diabatizations: Diabolical Singular Points.
Diabatizations achieved by diagonalization of a property operator or as the extremum of a molecular property are numerous and widely used, although for a particular system a given property method may have limited accuracy or even fail catastrophically. These failures are usually analyzed in terms of limitations of the chosen property or method. Here we introduce an alternative perspective, failure attributable to singularities in the defining equations. The singular subspace is analogous to the conical intersection seam in potential energy surfaces. Using the archetypical NH3 nonadiabatic photodissociation, it is shown that for two states the diabatization condition has singularities on a subspace of dimension N - 2, where N = 3N(atom) - 6, is the number of internal coordinates. This singular subspace is distinct from the N - 2-dimensional seam of conical intersections of the electronic Hamiltonian and results incorrectly, in singular derivative couplings between diabatic states in unexpected regions of nuclear coordinate space. Simple indicators are developed that provide ways to anticipate and avoid these singularities.


Charge transport in organic nanocrystal diodes based on rolled-up robust nanomembrane contacts.
The investigation of charge transport in organic nanocrystals is essential to understand nanoscale physical properties of organic systems and the development of novel organic nanodevices. In this work, we fabricate organic nanocrystal diodes contacted by rolled-up robust nanomembranes. The organic nanocrystals consist of vanadyl phthalocyanine and copper hexadecafluorophthalocyanine heterojunctions. The temperature dependent charge transport through organic nanocrystals was investigated to reveal the transport properties of ohmic and space-charge-limited current under different conditions, for instance, temperature and bias.


[Regulation of the expression of Escherichia coli genes coding for the proteins involved in translation].
We have described our present knowledge of the regulation of the expression of genes whose products are concerned with the protein biosynthesis in E. coli. In particular, we have discussed the mechanism of translational initiation which seems to be a crucial control point. Our own work on the organisation and regulation of the expression of a group of E. coli genes coding for initiation factor IF3 and two aminoacyl-tRNA synthetases was described in detail. This work illustrates the power of the new genetic engineering technology in studies on regulation at the molecular level.


The night eating syndrome in the general population and among postoperative obesity surgery patients.
To determine the prevalence of night-eating syndrome in the general population and among a new sample of obesity surgery patients. Night-eating syndrome was defined by presence of morning anorexia, excessive evening eating, evening tension and/or feeling upset, and insomnia. A randomly selected sample of 2,097 adults (survey sample) answered structured interview questions on night-eating syndrome. A self-report form was completed by 111 patients who had received gastric restriction surgery for obesity at a patient reunion (patient sample). Prevalence of night-eating syndrome in the survey sample was 1.5% (31 of 2,097). Prevalence in the patient sample was 27% (30 of 111). Weights for subjects in each sample, with and without the syndrome, were comparable. Prevalence of night-eating syndrome was higher in the patient sample than in the survey sample. Within each sample, presence of the syndrome was not related to weight. Prevalence in the survey sample was within the range reported for binge-eating disorder. Night-eating syndrome may warrant consideration as a distinct eating disorder.


Balanced identity in the minimal groups paradigm.
Balanced Identity Theory [1] formalizes a set of relationships between group attitude, group identification, and self-esteem. While these relationships have been demonstrated for familiar and highly salient social categories, questions remain regarding the generality of the balance phenomenon and its causal versus descriptive status. Supporting the generality and rapidity of cognitive balance, four studies demonstrate that the central predictions of balance are supported even for previously unfamiliar "minimal" social groups to which participants have just been randomly assigned. Further, supporting a causal as opposed to merely descriptive interpretation, manipulating any one component of the balance model (group attitude, group identification, or self-esteem) affects at least one of the related components. Interestingly, the broader pattern of cognitive balance was preserved across such manipulations only when the manipulation strengthens as opposes to weakens the manipulated construct. Taken together, these findings indicate that Balanced Identity Theory has promise as a general theory of intergroup attitudes, and that it may be able to shed light on prior inconsistencies concerning the relationship between self-esteem and intergroup bias.


[Quality of life survey on patients with chronic rhinosinusitis and nasal polyps].
To explore the health-related quality of life (QOL) status of patients with chronic rhinosinusitis and nasal polyps. One hundred and twenty patients with chronic rhinosinusitis and nasal polyps and two hundred individuals passing health examination were enrolled by random and their QOL scores were assessed by using QOL instruments including existing SF-36 questionnaire (Chinese version ) and SNOT-20 questionnaire translated into Chinese, of which clinimetric and psychometric properties were tested. The feasibility, reliability, validity, and responsibility of Chinese version of SNOT-20 questionnaire all passed the test. By the assessment of SF-36 questionnaire, it revealed that scores of six domains such as physical functioning, role physical, bodily pain, mental health, vitality, and general health from patients with chronic rhinosinusitis and nasal polyps were lower than that of control group except social functioning and role emotional (P < 0.05). It showed by Chinese version of SNOT-20 questionnaire that patients exceeded healthy individuals in the scores of twenty items of three domains including physical problems, functional limitations, and emotional consequences, of which the most five important items affecting health status were respectively need to blow nose, thick nasal discharge, lack of a good night's sleep, dizziness, and post-nasal discharge (P < 0.05). QOL instruments such as Chinese version of SF-36 and SNOT-20 questionnaires can effectively differentiate the QOL status between patients with chronic rhinosinusitis and nasal polyps and healthy individuals. The negative impact of chronic rhinosinusitis and nasal polyps on patients' QOL includes physical functioning, role physical, bodily pain, mental health, vitality, general health, and emotional consequences. The problems of nasal discharge, sleep, and dizziness should be sufficiently emphasized in clinical treatment.


In-vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists and thrombolytics on platelet/fibrin-mediated clot dynamics in human whole blood using thrombelastography.
Suppressing platelet activation improves efficacy of thrombolytic therapy for stroke and acute myocardial infarction. Combination treatment with recombinant tissue plasminogen activator (r-tPA) and glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor that binds with high affinity to platelets may therefore improve the efficacy of thrombolytic therapy. The effect of platelet GPIIb/IIIa antagonists and/or r-tPA on the dynamics of platelet/fibrin clot formation, strength, and lysis was determined using thrombelastography in human blood under thrombin or tissue factor stimulation. The study utilized platelet GPIIb/IIIa antagonists with high affinity and slow off-rate (Class I) from resting and activated platelets in comparison with Class II antagonists (lower affinity and fast off-rate from platelet GPIIb/IIIa receptors). The combination of the active form of roxifiban (XV459; Class I) or the active form of orbofiban (Class II) with a subeffective concentration of r-tPA resulted in a synergistic effect in clot lysis with roxifiban active form XV459 but not with that of orbofiban at therapeutically achievable concentrations that inhibit human platelet aggregation. These data indicate differential enhanced thrombolysis of low levels of r-tPA with high-affinity Class I but not with low-affinity Class II GPIIb/IIIa antagonists in the absence of anticoagulants.


A phase I study of intravenous bryostatin 1 in patients with advanced cancer.
Bryostatin 1 is a novel antitumour agent derived from Bugula neritina of the marine phylum Ectoprocta. Nineteen patients with advanced solid tumours were entered into a phase I study to evaluate the toxicity and biological effects of bryostatin 1. Bryostatin 1 was given as a one hour intravenous infusion at the beginning of each 2 week treatment cycle. A maximum of three treatment cycles were given. Doses were escalated in steps from 5 to 65 micrograms m-2 in successive patient groups. The maximum tolerated dose was 50 micrograms m-2. Myalgia was the dose limiting toxicity and was of WHO grade 3 in all three patients treated at 65 micrograms m-2. Flu-like symptoms were common but were of maximum WHO grade 2. Hypotension, of maximum WHO grade 1, occurred in six patients treated at doses up to and including 20 micrograms m-2 and may not have been attributable to treatment with bryostatin 1. Cellulitis and thrombophlebitis occurred at the bryostatin 1 infusion site of patients treated at all dose levels up to 50 micrograms m-2, attributable to the 60% ethanol diluent in the bryostatin 1 infusion. Subsequent patients treated at 50 and 65 micrograms m-2 received treatment with an intravenous normal saline flush and they did not develop these complications. Significant decreases of the platelet count and total leucocyte, neutrophil and lymphocyte counts were seen in the first 24 h after treatment at the dose of 65 micrograms m-2. Immediate decreases in haemoglobin of up to 1.9g dl-1 were also noted in patients treated with 65 micrograms m-2, in the absence of clinical evidence of bleeding or haemodynamic compromise. No effect was observed on the incidence of haemopoietic progenitor cells in the marrow. Some patients' neutrophils demonstrated enhanced superoxide radical formation in response to in vitro stimulation with opsonised zymosan (a bacterial polysaccharide) but in the absence of this additional stimulus, no bryostatin 1 effect was observed. Lymphocyte natural killing activity was decreased 2 h after treatment with bryostatin 1, but the effect was not consistently seen 24 h or 7 days later. With the dose schedule examined no antitumour effects were observed. We recommend that bryostatin 1 is used at a dose of 35 to 50 micrograms m-2 two weekly in phase II studies in patients with malignancies including lymphoma, leukaemia, melanoma or hypernephroma, for which pre-clinical investigations suggest antitumour activity.


