Biochemical effects of urapidil on red cell membrane ion transport systems in a population of elderly essential hypertensives.

The aim of our work was to verify the effect of urapidil on membrane ion transport systems. This was a randomized, double-blind, cross-over study which evaluated the clinical and biochemical effects of urapidil (30 mg twice daily in comparison with placebo) in a group of 10 elderly hypertensive patients (3 male, 7 female ranging from 68 to 90 years, mean age 79.2 +/- 7.6 years). For the evaluation in fresh erythrocytes of principal ion transport systems (cotransport Na+/K+, countertransport Na+/Li+, Na+/K+ ATPase pump. intracellular Na+ and K+) we used the nystatin technique. We found that urapidil activated the red cell membrane ions cotransport system (basal values: 83.7 +/- 50.3 mumol Na+ RBC 1-1.h-1, after 1 month of urapidil therapy: 181.5 +/- 89.3 mumol Na+ RBC 1-1.h-1) (P less than 0.01), without significant changes in the other biochemical parameters evaluated. Our data suggest that one of the mechanisms of the urapidil antihypertensive effect could involve an increase in the membrane sodium cotransport system

Устройство для перемещения датчиков в магнитном поле малогабаритного бетатрона

Рассматривается возможность увеличения точности измерений характеристик магнитного поля посредством более точной установки датчиков в исследуемой точке

Methods for performance evaluation of VBR video traffic models

Abstract-Models for predicting the performance of multiplexed variable bit rate video sources are important for engineering a network. However, models of a single source are also important for parameter negotiations and call admittance algorithms. In this paper we propose to model a single video source as a Markov renewal process whose states represent different bit rates. We also propose two novel goodness-of-fit metrics which are directly related to the specific performance aspects that we want to predict from the model. The first is a leaky bucket contour plot which can be used to quantify the burstiness of any traffic type. The second measure applies only to video traffic and measures how well the model can predict the compressed video quality. I. INTTtODUCTtON I T is well recognized that the viability of B-ISDN/ATM depends on the development of effective and implementable congestion control schemes. While many frameworks and techniques are under discussion (see, e.g., [l]), at least two capabilities have been agreed to as necessary in any framework that might arise.) The first is a comection admission control (CAC) by which the network will decide to accept or reject a new connection based on a set of agreed to traffic descriptors and on available resources. Once a connection is accepted, a second necessary control issome form of usage parameter control (UPC) which will insure that connections stay within their negotiated resource parameters. A popular UPC would involve a leaky bucket monitor of traffic entering the system, where traffic deemed as excessive by the monitor could either be dropped or tagged as low priority and allowed to proceed through the network to take advantage of potentially unused resources. Performance modeling is necessary to determine which techniques or set of techniques will be appropriate for eventual implementation in a B-ISDN network. Such models need to take into account traffic characteristics from realistic services that would be carried in a B-ISDN network. In particular, we need traffic models which will accurately represent the statistical nature of very high-speed, bursty services. Two classes of traffic models need to be developed: multiplexed source models and single source models. Although the same traffic model might be used in both cases, some models might be more suitable for one than the other. Multiplexed models will capture the effects of statistically multiplexing bursty sources and will predict to what extent the superposition of bursty streams is "smoothed". These models will be useful in traffic engineering the network (e.g., deciding how many links or virtual paths to put between different locations) and in traffic management (e.g., designing connection admission control algorithms, etc.) Several models have already been proposed in this direction (see, e.g., There are several areas where single source models are useful. They could be used to study what types of traffic descriptors make sense for parameter negotiation with the network at call setup. For example, if leaky bucket monitoring is used as a traffic descriptor, the negotiation might consist of the source specifying what parameters could be used in the leaky bucket for a given connection. Single source models can help in the selection of these parameters. Also, some applications may do some end-to-end rate control to ensure that minimal traffic is lost during periods of network congestion. Source models could be used in testing various rate control algorithms, Finally, these models are also useful in predicting the qualityof-service (QOS) that a particular application might experience during different levels of congestion. In deriving traffic models, we need metrics which can determine how "close" the model is to the actual traffic. Standard statistical measures such as means, variances, and other goodness-of-fit tests may not be appropriate here since they may not be measuring the characteristics of the process that are most important for either predicting the effect of the source on the resources in the network or the performance the source will experience. Instead, the goodness-of-fit metrics need to be directly related to the specific aspects of performance that we want to predict from the model; see e.g., [6]. In this paper, we propose two criteria for judging the appropriateness of a traffic model for bursty services. The first one applies to any high speed bursty data service and the second is specific to a variable-bit-rate (VBR) video application. To illustrate these measures we compare a previous model of VBR video with a new model proposed here. II. MODELING VARIABLE-BIT-RATE VIDEO The data we are modeling was recorded at an actual teleconference meeting. Each scene depicts the head and shoulders of one person, and is 5 rein, or 9000 frames, long. Since each 5 min of video required approximately one week to encode using software, the motivation for developing accurate models with a low computational burden is clear. A typical 10634692i94$04.0