Odors generated from the Maillard reaction affect autonomic nervous activity and decrease blood pressure through the olfactory system.
Systolic blood pressure (SBP) of rats decreases significantly following exposure to the odor generated from the Maillard reaction of protein digests with xylose. This study identified active odorants that affect blood pressure and demonstrated the mechanism of action. Among the four potent odorants that contribute most to the odor of the Maillard reaction sample, 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) and 5-methyl-2-pyrazinemethanol (MPM) decreased SBP significantly. The earliest decrease in blood pressure was observed 5 min after exposure to DMHF. Application of zinc sulfate to the nasal cavity eliminated the effect. Furthermore, gastric vagal (parasympathetic) nerve activity was elevated and renal sympathetic nerve activity was lowered after exposure to DMHF. It is indicated that DMHF affects blood pressure through the olfactory system, and the mechanism for the effect of DMHF on blood pressure involves the autonomic nervous system. © 2017 Society of Chemical Industry.


Species restriction of a monoclonal antibody reacting with residues 130 to 137 in encephalitogenic myelin basic protein.
A monoclonal antibody (immunoglobulin G1) has been produced that reacts against myelin basic protein present in or extracted from the brains of many mammals-with certain important exceptions. Because of known species differences in amino acid sequences of basic protein and of certain peptide fragments, the binding site for this particular antibody appeared likely to include residues 130 to 137. Confirmation of this hypothesis was obtained by amino acid composition of the major immunoreactive peptides produced by thermolysin digestion of human basic protein and isolated by high-performance liquid chromatography.


Functional muscle ischemia in Duchenne and Becker muscular dystrophy.
Duchenne and Becker muscular dystrophy (DMD/BMD) comprise a spectrum of devastating X-linked muscle wasting disease for which there is no treatment. DMD/BMD is caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that stabilizes the muscle membrane and also targets other proteins to the sarcolemma. Among these is the muscle-specific isoform of neuronal nitric oxide synthase (nNOSμ) which binds spectrin-like repeats within dystrophin's rod domain and the adaptor protein α-syntrophin. Dystrophin deficiency causes loss of sarcolemmal nNOSμ and reduces paracrine signaling of muscle-derived nitric oxide (NO) to the microvasculature, which renders the diseased muscle fibers susceptible to functional muscle ischemia during exercise. Repeated bouts of functional ischemia superimposed on muscle fibers already weakened by dystrophin deficiency result in use-dependent focal muscle injury. Genetic and pharmacologic strategies to boost nNOSμ-NO signaling in dystrophic muscle alleviate functional muscle ischemia and show promise as novel therapeutic interventions for the treatment of DMD/BMD.


Intraoperative implantation radiation therapy plus lumpectomy for carcinoma of the breast.
The preponderance of evidence indicates that lumpectomy plus radiation therapy produces the same survival as modified radical mastectomy in patients with early breast cancer and further suggests that the local failure rate may be lower in the patients who undergo irradiation. In this series, patients were treated with immediate implantation of the tumor bed with iridium Ir 192. There have been two recurrences in the breast from 110 breast cancers (44% had a clinical stage greater than T1, and 41% had axillary-node involvement) in 107 patients followed up for four to 52 months (25.8 +/- 13.3 months [mean +/- SD]). These preliminary data suggest that local treatment failure can be minimized by aggressive, immediate intraoperative implantation of the tumor bed with iridium Ir 192.


Protective immunity rate against monkeypox: expectation for present and future in case that there is no smallpox vaccine booster.
Monkeypox is now regarded as a major global public health concern. A common symptom of this disease is an acute febrile illness with skin sores. The likelihood of the virus spreading from person to person is increasing. The aim of the present study is to estimate the protective immunity rate against monkeypox. Based on the current situation in Africa, the authors forecast the protective immunity rate against monkeypox for the present and future if a smallpox vaccination booster is not available. The clinical mathematical model was used. The primary data for analysis include data on the current serological rate against smallpox and data on the declining rate of smallpox immunity after the last vaccination. According to the current clinical modeling study, protective immunity to monkeypox is limited. The rate among people who have previously been immunized against smallpox is still higher than the general population rate. If the present monkeypox outbreak (2022) is not successfully controlled, there could be a severe public health danger, such as a pandemic. On a larger scale, in a few years, no immunity will be a concern. To suppress the current monkeypox outbreak, it may be necessary to research the use of a novel monkeypox immunization or a traditional smallpox vaccine.


Mathematical Model Predicts Effective Strategies to Inhibit VEGF-eNOS Signaling.
The endothelial nitric oxide synthase (eNOS) signaling pathway in endothelial cells has multiple physiological significances. It produces nitric oxide (NO), an important vasodilator, and enables a long-term proliferative response, contributing to angiogenesis. This signaling pathway is mediated by vascular endothelial growth factor (VEGF), a pro-angiogenic species that is often targeted to inhibit tumor angiogenesis. However, inhibiting VEGF-mediated eNOS signaling can lead to complications such as hypertension. Therefore, it is important to understand the dynamics of eNOS signaling in the context of angiogenesis inhibitors. Thrombospondin-1 (TSP1) is an important angiogenic inhibitor that, through interaction with its receptor CD47, has been shown to redundantly inhibit eNOS signaling. However, the exact mechanisms of TSP1's inhibitory effects on this pathway remain unclear. To address this knowledge gap, we established a molecular-detailed mechanistic model to describe VEGF-mediated eNOS signaling, and we used the model to identify the potential intracellular targets of TSP1. In addition, we applied the predictive model to investigate the effects of several approaches to selectively target eNOS signaling in cells experiencing high VEGF levels present in the tumor microenvironment. This work generates insights for pharmacologic targets and therapeutic strategies to inhibit tumor angiogenesis signaling while avoiding potential side effects in normal vasoregulation.


Prediction of language and neurologic recovery after cerebral infarction with SPECT imaging using N-isopropyl-p-(I 123) iodoamphetamine.
Fourteen patients (10 with left-sided and 4 with right-sided cerebral infarction) were prospectively studied with single-photon emission computed tomography (SPECT) using N-isopropyl-p-(I 123) iodoamphetamine (IMP, SPECTamine) to determine its usefulness in predicting neurologic/language recovery after cerebral infarction. All neuro-SPECT imaging was performed within 30 days after infarction. Detailed assessment of neurologic and/or language recovery (after 3 months) was carried out prospectively in each patient. Patients with smaller volume IMP defects in the region of infarction demonstrated significantly better neurologic and language recovery than patients with large IMP defects. Analysis of the IMP "redistribution" phenomenon failed to demonstrate definitively a relationship with clinical recovery. It was concluded that the volume of the IMP defect can aid in predicting recovery potential after cerebral infarction.


Modeling senescence changes of the pubic symphysis in historic Italian populations: a comparison of the Rostock and forensic approaches to aging using transition analysis.
Age-related anatomical changes to the surface of the pubic symphysis are well-documented in the literature. However, aligning these morphological changes with chronological age has proven problematic, often resulting in biased age estimates. Statistical modeling provides an avenue for forensic anthropologists and bioarchaeologists to increase the accuracy of traditional aging methods. Locating appropriate samples to use as a basis for modeling age estimations can be challenging due to differing sample age distributions and potentially varying patterns of senescence. We compared two approaches, Rostock and Forensic, coupled with a Bayesian methodology, to address these issues. Transition analysis was run specific to each method (which differ by sample selection). A Gompertz model was derived from an informative prior that yielded the mortality and senescence parameters for constructing highest posterior density ranges, i.e., coverages, which are analogous to age ranges. These age ranges were generated from both approaches and are presented as reference tables useful for historic male and female Italian samples. The age ranges produced from each approach were tested on an historic Italian sample, using cumulative binomial tests. These two approaches performed similarly, with the Forensic approach showing a slight advantage. However, the Forensic approach is unable to identify varying senescence patterns between populations, thus preference for one approach over the other will depend on research design. Finally, we demonstrate that while populations exhibit similar morphological changes with advancing age, there are no significant sex differences in these samples, and the timing of these changes varies from population to population.


Association between age, distress, and orientations to happiness in individuals with disabilities.
To determine how age and distress are associated in individuals with disabilities, and how happiness and its components (meaning, pleasure, and engagement) mediate or moderate this relationship. These were cross-sectional analyses of survey data from 508 community-dwelling adults with a variety of self-reported health conditions and functional disabilities. Measures included the Orientations to Happiness Questionnaire and items from the Behavior Risk Factor Surveillance System. Greater distress was associated with lower global happiness in both mediation and moderation models. The mediation model showed that middle-aged participants (age: 45-64) scored lowest in global happiness, and the effect of age on distress was partially mediated by happiness. None of the happiness components mediated the relationship of age on distress. The moderation model showed a significant interaction effect for age and global happiness on distress, where younger participants low on happiness were significantly more distressed. Of the three happiness components, only meaning was significantly associated with distress. There was a significant interaction between age and meaning, where participants who were younger and scored low on the meaning scale reported significantly higher distress. Findings from this study lay groundwork for the development of clinical interventions to address distress in individuals with functional disabilities. Middle-aged and younger people with disabilities may be particularly affected by lower levels of happiness and might benefit from psychological interventions that focus on increasing overall well-being and providing meaning and purpose in life.


[Potentially pathogenic fungi in the waters of the Charzykowskie Lake in Zaborski Landscape Park].
The occurrence of potentially pathogenic fungal strains in the Charzykowskie Lake and runnels flowing into and out of it was investigated. The study material was obtained in 2005 and in 2006, in the periods of spring intermix and summer stagnation, and in 2005 in the period of autumn intermix. The fungi found in the Charzykowski Lake belonged to 5 genera: Rhodotorula (R. minuta, R. rubra and R. glutinis), Cryptoccocus (C. neoformans, C. laurentii, C. terreus and C. laurentii), Candida (C. inconspicua, C. lusitaniae, C. tropicalis, C. pelliculosa, C. kefir, C. glabrata, C. inconspicua, C. parapsilosis, C. ciferrii and C. colliculosa), Trichosporon (T. cutaneum) and Klockera (K. apiculata). The fungi found in runnels flowing into and out of the Charzykowskie Lake belonged to 4 genera: Rhodotorula (R. rubra and R. glutinis), Cryptoccocus (C. laurentii, C. neoformans, C. albidus and C. terreus), Candida (C. colliculosa, C. lusitaniae, C. tropicalis, C. pelliculosa, C. cifferii, C. glabrata) and Trichosporon (T. cutaneum).


Is the BESTest at its best? A suggested brief version based on interrater reliability, validity, internal consistency, and theoretical construct.
The Balance Evaluation Systems Test (BESTest) and Mini-BESTest are clinical examinations of balance impairment, but the tests are lengthy and the Mini-BESTest is theoretically inconsistent with the BESTest. The purpose of this study was to generate an alternative version of the BESTest that is valid, reliable, time efficient, and founded upon the same theoretical underpinnings as the original test. This was a cross-sectional study. Three raters evaluated 20 people with and without a neurological diagnosis. Test items with the highest item-section correlations defined the new Brief-BESTest. The validity of the BESTest, the Mini-BESTest, and the new Brief-BESTest to identify people with or without a neurological diagnosis was compared. Interrater reliability of the test versions was evaluated by intraclass correlation coefficients. Validity was further investigated by determining the ability of each version of the examination to identify the fall status of a second cohort of 26 people with and without multiple sclerosis. Items of hip abductor strength, functional reach, one-leg stance, lateral push-and-release, standing on foam with eyes closed, and the Timed "Up & Go" Test defined the Brief-BESTest. Intraclass correlation coefficients for all examination versions were greater than .98. The accuracy of identifying people from the first cohort with or without a neurological diagnosis was 78% for the BESTest versus 72% for the Mini-BESTest or Brief-BESTest. The sensitivity to fallers from the second cohort was 100% for the Brief-BESTest, 71% for the Mini-BESTest, and 86% for the BESTest, and all versions exhibited specificity of 95% to 100% to identify nonfallers. Limitations Further testing is needed to improve the generalizability of findings. Although preliminary, the Brief-BESTest demonstrated reliability comparable to that of the Mini-BESTest and potentially superior sensitivity while requiring half the items of the Mini-BESTest and representing all theoretically based sections of the original BESTest.


[Reconstruction of dia- and metaphyseal post-traumatic cortical bone defects].
Forty-one of 55 defect pseudarthroses, most of them with infections, were cured to healing in five years. Autogenic spongiosa proved to be best suitable for soft-tissue repair in cases of non-segmental defects, whereas structured corticalis worked better as a transplant for somewhat stretched and longish segmental defects. Compact osteomyocutaneous free tissue transfer was found to be accompanied by high rates of complications. The tactics of small steps seems to be more promising than anything else for both spongiosa transplantation and corticalis transfer. Fibula-pro-tibia transposition, comparable to the short-distance flap technique, as well as distractive corticotomy should be applied more often, especially to younger patients.


Orthodontic procedures that improve the periodontal prognosis.
Osseous defects not amenable to conventional resective or regenerative osseous surgery alone may respond to a combination of orthodontic and periodontal techniques. Two orthodontic procedures-correction of mesially tipped teeth and forced eruption-have been described that may enhance the periodontal prognosis. Each procedure is accomplished with use of sectional orthodontic appliances and each requires a short time for treatment. Beneficial results include improvement of the crown-to-root ratio, reception of the forces of occlusion in the long axis of the tooth, and reduction or elimination of infrabony defects.


Advanced oesophageal carcinoma in an 84-year-old treated with chemoradiotherapy.
We present a case of advanced oesophageal cancer with cardiac invasion in an 84-year-old male presenting with dysphagia and general malaise. Histological analysis of an endoscopic biopsy specimen revealed a poorly differentiated squamous cell carcinoma. Computed tomography indicated a thickened oesophageal wall that was compressing the left atrium, suggesting invasion of the heart, and oesophagography revealed a polypoid lesion 9 cm in length. No distant metastases were seen on computed tomography. The patient was given chemotherapy with 10 mg/m2 cisplatin on days 1 and 4 every week for 5 weeks and concurrent radiotherapy at a dose of 2 Gy five times per week (total dose 52 Gy). After 4 weeks, the mass was no longer visible on oesophagography or endoscopic examination. The patient was free of recurrence and metastases for 4.5 years. In conclusion, chemoradiotherapy may be curative in elderly patients with unresectable oesophageal carcinoma.


[Occurence of salmonellae in laying hens in different housing systems and inferences for control].
As eggs represent now as ever the most important source for Salmonella infection in human beings and because of the currently occurring shift in housing conditions for laying hens from conventional cages to alternative systems it was studied whether the Salmonella prevalence in layers is influenced by the housing system. Following systems were considered: organic farming with free range management systems, floor management systems with free range, floor management systems without free range, conventional cages. 453 pooled faecal samples as single or double examination per herd from 329 flocks in different housing systems for table egg production from three Federal Lander were examined bacteriologically. The share of layer flocks which were Salmonella positive at least once independently of the housing system amounted to 32.2%. Analysis of the Salmonella findings in the single housing systems revealed that the share of Salmonella positive flocks was higher in conventional cage systems (46.3%) than in alternative housing systems (32.996% in organic farming with free range management systems, 21.9% in floor management systems with free range, 23.4% in floor management systems without free range). The results of the study clearly show that Salmonella Enteritidis (mostly phage type 4, other phage types rarely) presents with a share of 78% the dominant serovar in laying hens. The total number of all other serovars (apart from Salmonella Enteritidis and subspecies I rough) reached a share of ca. 14%, however, no other single serovar was dominant. As Salmonella Enteritidis is the predominant serovar in laying hens it is strongly recommended to use Salmonella Enteritidis vaccines for immunisation programmes of chickens during the rearing period. Because of the high prevalence of Salmonella organisms in the different housing systems, detailed information on the epidemiology of Salmonella in laying hens are needed to introduce effective control measures. Of particular interest is the question whether the Salmonella findings in laying flocks are the result of multiplication of already existing Salmonella organisms in the animals or whether the bacteria are introduced only during the laying period.