Plasmodium transmission blocking activities of Vernonia amygdalina extracts and isolated compounds

BACKGROUND: Medicinal plants are a validated source for discovery of new leads and standardized herbal medicines. The aim of this study was to assess the activity of Vernonia amygdalina leaf extracts and isolated compounds against gametocytes and sporogonic stages of Plasmodium berghei and to validate the findings on field isolates of Plasmodium falciparum. METHODS: Aqueous (Ver-H2O) and ethanolic (Ver-EtOH) leaf extracts were tested in vivo for activity against sexual and asexual blood stage P. berghei parasites. In vivo transmission blocking effects of Ver-EtOH and Ver-H2O were estimated by assessing P. berghei oocyst prevalence and density in Anopheles stephensi mosquitoes. Activity targeting early sporogonic stages (ESS), namely gametes, zygotes and ookinetes was assessed in vitro using P. berghei CTRPp.GFP strain. Bioassay guided fractionation was performed to characterize V. amygdalina fractions and molecules for anti-ESS activity. Fractions active against ESS of the murine parasite were tested for ex vivo transmission blocking activity on P. falciparum field isolates. Cytotoxic effects of extracts and isolated compounds vernolide and vernodalol were evaluated on the human cell lines HCT116 and EA.hy926. RESULTS: Ver-H2O reduced the P. berghei macrogametocyte density in mice by about 50% and Ver-EtOH reduced P. berghei oocyst prevalence and density by 27 and 90%, respectively, in An. stephensi mosquitoes. Ver-EtOH inhibited almost completely (>90%) ESS development in vitro at 50 μg/mL. At this concentration, four fractions obtained from the ethylacetate phase of the methanol extract displayed inhibitory activity >90% against ESS. Three tested fractions were also found active against field isolates of the human parasite P. falciparum, reducing oocyst prevalence in Anopheles coluzzii mosquitoes to one-half and oocyst density to one-fourth of controls. The molecules and fractions displayed considerable cytotoxicity on the two tested cell-lines. CONCLUSIONS: Vernonia amygdalina leaves contain molecules affecting multiple stages of Plasmodium, evidencing its potential for drug discovery. Chemical modification of the identified hit molecules, in particular vernodalol, could generate a library of druggable sesquiterpene lactones. The development of a multistage phytomedicine designed as preventive treatment to complement existing malaria control tools appears a challenging but feasible goal

Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity

Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activityAntimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.The authors thank T.T. Diagana (Novartis Institute for Tropical Diseases, Singapore) for provision of the compounds, the Red Cross (Australia and the USA) for the provision of human blood for cell cultures, and G. Stevenson for assistance with the triaging of compounds following screening. The authors acknowledge the Bill and Melinda Gates Foundation (grant OPP1040399 to D.A.F. and V.M.A. and grant OPP1054480 to E.A.W. and D.A.F.), the National Institutes of Health (grant R01 AI103058 to E.A.W. and D.A.F., grant R01 AI50234 to D.A.F, and R01 AI110329 to T.J.E.), the Australian Research Council (LP120200557 to V.M.A.) and the Medicines for Malaria Venture for their continued support. P.E.F. and M.I.V. are supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER).info:eu-repo/semantics/publishedVersio