Minocycline Inhibits Candida albicans Budded-to-Hyphal-Form Transition and Biofilm Formation.
Candida albicans frequently causes bloodstream infections; its budded-to-hyphalform transition (BHT) and biofilm formation are major contributors to virulence. During an analysis of antibacterial compounds that inhibit C. albicans BHT, we found that the tetracycline derivative minocycline inhibited BHT and subsequent biofilm formation. Minocycline decreased expression of hypha-specific genes HWP1 and ECE1, and adhesion factor gene ALS3 of C. albicans. In addition, minocycline decreased cell surface hydrophobicity and the extracellular β-glucan level in biofilms. Minocycline has been widely used for catheter antibiotic lock therapy to prevent bacterial infection; this compound may also be prophylactically effective against Candida infection.


Investigation of a novel ring-cusp magnetically confined plasma bridge neutralizer.
The plasma bridge neutralizer (PBN) based on a tungsten filament is a promising technique of a thermionic DC electron source where a hot filament is immersed in an inert gas flow and electrons are "bridged" from a small orifice to the ion beam. PBNs have been widely used in space propulsion and industrial applications due to their relatively simple structure and low power consumption. However, they have well-known disadvantages, namely, low emission current density and short lifetime. In this article, we propose a novel ring-cusp magnetically confined PBN (RCM-PBN) to address these issues. In the RCM-PBN, electrons are confined by a ring-cusp magnetic field, which improves the ionization efficiency and reduces the discharge chamber wall losses. Electrical insulation of the orifice plate from the chamber wall prevents a large number of electrons from being collected by the orifice plate, which greatly improves the extracted electron current. The effects of different operating parameters on the extracted electron current were studied through experiments. It was found that the increase in the extracted electron current with the extraction voltage was related to the anode spot formation. Analysis of the gas utilization factor and electron extraction cost shows that the optimal operating condition was obtained at an argon mass flow rate of 1.2 SCCM and a heater power of 45 W. At its optimum, a stable electron current of 1.1 A was extracted from the RCM-PBN with a gas utilization factor of 12.8 and an electron extraction cost of 143 W/A.


[Investigation of occlusal force on lower first molar in function].
The purpose of this investigation is to detect vertically and buccolingually the occlusal force on the lower first molar in function and to make a two-dimensional vector analysis concerning the occlusal force. The subminiature occlusal force measuring apparatus, which makes use of two-dimension load cell, is developed with the apparatus equipped in the corona on the natural root of the tooth, each occlusal force on the single tooth is detected, when three subjects clench and masticate four kinds of test-foods. Conclusions are as follows: 1. Average occlusal force exerts 3.6 kgf during light clenching and 25.7 kgf during heavy clenching. The average direction of occlusal force against the tooth axis exerts 21.2 degrees during light clenching and 19.5 degrees during heavy clenching. 2. The masticatory force intensity exerts the differences in the phases of mastication and the properties of the test-foods. The maximal masticatory force is 33.1-7.9 kgf during the initial phase and 9.6-5.1 kgf during the last phase of mastication. 3. Average direction of masticatory force against the tooth axis is 19.9 degrees during the initial phase and 27.8 degrees during the last phase of mastication. 4. The operating period of masticatory force per cycle is 0.331 second on the average during the process of mastication. The longest period is in the initial phase of mastication, and as the mastication proceed it gradually decreases.


The effects of triptolide on enteric mucosal immune responses of DBA/1 mice with collagen-induced arthritis.
For investigating the effects of triptolide on enteric mucosal immune responses of DBA/1 mice with collagen-induced arthritis (CIA), the changes of the Peyer's patches, IEL (intraepithelial lymphocytes), LPL (lamina propria lymphocytes), periphery lymphocytes, and levels of TGF-beta in CIA mice were checked with flow cytometry or ELISA. Our results showed that triptolide could lower the arthritic scores and increase TGF-beta level. Triptolide also had an effect on enteric mucosal immune lymphocytes in Peyer's patch, IEL and LPL of CIA mice. The regulation of enteric mucosal lymphocytes might explain some of the immunosuppressive activities of triptolide.


ESR guidelines for the communication of urgent and unexpected findings.
The timely communication of radiological findings is important for patient care. When imaging reveals abnormalities that require urgent action, or shows significant unexpected findings, the usual methods of communication may not be reliable enough to ensure that those responsible for clinical care of the patient act promptly. These guidelines suggest methods for improving communication in these circumstances, using clear protocols and procedures agreed between imaging units and referrers. Main Messages • Communicating critical radiological findings will enable urgent or appropriate action to be taken. • Good communication helps to improve patient safety. • Clear departmental protocols become familiar to referrers within the organisation. • Referrers should be aware of their responsibility to read and act on radiological reports.


Insulin release : the fuel concept.
Insulin release evoked by nutrient secretagogues invariably coincides with an increase in the catabolism of exogenous and/or endogenous nutrients in pancreatic islet cells, resulting in an increased generation rate of reducing equivalents and ATP, and an increase in O2 consumption. This situation was documented in response to a number of carbohydrates, including the anomers of D-glucose and D-mannose, various 2-keto acids, including pyruvate and its poorly oxidized phenylated analog 3-phenylpyruvate, and selected amino acids, including the nonmetabolized analog of L-leucine 2-aminobicyclo[2, 2, 1]heptane-2-carboxylic acid. These convergent observations indicate that the B-cell should be considered as a fuel-sensor organ. Further progress in this field requires both the identification of those circulating nutrients used by the B-cell whether in the resting or stimulated state, and a better understanding of the coupling between the generation of second messengers (H+, NAD(P)H, ATP) and more distal events in the secretory sequence, such as the remodelling of ionic fluxes across the plasma membrane and within the pancreatic B-cell.


Effects of a novel perfluorocarbon emulsion on neutrophil chemiluminescence in human whole blood in vitro.
The effects have been studied of a novel perfluorochemical (PFC) emulsion (18.5% perfluorodecalin, 1.5% perfluorodimorpholine propane, 2.5% lecithin) on phorbol 12-myristate 13-acetate (PMA; 100 micrograms ml-1)-induced neutrophil chemiluminescence in citrated human whole blood in vitro. A transient, dose-dependent, decrease in chemiluminescence, to a maximum of 54% after 12 min (P < 0.05), occurred when blood was pre-incubated with 10-40 microliters of the PFC emulsion, compared to saline controls. The mean (+/- s.e.m., n = 6) chemiluminescence of neutrophils incubated with 30 microliters emulsion at 12 min following PMA stimulation (9.5 +/- 1.3 mV) was significantly lower (P < 0.05) than control (24.2 +/- 2.2 mV). Incubation of blood with lecithin up to 16 mg ml-1 and Pluronic F-68 or Pluronic PE 6800 up to 65 mg ml-1 did not affect chemiluminescence.