Just Click Here : A Brief Glance at Absurd Electronic Contracts and the Law Failing to Protect Consumers

As e-commerce explodes around the world, consumers’ rights have been left behind. Before the completion of virtually every transaction on the Internet, the onus is placed on consumers to read and agree to an onslaught of terms and conditions. Often hidden in the middle of this extremely lengthy list of terms are massive exemption and limitation of liability clauses that deny consumers most if not all of their rights as “equal” trading partners. The common law principle that all onerous clauses in a contract need to be brought to the attention of the consumer for them to be binding seems to have been lost with the invention of the “click here to agree” button for signing online contracts. As the courts in Canada have not provided clear guidance on this issue thus far, other means must be pursued in order to protect consumers from the near-tyrannical control of unencumbered electronic standard form contracts in e-commerce. This paper will describe the principle of sufficiency of notice as it applies to paper contracts, and then contrast it with the newer jurisprudence that has refused to apply the principle to electronic contracts. The reasons for the refusal will be explored, followed by an examination of why the principle of sufficiency of notice needs to be applied and strengthened to respond to the increasingly onerous provisions hidden in electronic contracts. Finally, some other options for achieving the goal of consumer protection from hidden onerous clauses will be briefly explored. These other options include introducing stiffer consumer protection legislation domestically, the creation of international treaties, developing voluntary standards of contracting, and relying on Internet self-regulation

Transmission blocking activity of a standardized neem (Azadirachta indica) seed extract on the rodent malaria parasite Plasmodium berghei in its vector Anopheles stephensi

<p>Abstract</p> <p>Background</p> <p>The wide use of gametocytocidal artemisinin-based combination therapy (ACT) lead to a reduction of <it>Plasmodium falciparum </it>transmission in several African endemic settings. An increased impact on malaria burden may be achieved through the development of improved transmission-blocking formulations, including molecules complementing the gametocytocidal effects of artemisinin derivatives and/or acting on <it>Plasmodium </it>stages developing in the vector. Azadirachtin, a limonoid (tetranortriterpenoid) abundant in neem (<it>Azadirachta indica</it>, Meliaceae) seeds, is a promising candidate, inhibiting <it>Plasmodium </it>exflagellation <it>in vitro </it>at low concentrations. This work aimed at assessing the transmission-blocking potential of NeemAzal^®, an azadirachtin-enriched extract of neem seeds, using the rodent malaria <it>in vivo </it>model <it>Plasmodium berghei</it>/<it>Anopheles stephensi</it>.</p> <p>Methods</p> <p><it>Anopheles stephensi </it>females were offered a blood-meal on <it>P. berghei </it>infected, gametocytaemic BALB/c mice, treated intraperitoneally with NeemAzal, one hour before feeding. The transmission-blocking activity of the product was evaluated by assessing oocyst prevalence, oocyst density and capacity to infect healthy mice. To characterize the anti-plasmodial effects of NeemAzal^®on early midgut stages, i.e. zygotes and ookinetes, Giemsa-stained mosquito midgut smears were examined.</p> <p>Results</p> <p>NeemAzal^®completely blocked <it>P. berghei </it>development in the vector, at an azadirachtin dose of 50 mg/kg mouse body weight. The totally 138 examined, treated mosquitoes (three experimental replications) did not reveal any oocyst and none of the healthy mice exposed to their bites developed parasitaemia. The examination of midgut content smears revealed a reduced number of zygotes and post-zygotic forms and the absence of mature ookinetes in treated mosquitoes. Post-zygotic forms showed several morphological alterations, compatible with the hypothesis of an azadirachtin interference with the functionality of the microtubule organizing centres and with the assembly of cytoskeletal microtubules, which are both fundamental processes in <it>Plasmodium </it>gametogenesis and ookinete formation.</p> <p>Conclusions</p> <p>This work demonstrated <it>in vivo </it>transmission blocking activity of an azadirachtin-enriched neem seed extract at an azadirachtin dose compatible with 'druggability' requisites. These results and evidence of anti-plasmodial activity of neem products accumulated over the last years encourage to convey neem compounds into the drug discovery & development pipeline and to evaluate their potential for the design of novel or improved transmission-blocking remedies.</p

Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms

A population-based case–control study of lymphomas in England collected height and weight details from 699 non-Hodgkin's lymphoma (NHL) cases and 914 controls. Obesity, defined as a body mass index (BMI) over 30 kg m−2 at five years before diagnosis,, was associated with an increased risk of NHL (OR=1.5, 95% CI 1.1–2.1). The excess was most pronounced for diffuse large B-cell lymphoma (OR=1.9, 95% CI 1.3–2.8). Genetic variants in the leptin (LEP 19G>A, LEP −2548G>A) and leptin receptor genes (LEPR 223Q>R), previously shown to modulate NHL risk, as well as a polymorphism in the energy regulatory gene adiponectin (APM1 276G>T), were investigated. Findings varied with leptin genotype, the risks being decreased with LEP 19AA (OR=0.7, 95% CI 0.5–1.0) and increased with LEP −2548GA (OR=1.3, 95% CI 1.0–1.7) and −2548AA (OR=1.4, 95% CI 1.0–1.9), particularly for follicular lymphoma. These genetic findings, which were independent of BMI, were stronger for men than women

L’indagine macrosismica: metodologia, parametri del terremoto, questioni aperte

Subito dopo l’evento del 6 aprile 2009, come di consueto è stata realizzata una lunga e complessa indagine macrosismica, promossa dal gruppo operativo QUEST, che ha avuto inizialmente l’obiettivo di delimitare l’area di danneggiamento, a supporto delle attività di pronto intervento della Protezione Civile, e successivamente quello di classificare nel modo più accurato e capillare possibile, gli effetti prodotti dall’evento, particolarmente nelle aree danneggiate. A questo scopo è stata prodotta una stima utilizzando la scala MCS (Sieberg, 1930); in un secondo momento è stata rifinita l’indagine per una cinquantina di località dell’area maggiormente danneggiata (Is MCS>VII), raccogliendo ed elaborando i dati in termini di scala macrosismica EMS98 (Grünthal, 1998). Per la complessità e la dimensione dei problemi affrontati, questo terremoto ha costituito un banco di prova di grande importanza per la macrosismologia italiana. In questo testo viene descritto il lavoro realizzato, discutendo in particolare alcuni aspetti che hanno messo alla prova le metodologie di indagine tradizionali (sistematiche irregolarità degli insediamenti monitorati, forti divergenze degli scenari di danno rispetto a quelli previsti dalle scale, difficile comparabilità con scenari storici, ecc.) e presentandone i risultati, in relazione ai parametri epicentrali che ne risultano e il loro contributo più diretto alla comprensione complessiva della sismicità dell’area

Novel, Meso-Substituted Cationic Porphyrin Molecule for Photo-Mediated Larval Control of the Dengue Vector Aedes aegypti

Dengue is a life-threatening viral disease of growing importance, transmitted by Aedes mosquito vectors. The control of mosquito larvae is crucial to contain or prevent disease outbreaks, and the discovery of new larvicides able to increase the efficacy and the flexibility of the vector control approach is highly desirable. Porphyrins are a class of molecules which generate reactive oxygen species if excited by visible light, thus inducing oxidative cell damage and cell death. In this study we aimed at assessing the potential of this photo-mediated cytotoxic mechanism to kill Aedes (Stegomyia) aegypti mosquito larvae. The selected porphyrin molecule, meso-tri(N-methylpyridyl),meso-mono(N-tetradecylpyridyl)porphine (C14 for simplicity), killed the larvae at doses lower than 1 µM, and at light intensities 50–100 times lower than those typical of natural sunlight, by damaging their intestinal tissues. The physicochemical properties of C14 make it easily adsorbed into organic material, and we exploited this feature to prepare an ‘insecticidal food’ which efficiently killed the larvae and remained active for at least 14 days after its dispersion in water. This study demonstrated that photo-sensitizing agents are promising tools for the development of new larvicides against mosquito vectors of dengue and other human and animal diseases