Influence of ultrasound on clinical decision making in acute appendicitis: a prospective study.
To assess the efficacy of ultrasound (US) as part of an algorithm to establish the indication for laparotomy in patients with suspected acute appendicitis. Prospective investigation. University department of surgery, Germany. 669 unselected patients admitted with suspected acute appendicitis. Clinicopathological and procedural diagnoses of the algorithm were evaluated by correlating clinical and US findings with the results of laparotomy in 171 patients of whom 143 had acute appendicitis (prevalence 21%), and clinical as well as follow up data in the remainder. The major clinicopathological variables were accuracy and positive predictive value; the rate of negative laparotomies and that of bad diagnostic errors served as the main procedural variables. The overall sensitivity, specificity, and accuracy of the clinical diagnosis were 0.503, 0.950, and 0.855, respectively (positive predictive value: PPV 0.734, negative predictive value: NPV 0.875), those of ultrasound: 0.797, 0.967, and 0.931 (PPV 0.870, NPV 0.946); and 0.853, 0.927, and 0.940 at the end of the algorithm (PPV 0.762, NPV 0.958). However, the algorithm would have resulted in a significant increase in the rate of unnecessary laparotomies (from 13% to 16%). A revised clinical algorithm gave an overall diagnostic accuracy of 0.940 (p < 0.001) together with a low rate of negative laparotomies (11%, p < 0.01) and a significantly reduced number of diagnostic errors (from 71 to 21, p < 0.001). Ultrasonography enabled us to diagnose acute appendicitis in more patients more often and more quickly than clinical evaluation alone, suggesting that US may produce a better outcome. The revised clinical algorithm may be helpful in the study of US in patients with suspected acute appendicitis in prospective randomised controlled clinical trials.


[Xiongcan Yishen Formula up-regulates the clock gene expressions in the testis tissue of the rats with late-onset hypogonadism].
To investigate the effect of Xiongcan Yishen Formula (XYF) on the expressions of the clock genes in the testis tissue of the rats with late-onset hypogonadism (LOH). Forty-eight 8-week-old male SD rats were randomly divided into 6 groups, normal control, model control, testosterone propionate (TP), and low-, medium- and high-dose XYF. The LOH model was made in the later 5 groups of rats by intraperitoneal injection of D-galactose at 480 mg/kg/d for 56 successive days, while the normal controls were injected with the same volume of normal saline. After modeling, the rats in the low-, medium- and high-dose XYF groups were treated intragastrically with XYF at 10.4, 20.8 and 41.6 g/kg/d, bid, respectively, those in the normal and model control groups with the same volume of distilled water, and those in the TP group intramuscularly with TP at 5.21 mg/kg/d, qd alt, all for 28 days. After treatment, the supernatant was obtained for measurement of the serum T level by ELISA, and the testis tissue collected for determination of the mRNA and protein expressions of BMAL1, NR1D1, PER2, CRY1, StAR and CYP11A1 by RT-qPCR and Western blot. Compared with the normal controls, the rats in the LOH model control group showed significantly decreased serum T and mRNA and protein expressions of BMAL1, NR1D1, PER2, CRY1, StAR and CYP11A1 (P < 0.05). In comparison with the findings in the model controls, the T level was remarkably increased in the TP and XYF groups (P < 0.05), the expressions of StAR mRNA and CYP11A1 mRNA and protein markedly up-regulated in the high-dose XYF group (P < 0.05), and so was the expression of the StAR protein in the XYF and TP groups (P < 0.05), those of BMAL1 and NR1D1 proteins and PER2 mRNA and protein in the high-dose XYF group (P < 0.05), those of BMAL1 mRNA and CRY1 protein in the medium- and high-dose XYF groups (P < 0.05), that of NR1D1 mRNA in the XYF and TP groups (P < 0.05), and that of CRY1 mRNA in the medium- and high-dose XYF and TP groups (P < 0.05). Xiongcan Yishen Formula could up-regulate the expressions of the clock genes in the testis tissue of the LOH rats and increase the serum T level as well, which may underlie the mechanisms of Xiongcan Yishen Formula acting on LOH.


A novel amino acid position in hemagglutinin glycoprotein of measles virus is responsible for hemadsorption and CD46 binding.
Three recent isolates of measles virus Fu, IMA, and SMD obtained by using B95a cells did not exhibit hemadsorption with African green monkey red blood cells (AGM-RBC). After long-term passage in Vero cells, these Vero cell-adapted strains derived from three isolates obtained the activity to agglutinate AGM-RBC. The primary sequences of the hemagglutinin (H protein) and fusion glycoproteins (F protein) from these two types of viruses were compared and revealed that several important amino acid residues in the H protein do not converge. After adaptation, Fu strain has an Asn to Tyr substitution at position 481 and IMA strain has two substitutions--an Asp to Asn at position 14 and a Ser to Gly at position 546, SMD strain also has a Ser to Gly substitution at position 546. Since the sequences of the F protein were identical between both types of viruses, the hemadsorption alteration from negative to positive might be the result of these substitutions. Site-directed mutagenesis of the H genes were performed to confirm that the substitution of Ser --> Gly at position 546 and Asn --> Tyr at position 481 in the H protein were responsible for hemadsorption alteration. Anti-CD46 monoclonal antibody (M75 and M160) study made clear that these two substitutions also governed the MV H protein's interaction with CD46 receptor. Our results showed that two important amino acid residues in MV H protein govern the binding to CD46 receptor and hemadsorption. In this paper, we reported a novel amino acid residue at position 546 in MV H protein, which was critical for hemadsorption and CD46 binding.


Mononuclear nonheme ferric-peroxo complex in aldehyde deformylation.
A mononuclear nonheme ferric-peroxo complex bearing a macrocyclic tetradentate N4 ligand, [(TMC)Fe(III)-O2]+, was prepared and used in mechanistic studies of aldehyde deformylation; a catalytic aldehyde deformylation by a nonheme iron(II) complex, [Fe(II)(TMC)]2+, and molecular oxygen is reported as well.


Rotational modes of oscillation of rodlike dust grains in a plasma.
Three dimensional rotatory modes of oscillations in a one-dimensional chain of rodlike charged particles or dust grains in a plasma are investigated. The dispersion characteristics of the modes are analyzed. The stability of different equilibrium orientations of the rods, phase transitions between the different equilibria, and a critical dependence on the relative strength of the confining potential are analyzed. The relations of these processes with liquid crystals, nanotubing, and plasma coating are discussed.


Synthesis and cytotoxic activity of N-(2-diethylamino)ethylcarboxamide and other derivatives of 10H-quindoline.
A series of mono- and dimeric N-methylquindoline carboxamides were prepared by Friedlander condensation between methyl 2-amino-3-formyl benzoate and 3-acetoxy-1-acetylindoles, followed by exhaustive methylation with methyl iodide to give N-methylquindoline esters. Direct amination of these, or hydrolysis to the acids and amine coupling via intermediate imidazolides gave the desired carboxamides. The compounds were evaluated in a panel of cell lines in culture. The monomeric compounds showed similar structure-activity relationships to the known indeno[1,2-b]quinolines, with a 4-methyl group increasing potency several-fold. Bis analogues linked through the carboxamide were more cytotoxic than the corresponding monomers in the human leukemia lines, but N-N linked dimers were generally less potent, except for a tetracationic derivative. The most potent monomeric analogue showed moderate growth delay (ca. 5 days) against sub-cutaneously implanted colon 38 tumors in mice.


On-line smoothing for an integrated navigation system with low-cost MEMS inertial sensors.
The integration of the Inertial Navigation System (INS) and the Global Positioning System (GPS) is widely applied to seamlessly determine the time-variable position and orientation parameters of a system for navigation and mobile mapping applications. For optimal data fusion, the Kalman filter (KF) is often used for real-time applications. Backward smoothing is considered an optimal post-processing procedure. However, in current INS/GPS integration schemes, the KF and smoothing techniques still have some limitations. This article reviews the principles and analyzes the limitations of these estimators. In addition, an on-line smoothing method that overcomes the limitations of previous algorithms is proposed. For verification, an INS/GPS integrated architecture is implemented using a low-cost micro-electro-mechanical systems inertial measurement unit and a single-frequency GPS receiver. GPS signal outages are included in the testing trajectories to evaluate the effectiveness of the proposed method in comparison to conventional schemes.


Biotin-rich, optically clear nuclei express estrogen receptor-beta: tumors with morules may develop under the influence of estrogen and aberrant beta-catenin expression.
Recent studies have indicated that aberrant beta-catenin expression may be a common denominator for the morular formation of tumors from various anatomic sites. The evidence for the influence of female sex hormones in the formation of morules has been circumstantial, most previous studies having failed to demonstrate female sex hormone receptors in the morular cells. We investigated a possible role of estrogen receptor (ER)-beta in the occurrence of tumors that form morules with biotin-rich optically clear nuclei (BROCN)(BROCN-family tumors) and its possible relationship with aberrant nuclear/cytoplasmic (N/C) beta-catenin expression. We immunostained 14 BROCN-family tumors, including 6 low-grade adenocarcinomas of the fetal lung type, 3 papillary thyroid carcinomas of cribriform-morular variant (CMV), 2 ovarian endometrioid tumors, 2 colonic adenocarcinomas, and 1 gallbladder adenoma, as well as 4 cases of endometrial tissue with BROCN during gestation, for ERbeta, ERalpha, progesterone receptor (PgR), beta-catenin, and, on a subset of cases, c-Fos and MIB-1 as well. BROCN in all 18 cases expressed ERbeta but not ERalpha or PgR. In the BROCN-family tumors, the morular cells and budding glandular cells expressed ERbeta in the cytoplasm and BROCN, which overlapped with the N/C expression pattern of beta-catenin. Beta-catenin showed only membranous expression in the endometrial glands during gestation. In CMV and ovarian endometrioid tumors, nuclear expression of ERalpha and PgR were observed in association with N/C beta-catenin expression only in the glandular component. C-Fos was also constantly and strongly expressed in BROCN in all cases examined. The MIB-1 labeling index was low in the morular area, ranging from 1% to 3%. The present study indicates that N/C co-localization of ERbeta and beta-catenin is a feature common to the morules with BROCN that appear in the BROCN-family tumors from various anatomic sites. Whether the estrogen-signaling pathway and the Wnt-signaling pathway have crosstalk, cooperating in the development of the BROCN-family tumors, awaits further study.


AlphaDDA: strategies for adjusting the playing strength of a fully trained AlphaZero system to a suitable human training partner.
Artificial intelligence (AI) has achieved superhuman performance in board games such as Go, chess, and Othello (Reversi). In other words, the AI system surpasses the level of a strong human expert player in such games. In this context, it is difficult for a human player to enjoy playing the games with the AI. To keep human players entertained and immersed in a game, the AI is required to dynamically balance its skill with that of the human player. To address this issue, we propose AlphaDDA, an AlphaZero-based AI with dynamic difficulty adjustment (DDA). AlphaDDA consists of a deep neural network (DNN) and a Monte Carlo tree search, as in AlphaZero. AlphaDDA learns and plays a game the same way as AlphaZero, but can change its skills. AlphaDDA estimates the value of the game state from only the board state using the DNN. AlphaDDA changes a parameter dominantly controlling its skills according to the estimated value. Consequently, AlphaDDA adjusts its skills according to a game state. AlphaDDA can adjust its skill using only the state of a game without any prior knowledge regarding an opponent. In this study, AlphaDDA plays Connect4, Othello, and 6x6 Othello with other AI agents. Other AI agents are AlphaZero, Monte Carlo tree search, the minimax algorithm, and a random player. This study shows that AlphaDDA can balance its skill with that of the other AI agents, except for a random player. AlphaDDA can weaken itself according to the estimated value. However, AlphaDDA beats the random player because AlphaDDA is stronger than a random player even if AlphaDDA weakens itself to the limit. The DDA ability of AlphaDDA is based on an accurate estimation of the value from the state of a game. We believe that the AlphaDDA approach for DDA can be used for any game AI system if the DNN can accurately estimate the value of the game state and we know a parameter controlling the skills of the AI system.


Generation of 5 fs, 0.5 TW pulses focusable to relativistic intensities at 1 kHz.
We have demonstrated the generation of 5 fs, 0.5 TW pulses at 1 kHz repetition rate using a pulse compression technique in a hollow fiber with a pressure gradient. Owing to the excellent beam quality by passing through the hollow fiber, the beam after pulse compression could be focused to a nearly diffraction-limited spot size. We obtained for the first time a peak intensity as high as 5x10(18) W/cm(2) in the 2-cycle regime.


On the relationship between two popular lattice models for polymer melts.
A mapping between two well known lattice bond-fluctuation models for polymers [I. Carmesin and K. Kremer, Macromolecules 21, 2819 (1988); J. S. Shaffer, J. Chem. Phys. 101, 4205 (1994)] is investigated by performing primitive path analysis to identify the average number of monomers per entanglement. Simulations conducted using both models, and previously published data are compared in an attempt to establish relationships between molecular weight, lengthscale, and timescale. Using these relationships, an examination of the self-diffusion coefficient yields excellent agreement not only between the two models, but also with experimental data on polystyrene, polybutadiene, and polydimethylsiloxane. However, it is shown that even with the limited set of criteria examined in this paper, a true mapping between these two models is elusive. Nevertheless, a practical guide to convert between models is provided.


A chromatographic analysis of capsid protein isolated from alfalfa mosaic virus: zinc binding and proteolysis cause distinct charge heterogeneity.
The capsid protein (CP) of alfalfa mosaic virus (AIMV) is required for viral replication when susceptible plants are inoculated with purified viral genomic RNA. The discovery of AIMV CP in the zinc activated RNA-dependent RNA polymerase complex prompted our further investigation of AIMV virions and the potential involvement of AIMV CP in metal binding. AIMV CP, isolated from nucleoprotein components, fractionated into four distinct ionic species when purified by cation exchange fast protein liquid chromatography. The CP existed as zinc complexed homodimers, metal-free homodimers, and two forms of proteolyzed heterodimers, as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, gel filtration chromatography, amino-terminal sequencing, and atomic absorption spectroscopy. Although the relative amounts of proteolyzed heterodimers varied, the ratio of zinc complexed homodimers to metal-free homodimers (1:10) was constant between virus and protein isolations for the strains 425 and WISC14. Purified metal-free and zinc-complexed homodimers could be interconverted in vitro by incubation with zinc chloride or with the metal chelator, sodium diethyldithiocarbamate (NaDDC). The potential role of zinc in AIMV nucleoprotein structure and infectivity was investigated by treatment of the virions with NaDDC. Electron microscopy and sucrose density gradient studies failed to detect any gross structural changes for zinc depleted virus; however, a decrease in infectivity was observed with local lesion leaf assays, suggesting a functional role for zinc in viral replication.


Urine Kidney Injury Biomarkers and Risks of Cardiovascular Disease Events and All-Cause Death: The CRIC Study.
CKD is an important risk factor for cardiovascular disease (CVD) and death. We investigated whether select urine kidney injury biomarkers were associated with higher risk of heart failure (HF), CVD, and death in persons with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, and N-acetyl-β-d-glucosaminidase were measured in urine of a subset of CRIC participants (n=2466). We used Cox proportional hazards regression to examine associations between these biomarkers indexed to urinary creatinine (Cr) and (1) HF, (2) a composite of atherosclerotic CVD events (myocardial infarction, ischemic stroke, or peripheral artery disease), and (3) all-cause death. At baseline, mean age of study participants was 59.5±10.8 years, 46% were women, and 34% had a self-reported history of any CVD. Median follow-up was 6.5 (interquartile range, 5.6-6.8) years. A total of 333 HF events, 282 atherosclerotic CVD events, and 440 deaths were observed during a median follow-up of 6.5 (interquartile range, 5.6-6.8) years. Those in the highest two quintiles of KIM-1/Cr levels had a higher risk of HF relative to the lowest quintile (quintile 5 versus quintile 1 adjusted hazard ratio [aHR] of 1.73 [95% confidence interval, 1.05 to 2.85]). N-acetyl-β-d-glucosaminidase/Cr was associated with HF in continuous analyses (aHR per log SD higher 1.18 [95% confidence interval, 1.01 to 1.38]). Only KIM-1/Cr was independently associated with atherosclerotic CVD events (aHR per log SD higher 1.21 [95% confidence interval, 1.02 to 1.41]), whereas both KIM-1/Cr (quintile 5 versus quintile 1 aHR of 1.56 [95% confidence interval, 1.06 to 2.31]) and neutrophil gelatinase-associated lipocalin/Cr (quintile 5 versus quintile 1 aHR of 1.82 [95% confidence interval, 1.19 to 2.8]) were associated with all-cause death. Selected urine kidney injury biomarkers were independently associated with higher risk of HF, CVD events, and death in CRIC. Among the biomarkers examined, only KIM-1/Cr was associated with each outcome. Further work is needed to determine the utility of these biomarkers to improve risk prediction for these adverse outcomes.


Population Diversity of Antibiotic Resistant Enterobacterales in Samples From Wildlife Origin in Senegal: Identification of a Multidrug Resistance Transposon Carrying bla CTX-M-15 in Escherichia coli.
The role of wildlife in the transmission of antimicrobial resistant (AMR) is suspected but scarcely reported in current studies. Therefore, we studied the dynamics and prevalence of antibiotic-resistant Enterobacterales in antibiotic-limited areas of Senegal. We collected fecal samples from monkeys and apes (N = 226) and non-fecal environmental samples (N = 113) from Senegal in 2015 and 2019. We grew the samples on selective media, subsequently isolated AMR Enterobacterales, and then sequenced their genomes. We isolated 72 different Enterobacterales among which we obtained a resistance rate of 65% for colistin (N = 47/72) and 29% for third generation-cephalosporin (C3G) (29%, N = 21/72). Interestingly, almost 46% of our isolates, among Enterobacter sp., Citrobacter cronae and Klebsiella aerogenes, belong to 34 new STs. Moreover, the genes bla CTX-M-15, bla TEM1B , sul2, dfrA14, qnrs, aph(3''), aph(6), tetA, and tetR harbored within a transposon on the IncY plasmid of ST224 Escherichia coli were transferred and inserted into a ST10 E. coli phage coding region. Wildlife constitutes a rich, unexplored reservoir of natural microbial diversity, AMR genes and international resistant clones pathogenic in humans. The presence of a transposon that carries AMR genes is intriguing since no antibiotics are used in the non-human primates we studied.


D-type potassium channels normalize action potential firing between dorsal and ventral CA1 neurons of the mouse hippocampus.
Specific memory processes and neurological disorders can be ascribed to different dorsoventral regions of the hippocampus. Recently, differences in the anatomical and physiological properties between dorsal and ventral hippocampal CA1 neurons were described for both the rat and mouse hippocampus and have greatly contributed to our understanding of these processes. While differences in the subthreshold properties were similar between rat and mouse neurons, differences in action potential output between dorsal and ventral neurons were strikingly less divergent in mouse compared with rat CA1 neurons. Here, we investigate the mechanism underlying the lack of difference in action potential firing between dorsal and ventral CA1 pyramidal neurons in mouse hippocampus. Consistent with rat, we found that ventral CA1 neurons had a more depolarized resting membrane potential and higher input resistance than dorsal CA1 neurons in the mouse hippocampus. Despite these differences, action potential output in response to current injection was not significantly different. We found that ventral neurons have a more depolarized action potential threshold compared with dorsal neurons and that threshold in ventral neurons was more sensitive to block of KV1 channels compared with dorsal neurons. Outside-out voltage-clamp recordings found that slowly inactivating K+ currents were larger in ventral CA1 neurons. These results suggest that, despite differences in subthreshold properties between dorsal and ventral CA1 neurons, action potential output is normalized by the differential functional expression of D-type K+ channels. NEW & NOTEWORTHY Understanding differences in neurons within a brain region is integral in the reliable interpretation of comparative studies. Our findings identify a novel mechanism by which D-type potassium channels normalize action potential firing between dorsal and ventral CA1 neurons of mouse hippocampus despite differences in subthreshold intrinsic properties. Action potential threshold in ventral neurons is influenced by a greater functional expression of D-type potassium channels resulting in a depolarized action potential threshold compared with dorsal hippocampus.


FYVE domain-containing protein ZFYVE28 regulates EGFR-signaling in podocytes but is not critical for the function of filtration barrier in mice.
The kidney ultrafiltration barrier is formed of endothelial cells, the glomerular basement membrane and podocytes. Podocytes have a central role in normal physiology and disease pathogenesis of the glomerulus. Signaling through epidermal growth factor receptor (EGFR) in podocytes mediates development of many glomerular disease processes. In this work, we have identified zinc finger FYVE-type containing 28 (ZFYVE28) as a novel highly podocyte-enriched gene. We localize ZFYVE28 in podocyte foot processes in adult kidney. During glomerulogenesis, Zfyve28 is first expressed at the early capillary loop glomerulus. In cultured podocytes, we show that overexpression of ZFYVE28 promotes EGF-signaling, possibly by up-regulating EGFR expression and by modulating its localization. To study the role of ZFYVE28 in vivo, we generated both conventional and podocyte-specific knockout mouse lines. Kidneys developed normally in ZFYVE28-deficient mice. In adult mice, the absence of ZFYVE28 did not affect the maintenance of the filtration barrier. Moreover, ZFYVE28-deficiency did not affect the outcome of glomerular damage induced by injection of nephrotoxic serum. Taken together, we have identified Zfyve28 as a new molecular component of podocyte foot processes and show that it mediates EGF-signaling in podocytes. However, ZFYVE28 is not essential for the development or maintenance of the glomerulus filtration barrier.


Comparison of human platelet membrane-cytoskeletal proteins with the plasma proteome: Towards understanding the platelet-plasma nexus.
Platelets are essential for maintaining vascular integrity. Given the anucleate nature of platelets, definition of their proteome is essential for understanding platelet pathophysiology. We describe here a detailed MS-based proteomic analysis of the platelet membrane/cytoskeletal sub-proteome from purified, normal, non-activated human platelets. In contrast to previous platelet proteomic purification strategies, the buffy-coat method was utilized in this study to isolate and purify minimally activated platelets, yielding significantly reduced contaminants for leukocytes (0.02 ± 0.007×10(6) /L) and erythrocytes (0.21 ± 0.02%). Using a false discovery rate of 1%, 203 proteins were identified and characterized with respect to their subcellular localization, biological function, and cellular processes. Of these, 16 have not been identified in previous human platelet proteome studies. As a first approach towards understanding the dynamic platelet-plasma protein composition nexus, we re-analysed the entire HUPO plasma proteome project dataset (647 plasma proteins identified) and compared these data with our platelet proteome dataset. Co-identified proteins (41) were further analysed with respect to their relative abundances (exponentially modified protein abundance index) and functional enrichment in these two proteomes, as well as their correlation with the platelet transcriptome. Both platelet membrane/cytoskeletal and plasma proteome reference datasets, comprising both processed and unprocessed MS/MS spectra, are publicly accessible (http://www.ludwig.edu.au/archive/).


The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases.
Progressive supranuclear palsy is characterised pathologically by the deposition of neurofibrillary tangles consisting of tau protein. Patients with the disease have been reported to have a more frequent occurrence of one allele of an intronic polymorphism of the tau gene. Other diseases which may involve tau deposition include frontotemporal dementia and corticobasal degeneration. This polymorphism has been studied in a series of subjects with progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, idiopathic Parkinson's disease, and normal controls to (1) confirm this association in a large series and (2) to investigate a possible role for this association in other disorders which involve tau deposition. The results confirm the finding of an overrepresentation of the A0 allele and the A0/A0 genotype in patients with progressive supranuclear palsy, in the largest series reported to date. The A0 allele was found in 91% of patients with progressive supranuclear palsy as opposed to 73% of controls (p<0.001) and the A0/A0 genotype was seen in 84% of patients as compared with 53% of controls (p<0.01). There was no significant difference between patients with Parkinson's disease, frontotemporal dementia, or corticobasal degeneration, and controls. The A0 allele may have a direct effect on tau isoform expression in progressive supranuclear palsy or it may be in linkage disequilibrium with an adjacent determinant of tau gene expression. The explanation for this difference between a predisposition factor to progressive supranuclear palsy and the other conditions may lie in the molecular pathology of these diseases.


Sclerosing cholangitis in acquired immunodeficiency syndrome. Case reports and review of the literature.
Four patients with acquired immunodeficiency syndrome (AIDS) (CDC group IV) were investigated for biliary disease because of the presence of both severe upper abdominal pain and raised levels of serum alkaline phosphatase. None was clinically jaundiced. Upper abdominal ultrasound was abnormal in three. All had endoscopic retrograde cholangiographic evidence of both an intrahepatic sclerosing cholangitis suggestive of primary sclerosing cholangitis and an irregular suprapapillary common bile duct dilation suggestive of papillary stenosis. Three had evidence of gastrointestinal cryptosporidiosis and two of disseminated cytomegalovirus infection. Endoscopic sphincterotomy, performed in two patients, gave good pain relief. We propose the name 'AIDS sclerosing cholangitis' for this form of secondary cholangitis. The cause of this disorder remains unclear. Recent evidence is discussed which suggests that it is not due to HIV itself but to an opportunistic infection. Cryptosporidium appears to be the most likely candidate.


The effects of word frequency and word predictability during first- and second-language paragraph reading in bilingual older and younger adults.
We used eye movement measures of paragraph reading to examine how word frequency and word predictability impact first-language (L1) and second-language (L2) word processing in matched bilingual older and younger adults, varying in amount of current L2 experience. Our key findings were threefold. First, across both early- and late-stage reading, word frequency effects were generally larger in older than in younger adults, whereas word predictability effects were generally age-invariant. Second, across both age groups and both reading stages, word frequency effects were larger in the L2 than in the L1, whereas word predictability effects were language-invariant. Third, graded differences in current L2 experience modulated L1 and L2 word processing in younger adults, but had no impact in older adults. Specifically, greater current L2 experience facilitated L2 word processing, but impeded L1 word processing among younger adults only. Taken together, we draw 2 main conclusions. First, bilingual older adults experience changes in word-level processing that are language-non-specific, potentially because lexical accessibility decreases with age. Second, bilingual older adults experience changes in word-level processing that are insensitive to graded differences in current L2 experience, potentially because lexical representations reach a functional ceiling over time. (PsycINFO Database Record


Compost odor control using high carbon wood ash.
A pilot study on the feasibility of using high carbon wood ash to control composting odor emissions was conducted at a green material composting facility. The study's treatments consisted of adding 0%, 12.5%, and 25% high carbon wood ash by volume to green-material compost feedstock in three separate windrows. The wood ash has properties similar to activated carbon with an active surface area of 105 square metres per gram on a dry weight basis. The odorant emission data suggest that the higher percentage wood ash treatment results in the most effective control of most compost odors and that wood ash provides effective treatment of volatile fatty acids and some aldehydes and ketones. The 25% wood ash treatment resulted in more effective treatment of odors for a longer time period than the 12.5% treatment. Acetaldehyde had the highest concentration in the control (14,000 times its odor threshold concentration), was reduced by high carbon ash by over 97% but remained 386 times its reported odor threshold concentration after 14 days. Ethyl mecaptan and ammonia were produced in the process and were also over their reported human detection limits.


Eucalyptus biodiesel as an alternative to diesel fuel: preparation and tests on DI diesel engine.
Nowadays, the increasing oil consumption throughout the world induces crucial economical, security, and environmental problems. As a result, intensive researches are undertaken to find appropriate substitution to fossil fuels. In view of the large amount of eucalyptus trees present in arid areas, we focus in this study on the investigation of using eucalyptus biodiesel as fuel in diesel engine. Eucalyptus oil is converted by transesterification into biodiesel. Eucalyptus biodiesel characterization shows that the physicochemical properties are comparable to those of diesel fuel. In the second phase, a single cylinder air-cooled, DI diesel engine was used to test neat eucalyptus biodiesel and its blends with diesel fuel in various ratios (75, 50, and 25 by v%) at several engine loads. The engine combustion parameters such as peak pressure, rate of pressure rise, and heat release rate are determined. Performances and exhaust emissions are also evaluated at all operating conditions. Results show that neat eucalyptus biodiesel and its blends present significant improvements of carbon monoxide, unburned hydrocarbon, and particulates emissions especially at high loads with equivalent performances to those of diesel fuel. However, the NOx emissions are slightly increased when the biodiesel content is increased in the blend.


The η-secretase-derived APP fragment ηCTF is localized in Golgi, endosomes and extracellular vesicles and contributes to Aβ production.
The processing of the amyloid precursor protein (APP) is one of the key events contributing to Alzheimer's disease (AD) etiology. Canonical cleavages by β- and γ-secretases lead to Aβ production which accumulate in amyloid plaques. Recently, the matrix metalloprotease MT5-MMP, referred to as η-secretase, has been identified as a novel APP cleaving enzyme producing a transmembrane fragment, ηCTF that undergoes subsequent cleavages by α- and β-secretases yielding the Aηα and Aηβ peptides, respectively. The functions and contributions of ηCTF and its related fragments to AD pathology are poorly understood. In this study, we designed a novel immunological probe referred to as ηCTF-NTer antibody that specifically interacts with the N-terminal part of ηCTF targeting ηCTF, Aηα, Aηβ but not C99, C83 and Aβ. We examined the fate and localization of ηCTF fragment in various cell models and in mice. We found that overexpressed ηCTF undergoes degradation in the proteasomal and autophagic pathways and accumulates mainly in the Golgi and in endosomes. Moreover, we observed the presence of ηCTF in small extracellular vesicles purified from neuroblastoma cells or from mouse brains expressing ηCTF. Importantly, the expression of ηCTF in fibroblasts devoid on APP leads to Aβ production demonstrating its contribution to the amyloidogenic pathway. Finally, we observed an ηCTF-like immunoreactivity around amyloid plaques and an age-dependent accumulation of ηCTF in the triple-transgenic mouse AD model. Thus, our study suggests that the ηCTF fragment likely contributes to AD pathology by its exosomal spreading and involvement in Aβ production.


Percutaneous computed tomography-guided stabilization of posterior pelvic fractures.
Nineteen patients with 21 unstable fractures of the posterior pelvic complex were treated with percutaneous computed tomography (CT)-guided posterior stabilization. CT allowed satisfactory visualization of the fracture and direction and length of the screw. It also allowed the authors to perform the procedure percutaneously, while causing only minimal blood loss. CT cuts that showed the best and safest sites for screw placement were selected. The length and direction of the screw was identified, and the skin entry site was determined. The guide pin was inserted across the fracture or disrupted sacroiliac joint; its correct position was confirmed and a cannulated screw was inserted over the pin. In the majority of patients, a pelvic external fixator was applied in the CT suite. Although assessing the deformity was possible, reduction was difficult but ultimately acceptable. All patients maintained reduction of their sacroiliac complex without loss of fixation, and all fractures healed without clinical or radiographic signs of pelvic instability. This technique was not associated with neurologic injury or deep infection. All but 2 patients returned to preinjury levels of activity and function. Two patients had associated injuries that affected their final functional outcome.


Serum nitrate levels as an index of endothelial function in pre-eclamsia and normal pregnancy.
The study was conducted in St. John's Medical College Hospital and Department of Physiology, with the aim of studying the serum nitrate levels in pre-eclampsia and normal pregnancy. The total number of subjects studied in various groups were 159, control (n = 55), first trimester (n = 13), second trimester normal (n = 42), second trimester pre-eclampsia/PET (n = 5), third trimester normal (n = 32), third trimester pre-eclampsia/PET (n = 12). The serum nitrate was measured by one step enzymatic assay using Nitrate reductase from Aspergillus species. The nitrate levels in the third trimester pre-eclamptic group was found to be significant lower (P = 0.02), as compared to normal subjects, however the renal functions were normal in all the subjects.


Emerging Strategies in Treating Double Hit Lymphomas.
Double hit lymphomas (DHLs) are a new category in the World Health Organization newest classification for lymphoid malignancies. DHL encompasses various histologies of lymphomas where the MYC oncogene and either BCL2 or BCL6 oncogenes are present concomitantly. Several observational studies and retrospective series have demonstrated that patients with DHL carry a poor prognosis and respond less and for a shorter duration to standard R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin, and prednisone). These studies have also proposed that dose intensification (with Burkitt-like regimens such as DA-EPOCH-R [dose-adjusted rituximab, etoposide, vincristine, Adriamycin, cyclophosphamide, and prednisone]) might offer patients with DHL better outcomes and improved prognosis. In this timely review, we discuss incidence of DHL, testing implications of MYC translocation, current treatment strategies, and future directions. Understanding this entity and its therapeutic consequences is essential to improve patients' outcomes.


Prostate Cancer Theranostics - An Overview.
Metastatic prostate cancer is incurable, and novel methods to detect the disease earlier and to direct definitive treatment are needed. Molecularly specific tools to localize diagnostic and cytotoxic radionuclide payloads to cancer cells and the surrounding microenvironment are recognized as a critical component of new approaches to combat this disease. The implementation of theranostic approaches to characterize and personalize patient management is beginning to be realized for prostate cancer patients. This review article summarized clinically translated approaches to detect, characterize, and treat disease in this rapidly expanding field.